Tissue-specific targeting of cell fate regulatory genes by E2f factors.

Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. Identification of the genes targeted by E2 promoter binding factor (E2f) transcription factors, effectors of the pRb/E2f cell cycle pathway, will provide essential insights into these mechanisms. We identified the promoter regions bound by three neurogenic E2f factors in neural precursor cells in a genome-wide manner. Through bioinformatic analyses and integration of published genomic data sets we uncovered hundreds of transcriptionally active E2f-bound promoters corresponding to genes that control cell fate processes, including key transcriptional regulators and members of the Notch, fibroblast growth factor, Wnt and Tgf-ß signaling pathways. We also demonstrate a striking enrichment of the CCCTC binding factor transcription factor (Ctcf) at E2f3-bound nervous system-related genes, suggesting a potential regulatory co-factor for E2f3 in controlling differentiation. Finally, we provide the first demonstration of extensive tissue specificity among E2f target genes in mammalian cells, whereby E2f3 promoter binding is well conserved between neural and muscle precursors at genes associated with cell cycle processes, but is tissue-specific at differentiation-associated genes. Our findings implicate the cell cycle pathway as a widespread regulator of cell fate genes, and suggest that E2f3 proteins control cell type-specific differentiation programs by regulating unique sets of target genes. This work significantly enhances our understanding of how the cell cycle machinery impacts cell fate and differentiation, and will importantly drive further discovery regarding the mechanisms of cell fate control and transcriptional regulation in the brain, as well as in other tissues.

[Evolution in the epidemiology of non-variceal upper digestive hemorrhage from 1985 to 2006]. / Evolución en la epidemiología de la hemorragia digestiva alta no varicosa desde el año 1985 hasta 2006.

OBJECTIVES: to describe changes occurred in the characteristics of patients suffering from non-variceal upper gastrointestinal bleeding, and in this condition s epidemiology. METHODS: a prospective study was carried out to examine the occurrence and causes of non-variceal upper digestive bleeding in the corresponding health department at Virgen de las Nieves Hospital in Granada, Spain. In this study three periods of time were compared. Group 1 (1985): 284 patients; group 2 (1996): 259 patients; and group 3 (2006) 291 patients. RESULTS: in group 1 the incidence was 71/100,000 inhabitants; in group 2, 64/100,000; and in group 3, 66/100,000. Mean age in 1985 was 57.4; in 1996, 59.6; and in 2006, 62.38. In all groups a majority of cases were men (75.4, 69.5, and 72.2%, respectively). Major causes included duodenal ulcer (1: 40.5%; 2: 43.2%; 3: 40.5%), gastric ulcer (1: 24.3%; 2: 30%; 3: 18.9%); LAMG (1: 53.3%; 2: 43.2%; 3: 9.6%); neoplasia (1: 1.7%; 2: 1.9%; 3: 5.2%), and vascular injuries (1: 0.5%; 2: 1.5%; 3: 9.3%). The death rate was 2.5% in 1985; 1.5% in 1996; and 1% in 2006. CONCLUSIONS: a significant increase in mean age over the years was detected. The most frequent cause of hemorrhage was duodenal ulcer followed by gastric ulcer. Of significance is an increase in the proportion of neoplasms above of vascular injuries in the later group as apposed to the earlier one. We found no significant difference in mortality between groups.

pRB-E2F1 complexes are resistant to adenovirus E1A-mediated disruption.

Disruption of pRB-E2F interactions by E1A is a key event in the adenoviral life cycle that drives expression of early viral transcription and induces cell cycle progression. This function of E1A is complicated by E2F1, an E2F family member that controls multiple processes besides proliferation, including apoptosis and DNA repair. Recently, a second interaction site in pRB that only contacts E2F1 has been discovered, allowing pRB to control proliferation separately from other E2F1-dependent activities. Based on this new insight into pRB-E2F1 regulation, we investigated how E1A affects control of E2F1 by pRB. Our data reveal that pRB-E2F1 interactions are resistant to E1A-mediated disruption. Using mutant forms of pRB that selectively force E2F1 to bind through only one of the two binding sites on pRB, we determined that E1A is unable to disrupt E2F1's unique interaction with pRB. Furthermore, analysis of pRB-E2F complexes during adenoviral infection reveals the selective maintenance of pRB-E2F1 interactions despite the presence of E1A. Our experiments also demonstrate that E2F1 functions to maintain cell viability in response to E1A expression. This suggests that adenovirus E1A's seemingly complex mechanism of disrupting pRB-E2F interactions provides selectivity in promoting viral transcription and cell cycle advancement, while maintaining cell viability.

Characterization of an E2F1-specific binding domain in pRB and its implications for apoptotic regulation.

The retinoblastoma protein (pRB) has the dual capability to negatively regulate both E2F-induced cell cycle entry and E2F1-induced apoptosis. In this report, we characterize a unique pRB-E2F1 interaction. Using mutagenesis to disrupt E2F1 binding, we find that the ability of pRB to regulate E2F1-induced apoptosis is diminished when this interaction is lost. Strikingly, this mutant form of pRB retains the ability to control E2F responsive cell cycle genes and blocks cell proliferation. These functional properties are the reciprocal of a previously described E2F binding mutant of pRB that interacts with E2F1, but lacks the ability to interact with other E2Fs. Our work shows that these distinct interactions allow pRB to separately regulate E2F-induced cell proliferation and apoptosis. This suggests a novel form of regulation whereby separate types of binding contacts between the same types of molecules can confer distinct functional outcomes.

[Thromboembolic complications in inflammatory bowel disease]. / Complicaciones tromboembólicas en la enfermedad inflamatoria intestinal.

Thromboembolic complications during the course of inflammatory bowel disease are infrequent but are mainly found in young patients and are associated with a high morbimortality. The etiopathogenesis of these complications has been widely debated and the existence of coagulation alterations and fibrinolysis have been suggested. Nonetheless, the mechanism must be complex since not only do not all the patients with these alterations present this complication but neither do all the patients with thromboembolism have recognized coagulation disorders. The most common clinical presentation is deep vein thrombosis with pulmonary embolism with arterial thrombosis being rare. Five patients with Crohn's disease and two with ulcerative colitis who presented a total of new thromboembolic episodes, six arterial (1 in primitive iliac artery, 1 in common femoral artery, 1 in humeral-axillary artery, 2 in internal carotid and 1 in superior mesenteric artery) and three of venous localization (1 in brachyocephalic-subclavian trunk, 1 axillary and 1 iliac-femoral/pulmonary thromboembolism) are reported. An updated review of the etiopathogenesis, presentation, treatment and prophylaxis of the thromboembolic complications of inflammatory bowel disease is presented.

[Pseudotumorous hepatic tuberculosis: laparoscopic appearance]. / Tuberculosis hepática seudotumoral. Aspecto laparoscópico.

Local hepatic tuberculosis without active pulmonary or miliary tuberculosis is an uncommon diagnosis. Even less common is the finding of a nodular form of local hepatic tuberculosis. There is a growing incidence of the disease related to human immunodeficiency virus. The authors report a case of pseudotumoral hepatic tuberculosis in a patient without AIDS, manifesting as prolonged fever, diagnosed previously as metastatic liver. Imaging studies of the liver and laparoscopic findings suggested metastatic disease. The correct diagnosis was made by histology of biopsies obtained in laparoscopy, which is an easy and cheap method, with less morbidity and mortality than surgical intervention. The case report illustrates the difficulty in reaching the correct diagnosis, most often confused with carcinoma of the liver, primary or metastatic. A greater awareness of this rare clinical entity may prevent needless surgical intervention since the majority of patients respond well to antituberculous chemotherapy.

[Purtscher's retinopathy and acute alcoholic pancreatitis]. / Retinopatía de Purtscher y pancreatitis aguda alcohólica.

We report the case of a 27-year-old man with alcoholic acute pancreatitis, who developed an acute loss of visual acuity; a bilateral Purtscher's retinopathy, a rare complication of acute pancreatitis, was confirmed by ophthalmoscopy.

[Caroli's syndrome: a variable entity]. / Síndrome de Caroli: una entidad variable.

We present the case of a 56 year old woman with Caroli's disease associated to congenital liver fibrosis, renal nephrocalcinosis and cutaneous vasculitis of the legs. Clinical signs of portal hypertension were treated by a shunt technique. After an asymptomatic period, the patient suffers now from crisis of angiocholitis.

The occurrence of fibromuscular dysplasia in the arteries of domestic turkeys.

Fibromuscular dysplasia (FMD) was found in 24 of 31 turkeys studied. This is the first species other than man in which FMD has been reported. FMD in turkeys simulates lesions variously known as fibromuscular dysplasia, fibromuscular hyperplasia, and medial hyperplasia in man. It occurred in turkeys from 8 weeks to 1 year of age and was evenly distributed between the sexes (11 males, 13 females). FMD in turkeys is a disease of arterioles and small arteries 44 mu to 666 mu in diameter. A lesion of more than 2.6 mm in length (in an artery 0.1 mm in diameter) was encountered. An adherent thrombus over 670 mu long was seen attached to an FMD lesion. Angiopathy appears to be basic to the pathogenesis of FMD and is characterized by endothelial hyperplasia, smooth-muscle vacuolization, and patchy necrosis of the media.