Progranulin is expressed within motor neurons and promotes neuronal cell survival

<p>Abstract</p> <p>Background</p> <p>Progranulin is a secreted high molecular weight growth factor bearing seven and one half copies of the cysteine-rich granulin-epithelin motif. While inappropriate over-expression of the progranulin gene has been associated with many cancers, haploinsufficiency leads to atrophy of the frontotemporal lobes and development of a form of dementia (frontotemporal lobar degeneration with ubiquitin positive inclusions, FTLD-U) associated with the formation of ubiquitinated inclusions. Recent reports indicate that progranulin has neurotrophic effects, which, if confirmed would make progranulin the only neuroprotective growth factor that has been associated genetically with a neurological disease in humans. Preliminary studies indicated high progranulin gene expression in spinal cord motor neurons. However, it is uncertain what the role of Progranulin is in normal or diseased motor neuron function. We have investigated progranulin gene expression and subcellular localization in cultured mouse embryonic motor neurons and examined the effect of progranulin over-expression and knockdown in the NSC-34 immortalized motor neuron cell line upon proliferation and survival.</p> <p>Results</p> <p><it>In situ </it>hybridisation and immunohistochemical techniques revealed that the <it>progranulin </it>gene is highly expressed by motor neurons within the mouse spinal cord and in primary cultures of dissociated mouse embryonic spinal cord-dorsal root ganglia. Confocal microscopy coupled to immunocytochemistry together with the use of a progranulin-green fluorescent protein fusion construct revealed progranulin to be located within compartments of the secretory pathway including the Golgi apparatus. Stable transfection of the human <it>progranulin </it>gene into the NSC-34 motor neuron cell line stimulates the appearance of dendritic structures and provides sufficient trophic stimulus to survive serum deprivation for long periods (up to two months). This is mediated at least in part through an anti-apoptotic mechanism. Control cells, while expressing basal levels of progranulin do not survive in serum free conditions. Knockdown of progranulin expression using shRNA technology further reduced cell survival.</p> <p>Conclusion</p> <p>Neurons are among the most long-lived cells in the body and are subject to low levels of toxic challenges throughout life. We have demonstrated that progranulin is abundantly expressed in motor neurons and is cytoprotective over prolonged periods when over-expressed in a neuronal cell line. This work highlights the importance of progranulin as neuroprotective growth factor and may represent a therapeutic target for neurodegenerative diseases including motor neuron disease.</p

A systematic review of physical activity correlates in alcohol use disorders

Background: Physical activity might promote mental and physical health in persons with alcohol use disorder. Understanding the barriers and facilitators of participation in physical activity in persons with alcohol use disorder is an essential first step in order to devise effective physical activity interventions. Objective: The present review provides a systematic quantitative review of the correlates of physical activity in people with alcohol use disorder. Methods: Major electronic databases were searched by two independent authors from inception till June 2014. Keywords included ‘physical activity’ or ‘exercise’ and ‘alcohol dependence’ or ‘alcohol abuse’ or ‘alcohol use disorders’ or ‘alcoholism’. Results: Five papers evaluating 14 correlates were included. Three studies reported that alcohol dependence was unrelated to physical activity behavior, while alcohol abuse showed positive associations in 2 studies. No demographic variable was related with physical activity participation. Functional impairments and distress associated with alcohol use disorders including increased smoking rates, obesity, anxiety, depression and a lower self-efficacy may limit one’s ability to be physically active. Data on social, environmental and policy related factors are currently lacking. No included study assessed physical activity levels utilizing objective measurements (e.g. pedometers, accelerometers). Conclusion: Although the literature on physical activity correlates in persons with alcohol use disorder still is equivocal, our varied findings support the hypothesis that the participation in physical activity by people with alcohol use disorder is determined by a range of complex factors

GaPP2, a multicentre randomised controlled trial of the efficacy of gabapentin for the management of chronic pelvic pain in women:study protocol

Introduction: Chronic pelvic pain (CPP) affects more than 1 million UK women with associated healthcare costs of £158 million annually. Current evidence supporting interventions when no underlying pathology is identified is very limited and treatment is frequently inadequate. Gabapentin (a GABA analogue) is efficacious and often well tolerated in other chronic pain conditions. We have completed a successful pilot randomised controlled trial (GaPP1) and here describe the protocol for the definitive multicentre trial to assess the efficacy of gabapentin in the management of CPP in women (GaPP2).Methods and analysis: We plan to perform a double blind placebo controlled randomised multi-centre clinical trial, recruiting 300 women with CPP from more than 8 NHS hospitals within the UK. After randomisation, women will titrate their medication (gabapentin or placebo) over a 4-week period to a maximum of 2700mg or placebo equivalent and will then maintain a stable dose for a 12 week period. Response to treatment will be monitored with validated questionnaires and co-primary outcome measures of average and worst pain scores will be employed. The primary objective is to test the hypothesis that treatment with gabapentin has the potential to provide an effective oral treatment to alleviate pain in women with CPP in the absence of any obvious pelvic pathology.Ethics and dissemination: Ethical approval has been obtained from the Coventry and Warwick Research Ethics Committee (REC 15/WM/0036). Data will be presented at international conferences and published in peer-reviewed journals. We will make the information obtained from the study available to the public through national bodies and charities.Trial registration number: ISRCTN7745176

Gabapentin for chronic pelvic pain in women (GaPP2):a multicentre, randomised, double-blind, placebo-controlled trial

BackgroundChronic pelvic pain affects 2–24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology.MethodsWe performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18–50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16–17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13–16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762.FindingsParticipants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13–16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was −1·4 (SD 2·3) in the gabapentin group and −1·2 (SD 2·1) in the placebo group (adjusted mean difference −0·20 [97·5% CI −0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was −1·1 (SD 2·0) in the gabapentin group and −0·9 (SD 1·8) in the placebo group (adjusted mean difference −0·18 [97·5% CI −0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group.InterpretationThis study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology.FundingNational Institute for Health Research

Plasma sphingosine-1-phosphate is elevated in obesity

Background: Dysfunctional lipid metabolism is a hallmark of obesity and insulin resistance and a risk factor for various cardiovascular and metabolic complications. In addition to the well known increase in plasma triglycerides and free fatty acids, recent work in humans and rodents has shown that obesity is associated with elevations in the bioactive class of sphingolipids known as ceramides. However, in obesity little is known about the plasma concentrations of sphinogsine-1-phosphate (S1P), the breakdown product of ceramide, which is an important signaling molecule in mammalian biology. Therefore, the purpose of this study was to examine the impact of obesity on circulating S1P concentration and its relationship with markers of glucose metabolism and insulin sensitivity. Methodology/Principal Findings: Plasma S1P levels were determined in high-fat diet (HFD)-induced and genetically obese (ob/ob) mice along with obese humans. Circulating S1P was elevated in both obese mouse models and in obese humans compared with lean healthy controls. Furthermore, in humans, plasma S1P positively correlated with total body fat percentage, body mass index (BMI), waist circumference, fasting insulin, HOMA-IR, HbA1c (%), total and LDL cholesterol. In addition, fasting increased plasma S1P levels in lean healthy mice. Conclusion: We show that elevations in plasma S1P are a feature of both human and rodent obesity and correlate with metabolic abnormalities such as adiposity and insulin resistance

Food parenting practices for 5 to 12 year old children: a concept map analysis of parenting and nutrition experts input

Abstract Background Parents are an important influence on children’s dietary intake and eating behaviors. However, the lack of a conceptual framework and inconsistent assessment of food parenting practices limits our understanding of which food parenting practices are most influential on children. The aim of this study was to develop a food parenting practice conceptual framework using systematic approaches of literature reviews and expert input. Method A previously completed systematic review of food parenting practice instruments and a qualitative study of parents informed the development of a food parenting practice item bank consisting of 3632 food parenting practice items. The original item bank was further reduced to 110 key food parenting concepts using binning and winnowing techniques. A panel of 32 experts in parenting and nutrition were invited to sort the food parenting practice concepts into categories that reflected their perceptions of a food parenting practice conceptual framework. Multi-dimensional scaling produced a point map of the sorted concepts and hierarchical cluster analysis identified potential solutions. Subjective modifications were used to identify two potential solutions, with additional feedback from the expert panel requested. Results The experts came from 8 countries and 25 participated in the sorting and 23 provided additional feedback. A parsimonious and a comprehensive concept map were developed based on the clustering of the food parenting practice constructs. The parsimonious concept map contained 7 constructs, while the comprehensive concept map contained 17 constructs and was informed by a previously published content map for food parenting practices. Most of the experts (52%) preferred the comprehensive concept map, while 35% preferred to present both solutions. Conclusion The comprehensive food parenting practice conceptual map will provide the basis for developing a calibrated Item Response Modeling (IRM) item bank that can be used with computerized adaptive testing. Such an item bank will allow for more consistency in measuring food parenting practices across studies to better assess the impact of food parenting practices on child outcomes and the effect of interventions that target parents as agents of change