RESUMEN
Objetivo Evaluar la posibilidad de terapia génica en pacientes con enfermedades oculares hereditarias con diagnóstico genético establecido. Los objetivos secundarios son revisar la tasa de diagnóstico genético y hacer una actualización de los genes para los cuales hay estudios clínicos o preclínicos en curso que pudieran permitir la terapia génica. Métodos Estudio observacional, retrospectivo y multicéntrico de 177 pacientes con enfermedades oculares hereditarias a quienes se realizó estudio genético.Resultados De 177 pacientes con estudio genético, se incluyeron 146. Se identificaron variantes causantes de enfermedad en 117 pacientes con lo que se obtuvo una tasa de detección de variantes del 80,1%. Se encontraron variantes patogénicas en 47 genes, siendo ABCA4 el gen más común (17,9%), seguido por CRB1 (11,9%). De los pacientes con diagnóstico genético, el 64,1% tienen una variante en un gen para el cual se ha estudiado terapia génica y solo el 40,1% presentan una variante en genes con estudios para su terapia génica en fase clínica. Conclusiones El estudio genético ha abierto nuevos horizontes en el manejo de pacientes con enfermedades oculares hereditarias. Cerca de dos tercios de los pacientes presentó variantes patogénicas en genes para los cuales se ha evaluado la posibilidad de terapia génica. Sin embargo, muchos estudios se encuentran en fase preclínica. Se debe adecuar las expectativas de los pacientes sometidos a estudio genético y sus familias (AU)
Objective To evaluate the possibility of gene therapy in patients with inherited ocular conditions and established genetic diagnosis. The secondary objectives were to determine the genetic diagnostic rate and to update the list of genes for which there are ongoing clinical trials or preclinical studies that could allow for gene therapy. Methods Observational, retrospective, multicentric study of 177 patients with inherited ocular conditions that underwent genetic testing. Results Of 177 patients with genetic testing, 146 were enrolled for this study. Disease-causing variants were identified in 117 patients (variant detection rate of 80.1%). Pathogenic variants were found in 47 genes, with ABCA4 being the most common gene (17.9%), followed by CRB1 (11.9%). 64.1% of patients with a genetic diagnosis have a variant in genes for which gene therapy has been studied and only 40.1% have a variant in genes with studies for gene therapy in clinical phase. Conclusions Genetic testing has opened new horizons in the management of patients with hereditary ocular diseases. About two-thirds of the patients had pathogenic variants in genes for which gene therapy has been evaluated. However, many studies are in the pre-clinical phase. The expectations of patients undergoing genetic study and their families should be managed accordingly (AU)
Asunto(s)
Humanos , Terapia Genética/métodos , Enfermedades de la Retina/terapia , Enfermedades Hereditarias del Ojo/terapia , Estudios RetrospectivosRESUMEN
OBJECTIVE: To evaluate the possibility of gene therapy in patients with inherited ocular conditions and established genetic diagnosis. The secondary objectives were to determine the genetic diagnostic rate and to update the list of genes for which there are ongoing clinical trials or preclinical studies that could allow for gene therapy. METHODS: Observational, retrospective, multicentric study of 177 patients with inherited ocular conditions that underwent genetic testing. RESULTS: Of 177 patients with genetic testing, 146 were enrolled for this study. Disease-causing variants were identified in 117 patients (variant detection rate of 80.1%). Pathogenic variants were found in 47 genes, with ABCA4 being the most common gene (17.9%), followed by CRB1 (11.9%). 64.1% of patients with a genetic diagnosis have a variant in genes for which gene therapy has been studied and only 40.1% have a variant in genes with studies for gene therapy in clinical phase. CONCLUSIONS: Genetic testing has opened new horizons in the management of patients with hereditary ocular diseases. About two-thirds of the patients had pathogenic variants in genes for which gene therapy has been evaluated. However, many studies are in the pre-clinical phase. The expectations of patients undergoing genetic study and their families should be managed accordingly.
Asunto(s)
Proteínas del Ojo , Enfermedades de la Retina , Humanos , Estudios Retrospectivos , Proteínas del Ojo/genética , Retina , Terapia Genética , Transportadoras de Casetes de Unión a ATP/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genéticaRESUMEN
ACTUALIZACIÓN: Este resumen Epistemonikos (Living FRISBEE: Living FRIendly Summary of the Body of Evidence using Epistemonikos) es una actualización del resumen publicado en diciembre de 2014. INTRODUCCIÓN: La retinopatía diabética proliferativa conlleva un alto riesgo de ceguera si no es tratada de manera oportuna. El tratamiento muchas veces incluye la vitrectomía. El uso preoperatorio de bevacizumab, un anti-factor de crecimiento endotelial vascular, podría mejorar variables intraoperatorias que facilitan la cirugía y mejorarían el curso postoperatorio. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos cinco revisiones sistemáticas que en conjunto incluyeron 16 estudios primarios, de los cuales 14 corresponden a ensayos aleatorizados. Concluimos que el uso preoperatorio de bevacizumab disminuye la incidencia de hemorragia vítrea en el postoperatorio temprano y probablemente también en el postoperatorio tardío, pero no está claro su efecto sobre la agudeza visual. Además, probablemente disminuye el tiempo quirúrgico, podría disminuir la incidencia de roturas retinianas iatrogénicas, y si bien no está claro que disminuya la ocurrencia de sangrado intraoperatorio, podría disminuir la necesidad de uso de endodiatermia.
UPDATE: This Living FRISBEE (Living FRIendly Summary of the Body of Evidence using Epistemonikos) is an update of the summary published in December 2014. INTRODUCTION: Proliferative diabetic retinopathy can cause severe vision loss and even blindness if left untreated. Vitrectomy is often required in the treatment of more severe cases. Preoperative administration of bevacizumab, a humanized anti-vascular endothelial growth factor would improve intraoperative variables that facilitate surgery and improve postoperative course. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified five systematic reviews including 16 studies overall, of which 14 were randomized trials. We concluded the preoperative use of intravitreal bevacizumab reduces the rate of vitreous hemorrhage in the early postoperative period, and probably also in the late postoperative period, but its effect on visual acuity is not clear. Furthermore, it probably decreases the surgical time and may decrease the incidence of iatrogenic retinal breaks. Although we are uncertain whether preoperative bevacizumab decreases intraoperative bleeding, it may reduce the need for endodiathermy.
Asunto(s)
Humanos , Vitrectomía/métodos , Retinopatía Diabética/terapia , Bevacizumab/administración & dosificación , Cuidados Preoperatorios , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores de la Angiogénesis/administración & dosificación , Inyecciones IntravítreasRESUMEN
Type 1 diabetes results from destruction of insulin-producing beta cells in pancreatic islets and is characterized by islet cell autoimmunity. Autoreactivity against non-beta cell-specific antigens has also been reported, including targeting of the calcium-binding protein S100ß. In preclinical models, reactivity of this type is a key component of the early development of insulitis. To examine the nature of this response in type 1 diabetes, we identified naturally processed and presented peptide epitopes derived from S100ß, determined their affinity for the human leucocyte antigen (HLA)-DRB1*04:01 molecule and studied T cell responses in patients, together with healthy donors. We found that S100ß reactivity, characterized by interferon (IFN)-γ secretion, is a characteristic of type 1 diabetes of varying duration. Our results confirm S100ß as a target of the cellular autoimmune response in type 1 diabetes with the identification of new peptide epitopes targeted during the development of the disease, and support the preclinical findings that autoreactivity against non-beta cell-specific autoantigens may have a role in type 1 diabetes pathogenesis.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Epítopos de Linfocito T/inmunología , Inmunidad Celular , Subunidad beta de la Proteína de Unión al Calcio S100/inmunología , Linfocitos T/inmunología , Autoantígenos/inmunología , Secuencia de Bases , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Epítopos de Linfocito T/genética , Femenino , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Masculino , Datos de Secuencia Molecular , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Linfocitos T/patologíaRESUMEN
Dendritic cells (DCs) are powerful antigen-presenting cells capable of maintaining peripheral tolerance. The possibility to generate tolerogenic DCs opens new therapeutic approaches in the prevention or remission of autoimmunity. There is currently no treatment inducing long-term tolerance and remission in type 1 diabetes (T1D), a disease caused by autoimmunity towards beta cells. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow islet regeneration. Apoptotic cells--a source of autoantigens--are cleared rapidly by macrophages and DCs through an immunologically silent process that contributes to maintaining tolerance. Our aims were to prevent T1D and to evaluate the re-establishment of peripheral tolerance using autologous DCs pulsed in vitro with apoptotic bodies from beta cells. Immature DCs derived from bone marrow of non-obese diabetic (NOD) mice were obtained and pulsed with antigen-specific apoptotic bodies from the beta cell line NIT-1. Those DCs that phagocytosed apoptotic cells diminished the expression of co-stimulatory molecules CD40 and CD86 and reduced secretion of proinflammatory cytokines. Moreover, these cells were resistant to increase the expression of co-stimulatory molecules after lipopolysaccharide activation. The administration of these cells to NOD transgenic mice expressing interferon-beta in their insulin-producing cells, a model of accelerated autoimmune diabetes, decreased diabetes incidence significantly and correlated positively with insulitis reduction. DCs pulsed with apoptotic cells that express disease-associated antigens constitutes a promising strategy to prevent T1D.
Asunto(s)
Apoptosis/inmunología , Autoantígenos/inmunología , Células Dendríticas , Diabetes Mellitus Tipo 1/prevención & control , Tolerancia Inmunológica/inmunología , Inmunoterapia/métodos , Células Secretoras de Insulina/inmunología , Animales , Autoantígenos/administración & dosificación , Células Cultivadas , Vesículas Citoplasmáticas/inmunología , Células Dendríticas/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Endocitosis , Epítopos , Femenino , Células Secretoras de Insulina/patología , Interferón beta/genética , Lipopolisacáridos/farmacología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Proteínas Recombinantes de Fusión/genética , Organismos Libres de Patógenos EspecíficosRESUMEN
Type 1 diabetes (T1D) is caused by the selective destruction of the insulin-producing beta cells of the pancreas by an autoimmune response. Due to ethical and practical difficulties, the features of the destructive process are known from a small number of observations, and transcriptomic data are remarkably missing. Here we report whole genome transcript analysis validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and correlated with immunohistological observations for four T1D pancreases (collected 5 days, 9 months, 8 and 10 years after diagnosis) and for purified islets from two of them. Collectively, the expression profile of immune response and inflammatory genes confirmed the current views on the immunopathogenesis of diabetes and showed similarities with other autoimmune diseases; for example, an interferon signature was detected. The data also supported the concept that the autoimmune process is maintained and balanced partially by regeneration and regulatory pathway activation, e.g. non-classical class I human leucocyte antigen and leucocyte immunoglobulin-like receptor, subfamily B1 (LILRB1). Changes in gene expression in islets were confined mainly to endocrine and neural genes, some of which are T1D autoantigens. By contrast, these islets showed only a few overexpressed immune system genes, among which bioinformatic analysis pointed to chemokine (C-C motif) receptor 5 (CCR5) and chemokine (CXC motif) receptor 4) (CXCR4) chemokine pathway activation. Remarkably, the expression of genes of innate immunity, complement, chemokines, immunoglobulin and regeneration genes was maintained or even increased in the long-standing cases. Transcriptomic data favour the view that T1D is caused by a chronic inflammatory process with a strong participation of innate immunity that progresses in spite of the regulatory and regenerative mechanisms.
Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Perfilación de la Expresión Génica , Islotes Pancreáticos/metabolismo , Páncreas/metabolismo , Páncreas/patología , Adolescente , Adulto , Antígenos CD/análisis , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Recuento de Células , Diabetes Mellitus Tipo 1/inmunología , Regulación hacia Abajo/genética , Femenino , Expresión Génica/genética , Células Secretoras de Glucagón/metabolismo , Antígenos HLA/genética , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Inmunidad Innata/genética , Inflamación/genética , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/patología , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Pancreatitis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba/genética , Adulto Joven , Antígenos HLA-ERESUMEN
OBJECTIVE: To assess the long-term results and prognostic factors in patients who have undergone open cordectomy (OC) for the treatment of T(1a) glottic laryngeal carcinoma. METHODS: One hundred four epidermoid cancer patients operated from January 1989 through December 1999 were included in the study. Clinical parameters, postoperative complications, and postoperative stay were retrospectively evaluated in all cases. RESULTS: Mean survival for the patients included in the study was 61.5+/-24.8 months after the date of operation (range: 11-121 months). Ninety-four patients did not have recurrent tumor (90.4%). Local, regional and distant recurrence were linked with a statistical negative impact on survival rates (p<0.05). Only sero-hematoma was significantly related to local recurrence (p<0.05), whereas the remainder complications did not. None of the complications was associated with neck recurrence or distant metastasis (p>0.05). CONCLUSIONS: Open cordectomy is nowadays a valid technique for the surgical treatment of T(1a) glottic laryngeal carcinoma. Its results are comparable with those of other more recent techniques.
Asunto(s)
Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/cirugía , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/cirugía , Pliegues Vocales/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Neoplasias Laríngeas/patología , Laringectomía , Masculino , Persona de Mediana Edad , Disección del Cuello , Recurrencia Local de Neoplasia/mortalidad , Complicaciones Posoperatorias , Estudios RetrospectivosRESUMEN
CONCLUSION: Inductively coupled plasma mass spectrometry (ICP-MS) can be applied to organic tissues obtained from experimental animals. Hearing loss does not correlate with the platinum (Pt) concentration found in the inner ear. Drug structure and affinity to inner ear proteins could explain ototoxicity caused by cisplatin. OBJECTIVES: To analyse Pt affinity for brain and ear tissues (of similar embryologic origin) in the Wistar rat and clearance gradient after a single dose, and to correlate these findings with hearing changes. MATERIALS AND METHODS: Thirty-two Wistar rats were intraperitoneally injected with cisplatin at a dose of 5 mg/kg. Animals were sacrificed after obtaining auditory brain responses (ABRs) at 3, 7, 30 and 90 days (nine, seven, seven and nine animals, respectively). Brain and both temporal bones were extracted from each animal and analysed by ICP-MS to determine the absolute concentrations of the metal. Eight non-treated animals were employed as a control group. RESULTS: The ABR thresholds were significantly elevated in animals from all groups after cisplatin treatment. A maximum accumulation of Pt for inner ear and brain was revealed around the first week: 3.175 (57%) and 0.342 (72%), respectively. Pt significantly accumulated in greater quantities in ear than in brain (p<0.01) and was cleared at a higher rate in brain than in ear (p<0.01) following cochlea/brain ratio analysis. No statistically significant correlation was found between amounts of Pt and hearing loss in the study animals.
Asunto(s)
Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Cisplatino/farmacocinética , Cisplatino/toxicidad , Sordera/inducido químicamente , Animales , Encéfalo/metabolismo , Permeabilidad de la Membrana Celular/fisiología , Sordera/sangre , Oído Interno/metabolismo , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Inyecciones Intraperitoneales , Líquido Intracelular/metabolismo , Tasa de Depuración Metabólica/fisiología , Ratas , Ratas WistarRESUMEN
Antitumoral Pt-containing drugs present side effects like nephrotoxicity and ototoxicity. Several systematic experiments have been carried out with Wistar rats treated with cisplatin, carboplatin, and oxaliplatin to study Pt-drugs accumulation and elimination, and Pt-biomolecule distribution in the cells and cytosols of ear, kidney, and liver. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis shows a cisplatin accumulation capability between oxaliplatin (the highest) and carboplatin (the lowest). The maximum concentration of Pt in all the organs studied was achieved around the first week after cisplatin treatment. During the first 30 days, the elimination was very fast, decreasing in the subsequent 60 days in all the organs. Analysis of cytosols by liquid chromatography (LC)-ICP-MS showed an analogous behavior. In most samples, the distribution of the three drugs in the cellular and cytosolic fractions was similar for all the tissues. For kidney and ear, approximately 60% and 30%, respectively, of the metal accumulated was present in the cytosol, the cytosolic fractions smaller than 50 KDa being especially important. Cisplatin-biomolecule interaction strength under denaturing conditions was evaluated by LC-ICP-MS and showed a quite strong bond.
Asunto(s)
Antineoplásicos/farmacocinética , Compuestos Organoplatinos/farmacocinética , Platino (Metal)/metabolismo , Animales , Antineoplásicos/análisis , Carboplatino/análisis , Carboplatino/farmacocinética , Fraccionamiento Celular , Cisplatino/análisis , Cisplatino/farmacocinética , Citosol/química , Citosol/metabolismo , Oído Interno/química , Oído Interno/metabolismo , Riñón/química , Riñón/metabolismo , Hígado/química , Hígado/metabolismo , Espectrometría de Masas , Compuestos Organoplatinos/análisis , Oxaliplatino , Platino (Metal)/análisis , Ratas , Distribución TisularRESUMEN
INTRODUCTION: The ototoxic effects of cisplatin include loss of outer hair cells, degeneration of the stria vascularis and a decrease in the number of spiral ganglion cells. Scanning microscopy has shown balloon-like protrusions (blebs) of the plasma membrane of inner hair cells following cisplatin administration. The present study was undertaken to identify the possible role of inner and outer hair cell blebs in the pathogenesis of cisplatin-induced ototoxicity. MATERIALS AND METHODS: Twenty-five guinea pigs were injected with cisplatin and their hearing tested at different time-points, before sacrifice and examination with scanning electron microscopy. RESULTS AND ANALYSIS: Seven animals showed blebs in the inner hair cells at different stages. Hearing thresholds were lower in animals showing blebs. DISCUSSION: Cisplatin seems to be able to induce changes in inner hair cells as well as in other structures in the organ of Corti. Blebbing observed in animals following cisplatin administration could play a specific role in the regulation of intracellular pressure.
Asunto(s)
Antineoplásicos/efectos adversos , Vesícula/inducido químicamente , Cisplatino/efectos adversos , Enfermedades del Oído/inducido químicamente , Células Ciliadas Auditivas/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Animales , Vesícula/patología , Potenciales Microfónicos de la Cóclea/efectos de los fármacos , Enfermedades del Oído/patología , Cobayas , Células Ciliadas Auditivas/ultraestructura , Células Ciliadas Auditivas Internas/efectos de los fármacos , Células Ciliadas Auditivas Internas/ultraestructura , Células Ciliadas Auditivas Externas/efectos de los fármacos , Células Ciliadas Auditivas Externas/ultraestructura , Microscopía Electrónica de Rastreo , Enfermedades del Sistema Nervioso Periférico/patologíaRESUMEN
The destruction of beta cells by the islet infiltrating lymphocytes causes type 1 diabetes. Transgenic mice models expressing interferon (IFN)-beta in beta cells, in the non-obese diabetic (NOD) strain and in a diabetes-free, major histocompatibility complex-matched, homologous strain, the non-obese resistant (NOR) mice, developed accelerated type 1 diabetes after 3 weeks of age. Our aim was to determine if natural killer (NK) cells could affect the acceleration of the disease. We determined the amount of NK cells in the pancreas, spleen and lymph nodes from NOD rat insulin promoter (RIP)-IFN-beta mice. Pancreatic cytokines were assessed by quantitative real-time polymerase chain reaction and protein arrays. To confirm the relevance of NK cells in the acceleration of autoimmune diabetes this subset was depleted with anti-asialo GM1 antibodies. An increase of intrapancreatic NK cells characterized the accelerated onset of diabetes both in NOD and NOR RIP-IFN-beta transgenic models. Cytokines involved in NK function and migration were found to be hyperexpressed in the pancreas from accelerated diabetic mice. Interestingly, the depletion of NK cells in vivo abolished completely the acceleration of diabetes. NK cells connect innate to adaptive immunity and might play a role in autoimmunity. We report here that NK cells are required critically in the pancreas for accelerated diabetes. This model links inflammation to acceleration of beta cell-specific autoimmunity mediated by NK cells.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Interferón beta/inmunología , Células Asesinas Naturales/inmunología , Animales , Linfocitos B/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Gangliósido G(M1)/inmunología , Islotes Pancreáticos/inmunología , Ganglios Linfáticos/inmunología , Subgrupos Linfocitarios/inmunología , Ratones , Ratones Endogámicos NODRESUMEN
BACKGROUND & AIMS: To determine the prevalence of dysphagia in head and neck cancer patients treated with surgery and radiotherapy or chemoradiotherapy. To study the impact of dysphagia on food habits, nutritional status, and quality of life. METHODS: Retrospective cross-sectional study of 87 head and neck cancer patients treated with surgery and radiotherapy or chemoradiotherapy from January 2000 through May 2005. Time since surgery was 28.5+/-17.8 months. A clinical test was used to detect dysphagia. A nutritional assessment was performed in all patients. A questionnaire was used to evaluate quality of life. RESULTS: Oropharyngeal dysphagia was present in 50.6% of patients, mostly to solid foods (72.4%). Patients with total glossectomy and chemoradiotherapy had the highest rate of dysphagia. Nutritional support was necessary in 57.1% of patients. Malnutrition was present in 20.3% of patients, mainly marasmus (81%). Fifty-one percent of patients reported a decrease in their quality of life due to dysphagia. CONCLUSIONS: We found a high prevalence of dysphagia in head and neck cancer patients treated with surgery and coadjuvant treatment. This problem negatively affects their quality of life. It is important that nutritional surveillance be provided to detect it and to prevent malnutrition.
Asunto(s)
Trastornos de Deglución/epidemiología , Neoplasias de Cabeza y Cuello/complicaciones , Desnutrición/epidemiología , Estado Nutricional , Calidad de Vida , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Estudios Transversales , Trastornos de Deglución/etiología , Femenino , Glosectomía/efectos adversos , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Desnutrición/etiología , Mandíbula/cirugía , Maxilar/cirugía , Persona de Mediana Edad , Evaluación Nutricional , Prevalencia , Desnutrición Proteico-Calórica/epidemiología , Desnutrición Proteico-Calórica/etiología , Radioterapia/efectos adversos , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND AND PURPOSE: Ototoxicity is a known adverse effect of cisplatin (CDDP). Since apoptosis is involved in the development of some pathological conditions associated with the administration of anticancer drugs, we examined, using immunohistochemical and electrophysiological techniques, the apoptotic changes in the cochlea of Sprague-Dawley (SD) rats after an injection of CDDP (5 mgkg(-1) body weight). EXPERIMENTAL APPROACH: Luciferase assays were used to determine the different caspase activities and ATP levels in protein extracts of whole cochleae. The expression of several apoptotic-related proteins was measured by means of Western blotting. These analyses were performed 2, 7 and 30 days after the CDDP injection. The auditory brain stem response was obtained before and at the different times after the injection of CDDP, before the animals were killed. KEY RESULTS: CDDP significantly increased the levels of caspase-3/7 activity and active caspase-3 protein expression and caspase-3 immunofluorescence staining, caspase-9 activity, and Bax protein expression but decreased Bcl-2 protein expression within the rat cochleae. Threshold shifts were significantly elevated 2 days after CDDP treatment. CONCLUSIONS AND IMPLICATIONS: These findings support the hypothesis that cisplatin-related apoptosis evokes an intrinsic pathway of pro-apoptotic signalling within the rat cochleae. Thus, selective inhibition of the sequence of events involved in the intrinsic apoptotic pathway could provide a strategy to minimize cisplatin-induced ototoxicity.
Asunto(s)
Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Cisplatino/toxicidad , Cóclea/efectos de los fármacos , Animales , Antineoplásicos/administración & dosificación , Apoptosis/inmunología , Caspasa 3/biosíntesis , Caspasa 3/efectos de los fármacos , Caspasa 3/inmunología , Cisplatino/administración & dosificación , Cóclea/inmunología , Cóclea/patología , Electrofisiología , Activación Enzimática/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Femenino , Inmunohistoquímica , Inyecciones Intraperitoneales , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/inmunologíaRESUMEN
CONCLUSION: The great variety of pathological entities related to the presence of circulating HSP-70 suggests a nonspecific cellular damage. As the present study shows, positive results decrease with respect to the time elapsed after the injection of the ototoxic agent. HSP-70 appears as an early and transient marker that could permit early detection of inner ear damage. OBJECTIVES: The aim of this study was to determine the presence of HSP-70 at different time points by means of Western blot immunoassay in the sera of rats treated with cisplatin. MATERIALS AND METHODS: Thirty-six Wistar rats were intraperitoneally injected with cisplatin at a dose of 5 mg/kg and blood samples were collected at 7 and 90 days. Determination of HSP-70 was made by means of a modified Western blot immunoassay kit originally used for human HSP-70 antigen detection. A control group of 18 animals was used for comparison. RESULTS: Western blot was positive in 77.8% of the animals in the 7 days group, decreasing to a 44.4% in the 90 days group. In the control group, Western blot was positive in 5.5%.
Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Oído Interno/efectos de los fármacos , Proteínas del Choque Térmico HSP72/metabolismo , Pérdida Auditiva Sensorineural/inducido químicamente , Pérdida Auditiva Sensorineural/metabolismo , Animales , Antineoplásicos/efectos adversos , Biomarcadores , Western Blotting , Cisplatino/efectos adversos , Cóclea/metabolismo , Cóclea/patología , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/inmunología , Proteínas del Choque Térmico HSP72/inmunología , Pérdida Auditiva Sensorineural/patología , Masculino , Ratas , Ratas WistarRESUMEN
Chemical compounds containing platinum have been employed since 1978 as drugs to beat certain type of tumours. Nevertheless, besides of their exceptional antitumoral properties, these drugs also have important deleterious side effects, such as, nephrotoxicity and ototoxicity. A study of Pt accumulation and a speciation analysis has been performed by ICP-MS in samples from kidney and inner ear in a controlled population of Wistar rats treated with, either, cisplatin, carboplatin or oxaliplatin. The results on Pt accumulation point out to drug structure and not only to Pt content as the responsible for the alteration of organ functionality. Speciation studies in the samples from kidney and inner ear were performed coupling two-dimensional liquid chromatography (2D-LC) to ICP-MS. Size exclusion (SEC) and anion exchange fast protein liquid chromatography (FPLC) was employed for 2D orthogonal separation. After these separations, free drug peaks were not observed in any of the samples. The binding of Pt to biomolecules was demonstrated by SEC and, independently of the drug used, Pt eluted as two main bands with molecular weights of 12kDa and 25-65kDa for inner ear samples, and as two different bands with 20kDa and 50-60kDa in the samples from kidney. However, the relative band intensity presented important differences for the three drugs. Using the same chromatographic conditions, it was shown that a metallothionein (MT) standard eluted in the same position as some of the cytosolic Pt-biomolecules. High Pt-containing fractions eluting from the SEC column were analysed by anion exchange FPLC after a preconcentration step. Among the different preconcentration methods tested, sample focusing on the head of the FPLC column shows main advantages. In this way, the separation by 2D chromatography of the high molecular Pt-species has been considerably improved.
RESUMEN
The presence of a skull base defect can lead to major complications such as cerebrospinal fluid leak, meningocele, encephalocele and meningitis. It is exceptional to find the existence of two concomitant defects in the skull base. We present the case of a patient with concomitant spontaneous defects of the anterior and middle skull base that were surgically repaired. After 18 years of right rhinorrhea the patient was referred after being diagnosed with a large right nasal fossa meningoencephalocele, which was surgically removed by functional endoscopic sinus surgery. Following the surgery the patient complained about unilateral ear fullness. A paracentesis revealed a highly suspicious cerebrospinal fluid collection. High resolution scans revealed a defect in the mastoid tegmen; subsequently a transmastoid approach was carried out. Greater defects or those lying around the internal auditory canal, are best treated via the middle fossa approach. In the anterior cranial fossa the treatment of choice is provided by endoscopic procedures, but frontal bone craniotomy should be considered if the defect is in the frontal sinus or greater than 5 cm in size.
Asunto(s)
Encefalocele/cirugía , Meningocele/cirugía , Neuroendoscopía/métodos , Base del Cráneo/patología , Rinorrea de Líquido Cefalorraquídeo/patología , Rinorrea de Líquido Cefalorraquídeo/cirugía , Fosa Craneal Anterior/patología , Fosa Craneal Anterior/cirugía , Craneotomía/métodos , Encefalocele/patología , Femenino , Seno Frontal/patología , Seno Frontal/cirugía , Humanos , Imagen por Resonancia Magnética , Apófisis Mastoides/patología , Apófisis Mastoides/cirugía , Meningocele/patología , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
External auditory canal cholesteatomas are a rare disease. Their usual clinical appearance is a mass eroding the bony external auditory canal, normally in the inferior or anterior parts, with an intact tympanic membrane and a normal middle ear. A case of this uncommon disease with a review of the scientific literature is presented. Guidelines for the prevention, diagnosis and management are examined.
Asunto(s)
Colesteatoma/etiología , Enfermedades del Oído/etiología , Oído Externo , Complicaciones Posoperatorias/etiología , Anciano , Colesteatoma/diagnóstico , Colesteatoma/cirugía , Enfermedades del Oído/diagnóstico , Enfermedades del Oído/cirugía , Femenino , Humanos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/cirugíaRESUMEN
AIMS/HYPOTHESIS: The expression of IFNbeta in beta cells results in accelerated type 1 diabetes. The REG family of beta cell proliferation factors have been described as autoantigens in autoimmune diabetes. The aim of this study was to determine the effect of IFNbeta on Reg expression, and the implications of this in terms of autoimmunity. METHODS: Reg gene expression was determined in islets from non-obese diabetic (NOD) RIP-HuIFNbeta mice by cDNA microarray, quantitative real-time PCR and immunohistochemistry. The effect of IFNbeta on Reg1 and Reg2 expression was assessed in the NOD insulinoma cell line NIT-1. IL-6, known to induce Reg expression, was measured in the insulitis microenvironment. Morphological studies were carried out to determine islet enlargement in this model. RESULTS: Reg2 was upregulated in islets from the NOD RIP-HuIFNbeta mice at the onset of the autoimmune attack. IFNbeta upregulates Reg1 and Reg2 genes in NIT-1 cells. The expression of Il6 was increased in islets from transgenic mice and in NIT-1 cells exposed to HuIFNbeta. Moreover, islets from transgenic mice were enlarged compared with those from wild-type mice. CONCLUSIONS/INTERPRETATION: Reg overexpression correlates well with the acceleration of diabetes in this model. The upregulation of Reg suggests that islets try to improve hyperglycaemia by regenerating the cells lost in the autoimmune attack. Reg expression is regulated by several factors such as inflammation. Therefore, the overexpression of an IFNbeta-induced autoantigen (REG) in the islets during inflammation might contribute to the premature onset of diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Regulación de la Expresión Génica , Interferón beta/fisiología , Islotes Pancreáticos/fisiopatología , Litostatina/genética , Animales , Línea Celular , Cruzamientos Genéticos , Femenino , Humanos , Insulina/genética , Islotes Pancreáticos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD/inmunología , Ratones Transgénicos , Regiones Promotoras Genéticas , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
HYPOTHESIS: Supporting cells have a crucial role in degenerative and regenerative events of primary sensorial hair cells of the organ of Corti. This new role should determine future studies about pathophysiology of hearing loss and its regenerative treatment. SUPPORTING EVIDENCE: Recent findings suggest an active role of supporting cells in the maintenance of hair cell function and structure. Evidences of high energy consumption and close proximity to auditory nervous fibers suggesting K+ active exchange, preferential expression of specific proteins and antigens, presence of glucocorticoids receptors, affinity for cisplatin and regenerative potential give the supporting cells an important role in homeostasis of the organ of Corti and in some specific diseases affecting this structure. CONCLUSION: As well as glial cells provide protection and regeneration to neural tissues, supporting cells may provide the necessary metabolic and electrolitic conditions for hair cells mechanical and bioelectrical function. This opens new possibilities for the treatment of apparently "irreversible" destruction of the inner ear.