RESUMEN
OBJECTIVE: Finding a non-invasive biomarker for Globus Pallidus interna Deep Brain Stimulation (GPi-DBS) efficacy. Dystonia heterogeneity leads to a wide variety of clinical response to GPi-DBS, making it hard to predict GPi-DBS efficacy for individual patients. METHODS: EEG-EMG recordings of twelve dystonia patients who received bilateral GPi-DBS took place pre- and 1â¯year post-surgery ON and OFF stimulation, during a rest, pinch, and flexion task. Dystonia severity was assessed using the BFMDRS and TWSTRS (pre- and post-surgery ON stimulation). Intermuscular coherence (IMC) and motorcortex corticomuscular coherence (CMC) were calculated. Low frequency (4-12â¯Hz) and beta band (13-30â¯Hz) peak coherences were studied. RESULTS: Dystonia severity improved after 1â¯year GPi-DBS therapy (BFMDRS: 30%, median 7.8 (IQR 3-10), TWSTRS: 22%, median 6.8 (IQR 4-9)). 86% of IMC were above the 95% confidence limit. The highest IMC peak decreased significantly with GPi-DBS in the low frequency and beta band. Low frequency and beta band IMC correlated partly with dystonia severity and severity improvement. CMC generally were below the 95% confidence limit. CONCLUSIONS: Peak low frequency IMC functioned as biomarker for GPi-DBS efficacy, and partly correlated with dystonia severity. SIGNIFICANCE: IMC can function as biomarker. Confirmation in a larger study is needed for use in clinical practice.
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Estimulación Encefálica Profunda/métodos , Distonía/terapia , Globo Pálido/fisiopatología , Músculo Esquelético/fisiopatología , Adulto , Distonía/diagnóstico , Electroencefalografía/métodos , Electromiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Corteza Motora/fisiopatologíaRESUMEN
A recent study in rheumatoid arthritis (RA) patients using electrical vagus nerve stimulation (VNS) to activate the inflammatory reflex has shown promising effects on disease activity. Innervation by the autonomic nerve system might be involved in the regulation of many endocrine and metabolic processes and could therefore theoretically lead to unwanted side effects. Possible effects of VNS on secretion of hormones are currently unknown. Therefore, we evaluated the effects of a single VNS on plasma levels of pituitary hormones and parameters of postprandial metabolism. Six female patients with RA were studied twice in balanced assignment (crossover design) to either VNS or no stimulation. The patients selected for this substudy had been on VNS therapy daily for at least 3 months and at maximum of 24 months. We compared 10-, 20-, and 30-min poststimulus levels to baseline levels, and a 4-h mixed meal test was performed 30 min after VNS. We also determined energy expenditure (EE) by indirect calorimetry before and after VNS. VNS did not affect pituitary hormones (growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, follicle-stimulating hormone, and luteinizing hormone), postprandial metabolism, or EE. Of note, VNS reduced early postprandial insulin secretion, but not AUC of postprandial plasma insulin levels. Cortisol and catecholamine levels in serum did not change significantly. Short stimulation of vagal activity by VNS reduces early postprandial insulin secretion, but not other hormone levels and postprandial response. This suggests VNS as a safe treatment for RA patients.
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Artritis Reumatoide/metabolismo , Péptido C/sangre , Metabolismo Energético/fisiología , Periodo Posprandial/fisiología , Estimulación del Nervio Vago , Hormona Adrenocorticotrópica/sangre , Adulto , Calorimetría Indirecta , Estudios Cruzados , Femenino , Hormona Folículo Estimulante/sangre , Hormona de Crecimiento Humana/sangre , Humanos , Hormona Luteinizante/sangre , Persona de Mediana Edad , Prolactina/sangre , Tirotropina/sangreRESUMEN
INTRODUCTION: With chronotherapy, drug administration is synchronized with daily rhythms in drug clearance and pharmacokinetics. Daily rhythms in gene expression are centrally mastered by the suprachiasmatic nucleus of the hypothalamus as well as by tissue clocks containing similar molecular mechanisms in peripheral organs. The central timing system is sensitive to changes in the external environment such as those of the light-dark cycle, meal timing and meal composition. We investigated how changes in diet composition and meal timing would affect the daily hepatic expression rhythms of the nuclear receptors PXR and CAR and of enzymes involved in P450 mediated drug metabolism, as such changes could have consequences for the practice of chronotherapy. MATERIALS AND METHODS: Rats were subjected to either a regular chow or a free choice high-fat-high-sugar (fcHFHS) diet. These diets were provided ad libitum, or restricted to either the light phase or the dark phase. In a second experiment, rats had access to chow either ad libitum or in 6 meals equally distributed over 24 hours. RESULTS: Pxr, Alas1 and Por displayed significant day-night rhythms under ad libitum chow fed conditions, which for Pxr was disrupted under fcHFHS diet conditions. Although no daily rhythms were detected in expression of CAR, Cyp2b2 and Cyp3a2, the fcHFHS diet did affect basal expression of these genes. In chow fed rats, dark phase feeding induced a diurnal rhythm in Cyp2b2 expression while light phase feeding induced a diurnal rhythm in Car expression and completely shifted the peak expression of Pxr, Car, Cyp2b2, Alas1 and Por. The 6-meals-a-day feeding only abolished the Pxr rhythm but not the rhythms of the other genes. CONCLUSION: We conclude that although nuclear receptors and enzymes involved in the regulation of hepatic drug metabolism are sensitive to meal composition, changes in meal timing are mainly effectuated via changes in the molecular clock.
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Conducta Alimentaria , Expresión Génica , Hígado/metabolismo , Preparaciones Farmacéuticas/metabolismo , Alimentación Animal , Animales , Cronoterapia , Ritmo Circadiano , Sistema Enzimático del Citocromo P-450/metabolismo , Masculino , Farmacocinética , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
OBJECTIVE: Cerebral palsy (CP) can be classified as spastic, dyskinetic, ataxic or combined. Correct classification is essential for symptom-targeted treatment. This study aimed to investigate agreement among professionals on the phenotype of children with CP based on standardized videos. METHODS: In a prospective, observational pilot study, videos of fifteen CP patients (8 boys, mean age 11 ± 5 y) were rated by three pediatric neurologists, three rehabilitation physicians and three movement disorder specialists. They scored the presence and severity of spasticity, ataxia or dyskinesias/dystonia. Inter- and intraobserver agreement were calculated using Cohen's and Fleiss' kappa. RESULTS: We found a fair inter-observer (κ = 0.36) and moderate intra-observer agreement (κ = 0.51) for the predominant motor symptom. This only slightly differed within the three groups of specialists (κ = 0.33-0.55). CONCLUSION: A large variability in the phenotyping of CP children was detected, not only between but also within clinicians, calling for a discussing on the operational definitions of spasticity, dystonia and ataxia. In addition, the low agreement found in our study questions the reliability of use of videos to measure intervention outcomes, such as deep brain stimulation in dystonic CP. Future studies should include functional domains to assess the true impact of management options in this highly challenging patient population.
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Ataxia/diagnóstico , Parálisis Cerebral/clasificación , Parálisis Cerebral/diagnóstico , Distonía/diagnóstico , Espasticidad Muscular/diagnóstico , Adolescente , Ataxia/etiología , Parálisis Cerebral/complicaciones , Niño , Diagnóstico Diferencial , Distonía/etiología , Femenino , Humanos , Masculino , Espasticidad Muscular/etiología , Variaciones Dependientes del Observador , Proyectos Piloto , Estudios Prospectivos , Reproducibilidad de los Resultados , Grabación de Cinta de VideoRESUMEN
A broad range of rare inherited metabolic disorders can present with dystonia. For clinicians, it is important to recognize dystonic features, but it can be complicated by the mixed and complex clinical picture seen in many neurometabolic patients. Careful phenotyping is the first step towards the diagnosis of the underlying condition and subsequent targeted treatment, further supported by imaging, biochemical diagnostics and the availability of modern diagnostic techniques such as next generation sequencing. As several neurometabolic disorders are treatable causes of dystonia, these should have priority in the diagnostic process. In the symptomatic treatment of dystonia, several therapeutic options are available. Awareness for the occurrence and optimal treatment of dystonia and other movement disorders in neurometabolic conditions is important because these symptoms can have a substantial impact on the quality of life and daily functioning; this effect is not only exerted by the dystonia itself, but also by the frequently associated non-motor features. In this paper, the highlights and key concepts of neurometabolic forms of dystonia are discussed, with a focus on phenomenology, the diagnostic approach, the most important neurometabolic aetiologies, co-occurring non-motor features and therapeutic options.
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Encefalopatías Metabólicas/complicaciones , Encefalopatías Metabólicas/terapia , Distonía/etiología , Distonía/terapia , Encefalopatías Metabólicas/diagnóstico , Distonía/diagnóstico , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/etiología , Trastornos Distónicos/terapia , Humanos , Actividad Motora/fisiología , Neuronas Motoras/fisiología , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/etiología , Trastornos del Movimiento/terapia , Calidad de VidaAsunto(s)
Acenocumarol/efectos adversos , Anticoagulantes/efectos adversos , Factor VIII/análisis , Hemofilia A/etiología , Acenocumarol/uso terapéutico , Anciano , Anticoagulantes/uso terapéutico , Quimioterapia Combinada , Estudios de Seguimiento , Hemofilia A/diagnóstico , Hemofilia A/tratamiento farmacológico , Humanos , Inmunosupresores/uso terapéutico , MasculinoRESUMEN
This study was designed to investigate a long-term therapeutic strategy for the management of recurring atopic dermatitis (AD) in adults using fluticasone propionate (FP) ointment (CutivateTM) whereby FP could help to prevent a relapse of AD once symptoms were under control. Adult patients with chronic, moderate to severe AD entered this multicentre study. All patients were initially treated with FP 0.005% (g/g) ointment in two different regimens. Patients whose AD had been completely healed by these treatments then entered a long-term treatment phase applying FP or placebo ointment once daily, two times per week for 16 weeks to 'known' healed lesions. By the end of the initial treatment period, mean SCORAD values had significantly (P < 0.0005) improved from baseline. Patients who entered the maintenance phase and were treated with intermittent FP for up to 16 weeks, demonstrated its superior efficacy (P = 0.018) over placebo, maintaining the improvements achieved after the initial treatment phase, reducing risk of relapse and delaying time to relapse (P = 0.013). No significant changes were detected in either treatment group in serum cortisol levels or in skin thickness measurements. Intermittent FP applied two times per week maintained a significant level of control, and delayed relapse of AD by comparison with placebo.
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Androstadienos/uso terapéutico , Antiinflamatorios/uso terapéutico , Dermatitis Atópica/prevención & control , Administración Tópica , Adolescente , Adulto , Dermatitis Atópica/sangre , Dermatitis Atópica/patología , Método Doble Ciego , Esquema de Medicación , Femenino , Fluticasona , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Pomadas , Piel/patologíaRESUMEN
A patient was presented with a non-gestational non-gonadal choriocarcinoma and hyperthyroidism. Five years earlier, at the age of 36, she underwent an abdominal hysterectomy with bilateral adnexectomy for endometrial carcinoma. Despite intensive treatment with multiple chemotherapy the patient died. We concluded that this non-gestational, non-gonadal choriocarcinoma was a recurrence of her previous endometrial carcinoma or a new extra (non) gonadal germcell tumor with choriocarcinoma.
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Adenocarcinoma Papilar/cirugía , Coriocarcinoma/patología , Neoplasias Endometriales/cirugía , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Coriocarcinoma/complicaciones , Coriocarcinoma/terapia , Gonadotropina Coriónica/metabolismo , Femenino , Humanos , Hipertiroidismo/complicaciones , Neoplasias Hepáticas/secundario , alfa-Fetoproteínas/metabolismoRESUMEN
In immunochemical assays of specific cell constituents in cytosols from tumors, the relationship between epithelial and stromal fractions is not taken into account. This may influence the outcome of the measurements and result in incorrect categorization as negative or positive. In a setting addressing pS2 (only detectable in epithelial cells) in breast carcinomas, we investigated three possibilities that may overcome this problem using histologic sections of breast carcinomas of 50 patients: (a) visual estimation of area percentage of immunohistochemical staining of the cell constituent of interest performed by three independent individuals, (b) quantification of area percentage of the immunohistochemical results by true color image analysis, and (c) quantification of the epithelial and stromal compartments of the tumors in Heidenhain's-azan-stained tissue sections, using the true color image analysis system, to assess the epithelial percentage in the tumors. This percentage was used as a correction factor for data on pS2 obtained by cytosolic determinations. Visual estimation appeared to be subject to interobserver variation and, subsequently, becomes less applicable in the absence of strict scoring rules. Based on tests for correlation, image analysis system quantification seemed reproducible in both quantification procedures. However, due to the high magnification necessary to visualize the immunohistochemical staining product, the effect of field selection caused systematic differences between repeat measurements (Friedman test). As a result of the contrasting colors of the azan staining, the calculation of the epithelia percentage could be performed at a low magnification. Consequently, here the effect of field selection was not present. Correction of cytosolic values for epithelial percentage resulted in 8% of the cases changing category.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Neoplasias de la Mama/patología , Inmunohistoquímica , Citosol/patología , Epitelio/patología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Reproducibilidad de los Resultados , Células del Estroma/patologíaRESUMEN
Most image analysis systems (IAS) use black-and-white cameras. However, true color IASs are considered to be useful for quantification of immunohistologically stained structures. Using a true color IAS, we evaluated two methods of segmentation for quantification of area percentage of staining: one using fixed, preset thresholds and one using thresholds interactively set per image. Furthermore, the effect of shading correction was evaluated, and measurements in both color and black-and-white mode were compared. The results of segmentation with fixed thresholds did not differ significantly from those of control percentages, established by interactive morphometry using a grid, which served as reference. Interactive segmentation was significantly different from the reference (t test, P = .0001). The effect of shading correction was negligible. Measurements with and without this procedure correlated highly (r = .99, P < .001). Comparison of the results obtained in color and black-and-white mode showed a significant difference in the latter from the reference (t test, P = .005). We conclude that it is possible to quantify, in a reliable way, area percentage of positive staining using a true color IAS with application of a segmentation method with fixed thresholds.
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Neoplasias de la Mama/ultraestructura , Color , Procesamiento de Imagen Asistido por Computador/métodos , Inmunohistoquímica , Proteínas de Neoplasias/análisis , Proteínas , Coloración y Etiquetado , Neoplasias de la Mama/química , Citoplasma/química , Factor Trefoil-1 , Proteínas Supresoras de TumorRESUMEN
Since 1983 there have been several reports on Pneumocystis carinii pneumonia (PCP), complicating low dose methotrexate (MTX) therapy for rheumatoid arthritis (RA). Two additional cases of this opportunistic infection are reported and a review of the literature on the complication is presented. It is concluded that PCP is a serious complication of low dose MTX therapy for RA and should always be ruled out when a patient presents with pulmonary symptoms. Several factors may play a role in the occurrence of this opportunistic infection, but the exact mechanism has not yet been elucidated.
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Artritis Reumatoide/tratamiento farmacológico , Metotrexato/administración & dosificación , Neumonía por Pneumocystis/inducido químicamente , Adulto , Humanos , Masculino , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Persona de Mediana EdadRESUMEN
A case of squamous cell carcinoma (SCC) arising in a mandibular residual cyst in a 62-year-old man is presented. The treatment included enucleation followed by primary closure. Histologic examination revealed a poorly differentiated SCC in the cyst lining without invasion through the connective tissue wall. Eight and a half years later, the patient was still free from recurrence.
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Carcinoma de Células Escamosas/etiología , Enfermedades Mandibulares/complicaciones , Neoplasias Mandibulares/etiología , Quistes Odontogénicos/complicaciones , Anciano , Carcinoma de Células Escamosas/patología , Humanos , Masculino , Enfermedades Mandibulares/patología , Neoplasias Mandibulares/patología , Quistes Odontogénicos/patologíaRESUMEN
This paper describes the evaluation of several factors with a possible influence on the performance of a commercially available image analysis system capable of true color image analysis. The software used by this system is VIDAS Version 2.0. The following factors were evaluated: illumination, power supply, warming up, shading correction, averaging of image intake, hue luminance and saturation images and relation of illumination to quantification of area percentage (area %) of positively staining structures. The first six factors were evaluated by using a macro, with which it is possible to obtain information on variations over the image and over time. The last factor was evaluated by repeated measurement of area % of positive staining in a routinely processed tissue section. In our setting, stability of illumination and warmup time of the camera appeared to be the most important factors with influence on the performance of the image analysis system.
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Procesamiento de Imagen Asistido por Computador/métodos , Inmunohistoquímica/métodos , Programas Informáticos , ColorAsunto(s)
Mastitis/etiología , Meningitis Viral/etiología , Paperas/complicaciones , Ooforitis/etiología , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Paperas/genéticaRESUMEN
In a case of epidermodysplasia verruciformis with impaired cell-mediated immunity and multiple skin cancers human papillomavirus type 5 (HPV5) DNA sequences were demonstrated in a cutaneous squamous cell carcinoma. HPV5 and HPV8 were detected in the benign disseminated skin lesions together with three newly characterized HPVs: HPV17, HPV19 and HPV24. A chronic infection with hepatitis B virus resulting in macronodular cirrhosis associated with a primary hepatocellular carcinoma was also acquired by this patient. This case provides an example of the circumstantial evidence which suggests that certain types of HPV are potentially oncogenic and stresses the importance of immune surveillance in the protection against virus-associated tumors.
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Carcinoma Hepatocelular/etiología , Carcinoma de Células Escamosas/etiología , ADN Viral/análisis , Hepatitis B/complicaciones , Enfermedades de la Piel/complicaciones , Neoplasias Cutáneas/etiología , Infecciones Tumorales por Virus/complicaciones , Adulto , Carcinoma Hepatocelular/patología , Carcinoma de Células Escamosas/análisis , Carcinoma de Células Escamosas/patología , Humanos , Neoplasias Hepáticas , Masculino , Papillomaviridae , Neoplasias Cutáneas/análisis , Neoplasias Cutáneas/patología , Infecciones Tumorales por Virus/patologíaRESUMEN
The characteristics and distribution of the inflammatory infiltrate in liver biopsies of 25 patients with hepatitis B viral (HBV) infection were studied in relation to the distribution and expression of HBV antigens. Mononuclear subsets were characterized with monoclonal (OKT, OKM, Leu) antibodies to surface antigens. For the demonstration of viral antigens directly conjugated antibodies to surface (HBsAg), core (HBcAg) and 'e' (HBeAg) antigen were used. For the study of mutual relations all methods were performed on serial cut tissue sections. In chronic active hepatitis B (CAH-B, n = 12) OKT8+ lymphocytes of T cell origin were the only cell type present in areas with liver cell degeneration and T cell cytotoxicity appears to be the only immune mechanism. In chronic persistent hepatitis B (CPH-B, n = 7) the only conspicuous feature was the presence of many Leu 3+ lymphocytes of the helper/inducer population in the portal tracts. In acute hepatitis B (AHB, n = 6) OKT8+ cells of non-T origin (OKT1-,3-) and Leu 7+ cells of presumed natural killer (NK) potential predominated in the areas with liver cell necrosis, and non-T cell cytotoxicity appears to be the predominant immune mechanism. In none of these disease entities a positive spatial relation could be established between the cytotoxic cells and the demonstrable expression of HBV antigens in hepatocytes. It is concluded that differences in immunological reaction pattern may explain the different course in the three forms of HBV infection studied.
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Antígenos de la Hepatitis B/análisis , Hepatitis B/inmunología , Hígado/inmunología , Linfocitos/clasificación , Enfermedad Aguda , Adulto , Anciano , Enfermedad Crónica , Femenino , Hepatitis B/patología , Antígenos del Núcleo de la Hepatitis B/análisis , Antígenos de Superficie de la Hepatitis B/análisis , Antígenos e de la Hepatitis B/análisis , Humanos , Recuento de Leucocitos , Hígado/patología , Masculino , Persona de Mediana Edad , Células Plasmáticas/inmunologíaRESUMEN
Serial graft biopsies (n = 78) from 12 liver transplant recipients (followed clinically up to 47 months) were studied with the use of histology, histochemistry, immunostaining, and electron microscopy. Planned-protocol needle biopsy specimens were taken from the graft before removal from the donor, 1 hour after transplantation, on the eighth day, and at yearly intervals. Nonprotocol biopsies were taken when deterioration of the clinical condition made a decision on changes in the regimen necessary. The protocol biopsies provided a baseline for graft condition and diagnostic histopathologic features. In these biopsies signs of hyperacute rejection, chronic rejection, or the recipient's previous liver disease were not observed. Mild acute rejection was regularly present on the eighth day, possibly due to a lag phase in the effect of immunosuppression. The syndromes in the nonprotocol biopsies included "pure" parenchymal cholestasis, reversible acute rejection resembling chronic active hepatitis, viral infection, and acute bacterial cholangitis. Each of these syndromes correlated with a separate histopathologic entity. Therefore, these entities proved to be of diagnostic value. It is concluded that a graft biopsy may substantially add to the pathogenetic interpretation, differential diagnosis, and management of major graft syndromes in orthotopic liver transplant recipients.