RESUMEN
An innovative electrochemical approach based on screen-printed carbon electrodes (SPCEs) modified with graphene quantum dots (GQDs) functionalized with γ-cyclodextrin (γ-CD) and assembled to chitosan (CHI) is designed for the assessment of the total content of fluoroquinolones (FQs) in animal source products. For the design of the bionanocomposite, carboxylated graphene quantum dots synthesized from uric acid as precursor were functionalized with γ-CD using succinic acid as a linker. Physic-chemical and nanostructural characterization of the ensuing nanoparticles was performed by high-resolution transmission scanning microscopy, dynamic light scattering, Z potential measurement, Fourier transformed infrared spectroscopy and X-ray diffraction. Electrochemical properties of assembled bionanocomposite like potential difference, kinetic electronic transfer constant and electroactive area among other parameters were assessed by cyclic voltammetry and differential pulse voltammetry using potassium ferricyanide as redox probe. The oxidation behaviour of four representative quinolones with distinctive structures was studied, obtaining in all cases the same number of involved e- (2) and H+ (2) in their oxidation. These results led us to propose a single and consistent oxidation mechanism for all the checked analytes. The γ-CD-GQDs-CHI/SPCE sensor displayed a boosted electroanalytical performance in terms of linear range (4-250 µM), sensibility (LOD = 1.2 µM) and selectivity. This electrochemical strategy allowed the determination of FQs total amount in complex processed food like broths, bouillon cubes and milkshakes at three concentration levels (150, 75 and 37.5 µM) for both equimolar and different ratio FQs mixtures with recovery values ranging from 90 to 106%.
Asunto(s)
Quitosano , Grafito , Puntos Cuánticos , gamma-Ciclodextrinas , Grafito/química , Puntos Cuánticos/química , Fluoroquinolonas , Técnicas Electroquímicas/métodos , ElectrodosRESUMEN
A current nourishment issue is the development of smart and reliable analytical strategies to control in a simple way main bioactive compounds of nutritional supplements whose increasing use is deemed a trend nowadays. With this aim a quick and highly sensitive plasmonic sensor using simple citrate coated gold nanoparticles (AuNPs) as optical probe, was developed for both qualitative and quantitative global assessment of all the proteinogenic amino acids in nutritional supplements. AuNPs of five different sizes (from 19 to 74 nm) were synthesized, characterized and evaluated as optimal transductor element for the sensing approach. Critical physic-chemical conditions controlling aggregation (pH, incubation time, AuNPs amount and ionic strength) were investigated on the main five types of aas, structurally different attending to their R-side chain and with expected distinctive behaviour on aggregation mechanisms, which are also discussed. All proteinogenic amino acids induced AuNPs aggregation at low pH (2.5) causing a change in the colour solution from red to blue, as well as a redshift in the plasmon band from 518 nm (disperse NPs) to 650 nm (aggregated NPs). Based on this sensing approach two different strategies are allowed, a preliminary qualitative/semi-quantitative screening just by the naked eye (simple spot test) and a second quantitative confirmation procedure using the analytical signal (A650/A518). Reliability of quantitative approach was assessed by an exhaustive validation procedure, where matrix effects and potential interferences usually present in commercial samples and affecting the analytical signal were mainly focussed. The results for the analysis of complex nutritional samples were validated by means of a statistical comparison with those ones of the official reference Kjeldahl method (paired Student test-t) at a 95% confidence level. This is the first sensing approach able to provide the global estimation of proteinogenic aas amount based on their simply AuNPs aggregation induction, irrespectively of their R-side chain structure.
Asunto(s)
Oro , Nanopartículas del Metal , Aminoácidos , Colorimetría , Humanos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND AND OBJECTIVES: To study the clinical and laboratory features of antineurofascin-155 (NF155)-positive autoimmune nodopathy (AN). METHODS: Patients with anti-NF155 antibodies detected on routine immunologic testing were included. Clinical characteristics, treatment response, and functional scales (modified Rankin Scale [mRS] and Inflammatory Rasch-built Overall Disability Scale [I-RODS]) were retrospectively collected at baseline and at the follow-up. Autoantibody and neurofilament light (NfL) chain levels were analyzed at baseline and at the follow-up. RESULTS: Forty NF155+ patients with AN were included. Mean age at onset was 42.4 years. Patients presented with a progressive (75%), sensory motor (87.5%), and symmetric distal-predominant weakness in upper (97.2%) and lower extremities (94.5%), with tremor and ataxia (75%). Patients received a median of 3 (2-4) different treatments in 46 months of median follow-up. Response to IV immunoglobulin (86.8%) or steroids (72.2%) was poor in most patients, whereas 77.3% responded to rituximab. HLA-DRB1*15 was detected in 91.3% of patients. IgG4 anti-NF155 antibodies were predominant in all patients; anti-NF155 titers correlated with mRS within the same patient (r = 0.41, p = 0.004). Serum NfL (sNfL) levels were higher in anti-NF155+ AN than in healthy controls (36.47 vs 7.56 pg/mL, p < 0.001) and correlated with anti-NF155 titers (r = 0.43, p = 0.001), with I-RODS at baseline (r = -0.88, p < 0.001) and with maximum I-RODS achieved (r = -0.58, p = 0.01). Anti-NF155 titers and sNfL levels decreased in all rituximab-treated patients. DISCUSSION: Anti-NF155 AN presents a distinct clinical profile and good response to rituximab. Autoantibody titers and sNfL are useful to monitor disease status in these patients. The use of untagged-NF155 plasmids minimizes the detection of false anti-NF155+ cases. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that anti-NF155 antibodies associate with a specific phenotype and response to rituximab.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso , Moléculas de Adhesión Celular/inmunología , Factores Inmunológicos/farmacología , Factores de Crecimiento Nervioso/inmunología , Nódulos de Ranvier/inmunología , Rituximab/farmacología , Adulto , Anciano , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: In a prior study of our group we found an up-regulation of CD46 expression in a cohort of Spanish multiple sclerosis (MS) patients. OBJECTIVE: To evaluate the potential role of CD46 in the response to interferon-beta treatment in MS patients through the analysis of five tagging single nucleotide polymorphisms (SNPs) and measurement of mRNA. METHODS: A total of 406 MS patients and 513 control patients were analysed for five SNPs at the CD46 locus. Furthermore, 163 MS patients and 163 matched control patients were analysed by RT-PCR for the CD46 mRNA expression in three blood samples (basal, and at 6 and 12 months of interferon-beta treatment) collected in the course of a 1-year follow-up. RESULTS: Two genotypes of rs2724385 polymorphism (AT and TT) could be markers of response to interferon-beta therapy in MS patients (p=0.007 and p=0.006, respectively). Furthermore, the frequency of interferon-beta responders was 44.4% (32/72) in MS patients with an increased CD46 mRNA expression, vs. 65.9% (60/91) in patients with a decreased CD46 mRNA expression (p=0.006). CONCLUSION: The present study shows that CD46 could be associated with the response to interferon-beta therapy; however, the genetic results should be replicated in an independent cohort and further studies are needed to confirm the role of CD46.
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Factores Inmunológicos/uso terapéutico , Interferón beta/uso terapéutico , Proteína Cofactora de Membrana/genética , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , ARN Mensajero/sangre , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Estudios de Cohortes , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Esclerosis Múltiple/inmunología , Oportunidad Relativa , Selección de Paciente , Farmacogenética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , España , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
The beneficial effects of interferon beta-1a (IFNbeta-1a) in multiple sclerosis (MS) remain only partially understood. CD8(+) T cells are key cells in MS pathogenesis that contribute to axonal damage in MS, whereas CD4(+) regulatory T cells (T(Reg)) and CD8(+) regulatory/suppressor T cells (Ts) play an important role in protecting against subsequent MS activity. We analysed ex vivo changes on T(Reg) and on the different subsets of CD4(+) and CD8(+) T lymphocytes, before IFNbeta-1a (Rebif) therapy and at 3, 6, and 12 months after treatment, in 23 MS patients and in 26 healthy controls. IFNbeta-1a significantly increased the proportions of CD4(+) T(Reg) and regulatory CD8(+) T cells (Tr). Memory CD8(+) T cells were significantly decreased after 1 year of treatment, maybe reflecting down-regulation of abnormally persistent systemic activation in MS patients. After 1 year of IFNbeta-1a, a direct correlation was observed between plasmacytoid dendritic cells and effector CD8(+) T cells.
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Adyuvantes Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Subgrupos de Linfocitos T/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Separación Celular , Citocinas/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Memoria Inmunológica/efectos de los fármacos , Memoria Inmunológica/inmunología , Interferón beta-1a , Estudios Longitudinales , Masculino , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Interferon beta-1a (IFNâ-1a) has demonstrated efficacy in multiple sclerosis (MS), although its mechanism of action remains only partly understood. We evaluated the ex vivo and in vitro effects of IFNâ-1a (Rebif) on regulatory T-cell (T(Reg)) function in 22 relapsing-remitting MS patients and 16 healthy controls. T(Reg) function was significantly enhanced after 3 and 6 months of IFNbeta-1a therapy. Furthermore, there was a trend towards increasing proportions of total CD4(+)CD25(+) and CD4(+)CD25(+)GITR(+) T(Reg) after 6 months of IFNbeta-1a therapy when compared with baseline. In conclusion, IFNbeta-1a therapy enhances T(Reg) function, and this may be relevant in the inflammatory environment of MS lesions.
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Adyuvantes Inmunológicos/uso terapéutico , Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Linfocitos T CD4-Positivos/metabolismo , Estudios de Cohortes , Femenino , Proteína Relacionada con TNFR Inducida por Glucocorticoide , Humanos , Técnicas In Vitro , Interferón beta-1a , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Subgrupos de Linfocitos T/patología , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: A functional promoter polymorphism in the FcRL3 gene, -169 T/C, has been shown to regulate gene expression and to play a role in several autoimmune diseases. We aimed at testing for the first time whether this gene was involved in multiple sclerosis (MS) pathogenesis. METHODS: Case-control study performed with 400 Spanish MS patients and 508 healthy subjects. Genotyping of -169 T/C and -110 G/A was ascertained by using TaqMan MGB chemistry following manufacturer suggestions (Applied Biosystems, CA, USA). RESULTS: As previously seen for other autoimmune diseases, a significant difference was observed in the distribution of -169 T/C FcRL3 genotypes between MS patients and healthy controls (p = 0.03; chi(2) = 6.99). The -169 T allele, recently associated with increased susceptibility to Addison's disease, showed a parallel effect in MS [(TT+TC) vs. CC: p = 0.013; OR = 1.55 (1.08-2.54)]. CONCLUSIONS: An increased susceptibility associated to the -169 T allele was found when MS patients and controls were compared, supporting the role of the FcRL3 locus in MS predisposition and therefore extending the evidence of its general influence on autoimmunity.
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Autoinmunidad/fisiología , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Polimorfismo Genético , Regiones Promotoras Genéticas/genética , Receptores Inmunológicos/genética , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Esclerosis Múltiple/etiología , España/epidemiologíaRESUMEN
Multiple sclerosis (MS) is an inflammatory disorder affecting the central nervous system, in which both genetic and environmental factors interact. Among these environmental contributors, herpesvirus has been proposed as an important etiologic factor. CIITA is a transcription factor controlling the expression of MHC class II genes, the main genetic determinants of MS susceptibility. This gene has been described as a target of the immunoevasive strategies, and it is therefore an attractive candidate gene to be at the genetic-viral crossroads. Two polymorphisms in MHC2TA gene (rs4,774G/C and rs3,087,456A/G) were studied in two groups: one in 22 multiple sclerosis patients with active human herpes virus 6 (HHV-6A) replication (HHV-6A-positive), and the other of 77 patients with no detectable HHV-6A active infection (HHV-6A-negative); a Spanish healthy control group (n = 520) was also included as external control. An association of the rs4,774C allele with the HHV-6A-positive group was found when compared with the HHV-6A-negative (47.7% vs 18.8%, p = 0.0001; odds ratio = 3.94) and also with the control group (47.7% vs 25.5%, p = 0.001, odds ratio = 2.67). No significant differences were observed between HHV-6A-negative subjects and healthy controls. Our data suggest that a strong gene-environment interaction occurs between HHV-6A active replication and MHC2TA rs4,774C or another polymorphism in tight linkage disequilibrium with it. Besides, this report indicates that when patients are grouped based upon a well-defined molecular event, complex diseases may reveal themselves as being constituted by distinct entities in which some genes may have a strong influence.
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Predisposición Genética a la Enfermedad , Herpesvirus Humano 6/fisiología , Esclerosis Múltiple/genética , Proteínas Nucleares/genética , Infecciones por Roseolovirus/virología , Transactivadores/genética , Adolescente , Adulto , Niño , Femenino , Herpesvirus Humano 6/aislamiento & purificación , Humanos , Masculino , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/virología , Proteínas Nucleares/inmunología , Polimorfismo de Nucleótido Simple , Infecciones por Roseolovirus/inmunología , Transactivadores/inmunologíaRESUMEN
Slowing of motor performance in human aging is a well demonstrated clinical observation. Age-related motor decline has been also confirmed in animal models including rodents and non human primates. We studied the motor performance of 60 normal subjects (age: 20-87). Motor study included the four timed tests (TT) recommended in CAPIT protocol: pronation-supination (PS), finger dexterity (FD), movement between two points (MTP) or tapping, and walking test (WT). Finally we compared normal controls with a group of 30 patients with Parkinson's disease (PD) of similar age. Age inversely correlated with TT performance in normal subjects (for PS, r:0.33, p<0.01; FD, r:0.44, p<0.0005; MTP, r:0.51, p<0.0001; WT, r:0.59, p<0.0001, Pearson). Our results confirm that motor performance (measured with CAPIT TT) deteriorates linearly with age. Simple tasks, such as CAPIT TT can help to study and quantify age-related motor decline.
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Envejecimiento/fisiología , Destreza Motora/fisiología , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/fisiopatología , Movimiento/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/etiología , Examen Neurológico , Enfermedad de Parkinson/fisiopatología , Valores de ReferenciaRESUMEN
BACKGROUND: This study was undertaken in order to investigate the possible relation of HHV-6 and EBV in relapsing-remitting MS (RRMS). MATERIALS AND METHODS: A one-year follow up study was performed analysing peripheral blood mononuclear cells and serum samples of 57 patients with RRMS and 57 healthy blood donors (HBD) by a quantitative real time PCR, to detect HHV-6 and EBV. Clinical data (starting age and EDSS increase) were collected. RESULTS: We did not find any statistically significant difference for EBV between RRMS patients and HBD. Regarding HHV-6: i) There was a higher prevalence of HHV-6 in RRMS patients than in controls: 80.7% versus 29.8% respectively. ii) HHV-6 active replication seems to be related to exacerbations. iii) Only variant A was detected among RRMS patients with HHV-6 active replication. iv) Although some difference was found when we compared clinical data in RRMS patients with and without HHV-6 active replication, the results did not reach statistical significance. CONCLUSIONS: A higher HHV-6A frequency of active infection (reactivation or new infection) would lead to a more frequent exposure of HHV-6A antigens to the immune system of RRMS patients; this active replication of HHV-6A seems to be specifically related with the exacerbations in a subset of RRMS patients.
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Herpesvirus Humano 6 , Esclerosis Múltiple Recurrente-Remitente/virología , Adolescente , ADN Viral/análisis , Femenino , Herpesvirus Humano 4/genética , Herpesvirus Humano 6/genética , Humanos , Masculino , Persona de Mediana Edad , Monocitos/virología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Viral/biosíntesis , ARN Viral/genética , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Carga ViralRESUMEN
BACKGROUND: Although the etiology of multiple sclerosis (MS) remains uncertain, clinical, epidemiological, and laboratory findings suggest that environmental factors may be involved in the disease. OBJECTIVE: This study was undertaken in order to investigate the possible relation of human herpesvirus-6 (HHV-6) in relapsing-remitting MS (RRMS). STUDY DESIGN: A one-year follow-up study was performed analyzing serum samples of 63 patients with RRMS and 63 healthy blood donors (HBD) by a quantitative real time PCR, to measure HHV-6 prevalence and viral load. Clinical data (starting age and EDSS increase) were collected. RESULTS: (i) We found 25.4% of RRMS patients with at least one positive serum sample along the one year follow-up. (ii) 19.1% of RRMS samples in relapse had HHV-6 active infection vs. 7.9% of RRMS samples in remission. (iii) We only found variant A. (iv) RRMS patients with HHV-6 active replication initiated the disease 1.9 years earlier, and they had a higher EDSS increase. CONCLUSIONS: A higher HHV-6A frequency of active infection seems to be related with the exacerbations in a subset of RRMS patients. Regarding the relationship between HHV-6A active infection and the clinical data in RRMS patients, further investigations are needed.
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Herpesvirus Humano 6/fisiología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/virología , Infecciones por Roseolovirus/virología , Adolescente , Adulto , ADN Viral/sangre , Femenino , Herpesvirus Humano 6/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Carga Viral , Replicación ViralRESUMEN
BACKGROUND: Recent studies have focused on the relationship between human herpesvirus 6 (HHV-6) and multiple sclerosis (MS). OBJECTIVE: To analyze HHV-6 messenger RNA expression in patients with relapsing-remitting (RR) MS vs healthy blood donors (HBDs). DESIGN: One hundred fifty-four subjects were enrolled in the study: 105 patients with RRMS (32 in relapse) and 49 HBDs. Total DNA and messenger RNA were extracted from serum and blood samples, respectively, and analyzed by quantitative real-time reverse transcription-polymerase chain reaction for the detection of 3 HHV-6 immediate-early genes (U16/U17,U89/U90, and U94) and both HHV-6 variants (HHV-6A and HHV-6B). RESULTS: Active HHV-6 infection was detected in 16% of patients with RRMS vs 0% of HBDs (P = .003). Seven patients with RRMS with exacerbation had HHV-6 active replication, and the virus remained latent in only 1 of them. We did not find any statistically significant difference between HHV-6 active or latent infection for patients in remission (P = .12). Among patients with RRMS with HHV-6 active replication, viral load was higher when they experienced an acute attack than when in remission (P = .04). In those patients with RRMS who had an active infection only, HHV-6A was found. Cell-free HHV-6 DNA detected in serum samples confirmed the results. CONCLUSIONS: The results show that a subset of patients with RRMS experience HHV-6 active infection, and there likely is an association between the viral active replication and relapses; therefore, HHV-6 active infection may imply a greater risk of exacerbations in a subgroup of patients with RRMS.
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Infecciones por Herpesviridae/virología , Herpesvirus Humano 6/aislamiento & purificación , Esclerosis Múltiple Recurrente-Remitente/virología , Adulto , ADN Viral/sangre , Femenino , Infecciones por Herpesviridae/sangre , Infecciones por Herpesviridae/complicaciones , Herpesvirus Humano 6/genética , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/complicaciones , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Carga Viral/estadística & datos numéricosRESUMEN
Bradykinesia is a frequent finding in Huntington's disease (HD), but some aspects are presently unknown; including the natural evolution of bradykinesia over time and the correlation between bradykinesia and functional capacity. We studied the motor performance of 20 genetically confirmed patients with HD (age: 40+/-10.8 years; age at onset 33.6+/-11 years; total functional capacity (TFC): 9.57+/-3; UHDRS total motor scale: 31.4+/-13, triplet length (CAG)n: 46.7+/-4 triplets). These patients were studied in baseline conditions and after 18.7+/-6 months of follow-up. In addition, HD patients were compared with 20 age-matched normal controls. Motor study included the four CAPIT timed tests commonly used for Parkinson's disease: pronation-supination (PS), finger dexterity (FD), movement between two points (MTP) and walking test (WT). HD patients were significantly slower than controls in all motor tasks. A significant deterioration occurred over time in three of the four motor tasks (especially FD and WT). A significant correlation between timed tests and TFC score was found (for MTP, r: -0.845; p < 0,0001). In addition a significant correlation between timed tests and the UHDRDS total motor scale was also found (for MTP, r: 0.864; p < 0.0001). In conclusion, simple timed motor tests can detect a deterioration of motor activity over time in HD. Timed tests might be useful to follow the natural evolution of HD and to assess the efficacy of new therapies.
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Enfermedad de Huntington/fisiopatología , Hipocinesia/fisiopatología , Desempeño Psicomotor/fisiología , Adulto , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Enfermedad de Huntington/complicaciones , Enfermedad de Huntington/diagnóstico , Hipocinesia/diagnóstico , Hipocinesia/etiología , Persona de Mediana Edad , Estudios Prospectivos , Estadísticas no ParamétricasRESUMEN
OBJECTIVES: The frequency of sleep disturbances in multiple sclerosis (MS), and their impact on the quality of life of MS patients, have traditionally been underestimated. Here we review the most common sleep disorders seen in this disease, their prevalence, pathophysiology, clinical manifestations and current treatments. METHOD: We begin with a brief description of epidemiological data on sleep disturbances in MS, explain how these disturbances increase potential associated morbidities, and discuss the bidirectional relationship established between these two comorbid conditions (i.e. MS worsens sleep disturbances and vice versa). We then analyze the main dyssomnias and parasomnias described in MS: insomnia, circadian rhythm disorders, drug-induced sleep disturbances, restless legs syndrome (RLS) and periodic leg movements (PLM), respiratory disorders during sleep, narcolepsy-cataplexy syndrome and REM sleep behavior disorder (RBD). We also review the relationship between sleep disturbances and chronic fatigue syndrome, which is very frequent in MS patients. CONCLUSION: Sleep disturbances are more common in MS patients than in the general population and limit these patients' quality of life. Therefore, we believe that these disturbances should be a focal point in any multidisciplinary treatment for MS.
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Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/fisiopatología , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/fisiopatología , Humanos , Esclerosis Múltiple/psicología , Narcolepsia/epidemiología , Narcolepsia/fisiopatología , Narcolepsia/psicología , Polisomnografía/métodos , Calidad de Vida/psicología , Trastorno de la Conducta del Sueño REM/epidemiología , Trastorno de la Conducta del Sueño REM/fisiopatología , Trastorno de la Conducta del Sueño REM/psicología , Síndrome de las Piernas Inquietas/epidemiología , Síndrome de las Piernas Inquietas/fisiopatología , Síndrome de las Piernas Inquietas/psicología , Trastornos del Sueño-Vigilia/psicologíaRESUMEN
Interleukin (IL)-2/IL-2R signalling promotes proliferation and survival of activated T cells and has an essential non-redundant role in the production of regulatory T cells. Associations with different autoimmune diseases of polymorphisms in a linkage disequilibrium block in which the IL2/IL21 genes map (4q27), and also in genes encoding the IL2RA and IL2RB subunits (located in 10p15 and 22q13, respectively), were identified through genome-wide studies. Polymorphisms in these three genes were studied in 430 multiple sclerosis (MS) patients and in 550 ethnically matched controls from Madrid (Spain). Replication and meta-analysis with results from an independent cohort of 771 MS patients and 759 controls from Andalucía (Spain) confirmed the association of polymorphisms in the IL2RA gene (P(Mantel-Haenszel,) odds ratio (OR)(M-H) (95% confidence interval, CI) for rs2104286: 0.0001, 0.75 (0.65-0.87); for rs11594656/rs35285258: 0.004, 1.19 (1.06-1.34); for rs41295061: 0.03, 0.77 (0.60-0.98)); showed a trend for association of the IL2/IL21 rs6822844 (P(M-H)=0.07, OR(M-H) (95% CI)=0.86 (0.73-1.01)), but did not corroborate the association for IL2RB. Regression analyses of the combined Spanish cohort revealed the independence of two IL2RA association signals: rs2104286 and rs11594656/rs35285258. The relevant role of the IL2RA gene on MS susceptibility adds support to its common effect on autoimmune risk and the suggestive association of IL2/IL21 warrants further investigation.
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Predisposición Genética a la Enfermedad , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/genética , Interleucina-2/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Frecuencia de los Genes/genética , Humanos , Desequilibrio de Ligamiento/genética , Modelos Logísticos , Persona de Mediana Edad , España , Adulto JovenRESUMEN
Many variables with association with better response to interferon-beta-1a (IFNbeta-1a) have been described, but none has yet been shown to be predictive of clinical response. In this real-life observational 1-year longitudinal study of 23 relapsing-remitting multiple sclerosis (RRMS) patients treated with subcutaneous IFNbeta-1a, we have shown a lower proportion of circulating myeloid dendritic cells (mDCs) than in healthy controls at baseline. Both univariate (Kaplan-Meier) and multivariate (Cox regression) analyses were conducted to determine which variables (age, sex, baseline EDSS, MS relapse rates 1 year and 2 years before initiating IFNbeta-1a, mDCs and plasmacytoid (pDCs) subsets, activated and regulatory CD4(+) T-cells (T(Reg))) were associated with clinical response to IFNbeta-1a. During 1 year of treatment, we observed a shift towards lower proportions of CD123(+) pDCs expression and higher numbers and function of the T(Reg). Univariate analysis disclosed that MS activity was significantly associated with baseline BDCA1(+) mDCs below < or = 0.4% (p<0.0025). Cox model analysis revealed that baseline BDCA1(+) mDCs was the most closely associated factor with MS activity on IFN treatment during the 1-year follow-up (p<0.01). A better understanding of the rules that govern the T(Reg)-DC relationship will enable scientists to better manage the immune response in MS patients.
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Antígenos de Superficie/sangre , Células Dendríticas/fisiología , Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Linfocitos T Reguladores/fisiología , Adulto , Antígenos CD1 , Femenino , Glicoproteínas , Humanos , Interferón beta-1a , Estudios Longitudinales , Masculino , Esclerosis Múltiple Recurrente-Remitente/inmunología , Estudios Prospectivos , RecurrenciaRESUMEN
Viral infections have been appointed as the main component of environmental susceptibility to multiple sclerosis (MS). Interferon beta is an immunomudulatory treatment that is able to modify the natural course of the disease; nonetheless, its mechanism of action in not well established yet. The objectives of the present study were (1) to evaluate the bioavailability of interferon beta through the measurement of the expression of myxovirus resistance protein (MxA), metalloproteinase 9 (MMP-9), and its inhibitor (TIMP-1); (2) to analyze its antiviral efficiency through the measurement of human herpesvirus-6 (HHV-6) prevalence; and (3) to correlate both parameters (bioavailability and antiviral efficiency) with the relapse rate in multiple sclerosis (MS) patients treated with interferon beta. Pairs of blood and serum samples were collected from 54 MS patients during five visits in 1 year: one before the start of the treatment and four during interferon beta treatment. Expression of MxA, MMP-9, and TIMP-1 was analyzed by quatitative real-time polymerase chain reaction (qRT-PCR) and HHV-6 genomes were detected by qPCR. The results showed a correlation between MxA and relapse rate (P = .014). MMP-9/TIMP-1 ratio was increased among the patients with relapses, and decreased among the relapse-free patients, although differences were not statistically significant. Furthermore, our results suggest a possible role for HHV-6 in MS, because 42.8% of patients with viral reactivations experienced at least one relapse versus 22.5% of patients without viral reactivations. Lastly, regarding the antiviral effectiveness of the interferon beta, the HHV-6 prevalence decreased from 58% to 36% in PBMCs and from 18.5% to 12.2% in sera; furthermore, a good correlation with the bioavailability of interferon beta was found, because patients with a decrease in HHV-6 prevalence had higher levels of MxA (P = .046, at the third month).
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Antivirales/uso terapéutico , Herpesvirus Humano 6/efectos de los fármacos , Interferón beta/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple/virología , Disponibilidad Biológica , Proteínas de Unión al GTP/metabolismo , Herpesvirus Humano 6/fisiología , Humanos , Interferón beta/administración & dosificación , Interferón beta/inmunología , Interferón beta/uso terapéutico , Metaloproteinasa 9 de la Matriz/metabolismo , Datos de Secuencia Molecular , Esclerosis Múltiple/sangre , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/enzimología , Proteínas de Resistencia a Mixovirus , Inhibidor Tisular de Metaloproteinasa-1/sangre , Inhibidor Tisular de Metaloproteinasa-1/genéticaRESUMEN
Recently, it has been suggested that human herpesvirus-6 (HHV-6) may play a role in the pathogenesis of relapsing-remitting multiple sclerosis (RRMS), but there is not enough information related to the role of HHV-6 in secondary-progressive MS (SPMS). To address this question, we evaluated HHV-6 prevalence, active viral replication and viral load measured by quantitative real-time PCR, in DNA and mRNA extracted from peripheral blood mononuclear cells (PBMCs) and DNA extracted from serum; the samples were collected from 31 SPMS and 31 RRMS patients in a one-year follow-up study, and sex- and age-matched controls. The results were as follows: i) We found a statistical significant difference in HHV-6 DNA prevalences between RRMS and SPMS patients in: DNA extracted from PBMCs (P=0.027), DNA extracted from serum (P=0.010) and mRNA extracted from PBMCs (P=0.010). When we compared HHV-6 prevalences from RRMS patients in relapse and in remission with those from SPMS patients, we only achieved a statistical significance for the relapses (P=0.003 in DNA from PBMCs, and P<0.001 in DNA from serum samples and mRNA from PBMCs). ii) We only found HHV-6 variant A among HHV-6 positive samples in serum. iii) We did not find any difference in HHV-6 viral loads. These results suggest that HHV-6A does not play an active role in SPMS, while this virus may contribute to the pathogenesis of RRMS triggering MS attacks in a subset of patients.
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Herpesvirus Humano 6/aislamiento & purificación , Esclerosis Múltiple Crónica Progresiva/epidemiología , Esclerosis Múltiple Crónica Progresiva/virología , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Esclerosis Múltiple Recurrente-Remitente/virología , Infecciones por Roseolovirus/epidemiología , Adulto , ADN Viral/sangre , Femenino , Estudios de Seguimiento , Herpesvirus Humano 6/genética , Humanos , Leucocitos Mononucleares/virología , Masculino , Persona de Mediana Edad , Prevalencia , ARN Mensajero , Carga Viral , Replicación ViralRESUMEN
OBJECTIVE: To evaluate the possible involvement of JC virus (JCV) in the aetiology of multiple sclerosis (MS), through the comparison of DNA prevalences and viral loads of JCV in cerebrospinal fluid (CSF) of MS patients at the first demyelinating event and subjects suffering from other neurological diseases (OND). METHODS: Seventy-three CSF samples (43 from MS patients at the first demyelinating event, and 30 from patients with OND) were collected; all MS cases were followed up from 1 to 6.7 years after they were diagnosed with clinically definite MS. DNA was extracted and analysed by real-time PCR for the detection of JCV genomes. RESULTS: We found JCV DNA in the CSF of two MS patients (4.7%) with a mean viral load of 2.1 and 6.7 copies/mL of CSF. Among the patients of the OND group we did not find any positive sample. We did not find any difference in the course of the disease between MS patients with and without JCV genomes in their CSF along the follow up. CONCLUSION: JCV seems to be only a bystander in the pathology of MS, and the presence of cell-free viral particles could be related to the immunological activation of the disease, mainly during relapses.
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Enfermedades Desmielinizantes/virología , Virus JC/metabolismo , Esclerosis Múltiple/virología , Infecciones por Polyomavirus/complicaciones , Infecciones Tumorales por Virus/complicaciones , Adulto , ADN Viral/líquido cefalorraquídeo , Enfermedades Desmielinizantes/líquido cefalorraquídeo , Femenino , Estudios de Seguimiento , Humanos , Virus JC/genética , Masculino , Esclerosis Múltiple/líquido cefalorraquídeo , Infecciones por Polyomavirus/líquido cefalorraquídeo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Infecciones Tumorales por Virus/líquido cefalorraquídeo , Carga ViralRESUMEN
To determine whether the DNA prevalence of human herpesvirus-6 (HHV-6), the viral load and the prevalence of both HHV-6 variants in relapsing-remitting multiple sclerosis (RRMS) patients in exacerbation are altered by beta-interferon (IFN-beta) treatment, in comparison with RRMS patients in remission, we analyzed HHV-6 (A and B) genomes in 189 serum samples by quantitative real-time polymerase chain reaction: 105 of the RRMS patients were receiving IFN-beta treatment (48 in exacerbation) and 84 were untreated (36 in relapse). The results were as follows. (1) Prevalence decrease because of IFN-beta treatment was not significant: 25% of RRMS patients in relapse vs. 15.9% in remission (p = 0.45). (2) Viral load was twice as much in untreated patients in relapse than in treated ones. (3) We only found variant A. Since IFN-beta treatment is able to significantly reduce HHV-6 viral load in RRMS patients in relapse, but not in remission, we suggest a role for HHV-6 in the pathogenesis of multiple sclerosis exacerbations and an antiviral role for IFN-beta treatment in RRMS.