Early mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
F Zipp
Publications and source records attributed to F Zipp.
Blockade of chemokine signaling in patients with multiple sclerosis.
We assessed the safety and efficacy of orally administered CC chemokine receptor 1 (CCR1) antagonist in 105 patients with relapsing/remitting MS (RRMS) in a 16-week, randomized, double-blind, placebo-controlled trial. The primary endpoint was the cumulative number of newly active lesions on serial MRI scans. Other MRI, immunologic, and clinical outcomes were also explored. No significant treatment difference was observed for any tested MRI variable. CCR1 does not contribute to initial leukocyte infiltration in RRMS.
Central Nervous System↗
[Relapsing reversible posterior leukoencephalopathy after chemotherapy with cisplatin and 5-fluorouracil].
We report a 37-year-old patient with gastric cancer who suffered two distinct episodes of generalized tonic-clonic seizures during ongoing chemotherapy with cisplatin and 5-fluorouracil. Cranial MRI revealed reversible posterior leukoencephalopathy (RPL) that remitted completely without any specific therapy after discontinuation of the chemotherapeutic drugs. Interestingly, RPL occurred repeatedly in our patient following the single chemotherapy cycles, which has not been described so far. This syndrome is clinically relevant for differential diagnosis of bilateral ischemia of the posterior cerebral arteries. An overview of the literature and necessary diagnostic procedures is given.
Adult↗
A case of recurrent Miller Fisher syndrome mimicking botulism.
Miller Fisher syndrome (MFS) is a rare and usually monophasic polyradiculoneuropathy characterised by ophthalmoplegia, decreased or absent tendon reflexes, and ataxia. The objective of this study was to report a case of recurrent MFS with a clinical presentation virtually indistinguishable from botulism. The patient was a young man with two episodes of increasing external ophthalmoplegia, ptosis, and ataxia with a long asymptomatic interval in between. The second episode occurred after consumption of rotten fish and was accompanied by gastrointestinal symptoms and an anticholinergic syndrome. Very rarely, MFS can present with a recurrent course. The importance of this case of recurrent MFS lies not only in its long asymptomatic period and identical clinical presentation, but also in its instructiveness regarding the differential diagnosis of MFS, particularly life-threatening botulism.
Acute Disease↗
Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity.
BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.
Adult↗
Escalating immunotherapy of multiple sclerosis--new aspects and practical application.
Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.
Clinical Trials as Topic↗
Self-tolerance in the immune privileged CNS: lessons from the entorhinal cortex lesion model.
Upon peripheral immunization with myelin epitopes, susceptible rats and mice develop T cell-mediated demyelination similar to that observed in the human autoimmune disease multiple sclerosis (MS). In the same animals, brain injury does not induce autoimmune encephalomyelitis despite massive release of myelin antigens and early expansion of myelin specific T cells in local lymph nodes, indicating that the self-specific T cell clones are kept under control. Using entorhinal cortex lesion (ECL) to induce axonal degeneration in the hippocampus, we identified possible mechanisms of immune tolerance after brain trauma. Following ECL, astrocytes upregulate the death ligand CD95L, allowing apoptotic elimination of infiltrating activated T cells. Myelin-phagocytosing microglia express MHC-II and the costimulatory molecule CD86, but lack CD80, which is found only on activated antigen presenting cells (APCs). Restimulation of invading T cells by such immature APCs (e.g. CD80 negative microglia) may lead to T cell anergy and/or differentiation of regulatory/Th3-like cells due to insufficient costimulation and presence of high levels of TGF-beta and IL-10 in the CNS. Thus, T cell -apoptosis, -anergy, and -suppression apparently maintain immune tolerance after initial expansion of myelin-specific T lymphocytes following brain injury. This view is supported by a previous metastatistical analysis which rejected the hypothesis that brain trauma is causative of MS (Goddin et al., 1999). However, concomitant trauma-independent proinflammatory signals, e.g., those evoked by clinically quiescent infections, may trigger maturation of APCs, thus shifting a delicate balance from immune tolerance and protective immune responses to destructive autoimmunity.
Animals↗
The role of apoptosis in neuroinflammation.
Explore the source record for details and available documents.
Animals↗
[Current recommendations for vaccination in multiple sclerosis].
Explore the source record for details and available documents.
Clinical Trials as Topic↗
Investigation of bax, bcl-2, bcl-x and p53 gene polymorphisms in multiple sclerosis.
Clinical course, outcome, radiological features, severity, and histopathology are heterogenous in multiple sclerosis (MS). Since MS is considered to be a polygenic disease, the genetic background may at least partly be responsible for this variability. Some MS cases are histopathologically characterized by a dramatic oligodendrocyte loss that is in part caused by apoptosis. A dysregulated apoptotic elimination of self-reactive T cells may also contribute to disease susceptibility. To analyze genetic differences in the apoptosis regulating factors bcl-2, bax, bcl-x and p53 we investigated polymorphisms of these genes in 105 patients with a relapsing remitting disease course and 99 controls by PCR-SSCP and direct sequencing. We identified so far unpublished sequence alterations in the promotor region of the bxl-x gene, in exon 7 of the p53 gene, and in exon 1 of the bax gene. No differences were observed between MS patients and controls. Additional known polymorphisms were found in intron 3 of the bax gene and in exon 6 of the p53 gene. No significant differences in the frequency of gene sequence variations were found between MS patients and controls. The apoptosis genes studied here therefore appear less likely to be important effector genes in MS.
Apoptosis↗
Rhabdomyolysis during interferon-beta 1a treatment.
Explore the source record for details and available documents.
Adult↗
Downregulation of transforming growth factor-beta1 in interferon-beta1a-treated MS patients.
The authors report an intense downregulation of transforming growth factor-beta1 (TGF-beta1) serum levels 4 weeks from start of interferon-beta1a (IFN-beta1a) treatment at 44 microg/week in 271 patients with relapsing-remitting MS, which was still present after 1 year (p < 0.001). In line with previous data, interleukin-10 serum levels did not vary significantly. These results indicate that the immunomodulatory effects of IFN-beta might not be restricted to the postulated anti-inflammatory mechanisms and address the role of TGF-beta in the pathogenesis of MS.
Adult↗
Peripheral blood cell bulk cultures are not suitable for the analysis of the genetic control of T-cell cytokine function.
Recently evidence has been provided for a genetic control of T-cell dependent cytokine production by HLA-class II. Candidate genes in multiple sclerosis, a T-cell mediated autoimmune disease, are the disease-associated DR2, DQ6, Dw2 haplotype. Previous observations by us and others imply a HLA-DR2 dependent propensity of antigen-specific T-cell lines to produce increased amounts of TNF-alpha/beta. Here, we tested a possible association between HLA or disease status with cytokine production employing the simple and widely used method of bulk cultures. Peripheral blood cells of 48 patients and 68 healthy individuals were analyzed. We observed no significant differences of the cytokine production in relation to disease status or any HLA polymorphism. Our data indicate that, in contrast to monoclonal T-cell cultures, bulk cultures are not suitable to detect immunogenetic control of T-cell function.
Alleles↗
Polyspecific immunoglobulins (IVIg) suppress proliferation of human (auto)antigen-specific T cells without inducing apoptosis.
Polyspecific immunoglobulins (IVIg) have been shown to reduce disease activity in multiple sclerosis (MS). To investigate the mechanisms of action of IVIg, we studied the impact of IVIg on growth and death (apoptosis) of human (auto)antigen-specific T cells. We observed a substantial suppression of proliferation of specifically activated T cells, in absence of caspase activation or DNA fragmentation. Further, neither susceptibility of T cells to undergo CD95-mediated apoptosis nor expression of apoptosis-blocking bcl-2 was modulated by IVIg. We conclude that IVIg may inhibit the reactivity of antigen-specific T cells in MS through suppression of proliferation rather than modulation of apoptosis.
Apoptosis↗
[Current concepts on vaccinations in multiple sclerosis].
Reports on adverse neurologic events after application of vaccines produced concern about vaccinations such as those against hepatitis B. The question is raised whether infectious agents or vaccines are involved in the pathogenesis or induce worsening of multiple sclerosis (MS). In the past few years, evidence has been provided that a single T cell is capable of recognizing several antigens. Thus, the possibility of activating autoantigen-specific T cells by pathogens or vaccines is raised. Very recent epidemiologic studies presented here have however demonstrated that the risk of MS is not elevated in hepatitis B-vaccinated individuals and that the course of MS is not worsened by hepatitis B, tetanus, or influenza vaccinations.
Case-Control Studies↗
Dual effect of glucocorticoids on apoptosis of human autoreactive and foreign antigen-specific T cells.
The efficacy of glucocorticoids in the treatment of multiple sclerosis may involve the induction of T cell apoptosis. Here, we report that glucocorticoids have two different effects on the vulnerability of human antigen-specific T cells: (i) steroids induce T cell apoptosis in a CD95-independent, but caspase-dependent manner; (ii) steroids protect T cells from CD95-mediated apoptosis which, however, is also caspase-dependent. An increase in BCL-2 expression is observed upon incubation with steroids. Thus, inhibition of CD95-mediated T cell apoptosis may be an undesirable side-effect resulting in survival of activated T cells and the maintenance of pathogenic immune responses might explain the lack of long-term glucocorticoid therapy.
Apoptosis↗
Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL)
Cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) was believed to occur exclusively in tumour cells, suggesting that this drug is safe to use as an antitumour therapy. Concerns were raised, however, when cultured normal human hepatocytes were shown to be susceptible to TRAIL. Here we report that TRAIL induces apoptosis in the human brain. Our finding therefore argues against the use of TRAIL for therapy of human brain tumours. However, neuroinflammatory T cells that express TRAIL might induce apoptosis of brain tissue, indicating a potential target for treatment of multiple sclerosis.
Adolescent↗
Partial synergy of bisindolylmaleimide with apoptotic stimulus in antigen-specific T cells--implications for multiple sclerosis.
In multiple sclerosis (MS), induction of T cell apoptosis constitutes a promising therapeutic strategy. Recently, bisindolylmaleimide has been shown to be an effective treatment of experimental autoimmune encephalomyelitis, presumably due to enhancement of CD95-mediated T cell apoptosis. Therefore, we studied the effects of bisindolylmaleimide on human (auto)antigen-specific T cells. We observed a synergistic effect of bisindolylmaleimide with apoptotic stimulus assessed via caspase activity and annexin V-binding, but no potentiation of DNA fragmentation or cell death. Thus, bisindolylmaleimide might be useful for modulating T cell apoptosis, yet more potent substances have to be generated re-establishing immunological control over auto-reactive T cells.
Annexin A5↗