RESUMEN

BACKGROUND: Angina without angiographic evidence of obstructive coronary artery disease (ANOCA) is a highly prevalent condition with insufficient pathophysiological knowledge and lack of evidence-based medical therapies. This affects ANOCA patients prognosis, their healthcare utilization and quality of life. In current guidelines, performing a coronary function test (CFT) is recommended to identify a specific vasomotor dysfunction endotype. The NetherLands registry of invasive Coronary vasomotor Function testing (NL-CFT) has been designed to collect data on ANOCA patients undergoing CFT in the Netherlands. METHODS: The NL-CFT is a web-based, prospective, observational registry including all consecutive ANOCA patients undergoing clinically indicated CFT in participating centers throughout the Netherlands. Data on medical history, procedural data and (patient reported) outcomes are gathered. The implementation of a common CFT protocol in all participating hospitals promotes an equal diagnostic strategy and ensures representation of the entire ANOCA population. A CFT is performed after ruling out obstructive coronary artery disease. It comprises of both acetylcholine vasoreactivity testing as well as bolus thermodilution assessment of microvascular function. Optionally, continuous thermodilution or Doppler flow measurements can be performed. Participating centers can perform research using own data, or pooled data will be made available upon specific request via a secure digital research environment, after approval of a steering committee. CONCLUSION: NL-CFT will be an important registry by enabling both observational and registry based (randomized) clinical trials in ANOCA patients undergoing CFT.

Asunto(s)

Enfermedad de la Arteria Coronaria , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Angiografía Coronaria/métodos , Países Bajos/epidemiología , Estudios Prospectivos , Calidad de Vida , Sistema de Registros , Vasos Coronarios

RESUMEN

BACKGROUND: Many patients with angina do not have obstructive coronary artery disease (CAD), also referred to as "Ischaemia with No Obstructive Coronary Arteries" (INOCA). Coronary vascular dysfunction is the underlying cause of this ischaemic heart disease in as much as 59-89% of these patients, including the endotypes of coronary microvascular dysfunction and epicardial coronary vasospasm. Currently, a coronary function test (CFT) is the only comprehensive diagnostic modality to evaluate all endotypes of coronary vascular dysfunction in patients with INOCA. OBJECTIVE: In this paper we discuss the relevance of performing a CFT, provide considerations for patient selection, and present an overview of the procedure and its safety. METHODS: We reviewed the latest published data, guidelines and consensus documents, combined with a discussion of novel original data, to present this point of view. RESULTS: The use of a CFT could lead to a more accurate and timely diagnosis of vascular dysfunction, identifies patients at risk for cardiovascular events, and enables stratified treatment which improves symptoms and quality of life. Current guidelines recommend considering a CFT in patients with INOCA and persistent symptoms. The safety of the procedure is comparable to that of a regular coronary angiography with physiological measurements. Non-invasive alternatives have limited diagnostic accuracy for the identification of coronary vascular dysfunction in patients with INOCA, and a regular coronary angiography and/or coronary computed tomography scan cannot establish the diagnosis. CONCLUSIONS: A complete CFT, including acetylcholine and adenosine tests, should be considered in patients with INOCA.

RESUMEN

Ischaemia with no obstructive coronary arteries (INOCA) is a common ischaemic heart disease with a female preponderance, mostly due to underlying coronary vascular dysfunction comprising coronary microvascular dysfunction and/or epicardial coronary vasospasm. Since standard ischaemia detection tests and coronary angiograms are not suitable to diagnose coronary vascular dysfunction, INOCA is often overlooked in current cardiology practice. Future research, including large outcome trials, is much awaited. Yet, adequate diagnosis is possible and treatment options are available and vital to reduce symptoms and most probably improve cardiovascular prognosis. This review intends to give a brief overview of the clinical presentation, underlying pathophysiology, and the diagnostic and treatment options in patients with suspected INOCA.

RESUMEN

OBJECTIVE: We aimed to assess the opinion of Dutch cardiologists on coronary microvascular disease (CMD) and its management in clinical practice, and to assess the need for a CMD guideline among Dutch cardiologists. METHODS: We developed an online questionnaire including different aspects of CMD which was reviewed by an expert panel. The questionnaire was distributed by e­mail among all members of the Dutch Society of Cardiology. RESULTS: A total of 103 cardiologists (70% male) completed the questionnaire (response rate: 10%). Median age and years of experience as a cardiologist were 49 ± 15 and 12 ± 12 years, respectively. Overall, 93% of the cardiologists had considered the CMD diagnosis, 85% had ever made such a diagnosis, 90% had treated a patient with CMD, and 61% had referred patients to tertiary care. The median (interquartile range) self-rated knowledge level was 7.0 (2.0) (scale of 0-10). 84% rated their knowledge as sufficient (>5.5) and 58% viewed CMD as a disease entity. Overall, 61% and 17%, respectively, agreed that evidence-based diagnostic and treatment modalities for CMD do not exist, while 56% believed that CMD patients have a higher risk for cardiovascular disease and mortality. Finally, 82% of the responders stated that a CMD guideline is needed, and 91% wanted to receive the guideline once developed. DISCUSSION: Fifty-eight per cent of the responders recognise CMD as a separate disease entity. Our study underscores the need for a dedicated CMD guideline for Dutch cardiology practice. However, the response rate was low (10%), and it is likely that mainly cardiologists interested in CMD have participated in our study.

RESUMEN

Using Triumf's neutral atom trap, Trinat, for nuclear ß decay, we have measured the ß asymmetry with respect to the initial nuclear spin in ^{37}K to be A_{ß}=-0.5707(13)_{syst}(13)_{stat}(5)_{pol}, a 0.3% measurement. This is the best relative accuracy of any ß-asymmetry measurement in a nucleus or the neutron, and is in agreement with the standard model prediction -0.5706(7). We compare constraints on physics beyond the standard model with other ß-decay measurements, and improve the value of V_{ud} measured in this mirror nucleus by a factor of 4.

RESUMEN

We measure the transport properties of two-dimensional ultracold Fermi gases during transverse demagnetization in a magnetic field gradient. Using a phase-coherent spin-echo sequence, we are able to distinguish bare spin diffusion from the Leggett-Rice effect, in which demagnetization is slowed by the precession of a spin current around the local magnetization. When the two-dimensional scattering length is tuned to be comparable to the inverse Fermi wave vector k_{F}^{-1}, we find that the bare transverse spin diffusivity reaches a minimum of 1.7(6)ℏ/m, where m is the bare particle mass. The rate of demagnetization is also reflected in the growth rate of the s-wave contact, observed using time-resolved spectroscopy. The contact rises to 0.28(3)k_{F}^{2} per particle, which quantifies how scaling symmetry is broken by near-resonant interactions, unlike in unitary three-dimensional systems. Our observations support the conjecture that, in systems with strong scattering, the local relaxation rate is bounded from above by k_{B}T/ℏ.

RESUMEN

BACKGROUND: Trastuzumab is successfully used for the treatment of HER2-positive breast cancer. Because of its association with cardiotoxicity, LVEF is monitored by MUGA, though this is a relatively late measure of cardiac function. Diastolic dysfunction (DD) is believed to be an early predictor of cardiac impairment. We evaluate the merit of MUGA-derived diastolic function parameters in the early detection of trastuzumab-induced cardiotoxicity (TIC). METHODS AND RESULTS: 77 trastuzumab-treated patients with normal baseline systolic and diastolic function were retrospectively selected (n = 77). All serial MUGA examinations were re-analyzed for systolic and diastolic function parameters. 36 patients (47%) developed SD and 45 patients (58%) DD during treatment. Both systolic and diastolic parameters significantly decreased. Of the patients with SD, 24 (67%) also developed DD. DD developed prior to systolic impairment in 54% of cases, in 42% vice versa, while time to occurrence did not differ significantly (P = .52). This also applied to the subgroup of advanced stage breast cancer patients (P = .1). CONCLUSIONS: Trastzumab-induced SD and DD can be detected by MUGA. An impairment of MUGA-derived diastolic parameters does not occur prior to SD and therefore cannot be used as earlier predictors of TIC.

Asunto(s)

Neoplasias de la Mama/tratamiento farmacológico , Angiografía Coronaria/métodos , Angiografía por Radionúclidos/métodos , Volumen Sistólico/efectos de los fármacos , Trastuzumab/efectos adversos , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/diagnóstico por imagen , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias de la Mama/complicaciones , Cardiotoxinas/efectos adversos , Cardiotoxinas/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Trastuzumab/uso terapéutico , Resultado del Tratamiento

RESUMEN

We observe that the diffusive spin current in a strongly interacting degenerate Fermi gas of (40)K precesses about the local magnetization. As predicted by Leggett and Rice, precession is observed both in the Ramsey phase of a spin-echo sequence, and in the nonlinearity of the magnetization decay. At unitarity, we measure a Leggett-Rice parameter γ=1.08(9) and a bare transverse spin diffusivity D(0)(⊥)=2.3(4)ℏ/m for a normal-state gas initialized with full polarization and at one-fifth of the Fermi temperature, where m is the atomic mass. One might expect γ=0 at unitarity, where two-body scattering is purely dissipative. We observe γ→0 as temperature is increased towards the Fermi temperature, consistent with calculations that show the degenerate Fermi sea restores a nonzero γ. Tuning the scattering length a, we find that a sign change in γ occurs in the range 0<(k(F)a)(-1)≲1.3, where k(F) is the Fermi momentum. We discuss how γ reveals the effective interaction strength of the gas, such that the sign change in γ indicates a switching of branch between a repulsive and an attractive Fermi gas.

RESUMEN

It is clear that neural differentiation from human pluripotent stem cells generates cells that are developmentally immature. Here, we show that the let-7 plays a functional role in the developmental decision making of human neural progenitors, controlling whether these cells make neurons or glia. Through gain- and loss-of-function studies on both tissue and pluripotent derived cells, our data show that let-7 specifically regulates decision making in this context by regulation of a key chromatin-associated protein, HMGA2. Furthermore, we provide evidence that the let-7/HMGA2 circuit acts on HES5, a NOTCH effector and well-established node that regulates fate decisions in the nervous system. These data link the let-7 circuit to NOTCH signaling and suggest that this interaction serves to regulate human developmental progression.

Asunto(s)

MicroARNs/genética , Neuroglía/metabolismo , Células Madre Pluripotentes/metabolismo , Receptores Notch/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular/genética , Línea Celular , Regulación del Desarrollo de la Expresión Génica , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Inmunohistoquímica , MicroARNs/metabolismo , Sistema Nervioso/citología , Sistema Nervioso/crecimiento & desarrollo , Sistema Nervioso/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neurogénesis/genética , Neuroglía/citología , Neuronas/citología , Neuronas/metabolismo , Oligodendroglía/citología , Oligodendroglía/metabolismo , Células Madre Pluripotentes/citología , Interferencia de ARN , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores Notch/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética

RESUMEN

BACKGROUND AND PURPOSE: Excess morbidity/mortality in rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease. In this 'proof-of-concept' study, vascular function was characterized in the murine collagen-induced arthritis (mCIA) model, the benchmark choice for evaluation of the pathological processes and assessment of new therapies. EXPERIMENTAL APPROACH: Mice in the very early stages of arthritis development [and appropriate naïve (non-immunized) age-matched controls] were used in the study. Blood pressure was measured using tail cuff plethysmography. Vascular function in rings of isolated aorta was studied with isometric tension myography. Levels of NO metabolites (NO(x)), MMP-9 protein and IL-1ß in plasma and MMP-9 protein in aortic homogenates were quantified. KEY RESULTS: Impaired vascular contractile responses in arthritis were unaffected by ex vivo inhibition of NOS (endothelial/neuronal and inducible) or COX activities. Endothelium-dependent and -independent relaxation, plasma NO(x) and blood pressure were unaffected by arthritis. Plasma and aortic homogenate MMP-9 protein levels were increased significantly in arthritis. Incubation of aortic tissues from naïve control animals with exogenous MMP-9 impaired subsequent contractile responses, mirroring that observed in arthritis. A role for IL-1ß in perpetuating contractile dysfunction and increasing aortic MMP-9 was excluded. CONCLUSIONS AND IMPLICATIONS: These data identify for the first time a relationship between early arthritis and contractile dysfunction and a possible role for MMP-9 therein, in the absence of overt endothelial dysfunction or increased NO production. As such, MMP-9 may constitute a significant target for early intervention in RA patients with a view to decreasing risk of cardiovascular disease.

Asunto(s)

Aorta Torácica/metabolismo , Artritis Experimental/fisiopatología , Metaloproteinasa 9 de la Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Animales , Aorta Torácica/enzimología , Artritis Experimental/complicaciones , Presión Sanguínea , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Interleucina-1beta/sangre , Masculino , Ratones , Ratones Endogámicos DBA , Contracción Muscular , Miografía , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo

RESUMEN

It has been demonstrated that aortic stiffness is an independent predictor of cardiovascular disease. We investigated whether this measure is of use in cardiovascular risk stratification in clinical practice for elderly subjects (mean age 71.5 years). Within the framework of the Rotterdam Study, we stratified subjects free of coronary heart disease (CHD) at baseline into categories of low (<10%), intermediate (10-20%) and high (>20%) 10-year risk of CHD based on Framingham risk factors. Within each risk category, we determined the percentages of subjects moving into a higher or lower risk category when adding aortic stiffness to the Framingham risk factors. Among 2849 participants, 223 CHD events occurred during a median follow-up of 7.9 years. In the low risk group, 5% of the subjects could be reclassified and in the high-risk group, 6% of the subjects could be reclassified to the intermediate-risk group. In the intermediate-risk group 3% could be reclassified to the high-risk group and 6% to the low-risk group. In a population of elderly subjects, aortic stiffness measurement in addition to Framingham risk factors leads to a limited reclassification of subjects in 10-year cardiovascular disease-risk categories. Therefore, aortic stiffness is associated with the risk of CHD in elderly, but provides no additional value in cardiovascular risk stratification.

Asunto(s)

Enfermedad Coronaria/epidemiología , Rigidez Vascular , Anciano , Antihipertensivos , Colesterol/sangre , Enfermedad Coronaria/tratamiento farmacológico , Enfermedad Coronaria/fisiopatología , Diabetes Mellitus/sangre , Diabetes Mellitus/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Hipolipemiantes/sangre , Masculino , Persona de Mediana Edad , Medición de Riesgo

RESUMEN

The endoderm is a multipotent progenitor cell population in the embryo that gives rise to the liver, pancreas, and other cell types and provides paradigms for understanding cell-type specification. Studies of isolated embryo tissue cells and genetic approaches in vivo have defined fibroblast growth factor/mitogen-activated protein kinase (FGF/MAPK) and bone morphogenetic protein (BMP) signaling pathways that induce liver and pancreatic fates in the endoderm. In undifferentiated endoderm cells, the FoxA and GATA transcription factors are among the first to engage silent genes, helping to endow competence for cell-type specification. FoxA proteins can bind their target sites in highly compacted chromatin and open up the local region for other factors to bind; hence, they have been termed "pioneer factors." We recently found that FoxA proteins remain bound to chromatin in mitosis, as an epigenetic mark. In embryonic stem cells, which lack FoxA, FoxA target sites can be occupied by FoxD3, which in turn helps to maintain a local demethylation of chromatin. By these means, a cascade of Fox factors helps to endow progenitor cells with the competence to activate genes in response to tissue-inductive signals. Understanding such epigenetic mechanisms for transcriptional competence coupled with knowledge of the relevant signals for cell-type specification should greatly facilitate efforts to predictably differentiate stem cells to liver and pancreatic fates.

Asunto(s)

Células Madre Embrionarias/citología , Hígado/embriología , Páncreas/embriología , Animales , Cromatina/genética , Cromatina/metabolismo , Células Madre Embrionarias/metabolismo , Endodermo/citología , Endodermo/embriología , Endodermo/metabolismo , Elementos de Facilitación Genéticos , Epigénesis Genética , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Hígado/citología , Hígado/metabolismo , Ratones , Mitosis , Modelos Biológicos , Células Madre Multipotentes/citología , Células Madre Multipotentes/metabolismo , Páncreas/citología , Páncreas/metabolismo , Embarazo , Transducción de Señal

Asunto(s)

Anticuerpos Monoclonales/efectos adversos , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Paraproteinemias/inducido químicamente , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Anciano , Progresión de la Enfermedad , Humanos , Infliximab , Masculino , Mieloma Múltiple/inducido químicamente , Lesiones Precancerosas/inducido químicamente

Asunto(s)

Angina de Pecho/etiología , Anomalías de los Vasos Coronarios , Fístula/complicaciones , Ventrículos Cardíacos/anomalías , Antagonistas Adrenérgicos beta/uso terapéutico , Angina de Pecho/tratamiento farmacológico , Angiografía Coronaria , Anomalías de los Vasos Coronarios/diagnóstico por imagen , Femenino , Fístula/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Persona de Mediana Edad

RESUMEN

The regulatory steps that lead to the differentiation of hematopoietic cells from a multipotential stem cell remain largely unknown. A beginning to the understanding of these steps has come from the study of DNA-binding proteins that are thought to regulate the expression of genes required for specific developmental events. Ikaros is the founding member of a small family of DNA-binding proteins required for lymphocyte development, but the members of this family differ from other key regulators of lymphopoiesis in that direct target genes have not been conclusively identified, and reasonable support has been presented for only a few potential targets. Therefore, the molecular mechanisms that Ikaros uses for regulating lymphocyte development remain largely unknown. Current data suggest that, in some instances, Ikaros may function as a typical transcription factor. However, recent results suggest that it may function more broadly, perhaps in the formation of silent and active chromatin structures. In this review, our current knowledge of the molecular functions of Ikaros will be discussed.

Asunto(s)

Factor de Transcripción Ikaros/fisiología , Linfocitos/fisiología , Linfopoyesis , Animales , Diferenciación Celular , Centrómero/metabolismo , Cromatina/metabolismo , Regulación de la Expresión Génica , Humanos , Factor de Transcripción Ikaros/química , Factor de Transcripción Ikaros/genética

RESUMEN

BACKGROUND: Previous researchers have shown that non-medical endoscopists can perform lower gastrointestinal endoscopy as safely and effectively as medical staff. However, it is not known if upper gastrointestinal endoscopy performed by medical and non-medical endoscopists in clinical practice yields similar results in terms of performance, patient discomfort, and satisfaction. AIM: To determine differences in the yield of diagnosis for significant disease during upper gastrointestinal endoscopy performed by nurse and medical endoscopists and to measure patient discomfort, satisfaction, and attitudes towards future endoscopy. PATIENTS: This two part study included 3009 patients in a retrospective analysis and 480 in a prospective study. METHODS: The first part of the study assessed indications for endoscopy, diagnoses, and procedures performed by medical and nurse endoscopists. In a second prospective study, 480 patients were included to determine the association between endoscopist type and sedation, patient anxiety, discomfort, satisfaction, and attitudes towards future sedation. RESULTS: No patient refused endoscopy by either a nurse or medical endoscopist and there were no complications in either group. Nurses performed 1487 procedures and reported fewer endoscopies as "normal" than medical staff (p=0.006). Multivariate analysis showed that male sex, older age, inpatient status, dysphagia, and gastrointestinal bleeding, but not endoscopist type, were all associated with significant disease. In relation to discomfort and satisfaction, a similar proportion of patients received sedation in both groups (p=0.81). There were no differences in pre-procedure anxiety (p=0.61), discomfort during intubation (p=0.97), discomfort during examination (p=0.90), or post-procedure examination rating (p=0.79) in patients examined by medical or nurse endoscopists. CONCLUSION: Experienced nurses perform routine diagnostic gastroscopy safely in everyday clinical practice and with as little discomfort and as much patient satisfaction as medical staff.

Asunto(s)

Endoscopía Gastrointestinal/enfermería , Enfermeras y Enfermeros/normas , Factores de Edad , Ansiedad/etiología , Competencia Clínica/normas , Sedación Consciente , Endoscopía Gastrointestinal/tendencias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Estudios Prospectivos , Estudios Retrospectivos

Asunto(s)

Regulación de la Expresión Génica/genética , Regiones Promotoras Genéticas , Animales , Elementos de Facilitación Genéticos

RESUMEN

While considerable progress has been made in understanding the mechanisms of transcription in higher eukaryotes, transcription in single-celled, primitive eukaryotes remains poorly understood. Promoters of protein-encoding genes in the parasitic protist Trichomonas vaginalis, which represents one of the deepest-branching eukaryotic lineages, have a bipartite structure with gene-specific regulatory elements and a conserved core promoter encompassing the transcription start site. Core promoters in T. vaginalis appear to consist solely of a highly conserved initiator (Inr) element that is both a structural and a functional homologue of its metazoan counterpart. Using DNA affinity chromatography, we have isolated an Inr-binding protein from T. vaginalis. Cloning of the gene encoding the Inr binding protein identified a novel 39-kDa protein (IBP39). We show that IBP39 binds to both double and single Inr motifs found in T. vaginalis genes and that binding requires the conserved nucleotides necessary for Inr function in vivo. Analyses of the cloned IBP39 gene revealed no homology at the protein sequence level with identified proteins in other organisms or the presence of known DNA-binding domains. The relationship between IBP39 and Inr-binding proteins in metazoa presents interesting evolutionary questions.

Asunto(s)

Proteínas de Unión al ADN/genética , Proteínas Protozoarias/genética , Sitio de Iniciación de la Transcripción , Trichomonas vaginalis/genética , Trichomonas vaginalis/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Sitios de Unión , Cromatografía de Afinidad/métodos , Clonación Molecular , ADN Protozoario , Proteínas de Unión al ADN/aislamiento & purificación , Proteínas de Unión al ADN/metabolismo , Células Eucariotas , Datos de Secuencia Molecular , Proteínas Protozoarias/aislamiento & purificación , Proteínas Protozoarias/metabolismo

RESUMEN

Non-steroidal anti-inflammatory drugs cause small-bowel inflammation in about 60% of patients receiving these drugs long-term. The inflammation is associated with small intestinal bleeding, protein loss, ulcers and occasionally strictures. Treatment options for NSAID enteropathy include metronidazole, sulphasalazine and misoprostol, and some patients may require surgery. The diagnosis of NSAID enteropathy is not always straightforward. It is especially difficult to differentiate it from the ileitis associated with spondylarthropathy and, at times, that of Crohn's disease. An investigational algorithm is suggested for this purpose. In the last decade a number of small-bowel diseases have been identified, where none were thought to exist, because of the increasing use of enteroscopy and new sensitive tests for intestinal inflammation. Optimal treatments of these conditions are still to be studied.

Asunto(s)

Antiinflamatorios no Esteroideos/efectos adversos , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/epidemiología , Mucosa Intestinal/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Algoritmos , Diagnóstico Diferencial , Humanos , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/etiología , Espondiloartropatías/complicaciones , Reino Unido/epidemiología

RESUMEN

Ikaros is a unique regulator of lymphopoiesis that associates with pericentromeric heterochromatin and has been implicated in heritable gene inactivation. Binding and competition experiments demonstrate that Ikaros dimers compete with an Ets activator for occupancy of the lymphocyte-specific TdT promoter. Mutations that selectively disrupt Ikaros binding to an integrated TdT promoter had no effect on promoter function in a CD4(+)CD8(+) thymocyte line. However, these mutations abolished down-regulation on differentiation, providing evidence that Ikaros plays a direct role in repression. Reduced access to restriction enzyme cleavage suggested that chromatin alterations accompany down-regulation. The Ikaros-dependent down-regulation event and the observed chromatin alterations appear to precede pericentromeric repositioning. Current models propose that the functions of Ikaros should be disrupted by a small isoform that retains the dimerization domain and lacks the DNA-binding domain. Surprisingly, in the CD4(+)CD8(+) thymocyte line, overexpression of a small Ikaros isoform had no effect on differentiation or on the pericentromeric targeting and DNA-binding properties of Ikaros. Rather, the small isoform assembled into multimeric complexes with DNA-bound Ikaros at the pericentromeric foci. The capacity for in vivo multimer formation suggests that interactions between Ikaros dimers bound to the TdT promoter and those bound to pericentromeric repeat sequences may contribute to the pericentromeric repositioning of the inactive gene.

Asunto(s)

ADN Nucleotidilexotransferasa/genética , Proteínas de Unión al ADN , Linfocitos T/fisiología , Factores de Transcripción/metabolismo , Sitios de Unión , Unión Competitiva , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/fisiología , Diferenciación Celular , Línea Celular , Centrómero , Cromatina/ultraestructura , ADN Nucleotidilexotransferasa/biosíntesis , Regulación hacia Abajo , Efrina-A2 , Factor de Transcripción Ikaros , Modelos Genéticos , Regiones Promotoras Genéticas , Unión Proteica , Conformación Proteica , Secuencias Repetitivas de Ácidos Nucleicos , Linfocitos T/citología , Timo/citología , Timo/fisiología , Transcripción Genética