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Aims: To analyse the effectiveness, safety and long-term outcomes of conventional non-powered mechanical systems for transvenous lead extraction (TLE) performed by experienced first operators. Outcomes were assessed according to lead location and type of operating room in which the procedure was performed., Methods and Results: Data from 2049 patients (mean age: 65 years), with infectious (40%) or non-infectious (60%) indications, were analysed over a mean of 3.37 (±2.29) years. A total of 3426 leads were extracted; and, overall, 95% full procedural, 4% partial procedural, and 98% clinical success were demonstrated. Within the patient cohort, 1.8% (37/2049) experienced major complications, with cardiac tamponade being predominant (30/37). Cardiac tamponade was identified as the main cause of mortality, as well as the cause of all procedure-related deaths (6/2049; 0.3%). Cardiac tamponade occurred in 1.8% of atrial and 0.3% of right ventricular lead extractions, with fatal tamponade reported in 9% of atrial, 40% of ventricular, and 67% of coronary sinus lead extractions. No association between lead location and cardiac tamponade-related mortality was observed; however, lead location did affect the success of pericardiocentesis. The cardiac tamponade-related mortality rate was 37% when TLE was performed in an electrophysiology laboratory. No deaths were reported when the procedure was performed in a cardiac surgery or hybrid operating room. Long-term survival was improved when TLE was performed due to non-infectious indications, rather than pocket infection or lead-related endocarditis (P < 0.001)., Conclusion: Using conventional non-powered mechanical sheaths, TLE was effective even in patients at high risk of complications.

In the present work we combine spectroscopic, DSC and computational approaches to examine the multiple extracellular Glu mutants E204Q/E194Q, E204Q/E194Q/E9Q and E204Q/E194Q/E9Q/E74Q of bacteriorhodopsin by varying solvent ionic strength and composition. Absorption spectroscopy data reveal that the absorption maxima of multiple EC Glu mutants can be tuned by the chloride concentration in the solution. Visible Circular dichroism spectra imply that the specific binding of Cl- can modulate weakened exciton chromophore coupling and reestablish wild type-like bilobe spectral features of the mutants. The DSC data display reappearance of the reversible thermal transition, higher Tm of denaturation and an increase in the enthalpy of unfolding of the mutants in 1 M KCl solutions. Molecular dynamics simulations indicate high affinity binding of Cl- to Arg82 and to Gln204 and Gln194 residues in the mutants. Analysis of the experimental data suggests that simultaneous elimination of the negatively charged side chain of Glu194 and Glu204 is the major cause for mutants' alterations. Specific Cl- binding efficiently coordinates distorted hydrogen bonding interactions of the EC region and reconstitutes the conformation and structure stability of mutated bR in WT-like fashion., Competing Interests: The authors have declared that no competing interests exist.

In the present study, we report on the structural features of the bacteriorhodopsin triple mutant E9Q/E194Q/E204Q (3Glu) of bacteriorhodopsin by combining experimental and molecular dynamics (MD) approaches. In 3Glu mutant, Glu9, Glu194 and Glu204 residues located at the extracellular side of the protein were mutated altogether to glutamines. UV-visible and differential scanning calorimetry experiments served as diagnostic tools for monitoring the resistance against thermal stress of the active site and the tertiary structures of the 3Glu. The analyses of the UV-visible thermal difference spectra demonstrate that the spectral forms at room temperature and the thermal unfolding path differ in the wild-type bacteriorhodopsin and the 3Glu. Even with these spectral differences, the thermal unfolding of the active site occurs at rather similar melting temperatures in both proteins. A noteworthy consequence of the mutations is the altered two-dimensional packing revealed by the lack of the pre-transition peak in differential scanning calorimetry traces of 3Glu mutant, as previously detected in wild-type and the corresponding single mutants. The infrared spectroscopy data agree with the loss of paracrystalinity, illustrating a substantial conversion of αII to αI helical conformation in the 3Glu mutant. Molecular dynamics simulations show higher dynamics flexibility of most of the extracellular regions of 3Glu, which may account for the somewhat lower tertiary structural stability of the mutated protein. Finally, hydrogen bond analysis reveals that the mutated Glu194 and Glu204 residues create ~ 50% less hydrogen bonds with water molecules compared to wild-type bacteriorhodopsin. These results exemplify the role of the water hydrogen-bonding network for structural integrity and conformational flexibility of bacteriorhodopsin., (© 2013 FEBS.)

Posterior cortical atrophy is a dementia syndrome with symptoms of cortical visual dysfunction, associated with amyloid plaques and neurofibrillary tangles predominantly affecting visual association cortex. Most patients diagnosed with posterior cortical atrophy will finally develop a typical Alzheimer's disease. However, there are a variety of neuropathological processes, which could lead towards a clinical presentation of posterior cortical atrophy. Mutations in the presenilin 1 gene, affecting the function of γ-secretase, are the most common genetic cause of familial, early-onset Alzheimer's disease. Here we present a patient with a clinical diagnosis of posterior cortical atrophy who harbors a novel Presenilin 1 mutation (I211M). In silico analysis predicts that the mutation could influence the interaction between presenilin 1 and presenilin1 enhancer-2 protein, a protein partner within the γ-secretase complex. These findings along with published literature support the inclusion of posterior cortical atrophy on the Alzheimer's disease spectrum.

The gamma-secretase complex has a decisive role in the development of Alzheimer's disease, in that it cleaves a precursor to create the amyloid beta peptide whose aggregates form the senile plaques encountered in the brains of patients. Gamma-secretase is a member of the intramembrane-cleaving proteases which process their transmembrane substrates within the bilayer. Many of the mutations encountered in early onset familial Alzheimer's disease are linked to presenilin 1, the catalytic component of gamma-secretase, whose active form requires its endoproteolytic cleavage into N-terminal and C-terminal fragments. Although there is general agreement regarding the topology of the N-terminal fragment, studies of the C-terminal fragment have yielded ambiguous and contradictory results that may be difficult to reconcile in the absence of structural information. Here we present the first structure of the C-terminal fragment of human presenilin 1, as obtained from NMR studies in SDS micelles. The structure reveals a topology where the membrane is likely traversed three times in accordance with the more generally accepted nine transmembrane domain model of presenilin 1, but contains unique structural features adapted to accommodate the unusual intramembrane catalysis. These include a putative half-membrane-spanning helix N-terminally harboring the catalytic aspartate, a severely kinked helical structure toward the C terminus as well as a soluble helix in the assumed-to-be unstructured N-terminal loop.