No abstract

cAMP-regulated transcription of the human vasoactive intestinal peptide gene is dependent upon a 17-basepair DNA element located 70 base pairs upstream from the transcriptional initiation site. This element is similar to sequences in other genes known to be regulated by cAMP and to sequences in several viral enhancers. We have demonstrated that the vasoactive intestinal peptide regulatory element is an enhancer that depends upon the integrity of two CGTCA sequence motifs for biological activity. Mutations in either of the CGTCA motifs diminish the ability of the element to respond to cAMP. Enhancers containing the CGTCA motif from the somatostatin and adenovirus genes compete for binding of nuclear proteins from C6 glioma and PC12 cells to the vasoactive intestinal peptide enhancer, suggesting that CGTCA-containing enhancers interact with similar transacting factors.DNA control elements that activate transcription in response to intracellular effectors such as cAMP or products of phosphoinositol metabolism have been identified in several cellular and viral genes (1-6). These genetic elements may be particularly important in neuroendocrine cells where the activation of intracellular second messenger pathways may couple secretion and biosynthesis of neuropeptides (7,8). The genetic element responsible for cAMP-regulated transcription of the human vasoactive intestinal peptide (VIP) gene consists ofa 17-base-pair (bp) sequence located between 70 and 86 bp upstream from the transcriptional initiation site (5). This sequence in the VIP gene is similar to the cAMPresponsive elements (CREs) of the rat somatostatin, human proenkephalin, human a-chorionic gonadotrophin, and rat phosphoenolpyruvate carboxykinase genes (1-5). All of these CREs contain one or multiple copies of the conserved sequence motif CGTCA and several have been shown to have properties of enhancers (2-4). The CGTCA motif is also found in several viral enhancers such as the 18-bp repeat of the cytomegalovirus gene and the ElA-inducible element of the adenovirus E4 promoter (9, 10). The presence of the CGTCA motif in these viral enhancers suggests that similar nuclear factors may activate transcription of both viral and cellular genes. In the VIP CRE, the two CGTCA motifs are present as inverted repeats, a structure characteristic of some other enhancers (11-13). It is not known whether the palindromic structure of the VIP CRE is necessary for biological activity.In this study, three major issues were addressed. First, we sought to determine whether the VIP CRE could be categorized as an enhancer. Second, we examined the importance of the CGTCA motifs for activity of the DNA element.

Thrombotic complications in patients with inflammatory bowel disease (IBD) are common and require improved awareness and prevention. In this review the interface between IBD and thrombosis is discussed, with emphasis on risk assessment and data to aid clinical decision making. Thromboembolic complications are 3-fold more likely in IBD patients than controls and the relative risk exceeds 15 during disease flares. Improved assessment of thrombosis risk for an individual patient includes thorough personal and family history and awareness of prothrombotic medications and lifestyle choices. Patients with the highest risk of thrombosis are those with active colonic disease, personal or strong family history of thrombosis, and those with significant acquired risk factors. Combined risk factors or hospitalization should prompt mechanical thromboprophylaxis. Indications for prophylactic anticoagulation are not defined currently by clinical studies, especially in pediatric patients, although some groups now advocate prophylactic anticoagulation for all hospitalized IBD patients and even some outpatients with disease flares. Thrombosis management requires a multidisciplinary therapeutic approach to balance anticoagulation and bleeding risk. While bleeding may occur with anticoagulation in IBD, data and experience indicate that therapeutic heparin is safe and bleeding manifestations can be managed supportively in most patients. Until prospective trials of prophylactic anticoagulation are published, management of thrombotic risk and prophylaxis in IBD will remain a clinical challenge.

Pediatric inpatients hospitalized with IBD with colonic involvement have increased risk of TE, including complications of pulmonary embolism, recurrence, persistence, and indefinite long-term anticoagulation. Therapeutic anticoagulation in patients with IBD with active colitis appears safe. We identified both inherited thrombophilias and acquired risk factors in patients with IBD and TE. We presently use risk stratification and recommend prophylactic anticoagulation in high-risk patients.