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Resumen: Objetivos: Los ensayos clínicos llevados a cabo con el interferón beta (INFB) en esclerosis múltiple remitente recidivante (EMRR) han mostrado que reducen la tasa de brotes. Sin embargo, no todos los pacientes responden a este tratamiento, si bien aún no hay un absoluto consenso a propósito de la definición de respuesta al tratamiento. Las razones para este fracaso terapéutico no son conocidas, y probablemente hay factores genéticos implicados, como se ha mostrado con los polimorfismos de los genes que codifican la interleuquina 10 o el interferón gamma. El papel del gen de la apolipoproteína E (APOE) en la EM ha sido investigado en los últimos años y no parece aumentar el riesgo de aparición de la enfermedad ni influir en su severidad. Variaciones en este gen influyen en la respuesta al tratamiento con inhibidores de la colinesterasa en la enfermedad de Alzheimer o a las estatinas en la hipercolesterolemia. Esto podría tener implicaciones futuras en la EM. Material y métodos: Hemos revisado retrospectivamente 38 pacientes diagnosticados de EMRR (32 mujeres y 6 varones) tratados con INFB durante al menos dos años. Los criterios para llevar a cabo el tratamiento eran uniformes de acuerdo con las indicaciones del Comité asesor para el tratamiento de la EM. Recogimos datos acerca de la edad y tiempo de evolución de la enfermedad. Al cabo de dos años del inicio del tratamiento los pacientes fueron clasificados como respondedores o no-respondedores de acuerdo con los criterios clínicos disponibles, basados en la presencia de brotes, evolución de la discapacidad, o ambos. El genotipo APOE se determinó de muestras sanguíneas utilizando métodos validados de reacción en cadena de la polimerasa. Se estudió la correlación entre la condición de respondedor o no respondedor y la presencia de los alelos E2 o E4. Resultados: Veinte pacientes (52,6%) recibían INFB1b subcutáneo (Betaferón®), 13 (34,2%) INFB1a intramuscular (Avonex®) y 5 (13,2%) INFB1a subcutáneo (Rebif®). Dos pacientes (5,2%) eran heterocigotos para el alelo E2 y 9 (23,7%) para el alelo E4. Ningún paciente era homocigoto para E2 o E4. La presencia o no de estos alelos no se correlacionó con la respuesta al tratamiento de acuerdo con las 10 variables estudiadas. Conclusión: Tras los resultados de un metanálisis que no muestran influencia del gen APOE en la susceptibilidad o severidad de la EM, no hemos encontrado en nuestra serie influencia de este gen en la respuesta de pacientes con EMRR al INFB. En cualquier caso, series más extensas son necesarias para validar estos resultados. Abstract: Objective: Clinical trials with interferon beta in relapsing remitting multiple sclerosis (RRMS) have demonstrated a reduction in the relapse rate. Nevertheless, not all patients respond to this treatment, although there is no consensus regarding the definition of response to therapy. The reasons for this failure are not known but genetic factors probably influence this, as has been previously shown with Interleukin 10 or Interferon gamma polymorphisms.The role of apolipoprotein E (APOE) gene in MS has been investigated and does not appear to increase risk for MS or influence disease severity. Interestingly APOE variation influences response to cholinesterase inhibitor treatment in Alzheimer disease or to statins in hypercholesterolemia. This might have future implications for MS. Material and methods: We retrospectively reviewed 38 RRMS patients (32 females and 6 males) treated with interferon beta (INFbeta) over at least two years. Criteria for treatment were uniform accordingly to an “Advisory Committee for the Treatment of Multiple Sclerosis”. We collected data variables including age, age of onset, clinical type or disease duration. Patients were classified, two years after the start of treatment, as responders and non-responders based upon clinical criteria available in the literature, which rely on the presence of relapses, increase of disability, or both. APOE genotype was determined from blood samples using validated polymerase chain reaction methods. Correlation between patient responding status with allele E2 or E4 was tested. Results: A total of 20 patients (52.6%) received subcutaneous INFbeta1b (Betaferón®), 13 (34.2%) INFbeta1a intramuscular (Avonex®), and 5 (13.2%) subcutaneous INFbeta1a (Rebif®). We found 2 patients (5.2%) heterozygous for the E2 allele and 9 (23.7%) for the E4 allele. No patient was homozygous for E2 or E4. Comparison of patients with and without E2 or E4 allele showed no significant differences in any of the ten therapy response variables assessed. Conclusion: Findings of a recent meta-analysis have not supported a role for APOE in MS susceptibility or severity. We have not found, in our data, any influence of this gene in the RRMS response to INFbeta. However, larger series would be required to validate these results. Palabras clave: Esclerosis múltiple, Respuesta al tratamiento, Farmacogenética, APOE, Keywords: Multiple sclerosis, Treatment response, Pharmacogenetics, APOE

Objective: Clinical trials with interferon beta in relapsing remitting multiple sclerosis (RRMS) have demonstrated a reduction in the relapse rate. Nevertheless, not all patients respond to this treatment, although there is no consensus regarding the definition of response to therapy. The reasons for this failure are not known but genetic factors probably influence this, as has been previously shown with Interleukin 10 or Interferon gamma polymorphisms.The role of apolipoprotein E (APOE) gene in MS has been investigated and does not appear to increase risk for MS or influence disease severity. Interestingly APOE variation influences response to cholinesterase inhibitor treatment in Alzheimer disease or to statins in hypercholesterolemia. This might have future implications for MS. Material and methods: We retrospectively reviewed 38 RRMS patients (32 females and 6 males) treated with interferon beta (INFbeta) over at least two years. Criteria for treatment were uniform accordingly to an “Advisory Committee for the Treatment of Multiple Sclerosis”. We collected data variables including age, age of onset, clinical type or disease duration. Patients were classified, two years after the start of treatment, as responders and non-responders based upon clinical criteria available in the literature, which rely on the presence of relapses, increase of disability, or both. APOE genotype was determined from blood samples using validated polymerase chain reaction methods. Correlation between patient responding status with allele E2 or E4 was tested. Results: A total of 20 patients (52.6%) received subcutaneous INFbeta1b (Betaferon®), 13 (34.2%) INFbeta1a intramuscular (Avonex®), and 5 (13.2%) subcutaneous INFbeta1a (Rebif®). We found 2 patients (5.2%) heterozygous for the E2 allele and 9 (23.7%) for the E4 allele. No patient was homozygous for E2 or E4. Comparison of patients with and without E2 or E4 allele showed no significant differences in any of the ten therapy response variables assessed. Conclusion: Findings of a recent meta-analysis have not supported a role for APOE in MS susceptibility or severity. We have not found, in our data, any influence of this gene in the RRMS response to INFbeta. However, larger series would be required to validate these results. Resumen: Objetivos: Los ensayos clínicos llevados a cabo con el interferón beta (INFB) en esclerosis múltiple remitente recidivante (EMRR) han mostrado que reducen la tasa de brotes. Sin embargo, no todos los pacientes responden a este tratamiento, si bien aún no hay un absoluto consenso a propósito de la definición de respuesta al tratamiento. Las razones para este fracaso terapéutico no son conocidas, y probablemente hay factores genéticos implicados, como se ha mostrado con los polimorfismos de los genes que codifican la interleuquina 10 o el interferón gamma. El papel del gen de la apolipoproteína E (APOE) en la EM ha sido investigado en los últimos años y no parece aumentar el riesgo de aparición de la enfermedad ni influir en su severidad. Variaciones en este gen influyen en la respuesta al tratamiento con inhibidores de la colinesterasa en la enfermedad de Alzheimer o a las estatinas en la hipercolesterolemia. Esto podría tener implicaciones futuras en la EM. Material y métodos: Hemos revisado retrospectivamente 38 pacientes diagnosticados de EMRR (32 mujeres y 6 varones) tratados con INFB durante al menos dos años. Los criterios para llevar a cabo el tratamiento eran uniformes de acuerdo con las indicaciones del Comité asesor para el tratamiento de la EM. Recogimos datos acerca de la edad y tiempo de evolución de la enfermedad. Al cabo de dos años del inicio del tratamiento los pacientes fueron clasificados como respondedores o no-respondedores de acuerdo con los criterios clínicos disponibles, basados en la presencia de brotes, evolución de la discapacidad, o ambos. El genotipo APOE se determinó de muestras sanguíneas utilizando métodos validados de reacción en cadena de la polimerasa. Se estudió la correlación entre la condición de respondedor o no respondedor y la presencia de los alelos E2 o E4. Resultados: Veinte pacientes (52,6%) recibían INFB1b subcutáneo (Betaferón®), 13 (34,2%) INFB1a intramuscular (Avonex®) y 5 (13,2%) INFB1a subcutáneo (Rebif®). Dos pacientes (5,2%) eran heterocigotos para el alelo E2 y 9 (23,7%) para el alelo E4. Ningún paciente era homocigoto para E2 o E4. La presencia o no de estos alelos no se correlacionó con la respuesta al tratamiento de acuerdo con las 10 variables estudiadas. Conclusión: Tras los resultados de un metanálisis que no muestran influencia del gen APOE en la susceptibilidad o severidad de la EM, no hemos encontrado en nuestra serie influencia de este gen en la respuesta de pacientes con EMRR al INFB. En cualquier caso, series más extensas son necesarias para validar estos resultados. Keywords: Multiple sclerosis, Treatment response, Pharmacogenetics, APOE, Palabras clave: Esclerosis múltiple, Respuesta al tratamiento, Farmacogenética, APOE

Objective: To explore the variations of brain natriuretic peptide (BNP) secretion after left atrial appendage occlusion., Background: Left atrial appendage occlusion has been increasingly performed in the last few years, however little is known about the physiological consequences of left atrial appendage occlusion. Left atrial appendage regulates partially intravascular volume via release of brain natriuretic peptide. Brain natriuretic peptide levels have been related to increased risk of stroke in atrial fibrillation patients., Methods: Venous blood samples were obtained in consecutive patients undergoing left atrial appendage occlusion before, 24 hr after device implantation and at the first visit after discharge (45-60 days) for BNP measurement., Results: Left atrial appendage occlusion was performed in 34 patients with non-valvular atrial fibrillation and contraindication to long-term oral anticoagulation or at high-risk of bleeding. There were no differences in BNP levels between baseline and 24 hr after device implantation. However left atrial appendage closure resulted in a significant decrease in BNP levels at the first follow-up visit (45-60 days) compared to baseline measurements (759.90 pg ml(-1) vs. 636.90 pg ml(-1) , P = 0.013)., Conclusions: Left atrial appendage occlusion modifies BNP levels. These levels decrease after left atrial appendage occlusion. The clinical consequences of these findings need to be evaluated in further studies. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Objective: Clinical trials with interferon beta in relapsing remitting multiple sclerosis (RRMS) have demonstrated a reduction in the relapse rate. Nevertheless, not all patients respond to this treatment, although there is no consensus regarding the definition of response to therapy. The reasons for this failure are not known but genetic factors probably influence this, as has been previously shown with Interleukin 10 or Interferon gamma polymorphisms. The role of apolipoprotein E (APOE) gene in MS has been investigated and does not appear to increase risk for MS or influence disease severity. Interestingly APOE variation influences response to cholinesterase inhibitor treatment in Alzheimer disease or to statins in hypercholesterolemia. This might have future implications for MS., Material and Methods: We retrospectively reviewed 38 RRMS patients (32 females and 6 males) treated with interferon beta (INFbeta) over at least two years. Criteria for treatment were uniform accordingly to an "Advisory Committee for the Treatment of Multiple Sclerosis". We collected data variables including age, age of onset, clinical type or disease duration. Patients were classified, two years after the start of treatment, as responders and non-responders based upon clinical criteria available in the literature, which rely on the presence of relapses, increase of disability, or both. APOE genotype was determined from blood samples using validated polymerase chain reaction methods. Correlation between patient responding status with allele E2 or E4 was tested., Results: A total of 20 patients (52.6%) received subcutaneous INFbeta1b (Betaferón(®)), 13 (34.2%) INFbeta1a intramuscular (Avonex(®)), and 5 (13.2%) subcutaneous INFbeta1a (Rebif(®)). We found 2 patients (5.2%) heterozygous for the E2 allele and 9 (23.7%) for the E4 allele. No patient was homozygous for E2 or E4. Comparison of patients with and without E2 or E4 allele showed no significant differences in any of the ten therapy response variables assessed., Conclusion: Findings of a recent meta-analysis have not supported a role for APOE in MS susceptibility or severity. We have not found, in our data, any influence of this gene in the RRMS response to INFbeta. However, larger series would be required to validate these results., (Copyright © 2010 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.)

Uric acid (UA) is an endogenous antioxidant. Some studies have described that multiple sclerosis (MS) patients have lower serum UA levels than controls, although it has not been established whether UA is primarily deficient, or secondarily reduced due to its scavenging activity. UA has also been proposed as an indicator of disease activity. We, retrospectively, reviewed 478 serum UA levels obtained in 94 MS patients. Ninety samples were collected during a relapse. Correlation between UA levels obtained during a relapse or in a relapse-free period, and comparison between UA and expanded disability status scale (EDSS) score was tested using a two-tailed Student's t test and Spearman correlation coefficients test. UA levels were significantly lower when measured during a relapse (n 90) than in a remission period (n 368) (r -0.16, p 0.003) UA levels measured outside a relapse inversely correlated with EDSS score (r -0.15, p 0.001). Lower uric acid levels in MS patients are associated with clinical relapse. This is the first description of an inverse correlation of serum UA levels with disability as assessed by EDSS score.

Introduction: The simultaneous occurrence of intracerebral haemorraghes in different arterial territories is an clinical event that develops in 2% to 3% of hemorrhagic strokes. Multiple risk factors have been associated with multiple intracerebral haemorraghes, but none of them are clearly defined. We reported clinical features, radiological findings, and outcome of 7 patients admitted to our department during last nine years and the diverse etiologic factors are discussed., Patients and Methods: We retrospectively reviewed all patients with acute stroke admitted to our department during the period January 1998-February 2007. Patients with a history of traumatic brain injury or suspected hemorrhagic infarctions were excluded. We collected data concerning age, risk factors, clinical features, number and location of haematomas and outcome., Results: We studied 7 patients (5 males and 2 females) Mean age was 78. The most common clinical manifestations were decreased alertness and weakness. Total number of haematomas was 20, 19 (95%) supratentorial and 15 (75%) in lobar area. One patient haemorrhage extended into the ventricular system. Three patients (43%) had hipertensive history, and in only one case was associated with oral anticoagulant (14%) and one blood dyscrasia (14%). Three patients died (43%)., Conclusion: In our series of patients with multiple intracerebral haemorraghes, clinical and radiological findings and outcome were comparable to others previously described, but our patients were older. The advanced age and lobar localization suggest amyloid angiopathy is an important risk factor to multiple intracerebral haemorraghes.

Uric acid (UA), a product of purine metabolism, may be an antioxidant, perhaps acting as a scavenger of peroxynitrite. Patients with gout have a reduced incidence of multiple sclerosis (MS). A number of studies found that patients with MS have low serum levels of UA, although it has not been established whether this represents a primary deficit or a secondary effect. UA has also been proposed as a marker of disease activity and response to immunosuppressive or immunomodulatory treatment. We retrospectively reviewed 83 relapsing-remitting or secondary progressive MS patients (64 females and 19 males) followed in our Neurology Unit. We collected data concerning demographic variables as age and sex, and clinical variables as age of onset, clinical type, disease duration, EDSS score and total number of relapses. We considered UA levels in three different situations: during a relapse, during remission period and during remission period under immunomodulatory treatment [Interferon Beta 1a i.m. (Avonex; Biogen Idec Inc., Cambridge, MA, USA), Interferon Beta 1a s.c. (Rebif; Serono Europe Limited, London, UK), Interferon Beta 1b (Betaferon; Bayer Schering Pharma AG, Berlin, Germany) or Glatiramer Acetate (Copaxone; TEVA Neuroscience LLC, Kansas City, MO, USA)]. A Wilcoxon matched pairs test was carried out to determine differences between groups. A P-value less than 0.05 was considered statistically significant. In 33 patients, we were able to compare at least one UA value obtained during a relapse with at least one when remission without treatment. Mean serum UA levels were significantly lower when measured during a relapse (r: 0.39, P: 0.024). In 27 cases, we compared at least one remission value without treatment with at least one obtained during remission and immunomodulatory treatment. Mean serum UA levels significantly increased when determined during Interferon Beta or Glatiramer Acetate therapy (r: 0.84, P < 0.001). Although we do not know exactly whether and how UA is involved in MS pathogenesis, our data suggest that UA might reflect disease activity or treatment response in MS.

Objectives: During the last years, the association between apolipoprotein E (APOE) polymorphism and disease severity in multiple sclerosis (MS) has been studied with conflicting results. As a result of a considerable individual variation in the clinical course of MS, there is no consensus method for measuring progression using single assessments of disability. Recently, Multiple Sclerosis Severity Score (MSSS) method has been proposed for comparing disease progression using single data. We evaluate in our population if there is any correlation between APOE genotype and severity according to MSSS., Methods: We studied 82 patients followed up in our Neurology Unit throughout the year 2005, diagnosed with MS, and with disease duration of at least 2 years. We collected data concerning demographic and clinical variables including age of onset, disease duration, Expanded Disability Status Scale (EDSS) score and the total number of relapses. When reached, we determined the latency to EDSS scores of 4.0 and 6.0. We calculated progression index (PI) and relapse rate (RR). We ascertained MSSS for our patients in the global MSSS table., Results: We found four patients heterozygous for the E2 allele and 16 for the E4 allele. No patient was homozygous for E2 or E4. RR (P = 0.017 with 95% CI: 0.005-0.57) and PI (P = 0.016 with 95% CI: 0.004-0.38) were significantly lower in E4 carriers. MSSS scores were not associated with carriership of E2 or E4., Conclusion: Our results show no effect of the APOE genotype on the severity of MS measured by MSSS, as a recently published meta-analysis has noticed. So, our data do not support a role for APOE in MS severity, in spite of the seeming influence shown using other measures such as PI. MSSS is probably the best method to measure severity with a single measure of disability and should be used more frequently when performing genetic research.

Theoretical electronic Structure methods have been employed to study the structure and activity of certain (free) quinolones and the interaction of their Cu(II)-complexes on a DNA model (Rhodamine 6G (rhod)). As a manner of assessing the generated geometries, the nalidixic acid geometrical parameters obtained were tested against the crystallographic ones and it was found that the average error in the calculated geometries is small. The present study allows us to (1) Rationalize the observed differences in antibiotic activities through their electronic hardnesses. (2) Suggest a plausible mechanism of action for these drugs through formation of a reactive intermediate (or carrier) which would consist of a quinolone anion coordinated to an adequate metal center (Cu(II) in this study). (3) We find that, through this model of DNA (modeled with rhod) the interaction seems to be mediated by an effective pi-pi stacking. (4) Finally, an in vitro experiment was designed so that the intercalation process in DNA could be experimentally modeled as well. The quenching of the rhod fluorescence is proportional to the strength of the Cu(II)-complex-rhod interaction and therefore provides a quantitative measurement of the "intercalating" capacity of the quinolones and their copper complexes. These results agree well with the theoretical total adduct formation energies.