Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia.

Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material.The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders

Think twice before starting a new trial; what is the impact of recommendations to stop doing new trials?

ObjectivesIn evidence-based medicine, we base our conclusions on the effectiveness of interventions on the results of high-quality meta-analysis. If a new randomized controlled trial (RCT) is unlikely to change the pooled effect estimate, conducting the new trial is a waste of resources. We evaluated whether recommendations not to conduct further RCTs reduced the number of trials registered for two scenarios.MethodsAnalysis of registered trials on the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP). We regarded trial protocols relevant if they evaluated the effectiveness of (1) exercise for chronic low back pain (LBP) and (2) cognitive behavioural therapy (CBT) for chronic pain. We calculated absolute and relative numbers and change of registered trials in a pre-set time window before and after publication of the recommendations, both published in 2012.ResultsWe found 1,574 trials registered in the WHO trial registry for exercise in LBP (459 before 2012; 1,115 after) and 5,037 trials on chronic pain (1,564 before 2012; 3,473 after). Before 2012, 13 trials on exercise for LBP (out of 459) fit the selection criteria, compared to 42 trials (out of 1,115) after, which represents a relative increase of 33%. Twelve trials (out of 1,564) regarding CBT for chronic pain, fit the selection criteria before 2012 and 18 trials (out of 3,473) after, representing a relative decrease of 32%. We found that visibility, media exposure and strength of the recommendation were related to a decrease in registered trials.ConclusionsRecommendations not to conduct further RCTs might reduce the number of trials registered if these recommendations are strongly worded and combined with social media attention

Ankles back in randomized controlled trial (ABrCt): braces versus neuromuscular exercises for the secondary prevention of ankle sprains. Design of a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Ankle sprains are the most common sports and physical activity related injury. There is extensive evidence that there is a twofold increased risk for injury recurrence for at least one year post injury. In up to 50% of all cases recurrences result in disability and lead to chronic pain or instability, requiring prolonged medical care. Therefore ankle sprain recurrence prevention in athletes is essential. This RCT evaluates the effect of the combined use of braces and neuromuscular training (e.g. proprioceptive training/sensorimotor training/balance training) against the individual use of either braces or neuromuscular training alone on ankle sprain recurrences, when applied to individual athletes after usual care.</p> <p>Methods/Design</p> <p>This study was designed as three way randomized controlled trial with one year follow-up. Healthy individuals between 12 and 70 years of age, who were actively participating in sports and who had sustained a lateral ankle sprain in the two months prior to inclusion, were eligible for inclusion. After subjects had finished ankle sprain treatment by means of usual care, they were randomised to any of the three study groups. Subjects in group 1 received an eight week neuromuscular training program, subjects in group 2 received a sports brace to be worn during all sports activities for the duration of one year, and group 3 received a combination of the neuromuscular training program and a sports brace to be worn during all sports activities for the duration of eight weeks. Outcomes were assessed at baseline and every month for 12 months therafter. The primary outcome measure was incidence of ankle sprain recurrences. Secondary outcome measures included the direct and indirect costs of recurrent injury, the severity of recurrent injury, and the residual complaints during and after the intervention.</p> <p>Discussion</p> <p>The ABrCt is the first randomized controlled trial to directly compare the secondary preventive effect of the combined use of braces and neuromuscular training, against the use of either braces or neuromuscular training as separate secondary preventive measures. This study expects to identify the most effective and cost-efficient secondary preventive measure for ankle sprains. The study results could lead to changes in the clinical guidelines on the prevention of ankle sprains, and they will become available in 2012.</p> <p>Trial registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2157">NTR2157</a></p

Adapting to climate change in The Netherlands: an inventory of climate adaptation options and ranking of alternatives

In many countries around the world impacts of climate change are assessed and adaptation options identified. We describe an approach for a qualitative and quantitative assessment of adaptation options to respond to climate change in the Netherlands. The study introduces an inventory and ranking of adaptation options based on stakeholder analysis and expert judgement, and presents some estimates of incremental costs and benefits. The qualitative assessment focuses on ranking and prioritisation of adaptation options. Options are selected and identified and discussed by stakeholders on the basis of a sectoral approach, and assessed with respect to their importance, urgency and other characteristics by experts. The preliminary quantitative assessment identifies incremental costs and benefits of adaptation options. Priority ranking based on a weighted sum of criteria reveals that in the Netherlands integrated nature and water management and risk based policies rank high, followed by policies aiming at 'climate proof' housing and infrastructure

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Efficacy of customised foot orthoses in the treatment of achilles tendinopathy : study protocol for a randomised trial

BACKGROUND: Achilles tendinopathy is a common condition that can cause marked pain and disability. Numerous non-surgical treatments have been proposed for the treatment of this condition, but many of these treatments have a poor or non-existent evidence base. The exception to this is eccentric calf muscle exercises, which have become a standard non-surgical intervention for Achilles tendinopathy. Foot orthoses have also been advocated as a treatment for Achilles tendinopathy, but the long-term efficacy of foot orthoses for this condition is unknown. This manuscript describes the design of a randomised trial to evaluate the efficacy of customised foot orthoses to reduce pain and improve function in people with Achilles tendinopathy. METHODS: One hundred and forty community-dwelling men and women aged 18 to 55 years with Achilles tendinopathy (who satisfy inclusion and exclusion criteria) will be recruited. Participants will be randomised, using a computer-generated random number sequence, to either a control group (sham foot orthoses made from compressible ethylene vinyl acetate foam) or an experimental group (customised foot orthoses made from semi-rigid polypropylene). Both groups will be prescribed a calf muscle eccentric exercise program, however, the primary difference between the groups will be that the experimental group receive customised foot orthoses, while the control group receive sham foot orthoses. The participants will be instructed to perform eccentric exercises 2 times per day, 7 days per week, for 12 weeks. The primary outcome measure will be the total score of the Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaire. The secondary outcome measures will be participant perception of treatment effect, comfort of the foot orthoses, use of co-interventions, frequency and severity of adverse events, level of physical activity and health-related quality of life (assessed using the Short-Form-36 questionnaire - Version two). Data will be collected at baseline, then at 1, 3, 6 and 12 months. Data will be analysed using the intention to treat principle. DISCUSSION: This study is the first randomised trial to evaluate the long-term efficacy of customised foot orthoses for the treatment of Achilles tendinopathy. The study has been pragmatically designed to ensure that the study findings are generalisable to clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number: ACTRN12609000829213

Effect of exercise therapy in patients with hip osteoarthritis: A systematic review and cumulative meta-analysis.

OBJECTIVE: To evaluate the existing evidence on the effect of exercise therapy in patients with hip osteoarthritis (OA) compared to no treatment and explore whether a further trial will change the current evidence. DESIGN: Systematic review and cumulative meta-analysis using randomized controlled trials (RCT) to determine the effect on pain and function post-treatment, and at 6-9 months after treatment. Standardized mean difference (SMD) ​≤ ​-0.37 was considered clinically worthwhile. Extended funnel plots were used to simulate the impact of a new trial on the pooled effect size of pain and function. RESULTS: 18 RCTs were included. Post-treatment we found a beneficial effect of exercise therapy on pain (SMD -0.38, 95% Confidence Interval (CI): 0.55 to -0.22) and function (SMD -0.31, 95% CI -0.49 to -0.11). A beneficial effect of exercise therapy on pain (SMD -0.23, 95% CI: 0.41 to -0.05) and function (SMD -0.29, 95% CI: 0.45 to -0.12) was found 6-9 months after treatment. Most effect estimates were small, and it is unclear whether these are clinically meaningful. Extended funnel plots and a simulation of a new trial showed that only a new trial with a larger effect than the current pooled effect or a trial including 74,843 participants would change the pooled effect estimate from an unclear to a clearly clinically worthwhile effect. CONCLUSIONS: We found a beneficial effect of exercise therapy on pain and function in hip OA. It is unlikely a new trial added to current evidence will change the conclusion

Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators

<p>Abstract</p> <p>Background</p> <p>Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter. A previous double blind study in Huntington disease (HD) demonstrated that TBZ effectively suppressed chorea, with a favorable short-term safety profile (<it>Neurology </it>2006;66:366-372). The objective of this study was to assess the long-term safety and effectiveness of TBZ for chorea in HD.</p> <p>Methods</p> <p>Subjects who completed the 13-week, double blind protocol were invited to participate in this open label extension study for up to 80 weeks. Subjects were titrated to the best individual dose or a maximum of 200 mg/day. Chorea was assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale.</p> <p>Results</p> <p>Of the 75 participants, 45 subjects completed 80 weeks. Three participants terminated due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics. One subject died due to breast cancer. The other 26 subjects chose not to continue on with each ensuing extension for various reasons. When mild and unrelated AEs were excluded, the most commonly reported AEs (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysphagia scores were significantly increased at week 80 compared to baseline. At week 80, chorea had significantly improved from baseline with a mean reduction in the TMC score of 4.6 (SD 5.5) units. The mean dosage at week 80 was 63.4 mg (range 12.5-175 mg).</p> <p>Conclusions</p> <p>TBZ effectively suppresses HD-related chorea for up to 80 weeks. Patients treated chronically with TBZ should be monitored for parkinsonism, dysphagia and other side effects including sleep disturbance, depression, anxiety, and akathisia.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov registration number (initial study): NCT00219804</p

Physical activity interventions to improve daily walking activity in cancer survivors

Background Cancer patients may benefit from physical exercise programs. It is unclear, however, how sustained levels of physical activity are best achieved in this population. A systematic review was performed to summarize the current evidence of the effect of physical activity interventions on daily walking activity enhancement in cancer survivors, and to review the literature for its methodological quality. Methods A search in Medline, PEDro and the Cochrane databases was performed for English literature citations (randomized controlled trials; `RCTs`). In a first step, one reviewer abstracted data from the included studies on patients, physical activity interventions and outcomes. Two independent reviewers reviewed the methodological quality of these studies. Data were pooled using random-effects calculations. Results Our search identified 201 citations. Five RCTs that reported changes in daily step activity over time were identified, and were reviewed for methodological quality and substantive results. The median score across studies for methodological quality based on the PEDro criteria was 8. These 5 RCTs evaluated 660 participants with a mean age of 53.6 (SD 4.2) years. The mean change in daily step activity for patients with a physical exercise intervention was 526 daily steps (SD 537), with a range from -92 to 1299 daily steps. The data of three studies reporting the effect of combined physical activity and counseling on daily walking activity in breast cancer survivors were pooled, however; the I2 was 79%, indicating statistical heterogeneity between the three trials. Conclusion The 5 RCTs reviewed were of good methodological quality. Together they suggest that combined physical activity and counseling improves daily step activity in (breast) cancer survivors. Studies that define a step goal appear to be more effective in improving daily walking activity than studies that do not do so. However, the current results should be interpreted with caution because of the observed clinical and statistical heterogeneity. Future studies are warranted to evaluate the effects of goal targeted physical activity, with or without counseling, on daily walking in various cancer populations