RESUMEN
Promoting translational research as a means to overcoming chasms in the translation of knowledge through successive fields of research from basic science to public health impacts and back is a central challenge for research managers and policymakers. Organizational leaders need to assess baseline conditions, identify areas needing improvement, and to judge the impact of specific initiatives to sustain or improve translational research practices at their institutions. Currently, there is a lack of such an assessment tool addressing the specific context of translational biomedical research. To close this gap, we have developed a new survey for assessing the organizational climate for translational research. This self-assessment tool measures employees' perceptions of translational research climate and underlying research practices in organizational environments and builds on the established Survey of Organizational Research Climate, assessing research integrity. Using this tool, we show that scientists at a large university hospital (Charité Berlin) perceive translation as a central and important component of their work. Importantly, local resources and direct support are main contributing factors for the practical implementation of translation into their own research practice. We identify and discuss potential leverage points for an improvement of research climate to foster successful translational research.
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Investigación Biomédica , Investigación Biomédica Traslacional , Humanos , Cultura Organizacional , Encuestas y CuestionariosRESUMEN
OBJECTIVES: Timely and comprehensive reporting of clinical trial results builds the backbone of evidence-based medicine and responsible research. The proportion of timely disseminated trial results can inform alternative national and international benchmarking of university medical centers (UMCs). STUDY DESIGN AND SETTING: For all German UMCs, we tracked all registered trials completed between 2009 and 2013. The results and an interactive website benchmark German UMCs regarding their performance in result dissemination. RESULTS: We identified and tracked 2,132 clinical trials. For 1,509 trials, one of the German UMCs took the academic lead. Of these 1,509 "lead trials," 39% published their results (mostly via journal publications) in a timely manner (<24 months after completion). More than 6 years after study completion, 26% of all eligible lead trials still had not disseminated results. CONCLUSION: Despite substantial attention from many stakeholders to the topic, there is still a strong delay or even absence of result dissemination for many trials. German UMCs have several opportunities to improve this situation. Further research should evaluate whether and how a transparent benchmarking of UMC performance in result dissemination helps to increase value and reduce waste in medical research.
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Ensayos Clínicos como Asunto , Edición/estadística & datos numéricos , Centros Médicos Académicos , Benchmarking , Medicina Basada en la Evidencia , Alemania , Humanos , Factores de TiempoRESUMEN
Background: Several meta-research studies and benchmarking activities have assessed how comprehensively and timely, academic institutions and private companies publish their clinical studies. These current "clinical trial tracking" activities differ substantially in how they sample relevant studies, and how they follow up on their publication. Methods: To allow informed policy and decision making on future publication assessment and benchmarking of institutions and companies, this paper outlines and discusses 10 variables that influence the tracking of timely publications. Tracking variables were initially selected by experts and by the authors through discussion. To validate the completeness of our set of variables, we conducted i) an explorative review of tracking studies and ii) an explorative tracking of registered clinical trials of three leading German university medical centres. Results: We identified the following 10 relevant variables impacting the tracking of clinical studies: 1) responsibility for clinical studies, 2) type and characteristics of clinical studies, 3) status of clinical studies, 4) source for sampling, 5) timing of registration, 6) determination of completion date, 7) timeliness of dissemination, 8) format of dissemination, 9) source for tracking, and 10) inter-rater reliability. Based on the description of these tracking variables and their influence, we discuss which variables could serve in what ways as a standard assessment of "timely publication". Conclusions: To facilitate the tracking and consequent benchmarking of how often and how timely academic institutions and private companies publish clinical study results, we have two core recommendations. First, the improvement in the link between registration and publication, for example via institutional policies for academic institutions and private companies. Second, the comprehensive and transparent reporting of tracking studies according to the 10 variables presented in this paper.
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Estudios Clínicos como Asunto/estadística & datos numéricos , Estudios Clínicos como Asunto/métodos , Estudios Clínicos como Asunto/normas , Toma de Decisiones , Medicina Basada en la Evidencia/métodos , Medicina Basada en la Evidencia/normas , Medicina Basada en la Evidencia/estadística & datos numéricos , Humanos , PublicacionesRESUMEN
INTRODUCTION: We analyzed the impact of myasthenia gravis (MG) on decision-making in family planning by women with the disease. METHODS: In a cross-sectional, anonymous survey, a standardized questionnaire was sent or handed out to 1,637 women with MG. RESULTS: In total, 801 questionnaires were eligible for analysis. Over fifty percent of the patients had abstained from having children due to MG. The concern mentioned most often was the possible influence of MG medication on the unborn child (87.1%). Spouses/partners (91.8%) and MG treating physicians (82.9%) were the most important persons involved in the decision-making process. Higher age and personal experience of intensive-care treatment for MG were independently associated with the decision to abstain from having children. Lower level of knowledge was independently associated with the probability of discouraging other MG patients from having children. CONCLUSIONS: Women with MG need specific guidance about family planning issues, which may lead to lower rates of voluntary childlessness. On the basis of our data, more specific hypotheses can be generated that require prospective investigation.
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Toma de Decisiones , Miastenia Gravis/psicología , Complicaciones del Embarazo/psicología , Conducta Reproductiva/psicología , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Servicios de Planificación Familiar , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Multiple sclerosis (MS) preferentially affects females at childbearing age. For this reason patients and treating physicians were frequently confronted with questions concerning family planning, pregnancy and birth. OBJECTIVE: The aim of this study was to evaluate the expertise about pregnancy related topics in multiple sclerosis of neurologists in private practice. METHODS: We developed a survey with 16 multiple choice questions about pregnancy related topics and sent it to neurologists in private practice in Berlin, Germany. RESULTS: 56 completed questionnaires were sent back. 54% of all questions were answered correctly, 21% of the questions were answered with "I don't know". Correct answers were more often given by physicians who treat more than 400 MS patients per year (pâ=â0.001). Further positive associations were found for assumed relevance of the topic (pâ=â0.002) and the degree of counseling (p<0.001). CONCLUSION: To provide a comprehensive counseling, MS patients with desire for children should be counseled by physicians with a lot of experience in MS treatment.
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Esclerosis Múltiple/patología , Médicos/psicología , Adulto , Consejo Dirigido , Femenino , Humanos , Masculino , Persona de Mediana Edad , Embarazo , Encuestas y CuestionariosRESUMEN
BACKGROUND: Trichuris suis ova is a probiotic treatment based on the hygiene hypothesis. It has been demonstrated as safe and effective in autoimmune inflammatory bowel diseases and clinical trials indicate that helminth infections also have an immunomodulatory effect in multiple sclerosis.We hypothesize that administering 2,500 Trichuris suis ova eggs orally every two weeks for 12 months is--due to its immunomodulatory and anti-inflammatory effect--significantly more effective than oral placebo in preventing new T2 and Gd+ lesions, as quantified by cerebral MRI and clinical examination, in relapsing-remitting multiple sclerosis and clinically isolated syndrome. METHODS/DESIGN: Fifty patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome with clinical activity, not undergoing any standard therapies, will be randomized 1:1 to Trichuris suis ova 2,500 eggs every two weeks or matching placebo. The safety, tolerability and effect on disease activity and in vivo mechanisms of action of Trichuris suis ova in MS will be assessed by neurological, laboratory and immunological exams and magnetic resonance imaging throughout the 12-month treatment period and over a follow-up period of 6 months. Various immunological analyses will be used to assess the overall patient immune response prior to and at varying time points following treatment with Trichuris suis ova. DISCUSSION: We anticipate that Trichuris suis ova will be well tolerated and more effective than the placebo in preventing new T2 and Gd+ lesions, as quantified by MRI. We also expect the Th1/Th17 proinflammatory response to shift towards the more anti-inflammatory Th2 response. This study has important clinical implications and will involve extensive research on the immunology of helminth therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01413243.
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Enfermedades Desmielinizantes/terapia , Esclerosis Múltiple Recurrente-Remitente/terapia , Probióticos/uso terapéutico , Proyectos de Investigación , Terapia con Helmintos , Trichuris/inmunología , Administración Oral , Animales , Protocolos Clínicos , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/inmunología , Alemania , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Óvulo/inmunología , Examen Físico , Valor Predictivo de las Pruebas , Probióticos/efectos adversos , Linfocitos T Colaboradores-Inductores/inmunología , Terapia con Helmintos/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Trichuris/crecimiento & desarrolloRESUMEN
BACKGROUND: 2-8% of all children aged between 6 months and 5 years have febrile seizures. Often these seizures cease spontaneously, however depending on different national guidelines, 20-40% of the patients would need therapeutic intervention. For seizures longer than 3-5 minutes application of rectal diazepam, buccal midazolam or sublingual lorazepam is recommended. Benzodiazepines may be ineffective in some patients or cause prolonged sedation and fatigue. Preclinical investigations in a rat model provided evidence that febrile seizures may be triggered by respiratory alkalosis, which was subsequently confirmed by a retrospective clinical observation. Further, individual therapeutic interventions demonstrated that a pCO2-elevation via re-breathing or inhalation of 5% CO2 instantly stopped the febrile seizures. Here, we present the protocol for an interventional clinical trial to test the hypothesis that the application of 5% CO2 is effective and safe to suppress febrile seizures in children. METHODS: The CARDIF (CARbon DIoxide against Febrile seizures) trial is a monocentric, prospective, double-blind, placebo-controlled, randomized study. A total of 288 patients with a life history of at least one febrile seizure will be randomized to receive either carbogen (5% CO2 plus 95% O2) or placebo (100% O2). As recurrences of febrile seizures mainly occur at home, the study medication will be administered by the parents through a low-pressure can fitted with a respiratory mask. The primary outcome measure is the efficacy of carbogen to interrupt febrile seizures. As secondary outcome parameters we assess safety, practicability to use the can, quality of life, contentedness, anxiousness and mobility of the parents. PROSPECT: The CARDIF trial has the potential to develop a new therapy for the suppression of febrile seizures by redressing the normal physiological state. This would offer an alternative to the currently suggested treatment with benzodiazepines. This study is an example of academic translational research from the study of animal physiology to a new therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01370044.
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Dióxido de Carbono/uso terapéutico , Convulsiones Febriles/terapia , Preescolar , Método Doble Ciego , Diseño de Equipo , Humanos , Lactante , Estudios Prospectivos , Calidad de Vida , Proyectos de Investigación , Investigación Biomédica Traslacional , Resultado del TratamientoRESUMEN
RATIONALE: Stroke-associated pneumonia is one of the most common causes of poor outcome in stroke patients. Clinical signs and laboratory parameters of stroke-associated infections are often inconclusive. Biomarkers may help to identify stroke patients at high risk for pneumonia and to guide physicians in an early antibiotic treatment, thereby improving stroke outcome. AIM: The aim of the present study is to investigate whether procalcitonin ultrasensitive-guided antibiotic treatment improves functional outcome after severe ischaemic stroke by early treatment of pneumonia. DESIGN: STRAWINSKI is an investigator-initiated, multicentre, randomized, controlled trial with blinded assessment of outcome comparing procalcitonin ultrasensitive-guided antibiotic treatment with standard care. STUDY: 200 patients with ischaemic stroke in the middle cerebral artery territory and a score >9 on the National Institutes of Health Stroke Scale will be included and randomly assigned to two groups. One group will receive procalcitonin-based antibiotic therapy guidance; the other group will receive standard stroke unit care. OUTCOMES: The primary endpoint is functional outcome at day 90 after stroke on the modified Rankin Scale, dichotomized as favourable (0-4) or unfavourable outcome (5-6). Secondary endpoints are time to first event of death, rehospitalization, or recurrent stroke; death rate, infection rate, and days with fever up to day 7; length of hospital stay and hospital discharge disposition; shift analysis of the modified Rankin Scale; Barthel Index and days alive and out of hospital at day 90; use of antibiotics until day 90; and modified Rankin Scale, Barthel Index, and infarct volume at day 180.
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Antibacterianos/uso terapéutico , Calcitonina/sangre , Infección Hospitalaria/tratamiento farmacológico , Neumonía/tratamiento farmacológico , Precursores de Proteínas/sangre , Accidente Cerebrovascular/complicaciones , Biomarcadores/sangre , Péptido Relacionado con Gen de Calcitonina , Infección Hospitalaria/sangre , Humanos , Neumonía/sangre , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Stroke-associated pneumonia (SAP) is associated with impaired outcome in acute stroke patients. Current European and American guidelines for acute stroke care are lacking standardised recommendations for the management of SAP. We investigated current diagnostic and treatment practice for SAP in German stroke units (SU). METHODS: We developed a standardised questionnaire including characteristics of SU, questions related to antibiotic treatment approaches of SAP and five case vignettes describing relevant clinical scenarios based on Centers for Disease Control and Prevention (CDC) criteria for 'clinically defined pneumonia'. All certified German SU were invited to take part in the survey. RESULTS: The survey took place from April to August 2010. Of all 162 German SU contacted, 83 (51%) responded. Classification and regression trees analysis suggested that SAP was diagnosed on the basis of clinical criteria such as fever and stroke severity. Chest x-ray showed only limited influence on the diagnosis of SAP. C-reactive protein was frequently requested as additional diagnostic information (38-76%). Group 3 cephalosporines and (acyl-) aminopenicillins/ß-lactamase inhibitors are the most frequently used antibiotics (46-60%) in empiric mono (58%) and combination (42%) therapy. A minority of SU (5%) use prophylactic antibiotic treatment. Standardised procedures are available in 61% of SU. CONCLUSION: Clinical criteria were the main determinants for SAP diagnosis. In contrast, chest x-ray--the central diagnostic item in CDC criteria--was of minor importance. Our survey demonstrates heterogeneous diagnostic and therapeutic strategies in German SU. Future studies need to establish and to evaluate standardised criteria for SAP care.
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Neumonía/diagnóstico , Neumonía/terapia , Accidente Cerebrovascular/complicaciones , Antibacterianos/uso terapéutico , Manejo de Caso , Sistemas de Apoyo a Decisiones Clínicas , Alemania , Guías como Asunto , Humanos , Neumonía/etiología , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
BACKGROUND: Optic neuritis is a frequent manifestation of multiple sclerosis. Visual deficits range from a minor impairment of visual functions through to complete loss of vision. Although many patients recover almost completely, roughly 35% of patients remain visually impaired for years, and therapeutic options for those patients hardly exist. Vision restoration therapy is a software-based visual training program that has been shown to improve visual deficits after pre- and postchiasmatic injury. The aim of this pilot study is to evaluate whether residual visual deficits after past or recent optic neuritis can be reduced by means of vision restoration therapy. METHODS/DESIGN: A randomized, controlled, patient- and observer-blinded clinical pilot study (VISION study) was designed to evaluate the efficacy of vision restoration therapy in optic neuritis patients. Eighty patients with a residual visual deficit after optic neuritis (visual acuity ≤0.7 and/or scotoma) will be stratified according to the time of optic neuritis onset (manifestation more than 12 months ago (40 patients, fixed deficit) versus manifestation 2 to 6 months ago (40 patients, recent optic neuritis)), and randomized into vision restoration therapy arm or saccadic training arm (control intervention). Patients will be instructed to complete a computer-based visual training for approximately 30 minutes each day for a period of 6 months. Patients and evaluators remain blinded to the treatment allocation throughout the study. All endpoints will be analyzed and P-values < 0.05 will be considered statistically significant. The primary outcome parameter will be the expansion of the visual field after 3 and 6 months of treatment as determined by static visual field perimetry and high resolution perimetry. Secondary outcome variables will include visual acuity at both low and high contrast, glare contrast sensitivity, visually evoked potentials, optical coherence tomography and other functional tests of the visual system, alertness, health-related quality of life, fatigue, and depression. DISCUSSION: If vision restoration therapy is shown to improve visual function after optic neuritis, this method might be a first therapeutic option for patients with incomplete recovery from optic neuritis. TRIAL REGISTRATION: NCT01274702.
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Neuritis Óptica/terapia , Proyectos de Investigación , Terapia Asistida por Computador , Trastornos de la Visión/terapia , Visión Ocular , Sensibilidad de Contraste , Método Doble Ciego , Potenciales Evocados Visuales , Alemania , Humanos , Neuritis Óptica/complicaciones , Neuritis Óptica/diagnóstico , Neuritis Óptica/fisiopatología , Selección de Paciente , Estimulación Luminosa , Proyectos Piloto , Calidad de Vida , Recuperación de la Función , Escotoma/etiología , Escotoma/terapia , Encuestas y Cuestionarios , Factores de Tiempo , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Trastornos de la Visión/diagnóstico , Trastornos de la Visión/etiología , Trastornos de la Visión/fisiopatología , Pruebas de Visión , Agudeza Visual , Campos VisualesRESUMEN
Post-stroke infections are the most important complications after acute stroke, accounting for almost 20% of in-hospital deaths and poor functional outcomes at discharge. Little is known about long-term effects of post-stroke infections on outcome. Here, we studied the impact of infections on long-term outcome in 64 patients which had suffered from severe middle cerebral artery infarction. Mean follow-up time in the survivors was 6.5 ± 0.9 years. Structured telephone interviews were performed to assess the patients' current functional outcome. Where re-contacting was not successful, vital status of the patients was requested at the registration office of Berlin. Multiple logistic regression analysis identified three independent risk factors associated with mortality: infections within the first 11 days after stroke, age>64 years, and female sex. Among surviving patients, functional outcome measured by Barthel Index was influenced by infections and immunocompetence measured by levels of monocytic HLA-DR expression on day 3 after stroke. In conclusion, the occurrence of post-stroke infections is the most important predictor of poor long-term outcome in this cohort of patients. Our observation warrants prospective trials on prevention or early treatment of post-stroke infections in order to improve long-term outcome after stroke.
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Infecciones del Sistema Nervioso Central/etiología , Infarto de la Arteria Cerebral Media/complicaciones , Accidente Cerebrovascular/complicaciones , Factores de Edad , Anciano , Infecciones del Sistema Nervioso Central/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Infarto de la Arteria Cerebral Media/mortalidad , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Factores Sexuales , Accidente Cerebrovascular/mortalidad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults. Despite the fact that numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D it still remains elusive whether multiple sclerosis patients benefit from boosting the serum level of 25-hydroxyvitamin D, mainly because interventional clinical trials that directly address the therapeutic effects of vitamin D in multiple sclerosis are sparse. We here present the protocol of an interventional clinical phase II study to test the hypothesis, that high-dose vitamin D supplementation of multiple sclerosis patients is safe and superior to low-dose supplementation with respect to beneficial therapeutic effects. METHODS/DESIGN: The EVIDIMS trial is a German multi-center, stratified, randomized, controlled and double-blind clinical phase II pilot study. Eighty patients with the diagnosis of definite multiple sclerosis or clinically isolated syndrome who are on a stable immunomodulatory treatment with interferon-ß1b will be randomized to additionally receive either high-dose (average daily dose 10.200 IU) or low-dose (average daily dose 200 IU) cholecalciferol for a total period of 18 months. The primary outcome measure is the number of new lesions detected on T2-weighted cranial MRI at 3 tesla. Secondary endpoints include additional magnetic resonance imaging and optical coherence tomography parameters for neuroinflammation and -degeneration, clinical parameters for disease activity, as well as cognition, fatigue, depression, and quality of life. Safety and tolerability of high-dose vitamin D supplementation are further outcome parameters. DISCUSSION: In light of the discrepancy between existing epidemiological and preclinical data on the one hand and available clinical data on the other the EVIDIMS trial will substantially contribute to the evaluation of the efficacy of high-dose vitamin D supplementation in MS patients. The study design presented here fulfills the criteria of a high-quality clinical phase II trial in MS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01440062.
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Colecalciferol/administración & dosificación , Suplementos Dietéticos , Esclerosis Múltiple/tratamiento farmacológico , Proyectos de Investigación , Encéfalo/efectos de los fármacos , Encéfalo/patología , Colecalciferol/efectos adversos , Suplementos Dietéticos/efectos adversos , Método Doble Ciego , Alemania , Humanos , Factores Inmunológicos/uso terapéutico , Interferon beta-1b , Interferón beta/uso terapéutico , Imagen por Resonancia Magnética , Esclerosis Múltiple/patología , Calidad de Vida , Factores de Tiempo , Tomografía de Coherencia Óptica , Resultado del TratamientoRESUMEN
OBJECTIVES: To analyse the association between retinal nerve fibre layer thickness (RNFLT) and total macular volume (TMV) as measured by optical coherence tomography, and contrast sensitivity (CS) measured by Functional Acuity Contrast Testing (FACT) in relapsing-remitting multiple sclerosis; and to investigate whether FACT testing by a contrast box device is feasible in multiple sclerosis (MS). METHODS: fact was performed using the Optec 6500 P vision testing system with best correction under photopic and mesopic conditions without glare. The Area Under the Log Contrast Sensitivity Function (AUC) was calculated. RNFLT and TMV were assessed by Stratus optical coherence tomography. All participants underwent visual acuity testing (Snellen), spherical refractive error testing and cylindrical refractive error testing. RESULTS: 85 relapsing-remitting multiple sclerosis patients (170 eyes) and 35 healthy controls (HC, 70 eyes) were measured. AUC Day and Night were lower in MS than in HC (p<0.001) when correcting for age, as were mean RNFLT and TMV (p<0.001 and p=0.018, respectively). Both RNFLT and TMV predicted contrast sensitivity in MS (AUC Day: standardised coefficient ß=0.277, p<0.001, and ß=0.262, p<0.001, respectively; AUC Night: ß=0.202, p=0.009 and ß=0.222, p=0.004, respectively, linear regressions). In HC, there was no correlation between RNFLT or TMV and contrast sensitivity. CONCLUSION: (1) Contrast sensitivity is reduced in MS versus HC; (2) RNFL and TMV as morphological measures of retinal axonal loss are predictors of contrast sensitivity as a functional visual parameter in MS but not in HC; and (3) FACT with the contrast box is a novel, feasible and rapid method to assess contrast sensitivity in MS.
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Sensibilidad de Contraste , Mácula Lútea/patología , Esclerosis Múltiple Recurrente-Remitente/patología , Trastornos de la Visión/patología , Agudeza Visual , Adulto , Estudios Transversales , Femenino , Humanos , Modelos Lineales , Mácula Lútea/fisiopatología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Fibras Nerviosas/patología , Fibras Nerviosas/fisiología , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Tomografía de Coherencia Óptica , Trastornos de la Visión/etiología , Trastornos de la Visión/fisiopatología , Adulto JovenRESUMEN
Bipolar disorder has a genetic component, but the mode of inheritance remains unclear. A previous genome scan conducted in 70 European families led to detect eight regions linked to bipolar disease. Here, we present an investigation of whether the phenotypic heterogeneity of the disorder corresponds to genetic heterogeneity in these regions using additional markers and an extended sample of families. The MLS statistic was used for linkage analyses. The predivided sample test and the maximum likelihood binomial methods were used to test genetic homogeneity between early-onset bipolar type I (cut-off of 22 years) and other types of the disorder (later onset of bipolar type I and early-onset bipolar type II), using a total of 138 independent bipolar-affected sib-pairs. Analysis of the extended sample of families supports linkage in four regions (2q14, 3p14, 16p23, and 20p12) of the eight regions of linkage suggested by our previous genome scan. Heterogeneity testing revealed genetic heterogeneity between early and late-onset bipolar type I in the 2q14 region (P = 0.0001). Only the early form of the bipolar disorder but not the late form appeared to be linked to this region. This region may therefore include a genetic factor either specifically involved in the early-onset bipolar type I or only influencing the age at onset (AAO). Our findings illustrate that stratification according to AAO may be valuable for the identification of genetic vulnerability polymorphisms. © 2010 Wiley-Liss, Inc.
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Edad de Inicio , Trastorno Bipolar/genética , Cromosomas Humanos Par 2/genética , Heterogeneidad Genética , Ligamiento Genético , Adolescente , Trastorno Bipolar/epidemiología , Mapeo Cromosómico , Interpretación Estadística de Datos , Europa (Continente) , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Adulto JovenRESUMEN
BACKGROUND: Fatigue is the most common symptom in multiple sclerosis patients, but is difficult to measure; quantification thus relies on self-assessed questionnaires. OBJECTIVE: To evaluate a battery of neuropsychological tests regarding their capacity to objectify self-reported fatigue. METHODS: We assessed the correlation between age, gender, education, Kurtzke's Expanded Disability Status Scale, depression, fatigue and neuropsychological testing using a cross-sectional approach in 110 multiple sclerosis patients. Fatigue was measured with the Fatigue Severity Scale. Cognition was measured using a series of neuropsychological tests including three subtests of the Test of Attentional Performance, the Brief Repeatable Battery of Neuropsychological Tests and the Faces Symbol Test. RESULTS: According to the Fatigue Severity Scale 51.4% of the cohort were fatigued (scores > or =4). Age, education and depression showed a significant correlation with the Fatigue Severity Scale. Only 5.5% of the cohort exhibited cognitive impairment in the Brief Repeatable Battery of Neuropsychological Tests scores. After correction for age, education, Expanded Disability Status Scale and depression, Fatigue Severity Scale scores were an independent predictor of performance in the alertness subtest of the Test of Attentional Performance (standardized coefficient beta = 0.298, p = 0.014). CONCLUSION: The alertness subtest of the Test of Attentional Performance may offer an objective method of evaluating self-reported fatigue, and may therefore - in addition to the Fatigue Severity Scale - be a suitable tool for the assessment of multiple sclerosis patients complaining of fatigue.
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Atención , Cognición , Fatiga/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Pruebas Neuropsicológicas , Autoevaluación (Psicología) , Encuestas y Cuestionarios , Adulto , Análisis de Varianza , Estudios Transversales , Evaluación de la Discapacidad , Función Ejecutiva , Fatiga/etiología , Fatiga/psicología , Femenino , Alemania , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/psicología , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Percepción Visual , Adulto JovenRESUMEN
OBJECTIVE: Optical coherence tomography (OCT) has gained increasing attention in multiple sclerosis (MS) research and has been suggested as outcome measure for neuroprotective therapies. However, to date it is not clear whether patterns of retinal nerve fiber layer thickness (RNFLT) loss are different in MS compared to other diseases such as glaucoma and data on RNFLT loss in MS patients with or without optic neuritis (ON/NON) have remained inconsistent or even contradictory. METHODS: In this large cross-sectional study we analyzed the patterns of axonal loss of retinal ganglion cells in MS eyes (n=262) with and without history of ON (MS/ON: 73 eyes; MS/NON: 189 eyes) and patients eyes with glaucomatous optic disc atrophy (GA: n=22; 39 eyes) in comparison to healthy control eyes (HC: n=406 eyes). RESULTS: We found that significant average and quadrant RNFLT loss is detectable by OCT in both MS and GA patients compared to healthy controls (p<0.01). The age- and gender adjusted average and quadrant RNFLT did not differ significantly between MS and GA patients (p>0.05). Average (p<0.0001) and quadrant (p<0.05) RNFL thinning is significantly more severe in MS/ON versus MS/NON eyes, and the extent of RNFL thinning varies across quadrants in MS/ON eyes with the highest degree of RNFLT loss in the temporal quadrant (p<0.001). CONCLUSION: RNFLT reduction across all four quadrants in MS patients as a whole as well as in MS/NON eyes argues for a diffuse neurodegenerative process. Superimposed inflammatory attacks to the optic nerve may cause additional axonal damage with a temporal preponderance. Future studies are necessary to further evaluate the capacity of OCT to depict disease specific damage patterns.
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Glaucoma/patología , Esclerosis Múltiple/patología , Degeneración Nerviosa/patología , Fibras Nerviosas Amielínicas/patología , Neuritis Óptica/patología , Células Ganglionares de la Retina/patología , Adulto , Atrofia , Axones/patología , Estudios de Casos y Controles , Estudios Transversales , Femenino , Glaucoma/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Degeneración Nerviosa/etiología , Disco Óptico/patología , Neuritis Óptica/complicaciones , Valores de Referencia , Tomografía de Coherencia ÓpticaRESUMEN
Conventional time domain optical coherence tomography has been established for the in vivo assessment of retinal axonal loss in multiple sclerosis. The innovative spectral domain imaging is superior to the conventional technique with respect to data acquisition speed, resolution and reproducibility. However, until now comparability of the two techniques has not been investigated in multiple sclerosis. In this study involving 55 multiple sclerosis patients, data obtained using both techniques (Stratus time domain optical coherence tomography and Cirrus spectral domain optical coherence tomography, Carl Zeiss Meditec) showed an excellent correlation (Pearson's r = 0.926, p < 0.001). However, owing to considerable differences in absolute retinal nerve fibre layer measurements (mean +/- standard deviation 8.1 microm +/- 6.2, range -12 to 23 microm), results from the two devices are not interchangeable.
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Axones/patología , Esclerosis Múltiple/diagnóstico , Neuronas Retinianas/patología , Tomografía de Coherencia Óptica/métodos , Adulto , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Estudios Transversales , Diseño de Equipo , Femenino , Alemania , Humanos , Interpretación de Imagen Asistida por Computador , Modelos Lineales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Valor Predictivo de las Pruebas , Factores de Tiempo , Tomografía de Coherencia Óptica/instrumentación , Agudeza Visual , Adulto JovenRESUMEN
Attention is one of the cognitive domains typically affected in multiple sclerosis. The Attention Network Test was developed to measure the function of the three distinct attentional networks, alerting, orienting, and executive control. The Attention Network Test has been performed in various neuropsychiatric conditions, but not in multiple sclerosis. Our objective was to investigate functions of attentional networks in multiple sclerosis by means of the Attention Network Test. Patients with relapsing-remitting multiple sclerosis (n = 57) and healthy controls (n = 57) matched for age, sex, and education performed the Attention Network Test. Significant differences between patients and controls were detected in the alerting network (p = 0.003), in contrast to the orienting (p = 0.696) and the conflict (p = 0.114) network of visual attention. Mean reaction time in the Attention Network Test was significantly longer in multiple sclerosis patients than in controls (p = 0.032), Multiple sclerosis patients benefited less from alerting cues for conflict resolution compared with healthy controls. The Attention Network Test revealed specific alterations of the attention network in multiple sclerosis patients which were not explained by an overall cognitive slowing.
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Atención/fisiología , Trastornos del Conocimiento/fisiopatología , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/psicología , Red Nerviosa/fisiopatología , Adulto , Trastornos del Conocimiento/etiología , Conflicto Psicológico , Estudios Transversales , Señales (Psicología) , Interpretación Estadística de Datos , Depresión/psicología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Fatiga/psicología , Femenino , Fijación Ocular , Humanos , Masculino , Esclerosis Múltiple/complicaciones , Estimulación Luminosa , Tiempo de Reacción/fisiologíaRESUMEN
OBJECTIVE: Neuroinflammation contributes to motor neuron degeneration in ALS. Thalidomide (THL) shows potent anti-inflammatory properties and increased the lifespan in ALS transgenic mice. Thalidomide was therefore suggested as atherapeutic intervention for the treatment of ALS.We conducted a pilot, randomized clinical trial of THL in patients with ALS to assess safety, feasibility, and preliminary estimates of treatment efficacy. METHODS: Patients were randomized to THL in combination with riluzole (n = 18) or riluzole alone (n = 19). THL was initiated at 100 mg per day for 6 weeks. Thereafter, the dose was increased every week by 50 mg until reaching the dose of 400 mg per day and planned to continue for another 12 weeks. RESULTS: Within 12 weeks of THL treatment, nine THL patients (50%) developed bradycardia defined as a heart rate below 60 beats per minute (bpm) and ranged from 46 to 59 bpm. Mean heart rate dropped by 17 bpm with THL treatment. Severe symptomatic bradycardia of 30 bpm occurred in one patient. A further patient died from sudden unexpected death. The study was terminated prematurely for safety concerns. The secondary outcome variables showed similar results for both groups. CONCLUSION: Bradycardia was the most common adverse event of THL treatment in ALS. THL-related bradycardia does not appear to be ALS-specific. It is conceivable, however, that the unexpected frequency and severity of THL-induced bradycardia may be related to subclinical involvement of the autonomic nervous system in ALS. The cardiac toxicity discourages further clinical trials and compassionate use of THL in ALS. ClinicalTrials.gov Identifier: NCT00231140.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Arritmia Sinusal/inducido químicamente , Bradicardia/inducido químicamente , Inflamación/tratamiento farmacológico , Parasístole/inducido químicamente , Talidomida/efectos adversos , Adulto , Anciano , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/inmunología , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Arritmia Sinusal/fisiopatología , Bradicardia/fisiopatología , Muerte Súbita/etiología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Electrocardiografía , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inflamación/inmunología , Persona de Mediana Edad , Parasístole/fisiopatología , Proyectos Piloto , Riluzol/administración & dosificación , Talidomida/administración & dosificación , Resultado del TratamientoRESUMEN
Mutations in ATP1A2 cause familial hemiplegic migraine (FHM) type 2, a rare monogenic form of migraine with aura (MA). Moreover, rare ATP1A2 missense variants are found in familial clustering of common forms of migraine in single pedigrees. To determine whether also common ATP1A2 polymorphisms contribute to MA pathogenesis, we performed systematic case-control association studies in 284 MA cases and 241 control individuals. By direct sequencing of the 23 coding exons and adjacent intronic regions in 45 MA patients, 16 polymorphisms (12 SNPs, 3 small indels, 1 microsatellite marker) were identified. The sequencing results were used to estimate seven common ATP1A2 haplotypes (with a frequency >5%) covering about 97% of total haplotype diversity for this region. Subsequently, six haplotype-tagging SNPs/polymorphisms were genotyped in 95 individuals with a family history of MA, in 189 individuals with sporadic MA, and in a gender-matched control sample. A haplotype analysis was performed using the program FAMHAP. No significant differences in the ATP1A2 haplotype distribution could be detected between MA patients (or patient subgroups) and the control group. In a single-marker analysis the allele and genotype frequencies of ATP1A2 polymorphisms between cases and controls were compared. Neither the six ht-SNPs nor a single allele of the microsatellite marker were significantly associated with MA. In summary, we found no evidence for a common contribution of ATP1A2 to the pathogenesis of complex inherited MA.