Ligand-Induced Tyrosine Phosphorylation of Cysteinyl Leukotriene Receptor 1 Triggers Internalization and Signaling in Intestinal Epithelial Cells

Leukotriene D(4) (LTD(4)) belongs to the bioactive lipid group known as eicosanoids and has implications in pathological processes such as inflammation and cancer. Leukotriene D(4) exerts its effects mainly through two different G-protein-coupled receptors, CysLT(1) and CysLT(2). The high affinity LTD(4) receptor CysLT(1)R exhibits tumor-promoting properties by triggering cell proliferation, survival, and migration in intestinal epithelial cells. In addition, increased expression and nuclear localization of CysLT(1)R correlates with a poorer prognosis for patients with colon cancer

Reliance on habits at the expense of goal-directed control following dopamine precursor depletion

Rationale Dopamine is well known to play an important role in learning and motivation. Recent animal studies have implicated dopamine in the reinforcement of stimulus-response habits, as well as in flexible, goal-directed action. However, the role of dopamine in human action control is still not well understood. Objectives We present the first investigation of the effect of reducing dopamine function in healthy volunteers on the balance between habitual and goal-directed action control. Methods The dietary intervention of acute dietary phenylalanine and tyrosine depletion (APTD) was adopted to study the effects of reduced global dopamine function on action control. Participants were randomly assigned to either the APTD or placebo group (ns = 14) to allow for a between-subjects comparison of performance on a novel three-stage experimental paradigm. In the initial learning phase, participants learned to respond to different stimuli in order to gain rewarding outcomes. Subsequently, an outcome-devaluation test and a slips-of-action test were conducted to assess whether participants were able to flexibly adjust their behaviour to changes in the desirability of the outcomes. Results APTD did not prevent stimulus-response learning, nor did we find evidence for impaired response-outcome learning in the subsequent outcome-devaluation test. However, when goal-directed and habitual systems competed for control in the slips-of-action test, APTD tipped the balance towards habitual control. These findings were restricted to female volunteers. Conclusions We provide direct evidence that the balance between goal-directed and habitual control in humans is dopamine dependent. The results are discussed in light of gender differences in dopamine function and psychopathologies

Nicotine patch preloading for smoking cessation (the preloading trial): study protocol for a randomized controlled trial

Background: The use of nicotine replacement therapy before quitting smoking is called nicotine preloading. Standard smoking cessation protocols suggest commencing nicotine replacement therapy only on the first day of quitting smoking (quit day) aiming to reduce withdrawal symptoms and craving. However, other, more successful smoking cessation pharmacotherapies are used prior to the quit day as well as after. Nicotine preloading could improve quit rates by reducing satisfaction from smoking prior to quitting and breaking the association between smoking and reward. A systematic literature review suggests that evidence for the effectiveness of preloading is inconclusive and further trials are needed. Methods/Design: This is a study protocol for a multicenter, non-blinded, randomized controlled trial based in the United Kingdom, enrolling 1786 smokers who want to quit, funded by the National Institute for Health Research, Health Technology Assessment program, and sponsored by the University of Oxford. Participants will primarily be recruited through general practices and smoking cessation clinics, and randomized (1:1) either to use 21 mg nicotine patches, or not, for four weeks before quitting, whilst smoking as normal. All participants will be referred to receive standard smoking cessation service support. Follow-ups will take place at one week, four weeks, six months and 12 months after quit day. The primary outcome will be prolonged, biochemically verified six-month abstinence. Additional outcomes will include point prevalence abstinence and abstinence of four-week and 12-month duration, side effects, costs of treatment, and markers of potential mediators and moderators of the preloading effect. Discussion: This large trial will add substantially to evidence on the effectiveness of nicotine preloading, but also on its cost effectiveness and potential mediators, which have not been investigated in detail previously. A range of recruitment strategies have been considered to try and compensate for any challenges encountered in recruiting the large sample, and the multicentre design means that knowledge can be shared between recruitment teams. The pragmatic study design means that results will give a realistic estimate of the success of the intervention if it were to be rolled out as part of standard smoking cessation service practice. Trial registration: Current Controlled Trials ISRCTN33031001. Registered 27 April 2012

Indirect effects of species interactions on habitat provisioning

Species that shelter in a biogenic habitat can influence their refugia and, in turn, play an essential role in shaping local patterns of biodiversity. Here we explore a positive feedback loop between the provisioning rate of habitat-forming branching corals and their associated fishes and show how interactions between two groups of fish—the planktivorous damselfish and predatory hawkfish—altered the feedback. A field experiment confirmed that skeletal growth of branching coral (genus Pocillopora) increased substantially with increasing numbers (biomass) of resident fishes, likely because they greatly increased the interstitial concentrations of nutrients. Because there is a positive relationship between colony size and number (biomass) of associated fishes (primarily damselfishes in the Family Pomacentridae), a structure–function feedback loop exists in which increasing numbers of damselfish enhance coral growth and larger corals host greater abundances (and species richness) of fish. However, interactions between damselfishes and arc-eye hawkfish, Paracirrhites arcatus, a largely solitary resident, can disrupt this positive feedback loop. Field surveys revealed a marked pattern of fish occupancy related to coral size: Pocillopora colonies of sufficient size to host fish (>40 cm circumference) had either groups of damselfish or an arc-eye hawkfish; only larger colonies (>75 cm) were occupied by both the damselfish and hawkfish. Subsequent short- and long-term experiments revealed that on intermediate-sized Pocillopora colonies, arc-eye hawkfish prevented the establishment of damselfish by suppressing their recruitment. The demographic consequences to the host coral were substantial; in a 1-year-long experiment, intermediate-size Pocillopora occupied by hawkfish grew at half the rate of corals that hosted groups of damselfish. These findings indicate that: (1) species which occupy a biogenic habitat can enhance the provisioning rate of their habitat; (2) such positive feedbacks between community structure and ecosystem function can be disrupted by a strong interactor; (3) even substantial consequences on ecosystem processes that arise can be difficult to discern

Disturbance Alters the Phylogenetic Composition and Structure of Plant Communities in an Old Field System

The changes in phylogenetic composition and structure of communities during succession following disturbance can give us insights into the forces that are shaping communities over time. In abandoned agricultural fields, community composition changes rapidly when a field is plowed, and is thought to reflect a relaxation of competition due to the elimination of dominant species which take time to re-establish. Competition can drive phylogenetic overdispersion, due to phylogenetic conservation of ‘niche’ traits that allow species to partition resources. Therefore, undisturbed old field communities should exhibit higher phylogenetic dispersion than recently disturbed systems, which should be relatively ‘clustered’ with respect to phylogenetic relationships. Several measures of phylogenetic structure between plant communities were measured in recently plowed areas and nearby ‘undisturbed’ sites. There was no difference in the absolute values of these measures between disturbed and ‘undisturbed’ sites. However, there was a difference in the ‘expected’ phylogenetic structure between habitats, leading to significantly lower than expected phylogenetic diversity in disturbed plots, and no difference from random expectation in ‘undisturbed’ plots. This suggests that plant species characteristic of each habitat are fairly evenly distributed on the shared species pool phylogeny, but that once the initial sorting of species into the two habitat types has occurred, the processes operating on them affect each habitat differently. These results were consistent with an analysis of correlation between phylogenetic distance and co-occurrence indices of species pairs in the two habitat types. This study supports the notion that disturbed plots are more clustered than expected, rather than ‘undisturbed’ plots being more overdispersed, suggesting that disturbed plant communities are being more strongly influenced by environmental filtering of conserved niche traits

Study protocol for a non-inferiority trial of cytisine versus nicotine replacement therapy in people motivated to stop smoking

<p>Abstract</p> <p>Background</p> <p>Smokers need effective support to maximise the chances of successful quit attempts. Current smoking cessation medications, such as nicotine replacement therapy (NRT), bupropion, nortriptyline or varenicline, have been shown to be effective in clinical trials but are underused by smokers attempting to quit due to adverse effects, contraindications, low acceptability and/or high cost. Cytisine is a low-cost, plant-based alkaloid that has been sold as a smoking cessation aid in Eastern Europe for 50 years. A systematic review of trial evidence suggests that cytisine has a positive impact on both short- and long-term abstinence rates compared to placebo. However, the quality of the evidence is poor and insufficient for licensing purposes in many Western countries. A large, well-conducted placebo-controlled trial (n = 740) of cytisine for smoking cessation has recently been published and confirms the findings of earlier studies, with 12-month continuous abstinence rates of 8.4% in the cytisine group compared to 2.4% in the placebo group (Relative risk = 3.4, 95% confidence intervals 1.7-7.1). No research has yet been undertaken to determine the effectiveness of cytisine relative to that of NRT.</p> <p>Methods/design</p> <p>A single-blind, randomised controlled, non-inferiority trial has been designed to determine whether cytisine is at least as effective as NRT in assisting smokers to remain abstinent for at least one month. Participants (n = 1,310) will be recruited through the national telephone-based Quitline service in New Zealand and randomised to receive a standard 25-day course of cytisine tablets (Tabex^®) or usual care (eight weeks of NRT patch and/or gum or lozenge). Participants in both study arms will also receive a behavioural support programme comprising an average of three follow-up telephone calls delivered over an eight-week period by Quitline. The primary outcome is continuous abstinence from smoking at one month, defined as not smoking more than five cigarettes since quit date. Outcome data will also be collected at one week, two months and six months post-quit date.</p> <p>Discussion</p> <p>Cytisine appears to be effective compared with placebo, and given its (current) relative low cost may be an acceptable smoking cessation treatment for smokers, particularly those in low- and middle-income countries. Cytisine's 'natural' product status may also increase its acceptability and use among certain groups of smokers, such as indigenous people, smokers in countries where the use of natural medicines is widespread (e.g. China, India), and in those people who do not want to use NRT or anti-depressants to help them quit smoking. However it is important to ascertain the effectiveness of cytisine compared with that of existing cessation treatments.</p> <p>Trial registration</p> <p>Australian New Zealand Clinical Trials Registry (<a href="http://www.anzctr.org.au/ACTRN12610000590066.aspx">ACTRN12610000590066</a>)</p

Physical activity as an aid to smoking cessation during pregnancy (LEAP) trial: study protocol for a randomized controlled trial

Background: Many women try to stop smoking in pregnancy but fail. One difficulty is that there is insufficient evidence that medications for smoking cessation are effective and safe in pregnancy and thus many women prefer to avoid these. Physical activity (PA) interventions may assist cessation; however, trials examining these interventions have been too small to detect or exclude plausible beneficial effects. The London Exercise And Pregnant smokers (LEAP) trial is investigating whether a PA intervention is effective and cost-effective when used for smoking cessation by pregnant women, and will be the largest study of its kind to date. Methods/design: The LEAP study is a pragmatic, multi-center, two-arm, randomized, controlled trial that will target pregnant women who smoke at least one cigarette a day (and at least five cigarettes a day before pregnancy), and are between 10 and 24 weeks pregnant. Eligible patients are individually randomized to either usual care (that is, behavioral support for smoking cessation) or usual care plus a intervention (entailing supervised exercise on a treadmill plus PA consultations). The primary outcome of the trial is self-reported and biochemically validated continuous abstinence from smoking between a specified quit date and the end of pregnancy. The secondary outcomes, measured at 1 and 4 weeks after the quit date, and at the end of pregnancy and 6 months after childbirth, are PA levels, depression, self-confidence, and cigarette withdrawal symptoms. Smoking status will also be self-reported at 6 months after childbirth. In addition, perinatal measures will be collected, including antenatal complications, duration of labor, mode of delivery, and birth and placental weight. Outcomes will be analyzed on an intention-to-treat basis, and logistic regression models used to compare treatment effects on the primary outcome. Discussion: This trial will assess whether a PA intervention is effective when used for smoking cessation during pregnancy

Relapse to smoking during unaided cessation: Clinical, cognitive, and motivational predictors

Rationale: Neurobiological models of addiction suggest that abnormalities of brain reward circuitry distort salience attribution and inhibitory control processes, which in turn contribute to high relapse rates. Objectives: To determine whether impairments of salience attribution and inhibitory control predict relapse in a pharmacologically unaided attempt at smoking cessation. Methods: 141 smokers were assessed on indices of nicotine consumption / dependence (e.g. the FTND, cigarettes per day, salivary cotinine), and three trait impulsivity measures. After overnight abstinence they completed experimental tests of cue reactivity, attentional bias to smoking cues, response to financial reward, motor impulsiveness, and response inhibition (antisaccades). They then started a quit attempt with follow-up after 7 days, 1 month, and 3 months; abstinence was verified via salivary cotinine levels ≤ 20ng/ml. Results: Relapse rates at each point were 52.5%, 64% and 76.3%. The strongest predictor was pre-cessation salivary cotinine; other smoking / dependence indices did not explain additional outcome variance and neither did trait impulsivity. All experimental indices except responsivity to financial reward significantly predicted one week outcome. Salivary cotinine, attentional bias to smoking cues and antisaccade errors explained unique as well as shared variance. At one and three months, salivary cotinine, motor impulsiveness and cue reactivity were all individually predictive; the effects of salivary cotinine and motor impulsiveness were additive. Conclusions: These data provide some support for the involvement of abnormal cognitive and motivational processes in sustaining smoking dependence and suggest that they might be a focus of interventions, especially in the early stages of cessation. Dawkins L, Powell JH, Pickering AD, Powell JF, and West RJ (2009) Addiction 104, 850-

Demographics of extra-articular calcaneal fractures: Including a review of the literature on treatment and outcome

Introduction: Extra-articular calcaneal fractures represent 25-40% of all calcaneal fractures and an even higher percentage of up to 60% is seen in children. A disproportionately small part of the literature on calcaneal fractures involves the extra-articular type. The aim of this study was to investigate the incidence of extra-articular calcaneal fractures in a Level 1 trauma centre, define the distribution of the various types of fractures and compare patient demographics between extra- and intra-articular calcaneal fractures. In addition the literature was reviewed for the most common types of extra-articular calcaneal fractures with regard to incidence, treatment and clinical outcome. Methods: The radiological records between 2003 and 2005 were reviewed for intra- and extra-articular calcaneal fractures. Patient gender-distribution and age were compared. A literature search was conducted for the treatment of extra-articular calcaneal fractures. Results: In this 3-year study period a total of 49 patients with 50 extra-articular calcaneal fractures and 91 patients with 101 intra-articular fractures were identified. The median age for the first group was 32.7 years, and for the second group 40.3 years; P = 0.04. Male predominance was significantly less pronounced for extra-articular (63%) compared with intra-articular fractures (79%; P = 0.04). Conclusion: One-third of all calcaneal fractures are extra-articular. Significant differences exist between the intra- and extra-articular groups, in terms of lower age and male-female ratio. The literature study shows inconsistencies in treatment options, but most extra-articular fractures are well manageable conservatively