RESUMEN
BACKGROUND: Glioblastoma is the most common and aggressive adult brain malignancy against which conventional surgery and chemoradiation provide limited benefit. Even when a good treatment response is obtained, recurrence inevitably occurs either locally (â¼80%) or distally (â¼20%), driven by cancer clones that are often genomically distinct from those in the primary tumour. Glioblastoma cells display a characteristic infiltrative phenotype, invading the surrounding tissue and often spreading across the whole brain. Cancer cells responsible for relapse can reside in two compartments of residual disease that are left behind after treatment: the infiltrated normal brain parenchyma and the sub-ventricular zone. However, these two sources of residual disease in glioblastoma are understudied because of the difficulty in sampling these regions during surgery. PATIENT AND METHODS: Here, we present the results of whole-exome sequencing of 69 multi-region samples collected using fluorescence-guided resection from 11 patients, including the infiltrating tumour margin and the sub-ventricular zone for each patient, as well as matched blood. We used a phylogenomic approach to dissect the spatio-temporal evolution of each tumour and unveil the relation between residual disease and the main tumour mass. We also analysed two patients with paired primary-recurrence samples with matched residual disease. RESULTS: Our results suggest that infiltrative subclones can arise early during tumour growth in a subset of patients. After treatment, the infiltrative subclones may seed the growth of a recurrent tumour, thus representing the 'missing link' between the primary tumour and recurrent disease. CONCLUSIONS: These results are consistent with recognised clinical phenotypic behaviour and suggest that more specific therapeutic targeting of cells in the infiltrated brain parenchyma may improve patient's outcome.
Asunto(s)
Evolución Clonal/genética , Secuenciación del Exoma , Glioblastoma/genética , Neoplasia Residual/genética , Encéfalo/metabolismo , Encéfalo/cirugía , Femenino , Genoma Humano/genética , Glioblastoma/patología , Glioblastoma/cirugía , Humanos , Masculino , Mutación/genética , Proteínas de Neoplasias/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Neoplasia Residual/patología , Neoplasia Residual/cirugía , Fenotipo , Filogenia , Polimorfismo de Nucleótido SimpleRESUMEN
Stem cells are responsible for tissue repair and maintenance and it is assumed that changes observed in the stem cell compartment with age underlie the concomitant decline in tissue function. Studies in murine models have highlighted the importance of intrinsic changes occurring in stem cells with age. They have also drawn the attention to other factors, such as changes in the local or systemic environment as the primary cause of stem cell dysfunction. Whilst knowledge in murine models has been advancing rapidly there has been little translation of these data to human aging. This is most likely due to the difficulties of testing the regenerative capacity of human stem cells in vivo and to substantial differences in the aging phenotype within humans. Here we summarize evidence to show how progeroid syndromes, integrated with other models, can be valuable tools in addressing questions about the role of stem cell aging in human degenerative diseases of older age and the molecular pathways involved.
Asunto(s)
Envejecimiento/genética , Senescencia Celular/genética , Animales , Humanos , Ratones , SíndromeRESUMEN
Stem cells are central to the development and maintenance of many tissues. This is due to their capacity for extensive proliferation and differentiation into effector cells. More recently it has been shown that the proliferative and differentiative ability of stem cells decreases with age, suggesting that this may play a role in tissue aging. Down syndrome (DS), is associated with many of the signs of premature tissue aging including T-cell deficiency, increased incidence of early Alzheimer-type, Myelodysplastic-type disease and leukaemia. Previously we have shown that both hematopoietic (HSC) and neural stem cells (NSC) in patients affected by DS showed signs of accelerated aging. In this study we tested the hypothesis that changes in gene expression in HSC and NSC of patients affected by DS reflect changes occurring in stem cells with age. The profiles of genes expressed in HSC and NSC from DS patients highlight pathways associated with cellular aging including a downregulation of DNA repair genes and increases in proapoptotic genes, s-phase cell cycle genes, inflammation and angiogenesis genes. Interestingly, Notch signaling was identified as a potential hub, which when deregulated may drive stem cell aging. These data suggests that DS is a valuable model to study early events in stem cell aging.
Asunto(s)
Senescencia Celular , Síndrome de Down/metabolismo , Regulación de la Expresión Génica , Modelos Biológicos , Receptores Notch/metabolismo , Transducción de Señal , Células Madre/metabolismo , Biología de Sistemas , Proteínas Wnt/metabolismo , Anciano , Anciano de 80 o más Años , Preescolar , Síndrome de Down/genética , Síndrome de Down/patología , Femenino , Perfilación de la Expresión Génica , Humanos , Lactante , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores Notch/genética , Células Madre/patología , Proteínas Wnt/genéticaRESUMEN
PURPOSE: To evaluate the incidence of intraocular lens (IOL) decentration and posterior capsule opacification (PCO) after implantation of a three-piece posterior chamber silicone IOL in a series of eyes examined postmortem. METHODS: Twenty-three pseudophakic enucleated human cadaver eyes, implanted with AMO SI40NB IOLs after phacoemulsification, were analyzed. Eyes obtained postmortem were sectioned at the equatorial plane and the anterior segment photographed from a posterior view. Location of IOL optic and haptics, type of fixation, and centration of IOL was evaluated. PCO was graded and the presence of Nd:YAG laser posterior capsulotomy was noted. RESULTS: Mean age at the time of surgery was 77.83 years, mean time since implantation was 18.26 months. In all the eyes examined, IOL haptics were positioned in the capsular bag. Mean decentration was 0.20+/-0.16 mm. No correlation was found between IOL decentration and time since implantation. The degree of peripheral PCO ranged from none (13.0%) to mild (39.1%) to moderate (26.1%) to severe (21.7%). The degree of central PCO ranged from none (52.2%) to mild (30.4%) to moderate (4.3%). Three patients (13.0%) underwent Nd:YAG laser posterior capsulotomy. CONCLUSIONS: A very good centration can be obtained when silicone AMOSI40NB IOLs are correctly implanted with the haptics inside the capsular bag. About half of the implants showed no central PCO while Nd:YAG laser posterior capsulotomy rates documented a relatively low PCO 18 months after surgery. A careful in the bag haptics placement is needed in order to reduce the IOL decentration and to prevent central PCO.
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Catarata/diagnóstico , Migración de Cuerpo Extraño/diagnóstico , Cápsula del Cristalino/patología , Implantación de Lentes Intraoculares , Lentes Intraoculares , Complicaciones Posoperatorias , Falla de Prótesis , Anciano , Anciano de 80 o más Años , Enucleación del Ojo , Humanos , Diseño de Prótesis , Elastómeros de Silicona , Donantes de TejidosRESUMEN
Prenatal glucocorticoids, commonly used in women at risk of preterm delivery, can predispose the newborn to disease in later life. Since male reproductive function is likely to reflect testis development during fetal life, we studied the effects of prenatal glucocorticoids on two key intra-testicular factors that play roles in cellular proliferation and differentiation, 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and inhibin-α. Pregnant sheep (n=42) were treated with betamethasone (0.5 mg/kg) or saline (control) at 104, 111 and 118 days of gestation (DG). Testicular tissue was sampled from fetuses at 121 and 132DG, and from lambs at 45 and 90 postnatal days (PD). Within the betamethasone treated group, 3ß-HSD immunostaining area was greater at 121DG than at 90PD (P=0.04), but the intensity of immunostaining was higher at 90PD than at 121DG (P=0.04), 132DG (P=0.04) and 45PD (P=0.03). Control animals showed no changes in 3ß-HSD area or intensity of immunostaining. No significant differences were observed between treated and control animals in immunostaining area, but immunostaining was more intense in the treated group than in the control group at 90PD (P=0.03). For inhibin-α, the proportion of immunostaining area declined in treated offspring from 121DG to 45PD, in contrast to control values, but recovered fully by 90PD, concomitantly with the onset of spermatogenesis. In conclusion, prenatal betamethasone increased the postnatal testicular expression of inhibin-α but reduced the expression of 3ß-HSD. These effects could compromise androgen-mediated testicular development and therefore adult capacity for spermatogenesis.
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17-Hidroxiesteroide Deshidrogenasas/metabolismo , Betametasona/farmacología , Feto/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Inhibinas/metabolismo , Testículo/metabolismo , Animales , Femenino , Feto/citología , Feto/efectos de los fármacos , Edad Gestacional , Técnicas para Inmunoenzimas , Masculino , Embarazo , Ovinos , Testículo/efectos de los fármacos , Testículo/crecimiento & desarrolloRESUMEN
Sludge management arises as a relevant problem after being accumulated in primary ponds of septage treatment plants. One of the most attractive options for sludge disposal is its use in agriculture and then specific guidelines regarding hygienic quality must be fulfilled. This study aimed at evaluating the storage time needed to inactivate Ascaris eggs and Salmonella in sludge accumulated in a primary pond treating septage. Raw septage exhibited very low concentrations of viable Ascaris eggs, thus experiments with Ascaris suum eggs spiking were conducted. The concentration of Ascaris eggs in the solids accumulated at the bottom of the pond was 20 eggs/g of total solids (g TS) at the time of pond closure. Although it decreased, some eggs remained viable (0.59 mean viable eggs/g TS) up to 20 months of in-pond storage of the biosolids. Salmonella survival was studied after developing an analytical method that inhibited the native flora. Sludge was seeded with Salmonella enteritidis. An equation adequately describing Salmonella die-off in biosolids subjected to 115 days of in-pond storage/dewatering, was found to be represented by the regression: y = log MPN Salmonella/g TS = 6.67 x t(-0.086), with t = storage time elapsed in days. The initial concentration was 7.0 x 10(6) MPN/g TS and the removal efficiency was 99%.
Asunto(s)
Helmintos/fisiología , Control de Infecciones , Salmonella enteritidis/fisiología , Aguas del Alcantarillado/microbiología , Eliminación de Residuos Líquidos/métodos , Microbiología del Agua , Agricultura , Animales , Guías como Asunto , Humedad , Óvulo/fisiología , Saneamiento , Estaciones del Año , Aguas del Alcantarillado/parasitología , Factores de TiempoRESUMEN
Waste stabilization ponds (WSP) are an often-used option to treat faecal sludges collected from on-site sanitation systems. Since agricultural use is one of the most attractive options for sludge disposal, specific guidelines on the hygienic sludge quality must be fulfilled, such as for viable helminth eggs and Salmonella sp. Although Salmonella isolation methods are well known for other types of samples, they are not suitable for faecal sludge. The reason can be attributed to the co-existence of a native bacterial sludge flora masking Salmonella development, especially if this bacteria is present at low concentrations. In order to select the best methodology for Salmonella recovery from septage sludge, different culture media were assayed at different incubation periods and temperatures. The proposed methodology for Salmonella recovery from sludge can be summarised as follows: (1) enrichment in Rappaport-Vassiliadis broth at 43 degrees C, 48 hours, and (2) isolation in XLD agar at 40 degrees C, 24 hours. Identification of suspected colonies by biochemical tests: TSI, LIA, urease and serological confirmation with Group O Antigen.
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Control de Infecciones , Salmonella/aislamiento & purificación , Aguas del Alcantarillado/microbiología , Eliminación de Residuos Líquidos/métodos , Microbiología del Agua , Agar , Animales , Medios de Cultivo , Huevos , Helmintos/aislamiento & purificación , Aguas del Alcantarillado/química , Temperatura , Factores de TiempoRESUMEN
We propose two strategies to improve the quality of tractography results computed from diffusion weighted magnetic resonance imaging (DW-MRI) data. Both methods are based on the same PDE framework, defined in the coupled space of positions and orientations, associated with a stochastic process describing the enhancement of elongated structures while preserving crossing structures. In the first method we use the enhancement PDE for contextual regularization of a fiber orientation distribution (FOD) that is obtained on individual voxels from high angular resolution diffusion imaging (HARDI) data via constrained spherical deconvolution (CSD). Thereby we improve the FOD as input for subsequent tractography. Secondly, we introduce the fiber to bundle coherence (FBC), a measure for quantification of fiber alignment. The FBC is computed from a tractography result using the same PDE framework and provides a criterion for removing the spurious fibers. We validate the proposed combination of CSD and enhancement on phantom data and on human data, acquired with different scanning protocols. On the phantom data we find that PDE enhancements improve both local metrics and global metrics of tractography results, compared to CSD without enhancements. On the human data we show that the enhancements allow for a better reconstruction of crossing fiber bundles and they reduce the variability of the tractography output with respect to the acquisition parameters. Finally, we show that both the enhancement of the FODs and the use of the FBC measure on the tractography improve the stability with respect to different stochastic realizations of probabilistic tractography. This is shown in a clinical application: the reconstruction of the optic radiation for epilepsy surgery planning.
Asunto(s)
Imagen de Difusión por Resonancia Magnética/métodos , Imagen de Difusión Tensora/métodos , Epilepsia/cirugía , Algoritmos , Encéfalo/patología , Simulación por Computador , Epilepsia/patología , Reacciones Falso Positivas , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Procesamiento de Imagen Asistido por Computador , Modelos Estadísticos , Reconocimiento de Normas Patrones Automatizadas/métodos , Fantasmas de Imagen , Probabilidad , Procesos Estocásticos , Sustancia Blanca/patologíaRESUMEN
PURPOSE: To describe a software program developed to provide an objective assessment of the amount of posterior capsular opacification (PCO) in high-resolution digital images of the posterior capsule after cataract surgery. METHODS: Images are analyzed by a set protocol of defining the area of the posterior capsule, removing the Purkinje light reflexes by intensity segmentation, contrast enhancement, filtering to enhance low-density PCO, and variance analysis using a co-occurrence matrix to assess texture. The accuracy of the system was tested for validity and repeatability. RESULTS: The software developed has been demonstrated to be an objective method of quantifying PCO. In validation tests, the image analysis-derived measure of PCO showed good agreement with clinically derived measures of PCO. Clinicians assessed PCO on a computer screen image and also under slit lamp examination (Pearson correlation coefficient for both methods >0.92). The entire acquisition and analysis system was demonstrated to have a confidence limit for 2 SDs of 9.8% for group data. CONCLUSIONS: This system is capable of producing an accurate and reproducible measure of PCO that is relevant to assessing techniques of PCO prevention.
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Extracción de Catarata/efectos adversos , Catarata/diagnóstico , Técnicas de Diagnóstico Oftalmológico , Procesamiento de Imagen Asistido por Computador/métodos , Cápsula del Cristalino/patología , Complicaciones Posoperatorias/diagnóstico , Anciano , Anciano de 80 o más Años , Algoritmos , Catarata/etiología , Humanos , Persona de Mediana Edad , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Programas InformáticosRESUMEN
PURPOSE: To assess the corneal epithelial function after prolonged topical administration of diclofenac 0.1% and flurbiprofen 0.03% single-dose eyedrops. SETTING: University Eye Clinic of Trieste, Trieste, Italy. METHODS: This randomized prospective study comprised 24 patients scheduled for phacoemulsification. The patients were randomly assigned to receive diclofenac or flurbiprofen eyedrops for 2 months after surgery. Corneal epithelial permeability was determined by fluorophotometry 7, 37, and 67 days after surgery. RESULTS: An increase in corneal epithelial permeability was observed in the diclofenac group 37 and 67 days after surgery. No epithelial function alterations occurred in the flurbiprofen group. CONCLUSIONS: Subclinical impairment of the epithelial function was observed during topical treatment with diclofenac 0.1% single-dose eyedrops after phacoemulsification. The mechanism responsible for this effect remains unknown.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Córnea/metabolismo , Diclofenaco/farmacocinética , Células Epiteliales/metabolismo , Flurbiprofeno/farmacocinética , Facoemulsificación , Anciano , Anciano de 80 o más Años , Femenino , Fluoresceína/metabolismo , Fluorofotometría , Humanos , Implantación de Lentes Intraoculares , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas , Permeabilidad , Estudios ProspectivosRESUMEN
PURPOSE: To evaluate the intraocular safety of an immunoconjugate (MDX-RA) developed to prevent posterior capsule opacification (PCO) in human eyes. SETTING: St. Thomas's Hospital Eye Department, London, United Kingdom. METHODS: Twenty-six patients had phacoemulsification and implantation of an intraocular lens (IOL). All were randomly allocated at the end of surgery to receive a 0.1 mL placebo or 0.1 mL of the immunotoxin MDX-RA intracamerally. Two doses of the drug were tested: 8 patients with a low dose (50 units), 9 patients with a high dose (100 units), and 9 with placebo. Follow-up at days 1, 14, 30, 60, 90, and 180 consisted of visual acuity measured by the Early Treatment of Diabetic Retinopathy Study test, contrast sensitivity, aqueous flare, specular microscopy of the IOL's anterior surface, and corneal endothelial counts. The percentage area of PCO was measured from retroillumination images of the posterior capsule. RESULTS: There was no decrease in corneal endothelial cell count in toxin-treated patients. Early postoperative flare, anterior chamber cell count, and corneal pachymetry were higher in toxin-treated patients. The median percentage area of PCO at 1 year was 32.0 in the placebo group, 3.8 in the low-dose group, and 7.4 in the high-dose group (P = .06). CONCLUSION: This prospective, randomized, placebo-controlled trial confirmed that MDX-RA is safe for intraocular use and is of potential value for further clinical trials of the prevention of PCO.
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Catarata/prevención & control , Inmunotoxinas/uso terapéutico , Cápsula del Cristalino/patología , Ricina , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Capsulorrexis/efectos adversos , Catarata/etiología , Catarata/patología , Recuento de Células , Método Doble Ciego , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Humanos , Implantación de Lentes Intraoculares , Cristalino/inmunología , Cristalino/patología , Masculino , Facoemulsificación/efectos adversos , Polimetil Metacrilato , Estudios Prospectivos , SeguridadRESUMEN
Benzene is a widespread pollutant whose main source in the environment is automotive emission. There is increasing interest in the exposure of the population to this pollutant as benzene is present also in the indoor environment due to cigarette smoke, drinking water, and food. The aim of this study was to evaluate, in an adult nonsmoking population not occupationally exposed to benzene, whether it is possible to detect differences in the urinary concentration of trans,trans-muconic acid (t,t-MA) between low and high environmental exposure to benzene. A study sample of 31 employees working in pharmacies in a large town in Italy with low environmental exposure to benzene (4.8 microg/m3) was compared to a high (8.1 microg/m3) benzene exposure group. Analysis of urinary t,t-MA was carried out by high-performance liquid chromatography (HPLC; photodiode array detector); analysis of environmental benzene samples was by gas chromatography/mass spectroscopy (GC-MS). The statistical analysis revealed no significant differences in urinary levels of t,t-MA of subjects with high (mean concentration: 157.9 microg/g creatinine) versus low exposure (mean concentration: 114.2 microg/g creatinine). Data show that it is difficult to correlate urinary t,t-MA with benzene exposure at parts per billion levels.
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Contaminación del Aire Interior/análisis , Benceno/análisis , Biomarcadores/análisis , Exposición a Riesgos Ambientales/análisis , Ácido Sórbico/análogos & derivados , Ácido Sórbico/análisis , Adulto , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Urinálisis , Emisiones de Vehículos/análisisRESUMEN
In urban centres of industrialising countries, the majority of houses are served by on-site sanitation systems such as septic tanks and unsewered toilets. The faecal sludges (FS) collected from these systems are usually discharged untreated into the urban and peri-urban environment, posing great risks to water resources and to public health. Contrary to wastewater management, the development of strategies to cope with faecal sludges, adapted to the conditions prevailing in developing countries, have long been neglected. The authors describe the current situation and discuss selected issues of FS management. A proposal is made for a rational setting of sludge quality or treatment standards in economically emerging countries. The authors stipulate that regulatory setting should take into account local economic, institutional and technical conditions. Defining suitable treatment options as critical control points in securing adequate sludge quality is better than setting and relying on numerical sludge quality standards. A separate section is devoted to the practice and to regulatory aspects of (faecal) sludge use in Argentina. An overview of treatment options, which may prove sustainable in less industrialized countries is provided. Planted sludge drying beds are one of these options. It has been piloted in Thailand for four years and details on its performance and operation are presented along with data on the hygienic quality of treated biosolids.
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Heces , Aguas del Alcantarillado/microbiología , Eliminación de Residuos Líquidos/métodos , Argentina , Ciudades , Salud Pública , Control de Calidad , Factores de Riesgo , Tailandia , Microbiología del Agua , Contaminantes del Agua/análisisRESUMEN
A one year study was carried out in a waste stabilization ponds system where septage and sewage are cotreated. The system consists of two septage ponds which operate alternately followed by two ponds in series which receive the combined effluent. The septage ponds also act as evaporation ponds for the accumulated sludge. The monitoring program was divided in two phases. The results of the first phase indicate that the effluent of septage ponds has an adequate quality to be discharged into the waste stabilization ponds designed to treat sewage and that is possible to use the septage ponds to dry the accumulated sludge. Further investigation is needed to find suitable post-treatment of the sludge in order to use it in agriculture.
Asunto(s)
Aguas del Alcantarillado , Eliminación de Residuos Líquidos/métodos , Agricultura , Arquitectura y Construcción de Instituciones de Salud , Vacio , Movimientos del AguaRESUMEN
AimTo study the solubility of perfluorohexyloctane (F6H8) in silicone oil (polydimethylsiloxane (PDMS) 1000) and to measure the viscosity and the specific gravity of the mixture obtained (heavy silicone oil or HSO tamponade) to define the ideal ratio of these components.MethodsThe solubility diagram of the mixture was obtained with the turbidimetric method, indicating the miscibility of F6H8 and silicone oil 1000 at all the useful temperatures. The viscosity was measured in steady shear conditions by using a controlled stress rheometer (Haake RS150) and a double cone/plate (DC 60/4) system, both at 25 and 37 degrees C for different volume per cent compositions of the mixture. The specific gravity was measured at 37 degrees C using a digital densimeter.ResultsA mixture of F6H8 30 v% and PDMS 70 v% was found to be transparent and stable at all the useful temperatures. By combining these proportions of the two substances, a resultant density of 1.06 g/cm(3) was obtained. The viscosity of the 30% F6H8 mixture was 203 mPa.s at 25 degrees C and 163 mPa.s at 37 degrees C respectively.ConclusionsThe ideal F6H8 and silicone oil mixture can be obtained combining 30% of F6H8 with 70% of silicone oil 1000. This mixture seems to have rheological properties useful for its use as an alternative intraocular heavy tamponade.Eye (2008) 22, 1082-1088; doi:10.1038/eye.2008.144; published online 6 June 2008.