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1. Four-year safety and effectiveness data from patients with multiple sclerosis treated with fingolimod: The Spanish GILENYA registry

Author: Meca-Lallana, J. E., Oreja-Guevara, C., Muñoz, D., Olascoaga, J., Pato, A., Ramió-Torrentà, L., Meca-Lallana, Virginia, Hernández, M. A., Marzo, M. E., Álvarez- Cermeño, J. C., Rodríguez-Antigüedad, A., Montalban, Xavier, Fernández, O., Universitat Autònoma de Barcelona. Departament de Medicina, Institut Català de la Salut, [Meca-Lallana JE] Neurology Department, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain. [Oreja-Guevara C] Neurology Department, Hospital Clínico San Carlos, Madrid, Spain. [Muñoz D] Neurology Department, Hospital Xeral de Vigo, Vigo, Spain. [Olascoaga J] Neurology Department, Hospital Universitario Donostia, San Sebastián, Spain. [Pato A] Neurology Department, Hospital Povisa, Vigo, Spain. [Ramió-Torrentà L] Neurology Department, Hospital Universitari de Girona Dr. Josep Trueta, IDIBGI, Medical Sciences Department, University of Girona, Girona, Spain. [Montalbán X] Servei de Neurologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Westerdijk Fungal Biodiversity Institute, and Westerdijk Fungal Biodiversity Institute - Evolutionary Phytopathology
Subjects: Male, European People, Medicaments immunosupressors - Ús terapèutic - Efectes secundaris, Spanish People, Drug research and development, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Biochemistry, Medical Conditions, Clinical trials, Natalizumab, Recurrence, Medicine and Health Sciences, Ethnicities, Registries, Hispanic People, education.field_of_study, Multidisciplinary, Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [DISEASES], Neurodegenerative Diseases, Middle Aged, Fingolimod, Phase III clinical investigation, Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Immunologic Factors::Immunosuppressive Agents [CHEMICALS AND DRUGS], Treatment Outcome, Neurology, Research Design, enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple [ENFERMEDADES], Medicine, Female, Immunosuppressive Agents, Research Article, medicine.drug, Adult, medicine.medical_specialty, Multiple Sclerosis, Clinical Research Design, Science, Urinary system, Immunology, Population, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Autoimmune Diseases, Signs and Symptoms, Adverse Reactions, Lymphopenia, Internal medicine, medicine, Humans, Glatiramer acetate, education, Adverse effect, Retrospective Studies, Pharmacology, Fingolimod Hydrochloride, business.industry, Multiple sclerosis, Biology and Life Sciences, Proteins, diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], medicine.disease, Demyelinating Disorders, Research and analysis methods, Spain, People and Places, Lesions, Avaluació de resultats (Assistència sanitària), Clinical Immunology, Population Groupings, Observational study, Interferons, Adverse Events, Clinical Medicine, business, Esclerosi múltiple - Tractament, acciones y usos químicos::acciones farmacológicas::efectos fisiológicos de los fármacos::factores inmunitarios::inmunosupresores [COMPUESTOS QUÍMICOS Y DROGAS]
Abstract: Esclerosis múltiple; Reacciones adversas; Infecciones respiratorias Esclerosi múltiple; Reaccions adverses; Infeccions respiratòries Multiple sclerosis; Adverse reactions; Respiratory infections Objective To describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. Methods An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. Results Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p
Published: 2021

2. Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack

Author: Chaturvedi, S, Zivin, J, Breazna, A, Amarenco, P, Callahan, A, Goldstein, LB, Hennerici, M, Sillesen, H, Rudolph, A, Welch, MA, SPARCL Investigators, Crimmins D, Davis S, Dimmitt S, Donnan G, Frayne J, Freilich D, Zagami A, Mikocki J, Schmidauer C, Schmidt R, De Bleecker J, Deceuninck F, Tack P, Thijs V, Gomes Fernandes J, Beaudry M, Cote R, Hoyte K, Lebrun LH, Mackey A, Sahlas D, Selchen D, Shuaib A, Spence JD, Teal P, Winger M, Matamala G, Cifkova R, Kalita Z, Rektor I, Rosolova H, Stipal R, Vaclavik D, Boysen G, Klingenberg H, Iversen, Sillesen H, Hillbom M, Kaste M, Numminen H, Pilke A, Salmivaara A, Sivenius J, Alamowitch S, Amarenco P, Boulliat J, De Broucker T, Chollet F, Mahagne MH, Milandre L, Moulin T, Bogdahn U, Diener HC, Dichgans M, Glahn J, Haberl R, Harms L, Hennerici MG, Knecht S, Kroczek G, Lichy C, Sander D, Schneider D, Kazis A, Karageorgiou C, Milonas I, Stathis P, Vogiatzoglou D, Bornstein N, Honigman S, Lampl Y, Streifler J, Capurso A, Comi G, Gandolfo C, Poloni M, Senin U, Rangel Guerra R, Boon AM, De Keyser JH, De Kort PL, Haas JA, Kamphuis DJ, Koudstaal PJ, Anderson N, Scott R, Singh G, Czlonkowska A, Drozdowski W, Gralewski Z, Kozubski W, Kuczynska Zardzewialy A, Podemski R, Stelmasiak Z, Szczudlik A, Da Costa Correia C, Ferro J, Salgueiro e. Cunha L, Lietava J, Raslova K, Carr J, Gardiner J, Kruger A, Alvarez Sabin J, Chamorro A, Diez Tejedor E, Fernández O, Trejo Gabriel y. Galán J, González Marcos J, Egido Herrero J, Jiménez Martínez M, Lago Martin A, Mostacero Miguel E, Vivancos Mora J, Moltó J, Viguera Romero J, Cuartero Rodriguez E, Rodriguez F, Serena J, Laska AC, Leijd B, Strand T, Terent A, Waegner A, Wallén T, Baumgartner R, Bogousslavsky J, Hungerbühler H, Lyrer P, Mattle H, Bath PM, Ekpo EB, Freeman A, Lees KR, MacLeod MJ, MacWalter RS, Sharma AK, Shetty HG, Albers G, Altafullah I, Benavente O, Book D, Broderick J, Callahan A. 3rd, Calder C, Carlini W, Chaturvedi S, Chippendale T, Clark W, Coull B, Davis P, Devlin T, Dick A, Dooneief G, Duff R, Estronza N, Forteza A, Frankel M, Frey J, Friday G, Graham G, Goldstein J, Hammer M, Harris J, Harper W, Hendin B, Hendin D, Hinton R, Hollander J, Hughes R, Kasner S, Kent T, Kim L, Kirshner H, LaMonte M, Ledbetter L, Lee Kwen P, Levin K, Libman R, Matlock J, McDowell P, McGee F. Jr, Meyer B, Minagar A, Moussouttas M, Munson R, Nash M, Nassief A, Orr S, Ratinov G, Salanga V, Silliman S, Singer R, Smith D, Sullivan H, Tietjen G, Thaler D, Tuchman M, Uskavitch D, Verro P, Vicari R, Weinstein R, Wilterdink J, Zweifler R, De Bastos M., FERRARESE, CARLO, Chaturvedi, S, Zivin, J, Breazna, A, Amarenco, P, Callahan, A, Goldstein, L, Hennerici, M, Sillesen, H, Rudolph, A, Welch, M, Sparcl, I, Crimmins, D, Davis, S, Dimmitt, S, Donnan, G, Frayne, J, Freilich, D, Zagami, A, Mikocki, J, Schmidauer, C, Schmidt, R, De Bleecker, J, Deceuninck, F, Tack, P, Thijs, V, Gomes Fernandes, J, Beaudry, M, Cote, R, Hoyte, K, Lebrun, L, Mackey, A, Sahlas, D, Selchen, D, Shuaib, A, Spence, J, Teal, P, Winger, M, Matamala, G, Cifkova, R, Kalita, Z, Rektor, I, Rosolova, H, Stipal, R, Vaclavik, D, Boysen, G, Klingenberg, H, Iversen, Hillbom, M, Kaste, M, Numminen, H, Pilke, A, Salmivaara, A, Sivenius, J, Alamowitch, S, Boulliat, J, De Broucker, T, Chollet, F, Mahagne, M, Milandre, L, Moulin, T, Bogdahn, U, Diener, H, Dichgans, M, Glahn, J, Haberl, R, Harms, L, Knecht, S, Kroczek, G, Lichy, C, Sander, D, Schneider, D, Kazis, A, Karageorgiou, C, Milonas, I, Stathis, P, Vogiatzoglou, D, Bornstein, N, Honigman, S, Lampl, Y, Streifler, J, Capurso, A, Comi, G, Ferrarese, C, Gandolfo, C, Poloni, M, Senin, U, Rangel Guerra, R, Boon, A, De Keyser, J, De Kort, P, Haas, J, Kamphuis, D, Koudstaal, P, Anderson, N, Scott, R, Singh, G, Czlonkowska, A, Drozdowski, W, Gralewski, Z, Kozubski, W, Kuczynska Zardzewialy, A, Podemski, R, Stelmasiak, Z, Szczudlik, A, Da Costa Correia, C, Ferro, J, Salgueiro e., C, Lietava, J, Raslova, K, Carr, J, Gardiner, J, Kruger, A, Alvarez Sabin, J, Chamorro, A, Diez Tejedor, E, Fernández, O, Trejo Gabriel y., G, González Marcos, J, Egido Herrero, J, Jiménez Martínez, M, Lago Martin, A, Mostacero Miguel, E, Vivancos Mora, J, Moltó, J, Viguera Romero, J, Cuartero Rodriguez, E, Rodriguez, F, Serena, J, Laska, A, Leijd, B, Strand, T, Terent, A, Waegner, A, Wallén, T, Baumgartner, R, Bogousslavsky, J, Hungerbühler, H, Lyrer, P, Mattle, H, Bath, P, Ekpo, E, Freeman, A, Lees, K, Macleod, M, Macwalter, R, Sharma, A, Shetty, H, Albers, G, Altafullah, I, Benavente, O, Book, D, Broderick, J, Callahan A., 3, Calder, C, Carlini, W, Chippendale, T, Clark, W, Coull, B, Davis, P, Devlin, T, Dick, A, Dooneief, G, Duff, R, Estronza, N, Forteza, A, Frankel, M, Frey, J, Friday, G, Graham, G, Goldstein, J, Hammer, M, Harris, J, Harper, W, Hendin, B, Hendin, D, Hinton, R, Hollander, J, Hughes, R, Kasner, S, Kent, T, Kim, L, Kirshner, H, Lamonte, M, Ledbetter, L, Lee Kwen, P, Levin, K, Libman, R, Matlock, J, Mcdowell, P, McGee F., J, Meyer, B, Minagar, A, Moussouttas, M, Munson, R, Nash, M, Nassief, A, Orr, S, Ratinov, G, Salanga, V, Silliman, S, Singer, R, Smith, D, Sullivan, H, Tietjen, G, Thaler, D, Tuchman, M, Uskavitch, D, Verro, P, Vicari, R, Weinstein, R, Wilterdink, J, Zweifler, R, and De Bastos, M
Subjects: Male, medicine.medical_specialty, Atorvastatin, medicine.medical_treatment, Coronary Disease, Pyrrole, Revascularization, Risk Assessment, Cohort Studies, Coronary artery disease, Internal medicine, Anticholesteremic Agent, Myocardial Revascularization, medicine, Clinical endpoint, Humans, Pyrroles, Age Factor, cardiovascular diseases, Stroke, Aged, Cerebral infarction, business.industry, Anticholesteremic Agents, Hazard ratio, Age Factors, Cholesterol, LDL, Middle Aged, medicine.disease, Surgery, Heptanoic Acid, Heptanoic Acids, Ischemic Attack, Transient, Cohort, Cardiology, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitor, Neurology (clinical), Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cohort Studie, business, Human, medicine.drug
Abstract: BACKGROUND: It is unclear whether patients age 65 years and over with a recent stroke or TIA benefit from statin treatment to a similar degree as younger patients. METHODS: The 4,731 patient cohort in the SPARCL study was divided into an elderly group (65 and over) and a younger group. The primary endpoint (fatal or nonfatal stroke) and secondary endpoints were analyzed, with calculation of the hazard ratio (HR) and p values from a Cox regression model. RESULTS: There were 2,249 patients in the elderly group and 2,482 in the younger group. The baseline LDL (133 mg/dL) and total cholesterol were comparable in the two groups. The elderly and younger groups had a 61.4 mg/dL and 58.7 mg/dL decrease in mean LDL during the trial. The primary endpoint was reduced by 26% in younger patients (HR 0.74, 0.57-0.96, p = 0.02) and by 10% in elderly subjects (HR 0.90, 0.73-1.11, p = 0.33). A test of heterogeneity for a treatment-age interaction was not significant (p = 0.52). The risk of stroke or TIA (HR 0.79, p = 0.01), major coronary events (HR 0.68, p = 0.035), any coronary heart disease event (HR 0.61, p = 0.0006), and revascularization procedures (HR 0.55, p = 0.0005) was reduced in the elderly group. CONCLUSIONS: There was no heterogeneity in the stroke reduction seen with atorvastatin in the elderly and younger groups. Cardiac events and revascularization procedures were also lower in both the elderly and younger subgroups treated with atorvastatin. These results support the use of atorvastatin in elderly patients with recent stroke or TIA.
Published: 2008
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3. Gene therapy with mesenchymal stem cells expressing IFN-ß ameliorates neuroinflammation in experimental models of multiple sclerosis

Author: Marin‐Bañasco, C., Benabdellah, K., Melero-Jerez, Carolina, Oliver, B., Pinto‐Medel, M. J., Hurtado‐Guerrero, I., Castro Soubriet, Fernando de, Clemente, Diego, Fernández, O., Martin, F., Leyva, Laura, Suardíaz, Margarita, Instituto de Salud Carlos III, European Commission, Junta de Andalucía, and Red Española de Esclerosis Múltiple
Subjects: Encephalomyelitis, Autoimmune, Experimental, Mesenchymal Stem Cells, Genetic Therapy, Interferon-beta, Multiple Sclerosis, Chronic Progressive, Flow Cytometry, Mesenchymal Stem Cell Transplantation, Severity of Illness Index, Mice, Inbred C57BL, Disease Models, Animal, Mice, Multiple Sclerosis, Relapsing-Remitting, Adipose Tissue, Animals, Female
Abstract: [Background and Purpose]: Recombinant IFN‐ß is one of the first‐line treatments in multiple sclerosis (MS), despite its lack of efficacy in some patients. In this context, mesenchymal stem cells (MSCs) represent a promising therapeutic alternative due to their immunomodulatory properties and multipotency. Moreover, by taking advantage of their pathotropism, these cells can be genetically modified to be used as carriers for delivering or secreting therapeutic drugs into injured tissues. Here, we report the therapeutic effect of systemic delivery of adipose‐derived MSCs (AdMSCs), transduced with the IFN‐β gene, into mice with experimental autoimmune encephalomyelitis (EAE)., [Experimental Approach]: Relapsing–remitting and chronic progressive EAE were induced in mice. Cells were injected i.v. Disease severity, inflammation and tissue damage were assessed clinically, by flow cytometry of spleens and histopathological evaluation of the CNS respectively., [Key Results]: Genetic engineering did not modify the biological characteristics of these AdMSCs (morphology, growth rate, immunophenotype and multipotency). Furthermore, the transduction of IFN‐ß to AdMSCs maintained and, in some cases, enhanced the functional properties of AdMSCs by ameliorating the symptoms of MS in EAE models and by decreasing indications of peripheral and central neuro‐inflammation., [Conclusion and Implications]: Gene therapy was found to be more effective than cell therapy in ameliorating several clinical parameters in both EAE models, presumably due to the continuous expression of IFN‐β. Furthermore, it has significant advantages over AdMSC therapy, and also over systemic IFN‐ß treatment, by providing long‐term expression of the cytokine at therapeutic concentrations and reducing the frequency of injections, while minimizing dose‐limiting side effects., This work was supported by Fondo de Investigaciones Sanitarias ISCIII (Spain) and Fondo Europeo de Desarrollo Regional (FEDER) from the European Union through the research grants PI12/01097 and PI15/00963 and ISCIII Red de Terapia Celular TerCel RD12/0019/0006 to F.M., by the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía‐FEDER/Fondo de Cohesion Europeo (FSE) de Andalucía through the research grants P09‐CTS‐04532, PI‐57069 and PAIDI‐Bio‐326 to F.M. and PI‐0160/2012 to K.B. M.J.P.‐M. has been supported by grants from Red Temática de Investigación Cooperativa Red Española de Esclerosis Múltiple REEM (RD07/0060 and RD12/0032). B.O. is financed by a contract from Excelent Project CTS‐7670/11 from Consejería de Economía, Innovación, Ciencia y Empleo (Junta de Andalucía).
Published: 2017

4. Phase III Dose-Comparison Study of Glatiramer Acetate for Multiple Sclerosis

Author: Comi, G, Cohen, Ja, Arnold, Dl, Wynn, D, Filippi, M, FORTE Study Group, Rocc, Ma, Perego, E, Absinta, M, Mesaros, S, Vuotto, R, Misci, P, Petrolini, M, Coyle, P, Wolinsky, J, Antel, J, Zamvil, S, Feigin, P, Carra, Aj, Bettinelli, Rj, Luetic, Gg, Vrech, Ca, Dubois, Bd, Metz, L, Bar Or, A, Bhan, V, Myles, M, Havrdova, E, Ehler, E, Kanovsky, P, Talab, R, Zapletalova, O, Gross Paju, K, Taba, P, Elovaara, I, Erälinna, Jp, Kinnunen, E, Koivisto, K, Reunanen, M, Brochet, B, Camu, W, Damier, P, Defer, G, Tumani, H, Becker, E, Buettner, T, Diener, Hc, Franz, P, Haas, J, Heesen, C, Heidenreich, F, Koelmel, Hw, Reifschneider, G, Retzlaff, K, Thoemke, F, Ziemssen, T, Rozsa, C, Bartos, L, Csanyi, A, Deme, I, Komoly, S, Panczel, G, Simo, M, Achiron, A, Milo, R, Bergamaschi, R, Bertolotto, A, Capra, R, Caputo, D, Cavalla, P, Centonze, D, Cottone, S, DE STEFANO, Nicola, Gasperini, C, Mancardi, G, Provinciali, L, Ruggieri, S, Scarpini, E, Zaffaroni, M, Metra, M, Kizlaitiene, R, Vaitkus, A, Zwanikken, Cp, Hupperts, Rm, Jongen, Pj, Szczudlik, A, Fryze, W, Kazibutowska, Z, Pierzchaa, K, Pniewski, J, Podemski, R, Stepień, A, Bajenaru, O, Campeanu, A, Marginean, I, Popescu, Cd, Toldisan, I, Boiko, A, Gustov, A, Malkova, N, Perfilyev, S, Poverennova, I, Saykhunov, M, Shutov, A, Skoromets, A, Spirin, N, Stolyarov, I, Volkova, L, Rodriguez Antigüedad, A, Arbizu, T, Arroyo, R, Barcena, J, Casanova, B, Fernández, O, Montalban, X, Ramió, L, Saiz Hinarejos, A, Sharrack, B, Silber, E, Young, C, Agius, M, Birnbaum, G, Campagnolo, D, Chaudhary, K, Cohen, J, Ford, C, Fox, E, Goodman, A, Green, B, Gupta, A, Hughes, B, Javed, A, Jeffery, D, Kasper, L, Kaufman, M, Khan, O, Kresa Reahl, K, Leist, T, Lynch, S, Markowitz, C, Mattson, D, Moses, H, Parks, B, Parry, G, Phillips, T, Picone, M, Rammohan, K, Rizvi, S, Royal, W, Scarberry, S, Sheppard, C, Simnad, V, Thrower, B, Whitham, R, Wynn, D., Comi, G, Cohen, Ja, Arnold, Dl, Wynn, D, Filippi, M, FORTE Study, Group, Diener, Hans Christoph (Beitragende*r), Klinische Neurowetenschappen, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: Male, Medizin, MULTICENTER, Relapsing-Remitting, Gastroenterology, law.invention, DOUBLE-BLIND, Randomized controlled trial, law, Recurrence, Drug Toxicity, Clinical endpoint, Secondary Prevention, administration /&/ dosage/adverse effects/therapeutic use, Middle Aged, drug therapy, Intention to Treat Analysis, Treatment Outcome, Neurology, Tolerability, Disease Progression, RELAPSE RATE, TRIAL, Female, Settore MED/26 - Neurologia, Drug, Immunosuppressive Agents, medicine.drug, Adult, medicine.medical_specialty, Multiple Sclerosis, Drug-Related Side Effects and Adverse Reactions, Adolescent, Endpoint Determination, DOUBLE-BLIND, RELAPSE RATE, FOLLOW-UP, DISABILITY, TRIAL, MULTICENTER, MS, Dose-Response Relationship, Multiple Sclerosis, Relapsing-Remitting, Adolescent, Adult, Disease Progression, Dose-Response Relationship, Drug, Drug Toxicity, Endpoint Determination, Female, Humans, Immunosuppressive Agents, administration /&/ dosage/adverse effects/therapeutic use, Intention to Treat Analysis, Male, Middle Aged, Multiple Sclerosis, drug therapy, Multiple Sclerosis, drug therapy, Peptides, administration /&/ dosage/adverse effects/therapeutic use, Recurrence, prevention /&/ control, Treatment Outcome, Internal medicine, medicine, Humans, Glatiramer acetate, Expanded Disability Status Scale, Intention-to-treat analysis, Peptides, Dose-Response Relationship, Drug, business.industry, DISABILITY, MS, Glatiramer Acetate, Confidence interval, Surgery, Relative risk, prevention /&/ control, Neurology (clinical), FOLLOW-UP, business
Abstract: Objective: To evaluate the safety, tolerability, and efficacy of glatiramer acetate (GA) 40mg compared to a 20mg dose. Methods: Patients with multiple sclerosis (MS) with ≥1 documented relapse in 12 months prior to screening, or ≥2 documented relapses in 24 months prior to screening, and Expanded Disability Status Scale (EDSS) score 0 to 5.5 were enrolled. Patients were evaluated at screening, baseline, and at months 1, 2, 3, 6, 9, and 12. Primary endpoint was rate of confirmed relapses observed during 12-month study. Analysis was by intent-to-treat. Results: A total of 1,155 patients randomized to GA 20mg (n = 586) or 40mg (n = 569). The groups were well-matched at baseline on demographic, clinical, and magnetic resonance imaging (MRI) characteristics. The primary endpoint was similar in both groups (relative risk [RR] = 1.07; 95% confidence interval [CI], 0.88–1.31; p = 0.486) with mean annualized relapse rates (ARRs) of 0.33 for the 20mg group, 0.35 for the 40mg group, and 0.27 for patients from both groups who completed the entire 1-year treatment. A total of 77% of patients remained relapse-free in both groups. Both groups showed a reduction in mean number of gadolinium-enhancing and new T2 lesions over time with trend for faster reduction in the first trimester with the 40mg dose compared with 20mg dose. Both doses were well-tolerated with a safety profile similar to that observed in previous studies of 20mg GA. Interpretation: In relapsing-remitting MS patients, both the currently-approved GA 20mg and 40mg doses were safe and well-tolerated, with no gain in efficacy for the higher dose. Ann Neurol 2011;69:75–82.
Published: 2011
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5. Relative effects of statin therapy on stroke and cardiovascular events in men and women: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study

Author: Goldstein, LB, Amarenco, P, Lamonte, M, Gilbert, S, Messig, M, Callahan, A, Hennerici, M, Sillesen, H, Welch, KMA, SPARCL investigators, Bogousslavsky J, Goldstein LB, Zivin J, Clark W, Dávalos A, Kaste M, Leiter L, Altafullah I, Graham G, Glahn J, Jiménez Hernández D, MacWalter R, Scott R, Shuaib A, Sivenius J, Stipal R, Hart R, Marsh J, Norrving B, Pocock S, Sacco R, Easton J, Brown M, Nagy Z, Whisnant J, O'Neill B, Kleber F, LaBlanche JM, Welty F, Crimmins D, Davis S, Dimmitt S, Donnan G, Frayne J, Freilich D, Zagami A, Mikocki J, Schmidauer C, Schmidt R, De Bleecker J, Deceuninck F, Tack P, Thijs V, Gomes Fernandes J, Beaudry M, Cote R, Hoyte K, Lebrun LH, Mackey A, Sahlas D, Selchen D, Spence JD, Teal P, Winger M, Matamala G, Cifkova R, Kalita Z, Rektor I, Rosolova H, Vaclavik D, Boysen G, Klingenberg H, Sillesen H, Hillbom M, Numminen H, Pilke A, Salmivaara A, Alamowitch S, Amarenco P, Boulliat J, De Broucker T, Chollet F, Mahagne MH, Milandre L, Moulin T, Milonas I, Stathis P, Vogiatzoglou D, Bornstein N, Honigman S, Lampl Y, Streifler J, Capurso A, Comi G, Gandolfo C, Poloni M, Senin U, Rangel Guerra R, Boon AM, De Keyser JH, De Kort PL, Haas JA, Kamphuis DJ, Koudstaal PJ, Anderson N, Singh G, Czlonkowska A, Drozdowski W, Gralewski Z, Kozubski W, Kuczynska Zardzewialy A, Podemski R, Stelmasiak Z, Szczudlik A, Da Costa Correia C, Ferro J, Salgueiro e. Cunha L, Lietava J, Raslova K, Carr J, Gardiner J, Kruger A, Alvarez Sabin J, Chamorro A, Diez Tejedor E, Fernández O, Trejo Gabriel y. Galán J, González Marcos J, Egido Herrero J, Jiménez Martínez M, Lago Martin A, Mostacero Miguel E, Vivancos Mora J, Moltó J, Viguera Romero J, Cuartero Rodriguez E, Rubio F, Serena J, Laska AC, Leijd B, Strand T, Terent A, Waegner A, Wallén T, Baumgartner R, Hungerbühler H, Lyrer P, Mattle H, Bath PM, Ekpo EB, Freeman A, Lees KR, MacLeod MJ, MacWalter RS, Sharma AK, Shetty HG, Albers G, Benavente O, Book D, Broderick J, Calder C, Carlini W, Chaturvedi S, Chippendale T, Coull B, Davis P, Devlin T, Dick A, Dooneief G, Duff R, Estronza N, Forteza A, Frankel M, Frey J, Friday G, Goldstein J, Hammer M, Harris J, Harper W, Hendin B, Hess D, Hinton R, Hollander J, Hughes R, Kasner S, Kent T, Kim L, Kirshner H, LaMonte M, Ledbetter L, Lee Kwen P, Levin K, Libman R, Matlock J, McDowell P, McGee F. Jr, Meyer B, Minagar A, Moussouttas M, Munson R, Nash M, Nassief A, Orr S, Ratinov G, Salanga V, Silliman S, Singer R, Smith D, Sullivan H, Tietjen G, Thaler D, Tuchman M, Uskavitch D, Verro P, Vicari R, Weinstein R, Wilterdink J, Zweifler R, De Bastos M., FERRARESE, CARLO, Goldstein, L, Amarenco, P, Lamonte, M, Gilbert, S, Messig, M, Callahan, A, Hennerici, M, Sillesen, H, Welch, K, Sparcl, I, Bogousslavsky, J, Zivin, J, Clark, W, Dávalos, A, Kaste, M, Leiter, L, Altafullah, I, Graham, G, Glahn, J, Jiménez Hernández, D, Macwalter, R, Scott, R, Shuaib, A, Sivenius, J, Stipal, R, Hart, R, Marsh, J, Norrving, B, Pocock, S, Sacco, R, Easton, J, Brown, M, Nagy, Z, Whisnant, J, O'Neill, B, Kleber, F, Lablanche, J, Welty, F, Crimmins, D, Davis, S, Dimmitt, S, Donnan, G, Frayne, J, Freilich, D, Zagami, A, Mikocki, J, Schmidauer, C, Schmidt, R, De Bleecker, J, Deceuninck, F, Tack, P, Thijs, V, Gomes Fernandes, J, Beaudry, M, Cote, R, Hoyte, K, Lebrun, L, Mackey, A, Sahlas, D, Selchen, D, Spence, J, Teal, P, Winger, M, Matamala, G, Cifkova, R, Kalita, Z, Rektor, I, Rosolova, H, Vaclavik, D, Boysen, G, Klingenberg, H, Hillbom, M, Numminen, H, Pilke, A, Salmivaara, A, Alamowitch, S, Boulliat, J, De Broucker, T, Chollet, F, Mahagne, M, Milandre, L, Moulin, T, Milonas, I, Stathis, P, Vogiatzoglou, D, Bornstein, N, Honigman, S, Lampl, Y, Streifler, J, Capurso, A, Comi, G, Ferrarese, C, Gandolfo, C, Poloni, M, Senin, U, Rangel Guerra, R, Boon, A, De Keyser, J, De Kort, P, Haas, J, Kamphuis, D, Koudstaal, P, Anderson, N, Singh, G, Czlonkowska, A, Drozdowski, W, Gralewski, Z, Kozubski, W, Kuczynska Zardzewialy, A, Podemski, R, Stelmasiak, Z, Szczudlik, A, Da Costa Correia, C, Ferro, J, Salgueiro e., C, Lietava, J, Raslova, K, Carr, J, Gardiner, J, Kruger, A, Alvarez Sabin, J, Chamorro, A, Diez Tejedor, E, Fernández, O, Trejo Gabriel y., G, González Marcos, J, Egido Herrero, J, Jiménez Martínez, M, Lago Martin, A, Mostacero Miguel, E, Vivancos Mora, J, Moltó, J, Viguera Romero, J, Cuartero Rodriguez, E, Rubio, F, Serena, J, Laska, A, Leijd, B, Strand, T, Terent, A, Waegner, A, Wallén, T, Baumgartner, R, Hungerbühler, H, Lyrer, P, Mattle, H, Bath, P, Ekpo, E, Freeman, A, Lees, K, Macleod, M, Sharma, A, Shetty, H, Albers, G, Benavente, O, Book, D, Broderick, J, Calder, C, Carlini, W, Chaturvedi, S, Chippendale, T, Coull, B, Davis, P, Devlin, T, Dick, A, Dooneief, G, Duff, R, Estronza, N, Forteza, A, Frankel, M, Frey, J, Friday, G, Goldstein, J, Hammer, M, Harris, J, Harper, W, Hendin, B, Hess, D, Hinton, R, Hollander, J, Hughes, R, Kasner, S, Kent, T, Kim, L, Kirshner, H, Ledbetter, L, Lee Kwen, P, Levin, K, Libman, R, Matlock, J, Mcdowell, P, McGee F., J, Meyer, B, Minagar, A, Moussouttas, M, Munson, R, Nash, M, Nassief, A, Orr, S, Ratinov, G, Salanga, V, Silliman, S, Singer, R, Smith, D, Sullivan, H, Tietjen, G, Thaler, D, Tuchman, M, Uskavitch, D, Verro, P, Vicari, R, Weinstein, R, Wilterdink, J, Zweifler, R, and De Bastos, M
Subjects: Male, Atorvastatin, Blood Pressure, Sex Factor, Pyrrole, Triglyceride, law.invention, Randomized controlled trial, law, Stroke, Sex Characteristics, Middle Aged, Heptanoic Acid, Cholesterol, Treatment Outcome, Data Interpretation, Statistical, Hypertension, Population study, Female, Cardiology and Cardiovascular Medicine, Human, medicine.drug, medicine.medical_specialty, Randomization, Logistic Model, Reproducibility of Result, Placebo, Sex Factors, Internal medicine, medicine, Humans, Pyrroles, Triglycerides, Advanced and Specialized Nursing, Apolipoprotein A-I, Proportional hazards model, business.industry, Reproducibility of Results, Sex Characteristic, medicine.disease, Surgery, Blood pressure, Logistic Models, Heptanoic Acids, Hydroxymethylglutaryl-CoA Reductase Inhibitor, Neurology (clinical), Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract: Background and Purpose— In SPARCL, treatment with atorvastatin 80 mg daily reduced stroke risk in patients with recent stroke or TIA and no known coronary heart disease by 16% versus placebo over 4.9 years of follow-up. The purpose of this secondary analysis was to determine whether men and women similarly benefited from randomization to statin treatment. Methods— The effect of sex on treatment-related reductions in stroke and other cardiovascular outcomes were analyzed with Cox regression modeling testing for sex by treatment interactions. Results— Women (n=1908) constituted 40% of the SPARCL study population. At baseline, men (n=2823) were younger (62.0±0.21versus 63.9±0.27 years), had lower systolic BPs (138.1±0.35 versus 139.5±0.47 mm Hg), higher diastolic BPs (82.2±0.20 versus 81.0±0.25 mm Hg), more frequently had a history of smoking (73% versus 38%), and had lower total cholesterol (207.0±0.54 versus 218.9±0.67 mg/dL) and LDL-C levels (132±0.45 versus 134±0.57 mg/dL) than women. Use of antithrombotics and antihypertensives were similar. After prespecified adjustment for region, entry event, time since event, and age, there were no sex by treatment interactions for the combined risk of nonfatal and fatal stroke (treatment Hazard Ratio, HR=0.84, 95% CI 0.68, 1.02 in men versus HR=0.84, 95% CI 0.63, 1.11 in women; treatment×sex interaction P =0.99), major cardiac events (HR=0.61, 95% CI 0.42, 0.87 in men versus HR=0.76, 95% CI 0.48, 1.21 in women; P =0.45), major cardiovascular events (HR=0.78, 95% CI 0.65, 0.93 in men versus HR=0.84, 95% CI 0.65, 1.07 in women; P =0.63), revascularization procedures (HR=0.50, 95% CI 0.37, 0.67 in men versus HR=0.76, 95% CI 0.46, 1.24 in women; P =0.17), or any CHD event (HR=0.54, 95% CI 0.41, 0.72 in men versus 0.67 95% CI 0.46, 0.98 in women; P =0.40). Conclusion— Stroke and other cardiovascular events are similarly reduced with atorvastatin 80 mg/d in men and women with recent stroke or TIA.
Published: 2008

6. Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis

Author: Villar LM, Casanova B, Ouamara N, Comabella M, Jalili F, Leppert D, de Andrés C, Izquierdo G, Arroyo R, Avsar T, Lapin SV, Johnson T, Montalbán X, Fernández O, Álvarez-Lafuente R, Masterman D, García-Sánchez MI, Coret F, Siva A, Evdoshenko E, Álvarez-Cermeño JC, and Bar-Or A
Subjects: Adult, Inflammation, Male, Cross-Sectional Studies, Phenotype, Immunoglobulin M, Oligoclonal Bands, Humans, Female, Longitudinal Studies, Middle Aged, Multiple Sclerosis, Chronic Progressive, Biomarkers
Abstract: Objective: To identify a biomarker distinguishing patients who, despite a primary progressive multiple sclerosis (PPMS) clinical course, may nonetheless benefit from immune therapy. Methods: The presence or absence of both immunoglobulin (Ig) G and IgM oligoclonal bands (OCB) was blindly examined in paired cerebrospinal fluid (CSF) and serum samples from a large PPMS patient cohort, and related to clinical and imaging evidence of focal inflammatory disease activity. Results: Using both cross-sectional samples and serial sampling in a subgroup of patients followed prospectively as part of the placebo-controlled OLYMPUS study of rituximab in PPMS, we found that the presence of CSF-restricted IgM OCB (but not of IgG OCB) is associated with an active inflammatory disease phenotype in PPMS patients. This finding was confirmed in an independent, multicenter validation cohort. Interpretation: The presence of CSF IgM OCB may be a biomarker for a subset of PPMS patients with more active inflammatory disease, who may benefit from immune-directed treatments.
Published: 2013

7. [The influence of smoking habits of Chilean physicians on the use of the structured medical advice about smoking]

Author: M Virginia, Araya A, Francisco, Leal S, Patricio, Huerta G, Nora, Fernández A, Gonzalo, Fernández O, and Juan P, Millones E
Subjects: Adult, Counseling, Male, Health Knowledge, Attitudes, Practice, Attitude of Health Personnel, Smoking, Smoking Prevention, Middle Aged, Age Distribution, Cardiovascular Diseases, Surveys and Questionnaires, Medical Staff, Hospital, Prevalence, Humans, Female, Smoking Cessation, Chile, Physician's Role
Abstract: Structured medical advice on smoking is the prevention strategy with better cost-effectiveness ratio.To evaluate smoking among health care providers affect the application of this preventive strategy.We surveyed 235 physicians working in public and private hospitals in different cities over the country, about their smoking habits, their views on smoking as cardiovascular risk factor and the implementation of three key points of the structured medical advice about smoking.Physicians aged less than 44 years had the lower frequency of smoking and the higher frequency of ex-smokers concentrated among those aged 60 years or more. All surveyed physicians agreed that smoking is a cardiovascular risk factor. However, 21% considered that this risk appears only among those that smoke more than three cigarettes per day. Independent of their smoking habits, 18% of physicians not always ask their patients about smoking, 25% do not warn about the risk of smoking and 22% not always give advice about quitting. This last action is carried out with a significantly lower frequency by smoking physicians.To improve physician's compliance with their preventive role in clinical practice, it is essential to consider their own smoking habits, and the information and attitudes that they have towards smoking as a cardiovascular risk factor.
Published: 2011

8. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

Author: Strasser Fuchs, S, Berger, T, Vass, K, Sindic, C, Dubois, B, Dive, D, Debruyne, J, Metz, L, Rice, G, Duquette, P, Lapierre, Y, Freedman, M, Traboulsee, A, O'Connor, P, Stourac, P, Taláb, R, Zapletalová, O, Kovárová, I, Medová, E, Fiedler, J, Frederiksen, J, Brochet, B, Moreau, T, Vermersch, P, Pelletier, J, Edan, G, Clanet, M, Clavelou, P, Lebrun Frenay, C, Gout, O, Kallela, M, Pirttilä, T, Ruutiainen, J, Koivisto, K, Reunanen, M, Elovaara, I, Villringer, A, Altenkirch, H, Wessel, K, Hartung, Hp, Steinke, W, Kölmel, H, Oschmann, P, Diem, R, Dressel, A, Hoff, F, Baum, K, Jung, S, Felicitas Petereit, H, Reske, D, Sailer, M, Köhler, J, Sommer, N, Hohlfeld, R, Henn, Kh, Steinbrecher, A, Tumani, H, Gold, R, Rieckmann, P, Komoly, R, Gács, G, Jakab, G, Csiba, L, Vécsei, L, Miller, A, Karussis, D, Chapman, J, Ghezzi, A, Comi, G, Gallo, Paolo, Cosi, V, Durelli, L, Anten, B, Visser, L, Myhr, Km, Szczudlik, A, Selmaj, K, Stelmasiak, Z, Podemski, R, Maciejek, Z, Cunha, L, Sega Jazbec, S, Montalbán, X, Arbizu, T, Saiz, A, Bárcena, J, Arroyo, R, Fernández, O, Izquierdo, G, Casanova, B, Lycke, J, Kappos, L, Mattle, H, Beer, K, Coleman, R, Chataway, J, O'Riordan, J, Howell, S, Miller, Dh, Polman, Ch, Bauer, L, Ghazi, M, Pohl, C, Sandbrink, R, Barkhof, F, Uitdehaag, B, de Vera, A, Wu, S, Radü, Ew, Mcfarland, Hf, Kesselring, J, Petkau, Aj, Toyka, K. V., Dubois, Bénédicte, Neurology, Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Subjects: Adult, Male, Questionnaires, medicine.medical_specialty, Multiple Sclerosis, Kaplan-Meier Estimate, Placebo, Risk Assessment, Young Adult, Disability Evaluation, Double-Blind Method, Surveys and Questionnaires, Internal medicine, medicine, Humans, Proportional Hazards Models, Intention-to-treat analysis, Expanded Disability Status Scale, Clinically isolated syndrome, business.industry, Multiple sclerosis, Interferon beta-1b, Hazard ratio, Interferon-beta, medicine.disease, Magnetic Resonance Imaging, Surgery, Tolerability, Data Interpretation, Statistical, Disease Progression, Female, Neurology (clinical), business
Abstract: BACKGROUND: The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. METHODS: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 microg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211. FINDINGS: 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0.63, 95% CI 0.48-0.83; p=0.003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0.76, 0.52-1.11; p=0.177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b. INTERPRETATION: Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes. FUNDING: Bayer Schering Pharma. ispartof: The Lancet Neurology vol:8 issue:11 pages:987-997 ispartof: location:England status: published
Published: 2009
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9. 250 mu g or 500 mu g interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study

Author: O'Connor, P., Filippi, M., Arnason, B., Comi, G., Cook, S., Goodin, D., Hartung, H., Jeffery, D., Kappos, L., Boateng, F., Filippov, V., Groth, M., Knappertz, V., Kraus, C., Sandbrink, R., Pohl, C., BogumilAbramsky O, T., Achiron, A, Agius, M, Aichner, F, Altenkirch, H, Amato, Mp, Anten, B, Arbizu, T, Ash, P, Ballario, C, Bashir, K, Baum, K, Baumhackl, U, Beaver, G, Belova, A, Berger, J, Berger, T, Berlit, P, Beuche, W, Bhan, V, Bigley, K, Bissay, V, Blake, C, Bö, L, Boyko, A, Brochet, B, Brown, M, Callegaro, D, Carra, A, Carroll, W, Cascione, M, Christie, S, Clanet, M, Clavelou, P, Clementino, Vi, Confavreux, C, Cooper, J, Cross, A, Csanyi, A, Czlonkowska, A, D'Hooghe, M, Damier, P, Debouverie, M, Defer, G, Demina, T, Deri, N, Diem, R, Dressel, A, Dubois, B, Dunne, P, Duquette, P, Durelli, L, Edan, G, Elias, S, Elovaara, I, Esfahani, F, Evtushenko, S, Fabijan, Th, Fernández, O, Ferreira, Ml, Fink, A, Flechter, S, Ford, C, Francesconi, C, Freedman, M, Fryze, W, Gabbai, A, Gács, G, Gallo, Paolo, Gazda, S, Gerloff, C, Glyman, S, Goodman, A, Gottesman, M, Grand'Maison, F, Guarnaccia, J, Gutierrez, A, Haas, J, Hansen, Hj, Hardiman, O, Heard, R, Heidenreich, F, Herbert, J, Herminia Scola, R, Hodgkinson, S, Hoffmann, F, Holub, R, Huddlestone, J, Hughes, B, Hughes, M, Hunter, S, Hurwitz, B, Izquierdo, G, Jacobasch, E, Jacques, F, Jakab, G, Jongen, P, Karageorgiou, C, Karni, A, Kasper, L, Kaufman, M, Keidel, M, Khatri, B, Kiefer, R, Kirzinger, S, Kita, M, Komoly, S, Kotov, S, Kozubski, W, Kumlien, E, Kwiecinski, H, Labouge, P, Laganke, C, Lapierre, Y, Lebrun Frenay, C, Leist, T, Leon, Sa, Luetic, G, Lynch, S, Lynch, T, Malkova, N, Maltezou, M, Markowitz, C, Martin, C, Mattle, H, Mattson, D, Metra, M, Meyding Lamadé, U, Milo, R, Milonas, I, Miller, A, Miller, T, Minagar, A, Mitchell, G, Moreau, T, Mosberg, R, Murphy, R, Nehrych, T, Nikl, J, Odinak, M, Oschmann, P, Owen King, J, Pagani, L, Pereira Damasceno, B, Podemski, R, Pöhlau, D, Pozzilli, C, Rammohan, K, Reunanen, M, Rice, G, Richardson, P, Rivera, V, Rizvi, S, Rogozhyn, V, Rolak, L, Rosenkranz, T, Rotta, R, Sanders, E, Sater, R, Satgur Gupta, A, Schwartz, R, Sedal, L, Sega Jazbec, S, Selchen, D, Selmaj, K, Sheremata, W, Shvets, T, Silver, D, Simsarian, J, Skoromets, A, Smiroldo, J, Sokolova, L, Solovyova, Y, Sommer, N, Spirin, N, Stangel, M, Stark, E, Steinbrecher, A, Stemper, B, Stolyarov, I, Strasser Fuchs, S, Sweeney, B, Tettenborn, B, Thrower, B, Tilbery, Cp, Traboulsee, A, Trojano, M, Tubridy, N, Tyor, W, Valikovics, A, Vermersch, P, Vollmer, T, Voloshyna, N, Vrech, C, Wajgt, A, Weller, B, Wendt, J, Yakhno, N, Yeung, M, Zavalishin, I., O'Connor, P, Filippi, Massimo, Arnason, B, Comi, G, Cook, S, Goodin, D, Hartung, Hp, Jeffery, D, Kappos, L, Boateng, F, Filippov, V, Groth, M, Knappertz, V, Kraus, C, Sandbrink, R, Pohl, C, Bogumil, T., and Dubois, Bénédicte
Subjects: Adult, Male, medicine.medical_specialty, interferon beta-1b, Adolescent, Pharmacology, relapsing-remitting multiple sclerosis, law.invention, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Randomized controlled trial, Double-Blind Method, law, Internal medicine, medicine, Humans, Immunologic Factors, Glatiramer acetate, Adverse effect, Expanded Disability Status Scale, Dose-Response Relationship, Drug, business.industry, Multiple sclerosis, Interferon beta-1b, Brain, Glatiramer Acetate, Interferon-beta, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical trial, Tolerability, glatiramer acetate, Female, Neurology (clinical), business, Peptides, medicine.drug
Abstract: BACKGROUND: The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial was to compare the efficacy, safety, and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis. METHODS: Between November, 2003, and June, 2005, 2447 patients with relapsing-remitting multiple sclerosis were screened and 2244 patients were enrolled in this prospective, multicentre, randomised trial. Patients were randomly assigned 2:2:1 by block randomisation with regional stratification to receive one of two doses of interferon beta-1b (250 microg or 500 microg) subcutaneously every other day or 20 mg glatiramer acetate subcutaneously every day. The primary outcome was relapse risk, defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. Secondary outcomes were progression on the expanded disability status scale (EDSS) and change in T1-hypointense lesion volume. Clinical outcomes were assessed quarterly for 2.0-3.5 years; MRI was done at screening and annually thereafter. Analysis was by per protocol. This study is registered, number NCT00099502. FINDINGS: We found no differences in relapse risk, EDSS progression, T1-hypointense lesion volume, or normalised brain volume among treatment groups. Flu-like symptoms were more common in patients treated with interferon beta-1b (p
Published: 2009

10. [Leuconostoc infections in patients with short gut syndrome, parenteral nutrition and continuous enteral feeding]

Author: Leonor, Jofré M, Andrea, Sakurada Z, M Teresa, Ulloa F, J Carlos, Hormázabal O, Viviana, Godoy M, Jorge, Fernández O, Marcela, Gutiérrez M, M Pilar, Monteverde O, Marcela, Castillo G, and Ana, Canales P
Subjects: Short Bowel Syndrome, Parenteral Nutrition, Enteral Nutrition, Humans, Infant, Female, Gram-Positive Bacterial Infections, Leuconostoc
Abstract: Leuconostoc is a gram-positive cocci, quite ubiquitous in nature. It is used in wine industry, and for aroma and texture of dairy products. Occasionally it has been isolated from humans in cases of bacteremia, catheter associated infections, sepsis, meningitis, pneumonia, UTI, osteomyelitis and hepatic dysfunction. Short bowel syndrome, patients with CVC and patients with gastrostomy undergoing enteral feeding, are described amongst the factors associated with this infection. The isolation of a gram-positive cocci, that does not hydrolyze arginine and that is resistant to vancomycin leads to this diagnostic possibility. Antibiotic treatment: penicillin or ampicillin.
Published: 2006

11. [Genetic markers in four Chilean families with familial Creutzfeldt-Jakob disease]

Author: Luis, Cartier R, Jorge, Fernández O, and Eugenio, Ramírez V
Subjects: Genetic Markers, Male, Base Sequence, Genotype, PrPSc Proteins, Prions, Polymerase Chain Reaction, Creutzfeldt-Jakob Syndrome, Pedigree, Mutation, Humans, Female, Genetic Predisposition to Disease, PrPC Proteins, Amino Acid Sequence, Chile, Codon
Abstract: Creutzfeldt-Jakob disease (CJD) is a form of transmissible spongiform encephalopathy, in which a prion protein (PrP Sc) accumulates in the brain of affected individuals. Chile has a prevalence of CJD that is more than twice than in the rest of the world and has the highest rate of familial forms. These later forms are associated with the heterozygocity of codon 200 of PrP protein gene.To search susceptibility genetic markers of CJD in members of families affected by CJD.A blood sample was obtained from 50 individuals pertaining to four families affected by CJD. DNA from peripheral mononuclear cells was amplified by polymerase chain reaction and sequenced for the gene that codifies PrP protein.In family A, 21 of 23 members were homozygotes for codon 129 (Met/Met) and eight were simultaneously heterozygotes for codon 200 (Glu/Lys). In family B, six of nine members were homozygotes for codon 129, five were heterozygotes for codon 200 and four had both mutations. In family C, the four analyzed subjects were homozygotes for codon 129 and two were simultaneously heterozygotes for codon 200. In family D, nine of 14 members were homozygotes for codon 129 and two were simultaneously homozygotes for codon 200. No family had polymorphisms for codon 219.Thirty two percent of analyzed subjects were homozygotes for codon 129 and heterozygotes for codon 200, condition that defines the genetic susceptibility to acquire CJD. The dominant tendency of these genotypes could explain the higher incidence of CJF in Chile.
Published: 2006

12. Resultados a medio y largo plazo de la utilización de videotoracoscopia en la cirugía de resección de las metástasis pulmonares

Author: Torre W, Rodríguez-Spiteri N, Villalobos W, Gurpide A, Fernández O, and Jm, López-Picazo
Subjects: Adult, Male, Lung Neoplasms, Time Factors, Adolescent, Video-assisted surgery, Humans, Metástasis pulmonar, Child, Cirugía videoasistida, Aged, Retrospective Studies, Videotoracoscopia, Videothorascopy, Thoracic Surgery, Video-Assisted, Sarcoma, Middle Aged, Survival Analysis, Kidney Neoplasms, Colorectal carcinoma, Pulmonary metastasis, Thoracotomy, Data Interpretation, Statistical, Positron-Emission Tomography, Drainage, Female, Radiography, Thoracic, Neoplasm Recurrence, Local, Colorectal Neoplasms, Tomography, X-Ray Computed, Carcinoma colorrectal
Abstract: La resección quirúrgica de las metástasis pulmonares es un método de tratamiento aceptado como habitual en la cirugía torácica. Sin embargo, continúa siendo un motivo de controversia si esta resección se debe realizar por toracotomía, o por las modernas técnicas vídeo asistidas. Con la finalidad de buscar una respuesta a dicha controversia en nuestro medio de trabajo, se efectuó una revisión de las intervenciones quirúrgicas realizadas con el objetivo de resecar metástasis pulmonares. Entre enero de 1997 y diciembre de 2001, se encontraron 56 pacientes a quienes se había resecado metástasis pulmonares por videotoracoscopia de entre un total de 252 metastasectomías (22,2%). Se clasificaron los tumores primarios en 4 grupos: sarcoma (n=11); colorrectal (n=25); renales (n=5); y otros (n=15). La videotoracoscopia se realizó en el hemitórax derecho (n=28), hemitórax izquierdo (n=22) o en ambos a la vez (n=6). La mortalidad operatoria fue nula y la única morbilidad atribuible a la técnica fue un defecto de reexpansión tras la retirada del drenaje torácico en un paciente. Utilizando el método de Kaplan-Meier, la probabilidad de supervivencia de esta serie de pacientes fue del 60,4% a los 5 años, con tiempo de supervivencia medio de 48 meses. Todos estos datos apoyan en nuestro medio el empleo de videotoracoscopia en pacientes con metástasis pulmonares. Sin embargo, y a la vista de los resultados, es importante al efectuar esta técnica poner un cuidado especial en conseguir buenos márgenes de resección, debido al riesgo real de recurrencia local sobre dichos márgenes a medio plazo. The surgical resection of pulmonary metastases is a method of treatment accepted as habitual in thoracic surgery. However, it continues to be a source of controversy if this resection must be realised by thoracotomy or by modern video-assisted techniques. With the aim of finding a response to this controversy in our work milieu, a review was made of the surgical interventions carried out in order to resect pulmonary metastases. Between January 1997 and December 2001, 56 patients were found whose pulmonary metastases had been resected by videothorascopy out of a total of 252 metastasectomies (22.2%). The primary tumours were classified in 4 groups: sarcoma (n=11); colorectal (n=25); renal (n=5); and others (n=15). Videothoroscopy was carried out on the right hemithorax (n=28), left hemithorax (n=22) or on both at once (n=6). Operational mortality was nil and the only morbidity attributable to the technique was a defect of re-expansion following the removal of the thoracic drainage in one patient. Using the Kaplan-Meier method, the probability of survival in this series of patients was 60.4% after 5 years, with an average survival time of 48 months. All of this data supports the use of videothorascopy in our milieu on patients with pulmonary metastases. However, in the light of the results, it is important in using this technique to place special emphasis on obtaining good margins of resection, due to the real risk of local recurrence on these margins in the medium term.
Published: 2006

13. [Natural interferon-beta in the treatment of relapsing-remitting multiple sclerosis: a multicenter, randomized, MRI-based, phase II clinical trial]

Author: Fernández O, Antigüedad A, Arbizu T, Burgués S, Capdevila A, de Castro P, Jc, Correa Sá, Ja, García-Merino, Izquierdo G, Magalhaes A, Montalbán X, and Jj, Zarranz
Subjects: Adult, Male, Multiple Sclerosis, Adolescent, Injections, Subcutaneous, Interferon-beta, Middle Aged, Antibodies, Adjuvants, Immunologic, Acute Disease, Disease Progression, Secondary Prevention, Humans, Female
Abstract: The ability of natural human interferon beta (n-hIFN beta) to reduce multiple sclerosis (MS) activity was investigated in 60 patients with relapsing-remitting MS (RRMS).Patients were randomized to receive either 9 MIU (33 micrograms) of n-hIFN beta by subcutaneous route, three times per week, on alternate days, during one year, or no treatment (control group) during the first six months and then switched to the same treatment for the following six months. Disease activity was monitored monthly by both magnetic resonance imaging (MRI) and clinical parameters. An intergroup analysis (first 6 months of the study) showed fewer active lesions and lower exacerbation rate in the treatment group than in the control group. Similarly, there were more exacerbation-free patients in the treatment group during this time.When switched to treatment, the control group showed a significant reduction in the number of active lesions (p = 0.00001) and the exacerbation rate decreased by half. Exacerbation-free patients more than doubled (p = 0.006) and the median time to first exacerbation was significantly prolonged (96 vs180 days; p = 0.019). Treatment was extended for 12 additional months at a dose of 6 MIU (22 micrograms) once a week and disease activity persisted under control in 88% of patients. Treatment with n-hIFN beta was well tolerated, adverse events being mild and self-limiting. Sera were analyzed for anti-IFN beta antibodies and neutralizing activity was found in 12% of the patients after two years.The results of this phase II study show, that n-hIFN beta promotes a significant reduction of disease activity in RRMS as shown by both MRI and clinical variables, and that the treatment is well tolerated, with low antigenicity.
Published: 2000

14. Candidate gene study of TRAIL and TRAIL receptors: association with response to interferon beta therapy in multiple sclerosis patients

Author: Elena Urcelay, María Jesús Pinto-Medel, Francisca Sánchez-Jiménez, Teresa Órpez-Zafra, Almudena Pino-Angeles, Cristina Guijarro-Castro, Begoña Oliver-Martos, Laura Leyva, Roberto Alvarez-Lafuente, Carlos López-Gómez, Oscar Fernandez, Carlos Arnaiz, Jezabel Varadé, Jesús Ortega-Pinazo, [López-Gomez,C, Órpez-ZafraT, Pinto-Medel,MJ, Oliver-Martos,B, Ortega-Pinazo,J, Leyva,L] Research Laboratory. Clinical Neurosciences Institute, Hospital Regional Universitario Carlos Haya, Málaga, Spain. [Pino-Ángeles,A, Sánchez-Jiménez,F] Department of Molecular Biology and Biochemistry, University of Málaga, Málaga, Spain. [Arnáiz,C, Fernández,O] Department of Neurology. Clinical Neurosciences Institute, Hospital Regional Universitario Carlos Haya, Málaga, Spain. [Guijarro-Castro,C] Department of Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain. [Varadé,J, Álvarez-Lafuente,R, Urcelay,E] Multiple Sclerosis Unit, Hospital Clínico San Carlos, IdISSC, Madrid, Spain. [Pino-Ángeles,A, Sánchez-Jiménez,F] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Málaga, Spain. [Órpez-Zafra,T, Guijarro-Castro,C, Varadé,J, Urcelay,E, Fernández,O, Leyva,L] Red Española de Esclerosis Múltiple (REEM RD 07/0060), Málaga, Spain., and Fondo de Investigación Sanitaria & Fondo Europeo de Desarrollo Regional (PS09/01764), Consejería de Salud de la Junta de Andalucía (SAS07/0231), Consejería de Innovación (P07-CTS-03223) and Biogen Idec Iberia S.L.
Subjects: Male, Models, Molecular, Candidate gene, España, Gene Expression, lcsh:Medicine, TNF-Related Apoptosis-Inducing Ligand, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Acidic [Medical Subject Headings], Receptor, lcsh:Science, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Alanine [Medical Subject Headings], Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Multidisciplinary, Alanina, Middle Aged, Neurology, Medicine, Biomarker (medicine), Female, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Protein Binding, Research Article, Adult, Multiple Sclerosis, Adolescent, Edad de Inicio, Single-nucleotide polymorphism, Biology, Diseases::Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], GPI-Linked Proteins, Polymorphism, Single Nucleotide, Peripheral blood mononuclear cell, Autoimmune Diseases, Receptors, Tumor Necrosis Factor, Member 10c, Genetics, medicine, Humans, Beta (finance), Genetic Association Studies, Aged, Evolutionary Biology, Binding Sites, Population Biology, Health Care::Environment and Public Health::Public Health::Epidemiologic Factors::Age Factors::Age of Onset [Medical Subject Headings], Multiple sclerosis, lcsh:R, Computational Biology, Human Genetics, Interferon-beta, Ácido glutámico, medicine.disease, Demyelinating Disorders, Receptors, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor Decoy Receptors, Esclerosis múltiple, Genetics of Disease, Immunology, Genetic Polymorphism, Clinical Immunology, lcsh:Q, Genotipo, Biomarkers, Population Genetics, CD8
Abstract: Journal Article; Research Support, Non-U.S. Gov't; TRAIL and TRAIL Receptor genes have been implicated in Multiple Sclerosis pathology as well as in the response to IFN beta therapy. The objective of our study was to evaluate the association of these genes in relation to the age at disease onset (AAO) and to the clinical response upon IFN beta treatment in Spanish MS patients. We carried out a candidate gene study of TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 genes. A total of 54 SNPs were analysed in 509 MS patients under IFN beta treatment, and an additional cohort of 226 MS patients was used to validate the results. Associations of rs1047275 in TRAILR-2 and rs7011559 in TRAILR-4 genes with AAO under an additive model did not withstand Bonferroni correction. In contrast, patients with the TRAILR-1 rs20576-CC genotype showed a better clinical response to IFN beta therapy compared with patients carrying the A-allele (recessive model: p = 8.88×10(-4), pc = 0.048, OR = 0.30). This SNP resulted in a non synonymous substitution of Glutamic acid to Alanine in position 228 (E228A), a change previously associated with susceptibility to different cancer types and risk of metastases, suggesting a lack of functionality of TRAILR-1. In order to unravel how this amino acid change in TRAILR-1 would affect to death signal, we performed a molecular modelling with both alleles. Neither TRAIL binding sites in the receptor nor the expression levels of TRAILR-1 in peripheral blood mononuclear cell subsets (monocytes, CD4+ and CD8+ T cells) were modified, suggesting that this SNP may be altering the death signal by some other mechanism. These findings show a role for TRAILR-1 gene variations in the clinical outcome of IFN beta therapy that might have relevance as a biomarker to predict the response to IFN beta in MS. Yes
Published: 2013

15. Soluble Receptor Isoform of IFN-Beta (sIFNAR2) in Multiple Sclerosis Patients and Their Association With the Clinical Response to IFN-Beta Treatment

Author: Pablo Aliaga-Gaspar, Isaac Hurtado-Guerrero, Nicolas Lundahl Ciano-Petersen, Patricia Urbaneja, Isabel Brichette-Mieg, Virginia Reyes, Jose Luis Rodriguez-Bada, Roberto Alvarez-Lafuente, Rafael Arroyo, Ester Quintana, Lluis Ramió-Torrentà, Ana Alonso, Laura Leyva, Oscar Fernández, Begoña Oliver-Martos, Institut Català de la Salut, [Aliaga-Gaspar P] Neuroimmunology and Neuroinflammation Group, Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica (UGC) Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain. Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Hurtado-Guerrero I] Neuroimmunology and Neuroinflammation Group, Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica (UGC) Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain. Neuroinflammation Unit, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, Copenhagen Biocentre, University of Copenhagen, Copenhagen, Denmark. [Ciano-Petersen NL, Urbaneja P, Reyes V] Neuroimmunology and Neuroinflammation Group, Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica (UGC) Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain. Red Andaluza de Investigación Clínica y Traslacional en Neurología (Neuro-Reca), Málaga, Spain. [Brichette-Mieg I] Neuroimmunology and Neuroinflammation Group, Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica (UGC) Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain. [Quintana E] Red Española de Esclerosis Múltiple (REEM), Madrid, Spain. Servicio de Neurología, Hospital Universitari de Girona Doctor Josep Trueta, Intitut Català de la Salut (ICS), Girona, Spain. [Ramió-Torrentà L] Red Española de Esclerosis Múltiple (REEM), Madrid, Spain. Servicio de Neurología, Hospital Universitari de Girona Doctor Josep Trueta, Intitut Català de la Salut (ICS), Girona, Spain. Institut d’Investigació Biomèdica de Girona (IDIBGI), Salt, Spain. Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, Girona, Spain, Hospital Universitari de Girona Dr Josep Trueta, [Aliaga-Gaspar,P, Hurtado-Guerrero,I, Ciano-Petersen,NL, Urbaneja,P, Brichette-Mieg,I, Reyes,V, Rodriguez-Bada,JL, Alonso,A, Leyva,L, Oliver-Martos,B] Neuroimmunology and Neuroinflammation Group, Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica (UGC) Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain. [Aliaga-Gaspar,P] Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Hurtado-Guerrero,I] Neuroinflammation Unit, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, Copenhagen Biocentre, University of Copenhagen, Copenhagen, Denmark. [Ciano-Petersen,NL, Oliver-Martos,B] Red Andaluza de Investigación Clínica y Traslacional en Neurología (Neuro-Reca), Málaga, Spain. [Alvarez-Lafuente,R] Grupo de Investigació n de Factores Ambientales en Enfermedades Degenerativas, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. [Alvarez-Lafuente,R, Quintana,E, Ramió-Torrentà,L, Oliver-Martos,B] Red Española de Esclerosis Múltiple (REEM), Madrid, Spain. [Arroyo,R] Servicio de Neurología, Hospital Universitario Quirónsalud, Madrid, Spain. [Quintana,E, Ramió-Torrentà,L] Servicio de Neurología, Hospital Universitari de Girona Doctor Josep Trueta, Girona, Spain. [Ramió-Torrentà,L] Girona Biomedical Research Institute (IDIBGI), Girona, Spain. [Ramió-Torrentà,L] Medical Sciences Department, University of Girona, Girona, Spain. [Fernández,O] Departmento de Farmacología, Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Oliver-Martos,B] Departamento de Biologéa Celular, Genética y Fisiología, Área de Fisiología, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain., and This research was funded by grants from the Instituto de Salud Carlos III and co-funded by European Regional Development Fund (ERDF), Technological Development Project in health DTS/1800045 to BO-M. BO-M holds a contract from Red Andaluza de Investigacion Clınica y Traslacional en Neurología (Neuro-reca) ́ (RIC-0111-2019). PA-G is supported by Promoción de Empleo Joven e Implantación de la Garantıa Juvenil 2018 (PEJ2018-002719- ́A). JR-B is supported by grantsfrom Red Temática de Investigación Cooperativa, Red Española de Esclerosis Multiple REEM (RD16/0015/0010). LL holds a Nicolás Monardes research contract (RC 002-2019) from the Andalusian Ministry of Health and Family. IB M holds a pFIS contract (FI19/00139)from the Spanish Science and Innovation Ministry.
Subjects: Male, soluble receptors, Drug Resistance, Interferó, Receptor, Interferon alpha-beta, IFNAR, Other subheadings::Other subheadings::/drug therapy [Other subheadings], multiple sclerosis, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Protein Isoforms, Immunology and Allergy, interferon beta, Original Research, Biological Factors::Intercellular Signaling Peptides and Proteins::Cytokines::Interferons::Interferon Type I::Interferon-beta [CHEMICALS AND DRUGS], Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [DISEASES], Interferon beta, Up-Regulation, Treatment Outcome, enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple [ENFERMEDADES], Female, Receptor de interferones alfa y beta, Drug Monitoring, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Monitoring, Physiologic::Drug Monitoring [Medical Subject Headings], Immunology, Check Tags::Male [Medical Subject Headings], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::RNA Processing, Post-Transcriptional::RNA Splicing::Alternative Splicing [Medical Subject Headings], Multiple sclerosis, alternative splicing, Multiple Sclerosis, Relapsing-Remitting, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Cytokine::Receptors, Interferon::Receptor, Interferon alpha-beta [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Follow-Up Studies [Medical Subject Headings], Humans, Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Interferons::Interferon Type I::Interferon-beta [Medical Subject Headings], RNA, Messenger, Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome [Medical Subject Headings], Soluble receptors, Interferón beta, factores biológicos::péptidos y proteínas de señalización intercelular::citocinas::interferones::interferón de tipo I::interferón beta [COMPUESTOS QUÍMICOS Y DROGAS], Interferon-beta, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger [Medical Subject Headings], RC581-607, Empalme alternativo, Check Tags::Female [Medical Subject Headings], Esclerosis múltiple, Immunologic diseases. Allergy, Esclerosi múltiple - Tractament, Biomarkers, Follow-Up Studies, Alternative splicing
Abstract: Alternative splicing; Soluble receptors; IFNAR; Interferon beta; Multiple sclerosis Empalmament alternatiu; Receptors solubles; IFNAR; Interferó beta; Esclerosi múltiple Splicing alternativo; Receptores solubles; IFNAR; Interferón beta; Esclerosis múltiple Purpose: Interferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the in vitro short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients. Methods: Ninety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation in vitro. Results: Protein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β in vitro induction of PBMC, 6/7 patients increased the sIFNAR2 expression. Conclusions: IFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy. This research was funded by grants from the Instituto de Salud Carlos III and co-funded by European Regional Development Fund (ERDF), Technological Development Project in health DTS/1800045 to BO-M. BO-M holds a contract from Red Andaluza de Investigacion Clínica y Traslacional en Neurología (Neuro-reca) (RIC-0111-2019). PA-G is supported by Promoción de Empleo Joven e Implantación de la Garantía Juvenil 2018 (PEJ2018-002719-A). JR-B is supported by grants from Red Temática de Investigación Cooperativa, Red Española de Esclerosis Multiple REEM (RD16/0015/0010). LL holds a Nicolás Monardes research contract (RC-002-2019) from the Andalusian Ministry of Health and Family. IB-M holds a pFIS contract (FI19/00139) from the Spanish Science and Innovation Ministry.
Published: 2021
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16. Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study

Author: O. Fernández, José García-Sánchez, Beatriz Suarez-Paniagua, Jose Carlos Villa Guzman, Carmen Santander-Lobera, Núria Sala-González, Miguel A. Climent-Duran, Montserrat Domenech, Nuria Lainez, Sergio Vazquez-Estevez, Enrique Gallardo, Marina Morán, Javier Puente, Martín Lázaro-Quintela, Cristina Caballero-Díaz, Emilio Esteban, Carmen Molins, Alvaro Pinto-Marin, F.J. Afonso, Maria Jose Lecumberri, Laura Basterretxea, Ricardo Sánchez-Escribano, Daniel Castellano, María Belén González, Iciar García-Carbonero, Marta López-Brea, Isabel Chirivella, Esther Martínez-Ortega, David Marrupe, M Isabel Sáez, Aranzazu Gonzalez del Alba, Irene Gil-Arnaiz, Begoña Mellado, Cristina Suárez-Rodríguez, Eva Fernandez Parra, Jesús García-Donas, María José Méndez-Vidal, Luis León, [Lainez,N, Lecumberri,MJ] Department of oncology, Complejo Hospitalario de Navarra, Servicio Oncología Médica, Navarra, Spain, [García-Doñas,J] Hospital Sanchinarro, Departamento Oncología, Spain, [Esteban,E] Hospital Universitario Central de Asturias, Departamento de Oncología, Oviedo, Spain, [Puente,J] Hospital Clínico de Madrid, Departamento de Oncología, Madrid, Spain, [Sáez, MI] Hospital Universitario Clínico Virgen de la Victoria, Departamento de Oncología, Málaga, Spain, [Gallardo,E] Parc Tauli Sabadell Hospital Universitario, Departamento de Oncología, Sabadell, Spain, [Pinto-Marín,A] Hospital Universitario La Paz, Departamento de Oncología, Madrid, Spain, [Vázquez-Estévez,S] Hospital Universitario Lucus Augusti, Departamento de Oncología, Lugo, Spain, [León,L] Hospital Santiago de Compostela, Departamento de Oncología, Santiago de Compostela, Spain, [García-Carbonero,I] Hospital Virgen de la Salud, Departamento de Oncología, Toledo, Spain, [Suárez-Rodríguez,C] Hospital Valle de Hebrón, Departamento de Oncología, Barcelona, Spain, [Molins,C] Hospital Universitario Dr. Peset, Departamento de Oncología, Valencia, Spain, [Climent-Durán,MA] Instituto Valenciano de Oncología, Departamento de Oncología, Valencia, Spain, [Lázaro-Quintela,M] Complexo Hospitalario Universitario de Vigo, Departamento de Oncología, Vigo, Spain, [González del Alba,A] Hospital Universitario Son Espases, Departamento de Oncología, Palma de Mallorca, Spain, [Méndez-Vidal,MJ] Hospital Universitario Reina Sofía, Departamento de Oncología, Córdoba, Spain, [Chirivella,I] Hospital Clínico de Valencia, Departamento Oncología, Valencia, Spain, [Afonso,FJ] Complejo Hospitalario Arquitecto Marcide, Departamento de Oncología, Ferrol, Spain, [López-Brea,M] Hospital Marqués de Valdecilla, Departamento de Oncología, Santander, Spain, [Sala-González,N] ICO Girona, Departamento de Oncología, Girona, Spain, [Domenech,M] Hospital Althaia Xarxa Asistencial Manresa, Departamento de Oncología, Barcelona, Spain, [Basterretxea,L] Hospital Donostia, Departamento de Oncología, San Sebastián, Spain, [Santander-Lobera,C] Hospital Miguel Servet, Departamento de Oncología, Zaragoza, Spain, [Gil-Arnáiz,I] Hospital Reina Sofía, Departamento Oncología, Tudela, Spain, [Fernández,O] Hospital Santa María Nai, Complejo Hospital Ourense, Departamento de Oncología, Orense, Spain, [Caballero-Díaz,C] Hospital Gen Universitario Valencia, Departamento de Oncología, Valencia, Spain, [Mellado,B] Hospital Clinic de Barcelona, Departamento de Oncología, IDIBAPS, Barcelona, Spain, [Marrupe,D] Hospital Universitario de Móstoles, Departamento de Oncología, Madrid, Spain, [García-Sánchez,J] Hospital Arnau Vilanova, Departamento de Oncología, Valencia, Spain, [Sánchez-Escribano,R] Hospital Universitario de Burgos, Departamento de Oncología, Burgos, Spain, [Fernández Parra,E] Hospital Universitario de Valme, Departamento de Oncología, Sevilla, Spain, [Villa Guzmán,JC] Hospital de Ciudad Real, Departamento de Oncología, Ciudad Real, Spain, [Martínez-Ortega,E] Hospital Ciudad de Jaén, Departamento de Oncología, Jaén, Spain, [González,MB] Hospital Son Llatzer, Departamento de Oncología, Palma de Mallorca, Spain, [Morán,M] Pfizer Madrid, Spain, [Suárez-Paniagua,B] Trial Form Support, Madrid, Spain, [Castellano,D] Hospital 12 Octubre, Departamento de Oncología, Madrid, Spain., and This study was funded by Pfizer, S.L.U. Medical writing assistance was provided by Esther Tapia, PhD and was founded by Pfizer.
Subjects: 0301 basic medicine, Male, Cancer Research, Diseases::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Urologic Neoplasms::Kidney Neoplasms [Medical Subject Headings], medicine.medical_treatment, humanos, Neoplasias renales, urologic and male genital diseases, Health Care::Health Services Administration::Patient Care Management::Disease Management [Medical Subject Headings], Targeted therapy, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, guías de práctica clínica como asunto, Renal cell carcinoma, Surgical oncology, antineoplásicos, Molecular Targeted Therapy, Neoplasm Metastasis, metástasis neoplásica, mediana edad, anciano, Health Care::Health Care Quality, Access, and Evaluation::Delivery of Health Care::Attitude to Health::Patient Acceptance of Health Care::Patient Compliance [Medical Subject Headings], Middle Aged, Kidney Neoplasms, Humanos, Oncology, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, Diseases::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Urologic Neoplasms::Kidney Neoplasms::Carcinoma, Renal Cell [Medical Subject Headings], terapia molecular selectiva, Female, Guideline Adherence, Research Article, medicine.medical_specialty, Antineoplastic Agents, Guidelines, 03 medical and health sciences, Diseases::Cardiovascular Diseases::Vascular Diseases::Hypertension [Medical Subject Headings], Internal medicine, Hipertensión, Carcinoma, medicine, Genetics, Humans, Cooperación del paciente, Adverse effect, Carcinoma, Renal Cell, Aged, neoplasias renales, Genitourinary system, business.industry, Renal Cell Carcinoma, Carcinoma de células renales, Guideline, medicine.disease, Surgery, 030104 developmental biology, Spain, Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Signs and Symptoms, Digestive::Diarrhea [Medical Subject Headings], Adverse events, business, Diarrea, Kidney cancer
Abstract: Background: The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice. Methods: Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle. Results: Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7 % out of 966 post-implementation cycles compared with 23.1 % out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33 % pre-implementation vs. 44.5 % post-implementation cycles; p < 0.0001), diarrhea (74.0 % vs. 80.5 %; p = 0.011) and dyslipemia (25.0 % vs. 44.6 %; p < 0.001). Conclusions: Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction., This study was funded by Pfizer, S.L.U. Medical writing assistance was provided by Esther Tapia, PhD and was founded by Pfizer. The authors gratefully say thanks to Ma Luz Samaniego for his help with the statistical analyses.
Published: 2016

17. Fine mapping and functional analysis of the multiple sclerosis risk gene CD6

Author: Rafael Arroyo, Bhairavi Swaminathan, Elena Urcelay, David Otaegui, Mª Jesus Pinto-Medel, Antonio Alcina, Koen Vandenbroeck, Alfredo Antigüedad, Fuencisla Matesanz, Miguel Lucas, María García-Barcina, María Fedetz, Oscar Fernandez, Eva Tolosa, Angelica Cuapio, Teresa Órpez, Javier Olascoaga, Miguel A. Ortiz, Iraide Alloza, Jorge R. Oksenberg, [Swaminathan,B, Alloza,I, Vandenbroeck,K] Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), Leioa, Spain. [Cuapio,A, Tolosa,E] Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [Matesanz,F, Alcina,A, Fedetz,M] Instituto de Parasitología y Biomedicina 'López Neyra' Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain. [García-Barcina,M] Servicio de Genética, Hospital de Basurto, Bilbao, Spain. [Fernández,O] Department of Neurology, Institute of Clinical Neurosciences, Hospital Regional Universitario Carlos Haya, Málaga, Spain. [ Lucas,M] Unidad de Esclerosis Múltiple, Hospital Virgen Macarena, Sevilla, Spain. [Orpez,T, Pinto-Medel,MJ] Research Laboratory, Institute of Clinical Neurosciences, Hospital Regional Universitario Carlos Haya, Málaga, Spain. [Otaegui,D] Área de Neurociencias, Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain. [ Olascoaga,J] Servicio de Neurología, Unidad de Esclerosis Múltiple, Hospital Donostia, San Sebastián, Spain. [Urcelay,E, Ortiz,MA] Immunology Department H. Clínico S. Carlos, Instituto de Investigación Sanitaria S. Carlos (IdISSC), Madrid, Spain. [Arroyo,R] Multiple Sclerosis Unit, Neurology Department H. Clínico S. Carlos, Instituto de Investigación Sanitaria S. Carlos (IdISSC), Madrid, Spain. [Oksenberg,JR] Department of Neurology, University of California San Francisco, San Francisco, California, United States of America. [Antigüedad,A] Servicio de Neurología, Hospital de Basurto, Bilbao, Spain. [Vandenbroeck,K] IKERBASQUE, Basque Foundation for Science, Bilbao, Spain, This work was supported from the European Community’s Seventh Framework Programme [FP7/2007–2013] under grant agreement no. 212877 (UEPHA*MS, and ref. IT512-10). UEPHA*MS (No 2121877). Ministerio de Ciencia e Innovación - FEDER (SAF2009-11491) and FIS_FEDER (CP10/00526), Junta de Andalucía-FEDER (P07-CVI-02551).
Subjects: Antigens, Differentiation, T-Lymphocyte, CD4-Positive T-Lymphocytes, Male, BIOCHEMISTRY AND MOLECULAR BIOLOGY, lcsh:Medicine, Genome-wide association study, Polimorfismo genético, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Linkage Disequilibrium, Phenomena and Processes::Genetic Phenomena::Genotype::Haplotypes [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [Medical Subject Headings], Gene Order, Cluster Analysis, Cytotoxic T cell, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, Genome-wide association, T Cells, Chromosome Mapping, Genomics, Helper 17 cells, Neurology, AGRICULTURAL AND BIOLOGICAL SCIENCES, Cytokines, Female, Haplotipos, Diseases::Immune System Diseases::Autoimmune Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Research Article, Adult, Multiple Sclerosis, Immune Cells, Immunology, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, Autoimmune Diseases, Central-nervous-system, Young Adult, 03 medical and health sciences, Antigen, Antigens, CD, Humans, SNP, Genetic Predisposition to Disease, Protein Interaction Domains and Motifs, 030304 developmental biology, Inflammation, MEDICINE, Haplotype, lcsh:R, Immunity, Timocitos, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic [Medical Subject Headings], Haplotypes, Genetic Loci, Spain, Esclerosis múltiple, estudio de asociación genómica completa, Genetic Polymorphism, Anatomy::Cells::Thymocytes [Medical Subject Headings], Clinical Immunology, Cytokine secretion, lcsh:Q, Population Genetics, CD8, 030215 immunology, Anti-CD6 monoclonal-antibody
Abstract: Art. nº e62376; v. 8; issue 4, CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2nd SRCR domain with susceptibility to MS (Pmax(T) permutation=161024). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. – CD4+ naı¨ve cells, P = 0.0001; CD8+ naı¨ve cells, P,0.0001; CD4+ and CD8+ central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4+ and CD8+ T cells., doi:10.1371/journal.pone.0062376, European Community 212877; Gobierno Vasco (Grupos de Investigacion del Sistema Universitario Vasco) IT512-10;Ministerio de Ciencia e Innovacion - FEDER SAF2009-11491;FIS_FEDER CP10/00526 ;Junta de Andalucia-FEDER P07-CVI-02551
Published: 2013

18. Genome-wide association study of multiple sclerosis confirms a novel locus at 5p13.1

Author: Guillermo Izquierdo, Laura Leyva, Serena Sanna, Fuencisla Matesanz, Magdalena Zoledziewska, Antonio Alcina, Juan Velasco, Oscar Fernández, Francesco Cucca, Agustín Ruiz, Juan Luis Ruiz-Peña, María L. Cavanillas, Rafael Arroyo, Javier Gayán, Marisa Marrosu, Ilenia Zara, Concha Moreno-Rey, María Fedetz, Antonio González-Pérez, Miguel Lucas, Maristella Pitzalis, Elena Urcelay, Luis Miguel Real, [Matesanz,F, Ruiz-Peña,JL, Izquierdo,G ] Unidad de Esclerosis Múltiple, Hospital Virgen Macarena, Sevilla, Spain. [González-Pérez,A, Gayán,J, Moreno-Rey,C, Velasco,J, Real,LM, Ruiz,A] Department of Structural Genomics, Neocodex, Sevilla, Spain. [Lucas,M] Servicio de Biología Molecular, Hospital Virgen Macarena, Sevilla, Spain. [Sanna,S, Cucca,F] Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy. [Urcelay,E, Cavanillas,ML] Immunology Department, H. Clínico S. Carlos, Instituto de Investigación Sanitaria S. Carlos (IdISSC), Madrid, Spain. [Zara,E] Center for Advanced Studies, Research and Development in Sardinia (CRS4), AGCT, Parco tecnologico della Sardegna, Pula, Italy. [Pitzalis,M, Zoledziewska,M, Cucca,F] Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy. [Arroyo,R] Multiple Sclerosis Unit, Neurology Department, H.Clínico S. Carlos, Instituto de Investigación Sanitaria S. Carlos (IdISSC), Madrid, Spain. [Marrosu,M] Dipartimento di Scienze Neurologiche e Cardiovascolari, Centro Sclerosi Multipla, Università di Cagliari, Cagliari, Italy. [Fernández,O, Leyva,L] Servicio de Neurología, Instituto de Neurociencias Clínicas, Hospital Regional Universitario Carlos Haya, Málaga, Spain. [Alcina,A, Fedetz,M] Instituto de Parasitología y Biomedicina 'López Neyra', CSIC, Granada, Spain., Funding: The Macarena MS project was supported by Neuroinvest, Carlos III, and Fonde de Investigaciones Sanitarias (FIS) grants. The project to collect and genotype the Spanish controls was supported in part by: Agencia IDEA, Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (830882), Corporación Tecnológica de Andalucía (07/124), Ministerio de Educación y Ciencia (PCT-A41502790-2007 and PCT-010000-2007-18), and Programa de Ayudas Torres Quevedo del Ministerio de Ciencia e Innovación (PTQ2002-0206, PTQ2003-0549, PTQ2003-0546, PTQ2003-0782, PTQ2003-0783, PTQ2004-0838, PTQ04-1-0006, PTQ04-3-0718, PTQ06-1-0002). CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is an ISCIII project. The validation project was supported by Fondos Europeos de Desarrollo Regional (P09-CTS-5218 FEDER), Ministerio de Ciencia e Innovación (SAF2009-11491) to Dr. Alcina, and Fondo de Investigación Sanitaria (PI081636) to Dr. Matesanz, and FIS PI10/1985. Funding support for the IMSGC GWAS of Multiple Sclerosis and the Genetic Multiple Sclerosis Associations (GeneMSA) projects were provided by National Institutes of Health (NIH) and GlaxoSmithKline, respectively, and the genotyping of samples was provided by the National Institute of Neurological Disorders and Stroke (NINDS). Some of the datasets used for the analyses described in this manuscript were obtained from the NINDS Database found at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession numbers phs000139.v1.p1 and phs000171.v1.p1. This study also makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. This Sardinian GWAS study was supported by the Fondazione Italiana Sclerosi Multipla (FISM) Cod. 2008/R/7 to Dr. Cucca, by the Italian Ministry of Scientific Research (MIUR grant 2007KXNKNP) and by US National Institutes of Health contract NO1-AG-1-2109 from National Institute of Aging (NIA) to the SardiNIA (‘ProgeNIA’) team. Sardinian GWAS authors are grateful to all cases and controls, and to the wide network of collaborators, clinicians and nurses of clinical and hospitals in the island. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Subjects: Male, Linkage disequilibrium, Desequilibrio de Ligamiento, Diseases::Digestive System Diseases::Gastrointestinal Diseases::Gastroenteritis::Inflammatory Bowel Diseases::Crohn Disease [Medical Subject Headings], Epidemiology, lcsh:Medicine, Genome-wide association study, Linkage Disequilibrium, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Crohn Disease, Named Groups::Persons::Population Groups::Continental Population Groups::European Continental Ancestry Group [Medical Subject Headings], Grupo de Ascendencia Continental Europea, lcsh:Science, Genetics, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], 0303 health sciences, Multidisciplinary, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Adulto, Estudios de Casos y Controles, Neurodegenerative Diseases, Genomics, Phenomena and Processes::Genetic Phenomena::Genetic Linkage::Linkage Disequilibrium [Medical Subject Headings], Neurology, Genetic Epidemiology, Chromosomes, Human, Pair 5, Medicine, Female, Research Article, Adult, Multiple Sclerosis, Named Groups::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Quantitative Trait Loci, Check Tags::Male [Medical Subject Headings], Locus (genetics), Single-nucleotide polymorphism, Quantitative trait locus, Biology, Diseases::Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Polymorphism, Single Nucleotide, White People, Autoimmune Diseases, 03 medical and health sciences, Young Adult, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], Genome Analysis Tools, medicine, Genome-Wide Association Studies, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], SNP, Humans, Genetic Predisposition to Disease, Enfermedad de Crohn, 030304 developmental biology, Genetic association, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Multiple sclerosis, lcsh:R, Computational Biology, Human Genetics, Sitios de Carácter Cuantitativo, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genetic Loci::Quantitative Trait Loci [Medical Subject Headings], Anatomy::Cells::Cellular Structures::Chromosomes::Chromosomes, Mammalian::Chromosomes, Human::Chromosomes, Human, 4-5::Chromosomes, Human, Pair 5 [Medical Subject Headings], medicine.disease, Demyelinating Disorders, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Molecular Epidemiology::Genome-Wide Association Study [Medical Subject Headings], Cromosomas Humanos Par 5, Esclerosis Múltiple, Check Tags::Female [Medical Subject Headings], Spain, Case-Control Studies, lcsh:Q, Clinical Immunology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36×10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS. © 2012 Matesanz et al.
Published: 2012

19. Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations

Author: Guillermo Izquierdo, Javier Gayán, Carmen Arnal, Dorothy Ndagire, Antonio Catalá-Rabasa, Agustín Ruiz, Fuencisla Matesanz, María Fedetz, Concepción Delgado, Miguel Lucas, María M. Abad-Grau, Oscar Fernández, Antonio Alcina, [Alcina, A, Fedetz, M, Ndagire, D, Catalá-Rabasa, A, Matesanz,F] Instituto de Parasitología y Biomedicina ‘López Neyra’, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain [Abad-Grau,M del M] Departamento de Lenguajes y Sistemas Informáticos, CITIC, Universidad de Granada, Granada, Spain.[Izquierdo,G, Matesanz,F] Unidad de Esclerosis Múltiple, Hospital Virgen Macarena, Sevilla, Spain.[Lucas,M] Servicio de Biología Molecular, Hospital Virgen Macarena, Sevilla, Spain. [Fernández,O] Servicio de Neurología, Instituto de Neurociencias Clínicas, Hospital Carlos Haya, Málaga, Spain. [Ruiz,A, Gayán,J] Departamento de Genómica Estructural, Neocodex, Sevilla, Spain.[Delgado,C] Centro Regional de Transfusión Sanguínea Granada-Almería, Granada, Spain.[Arnal,C] Servicio de Neurología, Hospital Virgen de las Nieves, Granada, Spain., and This work was supported by the Ministerio de Ciencia e Innovación - Fondos Feder [PN-SAF2009-11491 to AA], Junta de Andalucía [P07-CVI-02551 to AA], and Fondo de Investigación Sanitaria [FIS PI081636, CP10/00526 to FM]. MF and DN are holders of a fellowship from Fundación Española de Esclerosis Múltple (FEDEM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Subjects: Male, Genome-wide association study, Linkage Disequilibrium, Inflammatory bowel disease, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Named Groups::Persons::Population Groups::Continental Population Groups::European Continental Ancestry Group [Medical Subject Headings], Grupo de Ascendencia Continental Europea, Regulación de la Expresión Génica, Masculino, lcsh:Science, 0303 health sciences, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetics, Population [Medical Subject Headings], Genomics, Humanos, 3. Good health, Neurology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Logistic Models [Medical Subject Headings], Medicine, musculoskeletal diseases, Multiple Sclerosis, Immunology, Quantitative Trait Loci, Predisposición Genética a la Enfermedad, Check Tags::Male [Medical Subject Headings], Locus (genetics), Single-nucleotide polymorphism, Human leukocyte antigen, White People, Multiple sclerosis, 03 medical and health sciences, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens::HLA-D Antigens::HLA-DQ Antigens::HLA-DQ beta-Chains [Medical Subject Headings], Genetics, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Humans, Variant genotypes, Biology, Alleles, Haplotype, lcsh:R, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Molecular Epidemiology::Genome-Wide Association Study [Medical Subject Headings], Genetics, Population, Logistic Models, African americans, Esclerosis Múltiple, Check Tags::Female [Medical Subject Headings], lcsh:Q, Estudios de Asociación Genética, Polimorfismo de Nucleótido Simple, Gene expression, 030217 neurology & neurosurgery, Neuroscience, Desequilibrio de Ligamiento, Linkage disequilibrium, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], lcsh:Medicine, Genome-wide association studies, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genotype::Haplotypes [Medical Subject Headings], Risk Factors, HLA-DQ beta-Chains, Multidisciplinary, Cadenas HLA-DRB1, Adulto, Femenino, Phenomena and Processes::Genetic Phenomena::Genetic Linkage::Linkage Disequilibrium [Medical Subject Headings], Cadenas HLA-DRB5, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::Histocompatibility Antigens Class II::HLA-D Antigens::HLA-DQ Antigens::HLA-DQ beta-Chains [Medical Subject Headings], Female, Haplotipos, Alelos, Diseases::Immune System Diseases::Autoimmune Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Research Article, Adult, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::Histocompatibility Antigens Class II::HLA-D Antigens::HLA-DR Antigens::HLA-DR beta-Chains::HLA-DRB5 Chains [Medical Subject Headings], Polymorphism, Single Nucleotide, Estudio de Asociación del Genoma Completo, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], Systemic lupus erythematosus, Cadenas beta de HLA-DQ, Modelos Logísticos, Genetic Predisposition to Disease, Genética de Población, Allele, Genetic Association Studies, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], 030304 developmental biology, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Sitios de Carácter Cuantitativo, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genetic Loci::Quantitative Trait Loci [Medical Subject Headings], Demyelinating Disorders, HLA-DRB5 Chains, Gene Expression Regulation, Haplotypes, Expression quantitative trait loci, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone. Â© 2012 Alcina et al.
Published: 2012

20. Validation of the spanish version of the multiple sclerosis international quality of life (musiqol) questionnaire

Author: Oscar, Fernández, Victoria, Fernández, Karine, Baumstarck-Barrau, Luis, Muñoz, Maria del Mar, Gonzalez Alvarez, José Carlos, Arrabal, Antonio, León, Ana, Alonso, Jose Carlos, López-Madrona, Rafael, Bustamante, Gloria, Luque, Miguel, Guerrero, Elisabetta Verdun, di Cantogno, Pascal, Auquier, D, Rodriguez, MusiQoL Study group of Spain, [Fernández,O, Muñoz,L, Gonzalez Alvarez,MM, Arrabal,JC, León,A, Alonso,A, Lopez-Madrona,JC, Bustamante,R, Luque,G] Institute of Clinical Neurosciences. Service of Neurology. Hospital Regional Universitario Carlos Haya. [Fernández,V, Guerrero,M] Institute of Clinical Heurosciences. Service of Neurophisology. Hospital Regional Universitario Carlos Haya. [Baumstarck-Barray,K, Auquier, P] Department of Public Health, EA3279 Research Unit, University Hospital, Marseille. [Verdun di Cantogno,E] Global Medical Affairs Neurology. Merck Serono S.A. Geneva., This work has been performed using a grant from Merck-Serono S.A. - Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany, and MusiQoL study group of Spain
Subjects: Adult, Male, medicine.medical_specialty, Spanish Version, Multiple Sclerosis, Intraclass correlation, Clinical Neurology, Validity, Check Tags::Male [Medical Subject Headings], Clinical Global Impression, lcsh:RC346-429, External validity, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Publication Characteristics::Study Characteristics::Validation Studies [Medical Subject Headings], Cronbach's alpha, Quality of life, Surveys and Questionnaires, medicine, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Humans, Expand Disability Status Scale, Humanities::Humanities::Philosophy::Life::Quality of Life [Medical Subject Headings], Reliability (statistics), lcsh:Neurology. Diseases of the nervous system, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Publication Characteristics::Study Characteristics::Multicenter Study [Medical Subject Headings], business.industry, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Questionnaires [Medical Subject Headings], Reproducibility of Results, Spanish version, General Medicine, Checklist, Check Tags::Female [Medical Subject Headings], Spain, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Evaluation Studies as Topic::Reproducibility of Results [Medical Subject Headings], Physical therapy, Quality of Life, Female, Neurology (clinical), business, Diseases::Immune System Diseases::Autoimmune Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Research Article
Abstract: ditional file 1: table s1a: List of the 31 MusiQol items (english version). Complete list of the 31 MusiQol items used in t he English version. Additional file 2: Table s1b: List of the 31 MusiQol items (Spahish version). Complete list of the 31 MusiQol items used in the Spanish version.The MusiQoL study group of Spain consisted of the following investigators: Hospital Regional Universitario Carlos Haya, Málaga: O Fernández; Hospital de Bellvitge, Barcelona: T Arbizu; Hospital Gregorio Marañón, Madrid: C de Andrés; Hospital Universitario La Fe, Valencia: B Casanova, IB Blasco; Hospital Clínico Universitario, Zaragoza: C Íñiguez; Hospital Central de Asturias, Oviedo: DF Diaz; Hospital Universitario San Cecilio, Granada: M Guerrero; Hospital Universitario Dr. Josep Trueta, Girona: L Ramió; Hospital de Sabadell, Barcelona: MM Igual; Hospital Ramón y Cajal, Madrid: S Calleja; Mutua de Terrassa, Barcelona: IB Ibars; Hospital Arnau de Vilanova, Lleida: P Granes, L Brieva; Hospital del Mar, Barcelona: EM Olivas; Hospital Clínico Universitario de Valencia, Valencia; F Coret; Hospital Virgen de las Nieves, Granada: C Arnal; Complejo Hospitalaria de Jaén, Jaén: MH Pérez; Hospital de Alarcos, Ciudad Real: M Gudín; Hospital del Bierzo, Ponferrada, León: DP Ruiz; Hospital de Cruces, Baracaldo, Bilbao: M Mendibe; Hospital Univ. Virgen de la Arrixaca, Murcia: J Meca; Hospital de Cabueñes, Gijón: S Sanchez; Complejo Hospitalario de Orense, Orense: D Rodriguez. BACKGROUND: The Multiple Sclerosis International Quality Of Life (MusiQoL) questionnaire, a 31-item, multidimensional, self-administrated questionnaire that is available in 14 languages including Spanish, has been validated using a large international sample. We investigated the validity and reliability of the Spanish version of MusiQoL in Spain. METHODS: Consecutive patients with different types and severities of multiple sclerosis (MS) were recruited from 22 centres across Spain. All patients completed the MusiQoL questionnaire, the 36-Item Short Form (SF-36) health survey, and a symptoms checklist at baseline and 21 days later. External validity, internal consistency, reliability and reproducibility were tested. RESULTS: A total of 224 Spanish patients were evaluated. Dimensions of MusiQoL generally demonstrated a high internal consistency (Cronbach's alpha: 0.70-0.92 for all but two MusiQoL domain scores). External validity testing revealed that the MusiQoL index score correlated significantly with all SF-36 dimension scores (Pearson's correlation: 0.46-0.76), reproducibility was satisfactory (intraclass correlation coefficient: 0.60-0.91), acceptability was high, and the time taken to complete the 31-item questionnaire was reasonable (mean [standard deviation]: 9.8 [11.8] minutes). CONCLUSIONS: The Spanish version of the MusiQoL questionnaire appears to be a valid and reliable instrument for measuring quality of life in patients with MS in Spain and constitutes a useful instrument to measure health-related quality of life in the clinical setting. Yes
Published: 2011

21. TRAIL/TRAIL Receptor System and Susceptibility to Multiple Sclerosis

Author: Elena Urcelay, Juan Antonio García-León, Cristina Guijarro-Castro, Begoña Oliver-Martos, Margarita Suardíaz, Julián Benito-León, Isidro Prat, Jezabel Varadé, Roberto Alvarez-Lafuente, Oscar Fernández, Carlos López-Gómez, María Jesús Pinto-Medel, Laura Leyva, Jesús Ortega-Pinazo, Lucía García-Trujillo, [López,C, García,JA, Pinto,MJ, Oliver,B, Ortega,J, Suardíaz,M, Leyva,L] Research Laboratory, Clinical Neurosciences Institute, Hospital Universitario Carlos Haya and Fundación IMABIS, Málaga, Spain. [Fernández,O] Departament of Neurology, Clinical Neurosciences Institute, Hospital Regional Universitario Carlos Haya and Fundación IMABIS, Málaga, Spain. [Guijarro,C, Benito,J] Departament of Neurology, University Hospital 12 de Octubre, Madrid, Spain. [Benito,J] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid. Spain. Department of Medicine, Complutense University, Madrid, Spain. [Prat,I] Transfusion Center Blood Bank, Málaga, Spain. [Varadé,J, and Urcelay,E] Department of Immunology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain. [Álvarez,R] Department of Neurology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain.
Subjects: Male, Candidate gene, Susceptibilidad a Enfermedades, España, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Cohort Studies, TNF-Related Apoptosis-Inducing Ligand, Mediana Edad, Genotype, Genetics of the Immune System, Receptor, Masculino, Adolescente, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Multidisciplinary, Multiple Esclerosis, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Adulto, Femenino, Estudios de Casos y Controles, Adulto Joven, Genomics, Middle Aged, Humanos, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Death Domain::Receptors, TNF-Related Apoptosis-Inducing Ligand [Medical Subject Headings], Receptores del Ligando Inductor de Apoptosis Relacionado con TNF, Neurology, Named Groups::Persons::Age Groups::Adolescent [Medical Subject Headings], Medicine, Female, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Disease Susceptibility, Diseases::Immune System Diseases::Autoimmune Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Research Article, Adult, Multiple Sclerosis, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors::TNF-Related Apoptosis-Inducing Ligand [Medical Subject Headings], Named Groups::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Adolescent, Clinical Research Design, Science, Anciano, Phenomena and Processes::Physiological Phenomena::Body Constitution::Disease Susceptibility [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Autoimmune Diseases, Young Adult, Genomic Medicine, medicine, Genetic predisposition, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Humans, Allele, Named Groups::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Gene, Aged, Ligando Inductor de Apoptosis Relacionado con TNF, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Multiple sclerosis, medicine.disease, Demyelinating Disorders, Receptors, TNF-Related Apoptosis-Inducing Ligand, Check Tags::Female [Medical Subject Headings], Spain, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Case-Control Studies, Immunology, Clinical Immunology, Polimorfismo de Nucleótido Simple, Estudios de Cohortes, Genotipo
Abstract: The authors acknowledge the support from Fondo de Investigación Sanitaria & Fondo Europeo de Desarrollo Regional (PS09/01764) and Consejería de Salud de la Junta de Andalucía (SAS07/0231) to LL, and from Consejería de Innovación (P07-CTS-03223) to OF. The authors also thank the “Red Temática de Investigación Cooperativa Red Española de Esclerosis Múltiple REEM (RD07/0060/0019)” and Fundación Española de Esclerosis Múltiple (FEDEM). CLG is a holder of a fellowship from Consejería de Salud de la Junta de Andalucía (PI 0231-2007), MJPM is a holder of a FIS fellowship (PI 05/1878); JAGL and MS are holders of fellowships from Consejería de Innovación de la Junta de Andalucía (P07-0223). The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values
Published: 2011

22. Human Endogenous Retrovirus HERV-Fc1 Association with Multiple Sclerosis Susceptibility: A Meta-Analysis

Author: Ianire Astobiza, Guillermo Izquierdo, Elena Urcelay, María Fedetz, Laura Leyva, Koen Vandenbroeck, Fuencisla Matesanz, Jezabel Varadé, Rafael Arroyo, Alfredo Antigüedad, Marta Garcia-Montojo, Roberto Alvarez-Lafuente, Iraide Alloza, Antonio Alcina, Oscar Fernández, Belén de la Hera, [Hera,B de la, Varadé,J, Urdelay,E] Immunology Dept., Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. [García-Montojo,M, Arroyo,R, Álvarez-Lafuente,R] Multiple Sclerosis Unit, Neurology Dept., Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. [Alcina,A, Fedetz,M, Matesanz,F] Instituto de Parasitología y Biomedicina ‘‘López Neyra’’, Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain. [Alloza,I, Astobiza,I, and Vandenbroeck,K] Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain. [Leyva,L] Laboratorio de Investigación, Instituto de Neurociencias Clínicas, Hospital Regional Universitario, Málaga, Spain. [Fernández,O] Servicio de Neurología, Instituto de Neurociencias Clínicas, Hospital Regional Universitario, Málaga, Spain. [Izquierdo,G] Unidad de Esclerosis Múltiple, Hospital Virgen Macarena, Sevilla, Spain. [Antigüedad,A] Servicio de Neurología, Hospital de Basurto, Bilbao, Spain. [Vandenbroeck,K] Achucarro Basque Center for Neuroscience – UPV/EHU, Zamudio, Spain. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
Subjects: Male, epstein-barr-virus, BIOCHEMISTRY AND MOLECULAR BIOLOGY, Epidemiology, viruses, España, Prevalence, lcsh:Medicine, Endogenous retrovirus, Polimorfismo genético, Genome-wide association study, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Cohort Studies, Named Groups::Persons::Population Groups::Continental Population Groups::European Continental Ancestry Group [Medical Subject Headings], linkcage, lcsh:Science, risk-factors, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Chromosomes::Sex Chromosomes::X Chromosome [Medical Subject Headings], X chromosome, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Genetics, Multidisciplinary, Statistics, Middle Aged, Humanos, Neurology, AGRICULTURAL AND BIOLOGICAL SCIENCES, Genetic Epidemiology, Named Groups::Persons::Population Groups::Ethnic Groups [Medical Subject Headings], Female, Disease Susceptibility, Research Article, Adult, Multiple Sclerosis, Estudios de cohortes, Esclerosis multiple, Retrovirus endógenos, Single-nucleotide polymorphism, Biostatistics, Biology, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome [Medical Subject Headings], Autoimmune Diseases, Cromosoma X, expression, medicine, Diseases::Nervous System Diseases::Demyelinating Diseases::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Humans, Grupo de ascendencia continental europea, Allele, Organisms::Viruses::RNA Viruses::Retroviridae::Endogenous Retroviruses [Medical Subject Headings], Gene, Genoma, MEDICINE, Multiple sclerosis, lcsh:R, Endogenous Retroviruses, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic [Medical Subject Headings], medicine.disease, Demyelinating Disorders, Grupos étnicos, flip-flop, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Genetics of Disease, Immunology, Genetic Polymorphism, lcsh:Q, Clinical Immunology, Population Genetics, Mathematics
Abstract: Background Human endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts. Methods A single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls), Central (883 patients and 692 controls) and Southern (1021 patients and 1359 controls) Spain. Our results were pooled in a meta-analysis with previously published data. Results Significant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association [rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI) = 1.27 (1.11–1.45)]. Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed [pM-H = 0.0003, ORM-H (95% CI) = 1.32 (1.14–1.53)]. Conclusion Association of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts.
Published: 2014
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23. Guillain-Barré syndrome following the 2009 pandemic monovalent and seasonal trivalent influenza vaccination campaigns in Spain from 2009 to 2011: outcomes from active surveillance by a neurologist network, and records from a country-wide hospital discharge database

Author: Alcalde Cabero, Enrique, Almazan Isla, Javier, García López, Fernando J., Ara Callizo, José Ramón, Avellanal, Fuencisla, Casasnovas Pons, Carlos, Cemillán, Carlos, Cuadrado, José Ignacio, Duarte, Jacinto, Fernández Pérez, María Dolores, Fernández, Óscar, García Merino, Juan Antonio, García Montero, Rosa, Montero, Dolores, Pardo, Julio, Rodríguez Rivera, Francisco Javier, Ruiz Tovar, María, Pedro Cuesta, Jesús de, Spanish GBS Epidemiology Study Group, Universitat de Barcelona, Spanish GBS Epidemiology Study Group, [Alcalde-Cabero,E, Almazán-Isla,J, García López,FJ, Avellanal,F, Ruiz Tovar,M, and de Pedro-Cuesta,J] National Centre for Epidemiology, CIBERNED, Carlos III Health Institute, Madrid, Spain. [Ara-Callizo,JR] Neurology Department, Miguel Servet University Hospital, Zaragoza, Spain. [Casasnovas,C] Neuromuscular Unit, Neurology Department, Bellvitge University Hospital, Bellvitge. Biomedical Research Institute (Institut d’Investigació Biomèdica de Bellvitge/IDIBELL), L’Hospitalet de Llobregat, Spain. [Cemillán,C] Neurology Department, Severo Ochoa University Hospital, Leganés, Madrid, Spain. [Cuadrado,JI] Epidemiology Department, Regional Ministry of Health, Madrid Autonomous Region, Spain. [Duarte,J] Neurology Department, General Hospital, Segovia, Spain. [Fernández-Pérez,MD] Neurology Department, Virgen de las Nieves University Hospital, Granada, Spain. [Fernández,O] Neurology Department, Carlos Haya University Hospital, Málaga, Spain. [García Merino,JA] Neurology Department, Puerta de Hierro University Hospital, Majadahonda, Madrid, Spain. [García Montero,R] Neurology Department, Virgen de la Salud Hospital, Toledo, Spain. [Montero,D] Spanish Medicines & Medical Devices Agency (Agencia Española de Medicamentos y Productos Sanitarios), Madrid, Spain. [Pardo,J] Neurology Department, University Teaching Hospital Clínico, Santiago de Compostela (Corunna), Spain. [Rodríguez-Rivera,FJ] Neurology Department, La Paz University Hospital, Madrid, Spain.
Subjects: Male, Pediatrics, Hospitales generales, Time Factors, Síndrome de Guillain-Barré, Databases, Factual, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies::Retrospective Studies [Medical Subject Headings], Autoimmune diseases, España, Vacunas contra la influenza, Proyectos piloto, ICD-9-CM, Vacunes, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Influenza A Virus, H1N1 Subtype, Public health surveillance, Estudios prospectivos, Pandemic, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy::Immunization [Medical Subject Headings], Peripheral nerves, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Vaccines, Guillain-Barre syndrome, Malalties autoimmunitàries, Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::Hospitals::Hospitals, General [Medical Subject Headings], Incidence (epidemiology), Incidence, virus diseases, Síndrome de Miller Fisher, General Medicine, Middle Aged, Guillain-Barré syndrome, Phenomena and Processes::Physical Phenomena::Time::Periodicity::Seasons [Medical Subject Headings], Vaccination, Influenza vaccines, Chemicals and Drugs::Complex Mixtures::Biological Agents::Vaccines::Viral Vaccines::Influenza Vaccines [Medical Subject Headings], Inmunización, Epidemiological Monitoring, Sistema de registros, Female, Disciplines and Occupations::Health Occupations::Medicine::Neurology [Medical Subject Headings], Safety, Incidencia, Research Article, Subtipo H1N1 del virus de la influenza A, Trivalent influenza vaccine, Adult, Information Science::Information Science::Information Services::Documentation::Vocabulary, Controlled::International Classification of Diseases [Medical Subject Headings], medicine.medical_specialty, Phenomena and Processes::Mathematical Concepts::Probability::Risk [Medical Subject Headings], Clinical Neurology, Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebellar Diseases::Miller Fisher Syndrome [Medical Subject Headings], Nervis perifèrics, Estaciones del año, Guillain-Barre Syndrome, Riesgo, Influenzavirus, Clasificación internacional de enfermedades, Grip, Estudios retrospectivos, 03 medical and health sciences, Neuritis, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::Incidence [Medical Subject Headings], Organisms::Viruses::RNA Viruses::Orthomyxoviridae::Influenzavirus A::Influenza A virus::Influenza A Virus, H1N1 Subtype [Medical Subject Headings], Gripe Humana, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], medicine, Humans, Influenza viruses, Neurologists, Diseases::Nervous System Diseases::Neuromuscular Diseases::Peripheral Nervous System Diseases::Neuritis [Medical Subject Headings], Intensive care medicine, Pandemics, Aged, Retrospective Studies, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Pilot Projects [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy::Immunization::Immunotherapy, Active::Vaccination [Medical Subject Headings], business.industry, Vacunación, Retrospective cohort study, medicine.disease, Diseases::Nervous System Diseases::Autoimmune Diseases of the Nervous System::Polyradiculoneuropathy::Guillain-Barre Syndrome [Medical Subject Headings], Influenza, Spain, Influenza A virus H1N1 subtype, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Registries [Medical Subject Headings], Neurology (clinical), Diseases::Virus Diseases::RNA Virus Infections::Orthomyxoviridae Infections::Influenza, Human [Medical Subject Headings], business, 030217 neurology & neurosurgery
Abstract: BACKGROUND: Studies have shown a slight excess risk in Guillain-Barré syndrome (GBS) incidence associated with A(H1N1)pdm09 vaccination campaign and seasonal trivalent influenza vaccine immunisations in 2009-2010. We aimed to assess the incidence of GBS as a potential adverse effect of A(H1N1)pdm09 vaccination. METHODS: A neurologist-led network, active at the neurology departments of ten general hospitals serving an adult population of 4.68 million, conducted GBS surveillance in Spain in 2009-2011. The network, established in 1996, carried out a retrospective and a prospective study to estimate monthly alarm thresholds in GBS incidence and tested them in 1998-1999 in a pilot study. Such incidence thresholds additionally to observation of GBS cases with immunisation antecedent in the 42 days prior to clinical onset were taken as alarm signals for 2009-2011, since November 2009 onwards. For purpose of surveillance, in 2009 we updated both the available centres and the populations served by the network. We also did a retrospective countrywide review of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis from January 2009 to December 2011. RESULTS: Among 141 confirmed of 148 notified cases of GBS or Miller-Fisher syndrome, Brighton 1-2 criteria in 96 %, not a single patient was identified with clinical onset during the 42-day time interval following A(H1N1)pdm09 vaccination. In contrast, seven cases were seen during a similar period after seasonal campaigns. Monthly incidence figures did not, however, exceed the upper 95 % CI limit of expected incidence. A retrospective countrywide review of the registry of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis did not suggest higher admission rates in critical months across the period December 2009-February 2010. CONCLUSIONS: Despite limited power and underlying reporting bias in 2010-2011, an increase in GBS incidence over background GBS, associated with A(H1N1)pdm09 monovalent or trivalent influenza immunisations, appears unlikely Sí

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23. Guillain-Barré syndrome following the 2009 pandemic monovalent and seasonal trivalent influenza vaccination campaigns in Spain from 2009 to 2011: outcomes from active surveillance by a neurologist network, and records from a country-wide hospital discharge database

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