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Find video protocols related to scientific articles indexed in Pubmed.
Abundant kif21b is associated with accelerated progression in neurodegenerative diseases.
Acta Neuropathol Commun
PUBLISHED: 10-03-2014
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Kinesin family member 21b (kif21b) is one of the few multiple sclerosis (MS) risk genes with a presumed central nervous system function. Kif21b belongs to the kinesin family, proteins involved in intracellular transport of proteins and organelles. We hypothesised that kif21b is involved in the neurodegenerative component of MS and Alzheimer¿s (AD) disease. Post-mortem kinesin expression was assessed in 50 MS, 58 age and gender matched non-demented controls (NDC) and 50 AD. Kif21b expression was five-fold increased in AD compared to MS and NDC aged below 62 years (p¿=¿8*10¿5), three-fold between 62¿72 years (p¿=¿0.005) and not different above 72 years. No significant differences were observed between MS and NDC. In AD, kif21b expression was two-fold increased in Braak stage 6 (scoring for density of neurofibrillary tangles) compared with stage 5 (p¿=¿0.003). In MS patients, kif21b correlated with the extent of grey matter demyelination (Spearman¿s rho¿=¿0.31, p¿=¿0.03). Abundant kif21b, defined as expression above the median, was associated with a two-fold accelerated development of the Kurtzke Expanded Disability Status Scale (EDSS) 6.0 (median time in low kif21b group 16 years vs. high kif21b 7.5 years, log-rank test p¿=¿0.04) in MS. Given the genetic association of kif21b with MS, the results were stratified according to rs12122721[A] single nucleotide polymorphism (SNP). No association was found between kif21b expression or the time to EDSS 6 in kif21b risk SNP carriers compared to non-risk carriers. Kif21b was expressed in astrocytes in addition to neurons. Upon astrocyte activation, kif21b increased nine-fold. Abundant kif21b expression is associated with severe MS and AD pathology and with accelerated neurodegeneration independent of the kif21b risk SNP.
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Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders.
Neurology
PUBLISHED: 08-22-2014
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The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development.
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B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes.
Sci Transl Med
PUBLISHED: 08-08-2014
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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by autoimmune-mediated demyelination and neurodegeneration. The CNS of patients with MS harbors expanded clones of antigen-experienced B cells that reside in distinct compartments including the meninges, cerebrospinal fluid (CSF), and parenchyma. It is not understood whether this immune infiltrate initiates its development in the CNS or in peripheral tissues. B cells in the CSF can exchange with those in peripheral blood, implying that CNS B cells may have access to lymphoid tissue that may be the specific compartment(s) in which CNS-resident B cells encounter antigen and experience affinity maturation. Paired tissues were used to determine whether the B cells that populate the CNS mature in the draining cervical lymph nodes (CLNs). High-throughput sequencing of the antibody repertoire demonstrated that clonally expanded B cells were present in both compartments. Founding members of clones were more often found in the draining CLNs. More mature clonal members derived from these founders were observed in the draining CLNs and also in the CNS, including lesions. These data provide new evidence that B cells traffic freely across the tissue barrier, with the majority of B cell maturation occurring outside of the CNS in the secondary lymphoid tissue. Our study may aid in further defining the mechanisms of immunomodulatory therapies that either deplete circulating B cells or affect the intrathecal B cell compartment by inhibiting lymphocyte transmigration into the CNS.
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Fatigue at time of CIS is an independent predictor of a subsequent diagnosis of multiple sclerosis.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 07-24-2014
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Fatigue is a common, disabling symptom of multiple sclerosis (MS), but little is known about fatigue in patients with clinically isolated syndrome (CIS), often the presenting symptom of MS. We aimed to investigate the prevalence and severity of fatigue in patients with CIS, and its association with a diagnosis of clinically definite MS (CDMS).
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Prevalence of human Herpesviridae in cerebrospinal fluid of patients with multiple sclerosis and noninfectious neurological disease in the Netherlands.
J. Neurovirol.
PUBLISHED: 03-13-2014
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Prevalence of eight human herpesviruses (HHV1-8) was determined by real-time PCR in cell-rich cerebrospinal fluid (CSF) samples, obtained early after disease symptoms, of Dutch patients with multiple sclerosis (MS) and other noninfectious central nervous system diseases (NIND). Whereas HHV1-8 DNA was undetectable in CSF samples of MS patients, HHV6 DNA was detected in a plexus neuritis case and HHV7 DNA in an ependymoma and a Behçets' disease patient. However, intrathecal HHV infection was not detected. Data indicate that HHV1-8 are rarely detected in CSF of Dutch NIND patients and do not support the role of intrathecal HHV infection early after onset of disease symptoms in MS.
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Cerebrospinal fluid biomarker candidates associated with human WNV neuroinvasive disease.
PLoS ONE
PUBLISHED: 01-01-2014
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During the last decade, the epidemiology of WNV in humans has changed in the southern regions of Europe, with high incidence of West Nile fever (WNF) cases, but also of West Nile neuroinvasive disease (WNND). The lack of human vaccine or specific treatment against WNV infection imparts a pressing need to characterize indicators associated with neurological involvement. By its intimacy with central nervous system (CNS) structures, modifications in the cerebrospinal fluid (CSF) composition could accurately reflect CNS pathological process. Until now, few studies investigated the association between imbalance of CSF elements and severity of WNV infection. The aim of the present study was to apply the iTRAQ technology in order to identify the CSF proteins whose abundances are modified in patients with WNND. Forty-seven proteins were found modified in the CSF of WNND patients as compared to control groups, and most of them are reported for the first time in the context of WNND. On the basis of their known biological functions, several of these proteins were associated with inflammatory response. Among them, Defensin-1 alpha (DEFA1), a protein reported with anti-viral effects, presented the highest increasing fold-change (FC>12). The augmentation of DEFA1 abundance in patients with WNND was confirmed at the CSF, but also in serum, compared to the control individual groups. Furthermore, the DEFA1 serum level was significantly elevated in WNND patients compared to subjects diagnosed for WNF. The present study provided the first insight into the potential CSF biomarkers associated with WNV neuroinvasion. Further investigation in larger cohorts with kinetic sampling could determine the usefulness of measuring DEFA1 as diagnostic or prognostic biomarker of detrimental WNND evolution.
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Application of the 2012 revised diagnostic definitions for paediatric multiple sclerosis and immune-mediated central nervous system demyelination disorders.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 12-05-2013
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Recently, the International Paediatric Multiple Sclerosis Study Group (IPMSSG) definitions for the diagnosis of immune-mediated acquired demyelinating syndromes (ADS) of the central nervous system, including paediatric multiple sclerosis (MS), have been revised.
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Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS demyelination.
Neurology
PUBLISHED: 11-06-2013
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To investigate whether 57 genetic risk loci recently identified in a large-scale genome-wide association study in adult patients with multiple sclerosis (MS) are also associated with a risk for pediatric-onset MS and whether they can predict MS diagnosis in children presenting with acquired demyelinating syndromes (ADS).
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Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects.
PLoS Genet.
PUBLISHED: 11-01-2013
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The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.
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Cerebrospinal-fluid-derived Immunoglobulin G of Different Multiple Sclerosis Patients Shares Mutated Sequences in Complementarity Determining Regions.
Mol. Cell Proteomics
PUBLISHED: 08-22-2013
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B lymphocytes play a pivotal role in multiple sclerosis pathology, possibly via both antibody-dependent and -independent pathways. Intrathecal immunoglobulin G in multiple sclerosis is produced by clonally expanded B-cell populations. Recent studies indicate that the complementarity determining regions of immunoglobulins specific for certain antigens are frequently shared between different individuals. In this study, our main objective was to identify specific proteomic profiles of mutated complementarity determining regions of immunoglobulin G present in multiple sclerosis patients but absent in healthy controls. To achieve this objective, we purified immunoglobulin G from the cerebrospinal fluid of 29 multiple sclerosis patients and 30 healthy controls and separated the corresponding heavy and light chains via SDS-PAGE. Subsequently, bands were excised, trypsinized, and measured with high-resolution mass spectrometry. We sequenced 841 heavy and 771 light chain variable region peptides. We observed 24 heavy and 26 light chain complementarity determining regions that were solely present in a number of multiple sclerosis patients. Using stringent criteria for the identification of common peptides, we found five complementarity determining regions shared in three or more patients and not in controls. Interestingly, one complementarity determining region with a single mutation was found in six patients. Additionally, one other patient carrying a similar complementarity determining region with another mutation was observed. In addition, we found a skew in the ?-to-? ratio and in the usage of certain variable heavy regions that was previously observed at the transcriptome level. At the protein level, cerebrospinal fluid immunoglobulin G shares common characteristics in the antigen binding region among different multiple sclerosis patients. The indication of a shared fingerprint may indicate common antigens for B-cell activation.
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MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis.
Brain
PUBLISHED: 06-07-2013
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A recent genome-wide association study reported five loci for which there was strong, but sub-genome-wide significant evidence for association with multiple sclerosis risk. The aim of this study was to evaluate the role of these potential risk loci in a large and independent data set of ? 20,000 subjects. We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent. In addition, we assessed the overall evidence for association by combining these newly generated data with the results from the original genome-wide association study by meta-analysis. All five tested single nucleotide polymorphisms showed consistent and statistically significant evidence for association with multiple sclerosis in our validation data sets (rs228614: odds ratio = 0.91, P = 2.4 × 10(-6); rs630923: odds ratio = 0.89, P = 1.2 × 10(-4); rs2744148: odds ratio = 1.14, P = 1.8 × 10(-6); rs180515: odds ratio = 1.12, P = 5.2 × 10(-7); rs6062314: odds ratio = 0.90, P = 4.3 × 10(-3)). Combining our data with results from the previous genome-wide association study by meta-analysis, the evidence for association was strengthened further, surpassing the threshold for genome-wide significance (P < 5 × 10(-8)) in each case. Our study provides compelling evidence that these five loci are genuine multiple sclerosis susceptibility loci. These results may eventually lead to a better understanding of the underlying disease pathophysiology.
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Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.
Mult. Scler.
PUBLISHED: 05-21-2013
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The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
, Ashley H Beecham, Nikolaos A Patsopoulos, Dionysia K Xifara, Mary F Davis, Anu Kemppinen, Chris Cotsapas, Tejas S Shah, Chris Spencer, David Booth, An Goris, Annette Oturai, Janna Saarela, Bertrand Fontaine, Bernhard Hemmer, Claes Martin, Frauke Zipp, Sandra D'Alfonso, Filippo Martinelli-Boneschi, Bruce Taylor, Hanne F Harbo, Ingrid Kockum, Jan Hillert, Tomas Olsson, Maria Ban, Jorge R Oksenberg, Rogier Hintzen, Lisa F Barcellos, Cristina Agliardi, Lars Alfredsson, Mehdi Alizadeh, Carl Anderson, Robert Andrews, Helle Bach Søndergaard, Amie Baker, Gavin Band, Sergio E Baranzini, Nadia Barizzone, Jeffrey Barrett, Celine Bellenguez, Laura Bergamaschi, Luisa Bernardinelli, Achim Berthele, Viola Biberacher, Thomas M C Binder, Hannah Blackburn, Izaura L Bomfim, Paola Brambilla, Simon Broadley, Bruno Brochet, Lou Brundin, Dorothea Buck, Helmut Butzkueven, Stacy J Caillier, William Camu, Wassila Carpentier, Paola Cavalla, Elisabeth G Celius, Irène Coman, Giancarlo Comi, Lucia Corrado, Leentje Cosemans, Isabelle Cournu-Rebeix, Bruce A C Cree, Daniele Cusi, Vincent Damotte, Gilles Defer, Silvia R Delgado, Panos Deloukas, Alessia di Sapio, Alexander T Dilthey, Peter Donnelly, Bénédicte Dubois, Martin Duddy, Sarah Edkins, Irina Elovaara, Federica Esposito, Nikos Evangelou, Barnaby Fiddes, Judith Field, Andre Franke, Colin Freeman, Irene Y Frohlich, Daniela Galimberti, Christian Gieger, Pierre-Antoine Gourraud, Christiane Graetz, Andrew Graham, Verena Grummel, Clara Guaschino, Athena Hadjixenofontos, Hakon Hakonarson, Christopher Halfpenny, Gillian Hall, Per Hall, Anders Hamsten, James Harley, Timothy Harrower, Clive Hawkins, Garrett Hellenthal, Charles Hillier, Jeremy Hobart, Muni Hoshi, Sarah E Hunt, Maja Jagodic, Ilijas Jelcic, Angela Jochim, Brian Kendall, Allan Kermode, Trevor Kilpatrick, Keijo Koivisto, Ioanna Konidari, Thomas Korn, Helena Kronsbein, Cordelia Langford, Malin Larsson, Mark Lathrop, Christine Lebrun-Frenay, Jeannette Lechner-Scott, Michelle H Lee, Maurizio A Leone, Virpi Leppä, Giuseppe Liberatore, Benedicte A Lie, Christina M Lill, Magdalena Lindén, Jenny Link, Felix Luessi, Jan Lycke, Fabio Macciardi, Satu Mannisto, Clara P Manrique, Roland Martin, Vittorio Martinelli, Deborah Mason, Gordon Mazibrada, Cristin McCabe, Inger-Lise Mero, Julia Mescheriakova, Loukas Moutsianas, Kjell-Morten Myhr, Guy Nagels, Richard Nicholas, Petra Nilsson, Fredrik Piehl, Matti Pirinen, Siân E Price, Hong Quach, Mauri Reunanen, Wim Robberecht, Neil P Robertson, Mariaemma Rodegher, David Rog, Marco Salvetti, Nathalie C Schnetz-Boutaud, Finn Sellebjerg, Rebecca C Selter, Catherine Schaefer, Sandip Shaunak, Ling Shen, Simon Shields, Volker Siffrin, Mark Slee, Per Soelberg Sorensen, Melissa Sorosina, Mireia Sospedra, Anne Spurkland, Amy Strange, Emilie Sundqvist, Vincent Thijs, John Thorpe, Anna Ticca, Pentti Tienari, Cornelia van Duijn, Elizabeth M Visser, Steve Vucic, Helga Westerlind, James S Wiley, Alastair Wilkins, James F Wilson, Juliane Winkelmann, John Zajicek, Eva Zindler, Jonathan L Haines, Margaret A Pericak-Vance, Adrian J Ivinson, Graeme Stewart, David Hafler, Stephen L Hauser, Alastair Compston, Gil McVean, Philip De Jager, Stephen J Sawcer, Jacob L McCauley.
Nat. Genet.
PUBLISHED: 04-24-2013
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Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
Mult. Scler.
PUBLISHED: 04-09-2013
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There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope.
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Effects of natalizumab treatment on the cerebrospinal fluid proteome of multiple sclerosis patients.
J. Proteome Res.
PUBLISHED: 02-04-2013
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Natalizumab is a very effective, relatively new drug for the treatment of relapsing remitting multiple sclerosis. Inflammatory and neurodegenerative processes in the central nervous system are presumed to cause adverse effects during the course of this disease. To monitor the effects of natalizumab treatment on the cerebrospinal fluid (CSF) proteome of patients, CSF samples were taken from patients before commencing treatment as well as after 1 year of treatment. Profiling proteomics experiments using electrospray Orbitrap mass spectrometry and pair wise comparison of patients before and after 1 year of natalizumab treatment revealed a number of candidate biomarkers that were significantly differentially abundant between the before and after treatment groups. Three proteins were subsequently validated using selected reaction monitoring (SRM) in a new, independent sample set. All three proteins, Ig mu chain C region and haptoglobin, both known inflammation-related proteins, as well as Chitinase-3-like protein 1, were confirmed by SRM to be significantly lower abundant in CSF of multiple sclerosis patients after 1 year of natalizumab treatment. The findings for Chitinase-3-like protein 1, a presumed biomarker for more rapid progression from a first clinically isolated syndrome to clinically definite multiple sclerosis, was further confirmed by ELISA measurements.
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Antibodies against aquaporin-4 in neuromyelitis optica: distinction between recurrent and monophasic patients.
Mult. Scler.
PUBLISHED: 08-09-2011
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The detection of antibodies against aquaporin-4 (AQP4) has improved the diagnosis of neuromyelitis optica (NMO). We evaluated a recently established cell-based anti-AQP4 assay in 273 patients with inflammatory CNS demyelination. The assay had a specificity of 99% and a sensitivity of 56% to detect all NMO patients and of 74% to detect the recurrent NMO patients, similar to the initial studies reported. AQP4 antibodies were absent in monophasic NMO patients, while samples in recurrent cases remained positive during follow-up. We conclude that the pathogenesis of monophasic NMO may be different from that of relapsing NMO.
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Proteomics technologies for biomarker discovery in multiple sclerosis.
J. Neuroimmunol.
PUBLISHED: 07-26-2011
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Multiple sclerosis is a disabling inflammatory and neurodegenerative disorder that predominantly affects young adults. There is a great need for biomarkers, which could elucidate pathology as well as provide prognosis of disease progression and therapy response in multiple sclerosis. Rapidly evolving, technology driven applications such as mass spectrometry based proteomics are currently being developed for this purpose. In this review, we will outline the current status of the field and detail a number of the bottlenecks as well as future prospects of this type of biomarker research.
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Perspectives on the use of multiple sclerosis risk genes for prediction.
PLoS ONE
PUBLISHED: 05-13-2011
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A recent collaborative genome-wide association study replicated a large number of susceptibility loci and identified novel loci. This increase in known multiple sclerosis (MS) risk genes raises questions about clinical applicability of genotyping. In an empirical set we assessed the predictive power of typing multiple genes. Next, in a modelling study we explored current and potential predictive performance of genetic MS risk models.
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The association between cigarette smoking and multiple sclerosis.
J. Neurol. Sci.
PUBLISHED: 05-06-2011
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Genetic factors partially explain the susceptibility of multiple sclerosis (MS) and might even relate to the clinical course. Still, many epidemiological studies point at an important role for environmental factors in MS. Smoking is one of the major candidates. In this review we provide an overview of the epidemiological studies on cigarette smoking and the association on MS risk and MS clinical course. In addition, we discuss the possible biological pathways that may influence neurological damage in MS. Moreover, the relation of smoking with other environmental MS risk factors will be addressed.
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Consensus Guidelines for CSF and Blood Biobanking for CNS Biomarker Studies.
Mult Scler Int
PUBLISHED: 04-05-2011
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There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in cerebrospinal fluid (CSF) are being used in clinical practice. Anti-aquaporin-4 antibodies in serum are currently useful for the diagnosis of neuromyelitis optica (NMO), but we could expect novel CSF biomarkers that help define prognosis and response to treatment for this disease. One of the most critical factors in biomarker research is the inadequate powering of studies performed by single centers. Collaboration between investigators is needed to establish large biobanks of well-defined samples. A key issue in collaboration is to establish standardized protocols for biobanking to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by pre-analytical factors. Here, consensus guidelines for CSF collection and biobanking are presented, based on the guidelines that have been published by the BioMS-eu network for CSF biomarker research. We focussed on CSF collection procedures, pre-analytical factors and high quality clinical and paraclinical information. Importantly, the biobanking protocols are applicable for CSF biobanks for research targeting any neurological disease.
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The monocyte transcriptome during pregnancy in multiple sclerosis: prominent expression of the Fc-receptor CD64.
Mult. Scler.
PUBLISHED: 12-06-2010
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During the third trimester of pregnancy multiple sclerosis (MS) disease activity is reduced. It is not fully understood which factors mediate this disease amelioration.
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Quantitative proteomics and metabolomics analysis of normal human cerebrospinal fluid samples.
Mol. Cell Proteomics
PUBLISHED: 09-03-2010
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The analysis of cerebrospinal fluid (CSF) is used in biomarker discovery studies for various neurodegenerative central nervous system (CNS) disorders. However, little is known about variation of CSF proteins and metabolites between patients without neurological disorders. A baseline for a large number of CSF compounds appears to be lacking. To analyze the variation in CSF protein and metabolite abundances in a number of well-defined individual samples of patients undergoing routine, non-neurological surgical procedures, we determined the variation of various proteins and metabolites by multiple analytical platforms. A total of 126 common proteins were assessed for biological variations between individuals by ESI-Orbitrap. A large spread in inter-individual variation was observed (relative standard deviations [RSDs] ranged from 18 to 148%) for proteins with both high abundance and low abundance. Technical variation was between 15 and 30% for all 126 proteins. Metabolomics analysis was performed by means of GC-MS and nuclear magnetic resonance (NMR) imaging and amino acids were specifically analyzed by LC-MS/MS, resulting in the detection of more than 100 metabolites. The variation in the metabolome appears to be much more limited compared with the proteome: the observed RSDs ranged from 12 to 70%. Technical variation was less than 20% for almost all metabolites. Consequently, an understanding of the biological variation of proteins and metabolites in CSF of neurologically normal individuals appears to be essential for reliable interpretation of biomarker discovery studies for CNS disorders because such results may be influenced by natural inter-individual variations. Therefore, proteins and metabolites with high variation between individuals ought to be assessed with caution as candidate biomarkers because at least part of the difference observed between the diseased individuals and the controls will not be caused by the disease, but rather by the natural biological variation between individuals.
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Infectious mononucleosis-linked HLA class I single nucleotide polymorphism is associated with multiple sclerosis.
Mult. Scler.
PUBLISHED: 08-24-2010
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Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism.
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The management of multiple sclerosis in children: a European view.
Mult. Scler.
PUBLISHED: 08-04-2010
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About 3-5% of all patients with multiple sclerosis experience the onset of their disease under the age of 16. A significant proportion of paediatric multiple sclerosis patients develop significant cognitive disturbances and persistent physical disability. The high relapse rate and the morbidity in the paediatric multiple sclerosis population has triggered the use of disease-modifying therapies that have been shown to reduce relapse rate, disease progression and cognitive decline in adult patients with multiple sclerosis. Hard evidence for the right treatment and its appropriate timing is scarce in paediatric multiple sclerosis. Nevertheless, expertise in this field has grown thanks to recent open-label trials and experience generated in specialized centres. In spring 2009, a first meeting was held in Rotterdam with clinicians from 11 European countries (one from Canada) that are all active in the management of paediatric multiple sclerosis. One of the aims was to generate a common view on the management of paediatric multiple sclerosis patients. The result of this meeting is presented here to help standardize treatment and to support clinicians with less experience in this field.
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Evidence for acute neurotoxicity after chemotherapy.
Ann. Neurol.
PUBLISHED: 07-17-2010
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Chronic neurotoxicity is a recognized long-term complication following chemotherapy in a range of diseases. Neurotoxicity adversely affects patients quality of life. The objective of this study is to examine whether there is evidence of acute neurotoxicity.
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Pregnancy-induced fluctuations in functional T-cell subsets in multiple sclerosis patients.
Mult. Scler.
PUBLISHED: 07-07-2010
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During pregnancy, especially during the third trimester, multiple sclerosis (MS) disease activity is reduced. It is not known which factors mediate this disease amelioration.
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Acute disseminating encephalomyelitis following legionnaires disease.
Arch. Neurol.
PUBLISHED: 05-12-2010
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To describe 2 patients presenting with severe neurological deficits and extensive lesions on brain magnetic resonance imaging after having experienced Legionella pneumonia.
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Proteomics comparison of cerebrospinal fluid of relapsing remitting and primary progressive multiple sclerosis.
PLoS ONE
PUBLISHED: 04-13-2010
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Based on clinical representation of disease symptoms multiple sclerosis (MScl) patients can be divided into two major subtypes; relapsing remitting (RR) MScl (85-90%) and primary progressive (PP) MScl (10-15%). Proteomics analysis of cerebrospinal fluid (CSF) has detected a number of proteins that were elevated in MScl patients. Here we specifically aimed to differentiate between the PP and RR subtypes of MScl by comparing CSF proteins.
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No evidence for intrathecal IgG synthesis to Epstein Barr virus nuclear antigen-1 in multiple sclerosis.
J. Clin. Virol.
PUBLISHED: 02-10-2010
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Recent studies suggest an intrathecal IgG response against Epstein Barr virus (EBV) in multiple sclerosis (MS), implicating a pathogenic role for the virus in MS.
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Retinal nerve fiber layer thickness in subgroups of multiple sclerosis, measured by optical coherence tomography and scanning laser polarimetry.
J. Neurol.
PUBLISHED: 02-05-2010
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Optical coherence tomography (OCT) and scanning laser polarimetry (GDx ECC) are non-invasive methods used to assess retinal nerve fiber layer (RNFL) thickness, which may be a reliable tool used to monitor axonal loss in multiple sclerosis (MS). The objectives of this study are (1) to compare OCT with the GDx ECC; (2) to assess and compare the RNFL thickness in subgroups of MS. Ophthalmologic examination and RNFL assessment by OCT and GDx were performed in 65 MS patients (26 relapsing-remitting (RRMS), ten secondary-progressive (SPMS), 29 primary-progressive (PPMS)). Twenty-eight patients (43%) had a history of optic neuritis (ON). Adjustments were made for age and disease duration. RNFL thickness was reduced in eyes with previous ON (p < 0.01). No differences were found between PPMS and relapse-onset MS. OCT and GDx ECC measurements were moderately correlated (rho = 0.73, p < 0.01). Visual field-mean deviation (MD) values correlated with OCT means (r = 0.44, p < 0.01) and GDx ECC TSNIT average (r = 0.41, p < 0.01). In patients without previous ON, EDSS correlated with MD (r = -0.36, p < 0.01), visual field-pattern standard deviation (PSD) (r = 0.30, p < 0.05), OCT means (r = -0.31-0.30, p < 0.05) and macular volume (r = -0.37, p < 0.01). For MSIS-29 physical impact score, significant correlations were found with MD (r = -0.48, p < 0.01) and PSD (r = 0.48, p < 0.01). Conclusions: No differences between PPMS and relapse-onset MS subgroups were found. RNFL thickness was reduced in eyes with previous ON. Although OCT and GDx ECC findings were moderately correlated and showed significant correlations with measures of visual function in patients without previous ON, EDSS correlated significantly with visual and OCT measures, but not with GDx ECC.
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Replication of CD58 and CLEC16A as genome-wide significant risk genes for multiple sclerosis.
J. Hum. Genet.
PUBLISHED: 10-16-2009
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A recent genome-wide association study by the International Multiple Sclerosis Genetics Consortium (IMSGC) reported association of 17 single-nucleotide polymorphisms (SNPs) in 14 loci with multiple sclerosis (MS). Only two loci, HLA-DRA and IL2RA, reached genome-wide significance (P<5E-08). In our study, we determined whether we could replicate the results of the IMSGC and whether more SNPs are genome-wide significantly associated with MS. We assessed the association between the 17 IMSGC SNPs and MS in three cohorts (total number of subjects 3981, among these 1853 cases). We performed a meta-analysis of the results of our study, the original IMSGC results and the results of a recent replication study performed in the Australian population. Of the 17 IMSGC SNPs, five SNPs showed genome-wide significant association with MS: HLA-DRA (P=8E-124), IL7R (P=6E-09), IL2RA (P=1E-11), CD58 (P=4E-09) and CLEC16A (P=3E-12). Therefore, genome-wide significance has now been shown for SNPs in different non-HLA MS risk genes. Several of these risk genes, including CD58 and CLEC16A, are shared by different autoimmune diseases. Fine mapping studies will be needed to determine the functional contributions to distinct autoimmune phenotypes.
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Cigarette smoking and risk of MS in multiplex families.
Mult. Scler.
PUBLISHED: 10-13-2009
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Recent studies suggest that a history of cigarette smoking is a risk factor for multiple sclerosis (MS). We aimed to test the smoking effect in multiplex families, matching for both environmental and genetic factors. In a matched case-control study, 136 MS patients from 106 multiplex MS families were compared with their 204 healthy siblings as controls. Participants completed self-report questionnaires. Conditional logistic regression was used to analyse smoking and MS risk association while controlling for confounding by age and sex. Smoking history was classified in different variables. Within our survey the smoking history of MS patients and the controls did not differ. The odds of MS were comparable for different smoking levels. However, more intense exposure and women showed higher odds ratios, although non-significant. Association studies in families with relatively high genetic loading are unlikely to be confounded by smoking history.
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First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis.
Mult. Scler.
PUBLISHED: 09-29-2009
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Pregnancy has an ameliorating effect on multiple sclerosis (MS), but directly after delivery the risk of a relapse is increased. The pro-inflammatory chemokine interleukin 8 is associated with disease activity. We aimed to investigate whether pregnancy-induced fluctuations of interleukin 8 correlate with periods of enhanced and diminished disease activity. Thirty-six women with MS were prospectively studied before, during and after pregnancy. Serum levels of interleukin 8 were significantly decreased during the third trimester (p = 0.03). High first trimester serum levels of interleukin 8 were associated with a high risk of postpartum relapse (p = 0.007). These results help us to further understand the altered disease course during pregnancy.
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Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE.
J. Mol. Med.
PUBLISHED: 09-26-2009
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Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked.
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Fatigue and depression in children with multiple sclerosis and monophasic variants.
Eur. J. Paediatr. Neurol.
PUBLISHED: 07-14-2009
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Fatigue is an important symptom in adult multiple sclerosis (MS) and it is likely to occur in children with MS. It is currently unknown whether children who experienced a monophasic inflammatory demyelinating event of the central nervous system in the past also suffer from fatigue.
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Acute CNS white matter lesions in patients with inflammatory bowel disease.
Inflamm. Bowel Dis.
PUBLISHED: 07-14-2009
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Neurological manifestations in patients with inflammatory bowel disease supposedly are rare, although the exact frequency is not known. Most previous reports involve cerebral venous thrombosis, central nervous system vasculitis, or peripheral nerve inflammation.
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United Europeans for development of pharmacogenomics in multiple sclerosis network.
Pharmacogenomics
PUBLISHED: 05-20-2009
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Multiple sclerosis (MS) is a chronic inflammatory, disabling disease of the CNS. A recent study has estimated the annual cost of MS in Europe at euro12.5 billion. There is no definitive cure for the disease. Immunomodulatory therapies, such as IFN-beta and glatiramer acetate, are only partially effective. Various new therapies in the final stages of clinical trials are being developed in the absence of efficacy biomarkers. Hence, there is a pressing need for identification of MS treatment response biomarkers. The focus of the multicenter research initiative United Europeans for the development of pharmacogenomics in MS (UEPHA*MS) is to promote and improve training opportunities in the novel supradisciplinary area of pharmacogenomics, biomarker research and systems biology applied to MS. UEPHA*MS is a Marie Curie Initial Training network funded by the 7th Framework Programme of the European Commission. The main scientific goals of this network are both to enhance our knowledge of the mechanisms determining response outcomes of existing immunomodulatory therapies and to identify novel therapeutic opportunities. UEPHA*MS is composed of 11 internationally recognized research teams from five countries with an assortment of expertise in complementary disciplines. The UEPHA*MS network will provide a coherent and internationally competitive platform for the training of young scientists based on multidisciplinary state-of-the-art laboratory-based and network-wide activities. This network will be instrumental in priming young scientists for Europes collective effort toward improved provision of healthcare based on personalized medicine.
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Neurofilament ELISA validation.
J. Immunol. Methods
PUBLISHED: 05-03-2009
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Neurofilament proteins (Nf) are highly specific biomarkers for neuronal death and axonal degeneration. As these markers become more widely used, an inter-laboratory validation study is required to identify assay criteria for high quality performance.
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Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis.
J. Pathol.
PUBLISHED: 03-26-2009
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Despite lack of classical lymphatic vessels in the central nervous system (CNS), cells and antigens do reach the CNS-draining lymph nodes. These lymph nodes are specialized to mediate mucosal immune tolerance, but can also generate T- and B-cell immunity. Their role in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) therefore remains elusive. We hypothesized that drainage of CNS antigens to the CNS-draining lymph nodes is vital for the recurrent episodes of CNS inflammation. To test this, we surgically removed the superficial cervical lymph nodes, deep cervical lymph nodes, and the lumbar lymph nodes prior to disease induction in three mouse EAE models, representing acute, chronic, and chronic-relapsing EAE. Excision of the CNS-draining lymph nodes in chronic-relapsing EAE reduced and delayed the relapse burden and EAE pathology within the spinal cord, which suggests initiation of CNS antigen-specific immune responses within the CNS-draining lymph nodes. Indeed, superficial cervical lymph nodes from EAE-affected mice demonstrated proliferation against the immunizing peptide, and the deep cervical lymph nodes, lumbar lymph nodes, and spleen demonstrated additional proliferation against other myelin antigen epitopes. This indicates that intermolecular epitope spreading occurs and that CNS antigen-specific immune responses are differentially generated within the different CNS-draining lymphoid organs. Proliferation of splenocytes from lymphadenectomized and sham-operated mice against the immunizing peptide was similar. These data suggest a role for CNS-draining lymph nodes in the induction of detrimental immune responses in EAE relapses, and conclusively demonstrate that the tolerance-inducing capability of cervical lymph nodes is not involved in EAE.
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Multiple sclerosis - a response-to-damage model.
Trends Mol Med
PUBLISHED: 02-24-2009
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According to a widely supported but unproven concept, the autoimmune mechanisms that drive neuroinflammation in multiple sclerosis (MS) are triggered by virus infection. However, a direct viral trigger of MS has not been identified. MS models in non-human primates suggest that lifelong asymptomatic infection with certain herpesviruses (e.g. cytomegalovirus) creates a repertoire of potentially autoreactive memory T cells. When these are exposed to antigens released after central nervous system injury as a consequence of an unknown pathogenic event, they are reactivated and induce autoimmune neurological disease. This response-to-damage of antiviral memory cells can take place years after the initiating infection. Consequently, elucidating the anti-herpesvirus T-cell repertoire might provide new targets for preventive diagnosis and therapy.
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T-cell responses to neurofilament light protein are part of the normal immune repertoire.
Int. Immunol.
PUBLISHED: 02-24-2009
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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system in which axonal damage and degeneration contribute significantly to the progressive irreversible neurological disability. Similar to pathogenic myelin autoimmunity, autoimmune responses to neuronal antigens may contribute to axonal damage and irreversible disability in MS. Auto-antibodies to the axonal cytoskeletal protein neurofilament light (NF-L) are associated with cerebral atrophy in MS and we have recently reported that NF-L autoimmunity is pathogenic in mice. However, the T-cell response to NF-L in MS patients has not been examined. Here, we identify and characterize T-cell proliferative responses to NF-L as compared with myelin oligodendrocyte glycoprotein (MOG) in MS patients and healthy controls. Using a carboxyfluorescein succinimidyl ester dilution assay, we show that while responses to MOG are dominated by CD3(+)CD4(+) T cells, responses to NF-L were observed in both CD3(+)CD4(+) and CD3(+)CD8(+) T-cell populations. Both MOG- and NF-L-reactive cells expressed CD45RO(+), indicative of a memory phenotype. Moreover, in contrast to MOG stimulation which predominantly induced IFN-gamma, both T(h)1- and T(h)2-type T-cell responses to NF-L were observed as indicated by the induction of IFN-gamma, tumor necrosis factor-alpha as well as IL-4. The finding of T-cell responses to NF-L in MS patients may reflect transient activation of pathogenic potential but their presence also in healthy controls indicates that these cells are part of the normal immune repertoire.
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Spinal cord involvement in Balos concentric sclerosis.
J. Neurol. Sci.
PUBLISHED: 01-31-2009
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We present a patient with a history of myelitis, who had a steroid refractory attack of CNS inflammatory demyelinating disease that developed into cerebral concentric sclerosis of Balo after plasma exchange. The acute inflammatory disease involved the spinal cord, a phenomenon rarely demonstrated. This patient fulfilled the McDonald criteria for multiple sclerosis. Plasmapheresis did not have a beneficial effect, but the patient stabilised at high EDSS after treatment with mitoxantron.
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Quantitative matrix-assisted laser desorption ionization-fourier transform ion cyclotron resonance (MALDI-FT-ICR) peptide profiling and identification of multiple-sclerosis-related proteins.
J. Proteome Res.
PUBLISHED: 01-23-2009
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We introduce a matrix-assisted laser desorption ionization-Fourier transform ion cyclotron resonance (MALDI-FT-ICR) method for quantitative peptide profiling, using peak height as a measure for abundance. Relative standard deviations in peak height of peptides spiked over 3 orders of magnitude in concentration were below 10% and allowed for accurate comparisons between multiple sclerosis and controls. Application on a set of 163 cerebrospinal fluid (CSF) samples showed significantly differential abundant peptides, which were subsequently identified into proteins (e.g., chromogranin A, clusterin, and complement C3).
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Endotoxin- and ATP-neutralizing activity of alkaline phosphatase as a strategy to limit neuroinflammation.
J Neuroinflammation
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Alkaline phosphatase (AP) is a ubiquitously expressed enzyme which can neutralize endotoxin as well as adenosine triphosphate (ATP), an endogenous danger signal released during brain injury. In this study we assessed a potential therapeutic role for AP in inhibiting neuroinflammation using three complementary approaches.
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Minocycline effects on the cerebrospinal fluid proteome of experimental autoimmune encephalomyelitis rats.
J. Proteome Res.
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To identify response biomarkers for pharmaceutical treatment of multiple sclerosis, we induced experimental autoimmune encephalomyelitis (EAE) in rats and treated symptomatic animals with minocycline. Cerebrospinal fluid (CSF) samples were collected 14 days after EAE induction at the peak of neurological symptoms, and proteomics analysis was performed using nano-LC-Orbitrap mass spectrometry. Additionally, the minocycline concentration in CSF was determined using quantitative matrix-assisted laser desorption/ionization-triple-quadrupole tandem mass spectrometry (MALDI-MS/MS) in the selected reaction monitoring (SRM) mode. Fifty percent of the minocycline-treated EAE animals did not show neurological symptoms on day 14 ("responders"), while the other half displayed neurological symptoms ("nonresponders"), indicating that minocycline delayed disease onset and attenuated disease severity in some, but not all, animals. Neither CSF nor plasma minocycline concentrations correlated with the onset of symptoms or disease severity. Analysis of the proteomics data resulted in a list of 20 differentially abundant proteins between the untreated animals and the responder group of animals. Two of these proteins, complement C3 and carboxypeptidase B2, were validated by quantitative LC-MS/MS in the SRM mode. Differences in the CSF proteome between untreated EAE animals and minocycline-treated responders were similar to the differences between minocycline-treated responders and nonresponders (70% overlap). Six proteins that remained unchanged in the minocycline-treated animals but were elevated in untreated EAE animals may be related to the mechanism of action of minocycline.
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Interpretation and visualization of non-linear data fusion in kernel space: study on metabolomic characterization of progression of multiple sclerosis.
PLoS ONE
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In the last decade data fusion has become widespread in the field of metabolomics. Linear data fusion is performed most commonly. However, many data display non-linear parameter dependences. The linear methods are bound to fail in such situations. We used proton Nuclear Magnetic Resonance and Gas Chromatography-Mass Spectrometry, two well established techniques, to generate metabolic profiles of Cerebrospinal fluid of Multiple Sclerosis (MScl) individuals. These datasets represent non-linearly separable groups. Thus, to extract relevant information and to combine them a special framework for data fusion is required.
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Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis.
Neurology
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There is increasing evidence that vitamin D can be protective against the development of multiple sclerosis (MS), but it may also be beneficial for the clinical course of the disease. Our objective was to prospectively investigate if 25-hydroxy-vitamin D (25-OH-D) levels are associated with exacerbation risk in MS in a study with frequent serum measurements.
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Profiling and identification of cerebrospinal fluid proteins in a rat EAE model of multiple sclerosis.
J. Proteome Res.
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The experimental autoimmune encephalomyelitis (EAE) model resembles certain aspects of multiple sclerosis (MScl), with common features such as motor dysfunction, axonal degradation, and infiltration of T-cells. We studied the cerebrospinal fluid (CSF) proteome in the EAE rat model to identify proteomic changes relevant for MScl disease pathology. EAE was induced in male Lewis rats by injection of myelin basic protein (MBP) together with complete Freunds adjuvant (CFA). An inflammatory control group was injected with CFA alone, and a nontreated group served as healthy control. CSF was collected at day 10 and 14 after immunization and analyzed by bottom-up proteomics on Orbitrap LC-MS and QTOF LC-MS platforms in two independent laboratories. By combining results, 44 proteins were discovered to be significantly increased in EAE animals compared to both control groups, 25 of which have not been mentioned in relation to the EAE model before. Lysozyme C1, fetuin B, T-kininogen, serum paraoxonase/arylesterase 1, glutathione peroxidase 3, complement C3, and afamin are among the proteins significantly elevated in this rat EAE model. Two proteins, afamin and complement C3, were validated in an independent sample set using quantitative selected reaction monitoring mass spectrometry. The molecular weights of the identified differentially abundant proteins indicated an increased transport across the blood-brain barrier (BBB) at the peak of the disease, caused by an increase in BBB permeability.
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The IL-7R? pathway is quantitatively and functionally altered in CD8 T cells in multiple sclerosis.
J. Immunol.
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The IL-7R? single nucleotide polymorphism rs6897932 is associated with an increased risk for multiple sclerosis (MS). IL-7R? is a promising candidate to be involved in autoimmunity, because it regulates T cell homeostasis, proliferation, and antiapoptotic signaling. However, the exact underlying mechanisms in the pathogenesis of MS are poorly understood. We investigated whether CD4 and CD8 lymphocyte subsets differed in IL-7R? expression and functionality in 78 MS patients compared with 59 healthy controls (HC). A significantly higher frequency of IL-7R?(+) CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7R? membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055). No correlation was found between the expression level or frequency of IL-7R?(+)CD8(+) and rs6897932 risk allele carriership. Upon IL-7 stimulation, MS patients had stronger STAT5 activation in CD8EM compared with HC. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B between MS and HC. Stainings of different lesions in postmortem MS brain material showed expression of IL-7 and CD8(+)IL-7R?(+) in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7R?(+) lymphocytes in lesion development. The intralesional production of IL-7 in combination with the lower threshold for IL-7-induced cytotoxicity in MS may enhance the pathogenicity of these CD8 T cells. This is of special interest in light of the established demyelinating and cytotoxic actions of granzyme A.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.