Optimism and Adaptation to Multiple Sclerosis: What Does Optimism Mean?

The aim of the present study was to determine the meaning of optimism by explicating the dimensions underlying the notion and their links to adjusting to MS. Seventy-three patients responded to optimism questionnaires (i.e., the LOT, Generalized Self-Efficacy Scale) and outcome questionnaires. In confirmatory factor analyses, the underlying dimensions of optimism were specified. Explanatory structural equation modeling was used to examine the relation of the dimensions of optimism to coping (CISS), depression (BDI), and impaired mobility range (SIP). Optimism was found to consist of three dimensions, namely, outcome expectancies, efficacy expectancies, and unrealistic thinking. Outcome and efficacy expectancies explained depression via emotion-oriented coping but did not explain impaired mobility range either directly or indirectly. Unrealistic thinking directly explained impaired mobility range. The present study can be seen as a first step in explicating the role of optimism in the management of chronic disease.     

Sleep Disturbances – an Important Factor in Combination with “Minor” Symptoms of Multiple Sclerosis

Neuroscience and Behavioral Physiology - Objectives. To study the clinical and neurophysiological features of sleep disturbances in patients with different forms of multiple sclerosis (MS) and...     

IL-2, IFN-γ, and IL-12 Gene Polymorphisms and Susceptibility to Multiple Sclerosis

Background  

Multiple sclerosis (MS) is a multifactorial disease. Positive genetic background could predispose individuals to this chronic disabling disease. In order to investigate the role of some proinflammatory cytokines (interleukin (IL)-2, IL-12, and interferon-gamma (IFN-γ)) as a risk factor for MS, this study was performed.     

Treatment of Multiple Sclerosis with the Interferon-βs

Several inteferons (IFNs) have recently been introduced for the treatment of multiple sclerosis (MS). These are IFNbeta-1b (Betaseron((R))) and 2 IFNbeta-1a preparations (Avonex((R)) and Rebif((R))). All 3 drugs reduce the number of acute exacerbations in relapsing remitting MS by about one-third but, because of differences in the trials and trial design, direct comparison of efficacy is difficult. Only the IFNbeta-1a preparations have been demonstrated to have an effect in slowing disability. Possible reasons for disparate results with the 3 IFNbetas include substantial differences in trial design, antigenicity, route of administration and bioavailability. Adverse effects differ among the various preparations. Avonex((R)), which is given intramuscularly once weekly, has the fewest adverse effects and the lowest incidence of neutralising antibody formation at 5 to 7%. IFNbeta-1b has the highest incidence at 30 to 39%, and Rebif((R)) is intermediate at 13 to 24%. Additionally, IFNbeta-1b and Rebif((R)) often cause significant skin reactions, and the former causes occasional skin necrosis at injection sites, a problem not seen with Avonex((R)). On the basis of the available information, the IFNbeta-1a preparations are preferred in terms of tolerability, effects on exacerbation rate and disability, less frequent antibody formation and convenience. The available preparations, Avonex((R)) and Rebif((R)), have shown similar effectiveness although dose, route of administration and dosage regimens differ. The administered dose of IFNbeta-1b and Rebif((R)) appears to be somewhat higher than that of Avonex((R)), but the differences in effect are small. Further information regarding the effect of different doses and dosage regimens with the various preparations is expected to become available over the next few years.     

Spotlight on Interferon-β-1b in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis

Interferon-beta-1b (Betaseron, Betaferon) is a non-glycosylated recombinant human interferon-beta approved for high-frequency, subcutaneous (SC) administration in the treatment of multiple sclerosis (MS). Its mechanism of action is unknown, but may involve modulation of the autoimmune pathogenic processes of MS. In a randomized, double-blind trial in patients with relapsing-remitting MS (RRMS), SC interferon-beta-1b 250 micro g (8 million International Units [MIU]) every other day reduced the annual relapse rate and increased the proportion of relapse-free patients compared with placebo. It also reduced relapse severity, hospitalizations, and disease activity assessed by magnetic resonance imaging (MRI), and increased the time to first relapse. Progression of disability showed a trend towards reduction relative to placebo and baseline, but did not reach statistical significance. SC interferon-beta-1b 250 micro g every other day was shown in a randomized trial to be superior to intramuscular (IM) interferon-beta-1a 30 micro g (6 MIU) once weekly with respect to reductions in relapse-related parameters, disability progression and MRI-assessed disease activity. In patients with secondary progressive MS (SPMS), SC interferon-beta-1b 250 micro g every other day slowed progression of the disease relative to placebo in one randomized, double-blind trial, but not in another. In both studies, interferon-beta-1b 250 micro g recipients had fewer relapses and less MRI-assessed disease activity than placebo recipients. The difference in primary outcome may reflect differences in patient entry criteria. Interferon-beta-1b is generally well tolerated and the common adverse events (e.g. injection site reactions, asthenia and an influenza-like symptom complex) are clinically manageable. In a randomized trial, the tolerability of SC interferon-beta-1b 250 micro g every other day was generally similar to that of IM interferon-beta-1a 30 micro g once weekly, except for higher incidences of injection site reactions and neutralizing anti-interferon-beta antibodies with SC interferon-beta-1b. In conclusion, SC interferon-beta-1b 250 micro g every other day reduces the frequency and severity of relapses and MRI measures of disease activity and may delay the progression of disability in RRMS. The drug appeared to be more effective than, and as well tolerated as, IM interferon-beta-1a 30 micro g once weekly. Interferon-beta-1b also has positive effects on relapse rates and disease activity in patients with SPMS, although its effects on disease progression remain uncertain. The drug is generally well tolerated, and the common adverse events are clinically manageable. Thus, interferon-beta-1b is a valuable first-line therapy for patients with RRMS and a potentially useful option in those with SPMS.     

Immunomodulatory Effects of IFN-β and Lovastatin on Immunophenotype of Monocyte-Derived Dendritic Cells in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and current MS treatment is only partially effective. Recent data suggest that statins may be potent immunomodulatory agents. In order to evaluate their role in MS, we analyzed the in vitro effects of interferon (IFN)-β and lovastatin on the differentiation and maturation of monocyte-derived dendritic cells (DCs) of MS patients. Twenty-seven patients with relapsing–remitting MS were recruited for the study. DC differentiation and maturation were evaluated based on surface phenotypic changes and the expressions of CD14, CD83, CD1a, CD80, CD86, CD206, and C209 were analyzed by flow cytometry. The results showed that IFN-β and lovastatin affect DC phenotype. Both agents decrease the expression of CD1a, which indicates a weakened presentation of glycolipid antigens. IFN-β causes up-regulated and lovastatin down-regulated expression of CD86, which results in a biased Th-cell responses in MS. Furthermore, high doses of lovastatin cause a decrease in CD209 expression on the surface of DCs and can limit their migration to various tissues. One of the mechanisms of the beneficial action of IFN-β and statins may be associated with their influence on DCs.     

Do Flexible Goal Adjustment and Acceptance Help Preserve Quality of Life in Patients with Multiple Sclerosis?

Background

Goal regulation strategies such as flexible goal adjustment and acceptance are believed to be protective factors in persons with chronic illness, but research on their relative contributions to quality of life in multiple sclerosis (MS) is lacking.

Purpose

We aimed to test the idea that acceptance and flexible goal adjustment (in contrast to tenacious goal pursuit) may help preserve the quality of life in persons with MS.

Method

A sample of 117 patients with MS was recruited. They completed questionnaires measuring quality of life (physical functioning, psychological distress), acceptance, flexible goal adjustment, and tenacious goal pursuit.

Results

Acceptance significantly accounted for variance in all three indexes of quality of life, beyond the effects of demographic and illness characteristics. The role of goal regulation style was less clear. Flexible goal adjustment significantly accounted for psychological well-being only. Surprisingly, tenacious goal pursuit predicted better psychological functioning and less psychological distress. No support was found for the hypothesis that acceptance and flexible goal adjustment would moderate the relation between illness severity and quality of life.

Conclusion

The findings suggest the potential importance of acceptance in understanding MS patients’ quality of life, although its hypothesized protective function could not be confirmed. Further conceptual work on acceptance and goal regulation style is needed, as well as prospective work investigating their causal status.

     

Current concepts in serological testing – TTID

Introduction Blood components play a major part in a huge number of therapeutic interventions in oncology, haematology, surgery and other medicine disciplines. Therefore, the supply of safe blood products is a major ongoing challenge for blood transfusion services. Serology screening tests were developed to improve blood safety. As screening for antibodies reflects an immune reaction in response to infection, the diagnostic window period is longer for antibody tests than for direct screening assays, such as nucleic amplification tests (NAT). The introduction of mini-pool NAT (MP-NAT) and individual donation NAT (ID-NAT) as well as the development of antigen screening assays, such as the hepatitis C virus antigen test (which detects the NS3 antigen) and the p24 antigen assay for HIV-1, have been able to reduce the diagnostic window period. Methods Currently, blood donor screening for HBsAg, anti-HBc, anti-HCV, anti-HIV-1/2 and syphilis antibodies is mandated by the German authority (the Paul Ehrlich Institute). All blood donations must also be screened for HCV and HIV-1 using MP-NAT. The German Red Cross Blood Donor Services Baden-Württemberg-Hessen has implemented additional blood donor screening for anti-CMV (for platelet products from repeat donors) and MP-NAT screening for HBV, HAV and Parvovirus B19 on a voluntary basis. Results The epidemiology data within the last 4 years have found that 98% and 89% of hepatitis B and hepatitis C positive donors belonged to the first time donor population. Between 1997 and 2005, the German Red Cross Blood Donor Services detected hepatitis B, hepatitis C and HIV-1 in 43, 23 and 7 donors, respectively, using NAT. About 50% (22 out of 43) of these HBV-infected donors were in the acute phase of infection, while 21 were in the occult phase. Improvements in NAT technology, especially the introduction of full-automated extraction robot systems (e.g. the Zelos × 100), have been able to reduce the diagnostic window period, especially for hepatitis B, by improving the 95% level of detection. Nevertheless, five cases of NAT failures in detecting HIV-1 have been reported to the Paul-Ehrlich-Institute within the last decade. In 2010 in particular, three cases occurred in Germany due to mutations in the primer and probe binding regions. These cases restarted a discussion about risk analysis for NAT screening tests and serology methods in general. Conclusion In Germany, blood donor screening is performed using parallel serological assays (antigen and antibody detection) and by MP-NAT for hepatitis B, hepatitis C and HIV-1. The risk of false-negative test results due to mutations in primer and probe binding regions is higher for NAT systems than for antibody/antigen detection tests. Therefore, the manufactures of the NAT systems are advised to improve their systems by utilising amplification in at least two conserved regions (dual- or triple-targeting). The diagnostic window period for new screening strategies (e.g., antigen screening for HCV)     

Appearance of Tissue Transglutaminase in Astrocytes in Multiple Sclerosis Lesions: A Role in Cell Adhesion and Migration?

Multiple Sclerosis (MS) is a neuroinflammatory disease mainly affecting young adults. A major pathological hallmark of MS is the presence of demyelinated lesions in the central nervous system. In the active phase of the disease, astrocytes become activated, migrate and contribute to local tissue remodeling that ultimately can result in an astroglial scar. This process is facilitated by extracellular matrix proteins, including fibronectin. Tissue Transglutaminase (TG2) is a multifunctional enzyme with a ubiquitous tissue distribution and it has been shown that inflammatory cytokines can induce TG2 activity. In addition, TG2 is known to mediate cell adhesion and migration. We therefore hypothesized that TG2 is present in MS lesions and plays a role in cell adhesion and/or migration. Our studies showed that TG2 immunoreactivity appeared in astrocytes in active and chronic active MS lesions. These TG2 positive astrocytes partly co‐localized with fibronectin. Additional in vitro studies showed that TG2 mediated astrocytoma adhesion to and migration on the extracellular matrix protein fibronectin. We therefore speculate that TG2 mediates the enhanced interaction of astrocytes with fibronectin in the extracellular matrix of MS lesions, thereby contributing to astrocyte adhesion and migration, and thus in tissue remodeling and possibly glial scarring.     

Autologous Stem Cell Transplantation in Progressive Multiple Sclerosis—An Interim Analysis of Efficacy

Based on the good results of experimental transplantation in animal models of multiple sclerosis and of other autoimmune diseases, we have treated 24 patients suffering from chronic progressive multiple sclerosis with high-dose chemotherapy (BEAM regimen) followed by autologous blood stem cell rescue and antithymocyte globulin. Blood stem cells were mobilised with cyclophosphamide at 4g/m² and G- (or GM-) CSF. In 9 cases, additional CD34⁺ cell-selection of the graft was performed. Here we update previously published results of this novel treatment, mainly with regard to clinical efficacy, as the median follow-up time has reached 40 months (range, 21–51). Infections were the principal toxicity early after the procedure, with death of a patient from aspergillosis 65 days post stem cell infusion. No serious late events occurred apart from a case of autoimmune thyroiditis that developed 11 months after transplant in a patient who had received a CD34⁺ cell-depleted graft. Mild and transient neurotoxicity was observed in 10 patients (42%), most probably associated with fever and infections. Eighteen patients (18/23; 78%) responded to the treatment, i.e., they were improved or stabilized, while five patients progressed, of which 4 had primary progressive disease. Of those improved or stabilised (18), 9 patients have maintained stable condition whereas 9 developed relapses or they slowly resumed progression, although their disability scores have not gotten worse than they were before transplantation. The probability of progression-free survival (compared to entry status) at 3 years is 92% for patients with secondary progressive disease and 39% for the primary progressive type. CD34⁺ cell-selection did not seem to yield better results except for a delay in progression or in relapse after transplantation. These results appear better than those achieved by any other treatment of progressive multiple sclerosis, including beta-interferon, but they need to be confirmed by other open or controlled studies in view of the well-known difficulty of judging objectively the effect of a treatment in patients with this disease.     

Is Poor Sleep Quality Associated With Greater Disability in Patients With Multiple Sclerosis?

Poor sleep is a serious burden for patients with multiple sclerosis (MS). The aim of this study is to assess whether the association between sleep quality and disability in MS patients is direct or mediated by depression, pain, and fatigue. We collected data from 152 patients with MS who filled out the Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Inventory and one item of the Short Form-36 regarding pain. The relationship between poor sleep and disability was found to be indirect, mediated by depression (p < 0.05), pain (p < 0.001) and physical fatigue (p < 0.01). Treatment of sleep disturbances may have beneficial effects beyond improving sleep. It may reduce depression, pain, and physical fatigue, which in turn may lessen disability.     

Vaccination and autoimmunity-'vaccinosis': a dangerous liaison?

The question of a connection between vaccination and autoimmune illness (or phenomena) is surrounded by controversy. A heated debate is going on regarding the causality between vaccines, such as measles and anti-hepatitis B virus (HBV), and multiple sclerosis (MS). Brain antibodies as well as clinical symptoms have been found in patients vaccinated against those diseases. Other autoimmune illnesses have been associated with vaccinations. Tetanus toxoid, influenza vaccines, polio vaccine, and others, have been related to phenomena ranging from autoantibodies production to full-blown illness (such as rheumatoid arthritis (RA)). Conflicting data exists regarding also the connection between autism and vaccination with measles vaccine. So far only one controlled study of an experimental animal model has been published, in which the possible causal relation between vaccines and autoimmune findings has been examined: in healthy puppies immunized with a variety of commonly given vaccines, a variety of autoantibodies have been documented but no frank autoimmune illness was recorded. The findings could also represent a polyclonal activation (adjuvant reaction). The mechanism (or mechanisms) of autoimmune reactions following immunization has not yet been elucidated. One of the possibilities is molecular mimicry; when a structural similarity exists between some viral antigen (or other component of the vaccine) and a self-antigen. This similarity may be the trigger to the autoimmune reaction. Other possible mechanisms are discussed. Even though the data regarding the relation between vaccination and autoimmune disease is conflicting, it seems that some autoimmune phenomena are clearly related to immunization (e.g. Guillain-Barre syndrome). The issue of the risk of vaccination remains a philosophical one, since to date the advantages of this policy have not been refuted, while the risk for autoimmune disease has not been irrevocably proved. We discuss the pros and cons of this issue (although the temporal relationship (i.e. always 2-3 months following immunization) is impressive).     

Lymphocyte Subpopulations,Oxidative Burst and Apoptosis in Peripheral Blood Cells of Patients with Multiple Sclerosis–Effect of Interferon-β

At present, the most efficient therapeutical treatment of multiple sclerosis (MS) is achieved by IFN-β. However, its in vivo effects remain incompletely understood. If applied parenterally, the hydrophobic IFN-β acts primarily on blood cells with probable selectivity for functionally different lymphocyte subpopulations, monocytes and granulocytes. We have investigated the expression of the activation marker interleukin-2 receptor-α (CD25) on CD3⁺ T cells, CD19⁺ B cells, foetal-type γδ⁺CD3⁺ T cells and foetal-type CD5⁺CD19⁺ B cells of the peripheral blood. In addition, the oxidative burst activity and apoptosis have been determined in mononuclear and polymorphonuclear blood cells, respectively. The study accompanied a phase III trial with IFN-β1b (BETAFERON^®, Schering). Two groups of MS patients with relapsing-remitting course of the disease have been investigated at 8 time points (days 0, 5, 15, 31, 60, 90, 180 and 270 after starting therapy): (1) verum group (n=8) with application of 8 Mill. units IFN-β1b every other day, and (2) placebo group (n=4) with application of placebo for 3 months and therapy as in (1) from day 90 onward. The main results were: (1) Activated T cells decreased until day 180 in the verum group and return thereafter to pre-treatment values, whereas in the placebo group the values remained relatively stable over the whole observation period. (2) Activated B cells increased between days 90 and 270 in both groups, i.e. after verum application in both groups. (3) Foetal-type B cells were more activated than total B and T cells with increase over time in both groups. (4) Foetal-type T cells exerted relatively stable intra-individual levels with generally low CD25 expression, but punctual CD25 peaks in both groups. (5) The spontaneous oxidative burst was higher in lymphocytes, more variable in monocytes and faster increasing in granulocytes in the verum group than in the placebo group. (6) Apoptosis of mononuclear cells and granulocytes showed similar variations in the verum and placebo groups with the exception of a selective increase over time of the proportion of granulocytes undergoing induced apoptosis in the verum group. It is concluded that IFN-β has the following main effects on the immune system of MS patients: (1) the T cell immunity is systemically and reversibly suppressed, (2) the foetal-type lymphocytes, which are responsible for the first line of defence of infections, are stimulated in the long range, (3) the oxidative burst activity is increased in lymphocytes and granulocytes and instable in monocytes, and (4) the inducibility of apoptosis in granulocytes is increased. Re-examination of the altered blood cell parameters after long-term IFN-β therapy is warranted.