A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study.

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

A Three-Dimensional Scanning System for Digital Archiving and Quantitative Evaluation of Arabidopsis Plant Architectures.

A plant's architecture contributes to its ability to acquire resources and reduce mechanical load. Arabidopsis thaliana is the most common model plant in molecular biology, and there are several mutants and transgenic lines with modified plant architecture regulation, such as lazy1 mutants, which have reversed angles of lateral branches. Although some phenotyping methods have been used in larger agricultural plants, limited suitable methods are available for three-dimensional reconstruction of Arabidopsis, which is smaller and has more uniform surface textures and structures. An inexpensive, easily adopted three-dimensional reconstruction system that can be used for Arabidopsis is needed so that researchers can view and quantify morphological changes over time. We developed a three-dimensional reconstruction system for A. thaliana using the visual volume intersection method, which uses a fixed camera to capture plant images from multiple directions while the plant slowly rotates. We then developed a script to autogenerate stack images from the obtained input movie and visualized the plant architecture by rendering the output stack image using the general bioimage analysis software. We successfully three-dimensionally and time-sequentially scanned wild-type and lazy1 mutant A. thaliana plants and measured the angles of the lateral branches. This non-contact, non-destructive method requires no specialized equipment and is space efficient, inexpensive and easily adopted by Arabidopsis researchers. Consequently, this system will promote three- and four-dimensional phenotyping of this model plant, and it can be used in combination with molecular genetics to further elucidate the molecular mechanisms that regulate Arabidopsis architecture.

Three-dimensional reconstruction of the human capillary network and the intramyocardial micronecrosis.

Three-dimensional reconstruction of the human heart was performed to define the structure of the intramyocardial microvasculature. A total of 200 consecutive serial sections of 6 µm each were prepared from the left ventricular tissue of an autopsied human heart with normal coronary arteries. The corresponding arteriole, venule, and all capillaries were reconstructed using three-dimensional software. The capillary network extended right and left along the cardiomyocyte with major and minor axes of about 130 and 120 µm, respectively. The capillary length from an arteriole to an adjacent venule was about 350 µm. Two types of sack-like structures, the precapillary sinus and the capillary sinus, were present in the capillary network, and many capillaries diverged from these sinuses. The cardiomyocytes were covered with reticular capillaries. In contrast, the precapillary and capillary sinuses were surrounded by many cardiomyocytes. The arterial and venous capillaries were positioned alternately, forming a lattice pattern. Intramyocardial microcirculatory units forming a capillary network from an arteriole to adjacent venules on both sides were present. The sizes of myocardial micronecroses corresponded to that of the intramyocardial microcirculatory unit. These results show that the capillary network is an ordered and anatomically regulated structure and that the microcirculatory unit and the precapillary and capillary sinuses may play an important role in maintaining the intramyocardial microcirculation during contraction and relaxation.

Wearable electromyography measurement system using cable-free network system on conductive fabric.

OBJECTIVE: To solve the complicated wires and battery maintenance problems in the application of wearable computing for biomedical monitoring, the electromyography (EMG) measurement system using conductive fabric for power supply and electric shield for noise reduction is proposed. MATERIAL AND METHODS: The basic cable-free network system using conductive fabric, named as "TextileNet" is developed. The conductive fabric has the function of electric shield for noise reduction in EMG measurement, and it enables the precise EMG measurement with wearable system. RESULTS: The specifications of the developed prototype TextileNet system using wear with conductive fabric were communication speed of 9600bit/s and power supply of 3W for each device. The electric shield effect was evaluated for precise EMG measurement, and the shield efficacy of conductive fabric was estimated as high as that of shield room. CONCLUSIONS: TextileNet system solves both the problems of complicated wires and battery maintenance in wearable computing systems. Conductive fabric used in TextileNet system is also effective for precise EMG measurement as electric shield. The combination of TextileNet system and EMG measurement device will implement the cable-free, battery-free wearable EMG measurement system.

Clinical significance of measurement of plasma annexin V concentration of patients in the emergency room.

Annexin V, a calcium-binding protein, is widely present in various organs and tissues. In the present study, plasma annexin V concentration was measured in 158 patients who were brought to the emergency room, including 25 patients suffering from acute myocardial infarction (AMI), 14 with cerebrovascular disease, 11 with trauma of the extremities, 11 with severe trauma associated with visceral damage, and 35 with witnessed cardiac arrest. Annexin V concentration in normal healthy individuals (n=110) was 1.9+/-0.7 ng/ml. Annexin V concentration in AMI and cardiac arrest patients was 11.0+/-4.9 and 15.3+/-7.9 ng/ml, respectively, being significantly higher than that in patients with cerebrovascular disease (5.4+/-2.7 ng/ml). The value in severe trauma patients was 15.9+/-9.4 ng/ml, being significantly higher than that in patients with trauma of the extremities (5.6+/-1.2 ng/ml). Annexin V concentrations in the cardiac arrest and AMI patients who survived more than 24 h after admission were lower than those in patients who died within 24 h after the onset of symptoms. Annexin V content in the lungs and myocardium in normal rats was extremely high in comparison to that in brain and skeletal muscle. These results suggest that the high levels of plasma annexin V in patients with AMI, cardiac arrest and severe trauma reflect the severity of damage of the myocardium and/or other visceral organs, and measurement of plasma annexin V concentration may help to assess the prognosis of patients brought to the emergency room.