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4. Cirugía abdominal y embarazo

Author

P. Troncoso C., C. Fernández O., and M. Allende M.

Subjects
Abdomen -- Cirugía, Embarazo, Medicine
Abstract

La incidencia de patologías que afectan a la mujer grávida y en particular las de terapéuticas quirúrgica, constituyen factores de riesgo de morbimortalidad maternofetal y plantean complejos problemas de diagnóstico y decisión terapéutica. Las patologías quirúrgicas abdominales revisten una particular dificultad, por las modificaciones anatómicas propias de la gravidez y por los cambios fisiológicos que modifican algunos parámetros de laboratorio utilizados habitualmente en el diagnóstico, lo que obliga a interpretarlos con cautela. El Comité Editorial del Boletín de la Escuela de Medicina, ha considerado de la mayor utilidad para el médico general, entregar una revisión de la literatura nacional y extranjera, sobre el tema de la cirugía abdominal y embarazo. Se ha encomendado al Dr. Lorenzo Cubillos, como Editor Invitado, la preparación de una serie de artículos que cubrirán secuencialmente este campo.

Published
2017
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6. 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

7. 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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8. 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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9. 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

10. Consumo de tabaco y uso del consejo médico estructurado como estrategia preventiva del tabaquismo en médicos chilenos

Author

M. Virginia Araya A, Francisco Leal S, Patricio Huerta G, Nora Fernández A, Gonzalo Fernández O, and Juan P Millones E

Subjects
Gerontology, Questionnaires, medicine.medical_specialty, Preventive strategy, business.industry, Smoking habit, Smoking, General Medicine, Affect (psychology), Clinical Practice, Medical advice, Family medicine, Physicians, Health care, Tobacco, medicine, Risk factor, business
Abstract

THE INFLUENCE OF SMOKING HABITS OF CHILEAN PHYSICIANS ON THE USE OF THE STRUCTURED MEDICAL ADVICE ABOUT SMOKING Background: Structured medical advice on smoking is the prevention strategy with better cost-effectiveness ratio. Aim: To evaluate smoking among health care providers affect the application of this preventive strategy. Material and methods: 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. Results: 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. Conclusions: To improve physician's compliance with their preventive role in clinical practice it is essential to consider their smoking habits, and the information and attitudes that they have towards smoking as a cardiovascular risk factor. Normal 0 21 false false false MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Tabla normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-ansi-language:#0400; mso-fareast-language:#0400; mso-bidi-language:#0400;}

Published
2012

11. Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome

Author

Hartung, Hp, 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, Kováøová, 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, Steinke, W, Kölmel, H, Oschmann, P, Diem, R, Dressel, A, Hoffmann, F, Baum, K, Jung, S, Petereit, Hf, 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, Montalba, 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. ., Neurology, Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Multiple Sclerosis, Injections, Subcutaneous, Relapse rate, Brain mri, Medicine, Humans, Longitudinal Studies, Prospective Studies, Clinically isolated syndrome, biology, business.industry, Immunogenicity, Interferon-beta, Antibodies, Neutralizing, Titer, Interferon β 1b, Cross-Sectional Studies, Immunology, biology.protein, Neurology (clinical), Antibody, business, Demyelinating Diseases, Follow-Up Studies, Interferon beta-1b
Abstract

To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b).In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 μg IFNβ-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNβ-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer20 NU/mL was considered NAb-positive, with low (≥20-100 NU/mL), medium (≥100-400 NU/mL), and high (≥400 NU/mL) titer categories. Here we examine early-treated patients, who received IFNβ-1b for up to 5 years.NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers.Although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNβ-1b and may also result from temporal changes in NAb titers and biology.

Published
2011
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12. Reporte de cuatro casos clínicos de bacteriemia por Hafnia alvei en una unidad cardio-quirúrgica pediátrica

Author

Mercedes Troncoso V, Cecilia Nuñez F, Jorge Fernández O, Pamela Araya R, Claudia Moreno M, Walter Ledermann D., Paulina Coria De la H, Alda Fernández R., and Gladys Del Valle M.

Subjects
Gynecology, medicine.medical_specialty, Fatal outcome, business.industry, hemocultivos, Public Health, Environmental and Occupational Health, Recem nascido, Hafnia alvei, Infectious Diseases, pediátrico, medicine, Bacteriemia, business
Abstract

Introduccion: Hajhia alvei, bacilo Gram negativo, constituye la unica especie del genero Hajhia, familia Enterobacteriaceae. En el humano se comporta ocasionalmente como oportunista produciendo infeccion intestinal, respiratoria y sepsis. Es causa infrecuente de bacteriemias, generalmente de foco infeccioso desconocido. Objetivo: Describir un brote intrahospitalario de cuatro pacientes pediatricos con bacteriemias por Hajhia alvei. Metodo: Estudio descriptivo retrospectivo de los registros clinicos de cuatro pacientes pediatricos con diagnostico de bacte-riemia por Hajhia alvei en una unidad cardioquirurgica pediatrica identificados en octubre del 2008. Resultados: La tasa de ataque fue 4/8 (50%), tasa de letalidad 2/4 (50%) y de mortalidad de 2/8 (25%). El estudio micro-biologico y la electroforesis de campo pulsado confirman la misma cepa bacteriana clonal. Discusion: Se identifico el origen de la bacteriemia solo en dos pacientes asociado a cateter venoso central. Los otros dos casos no tuvieron foco infeccioso conocido. Se debe mantener vigilancia epidemiologica de agentes emergentes.

Published
2010

13. 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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14. 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

15. Infección por Leuconostoc en pacientes con síndrome de intestino corto, nutrición parenteral y alimentación enteral continua

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
alimentación enteral, medicine.drug_class, Antibiotics, Enteral administration, Microbiology, Sepsis, Ampicillin, medicine, Leuconostoc, síndrome de intestino corto, nutrición parenteral, biology, business.industry, Public Health, Environmental and Occupational Health, food and beverages, bacteriemia, medicine.disease, biology.organism_classification, Infectious Diseases, Bacteremia, Vancomycin, Leuconostoc garlicum, business, Meningitis, medicine.drug
Abstract

Leuconostoc es una cocácea grampositiva parecida a los Streptococcus, que se encuentra ampliamente distribuida en la naturaleza; es usada en la industria de vinos, productos lácteos y quesos para la producción de aromas y texturas. Leuconostoc causa ocasionalmente infecciones en humanos, puede producir bacteriemia, infección asociada a catéter, síndrome séptico, meningitis, neumonía, infección del tracto urinario, osteomielitis y compromiso hepático, entre otros. Se describen como factores de riesgo para una infección por este agente: el síndrome de intestino corto, uso de catéter venoso central y la alimentación enteral por gastrostomía. Orientan a la presencia de este agente el aislamiento de una cocácea grampositiva, catalasa negativa, PYR y LAP negativas, resistente a vancomicina. El tratamiento de elección es penicilina o ampicilina

Published
2006

16. Forma familiar de la enfermedad de Creutzfeldt-Jakob: marcadores genéticos en 4 familias chilenas

Author

Luis Cartier R, Eugenio Ramírez, and Jorge Fernández O

Subjects
Genetics, Mutation, Gene components, PrPSc proteins, General Medicine, Biology, Creutzfeldt-Jakob Syndrome, medicine.disease_cause, law.invention, nervous system diseases, Genetic marker, law, Genotype, mental disorders, medicine, Familial Creutzfeldt-Jakob, Genetic predisposition, CJD (Creutzfeldt-Jakob disease), Gene, Polymerase chain reaction
Abstract

Background: 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. Aim: To search susceptibility genetic markers of CJD in members of families affected by CJD. Material and methods: 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. Results: 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. Conclusions: 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

17. Estudio clínico y determinación de la parasitemia en un grupo de pacientes infectados por Trypanosoma cruzi de la región de Atacama, Chile

Author

María Isabel Jercic L, Juan Rivera Q, Luis González A, Eugenio Ramírez, Mauricio Carrasco, Claudio Miranda C, Winston Andrade L, Jorge Fernández O, and Jorge González

Subjects
Chagas disease, Cardiomyopathy, Trypanosoma cruzi, General Medicine, Parasitemia, Biology, medicine.disease, biology.organism_classification, Molecular biology, Polymerase chain reaction, congestive, parasitic diseases, medicine
Abstract

Trypanosoma cruzi infection is endemic in Northern/Central Chile. Aim: To perform a clinical assessment of patients infected with Trypanosoma cruzi. Patients and methods: Two hundred sixty three subjects with a positive serology for Trypanosoma cruzi, were invited by mail to a clinical assessment in a Regional Hospital. In a subsample of these, a polymerase chain reaction for Trypanosoma cruzi, was done. Results: Of all the invited subjects, 183 responded and were assessed at the hospital. Of these, 60 had cardiac affections, 52 had colon problems and 17, esophageal disease. Seventy four were asymptomatic. Of the 64 patients in whom polymerase chain reaction was done, 35 had a positive result. Conclusions: A high percentage of subjects infected with Trypanosoma cruzi, had clinical consequences of the infection. Polymerase chain reaction showed persistency of the parasite in more than half of the infected patients (Rev Méd Chile 2003; 131: 881-6)

Published
2003

18. Epidemiología molecular de un brote de infecciones por Streptococcus pyogenes en una unidad de quemados

Author

Catalina Alonso M, Ana María Frola M, María Teresa Ulloa F, Soledad Prat M., Erna Cona T, Germán Ebensperger D, Andrea Galanti D, Jorge Fernández O, and Alberto Fica C

Subjects
Molecular epidemiology, Streptococcus pyogenes, Outbreak, Toxic shock syndrome, General Medicine, Biology, medicine.disease_cause, medicine.disease, Group A, RAPD, Microbiology, law.invention, law, Molecular sequence data, medicine, Pulsed-field gel electrophoresis, Molecular probe technics, Disease outbreaks, Polymerase chain reaction
Abstract

Group A Streptococcal (GAS) infections have increased in frequency and severity worldwide. During April 1996, a nosocomial outbreak associated to GAS infections affected seven patients admitted to a pediatric burn unit. The causative organism was likely disseminated from the source patient to another child in the emergency room before he was transferred to the burn unit. Patients developed burn infections or invasive disease. One of them died due to a toxic shock syndrome and 3 other lost their skin grafts. Perineal and nasal microbiological surveillance of 42 related health care workers identified only one of them as carrier of S pyogenes. Aim: To report a molecular analysis of an apparently clonal outbreak. Material and methods: The available isolates were analyzed by molecular methods including random amplified polymorphic DNA analysis (RAPD) with 4 different primers, Sma-I pulsed field gel electrophoresis (PFGE) analysis, and speA, speB and speC detection by polymerase chain reaction (PCR). Results: Two phylogenetically distant and sequentially isolated bacterial groups were identified either by RAPD analysis with selected primers or by Smal-PFGE analysis. The first group involved isolates identified in two patients that included the lethal case. The second bacterial group comprised 5 clinical isolates and the perineal and nasal isolates obtained from a health care worker. Only strains belonging to the first group harbored the speA gene and were associated with invasive disease. The second group could be split further in two subgroups according to their speB profile. Conclusions: RAPD analysis with selected primers can reproduce the PFGE-discriminating ability on the epidemiological analysis of GAS infections (Rev Med Chile 2003; 131: 145-54)

Published
2003

19. Alteraciones subclínicas de la atención en accidentes isquémicos transitorios de la región vertebrobasilar

Author

Alonso E, Alvarez Ma, Mestre R, Calixto Machado, Pando A, Fernández O, and Barroso E

Subjects
medicine.medical_specialty, Physical medicine and rehabilitation, business.industry, Medicine, Cognition, In patient, Neurology (clinical), General Medicine, Attention deficits, Attention disorders, business, Affect (psychology), Subclinical infection
Abstract

INTRODUCTION A significant number of patients who have had cerebrovascular illness apparently recover their former abilities completely but return to normal life with subtle cognitive deficits which may affect their daily lives. Such is the situation of patients with transitory ischemic accidents who present with sustained, undiagnosed attention deficits. OBJECTIVES To identify subclinical alterations due to attention deficits in patients with transitory ischemic accidents, and to contribute to the study of the physiopathological mechanisms involved in the integration of this function. PATIENTS AND METHODS We examined 44 persons, divided into three groups for this study: one group had vertebro-basilar transitory ischemic accidents, a second group had supratentorial infarct and a third was healthy. All were given a specially designed computerized test of continuous work to evaluate the sustained attention component. RESULTS Significant differences were found between the transitory ischemic accidents and healthy groups, regarding the variables including correct answers, omissions and indications of attention. This was not seen with the variables involving reaction time and number of errors. This demonstrated the existence of attention disorders involving omission in the group of patients with transitory ischemic accidents. CONCLUSION These findings suggest the hypothesis that in the vertebro-basilar region there are important mechanisms involved in the process of sustained attention.

Published
1999
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20. 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

21. Neuronal Metabolism and Neuroprotection: Neuroprotective Effect of Fingolimod on Menadione-Induced Mitochondrial Damage

Author

Nadia Valverde, Silvana-Yanina Romero-Zerbo, Silvia Claros, José Pavia, María García-Fernández, Federica Boraldi, Estrella Lara, Elisa Martín-Montañez, Antonio Gil, Oscar Fernández, [Gil,A, Martín-Montañez,E, Fernández,O, Pavia,J] Department of Pharmacology and Pediatrics, Faculty of Medicine, Malaga University, Malaga, Spain. [Martín-Montañez,E, Valverde,N, Lara,E, Claros,S, Pavia,J, Garcia-Fernandez,M] Neuroscience Unit, Biomedical Research Institute of Malaga (IBIMA), Malaga University Hospital, Malaga, Spain. [Valverde,N, Romero-Zerbo,SY, Garcia-Fernandez,M] Department of Human Physiology, Faculty of Medicine, Malaga University, Malaga, Spain. [Boraldi,F] Department of Life Sciences, University of Modena e Reggio Emilia, Modena, Italy., This research was supported by the following projects: PS13/14: Study of the non immunological mechanisms of action of Gilenya (Fingolimod) as therapeutic tool in Multiple Sclerosis and/or other neurodegenerative diseases, Novartis Farmacéutica S.A., and CTS507 and CTS156 from Consejería de Economía Innovación Ciencia y Empresa, Junta de Andalucía. N. Valverde was supported by Proyectos I+D+I-Programa Operativo FEDER Andalucía 2014-2020 (UMA18-FEDERJA 004) Junta de Andalucía and Fondo Social Europeo (EU).

Subjects
Antioxidant, Receptores de esfingosina-1-fosfato, mitochondrial damage, medicine.medical_treatment, Pharmacology, Antioxidants, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Antioxidants [Medical Subject Headings], chemistry.chemical_compound, Mice, Anatomy::Cells::Cells, Cultured::Cell Line [Medical Subject Headings], Menadione, Organisms::Eukaryota::Animals [Medical Subject Headings], Homeostasis, Glycolysis, Phenomena and Processes::Metabolic Phenomena::Metabolism::Oxidative Stress [Medical Subject Headings], lcsh:QH301-705.5, Anatomy::Nervous System::Neurons [Medical Subject Headings], Mitocondrias, Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria [Medical Subject Headings], Phenomena and Processes::Metabolic Phenomena::Metabolism::Carbohydrate Metabolism::Glycolysis [Medical Subject Headings], Neurons, Chemistry, Neuroprotección, Vitamin K 3, Neurodegenerative Diseases, General Medicine, Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Polycyclic Hydrocarbons, Aromatic::Naphthalenes::Naphthoquinones::Vitamin K::Vitamin K 3 [Medical Subject Headings], Fingolimod, Neuroprotection, Mitochondria, Neuroprotective Agents, medicine.drug, sphingosine-1-phosphate receptor analogue, fingolimod phosphate, neuroprotection, glycolytic pathway, pentose phosphate pathway, redox homeostasis, Oxidative phosphorylation, Pentose phosphate pathway, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Protective Agents::Neuroprotective Agents [Medical Subject Headings], Article, Cell Line, Oxidación-reducción, Vía de la pentosa-fosfato, Diseases::Nervous System Diseases::Neurodegenerative Diseases [Medical Subject Headings], medicine, Animals, Sphingosine-1-Phosphate Receptors, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Protein nitrosylation, Fingolimod Hydrochloride, Glucólisis, Oxidative Stress, lcsh:Biology (General)
Abstract

Imbalance in the oxidative status in neurons, along with mitochondrial damage, are common characteristics in some neurodegenerative diseases. The maintenance in energy production is crucial to face and recover from oxidative damage, and the preservation of different sources of energy production is essential to preserve neuronal function. Fingolimod phosphate is a drug with neuroprotective and antioxidant actions, used in the treatment of multiple sclerosis. This work was performed in a model of oxidative damage on neuronal cell cultures exposed to menadione in the presence or absence of fingolimod phosphate. We studied the mitochondrial function, antioxidant enzymes, protein nitrosylation, and several pathways related with glucose metabolism and glycolytic and pentose phosphate in neuronal cells cultures. Our results showed that menadione produces a decrease in mitochondrial function, an imbalance in antioxidant enzymes, and an increase in nitrosylated proteins with a decrease in glycolysis and glucose-6-phosphate dehydrogenase. All these effects were counteracted when fingolimod phosphate was present in the incubation media. These effects were mediated, at least in part, by the interaction of this drug with its specific S1P receptors. These actions would make this drug a potential tool in the treatment of neurodegenerative processes, either to slow progression or alleviate symptoms.

Published
2020

22. 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

23. 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

24. 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

25. 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. © 2012 Alcina et al.

Published
2012

26. 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

27. 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

28. 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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29. DRB1*03:01 Haplotypes: Differential Contribution to Multiple Sclerosis Risk and Specific Association with the Presence of Intrathecal IgM Bands

Author

José C. Álvarez-Cermeño, Luisa M. Villar, M. Carmen Cénit, Rafael Arroyo, Laura Leyva, Elena Urcelay, Concepción Núñez, Oscar Fernandez, Emilio G. de la Concha, María L. Cavanillas, [Concha,E G de la, Cavanillas, ML, Cénit, MC, Ircelay, E, Núñez, C] Department of Clinical Immunology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain. [Arroyo, R] Department of Neurology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain. [Fernández, O] Department of Neurology, Clinical Neurosciences Institute, Hospital Regional Universitario Carlos Haya, Málaga, Spain. [Álvarez-Cermeño, JC] Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain. [Leyva, L] Research Laboratory. Clinical Neurosciences Institute, Hospital Regional Universitario Carlos Haya and Fundación IMABIS, Málaga, Spain. [Villar, LM] Department of Immunology, Hospital Ramón y Cajal, Madrid, Spain., and This work was supported by project PI10/1985 from ‘‘Fondo de Investigaciones Sanitarias’’. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Subjects
Inmunoglobulina M, 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], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Risk Factors, Factores de Riesgo, Genetics, Multidisciplinary, Cadenas HLA-DRB1, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Predisposición genética a la enfermedad, Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease [Medical Subject Headings], Humanos, Neurology, 01 antigen [HLA-DRB1*03], Medicine, Haplotipos, Research Article, Multiple Sclerosis, Science, Immunology, Chemicals and Drugs::Biological Factors::Antigens::Isoantigens::Histocompatibility Antigens::HLA Antigens::HLA-D Antigens::HLA-DR Antigens::HLA-DR beta-Chains::HLA-DRB1 Chains [Medical Subject Headings], Human leukocyte antigen, Biology, Autoimmune Diseases, Estudios caso-control, medicine, Humans, Diseases::Nervous System Diseases::Demyelinating Diseases::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings], Genetic Predisposition to Disease, Allele, Risk factor, Genotyping, Genetic Association Studies, Evolutionary Biology, Population Biology, Estudios de asociación genética, Multiple sclerosis, Haplotype, Case-control study, Computational Biology, Human Genetics, medicine.disease, Demyelinating Disorders, 01 [Antigeno HLA-DRB1*03], Haplotypes, Immunoglobulin M, Esclerosis Múltiple, Case-Control Studies, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Globulins::Serum Globulins::Immunoglobulins::Antibodies::Immunoglobulin Isotypes::Immunoglobulin M [Medical Subject Headings], biology.protein, Clinical Immunology, Population Genetics, HLA-DRB1 Chains
Abstract

Journal Article; Research Support, Non-U.S. Gov't; BACKGROUND Multiple sclerosis (MS) is a multifactorial disease with a genetic basis. The strongest associations with the disease lie in the Human Leukocyte Antigen (HLA) region. However, except for the DRB1*15:01 allele, the main risk factor associated to MS so far, no consistent effect has been described for any other variant. One example is HLA-DRB1*03:01, with a heterogeneous effect across populations and studies. We postulate that those discrepancies could be due to differences in the diverse haplotypes bearing that allele. Thus, we aimed at studying the association of DRB1*03:01 with MS susceptibility considering this allele globally and stratified by haplotypes. We also evaluated the association with the presence of oligoclonal IgM bands against myelin lipids (OCMB) in cerebrospinal fluid. METHODS Genotyping of HLA-B, -DRB1 and -DQA1 was performed in 1068 MS patients and 624 ethnically matched healthy controls. One hundred and thirty-nine MS patients were classified according to the presence (M+, 58 patients)/absence (M-, 81 patients) of OCMB. Comparisons between groups (MS patients vs. controls and M+ vs. M-) were performed with the chi-square test or the Fisher exact test. RESULTS Association of DRB1*03:01 with MS susceptibility was observed but with different haplotypic contribution, being the ancestral haplotype (AH) 18.2 the one causing the highest risk. Comparisons between M+, M- and controls showed that the AH 18.2 was affecting only M+ individuals, conferring a risk similar to that caused by DRB1*15:01. CONCLUSIONS The diverse DRB1*03:01-containing haplotypes contribute with different risk to MS susceptibility. The AH 18.2 causes the highest risk and affects only to individuals showing OCMB. Yes

Published
2012
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30. 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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