Effects of linalool on extinction of mouse operant behaviour.

Linalool is an enanitomer monoterpene compound identified as the pharmacologically active constituent in a number of essential oils and has been reported to display anxiolytic properties in humans and in animal models and to exert both GABAergic and glutamatergic effects. In Experiment 1 linalool (100, 200, and 300, i.p.) had no significant effects compared with saline in an activity tracker with C57BL/6j mice. Experiment 2 assessed the effects on operant extinction with mice of chlordiazepoxide at a dose (15 mg/kg, i.p.) previously shown to facilitate extinction, and the same doses of linalool, compared with saline. Linalool had a dose-related facilitatory effect on extinction. While the effects of the highest dose of linalool most closely resembled the effects of chlordiazepoxide, the pattern of results suggested that linalool may affect both the acquisition of extinction learning, which is influenced by glutamatergic processes, and the expression of extinction, known to be affected by GABAergic agents such as chlordiazepoxide.

Nurse-led advance care planning with older people who have end-stage kidney disease: feasibility of a deferred entry randomised controlled trial incorporating an economic evaluation and mixed methods process evaluation (ACReDiT).

BACKGROUND: Advance Care Planning is recommended for people with end-stage kidney disease but evidence is limited. Robust clinical trials are needed to investigate the impact of advance care planning in this population. There is little available data on cost-effectiveness to guide decision makers in allocating resources for advance care planning. Therefore we sought to determine the feasibility of a randomised controlled trial and to test methods for assessing cost-effectiveness. METHODS: A deferred entry, randomised controlled feasibility trial, incorporating economic and process evaluations, with people with end-stage kidney disease, aged 65 years or older, receiving haemodialysis, in two renal haemodialysis units in Northern Ireland, UK. A nurse facilitator helped the patient make an advance care plan identifying: a surrogate decision-maker; what the participant would like to happen in the future; any advance decision to refuse treatment; preferred place of care at end-of-life. RESULTS: Recruitment lasted 189 days; intervention and data collection 443 days. Of the 67 patients invited to participate 30 (45%) declined and 36 were randomised to immediate or deferred advance care plan groups. Twenty-two (61%) made an advance care plan and completed data collection at 12 weeks; 17 (47.2%) were able to identify a surrogate willing to be named in the advance care plan document. The intervention was well-received and encouraged end-of-life conversations, but did not succeed in helping patients to fully clarify their values or consider specific treatment choices. There was no significant difference in health system costs between the immediate and deferred groups. CONCLUSIONS: A trial of advance care planning with participants receiving haemodialysis is feasible and acceptable to patients, but challenging. A full trial would require a pool of potential participants five times larger than the number required to complete data collection at 3 months. Widening eligibility criteria to include younger (under 65 years of age) and less frail patients, together with special efforts to engage and retain surrogates may improve recruitment and retention. Traditional advance care planning outcomes may need to be supplemented with those that are defined by patients, helping them to participate with clinicians in making medical decisions. TRIAL REGISTRATION: Registered December 16, 2015. ClinicalTrials.gov Identifier: NCT02631200 .

Qualitative study investigating the professional and personal effects of patient suicide on general practitioners in Northern Ireland.

OBJECTIVE: There is a dearth in suicide literature addressing the impact on general practitioners (GPs) of losing a patient. We aimed to examine the personal and professional impact as well as the availability of support and why GPs did or did not use it. DESIGN: A qualitative study using one-to-one interviews with participants recruited using snowball sampling. SETTING: The study was conducted in a primary care setting. PARTICIPANTS: Interviews were held with 19 GPs within primary care in Northern Ireland. RESULTS: GPs are impacted both personally and professionally when they lose a patient to suicide, but may not access formal help due to commonly held idealised notions of a 'good' GP who is regarded as having solid imperturbability. Fear of professional repercussions also plays a major role in deterring help-seeking. CONCLUSIONS: There is a need for a systemic culture shift within general practice which allows doctors to seek support when their physical or mental health require it. This may help prevent stress, burnout and early retirement.

Facilitation of extinction and re-extinction of operant behavior in mice by chlordiazepoxide and D-cycloserine.

The aim was to compare operant extinction with re-extinction following re-acquisition and to investigate neuropharmacological mechanisms through administration of drugs potentiating GABAergic or glutamatergic systems. Groups of C57Bl/6 mice were trained to lever press for food on a fixed ratio schedule, then extinguished with or without pre-session chlordiazepoxide or post-session d-cycloserine administration (15mg/kg in each case), then retrained to lever press for food, then re-extinguished with or without pre-session chlordiazepoxide or post-session d-cycloserine. Under vehicle injections, extinction and re-extinction curves were indistinguishable, but drug treatments showed that there was less resistance to extinction in the re-extinction phase. Chlordiazepoxide facilitated extinction and re-extinction, with an earlier effect during re-extinction. d-Cycloserine also facilitated extinction and re-extinction, with some evidence of an earlier effect during re-extinction. These results replicate and extend earlier findings with operant extinction, but differ from some previous reports of d-cycloserine on re-extinction of Pavlovian conditioned fear. Implications for accounts of the similarities and differences between neural mechanisms of extinction following either Pavlovian or operant conditioning, and applications of these findings, are discussed.

Effects of chlordiazepoxide on runway behaviours of C57Bl/6 mice under continuous or partial reinforcement.

An earlier history of partial or continuous reinforcement produces differential behavioural effects during extinction in the runway, with an earlier partial reinforcement (PRF) leading to an increased resistance to extinction. This effect has been attributed to conditioned frustration or generalization-decrement processes. The actions of antianxiety drugs in this procedure are most easily interpreted as for reducing the emotional or aversive effects of nonreinforcement. In this study, C57Bl/6 mice were trained to asymptotic performance with food reinforcement on 50 or 100% of six trials in daily sessions. The anxiolytic benzodiazepine, chlordiazepoxide (15 mg/kg, intraperitoneally) or saline was administered before subsequent daily extinction sessions. Under saline, earlier PRF produced an increased resistance to extinction. Drug administration increased resistance to extinction, as measured by start, run and goal times, after either continuous or PRF. These findings are consistent with earlier findings of rats, but different from those obtained with chlordiazepoxide during extinction after operant training with either rats or mice. These findings can be interpreted in terms of frustration, anxiety or generalization-decrement theories of PRF.

Assessment of pain in people living with dementia at the end of life: a systematic review.

BACKGROUND: People with dementia may not receive the same quality of palliative care as those with other life-limiting conditions, particularly at end of life (EoL). AIMS: To understand the best way to examine pain in people with dementia. METHODS: A systematic review of tools to assess pain in patients with dementia near the end of life; PubMed, Medline, Embase, EBSCO Host, CINAHL Plus, Web of Science, Psycinfo, PsycArticles and Scopus were searched. FINDINGS: A total of 15 articles were identified, which were qualitatively synthesised. CONCLUSION: There are a range of pain assessment tools that are appropriate for use in people with dementia, but all 15 studies used a formal tool. A more robust approach is needed to improve the quality of research for measurement and management of pain in this population.

Advance Care Planning With Patients Who Have End-Stage Kidney Disease: A Systematic Realist Review.

CONTEXT: Patients with end-stage kidney disease have a high mortality rate and disease burden. Despite this, many do not speak with health care professionals about end-of-life issues. Advance care planning is recommended in this context but is complex and challenging. We carried out a realist review to identify factors affecting its implementation. OBJECTIVES: The objectives of this study are 1) to identify implementation theories; 2) to identify factors that help or hinder implementation; and 3) to develop theory on how the intervention may work. METHODS: We carried out a systematic realist review, searching seven electronic databases: Medline, Embase, CINAHL, PsycINFO, Cochrane Library, Google Scholar, and ScienceDirect. RESULTS: Sixty-two papers were included in the review. CONCLUSION: We identified two intervention stages-1) training for health care professionals that addresses concerns, optimizes skills, and clarifies processes and 2) use of documentation and processes that are simple, individually tailored, culturally appropriate, and involve surrogates. These processes work as patients develop trust in professionals, participate in discussions, and clarify values and beliefs about their condition. This leads to greater congruence between patients and surrogates; increased quality of communication between patients and professionals; and increased completion of advance directives. Advance care planning is hindered by lack of training; administrative complexities; pressures of routine care; patients overestimating life expectancy; and when patients, family, and/or clinical staff are reluctant to initiate discussions. It is more likely to succeed where organizations treat it as core business; when the process is culturally appropriate and takes account of patient perceptions; and when patients are willing to consider death and dying with suitably trained staff.

Plant molecular biology in the space station era: utilization of KSC fixation tubes with RNAlater.

Spaceflight experiments involving biological specimens face unique challenges with regard to the on orbit harvest and preservation of material for later ground-based analyses. Preserving plant material for gene expression analyses requires that the tissue be prepared and stored in a manner that maintains the integrity of RNA. The liquid preservative RNAlater (Ambion) provides an effective alternative to conventional freezing strategies, which are limited or unavailable in current spaceflight experiment scenarios. The spaceflight use of RNAlater is enabled by the Kennedy space center fixation tube (KFT), hardware designed to provide the necessary containment of fixatives during the harvest and stowage of biological samples in space. Pairing RNAlater with the KFT system provides a safe and effective strategy for preserving plant material for subsequent molecular analyses, a strategy that has proven effective in several spaceflight experiments. Possible spaceflight scenarios for the use of RNAlater and KFTs are explored and discussed.

Facilitation of extinction of operant behaviour in C57Bl/6 mice by chlordiazepoxide and D-cycloserine.

RATIONALE AND OBJECTIVE: Effects on the extinction of GABAergic drug, chlordiazepoxide (CDP), and glutamatergic drug, D: -cycloserine (DCS), in C57BL/6 mice were compared. MATERIALS AND METHODS: Following a palatability test (Experiment 1), Experiments 2-6 involved food-reinforced lever press training followed by extinction sessions at 1- or 4-day intervals. The effects of drugs were examined. Experiment 7 involved a two-lever task. RESULTS: CDP did not affect food palatability (Experiment 1), but facilitated extinction when administered prior to extinction sessions via intracerebral (Experiment 2) or peripheral administration at 1-day (Experiments 3-7) or 4-day intervals (Experiment 6). Reducing the amount of training prior to extinction reduced the delay in the effect of CDP typically seen, and CDP had a larger effect in early sessions on mice that had received less training (Experiment 3). There was some evidence that CDP could be blocked by flumazenil (Experiment 4), and CDP withdrawal reversed extinction facilitation (Experiments 5 and 7). With 4-day intervals, DCS administered immediately following extinction sessions, or pre-session CDP, facilitated extinction with 48-trial sessions (experiment 6B). With six-trial sessions, the co-administration of post-session DCS enhanced facilitation produced by pre-session CDP (experiment 6A). Finally, CDP facilitated extinction in a dose-related fashion following training on a two-lever food-reinforced task (Experiment 7). CONCLUSIONS: The findings are consistent with the hypotheses that two neurotransmitter systems have different roles in operant extinction and that glutamatergic systems are involved in extinction learning and GABAergic systems involved in the expression of that learning. This parallels findings with extinction following Pavlovian conditioning, which has been more extensively investigated.

RS-0406 arrests amyloid-beta oligomer-induced behavioural deterioration in vivo.

Clinically accessible compounds that arrest or reverse the effects of amyloid-beta (Abeta) on progressively developing behavioural symptomatology and neuropathology in Alzheimer's disease (AD) have yet to become available. However, a viable strategy may be to target and neutralise soluble Abeta oligomers, which have been shown to mediate synaptic dysfunction and to produce cognitive deficits in the intact organism. Inhibiting the aggregation of Abeta is therapeutically attractive, as Abeta aggregation is a pathological event and pharmacological interventions targeting this are likely to have a non-toxic profile. A behavioural assay, the alternating-lever cyclic-ratio schedule, was used to assess the effect of Abeta oligomers and the non-peptide small molecule RS-0406 in male Sprague-Dawley rats. RS-0406 has been shown to inhibit Abeta(1-42) fibrillogenesis and protect against Abeta(1-42)-induced cytotoxicity in primary hippocampal neurons. In the current study, RS-0406 ameliorated the adverse effects of secreted oligomers of human Abeta on behaviour and dose dependently reduced the behavioural effects of Abeta oligomers, with the highest dose, 10microM, maintaining behaviour approximately at control levels. This effect appeared to be central; peripheral confounds having been extensively investigated. This is the first published report on the effects of RS-0406 in vivo and indicates that RS-0406 has potential as a pharmacotherapeutic intervention for behavioural deficits seen in the early stages of AD, and possibly as an intervention in the development of AD neuropathology. Indeed, an analogue of RS-0406 that could be administered peripherally might be a realistic candidate for the clinical treatment of AD.

Facilitation of extinction of operant behaviour in mice by D-cycloserine.

RATIONALE AND OBJECTIVE: The N-methyl-D-aspartate receptor agonist D-cycloserine (DCS) facilitates extinction following Pavlovian fear conditioning or conditioned place preference in rats, but its effects on extinction following operant conditioning are not previously established. We studied the effects of DCS on operant extinction with mice, previously shown to be facilitated by GABAergic potentiators including chlordiazepoxide. MATERIALS AND METHODS: Following training of lever pressing by C57Bl/6 male mice on a discrete-trial fixed-ratio food reinforcement schedule with six reinforcers per session, 48-trial extinction sessions were conducted at 3- (Experiment 1) or 4-day intervals (Experiment 2). Effects of DCS (15 or 30 mg/kg, i.p.) administered immediately after 48-trial extinction sessions were compared with those of saline injections. RESULTS: With 3-day intervals between extinction sessions, post-session administration of DCS facilitated extinction, and this effect was stronger with 4-day intervals between extinction sessions. Facilitation of extinction by post-session drug administration persisted over a number of extinction sessions. CONCLUSIONS: Operant extinction in mice can be facilitated by DCS, a glutamatergic agonist, as well as by GABAergic potentiators. The relationship between glutamatergic and GABAergic processes in operant extinction is yet to be established. These findings strengthen the basis for clinical uses of DCS.

Media ion composition controls regulatory and virulence response of Salmonella in spaceflight.

The spaceflight environment is relevant to conditions encountered by pathogens during the course of infection and induces novel changes in microbial pathogenesis not observed using conventional methods. It is unclear how microbial cells sense spaceflight-associated changes to their growth environment and orchestrate corresponding changes in molecular and physiological phenotypes relevant to the infection process. Here we report that spaceflight-induced increases in Salmonella virulence are regulated by media ion composition, and that phosphate ion is sufficient to alter related pathogenesis responses in a spaceflight analogue model. Using whole genome microarray and proteomic analyses from two independent Space Shuttle missions, we identified evolutionarily conserved molecular pathways in Salmonella that respond to spaceflight under all media compositions tested. Identification of conserved regulatory paradigms opens new avenues to control microbial responses during the infection process and holds promise to provide an improved understanding of human health and disease on Earth.