The effect of an interactive cycling training on cognitive functioning in older adults with mild dementia: study protocol for a randomized controlled trial

Contains fulltext : 168861.pdf (publisher's version ) (Open Access)Background: To date there is no cure or an effective disease-modifying drug to treat dementia. Available acetylcholine-esterase inhibiting drugs or memantine only produce small benefits on cognitive and behavioural functioning and their clinical relevance remains controversial. Combined cognitive-aerobic interventions are an appealing alternative or add-on to current pharmacological treatments. The primary aim of this study is to investigate the efficacy of a combined cognitive-aerobic training and a single aerobic training compared to an active control group in older adults with mild dementia. We expect to find a beneficial effect on executive functioning in both training regimes, compared to the control intervention, with the largest effect in the combined cognitive-aerobic group. Secondary, intervention effects on cognitive functioning in other domains, physical functioning, physical activity levels, activities of daily living, frailty and quality of life are studied. Methods: The design is a single-blind, randomized controlled trial (RCT) with three groups: a combined cognitive-aerobic bicycle training (interactive cycling), a single aerobic bicycle training and a control intervention, which consists of stretching and toning exercises. Older adults with mild dementia follow a 12-week training program consisting of three training sessions of 30-40 min per week. The primary study outcome is objective executive functioning measured with a neuropsychological assessment. Secondary measures are objective cognitive functioning in other domains, physical functioning, physical activity levels, activities of daily living, frailty, mood and quality of life. The three groups are compared at baseline, after 6 and 12 weeks of training, and at 24-week follow-up. Discussion: This study will provide novel information on the effects of an interactive cycling training on executive function in older adults with mild dementia. Furthermore, since this study has both a combined cognitive-aerobic training and a single aerobic training group the effectiveness of the different components of the intervention can be identified. The results of this study may be used for physical and mental activity recommendations in older adults with dementia.8 p

The shufflon of IncI1 plasmids is rearranged constantly during different growth conditions

One of the factors that can affect conjugation of IncI1 plasmids, amongst others, is the genetic region known as the shufflon. This multiple inversion system modifies the pilus tip proteins used during conjugation, thus affecting the affinity for different recipient cells. Although recombination is known to occur in in vitro conditions, little is known about the regulation and the extent of recombination that occurs. To measure the recombination of the shufflon, we have amplified the entire shufflon region and sequenced the amplicons using nanopore long-read sequencing. This method was effective to determine the order of the segments of the shufflon and allow for the analysis of the shufflon variants that are present in a heterogeneous pool of templates. Analysis was performed over different growth phases and after addition of cefotaxime. Furthermore, analysis was performed in different E. coli host cells to determine if recombination is likely to be influenced. Recombination of the shufflon was constantly ongoing in all conditions that were measured, although no differences in the amount of different shufflon variants or the rate at which novel variants were formed could be found. As previously reported, some variants were abundant in the population while others were scarce. This leads to the conclusion that the shufflon is continuously recombining at a constant rate, or that the method used here was not sensitive enough to detect differences in this rate. For one of the plasmids, the host cell appeared to have an effect on the specific shufflon variants that were formed which were not predominant in another host, indicating that host factors may be involved. As previously reported, the pilV-A and pilV-A' ORFs are formed at higher frequencies than other pilV ORFs. These results demonstrate that the recombination that occurs within the shufflon is not random. While any regulation of the shufflon affected by these in vitro conditions could not be revealed, the method of amplifying large regions for long-read sequencing for the analysis of multiple inversion systems proved effective.</p

Volume Load-Induced Right Ventricular Failure in Rats Is Not Associated With Myocardial Fibrosis

Background Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. Myocardial fibrosis is regarded as a contributing factor to heart failure, but its importance in RV failure has been challenged. This study aims to assess whether myocardial fibrosis drives the transition from compensated to decompensated volume load-induced RV dysfunction. Methods Wistar rats were subjected to aorto-caval shunt (ACS, n = 23) or sham (control, n = 15) surgery, and sacrificed after 1 month, 3 months, or 6 months. Echocardiography, RV pressure-volume analysis, assessment of gene expression and cardiac histology were performed. Results At 6 months, 6/8 ACS-rats (75%) showed clinical signs of RV failure (pleural effusion, ascites and/or liver edema), whereas at 1 month and 3 months, no signs of RV failure had developed yet. Cardiac output has increased two- to threefold and biventricular dilatation occurred, while LV ejection fraction gradually decreased. At 1 month and 3 months, RV end-systolic elastance (Ees) remained unaltered, but at 6 months, RV Ees had decreased substantially. In the RV, no oxidative stress, inflammation, pro-fibrotic signaling (TGF beta 1 and pSMAD2/3), or fibrosis were present at any time point. Conclusions In the ACS rat model, long-term volume load was initially well tolerated at 1 month and 3 months, but induced overt clinical signs of end-stage RV failure at 6 months. However, no myocardial fibrosis or increased pro-fibrotic signaling had developed. These findings indicate that myocardial fibrosis is not involved in the transition from compensated to decompensated RV dysfunction in this model

Metabolic Remodeling in the Pressure-Loaded Right Ventricle:Shifts in Glucose and Fatty Acid Metabolism-A Systematic Review and Meta-Analysis

Background-—Right ventricular (RV) failure because of chronic pressure load is an important determinant of outcome in pulmonary hypertension. Progression towards RV failure is characterized by diastolic dysfunction, fibrosis and metabolic dysregulation. Metabolic modulation has been suggested as therapeutic option, yet, metabolic dysregulation may have various faces in different experimental models and disease severity. In this systematic review and meta-analysis, we aimed to identify metabolic changes in the pressure loaded RV and formulate recommendations required to optimize translation between animal models and human disease. Methods and Results-—Medline and EMBASE were searched to identify original studies describing cardiac metabolic variables in the pressure loaded RV. We identified mostly rat-models, inducing pressure load by hypoxia, Sugen-hypoxia, monocrotaline (MCT), pulmonary artery banding (PAB) or strain (fawn hooded rats, FHR), and human studies. Meta-analysis revealed increased Hedges’ g (effect size) of the gene expression of GLUT1 and HK1 and glycolytic flux. The expression of MCAD was uniformly decreased. Mitochon

Cellular senescence impairs the reversibility of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) in congenital cardiac shunts can be reversed by hemodynamic unloading (HU) through shunt closure. However, this reversibility potential is lost beyond a certain point in time. The reason why PAH becomes irreversible is unknown. In this study, we used MCT+shunt-induced PAH in rats to identify a dichotomous reversibility response to HU, similar to the human situation. We compared vascular profiles of reversible and irreversible PAH using RNA sequencing. Cumulatively, we report that loss of reversibility is associated with a switch from a proliferative to a senescent vascular phenotype and confirmed markers of senescence in human PAH-CHD tissue. In vitro, we showed that human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells. To support the concept that vascular cell senescence is causal to the irreversible nature of end-stage PAH, we targeted senescence using ABT263 and induced reversal of the hemodynamic and structural changes associated with severe PAH refractory to HU. The factors that drive the transition from a reversible to irreversible pulmonary vascular phenotype could also explain the irreversible nature of other PAH etiologies and provide new leads for pharmacological reversal of end-stage PAH

Developing health science students into integrated health professionals: a practical tool for learning

BACKGROUND:An integrated sense of professionalism enables health professionals to draw on relevant knowledge in context and to apply a set of professional responsibilities and ethical principles in the midst of changing work environments 12. Inculcating professionalism is therefore a critical goal of health professional education. Two multi-professional courses for first year Health Science students at the University of Cape Town, South Africa aim to lay the foundation for becoming an integrated health professional 3. In these courses a diagram depicting the domains of the integrated health professional is used to focus the content of small group experiential exercises towards an appreciation of professionalism. The diagram serves as an organising framework for conceptualising an emerging professional identity and for directing learning towards the domains of 'self as professional' 45.OBJECTIVE:This paper describes how a diagrammatic representation of the core elements of an integrated health professional is used as a template for framing course content and for organising student learning. Based on the assumption that all health care professionals should be knowledgeable, empathic and reflective, the diagram provides students and educators with a visual tool for investigating the subjective and objective dimensions of professionalism. The use of the diagram as an integrating point of reference for individual and small group learning is described and substantiated with relevant literature. CONCLUSION: The authors have applied the diagram with positive impact for the past six years with students and educators reporting that "it just makes sense". The article includes plans for formal evaluation. Evaluation to date is based on preliminary, informal feedback on the value of the diagram as a tool for capturing the domains of professionalism at an early stage in the undergraduate education of health professional students

Implementing Individually Tailored Prescription of Physical Activity in Routine Clinical Care:Protocol of the Physicians Implement Exercise = Medicine (PIE=M) Development and Implementation Project

BACKGROUND: The prescription of physical activity (PA) in clinical care has been advocated worldwide. This "exercise is medicine" (E=M) concept can be used to prevent, manage, and cure various lifestyle-related chronic diseases. Due to several challenges, E=M is not yet routinely implemented in clinical care. OBJECTIVE: This paper describes the rationale and design of the Physicians Implement Exercise = Medicine (PIE=M) study, which aims to facilitate the implementation of E=M in hospital care. METHODS: PIE=M consists of 3 interrelated work packages. First, levels and determinants of PA in different patient and healthy populations will be investigated using existing cohort data. The current implementation status, facilitators, and barriers of E=M will also be investigated using a mixed-methods approach among clinicians of participating departments from 2 diverse university medical centers (both located in a city, but one serving an urban population and one serving a more rural population). Implementation strategies will be connected to these barriers and facilitators using a systematic implementation mapping approach. Second, a generic E=M tool will be developed that will provide tailored PA prescription and referral. Requirements for this tool will be investigated among clinicians and department managers. The tool will be developed using an iterative design process in which all stakeholders reflect on the design of the E=M tool. Third, we will pilot-implement the set of implementation strategies, including the E=M tool, to test its feasibility in routine care of clinicians in these 2 university medical centers. An extensive learning process evaluation will be performed among clinicians, department managers, lifestyle coaches, and patients using a mixed-methods design based on the RE-AIM framework. RESULTS: This project was approved and funded by the Dutch grant provider ZonMW in April 2018. The project started in September 2018 and continues until December 2020 (depending on the course of the COVID-19 crisis). All data from the first work package have been collected and analyzed and are expected to be published in 2021. Results of the second work package are described. The manuscript is expected to be published in 2021. The third work package is currently being conducted in clinical practice in 4 departments of 2 university medical hospitals among clinicians, lifestyle coaches, hospital managers, and patients. Results are expected to be published in 2021. CONCLUSIONS: The PIE=M project addresses the potential of providing patients with PA advice to prevent and manage chronic disease, improve recovery, and enable healthy ageing by developing E=M implementation strategies, including an E=M tool, in routine clinical care. The PIE=M project will result in a blueprint of implementation strategies, including an E=M screening and referral tool, which aims to improve E=M referral by clinicians to improve patients' health, while minimizing the burden on clinicians

A Cross-Study Transcriptional Analysis of Parkinson's Disease

The study of Parkinson's disease (PD), like other complex neurodegenerative disorders, is limited by access to brain tissue from patients with a confirmed diagnosis. Alternatively the study of peripheral tissues may offer some insight into the molecular basis of disease susceptibility and progression, but this approach still relies on brain tissue to benchmark relevant molecular changes against. Several studies have reported whole-genome expression profiling in post-mortem brain but reported concordance between these analyses is lacking. Here we apply a standardised pathway analysis to seven independent case-control studies, and demonstrate increased concordance between data sets. Moreover data convergence increased when the analysis was limited to the five substantia nigra (SN) data sets; this highlighted the down regulation of dopamine receptor signaling and insulin-like growth factor 1 (IGF1) signaling pathways. We also show that case-control comparisons of affected post mortem brain tissue are more likely to reflect terminal cytoarchitectural differences rather than primary pathogenic mechanisms. The implementation of a correction factor for dopaminergic neuronal loss predictably resulted in the loss of significance of the dopamine signaling pathway while axon guidance pathways increased in significance. Interestingly the IGF1 signaling pathway was also over-represented when data from non-SN areas, unaffected or only terminally affected in PD, were considered. Our findings suggest that there is greater concordance in PD whole-genome expression profiling when standardised pathway membership rather than ranked gene list is used for comparison

Effective Gene Therapy in a Mouse Model of Prion Diseases

Classical drug therapies against prion diseases have encountered serious difficulties. It has become urgent to develop radically different therapeutic strategies. Previously, we showed that VSV-G pseudotyped FIV derived vectors carrying dominant negative mutants of the PrP gene are efficient to inhibit prion replication in chronically prion-infected cells. Besides, they can transduce neurons and cells of the lymphoreticular system, highlighting their potential use in gene therapy approaches. Here, we used lentiviral gene transfer to deliver PrPQ167R virions possessing anti-prion properties to analyse their efficiency in vivo. Since treatment for prion diseases is initiated belatedly in human patients, we focused on the development of a curative therapeutic protocol targeting the late stage of the disease, either at 35 or 105 days post-infection (d.p.i.) with prions. We observed a prolongation in the lifespan of the treated mice that prompted us to develop a system of cannula implantation into the brain of prion-infected mice. Chronic injections of PrPQ167R virions were done at 80 and 95 d.p.i. After only two injections, survival of the treated mice was extended by 30 days (20%), accompanied by substantial improvement in behaviour. This delay was correlated with: (i) a strong reduction of spongiosis in the ipsilateral side of the brain by comparison with the contralateral side; and (ii) a remarkable decrease in astrocytic gliosis in the whole brain. These results suggest that chronic injections of dominant negative lentiviral vectors into the brain, may be a promising approach for a curative treatment of prion diseases