RESUMEN
BACKGROUND: This study evaluated the use of prophylactic dressings (silicone foam, silicone tape, hydrocolloid) under N95/P2 respirators to determine which dressings fit successfully. AIM: The aim was to develop a health service protocol for one state in Australia. METHODS: Data were collected during August and September 2021 as part of the Respiratory Protection Programme on 600 health workers using three types of prophylactic dressings. Five different types of respirators were used. Participant healthcare workers rated comfort on a four-point Likert scale. RESULTS: Successful fit was achieved by 63.6% of the respirator-dressing combinations. The best-performing respirator-dressing combination was the Trident® respirator with dressing Mepilex® Lite silicone foam (90.2% pass rate). High pass rates were found in the Trident® respirator with Mepilex® Border Lite with SofSicure silicone tape (79.1%); the 3M™ 1860 respirator with Mepilex® Border Lite with SofSicure silicone tape (74%); and the BSN orange duckbill respirator with Mepilex® Lite silicone foam (69.8%). The poorest-performing combination was the BYD™ respirator with Mepilex® Border Lite with SofSicure silicone tape (25.9% pass rate). Uncorrected chi-squared tests for association revealed significant associations between dressing type and outcome (P=0.004) and respirator type and outcome (P<0.001). Most respondents (82%) found the dressing combination markedly comfortable. CONCLUSIONS: When using prophylactic dressings under N95/P2 respirators, it is necessary to perform a fit test. In this study Trident® respirators had the highest probability of successful fit, while BYD™ respirators had the lowest. Combining Trident® respirators with Mepilex® Lite dressing was optimal. Most participants reported greater comfort with the dressings under the respirators.
Asunto(s)
Exposición Profesional , Dispositivos de Protección Respiratoria , Vendajes , Personal de Salud , Servicios de Salud , Humanos , Exposición Profesional/prevención & control , Siliconas , Ventiladores MecánicosRESUMEN
INTRODUCTION: First, this study aimed to assess the prognostic value of different definitions for resection margin status on disease-free survival (DFS) and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC). Second, preoperative predictors of direct margin involvement were identified. MATERIALS AND METHODS: This nationwide observational cohort study included all patients who underwent upfront PDAC resection (2014-2016), as registered in the prospective Dutch Pancreatic Cancer Audit. Patients were subdivided into three groups: R0 (≥1 mm margin clearance), R1 (<1 mm margin clearance) or R1 (direct margin involvement). Survival was compared using multivariable Cox regression analysis. Logistic regression with baseline variables was performed to identify preoperative predictors of R1 (direct). RESULTS: 595 patients with a median OS of 18 months (IQR 10-32 months) months were analysed. R0 (≥1 mm) was achieved in 277 patients (47%), R1 (<1 mm) in 146 patients (24%) and R1 (direct) in 172 patients (29%). R1 (direct) was associated with a worse OS, as compared with both R0 (≥1 mm) (hazard ratio (HR) 1.35 [95% and confidence interval (CI) 1.08-1.70); P < 0.01) and R1 (<1 mm) (HR 1.29 [95%CI 1.01-1.67]; P < 0.05). No OS difference was found between R0 (≥1 mm) and R1 (<1 mm) (HR 1.05 [95% CI 0.82-1.34]; P = 0.71). Preoperative predictors associated with an increased risk of R1 (direct) included age, male sex, performance score 2-4, and venous or arterial tumour involvement. CONCLUSION: Resection margin clearance of <1 mm, but without direct margin involvement, does not affect survival, as compared with a margin clearance of ≥1 mm. Given that any vascular tumour involvement on preoperative imaging was associated with an increased risk of R1 (direct) resection with upfront surgery, neoadjuvant therapy might be considered in these patients.
Asunto(s)
Carcinoma Ductal Pancreático/cirugía , Márgenes de Escisión , Neoplasias Pancreáticas/cirugía , Anciano , Carcinoma Ductal Pancreático/patología , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Países Bajos , Neoplasias Pancreáticas/patología , Pronóstico , Modelos de Riesgos Proporcionales , Tasa de SupervivenciaRESUMEN
BACKGROUND: Research in postoperative mortality is scarce. Insight into mortality and cause of death might improve and innovate perioperative care. The objective for this study was to report the 24-hour and 30-day overall, and surgery and anaesthesia-related, in-hospital mortality at a tertiary paediatric hospital. METHODS: All patients <18 yr old who underwent anaesthesia with or without surgery between January 1, 2006, and December 31, 2012, at the Wilhelmina Children's Hospital, Utrecht, The Netherlands, were included in this retrospective cohort study. Causes of death within 30 days were identified and tabulated into four major categories according to principal cause. RESULTS: A total of 45,182 anaesthetics were administered during this 7-yr period. The all-cause 24-hour hospital mortality was 13.1 per 10,000 anaesthetics (95% CI: 9.9-16.8) and the all-cause 30-day in-hospital mortality was 41.6 per 10,000 anaesthetics (95% CI: 35.9-48.0). In total five patients were partially contributable to anaesthesia (30-day mortality: 1.1/10,000, 95% CI: 0.4-2.6) and four patients were partially contributable to surgery (30-day mortality: 0.9/10,000, 95% CI: 0.2-2.3). Mortality was higher in neonates and infants, children with ASA physical status III and IV, and emergency- and cardiothoracic surgery. CONCLUSIONS: Neonates and infants, children with ASA physical status III or poorer, and emergency- and cardiothoracic surgery are associated with a higher postoperative mortality. Anaesthesia- or surgery-related complications contribute to mortality in only a small amount of the deaths, indicating the relative safety of paediatric surgical and anaesthetic procedures.
Asunto(s)
Anestesia/estadística & datos numéricos , Mortalidad Hospitalaria , Hospitales Pediátricos/estadística & datos numéricos , Periodo Perioperatorio/estadística & datos numéricos , Centros de Atención Terciaria/estadística & datos numéricos , Adolescente , Factores de Edad , Anestesia/efectos adversos , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Países Bajos , Estudios RetrospectivosRESUMEN
Glucocorticoids (GCs) secreted after stress reduce adult hippocampal neurogenesis, a process that has been implicated in cognitive aspects of psychopathology, amongst others. Yet, the exact role of the GC receptor (GR), a key mediator of GC action, in regulating adult neurogenesis is largely unknown. Here, we show that GR knockdown, selectively in newborn cells of the hippocampal neurogenic niche, accelerates their neuronal differentiation and migration. Strikingly, GR knockdown induced ectopic positioning of a subset of the new granule cells, altered their dendritic complexity and increased their number of mature dendritic spines and mossy fiber boutons. Consistent with the increase in synaptic contacts, cells with GR knockdown exhibit increased basal excitability parallel to impaired contextual freezing during fear conditioning. Together, our data demonstrate a key role for the GR in newborn hippocampal cells in mediating their synaptic connectivity and structural as well as functional integration into mature hippocampal circuits involved in fear memory consolidation.
Asunto(s)
Hipocampo/citología , Motivación/genética , Neurogénesis/genética , Neuronas/fisiología , Receptores de Glucocorticoides/deficiencia , Animales , Movimiento Celular/genética , Condicionamiento Clásico/fisiología , Corticosterona/metabolismo , Dendritas/metabolismo , Dendritas/ultraestructura , Espinas Dendríticas/metabolismo , Espinas Dendríticas/ultraestructura , Miedo , Vectores Genéticos/fisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Técnicas In Vitro , Trastornos de la Memoria/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Neuronas/ultraestructura , Terminales Presinápticos/metabolismo , ARN Interferente Pequeño/metabolismo , RadioinmunoensayoRESUMEN
BACKGROUND: Because deep hypothermic circulatory arrest (DHCA) carries a risk for neurological damage, antegrade cerebral perfusion (ACP) is used increasingly for aortic arch surgery in infants. We assessed the short-term effects of minimal DHCA (< 30 minutes) versus prolonged DHCA (> 30 minutes) during biventricular aortic arch reconstruction. METHODS: Twenty-six infants (< 3 months of age) who had undergone aortic arch reconstruction were retrospectively analyzed: 15 infants without DHCA (group A) and 11 infants with DHCA (group B). Group B was further divided into < 30 minutes DHCA (group B1, n = 6), and >or= 30 minutes DHCA (group B2, n = 5). Additionally, minimal DHCA (group A + B1) was compared to prolonged DHCA (group B2). RESULTS: In the minimal DHCA group (A + B1), 29 % of the patients had a postoperative adverse event, compared to 80 % in the prolonged DHCA group (B2) ( P < 0.05). Average length of stay in hospital was 25 days shorter for the minimal DHCA group (15 days versus 40 days, P < 0.01). CONCLUSION: Minimal DHCA results in fewer adverse events and a reduced length of stay, compared with prolonged DHCA. Therefore, during aortic arch surgery in infants, DHCA should be minimized by using antegrade cerebral perfusion.
Asunto(s)
Aorta Torácica/cirugía , Paro Circulatorio Inducido por Hipotermia Profunda/efectos adversos , Tiempo de Internación , Perfusión/métodos , Complicaciones Posoperatorias/prevención & control , Circulación Cerebrovascular , Femenino , Humanos , Recién Nacido , Masculino , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Stimulation of the PC12 pheochromocytoma cell line with the prototypical neurotrophin Nerve Growth Factor (NGF) induces a cellular response of neuronal differentiation and is therefore a widely used model to gain molecular insight into this process. Classically, the transcriptional response to extracellular stimuli such as NGF is divided in genes that require no protein synthesis prior to their induction (immediate-early genes) and genes that do (delayed-response genes). Because an increasing number of studies have reported important roles for immediate-early genes (IEGs) in neuronal differentiation, the goal of the present study was to identify previously unrecognized NGF-responsive IEGs. Stimulation with NGF for 15, 30, 60 and 120 min resulted in a typical transient induction of many known NGF-responsive IEGs. To identify candidate new genes, we analyzed 27000 measured expression profiles and selected 10 genes for further study. Five genes, including Cbp/p300-interacting transactivator 2 (Cited2), Kruppel-like factor 4 (Klf4), v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein F (Maff), Kruppel-like factor 10 (Klf10 or Tieg) and Activating transcription factor 3 (Atf3) were selected and positively validated by qPCR. NGF-induced activation of all five genes seems to be mediated by MAPK and PI3K-mediated pathways. Additionally, we tested translation-independent induction and showed that NGF induced upregulation of these genes in both the subclonal Neuroscreen-1 PC12 and parental PC12 cell line. These 5 transcription factors have not been previously reported as NGF-responsive IEGs, however have previously been reported as important regulators of cell differentiation and proliferation in different systems. These observations may therefore provide important new information on the molecular mechanisms underlying NGF-induced differentiation.
Asunto(s)
Genes Inmediatos-Precoces/fisiología , Factor de Crecimiento Nervioso/metabolismo , Neuronas/metabolismo , Factor de Transcripción Activador 3/biosíntesis , Factor de Transcripción Activador 3/genética , Análisis de Varianza , Animales , Western Blotting , Células Cultivadas , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Análisis por Micromatrices , Factor de Crecimiento Nervioso/genética , Proteína Oncogénica v-maf/genética , Células PC12 , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas c-fos/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Factores de Transcripción/genéticaRESUMEN
We describe a successful cardiac intervention in an infant, born at 32 weeks of gestation, with a birth weight of 1040 g, who had a critical pulmonary valve stenosis with the right ventricular pressure twice the systemic pressure. Continuous prostaglandin E infusion kept the arterial duct open and at the age of four weeks and a weight of 1500 g a balloon valvuloplasty was performed, which reduced the systolic right ventricular pressure to below the systemic pressure. Two weeks later the procedure was repeated because of increasing right ventricular pressure. At two months of age the mean systolic transpulmonary Doppler gradient was 30 mmHg with an adequate right ventricular volume. The neurological status of the infant was normal and the femoral vein was patent. Timely interventional heart catheterisation is a successful method of treatment in critical pulmonary valve stenosis in infants with a low birth weight. (Neth Heart J 2008;16:264-6.).
RESUMEN
BACKGROUND: Adipose tissue contains a stromal vascular fraction that can be easily isolated and provides a rich source of adipose tissue-derived mesenchymal stem cells (ASC). These ASC are a potential source of cells for tissue engineering. We studied whether the yield and growth characteristics of ASC were affected by the type of surgical procedure used for adipose tissue harvesting, i.e. resection, tumescent liposuction and ultrasound-assisted liposuction. METHODS: Frequencies of ASC in the stromal vascular fraction were assessed in limiting dilution assays. The phenotypical marker profile of ASC was determined, using flow cytometry, and growth kinetics were investigated in culture. ASC were cultured under chondrogenic and osteogenic conditions to confirm their differentiation potential. RESULTS: The number of viable cells in the stromal vascular fraction was affected by neither the type of surgical procedure nor the anatomical site of the body from where the adipose tissue was harvested. After all three surgical procedures, cultured ASC did express a CD34+ CD31- CD105+ CD166+ CD45- CD90+ ASC phenotype. However, ultrasound-assisted liposuction resulted in a lower frequency of proliferating ASC, as well as a longer population doubling time of ASC, compared with resection. ASC demonstrated chondrogenic and osteogenic differentiation potential. DISCUSSION: We conclude that yield and growth characteristics of ASC are affected by the type of surgical procedure used for adipose tissue harvesting. Resection and tumescent liposuction seem to be preferable above ultrasound-assisted liposuction for tissue-engineering purposes.
Asunto(s)
Tejido Adiposo/citología , Proliferación Celular , Células Madre Mesenquimatosas/citología , Recolección de Tejidos y Órganos/métodos , Adipocitos/citología , Adipocitos/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Diferenciación Celular/fisiología , Supervivencia Celular/fisiología , Células Cultivadas , Niño , Condrogénesis/fisiología , Femenino , Expresión Génica , Humanos , Masculino , Células Madre Mesenquimatosas/metabolismo , Persona de Mediana Edad , Osteogénesis/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ingeniería de TejidosRESUMEN
Assessment of immunoglobulin A (IgA) antibody responses to various Epstein-Barr virus (EBV) antigen complexes, usually involving multiple serological assays, is important for the early diagnosis of nasopharyngeal carcinoma (NPC). Through combination of two synthetic peptides representing immunodominant epitopes of EBNA1 and viral capsid antigen (VCA)-p18 we developed a one-step sandwich enzyme-linked immunosorbent assay (ELISA) for the specific detection of EBV reactive IgG and IgA antibodies in NPC patients (EBV IgG/IgA ELISA). Sera were obtained from healthy donors (n = 367), non-NPC head and neck cancer patients (n = 43), and biopsy-proven NPC patients (n = 296) of Indonesian and Chinese origin. Higher values of optical density at 450 nm for EBV IgG were observed in NPC patients compared to the healthy EBV carriers, but the large overlap limits its use for NPC diagnosis. Using either EBNA1 or VCA-p18 peptides alone IgA ELISA correctly identified 88.5% and 79.8% of Indonesian NPC patients, with specificities of 80.1% and 70.9%, whereas combined single-well coating with both peptides yielded sensitivity and specificity values of 90.1 and 85.4%, respectively. The positive and negative predictive values (PPV and NPV, respectively) for the combined EBNA1 plus VCA EBV IgA ELISA were 78.7% and 93.9%, respectively. In the Indonesia panel, the level of EBV IgA reactivity was not associated with NPC tumor size, lymph node involvement, and metastasis stage, sex, and age group. In the China panel the sensitivity/specificity values were 86.2/92.0% (EBNA1 IgA) and 84.1/90.3% (VCA-p18 IgA) for single-peptide assays and 95.1/90.6% for the combined VCA plus EBNA1 IgA ELISA, with a PPV and an NPV for the combined EBV IgA ELISA of 95.6 and 89.3%, respectively. Virtually all NPC patients had abnormal anti-EBV IgG diversity patterns as determined by immunoblot analysis. On the other hand, healthy EBV carriers with positive EBV IgA ELISA result showed normal IgG diversity patterns. By using EBV IgG immunoblot diversity as confirmation assay for EBV IgA ELISA-positive samples, the sensitivity and specificity for NPC diagnosis increased to 98% and 99.2%, respectively, in the Indonesian NPC samples. The use of these combined methods for seroepidemiological screening studies is proposed.
Asunto(s)
Antígenos Virales/inmunología , Proteínas de la Cápside/inmunología , Proteínas Portadoras/inmunología , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Neoplasias Nasofaríngeas/inmunología , Neoplasias Nasofaríngeas/virología , Antígenos Virales/genética , Proteínas de la Cápside/genética , Proteínas Portadoras/genética , Ensayo de Inmunoadsorción Enzimática , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/inmunología , Humanos , Proteínas de Unión al ARNRESUMEN
The two structurally related nuclear receptor corepressor (N-CoR) and silencing mediator of retinoid and thyroid receptors (SMRT) proteins have been found to differentially affect the transcriptional activity of numerous nuclear receptors, such as thyroid hormone, retinoic acid and steroid receptors. Because of the numerous effects mediated by nuclear receptors in brain, it is of interest to extend these in vitro data and to explore the cellular distribution of both corepressors in brain tissue. We therefore examined, using in situ hybridisation, whether the relative abundance of these two functionally distinct corepressors differed in rat brain and pituitary. We find that although both N-CoR and SMRT transcripts are ubiquitously expressed in brain, striking differences in their respective levels of expression could be observed in discrete areas of brain stem, thalamus, hypothalamus and hippocampus. Using dual-label immunofluorescence, we examined in selected glucocorticoid sensitive areas involved in the regulation of the hypothalamus-pituitary-adrenal axis activity, the respective protein abundance of N-CoR and SMRT. Protein abundance was largely concurrent with the mRNA expression levels, with SMRT relatively more abundant in hypothalamus and brain stem areas. Colocalisation of N-CoR and SMRT was demonstrated by confocal microscopy in most areas studied. Taken together, these findings are consistent with the idea that the uneven neuroanatomical distribution of N-CoR and SMRT protein may contribute to the site-specific effects exerted by hormones, such as glucocorticoids, in the brain.
Asunto(s)
Mapeo Encefálico , Encéfalo/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Hipófisis/metabolismo , Proteínas Represoras/metabolismo , Animales , Proteínas de Unión al ADN/genética , Sistema Hipotálamo-Hipofisario/metabolismo , Hibridación in Situ , Masculino , Proteínas Nucleares/genética , Co-Represor 1 de Receptor Nuclear , Co-Represor 2 de Receptor Nuclear , Sistema Hipófiso-Suprarrenal/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Wistar , Proteínas Represoras/genética , Transducción de Señal/genética , Transducción de Señal/fisiología , Distribución Tisular , Transcripción Genética/genética , Transcripción Genética/fisiologíaRESUMEN
This study was designed to identify the role of a recently identified Ca(2+)/calmodulin-dependent protein kinase (CaMK)-like kinase (CaMKLK) in neuronal apoptosis. For this purpose, we studied proteolytic cleavage of CaMKLK by caspases in vitro and in neuronal NG108 cells. In addition, we have investigated the effect of overexpression of wild type and mutant CaMKLK proteins on staurosporine- and serum deprivation-induced apoptosis of NG108 cells. We found that CaMKLK is a substrate for caspase-3 and -8, both in vitro and in NG108 cells during staurosporine- and serum withdrawal-induced apoptosis. Substitution of an aspartic acid residue at position 62 in an asparagine residue within a putative caspase cleavage site completely blocked cleavage of CaMKLK, strongly indicating that (59)DEND(62) is the caspase recognition site. Overexpression of an Asp(62) --> Asn CaMKLK mutant protected NG108 cells from staurosporine-induced apoptosis to a similar extent as Bcl-x(L). In contrast, overexpression of wild type CaMKLK did not lead to protection. Moreover, microinjection of Asp(62) --> Asn CaMKLK protected NG108 cells from serum deprivation-induced apoptosis, while overexpression of a caspase-generated noncatalytic N-terminal CaMKLK fragment exacerbated apoptosis. Together, our data suggest that cleavage of CaMKLK and generation of the noncatalytic N-terminal domain of CaMKLK facilitate neuronal apoptosis.
Asunto(s)
Apoptosis , Proteínas Quinasas Dependientes de Calcio-Calmodulina/química , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Calcio/metabolismo , Calmodulina/metabolismo , Caspasas/metabolismo , Neuronas/metabolismo , Animales , Asparagina/química , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Sitios de Unión , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina , Caspasa 3 , Caspasa 8 , Caspasa 9 , Línea Celular , Células Cultivadas , Medio de Cultivo Libre de Suero/metabolismo , ADN/metabolismo , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Humanos , Inmunohistoquímica , Plásmidos/metabolismo , Pruebas de Precipitina , Unión Proteica , Estructura Terciaria de Proteína , Inhibidores de la Síntesis de la Proteína/farmacología , Conejos , Reticulocitos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estaurosporina/farmacología , Fracciones Subcelulares , Células Tumorales CultivadasRESUMEN
The alkylating agent methylmethanesulfonate (MMS) activates the c-jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and the p38 mitogen-activated protein kinase (p38MAPK) pathways via different mechanisms of action. Activation of p38MAPK by MMS involves the pp125 focal adhesion kinase-related tyrosine kinase RAFTK and the MAPK kinase 3. The way in which MMS can activate JNK/SAPK has not been elucidated. Here we describe the identification by differential display of human mitogen-activated gene-6 (MIG-6) as a novel MMS-inducible gene. Induction of MIG-6 by MMS was found in human diploid skin fibroblasts and in simian virus 40-transformed skin fibroblasts, indicating that the enhanced expression of MIG-6 after MMS-treatment did not require p53. The signal leading to activation of MIG-6 appeared to be independent of DNA damage. High MIG-6 expression was found in the liver, lung, and placenta. MIG-6 is an adapter protein that binds to the activated form of cdc42Hs and to 14-3-3 proteins, thereby activating JNK/SAPKs. Our results suggest that activation of JNK/SAPKs by MMS may involve the induction of MIG-6.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Alquilantes/farmacología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Metilmetanosulfonato/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Northern Blotting , Línea Celular , Línea Celular Transformada , Células Cultivadas , Daño del ADN , ADN Complementario/metabolismo , Diploidia , Activación Enzimática , Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Humanos , Hígado/metabolismo , Pulmón/metabolismo , Proteína Quinasa 8 Activada por Mitógenos , Placenta/metabolismo , Unión Proteica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Virus 40 de los Simios/metabolismo , Factores de Tiempo , Distribución Tisular , Proteínas Supresoras de Tumor , Rayos UltravioletaRESUMEN
UNLABELLED: Occupational exposure to polycyclic aromatic hydrocarbons (PAH) increases the risk of developing lung cancer. Human exposure is often demonstrated by increased internal levels of PAH metabolites and of markers for early biological effects, like DNA adducts and cytogenetic aberrations. OBJECTIVE: This study aimed to assess whether the current exposure to PAH of coke oven workers in a Dutch plant induced biological effects, and to determine if these effects are influenced by tobacco smoking and by genetic polymorphisms for the glutathione S-transferase genes GSTM1 and GSTT1. METHODS: Urinary 1-hydroxypyrene (1-OHpyr) levels were used to monitor the internal dose, while the internal effective dose was assessed by monitoring PAH-DNA adducts, DNA strand breaks (Comet assay), sister-chromatid exchanges (SCE) and cells with a high frequency of SCE (HFC) in lymphocytes together with micronuclei (MN) in exfoliated urothelial cells. RESULTS: Occupational exposure to PAH resulted in statistically significant increased 1-OHpyr levels (P<0.001), but it did not cause a significant induction of SCE, HFC, MN, DNA strand breaks or DNA adducts. Smoking caused a significant increase of 1-OHpyr (P<0.05), SCE (P<0.001), HFC (P<0.001) and DNA adducts (P<0.05), but not of MN or DNA strand breaks. Following correction for the smoking-related effects, no occupational induction of the effect biomarkers could be discerned. Multi-variate analysis did not show a significant influence of GSTM1 and GSTT1 polymorphisms on any biomarker. Also no significant interactions were observed between the various biomarkers. CONCLUSION: This study shows that in the examined plant, the occupational exposure to PAH does not result in measurable early biological effects
Asunto(s)
Glutatión Transferasa/genética , Exposición Profesional , Hidrocarburos Policíclicos Aromáticos , Polimorfismo Genético , Fumar/fisiopatología , Adulto , Coque , Aductos de ADN/sangre , Humanos , Persona de Mediana Edad , Análisis Multivariante , Intercambio de Cromátides HermanasRESUMEN
In a search for genes induced by DNA-damaging agents, we identified two genes that are activated by methyl methanesulfonate (MMS). Expression of both genes is regulated after endoplasmic reticulum (ER) stress via the unfolded protein response (UPR) pathway. The first gene of those identified is the molecular chaperone BiP/GRP78. The second gene, Mif1, is identical to the anonymous cDNA KIAA0025. Treatment with the glycosylation inhibitor tunicamycin both enhances the synthesis of Mif1 mRNA and protein. The Mif1 5' flanking region contains a functional ER stress-responsive element which is sufficient for induction by tunicamycin. MMS, on the other hand, activates Mif1 via an UPR-independent pathway. The gene encodes a 52 kDa protein with homology to the human DNA repair protein HHR23A and contains an ubiquitin-like domain. Overexpressed Mif1 protein is localized in the ER.
Asunto(s)
Daño del ADN , Metilmetanosulfonato/farmacología , Secuencia de Aminoácidos , Línea Celular , Clonación Molecular , Enzimas Reparadoras del ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/metabolismo , Chaperón BiP del Retículo Endoplásmico , Regulación de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Datos de Secuencia Molecular , Pliegue de Proteína , ARN Mensajero/metabolismo , Alineación de Secuencia , Tunicamicina/farmacologíaRESUMEN
The effect of the genetic background on the tumor spectrum of Apc1638N, a mouse model for attenuated familial adenomatous polyposis (FAP), has been investigated in X-irradiated and untreated F1 hybrids between C57BL/6JIco-Apc1638N (B6) and A/JCrIBR (A/J), BALB/cByJIco (C) or C3H/HeOuJIco (C3). Similar to the ApcMin model, the Apc1638N intestinal tumor multiplicity seems to be modulated by Mom1. Moreover, several additional (X-ray-responsive) modifier loci appear also to affect the Apc1638N intestinal tumor number. The genetic background did not significantly influence the number of spontaneous desmoids and cutaneous cysts in Apc1638N. In general, X-irradiation increased the desmoid multiplicity in Apc1638N females but had no effect in males. The opposite was noted for the cyst multiplicity after X-rays. Surprisingly, X-irradiated CB6F1-Apc1638N females were highly susceptible to the development of ovarian tumors, which displayed clear loss of the wild-type Apc allele.
Asunto(s)
Neoplasias Inducidas por Radiación/genética , Poliposis Adenomatosa del Colon/genética , Animales , Quiste Epidérmico/genética , Femenino , Fibromatosis Agresiva/genética , Neoplasias Gastrointestinales/genética , Predisposición Genética a la Enfermedad/genética , Pérdida de Heterocigocidad/genética , Masculino , Neoplasias Mamarias Animales/genética , Ratones , Ratones Endogámicos A , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Mutantes , Neoplasias Primarias Múltiples/genética , Neoplasias Ováricas/genética , Neoplasias Cutáneas/genética , Rayos XRESUMEN
Differential display is an easily applied method for comparing gene expression in a variety of systems. We used a nonradioactive differential display technique to analyze X-ray-induced lymphomas derived from Emu-pim-1 transgenic and nontransgenic mice. Fragments of 11 differentially regulated genes were identified, three of which are novel sequences. One of the cloned fragments contained sequences of a mouse VL30 retroelement that was significantly overexpressed in a subset of lymphomas as compared with non-lymphomatous tissue. Interestingly, these lymphomas also displayed high levels of c-myc transcripts. An altered expression pattern of a glutathione S-transferase homologue was identified in several lymphomas. Moreover, a cytotoxic T-lymphocyte lipase appeared to be overexpressed specifically in lymphoma-containing spleen tissue, and the results suggest that it may be related to the endogenous immune response against lymphoma development.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Genes myc , Linfoma/genética , Neoplasias Inducidas por Radiación/genética , Transcripción Genética , Animales , Clonación Molecular , Presentación de Datos , Digoxigenina , Genotipo , Glutatión Transferasa/genética , Lipasa/genética , Ratones , Reacción en Cadena de la Polimerasa/métodos , Retroelementos , Linfocitos T Citotóxicos/enzimología , Rayos XRESUMEN
Transgenic mice overexpressing the pim-1 oncogene in their lymphoid compartment display a low incidence of spontaneous T-cell lymphomas, but are highly susceptible to point mutation-inducing genotoxic carcinogens. We show here that total body X-irradiation, which causes mainly chromosomal deletions, rearrangements and amplifications, significantly enhances lymphoma development in E mu-pim-1 transgenic mice. The X-ray-induced E mu-pim-1 and non-transgenic lymphomas have a comparable high cell turnover as shown by a relatively high S-phase fraction and a high apoptotic activity. Consistent with previous observations, in 75% of all lymphomas c-myc mRNA levels are 5- to 20-fold higher than in control, non-lymphomatous spleen/thymus. The expression of other oncogenes, which have previously found to be activated in combination with pim-1 in lymphomagenesis, such as gfi-1/pal-1, frat-1 and tiam-1, and also of the mdm-2 and mdm-x oncogenes, appeared not to be affected. Deletions and/or rearrangements of the p16INK4A and p15INK4B tumor suppressor genes were seldom observed (in three out of 92 X-ray-induced lymphomas). Strikingly, in addition to the high mRNA levels of the pim-1 transgene, the levels of the endogenous pim-1 transcripts were elevated significantly in 16% of the X-ray-induced E mu-pim-1 lymphomas compared with control spleen, even surpassing the level of the pim-1 transgene mRNA by 3- to 5-fold. In combination with previous results, which showed that the lymphoma incidence increased concordantly with higher levels of pim-1, this supports the notion that pim-1 can contribute to lymphomagenesis in a dose-dependent manner.
Asunto(s)
Proteínas de Ciclo Celular , Linfoma/genética , Neoplasias Inducidas por Radiación/genética , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/genética , Neoplasias del Timo/genética , Proteínas Supresoras de Tumor , Animales , Proteínas Portadoras/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Eliminación de Gen , Linfoma/etiología , Linfoma/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias Inducidas por Radiación/patología , Proteínas Proto-Oncogénicas c-pim-1 , Irradiación Corporal TotalRESUMEN
UNLABELLED: Lemierre syndrome used to be a complication of severe oropharyngeal infection with regional thrombophlebitis, septicaemia and septic metastatic infections caused by Fusobacterium necrophorum in the pre-antibiotic era. A case of septic arthritis of the hip caused by F. necrophorum as a complication of tonsillectomy is reported in a 9-year-old boy. CONCLUSION: Lemierre syndrome, usually seen after an oropharyngeal infection, can also complicate tonsillectomy.
Asunto(s)
Artritis Infecciosa/etiología , Infecciones por Fusobacterium , Fusobacterium necrophorum , Infección de la Herida Quirúrgica/complicaciones , Tonsilectomía , Artritis Infecciosa/microbiología , Niño , Infecciones por Fusobacterium/complicaciones , Infecciones por Fusobacterium/etiología , Articulación de la Cadera , Humanos , Masculino , Infección de la Herida Quirúrgica/microbiologíaRESUMEN
Three different methods were investigated to determine their ability to detect and classify various categories of diffuse liver disease. A statistical method, i.e., discriminant analysis, a supervised neural network called backpropagation and a nonsupervised, self-organizing feature map were examined. The investigation was performed on the basis of a previously selected set of acoustic and image texture parameters. The limited number of patients was successfully extended by generating additional but independent data with identical statistical properties. The generated data were used for training and test sets. The final test was made with the original patient data as a validation set. It is concluded that neural networks are an attractive alternative to traditional statistical techniques when dealing with medical detection and classification tasks. Moreover, the use of generated data for training the networks and the discriminant classifier has been shown to be justified and profitable.