RESUMEN
OBJECTIVE: In stiff person syndrome (SPS), an antibody-mediated impaired γ-aminobutyric acidergic (GABAergic) neurotransmission is believed to cause muscle stiffness and spasms. Most patients improve with GABA-enhancing drugs and intravenous immunoglobulin, but some respond poorly and remain disabled. The need for more effective therapy prompted a trial with the anti-CD20 monoclonal antibody rituximab. METHODS: This was a placebo-controlled randomized trial of rituximab (2 biweekly infusions of 1g each). The primary outcome was a change in stiffness scores at 6 months. Secondary outcomes were changes in heightened-sensitivity and quality of life scores. Enrolling 24 patients was calculated to detect 50% change in stiffness scores. RESULTS: Randomization was balanced for age, sex, disease duration, and glutamic acid decarboxylase autoantibody titers. No significant changes were noted at 6 months after treatment in all outcomes. Specifically, no differences were noted in the stiffness index, the primary outcome, or sensitivity scores, the secondary outcome, at 3 or 6 months. Quality of life scores improved significantly (p < 0.01) at 3 months in both groups, but not at 6 months, denoting an early placebo effect. Blinded self-assessment rating of the overall stiffness for individual patients revealed improvement in 4 patients in each group. At 6 months, improvement persisted in 1 patient in the placebo group versus 3 of 4 in the rituximab group, where these meaningful improvements were also captured by video recordings. INTERPRETATION: This is the largest controlled trial conducted in SPS patients and demonstrates no statistically significant difference in the efficacy measures between rituximab and placebo. Rituximab's lack of efficacy could be due to a considerable placebo effect; insensitivity of scales to quantify stiffness, especially in the less severely affected patients; or drug effectiveness in only a small patient subset. Ann Neurol 2017;82:271-277.
Asunto(s)
Rituximab/uso terapéutico , Síndrome de la Persona Rígida/tratamiento farmacológico , Autoanticuerpos/sangre , Método Doble Ciego , Femenino , Glutamato Descarboxilasa/inmunología , Humanos , Factores Inmunológicos/uso terapéutico , Masculino , Persona de Mediana Edad , Síndrome de la Persona Rígida/sangre , Resultado del TratamientoRESUMEN
UNLABELLED: Assessing the skeletal response to enzyme replacement therapy (ERT) in Gaucher disease (GD) is problematic. We investigated the reliability of (99m)Tc-sestamibi scintigraphy in monitoring changes in bone marrow involvement induced by ERT. METHODS: In 52 GD patients, the efficacy of ERT on bone marrow disease was monitored using at least 2 sequential (99m)Tc-sestamibi scans; 17 patients were receiving ERT at enrollment, and 35 were ERT-naïve. We elaborated a dose-response model by statistical analysis based on linear mixed models. RESULTS: Patients whose marrow disease improved had received a significantly higher ERT dose per month than patients who did not improve. Significantly more patients reached near-disappearance of marrow disease if their disease burden at enrollment had been lower and the duration of clinical signs shorter. The response of the marrow scintigraphic score was more pronounced in ERT-naïve patients. No relevant effect of ERT on marrow disease was observed until platelet count and splenomegaly had improved. CONCLUSION: Although based on localized evaluation, changes in the (99m)Tc-sestamibi score closely correlated with the main determinants of ERT, with a definite dose-response relationship. The threshold at which ERT induced any improvement in bone marrow disease was 35-36 U/kg/mo; in ERT-naïve patients, the scintigraphic score declined by 1 unit after ERT at 28 U/kg/mo.
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Enfermedades de la Médula Ósea/complicaciones , Enfermedades de la Médula Ósea/diagnóstico por imagen , Terapia de Reemplazo Enzimático , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/terapia , Tecnecio Tc 99m Sestamibi , Adulto , Femenino , Enfermedad de Gaucher/diagnóstico por imagen , Humanos , Masculino , Cintigrafía , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture > or =10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients' total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P < 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P < 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA(+)CD62L(-) cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P < 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and alphaB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Inmunosupresores/uso terapéutico , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Alemtuzumab , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/efectos adversos , Biopsia , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Femenino , Estudios de Seguimiento , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunosupresores/efectos adversos , Mediadores de Inflamación/metabolismo , Recuento de Linfocitos , Depleción Linfocítica/métodos , Masculino , Persona de Mediana Edad , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miositis por Cuerpos de Inclusión/inmunología , Miositis por Cuerpos de Inclusión/patología , Miositis por Cuerpos de Inclusión/fisiopatología , ARN Mensajero/genética , Recuperación de la Función , Resultado del TratamientoRESUMEN
OBJECTIVE: Report a double-blind, placebo-controlled study of rituximab in patients with anti-MAG demyelinating polyneuropathy (A-MAG-DP). METHODS: Twenty-six patients were randomized to four weekly infusions of 375 mg/m(2) rituximab or placebo. Sample size was calculated to detect changes of > or = 1 Inflammatory Neuropathy Course and Treatment (INCAT) leg disability scores at month 8. IgM levels, anti-MAG titers, B cells, antigen-presenting cells, and immunoregulatory T cells were monitored every 2 months. RESULTS: Thirteen A-MAG-DP patients were randomized to rituximab and 13 to placebo. Randomization was balanced for age, electrophysiology, disease duration, disability scores, and baseline B cells. After 8 months, by intention to treat, 4 of 13 rituximab-treated patients improved by > or = 1 INCAT score compared with 0 of 13 patients taking placebo (p = 0.096). Excluding one rituximab-randomized patient who had normal INCAT score at entry, and thus could not improve, the results were significant (p = 0.036). The time to 10m walk was significantly reduced in the rituximab group (p = 0.042) (intention to treat). Clinically, walking improved in 7 of 13 rituximab-treated patients. At month 8, IgM was reduced by 34% and anti-MAG titers by 50%. CD25+CD4+Foxp3+ regulatory cells significantly increased by month 8. The most improved patients were those with high anti-MAG titers and most severe sensory deficits at baseline. INTERPRETATION: Rituximab is the first drug that improves some patients with A-MAG-DP in a controlled study. The benefit may be exerted by reducing the putative pathogenic antibodies or by inducing immunoregulatory T cells. The results warrant confirmation with a larger trial.
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Anticuerpos Monoclonales/uso terapéutico , Enfermedades Desmielinizantes/inmunología , Inmunoglobulina M/sangre , Factores Inmunológicos/uso terapéutico , Glicoproteína Asociada a Mielina/inmunología , Polineuropatías/inmunología , Anciano , Anticuerpos Monoclonales de Origen Murino , Linfocitos B/efectos de los fármacos , Enfermedades Desmielinizantes/complicaciones , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Polineuropatías/complicaciones , Rituximab , Liberación Accidental en Seveso , Linfocitos T/efectos de los fármacos , Resultado del TratamientoRESUMEN
The Guide for the Care and Use of Laboratory Animals (Guide) recommends minimum floor space per mouse based on weight, with no other factors considered. We conducted a randomized experiment to evaluate the effect of housing density on reproductive indices and corticosterone levels in lactating mice. Female mice matched for age, strain, and date-of-pregnancy were housed individually. At parturition the dams were randomly allocated to have litters culled or remain intact. The experimental group had litters culled to meet the Guide's space density requirement. Litters of the second group were maintained as the numbers born to each dam. Fecal corticosterone levels (first-generation mice only), growth, and weaning weights were measured for mice in all cages; in addition, the reproductive behavior of progeny generated under both housing conditions was assessed to determine whether a space x litter size interaction affected subsequent reproduction. The growth rates for pups from culled litters were significantly greater than those from intact litters. The first-generation pups showed no statistically significant differences in fecal corticosterone or reproductive parameters. The second-generation pups showed no statistically significant differences in growth rates. The results of the study suggest that a strict interpretation of space requirements as listed in Table 2.1 of the Guide is not warranted for lactating dams with litters.
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Corticosterona/sangre , Vivienda para Animales , Lactancia/sangre , Reproducción/fisiología , Animales , Peso Corporal/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , Regulación de la Población , Densidad de Población , Distribución Aleatoria , Aislamiento Social , DesteteRESUMEN
CONTEXT: Endolymphatic sac tumors (ELSTs) are associated with von Hippel-Lindau disease and cause irreversible sensorineural hearing loss (SNHL) and vestibulopathy. The underlying mechanisms of audiovestibular morbidity remain unclear and optimal timing of treatment is not known. OBJECTIVE: To define the mechanisms underlying audiovestibular pathophysiology associated with ELSTs. DESIGN, SETTING, AND PATIENTS: Prospective and serial evaluation of patients with von Hippel-Lindau disease and ELSTs at the National Institutes of Health between May 1990 and December 2006. MAIN OUTCOME MEASURES: Clinical findings and audiologic data were correlated with serial magnetic resonance imaging and computed tomography imaging studies to determine mechanisms underlying audiovestibular dysfunction. RESULTS: Thirty-five patients with von Hippel-Lindau disease and ELSTs in 38 ears (3 bilateral ELSTs) were identified. Tumor invasion of the otic capsule was associated with larger tumors (P = .01) and occurred in 7 ears (18%) causing SNHL (100%). No evidence of otic capsule invasion was present in the remaining 31 ears (82%). SNHL developed in 27 of these 31 ears (87%) either suddenly (14 ears; 52%) or gradually (13 ears; 48%) and 4 ears had normal hearing. Intralabyrinthine hemorrhage was found in 11 of 14 ears with sudden SNHL (79%; P < .001) but occurred in none of the 17 ears with gradual SNHL or normal hearing. Tumor size was not related to SNHL (P = .23) or vestibulopathy (P = .83). CONCLUSIONS: ELST-associated SNHL and vestibulopathy may occur suddenly due to tumor-associated intralabyrinthine hemorrhage, or insidiously, consistent with endolymphatic hydrops. Both of these pathophysiologic mechanisms occur with small tumors that are not associated with otic capsule invasion.
Asunto(s)
Neoplasias del Oído/complicaciones , Saco Endolinfático , Pérdida Auditiva/etiología , Enfermedad de von Hippel-Lindau/complicaciones , Adolescente , Adulto , Audiometría , Neoplasias del Oído/diagnóstico , Neoplasias del Oído/fisiopatología , Edema , Femenino , Hemorragia , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Tomografía Computarizada por Rayos XRESUMEN
Nuclear receptor corepressor (N-CoR) is a critical regulator of neural stem cell differentiation. Nuclear localization of N-CoR is a feature of undifferentiated neural stem cells and cytoplasmic translocation of N-CoR leads to astrocytic differentiation. Comparative proteomic analysis of microdissected glioblastoma multiforme (GBM) specimens and matched normal glial tissue reveals increased expression of N-CoR in GBM. In GBM primary cell cultures, tumor cells with nuclear localization of N-CoR demonstrate an undifferentiated phenotype, but are subject to astroglial differentiation upon exposure to agents promoting phosphorylation of N-CoR and its subsequent translocation to the cytoplasm. Treatment of glioma cell lines with a combination of retinoic acid and low-dose okadaic acid decreases the corepressor effect of N-CoR and has a striking synergistic effect on growth inhibition. The identification of N-CoR in GBM provides insights into the tumorigenesis process and supports the development of differentiation-based therapeutic strategies.
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Neoplasias Encefálicas/patología , Glioblastoma/patología , Células Madre Neoplásicas/patología , Proteínas Nucleares/fisiología , Proteínas Represoras/fisiología , Biomarcadores/análisis , Neoplasias Encefálicas/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Células Madre Neoplásicas/metabolismo , Proteínas Nucleares/análisis , Proteínas Nucleares/metabolismo , Co-Represor 1 de Receptor Nuclear , Ácido Ocadaico/administración & dosificación , Ácido Ocadaico/farmacología , Fosforilación , Transporte de Proteínas , Proteínas Represoras/análisis , Proteínas Represoras/metabolismo , Transducción de Señal/efectos de los fármacos , Tretinoina/farmacología , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To examine whether selected genetic polymorphisms in the infant are associated with spontaneous preterm birth (less than 37 weeks) among children with or without later-diagnosed cerebral palsy. METHODS: Exploratory case-control study investigating the relationship of gestational age at delivery to 31 single nucleotide polymorphisms measured in newborn screening bloodspots. Among all 443 children with later-diagnosed cerebral palsy born to white women in South Australia in 1986-1999, 234 were born after spontaneous onset of labor, and 108 of these were preterm (gestational age less than 37 weeks). The comparison group was 549 infants born after spontaneous onset of labor, of whom 147 were preterm. Distributions of genotypic frequencies were examined in preterm compared with term infants with and without cerebral palsy. Genotyping was performed using a Taqman assay. RESULTS: In children without cerebral palsy, preterm birth after spontaneous onset of labor was more frequent in association with a variant of the beta2 adrenergic receptor gene (ADRB2 Q27E, P=.003), inducible nitric oxide synthase (iNOS or NOS2A, P=.042), or thrombomodulin (G127A, P=.006). Among children with cerebral palsy, preterm birth was associated with polymorphisms in genes for endothelial nitric oxide synthase (eNOS -922, P=.012), plasminogen activator inhibitor-2 (P=.015 and .019), and alpha adducin (ADD1, P=.047). CONCLUSION: We confirm previous observations that variants of the beta adrenergic receptor and of nitric oxide synthase are associated with prematurity, and suggest that genetic variants of the placental antifibrinolytic plasminogen activator inhibitor-2, and thrombomodulin and alpha adducin may be contributors to risk of spontaneous preterm birth. LEVEL OF EVIDENCE: II.
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Parálisis Cerebral/genética , Enfermedades del Prematuro/genética , Polimorfismo de Nucleótido Simple/genética , Nacimiento Prematuro/genética , Población Blanca/genética , Estudios de Casos y Controles , Parálisis Cerebral/etnología , Femenino , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/etnología , Masculino , Embarazo , Australia del Sur/epidemiologíaRESUMEN
BACKGROUND: Lumbar discectomy is among the most frequently performed procedures by spine surgeons. Among the potential difficulties encountered during this procedure, incorrect spinal level surgery remains a significant concern for surgeons and patients. Multiple groups have advocated the use of intraoperative x-ray to reduce the incidence of incorrect level surgery; however, this technique has not been prospectively evaluated. METHODS: In an effort to determine the incidence of incorrect level exposure during lumbar discectomy and to define patient characteristics predictive of wrong level exposure, we examined 100 consecutive patients who underwent lumbar discectomy by a single surgeon. After exposure, the surgeon was asked to identify the level exposed, which was confirmed by intraoperative x-ray. Several patient characteristics were then examined by logistical regression to identify features predictive of a mismatch between level of exposure and level of pathology. RESULTS: The study population was composed of 48 men and 52 women who were aged 18 to 83 years. Patient weights ranged from 105 to 410 lb. There were 51 patients who had pathology at the L5-S1 level; 44 patients, L4-L5; 3 patients, L3-L4; and 1 patient, L2-L3. Four patients had transitional vertebrae. The intended level was initially exposed in 85% of cases. Age and level of pathology (P < .05) were identified as factors predictive of a mismatch between intraoperative level of exposure and preoperative level of pathology. CONCLUSIONS: Pathology above L5-S1 and patient age have been shown to reliably predict incorrect level exposure. Based upon the findings of this study, the routine use of intraoperative x-ray to confirm the level of exposure should be considered in all cases of lumbar discectomy.
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Discectomía/métodos , Desplazamiento del Disco Intervertebral/cirugía , Complicaciones Intraoperatorias/prevención & control , Vértebras Lumbares/diagnóstico por imagen , Monitoreo Intraoperatorio/métodos , Radiografía/métodos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Progresión de la Enfermedad , Discectomía/efectos adversos , Discectomía/normas , Femenino , Humanos , Disco Intervertebral/diagnóstico por imagen , Disco Intervertebral/patología , Disco Intervertebral/cirugía , Desplazamiento del Disco Intervertebral/diagnóstico por imagen , Desplazamiento del Disco Intervertebral/patología , Complicaciones Intraoperatorias/etiología , Vértebras Lumbares/anatomía & histología , Vértebras Lumbares/cirugía , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio/normas , Monitoreo Intraoperatorio/tendencias , Mielografía , Valor Predictivo de las Pruebas , Cuidados Preoperatorios , Estudios Prospectivos , Radiografía/normas , Radiografía/tendenciasRESUMEN
OBJECT: In the course of their lives most patients with von Hippel-Lindau (VHL) disease require treatment for several symptom-producing hemangioblastomas of the cerebellum, brainstem, or spinal cord. However, many tumors never produce symptoms and do not require treatment. Detection at an early stage of lesions that will later produce symptoms and ultimately require treatment would allow for earlier excision of hemangioblastomas of the spinal cord, brainstem, or cerebellum, and may identify cerebellar hemangioblastomas that can be treated with radiosurgery at a stage before treatment is contraindicated because of tumor size or the presence of an associated cyst. METHODS: To identify features predictive of symptom development that might allow for earlier treatment of smaller, presymptomatic hemangioblastomas in patients with VHL disease, the authors reviewed and analyzed the serial clinical and imaging findings in all patients with VHL disease who were followed up at the National Institutes of Health for more than 10 years. Features predictive of symptom formation were determined by recursive partition and regression analyses. Nineteen patients (10 men and nine women; mean age 32.6 +/- 11.6 years) harboring a total of 143 hemangioblastomas were identified (mean follow-up duration 12.4 +/- 1.4 years). Hemangioblastomas were located in the cerebellum (68 hemangioblastomas, 48% of patients), brainstem (17 hemangioblastomas, 12% of patients), and spinal cord (58 hemangioblastomas, 40% of patients). Despite measurable growth in almost all hemangioblastomas (138 lesions, 97% of patients), only 58 (41% of patients) became symptomatic. Hemangioblastomas grew in a stuttering pattern. (mean growth period 13 +/- 15 months, mean quiescent period 25 +/- 19 months). Twenty-six (45%) of the hemangioblastomas that eventually produced symptoms were not among the tumors that were apparent on the initial MR imaging study. Depending on location, the hemangioblastoma size and/or tumor and cyst growth rates predicted symptom development and the need for treatment (p < 0.05). Cerebellar hemangioblastomas growing faster than 112 mm3/ month or larger than 69 mm3 with associated tumor and cyst growth rates greater than 14 mm3/month became symptomatic (100% sensitivity, 72% specificity). Brainstem hemangioblastomas larger than 245 mm3 with growth rates greater than 0.1 mm3/month became symptomatic (75% sensitivity, 89% specificity). Spinal hemangioblastomas larger than 22 mm3 became symptomatic (79% sensitivity, 94% specificity). CONCLUSIONS: Because hemangioblastomas exhibit a stuttering growth pattern, frequently remain asymptomatic, and do not require treatment for long intervals, unqualified radiographic progression is not an indication for treatment. Basing the decision to intervene in individual tumors solely on radiographic progression would have resulted in approximately four additional procedures per patient during the 10-year study period. Threshold values are presented for tumor size and/or tumor and cyst growth rates that can be used to predict symptom formation and future need for treatment.
Asunto(s)
Neoplasias del Tronco Encefálico/diagnóstico , Neoplasias Cerebelosas/diagnóstico , Hemangioblastoma/diagnóstico , Imagen por Resonancia Magnética , Neoplasias de la Médula Espinal/diagnóstico , Enfermedad de von Hippel-Lindau/diagnóstico , Adulto , Neoplasias del Tronco Encefálico/cirugía , Neoplasias Cerebelosas/cirugía , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Estudios de Seguimiento , Hemangioblastoma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico , Planificación de Atención al Paciente , Pronóstico , Neoplasias de la Médula Espinal/cirugía , Enfermedad de von Hippel-Lindau/cirugíaRESUMEN
During individual finger movement, two opposite phenomena occur at the level of the central nervous system that could affect other intrinsic hand muscle representations, unintentional co-activation, and surround inhibition (SI). At rest, excitability in the motor cortex (M1) is inhibited at about 20 ms after electric stimulation of a peripheral nerve [short-latency afferent inhibition (SAI)]. We sought to determine whether SAI changes during selective index finger movement. Effects were measured by the response to transcranial magnetic stimulation in two functionally distinct target muscles of the hand [abductor digiti minimi muscle (ADM), first dorsal interosseus muscle (FDI)]. An increase in SAI in the ADM during index finger movement compared to at rest could help explain the genesis of SI. Electrical stimulation was applied to either the little finger (homotopic for ADM, heterotopic for FDI) or the index finger (heterotopic for ADM, homotopic for FDI). During index finger movement, homotopic SAI was present only in the ADM, and the effect of peripheral stimulation was greater when there was less co-activation. Heterotopic SAI found at rest disappeared with movement. We conclude that during movement, homotopic SAI on the muscle in the surround of the intended movement may contribute to SI.
Asunto(s)
Dedos , Movimiento/fisiología , Inhibición Neural/fisiología , Tiempo de Reacción/fisiología , Adulto , Vías Aferentes , Análisis de Varianza , Estimulación Eléctrica/métodos , Electromiografía , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tractos Piramidales/fisiología , Piel/inervación , Estimulación Magnética Transcraneal/métodosRESUMEN
Using a double-antibody immunoaffinity assay (Luminex) and ELISA technology, we measured concentrations of certain neurotrophins, neuropeptides, and cytokines in pooled samples (one to three subjects per sample) eluted from archived neonatal blood of children with later-diagnosed autism, Down syndrome, very preterm birth, or term control infants. We also measured analytes in blood from healthy adult controls. Case or control status for infant subjects was ascertained by retrospective review of service agency medical records. We observed inhibitory substances in eluates from archived bloodspots, especially marked for measurement of BDNF. Concentrations in control subjects differed by age: BDNF rose markedly with age, while NT-3 and NT-4/5 concentrations were lower in adults than in newborn infants. IL-8 concentrations were higher in newborn infants, preterm and term, than in adults. Considered by diagnostic group, total protein was higher in Down syndrome than in either autism or control subjects. In infants with Down syndrome, concentrations of IL-8 levels were higher than in controls, whether or not corrected for total protein; NT-3 and CGRP were lower and VIP higher. In samples from autistic subjects, NT-3 levels were significantly lower than controls and an increase in VIP approached statistical significance. Concentrations of NT-4/5 and CGRP were correlated in infants with autism but not in Down syndrome or controls. Some of these results differ from earlier findings using a single-antibody recycling immunoaffinity chromatography (RIC) system. We discuss interrelationships of VIP, NT-3 and IL-8 and their potential relevance to features of the neuropathology of autism or Down syndrome.
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Trastorno Autístico/sangre , Síndrome de Down/sangre , Interleucina-8/sangre , Neurotrofina 3/sangre , Péptido Intestinal Vasoactivo/sangre , Adulto , Factores de Edad , Animales , Factor Neurotrófico Derivado del Encéfalo/sangre , Péptido Relacionado con Gen de Calcitonina/sangre , Niño , Ensayo de Inmunoadsorción Enzimática , Femenino , Edad Gestacional , Humanos , Lactante , Recién Nacido , Factores de Crecimiento Nervioso/sangre , Embarazo , Estudios RetrospectivosAsunto(s)
Neoplasias del Sistema Nervioso Central/etiología , Neoplasias del Sistema Nervioso Central/patología , Hemangioblastoma/etiología , Hemangioblastoma/patología , Enfermedad de von Hippel-Lindau/complicaciones , Adulto , Distinciones y Premios , Neoplasias del Sistema Nervioso Central/terapia , Femenino , Estudios de Seguimiento , Hemangioblastoma/terapia , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Necesidades , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Stimulation of a peripheral nerve of a hand at rest modulates excitability in the motor cortex and, in particular, leads to inhibition when applied at an interval of approximately 200 ms (long-latency afferent inhibition; LAI). Surround inhibition (SI) is the process that inhibits neighboring muscles not involved in a particular task. The neuronal mechanisms of SI are not known, and it is possible that LAI might contribute to it. Using transcranial magnetic stimulation (TMS) with and without movement of the index finger, the motor-evoked potentials (MEPs) were measured of two functionally distinct target muscles of the hand (abductor digiti minimi muscle = ADM, 1st dorsal interosseus muscle = FDI). Electrical stimulation was applied 180 ms before TMS to either the fifth finger or the index finger. Both homotopic and heterotopic finger stimulation resulted in LAI without movement. With index finger movement, motor output further decreased with homo- and heterotopic stimulation in the ADM. In the moving FDI, however, there was no change with either homo- or heterotopic stimulation. Additionally, in the unstimulated movement trials, LAI increased with the amount of unintentional co-activation that occurred despite attempts to maintain the ADM at rest. However, with finger stimulation added, there were almost no increased MEPs despite co-activation. These findings suggest that LAI increases during movement and can enhance SI.
Asunto(s)
Vías Aferentes/fisiología , Dedos/fisiología , Movimiento/fisiología , Inhibición Neural/fisiología , Tiempo de Reacción/fisiología , Adulto , Vías Aferentes/efectos de la radiación , Análisis de Varianza , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica/métodos , Electromiografía/métodos , Potenciales Evocados/fisiología , Potenciales Evocados/efectos de la radiación , Femenino , Humanos , Magnetismo , Masculino , Persona de Mediana Edad , Movimiento/efectos de la radiación , Inhibición Neural/efectos de la radiación , Tiempo de Reacción/efectos de la radiación , Factores de TiempoRESUMEN
Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immune-mediated inflammatory disorder of the central nervous system. Immune activation in the host, which results from high levels of persistent antigenic stimulation and from transactivation of host immunoregulatory genes by HTLV-I, appears important in the pathogenesis of HAM/TSP. In a single-center, open-label trial, 12 patients with HAM/TSP were treated with doses of interferon-beta1a of up to 60mug twice weekly, based on its antiviral and immunomodulatory effects. Primary end points were immunological and virological measures that are potential biomarkers for HAM/TSP. Interferon-beta1a therapy reduced the HTLV-I tax messenger RNA load and the frequency of potentially pathogenic HTLV-I-specific CD8(+) cells. The HTLV-I proviral DNA load remained unchanged. Spontaneous lymphoproliferation, a marker of T-cell activation in HAM/TSP, also was reduced. Some measures of motor function were improved, and no significant clinical progression occurred during therapy. These results indicate that interferon-beta1a may beneficially affect the immune mechanisms central to the pathogenesis of HAM/TSP.
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Interferón beta/uso terapéutico , Paraparesia Espástica Tropical/tratamiento farmacológico , Adulto , Anciano , Biomarcadores , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/virología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , ADN Viral/efectos de los fármacos , Femenino , Citometría de Flujo , Virus Linfotrópico T Tipo 1 Humano/efectos de los fármacos , Humanos , Activación de Linfocitos/efectos de los fármacos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Provirus/efectos de los fármacos , Recuperación de la Función/efectos de los fármacosRESUMEN
In the present study, we examine whether selected genetic polymorphisms contribute to the development of cerebral palsy (CP) in very preterm infants. Subjects were 96 singleton infants with later-diagnosed CP and 119 control children, white non-Hispanic (n for CP=74, controls=88) or white Hispanic (CP=22, controls=31), born <32 wk gestation. Presence of CP was identified through state service agencies, with review of medical records. DNA extracted from archived neonatal blood was genotyped using multi-locus polymerase chain reaction amplification and immobilized sequence-specific oligonucleotide probes. Single nucleotide polymorphisms (SNPs) showing evidence of association with development of CP were endothelial nitric oxide synthase (eNOS) A(-922)G, factor 7 (F7) arg353gln and del(-323)10bp-ins, and lymphotoxin A (LTA) thr26asn. In white non-Hispanic children, beta-2 adrenergic receptor gln27glu was associated with CP risk; in Hispanic children, plasminogen activator inhibitor-1 (PAI-1) 4G(-675)5G and G11053T were associated with risk of CP. In a logistic regression considering these SNPs simultaneously in non-Hispanics, an association with CP was observed for heterozygotes of eNOS -922 (OR 3.0, CI 1.4-6.4), F7 (OR 2.7, CI 1.1-6.5), LTA (OR 2.1, CI 1.0-4.6), and PAI-1 (OR 3.2, CI 1.2-8.7). Factor 5, Factor 2, methylene tetrahydrofolate reductase, tumor necrosis factor-alpha, and other SNPs tested were not significantly associated with CP risk. We conclude that further study of genetic factors that may influence susceptibility to CP in very preterm infants is warranted.
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Parálisis Cerebral/genética , Recien Nacido Prematuro , Polimorfismo Genético , Estudios de Casos y Controles , Parálisis Cerebral/diagnóstico , Preescolar , Citocinas/genética , Femenino , Genotipo , Edad Gestacional , Humanos , Hipertensión/genética , Lactante , Recién Nacido , Óxido Nítrico/genética , Embarazo , Trombosis/genéticaRESUMEN
BACKGROUND: Fabry disease is an underdiagnosed, treatable, X-linked, multisystem disorder. OBJECTIVES: To test the hypothesis that quality of life and sweating are decreased among pediatric patients with Fabry disease, compared with control subjects, and to provide quantitative natural history data and novel clinical end points for therapeutic trials. DESIGN: Prospective, cross-sectional, observational study. SETTING: Referral to the National Institutes of Health. PARTICIPANTS: Twenty-five male children with Fabry disease (mean age: 12.3 +/- 3.5 years) and 21 age-matched control subjects. MAIN OUTCOME MEASURES: Quality of life (measured with the Child Health Questionnaire) and sweating (assessed with the quantitative sudomotor axon reflex test). RESULTS: Quality of life scores for pediatric patients <10 years of age with Fabry disease, compared with published normative values, were 55 +/- 17 vs 83 +/- 19 for bodily pain and 62 +/- 19 vs 80 +/- 13 for mental health. Bodily pain scores for patients > or =10 years of age were 54 +/- 22 vs 74 +/- 23. Sweat volume in the Fabry disease group was 0.41 +/- 0.46 microL/mm2, compared with 0.65 +/- 0.44 microL/mm2 in the control group. Renal function, urinary protein excretion, and cardiac function and structure were normal for the majority of patients. The 3 patients with residual alpha-galactosidase A activity > or =1.5% of normal values were free of cornea verticillata and had normal serum and urinary globotriaosylceramide levels. All other children had glycolipid levels comparable to those of adult patients with Fabry disease. Acroparesthesia and cardiac abnormalities were generally present before anhidrosis and proteinuria. Mapping of the missense mutations on the crystallographic structure of alpha-galactosidase A revealed that the mutations were partially surface-exposed and distal to the active site among individuals with residual enzyme activity. Mutations associated with left ventricular hypertrophy (defined as left ventricular mass index of >51 g/m2.7) were localized near the catalytic site of the enzyme. CONCLUSIONS: Despite the absence of major organ dysfunction, Fabry disease demonstrates significant morbidity already in childhood. We have identified important, potentially correctable or preventable, outcome measures for future therapeutic trials. Prevention of complications involving major organs should be the goal for long-term specific therapy.
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Enfermedad de Fabry/complicaciones , Salud Mental/estadística & datos numéricos , Dolor/epidemiología , Calidad de Vida , Adolescente , Recuento de Células Sanguíneas , Tamaño Corporal , Estudios de Casos y Controles , Niño , Estudios Transversales , Enfermedad de Fabry/fisiopatología , Enfermedad de Fabry/psicología , Tasa de Filtración Glomerular , Humanos , Hipertrofia Ventricular Izquierda/epidemiología , Hipertrofia Ventricular Izquierda/etiología , Masculino , Mutación , Dolor/etiología , Sudoración , Trihexosilceramidas/sangre , alfa-Galactosidasa/genéticaRESUMEN
Focal hand dystonia may arise as a result of aberrant plasticity from excessive repetitive use. Improvement might be possible with appropriate motor training. Focusing on trying to decrease abnormal overflow of movement to fingers not involved in a task, we developed a motor training program for individualized finger movements. Ten patients with writer's cramp participated in the motor training program. Evaluation was done with the Fahn dystonia scale, kinematic analysis of handwriting, transcranial magnetic stimulation (TMS), and electroencephalography (EEG). Clinical improvement of dystonia was significant using the Fahn dystonia scale, and 6 patients reported an improvement in writing. The handwriting analysis showed a trend for improvement after training in simple exercises. There were no changes in cortical excitability measured by TMS and EEG. Whereas this method of motor training for 4 weeks led to mild subjective improvement and some improvement in handwriting, it is not sufficient to reverse motor cortex abnormalities measured by TMS and EEG.
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Distonía/fisiopatología , Distonía/terapia , Mano/fisiopatología , Magnetismo/instrumentación , Enseñanza/métodos , Corteza Cerebral/fisiología , Distonía/diagnóstico , Trastornos Distónicos/fisiopatología , Trastornos Distónicos/terapia , Electroencefalografía , Electromiografía/instrumentación , Potenciales Evocados Motores/fisiología , Dedos/fisiología , Humanos , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Muñeca/fisiologíaRESUMEN
BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have neuroprotective effects in experimental stroke models and are commonly prescribed in clinical practice. The aim of this study was to determine if patients taking statins before hospital admission for stroke had an improved clinical outcome. METHODS: This was an observational study of 436 patients admitted to the National Institutes of Health Suburban Hospital Stroke Program between July 2000 and December 2002. Self-reported risk factors for stroke were obtained on admission. Stroke severity was determined by the admission National Institutes of Health Stroke Scale score. Good outcome was defined as a Rankin score < 2 at discharge. Statistical analyses used univariate and multivariate logistic regression models. RESULTS: There were 436 patients with a final diagnosis of ischemic stroke; statin data were available for 433 of them. A total of 95/433 (22%) of patients were taking a statin when they were admitted, rising from 16% in 2000 to 26% in 2002. Fifty-one percent of patients taking statins had a good outcome compared to 38% of patients not taking statins (p = 0.03). After adjustment for confounding factors, statin pretreatment was associated with a 2.9 odds (95% CI: 1.2-6.7) of a good outcome at the time of hospital discharge. CONCLUSIONS: The proportion of patients taking statins when they are admitted with stroke is rising rapidly. Statin pretreatment was significantly associated with an improved functional outcome at discharge. This finding could support the early initiation of statin therapy after stroke.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Accidente Cerebrovascular/terapia , Anciano , Isquemia Encefálica/terapia , Hemorragia Cerebral/terapia , Femenino , Humanos , Ataque Isquémico Transitorio/terapia , Tiempo de Internación , Modelos Logísticos , Masculino , Oportunidad Relativa , Accidente Cerebrovascular/mortalidad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Fabry disease is an X-linked disorder caused by a deficiency of lysosomal alpha-galactosidase A resulting in accumulation of alpha-D-galatosyl conjugated glycosphingolipids. Clinical manifestations include a small-fiber neuropathy associated with debilitating pain and hypohidrosis. We report the effect of a 3-year open-label extension of a previously reported 6-month placebo-controlled enzyme replacement therapy (ERT) trial in which 26 hemizygous patients with Fabry disease received 0.2 mg/kg of alpha-galactosidase A every 2 weeks. The effect of ERT on neuropathic pain scores while off pain medications, quantitative sensory testing, quantitative sudomotor axon reflex test (QSART), and thermoregulatory sweat test (TST) is reported. In the patients who crossed-over from placebo to ERT (n = 10), mean pain-at-its-worst scores on a 0-10 scale decreased (from 6.9 to 4.5). There was a significant reduction in the threshold for cold and warm sensation in the foot. At the 3-year time-point, pre-ERT sweat excretion in 17 Fabry patients was 0.24 +/- 0.33 microl/mm(2) vs. 1.05 +/- 0.81 in concurrent controls (n = 38). Sweat function improved 24-72 h post-enzyme infusion (0.57 +/- 0.71 microl/mm(2)) and normalized in four anhidrotic patients. TST confirmed the QSART results. We conclude that prolonged ERT in Fabry disease leads to a modest but significant improvement in the clinical manifestations of the small-fiber neuropathy associated with this disorder. QSART may be useful to further optimize the dose and frequency of ERT.