The neuromodulatory and hormonal effects of transcutaneous vagus nerve stimulation as evidenced by salivary alpha amylase, salivary cortisol, pupil diameter, and the P3 event-related potential.

BACKGROUND: Transcutaneous vagus nerve stimulation (tVNS) is a new, non-invasive technique being investigated as an intervention for a variety of clinical disorders, including epilepsy and depression. It is thought to exert its therapeutic effect by increasing central norepinephrine (NE) activity, but the evidence supporting this notion is limited. OBJECTIVE: In order to test for an impact of tVNS on psychophysiological and hormonal indices of noradrenergic function, we applied tVNS in concert with assessment of salivary alpha amylase (SAA) and cortisol, pupil size, and electroencephalograph (EEG) recordings. METHODS: Across three experiments, we applied real and sham tVNS to 61 healthy participants while they performed a set of simple stimulus-discrimination tasks. Before and after the task, as well as during one break, participants provided saliva samples and had their pupil size recorded. EEG was recorded throughout the task. The target for tVNS was the cymba conchae, which is heavily innervated by the auricular branch of the vagus nerve. Sham stimulation was applied to the ear lobe. RESULTS: P3 amplitude was not affected by tVNS (Experiment 1A: N = 24; Experiment 1B: N = 20; Bayes factor supporting null model = 4.53), nor was pupil size (Experiment 2: N = 16; interaction of treatment and time: p = .79). However, tVNS increased SAA (Experiments 1A and 2: N = 25) and attenuated the decline of salivary cortisol compared to sham (Experiment 2: N = 17), as indicated by significant interactions involving treatment and time (p = .023 and p = .040, respectively). CONCLUSION: These findings suggest that tVNS modulates hormonal indices but not psychophysiological indices of noradrenergic function.

A myosin activator improves actin assembly and sarcomere function of human-induced pluripotent stem cell-derived cardiomyocytes with a troponin T point mutation.

We have investigated cardiac myocytes derived from human-induced pluripotent stem cells (iPSC-CMs) from two normal control and two family members expressing a mutant cardiac troponin T (cTnT-R173W) linked to dilated cardiomyopathy (DCM). cTnT is a regulatory protein of the sarcomeric thin filament. The loss of this basic charge, which is strategically located to control tension, has consequences leading to progressive DCM. iPSC-CMs serve as a valuable platform for understanding clinically relevant mutations in sarcomeric proteins; however, there are important questions to be addressed with regard to myocyte adaptation that we model here by plating iPSC-CMs on softer substrates (100 kPa) to create a more physiologic environment during recovery and maturation of iPSC-CMs after thawing from cryopreservation. During the first week of culture of the iPSC-CMs, we have determined structural and functional characteristics as well as actin assembly dynamics. Shortening, actin content, and actin assembly dynamics were depressed in CMs from the severely affected mutant at 1 wk of culture, but by 2 wk differences were less apparent. Sarcomeric troponin and myosin isoform composition were fetal/neonatal. Furthermore, the troponin complex, reconstituted with wild-type cTnT or recombinant cTnT-R173W, depressed the entry of cross-bridges into the force-generating state, which can be reversed by the myosin activator omecamtiv mecarbil. Therapeutic doses of this drug increased both contractility and the content of F-actin in the mutant iPSC-CMs. Collectively, our data suggest the use of a myosin activation reagent to restore function within patient-specific iPSC-CMs may aid in understanding and treating this familial DCM.

Mobility and dementia: is physiotherapy treatment during respite care effective?

BACKGROUND: Mobility problems experienced by elderly people with a dementia are associated with falls, fractures and admission to long-term care. A hospital respite care admission is therefore often seen as an opportunity to provide physiotherapy treatment. AIM: To find whether elderly people with a dementia and a mobility problem show a greater improvement in mobility skills if given physiotherapy treatment than if given non-physical activities intervention during a hospital respite admission. METHOD: A controlled randomized multicentre trial with independent blinded assessment. The Southampton Mobility Assessment (mobility score) and Two Minute Walking Test (distance walked) were undertaken at the beginning and end of the study admission and beginning of the next respite admission. Following the first assessment, participants were randomized to either physiotherapy or activities. RESULTS: Eighty-one participants, from 12 clinical centres, with a mean age of 81.9 years and CAPE I/O score of 2. During the study admission there was a non-significant trend for a lower reduction in mobility score of the physiotherapy group (Mann-Whitney; p = 0.614) and a non-significant trend for greater decrease in distance walked in the activities group (t-test; p = 0.325). DISCUSSION: The results of this trial do not support the positive changes demonstrated elsewhere. However, changes in respite care during the early stages of this trial may have produced differences between the sample for this trial and that for the pilot study. This trial was therefore underpowered. CONCLUSION: This trial suggests that future research needs to change the focus from clinical settings to presentations.