RESUMEN
INTRODUCTION: There is a national drive to increase allied health professions simulation training. However, there is a paucity of literature within diagnostic radiography in relation to clinical simulation. No research could be found regarding the impact of simulation in radiography with complex clinical burns scenarios. This research aims to explore the perceptions of radiography undergraduate students regarding their preparedness for the complex care requirements in imaging examinations of clinical burns cases using a mixed methods approach. METHOD: A small-scale simulation-based teaching session was developed in a Scottish HEI, using role play and moulage to create realism. Twenty-eight undergraduate student radiographers participated in the scenario. Students completed pre and post-scenario questionnaires using Likert scale and free response data. Focus groups were undertaken three months after the simulation to obtain rich qualitative data. Common themes were identified via a process of initial coding and a 6-phase thematic analysis. RESULTS: Thematic analysis demonstrated a marked increased perception of preparedness post-scenario; students felt more prepared to undertake their role in the imaging of complex care patients (Likert scoring increased with both mode and median post-scenario). Common themes that were identified were patient centeredness, realism and learning. CONCLUSION: Within this limited pilot project, the use of simulation was an effective means of preparing students to understand their role within the complex care setting (with respect to the traumatic realism of burns) in preparedness for professional practice. Additionally, students related to the practical understanding of the complexity of human factors that exist within clinical practice.
Asunto(s)
Educación de Pregrado en Medicina/métodos , Modelos Anatómicos , Radiología/educación , Entrenamiento Simulado/métodos , Actitud del Personal de Salud , Quemaduras/diagnóstico por imagen , Humanos , Percepción , Estudiantes de Medicina/psicología , Encuestas y CuestionariosRESUMEN
Early loss of CB1 receptors is a hallmark of human Huntington's disease. Data from rodent studies suggest that preservation and activation of CB1 receptors may be protective against disease progression. R6/1 transgenic mice are considered to be a model of early pathogenic changes in Huntington's disease. We have shown previously that levels of CB1 in R6/1 mice prior to the onset of motor symptoms (12 weeks of age) remain high enough to justify commencement of cannabinoid drug treatment. Eight weeks of daily treatment with the cannabinoid agonists HU210 (0.01 mg/kg) and Delta(9)-tetrahydrocannabinol (THC, 10.00 mg/kg), or the inhibitor of endocannabinoid metabolism URB597 (0.30 mg/kg), did not alter the progressive deterioration of performance observed in motor behavioural testing. HU210-treated R6/1 mice experienced a significant increase in seizure events suggesting that this therapy may lower the seizure threshold and cautioning against highly efficacious agonists as potential therapy in this disease. Molecular characterisation of brains at the end of the study showed that there were no significant effects of HU210 or THC treatment on the ligand binding of cannabinoid CB1, dopamine D1, D2, serotonin 5HT2A or GABA(A) receptors, nor CB1 or fatty acid amide hydrolase (FAAH) mRNA expression in R6/1 mice. Intriguingly, a significant increase in the number of ubiquitinated aggregates was observed in the striatum with HU210 treatment, indicating an influence of CB1 on the disease process. Chronic URB597 treatment preserved CB1 receptors in the R6/1 striatum, suggesting that the manipulation of endocannabinoid levels warrants further exploration.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cannabinoides/administración & dosificación , Modelos Animales de Enfermedad , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/psicología , Aprendizaje por Laberinto/fisiología , Animales , Conducta Animal/fisiología , Estudios de Cohortes , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dronabinol/administración & dosificación , Dronabinol/análogos & derivados , Esquema de Medicación , Enfermedad de Huntington/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Distribución Aleatoria , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/biosíntesis , Receptor Cannabinoide CB1/genética , Resultado del TratamientoRESUMEN
Huntington's disease (HD) is an inherited neurodegenerative disease characterised by cell dysfunction and death in the basal ganglia and cortex. Currently there are no effective pharmacological treatments available. Loss of cannabinoid CB1 receptor ligand binding in key brain regions is detected early in HD in human postmortem tissue [Glass M, Dragunow M, Faull RL (2000) The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. Neuroscience 97:505-519]. In HD transgenic mice environmental enrichment upregulates the CB1 receptors and slows disease progression [Glass M, van Dellen A, Blakemore C, Hannan AJ, Faull RL (2004) Delayed onset of Huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors. Neuroscience 123:207-212]. These findings, combined with data from lesion studies have led to the suggestion that activation of cannabinoid receptors may be protective. However, studies suggest that CB1 mRNA may be decreased early in the disease progression in HD mice, making this a poor drug target. We have therefore performed a detailed analysis of CB1 receptor ligand binding, protein, gene expression and levels of endocannabinoids just prior to motor symptom onset (12 weeks of age) in R6/1 transgenic mice. We demonstrate that R6/1 mice exhibit a 27% decrease in CB1 mRNA in the striatum compared to wild type (WT). Total protein levels, determined by immunohistochemistry, are not significantly different to WT in the striatum or globus pallidus, but are significantly decreased by 19% in the substantia nigra. CB1 receptor ligand binding demonstrates significant but small decreases (<20%) in all basal ganglia regions evaluated. The levels of the endocannabinoid 2-arachidonoyl glycerol are significantly increased in the cortex (147%) while anandamide is significantly decreased in the hippocampus to 67% of WT. Decreases are also apparent in the ligand binding of neuronal D1 and D2 dopamine receptors co-located with CB1, while there is no change in GABA(A) receptor ligand binding. These results suggest that in this R6/1 mouse colony at 12 weeks there are only very small changes in CB1 protein and receptors and thus this would be an appropriate time point to evaluate therapeutic interventions.
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Encéfalo/metabolismo , Moduladores de Receptores de Cannabinoides/metabolismo , Endocannabinoides , Enfermedad de Huntington/metabolismo , Receptor Cannabinoide CB1/metabolismo , Animales , Ácidos Araquidónicos/metabolismo , Unión Competitiva/efectos de los fármacos , Unión Competitiva/fisiología , Encéfalo/patología , Encéfalo/fisiopatología , Cannabinoides/farmacología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Regulación hacia Abajo/fisiología , Discinesias/etiología , Discinesias/metabolismo , Discinesias/fisiopatología , Glicéridos/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiopatología , Enfermedad de Huntington/patología , Enfermedad de Huntington/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Alcamidas Poliinsaturadas/metabolismo , ARN Mensajero/metabolismo , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB1/genética , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/metabolismo , Sustancia Negra/metabolismo , Sustancia Negra/fisiopatologíaRESUMEN
Usnic acid is a component of nutritional supplements promoted for weight loss that have been associated with liver-related adverse events including mild hepatic toxicity, chemical hepatitis, and liver failure requiring transplant. To determine if metabolism factors might have had a role in defining individual susceptibility to hepatotoxicity, in vitro metabolism studies were undertaken using human plasma, hepatocytes, and liver subcellular fractions. Usnic acid was metabolized to form three monohydroxylated metabolites and two regio-isomeric glucuronide conjugates of the parent drug. Oxidative metabolism was mainly by cytochrome P450 (CYP) 1A2 and glucuronidation was carried out by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A3. In human hepatocytes, usnic acid at 20 microM was not an inducer of CYP1A2, CYP2B6, or CYP3A4 relative to positive controls omeprazole, phenobarbital, and rifampicin, respectively. Usnic acid was a relatively weak inhibitor of CYP2D6 and a potent inhibitor of CYP2C19 (the concentration eliciting 50% inhibition (IC(50)) = 9 nM) and CYP2C9 (IC(50) = 94 nM), with less potent inhibition of CYP2C8 (IC(50) = 1.9 microM) and CYP2C18 (IC(50) = 6.3 microM). Pre-incubation of microsomes with usnic acid did not afford any evidence of time-dependent inhibition of CYP2C19, although evidence of slight time-dependent inhibition of CYP2C9 (K(I) = 2.79 microM and K(inact) = 0.022 min(-1)) was obtained. In vitro data were used with SimCYP(R)to model potential drug interactions. Based on usnic acid doses in case reports of 450 mg to >1 g day(-1), these in vitro data indicate that usnic acid has significant potential to interact with other medications. Individual characteristics such as CYP1A induction status, co-administration of CYP1A2 inhibitors, UGT1A1 polymorphisms, and related hyperbilirubinaemias, or co-administration of low therapeutic index CYP2C substrates could work alone or in consort with other idiosyncrasy risk factors to increase the risk of adverse events and/or hepatotoxicity. Thus, usnic acid in nutritional supplements might be involved as both victim and/or perpetrator in clinically significant drug-drug interactions.
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Benzofuranos/efectos adversos , Benzofuranos/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas , Suplementos Dietéticos/efectos adversos , Benzofuranos/química , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/biosíntesis , Interacciones Farmacológicas , Inducción Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Cinética , Hepatopatías/enzimología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Moleculares , Unión Proteica/efectos de los fármacos , Factores de Riesgo , Especificidad por Sustrato/efectos de los fármacosRESUMEN
Huntington's disease is a fatal neurodegenerative disorder caused by a mutation of the huntingtin gene and involves progressive motor abnormalities (including chorea), cognitive deficits (dementia) as well as psychiatric symptoms. We have previously demonstrated that environmental enrichment slows the onset and progression of Huntington's disease in transgenic mice. Here, we investigated the effects of enhanced physical exercise on disease progression and brain-derived neurotrophic factor expression. Standard-housed Huntington's disease mice developed phenotypic rear-paw clasping by 16 weeks of age, displayed abnormal rearing behavior, deficits in motor co-ordination and of spatial working memory. Huntington's disease mice with access to running wheels exhibited delayed onset of rear-paw clasping, normalized levels of rearing behavior and amelioration of the cognitive deficits. However, in contrast to our previous environmental enrichment studies, there was no rescue of motor coordination deficits in wheel-running Huntington's disease mice. An abnormal accumulation of brain-derived neurotrophic factor protein in the frontal cortex of Huntington's disease mice was unaffected by running. Striatal and hippocampal brain-derived neurotrophic factor protein levels were unchanged. Brain-derived neurotrophic factor mRNA levels were reduced in the anterior cortex, striatum and hippocampus of Huntington's disease mice, and only striatal deficits were ameliorated by running. Overall, we show that voluntary physical exercise delays the onset of Huntington's disease and the decline in cognitive ability. In addition, our results reveal that some aspects of hippocampal dependent memory are not entirely reliant on sustained hippocampal brain-derived neurotrophic factor expression.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/deficiencia , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/rehabilitación , Condicionamiento Físico Animal/métodos , Factores de Edad , Análisis de Varianza , Animales , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/genética , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica/genética , Proteína Huntingtina , Enfermedad de Huntington/genética , Enfermedad de Huntington/fisiopatología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Desempeño Psicomotor/fisiología , ARN Mensajero/metabolismo , Tiempo de Reacción/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Carrera/fisiología , Factores de TiempoAsunto(s)
Acúfeno/terapia , Terapia por Acupuntura/métodos , Anestésicos Locales/uso terapéutico , Biorretroalimentación Psicológica , Ginkgo biloba , Historia del Siglo XVI , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Lidocaína/uso terapéutico , Fitoterapia/métodosRESUMEN
The role of urokinase plasminogen activator (uPA) in osteosarcoma is poorly understood. We examined the importance of uPA, its receptor, uPAR, and its inhibitor, PAI-1, in our in vivo model of metastatic osteosarcoma. Rodent osteosarcoma cells (UMR 106-01) were inoculated into the tibia of athymic mice. Animals were sacrificed and autopsied at 4 days to 5 weeks after inoculation. Tibiae and lungs were excised, fixed, and examined histologically and by in situ hybridization. Osteosarcoma development was associated with tibial swelling and lameness, and radiographic changes included osteolysis and new bone formation. Lung metastases developed spontaneously. In the tibial tumors, uPAR mRNA was expressed early (4 days), whereas uPA and PAI-1 mRNA increased as the tumor invaded the surrounding tissue (3 weeks). There was also an increase in the mRNA expression of the osteoblast-related genes, alpha1(I) procollagen and osteopontin, but not matrix Gla protein. Lung metastases also expressed mRNA for the uPA system and the bone-related proteins. We have produced a model of metastatic osteosarcoma, which typifies the characteristics of the human tumor. Our results suggest that the uPA system plays a role in the local aggressiveness and metastasis of osteosarcoma and, in particular, indicates a possible therapeutic role for uPAR antagonists in the treatment of osteosarcoma.
Asunto(s)
Modelos Animales de Enfermedad , Neoplasias Experimentales , Osteosarcoma/metabolismo , Osteosarcoma/patología , Receptores de Superficie Celular/biosíntesis , Animales , Progresión de la Enfermedad , Femenino , Hibridación in Situ , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , ARN Mensajero/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Tibia/patología , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
BACKGROUND AND AIMS: Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) is a critical enzyme in the elimination of bilirubin and it also plays a role in the metabolism of bile acids. The aim of this study was to determine whether bilirubin and bile acids could modulate their own metabolism by regulating UGT levels in cultured rat hepatocytes. METHODS AND RESULTS: Incubation of hepatocytes with bilirubin (48 micromol/L) for 24 h significantly increased the mRNA expression of UGT1A1 and UGT1A5, two UGT isoforms responsible for the conjugation of bilirubin. The induction of UGT1A1 and UGT1A5 by bilirubin was concentration and time dependent. Treatment with chenodeoxycholic acid, cholic acid, deoxycholic acid, hyodeoxycholic acid and lithocholic acid at a concentration of 100 micromol/L for 48 h significantly enhanced the mRNA expression of UGT2B1, a UGT isoform responsible for the glucuronidation of bile acids. The UGT2B3 mRNA level was also increased by hyodeoxycholic acid. The regulation of UGT2B1 mRNA by chenodeoxycholic acid and hyodeoxycholic acid was dose and time dependent. CONCLUSION: Our results suggest that bilirubin and bile acids can induce UGT expression and as a result, these compounds may modulate their own metabolism. Such regulation could play a compensatory role in the pathological increased concentrations of these compounds in some hepatobiliary diseases.
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Ácidos y Sales Biliares/metabolismo , Bilirrubina/metabolismo , Glucuronosiltransferasa/metabolismo , Hepatocitos/metabolismo , ARN Mensajero/metabolismo , Uridina Difosfato/metabolismo , Animales , Ácidos y Sales Biliares/farmacología , Bilirrubina/farmacología , Northern Blotting , Células Cultivadas , Ácido Clofíbrico/farmacología , Relación Dosis-Respuesta a Droga , Hepatocitos/enzimología , Isoenzimas/metabolismo , Masculino , Metilcolantreno/farmacología , Ratas , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
The interactions between alcohol and cytochrome P-450 enzymes have been well investigated. However, the data regarding the effect of alcohol on the regulation of UDP-glucuronosyltranferase (UGT) activity are less clear. The aim of the present study was to determine the role of alcohol in the regulation of UGT mRNA expression by using whole animal and primary cultured hepatocytes. Chronic ethanol feeding of rats significantly increased the expression of liver UGT1A1 mRNA to 177% of control. The mRNA levels for UGT1A5, UGT2B1 and UGT2B3 were also enhanced, but did not reach statistical significance. In cultured hepatocytes, treatment with either ethanol or isopentanol significantly increased the expression of UGT1A1, UGT1A5, UGT2B1, and UGT2B3 mRNAs, but to different degrees. The induction of UGT1A1 and UGT2B1 mRNAs by ethanol or isopentanol was time-dependent and maximal changes occurred at 48 h. The expression of UGT1A6 mRNA was not significantly modified by either ethanol or isopentanol. In conclusion, ethanol and isopentanol have direct roles in the regulation of UGT.
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Etanol/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucuronosiltransferasa/genética , Isoenzimas/genética , Hígado/enzimología , Pentanoles/farmacología , Animales , Células Cultivadas , Hígado/citología , Masculino , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
PURPOSE: To investigate the direct effects of sex hormones, growth hormone, thyroid hormones and dexamethasone on the regulation of UDP-glucuronosyltransferase (UGT). METHODS: Rat hepatocytes were cultured on matrigel and treated with various hormones. Northern blot analysis was carried out using cDNA probes to family 1 and family 2 isoforms. RESULTS: Treatment with 10(-5) M testosterone increased the mRNA levels of UGT 2B1 by 29% and UGT2B3 by 32%. Incubation of growth hormone (10 mU) with hepatocytes suppressed the expression of UGT2B1 and UGT2B3 by 17% and 38%, respectively. T3 administration resulted in a time and dose-dependent effect on the expression of UGT 1 isoforms, with increased UGT1A6 by 70%, and decreased UGT1A1 by 38% and UGT1A5 by 35%. All UGT isoforms except UGT 1A6 studied in this assay were up-regulated by dexamethasone, but to different degrees. The regulation of UGT1A1 and UGT2B1 by dexamethasone was dose and time dependent, and the induction of dexamethasone in the expression of UGT1A1 and UGT2B1 was blocked by cycloheximide but not dichloro-1-D-ribofuranosylbenzimidazole. CONCLUSIONS: This study demonstrates that multiple hormones take part in the regulation of UGT mRNA expression in the rat and individual genes can be differentially modulated.
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Glucuronosiltransferasa/biosíntesis , Hormonas/farmacología , Isoenzimas/biosíntesis , Hígado/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Células Cultivadas , Dexametasona/farmacología , Glucuronosiltransferasa/metabolismo , Hormonas Esteroides Gonadales/farmacología , Hormona del Crecimiento/farmacología , Hígado/citología , Hígado/enzimología , Masculino , Ratas , Ratas Sprague-Dawley , Hormonas Tiroideas/farmacologíaRESUMEN
Human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase (PDE5A) cDNAs were isolated. A 3.1-kb composite DNA sequence assembled from overlapping cDNAs encodes an 875-amino-acid protein with a predicted molecular mass of 100012 Da (PDE5A1). Extracts prepared from yeast expressing human PDE5A1 hydrolyzed cGMP. This activity was inhibited by the selective PDE5 inhibitors zaprinast and DMPPO. PDE5A mRNA is expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle and pancreas and, to a much lesser extent, in brain, liver and lung. A 5'-splice variant, PDE5A2, encodes an 833-amino-acid protein with eight unique amino acids at the amino terminus. PDE5A maps to chromosome 4q 25-27.
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3',5'-GMP Cíclico Fosfodiesterasas/genética , ADN Complementario/genética , ADN Complementario/aislamiento & purificación , 3',5'-GMP Cíclico Fosfodiesterasas/metabolismo , Empalme Alternativo/genética , Secuencia de Aminoácidos , Animales , Aorta/química , Aorta/citología , Aorta/metabolismo , Secuencia de Bases , Northern Blotting , Bovinos , Mapeo Cromosómico , Cromosomas Humanos Par 4/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , ADN Complementario/química , Expresión Génica/genética , Variación Genética/genética , Humanos , Datos de Secuencia Molecular , Músculo Liso/química , Músculo Liso/citología , Músculo Liso/metabolismo , ARN Mensajero/análisis , ARN Mensajero/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Homología de Secuencia de AminoácidoAsunto(s)
Ética Médica , Sistemas Prepagos de Salud , Atención a la Salud/normas , Humanos , Estados UnidosRESUMEN
Numerous studies have elucidated the benefits of endoscopy before surgery for carcinoma of the colon and rectum. In patients with known colon cancer, the incidence of synchronous colon cancers is 1.5 to 7.6 per cent and synchronous colon polyps is 25 to 40 per cent. Standard barium contrast studies are inferior to endoscopic examination in detecting these synchronous lesions. Endoscopy has been shown to alter the planned surgical procedure in 11 to 13 per cent of patients with colorectal cancer. Nevertheless, some authors avoid preoperative endoscopy because of concern that neoplastic cells may be seeded throughout the colon during the examination. They fear that manipulation of the tumor may promote hematogenous or lymphatic spread. Our study seeks to demonstrate whether this concern is valid by comparing rates of local recurrence, distant metastases, and survival between patients who have undergone preoperative endoscopy with those who have not.
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Colonoscopía , Neoplasias Colorrectales/cirugía , Neoplasias Primarias Múltiples , Adulto , Anciano , Sulfato de Bario , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/prevención & control , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/prevención & control , Recurrencia Local de Neoplasia/prevención & control , Cuidados PreoperatoriosRESUMEN
Despite extensive preoperative staging, unresectability of a bronchogenic carcinoma may not be known until an exploratory thoracotomy is done. Failures in anatomic staging occur because of inability to detect local extent of hilar lesions and inability to detect small deposits of metastatic disease. At the University of South Carolina, nine of 75 patients who underwent thoracotomies were found to be unresectable. Using an extensive staging protocol, the "back out" thoracotomy rate can be reduced to a minimum whereas no patient is denied a chance for surgical cure.