IntroductionRhoA has been shown to be beneficial in cardiac disease models when overexpressed in cardiomyocytes, whereas its role in cardiac fibroblasts (CF) is still poorly understood. During cardiac remodeling CF undergo a transition towards a myofibroblast phenotype thereby showing an increased proliferation and migration rate. Both processes involve the remodeling of the cytoskeleton. Since RhoA is known to be a major regulator of the cytoskeleton, we analyzed its role in CF and its effect on myofibroblast characteristics in 2 D and 3D models.ResultsDownregulation of RhoA was shown to strongly affect the actin cytoskeleton. It decreased the myofibroblast marker α-sm-actin, but increased certain fibrosis-associated factors like TGF-β and collagens. Also, the detailed analysis of CTGF expression demonstrated that the outcome of RhoA signaling strongly depends on the involved stimulus. Furthermore, we show that proliferation of myofibroblasts rely on RhoA and tubulin acetylation. In assays accessing three different types of migration, we demonstrate that RhoA/ROCK/Dia1 are important for 2D migration and the repression of RhoA and Dia1 signaling accelerates 3D migration. Finally, we show that a downregulation of RhoA in CF impacts the viscoelastic and contractile properties of engineered tissues.ConclusionRhoA positively and negatively influences myofibroblast characteristics by differential signaling cascades and depending on environmental conditions. These include gene expression, migration and proliferation. Reduction of RhoA leads to an increased viscoelasticity and a decrease in contractile force in engineered cardiac tissue.

IntroductionIdiopathic Parkinson syndrome (iPS) is one of the most common neurodegenerative disorders characterised by the triad of bradykinesia, rigidity and tremor. Tremor at rest predominantly at one side is often perceived by patients as severely disabling and yet ranges among the most difficult symptoms to treat. In medically refractory cases, lesional approaches have proven to be effective alternatives. However, to date, there is no comprehensive analysis of non-surgical therapies to manage iPS-patients’ tremor. We therefore present a detailed study protocol for a systematic literature review assessing efficacy/effectiveness and safety of non-lesional treatments for tremor in iPS.Methods and analysisWe will search three electronic databases (MEDLINE, EMBASE and PsycINFO) using a combination of title/abstract keywords. Additionally, hand-searched reference and citation lists of key reviews identified through the search strategy will be screened. Eligible studies should investigate the efficacy/effectiveness and safety of therapeutic options for tremor in iPS excluding lesional interventions. Publications will be independently assessed for inclusion criteria by two investigators and study information summarised using a standardised template including quality assessment according to the QualSyst tool. We will provide a narrative synthesis of results and conduct a meta-analysis whenever possible.Ethics and disseminationWe commit to present contemporary evidence on the efficacy/effectiveness and safety of non-lesional interventions for tremor in iPS in a future publication. We aim to compile rich data of published studies to inform healthcare professionals in order to ultimately improve patient outcomes.PROSPERO registration numberCRD42020202911).

Introduction Tremor is often perceived as severely disabling by patients with idiopathic Parkinson's disease (iPD) and yet ranges among the most difficult symptoms to treat. To date, no comprehensive analysis of non‐lesional therapies to manage tremor in iPD exists to base recommendations upon. We therefore present a systematic literature review and meta‐analysis assessing the efficacy/effectiveness and safety of non‐lesional treatments for tremor in iPD. Methods Three electronic databases were searched using a combination of title/abstract keywords complemented by hand‐searching of reference lists. A random‐effects meta‐analysis of standardized mean change scores was conducted where appropriate. Results Some 114 studies met inclusion criteria involving 8045 patients. The meta‐analysis revealed an overall reduction of standardized mean change scores by (−0.93 [CI: −1.42; −0.43], p < 0.001) by 14 different dopaminergic and non‐dopaminergic classes of agents. No significant differences were identified between direct comparisons. Subgroup analysis comparing dopamine receptor agonists resulted in superior effects of pramipexole and rotigotine compared with ropinirole. There was little cumulative evidence to support the use of individual non‐pharmacological interventions for tremor, except for electrical stimulation. Conclusions The results of this meta‐analysis suggest a large but nonspecific effect of established pharmacological therapies on tremor in iPD. Based on high‐quality studies, there is sufficient evidence to support that levodopa, dopamine receptor agonists, and monoamine oxidase inhibitors provide tremor relief in most patients, while evidence supporting other treatments is less well established. Sufficient evidence to draw conclusions on effects of non‐lesional treatments in cases with refractory tremor is lacking.

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