Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency

Creatine transporter deficiency (CTD), a leading cause of intellectual disability is a result of the mutation in the gene encoding the creatine transporter SLC6A8, which prevents creatine uptake into the brain, causing mental retardation, expressive speech and language delay, autistic-like behavior and epilepsy. Preclinical in vitro and in vivo data indicate that dodecyl creatine ester (DCE) which increases the creatine brain content, might be a therapeutic option for CTD patients. To gain a better understanding of the pathophysiology and DCE treatment efficacy in CTD, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8−/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content. Shotgun proteomics analysis of 4,035 proteins in four different brain regions; the cerebellum, cortex, hippocampus (associated with cognitive functions) and brain stem, and muscle as a control, was performed in 24 mice. Comparison of the protein abundance in the four brain regions between DCE-treated intranasally Slc6a8−/y mice and wild type and DCE-treated Slc6a8−/y and vehicle group identified 14 biomarkers, shedding light on the mechanism of action of DCE. Integrative bioinformatics and statistical modeling identified key proteins in CTD, including KIF1A and PLCB1. The abundance of these proteins in the four brain regions was significantly correlated with both the object recognition and the Y-maze tests. Our findings suggest a major role for PLCB1, KIF1A, and associated molecules in the pathogenesis of CTD

Sutureless Stented Aortic Valve Implantation Under Direct Vision: Lessons From a Negative Experience in Sheep

ABSTRACT Background and Aim of the Study: Percutaneous aortic valve replacement has been proposed as a valid alternative to surgery in selected cases; however, it still has many problems. As a less radical preliminary step, we implanted a balloon-expandable stented aortic valve under direct vision in sheep. Methods: Under cardiopulmonary bypass (CPB) and through a transverse aortotomy, an aortic valve mounted in a long tubular balloon-expandable stent was implanted in six acute sheep. The leaflets were not excised and no anchoring sutures were used between stent and native annulus. Epicardial, two-dimensional color Doppler echocardiography was used to assess the function of the stented valve followed by macroscopic inspection at necropsy. Results: Direct visualization of the entire annulus when the collapsed, valved stent was placed within the aortic root was difficult in all animals. Valve deployment took less than 1 minute. The surgical procedure resulted in major complications in all cases. Migration (3/6), paravalvular leak (2/6), mitral conflicts resulting in mitral regurgitation (1/6), and coronary ostia obstruction (2/6) were the major events at the origin of the failure. Only three animals could be weaned from CPB but did not recover enough to survive the procedure. Conclusions: Sutureless implantation of a stented aortic valve through standard CPB and aortotomy is far more complex than expected. Changes in stent design and surgical approach are indicated

Dodecyl Creatine Ester Improves Cognitive Function and Identifies Drivers of Creatine Deficiency

Abstract Creatine transporter deficiency prevents creatine uptake into the brain, leading to mental retardation. To better understand the pathophysiology, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content. Shotgun proteomics analysis of 4,035 proteins in four different brain regions; the cerebellum, cortex, hippocampus (associated with cognitive functions) and brain stem, and muscle as a control, was performed in 24 mice. Comparisons of the protein abundance in the four brain regions between DCE-treated intranasally Slc6a8-/y mice and wild type and DCE-treated Slc6a8-/y and vehicle group identified 14 biomarkers, shedding light on the mechanism of action of DCE. Integrative bioinformatics and statistical modeling identified key proteins associated with CTD, including KIF1A and PLCB1. The abundance of these proteins in the four brain regions was significantly correlated with both the object recognition and the Y-maze tests. Functional analysis confirmed their key roles and associated molecules in CTD pathogenesis