Effects of contractile protein phosphorylation on force development in permeabilized rat cardiac myocytes

The phosphorylation status of myofibrillar proteins influences the Ca2+ responsiveness of the myofilaments,but the contribution of and the interaction between the individual components is poorly characterized. Therefore, in Langendorff perfused rat hearts (n=30), the phosphorylation levels of cardiac myosin binding protein-C (cMyBP-C), troponin I and T (cTnI, cTnT) and myosin light chain 1 and 2 (MLC-1, MLC-2) were determined by 1- and 2-dimensional gel electrophoresis. Isometric force development, its Ca2+-sensitivity, the rate of tension redevelopment (ktr) and passive force (Fpas) were studied at optimal sarcomere length (2.2 μm) in mechanically isolated,permeabilized cardiomyocytes at 15 °C. Protein phosphorylation was varied by: 1) blocking spontaneous cardiac activity by lidocaine (0.35 mM; Quiescence); 2) electrical stimulation of the hearts at 5 Hz (Contraction) and 3. treatment of contracting hearts with Isoprenaline (1 μM). MLC-2 phosphorylation was increased in the Contraction group almost 2-fold, relative to the Quiescence group, whereas cMyBP-C and cTnI phosphorylation remained the same. Isoprenaline resulted in 3.7-fold increases in both cMyBP-C and cTnI phosphorylation, but did not result in a further increase in MLC-2 phosphorylation.No significant differences were found in maximum force and ktr between groups, both before and after protein kinase A (PKA) treatment. Ca2+-sensitivity in the Contraction and Isoprenaline groups was significantly reduced in comparison to the Quiescence group. These differences were largely abolished by PKA and Fpas was reduced. These results highlight the impact of PKA-dependent phosphorylation on Ca2+-sensitivity and provide evidence for an interaction between the effects of TnI and MLC-2 phosphorylation

A conceptual exoskeleton shoulder design for the assistance of upper limb movement

© Springer International Publishing AG, part of Springer Nature 2018. There is an increased interest on wearable technologies for rehabilitation and human augmentation. Systems focusing on the upper limbs are attempting to replicate the musculoskeletal structures found in humans, reproducing existing behaviors and capabilities. The current work is expanding on existing systems with a novel design that ensures the maximum range of motion while at the same time allowing for lockable features ensuring higher manipulation payloads at minimum energy and fatigue costs. An analysis of the biomechanics of the shoulder is being done and a detailed system design for structural as well actuation elements of a parallel mechanism is given. The benefits for the use are discussed of reduced weight, maximum range of motion at minimum energy cost

Design, development and deployment of a hand/wrist exoskeleton for home-based rehabilitation after stroke - SCRIPT project

YesChanges in world-wide population trends have provided new demands for new technologies in areas such as care and rehabilitation. Recent developments in the the field of robotics for neurorehabilitation have shown a range of evidence regarding usefulness of these technologies as a tool to augment traditional physiotherapy. Part of the appeal for these technologies is the possibility to place a rehabilitative tool in one’s home, providing a chance for more frequent and accessible technologies for empowering individuals to be in charge of their therapy. Objective: this manuscript introduces the Supervised Care and Rehabilitation Involving Personal Tele-robotics (SCRIPT) project. The main goal is to demonstrate design and development steps involved in a complex intervention, while examining feasibility of using an instrumented orthotic device for home-based rehabilitation after stroke. Methods: the project uses a user-centred design methodology to develop a hand/wrist rehabilitation device for home-based therapy after stroke. The patient benefits from a dedicated user interface that allows them to receive feedback on exercise as well as communicating with the health-care professional. The health-care professional is able to use a dedicated interface to send/receive communications and remote-manage patient’s exercise routine using provided performance benchmarks. Patients were involved in a feasibility study (n=23) and were instructed to use the device and its interactive games for 180 min per week, around 30 min per day, for a period of 6 weeks, with a 2-months follow up. At the time of this study, only 12 of these patients have finished their 6 weeks trial plus 2 months follow up evaluation. Results: with the “use feasibility” as objective, our results indicate 2 patients dropping out due to technical difficulty or lack of personal interests to continue. Our frequency of use results indicate that on average, patients used the SCRIPT1 device around 14 min of self-administered therapy a day. The group average for the system usability scale was around 69% supporting system usability. Conclusions: based on the preliminary results, it is evident that stroke patients were able to use the system in their homes. An average of 14 min a day engagement mediated via three interactive games is promising, given the chronic stage of stroke. During the 2nd year of the project, 6 additional games with more functional relevance in their interaction have been designed to allow for a more variant context for interaction with the system, thus hoping to positively influence the exercise duration. The system usability was tested and provided supporting evidence for this parameter. Additional improvements to the system are planned based on formative feedback throughout the project and during the evaluations. These include a new orthosis that allows a more active control of the amount of assistance and resistance provided, thus aiming to provide a more challenging interaction.This work has been partially funded under Grant FP7-ICT-288698(SCRIPT) of the European Community Seventh Framework Programme

Mesothelin/CD3 half-life extended bispecific T-cell engager molecule shows specific tumor uptake and distributes to mesothelin and CD3 expressing tissues

BiTE ® (bispecific T-cell engager) molecules exert antitumor activity by binding one arm to CD3 on cytotoxic T-cells and the other arm to a tumor-associated antigen. We generated a fully mouse cross-reactive mesothelin (MSLN)-targeted BiTE molecule that is genetically fused to a Fc-domain for half-life extension, and evaluated biodistribution and tumor targeting of a zirconium-89 (89Zr)-labeled MSLN HLE BiTE molecule in 4T1 breast cancer bearing syngeneic mice with positron emission tomography (PET). Biodistribution of 50 µg 89Zr-MLSN HLE BiTE was studied over time by PET imaging in BALB/c mice and revealed uptake in tumor and lymphoid tissues with an elimination half-life of 63.4 hours. Compared to a non-targeting 89Zr-control HLE BiTE, the 89Zr-MLSN HLE BiTE showed a 2-fold higher tumor uptake and higher uptake in lymphoid tissues. Uptake in the tumor colocalized with mesothelin expression, while uptake in the spleen colocalized with CD3 expression. Evaluation of the effect of protein doses on the biodistribution and tumor targeting of 89Zr-MSLN HLE BiTE revealed for all dose groups that uptake in the spleen was faster than in the tumor (day 1 vs day 5). The lowest dose of 10 µg 89Zr-MSLN HLE BiTE had higher spleen uptake and faster blood clearance compared to higher doses of 50 µg and 200 µg. 89Zr-MSLN HLE BiTE tumor uptake was similar at all doses. Conclusion: The MSLN HLE BiTE showed specific tumor uptake and both arms contributed to the biodistribution profile. These findings support the potential for clinical translation of HLE BiTE molecules

Eplerenone prevents an increase in serum carboxy-terminal propeptide of procollagen type I after myocardial infarction complicated by left ventricular dysfunction and/or heart failure

No abstract available

Self-adjustment mechanisms and their application for orthosis design

Medical orthoses aim at guiding anatomical joints along their natural trajectories while preventing pathological movements, especially in case of trauma or injuries. The motions that take place between bone surfaces have complex kinematics. These so-called arthrokinematic motions exhibit axes that move both in translation and rotation. Traditionally, orthoses are carefully adjusted and positioned such that their kinematics approximate the arthrokinematic movements as closely as possible in order to protect the joint. Adjustment procedures are typically long and tedious. We suggest in this paper another approach. We propose mechanisms having intrinsic self-aligning properties. They are designed such that their main axis self-adjusts with respect to the joint’s physiological axis during motion. When connected to a limb, their movement becomes homokinetic and they have the property of automatically minimizing internal stresses. The study is performed here in the planar case focusing on the most important component of the arthrokinematic motions of a knee joint