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Complete Abolition (complete + abolition)
Selected AbstractsInhibition of human ether à go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-terminiFEBS JOURNAL, Issue 5 2006Ulrike Ziechner Human ether à go-go potassium channels (hEAG1) open in response to membrane depolarization and they are inhibited by Ca2+/calmodulin (CaM), presumably binding to the C-terminal domain of the channel subunits. Deletion of the cytosolic N-terminal domain resulted in complete abolition of Ca2+/CaM sensitivity suggesting the existence of further CaM binding sites. A peptide array-based screen of the entire cytosolic protein of hEAG1 identified three putative CaM-binding domains, two in the C-terminus (BD-C1: 674,683, BD-C2: 711,721) and one in the N-terminus (BD-N: 151,165). Binding of GST-fusion proteins to Ca2+/CaM was assayed with fluorescence correlation spectroscopy, surface plasmon resonance spectroscopy and precipitation assays. In the presence of Ca2+, BD-N and BD-C2 provided dissociation constants in the nanomolar range, BD-C1 bound with lower affinity. Mutations in the binding domains reduced inhibition of the functional channels by Ca2+/CaM. Employment of CaM-EF-hand mutants showed that CaM binding to the N- and C-terminus are primarily dependent on EF-hand motifs 3 and 4. Hence, closure of EAG channels presumably requires the binding of multiple CaM molecules in a manner more complex than previously assumed. [source] Transcatheter Closure of Congenital Ventricular Septal Defects: Experience with Various DevicesJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 1 2003RAMESH ARORA D.M. Transcatheter closure of congenital ventricular septal defect (VSD) using various devices is gaining acceptance in selected cases of perimembranous and muscular defects, avoiding the inherent risks of cardiopulmonary bypass. The procedure was attempted in 137 patients having congenital defects using Rashkind Umbrella Device (RUD) in 29 patients, Amplatzer ventricular septal occluder (AVSO) in 107 patients, and Detachable Coil in one. All patients were selected using stringent criteria by detailed transthoracic echocardiography and/or transesophageal echocardiography. The location of VSD was perimembranous in 91 patients and was muscular trabecular in 46 patients. Seven patients had left ventricle (LV) to right atrium (RA) communication. Thirty-five patients with perimembranous and two with muscular VSD had aneurysm formation. The patients were 3 to 33 years old, and the diameter of VSD ranged from 3 to 12 mm. The pulmonary to systemic flow ratio was ,2:1 in 47 (34.3%) patients. The procedure was successful in 130 (94.8%) patients, with a success rate of 86.2% with RUD and 97.1% with AVSO. Residual shunt at 24 hours was seen in eight (32%) patients with RUD and in one patient (0.9%) with AVSO. Three (2.8%) developed transient bundle branch block, and two (1.9%) patients had complete heart block. New tricuspid stenosis and tricuspid regurgitation was observed in one patient each with AVSO. After immediate balloon dilatation, the mean pressure gradient across tricuspid valve decreased from 11 to 3 mmHg in the patient with tricuspid stenosis. On a follow-up of 1 to 66(mean 35.2 ± 10.7)months, the device was in position in all. None developed late conduction defect, aortic regurgitation, infective endocarditis, or hemolysis. At 9-month follow-up, the mean pressure gradient across the tricuspid valve was 3 mmHg in the patient with tricuspid stenosis. Complete occlusion of the shunt was achieved in 129 (99.2%) patients. One patient with RUD having persistent residual shunt underwent a second procedure with AVSO. Three out of 107 patients with AVSO had an unsuccessful procedure where the defect was perimembranous with a superior margin of defect less than 3 mm away from the aortic valve, and the specially designed perimembranous AVSO had to be retrieved because of hemodynamic compromise due to significant acute aortic regurgitation, whereas in all others, the defect was either ,3 mm away from the aortic valve or had aneurysm formation. All seven patients with LV to RA communication showed complete abolition of the shunt. Thus, in properly selected cases of perimembranous and muscular ventricular septal defects, the transcatheter closure is safe and efficacious using appropriate devices. The success rate is higher with AVSO compared with the previously used devices, as well as more successful for the muscular defects than those that are perimembranous in location. (J Interven Cardiol 2003;16:83,91) [source] Kinetic studies on aminopeptidase M-mediated degradation of human hemorphin LVV-H7 and its N -terminally truncated productsJOURNAL OF PEPTIDE SCIENCE, Issue 7 2008Harald John Abstract The human hemorphin LVV-H7 belongs to the class of µ-opiod receptor-binding peptides, which also exhibits significant affinity to insulin-regulated aminopeptidase (IRAP) thereby affecting IRAP inhibition. The inhibitory potency towards IRAP is of pharmaceutical interest for the treatment of Alzheimer's disease. Consecutive N -terminal cleavage of the first two amino acid residues of LVV-H7 affects a drastic increase of the binding affinity (V-H7) but ultimately leads to its complete abolition after cleavage of the next amino acid residue (H7). Therefore, we investigated LVV-H7 truncation by aminopeptidase M (AP-M) identified as a LVV-H7 degrading enzyme potentially regulating hemorphin activity towards IRAP in vivo. Using a selective quantitative multi-component capillary zone electrophoretic method (CZE-UV), we analyzed the AP-M-mediated subsequent proteolysis of the hemorphins LVV-H7 (L32 -F41), VV-H7 (V33 -F41), and V-H7 (V34 -F41) in vitro. Incubations were carried out with synthetic hemorphins applied as single substrates or in combination. Maximum velocities (Vmax), catalytic constants (turnover numbers, kcat), and specific enzyme activities (EA) were calculated. L32 cleavage from LVV-H7 happens more than two-times faster (kcat: 140 min,1 ± 9%, EA: 1.0 U/mg ± 9%) than V33 cleavage from VV-H7 (kcat: 61 min,1 ± 10%, EA: 0.43 U/mg ± 10%) or V32 deletion from V-H7 (kcat: 62 min,1 ± 8%, EA: 0.46 U/mg ± 8%). In contrast, we showed that H7 (Y35 -F41) was neither degraded by porcine AP-M nor did it act as an inhibitor for this enzyme. Determined turnover numbers were in the same dimension as those reported for dynorphin degradation. This is the first time that AP-M-mediated truncation of natural underivatized LVV-H7 and its physiological metabolites was analyzed to determine kinetic parameters useful for understanding hemorphin processing and designing hemorphin-derived drug candidates. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd. [source] MINOR PAPILLA SPHINCTEROTOMY FOR PANCREATITIS DUE TO PANCREAS DIVISUMANZ JOURNAL OF SURGERY, Issue 4 2008Vu Kwan Background: Pancreas divisum (PD) is the commonest congenital pancreatic abnormality and is implicated as a cause of acute recurrent pancreatitis (ARP). We report our experience in minor papilla sphincterotomy (MPS) for this condition. Studies published at present have not examined MPS as the primary treatment method in a homogenous (i.e. only those with ARP) patient group. Methods: Patients with PD and ARP were identified from an endoscopic database. Treatment protocol consisted of minor papilla guidewire cannulation and sphincterotomy with either sphincterotome over the wire or needle knife over pancreatic stent. A 5-Fr stent was placed for 1 week. Adjunctive therapy was carried out as required. Follow-up data was collected by interview with the patient and referring doctors and review of the medical record. Results: Twenty-one patients underwent MPS for PD and ARP (median age = 33 years, range 9,77 years, men = 14). Median number of procedures to achieve cannulation and MPS was 1 (range 1,3). Complications encountered were pancreatitis (n = 2) and pain (n = 3). MPS restenosis occurred in 2. Adjuvant therapy was required in 14: stricture dilatation (n = 9), stone extraction (n = 7) and extracorporeal shock-wave lithotripsy (n = 6). Complete stone clearance was achieved in 7/7. Median follow up was 38 months (range 4,67 months). Median total number of pancreatitis episodes and hospitalizations pre-MPS were 4 and 2, respectively (range 1,20 and 0,5, respectively). Post-MPS these were reduced to 0 and 0, respectively (range 0,8 and 0,4; P = 0.0007 and P = 0.0003), with complete abolition of episodes in 13 patients. Conclusion: MPS in association with other endoscopic therapies imparts a significant clinical benefit to patients with ARP and PD. Complete clinical resolution occurs in the majority. Treatment is safe, and the response is durable. [source] | |||||||||||||