Aging Differentially Affects Multiple Aspects of Vesicle Fusion Kinetics

How fusion pore formation during exocytosis affects the subsequent release of vesicle contents remains incompletely understood. It is unclear if the amount released per vesicle is dependent upon the nature of the developing fusion pore and whether full fusion and transient kiss and run exocytosis are regulated by similar mechanisms. We hypothesise that if consistent relationships exist between these aspects of exocytosis then they will remain constant across any age. Using amperometry in mouse chromaffin cells we measured catecholamine efflux during single exocytotic events at P0, 1 month and 6 months. At all ages we observed full fusion (amperometric spike only), full fusion preceded by fusion pore flickering (pre-spike foot (PSF) signal followed by a spike) and pure “kiss and run” exocytosis (represented by stand alone foot (SAF) signals). We observe age-associated increases in the size of all 3 modes of fusion but these increases occur at different ages. The release probability of PSF signals or full spikes alone doesn't alter across any age in comparison with an age-dependent increase in the incidence of “kiss and run” type events. However, the most striking changes we observe are age-associated changes in the relationship between vesicle size and the membrane bending energy required for exocytosis. Our data illustrates that vesicle size does not regulate release probability, as has been suggested, that membrane elasticity or flexural rigidity change with age and that the mechanisms controlling full fusion may differ from those controlling “kiss and run” fusion

Subacute and chronic, non-specific back and neck pain: cognitive-behavioural rehabilitation versus primary care. A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>In the industrial world, non-specific back and neck pain (BNP) is the largest diagnostic group underlying sick-listing. For patients with subacute and chronic (= full-time sick-listed for 43 – 84 and 85 – 730 days, respectively) BNP, cognitive-behavioural rehabilitation was compared with primary care. The specific aim was to answer the question: within an 18-month follow-up, will the outcomes differ in respect of sick-listing and number of health-care visits?</p> <p>Methods</p> <p>After stratification by age (≤ 44/≥ 45 years) and subacute/chronic BNP, 125 Swedish primary-care patients were randomly allocated to cognitive-behavioural rehabilitation (rehabilitation group) or continued primary care (primary-care group). Outcome measures were <it>Return-to-work share </it>(percentage) and <it>Return-to-work chance </it>(hazard ratios) over 18 months, <it>Net days </it>(crude sick-listing days × degree), and the number of <it>Visits </it>(to physicians, physiotherapists etc.) over 18 months and the three component six-month periods. Descriptive statistics, Cox regression and mixed-linear models were used.</p> <p>Results</p> <p>All patients: <it>Return-to-work share </it>and <it>Return-to-work chance </it>were equivalent between the groups. <it>Net days </it>and <it>Visits </it>were equivalent over 18 months but decreased significantly more rapidly for the rehabilitation group over the six-month periods (<it>p </it>< .05). Subacute patients: <it>Return-to-work share </it>was equivalent. <it>Return-to-work chance </it>was significantly greater for the rehabilitation group (hazard ratio 3.5 [95%CI1.001 – 12.2]). <it>Net days </it>were equivalent over 18 months but decreased significantly more rapidly for the rehabilitation group over the six-month periods and there were 31 days fewer in the third period. <it>Visits </it>showed similar though non-significant differences and there were half as many in the third period. Chronic patients: <it>Return-to-work share, Return-to-work chance </it>and <it>Net days </it>were equivalent. <it>Visits </it>were equivalent over 18 months but tended to decrease more rapidly for the rehabilitation group and there were half as many in the third period (non-significant).</p> <p>Conclusion</p> <p>The results were equivalent over 18 months. However, there were indications that cognitive-behavioural rehabilitation in the longer run might be superior to primary care. For subacute BNP, it might be superior in terms of sick-listing and health-care visits; for chronic BNP, in terms of health-care visits only. More conclusive results concerning this possible long-term effect might require a longer follow-up.</p> <p>Trial registration</p> <p>NCT00488735.</p

A Participatory Return-to-Work Intervention for Temporary Agency Workers and Unemployed Workers Sick-Listed Due to Musculoskeletal Disorders: Results of a Randomized Controlled Trial

Introduction Within the labour force workers without an employment contract represent a vulnerable group. In most cases, when sick-listed, these workers have no workplace/employer to return to. Therefore, the aim of this study was to evaluate the effectiveness on return-to-work of a participatory return-to-work program compared to usual care for unemployed workers and temporary agency workers, sick-listed due to musculoskeletal disorders. Methods The workers, sick-listed for 2–8 weeks due to musculoskeletal disorders, were randomly allocated to the participatory return-to-work program (n = 79) or to usual care (n = 84). The new program is a stepwise procedure aimed at making a consensus-based return-to-work plan, with the possibility of a temporary (therapeutic) workplace. Outcomes were measured at baseline, 3, 6, 9 and 12 months. The primary outcome measure was time to sustainable first return-to-work. Secondary outcome measures were duration of sickness benefit, functional status, pain intensity, and perceived health. Results The median duration until sustainable first return-to-work was 161 days in the intervention group, compared to 299 days in the usual care group. The new return-to-work program resulted in a non-significant delay in RTW during the first 90 days, followed by a significant advantage in RTW rate after 90 days (hazard ratio of 2.24 [95% confidence interval 1.28–3.94] P = 0.005). No significant differences were found for the measured secondary outcomes. Conclusions The newly developed participatory return-to-work program seems to be a promising intervention to facilitate work resumption and reduce work disability among temporary agency workers and unemployed workers, sick-listed due to musculoskeletal disorders

Decoding the dopamine signal in Macaque prefrontal cortex: a simulation study using the Cx3Dp simulator

Dopamine transmission in the prefrontal cortex plays an important role in reward based learning, working memory and attention. Dopamine is thought to be released non-synaptically into the extracellular space and to reach distant receptors through diffusion. This simulation study examines how the dopamine signal might be decoded by the recipient neuron. The simulation was based on parameters from the literature and on our own quantified, structural data from macaque prefrontal area 10. The change in extracellular dopamine concentration was estimated at different distances from release sites and related to the affinity of the dopamine receptors. Due to the sparse and random distribution of release sites, a transient heterogeneous pattern of dopamine concentration emerges. Our simulation predicts, however, that at any point in the simulation volume there is sufficient dopamine to bind and activate high-affinity dopamine receptors. We propose that dopamine is broadcast to its distant receptors and any change from the local baseline concentration might be decoded by a transient change in the binding probability of dopamine receptors. Dopamine could thus provide a graduated ‘teaching’ signal to reinforce concurrently active synapses and cell assemblies. In conditions of highly reduced or highly elevated dopamine levels the simulations predict that relative changes in the dopamine signal can no longer be decoded, which might explain why cognitive deficits are observed in patients with Parkinson’s disease, or induced through drugs blocking dopamine reuptake

Physical exercise interventions to improve disability and return to work in low back pain: Current insights and opportunities for improvement

INTRODUCTION: There is a body of literature that indicates that physical exercise interventions, with a primary focus on improvement of functioning instead of pain relief, might be effective to stimulate return to work and improve function in workers who are absent from work due to low back pain (LBP). Successful application and implementation of these interventions however, depends on multiple factors that need to be addressed carefully in clinical practice as well as research. METHODS: Descriptive literature review, to identify an overview of current knowledge with respect to the safety, content- and context-related aspects of physical exercise interventions, issues relating to timing, the influence of treatment confidence and patient expectations, and the process of changing provider and employer behavior. RESULTS: Physical exercises are not associated with an increased risk for recurrences. The effects of interventions may vary depending on content-related factors (i.e., type of exercises, dosage, frequency, skills of the healthcare providers, etc.) and contextual factors (i.e., treatment setting, compensation system, etc.). Treatment confidence and patients' expectations also significantly influence outcomes of physical exercise interventions. Timing is also important; interventions targeting return to work, applied during the acute phase of work absenteeism, compete with a high rate of spontaneous recovery and may therefore be inefficient. CONCLUSIONS: Despite numerous studies, more quantitative and qualitative investigations are needed to further clarify the requirements for a successful application and implementation of physical exercise interventions for disabled workers with low back pain