Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): multicentre, randomised controlled, endpoint blinded trial.

OBJECTIVE: To determine the safety and efficacy of aerobic exercise on activities of daily living in the subacute phase after stroke. DESIGN: Multicentre, randomised controlled, endpoint blinded trial. SETTING: Seven inpatient rehabilitation sites in Germany (2013-17). PARTICIPANTS: 200 adults with subacute stroke (days 5-45 after stroke) with a median National Institutes of Health stroke scale (NIHSS, range 0-42 points, higher values indicating more severe strokes) score of 8 (interquartile range 5-12) were randomly assigned (1:1) to aerobic physical fitness training (n=105) or relaxation sessions (n=95, control group) in addition to standard care. INTERVENTION: Participants received either aerobic, bodyweight supported, treadmill based physical fitness training or relaxation sessions, each for 25 minutes, five times weekly for four weeks, in addition to standard rehabilitation therapy. Investigators and endpoint assessors were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary outcomes were change in maximal walking speed (m/s) in the 10 m walking test and change in Barthel index scores (range 0-100 points, higher scores indicating less disability) three months after stroke compared with baseline. Safety outcomes were recurrent cardiovascular events, including stroke, hospital readmissions, and death within three months after stroke. Efficacy was tested with analysis of covariance for each primary outcome in the full analysis set. Multiple imputation was used to account for missing values. RESULTS: Compared with relaxation, aerobic physical fitness training did not result in a significantly higher mean change in maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), P=0.23) or mean change in Barthel index score (0 (-5 to 5), P=0.99) at three months after stroke. A higher rate of serious adverse events was observed in the aerobic group compared with relaxation group (incidence rate ratio 1.81, 95% confidence interval 0.97 to 3.36). CONCLUSIONS: Among moderately to severely affected adults with subacute stroke, aerobic bodyweight supported, treadmill based physical fitness training was not superior to relaxation sessions for maximal walking speed and Barthel index score but did suggest higher rates of adverse events. These results do not appear to support the use of aerobic bodyweight supported fitness training in people with subacute stroke to improve activities of daily living or maximal walking speed and should be considered in future guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT01953549.

Pro-inflammatory cytokines upregulate the skin immunoreactivity for NGF, NT-3, NT-4 and their receptor, p75NTR in vivo: a preliminary report.

Skin and hair follicles are both source and target of various cytokines and neurotrophins (NTs). While several pro-inflammatory cytokines are recognized to alter the expression of NTs and their receptors (NTRs), for example, on brain cells and fibroblasts in vitro, it is unknown whether this also occurs in normal mammalian skin in vivo. As a first step toward exploring this, we studied in murine back skin (C57BL/6) whether intradermally injected interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) altered the cutaneous immunoreactivity patterns of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), Trk-A, Trk-B, Trk-C and p75NTR and their receptors (TrkA, TrkB, TrkC, p75NTR) on the protein level in situ. By immunohistology, IFNgamma, IL-1beta, and TNF-alpha as well as a cocktail of all three cytokines increased NGF immunoreactivity (IR) in the proximal outer root sheath and hair matrix of anagen VI pelage hair follicles. The cytokine cocktail upregulated NT-3 and NT-4 IR in the epidermis, increased NT-4 IR in selected cells of the proximal outer root sheath, and also enhanced IR of p75NTR, in the follicular dermal papilla. Therefore, this pilot study provides the first preliminary indications that proinflammatory cytokines upregulate the cutaneous immunoreactivity of NGF, NT-3, NT-4 and their receptor p75NTR in vivo. This raises the question to which extent several of the recognized cutaneous effects of IFNgamma, IL-1beta and TNF-alpha are mediated indirectly via modulating the expression of selected NTs and/or NTRs.