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1.  External Validation of a Prognostic Model for Seizure Recurrence Following a First Unprovoked Seizure and Implications for Driving 
PLoS ONE  2014;9(6):e99063.
Objective
In the United Kingdom and other European Union countries guidelines for driving following a first unprovoked seizure require the risk of another seizure in the next year to be less than 20%. Using data from one clinical trial, we previously developed a prognostic model to inform driving guidelines. The objective of this work is to externally validate our published model and demonstrate its generalisability.
Methods
A cohort of 620 people with a first unprovoked seizure was used to develop the original model which included variables for aetiology, first degree relative with epilepsy, seizures only while asleep, electroencephalogram, computed tomography or magnetic resonance scan result, and treatment policy. The validation cohorts consisted of 274 (United Kingdom), 305 (Italy), and 847 (Australia) people. The model was evaluated using discrimination and calibration methods. A covariate, missing from the Italian dataset, was handled via five imputation methods. Following external validation, the model was fitted to a pooled population comprising all validation datasets and the development dataset. The model was stratified by dataset.
Results
The model generalised relatively well. All methods of imputation performed fairly similarly. At six months, the risk of a seizure recurrence following a first ever seizure, based on the pooled datasets, is 15% (95% CI: (12% to 18%)) for patients who are treated immediately and 18% (95% CI: (15 to 21%)) otherwise. Individuals can be reliably stratified into risk groups according to the clinical factors included in the model.
Significance
Our prognostic model, used to inform driving regulations, has been validated and consequently has been proven as a valuable tool for predicting risk of seizure recurrence following a first seizure in people with various combinations of risk factors. Additionally, there is evidence to support one worldwide overall prognostic model for risk of second seizure following a first.
doi:10.1371/journal.pone.0099063
PMCID: PMC4053525  PMID: 24919184
2.  Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis 
Beecham, Ashley H | Patsopoulos, Nikolaos A | Xifara, Dionysia K | Davis, Mary F | Kemppinen, Anu | Cotsapas, Chris | Shahi, Tejas S | Spencer, Chris | Booth, David | Goris, An | Oturai, Annette | Saarela, Janna | Fontaine, Bertrand | Hemmer, Bernhard | Martin, Claes | Zipp, Frauke | D’alfonso, Sandra | Martinelli-Boneschi, Filippo | Taylor, Bruce | Harbo, Hanne F | Kockum, Ingrid | Hillert, Jan | Olsson, Tomas | Ban, Maria | Oksenberg, Jorge R | Hintzen, Rogier | Barcellos, Lisa F | Agliardi, Cristina | Alfredsson, Lars | Alizadeh, Mehdi | Anderson, Carl | Andrews, Robert | Søndergaard, Helle Bach | Baker, Amie | Band, Gavin | Baranzini, Sergio E | Barizzone, Nadia | Barrett, Jeffrey | Bellenguez, Céline | Bergamaschi, Laura | Bernardinelli, Luisa | Berthele, Achim | Biberacher, Viola | Binder, Thomas M C | Blackburn, Hannah | Bomfim, Izaura L | Brambilla, Paola | Broadley, Simon | Brochet, Bruno | Brundin, Lou | Buck, Dorothea | Butzkueven, Helmut | Caillier, Stacy J | Camu, William | Carpentier, Wassila | Cavalla, Paola | Celius, Elisabeth G | Coman, Irène | Comi, Giancarlo | Corrado, Lucia | Cosemans, Leentje | Cournu-Rebeix, Isabelle | Cree, Bruce A C | Cusi, Daniele | Damotte, Vincent | Defer, Gilles | Delgado, Silvia R | Deloukas, Panos | di Sapio, Alessia | Dilthey, Alexander T | Donnelly, Peter | Dubois, Bénédicte | Duddy, Martin | Edkins, Sarah | Elovaara, Irina | Esposito, Federica | Evangelou, Nikos | Fiddes, Barnaby | Field, Judith | Franke, Andre | Freeman, Colin | Frohlich, Irene Y | Galimberti, Daniela | Gieger, Christian | Gourraud, Pierre-Antoine | Graetz, Christiane | Graham, Andrew | Grummel, Verena | Guaschino, Clara | Hadjixenofontos, Athena | Hakonarson, Hakon | Halfpenny, Christopher | Hall, Gillian | Hall, Per | Hamsten, Anders | Harley, James | Harrower, Timothy | Hawkins, Clive | Hellenthal, Garrett | Hillier, Charles | Hobart, Jeremy | Hoshi, Muni | Hunt, Sarah E | Jagodic, Maja | Jelčić, Ilijas | Jochim, Angela | Kendall, Brian | Kermode, Allan | Kilpatrick, Trevor | Koivisto, Keijo | Konidari, Ioanna | Korn, Thomas | Kronsbein, Helena | Langford, Cordelia | Larsson, Malin | Lathrop, Mark | Lebrun-Frenay, Christine | Lechner-Scott, Jeannette | Lee, Michelle H | Leone, Maurizio A | Leppä, Virpi | Liberatore, Giuseppe | Lie, Benedicte A | Lill, Christina M | Lindén, Magdalena | Link, Jenny | Luessi, Felix | Lycke, Jan | Macciardi, Fabio | Männistö, Satu | Manrique, Clara P | Martin, Roland | Martinelli, Vittorio | Mason, Deborah | Mazibrada, Gordon | McCabe, Cristin | Mero, Inger-Lise | Mescheriakova, Julia | Moutsianas, Loukas | Myhr, Kjell-Morten | Nagels, Guy | Nicholas, Richard | Nilsson, Petra | Piehl, Fredrik | Pirinen, Matti | Price, Siân E | Quach, Hong | Reunanen, Mauri | Robberecht, Wim | Robertson, Neil P | Rodegher, Mariaemma | Rog, David | Salvetti, Marco | Schnetz-Boutaud, Nathalie C | Sellebjerg, Finn | Selter, Rebecca C | Schaefer, Catherine | Shaunak, Sandip | Shen, Ling | Shields, Simon | Siffrin, Volker | Slee, Mark | Sorensen, Per Soelberg | Sorosina, Melissa | Sospedra, Mireia | Spurkland, Anne | Strange, Amy | Sundqvist, Emilie | Thijs, Vincent | Thorpe, John | Ticca, Anna | Tienari, Pentti | van Duijn, Cornelia | Visser, Elizabeth M | Vucic, Steve | Westerlind, Helga | Wiley, James S | Wilkins, Alastair | Wilson, James F | Winkelmann, Juliane | Zajicek, John | Zindler, Eva | Haines, Jonathan L | Pericak-Vance, Margaret A | Ivinson, Adrian J | Stewart, Graeme | Hafler, David | Hauser, Stephen L | Compston, Alastair | McVean, Gil | De Jager, Philip | Sawcer, Stephen | McCauley, Jacob L
Nature genetics  2013;45(11):10.1038/ng.2770.
Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 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 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 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 catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.
doi:10.1038/ng.2770
PMCID: PMC3832895  PMID: 24076602
3.  Oxidation Enhances Human Serum Albumin Thermal Stability and Changes the Routes of Amyloid Fibril Formation 
PLoS ONE  2014;9(1):e84552.
Oxidative damages are linked to several aging-related diseases and are among the chemical pathways determining protein degradation. Specifically, interplay of oxidative stress and protein aggregation is recognized to have a link to the loss of cellular function in pathologies like Alzheimer's and Parkinson's diseases. Interaction between protein and reactive oxygen species may indeed induce small changes in protein structure and lead to the inhibition/modification of protein aggregation process, potentially determining the formation of species with different inherent toxicity. Understanding the temperate relationship between these events can be of utmost importance in unraveling the molecular basis of neurodegeneration. In this work, we investigated the effect of hydrogen peroxide oxidation on Human Serum Albumin (HSA) structure, thermal stability and aggregation properties. In the selected conditions, HSA forms fibrillar aggregates, while the oxidized protein undergoes aggregation via new routes involving, in different extents, specific domains of the molecule. Minute variations due to oxidation of single residues affect HSA tertiary structure leading to protein compaction, increased thermal stability, and reduced association propensity.
doi:10.1371/journal.pone.0084552
PMCID: PMC3885593  PMID: 24416244
4.  External validation of a prognostic index 
Trials  2013;14(Suppl 1):P43.
doi:10.1186/1745-6215-14-S1-P43
PMCID: PMC3981617
5.  A reliability study of colour-Doppler sonography for the diagnosis of chronic cerebrospinal venous insufficiency shows low inter-rater agreement 
BMJ Open  2013;3(11):e003508.
Objective
Chronic cerebrospinal venous insufficiency (CCSVI) has been extremely variable, associated with multiple sclerosis in colour-Doppler sonographic studies. We aimed to evaluate inter-rater agreement in a colour-Doppler sonography venous examination.
Design
Inter-rater agreement study.
Setting
First-referral multiple sclerosis centre.
Participants
38 patients with multiple sclerosis and 55 age-matched (±5 years) controls.
Intervention
Sonography was carried out in accordance with Zamboni’s five criteria by eight sonographers with different expertise, blinded to the status of cases and controls. Each participant was evaluated by two operators.
Primary and secondary outcome measures
Inter-rater agreement was measured through the κ statistics and the intraclass correlation coefficient.
Results
The agreement was no higher than chance for criterion 2—reflux in the deep cerebral veins (κ=−0.02) and criterion 4—flow not Doppler detectable in one or both the internal jugular veins (IJVs) or vertebral veins (VVs; −0.09). It was substantially low for criterion 1—reflux in the IJVs and/or VVs (0.29), criterion 3—IJV stenosis or malformations (0.23) and criterion 5—absence of IJV diameter increase when passing from the sitting to the supine position (0.22). The κ value for CCSVI as a whole was 0.20 (95% confidence limit −0.01 to 0.42). Intraclass correlation coefficients for the measure of cross-sectional area ranged from 0.05 to 0.25. Inter-rater agreement was low for CCSVI experts (κ=0.24; −0.11 to 0.59) and non-experts (0.20; −0.33 to 0.73); neurologists (0.21; −0.06 to 0.47) and non-neurologists (0.18; −0.20 to 0.56); cases (0.19; −0.14 to 0.52) and controls (0.21; −0.08 to 0.49). Zamboni-trained neurosonographers ascertained CCSVI more frequently than the non-trained neurosonographers.
Conclusions
Agreement was unsatisfactory for the diagnosis of CCSVI as a whole, for each of its five criteria and according to the different subgroups. Standardisation of the method is urgently needed prior to its further application in studies of patients with multiple sclerosis or other neurological diseases.
doi:10.1136/bmjopen-2013-003508
PMCID: PMC3831103  PMID: 24240139
6.  Unlocked Concanavalin A Forms Amyloid-like Fibrils from Coagulation of Long-lived “Crinkled” Intermediates 
PLoS ONE  2013;8(7):e68912.
Understanding the early events during amyloid aggregation processes is crucial to single out the involved molecular mechanisms and for designing ad hoc strategies to prevent and reverse amyloidogenic disorders. Here, we show that, in conditions in which the protein is positively charged and its conformational flexibility is enhanced, Concanavalin A leads to fibril formation via a non-conventional aggregation pathway. Using a combination of light scattering, circular dichroism, small angle X-ray scattering, intrinsic (Tryptophan) and extrinsic (ANS) fluorescence and confocal and 2-photon fluorescence microscopy we characterize the aggregation process as a function of the temperature. We highlight a multi-step pathway with the formation of an on-pathway long-lived intermediate and a subsequent coagulation of such “crinkled” precursors into amyloid-like fibrils. The process results in a temperature-dependent aggregation-coagulation pathway, with the late phase of coagulation determined by the interplay between hydrophobic and electrostatic forces. Our data provide evidence for the complex aggregation pathway for a protein with a highly flexible native conformation. We demonstrate the possibility to generate a long-lived intermediate whose proportion and occurrence are easily tunable by experimental parameters (i.e. temperature). As a consequence, in the case of aggregation processes developing through well-defined energy barriers, our results can open the way to new strategies to induce more stable in vitro on-pathway intermediate species through a minute change in the initial conformational flexibility of the protein. This will allow isolating and experimentally studying such transient species, often indicated as relevant in neurodegenerative diseases, both in terms of structural and cytotoxic properties.
doi:10.1371/journal.pone.0068912
PMCID: PMC3712988  PMID: 23874809
7.  Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients 
PLoS ONE  2013;8(6):e64408.
Objective
to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.
Methods
We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.
Results
HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1–2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09–1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB− (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10−7) outside the HLA region (65 Mb).
Discussion
genetic factors predispose to the development of OCB.
doi:10.1371/journal.pone.0064408
PMCID: PMC3681825  PMID: 23785401
8.  Reliability of the modified Rankin Scale applied by telephone 
Neurology International  2013;5(1):e2.
We aimed to evaluate the reliability of the modified Rankin Scale applied telephonically compared with face-to-face assessment in clinically stable hospitalized patients with acute stroke. One hundred and thirty-one patients were interviewed twice by 2 certified nurses (unstructured interview). Half of the patients were randomized to be interviewed by telephone followed by the face-to-face assessment, and half in the reverse order. The median value of the modified Rankin Scale score was 4 (first to third interquartile range 3–5) by telephone as well as by face-to-face assessment (P=0.8). The weighted kappa between the two methods was 0.82 (95% confidence interval: 0.77–0.88). Sensitivity of the telephone assessment was lower for scores 2 and 3 (17% and 46%, respectively) than for the other scores (range 67–90%). Telephone assessment of stroke disability with the modified Rankin Scale is reliable in comparison to direct face-to-face assessment.
doi:10.4081/ni.2013.e2
PMCID: PMC3661983  PMID: 23717781
stroke; modified Rankin Scale; telephone; reliability; interview.
9.  Chronic Cerebrospinal Venous Insufficiency Is Not Associated with Multiple Sclerosis and Its Severity: A Blind-Verified Study 
PLoS ONE  2013;8(2):e56031.
Background
Chronic Cerebrospinal Venous Insufficiency (CCSVI) has been associated with multiple sclerosis (MS) with a risk ranging from as high as two-hundred-fold to a protective effect. However, not all studies were blinded, and the efficacy of blinding was never assessed.
Objective
To evaluate the association of CCSVI with MS in a cross-sectional blinded study and look for any association of CCSVI with the severity of MS.
Methodology/Principal Findings
The Echo-color Doppler examination was carried out in accordance with Zamboni’s five criteria in 68 consecutive MS patients and 68 healthy controls, matched by gender and age (±5 years). Four experienced neurosonologists, blinded to the status of cases and controls, performed the study and were then asked to guess the status (case or control) of each participant. The number of positive CCSVI criteria was similar in the two groups. CCSVI, defined as the presence of two or more criteria, was detected in 21 cases (30.9%) and 23 controls (33.8%), with an OR of 0.9 (95%CL = 0.4–1.8, p = 0.71). The prevalence of CCSVI was related to age in cases (OR increasing from 0.2 to 1.4), but not in controls. CCSVI positive (N = 21) and negative (N = 47) MS patients were similar in clinical type, age at disease onset, disability, and fatigue. Disease duration was longer (16.5±9.8 years) in CCSVI positive than negative patients (11.5±7.4; p = 0.04). The operators correctly guessed 34/68 cases (50%) and 45/68 controls (66%) (p = 0.06), indicating a different success of blinding.
Conclusions/Significance
CCSVI was not associated with MS itself, nor its severity. We cannot rule out the possibility that CCSVI is a consequence of MS or of aging. Blinding of sonographers is a key point in studying CCSVI and its verification should be a requisite of future studies.
doi:10.1371/journal.pone.0056031
PMCID: PMC3572163  PMID: 23418501
10.  The Impact of Osteopontin Gene Variations on Multiple Sclerosis Development and Progression 
Osteopontin is a proinflammatory molecule, modulating TH1 and TH17 responses. Several reports suggest its involvement in multiple sclerosis (MS) pathogenesis. We previously reported that OPN gene variations at the 3′ end are a predisposing factor for MS development and evolution. In this paper, we extended our analysis to a gene variation at the 5′ end on the −156G > GG single nucleotide polymorphism (SNP) and replicated our previous findings at the 3′ end on the +1239A > C SNP. We found that only +1239A > C SNP displayed a statistically significant association with MS development, but both +1239A > C and −156G > GG had an influence on MS progression, since patients homozygous for both +1239A and −156GG alleles displayed slower progression of disability and slower switch to secondary progression than those carrying +1239C and/or −156G and those homozygous for +1239A only. Moreover, patients homozygous for +1239A also displayed a significantly lower relapse rate than those carrying +1239C, which is in line with the established role of OPN in MS relapses.
doi:10.1155/2012/212893
PMCID: PMC3447190  PMID: 23008732
11.  Polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis 
BMC Medical Genetics  2012;13:70.
Background
Iron involvement/imbalance is strongly suspected in multiple sclerosis (MS) etiopathogenesis, but its role is quite debated. Iron deposits encircle the veins in brain MS lesions, increasing local metal concentrations in brain parenchyma as documented by magnetic resonance imaging and histochemical studies. Conversely, systemic iron overload is not always observed. We explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes in MS patients.
Methods
By the pyrosequencing technique, we investigated 414 MS cases [Relapsing-remitting (RR), n=273; Progressive, n=141, of which: Secondary (SP), n=103 and Primary (PP), n=38], and 414 matched healthy controls. Five SNPs in 4 genes were assessed: hemochromatosis (HFE: C282Y, H63D), ferroportin (FPN1: -8CG), hepcidin (HEPC: -582AG), and transferrin (TF: P570S).
Results
The FPN1-8GG genotype was overrepresented in the whole MS population (OR=4.38; 95%CI, 1.89-10.1; P<0.0001) and a similar risk was found among patients with progressive forms. Conversely, the HEPC -582GG genotype was overrepresented only in progressive forms (OR=2.53; 95%CI, 1.34-4.78; P=0.006) so that SP and PP versus RR yielded significant outputs (P=0.009). For almost all SNPs, MS disability score (EDSS), severity score (MSSS), as well as progression index (PI) showed a significant increase when comparing homozygotes versus individuals carrying other genotypes: HEPC -582GG (EDSS, 4.24±2.87 vs 2.78±2.1; P=0.003; MSSS, 5.6±3.06 vs 3.79±2.6; P=0.001); FPN1-8GG (PI, 1.11±2.01 vs 0.6±1.31; P=0.01; MSSS, 5.08±2.98 vs 3.85±2.8; P=0.01); HFE 63DD (PI, 1.63±2.6 vs 0.6±0.86; P=0.009). Finally, HEPC -582G-carriers had a significantly higher chance to switch into the progressive form (HR=3.55; 1.83-6.84; log-rank P=0.00006).
Conclusions
Polymorphisms in the genes coding for iron binding and transporting proteins, in the presence of local iron overload, might be responsible for suboptimal iron handling. This might account for the significant variability peculiar to MS phenotypes, particularly affecting MS risk and progression paving the way for personalized pharmacogenetic applications in the clinical practice.
doi:10.1186/1471-2350-13-70
PMCID: PMC3490944  PMID: 22883388
12.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis 
Sawcer, Stephen | Hellenthal, Garrett | Pirinen, Matti | Spencer, Chris C.A. | Patsopoulos, Nikolaos A. | Moutsianas, Loukas | Dilthey, Alexander | Su, Zhan | Freeman, Colin | Hunt, Sarah E. | Edkins, Sarah | Gray, Emma | Booth, David R. | Potter, Simon C. | Goris, An | Band, Gavin | Oturai, Annette Bang | Strange, Amy | Saarela, Janna | Bellenguez, Céline | Fontaine, Bertrand | Gillman, Matthew | Hemmer, Bernhard | Gwilliam, Rhian | Zipp, Frauke | Jayakumar, Alagurevathi | Martin, Roland | Leslie, Stephen | Hawkins, Stanley | Giannoulatou, Eleni | D’alfonso, Sandra | Blackburn, Hannah | Boneschi, Filippo Martinelli | Liddle, Jennifer | Harbo, Hanne F. | Perez, Marc L. | Spurkland, Anne | Waller, Matthew J | Mycko, Marcin P. | Ricketts, Michelle | Comabella, Manuel | Hammond, Naomi | Kockum, Ingrid | McCann, Owen T. | Ban, Maria | Whittaker, Pamela | Kemppinen, Anu | Weston, Paul | Hawkins, Clive | Widaa, Sara | Zajicek, John | Dronov, Serge | Robertson, Neil | Bumpstead, Suzannah J. | Barcellos, Lisa F. | Ravindrarajah, Rathi | Abraham, Roby | Alfredsson, Lars | Ardlie, Kristin | Aubin, Cristin | Baker, Amie | Baker, Katharine | Baranzini, Sergio E. | Bergamaschi, Laura | Bergamaschi, Roberto | Bernstein, Allan | Berthele, Achim | Boggild, Mike | Bradfield, Jonathan P. | Brassat, David | Broadley, Simon A. | Buck, Dorothea | Butzkueven, Helmut | Capra, Ruggero | Carroll, William M. | Cavalla, Paola | Celius, Elisabeth G. | Cepok, Sabine | Chiavacci, Rosetta | Clerget-Darpoux, Françoise | Clysters, Katleen | Comi, Giancarlo | Cossburn, Mark | Cournu-Rebeix, Isabelle | Cox, Mathew B. | Cozen, Wendy | Cree, Bruce A.C. | Cross, Anne H. | Cusi, Daniele | Daly, Mark J. | Davis, Emma | de Bakker, Paul I.W. | Debouverie, Marc | D’hooghe, Marie Beatrice | Dixon, Katherine | Dobosi, Rita | Dubois, Bénédicte | Ellinghaus, David | Elovaara, Irina | Esposito, Federica | Fontenille, Claire | Foote, Simon | Franke, Andre | Galimberti, Daniela | Ghezzi, Angelo | Glessner, Joseph | Gomez, Refujia | Gout, Olivier | Graham, Colin | Grant, Struan F.A. | Guerini, Franca Rosa | Hakonarson, Hakon | Hall, Per | Hamsten, Anders | Hartung, Hans-Peter | Heard, Rob N. | Heath, Simon | Hobart, Jeremy | Hoshi, Muna | Infante-Duarte, Carmen | Ingram, Gillian | Ingram, Wendy | Islam, Talat | Jagodic, Maja | Kabesch, Michael | Kermode, Allan G. | Kilpatrick, Trevor J. | Kim, Cecilia | Klopp, Norman | Koivisto, Keijo | Larsson, Malin | Lathrop, Mark | Lechner-Scott, Jeannette S. | Leone, Maurizio A. | Leppä, Virpi | Liljedahl, Ulrika | Bomfim, Izaura Lima | Lincoln, Robin R. | Link, Jenny | Liu, Jianjun | Lorentzen, Åslaug R. | Lupoli, Sara | Macciardi, Fabio | Mack, Thomas | Marriott, Mark | Martinelli, Vittorio | Mason, Deborah | McCauley, Jacob L. | Mentch, Frank | Mero, Inger-Lise | Mihalova, Tania | Montalban, Xavier | Mottershead, John | Myhr, Kjell-Morten | Naldi, Paola | Ollier, William | Page, Alison | Palotie, Aarno | Pelletier, Jean | Piccio, Laura | Pickersgill, Trevor | Piehl, Fredrik | Pobywajlo, Susan | Quach, Hong L. | Ramsay, Patricia P. | Reunanen, Mauri | Reynolds, Richard | Rioux, John D. | Rodegher, Mariaemma | Roesner, Sabine | Rubio, Justin P. | Rückert, Ina-Maria | Salvetti, Marco | Salvi, Erika | Santaniello, Adam | Schaefer, Catherine A. | Schreiber, Stefan | Schulze, Christian | Scott, Rodney J. | Sellebjerg, Finn | Selmaj, Krzysztof W. | Sexton, David | Shen, Ling | Simms-Acuna, Brigid | Skidmore, Sheila | Sleiman, Patrick M.A. | Smestad, Cathrine | Sørensen, Per Soelberg | Søndergaard, Helle Bach | Stankovich, Jim | Strange, Richard C. | Sulonen, Anna-Maija | Sundqvist, Emilie | Syvänen, Ann-Christine | Taddeo, Francesca | Taylor, Bruce | Blackwell, Jenefer M. | Tienari, Pentti | Bramon, Elvira | Tourbah, Ayman | Brown, Matthew A. | Tronczynska, Ewa | Casas, Juan P. | Tubridy, Niall | Corvin, Aiden | Vickery, Jane | Jankowski, Janusz | Villoslada, Pablo | Markus, Hugh S. | Wang, Kai | Mathew, Christopher G. | Wason, James | Palmer, Colin N.A. | Wichmann, H-Erich | Plomin, Robert | Willoughby, Ernest | Rautanen, Anna | Winkelmann, Juliane | Wittig, Michael | Trembath, Richard C. | Yaouanq, Jacqueline | Viswanathan, Ananth C. | Zhang, Haitao | Wood, Nicholas W. | Zuvich, Rebecca | Deloukas, Panos | Langford, Cordelia | Duncanson, Audrey | Oksenberg, Jorge R. | Pericak-Vance, Margaret A. | Haines, Jonathan L. | Olsson, Tomas | Hillert, Jan | Ivinson, Adrian J. | De Jager, Philip L. | Peltonen, Leena | Stewart, Graeme J. | Hafler, David A. | Hauser, Stephen L. | McVean, Gil | Donnelly, Peter | Compston, Alastair
Nature  2011;476(7359):214-219.
Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.
doi:10.1038/nature10251
PMCID: PMC3182531  PMID: 21833088
multiple sclerosis; GWAS; genetics
13.  No evidence of association of the rare nsSNP rs35667974 in IFIH1 with Multiple Sclerosis 
Journal of neuroimmunology  2010;221(1-2):112-114.
Studies suggest that different autoimmune diseases share a common genetic background, in particular, an overlap between multiple sclerosis (MS) and type 1 diabetes (T1D) susceptibility loci has been established. A recent study found that four rare SNPs in the IFIH1 (interferon induced with helicase C domain 1) were significantly associated with T1D.
To establish if these SNPs were also involved in MS susceptibility, we chose to examine the nonsynonymous SNP rs35667974/Ile923Val which displayed the strongest effect in T1D and was also shown to lead to a loss of IFIH1 function in an in vitro study. We have performed the first association study to test if this rare variant is involved in MS susceptibility in a very large sample consisting of 3037 MS patients and 10657 healthy controls recruited from Italy and the UK. This study has 99% power to demonstrate an association at the 5% level with this rare variant. Our analysis shows that the nsSNP rs35667974/Ile923Val does not have a role in susceptibility to MS.
doi:10.1016/j.jneuroim.2010.01.005
PMCID: PMC2854891  PMID: 20116863
Multiple Sclerosis; genetics; IFIH1
14.  Genetic Association and Altered Gene Expression of Mir-155 in Multiple Sclerosis Patients 
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system characterized by chronic inflammation, demyelination, and axonal damage. As microRNA (miRNA)-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response, miRNA deregulation may result in defects in immune tolerance. In this frame, we sought to explore the possible involvement of miRNAs in MS pathogenesis by monitoring the differential expression of 22 immunity-related miRNAs in peripheral blood mononuclear cells of MS patients and healthy controls, by using a microbead-based technology. Three miRNAs resulted >2 folds up-regulated in MS vs controls, whereas none resulted down-regulated. Interestingly, the most up-regulated miRNA (mir-155; fold change = 3.30; P = 0.013) was previously reported to be up-regulated also in MS brain lesions. Mir-155 up-regulation was confirmed by qPCR experiments. The role of mir-155 in MS susceptibility was also investigated by genotyping four single nucleotide polymorphisms (SNPs) mapping in the mir-155 genomic region. A haplotype of three SNPs, corresponding to a 12-kb region encompassing the last exon of BIC (the B-cell Integration Cluster non-coding RNA, from which mir-155 is processed), resulted associated with the disease status (P = 0.035; OR = 1.36, 95% CI = 1.05–1.77), suggesting that this locus strongly deserves further investigations.
doi:10.3390/ijms12128695
PMCID: PMC3257096  PMID: 22272099
multiple sclerosis; miRNA; expression profile; mir-155; association analysis
15.  Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population 
PLoS ONE  2010;5(2):e9287.
Background
Albeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis.
Methodology/Principal Findings
Immunoproteasomes and PA28-αβ regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP111–119.
Conclusion/Significance
The immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLA-A*02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis.
doi:10.1371/journal.pone.0009287
PMCID: PMC2823778  PMID: 20174631
16.  Stroke in neurological services in Italy 
Neurology International  2009;1(1):e8.
To assess the stroke workload of Italian neurological services and to correlate it with indicators of each hospital’s emergency setting. A semi-structured questionnaire was sent to the 220 neurology units (NU) located in hospitals with an emergency room (ER) (155 responders, 71%). Stroke was the most common discharge diagnosis (29%) (273 patients/year/NU on average) and condition requiring consultation in ER (28%). A stroke unit was available in 28% of NU, bedside monitors in 45%, a 24 hour/day and 7 day/week (24/7) CT scan in 90%, a 24/7-MRI in 32%, a 24/7 on-duty neurologist in 36%. The stroke workload was correlated only with the number of ER consultations per year, and marginally to the presence of stroke units and the number of monitored beds in the univariate, but not in the multivariate analysis. The stroke workload in Italian NU is very high, but is largely unrelated to their structural and functional characteristics, in contrast with the international indications requiring several essential criteria for the best hospital management of all stroke patients.
doi:10.4081/ni.2009.e8
PMCID: PMC3093231  PMID: 21577366
stroke; neurology services; neurologist; emergency service hospitals; workload.

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