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Das Spektrum der Immuntherapien bei Multipler Sklerose wird kontinuierlich erweitert. Durch die Zulassung von Cladribin und Ocrelizumab in Europa stehen aktuell zwei neue Medikamente zur Verfügung, wobei Ocrelizumab die erste Behandlungsoption für die primär progrediente Verlaufsform der Multiplen Sklerose darstellt. Mit der zunehmenden Bandbreite hochwirksamer Therapien steigt jedoch auch die Häufigkeit schwerer Nebenwirkungen. Besondere Beachtung fanden hierbei in den vergangenen Monaten die neue PML(progressive multifokale Leukenzephalopathie)-Risikoabschätzung unter Natalizumab, kardiale Nebenwirkungen unter Fingolimod, Fälle von idiopathischer thrombozytopenischer Purpura und Listerieninfektionen unter Alemtuzumab und das Auftreten von Leberversagen und Enzephalitiden unter Daclizumab. Diese Fallberichte unterstreichen die Bedeutung eines sorgfältigen Monitorings aller Patienten, die eine immunmodulatorische Therapie erhalten. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a genetically complex disease caused by the interplay of genetic and environmental factors. While it shows substantial familial accumulation, there is no evidence for typical Mendelian transmission within families. Instead, MS risk is likely governed by dozens to hundreds of genetic variants, which can also be present in the general population. The strongest genetic risk factor for MS was identified 40 years ago and lies within the HLA locus. It increases the risk of developing MS by two- to threefold. Within the last few years, genome-wide association studies (GWAS) have led to the identification of nearly 60 additional genetic risk loci. Each of these loci yields a modest to moderate risk increase (odds ratios of 1.1-1.3). Even in combination, however, the currently known risk variants merely account for a small fraction of the disease's heritability. It is likely that a major fraction of genetic MS risk that cannot be explained by GWAS, sometimes termed the 'dark matter' of GWAS, is caused by other factors, such as structural variations of the genome, rare sequence variants, or inherited epigenetic modifications. [ABSTRACT FROM AUTHOR]

Atrophy, the wasting or shrinkage of tissue, of the nervous system is the main feature of neurodegeneration, i.e. the umbrella term for the progressive loss of structure or function of neurons. Loss of neurons due to cell death and axonal degeneration characterize neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis. In these illnesses, it still has to be elucidated to which extent inflammation is part of the pathology. Conversely, in chronic inflammation of the central nervous system (CNS), atrophy has previously also been described and neurodegeneration is discussed as a pathologic feature. The most frequent chronic inflammatory disease of the CNS is multiple sclerosis (MS), which leads to devastating relapsing-remitting symptoms and disability during the relapses, increasingly during the course of disease in patients. Meanwhile it became clear that axons already reveal pathology early in the disease and neurons are affected in the cortex and the spinal cord, albeit to a different extent. The broadening of understanding neurodegenerative aspects of MS pathology demands and creates new therapeutic strategies. Current medication used in MS treatment as well as medications about to be approved are primarily anti-inflammatory therapies. By modulating the immune system and thereby blocking key steps of the pathology, the immunomodulation therapies in MS have a slight impact on disability progression. There is, however, clinical and experimental data concerning the potential neuroprotective properties of novel therapies. Combining anti-inflammatory and direct neuroprotective or even neuroregenerative therapy strategies would be a step forward in the treatment of multiple sclerosis. [ABSTRACT FROM AUTHOR]

The T helper-1 (Th-1)/T helper-2 (Th-2) paradigm is relevant for the pathogenesis and therapy of multiple sclerosis. In experimental autoimmune encephalomyelitis, a shift towards a Th-2 immune response serves as treatment of the disease. In the human immune system, the factors which determine and modulate the differentiation of CD4+ T cells into the Th-1 or Th-2 phenotype have yet to be elucidated completely. Here, the split-well approach was used to analyse costimulatory requirements for the generation of myelin basic protein-specific T-cell subsets considered to play a major role in the pathogenesis of multiple sclerosis. Myelin basic protein-specific T-cell lines were isolated from peripheral blood cells of healthy individuals in the presence or absence of a blockade of the costimulatory molecule B7-1, previously reported to be involved in the development of Th-1 cells. T-helper type was determined by the interferon/interleukin ratio. Blockade of B7-1 did not increase the number of Th-2-like myelin basic protein-specific T-cell lines. Thus, these data show no evidence for an influence of B7-1 blockade on the development of human myelin basic protein-specific T-cell subsets. These results have to be taken into account when discussing whether antibody-mediated B7-1 blockade might be a suitable therapy in multiple sclerosis, as demonstrated in experimental autoimmune encephalomyelitis. [ABSTRACT FROM AUTHOR]

2012 witnessed important developments for multiple sclerosis, including successful phase III trials of novel oral therapeutics and identification of the potassium channel KIR4.1 as an autoimmune target. Additionally, the lung was highlighted as an important site for immune-cell programming, and the relevance of a TNF receptor variant was clarified. [ABSTRACT FROM AUTHOR]

The purpose of this study was to correlate magnetic resonance imaging (MRI)-based lesion load assessment with clinical disability in early relapsing remitting multiple sclerosis (RRMS). Seventeen untreated patients (ten women, seven men; mean age 33.0 +/- 7.9 years) with the initial diagnosis of RRMS were included for cross-sectional as well as longitudinal (24 months) clinical and MRI-based assessment in comparison with age-matched healthy controls. Conventional MR sequences, MR spectroscopy (MRS) and magnetisation transfer imaging (MTI) were performed at 1.5 T. Lesion number and volume, MRS and MTI measurements for lesions and normal appearing white matter (NAWM) were correlated to clinical scores [Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC)] for monitoring disease course after treatment initiation (interferon beta-1a). MTI and MRS detected changes [magnetisation transfer ratio (MTR), N-acetylaspartate (NAA)/creatine ratio] in NAWM over time. EDSS and lesional MTR increases correlated throughout the disease course. Average MTR of NAWM raised during the study (p < 0.05) and correlated to the MSFC score (r = 0.476, p < 0.001). At study termination, NAA/creatine ratio of NAWM correlated to the MSFC score (p < 0.05). MTI and MRS were useful for initial disease assessment in NAWM. MTI and MRS correlated with clinical scores, indicating potential for monitoring the disease course and gaining new insights into treatment-related effects. [ABSTRACT FROM AUTHOR]

A letter concerning multiple sclerosis following etanercept treatment for ankylosing spondylitis is presented.

Background: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS.Methods: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses.Results: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-)  = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-)  = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex.Conclusions: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease. [ABSTRACT FROM AUTHOR]

The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNβ)-1a (Avonex reference arm). RRMS patients age 18-55 years with Expanded Disability Status Scale (EDSS) scores of 0-5.5 and documented pre-study relapse (≥ 1 in previous year, 2 in previous 2 years, or 1 in previous 1-2 years and ≥ 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or IFNβ-1a IM 30 μg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod ( n = 434), placebo ( n = 450), and IFNβ-1a ( n = 447). ARR was not significantly reduced with laquinimod [−18 %, risk ratio (RR) = 0.82, 95 % CI 0.66-1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p < 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was −31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was −77 % ( p = 0.150), vs. placebo. IFNβ-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60-0.92, p = 0.007), showed no effect on PBVC loss (+11 %, p = 0.14), and changes in disability worsening were −26 and −66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC ( p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNβ-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated. [ABSTRACT FROM AUTHOR]

Abstract: Several lines of evidence indicate that remyelination represents one of the most effective mechanisms to achieve axonal protection. For reasons that are not yet understood, this process is often incomplete or fails in multiple sclerosis (MS). Activated astrocytes appear to be able to boost or inhibit endogenous repair processes. A better understanding of remyelination in MS and possible reasons for its failure is needed. Using the well-established toxic demyelination cuprizone model, we created lesions with either robust or impaired endogenous remyelination capacity. Lesions were analyzed for mRNA expression levels by Affymetrix GeneChip® arrays. One finding was the predominance of immune and stress response factors in the group of genes which were classified as remyelination-supporting factors. We further demonstrate that lesions with impaired remyelination capacity show weak expression of the radial-glia cell marker brain lipid binding protein (BLBP, also called B-FABP or FABP7). The expression of BLBP in activated astrocytes correlates with the presence of oligodendrocyte progenitor cells. BLBP-expressing astrocytes are also detected in experimental autoimmune encephalomyelitis during the remission phase. Furthermore, highest numbers of BLBP-expressing astrocytes were evident in lesions of early MS, whereas significantly less are present at the rim of (chronic)-active lesions from patients with long disease duration. Transfection experiments show that BLBP regulates growth factor expression in U87 astrocytoma cells. In conclusion, we provide evidence that expression of BLBP in activated astrocytes negatively correlates with disease duration and in parallel with remyelination failure. [Copyright &y& Elsevier]

JC virus (JCV)-associated progressive multifocal leukoencephalopathy (PML) represents a rare but serious side effect of natalizumab (Tysabri®) in the treatment of patients with relapsing forms of multiple sclerosis (MS). Two factors that may increase the risk of PML have been identified: treatment duration beyond 24 months and prior immunosuppressive therapy. Recently determination of anti-JCV antibodies mirroring JCV infection has allowed a third factor to be added to this list, and a positive serological test has been included as a risk factor on the label of natalizumab. Clearly, JCV serology represents a tool for PML risk stratification in MS patients treated with natalizumab. However, current data as well as the experimental development of the underlying assay have not been validated by an independent laboratory. The present article discusses possibilities and challenges of this assay and, based on our present knowledge, provides recommendations for the clinical implementation in daily practice. [ABSTRACT FROM AUTHOR]

In 2010, the second revision of the McDonald criteria for diagnosis of multiple sclerosis was proposed. Based on new evidence, the imaging criteria for demonstration of dissemination of central nervous system lesions in space and time have been simplified, which will allow broader application in a more uniform manner. In some circumstances, dissemination in space and time can be demonstrated in a single scan. The revision simplifies the criteria and allows accelerated diagnostic procedures while preserving their sensitivity and specificity. Additionally, the applicability across populations and in children is addressed. [ABSTRACT FROM AUTHOR]

Background: Sleep disorders can cause tiredness. The relationship between sleep disorders and fatigue in patients with multiple sclerosis (MS) has not yet been investigated systematically.Objective: To investigate the relationship between fatigue and sleep disorders in patients with MS.Methods: Some 66 MS patients 20 to 66 years old were studied by overnight polysomnography. Using a cut-off point of 45 in the Modified Fatigue Impact Scale (MFIS), the entire cohort was stratified into a fatigued MS subgroup (n = 26) and a non-fatigued MS subgroup (n = 40).Results: Of the fatigued MS patients, 96% (n = 25) were suffering from a relevant sleep disorder, along with 60% of the non-fatigued MS patients (n = 24) (p = 0.001). Sleep-related breathing disorders were more frequent in the fatigued MS patients (27%) than in the non-fatigued MS patients (2.5%). Significantly higher MFIS values were detected in all (fatigued and non-fatigued) patients with relevant sleep disorders (mean MFIS 42.8; SD 18.3) than in patients without relevant sleep disorders (mean MFIS 20.5; SD 17.0) (p < 0.001). Suffering from a sleep disorder was associated with an increased risk of fatigue in MS (odds ratio: 18.5; 95% CI 1.6–208; p = 0.018).Conclusion: Our results demonstrate a clear and significant relationship between fatigue and sleep disorders. [ABSTRACT FROM AUTHOR]

Abstract: Ubiquitous viruses have frequently been proposed as a cause or trigger of chronic immune-mediated diseases. Infections are reported to be temporally associated with clinical exacerbations in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We examined immunological parameters of herpesvirus infections in untreated patients with CIDP compared to demographically matched controls. Patients with CIDP were uniformly seropositive for EBV-specific IgG and the disease was associated with a moderately enhanced IgG reactivity to EBV-encoded antigens expressed during both B cell transformation and productive viral replication. Moreover, cellular EBV copy numbers were 3-fold increased in patients with CIDP. In contrast, humoral immune responses to other herpesviruses (HCMV, HSV) as well as virus-specific IgM responses were unchanged in CIDP. These data indicate that host–pathogen interactions during chronic EBV infection are dysregulated in treatment-naïve patients with CIDP. [Copyright &y& Elsevier]

Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677G>T, 3435C>T and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2% of patients) was 37.7% lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P < 0.05, 14.8% of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2–/– animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2–/– mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n = 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate [overall 121 of 155 patients (78.1%)] increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function [ABCB1/ABCG2-H 15/24 (62.5%) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6%), ABCB1/ABCG2-L 28/33 (84.8%), exact Cochran-Armitage test P = 0.039]. The odds ratio for response was 1.9 (95% CI 1.0–3.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to –I-, and –I to –L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m2 MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation. [ABSTRACT FROM PUBLISHER]

We are currently witnesses to and authors of a paradigm shift in neuropathology. While classical acute and chronic neuroinflammatory diseases such as meningitis or multiple sclerosis (MS) present aspects of neurodegeneration, the disease course of progressive degenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), or stroke-mediated neuronal deficit are demonstrably affected by inflammation. These insights have immediate consequences both for research methods and for the development of novel, more efficient therapies for these diseases. In this review, we analyze the inflammatory and degenerative pathological mechanisms in the brain with particular emphasis on the classical chronic inflammatory disease MS. We demonstrate that the latest pathological considerations not only require the application of advanced research technologies to investigate new pathomechanistic pathways, but also affect the investigation, development, and monitoring of novel potential therapeutic tools. [ABSTRACT FROM AUTHOR]

Abstract: This review deals with the effects of kinins, a family of octa- to decapeptides structurally related to bradykinin (BK), in adaptive immune responses. Herein, we discuss the experimental evidence that kinins may exert influence on multiple players of the immune system (i.e. macrophages, dendritic cells, T and B lymphocytes), and modulate the activation, proliferation, migration and effector functions of these cells. We also give an overview of the possible impact of kinins in human autoimmune diseases and corresponding animal models, with special emphasis on autoimmune neuroinflammation and arthritis. These studies indicate a possible immunomodulatory capacity of kinins beyond our current knowledge of kinin actions regarding the vascular system, and thus the way towards future therapeutic approaches. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Deletion of T cells due to apoptosis induction is a regulatory mechanism in the human immune system that may be impaired in autoimmune diseases such as multiple sclerosis (MS). Involvement of the apoptosis-mediating CD95/CD95 ligand system in MS has been demonstrated. Here, we report that (auto)antigen-specific human T cells are not killed in vitro by soluble TNF-related apoptosis-inducing ligand (TRAIL) although expressing death-inducing receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2. Apoptosis was assessed by caspase activation and DNA fragmentation, receptor expression was detected by RT-PCR and flow cytometry. The (auto)antigen-specific T cells were also resistant to specific TRAIL-R1/TRAIL-R2-directed induction of apoptosis, indicating that coexpression of the truncated TRAIL-R3 and TRAILR4 in these T cells is not responsible for the observed resistance. Upon stimulation, levels of death-inducing TRAIL receptors decreased whereas TRAIL was up-regulated on the cell surface. In contrast to CD95, the role of TRAIL receptors in MS might not involve regulation of T cell vulnerability. [ABSTRACT FROM AUTHOR]

The article presents a case study of early mitoxantrone-induced cardioxicity in secondary progressive multiple sclerosis in four patients. Using a retrospective analysis in the patients, asymptomatic decrease of left ventricular ejection fraction (LVEF) was revealed. Researchers said that the increasing evidence for early cardiotoxicity calls for regular and frequent cardiac monitoring from the beginning of mitoxantrone treatment.

Introduction Life on Earth developed in the presence and under the constant influence of gravity. Thus, it is a fundamental biological question, whether gravity is required for cellular functions at the molecular level in mammalian cells. Their special sensitivity to altered gravity renders cells of the immune system an ideal model system to understand if and how gravity on Earth is required for normal mammalian cell function and signal transduction. Methods Experiments have been performed using ground-based facilities such as fast-rotating 2D clinostat and hyper-g-centrifuges, and real microgravity provided by parabolic flights. For parabolic flight experiments on board the Airbus A300 ZERO-G, we developed RP (rapid prototyping)-based experimental equipment, which allows cell culture experiments with living mammalian cells in microgravity. We investigated the influence of altered gravity on T lymphocytes and on monocytic cells. Results In experiments with a fast rotating 2D clinostat, we detected strong and rapid initial changes of human T lymphocyte signal transduction within minutes of simulated weightlessness. However, most of the initial alterations returned to "normal" levels after 15 min-simulated weightlessness. Only the expression of p21 protein remained constantly elevated, compared to normogravity controls. In simulated weightlessness, human monocytic cells responded with tyrosine-phosphorylation of several proteins, whereas in PMA-stimulated monocytic cells, tyrosine-phosphorylation was nearly abrogated. Hypergravity of 1.8 g had no effects of the signal pathways investigated. In parabolic flight experiments, we found that 20 s microgravity resulted in distinct changes of expression of cell-cycle regulatory genes such as p21 and p27 on the transcriptional level in primary human T lymphocytes. In human monocytic cells, we detected a distinct downregulation of ICAM-1 (CD54) in non-stimulated and in PMAstimulated cells. Conclusion Thus we conclude that dysregulation of immune function in microgravity might be a consequence of 1) sustained induction of p21 as a cell cycle arrest signal in T lymphocytes and 2) Downregulation of ICAM-1 in monocytes/ macrophages, which are then no longer capable of interacting with T lymphocytes in the appropriate way. Since immune cells can respond and adapt to altered environmental conditions very effectively, it is indispendable to investigate whether the observed effects are still active after long-term exposure to altered gravity in the situation of adaptation and steady state. Thus, we are now the phase of preparation of two Space Experiments investigating the function of cells of the innate immunity, one scheduled for autumn 2009 on board of the International Space Station and one as a common Sino-German space life science mission scheduled for January 2010 on board of Shenzhou-8 Spacecraft. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Inflammatory reactions in the CNS, resulting from a loss of control and involving a network of non-neuronal and neuronal cells, are major contributors to the onset and progress of several major neurodegenerative diseases. Therapeutic strategies should therefore keep or restore the well-controlled and finely-tuned balance of immune reactions, and protect neurons from inflammatory damage. In our study, we selected plants of the Malaysian rain forest by an ethnobotanic approach, and investigated them in cell-based-assay-systems and in living brain tissue cultures in order to identify anti-inflammatory and neuroprotective effects. We found that extracts from the tropical plant Knema laurina (Black wild nutmeg) exhibited highly antiinflammatory and neuroprotective effects in cell culture experiments, reduced NO- and IL-6-release from activated microglia cells dose-dependently, and protects living brain tissue from microglia-mediated inflammatory damage. On the intracellular level, the extract inhibited ERK-1/2-phosphorylation, I-kappaB-phosphorylation and subsequently NF-kappaB-translocation in microglia cells. Knema laurina belongs to the family of Myristicaceae, which have been used for centuries for treatment of digestive and inflammatory diseases and is also a major food plant of the Giant Hornbill. Moreover, extract from Knema laurina promotes also neurogenesis in living brain tissue after oxygen-glucose deprivation. In conclusion, extract from Knema laurina not only controls and limits inflammatory reaction after primary neuronal damage, it promotes moreover neurogenesis if given hours until days after stroke-like injury in levels comparable to the best neurotrophic factors known today. [ABSTRACT FROM AUTHOR]

We have previously shown that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (HMGCRI) atorvastatin is therapeutic in experimental autoimmune encephalomyelitis (EAE) while also inducing a sustained phosphorylation of the MAPK Erk1 that is important for inducing T cell anergy. However it is also known, that HMGCRI also influence the antigen presenting cell compartment including dendritic cells (DC). This led us to investigate the role of Erk1 in DC biology in more detail. Indeed bone-marrow derived dendritic cells from Erk1 deficient mice had an increased migratory capacity when compared with DC isolated from wildtype littermate mice. As a likely consequence to cytoskeletal regulation, Erk1-/- DC had an increased surface expression of costimulatory molecules and were more potent to prime T cells in vivo. To investigate the implications of these findings in an inflammatory scenario, we induced EAE (experimental autoimmune encephalomyelitis) in Erk1-/- and Erk1+/+ mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) and could show that a deficiency of this MAPK results in a moderate increase in disease severity. To differentiate the role of Erk1 between peripheral immune system and the brain compartment we induced EAE in Erk1+/+ mice harboring Erk1-/- immune cells by applying bone marrow chimeras (Erk1-/- --> Erk1+/+). We report that Erk1 has an important regulatory function in the immune system as shown by pronounced disease severity in Erk1-/- --> Erk1+/+ bone marrow chimeras. All together these results indicate the significance of Erk1 in regulating DC functions that are relevant for T cell priming and neuroinflammation, and thus signal the importance of therapeutically targeting this MAPK for the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]