Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Effectiveness of a Multicomponent Positive Psychology Intervention on Depression and Optimism in a Heart Failure Clinic: A Program Design and Evaluation Initiative

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Effectiveness of a Multicomponent Positive Psychology Intervention on Depression and Optimism in a Heart Failure Clinic: A Program Design and Evaluation Initiative

Purpose: Depression, a significant problem in the Heart Failure (HF) population, is prospectively associated with increased hospital readmissions and doubled mortality risk when compared to non-depressed HF patients. Whether a Positive Psychology Intervention (PPI) can result in increased optimism and improved depression symptoms is not known. Design: Our aim was to examine the efficacy of a 6-week, phone-based, PPI in patients with heart failure. In this prospective, cohort study, we explored the feasibility of implementing this approach in a HF clinic (HFC) at a large, academic institution. All patients attending a HFC complete the patient-reported outcomes assessment including the PROMIS Depression (PROMIS-D). Patients with PROMIS-D score ≥ 55 were eligible for the pilot. Study interventions consisted of a 6-week PPI with treatment manual along with serial PHQ-9, one Likert-style optimism question, and repeat PROMIS-D. Results: Out of 305 patients screened, 47 were approached for PROMIS-D scores ≥ 55, 37 started the PPI, and 13 completed at least 3 exercises, and 6 completed the full 6-week course. Average completion time among finishers was 7.5 weeks (range 47-60 days). The PPI resulted in significant decreases in PHQ-9 scores (median difference= -1, p=0.016) and PROMIS-D scores (median difference= -7, p=0.03) and an increase in optimism score (median difference= +1, p=0.016) (refer to Figure 1). Conclusions: In HF patients completing at least three weeks of PPI, we observed promising improvement in patient-reported symptoms of depression and optimism. Approaches to improve acceptance and adherence to PPI should be explored, coupled with repeated testing of this PPI with larger samples. This project will continue to evolve in Cardiac Rehabilitation, where it is anticipated that flexible workflow dynamics and increased follow-up will improve adherence

The Effects of response operandum and prior food training on intravenous nicotine self-administration in rats

Rationale: Nicotine intravenous self-administration (IVSA) in rats has been conducted using a variety of methodological procedures with equally variable results. Objectives: Here, we addressed the importance of the type of response operandum and prior instrumental training with a natural reinforcer on nicotine IVSA and reinstatement. Methods: Rats were tested for spontaneous acquisition of IVSA using either nose poke (NP) or lever press (LVR) operandum. A dose-response test was then conducted, followed by extinction and cue- and nicotine-induced reinstatement. Results: The use of the NP operandum resulted in markedly higher levels of IVSA across acquisition and across dose-response testing compared with the LVR group. Whereas both groups reinstated following a nicotine prime, only the LVR group demonstrated cue-induced reinstatement. As a positive control, the experiment was repeated with cocaine as the reinforcer: equivalent levels of IVSA were observed across all tests, irrespective of operandum. When rats self-administering nicotine received instrumental training with a sucrose reinforcer prior to IVSA, a facilitated acquisition of IVSA was observed in both LVR and NP groups to a similar extent (the effect of operandum remained), but had little effect on responding thereafter. During reinstatement testing, both groups now displayed cue- and nicotine-induced reinstatement, but this was also evident in saline control animals that had never received nicotine. Conclusions: These results suggest that, unlike cocaine, an increased physical response requirement can decrease nicotine intake. It also indicates that operandum and prior sucrose training may influence the role that visual cues play in nicotine dependence.12 page(s

Repeated Episodes of Heroin Cause Enduring Alterations of Circadian Activity in Protracted Abstinence

Opiate withdrawal is followed by a protracted abstinence syndrome consisting of craving and physiological changes. However, few studies have been dedicated to both the characterization and understanding of these long-term alterations in post-dependent subjects. The aim of the present study was to develop an opiate dependence model, which induces long-lasting behavioral changes in abstinent rats. Here, we first compared the effects of several protocols for the induction of opiate dependence (morphine pellets, repeated morphine or heroin injections) on the subsequent response to heroin challenges (0.25 mg/kg) at different time points during abstinence (3, 6, 9 and 18 weeks). In a second set of experiments, rats were exposed to increasing doses of heroin and subsequently monitored for general circadian activity up to 20 weeks of abstinence. Results show that heroin injections rather than the other methods of opiate administration have long-term consequences on rats’ sensitivity to heroin with its psychostimulant effects persisting up to 18 weeks of abstinence. Moreover, intermittent episodes of heroin dependence rather than a single exposure produce enduring alteration of the basal circadian activity both upon heroin cessation and protracted abstinence. Altogether, these findings suggest that the induction of heroin dependence through intermittent increasing heroin injections is the optimal method to model long-term behavioral alterations during protracted abstinence in rats. This animal model would be useful in further characterizing long-lasting changes in post-dependent subjects to help understand the prolonged vulnerability to relapse

Repeated Episodes of Heroin Cause Enduring Alterations of Circadian Activity in Protracted Abstinence

Opiate withdrawal is followed by a protracted abstinence syndrome consisting of craving and physiological changes. However, few studies have been dedicated to both the characterization and understanding of these long-term alterations in post-dependent subjects. The aim of the present study was to develop an opiate dependence model, which induces long-lasting behavioral changes in abstinent rats. Here, we first compared the effects of several protocols for the induction of opiate dependence (morphine pellets, repeated morphine or heroin injections) on the subsequent response to heroin challenges (0.25 mg/kg) at different time points during abstinence (3, 6, 9 and 18 weeks). In a second set of experiments, rats were exposed to increasing doses of heroin and subsequently monitored for general circadian activity up to 20 weeks of abstinence. Results show that heroin injections rather than the other methods of opiate administration have long-term consequences on rats’ sensitivity to heroin with its psychostimulant effects persisting up to 18 weeks of abstinence. Moreover, intermittent episodes of heroin dependence rather than a single exposure produce enduring alteration of the basal circadian activity both upon heroin cessation and protracted abstinence. Altogether, these findings suggest that the induction of heroin dependence through intermittent increasing heroin injections is the optimal method to model long-term behavioral alterations during protracted abstinence in rats. This animal model would be useful in further characterizing long-lasting changes in post-dependent subjects to help understand the prolonged vulnerability to relapse

Maternal high fat diet and early life stress induce metabolic disturbances and enhance motivation for palatable food in offspring

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Exploring the effects of tetrahydrobiopterin on motivation, dopamine release and acute inflammation in mice

Inflammation can affect mesodopaminergic system and mediates depressive symptoms related to motivation and locomotion. Precisely, pro-inflammatory cytokines can alter dopamine synthesis and thus availability. Tetrahydrobiopterin (BH4) is the mandatory co-factor for phenylalanine and tyrosine hydroxylase activities and therefore essential for dopamine synthesis. Interestingly, inflammation can decrease BH4 by acting on its synthesis and degradation. So, lower BH4 level could participate to the dopaminergic and motivational deficits that occur frequently in chronic inflammatory conditions. Despite its importance, the effects of BH4 administration on dopamine synthesis and related behaviors have been poorly characterized. We hypothesized that BH4 administration can improve dopaminergic function and motivational processes and could be used to counteract inflammation-induced alterations. We first demonstrated that peripheral administration of BH4 (50mg/kg;intraperitoneally) was sufficient to double BH4 brain content within 3h. Using in-situ brain perfusion, we found that the brain uptake clearance (Clup) of BH4 was approximately 0.08μl/g/sec, consistent with a modest transfer across the blood brain barrier. BH4 injection neither changed the expression of main enzymes involved in BH4 and DA synthesis nor total striatal dopamine content. However, using in vivo microdialysis in freely moving mice, we showed that BH4 administration induced a slight increase in dopamine release in the nucleus accumbens during food presentation and a higher amphetamine-induced DA release (3mg/kg). Furthermore, BH4 injection increased motivation in a progressive ratio task in operant conditioning without affecting sucrose consumption and anhedonia. Surprisingly, BH4 injection led to a moderate decrease in spontaneous locomotion and to a blunted locomotor sensitization after second exposure to amphetamine. Last, BH4 injection reduced brain pro-inflammatory cytokines expression in an acute inflammation model induced by lLipopolysaccharide injection (830μg/kg). Here, we showed that increased BH4 content leads to increased dopamine release and motivation, and reduces the proinflammatory response to an acute inflammatory challenge. This suggests that BH4 could be a promising treatment for behavioral deficits related to dopaminergic disturbances related to inflammatory condition

Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial.

International audienceAbstract Background: Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults. Methods: This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/ parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm2. For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment. Discussion: For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment.

Completeness of reporting and risks of overstating impact in cluster randomised trials: a systematic review

Overstating the impact of interventions through incomplete or inaccurate reporting can lead to inappropriate scale-up of interventions with low impact. Accurate reporting of the impact of interventions is of great importance in global health research to protect scarce resources. In global health, the cluster randomised trial design is commonly used to evaluate complex, multicomponent interventions, and outcomes are often binary. Complete reporting of impact for binary outcomes means reporting both relative and absolute measures. We did a systematic review to assess reporting practices and potential to overstate impact in contemporary cluster randomised trials with binary primary outcome. We included all reports registered in the Cochrane Central Register of Controlled Trials of two-arm parallel cluster randomised trials with at least one binary primary outcome that were published in 2017. Of 73 cluster randomised trials, most (60 [82%]) showed incomplete reporting. Of 64 cluster randomised trials for which it was possible to evaluate, most (40 [63%]) reported results in such a way that impact could be overstated. Care is needed to report complete evidence of impact for the many interventions evaluated using the cluster randomised trial design worldwide