A paREDOX in the control of cholesterol biosynthesis: Does the NADPH sensor and E3 ubiquitin ligase MARCHF6 protect mammalian cells during oxidative stress by controlling sterol biosynthesis?

Sterols and the reductant nicotinamide adenine dinucleotide phosphate (NADPH), essential for eukaryotic life, arose because of, and as an adaptation to, rising levels of molecular oxygen (O2). Hence, the NADPH and O2-intensive process of sterol biosynthesis is inextricably linked to redox status. In mammals, cholesterol biosynthesis is exquisitely regulated post-translationally by multiple E3 ubiquitin ligases, with membrane associated Really Interesting New Gene (RING) C3HC4 finger 6 (MARCHF6) degrading at least six enzymes in the pathway. Intriguingly, all these MARCHF6-dependent enzymes require NADPH. Moreover, MARCHF6 is activated by NADPH, although what this means for control of cholesterol synthesis is unclear. Indeed, this presents a paradox for how NADPH regulates this vital pathway, since NADPH is a cofactor in cholesterol biosynthesis and yet, low levels of NADPH should spare cholesterol biosynthesis enzymes targeted by MARCHF6 by reducing its activity. We speculate MARCHF6 helps mammalian cells adapt to oxidative stress (signified by low NADPH levels) by reducing degradation of cholesterogenic enzymes, thereby maintaining synthesis of protective cholesterol.

Skin temperature of the knee was effectively reduced when using a new continuous cold-flow cryocompression device: a randomised controlled crossover trial.

OBJECTIVE: To determine which temperature settings on a new continuous cold-flow cryocompression device effectively reduce knee skin temperature to 10-15 °C, where pain and swelling are expected to be attenuated. DESIGN: Randomised controlled crossover trial. SETTING: University laboratory. PARTICIPANTS: 32 healthy adult participants recruited (1 dropout) with no contraindications to cryocompressive therapy. INTERVENTION: A k-type thermocouple was used to record skin temperature at baseline and every five minutes during a 30-minute cryocompression treatment in a control condition and when using four different device temperature settings (6 °C, 8 °C, 10 °C, and 12 °C) on a continuous cold-flow cryocompression device. Conditions were labelled Control, Con-6, Con-8, Con-10, and Con-12, respectively. MAIN OUTCOME MEASURES: Skin temperature change (°C) throughout cryocompression; time taken (mins) to achieve skin temperature < 15 °C; and the difference between final skin temperature and device temperature setting (°C). RESULTS: Median (IQR) skin temperature after cryocompression was 32.1 °C (29.3-33.4), 12.8 °C (12.1-14.6), 14.3 °C (13.8-15.7), 16.1 °C (15.2-17.3), and 17.7 °C (16.9-18.9) for the Control condition and Con-6, Con-8, Con-10 and Con-12, respectively. It took 20 min (Con-6) and 25 min (Con-8) for skin temperature to reach < 15 °C. A median (IQR) difference of 6.8 °C (6.1-8.6), 6.3 °C (5.8-7.7), 6.1 °C (5.2-7.3), and 5.7 °C (4.9-6.9) for Con-6, Con-8, Con-10, and Con-12, respectively was observed between device temperature setting and final skin temperature. CONCLUSIONS: The device is recommended as it reduced skin temperature to the therapeutic range of 10-15 °C during a 30-minute treatment when using the 6 °C or 8 °C device temperature settings. Future research should determine optimal treatment lengths for cryocompression. CONTRIBUTION OF THE PAPER.

A randomised crossover trial of five cryocompression devices' ability to reduce skin temperature of the knee.

BACKGROUND: The application of cold and pressure to the knee is a common part of post-operative rehabilitation. Skin temperature should be reduced to within 10-15 °C to optimise the therapeutic benefits of cryocompression. The purpose of this study was to investigate the ability of five different cryocompression devices to reduce skin temperature to within this therapeutic range. MATERIALS AND METHODS: 32 healthy adult participants (mean (SD): age 26.3 (7.9) years; BMI 24.8 (2.7) kg/m2; 20 males) were recruited for this randomised crossover study. Skin temperature was measured 20 mm distal to the patella using a k-type thermocouple every five minutes during a 30-minute treatment with one of five different cryocompression devices (Physiolab S1, GameReady, Cryo/Cuff, VPulse, and a Gel Wrap). Changes in skin temperature over time were compared to baseline within and between conditions. A subjective rating of comfort was also recorded for each device. RESULTS: The Physiolab S1 and GameReady devices caused significantly lower skin temperatures compared to the VPulse, Gel Wrap, and Cryo/Cuff after 30 minutes (p<0.05). 87-96% reported a positive comfort rating for the Physiolab S1, VPulse, Cryo/Cuff and Gel Wrap, whereas 53% of participants reported a positive comfort rating for the GameReady. CONCLUSIONS: Only the Physiolab S1 and GameReady devices reduced skin temperature of the knee to within the target range of 10-15 °C. The Physiolab S1 was reportedly more comfortable than the GameReady. Clinicians should be aware of the performance differences of different cryocompression devices to understand which is most likely to provide an effective dose of cold therapy to a joint.

Effect of home-based, overground robotic-assisted gait training on vascular health in people with chronic stroke.

Overground robotic-assisted gait training (O-RAGT) has been shown to improve clinical functional outcomes in people living with stroke. The purpose of this study was to identify whether a home-based O-RAGT program, in combination with usual care physiotherapy, would demonstrate improvements in vascular health in individuals with chronic stroke, and, whether any changes in vascular outcomes would be sustained 3 months after completing the program. Thirty-four participants with chronic stroke (between 3 months and 5 years post-stroke) were randomized to either a 10-week O-RAGT program in combination with usual care physiotherapy, or to a usual care physiotherapy only control group. Participants' (n = 31) pulse wave analysis (PWA), and regional [carotid-femoral pulse wave analysis (cfPWV)] and local (carotid) measures of arterial stiffness were assessed at baseline, post-intervention, and 3-month post-intervention. Analysis of covariance demonstrated a significant reduction (improvement) in cfPWV between BL and PI for O-RAGT (8.81 ± 2.51 vs. 7.92 ± 2.17 m/s, respectively), whilst the control group remained unchanged (9.87 ± 2.46 vs. 9.84 ± 1.76 m/s, respectively; p < 0.05; ηp2 = 0.14). The improvement in cfPWV was maintained 3 months after completing the O-RAGT program. There were no significant Condition by Time interactions for all PWA and carotid arterial stiffness measures (p > 0.05). A significant increase in physical activity, as determined by the time spent stepping, was observed for O-RAGT between baseline and post-intervention assessments (3.2 ± 3.0-5.2 ± 3.3%, respectively) but not for CON (p < 0.05). The improvement in cfPWV, in combination with an increase in physical activity whilst wearing the O-RAGT and concomitant reduction in sedentary behavior, are important positive findings when considering the application of this technology for "at home" rehabilitation therapy for stroke survivors. Further research is needed to determine whether implementing "at home" O-RAGT programs should be a part of the stroke treatment pathway. Clinical trial registration: https://clinicaltrials.gov, identifier NCT03104127.

Effects of robotic-assisted gait training on the central vascular health of individuals with spinal cord injury: A pilot study.

Objective: To investigate the effect of a short-term, robotic-assisted (exoskeleton) gait training (RGT) program on central and peripheral hemodynamic measures in patients with spinal cord injury (SCI).Design: Parallel group, non-randomized trial with before (baseline) and after (follow-up) assessments.Setting: Single-center, community-based neuro-physiotherapy practice.Participants: Twelve individuals with SCI (ASI A to C).Interventions: Participants completed either a 5-day RGT program plus physiotherapy (n = 6), or a usual care physiotherapy only program (control group; n = 6). The RGT program consisted of daily 60-min physiotherapy and 90-min of RGT. Outcome measures were measured before and after the rehabilitation program.Main outcome measure(s): The primary outcome measure was arterial wave reflection (Augmentation index [AIx]), with central and peripheral blood pressures also reported. Data are presented as mean (SD) and effect sizes (partial eta squared; η2p).Results: There was a significant reduction in AIx (30 ± 18-21 ± 15%; η2p=0.75) and mean arterial pressure (89 ± 11-82 ± 10 mmHg; η2p=0.47) following completion of the RGT program (both P < 0.05). There were no changes in these measures for the control group. Although not significantly different, medium to large effects were observed in favor of RGT for all other central and peripheral measures (η2p=0.06-0.21), except for heart rate and pulse pressure (η2p<0.04).Conclusions: RGT using an exoskeleton is a promising therapy for improving cardiovascular health in patients with SCI. Specifically, this study indicates decreased arterial wave reflection and supports the need for larger randomized controlled trials.Trial Registration: Clinical trials Registry (https://clinicaltrials.gov/; NCT03611803).