Patent: Dual Function Proteins for Treating Metabolic Disorders

The present invention relates to new proteins comprising fibroblast growth factor 2 1 (FGF21 ) and other metabolic regulators known to improve metabolic profiles in subjects to whom they are administered

Modulation of a protein free-energy landscape by circular permutation

Circular permutations usually retain the native structure and function of a protein while inevitably perturb its folding dynamics. By using simulations with a structure-based model and a rigorous methodology to determine free-energy surfaces from trajectories we evaluate the effect of a circular permutation on the free-energy landscape of the protein T4 lysozyme. We observe changes which, while subtle, largely affect the cooperativity between the two subdomains. Such a change in cooperativity has been previously experimentally observed and recently also characterized using single molecule optical tweezers and the Crooks relation. The free-energy landscapes show that both the wild type and circular permutant have an on-pathway intermediate, previously experimentally characterized, where one of the subdomains is completely formed. The landscapes, however, differ in the position of the rate-limiting step for folding, which occurs before the intermediate in the wild-type and after in the circular permutant. This shift of transition state explains the observed change in the cooperativity. The underlying free-energy landscape thus provides a microscopic description of the folding dynamics and the connection between circular permutation and the loss of cooperativity experimentally observed

Midterm outcomes and evolution of gutter area after endovascular aneurysm repair with the chimney graft procedure

Objective The objective of this study was to describe our experience with endovascular aneurysm repair (EVAR) with the use of chimney grafts for branch vessel preservation. Methods Patients treated with a chimney graft procedure between October 2009 and May 2015 were included for analysis. Patients who were not considered eligible for open surgical repair or for conventional, branched, or fenestrated endovascular repair were selected. A standardized operating procedure with left brachial or axillary artery cutdown access for the chimney grafts and bilateral femoral artery cutdown access for the aortic main device was used. Outcomes were noted according to the Society for Vascular Surgery reporting standards. In addition, evolution of gutter area over time was determined. Estimated rates of survival, freedom from aneurysm growth, and clinical success at 24 months of follow-up were calculated. Results Thirty-three patients (mean age, 77.6 \uc2\ub1 6.8 years; 87.9% male) with a mean preoperative maximum aneurysm diameter of 71.7 \uc2\ub1 13.5 mm were included. A total of 54 of an intended 54 chimney grafts were deployed. Primary technical success and 30-day secondary clinical success rates were 87.9% and 84.8%, respectively. The early mortality rate was 6.1% (n = 2). The early type IA endoleak rate was 6.1% (n = 2), and the chimney graft occlusion rate was 6.1% (n = 2). Median follow-up duration was 26 months (interquartile range, 14.8-37.3 months). The estimated 2-year actuarial survival rate was 78.1% (standard error, \uc2\ub17.4%). Late complications included type IA endoleak (n = 1), chimney graft occlusion (n = 2), type II endoleak with aneurysm growth (n = 4), and distal stent graft limb kinking and occlusion (n = 1). Late reinterventions included coil or glue embolization (n = 3), distal limb extension (n = 2), open endoleak ligation (n = 2), Palmaz stent placement (n = 1), repeated EVAR (n = 1), and femorofemoral bypass graft (n = 1). At 2 years, the estimated secondary clinical success and freedom from aneurysm growth rates were 80.5% (\uc2\ub17.2%) and 84.4% (\uc2\ub17.2%). Gutter size showed a small but significant decrease over time at the level of the proximal markers and at 10 mm distal from the markers. Conclusions Midterm results show that a standardized procedure for EVAR using chimney grafts for branch vessel preservation is an acceptable option for high-risk patients with large, complex aneurysms who are unfit for open repair and who have been excluded from fenestrated EVAR. Gutter size decreases over time, but the rate of branch vessel loss and reinterventions demonstrate that this approach should remain reserved for those who are at truly prohibitive risk for open or fenestrated stent graft repair

Midterm outcomes and evolution of gutter area after endovascular aneurysm repair with the chimney graft procedure

Objective The objective of this study was to describe our experience with endovascular aneurysm repair (EVAR) with the use of chimney grafts for branch vessel preservation. Methods Patients treated with a chimney graft procedure between October 2009 and May 2015 were included for analysis. Patients who were not considered eligible for open surgical repair or for conventional, branched, or fenestrated endovascular repair were selected. A standardized operating procedure with left brachial or axillary artery cutdown access for the chimney grafts and bilateral femoral artery cutdown access for the aortic main device was used. Outcomes were noted according to the Society for Vascular Surgery reporting standards. In addition, evolution of gutter area over time was determined. Estimated rates of survival, freedom from aneurysm growth, and clinical success at 24 months of follow-up were calculated. Results Thirty-three patients (mean age, 77.6 ± 6.8 years; 87.9% male) with a mean preoperative maximum aneurysm diameter of 71.7 ± 13.5 mm were included. A total of 54 of an intended 54 chimney grafts were deployed. Primary technical success and 30-day secondary clinical success rates were 87.9% and 84.8%, respectively. The early mortality rate was 6.1% (n = 2). The early type IA endoleak rate was 6.1% (n = 2), and the chimney graft occlusion rate was 6.1% (n = 2). Median follow-up duration was 26 months (interquartile range, 14.8-37.3 months). The estimated 2-year actuarial survival rate was 78.1% (standard error, ±7.4%). Late complications included type IA endoleak (n = 1), chimney graft occlusion (n = 2), type II endoleak with aneurysm growth (n = 4), and distal stent graft limb kinking and occlusion (n = 1). Late reinterventions included coil or glue embolization (n = 3), distal limb extension (n = 2), open endoleak ligation (n = 2), Palmaz stent placement (n = 1), repeated EVAR (n = 1), and femorofemoral bypass graft (n = 1). At 2 years, the estimated secondary clinical success and freedom from aneurysm growth rates were 80.5% (±7.2%) and 84.4% (±7.2%). Gutter size showed a small but significant decrease over time at the level of the proximal markers and at 10 mm distal from the markers. Conclusions Midterm results show that a standardized procedure for EVAR using chimney grafts for branch vessel preservation is an acceptable option for high-risk patients with large, complex aneurysms who are unfit for open repair and who have been excluded from fenestrated EVAR. Gutter size decreases over time, but the rate of branch vessel loss and reinterventions demonstrate that this approach should remain reserved for those who are at truly prohibitive risk for open or fenestrated stent graft repair

Extensibility and Distensibility of the Thoracic Aorta in Patients with Aneurysm

Objectives Reference values of aortic deformation during the cardiac cycle can be valuable for the pre-operative planning of thoracic endovascular aortic repair (TEVAR) and for facilitating computational fluid dynamics. This study aimed to quantify normal aortic extensibility (longitudinal extension) and distensibility (radial expansion), as well as pulsatile strain, in a group of 10 (>60 years) individuals with abdominal or thoracic aortic aneurysms. Methods ECG gated CT images of the thoracic aorta were reconstructed into virtual 3D models of aortic geometry. The centre lumen line length of the thoracic aorta and three longitudinal segments, and the aortic diameter and luminal areas of four radial intersections were extracted with a dedicated software script to calculate extensibility, longitudinal strain, distensibility, and circumferential area strain. Results Mean extensibility and longitudinal strain of the entire thoracic aorta were 3.5 [1.3–6.8] × 10−3 N−1, and 2.7 [1.0–4.5]%, respectively. Extensibility and longitudinal strain were most pronounced in the ascending aorta (20.6 [5.7–36.2] × 10−3 N−1 and 15.9 [6.6–31.9]%) and smallest in the descending aorta (4.4 [1.6–12.3] × 10−3 N−1 and 2.2 [0.7–4.7]%). Mean distensibility and circumferential area strain were most pronounced at the sinotubular junction (1.7 [0.5–2.9] × 10−3 mmHg−1 and 11.3 [3.3–18.5]%, respectively). Distensibility varied between 0.9 [0.3–2.5] × 10−3 mmHg−1 and 1.2 [0.3–3.3] × 10−3 mmHg−1 at the intersections in the aortic arch and descending aorta. Conclusions Pulsatile deformations in both longitudinal and circumferential directions are considerable throughout the thoracic aorta. These findings may have implications for pre-operative TEVAR planning and highlight the need for devices that can mimic the significant aortic longitudinal and circumferential strains

Extensibility and Distensibility of the Thoracic Aorta in Patients with Aneurysm

Objectives Reference values of aortic deformation during the cardiac cycle can be valuable for the pre-operative planning of thoracic endovascular aortic repair (TEVAR) and for facilitating computational fluid dynamics. This study aimed to quantify normal aortic extensibility (longitudinal extension) and distensibility (radial expansion), as well as pulsatile strain, in a group of 10 (>60 years) individuals with abdominal or thoracic aortic aneurysms. Methods ECG gated CT images of the thoracic aorta were reconstructed into virtual 3D models of aortic geometry. The centre lumen line length of the thoracic aorta and three longitudinal segments, and the aortic diameter and luminal areas of four radial intersections were extracted with a dedicated software script to calculate extensibility, longitudinal strain, distensibility, and circumferential area strain. Results Mean extensibility and longitudinal strain of the entire thoracic aorta were 3.5 [1.3–6.8] × 10−3 N−1, and 2.7 [1.0–4.5]%, respectively. Extensibility and longitudinal strain were most pronounced in the ascending aorta (20.6 [5.7–36.2] × 10−3 N−1 and 15.9 [6.6–31.9]%) and smallest in the descending aorta (4.4 [1.6–12.3] × 10−3 N−1 and 2.2 [0.7–4.7]%). Mean distensibility and circumferential area strain were most pronounced at the sinotubular junction (1.7 [0.5–2.9] × 10−3 mmHg−1 and 11.3 [3.3–18.5]%, respectively). Distensibility varied between 0.9 [0.3–2.5] × 10−3 mmHg−1 and 1.2 [0.3–3.3] × 10−3 mmHg−1 at the intersections in the aortic arch and descending aorta. Conclusions Pulsatile deformations in both longitudinal and circumferential directions are considerable throughout the thoracic aorta. These findings may have implications for pre-operative TEVAR planning and highlight the need for devices that can mimic the significant aortic longitudinal and circumferential strains