RESUMEN
BACKGROUND: Image quality is an important factor in imaging optimisation and diagnosis. Many determinants of image quality are controlled by the radiographer; therefore, radiographer-led strategies may be key to improving X-ray image quality. This review examines the literature on radiographer-led diagnostic evaluation to establish its potential to improve X-ray image quality. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews and the Joanna Briggs Institute Manual for Evidence Synthesis Scoping Review were used to review studies relevant to the impact of radiographer-led diagnostic evaluation on image quality. CINHAL, Embase, Scopus, Web of Science and Medline databases were searched for relevant articles. Search terms synonymous with radiographer, commenting, and image quality were used and studies that examined any type of radiographer-led image interpretation and its relationship to image quality in X-ray based modalities were reviewed. RESULTS: Fourteen studies that met the inclusion criteria were reviewed. All the studies reviewed unanimously reported a positive association between radiographer image interpretation and image quality in X-ray based modalities. Five emerging themes were identified to be responsible for the improvement in image quality: increased understanding of image quality requirements, improved technical skills, enhanced ability to utilise supplementary imaging and repeats, collaborative upskilling of colleagues, and a complementary interaction between diagnostic and radiographic skills that serves to enhance image quality. CONCLUSIONS: The findings demonstrate that radiographer image interpretation is a useful strategy to optimise the quality of X-ray examinations. IMPLICATIONS FOR PRACTICE: The findings highlight a new avenue to improve X-ray quality in the clinical environment and support evidence-based uptake of preliminary image evaluation systems. These findings also support the integration of radiographer commenting alongside technical image quality in teaching curricula.
Asunto(s)
Interpretación de Imagen Asistida por Computador , Radiografía , Humanos , Técnicos Medios en Salud , Competencia Clínica , Examen Físico , Rayos XRESUMEN
INTRODUCTION: The timely communication of clinically significant image appearances to Emergency Department (ED) referrers is necessary for optimum patient care. Australian reliance on verbal communication only is time-limited, open to misinterpretation and lacks transparency. A combined radiographer alert and comment model was designed to reliably communicate image abnormalities to ED referrers in real-time. METHODS: A multidisciplinary steering group designed the model for all ED general imaging. Protocols were developed to document radiographer comments (critical, urgent and clinically significant) in patients' medical records. Critical findings were communicated directly to ED. Five NSW hospitals varying in size, complexity and population demographics piloted the model between three to twelve months during 2021-2022. Site auditors compared comments with the radiology report and designated each as True Positive (TP), False Positive (FP), indeterminate and clinically significant. Indeterminate cases were analysed by an external radiologist. Inter-observer consensus was obtained for all classifications via two independent auditors. The Positive Predictive Value (PPV), or precision of the comment, was calculated for each site. RESULTS: Radiographers (n = 69) provided comments for 1102 cases. The pooled average PPV for TP was 0.96; (0.947-0.971; 95% CI). The weighted mean error (FP comments) was 3.9%; (2.9% - 5.3%.; 95% CI). CONCLUSION: The Radiographer Comment model provided consistent levels of commenting precision and reproducibility across a range of sites with a pooled average PPV (0.96). The False Positive rate or weighted mean error (FP) of 3.9% (2.9% - 5.3%.; 95% CI) was low. IMPLICATIONS FOR FUTURE PRACTICE: A strategic, interprofessional approach in the implementation of an image alert combined with a Radiographer Comment can be adapted across a variety of hospital settings for ED and other departments.
Asunto(s)
Servicio de Urgencia en Hospital , Humanos , Rayos X , Reproducibilidad de los Resultados , Proyectos Piloto , AustraliaRESUMEN
Despite extensive investigations, an effective treatment for sepsis remains elusive and a better understanding of the inflammatory response to infection is required to identify potential new targets for therapy. In this study we have used RNAi technology to show, for the first time, that the inducible lysophosphatidylcholine acyltransferase 2 (LPCAT2) plays a key role in macrophage inflammatory gene expression in response to stimulation with bacterial ligands. Using siRNA- or shRNA-mediated knockdown, we demonstrate that, in contrast to the constitutive LPCAT1, LPCAT2 is required for macrophage cytokine gene expression and release in response to TLR4 and TLR2 ligand stimulation but not for TLR-independent stimuli. In addition, cells transfected to overexpress LPCAT2 exhibited increased expression of inflammatory genes in response to LPS and other bacterial ligands. Furthermore, we have used immunoprecipitation and Western blotting to show that in response to LPS, LPCAT2, but not LPCAT1, rapidly associates with TLR4 and translocates to membrane lipid raft domains. Our data thus suggest a novel mechanism for the regulation of inflammatory gene expression in response to bacterial stimuli and highlight LPCAT2 as a potential therapeutic target for development of anti-inflammatory and anti-sepsis therapies.
Asunto(s)
1-Acilglicerofosfocolina O-Aciltransferasa/metabolismo , Macrófagos Peritoneales/inmunología , Monocitos/inmunología , Sepsis/inmunología , 1-Acilglicerofosfocolina O-Aciltransferasa/genética , Animales , Línea Celular Tumoral , Regulación de la Expresión Génica/inmunología , Técnicas de Silenciamiento del Gen , Humanos , Lipopolisacáridos/inmunología , Macrófagos Peritoneales/citología , Macrófagos Peritoneales/metabolismo , Microdominios de Membrana/metabolismo , Ratones , Monocitos/citología , Monocitos/metabolismo , Cultivo Primario de Células , Células RAW 264.7 , ARN Interferente Pequeño/metabolismo , Sepsis/microbiología , Transducción de Señal/genética , Transducción de Señal/inmunología , Receptor Toll-Like 4/metabolismoAsunto(s)
Antígenos CD/metabolismo , Antígeno B7-H1/metabolismo , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Antígenos CD/genética , Antígeno B7-H1/genética , Humanos , Inmunoterapia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Linfocitos T/patologíaRESUMEN
OBJECTIVE: The objective of this study was to determine trends in prenatal detection and current estimates of prevalence for trisomies 18 (T18) and 13 (T13) and their implications for screening policy. METHODS: We conducted a cohort study from a population-based regional anomaly register covering 995 003 births (1995-2009). RESULTS: There were 786 affected cases. Total prevalence of T18 increased from 3.95 in 1995-1999 to 6.94 per 10 000 births in 2005-2009 (annual trend χ(2) = 25.99, p < 0.001) and live birth prevalence, when adjusted for in utero attrition, increased from 1.47 to 2.30 per 10 000 births over the same time (annual trend χ(2) = 6.36, p = 0.01). For T18 and T13 combined, the proportion of cases diagnosed by prenatal karyotype or suspected by ultrasound increased from 85.1% (165/194) in 1995-1999 to 95.2% (299/314) in 2005-2009 (p < 0.001). In 2005-2009, 50.3% of prenatal cytogenetic diagnoses for T18 and 38.5% of T13 were made after the discovery of first trimester ultrasound anomalies, and the majority, 56.4% (185/328), of affected pregnancies were karyotyped or had ended before 18 weeks. CONCLUSION: T18 is increasing in prevalence because of maternal age and earlier surveillance. Prenatal diagnosis occurs mostly in the first trimester, without the intrinsic structures of a formal screening programme. These findings support the extension of first trimester combined screening to include T18 and T13.
Asunto(s)
Síndrome de Down/diagnóstico , Síndrome de Down/epidemiología , Diagnóstico Prenatal/estadística & datos numéricos , Trisomía/diagnóstico , Adulto , Cromosomas Humanos Par 18 , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Población , Embarazo , Prevalencia , Sistema de Registros , Síndrome de la Trisomía 18 , Adulto JovenAsunto(s)
Diferenciación Celular , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/citología , Monocitos/citología , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , gamma Catenina/metabolismo , Médula Ósea/metabolismo , Células Cultivadas , Sangre Fetal/citología , Sangre Fetal/metabolismo , Citometría de Flujo , Células Madre Hematopoyéticas/metabolismo , Humanos , Monocitos/metabolismo , ARN Interferente Pequeño/genética , gamma Catenina/antagonistas & inhibidores , gamma Catenina/genéticaRESUMEN
Canonical Wnt signaling regulates the transcription of T-cell factor (TCF)-responsive genes through the stabilization and nuclear translocation of the transcriptional co-activator, ß-catenin. Overexpression of ß-catenin features prominently in acute myeloid leukemia (AML) and has previously been associated with poor clinical outcome. Overexpression of γ-catenin mRNA (a close homologue of ß-catenin) has also been reported in AML and has been linked to the pathogenesis of this disease, however, the relative roles of these catenins in leukemia remains unclear. Here we report that overexpression and aberrant nuclear localization of γ-catenin is frequent in AML. Significantly, γ-catenin expression was associated with ß-catenin stabilization and nuclear localization. Consistent with this, we found that ectopic γ-catenin expression promoted the stabilization and nuclear translocation of ß-catenin in leukemia cells. ß-Catenin knockdown demonstrated that both γ- and ß-catenin contribute to TCF-dependent transcription in leukemia cells. These data indicate that γ-catenin expression is a significant factor in the stabilization of ß-catenin in AML. We also show that although normal cells exclude nuclear translocation of both γ- and ß-catenin, this level of regulation is lost in the majority of AML patients and cell lines, which allow nuclear accumulation of these catenins and inappropriate TCF-dependent transcription.
Asunto(s)
Núcleo Celular/metabolismo , Leucemia Mieloide Aguda/metabolismo , Factores de Transcripción TCF/genética , Transcripción Genética/genética , beta Catenina/química , gamma Catenina/metabolismo , Western Blotting , Células Cultivadas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Regiones Promotoras Genéticas/genética , Transporte de Proteínas , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Factores de Transcripción TCF/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , gamma Catenina/genéticaRESUMEN
OBJECTIVE: To determine the prevalence and outcome of lower urinary tract obstruction (LUTO), including the sensitivity of antenatal diagnosis. DESIGN: A retrospective population-based study. SETTING: Regional population-based congenital anomalies register (WMCAR). POPULATION: Fetuses affected by LUTO delivered between 1995 and 2007 to women resident in the West Midlands. METHODS: Cases were selected from the WMCAR using codes and keyword terms from the International Classification of Diseases, tenth revision (ICD10). Diagnoses were validated using additional data sets from Regional Fetal Medicine, Perinatal Pathology and Paediatric services. MAIN OUTCOME MEASURES: Rates of prevalence, prenatal diagnosis and mortality, with trends. RESULTS: There were 284 LUTO cases in 851 419 births during the study period, representing a total prevalence of 3.34 (2.95-3.72) per 10 000 births, and this prevalence did not change significantly over time. The prevalence of LUTO was significantly higher in Black and minority ethnic groups when compared with white Europeans (OR 2.38; 95% CI 1.87-3.03), and are associated with area-based deprivation measures (P < 0.01). Of all LUTO cases, 221 (77.8%) were isolated, and the remainder were associated with other structural or chromosomal anomalies. The most common subtype was posterior urethral valves (PUVs; n = 179, 63%). In total there were 211 (74.3%) cases of isolated, non-female, singleton fetuses that fitted the referral criteria for in utero vesico-amniotic shunting, giving a prevalence of 2.48 (2.14-2.81) per 10 000 live births. Within this group, the prenatal diagnosis rate was 46.9% (99/211). CONCLUSION: This is the largest population-based study of LUTO that has been performed to date, and provides accurate estimates for prevalence. The low prevalence and relatively low rate of antenatal detection limit the number of cases amenable to prenatal surgical intervention.
Asunto(s)
Ultrasonografía Prenatal , Uretra/anomalías , Obstrucción del Cuello de la Vejiga Urinaria/congénito , Anomalías Urogenitales/epidemiología , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/epidemiología , Anomalías Múltiples/genética , Aborto Eugénico/estadística & datos numéricos , Aborto Espontáneo/epidemiología , Adulto , Aberraciones Cromosómicas , Inglaterra/epidemiología , Reacciones Falso Positivas , Femenino , Humanos , Mortalidad Infantil , Recién Nacido , Masculino , Embarazo , Prevalencia , Sistema de Registros , Estudios Retrospectivos , Sensibilidad y Especificidad , Mortinato/epidemiología , Ultrasonografía Prenatal/estadística & datos numéricos , Uretra/diagnóstico por imagen , Obstrucción del Cuello de la Vejiga Urinaria/diagnóstico por imagen , Obstrucción del Cuello de la Vejiga Urinaria/epidemiología , Obstrucción del Cuello de la Vejiga Urinaria/genética , Anomalías Urogenitales/diagnóstico por imagen , Anomalías Urogenitales/genéticaAsunto(s)
Antígenos CD/metabolismo , Crisis Blástica/inmunología , Crisis Blástica/patología , Memoria Inmunológica , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Linfocitos T/inmunología , Crisis Blástica/metabolismo , Citometría de Flujo , Humanos , Leucemia Mieloide Aguda/metabolismo , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
BACKGROUND: Screening for congenital heart defects (CHDs) relies on antenatal ultrasound and postnatal clinical examination; however, life-threatening defects often go undetected. OBJECTIVE: To determine the accuracy, acceptability and cost-effectiveness of pulse oximetry as a screening test for CHDs in newborn infants. DESIGN: A test accuracy study determined the accuracy of pulse oximetry. Acceptability of testing to parents was evaluated through a questionnaire, and to staff through focus groups. A decision-analytic model was constructed to assess cost-effectiveness. SETTING: Six UK maternity units. PARTICIPANTS: These were 20,055 asymptomatic newborns at ≥ 35 weeks' gestation, their mothers and health-care staff. INTERVENTIONS: Pulse oximetry was performed prior to discharge from hospital and the results of this index test were compared with a composite reference standard (echocardiography, clinical follow-up and follow-up through interrogation of clinical databases). MAIN OUTCOME MEASURES: Detection of major CHDs - defined as causing death or requiring invasive intervention up to 12 months of age (subdivided into critical CHDs causing death or intervention before 28 days, and serious CHDs causing death or intervention between 1 and 12 months of age); acceptability of testing to parents and staff; and the cost-effectiveness in terms of cost per timely diagnosis. RESULTS: Fifty-three of the 20,055 babies screened had a major CHD (24 critical and 29 serious), a prevalence of 2.6 per 1000 live births. Pulse oximetry had a sensitivity of 75.0% [95% confidence interval (CI) 53.3% to 90.2%] for critical cases and 49.1% (95% CI 35.1% to 63.2%) for all major CHDs. When 23 cases were excluded, in which a CHD was already suspected following antenatal ultrasound, pulse oximetry had a sensitivity of 58.3% (95% CI 27.7% to 84.8%) for critical cases (12 babies) and 28.6% (95% CI 14.6% to 46.3%) for all major CHDs (35 babies). False-positive (FP) results occurred in 1 in 119 babies (0.84%) without major CHDs (specificity 99.2%, 95% CI 99.0% to 99.3%). However, of the 169 FPs, there were six cases of significant but not major CHDs and 40 cases of respiratory or infective illness requiring medical intervention. The prevalence of major CHDs in babies with normal pulse oximetry was 1.4 (95% CI 0.9 to 2.0) per 1000 live births, as 27 babies with major CHDs (6 critical and 21 serious) were missed. Parent and staff participants were predominantly satisfied with screening, perceiving it as an important test to detect ill babies. There was no evidence that mothers given FP results were more anxious after participating than those given true-negative results, although they were less satisfied with the test. White British/Irish mothers were more likely to participate in the study, and were less anxious and more satisfied than those of other ethnicities. The incremental cost-effectiveness ratio of pulse oximetry plus clinical examination compared with examination alone is approximately £24,900 per timely diagnosis in a population in which antenatal screening for CHDs already exists. CONCLUSIONS: Pulse oximetry is a simple, safe, feasible test that is acceptable to parents and staff and adds value to existing screening. It is likely to identify cases of critical CHDs that would otherwise go undetected. It is also likely to be cost-effective given current acceptable thresholds. The detection of other pathologies, such as significant CHDs and respiratory and infective illnesses, is an additional advantage. Other pulse oximetry techniques, such as perfusion index, may enhance detection of aortic obstructive lesions. FUNDING: The National Institute for Health Research Health Technology programme.
Asunto(s)
Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/epidemiología , Tamizaje Neonatal/métodos , Oximetría/normas , Adulto , Análisis de Varianza , Actitud del Personal de Salud , Estudios de Cohortes , Análisis Costo-Beneficio , Ecocardiografía/economía , Femenino , Humanos , Recién Nacido , Masculino , Madres/psicología , Tamizaje Neonatal/economía , Tamizaje Neonatal/psicología , Servicio de Ginecología y Obstetricia en Hospital , Oximetría/economía , Oximetría/psicología , Satisfacción del Paciente , Factores de Riesgo , Sensibilidad y Especificidad , Encuestas y Cuestionarios , Reino Unido/epidemiología , Adulto JovenAsunto(s)
Proliferación Celular , Subunidad alfa 2 del Factor de Unión al Sitio Principal/fisiología , Células Madre Hematopoyéticas/fisiología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas Nucleares/fisiología , Proteínas Proto-Oncogénicas/fisiología , Factores de Transcripción/fisiología , Humanos , Proteína 1 Compañera de Translocación de RUNX1 , Proteínas Recombinantes de Fusión/metabolismoRESUMEN
Upregulation of the immunosuppressive cell surface glycoprotein, CD200, is a common feature of acute myeloid leukemia (AML) and is associated with poor patient outcome. We investigated whether CD200 overexpression on AML cells could specifically compromise patient natural killer (NK) cell anti-tumor responses. We found that CD200(hi) patients showed a 50% reduction in the frequency of activated NK cells (CD56(dim)CD16(+)) compared with CD200(lo) patients. Additionally, NK receptor expression (NKp44 and NKp46) on these cells was also significantly downregulated in CD200(hi) patients. To assess whether NK cell activity was directly influenced by CD200 expression, we examined the effect of ectopic expression of CD200. These assays revealed that both NK cell cytolytic activity and interferon-γ response were significantly reduced toward CD200(+) leukemic targets and that these targets showed increased survival compared with CD200(-) cells. Similarly, NK cells isolated from AML patients were less functionally active toward CD200(hi) autologous blasts from both cytolytic and immunoregulatory perspectives. Finally, blocking CD200 alone was sufficient to recover a significant proportion of NK cell cytolytic activity. Together, these findings provide the first evidence that CD200 has a direct and significant suppressive influence on NK cell activity in AML patients and may contribute to the increased relapse rate in CD200(+) patients.
Asunto(s)
Antígenos CD/metabolismo , Citotoxicidad Inmunológica/inmunología , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/inmunología , Crisis Blástica , Estudios de Casos y Controles , Células Cultivadas , Citometría de Flujo , Humanos , InmunofenotipificaciónRESUMEN
OGG1 (8-oxoguanine DNA glycosylase) constitutes a key component of the DNA base excision repair pathway, catalysing the removal of 8-oxoguanine nucleotides from DNA, thereby suppressing mutagenesis and cell death. We found that OGG1 expression was significantly downregulated by the RUNX1-ETO fusion protein product of the t(8;21) chromosome translocation in normal haematopoietic progenitor cells and in patients with acute myeloid leukaemia (AML). Further examination of OGG1 expression in 174 AML trial patients using Affymetrix microarrays showed that the prevalence rate of OGG1 expression was 33% and correlated strongly with adverse cytogenetics. OGG1-expressing patients had a worse relapse-free survival and overall survival and an increased risk of relapse at 5-years of follow-up. There remained a trend towards increased relapse rate among OGG1-expressing patients, even after adjusting for other known risk factors in comprehensive stratified analyses. We also determined a trend for OGG1 expression to have a more adverse impact on disease outcome in the context of the FLT3-ITD mutation. This study highlights OGG1 as a valuable prognostic marker that could be used to sub-stratify AML patients to predict those likely to fail conventional chemotherapies but those likely to benefit from novel therapeutic approaches that modulate DNA repair activity.
Asunto(s)
Biomarcadores de Tumor/metabolismo , ADN Glicosilasas/metabolismo , Guanina/análogos & derivados , Leucemia Mieloide Aguda/diagnóstico , Pronóstico , Biomarcadores de Tumor/genética , ADN Glicosilasas/genética , Estudios de Seguimiento , Guanina/metabolismo , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/metabolismo , MutaciónRESUMEN
The major phospholipid in pulmonary surfactant dipalmitoyl phosphatidylcholine (DPPC) has been shown to modulate inflammatory responses. Using human monocytes, this study demonstrates that DPPC significantly increased PGE(2) (P<0.05) production by 2.5-fold when compared to untreated monocyte controls. Mechanistically, this effect was concomitant with an increase in COX-2 expression which was abrogated in the presence of a COX-2 inhibitor. The regulation of COX-2 expression was independent of NF-kappaB activity. Further, DPPC increased the phosphorylation of the cyclic AMP response element binding protein (CREB; an important nuclear transcription factor important in regulating COX-2 expression). In addition, we also show that changing the fatty acid groups of PC (e.g. using l-alpha-phosphatidylcholine beta-arachidonoyl-gamma-palmitoyl (PAPC)) has a profound effect on the regulation of COX-2 expression and CREB activation. This study provides new evidence for the anti-inflammatory activity of DPPC and that this activity is at least in part mediated via CREB activation of COX-2.
Asunto(s)
1,2-Dipalmitoilfosfatidilcolina/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/antagonistas & inhibidores , Ciclooxigenasa 2/metabolismo , Monocitos/enzimología , Surfactantes Pulmonares/metabolismo , 1,2-Dipalmitoilfosfatidilcolina/química , 1,2-Dipalmitoilfosfatidilcolina/farmacología , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ciclooxigenasa 2/genética , Dinoprostona/biosíntesis , Dinoprostona/metabolismo , Humanos , Monocitos/efectos de los fármacos , Fosforilación , Surfactantes Pulmonares/química , Surfactantes Pulmonares/farmacologíaRESUMEN
OBJECTIVE: To identify in a case cohort study, overall outcome following prenatal diagnosis of complete AVSD (cAVSD) in a tertiary referral fetal cardiology center. METHOD: We retrospectively reviewed all pregnancies from 1997 to 2004 in which the fetus was identified on ultrasound examination as having a cAVSD. RESULTS: A prenatal diagnosis of cAVSD was made using fetal echocardiography in 99 fetuses. The median (range) gestational age at diagnosis was 23 weeks (17-37). In 41 cases, cAVSD was the sole cardiac lesion. The remaining 58 fetuses had associated additional intracardiac malformations. Prenatal karyotype was obtained in 43 fetuses and was abnormal in 23. Extracardiac anomalies were also identified in 25 fetuses. Following prenatal counseling, 35 couples chose termination. Of the 64 continuing pregnancies, 12 were stillbirths and 4 were lost to follow-up. Of the 48 live births, 16 were neonatal deaths without surgery while 32 babies underwent surgery and 19 have survived to date (follow-up between 2 years 10 months to 9 years 10 months). CONCLUSION: At the time of prenatal diagnosis at a regional fetal medicine center, the overall survival rate for fetuses with cAVSD is 32% (excluding termination and those lost to follow-up). This information has important implication for parents of fetuses with cAVSD and when undergoing prenatal counseling.
Asunto(s)
Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interventricular/diagnóstico por imagen , Resultado del Embarazo , Ultrasonografía Prenatal , Adolescente , Adulto , Aberraciones Cromosómicas , Estudios de Cohortes , Ecocardiografía , Femenino , Estudios de Seguimiento , Edad Gestacional , Defectos del Tabique Interatrial/cirugía , Defectos del Tabique Interventricular/cirugía , Humanos , Persona de Mediana Edad , Embarazo , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
The t(8;21)(q22;q22) occurs frequently in acute myelogenous leukaemia and gives rise to the transcription factor fusion protein, RUNX1-RUNX1T1 (also known as AML1-ETO). To identify the genes dysregulated by the aberrant transcriptional activity of RUNX1-RUNX1T1, we used microarrays to determine the effect of this mutation on gene expression in human progenitor cells and during subsequent development. Gene signatures of these developmental subsets were very dissimilar indicating that effects of RUNX1-RUNX1T1 are highly context dependent. We focused on gene changes associated with the granulocytic lineage and identified a clinically relevant subset of these by comparison with 235 leukaemia patient transcriptional signatures. We confirmed the overexpression of a number of significant genes (Sox4, IL-17BR, CD200 and gamma-catenin). Further, we show that overexpression of CD200 and gamma-catenin is also associated with the inv(16) abnormality which like RUNX1-RUNX1T1 disrupts core binding factor activity. We investigated the functional significance of CD200 and gamma-catenin overexpression in normal human progenitor cells. The effect of IL17 on growth was also assessed. Individually, none of these changes were sufficient to recapitulate the effects of RUNX1-RUNX1T1 on normal development. These data provide the most comprehensive and pertinent assessment of the effect of RUNX1-RUNX1T1 on gene expression and demonstrate the highly context-dependent effects of this fusion gene.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/fisiología , Regulación Leucémica de la Expresión Génica/genética , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/fisiología , Transcripción Genética/genética , Antígenos CD/biosíntesis , Antígenos CD/genética , Línea Celular Tumoral/metabolismo , Linaje de la Célula , Células Cultivadas/metabolismo , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 21/ultraestructura , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/ultraestructura , Desmoplaquinas/genética , Desmoplaquinas/fisiología , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/patología , Proteínas del Grupo de Alta Movilidad/biosíntesis , Proteínas del Grupo de Alta Movilidad/genética , Humanos , Leucemia Mieloide Aguda/patología , Proteínas de Neoplasias/biosíntesis , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Proteína 1 Compañera de Translocación de RUNX1 , Receptores de Interleucina-17/biosíntesis , Receptores de Interleucina-17/genética , Proteínas Recombinantes de Fusión/fisiología , Factores de Transcripción SOXC , Transactivadores/biosíntesis , Transactivadores/genética , Translocación Genética , gamma Catenina/genética , gamma Catenina/fisiologíaRESUMEN
Honey is used as a therapy to aid wound healing. Previous data indicate that honey can stimulate cytokine production from human monocytes. The present study further examines this phenomenon in manuka honey. As inflammatory cytokine production in innate immune cells is classically mediated by pattern recognition receptors in response to microorganisms, bacterial contamination of honey and the effect of blocking TLR2 and -4 on stimulatory activity were assessed. No vegetative bacteria were isolated from honey; however, bacterial spores were cultured from one-third of samples, and low levels of LPS were detected. Blocking TLR4 but not TLR2 inhibited honey-stimulated cytokine production significantly. Cytokine production did not correlate with LPS levels in honey and was not inhibited by polymyxin B. Further, the activity was reduced significantly following heat treatment, indicating that component(s) other than LPS are responsible for the stimulatory activity of manuka honey. To identify the component responsible for inducing cytokine production, honey was separated by molecular weight using microcon centrifugal filtration and fractions assessed for stimulatory activity. The active fraction was analyzed by MALDI-TOF mass spectroscopy, which demonstrated the presence of a number of components of varying molecular weights. Additional fractionation using miniaturized, reverse-phase solid-phase extraction resulted in the isolation of a 5.8-kDa component, which stimulated production of TNF-alpha via TLR4. These findings reveal mechanisms and components involved in honey stimulation of cytokine induction and could potentially lead to the development of novel therapeutics to improve wound healing for patients with acute and chronic wounds.
Asunto(s)
Miel , Leptospermum , Monocitos/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Médula Ósea/metabolismo , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos C57BL , Peso Molecular , Monocitos/citología , Monocitos/inmunología , Polimixina B/farmacología , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/inmunología , Staphylococcus aureus/metabolismo , Receptor Toll-Like 2/antagonistas & inhibidores , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Terminations of pregnancy for fetal anomaly (TOPFAs) were analysed over a 10-year period from a population-based congenital anomaly register covering 646,342 births. A total of 3189 cases of TOPFA were identified, prevalence of 49.3 per 10,000 registerable births. The rate of TOPFA at all gestations and at less than 16 weeks increased significantly. There were 102 cases of liveborn TOPFAs (3.2%). The proportion of liveborn TOPFAs after 22 weeks of gestation decreased significantly but below 22 weeks remains unchanged. TOPFA is increasing in frequency, occurring earlier in pregnancy. Live birth is a possible important outcome.
Asunto(s)
Aborto Inducido/métodos , Feto/anomalías , Nacimiento Vivo/epidemiología , Inglaterra/epidemiología , Femenino , Edad Gestacional , Humanos , Embarazo , PrevalenciaRESUMEN
BACKGROUND: Adequate contemporary information to counsel patients with a prenatal diagnosis of holoprosencephaly is lacking. We addressed this using data from the West Midlands Congenital Anomaly Register (WMCAR), a population-based malformation register, during a time where technological improvements have been stable and anomaly screening is well established. METHODS: Cases were defined using the ICD 10 code for holoprosencephaly. Cases of livebirths, stillbirths and termination at all gestations were included in the study. The diagnosis was verified by a pathology or definitive radiological report with cross validation from the regional pathology, clinical genetics, cytogenetics and fetal medicine databases. RESULTS: There were 113 cases reported of holoprosencephaly for the years 1995-2004. This represents a prevalence of 1.7 per 10,000 births and terminations, with no change in prevalence over time. There was a decreased risk of holoprosencephaly in the white population [white vs. nonwhite; RR 0.53(0.36-0.79)]. Karyotypical abnormality was noted in 46% of cases where the karyotype was known. Trisomy 13 was the most common chromosomal abnormality. Correct allocation of a diagnosis of holoprosencephaly by ultrasound occurred in 77% of cases, with another 12% having a severe intracranial abnormality but was not reported as holoprosencephaly. In 4%, a prenatal diagnosis of holoprosencephaly was not made. Termination of pregnancy was performed in 80% of all cases. CONCLUSION: Holoprosencephaly is a morbid condition associated with significant secondary etiologies.