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Back to Multiple Sclerosis (MS)

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MS and Stress

(58 References)

Yamashita, K., T. Yokoyama, et al. (2003). "[Anesthetic management for a patient with multiple sclerosis at exacerbation stage under general anesthesia]." Masui 52(5): 521-3.

            A 39-year-old woman with multiple sclerosis (MS) at exacerbation stage underwent dilatation and curettage. MS is characterized by chronic inflammation, demyelination, and gliosis in the central nervous system. Surgical stress often induces exacerbation of MS symptoms. Therefore, deep anesthesia is required for anesthetic management in cases of MS. We monitored electroencephalograph (EEG), spectral edge frequency 90 (SEF 90), spectral median frequency (SMF) and delta-amplitude for depth of anesthesia using pEEG (Drager, Germany). In this case, anesthesia was induced with sevoflurane and gradually increased to 5% in oxygen 4 l.min-1 and maintained with sevoflurane 2-3% in 2 nitrous oxide l.min-1 and 2 l.min-1 oxygen. Surgery was completed and no spike wave was observed by pEEG monitoring during surgery. In conclusion, sevoflurane anesthesia was useful for a patient with MS during exacerbation stage.

Tesar, N., U. Baumhackl, et al. (2003). "Effects of psychological group therapy in patients with multiple sclerosis." Acta Neurol Scand 107(6): 394-9.

            OBJECTIVES: The aim of this pilot study was to evaluate a psychological therapy program used in the treatment of multiple sclerosis (MS) and including cognitive/behavioral strategies, relaxation training and physical exercise. MATERIAL AND METHODS: The participants were 29 patients with MS recruited from an outpatient unit; 14 patients were assigned to the 7-week psychological therapy group (one session per week), the remainder formed a control group. Before and immediately after the course of therapy and after a 2-month follow-up, the participants completed a series of questionnaires measuring factors such as depression, anxiety, coping and body image. RESULTS: Compared with the control group the therapy group showed long-term improvements in depressive stress coping style and a short-term improvement in "vitality and body dynamics". CONCLUSION: Further studies should investigate the differential effects of specific units of the therapy program and how the short-term improvements in "vitality and body dynamics" could be maintained for longer periods.

Stuifbergen, A. K., H. Becker, et al. (2003). "The use of individualized goal setting to facilitate behavior change in women with multiple sclerosis." J Neurosci Nurs 35(2): 94-9, 106.

            Setting goals is a useful strategy for changing behavior. The purpose of this study was to examine the effectiveness of a wellness intervention for women with multiple sclerosis (MS) on achieving health-related goals set individually by each participant in the experimental group (N = 57) using goal attainment scaling. The two-phase intervention included lifestyle-change classes over 8 weeks, then telephone follow-up over 3 months. Participants were followed over an 8-month period. Goal achievement was assessed at baseline, 2 months (following class), 3 1/2 months (6 weeks after class), 5 months (following 3 months of telephone follow-up), and at 8 months. The majority of the women met or exceeded all their individualized goals for changing behavior at the 6-week postclass assessment. Achievement and maintenance of individual goals remained high (59%-84%) over the 5 months after class follow-ups. These data support the positive effects of wellness interventions for helping women with MS to meet their own individualized health goals. Setting goals with incremental steps helped participants to articulate their individual goals and monitor achievement over time.

Penkowa, M. and J. Hidalgo (2003). "Treatment with metallothionein prevents demyelination and axonal damage and increases oligodendrocyte precursors and tissue repair during experimental autoimmune encephalomyelitis." J Neurosci Res 72(5): 574-86.

            Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human demyelinating disease multiple sclerosis (MS). EAE and MS are characterized by significant inflammation, demyelination, neuroglial damage, and cell death. Metallothionein-I and -II (MT-I + II) are antiinflammatory and neuroprotective proteins that are expressed during EAE and MS. We have shown recently that exogenous administration of Zn-MT-II to Lewis rats with EAE significantly reduced clinical symptoms and the inflammatory response, oxidative stress, and apoptosis of the infiltrated central nervous system areas. We show for the first time that Zn-MT-II treatment during EAE significantly prevents demyelination and axonal damage and transection, and stimulates oligodendroglial regeneration from precursor cells, as well as the expression of the growth factors basic fibroblast growth factor (bFGF), transforming growth factor (TGF)beta, neurotrophin-3 (NT-3), NT-4/5, and nerve growth factor (NGF). These beneficial effects of Zn-MT-II treatment could not be attributable to its zinc content per se. The present results support further the use of Zn-MT-II as a safe and successful therapy for multiple sclerosis.

Penkowa, M., C. Espejo, et al. (2003). "Metallothionein expression in the central nervous system of multiple sclerosis patients." Cell Mol Life Sci 60(6): 1258-66.

            Multiple sclerosis (MS) is a major chronic demyelinating and inflammatory disease of the central nervous system (CNS) in which oxidative stress likely plays a pathogenic role in the development of myelin and neuronal damage. Metallothioneins (MTs) are antioxidant proteins induced in the CNS by tissue injury, stress and some neurodegenerative diseases, which have been postulated to play a neuroprotective role. In fact, MT-I+II-deficient mice are more susceptible to developing experimental autoimmune encephalomyelitis (EAE), and treatment of Lewis rats with Zn-MT-II reduces EAE severity. We show here that, as in EAE, MT-I+II proteins were expressed in brain lesions of MS patients. Cells expressing MT-I+II were mainly astrocytes and activated monocytes/macrophages. Interestingly, the levels of MT-I+II were slightly increased in the inactive MS lesions in comparison with the active lesions, suggesting that MTs may be important in disease remission.

Mohamed, A., A. Shoker, et al. (2003). "Improvement of experimental allergic encephalomyelitis (EAE) by thymoquinone; an oxidative stress inhibitor." Biomed Sci Instrum 39: 440-5.

            Experimental Allergic Encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system that is widely accepted as an animal model for the human multiple sclerosis. Oxidative stress appears to play a role in the onset and progression of EAE. We reasoned that decreasing oxidative stress might ameliorate symptoms and signs of EAE. Thymoquinone is reported to inhibit oxidative stress. One way of decreasing oxidative stress is to induce glutathione (GSH). We tested the impact of Thymoquinone (1 mg/kg, injected at tail vein) in our EAE model. We induced (EAE) in female Lewis rats using myelin basic protein emulsified with complete Freund's adjuvant. 24 animals were placed into three groups: A) Rats with EAE B) EAE rats with concomitant five day injection of Thymoquinone days 1-5, C) EAE rats with five doses of Thymoquinone injected at day 12-17. Twenty-eight days later, animals were sacrificed; spinal cord tissues collected for glutathione (GSH). RESULTS: 63% of animals in group "A" developed hind limb weakness and/or paralysis while 37% developed mild tail weakness, perivascular inflammation and low spinal cord GSH level. 25% of animals in group "B" exhibited mild tail and hind limb weakness and 75% animals had no symptoms, no perivascular inflammation and high spinal cord GSH level. 63% of animals of group "C" showed improving symptoms following Thymoquinone injections, no perivascular inflammation and higher GSH level while 37% of animals showed no symptoms prior and post Thymoquinone injections. Clinical symptoms correlated well with perivascular inflammation and GSH level. Animals received Thymoquinone at day 12-17 had higher GSH level, no perivascular inflammation and no symptoms compared with other groups. CONCLUSION: Thymoquinone inhibited oxidative stress which leads into improvement in our EAE animals. Thymoquinone may have a role in treatment of Multiple Sclerosis.

Matsuura, E., A. Ohta, et al. (2003). "Frequency and analysis of factors closely associated with the development of depressive symptoms in patients with scleroderma." J Rheumatol 30(8): 1782-7.

            OBJECTIVE: To examine the frequency of depressive symptoms and also to identify factors closely associated with their development in patients with scleroderma (systemic sclerosis, SSc). METHODS: We evaluated 50 patients with SSc for factors associated with depressive symptoms using the following established scales: the Beck Depression Inventory (BDI); the Rheumatology Attitude Index for measuring helplessness; the Sense of Coherence (SOC) scale (a measure of an individual's resilience in the face of stress and capacity to cope with it); the modified Health Assessment Questionnaire for physical disability, working, and social function; support domains of Arthritis Impact Measurement Scales version 2; and a visual analog pain scale. In addition, disease severity of SSc, including skin thickness and internal organ involvement, was also examined in each patient. Multiple regression analysis was used to determine which factors correlated with depressive symptoms. RESULTS: Depressive symptoms ranging from mild to severe state were seen in 46% of the patients. Total BDI scores were significantly correlated with low working ability, low social activity, low SOC, pain, and helplessness, and not associated with disease severity variables including skin score and internal organ involvement. Multiple regression analysis showed that a high level of helplessness and a low level of SOC might be closely associated with depressive symptoms in SSc. CONCLUSION: Our results indicate that depressive symptoms are frequent in SSc patients. Medical staffs should pay attention to the possible risk factors for depressive symptoms, such as patient's helplessness and SOC.

Liu, Y., B. Zhu, et al. (2003). "Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis." J Neuroimmunol 139(1-2): 27-35.

            Increasing evidence shows that oxidative stress plays an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). In recent years, bilirubin has been demonstrated to be a potent antioxidant in vitro. In this study, we administered bilirubin to rats with acute and chronic EAE. Bilirubin prevented both acute and chronic EAE effectively. More significantly, bilirubin suppressed ongoing clinical EAE and halted EAE progression when given after disease onset. Subsequent histological examination showed that if administered to rats before the onset of EAE, bilirubin interfered with the invasion of inflammatory cells into the central nervous system (CNS) because it protected the blood-brain barrier (BBB) from free radical-induced permeability changes. However, in some cases, inflammation still occurred even when no clinical illness was observed. In rats with treatment initiated after the onset of EAE, despite the clinical improvements, treatment with bilirubin did not reduce the degree of CNS inflammation, or change cytokine expression in CNS lesions, indicating a lack of immunosuppressive effect of this treatment. By contrast, bilirubin treatment significantly alleviated oxidative damage in the spinal cord, and the clinical signs of EAE correlated well with the degree of oxidative injury in the lesions. Our results suggest that free radicals play an important role in the final effector stages of EAE, and that antioxidant therapies may have potential for the treatment of MS.

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.

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.

Jurewicz, A., M. Matysiak, et al. (2003). "TNF-induced death of adult human oligodendrocytes is mediated by c-jun NH2-terminal kinase-3." Brain 126(Pt 6): 1358-70.

            Tumour necrosis factor (TNF) induces death of oligodendrocytes, the putative cell target in multiple sclerosis. We defined that the intracellular transduction pathway involved in TNF-induced death of human adult oligodendrocytes (hOLs) is dependent on c-jun NH(2)-terminal kinase (JNK) activation, but not the other mitogen-activated protein kinase (MAPK), p38. JNK activation, measured by c-jun phosphorylation and induction of the phosphorylated form of JNK, was enhanced, prolonged and correlated with cell death in hOLs exposed to TNF. Comparative autoradiographic analysis revealed that JNK-3, but not JNK-1 or JNK-2, is responsible for prolonged JNK activation in TNF exposed hOLs. Expression of a dominant-negative mutant of JNK upstream kinase, MKK4/SEK1, inhibited apoptosis induced by TNF, whereas expression of a constitutive active mutant of MEKK1, an upstream kinase to JNK, accelerates TNF-induced apoptosis. JNK activation occurred prior to changes of mitochondrial membrane potential in hOLs exposed to TNF. These results demonstrate that TNF-induced death in adult hOLs depends on prolonged JNK-3 activation, and that this apoptosis requires the mitochondrial dysfunction that occurs after JNK activation. This is the first evidence that a JNK-3 isoform is involved in oligodendrocyte death and might have significant importance in designing new molecules to protect hOLs demise in multiple sclerosis.

Johnson, J. (2003). "On receiving the diagnosis of multiple sclerosis: managing the transition." Mult Scler 9(1): 82-8.

            This article reports on one aspect of a wider study into multiple sclerosis (MS) specialist nurse roles in the UK. Insights gained from in-depth patient interviews are discussed in relation to literature regarding the meaning of health-related events, such as diagnosis. The findings of this project indicated that for many people, intense feelings of abandonment and isolation were generated at the time of diagnosis and stayed with the person for many months or years. Differing expectations between patient and neurologist following confirmation of diagnosis could contribute to these findings. It is suggested that imparting a diagnosis of MS should be seen as the start of a transition that needs to be made explicit to the patient and closely linked to the provision of sources of information, advice and ongoing support as people learn to live with and manage the disease.

Hisahara, S., H. Okano, et al. (2003). "Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination." Neurosci Res 46(4): 387-97.

            Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. MS is believed to be an autoimmune disorder mediated by activated immune cells such as T- and B-lymphocytes and macrophages/microglia. Lymphocytes are primed in the peripheral tissues by antigens, and clonally expanded cells infiltrate the CNS. They produce large amounts of inflammatory and cytokines that lead to demyelination and axonal degeneration. Although several studies have shown that oligodendrocytes (OLGs), the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli, such as cytotoxic cytokines, anti-myelin antibodies, nitric oxide, and oxidative stress, in vitro, the mechanisms underlying injury to the OLGs in MS/EAE remain unclear. Transgenic mice that express the anti-apoptotic protein specifically in OLGs and caspase-11-deficient mice are significantly resistant to EAE induction. Histopathological analyses show that the number of caspase-activated OLGs and dead OLGs are reduced in the CNS of these mice. The numbers of infiltrating immune cells and the amounts of cytokines are also markedly reduced in EAE lesions. Therefore, caspase-mediated OLG death leads to the exacerbation of demyelination and the deterioration of neurological manifestations by inducing local inflammatory events.

Hartelius, L., D. Theodoros, et al. (2003). "Comparability of perceptual analysis of speech characteristics in Australian and Swedish speakers with multiple sclerosis." Folia Phoniatr Logop 55(4): 177-88.

            The aims of the present study were to compare the perceptual assessments of deviant speech signs (dysarthria) exhibited by Australian and Swedish speakers with multiple sclerosis (MS) and to explore whether judgements of dysarthria differed depending on whether the speakers and the judges spoke the same or different languages. Ten Australian and 10 Swedish individuals with MS (matched as closely as possible for age, gender, progression type and severity of dysarthria) were assessed by 2 Australian and 2 Swedish clinically experienced judges using a protocol including 33 speech parameters. Results show that the following perceptual dimensions were identified by both pairs of judges in both groups of speakers to a just noticeable or moderate degree: imprecise consonants, inappropriate pitch level, reduced general rate, and glottal fry. The reliability (Spearman rank-order correlation) of the consensus ratings from the Australian and the Swedish judges was high, with a mean rho of 85.7 for the Australian speakers and mean rho of 84.3 for the Swedish speakers. The most difficult perceptual parameters to assess (i.e. to agree on) included harshness, level of pitch and loudness, precision of consonants and general stress pattern. The study indicated that perceptual assessments of speech characteristics in individuals with MS are informative and can be achieved with high inter-judge reliability irrespective of the judge's knowledge of the speaker's language.

Halper, J., P. Kennedy, et al. (2003). "Rethinking cognitive function in multiple sclerosis: a nursing perspective." J Neurosci Nurs 35(2): 70-81.

            Cognitive impairment is a common problem in multiple sclerosis (MS); up to 65% of patients exhibit some neuropsychological dysfunction during the course of their disease. It is a major contributing factor to unemployment, accidents, impairment of daily functioning, and loss of social activity in those affected by MS. The areas of cognition typically impaired are memory, attention, information processing, executive functions, and visuospatial skills. Cognitive dysfunction is independent of disease duration and level of disability; cognitive decline may begin in the earliest stages of MS before patients become even mildly disabled. Structural brain imaging studies show a positive correlation between the extent of brain atrophy and cognitive dysfunction. Despite its prevalence in MS, cognitive dysfunction often goes undiagnosed or is misdiagnosed as depression, stress, stubbornness, lack of intelligence, or psychosis. Because nurses play such an important role in the care of patients with MS, they are in a position to identify patients with cognitive dysfunction, educate patients and their families on ways to cope with cognitive deficits, and counsel patients on available treatment options. Practical guidelines help nurses identify and care for cognitively impaired MS patients.

Franzen, B., K. Duvefelt, et al. (2003). "Gene and protein expression profiling of human cerebral endothelial cells activated with tumor necrosis factor-alpha." Brain Res Mol Brain Res 115(2): 130-46.

            An increase in permeability of the blood-brain barrier is a critical event in the pathophysiological process of multiple sclerosis and other neurodegenerative diseases. Tumor necrosis factor alpha (TNFalpha) is known to play a crucial role in this process and is a powerful activator of endothelial cell inflammatory responses. Although many reports describe effects of TNFalpha activation in endothelial cells, the molecular mechanisms specific for activation of cerebral endothelial cells remains unclear. The objective of this study was to identify potential pharmaceutical targets for the treatment of multiple sclerosis using molecular profiling techniques. Gene expression measurements (Affymetrix Hu6800 oligonucleotide arrays) and proteomics (two-dimensional gel electrophoresis and mass spectrometry) were applied to analyze early alterations in human cerebral endothelial cells (HCEC) activated by TNFalpha. Human umbilical vein endothelial cells (HUVEC) were used as the reference system. The results presented show that HCEC and HUVEC respond similarly with respect to cell adhesion molecules, chemotaxis, apoptosis and oxidative stress molecules. However, nuclear factors NFkB1 and NFkB2, plasminogen activator inhibitor 1 and cofilin 1 are examples of cerebral specific responses. Our results indicate involvements of the urokinase plasminogen activator system and cytoskeletal rearrangements unique to TNFalpha activation of cerebral endothelial cells.

Fardet, L., T. Genereau, et al. (2003). "Devic's neuromyelitis optica: study of nine cases." Acta Neurol Scand 108(3): 193-200.

            OBJECTIVE: Multiple sclerosis (MS) is by far the most popular diagnosis for patients with multifocal neurological disease. Owing to demyelinating inflammatory non-necrotic plaques of the white matter, MS can give remitting symptoms of virtually every part of the central nervous system. Corticosteroids are usually helpful. Devic's neuromyelitis optica (DNMO) is a neurological disease involving only the optic nerves and the spinal cord, where demyelination evolves towards necrosis and atrophy; the prognosis is poor and no satisfactory treatment is known. The objectives of this study are to describe clinical, biological, pathological and radiological data of patients with DNMO and to differentiate DNMO from MS. MATERIAL AND METHODS: We studied the files of 14 patients diagnosed with possible DNMO in three French hospitals between 1980 and 1999 and reviewed the literature. RESULTS: Nine patients were included as definite DNMO. Five were excluded because they did not fulfil the diagnostic criteria. For the nine patients with definite DNMO, DNMO was either monophasic or multiphasic. The prognosis was generally poor: two patients died and five others developed severe disability such as blindness, para or quadriplegia or both. Cerebrospinal fluid study and neuroimaging were essential to confirm the diagnosis of DNMO. Various immunosuppressive treatments generally failed to benefit the patients. CONCLUSION: In the literature (as well as our 14 initial patients) only a few cases of patients described as suffering from DNMO fulfilled the diagnostic criteria. The others showed evidence that another disease like MS was involved. We stress that inclusion and exclusion criteria have to be kept in mind to differentiate clearly DNMO from MS and other central nervous system white matter diseases.

Dimayuga, F. O., Q. Ding, et al. (2003). "The neuregulin GGF2 attenuates free radical release from activated microglial cells." J Neuroimmunol 136(1-2): 67-74.

            The neuregulin glial growth factor 2 (GGF2) is a neural growth factor that is best known for its ability to promote the survival and proliferation of oligodendrocytes and Schwann cells. While it has been shown in recent years that GGF2 is effective in the treatment of autoimmune models of brain injury, it is not known if the beneficial effects of GGF2 are based in part on modulation of brain inflammation. In this report, we document the anti-inflammatory effects of recombinant human GGF2 (rhGGF2) on microglial free radical production in vitro. The presence of the neuregulin receptors ErbB2, 3, and 4 was confirmed in N9 microglial cells by Western blot analysis. Pretreatment of N9 cells with 10-100 ng/ml rhGGF2 24 h before either phorbol 12-myristate 3-acetate (PMA) or interferon gamma (IFNgamma) caused dose-dependent decreases in oxidative burst activity and nitrite release, respectively, with 50 and 100 ng/ml causing significant effects. When cells were co-treated with increasing doses of rhGGF2 and PMA or IFNgamma, only concentrations of 50 ng/ml, but not 10 or 100 ng/ml, were able to decrease oxidative burst activity and nitrite release. Finally, when microglial cell viability following treatment of cells with IFNgamma with or without rhGGF2 was evaluated, it was observed that 50 and 100 ng/ml rhGGF2 conferred significant protection against IFNgamma-induced cell death in microglial cells. Overall, these results indicate that the neuregulin rhGGF2 may have anti-inflammatory and antioxidant properties in the brain, and may also provide trophic support for brain-resident microglial cells.

Dalton, C. C. and L. N. Gottlieb (2003). "The concept of readiness to change." J Adv Nurs 42(2): 108-17.

            AIM: Readiness is associated with change, yet there is little understanding of this construct. The purpose of this study was to examine readiness; its referents, associated factors and the resulting consequences. METHODS: In the course of nursing five clients living with multiple sclerosis over a 7-month period using a Reflective Practice Model, data were systematically gathered using open-ended and then more focused questioning. Data collected during 42 client encounters (28 face-to-face encounters; 14 telephone contacts) were analysed using Chinn and Kramer's concept analysis technique. Findings. The concept of readiness was inductively derived. Readiness is both a state and a process. Before clients can create change they need to become ready to change. A number of factors trigger readiness. These include when: (a) clients perceive that a health concern is not going to resolve, (b) a change in a client's physical condition takes on new significance, (c) clients feel better able to manage their stress, (d) clients have sufficient energy, (e) clients perceive that they have adequate support in undertaking change. When one or more of these factors is present clients become ready to consider change. The process of readiness involves recognizing the need to change, weighing the costs and benefits and, when benefits outweigh costs, planning for change. The desire to change and to take action determines clients' degree of readiness. When they experience a high degree of readiness they report less anger, less depression, and view their condition in a more positive light. In contrast, when they experience a low degree of readiness they report feeling depressed, afraid and vulnerable in the face of change. CONCLUSION: Nursing has an important role to play in creating conditions to support change. To fulfil this role, nurses need to be able to assess readiness for change and the factors that enable it and then to intervene in ways that facilitate readiness.

Clausen, J. (2003). "Endogenous retroviruses and MS: using ERVs as disease markers." Int MS J 10(1): 22-8.

            Multiple sclerosis (MS) has an unknown cause, but its epidemiology suggests an interplay between environmental factors, possibly including viruses, and genetic components. Endogenous retroviruses (ERVs) are elements of the human genome that potentially may act as either genetic markers for polymorphisms related to MS, or markers of environmental/endogenous stress. Activation of the ERVs HERV-H/RGH, HERV-W and ERV-9 was reported when specific cell types (mainly B cells) from MS patients were cultivated in vitro. Viral RNA from these ERVs has been detected by reverse-transcriptase polymerase chain reaction in sera/plasma and brain tissues from MS patients, although not exclusively from these patients. ERVs play unknown roles in MS: their activation may represent an inflammatory cytokine-mediated epiphenomenon; alternatively, preliminary evidence suggests that specific ERVs may act as auto-, super- or neoantigens with the potential to enhance inflammatory responses or induce autoimmune reactions. ERVs that occur in few copies in the human genome (e.g. ERV-3 and human endogenous retrovirus, HRES-1) may show polymorphic patterns in MS. Studies show that the sequences encoding the envelope protein of ERV-3 are polymorphic to a degree where it becomes impossible to link them with MS. In contrast, the HRES-1 long terminal repeat sequence has a polymorphic pattern with haplotypes characteristic of MS. Haplotypes from non-MS control groups were identical between different topographic areas, but haplotypes from MS patients were different, depending on the population.

Chakrabarty, A., M. R. Emerson, et al. (2003). "Heme oxygenase-1 in SJL mice with experimental allergic encephalomyelitis." Mult Scler 9(4): 372-81.

            The expression of heme oxygenase-1 (HO-1) is increased in the CNS of mice and rats with experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). To investigate the role of HO-1 in EAE, a putative inhibitor [tin-protoporphyrin IX (Sn-PP IX)] of HO-1 was administered to SJL mice during active disease. Sn-PP IX (200 micromol/kg) attenuated clinical scores, weight loss, and some signs of pathology in comparison to vehicle treatment. Glutathione levels were greater in treated EAE mice than in those receiving vehicle, indicating lower oxidative stress in the former group. These data suggest that inhibition of HO-1 attenuated disease and suppressed free radical production. In the SJL model of EAE, extravasated blood is present in the CNS, and iron released by HO-1 from this heme source may not be adequately sequestered by ferritin, allowing for iron-mediated tissue damage. Thus, HO-1 may act to amplify the disease process in this model.

Calabrese, V., G. Scapagnini, et al. (2003). "Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine." Neurochem Res 28(9): 1321-8.

            Recent studies suggest that NO and its reactive derivative peroxynitrite are implicated in the pathogenesis of multiple sclerosis (MS). Patients dying with MS demonstrate increased astrocytic inducible nitric oxide synthase activity, as well as increased levels of iNOS mRNA. Peroxynitrite is a strong oxidant capable of damaging target tissues, particularly the brain, which is known to be endowed with poor antioxidant buffering capacity. Inducible nitric oxide synthase is upregulated in the central nervous system (CNS) of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. We have recently demonstrated in patients with active MS a significant increase of NOS activity associated with increased nitration of proteins in the cerebrospinal fluid (CSF). Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, in the present study, MS patients were treated for 6 months with acetylcarnitine and compared with untreated MS subjects or with patients noninflammatory neurological conditions, taken as controls. Western blot analysis showed in MS patients increased nitrosative stress associated with a significant decrease of reduced glutathione (GSH). Increased levels of oxidized glutathione (GSSG) and nitrosothiols were also observed. Interestingly, treatment of MS patients with acetylcarnitine resulted in decreased CSF levels of NO reactive metabolites and protein nitration, as well as increased content of GSH and GSH/GSSG ratio. Our data sustain the hypothesis that nitrosative stress is a major consequence of NO produced in MS-affected CNS and implicate a possible important role for acetylcarnitine in protecting brain against nitrosative stress, which may underlie the pathogenesis of MS.

Buljevac, D., W. C. Hop, et al. (2003). "Self reported stressful life events and exacerbations in multiple sclerosis: prospective study." Bmj 327(7416): 646.

            OBJECTIVE: To study the relation between self reported stressful life events not related to multiple sclerosis and the occurrence of exacerbations in relapsing-remitting multiple sclerosis. DESIGN: Longitudinal, prospective cohort study. SETTING: Outpatient clinic of department of neurology in the Netherlands. PARTICIPANTS: Patients aged 18-55 with relapsing-remitting multiple sclerosis, who could walk with a cane or better (score of 0-6.0 on the expanded disability status scale), and had had at least two exacerbations in 24 months before inclusion in the study. Patients with other serious conditions were excluded. MAIN OUTCOME MEASURE: The risk of increased disease activity as measured by the occurrence of exacerbations after weeks with stressful events. RESULTS: Seventy out of 73 included patients (96%) reported at least one stressful event. In total, 457 stressful life events were reported that were not related to multiple sclerosis. Average follow up time was 1.4 years. Throughout the study, 134 exacerbations occurred in 56 patients and 136 infections occurred in 57 patients. Cox regression analysis with time dependent variables showed that stress was associated with a doubling of the exacerbation rate (relative risk 2.2, 95% confidence interval 1.2 to 4.0, P = 0.014) during the subsequent four weeks. Infections were associated with a threefold increase in the risk of exacerbation, but this effect was found to be independent of experienced stress. CONCLUSION: Stressful events were associated with increased exacerbations in relapsing-remitting multiple sclerosis. This association was independent of the triggering effect of infections on exacerbations of multiple sclerosis.

Besler, H. T. and S. Comoglu (2003). "Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis." Nutr Neurosci 6(3): 189-96.

            Free radical-mediated peroxidation of biological molecules, especially of lipids, is implicated in the pathogenesis of a number of diseases like multiple sclerosis. Low concentration of antioxidant vitamins: beta carotene, retinol, alpha tocopherol and ascorbic acid have been observed in serum or cerebrospinal fluid of multiple sclerosis patients. On the basis of these observations, we studied the potential lipoprotein oxidation and total antioxidant capacity in the pathogenesis of multiple sclerosis. Lipoprotein oxidizability for plasma in vitro, serum levels of autoantibodies against oxidized low-density lipoproteins, plasma total homocysteine levels with vitamin B12 and folate, and plasma total antioxidant capacity were measured in twenty four patients with multiple sclerosis and twenty four healthy sex- and age-matched person as control. In multiple sclerosis patients during an attack, a significant increase in both in vitro lipid oxidizability for plasma and in the levels of autoantibodies against oxidized low-density lipoproteins, and a strong decrease in plasma total antioxidant capacity were detected. Plasma total homocysteine levels were significantly higher in multiple sclerosis patients whose plasma vitamin B12 and folate levels were lower but not statistically significant, than controls. The present study indicates that lipoprotein oxidation may be important factor in the course of multiple sclerosis and in vitro measurements of plasma oxidation kinetics as an indication for lipoprotein oxidation might be useful as an additional tool for the clinical diagnosis of multiple sclerosis.

Benjamins, J. A., L. Nedelkoska, et al. (2003). "Protection of mature oligodendrocytes by inhibitors of caspases and calpains." Neurochem Res 28(1): 143-52.

            Mature mouse oligodendrocytes (OLs) are susceptible to death in demyelinating diseases such as multiple sclerosis and in brain injury following neurotrauma, ischemia, or stroke. To understand mechanisms leading to death of mature OLs and develop strategies for protection, we utilized cultures of mature mouse OLs to investigate the role of caspases and calpains in OL cell death mediated by different mechanisms. The agents used were (i) staurosporine, which induces apoptotic death via inhibition of protein kinases; (ii) kainate, which activates non-NMDA glutamate receptors; (iii) thapsigargin, which releases intracellular calcium stores; and (iv) SNAP, which releases active NO species and causes necrotic cell death. Inhibitors blocking primary effector caspases (including caspase 3), the FAS (death receptor)-mediated initiator caspases (including caspase 8), and stress-induced caspases (including caspase 9), were tested for their protective effects. Inhibition of caspases 3, 8, and 9 each robustly protected OLs following insult with staurosporine, thapsigargin, or kainate when added at optimal times. The time of addition of the inhibitors for maximal protection varied with the agent, from 1 h of preincubation before addition of staurosporine to 6 h after addition of kainate. Much less protection was seen for the NO generator SNAP under any condition. The role of calcium in OL death in each model was investigated by chelating extracellular Ca++ with EGTA, and by inhibiting the Ca++-activated calpain proteases. Calcium chelation did not protect against staurosporine, but decreased OL death initiated by kainate, thapsigargin, or NO. The calpain inhibitors PD150606 and calpain inhibitor I protected from cell death initiated by staurosporine, kainate, and thapsigargin, but not from cell death initiated by the NO donor SNAP.

Aruoma, O. I. (2003). "Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods." Mutat Res 523-524: 9-20.

            The study of free radicals and antioxidants in biology is producing medical revolution that promises a new age of health and disease management. From prevention of the oxidative reactions in foods, pharmaceuticals and cosmetics to the role of reactive oxygen species (ROS) in chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular and neurodegenerative (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Downs syndrome) and aging challenges continue to emerge from difficulties associated with methods used in evaluating antioxidant actions in vivo. Our interest presently is focused on development of neurodegeneration models based on the integrity of neuronal cells in the central nervous system and how they are protected by antioxidants when challenged by neurotoxins as well as Fenton chemistry models based on the profile of polyunsaturated fatty acids (PUFAs) for the assessment of antioxidant actions in vivo. Use continues to be made of several in vitro analytical tools to characterise the antioxidant propensity of bioactive compounds in plant foods and supplements. For example, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), total oxidant scavenging capacity (TOSC), the deoxyribose assay, assays involving oxidative DNA damage, assays involving reactive nitrogen intermediates (e.g. ONOO(-)), Trolox equivalent antioxidant capacity (TEAC) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. There is need to agree governance on in vitro antioxidant methods based on an understanding of the mechanisms involved. Because some of the assays are done in non-physiological pH values, it is impossible to extrapolate the results to physiological environment. The consensus of opinion is that a mix of these tools should be used in assessing the antioxidant activities in vitro. The proof of bio-efficacy must emanate from application of reliable in vivo models where markers of baseline oxidative damage are examined from the standpoint of how they are affected by changes in diet or by antioxidant supplements.

Anane, R., M. Geffard, et al. (2003). "Effects of GSM-900 microwaves on the experimental allergic encephalomyelitis (EAE) rat model of multiple sclerosis." Bioelectromagnetics 24(3): 211-3.

            The effects of acute exposure to GSM-900 microwaves (900 MHz, 217 Hz pulse modulation) on the clinical parameters of the acute experimental allergic encephalomyelitis (EAE) model in rats were investigated in two independent experiments: rats were either habituated or nonhabituated to the exposure restrainers. EAE was induced with a mixture of myelin basic protein and Mycobacterium tuberculosis. Female Lewis rats were divided into cage control, sham exposed, and two groups exposed either at 1.5 or 6.0 W/kg local specific absorption rate (SAR averaged over the brain) using a loop antenna placed over their heads. There was no effect of a 21 day exposure (2 h/day) on the onset, duration, and termination of the EAE crisis.

Ackerman, K. D., A. Stover, et al. (2003). "2002 Robert Ader New Investigator award. Relationship of cardiovascular reactivity, stressful life events, and multiple sclerosis disease activity." Brain Behav Immun 17(3): 141-51.

            Previous studies of stress in multiple sclerosis patients have suggested that life events may alter the onset and development of MS. However, results have been inconsistent because of infrequent monitoring and reporting bias. We followed fifty female MS patients for 1 year to determine characteristics of life events associated with MS exacerbations, and examine the influence of cardiovascular activity. Subjects completed weekly life-event checklists. The short- and long-term threat of each event was determined using the Life Events and Difficulties Schedule. Neurologic symptoms were also monitored weekly. MS exacerbations were confirmed by a neurologist blinded to psychosocial events. Cardiovascular reactivity to an acute psychological stressor was determined at study onset, and resting heart rate and blood pressure were monitored monthly. Forty-two percent of life events were associated with exacerbations in the subsequent 6 weeks. Logistic regression confirmed that exacerbations were more likely during at-risk periods following life events and were relatively independent of the threat level and type of stressor. Participants with higher cardiovascular reactivity to acute stress and higher baseline heart rate demonstrated a greater number of exacerbations and proportion of weeks ill. Using multiple regression, we found that disability level, medication usage, cardiovascular reactivity, baseline heart rate, and life event density explained approximately 30% of the variance in the proportion of weeks ill. These results are consistent with the hypothesis that stress is a potential trigger of MS disease activity and suggest that autonomic tone and stress reactivity may play a role in the development of stress-related exacerbations.

Yapici, Z. and M. Eraksoy (2002). "Bilateral demyelinating tumefactive lesions in three children with hemiparesis." J Child Neurol 17(9): 655-60.

            We present the results from the evaluations of three children ages of 2, 7, and 11 years with hemiparesis and multiple white-matter lesions on magnetic resonance images (MRIs). The initial symptoms were mainly acute/subacute hemiparesis in all and headache/vomiting in one of them. Before admission, one of them had a history of upper respiratory tract infection, whereas another had undergone urinary tract surgery, and the other reported no history of any infection or stress-related factor. In all of the children, MRI showed multiple superficial and deep white-matter hyperintensity in T2-weighted and proton density images with perifocal edema in the acute phase. During the symptomatic period, all of the patients underwent corticosteroid treatment. Whereas two of the patients demonstrated signs of recovery during the first week of treatment, the other patient demonstrated almost a full recovery with minimal neurologic sequela. Follow-up MRI demonstrated not only a remarkable decrease in the size and number of the lesions, with complete resolution for many of them, it also demonstrated a loss of contrast enhancement. None of these three patients, who had been followed up clinically and through MRI for 5 years, have shown either a clinical relapse or new lesions. The clinical pictures and MRI of the children were different in some aspects from acute multiple sclerosis and acute disseminated encephalomyelitis. Regarding both the clinical follow-up and treatment strategy, it is essential and interesting to state the fact that tumefactive lesions involving both hemispheres are likely to appear during the monitoring of the monophasic courses among inflammatory demyelinating diseases of childhood such as acute disseminated encephalomyelitis.

Ward, N., N. Embrey, et al. (2002). "Specialist nurse network improves MS practice." Nurs Times 98(30): 34-6.

            This article looks at the development of a group dedicated to meeting the clinical supervision and networking needs of multiple sclerosis nurse specialists. It describes the evolution of the group, the structure and content of group meetings and how they have both improved practice and reduced the isolation of MS specialists who work independently. The nurses involved have found that working collaboratively and developing an interactive network has not only significantly affected their clinical practice but also helped to address work-related stress.

Vedhara, K., M. P. McDermott, et al. (2002). "Chronic stress in nonelderly caregivers: psychological, endocrine and immune implications." J Psychosom Res 53(6): 1153-61.

            OBJECTIVE: This investigation examined whether the immune dysregulation that characterises elderly informal caregivers (e.g., spousal caregivers of dementia patients) extends to a younger caregiver population, specifically spousal carers of patients with multiple sclerosis (MS). METHOD: MS spousal caregivers (n=41, mean age 43 years, 14 women, 27 men) and noncaregiving controls (n=62, mean age 33 years, 44 women, 18 men) were recruited. Psychological morbidity (i.e., self-reported stress, anxiety and depression), endocrine activity (i.e., salivary cortisol and DHEAs) and immunity (i.e., IgG and HAI responses to influenza vaccination and IFN-gamma and IL-4 levels) were assessed. RESULTS AND CONCLUSIONS: MS caregivers and noncaregivers did not differ significantly in their IgG or HAI responses to influenza vaccination or in levels of IFN-gamma and IL-4. However, it remains unclear whether the "preserved" immune response of these younger caregivers was due to (1) an absence of immune senescence, (2) a relative absence of psychological morbidity, or both.

Urushitani, M., J. Kurisu, et al. (2002). "Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis." J Neurochem 83(5): 1030-42.

            Accumulating evidence indicates that abnormal conformation of mutant superoxide dismutase 1 (SOD1) is an essential feature underlying the pathogenesis of mutant SOD1-linked familial amyotrophic lateral sclerosis (ALS). Here we investigated the role of ubiquitin-proteasome pathway in the mutant SOD1-related cell death and the effect of oxidative stress on the misfolding of mutant SOD1. Transient overexpression of ubiquitin with human SOD1 (wild-type, ala4val, gly85arg, gly93ala) in Neuro2A cells decreased the amount of mutant SOD1, but not of wild-type, while only mutants were co-immunoprecipitated with poly-ubiquitin. Proteasome inhibition by lactacystin augmented accumulation of mutant SOD1 in the non-ionic detergent-insoluble fraction. The spinal cord lysates from mutant SOD1 transgenic mice showed multiple carbonylated proteins, including mutant SOD1 with SDS-resistant dimer formation. Furthermore, the treatment of hSOD1-expressing cells with hydrogen peroxide promoted the oligomerization, and detergent-insolubility of mutant SOD1 alone, and the oxidized mutant SOD1 proteins were more heavily poly-ubiquitinated. In Neuro2A cells stably expressing human SOD1 protein, the proteasome function measured by chymotrypsin-like activity, was decreased over time without a quantitative alteration of the 20S proteasomal component. Finally, primary motor neurons from the mouse embryonic spinal cord were more vulnerable to lactacystin than non-motor neurons. These results indicate that the sustained expression of mutant SOD1 leads to proteasomal inhibition and motor neuronal death, which in part explains the pathogenesis of mutant SOD1-linked ALS.

Stephan, M., R. H. Straub, et al. (2002). "Postnatal maternal deprivation aggravates experimental autoimmune encephalomyelitis in adult Lewis rats: reversal by chronic imipramine treatment." Int J Dev Neurosci 20(2): 125-32.

            Stressful experiences can modulate multiple sclerosis, but stress protection is currently not considered a treatment option. Here, we show that maternal deprivation, an adverse stress experience in infancy, increases emotionality in behavioral tests of adult female Lewis rats and concomitantly causes a more severe course of experimental autoimmune encephalomyelitis. Treatment of these effects in adulthood by chronic antidepressants (imipramine) reversed the behavioral symptoms and attenuated the course of the encephalomyelitis in deprived rats. Increased IL-4 plasma levels accompanied the protective-like effects of antidepressants. In contrast, attempts to prevent these effects in infancy by tactile stimulation aggravated the encephalomyelitis, possibly by decreasing corticosterone and increasing IFN-gamma levels during the disease. This indicates that antidepressants exert protective effects in an animal model of multiple sclerosis, and suggests that drugs modifying stress responsiveness may have a potential role as adjuvant treatment of the disease.

Sharpe, M. A., R. Ollosson, et al. (2002). "Oxidation of nitric oxide by oxomanganese-salen complexes: a new mechanism for cellular protection by superoxide dismutase/catalase mimetics." Biochem J 366(Pt 1): 97-107.

            Manganese-salen complexes (Mn-Salen), including EUK-8 [manganese N,N'-bis(salicylidene)ethylenediamine chloride] and EUK-134 [manganese 3-methoxy N,N'-bis(salicylidene)ethylenediamine chloride], have been reported to possess combined superoxide dismutase (SOD) and catalase mimetic functions. Because of this SOD/catalase mimicry, EUK-8 and EUK-134 have been investigated as possible therapeutic agents in neurological disorders resulting from oxidative stress, including Alzheimer's disease, Parkinson's disease, stroke and multiple sclerosis. These actions have been explained by the ability of the Mn-Salen to remove deleterious superoxide (O(2)(-)) and H(2)O(2). However, in addition to oxidative stress, cells in models for neurodegenerative diseases may also be subjected to damage from reactive nitrogen oxides (nitrosative stress), resulting from elevated levels of NO and sister compounds, including peroxynitrite (ONOO(-)). We have been examining the interaction of EUK-8 and EUK-134 with NO and ONOO(-). We find that in the presence of a per-species (H(2)O(2), ONOO(-), peracetate and persulphate), the Mn-Salen complexes are oxidized to the corresponding oxo-species (oxoMn-Salen). OxoMn-Salens are potent oxidants, and we demonstrate that they can rapidly oxidize NO to NO(2) and also oxidize nitrite (NO(2)(-) to nitrate (NO(2)(-)). Thus these Mn-Salens have the potential to ameliorate cellular damage caused by both oxidative and nitrosative stresses, by the catalytic breakdown of O(2)(-), H(2)O(2), ONOO(-) and NO to benign species: O(2), H(2)O, NO(2)(-) and NO(3)(-).

Scott, G. S., S. V. Spitsin, et al. (2002). "Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors." Proc Natl Acad Sci U S A 99(25): 16303-8.

            Uric acid (UA) is a purine metabolite that selectively inhibits peroxynitrite-mediated reactions implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative diseases. Serum UA levels are inversely associated with the incidence of MS in humans because MS patients have low serum UA levels and individuals with hyperuricemia (gout) rarely develop the disease. Moreover, the administration of UA is therapeutic in experimental allergic encephalomyelitis (EAE), an animal model of MS. Thus, raising serum UA levels in MS patients, by oral administration of a UA precursor such as inosine, may have therapeutic value. We have assessed the effects of inosine, as well as inosinic acid, on parameters relevant to the chemical reactivity of peroxynitrite and the pathogenesis of EAE. Both had no effect on chemical reactions associated with peroxynitrite, such as tyrosine nitration, or on the activation of inflammatory cells in vitro. Moreover, when mice treated with the urate oxidase inhibitor potassium oxonate were fed inosine or inosinic acid, serum UA levels were elevated markedly for a period of hours, whereas only a minor, transient increase in serum inosine was detected. Administration of inosinic acid suppressed the appearance of clinical signs of EAE and promoted recovery from ongoing disease. The therapeutic effect on animals with active EAE was associated with increased UA, but not inosine, levels in CNS tissue. We, therefore, conclude that the mode of action of inosine and inosinic acid in EAE is via their metabolism to UA.

Noor, R., S. Mittal, et al. (2002). "Superoxide dismutase--applications and relevance to human diseases." Med Sci Monit 8(9): RA210-5.

            Reactive oxygen species, such as superoxide radicals, are thought to underlie the pathogenesis of various diseases. Almost 3 to 10% of the oxygen utilized by tissues is converted to its reactive intermediates, which impair the functioning of cells and tissues. Superoxide dismutase (SOD) catalyzes the conversion of single electron reduced species of molecular oxygen to hydrogen peroxide and oxygen. There are several classes of SOD that differ in their metal binding ability, distribution in different cell compartments, and sensitivity to various reagents. Among these, Cu, Zn superoxide dismutase (SOD1) is widely distributed and comprises 90% of the total SOD. This ubiquitous enzyme, which requires Cu and Zn for its activity, has great physiological significance and therapeutic potential. The present review describes the role of SODs, especially Cu, Zn SOD, in several diseases, such as familial amyotrophic lateral sclerosis (FALS), Parkinson's disease, Alzheimer's disease, dengue fever, cancer, Down's syndrome, cataract, and several neurological disorders. Mutations in the SOD1 gene cause a familial form of amyotrophic lateral sclerosis. The mechanism by which mutant SOD1 causes the degeneration of motor neurons is not well understood. Transgenic mice expressing multiple copies of FALS-mutant SOD1s develop an ALS-like motor neuron disease. Vacuolar degeneration of mitochondria has been identified as the main pathological feature associated with motor neuron death and paralysis in several lines of FALS-SOD1 mice. Various observations and conclusions linking mutant SOD1 and FALS are discussed in this review in detail.

Nazliel, B., C. Irkec, et al. (2002). "The roles of blink reflex and sympathetic skin response in multiple sclerosis diagnosis." Mult Scler 8(6): 500-4.

            The neurological history and examination are important in multiple sclerosis (MS) diagnosis, but early and accurate diagnosis of MS often requires judicious use of paraclinical information. Electrophysiologic techniques have an important role in demonstrating lesions that are clincally silent but magnetic resonance imaging (MRI) is accepted as the most sensitive paraclincal test for detecting asymptomatic dissemination in space for MS patients. In order to test the sensitivity of electrophysiologic techniques in diagnosing asymptomatic MS lesions, we performed blink reflex (BR) and sympathetic skin response (SSR) studies on 13 female (mean age 39 -/+ 9 years) and 8 male (mean age 35 -/+ 14 years) patients with a diagnosis of definite MS who do not have any clinical symptoms nor signs referable to brainstem or autonomic system dysfunction. Forty three percent of patients on SSR testing and 40% of patients on BR testing demonstrated abnormal results. In countries with unfavorable economic conditions, diagnosis, especially the follow-up evaluation of MS patients, poses a major dilemma. The role of diagnostic techniques in MS diagnosis when MRI is available is an economic problem. Diagnostic evaluation adds to the cost of health expenses. We usually choose to perform MRI only at the initial diagnosis of MS and perform follow-up evaluations during remissions and exacerbations with the aid of electrophysiologic techniques. We stress the importance of electrophysiologic screenings in MS patients because they provide data that cannot be obtained through clinical evaluations only with a little cost.

Molina-Holgado, E., A. Arevalo-Martin, et al. (2002). "Interleukin-4 and interleukin-10 modulate nuclear factor kappaB activity and nitric oxide synthase-2 expression in Theiler's virus-infected brain astrocytes." J Neurochem 81(6): 1242-52.

            In brain astrocytes, nuclear factor kappaB (NF-kappaB) is activated by stimuli that produce cellular stress causing the expression of genes involved in defence, including the inducible nitric oxide synthase (NOS-2). Theiler's murine encephalomyelitis virus (TMEV) induces a persistent CNS infection and chronic immune-mediated demyelination, similar to human multiple sclerosis. The cytokines interleukin (IL)-4 and IL-10 inhibit the expression of proinflammatory cytokines, counteracting the inflammatory process. Our study reports that infection of cultured astrocytes with TMEV resulted in a time-dependent phosphorylation of IkappaBalpha, degradation of IkappaBalpha and IkappaBbeta, activation of NF-kappaB and expression of NOS-2. The proteasome inhibitor MG-132 blocked TMEV-induced nitrite accumulation, NOS-2 mRNA expression and phospho-IkappaBalpha degradation, suggesting NF-kappaB-dependent NOS-2 expression. Pretreatment of astrocytes with IL-4 or IL-10 decreased p65 nuclear translocation, NF-kappaB binding activity and NOS-2 transcription. IL-4 and IL-10 caused an accumulation of IkappaBalpha in TMEV-infected astrocytes without affecting IkappaBbeta levels. The IkappaB kinase activity and the degradation rate of both IkappaBs were not modified by either cytokine, suggesting de novo synthesis of IkappaBalpha. Indeed, IL-4 or IL-10 up-regulated IkappaBalpha mRNA levels after TMEV infection. Therefore, the accumulation of IkappaBalpha might impair the translocation of the NF-kappaB to the nucleus, mediating the inhibition of NF-kappaB activity. Overall, these data suggest a novel mechanism of action of IL-4 and IL-10, which abrogates NOS-2 expression in viral-infected glial cells.

Mohr, D. C., D. E. Goodkin, et al. (2002). "Moderating effects of coping on the relationship between stress and the development of new brain lesions in multiple sclerosis." Psychosom Med 64(5): 803-9.

            OBJECTIVE: Many patients with multiple sclerosis (MS) report that stress can trigger disease exacerbations. Considerable research has supported a relationship between stress and both clinical exacerbation and the development of new brain lesions. However, these relationships are not always consistent either within patients or across patients, suggesting the presence of moderators. This study examined the hypothesis that coping moderates the subsequent relationship between stress and the development of new brain lesions in MS. METHODS: Thirty-six patients (mean age = 44.4; 22 women, 14 men) with relapsing forms of MS were assessed once every 4 weeks for 28-100 weeks. New brain lesions were identified using monthly Gd+ MRI. Stress was measured within 24 hours before MRI using a modified version of the Social Readjustment Rating Scale that assessed Conflict and Disruption in Routine. Coping was measured at baseline using the Coping with Health Injuries and Problems questionnaire, which produces four scales: distraction, instrumental, palliative, and emotional preoccupation. Data were analyzed using mixed effects logistic regression to account for within-subject correlations. Analyses were lagged such that stress assessments predicted new Gd+ MRI brain lesions 8 weeks later. RESULTS: As reported previously, stress was significantly related to the development of new Gd+ brain lesions 8 weeks later (OR = 1.62, p =.009). Greater use of distraction was found to be a significant moderator of the relationship between stress and new Gd+ lesions (OR = 0.69, p =.037) such that greater use of distraction was associated with a decreased relationship between stress and new Gd+ lesions. Increased instrumental coping was marginally associated with a decreased relationship between stress and new Gd+ lesions (OR = 0.77, p =.081), while increased emotional preoccupation was marginally associated with an increased relationship between stress and new Gd+ lesions (OR = 1.46, p =.088). There was no significant moderating effect for palliative coping (p =.27) and no significant main effects for any coping variables and the subsequent development of new Gd+ brain lesions (p values >.21). CONCLUSIONS: These findings provide modest support for the hypothesis that coping can moderate the relationship between stress and the MS disease activity. Several limitations in this study are discussed. While these findings suggest areas of potentially fruitful research, readers are cautioned that these are preliminary results; inferences regarding the clinical importance of these findings are premature.

Mohamed, A. A., J. G. Avila, et al. (2002). "Amelioration of experimental allergic encephalitis (EAE) through phase 2 enzyme induction." Biomed Sci Instrum 38: 9-13.

            The multiple sclerosis (MS) lesion is characterized by an inflammatory cell mediated attack on white matter. Oxidative stress appears to play a role in the onset and progression of MS. We reasoned that decreasing oxidative stress might ameliorate MS. One way of decreasing oxidative stress is to induce phase 2 enzymes. The model chosen to test this hypothesis was experimental allergenic encephalomyelitis (EAE) induced in the Lewis rat. The 26 animals were placed into two groups: 1) those on normal rat chow, 2) those on rat chow containing 250 mumoles t-butylhydroxyanisole (BHA)/kg. After 2 weeks, animals were administered 100 micrograms guinea pig myelin basic protein and examined daily in a blinded fashion. Twenty-nine days later, animals were sacrificed, blood collected for glutathione (GSH) measurements and tissues collected for histology. Six of the 13 control chow animals developed hindlimb weakness or paralysis while 5 developed tail weakness only. Only 1 BHA fed animal exhibited symptoms--hindlimb weakness. Clinical symptoms correlated well with the extent of perivascular lymphocyte infiltration. Animals with BHA in the diet had 20% higher red cell GSH indicting induction of phase 2 enzymes. We conclude that dietary phase 2 enzyme inducers should be examined for their ability to ameliorate MS.

Manderson, L. (2002). "My left arm: experiencing brachial plexopathy." Intern Med J 32(7): 353-6.

Malysheva, O. A., S. V. Trufakin, et al. (2002). "[Nerve regulation of cardiac rhythm in rheumatoid arthritis and multiple sclerosis patients]." Ter Arkh 74(10): 48-52.

            AIM: To study nervous regulation of cardiac rhythm (CR) in patients with rheumatoid arthritis (RA) and multiple sclerosis (MS). MATERIAL AND METHODS: Nervous regulation of cardiac rhythm was studied in 57 patients with RA and MS vs 40 healthy subjects. RESULTS: It was found that nervous regulation of CR in RA and MS patients at rest is characterized by imbalance of functions of the autonomic nervous system with enhancement of ergotropic effects in patients with RA and deficiency of trophotropic impacts in growing ergotropic component in patients with MS. Stress tests led to dysfunction of CR central regulation with disturbed activity of the subcortical nervous centers (SNC) and autonomic maintenance of the processes, were characterized in emotional stress by insufficient activity of SNC and enhancement of parasympathetic effects in RA patients, hyperactivation of SNC with intensification of sympathetic impacts in MS patients manifesting in destabilizing effect of the sympathetic nervous system in both groups of patients. CONCLUSION: The findings should be taken into consideration when vegetotropic drugs are used in the treatment of RA and MS patients.

Lalive, P. H., P. R. Burkhard, et al. (2002). "TNF-alpha and psychologically stressful events in healthy subjects: potential relevance for multiple sclerosis relapse." Behav Neurosci 116(6): 1093-7.

            The authors conducted a prospective and descriptive pilot study in 14 healthy medical students, investigating whether a psychologically stressful event (final examination) may modify serum tumor necrosis factor alpha (TNF-alpha) levels. There was a dramatic and sustained decrease of phytohemagglutinin (PHA)-induced TNF-alpha several weeks before and the day of the examination, followed by a significant increase of TNF-alpha starting the next day. Examination-induced stress was confirmed by both elevated urinary cortisol concentration and significant increase in stress scale scores. Extending these results to patients suffering from multiple sclerosis (MS) leads to the hypothesis that psychological stress may influence the course of MS by substantially altering TNF-alpha levels, and suggests the need for further studies in MS patients exposed to stressful conditions.

Kikuchi, A., A. Takeda, et al. (2002). "Systemic increase of oxidative nucleic acid damage in Parkinson's disease and multiple system atrophy." Neurobiol Dis 9(2): 244-8.

            8-hydroxy-2'-deoxyguanosine (8-OHdG) or 8-hydroxyguanosine (8-OHG), a product of oxidized DNA or RNA, is a good marker of oxidative cellular damage. In this study, we measured the 8-OHdG/8-OHG levels in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) and multiple system atrophy (MSA). Compared to age-matched controls, the mean levels of serum 8-OHdG/8-OHG were significantly higher in PD (P < 0.0001). Although no gender differences were observed in the controls, the mean values of serum 8-OHdG/8-OHG were significantly higher in female PD cases (P < 0.005) than in male patients. 8-OHdG/8-OHG levels in CSF were also increased significantly in patients with PD and MSA, however, their relative values were generally much lower than those in the serum. Together with previous studies showing increased peripheral 8-OHdG levels in Alzheimer's disease and amyotrophic lateral sclerosis, the data presented here suggest that systemic DNA/RNA oxidation is commonly observed in neurodegenerative diseases. Our results also imply that female patients with PD show higher levels of oxidative stress, which may explain the faster progression of this disease in females.

Hidalgo, J., M. Penkowa, et al. (2002). "Metallothionein expression and oxidative stress in the brain." Methods Enzymol 348: 238-49.

Heesen, C., H. Schulz, et al. (2002). "Endocrine and cytokine responses to acute psychological stress in multiple sclerosis." Brain Behav Immun 16(3): 282-7.

            Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system. An impaired hypothalamopituitary axis and stress reactivity have extensively been discussed without convincing experimental evidence. We choose a standardized acute psychological stressor to determine whether MS patients show altered endocrine and immune responses to stress. In 35 relapsing-remitting MS patients we found elevated baseline levels for catecholamines, prolactin, and IL-6 compared to 15 healthy controls. All neuroendocrine parameters declined during the stress intervention in MS as well as in stress-exposed controls. But only prolactin showed a significantly larger decline in stressed MS patients versus controls. During exposure to the stress we found no significant changes in serum levels of IL-6, IL-6 receptor, or TNF-alpha in either MS patients or controls after stimulation of a whole blood culture. An altered neural immune signaling in relapsing-remitting MS patients during acute experimental stress could not be proven for the parameters analyzed.

Harbuz, M. (2002). "Neuroendocrine function and chronic inflammatory stress." Exp Physiol 87(5): 519-25.

            The factors regulating susceptibility and severity of autoimmune diseases are poorly understood. That neuroendocrine factors are critical modulators in this regard is self-evident. For example, there are major gender differences in susceptibility with women at greater risk than men of, for example, rheumatoid arthritis (RA) and multiple sclerosis (MS). The hypothalamo-pituitary-adrenal (HPA) axis has rightly attracted a considerable amount of attention. Of particular interest has been the hypothesis that susceptibility to autoimmune disease may be related to an impaired responsiveness of the HPA axis; that is, an inability to mount an appropriate cortisol response with which to down-regulate the immune system might allow the immune system to rampage unchecked and attack self. This hypothesis links regulation of the release from the adrenal gland of the potent anti-inflammatory glucocorticoids to the disease process. Endogenous glucocorticoids are crucial for the regulation of the severity of the disease process. The hypothesis proposing a link between a hyporesponsive HPA axis and susceptibility to disease is compelling. However, evidence from a number of sources has suggested that this may not be the entire story and alterations in the activity of the HPA axis have not been consistently observed in patients with RA. This review will concentrate on recent findings concerning the HPA axis in determining susceptibility to, and in regulating the severity of, inflammatory processes in autoimmune disease. These studies have revealed that a single exposure to endotoxin can confer protection to subsequent development of inflammation in an arthritis model in both neonatal and adult rats. Behavioural differences within a single population of rats are associated with differences in the plasma corticosterone responses to stress. However, relative hyporesponsiveness is not reflected by an increase in the severity of inflammation. In humans with RA the dexamethasone-corticotrophin-releasing factor (CRF) test has revealed two distinct sub-populations of patients. Studies in patients with MS have shown that this is not related to depression but rather to the severity of the disease. A better understanding of these complex neuroendocrine interactions may lead to novel clinical interventions.

Feinstein, A. (2002). "An examination of suicidal intent in patients with multiple sclerosis." Neurology 59(5): 674-8.

            OBJECTIVE: To examine neurologic and psychiatric correlates of suicidal intent in a community sample of 140 patients with MS. METHODS: Patients with (28.6%) and without lifetime suicidal intent were compared across MS disease-related and psychiatric variables. All subjects were interviewed with 1) the Structured Clinical Interview for DSM-IV Axis 1 disorders (SCID-IV) to determine lifetime prevalence of major depression and anxiety disorders; and 2) the Social Stress and Support Interview to assess psychological stressors. Suicidal intent was documented with questions from the SCID-IV and Beck Suicide Scale. Patients also completed the Hospital Anxiety and Depression Scale and cognitive testing. RESULTS: Suicidal patients were significantly more likely to live alone, have a family history of mental illness, report more social stress, and have lifetime diagnoses of major depression, anxiety disorder, comorbid depression-anxiety disorder, and alcohol abuse disorder. By logistic regression analysis, the severity of major depression, alcohol abuse, and living alone had an 85% predictive accuracy for suicidal intent. A third of suicidal patients had not received psychological help. Two-thirds of subjects with current major depression, all suicidal, had not received antidepressant medication. CONCLUSIONS: Suicidal intent, a potential harbinger for suicide, is common in MS and is strongly associated with major depression, alcohol abuse, and social isolation. Suicidal intent is a potentially treatable cause of morbidity and mortality in MS.

Esposito, P., N. Chandler, et al. (2002). "Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress." J Pharmacol Exp Ther 303(3): 1061-6.

            Stress activates the hypothalamic-pituitary-adrenal axis through release of corticotropin releasing hormone (CRH), leading to production of glucocorticoids that down-regulate immune responses. Acute stress, however, also has proinflammatory effects that seem to be mediated through the activation of mast cells. Stress and mast cells have been implicated in the pathophysiology of various inflammatory conditions, including some in the central nervous system, such as multiple sclerosis in which disruption of the blood-brain barrier (BBB) precedes clinical symptoms. We previously showed that acute restraint stress increases rat BBB permeability to intravenous 99Tc gluceptate and that administration of the "mast cell stabilizer" disodium cromoglycate (cromolyn) inhibits this effect. In this study, we show that the CRH-receptor antagonist Antalarmin blocks stress-induced 99Tc extravasation, whereas site-specific injection of CRH in the paraventricular nucleus (PVN) of the hypothalamus mimics acute stress. This latter effect is blocked by pretreatment of the PVN with cromolyn; moreover, restraint stress cannot disrupt the BBB in the diencephalon and cerebellum of W/W(v) mast cell-deficient mice. These results demonstrate that CRH and mast cells are involved in regulating BBB permeability and, possibly, brain inflammatory disorders exacerbated by acute stress.

Espejo, C., M. Penkowa, et al. (2002). "Interferon-gamma regulates oxidative stress during experimental autoimmune encephalomyelitis." Exp Neurol 177(1): 21-31.

            Experimental autoimmune encephalomyelitis (EAE) is an induced inflammatory and demyelinating disease of the central nervous system which shares many clinical and pathological features with and is considered the animal model of multiple sclerosis. There is extensive evidence that EAE is a Th1 disease eliciting secretion of proinflammatory cytokines like IFN-gamma or TNF-alpha, and it has been suggested that cytokine-induced oxidative stress could have a role in EAE neuropathology. However, the individual roles of these and other cytokines in the pathogenesis of the disease are still uncertain. Here we analyze the role of IFN-gamma during EAE by using both IFN-gamma receptor-knockout (IFN-gamma R(-/-)) and wild-type mice, both strains immunized with peptide 40-55 from rat myelin oligodendrocyte glycoprotein. The levels of oxidative stress were determined through the analysis of immunoreactivity for inducible NO synthase, nitrotyrosine, and malondialdehyde, as well as through the expression of the tissue-protective antioxidant factors metallothionein I+II (MT-I+II). We also examined the number of cells undergoing apoptosis as judged by using the TUNEL technique. The levels of oxidative stress, MT-I+II, and apoptotic cell death by EAE were significantly increased in all mice, though more so in IFN-gamma R(-/-) mice compared with wild-type mice. These data support the notion that IFN-gamma has a protective role against EAE.

Esch, T., G. B. Stefano, et al. (2002). "The role of stress in neurodegenerative diseases and mental disorders." Neuroendocrinol Lett 23(3): 199-208.

            OBJECTIVE: Evidence for a connection between stress and selected neurodegenerative diseases as well as mental disorders is analyzed. Does stress cause or exacerbate related pathophysiological disease processes? METHOD: The stress phenomenon is illustrated and the impact of stress on the nervous system, neurodegenerative diseases, and mental disorders is examined. The connection between stress and the hippocampus - and its association with memory functions - is described. In particular, the pathophysiological significance of stress in Alzheimer's disease, multiple sclerosis, anxiety, depression, posttraumatic stress disorder, and schizophrenia is investigated. RESULTS: Stress plays a major role in various (patho)physiological processes associated with neurodegenerative diseases and mental disorders. In principle, stress has the potency to exert either ameliorating or detrimental effects. The specific outcome depends on multiple variables. However, the amount of stress experienced in relation to activated physiological processes that aim at successful coping and positive adjustments (i.e., stress response) most often is overwhelming - and may thus become detrimental in the long-term. Moreover, the hippocampus is sensitive to stress, and its involvement in neurodegeneration - in the course of stress-related disease processes - may account for severe clinical disabilities (e.g., memory loss). DISCUSSION/CONCLUSION: Stress has a major impact upon neurodegenerative diseases and mental disorders. It plays a significant role in susceptibility, progress, and actual outcome. Also, subjective or individual differences have to be taken into account. However, stress - especially 'adequate' acute stress (stress that is not overwhelming) - may even improve performance/biological functions and be beneficial in certain cases.

Dandekar, S. S., E. M. Graham, et al. (2002). "Ladies with Leber's hereditary optic neuropathy: an atypical disease." Eur J Ophthalmol 12(6): 537-41.

            PURPOSE: Leber's Hereditary Optic Neuropathy (LHON) is considered to be a disease predominantly affecting young males. The risk of women becoming symptomatic if they are carriers of a primary mutation is 1/5 of that in males. The disease however appears to behave differently in women in some instances. We describe three cases of ladies with LHON and discuss the importance of making the diagnosis. CASE REPORTS: A 28-year-old female presented with blurring of vision in her left eye with bilateral small hyperemic discs and telangiectatic vessels adjacent to them. DNA analysis confirmed the 11778 mutation and the second eye remains unaffected 10 years later. The second case was 49 years old and presented with bilateral visual loss developing over 3 months. She had no family history of visual loss but had a past history of Wolf Parkinson White syndrome and 3460 mutation was confirmed. The last case was diagnosed with multiple sclerosis at age 24 and went on to develop visual loss with poor recovery. DNA analysis demonstrated the 11778 mutation and confirmed LHON. CONCLUSIONS: All three cases, although not unique, posed considerable diagnostic difficulties over a long period of time. The authors have highlighted important associations of the disease and stress the importance of making the diagnosis in women. They are at increased risk of having affected children, unlike the affected males, especially if they are affected themselves and may wish to seek further genetic advice.

Calabrese, V., G. Scapagnini, et al. (2002). "Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels." J Neurosci Res 70(4): 580-7.

            Nitric oxide (NO) is hypothesized to play a role in the immunopathogenesis of multiple sclerosis (MS). Increased levels of NO metabolites have been found in patients with MS. Peroxynitrite, generated by the reaction of NO with superoxide at sites of inflammation, is a strong oxidant capable of damaging tissues and cells. Inducible NO synthase (iNOS) is up-regulated in the CNS of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. In this study, Western blots of cerebrospinal fluid (CSF) from patients with MS demonstrated the presence of iNOS, which was absent in CSF from control subjects. There was also NOS activity present in both MS and control CSF. Total NOS activity was increased (by 24%) in the CSF from MS patients compared with matched controls. The addition of 0.1 mM ITU (a specific iNOS inhibitor) to the samples did not change the activity of the control samples but decreased the NOS activity in the MS samples to almost control levels. The addition of 1 mM L-NMMA (a nonisoform specific NOS inhibitor), completely inhibited NOS activity in CSF from control and MS subjects. Nitrotyrosine immunostaining of CSF proteins was detectable in controls but was greatly increased in MS samples. There were also significant increases in CSF nitrate + nitrite and oxidant-enhanced luminescence in MS samples compared with controls. Additionally, a significant decrease in reduced glutathione and significant increases in oxidized glutathione and S-nitrosothiols were found in MS samples compared with controls. Parallel changes in NO metabolites were observed in the plasma of MS patients, compared with controls, and accompanied a significant increase of reduced glutathione. These data strongly support a role for nitrosative stress in the pathogenesis of MS and indicate that therapeutic strategies focussed on decreasing production of NO by iNOS and/or scavenging peroxynitrite may be useful in alleviating the neurological impairments that occur during MS relapse.

Butzkueven, H., J. G. Zhang, et al. (2002). "LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival." Nat Med 8(6): 613-9.

            Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults. Available therapies can inhibit the inflammatory component of MS but do not suppress progressive clinical disability. An alternative approach would be to inhibit mechanisms that drive the neuropathology of MS, which often includes the death of oligodendrocytes, the cells responsible for myelinating the CNS. Identification of molecular mechanisms that mediate the stress response of oligodendrocytes to optimize their survival would serve this need. This study shows that the neurotrophic cytokine leukemia inhibitory factor (LIF) directly prevents oligodendrocyte death in animal models of MS. We also demonstrate that this therapeutic effect complements endogenous LIF receptor signaling, which already serves to limit oligodendrocyte loss during immune attack. Our results provide a novel approach for the treatment of MS.

Butterfield, D. A., A. Castegna, et al. (2002). "Vitamin E and neurodegenerative disorders associated with oxidative stress." Nutr Neurosci 5(4): 229-39.

            Several neurodegenerative disorders are associated with oxidative stress that is manifested by lipid peroxidation, protein oxidation and other markers. Included in these disorders in which oxidative stress is thought to play an important role in their pathogenesis are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tardive dyskinesia, Huntington's disease (HD), and multiple sclerosis. This review presents some of the chemistry of vitamin E as an antioxidant and summarizes studies in which vitamin E has been employed in these disorders and models thereof.

Buntinx, M., P. Stinissen, et al. (2002). "Immune-mediated oligodendrocyte injury in multiple sclerosis: molecular mechanisms and therapeutic interventions." Crit Rev Immunol 22(5-6): 391-424.

            In this review, new insights into the immunopathogenesis of multiple sclerosis (MS) are discussed, with special focus on the potential mechanisms leading to neuroinflammation in MS--that is, the role of autoreactive T cells, infections, and neurodegenerative events. Oligodendrocytes are considered to be the target of autoimmune inflammation in the CNS of MS patients. Some important features of oligodendrocyte biology are discussed, together with the molecular mechanisms that are potentially involved in oligodendrocyte injury. These include injury mechanisms that might be executed by the adaptive and innate immune system, via cytokines and/or oligodendrocyte receptors, or as a consequence of nitrative and oxidative stress, and excitotoxicity. The mode of cell death of oligodendrocytes in MS is discussed, in addition to the mechanisms of axonal injury as observed in pathology- and imaging-based studies. Finally, recent progress in therapeutic strategies that may interfere with these pathological processes are reviewed, with a focus on repair strategies, such as gene therapy, antibody-mediated remyelination, and stem cell therapy.

Arnett, P. A., C. I. Higginson, et al. (2002). "Relationship between coping, cognitive dysfunction and depression in multiple sclerosis." Clin Neuropsychol 16(3): 341-55.

            Given its relatively high prevalence, one possible source of stress for patients with multiple sclerosis (MS) is cognitive dysfunction. The authors' study was guided by a new theoretical model suggesting that cognitive dysfunction in MS may be most likely to lead to depression when patients use high levels of avoidance coping and/or low levels of active coping. To test this model, 55 patients with definite MS were administered a neuropsychological battery and measures of depression and coping. Consistent with predictions, regression analyses showed that coping significantly moderated the relationship between cognitive dysfunction and depression. Specifically, cognitive dysfunction was most likely to be associated with depression when patients used either high levels of avoidance or low levels of active coping. Implications of these data for clinical applications and for our theoretical conceptualization are discussed and limitations of the model explored.

Ackerman, K. D., R. Heyman, et al. (2002). "Stressful life events precede exacerbations of multiple sclerosis." Psychosom Med 64(6): 916-20.

            OBJECTIVE: We longitudinally monitored life events and health changes in patients with multiple sclerosis (MS) to determine whether stressful events may trigger exacerbation of MS. METHODS: Twenty-three women with MS were followed for 1 year. Each subject completed the Psychiatric Epidemiologic Research Interview on a weekly basis. Further information on potentially stressful events was acquired using the Life Events and Difficulties Schedule. Neurologic symptoms were also monitored on a weekly basis throughout the year. Potential MS exacerbations were confirmed by a neurologist who was blind to the presence and timing of stressors. RESULTS: Eighty-five percent of MS exacerbations were associated with stressful life events in the preceding 6 weeks. Stressful life events occurred an average of 14 days before MS exacerbations, compared with 33 days before a randomly selected control date (p < .0001). Survival analysis confirmed that an increase in frequency of life events was associated with greater likelihood of MS exacerbations (hazard ratio = 13.18, p < .05). CONCLUSIONS: These results are consistent with the hypothesis that stress is a potential trigger of disease activity in patients with relapsing-remitting MS.

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