RESUMEN
Photoreceptor outer segments are surrounded by a carbohydrate-rich matrix, the interphotoreceptor matrix, necessary for physiological retinal function. Few roles for molecules characterizing the interphotoreceptor matrix have been clearly defined. Recent studies have found the presence of nonsense mutations in the interphotoreceptor matrix proteoglycan 2 (IMPG2) gene in patients affected by retinal dystrophies. IMPG2 encodes for a proteoglycan synthesized by photoreceptors and secreted in the interphotoreceptor matrix. Little is known about the structure and function of this protein, we thus decided to characterize zebrafish impg2. In zebrafish there are two Impg2 proteins, Impg2a and Impg2b. We generated a phylogenetic tree based on IMPG2 protein sequence similarity among vertebrates, showing a significant similarity between humans and teleosts. The human and zebrafish proteins share conserved domains, as also shown by homology models. Expression analyses of impg2a and impg2b show a continued expression in the photoreceptor layer starting from developmental stages and continuing through adulthood. Between 1 and 6 months post-fertilization, there is a significant shift of Impg2 expression toward the outer segment region, suggesting an increase in secretion. This raises intriguing hypotheses about its possible role(s) during retinal maturation, laying the groundwork for the generation of most needed models for the study of IMPG2-related inherited retinal dystrophies.
Asunto(s)
Proteoglicanos , Distrofias Retinianas , Animales , Humanos , Proteoglicanos/genética , Proteoglicanos/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Filogenia , Retina/metabolismoRESUMEN
Prion diseases are phenotypically diverse, transmissible, neurodegenerative disorders affecting both animals and humans. Misfolding of the normal prion protein (PrPC) into disease-associated conformers (PrPSc) is considered the critical etiological event underpinning prion diseases, with such misfolded isoforms linked to both disease transmission and neurotoxicity. Although important advances in our understanding of prion biology and pathogenesis have occurred over the last 3-4 decades, many fundamental questions remain to be resolved, including consensus regarding the principal pathways subserving neuronal dysfunction, as well as detailed biophysical characterization of PrPSc species transmitting disease and/or directly associated with neurotoxicity. In vivo and in vitro models have been, and remain, critical to furthering our understanding across many aspects of prion disease patho-biology. Prion animal models are arguably the most authentic in vivo models of neurodegeneration that exist and have provided valuable and multifarious insights into pathogenesis; however, they are expensive and time-consuming, and it can be problematic to clearly discern evidence of direct PrPSc neurotoxicity in the overall context of pathogenesis. In vitro models, in contrast, generally offer greater tractability and appear more suited to assessments of direct acute neurotoxicity but have until recently been relatively simplistic, and overall there remains a relative paucity of validated, biologically relevant models with heightened reliability as far as translational insights, contributing to difficulties in redressing our knowledge gaps in prion disease pathogenesis. In this review, we provide an overview of the spectrum and methodological diversity of in vivo and in vitro models of prion acute toxicity, as well as the pathogenic insights gained from these studies.
Asunto(s)
Síndromes de Neurotoxicidad/metabolismo , Proteínas PrPSc/metabolismo , Enfermedades por Prión/metabolismo , Priones/metabolismo , Animales , Humanos , Modelos Biológicos , Neuronas/metabolismoRESUMEN
Excitotoxicity following cerebral ischemia elicits a molecular cascade, which leads to neuronal death. c-Jun-N-terminal kinase (JNK) has a key role in excitotoxic cell death. We have previously shown that JNK inhibition by a specific cell-permeable peptide significantly reduces infarct size and neuronal death in an in vivo model of cerebral ischemia. However, systemic inhibition of JNK may have detrimental side effects, owing to blockade of its physiological function. Here we designed a new inhibitor peptide (growth arrest and DNA damage-inducible 45ß (GADD45ß-I)) targeting mitogen-activated protein kinase kinase 7 (MKK7), an upstream activator of JNK, which exclusively mediates JNK's pathological activation. GADD45ß-I was engineered by optimizing the domain of the GADD45ß, able to bind to MKK7, and by linking it to the TAT peptide sequence, to allow penetration of biological membranes. Our data clearly indicate that GADD45ß-I significantly reduces neuronal death in excitotoxicity induced by either N-methyl-D-aspartate exposure or by oxygen-glucose deprivation in vitro. Moreover, GADD45ß-I exerted neuroprotection in vivo in two models of ischemia, obtained by electrocoagulation and by thromboembolic occlusion of the middle cerebral artery (MCAo). Indeed, GADD45ß-I reduced the infarct size when injected 30 min before the lesion in both models. The peptide was also effective when administrated 6 h after lesion, as demonstrated in the electrocoagulation model. The neuroprotective effect of GADD45ß-I is long lasting; in fact, 1 week after MCAo the infarct volume was still reduced by 49%. Targeting MKK7 could represent a new therapeutic strategy for the treatment of ischemia and other pathologies involving MKK7/JNK activation. Moreover, this new inhibitor can be useful to further dissect the physiological and pathological role of the JNK pathway in the brain.
Asunto(s)
Infarto de la Arteria Cerebral Media/tratamiento farmacológico , MAP Quinasa Quinasa 7/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Péptidos/farmacología , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Antígenos de Diferenciación/química , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/metabolismo , Hipoxia de la Célula , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Electrocoagulación , Regulación de la Expresión Génica , Glucosa/toxicidad , Infarto de la Arteria Cerebral Media/genética , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , MAP Quinasa Quinasa 7/química , MAP Quinasa Quinasa 7/genética , MAP Quinasa Quinasa 7/metabolismo , Masculino , Simulación del Acoplamiento Molecular , Datos de Secuencia Molecular , N-Metilaspartato/toxicidad , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/síntesis química , Péptidos/síntesis química , Cultivo Primario de Células , Ingeniería de Proteínas , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Tromboembolia , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Renal cell carcinomas (RCCs) are rarely described in transplanted kidneys. Available therapeutic strategies range from allograft nephrectomy to nephron-sparing procedures such as partial nephrectomy or image-guided thermal ablation. Percutaneous radiofrequency ablation (RFA) is a minimally invasive technique which provides promising oncologic outcomes in small allograft RCCs while preserving allograft function. So far, only a few cases have been reported in the transplant setting. We describe a renal transplant RCC successfully approached by ultrasound-guided RFA. METHODS: A 42-year-old renal transplant recipient developed a small subcapsular allograft RCC at 11 years after transplantation. The decline in glomerular filtration rare prompted us to preserve as much parenchyma as possible. Ultrasound-guided RFA was performed under light sedation and local analgesia in a single session with a Starbust Talon needle. RESULTS: Postablation contrast-enhanced ultrasound displayed a 25×23 mm avascular area of complete necrosis. After 3 months gadolinium-enhanced magnetic resonance imaging confirmed the absence of viable tumor tissue and while the patient did not experience any graft function reduction (serum creatinine 2.6 mg/dL). CONCLUSIONS: Image-guided RFA represents a promising therapeutic modality for small allograft RCCs in recipients with mild graft dysfunction and/or elevated surgical risk. It is associated with low morbidity and parenchymal preservation.
Asunto(s)
Carcinoma de Células Renales/cirugía , Ablación por Catéter , Neoplasias Renales/cirugía , Trasplante de Riñón/efectos adversos , Ultrasonografía Intervencional , Adulto , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/etiología , Humanos , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/etiología , Masculino , Factores de Tiempo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
The Authors according to their previous experience, report on the possibility of thoracic surgery in patients older than 70 with lung cancer. Fourty-seven patients older than 70 have been operated in the period 1984-1988 for lung cancer. The Authors performed 34 lobectomy, 11 pneumonectomy, and 4 wedge resection. The mortality rate was 4.25% (2 patients). Thirty-four patients are still living (follow-up range 12-60 months). Ten patients died. The Authors report a diagnostic and therapeutic guideline for this kind of pathology.
Asunto(s)
Neoplasias Pulmonares/cirugía , Neumonectomía/mortalidad , Toracotomía/mortalidad , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , MasculinoRESUMEN
The effects of continuous versus bolus administration of ranitidine on gastric pH were compared in critically ill patients admitted to our intensive care unit. Patients were randomized to receive 0.2 mg/kg/hr ranitidine in continuous infusion or 50 mg in bolus every 4 hr. The pH was monitored throughout a 24-hr period, 2 hr in basal conditions and 22 hr during treatment, with a gastric probe. Basal gastric pH was 2.1 +/- 0.2 in the infused and 2.4 +/- 0.2 in the bolus group (P greater than 0.05). The hydrogen ion concentrations were 25.1 +/- 8 and 20.0 +/- 7 mmol/liter, respectively (P greater than 0.05). After ranitidine administration, mean pH was 6.3 +/- 0.6 in patients treated by infusion and 4.5 +/- 0.5 (P less than 0.001) in those who received the drug in bolus; hydrogen ion concentration was 2.5 +/- 2 and 6.9 +/- 6, respectively, (P less than 0.001). Percent of inhibition of acid secretion was 90% in the infused and 68% in the bolus group. Infusion raised pH to values constantly above 4, whereas bolus administration resulted in wide fluctuations. These data indicate that continuous infusion of ranitidine is superior to bolus administration in controlling gastric acidity in critically ill patients.