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1.
Colorectal Dis ; 22(12): 2232-2242, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32663361

RESUMEN

AIM: The aim was to develop and operationally define 'performance metrics' that characterize a reference approach to robotic-assisted low anterior resection (RA-LAR) and to obtain face and content validity through a consensus meeting. METHOD: Three senior colorectal surgeons with robotic experience and a senior behavioural scientist formed the Metrics Group. We used published guidelines, training materials, manufacturers' instructions and unedited videos of RA-LAR to deconstruct the operation into defined, measurable components - performance metrics (i.e. procedure phases, steps, errors and critical errors). The performance metrics were then subjected to detailed critique by 18 expert colorectal surgeons in a modified Delphi process. RESULTS: Performance metrics for RA-LAR had 15 procedure phases, 128 steps, 89 errors and 117 critical errors in women, 88 errors and 118 critical errors in men. After the modified Delphi process the final performance metrics consisted of 14 procedure phases, 129 steps, 88 errors and 115 critical errors in women, 87 errors and 116 critical errors in men. After discussion by the Delphi panel, all procedure phases received unanimous consensus apart from phase I (patient positioning and preparation, 83%) and phase IV (docking, 94%). CONCLUSION: A robotic rectal operation can be broken down into procedure phases, steps, with errors and critical errors, known as performance metrics. The face and content of these metrics have been validated by a large group of expert robotic colorectal surgeons from Europe. We consider the metrics essential for the development of a structured training curriculum and standardized procedural assessment for RA-LAR.


Asunto(s)
Procedimientos Quirúrgicos Robotizados , Benchmarking , Competencia Clínica , Consenso , Técnica Delphi , Femenino , Humanos , Masculino
2.
Ir Med J ; 113(7): 130, 2020 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-35575630

RESUMEN

Presentation A 76-year-old man presented with acute left upper limb pain and subsequent large ecchymosis. Diagnosis An ultrasound study was performed which showed partial left biceps tendon rupture. Treatment He was managed conservatively with Orthopaedic input. The patient was given analgesia and reassured. Discussion Tendon rupture is an unusual but serious complication of quinolone exposure. This case highlights that this should be included in the differential for acute limb pain in patients who have been prescribed these drugs.

3.
BMC Health Serv Res ; 19(1): 226, 2019 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-30987610

RESUMEN

BACKGROUND: Effective collaboration between speech and language therapists (SLTs) and teachers is essential in meeting the needs of children with developmental language disorders in school, but it is difficult to achieve. Currently, many children receive inadequate speech and language therapy services and/or support in school. The aim of this study was to engage key stakeholders (SLTs, teachers, parents and children with DLD) in the co-design of their ideal speech and language therapy service and support in school. The study was undertaken in order to inform the development of a conceptual model to guide collaborative practice when working with this population. METHODS: A qualitative study involving a diverse range of key stakeholders and using appreciative inquiry. This is a method which enables those involved to construct their 'ideal' about a topic of interest. Recruitment was carried out using purposive sampling. We conducted focus groups with practitioners (SLTs and teachers) and parents as well as semi-structured interviews with children who have DLD using 'draw and tell' techniques. A total of five focus groups and nine interviews were conducted with participants (n = 27). RESULTS: The children described their ideal supports as those which enabled them to connect, contribute and achieve. They describe ways in which environmental barriers in school needed to be addressed to allow them to do so. The professionals primarily described ways in which the language skills of the child could be improved. Both parents and practitioner groups described the importance of strengthening networks between service providers and service users. They also highlighted the need to promote a collaborative culture if stakeholders are to work effectively together across sectors. CONCLUSIONS: There were differences in perspectives about the ways in which speech and language therapy services and supports could be improved, demonstrating the importance of engaging a diverse group of stakeholders. Of note were the unique insights the children brought about the barriers they faced as a result of their difficulties. Based on our findings we propose that children should be given influence in decisions about the supports that they receive in school. Implications for policy, research and practice are discussed.


Asunto(s)
Trastornos del Desarrollo del Lenguaje/terapia , Terapia del Lenguaje/normas , Servicios de Salud Escolar/normas , Logopedia/normas , Niño , Preescolar , Femenino , Humanos , Relaciones Interprofesionales , Padres/psicología , Investigación Cualitativa , Mejoramiento de la Calidad
5.
Anaesthesia ; 72(9): 1117-1124, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28741649

RESUMEN

The objective of this study was to examine the effect of metrics-based vs. non-metrics-based feedback on novices learning predefined competencies for acquisition and interpretation of sonographic images relevant to performance of ultrasound-guided axillary brachial plexus block. Twelve anaesthetic trainees were randomly assigned to either metrics-based-feedback or non-metrics-based feedback groups. After a common learning phase, all participants attempted to perform a predefined task that involved scanning the left axilla of a single volunteer. Following completion of the task, all participants in each group received feedback from a different expert in regional blocks (consultant anaesthetist) and were allowed to practise the predefined task for up to 1 h. Those in the metrics-based feedback group received feedback based on previously validated metrics, and they practised each metric item until it was performed satisfactorily, as assessed by the supervising consultant. Subsequently, each participant attempted to perform ultrasonography of the left axilla on the same volunteer. Two trained consultant anaesthetists independently scored the video recording pre- and post-feedback scans using the validated metrics list. Both groups showed improvement from pre-feedback to post-feedback scores. Compared with participants in the non-metrics-based feedback group, those in the metrics-based feedback group completed more steps: median (IQR [range]) 18.8 (1.5 [17-20]) vs. 14.3 (4.5 [11-18.5]), p = 0.009, and made fewer errors 0.5 (1 [0-1.5]) vs. 1.5 (2 [1-6]), p = 0.041 postfeedback. In this study, novices' sonographic skills showed greater improvement when feedback was combined with validated metrics.


Asunto(s)
Anestesiología/educación , Plexo Braquial/diagnóstico por imagen , Competencia Clínica , Bloqueo Nervioso/métodos , Ultrasonografía Intervencional , Adulto , Axila/diagnóstico por imagen , Retroalimentación , Femenino , Hospitales de Enseñanza , Humanos , Internado y Residencia , Masculino , Variaciones Dependientes del Observador , Adulto Joven
7.
Anaesthesia ; 71(11): 1324-1331, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27634361

RESUMEN

The purpose of this study was to examine the construct validity and reliability of a novel metrics-based assessment tool, previously developed for ultrasound-guided axillary brachial plexus block. Five expert and eight novice anaesthetists performed a total of 18 ultrasound-guided axillary brachial plexus blocks on the same number of patients. A trained investigator video-taped procedures according to a pre-defined protocol. Two trained consultant anaesthetists independently scored the videos using the assessment tool. Compared with novices, experts completed more steps (mean 41.0 vs. 33.1, p = 0.001), had fewer procedural errors (2.8 vs. 7.9, p < 0.0001), had fewer critical errors (0.8 vs. 1.3, p = 0.030), and fewer total errors (3.5 vs. 9.1, p < 0.0001). The mean inter-rater reliability for scoring of experts' performance was 0.91, for novices' performance was 0.84, and for all performance combined (n = 18) was 0.88. This assessment tool is valid, and discriminates reliably between expert and novice performance for placement of ultrasound-guided axillary brachial plexus blocks.


Asunto(s)
Bloqueo del Plexo Braquial/normas , Plexo Braquial/diagnóstico por imagen , Competencia Clínica , Ultrasonografía Intervencional/normas , Adulto , Anestesiología/educación , Bloqueo del Plexo Braquial/métodos , Educación de Postgrado en Medicina , Evaluación Educacional/métodos , Femenino , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Ultrasonografía Intervencional/métodos , Grabación de Cinta de Video
10.
Int J Obes (Lond) ; 38(2): 252-8, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23732655

RESUMEN

BACKGROUND: Epidemiologic evidence on the influence of dietary glycemic index (GI) and glycemic load (GL) on the development of obesity is limited. OBJECTIVE: This prospective study examined the associations between dietary GI and GL and changes in body composition measures during adolescence. DESIGN: In a representative sample of Northern Irish adolescents aged 12 years at baseline and 15 years at follow-up (n=426), dietary intake was assessed by a diet history interview. Body composition measures included body mass index (BMI; kg m(-2)), BMI z-score, sum of four skinfold thicknesses, percentage body fat, fat mass index (FMI; kg m(-2)) and fat-free mass index (kg m(-2)). RESULTS: After adjustment for potential confounding factors, baseline GI was associated with increased change in FMI. Mean (95% confidence interval) values of changes in FMI according to tertiles of baseline GI were 0.41 (0.25, 0.57), 0.42 (0.26, 0.58) and 0.67 (0.51, 0.83) kg m(-2), respectively (P for trend=0.03). There was no significant association of baseline GI with changes in other body composition measures (P for trend≥0.054). Conversely, baseline GL showed no association with changes in any of the measures (P for trend≥0.41). Furthermore, changes in GI or GL were not associated with changes in any of the measures (P for trend≥0.16). CONCLUSION: Dietary GI at age 12 years was independently associated with increased change in FMI between ages 12 and 15 years in a representative sample from Northern Ireland, whereas dietary GL showed no association with changes in any of the body composition measures examined.


Asunto(s)
Glucemia/metabolismo , Composición Corporal , Carbohidratos de la Dieta/metabolismo , Ingestión de Energía , Índice Glucémico , Pubertad/metabolismo , Adolescente , Composición Corporal/fisiología , Índice de Masa Corporal , Niño , Dieta , Femenino , Estudios de Seguimiento , Humanos , Resistencia a la Insulina , Masculino , Irlanda del Norte , Obesidad/metabolismo , Obesidad/fisiopatología , Obesidad/prevención & control , Estudios Prospectivos , Pubertad/fisiología , Factores de Riesgo , Grosor de los Pliegues Cutáneos
11.
J Electrocardiol ; 47(6): 895-906, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25110276

RESUMEN

INTRODUCTION: It is well known that accurate interpretation of the 12-lead electrocardiogram (ECG) requires a high degree of skill. There is also a moderate degree of variability among those who interpret the ECG. While this is the case, there are no best practice guidelines for the actual ECG interpretation process. Hence, this study adopts computerized eye tracking technology to investigate whether eye-gaze can be used to gain a deeper insight into how expert annotators interpret the ECG. Annotators were recruited in San Jose, California at the 2013 International Society of Computerised Electrocardiology (ISCE). METHODS: Each annotator was recruited to interpret a number of 12-lead ECGs (N=12) while their eye gaze was recorded using a Tobii X60 eye tracker. The device is based on corneal reflection and is non-intrusive. With a sampling rate of 60Hz, eye gaze coordinates were acquired every 16.7ms. Fixations were determined using a predefined computerized classification algorithm, which was then used to generate heat maps of where the annotators looked. The ECGs used in this study form four groups (3=ST elevation myocardial infarction [STEMI], 3=hypertrophy, 3=arrhythmias and 3=exhibiting unique artefacts). There was also an equal distribution of difficulty levels (3=easy to interpret, 3=average and 3=difficult). ECGs were displayed using the 4x3+1 display format and computerized annotations were concealed. RESULTS: Precisely 252 expert ECG interpretations (21 annotators×12 ECGs) were recorded. Average duration for ECG interpretation was 58s (SD=23). Fleiss' generalized kappa coefficient (Pa=0.56) indicated a moderate inter-rater reliability among the annotators. There was a 79% inter-rater agreement for STEMI cases, 71% agreement for arrhythmia cases, 65% for the lead misplacement and dextrocardia cases and only 37% agreement for the hypertrophy cases. In analyzing the total fixation duration, it was found that on average annotators study lead V1 the most (4.29s), followed by leads V2 (3.83s), the rhythm strip (3.47s), II (2.74s), V3 (2.63s), I (2.53s), aVL (2.45s), V5 (2.27s), aVF (1.74s), aVR (1.63s), V6 (1.39s), III (1.32s) and V4 (1.19s). It was also found that on average the annotator spends an equal amount of time studying leads in the frontal plane (15.89s) when compared to leads in the transverse plane (15.70s). It was found that on average the annotators fixated on lead I first followed by leads V2, aVL, V1, II, aVR, V3, rhythm strip, III, aVF, V5, V4 and V6. We found a strong correlation (r=0.67) between time to first fixation on a lead and the total fixation duration on each lead. This indicates that leads studied first are studied the longest. There was a weak negative correlation between duration and accuracy (r=-0.2) and a strong correlation between age and accuracy (r=0.67). CONCLUSIONS: Eye tracking facilitated a deeper insight into how expert annotators interpret the 12-lead ECG. As a result, the authors recommend ECG annotators to adopt an initial first impression/pattern recognition approach followed by a conventional systematic protocol to ECG interpretation. This recommendation is based on observing misdiagnoses given due to first impression only. In summary, this research presents eye gaze results from expert ECG annotators and provides scope for future work that involves exploiting computerized eye tracking technology to further the science of ECG interpretation.


Asunto(s)
Arritmias Cardíacas/diagnóstico , Inteligencia Artificial , Electrocardiografía/métodos , Movimientos Oculares/fisiología , Fijación Ocular/fisiología , Percepción Visual/fisiología , Adulto , Competencia Clínica , Femenino , Humanos , Masculino , Lectura
12.
Diabetologia ; 55(3): 654-65, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22127412

RESUMEN

INTRODUCTION: Recent studies suggesting an increased cancer risk with glucose-lowering agents have received widespread publicity. The objectives of this study were to evaluate the comparability in underlying cancer risk and patterns of cancer risk over time with different glucose-lowering agents. METHODS: The General Practice Research Database (GPRD) was used to identify cohorts of new users. Cancer outcomes were obtained from the GPRD, Hospital Episode Statistics and cancer registries. Relative rates of cancer comparing different glucose-lowering agents were estimated using Poisson regression. RESULTS: A total of 206,940 patients was identified. There was no difference in cancer risk and quartile for HbA(1c) value. There were differences in cancer incidence in the first 6 months after starting treatment (adjusted relative rate of 0.83 [95% CI 0.70, 0.99] with thiazolidinediones, 1.34 [95% CI 1.19, 1.51] with sulfonylureas and 1.79 [95% CI 1.53, 2.10] with insulin, compared with metformin). Insulin users had decreasing cancer incidence over time (adjusted relative rate of 0.58 [95% CI 0.50, 0.68] during months 6-24, relative rate of 0.50 [95% CI 0.42, 0.59] during months 25-60 and relative rate of 0.48 [95% CI 0.40, 0.59] during months 60+) compared with months 0-6 after starting insulin. Similar patterns were found with sulfonylureas and metformin. There were no increases over time with insulin glargine (A21Gly, B31Arg, B32Arg human insulin; relative rate of 0.70 [95% CI 0.52, 0.95], 0.77 [95% CI 0.56, 1.07] and 0.60 [95% CI 0.36, 1.02], respectively, for 6-24, 25-60 and >60 months). CONCLUSIONS: These findings do not provide evidence of either beneficial or adverse effects of glucose-lowering agents on cancer risk and are consistent with changes in diabetes treatment in the few months prior to the diagnosis of cancer.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Neoplasias/inducido químicamente , Neoplasias/epidemiología , Anciano , Estudios de Cohortes , Bases de Datos Factuales , Registros Electrónicos de Salud , Femenino , Estudios de Seguimiento , Medicina General , Humanos , Hipoglucemiantes/uso terapéutico , Incidencia , Insulina Glargina , Insulina de Acción Prolongada/efectos adversos , Insulina de Acción Prolongada/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Distribución de Poisson , Sistema de Registros , Compuestos de Sulfonilurea/efectos adversos , Compuestos de Sulfonilurea/uso terapéutico , Tiazolidinedionas/efectos adversos , Tiazolidinedionas/uso terapéutico , Reino Unido/epidemiología
13.
J Fish Biol ; 80(5): 1727-48, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22497405

RESUMEN

Ecological risk assessments (ERAs) are employed to quantify and predict the vulnerability of a particular species, stock or population to a specific stressor, e.g. pollution, harvesting, climate change, by-catch. Data generated from ERAs are used to identify and prioritize species for implementation of effective conservation and management strategies. At this time, ERAs are of particular importance to elasmobranchs, given the ecological importance and documented global population declines of some elasmobranch species. Here, ERAs as a tool for elasmobranch conservation and management are reviewed and a theoretical roadmap provided for future studies. To achieve these goals, a brief history of ERAs and approaches used within them (in the context of elasmobranchs) are given, and a comprehensive review conducted of all ERA studies associated with elasmobranchs published between 1998 and 2011. The hazards assessed, species evaluated and methodological approaches taken are recorded. Chronological and geographical patterns suggest that this tool has grown in popularity as a commercial fishery management instrument, while also signalling a recent precautionary approach to elasmobranch management in commercial fisheries globally. The analysis demonstrates that the predominant parameters incorporated in previous ERAs are largely based on life-history characteristics, and sharks have received the majority of attention; batoids (including skates) have received less attention. Recreational fishing and habitat degradation are discussed as hazards which warrant future investigation through ERA. Lastly, suggestions are made for incorporating descriptive ecological data to aid in the continued development and evolution of this management tool as it applies to future elasmobranch conservation.


Asunto(s)
Conservación de los Recursos Naturales , Ecología/métodos , Elasmobranquios , Animales , Ecosistema , Explotaciones Pesqueras , Océanos y Mares , Medición de Riesgo
15.
Proc Natl Acad Sci U S A ; 105(8): 2853-8, 2008 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-18287022

RESUMEN

Cilia are present on nearly all cell types in mammals and perform remarkably diverse functions. However, the mechanisms underlying ciliogenesis are unclear. Here, we cloned a previously uncharacterized highly conserved gene, stumpy, located on mouse chromosome 7. Stumpy was ubiquitously expressed, and conditional loss in mouse resulted in complete penetrance of perinatal hydrocephalus (HC) and severe polycystic kidney disease (PKD). We found that cilia in stumpy mutant brain and kidney cells were absent or markedly deformed, resulting in defective flow of cerebrospinal fluid. Stumpy colocalized with ciliary basal bodies, physically interacted with gamma-tubulin, and was present along ciliary axonemes, suggesting that stumpy plays a role in ciliary axoneme extension. Therefore, stumpy is essential for ciliogenesis and may be involved in the pathogenesis of human congenital malformations such as HC and PKD.


Asunto(s)
Cilios/fisiología , Predisposición Genética a la Enfermedad , Hidrocefalia/genética , Enfermedades Renales Poliquísticas/genética , Animales , Secuencia de Bases , Northern Blotting , Encéfalo/patología , Clonación Molecular , Biología Computacional , Perfilación de la Expresión Génica , Histocitoquímica , Hidrocefalia/metabolismo , Hibridación in Situ , Riñón/patología , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Enfermedades Renales Poliquísticas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tubulina (Proteína)/metabolismo
16.
Disabil Rehabil ; 43(20): 2909-2918, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-32064960

RESUMEN

PURPOSE: To ascertain stakeholders' agreement and disagreement about inter-professional collaboration (IPC) when supporting the child with a developmental language disorder (DLD) in school. MATERIALS AND METHODS: Two rounds of an online Delphi survey were undertaken with a purposive sample of 26 participants (researchers, practitioners and parents). Topics were informed by the views of children engaged in an earlier phase of the research. Agreement was set at an inter-quartile range of 1, with level of agreement measured using a five-point semantic differential scale. Qualitative data were examined using content analysis. RESULTS: There was strong agreement across the stakeholder groups about the child-led goals of IPC. Stakeholders also agreed that DLD is best viewed as a learning difference rather than a disorder. We identified ambivalence across the groups about the right of the child with DLD to have influence in decision-making about supports in school. CONCLUSIONS: We propose that IPC should be viewed as a means of ensuring the inclusion of the child in school. A shift in focus from remediating perceived deficits of the child, to affecting change in classroom practice, is also indicated. The need to reinforce the unconditional right of the child to have influence in decisions about supports is highlighted. Implications for IPC when meeting the needs of children with a developmental disability in school are outlined.IMPLICATIONS FOR REHABILITATIONThe goal of inter-professional collaboration should be to ensure the inclusion of the child with a developmental disability in school.Interventions delivered in school should focus on changing practice in the classroom, rather than on the child's perceived deficits.The child with a developmental disability should be given influence in collaborative decision-making to ensure supports are relevant and responsive to their needs.


Asunto(s)
Práctica Profesional , Instituciones Académicas , Humanos , Padres
18.
Psychol Med ; 39(11): 1913-21, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19366500

RESUMEN

BACKGROUND: Fatigue syndromes and irritable bowel syndrome (IBS) often occur together. Explanations include being different manifestations of the same condition and simply sharing some symptoms. METHOD: A matched case-control study in UK primary care, using data collected prospectively in the General Practice Research Database (GPRD). The main outcome measures were: health-care utilization, specific symptoms and diagnoses. Risk markers were divided into distant (from 3 years to 1 year before diagnosis) and recent (1 year before diagnosis). RESULTS: A total of 4388 patients with any fatigue syndrome were matched to two groups of patients: those attending for IBS and those attending for another reason. Infections were specific risk markers for both syndromes, with viral infections being a risk marker for a fatigue syndrome [odds ratios (ORs) 2.3-6.3], with a higher risk closer to onset, and gastroenteritis a risk for IBS (OR 1.47, compared to a fatigue syndrome). Chronic fatigue syndrome (CFS) shared more distant risk markers with IBS than other fatigue syndromes, particularly other symptom-based disorders (OR 3.8) and depressive disorders (OR 2.3), but depressive disorders were a greater risk for CFS than IBS (OR 2.4). Viral infections were more of a recent risk marker for CFS compared to IBS (OR 2.8), with gastroenteritis a greater risk for IBS (OR 2.4). CONCLUSIONS: Both fatigue and irritable bowel syndromes share predisposing risk markers, but triggering risk markers differ. Fatigue syndromes are heterogeneous, with CFS sharing predisposing risks with IBS, suggesting a common predisposing pathophysiology.


Asunto(s)
Síndrome de Fatiga Crónica/epidemiología , Síndrome del Colon Irritable/epidemiología , Adulto , Estudios de Casos y Controles , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/epidemiología , Trastorno Depresivo/psicología , Síndrome de Fatiga Crónica/diagnóstico , Síndrome de Fatiga Crónica/psicología , Femenino , Gastroenteritis/diagnóstico , Gastroenteritis/epidemiología , Gastroenteritis/psicología , Humanos , Síndrome del Colon Irritable/diagnóstico , Síndrome del Colon Irritable/psicología , Masculino , Persona de Mediana Edad , Atención Primaria de Salud/estadística & datos numéricos , Estudios Prospectivos , Factores de Riesgo , Reino Unido , Revisión de Utilización de Recursos/estadística & datos numéricos , Virosis/diagnóstico , Virosis/epidemiología , Virosis/psicología
19.
Mucosal Immunol ; 12(1): 51-63, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30356098

RESUMEN

Innate lymphoid cells (ILCs) play an important role in regulating immune responses at mucosal surfaces. The transcription factor T-bet is crucial for the function of ILC1s and NCR+ ILC3s and constitutive deletion of T-bet prevents the development of these subsets. Lack of T-bet in the absence of an adaptive immune system causes microbiota-dependent colitis to occur due to aberrant ILC3 responses. Thus, T-bet expression in the innate immune system has been considered to dampen pathogenic immune responses. Here, we show that T-bet plays an unexpected role in negatively regulating innate type 2 responses, in the context of an otherwise intact immune system. Selective loss of T-bet in ILCs leads to the expansion and increased activity of ILC2s, which has a functionally important impact on mucosal immunity, including enhanced protection from Trichinella spiralis infection and inflammatory colitis. Mechanistically, we show that T-bet controls the intestinal ILC pool through regulation of IL-7 receptor signalling. These data demonstrate that T-bet expression in ILCs acts as the key transcriptional checkpoint in regulating pathogenic vs. protective mucosal immune responses, which has significant implications for the understanding of the pathogenesis of inflammatory bowel diseases and intestinal infections.


Asunto(s)
Colitis/inmunología , Mucosa Intestinal/inmunología , Proteínas de Dominio T Box/metabolismo , Trichinella spiralis/fisiología , Triquinelosis/inmunología , Animales , Células Cultivadas , Humanos , Inmunidad Celular , Inmunidad Innata , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-7/metabolismo , Transducción de Señal , Proteínas de Dominio T Box/genética , Células Th2/inmunología
20.
Br J Pharmacol ; 153(8): 1669-77, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18297106

RESUMEN

BACKGROUND AND PURPOSE: Galegine and guanidine, originally isolated from Galega officinalis, led to the development of the biguanides. The weight-reducing effects of galegine have not previously been studied and the present investigation was undertaken to determine its mechanism(s) of action. EXPERIMENTAL APPROACH: Body weight and food intake were examined in mice. Glucose uptake and acetyl-CoA carboxylase activity were studied in 3T3-L1 adipocytes and L6 myotubes and AMP activated protein kinase (AMPK) activity was examined in cell lines. The gene expression of some enzymes involved in fat metabolism was examined in 3T3-L1 adipocytes. KEY RESULTS: Galegine administered in the diet reduced body weight in mice. Pair-feeding indicated that at least part of this effect was independent of reduced food intake. In 3T3-L1 adipocytes and L6 myotubes, galegine (50 microM-3 mM) stimulated glucose uptake. Galegine (1-300 microM) also reduced isoprenaline-mediated lipolysis in 3T3-L1 adipocytes and inhibited acetyl-CoA carboxylase activity in 3T3-L1 adipocytes and L6 myotubes. Galegine (500 microM) down-regulated genes concerned with fatty acid synthesis, including fatty acid synthase and its upstream regulator SREBP. Galegine (10 microM and above) produced a concentration-dependent activation of AMP activated protein kinase (AMPK) in H4IIE rat hepatoma, HEK293 human kidney cells, 3T3-L1 adipocytes and L6 myotubes. CONCLUSIONS AND IMPLICATIONS: Activation of AMPK can explain many of the effects of galegine, including enhanced glucose uptake and inhibition of acetyl-CoA carboxylase. Inhibition of acetyl-CoA carboxylase both inhibits fatty acid synthesis and stimulates fatty acid oxidation, and this may to contribute to the in vivo effect of galegine on body weight.


Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Guanidinas/farmacología , Complejos Multienzimáticos/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Proteínas Quinasas Activadas por AMP , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/metabolismo , Animales , Línea Celular , Ácidos Grasos/metabolismo , Galega/química , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Complejos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas
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