Multiple Sclerosis References 2003; Authors: K
(46 References)
Kadhim, H., C. De Prez, et al. (2003). "In situ cytokine immune responses in acute disseminated encephalomyelitis: insights into pathophysiologic mechanisms." Hum Pathol 34(3): 293-7.
Acute disseminated encephalomyelitis (ADEM) is thought to be an autoimmune disorder of the central nervous system in which myelin is targeted. Pathological studies on closely related human diseases (eg, multiple sclerosis) and on animal models for these demyelinating disorders have suggested the involvement of cytokines. Studies on peripheral immunocytes and on cerebrospinal fluid revealed the presence of cytokine-mediated responses in ADEM. We carried out this neuroimmunopathologic exploration and report for the first time the in situ expression of "inflammatory" cytokines in ADEM. Moreover, we note a particular spatial and molecular pattern whereby tumor necrosis factor-alpha and interleukin (IL)-1beta are intensely expressed, whereas IL-6 is absent. Differential expression at different levels of the neuraxis was also noticed. Our findings suggest that these cytokines, reported to be toxic to myelin, are implicated in the molecular cascade, resulting in the neural damage. These observations might provide insights into molecular pathways involved in the immunopathogenesis of ADEM and might open new horizons in neuroimmunomodulation and anticytokine treatment.
Kahl, K. G., J. Zielasek, et al. (2003). "Protective role of the cytokine-inducible isoform of nitric oxide synthase induction and nitrosative stress in experimental autoimmune encephalomyelitis of the DA rat." J Neurosci Res 73(2): 198-205.
The pathogenic role of nitric oxide (NO) in multiple sclerosis (MS) remains controversial. Some groups have reported a pathogenic role of NO in experimental autoimmune encephalomyelitis (EAE), an animal model of some aspects of MS, whereas we and others have found a disease-suppressive effect of NO in EAE. Because the previously used EAE models have a mainly monophasic inflammatory disease course, distinct from MS, we here studied EAE in the DA rat, which better models the demyelinating and relapsing disease course of human MS. The induction of EAE in DA rats led to 1) severe inflammatory infiltrates mainly in the lumbar spinal cord; 2) an up-regulation of the activity of the cytokine-inducible isoform of NO synthases (NOS-II); and 3) increased tissue protein tyrosine nitration, as indicated by peroxynitrite (ONOO(-)), as a marker of nitrosative stress. Sources of superoxide metabolism, i.e., NADPH oxidase, myeloperoxidase, and superoxide dismutase, remained unchanged. Early treatment of animals with aminoguanidine, a relatively selective inhibitor of NOS-II, lowered nitrotyrosine immunoreactivity but at the same time led to more severe disease and pronounced inflammatory infiltrates in the lumbar spinal cord. Our results suggest a rather protective role of NOS-II induction and nitrosative stress in EAE in DA rats and support the hypothesis of a disease-mitigating immunomodulatory role of NO in this animal model of MS.
Kalanie, H., K. Gharagozli, et al. (2003). "Multiple sclerosis: report on 200 cases from Iran." Mult Scler 9(1): 36-8.
Clinical findings of 200 patients in Iran with definite multiple sclerosis (MS) according to Poser et al.'s criteria and positive findings on magnetic resonance imaging (MRI) have been reviewed. The clinical course was relapsing-remitting (RR) for 88%, primary progressive (PP) for 7% and secondary progressive (SP) for 5% of cases. The mean age of onset was 27 +/- 7.4 years for the whole group and 37.1 +/- 8.8 years for PPMS. The gender ratio was 2.5:1 female:male. Involvement of the pyramidal system was the most common mode of presentation. Five per cent of patients had positive family history for the disease, 14% of patients had benign MS and 12% with disease duration longer than five years had an Expanded Disability Status Scale < or = 2. The optico-spinal form was not a common form of presentation in the group.
Kalman, B. and T. P. Leist (2003). "A mitochondrial component of neurodegeneration in multiple sclerosis." Neuromolecular Med 3(3): 147-58.
Neurodegeneration is the main pathological correlate of accumulating disability in progressive stages of Multiple Sclerosis (MS), but both histologic and imaging studies detect significant tissue loss even in early disease. These observations raise the question as to whether neurodegeneration in MS is a primary mechanism or whether it develops secondary to inflammation and demyelination. Recent data suggest that the atrophy of brain and cord is directly linked to inflammation and may partly be independent of demyelination. Released products of both residential and infiltrating immune cells can induce ultrastructural changes and celldeath by multiple mechanism. We propose that the inflammation-induced tissue response is controlled by genetic variations and to some extent involves a mitochondrion-driven mechanism in MS, similar to that described in the final pathway of other neurodegenerative disorders. Current therapeutic strategies primarily target the immune system which results in a successful down-regulation of plaque formation and of relapse rate. However, measures of clinical disability best correlate with the degree of neurodegeneration rather than with the volume of plaques, and these immune-modulating regimens may only incompletely affect the accumulating tissue loss. Considering the need for additional therapeutic strategies, we emphasize the degenerative components, and review a mitochondrial mechanism of tissue loss potentially involved in the process of MS.
Kankonkar, S., G. Jeyanti, et al. (2003). "Evidence for novel DRB1*15 allele association among clinically definite multiple sclerosis patients from mumbai, india." Hum Immunol 64(4): 478-82.
Multiple sclerosis (MS) is a clinically heterogeneous demylinating disease and an important cause of acquired neurologic disability. MS has been reported from different regions of India and its infrequency has been attributed to have genetic implications. Further, a high incidence of MS and its human leukocyte antigen B12 (HLA-B12) associations have been reported among highly inbred Parsi population from Mumbai. However, consistent HLA associations have not been reported from India. We analyzed the HLA-B, -Cw, and -DRB1 allele associations among 23 clinically definite Western Indian non-Parsi MS patients and compared them with 146 ethnically matched clinically normal individuals. HLA serologic (A, B, and Cw) as well as molecular (DRB1) typing methodology was followed. The study revealed a significant increase of HLA-A11 (24% vs. 13%; OR = 2.6; EF = 0.14; 95%CI = 1.1-3.05), B16 (4.3% vs 0.3%; OR = 13.8; EF = 0.03; 95% CI = 1.19-134.44), Cw7 (15.2% vs 3.7%; OR = 5.46; EF = 0.12; 95% CI = 0.944-17.86), and DRB1*15 (21.7% vs 2.2%; OR = 16.15; EF = 0.19; 95% CI = 1.33-68.64). Further molecular subtyping of HLA-DRB1*15 among the patients revealed two novel alleles, DRB1*1506 (20%) and DRB1*1508 (30%), along with the commonly reported DRB1*1501 (50%) for the first time in MS patients that were hitherto unidentified from other parts of India and world as well. This study reveals that there is a complexity of the genetic susceptibility to MS in different populations studied and reported.
Kantarci, O. H., J. L. Schaefer-Klein, et al. (2003). "A population-based study of IL4 polymorphisms in multiple sclerosis." J Neuroimmunol 137(1-2): 134-9.
Previous studies have suggested a role for interleukin-4 gene (IL4) in susceptibility to multiple sclerosis (MS) as well as other autoimmune diseases. We screened the promoter region, exons 1-4 and their splice sites for polymorphisms and tested the association between novel polymorphisms E1(33)*C-->T and I3(2580)*C-->A, and the established 5'(-523)*C-->T and I3(709)*VNTR polymorphisms with susceptibility to, age of onset in, and course and severity of MS in sporadic cases. I3(709)*VNTR was associated with susceptibility to MS (p=0.004) due to a dearth of heterozygotes in patients (29/122; 23.8%) compared to controls (91/244; 37.3%). Homozygotes for the uncommon I3(709)*allele-2 may have increased susceptibility (p=0.044; OR=5.17, 95% CI: 0.83-54.95) as might carriers for the extended haplotypes 5'(-523)*T/E1(33)*T/I3(709)*allele-2/I3(2580)*C (p=0.003; OR: 3.75, 95% CI: 1.18-11.93) or 5'(-523)*C/E1(33)*C/I3(709)*allele-1/I3(2580)*A (p=0.004; OR: 4.22, 95% CI: 1.22-14.54). We could not confirm the previously reported association between carriage of I3(709)*allele-2 and older age of onset. However, we found a trend for association between the homozygous state for this allele and older age of onset.
Kantarci, O. H., D. D. Hebrink, et al. (2003). "CTLA4 is associated with susceptibility to multiple sclerosis." J Neuroimmunol 134(1-2): 133-41.
We comprehensively screened CTLA4 for novel genetic variations in patients with MS. We studied genetic variations by association methods in a population-based sample of 122 sporadic patients with MS and 244 age-, gender- and ethnicity-matched controls, and by linkage and family-based association methods in 395 individuals from 59 American multiplex pedigrees with 141 affected individuals. Being homozygous for AT(8) (common) allele of the 3'(514) microsatellite (OR: 1.69; CI: 0.99-2.86) and for the common 5'(318)*C/E1(49)*A/3'(514*AT(8) haplotype (OR: 1.96; CI: 1.13-3.39) was associated with increased susceptibility to MS in Olmsted County. The genotype frequencies of other individual polymorphisms were not significantly different between cases and controls. A pooled analysis of association studies revealed an odds ratio of 1.28 (95% CI: 1.01-1.63; p=0.043) for 5'(-318)*C homozygotes and 1.28 (95% CI: 1.08-1.51; p=0.005) for the 3'(514)*AT(8) allele. We did not detect linkage with MS susceptibility in multiplex families. We did not find a strong association with age at onset, disease course or severity. CTLA-4 is associated with susceptibility to MS.
Kantor, R., M. Bakhanashvili, et al. (2003). "A mutated CCR5 gene may have favorable prognostic implications in MS." Neurology 61(2): 238-40.
The authors investigated the association between Delta32CCR5, a mutated allele of the chemokine receptor CCR5, and disease progression in 256 patients with multiple sclerosis (MS). The mutated allele frequency in the study cohort was 7.4%, similar to that reported in the general Israeli population. Progression to disability was prolonged in Delta32CCR5 homozygotes and heterozygotes compared with MS patients with the CCR5 wild-type genotype (p < 0.005). Mutated CCR5 allele may be considered a favorable prognostic factor in MS.
Kapoor, R., M. Davies, et al. (2003). "Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration." Ann Neurol 53(2): 174-80.
Axonal degeneration can be an important cause of permanent disability in neurological disorders in which inflammation is prominent, including multiple sclerosis and Guillain-Barre syndrome. The mechanisms responsible for the degeneration remain unclear, but it is likely that axons succumb to factors produced at the site of inflammation, such as nitric oxide (NO). We previously have shown that axons exposed to NO in vivo can undergo degeneration, especially if the axons are electrically active during NO exposure. The axons may degenerate because NO can inhibit mitochondrial respiration, leading to intraaxonal accumulation of Na(+) and Ca(2+) ions. Here, we show that axons can be protected from NO-mediated damage using low concentrations of Na(+) channel blockers, or an inhibitor of Na(+)/Ca(2+) exchange. Our findings suggest a new strategy for axonal protection in an inflammatory environment, which may be effective in preventing the accumulation of permanent disability in patients with neuroinflammatory disorders.
Kappos, L. and J. Kesselring (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1821-2; author reply 1823-4.
Kargwell, H., B. A. Yaqub, et al. (2003). "Response to beta interferon 1b among Saudi patients with multiple sclerosis." Saudi Med J 24(1): 44-8.
OBJECTIVE: To determine the efficacy and tolerability of subcutaneous beta interferon 1b (B1F1b) among Saudi patients with remitting-relapsing multiple sclerosis (R-R MS). METHODS: An open label study held at the Neurology Division of the Armed Forces Hospital, Riyadh from March 1997 until December 2001. Thirty-two consecutive patients below the age of 50 years with clinically definite R-R MS according to Poser's Criteria and expanded disability status scale below 5.5 were enrolled in treatment with subcutaneous B1F1b 8 million IU 3 times a week. The primary outcome measures used were: reduction in annual relapses, proportion of relapse-free patients, and the mean time to the first relapse after treatment was started. The secondary outcome measures used were the time to progression in disability, tolerability and safety of the beta interferon. RESULTS: Only 28 patients were analyzed to assess the outcome measures, the other 4 patients dropped out and were followed-up. Twenty were women and 8 were men (female:male ratio of 2.5:1). There was a significant reduction in relapse-rate in all patients, 32.5% were relapse-free, while 37.5% showed reduction in the number of relapses. None of our patients showed progression of disability (P<0.0249). Mild adverse reactions were seen in 38.5%, influenza-like illness occurred in 53.6%, and injection-site reaction in 35.7%. CONCLUSION: Subcutaneous B1F1b is effective in patients with R-R MS, especially in reducing relapse rate, probable disability, and it is well tolerated. However, longer follow-up is necessary to evaluate the role of B1F1b in preventing disability.
Karni, A., E. Kahana, et al. (2003). "The frequency of multiple sclerosis in jewish and arab populations in greater jerusalem." Neuroepidemiology 22(1): 82-6.
A comparison of the incidence rate (IR) and the prevalence rate (PR) of multiple sclerosis (MS) in subgroups of the same ethnic origin, but born and living in different geographical areas, may delineate the relationship between environmental and genetic risk factors for MS. Previous epidemiological studies of MS in Israel did not include the Arab population and used diagnostic criteria that did not include MRI findings. Therefore, we studied the age-adjusted IR and PR of MS in a more recent sample in different population groups, including Arabs, of Greater Jerusalem. We found that the PR of MS in Israeli Jews is higher than previously described. Furthermore, the PR was significantly lower among immigrant Jews from Asia/Africa (A/A) than among native-born Jews of Asian/African origin (I-A/A). Since these groups have similar genetic susceptibilities to MS, the higher PR in the latter is probably due to environmental factors. Our study does not support the effect of latitude on the risk of developing MS since no difference in the PR was found between immigrant Jews from Europe/America (E/A) and native-born Jews of European/American origin (I-E/A). Among Arabs, the PR was similar to that among A/A. Therefore, we hypothesized similarity in environmental etiologic factors for MS between the countries of origin of A/A immigrants and of Arabs communities in Greater Jerusalem. The IR of I-E/A was higher than that of I-A/A and Arabs, although this difference did not reach statistical significance.
Karpus, W. J., B. T. Fife, et al. (2003). "Immunoneutralization of chemokines for the prevention and treatment of central nervous system autoimmune disease." Methods 29(4): 362-8.
Chemokine-induced lymphocyte migration has long been hypothesized to regulate the appearance and continued presence of lymphocytes and monocytes in tissue-specific autoimmune diseases, including central nervous system autoimmune diseases such as multiple sclerosis. For instance, a large body of evidence points to the temporal association of chemokine expression with the appearance of T lymphocytes and monocytes/macrophages. Furthermore, experiments using mice with targeted mutations for chemokines have shown the importance of those molecules in the development of central nervous system autoimmune disease. We have hypothesized that temporal and spatial expression of chemokines is a key factor in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis. To test our hypothesis we have employed the strategy of eliminating chemokine function by the passive transfer of chemokine-specific polyclonal antibodies. This approach has allowed us not only to test the function of chemokines in experimental autoimmune encephalomyelitis development, but also to ask questions about the roles of chemokines during disease progression. Moreover, this approach has allowed us to assess the efficacy of targeting chemokines and their receptors for treatment of ongoing disease. In the present report we summarize our experience using anti-chemokine administration for the prevention and treatment of experimental autoimmune encephalomyelitis as well as provide specific examples of how this approach is efficacious for disease treatment.
Kasser, S. L., J. A. McCubbin, et al. (2003). "Variability in constraints and functional competence in adults with multiple sclerosis." Am J Phys Med Rehabil 82(7): 517-25.
OBJECTIVE: Examine intraindividual change in physical and psychological impairments associated with multiple sclerosis and assess the relationship between changes in specific deficits and functional competence in activities of daily living. DESIGN: A multivariate, replicated, single-subject, repeated-measures design was used to examine variability patterns across subjects. Five adults with multiple sclerosis were assessed on leg strength, upright postural control, mood, fatigue, stress, and self-efficacy for 4 mo. Functional competence in three activities of daily living was also evaluated. P-technique factor analyses were performed to examine which variables covaried with time. RESULTS: Analyses revealed covariation among physical and psychological variables for four of the five participants. Across all participants, coefficients of variation revealed greater variability in stress (32.3%-53.4%) and fatigue (23.4%-5.9%) than in any of the physical variables (<20%), and variability in all impairments was greater than variability in the functional tasks (0%-12.6%). CONCLUSIONS: The greater stability in functional performance compared with both physical and psychological constraints provides important insight into symptom management and clinical intervention. The magnitude of variability found in the psychological variables across individuals also has implications concerning psychological adjustment to the disease.
Kassubek, J., H. Tumani, et al. (2003). "Age-related brain parenchymal fraction is significantly decreased in young multiple sclerosis patients: a quantitative MRI study." Neuroreport 14(3): 427-30.
The extent of brain atrophy was determined in 33 patients with multiple sclerosis (MS) and in 60 healthy subjects (21-76 years) by calculating brain parenchymal fractions (BPF, the ratio of brain parenchymal to intracranial volume) from 3D MRI. Within the normal data base, subjects at higher ages showed significantly lower BPF values. In younger MS patients, BPF was significantly decreased compared with age-matched controls (20-29 years, p= 0.0022; 30-39 years, =p 0.0001; 40-49 years,p = 0.0444) and was significantly correlated with disease duration and disease severity, but not with the number of detectable MS lesions. Determination of age-related BPF demonstrated significant brain atrophy in early MS and can be considered as a useful biological marker for monitoring MS.
Kastenbauer, S., U. Koedel, et al. (2003). "CSF and serum levels of soluble fractalkine (CX3CL1) in inflammatory diseases of the nervous system." J Neuroimmunol 137(1-2): 210-7.
The new CX(3)C-chemokine fractalkine (CX(3)CL1) was measured by Western blot in the cerebrospinal fluid (CSF) and serum of patients with inflammatory diseases of the peripheral and central nervous system (Bell's palsy, BP; Guillain-Barre Syndrome, GBS; multiple sclerosis, MS; viral meningitis, VM; bacterial meningitis, BM) and patients with noninflammatory neurological diseases (controls). In controls, fractalkine was detectable at low concentrations in the CSF and, at much higher levels, in serum. In all inflammatory neurological diseases under study, CSF fractalkine levels were significantly (p<0.01) increased vs. controls (BM>>GBS>VM>MS>BP>controls). In serum, fractalkine levels were significantly increased only in MS patients. The fractalkine CSF/serum ratios (a measure of the chemotactic gradient) were significantly elevated in BM, VM and GBS; furthermore, they tended to be increased in BP and to be decreased in MS. The elevated fractalkine CSF/serum ratios in diseases without CSF pleocytosis (GBS, BP) and a lack of correlation between fractalkine levels and CSF leukocyte counts suggested that soluble fractalkine is not a major chemokine in the CSF. There was no evidence of significant intrathecal production of fractalkine as the mean fractalkine indices (fractalkine CSF/serum ratio:albumin CSF/serum ratio) were <1 in all inflammatory diseases and not significantly elevated vs. controls.
Kaufman, M. D., S. K. Johnson, et al. (2003). "Multiple sclerosis: severity and progression rate in african americans compared with whites." Am J Phys Med Rehabil 82(8): 582-90.
ABSTRACT Kaufman MD, Johnson SK, Moyer D, Bivens J, Norton HJ: Multiple sclerosis: Severity and progression rate in African Americans compared with whites. Am J Phys Med Rehabil 2003;82:582-590.OBJECTIVE Although epidemiology indicates that multiple sclerosis is more common among whites than African Americans, the course of disease may be more aggressive among African Americans. This study examines disease course in a large multiple sclerosis clinic population.DESIGN A case-controlled, retrospective record review compared the severity of multiple sclerosis for African Americans and for whites. Because the baseline demographics of the two groups differed, we performed analyses of multiple subgroups in an attempt to control for various characteristics.RESULTS Consistent evidence of more disability in African Americans compared with whites was found, although subgroups were often too small to establish statistical significance. African Americans had a higher mean Expanded Disability Status Scale score than whites in a subgroup selected to minimize differences in access to care and disease perceptions. African Americans reported limb weakness as a presenting symptom of multiple sclerosis more frequently than did whites. When patients were followed at our multiple sclerosis center, rates of disease progression were nearly identical.CONCLUSIONS More African Americans than whites experience pyramidal system involvement early in multiple sclerosis, leading to greater disability as measured by the ambulation-sensitive Expanded Disability Status Scale. Once patients have moderate difficulty walking, the rate of progression is the same for both groups, albeit occurring at a later age for whites than for African Americans.
Kennel De March, A., M. De Bouwerie, et al. (2003). "Anti-myelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis." J Neuroimmunol 135(1-2): 117-25.
Humoral auto-immunity to the myelin oligodendrocyte glycoprotein (MOG) is likely involved in the pathogenesis of multiple sclerosis (MS). In 44 MS patients and 30 controls, Ig-producing B cells were identified by their isotype and as MOG-specific spot-forming cells (SFC). Peripheral anti-MOG antibodies were assayed in ELISA as well as anti-butyrophilin antibodies to investigate for molecular mimicry. MS patients had significantly higher levels of IgA- and MOG-SFC than controls, as well as significantly higher antibody responses to MOG and butyrophilin. These data provide added support for the implication of anti-MOG humoral immunity in the pathophysiology of MS, and suggest a balance of systemic (anti-self) and mucosal (environment-modulated) immune reactions in an attempt at regulating the pathogenic specific immune response.
Kerschensteiner, M., C. Stadelmann, et al. (2003). "Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases." Ann Neurol 53(3): 292-304.
Inflammatory reactions in the central nervous system usually are considered detrimental, but recent evidence suggests that they also can be beneficial and even have neuroprotective effects. Intriguingly, immune cells can produce various neurotrophic factors of various molecular families. The concept of "neuroprotective immunity" will have profound consequences for the pathogenesis and treatment of neuroinflammatory diseases such as multiple sclerosis. It also will prove important for neurodegenerative disorders, in which inflammatory reactions often occur. This review focuses on recent findings that immune cells produce brain-derived neurotrophic factor in multiple sclerosis lesions, whereas neurons and astrocytes express the appropriate tyrosine kinase receptor TrkB. Together with functional evidence for the neuroprotective effects of immune cells, these observations support the concept of "neuroprotective immunity." We next examine current and future therapeutic strategies for multiple sclerosis and experimental autoimmune encephalomyelitis in light of neuroprotective immunity and finally address the broader implications of this new concept for other neuroinflammatory and neurodegenerative diseases.
Khare, M., M. Rodriguez, et al. (2003). "HLA class II transgenic mice authenticate restriction of myelin oligodendrocyte glycoprotein-specific immune response implicated in multiple sclerosis pathogenesis." Int Immunol 15(4): 535-46.
Myelin oligodendrocyte glycoprotein (MOG) is a potential target antigen of the central nervous system (CNS), known to induce autoreactive T cell response and demyelinating anti-MOG antibodies in multiple sclerosis (MS) patients. Association of HLA class II genes with MS is well established. To better understand the role of HLA class II molecules in disease pathogenesis, we generated transgenic mice that express HLA-DR2, -DR3, -DR4, -DQB1*0601, -DQB1*0604 and -DQ8 without mouse class II (Abeta(0)). We have for the first time characterized the T and B cell epitopes of human MOG restricted by different HLA class II molecules. Immunization with recombinant MOG (rMOG) generated a strong CD4(+) T cell-mediated response in an HLA class II-restricted manner. Cytokine analysis revealed an increase in pro-inflammatory (IFN-gamma, IL-12 and IL-6) and anti-inflammatory (IL-10) cytokines. T cell autoreactivity to MOG was directed against peptides 1-20, 31-50, 61-80 and 91-110, of which three are also immunodominant epitopes for MOG in MS. A strong B cell response to MOG was observed in all transgenic mice, and major B cell epitopes recognized were located within amino acids 1-30, 51-80 and 101-120 of human MOG, which consists of two epitopes reported in MS. Transgenic mice used in this study recognized the immunodominant MOG epitopes similar to HLA class II-restricted human T cells, and would therefore be valuable in elucidating the roles of HLA class II genes and autoantigens in MS.
Kielian, T. and P. D. Drew (2003). "Effects of peroxisome proliferator-activated receptor-gamma agonists on central nervous system inflammation." J Neurosci Res 71(3): 315-25.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a critical role in glucose and lipid metabolism. More recently, PPAR-gamma ligands have been reported to inhibit the expression of proinflammatory molecules by monocytes/macrophages. Of relevance to CNS disease is that PPAR-gamma agonists have been demonstrated to have similar effects on microglia. PPAR-gamma agonists also ameliorate experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. This Mini-Review summarizes the effects of PPAR-gamma agonists in mediating immune responses and the potential of these agonists in the treatment of inflammatory disorders of the CNS.
Kieseier, B. C. and H. P. Hartung (2003). "Multiple paradigm shifts in multiple sclerosis." Curr Opin Neurol 16(3): 247-52.
PURPOSE OF REVIEW: The present article reviews the currently ongoing scientific debate of our changing views on the pathogenesis of multiple sclerosis and the therapeutic strategies currently available for multiple sclerosis. RECENT FINDINGS: The most important observations include that (a) axonal loss accounts for permanent disability in multiple sclerosis, (b) remyelination should be possible in theory but fails for unknown reasons in the multiple sclerosis lesion, (c) inflammation can be beneficial, (d) treatment should be initiated early, and (e) immunosuppressive strategies exhibit beneficial effects in progressive forms of the disease. SUMMARY: Our current understanding of the immunopathogenesis of multiple sclerosis has changed in the past. Whereas demyelination was originally thought to be relevant for the lasting neurological deficit, it is nowadays commonly accepted that the extent of axonal loss dictates the degree of permanent clinical disability. How axonal damage can be prevented remains elusive. The interaction between the myelinating cell and the neuron gains increasing attention, however the evolving knowledge has not yet yielded new treatment concepts. Hence for the time being, it seems prudent to make optimal use of current approved therapies. Recent trials underlined the need for early initiation of treatment with immunomodulatory drugs. The superiority of one of the interferons is still a matter of debate, and a conclusive answer cannot be given at present. Finally, with mitoxantrone we have a drug at hand which can be used in progressive forms of multiple sclerosis, especially when other disease modifying drugs are not or no longer effective.
Kieseier, B. C., H. Pischel, et al. (2003). "ADAM-10 and ADAM-17 in the inflamed human CNS." Glia 42(4): 398-405.
Inflammatory demyelinating disorders of the CNS, such as multiple sclerosis (MS), are mediated, at least in part, by various cytokines and proteases. In the present study, we investigated the expression of A disintegrin and metalloproteinase (ADAM)-17, an important sheddase for various proteins, including tumor necrosis factor-alpha (TNF-alpha), and the p75- and p55-TNF receptors, as well as ADAM-10, a protease implicated in myelin degradation, in post mortem CNS tissue samples from patients with MS, and normal brain tissue (as control) by immunohistochemistry. ADAM-10 was found to be expressed by astrocytes in all MS and control sections studied; however, in some MS sections, perivascular macrophages were determined as an additional cellular source as well. ADAM-17 could be observed exclusively in acute and chronic active MS plaques and localized to invading T lymphocytes. The staining pattern of ADAM-17 in MS plaques was mirrored in distribution and extent by the pattern obtained with an antibody against the p75-TNF-receptor (TNFR-2), whereas TNF-alpha was found to be expressed primarily by perivascular macrophages. In studying cerebrospinal fluid (CSF) samples from MS patients, we were able to detect increased protein levels of ADAM-17 as compared with noninflammatory controls. In addition, increased levels of soluble TNFR-2 could be measured, suggestive of an active shedding process mediated by ADAM-17. The stimulation of peripheral blood mononuclear cells (PBMC) obtained from MS patients and healthy individuals corroborated these findings by revealing expression of ADAM-17 by T lymphocytes and ADAM-10 by macrophages in vitro. Our results indicate that ADAM-10 is expressed constitutively by astrocytes in the normal and inflamed human CNS. In contrast, under inflammatory conditions, ADAM-10, expressed by perivascular macrophages, and ADAM-17, expressed by invading T cells, may actively contribute to the pathogenesis of inflammatory disorders of the CNS. GLIA 42:398-405, 2003. Copyright 2003 Wiley-Liss, Inc.
Kilinc, M., I. Saatci-Cekirge, et al. (2003). "Serial Analysis of Soluble Intercellular Adhesion Molecule-1 Level in Relapsing-Remitting Multiple Sclerosis Patients During IFN-beta1b Treatment." J Interferon Cytokine Res 23(3): 127-33.
In this controlled study, we investigated the serum and cerebrospinal fluid (CSF) levels of soluble intercellular adhesion molecule-1 (sICAM-1) in relapsing-remitting multiple sclerosis (RRMS) patients and changes in the levels of this adhesion molecule during interferon-beta1b (IFN-beta1b) treatment. We also investigated the changes in the levels of sICAM-1 in correlation with disease activity and with findings on magnetic resonance images (MRI). The study included 24 patients (16 females and 8 males) who were confirmed to have RRMS based on the criteria of Poser et al. Sixteen of the patients received IFN-beta1b (Betaseron((R)), Berlex Laboratories, Schering AG Germany, Berlin) treatment, and 8 did not receive this therapy. The levels of sICAM-1 in the MS patients' serum and CSF were significantly higher than levels in individuals with noninflammatory neurologic disease (p = 0.0081 and p = 0.0001, respectively). In the first 3 months of the study, MS patients treated with IFN-beta1b showed a significant rise in sICAM-1 levels (p = 0.0023), whereas their untreated counterparts showed no significant change. Neither of the groups showed a significant correlation between sICAM-1 level and disease activity demonstrated by MRI or between sICAM-1 level and clinical disease activity. The findings suggest that IFN-beta1b treatment may have a short-term upregulating effect on sICAM-1.
Killestein, J., E. L. Hoogervorst, et al. (2003). "Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis." J Neuroimmunol 137(1-2): 140-3.
Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-alpha in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS.
Kim, H., J. M. Suh, et al. (2003). "Thyrotropin-mediated repression of class II trans-activator expression in thyroid cells: involvement of STAT3 and suppressor of cytokine signaling." J Immunol 171(2): 616-27.
It has been suggested that class I and class II MHC are contributing factors for numerous diseases including autoimmune thyroid diseases, type 1 diabetes, rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis. The class II trans-activator (CIITA), which is a non-DNA-binding regulator of class II MHC transcription, regulates the constitutive and inducible expression of the class I and class II genes. FRTL-5 thyroid cells incubated in the presence of IFN-gamma have a significantly higher level of cell surface rat MHC class II RTI.B. However, the IFN-gamma-induced RT1.B expression was suppressed significantly in cells incubated in the presence of thyrotropin. Thyrotropin (TSH) represses IFN-gamma-induced CIITA expression by inhibiting type IV CIITA promoter activity through the suppression of STAT1 activation and IFN regulatory factor 1 induction. This study found that TSH induces transcriptional activation of the STAT3 gene through the phosphorylation of STAT3 and CREB activation. TSH induces SOCS-1 and SOCS-3, and TSH-mediated SOCS-3 induction was dependent on STAT3. The cell line stably expressing the wild-type STAT3 showed a higher CIITA induction in response to IFN-gamma and also exhibited TSH repression of the IFN-gamma-mediated induction of CIITA. However, TSH repression of the IFN-gamma-induced CIITA expression was not observed in FRTL-5 thyroid cells, which stably expresses the dominant negative forms of STAT3, STAT3-Y705F, and STAT3-S727A. This report suggests that TSH is also engaged in immunomodulation through signal cross-talk with the cytokines in thyroid cells.
Kim, J. K., F. G. Mastronardi, et al. (2003). "Multiple Sclerosis: An important role for post-translational modifications of myelin basic protein in pathogenesis." Mol Cell Proteomics.
SUMMARY Myelin basic protein (MBP) represents a candidate autoantigen in multiple sclerosis (MS). We isolated MBP from normal and MS human white matter and purified six components (charge isomers) to compare the post-translational modifications on each. The sites and extent of methylation, deimination and phosphorylation were documented for all tryptic peptides by mass spectrometry. We found that mono and dimethylated arginine 107 was increased in MS samples; deimination of arginine occurred at a number of sites and was elevated in MS; phosphorylation was observed in 10 peptides in normal samples but was greatly reduced or absent in most peptides from MS samples. Data obtained with MBP isolated from fresh brain obtained from a spontaneously demyelinating mouse model supported the view that the changes observed in human brain were probably related to pathogenesis of demyelination, i.e., we found decreased phosphorylation and decreased amounts of glycogen synthesis kinase (GSK) in brain homogenates using specific antibodies. This study represents the first to define post-translational modifications in demyelinating disease and suggest an important role in pathogenesis.
Kim, N. R., M. P. Chung, et al. (2003). "Pulmonary lymphangioleiomyomatosis and multiple hepatic angiomyolipomas in a man." Pathol Int 53(4): 231-5.
Pulmonary lymphangioleiomyomatosis (LAM) is an uncommon disease that to this point has been known to occur exclusively in reproductive women. To our knowledge, only one case of pulmonary LAM that was proven pathologically has been reported in a genotypical and phenotypical man. Multiple occurrence of hepatic angiomyolipomas is also rare, and only six cases have been found in the literature. Here, we report a biological and phenotypical man who had pulmonary LAM and multiple hepatic angiomyolipomas, leading to a presumptive diagnosis of tuberous sclerosis. This unsual presentation further broadens the wide spectrum of various clinicopathological aspects of pulmonary lymphangioleiomyomatosis and hepatic angiomyolipoma. Here, we emphasize that multiple hepatic angiomyolipomas should be distinguished from hepatic tumors, particularly in an endemic area for hepatocellular carcinoma. Further, pulmonary lymphangioleiomyomatosis can be a cause of cystic pulmonary disease even in a man.
Kira, J. (2003). "Multiple sclerosis in the Japanese population." Lancet Neurol 2(2): 117-27.
Multiple sclerosis (MS) in Asian populations is characterised by the selective and severe involvement of the optic nerve and spinal cord as well as low prevalence rates. 15-40% of cases of MS in Japan are of this "opticospinal" type. This form of MS generally has a higher age at onset and a higher female to male ratio than conventional MS. Opticospinal MS is also characterised by frequent relapses, severe disability, few brain lesions visible on MRI, long lesions extending over many vertebral segments visible on spinal-cord MRI, pleocytosis and an absence of oligoclonal bands in the CSF, and a pronounced shift in the responses of T-helper-1 and T-cytotoxic-1 cells throughout relapse and remission phases. Conventional MS in Japanese people is, like MS in white people, associated with HLA-DRB1*1501, whereas opticospinal MS is associated with HLA-DPB1*0501. In Japanese people born after modernisation in the 1960s, the ratio of conventional to opticospinal MS has increased rapidly. Opticospinal MS is likely to have a distinct immune-mediated mechanism, which is not operative in conventional MS.
Kneebone, II, E. C. Dunmore, et al. (2003). "Symptoms of depression in older adults with multiple sclerosis (MS): comparison with a matched sample of younger adults." Aging Ment Health 7(3): 182-5.
Kob, M., J. Harvey, et al. (2003). "A novel and rapid assay for the detection of neutralizing antibodies against interferon-beta." Mult Scler 9(1): 32-5.
There is evidence that neutralizing antibodies (NAB) have a negative influence on the clinical and magnetic resonance imaging effects of interferon-beta (IFNbeta) in multiple sclerosis (MS) patients. The current methods for NAB detection are restricted to specialized laboratories because they require a cell culture and sometimes a viral culture. Results are typically obtained after several weeks. Therefore, the development of a simple and rapid assay for the detection of NAB was sought. Whole blood samples from 28 NAB-positive patients and 110 NAB-negative patients (52 with IFNbeta and 58 without IFNbeta therapy) were incubated with IFNbeta 976 IU/mL for 24 hours. MxA protein levels--a specific marker of class I IFN bioactivity--were measured in paired samples with and without IFNbeta incubation and the difference in MxA levels was calculated. The mean increase of MxA levels after stimulation with IFNbeta in the NAB-positive group was 8 ng/mL (range 0-44 ng/mL) and in the NAB-negative group was 84 ng/mL (range 0-302 ng/mL). Using an increase of 22.5 ng/mL as cut-off) the specificity of the MxA stimulation assay was 81.2% and the sensitivity was 96.4%. The whole blood MxA stimulation assay is virtually as sensitive as the conventional NAB assay but somewhat less specific. However, this is outweighed by the procedural advantage of the assay, which is simpler, quicker and much less expensive.
Koike, F., J. Satoh, et al. (2003). "Microarray analysis identifies interferon beta-regulated genes in multiple sclerosis." J Neuroimmunol 139(1-2): 109-18.
The molecular mechanisms for the interferon beta (IFNbeta) treatment of multiple sclerosis (MS) remain to be characterized. Using cDNA microarray technology, we have compared the gene expression profile of T and non-T cells derived from relapsing-remitting MS before and after treatment with IFNbeta-1b. IFNbeta treatment significantly altered expression of 21 genes out of 1263 at 3 and 6 months after treatment. These genes included nine with IFN-responsive promoter elements. Whereas there was no change in Th1 or Th2 marker genes, some of the changes were unexpected but coincided with the beneficial effect of IFNbeta in MS.
Kolar, O. J., J. A. Bauerle, et al. (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1825.
Kolitz, B. P., R. D. Vanderploeg, et al. (2003). "Development of the Key Behaviors Change Inventory: a traumatic brain injury behavioral outcome assessment instrument." Arch Phys Med Rehabil 84(2): 277-84.
OBJECTIVE: To describe the development and initial validation of a neurobehavioral outcome measure, the Key Behaviors Change Inventory (KBCI), for individuals with traumatic brain injury (TBI). DESIGN: Scale construction and development, and validity study. SETTING: Large state university and postal survey. PARTICIPANTS: Seventy-five volunteer undergraduate students and 25 volunteer collateral informants of individuals with TBI participated in the item-analysis phase. Thirty members of the Brain Injury Association and 20 members of the National Multiple Sclerosis Society rated both an identified patient and an age- and gender-equated control in the validation phase. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Content validity was examined through expert panel item sorts. Scale internal consistencies were examined with the Cronbach alpha. Construct validity was examined by comparing scale elevations between controls and 2 neurologic groups. RESULTS: Item-analysis procedures resulted in 8 scales of 8 items each: inattention, impulsivity, unawareness of problems, apathy, interpersonal difficulties, communication problems, somatic difficulties, and emotional adjustment. Internal consistency reliability coefficients ranged from.82 to.91. Multivariate analysis of variance revealed significant (P</=.001) differences in scale elevations among TBI, multiple sclerosis (MS), and control groups. The TBI and MS groups scored significantly higher than the control group on all scales; a subset of KBCI scales discriminated between the 2 neurologic groups. CONCLUSION: The KBCI was both sensitive and specific to typical behavioral changes after TBI, thus supporting its usefulness in rehabilitation settings. Cross-validation and development of a normative database are future steps necessary in its development.
Koopman, W. (2003). "Needs assessment of persons with multiple sclerosis and significant others: using the literature review and focus groups for preliminary survey questionnaire development." Axone 24(4): 10-5.
The purpose of this study was to conduct focus group interviews to obtain information for development of a needs assessment questionnaire. Four focus groups were conducted with 10 people with multiple sclerosis (MS) and five significant others. A facilitator from the learning services department at the hospital conducted the interviews guided by questions developed by the researcher. The focus group interviews were audiotaped and transcribed. The researcher analyzed the transcribed interviews. Content analysis was used to analyze the transcribed data creating categories from key words and phrases as they appeared. The findings were grouped by themes. The results highlighted the participants' experiences and needs regarding physical changes; sources of assistance; unmet needs; psychological, employment, leisure, and informational needs. A comparison of themes developed from the focus groups and in the literature captured categories for questionnaire development. One new theme, leisure, was not found in the literature and was incorporated based on the findings of this study. The final categories for questionnaire development were: physical, health, psychological, financial, employment/meaningful daytime activity and leisure, accessibility and information. A survey questionnaire was developed from the focus group data using the phraseology of the participants.
Kottler, U. B., H. J. Trojan, et al. (2003). "[Multiple tumors of the facial skin]." Ophthalmologe 100(4): 338-9.
Kozuka, T., K. Kojima, et al. (2003). "Autoimmune neutropenia associated with multiple sclerosis." Intern Med 42(1): 102-4.
A 53-year-old Japanese man with multiple sclerosis developed autoimmune neutropenia. The neutrophil count was consistently less than 0.2 x 10(9)/l, irrespective of the disease activity of multiple sclerosis or the administration of immunosuppressive agents or granulocyte colony-stimulating factor. After high-dose gamma-globulin therapy was started, temporary increases in the neutrophil count were observed. Despite a wide spectrum of clinical manifestations in multiple sclerosis, autoimmune neutropenia has never been reported previously.
Kralik, D., T. Koch, et al. (2003). "The salience of the body: transition in sexual self-identity for women living with multiple sclerosis." J Adv Nurs 42(1): 11-20.
AIM: The purpose of this paper is to outline understandings about the construction of sexuality and the impact of a changing body for women living with multiple sclerosis (MS). We suggest that the process of transition towards incorporating the experience of chronic illness into one's life is influenced by the (re)construction of self-identity. DESIGN AND METHODS: A participatory action process guided the research. The women joined the authors for five group sessions that totalled 15 hours of contact time. In addition, we offered women the opportunity for one-to-one interviews at home. Nine women volunteered to participate. This allowed us to gain additional in-depth data about individual experiences. The interpretive framework was guided by the self-identity literature. When reading the transcripts we questioned: What is going on here? What does this say about the construction of self? What does this say about the construction of identity? What influence does the body have in the construction of self-identity? Analysis was collaborative (with the women) and the resultant emerging construction of sexuality is shared in this paper. Data generated during one-to-one interviews are privileged and we include two accounts from women who live with MS. The women's stories focus on sexuality, however, within this sexual context, we observed shifts in self-identity which we contend may shape the illness transition experience. FINDINGS: The rationale for privileging only two accounts is to expand understanding of Ordinariness and Extraordinariness with particular focus on the salience of the body in the 'sexual' lives of the women. Self-identity was shaped by how they felt about themselves as sexual beings, how they experienced their body, how they felt about sexual activities and by the way others reacted to them. Importantly, we view the women's sense of self, identity and the relationship to the body and find that shifts in self identity shape the woman's transition towards Ordinariness. CONCLUSIONS: This exploration of illness experiences is a reminder that our bodies are vehicles for our sense of self and identity. Cultural, educational, social, religious and family contexts all impact on women's capacity to shape the consequences of illness and the choices available to them. Facilitating women towards an awareness of the choices available in order to sustain or reclaim self may in turn expedite transition towards Ordinariness so that illness may become a part of their life.
Kreisler, A., J. de Seze, et al. (2003). "Multiple sclerosis, interferon beta and clinical thyroid dysfunction." Acta Neurol Scand 107(2): 154-7.
The objective of this study was to investigate frequency and presentation of clinical thyroid dysfunction in patients treated with interferon beta (IFN-beta). We have collected the cases of clinical thyroid dysfunction in 700 consecutive patients receiving IFN-beta for multiple sclerosis (MS). Five patients (four women, one man) treated with IFN-beta1b developed hyperthyroidism. Three of them have secondary progressive MS, and two have relapsing-remitting MS. It was necessary to stop IFN-beta in three cases; these patients still require carbimazole after several months. In the two other cases, hyperthyroidism disappeared spontaneously. Two patients (one man and one woman) treated with IFN-beta1a developed hypothyroidism. One of them required l-thyroxine. Lastly, an increased thyroid volume without modification of thyroid hormones plasma levels was discovered in a patient receiving IFN-beta1a. Among patients treated with IFN-beta, clinical thyroid dysfunction is much rarer than laboratory thyroid dysfunction. However, this side-effect is sometimes severe.
Krivickas, L. S. (2003). "Amyotrophic lateral sclerosis and other motor neuron diseases." Phys Med Rehabil Clin N Am 14(2): 327-45.
The anterior horn cell diseases, with the exception of polio, are progressive degenerative diseases of the motor neurons. These disorders include SMA types I to III in children and familial and sporadic ALS and its variants (PMA, PLS, and PBP), Kennedy's disease, and SMA type IV in adults. The electrodiagnostic study is a crucial step in the diagnostic process for all of these disorders. In general, motor NCS may be normal or reveal low CMAP amplitudes with relatively normal conduction velocities. Sensory NCS, except in the case of Kennedy's disease, are normal. The NEE is notable for the often abundant presence of abnormal spontaneous activity, including fibrillation potentials and positive sharp waves, fasciculation potentials, and complex repetitive discharges. Motor unit morphology is abnormal, with polyphasic motor units and large amplitude and duration MUAPs when the disease is slowly progressive. Recruitment in affected muscles is reduced with abnormally rapidly firing motor units. To diagnose a widespread disorder of the motor neurons, abnormalities must be present in multiple muscles with different nerve root and peripheral nerve innervation in multiple limbs. The Lambert Criteria and the El Escorial Criteria are the two most widely accepted sets of electrodiagnostic criteria for ALS. The electrodiagnostic diagnosis must be supported by appropriate history and physical examination findings and the exclusion, via neuroimaging and laboratory testing, of other diseases that may mimic a generalized disorder of the motor neurons.
Kriz, J., G. Gowing, et al. (2003). "Efficient three-drug cocktail for disease induced by mutant superoxide dismutase." Ann Neurol 53(4): 429-36.
There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because evidence suggests that multiple pathways may contribute to ALS pathogenesis, we tested in a mouse model of ALS (SOD1(G37R) mice) a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death: minocycline, an antimicrobial agent that inhibits microglial activation, riluzole, a glutamate antagonist, and nimodipine, a voltage-gated calcium channel blocker. The efficacy of this three-drug cocktail was remarkable when administered in the diet from late presymptomatic stage (8-9 months). It delayed the onset of disease, slowed the loss of muscle strength, and increased the average longevity of SOD1(G37R) mice by 6 weeks. The protective effect of the treatment was corroborated by the reduced immunodetection signals for markers of gliosis and neurodegeneration in the spinal cord of SOD1(G37R) mice. These results indicate that such three-drug combination may represent an effective strategy for ALS treatment.
Kroll, T., P. W. Beatty, et al. (2003). "Primary care satisfaction among adults with physical disabilities: the role of patient-provider communication." Manag Care Q 11(1): 11-9.
OBJECTIVES: To determine overall satisfaction with primary care among people with cerebral palsy, multiple sclerosis, and spinal cord injury, and to identify potential differences in primary care satisfaction between managed care (MC) and fee-for-service (FFS) enrollees with these physical disabilities. PARTICIPANTS: The sample consisted of 195 people with cerebral palsy (CP), multiple sclerosis (MS), and spinal cord injury (SCI), between the ages of 18 and 65 who had received primary care services in the six months prior to the survey. MEASUREMENTS: Satisfaction with various aspects of primary care were assessed using a 10-item self-report measure. Respondents were compared with regard to service satisfaction based on disability and insurance type (MC vs. FFS). Satisfaction items were summed up to produce an unweighted index of overall satisfaction. In the analysis we used non-parametric statistics, such as Kruskal-Wallis One Way ANOVA and Mann-Whitney Rank tests. Post hoc alpha corrections were performed using the Holms Stepdown Procedure. CONCLUSIONS: The lack of disability-specific knowledge among primary care providers is consistent with findings of other studies. People with physical disabilities in managed care plans are less satisfied with how their providers communicate with them, relative to those in FFS plans. Poor patient-provider communication may place individuals with certain physical disabilities at risk for not receiving appropriate care.
Krum, H. and D. Liew (2003). "Current status of endothelin blockade for the treatment of cardiovascular and pulmonary vascular disease." Curr Opin Investig Drugs 4(3): 298-302.
With recognition of the significant role of the endothelin system in cardiovascular and pulmonary vascular diseases, attention has turned to the therapeutic application of agents that antagonize this system. Three strategies can be employed: dual endothelin receptor (ETA and ETB) antagonism, selective ETA antagonism and inhibition of endothelin-converting enzymes. The first two strategies have been evaluated in late-phase clinical trials, with mixed results. The use of the dual endothelin receptor antagonist bosentan in pulmonary arterial hypertension has been successful. Available data are less compelling, but nonetheless promising, for the use of bosentan in digital ulceration secondary to systemic sclerosis, and tezosentan (another dual receptor blocker) in acute heart failure. Both types of receptor antagonists, however, have been evaluated in systemic hypertension and chronic systolic heart failure and are unlikely to be further developed in these areas. For the treatment of hypertension, their (moderate) efficacy and safety/tolerability profiles appear no more favorable than existing antihypertensive agents. In terms of treatment for chronic heart failure, these agents appear to offer no further benefit over standard therapy for the treatment of chronic heart failure, and in fact, may be associated with poorer outcomes. The complexity of the endothelin system and its diverse roles in multiple disease states will ensure its position as a target for drug development.
Krupp, L. B. (2003). "Fatigue in multiple sclerosis: definition, pathophysiology and treatment." CNS Drugs 17(4): 225-34.
Fatigue is a common disabling symptom of multiple sclerosis (MS). It is often considered a state of exhaustion distinct from depressed mood or physical weakness. Fatigue can be assessed by either self-report scales or performance-based measures; however, neither method captures all features of fatigue. Fatigue in MS frequently leads to unemployment. It is associated with a sense of loss of control over one's environment, low positive affect, psychological distress and neurological impairment. To date there is no reproducible neuroimaging marker or biological correlate that has been identified. Proposed pathological mechanisms of fatigue in MS include neuronal factors such as dysfunction of premotor, limbic, basal ganglia or hypothalamic areas; disruption of the neuroendrocrine axis leading to low arousal; alteration in serotoninergic pathways; changes in neurotransmitter levels; and altered CNS functioning caused by a disruption of the immune response. Treatment of fatigue is best approached in a multidisciplinary fashion that incorporates nonpharmacological interventions as well as medication. Amantadine and modafinil are among the most commonly used medications for fatigue associated with MS. Both medications have been studied with positive results in controlled clinical trials. Additional research towards measurement and pathogenesis of fatigue will hopefully lead to improved therapies.
Kumakura, S. and S. Kobayashi (2003). "Autoimmune neutropenia." Intern Med 42(2): 133-4.
Kwiatkowska-Patzer, B., B. Baranowska, et al. (2003). "Influence of spinal cord protein hydrolysate upon the blood brain barrier changes due to experimental allergic encephalomyelitis in Lewis rats. Ultrastructural study." Folia Neuropathol 41(1): 29-34.
A specific protein (antigen) given orally is a known method of introducing tolerance of immunological response to this antigen. This method has recently been reviewed by some authors as a possible tool in the treatment of autoaggressive diseases, such as multiple sclerosis. The experimental allergic encephalomyelitis (EAE) respected animal model for MS was used for the study. The aim of the study was the evaluation of the effect of pig spinal cord protein hydrolysate given orally upon the ultrastructural changes in the blood-brain barrier image in EAE. Changes of EAE are as follows: opened channels from basal membrane (tight junction) on the border with astrocytes, fragments of organelles of the cells, oedema of astrocytes, presence of vesicles with fluid, presence of macrophages with phagolysosomes. After pre-treatment with spinal cord hydrolysate up to 6 weeks all the above changes were normalised. These findings are promising as a possible tool in the clinical treatment of sclerosis multiplex.