Sodium-glucose co-transporter 2 Inhibitors Act Independently of to Confer Benefit for Heart Failure with Reduced Ejection Fraction in Mice.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are novel, potent heart failure medications with an unknown mechanism of action. We sought to determine if the beneficial actions of SGLT2i in heart failure were on- or off-target, and related to metabolic reprogramming, including increased lipolysis and ketogenesis. The phenotype of mice treated with empagliflozin and genetically engineered mice constitutively lacking SGLT2 mirrored metabolic changes seen in human clinical trials (including reduced blood glucose, increased ketogenesis, and profound glucosuria).

Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound , a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity.

Titin-truncating variants in hiPSC cardiomyocytes induce pathogenic proteinopathy and sarcomere defects with preserved core contractile machinery.

Titin-truncating variants (TTNtv) are the single largest genetic cause of dilated cardiomyopathy (DCM). In this study we modeled disease phenotypes of A-band TTNtv-induced DCM in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using genome editing and tissue engineering technologies. Transcriptomic, cellular, and micro-tissue studies revealed that A-band TTNtv hiPSC-CMs exhibit pathogenic proteinopathy, sarcomere defects, aberrant Na channel activities, and contractile dysfunction.

Structural and Thermodynamic Model for the Activation of Cardiac Troponin.

Cardiac troponin is a regulatory protein complex located on the sarcomere that regulates the engagement of myosin on actin filaments. Low-molecular weight modulators of troponin that bind allosterically with the calcium ion have the potential to improve cardiac contractility in patients with reduced cardiac function. Here we propose an approach to the rational design of troponin modulators through the combined use of solution nuclear magnetic resonance and isothermal titration calorimetry methods.

MPFL reconstruction: technique and results.

Patellar instability is a common problem, and medial patellofemoral ligament (MPFL) injury is inherent with traumatic patellar dislocations. Initial nonoperative management is focused on reconditioning and strengthening the dynamic stabilizers of the patella. For those patients who progress to recurrent instability, further investigation into the predisposing factors is required.

Suture placement near the musculotendinous junction in the supraspinatus: implications for rotator cuff repair.

Background: Transosseous-equivalent rotator cuff repair has an increased incidence of medial rotator cuff failure compared with single-row repair. No studies have evaluated the influence of the proximity of the suture row to the musculotendinous junction (MTJ) on cyclic gapping and failure properties.

Hypothesis: A single row of horizontal mattress sutures placed within the supraspinatus tendon lateral to the MTJ will experience less gap formation and higher failure loads than a similar suture row placed at the MTJ.

MPFL reconstruction: technique and results.

MPFL reconstruction is a viable option for treating patients with recurrent patellar instability, in whom nonoperative methods have failed to provide relief. It is important to evaluate patients for predisposing factors for patellar instability. This technique of MPFL reconstruction uses a reliable method to obtain anatomic tunnel position.

External fixation of femoral defects in athymic rats: Applications for human stem cell implantation and bone regeneration.

An appropriate animal model is critical for the research of stem/progenitor cell therapy and tissue engineering for bone regeneration in vivo. This study reports the design of an external fixator and its application to critical-sized femoral defects in athymic rats. The external fixator consists of clamps and screws that are readily available from hardware stores as well as Kirschner wires.

Distinct phenotypes and regenerative potentials of early endothelial progenitor cells and outgrowth endothelial progenitor cells derived from umbilical cord blood.

The capability of postnatal neovascularization makes circulating endothelial progenitor cells (EPCs) promising for regenerative medicine and tissue engineering. Using EPCs isolated from umbilical cord blood, this study aimed to clarify the transition of functional properties from early EPCs (e-EPCs) to outgrowth EPCs (og-EPCs) for potential applications in regenerative medicine. Mononuclear cells were collected from umbilical cord blood via density gradient centrifugation and further negatively selected by CD45.

Can computed tomography predict hip stability in posterior wall acetabular fractures?

Background: In a pilot study, two-dimensional (2-D) CT assessment of posterior wall fracture fragments predicted hip stability with small fracture fragments and instability for large fracture fragments.

Questions/purposes: To confirm the previous findings, we determined whether there is sufficient observer consistency and accuracy to predict hip stability in posterior wall acetabular fractures for this CT assessment method and assessed its ease of clinical use.

Methods: We selected 10 fractures having variable characteristics with known clinical outcome and created three study participant groups, based on level of training, for evaluation.

Comparison between rigid and flexible systems for drilling the femoral tunnel through an anteromedial portal in anterior cruciate ligament reconstruction.

Purpose: The purpose of this study was to compare the differences in femoral tunnel length and distance to the lateral anatomic structures when using standard and flexible guide pins for anterior cruciate ligament (ACL) femoral tunnel drilling through a medial portal.

Methods: Using a medial arthroscopic portal in 10 cadaveric knees, we sequentially drilled straight and flexible guide pins into the center of the ACL femoral footprint using the same starting point. We recorded the interosseous length and distances to the peroneal nerve and the femoral origin of the lateral collateral ligament (LCL) for each pin.