The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase

Notch signaling is involved in numerous cell fate decisions in invertebrates and vertebrates. The Notch receptor is a type I transmembrane (TM) protein that undergoes two proteolytic steps after ligand binding, first by an ADAM (a distintegrin and metalloprotease) in the extracellular region, followed by gamma-secretase-mediated cleavage inside the TM domain. We demonstrate here that the murine ligand Delta1 (Dll1) undergoes the same sequence of cleavages, in an apparently signal-independent manner. Identification of the ADAM-mediated shedding site localized 10 aa N-terminal to the TM domain has enabled us to generate a noncleavable mutant. Kuzbanian/ADAM10 is involved in this processing event, but other proteases can probably substitute for it. We then show that Dll1 is part of a high-molecular-weight complex containing presenilin1 and undergoes further cleavage by a gamma-secretase-like activity, therefore releasing the intracellular domain that localizes in part to the nucleus. Using the shedding-resistant mutant, we demonstrate that this gamma-secretase cleavage depends on prior ectodomain shedding. Therefore Dll1 is a substrate for regulated intramembrane proteolysis, and its intracellular region possibly fulfills a specific function in the nucleus.     

Assessment of atrial septal defect size with 3D-transesophageal echocardiography: comparison with balloon method

BACKGROUND: Transcatheter closure of atrial septal defect (ASD) is an alternative approach to surgery in selected patients. Balloon stretched diameter (BSD) is considered as the standard way of measuring ASD size. Three-dimensional transesophageal echocardiography (3D-TEE) provides views of the ASD allowing its measurement and identifying its spatial relation with neighboring structures. Our aim was to compare the BSD and 3D-TEE methods to measure the ASD size before transcatheter closure. METHODS AND RESULTS: Seventy-six consecutive patients were enrolled for ASD device closure. Three-dimensional transesophageal echocardiography and balloon sizing were adequately performed in 70 patients before the defect closure. The mean maximal diameter measured by 3D-TEE was 20 +/- 15 mm (range 10-28) while the mean BSD was 22 +/- 4.8 mm (range 9-31). When comparing the 3D-TEE and transcatheter measurements, there was a good correlation between the two methods (y = 3.15 + 0.77x; r = 0.8). The defect as viewed by 3D-TEE was unique in 54 patients and multiple in 16 patients. In patients with a single defect, the correlation between the two methods was high (y = 1.74 + 0.84x; r = 0.85) while patients with multiple ASDs, the correlation was poor (y = 12.4 + 0.4x; r = 0.45). Transcatheter closure was performed successfully in 86%. The mean size of the Amplatzer device was 23 +/- 4.8 mm (range 4-32). The reference to choose the size of the device was the BSD in single defects and the 3D-TEE maximal diameter in multiple defects. CONCLUSION: Three-dimensional transesophageal echocardiography and transcatheter methods are two complementary techniques for the success of transcatheter ASDs closure.     

Radiotherapy for head and neck cancer in nonagenarian patients: a possible cornerstone?

European Archives of Oto-Rhino-Laryngology - In the field of radiotherapy, there is very little scientific data on the management of nonagenarians, especially in patients aged 90 years or...     

Perforation of the atretic pulmonary valve. Long-term follow-up

OBJECTIVES: We evaluated the long-term results of perforation of the pulmonary valve in patients with pulmonary atresia with an intact ventricular septum (PA-IVS). BACKGROUND: Interventional perforation of the pulmonary valve is considered the elective first stage treatment for PA-IVS, particularly in patients with a tripartite right ventricle (RV) and normal coronary circulation. However, the long-term results of this procedure are lacking. METHODS: Between January 1991 and December 2001, 39 newborns with a favorable form of PA-IVS underwent attempted perforation of the pulmonary valve. We evaluated the early and long-term outcomes. RESULTS: Median tricuspid and pulmonary z values were -1.2 and -2.4, respectively. Perforation was successful in 33 patients. Among them, 17 needed neonatal surgery, 13 did not need any surgery, and 3 had elective surgery after the first month of life. There were two procedure-related deaths, seven nonfatal procedural complications, and four postsurgical deaths. Compared with patients needing neonatal surgery, those having no or elective surgery had a higher incidence of a tripartite RV and a higher median tricuspid z value (92% vs. 53%, p = 0.04 and -1.7 vs. -0.5, p = 0.03). At a median follow-up of 5.5 years (range 0.5 to 11.5), survival was 85% and freedom from surgery was 35%. Five patients, four of whom had neonatal surgery, underwent a partial cavo-pulmonary connection. CONCLUSIONS: Our results show that this technique, although burdened by non-negligible mortality and morbidity, is effective in selected patients with a normal-sized RV. Preselection of patients allows interventional or surgical biventricular correction in the majority of cases.