MS Abstracts 04e-2g1

ExtraCellular Matrix (ECM) molecules play important roles in the PathoBiology of the major human Central Nervous System (CNS) Inflammatory/DeMyelinating Disease Multiple Sclerosis (MS).

This mini-review highlights some recent work on CNS Endothelial Cell interactions with Vascular Basement Membrane ECM.

As part of the Cellular Immune Response, and roles for White Matter ECM molecules in DeMyelination and ReMyelination in MS lesions.

Recent basic and clinical investigations of MS emphasize Axonal Injury, not only in chronic MS plaques, but also in acute lesions; progressive Axonal degeneration in Normal-Appearing White Matter also may contribute to Brain and Spinal Cord Atrophy in MS patients.

Remodeling of the interstitial White Matter ECM molecules that affect Axon regeneration, however, is incompletely characterized.

Our ongoing ImmunoHistoChemical studies demonstrate enhanced ECM versican, a Neurite and Axon growth-inhibiting White Matter ECM ProteoGlycan, and Dermatan Sulfate ProteoGlycans at the edges of inflammatory MS lesions.

This suggests that enhanced ProteoGlycan deposition in the ECM and Axonal growth inhibition may occur early and are involved in expansion of active lesions.

Decreased ECM ProteoGlycans and their Phagocytosis by Macrophages along with Myelin in plaque centers imply that there is "injury" to the ECM itself.

These results indicate that White Matter ECM ProteoGlycan alterations are integral to MS pathology at all disease stages and that they contribute to a CNS ECM that is inhospitable to Axon regrowth/regeneration.

Identified as the first and prototypic TransMembrane Protein Tyrosine Phosphatase (PTPase), CD45 has been extensively studied for over two decades.

And is thought to be important for positively regulating Antigen-Receptor signaling via the DePhosphorylation of Src kinases.

However, new evidence indicates that CD45 can function as a Janus kinase PTPase that negatively controls Cytokine-receptor signaling.

A point mutation in CD45, which appears to affect CD45 dimerization, and a Genetic polymorphism that affects alternative CD45 splicing are implicated in AutoImmunity in mice and Multiple Sclerosis in humans.

CD45 is expressed in multiple isoforms and the modulation of specific CD45 splice variants with AntiBodies can prevent transplant rejections.

In addition, loss of CD45 can affect Microglia activation in a mouse model for Alzheimer's Disease.

Thus, CD45 is moving rapidly back into the spotlight as a drug target and central regulator involved in differentiation of multiple Hematopoietic Cell lineages, AutoImmunity and AntiViral Immunity.

Multiple Sclerosis (MS) is a disease of the Central Nervous System with presumed AutoImmune etiology. Experimental AutoImmune EncephaloMyelitis (EAE), an inducible AutoImmune Disease in laboratory animals, is a widely accepted animal model of MS.

It is well known that EAE is induced by AutoReactive CD4⁺ T-Cells specific for Myelin Antigens.

The DeMyelination process is manifested as a result of complex interactions among Encephalitogenic, regulatory and accessory cell populations and factors produced by these cells.

The outcome of the disease depends on which components become dominant. Examination of these components using Genetically manipulated transgenic or gene-disrupted animal models has proved to be very useful.

Here we examine the main processes leading to the development of EAE. The participation of different Leukocyte populations such as T, B-Cells or NK Cells, as well as regulatory molecules.

And Cytokines in the induction and regulation of EAE is discussed in the light of transgenic and knockout animal experiments.

These animal models clearly show that AutoImmune processes are regulated in a complex way, and that a given factor in this regulation can have very different effects according to the given MicroEnvironment in which it acts.

MHC Class II alleles have been linked to several human AutoImmune Diseases such as Rheumatoid Arthritis (RA), Type I Diabetes, and Multiple Sclerosis (MS).

Although the mechanisms by which expression of certain MHC Class II molecules predispose an individual to a particular AutoImmune Disease are not known.

It is clear that increased susceptibility is associated with the polymorphic regions unique to these predisposing HLA alleles.

These polymorphic differences may influence susceptibility by selecting potential AutoReactive T-Cells during Thymic education.

Alternatively, nonsusceptible alleles may either delete or fail to select these potential AutoImmune T-Cells, thus reducing the possibility of developing disease.

In the periphery, the unique specificity of the HLA molecule derived from a susceptible allele may then recognize and present an AutoAntigenic Peptide or foreign peptide.

That may cross-react with an AutoAntigen, activating these AutoReactive T-Cells and leading to disease.

To dissect these possibilities and to determine the exact role of particular HLA-DR or DQ molecules in disease susceptibility, we have generated several lines of HLA-DR and DQ transgenic mice.

In this review, we present data summarizing the functions of these HLA Class II molecules using well-established mouse models for AutoImmune Diseases.

Experimental Allergic EncephaloMyelitis (EAE) is an AutoImmune Disease characterized by a disruption of the Blood-Brain Barrier (BBB), DeMyelination and a relevant inflammatory reaction with an intense infiltration of Macrophages.

These Neurological Disorders are similar to those observed in the Multiple Sclerosis (MS) Disease. The use of different Liposomes and Adeno-Associated Virus has been proposed for improving the treatment of this PathoGenesis.

The aim of this work was to evaluate the potential and capacity of Albumin NanoParticles to reach the Central Nervous System (CNS) in EAE-induced rats. For this purpose, the distribution of Biotinylated NanoParticles within the CNS was studied.

Albumin carriers were mainly found in the Lumbar portion of the Spinal Cord, overlying the Meningeal and PeriVascular areas.

The Optic Chiasma, Iris and the area of the Purkinje Cells of the Cerebellum revealed also an intense presence of these carriers.

Finally, ImmunoHistoChemical studies also revealed that circulating Macrophages (ED1), which migrate to damaged sites, and resident activated Microglial Cells (OX42) were involved in the distribution of Albumin NanoParticles.

In summary, the use of NanoParticles may be useful for the design of new pharmaceutical dosage forms able to target the Lesions associated with alterations of the BBB.

Aims Of The Study
The aims of this study were to describe the number, kind, and intensity of caregiving activities performed by individuals who assumed caregiving responsibilities.

As youngsters, for adults with chronic physical illnesses; to explore the meaning and effects of the caregiving experience on those individuals; and to examine positive and negative effects of caregiving then and now.

Background/Rationale
Family mobility, demographic changes, and health care system changes in the United States of America (USA) have contributed to an increasing number of youngsters under the age of 18 caring for adults with chronic physical illnesses in the home.

The effects of such caregiving on youngsters and the long-term effects on them as adults require study.

Design/Methods
This descriptive, retrospective study had a convenience sample of 51 adults (age range 19-68 years now, 3-19 years then).

Who cared for their family members diagnosed with Cancer, Stroke, Cardiovascular Disease, Multiple Sclerosis or Amyotrophic Lateral Sclerosis, Respiratory Disease, Diabetes, or Arthritis.

Demographic data and caregiving data were analyzed using descriptive statistics. The semistructured interview data were analyzed using content analysis.

Results/Findings
Of the caregiving care tasks most frequently performed, personal care was most difficult and household tasks were most time consuming.

Family life, school, and time with friends were areas most likely to be affected by caregiving.

Most subjects indicated they would permit their own children to assist with care as long as the youngster was not the sole caregiver.

Youngsters need to be informed about the illness and caregiving tasks, have adequate support systems, and have some time to 'still be a child'.

Conclusions
Professional caregivers should raise questions in their practice regarding involvement in caregiving by both adults and youngsters.

If youngsters participate in caregiving in the home, they need to receive adequate information regarding care and the illness trajectory.

Family-related research including the long-term effects of such experiences on the youngsters and their families is recommended.

Objective
To estimate the prevalence and clinical characteristics of Multiple Sclerosis (MS) in Vasterbotten County in northern Sweden.

Methods
Individuals with MS were identified from several sources. A follow-up interview and/or examination was performed in 94% of cases still living in the area during 1997-99.

Onset adjusted prevalence and a definition of onset symptoms were applied.

Results
A total of 313 cases were identified, resulting in an onset adjusted crude prevalence of MS for January 1990 of 125/105 (95% confidence interval (CI): 112-140).

Female predominance was evident (163/105 (95% CI: 142-187) vs 86/105 (95% CI: 71-104)). Diagnostic coding registers were the most important source for identification of cases.

Conclusions
The crude prevalence of MS in Vasterbotten was higher than previous reports from other major areas in Scandinavia.

The adjusted prevalence was significantly higher when compared with a previous study from Goteborg, south-western Sweden.

The methodology used in this study gives a high degree of case ascertainment and increases the comparability of Multiple Sclerosis Epidemiological studies.

Fast Spin-Echo (FSE) pulse sequences enable T₂-weighted imaging in a fraction of the time required for T₂-weighted Conventional Spin-Echo (CSE) imaging.

Due to concerns that the altered contrast characteristics of FSE may interfere with the visualization of Multiple Sclerosis (MS) Lesions.

The sensitivity of T₂-weighted FSE sequences was compared to comparably weighted CSE sequences in the imaging of the Brain in 100 patients with clinically suspected MS.

The proton-density FSE sequence revealed more MS lesions than its CSE counterpart, while the T₂-weighted CSE sequences were found to be more sensitive than the T₂-weighted FSE sequence.

Contrast-to-noise ratios and signal-to-noise ratios compared favorably between sequences. Overall, there was little difference in the specificity between FSE and CSE in the Diagnosis of MS.

The higher sensitivity and the reduction in time attainable through the use of FSE warrants its replacement of CSE when imaging the Brain in patients with Clinically Suspected MS.

J. Magn. Reson. Imaging 2001;13:657-667. Copyright 2001 Wiley-Liss, Inc.

Ankylosing Spondylitis is reported to involve not only the joints but other organs as well.

Among these extra-articular involvements, uncommon complications associated with Nervous System such as single root lesions, compression of the Myelum and Cauda Equina Syndrome have also been documented.

Here we present a patient with long-standing Ankylosing Spondylitis who developed Spastic Paraparesis.

Extensive study to find the cause of a Spastic Paraparesis failed and therefore led to the conclusion that this patient was suffering from Transverse Myelitis.

Similar reports in the past have been attributed to an association with Multiple Sclerosis.

However, we suggest that the findings support the diagnosis of a rare complication of Ankylosing Spondylitis with an unknown etiology.