The role of cardiolipin in mitophagy

Mitophagy allows for the removal of damaged and dysfunctional mitochondria from the cell thereby attenuating any deleterious, potentially tumorigenic effects malfunctioning mitochondria may cause. Mitophagy is a specific from of macro-autophagy whereby mitochondria are selectively degraded. What controls this specificity is an area of active research. The translocation of various proteins such as PINK1 and PARKIN, to the mitochondria prior to mitophagy is thought to act as signals for recruitment of the autophagosome to the mitochondria. However what is the initiating signal for mitophagy that causes these proteins to act remains unclear. Damaged and dysfunctional mitochondria generate increased levels of reactive oxygen species and we hypothesized that these cause the oxidation of the mitochondrial membrane poly-unsaturated lipid, cardiolipin (CL), which acts as an indicator of mitochondrial health and as an initiating signal to the mitophagic machinery. Using human fibroblasts (derived from Barth’s syndrome patients) deficient in functional tafazzin (Taz), the enzyme responsible for CL maturation (poly-unsaturation), and control fibroblasts created by re-introducing a fully functional Taz gene into the parental Barth’s syndrome cells. The frequency at which mitophagy occurs in these deficient and revertant cell lines was analysed under different oxidative stress conditions, in conjunction with other factors known to affect the occurrence of mitophagy; such as mitochondrial morphology, dynamics, mass, membrane potential and function. We observed that not only were mitochondrial morphology, dynamics and function affected by the levels of polyunsaturated CL, but that indeed mitophagy is abrogated in cells lacking expression of functional TAZ and therefore lacking mature polyunsaturated CL. Further to this initial experiments have confirmed reduced levels of oxidized CL in the Barth’s syndrome cells, which combined with the evidence of reduced mitophagy suggests this could indeed be the initiating signal for mitophagy. Thus the data presented within this thesis provides evidence of the role of polyunsaturated CL, in mitophagy and suggests that through its oxidation it provides the initiating signal for mitophagy

Recruitment challenges in stroke rehabilitation randomized controlled trials: a qualitative exploration of trialists’ perspectives using Framework analysis

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This research was part of a Glasgow Caledonian University funded studentship PhD based at, the Nursing Midwifery and Allied Health Professions Research Unit. The NMAHP RU and MCB are funded by the Chief Science Office, Scottish Government Health and Social Care Directorate. The views expressed here are that of the authors and not necessarily the funders.Peer reviewedPostprin

Comparing different data collection and analysis techniques for quantifying healthy knee joint function during stair ascent and descent

There is currently no standard data collection or analysis method for the assessment of stair gait using motion analysis. This makes the comparison of results from different studies difficult. It is important to gain an appreciation of the discrepancies in kinematic and kinetic information generated by employing different computational approaches, as these differences may be critical in cases where methodologies were to change over a long-term study. This study explores the effect of using different methodologies for the assessment of non-pathological knee function of ten subjects during stair ascent and descent. Two methods of computing knee kinematics were compared: (a) using in-house software and a pointer method of anatomical calibration and (b) using commercial software, Visual3D (C-motion, Inc.) and skin-mounted markers. Significant differences were found between the two methods when calculating a frontal plane range of motion (p<0.05). Three methods of computing knee moments were compared. Knee moments computed using the inverse dynamic analysis (IDA) approach of Visual3D (C-motion, Inc.) were significantly different (p<0.05) to those calculated using in-house IDA software that ignores the foot and ankle and to those computed using a vector cross-product approach. This study highlights the implications of comparing data generated from different collection and analysis methods

Visual Function Questionnaire as an outcome measure for homonymous hemianopia: subscales and supplementary questions, analysis from the VISION trial

Background: We conduct supplementary analyses of the NEI VFQ-25 data to evaluate where changes occurred within subscales of the NEI VFQ-25 leading to change in the composite scores between the three treatment arms, and evaluate the NEI VFQ-25 with and without the Neuro 10 supplement. Methods: A prospective, multicentre, parallel, single-blind, three-arm RCT of fourteen UK acute stroke units was conducted. Stroke survivors with homonymous hemianopia were recruited. Interventions included: Fresnel prisms for minimum 2 h, 5 days/week over 6-weeks (Arm a), Visual search training for minimum 30 min, 5 days/week over 6-weeks (Arm b) and standard care-information only (Arm c). Primary and secondary outcomes (including NEI VFQ-25 data) were measured at baseline, 6, 12 and 26 weeks after randomisation. Results: Eighty seven patients were recruited (69% male; mean age (SD) equal to 69 (12) years). At 26 weeks, outcomes for 24, 24 and 22 patients, respectively, were compared to baseline. NEI VFQ-25 (with and without Neuro 10) responses improved from baseline to 26 weeks with visual search training compared to Fresnel prisms and standard care. In subscale analysis, the most impacted across all treatment arms was ‘driving’ whilst the least impacted were ‘colour vision’ and ‘ocular pain’. Conclusions: Composite scores differed systematically for the NEI VFQ-25 (Neuro 10) versus NEI VFQ-25 at all time points. For subscale scores, descriptive statistics suggest clinically relevant improvement in distance activities and vision-specific dependency subscales for NEI VFQ-25 scores in the visual search treatment arm. Trial Registration: Current Controlled Trials ISRCTN05956042

Assistive devices, hip precautions, environmental modifications and training to prevent dislocation and improve function after hip arthroplasty (Review)

Background: Total hip arthroplasty (THA) is one of the most common orthopaedic operations performed worldwide. Painful osteoarthritis of the hip is the primary indication for THA. Following THA, people have conventionally been provided with equipment, such as raised toilet seats and chairs, and educated to avoid activities that could cause the hip joint to be in a position of flexion over 90 degrees, or adduction or rotation past the midline. These aspects of occupational therapy have been advocated to reduce the risks of prosthesis dislocation. However, the appropriateness of these recommendations has been questioned. Objectives: To assess the effects of provision of assistive devices, education on hip precautions, environmental modifications and training in activities of daily living (ADL) and extended ADL (EADL) for people undergoing THA. Search methods: We searched MEDLINE (1946 to April 2016), EMBASE (1947 to April 2016), the Cochrane Library including CENTRAL (Issue 4 of 12, 2016), Database of Reviews of Effects (DARE), Health Technology Assessment (HTA), Economic Evaluations Database (EED), CINAHL, PEDro and CIRRIE from inception to April 2016. In addition we checked Controlled Clinical Trials, Clinicaltrials.gov, the National Institutes of Health Trial Registry, theWorld Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and the OpenGrey database from inception to April 2016. Selection criteria: We included randomised controlled trials (RCTs), quasi-RCTs and cluster-RCTs that evaluated the effectiveness of the provision of assistive devices, education on hip precautions, environmental modifications, or training in ADL and EADL for people undergoing THA. The main outcomes of interest were pain, function, health-related quality of life (HRQOL), global assessment of treatment success, reoperation rate, hip dislocation and adverse events. Data collection and analysis: We used standard methodological procedures recognised by Cochrane. We conducted a systematic literature search using several databases and contacted corresponding authors, appraised the evidence using the Cochrane risk of bias tool, analysed the data using a narrative analysis approach (as it was not possible to conduct a meta-analysis due to heterogeneity in interventions), and interpreted all outcomes using the GRADE approach. Main results: We included three trials with a total of 492 participants who had received 530 THA. The evidence presented with a high risk of performance, detection and reporting bias. One study (81 participants) compared outcomes for participants randomised to the provision of hip precautions, equipment and functional restrictions versus no provision of hip precautions, equipment or functional restrictions. Due to the quality of evidence being very low, we are uncertain if the provision of hip precautions, equipment and functional restrictions improved function measured using the Harris Hip Score at 12 month follow-up, or health-related quality of life (HRQOL) measured by the Short Form-12 at four week follow-up, compared to not providing this. There were no incidences of hip dislocation or adverse events in either group during the initial 12 postoperative months. The study did not measure pain score, global assessment of treatment success or total adverse events. One study (265 participants; 303THAs) evaluated the provision of hip precautions with versus without the prescription of postoperative equipment and restrictions to functional activities. Due to the quality of evidence being very low, we are uncertain if perceived satisfaction in the rate of recovery differed in people who were not prescribed postoperative equipment and restrictions (135/151 satisfied) compared to those prescribed equipment and restrictions (113/152) (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.93; 265 participants, one trial; number needed to treat for an additional beneficial outcome (NNTB) = 7). Due to the low quality evidence, we are uncertain if the incidence of hip dislocation differed between participants provided with hip precautions with (1/152) compared to without providing equipment or restrictions post-THA (0/151) (RR 2.98, 95% CI 0.12 to 72.59). The study did not measure pain, function, HRQOL, re-operation rates or total adverse events. One study (146 participants) investigated the provision of an enhanced postoperative education and rehabilitation service on hospital discharge to promote functional ADL versus a conventional rehabilitation intervention in the community. This study was of very low quality evidence. We were uncertain if the provision of enhanced postoperative education and rehabilitation improved function at six months follow-up, when assessed using the Objective and Subjective Functional Capability Index (146 participants, one trial; P > 0.05; no numerical results provided) compared to conventional rehabilitation. The study did not measure pain score, HRQOL, global assessment of treatment success, hip dislocation, re-operation rate or total adverse events. Authors’ conclusions: Very low quality evidence is available from single trials, thus we are uncertain if hip precautions with or without the addition of equipment and functional restrictions are effective in preventing dislocation and improving outcomes after THA. There is also insufficient evidence to support or refute the adoption of a postoperative community rehabilitation programme consisting of functional reintegration and education compared to conventional rehabilitation strategies based on functional outcomes. Further high-quality trials are warranted to assess the outcomes of different occupational therapy interventions both in the short and longer-term for those who undergo THA. An assessment of the impact of such interventions on pain and restriction on personal ADL, EADL and instrumental ADL is needed, and also of functional integration-type interventions rather than just hip precautions,equipment and restrictions