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A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling

Tue, 06/09/2015 - 1:48pm

Toll-like receptors (TLRs) are involved in sensing invading microbes by host innate immunity. TLR2 recognizes bacterial lipoproteins/lipopeptides, and lipopolysaccharide activates TLR4. TLR2 and TLR4 signal via the Toll/interleukin-1 receptor adaptors MyD88 and MAL, leading to NF-kappaB activation. TLR4 also utilizes the adaptors TRAM and TRIF, resulting in activation of interferon regulatory factor (IRF) 3. Here, we report a new role for TRAM and TRIF in TLR2 regulation and signaling. Interestingly, we observed that TLR2-mediated induction of the chemokine Ccl5 was impaired in TRAM or TRIF deficient macrophages. Inhibition of endocytosis reduced Ccl5 release, and the data also suggested that TRAM and TLR2 co-localize in early endosomes, supporting the hypothesis that signaling may occur from an intracellular compartment. Ccl5 release following lipoprotein challenge additionally involved the kinase Tbk-1 and Irf3, as well as MyD88 and Irf1. Induction of Interferon-beta and Ccl4 by lipoproteins was also partially impaired in cells lacking TRIF cells. Our results show a novel function of TRAM and TRIF in TLR2-mediated signal transduction, and the findings broaden our understanding of how Toll/interleukin-1 receptor adaptor proteins may participate in signaling downstream from TLR2.

STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors

Tue, 06/09/2015 - 1:48pm

Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.

Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection

Tue, 06/09/2015 - 1:48pm

Herpesviruses are DNA viruses harboring the capacity to establish lifelong latent-recurrent infections. There is limited knowledge about viruses targeting the innate DNA-sensing pathway, as well as how the innate system impacts on the latent reservoir of herpesvirus infections. In this article, we report that murine gammaherpesvirus 68 (MHV68), in contrast to alpha- and beta-herpesviruses, induces very limited innate immune responses through DNA-stimulated pathways, which correspondingly played only a minor role in the control of MHV68 infections in vivo. Similarly, Kaposi's sarcoma-associated herpesvirus also did not stimulate immune signaling through the DNA-sensing pathways. Interestingly, an MHV68 mutant lacking deubiquitinase (DUB) activity, embedded within the large tegument protein open reading frame (ORF)64, gained the capacity to stimulate the DNA-activated stimulator of IFN genes (STING) pathway. We found that ORF64 targeted a step in the DNA-activated pathways upstream of the bifurcation into the STING and absent in melanoma 2 pathways, and lack of the ORF64 DUB was associated with impaired delivery of viral DNA to the nucleus, which, instead, localized to the cytoplasm. Correspondingly, the ORF64 DUB active site mutant virus exhibited impaired ability to establish latent infection in wild-type, but not STING-deficient, mice. Thus, gammaherpesviruses evade immune activation by the cytosolic DNA-sensing pathway, which, in the MHV68 model, facilitates establishment of infections.

Mechanisms of inflammasome activation: recent advances and novel insights

Tue, 06/09/2015 - 1:48pm

Inflammasomes are cytosolic multiprotein platforms assembled in response to invading pathogens and other danger signals. Typically inflammasome complexes contain a sensor protein, an adaptor protein, and a zymogen - procaspase-1. Formation of inflammasome assembly results in processing of inactive procaspase-1 into an active cysteine-protease enzyme, caspase-1, which subsequently activates the proinflammatory cytokines, interleukins IL-1beta and IL-18, and induces pyroptosis, a highly-pyrogenic inflammatory form of cell death. Studies over the past year have unveiled exciting new players and regulatory pathways that are involved in traditional inflammasome signaling, some of them even challenging the existing dogma. This review outlines these new insights in inflammasome research and discusses areas that warrant further exploration.

Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment

Tue, 06/09/2015 - 1:48pm

Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 and the remaining six segments from H3N2. By deep sequencing the entire viral genome, we monitored the evolution of reassortment, quantifying the relative abundance of all IAV genome segments from the two parent strains over time and measuring the selection coefficients of the reassorting segments. Additionally, we observed several mutations coemerging with reassortment that were not found during passaging of pure parental IAV strains. Our results demonstrate how reassortment of the segmented genome can accelerate viral evolution in IAV, potentially enabled by the emergence of a small number of individual mutations. Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail:

The Family Physician's Role in Identifying and Treating Tobacco Addiction among Adolescents

Mon, 06/08/2015 - 2:49pm

Smoking and tobacco addiction are serious public health problems worldwide. New research reveals that addiction to tobacco can begin very early, with very low levels of smoking. Family physicians are in a unique position to prevent smoking initiation by youths and to diagnose and treat tobacco addiction in young smokers. In this paper we discuss the factors that prompt youths to try smoking, how quickly addiction to tobacco begins after the onset of smoking, how a family physician can determine whether a young patient is addicted, and what the physician can do to prevent adolescent patients from beginning to smoke or to assist them to quit if they already smoke.

The Impact of Personal Expectations on Counterfactual Thinking About Life and Death Medical Decisions

Mon, 06/08/2015 - 2:49pm

We examined the impact of social perceivers' self-referent norms (i.e., their own expectations of what should occur) on counterfactual thinking in health care decision making regarding treatment termination. We presented participants with a "patient's dilemma" in which continuing or stopping medical treatment raised the risk of death for the patient and/or her developing fetus. Participants (N = 217) recommended a course of action to the patient, predicted consensus with that recommendation, and assessed the likely risks of both actions. We exposed them to an outcome in which the patient either continued or stopped treatment with either positive or negative consequences. Disagreement with the patient's treatment decision was associated with attributions of greater predictability, regret, and responsibility when the outcome was negative, suggesting the prompting of counterfactual processes.

Systematic review of randomized controlled trials of smoking cessation interventions for youth

Mon, 06/08/2015 - 2:49pm

Background: Cigarette use remains common among young people but little is known about how to help adolescent smokers quit. There are few systematic reviews of randomized controlled trials (RCTs) that evaluate the effectiveness of cessation interventions for youth.

Objective: To synthesize knowledge on the effectiveness of cessation interventions targeted to youth based on evidence from RCTs.

Selection of studies and data extraction: We retained all published RCTs with intention to treat analyses that evaluated cessation interventions targeted to youth aged = 20 years. Relevant studies were identified from eight review articles of smoking cessation intervention studies published between 2002 and 2006, and from a search conducted in PubMed and PsycINFO databases from 2001 to November 2006. The outcome of primary interest was abstinence at the longest reported follow-up. Extraction of data was by consensus of the authors.

Results: We identified 16 RCTs with a total of 6623 participants; 11 studies that included 5764 participants evaluated behavioural interventions, four with 529 participants evaluated pharmacological interventions, and one with 330 participants evaluated a laser acupuncture intervention. Three of four behavioural interventions conducted in school settings, and one of four conducted in a health care setting significantly increased abstinence four weeks to 24 months after the interventions. Of four RCTs that evaluated pharmacological interventions using either bupropion or nicotine patch or gum, one study using the nicotine patch coupled with cognitive-behavioural counselling showed a marked albeit non-significant increase in abstinence six months after quit date.

Conclusion: There is still limited evidence demonstrating the efficacy of smoking cessation interventions in youth. Four school-based programs and one intervention in a health care setting have shown efficacy, while results for pharmacological therapy are inconsistent across studies.

Tobacco Dependence

Mon, 06/08/2015 - 2:49pm

Provides guidance to health professionals about tobacco dependence and how best to provide preventive health services for children as suggested in the Bright Futures Guidelines.

Measures of nicotine dependence in adolescents: An update of the evidence 2000–2010

Mon, 06/08/2015 - 2:49pm

Nicotine withdrawal and the compulsion to use tobacco resulting from withdrawal form the core clinical features of nicotine dependence (ND). However, some ND measures show little or no content overlap with these clinical features. Our objective was to review the content and psychometric properties of available measures of ND for youth. A literature search identified 27 English language articles published in 2000–2010 that evaluated ND measures in adolescents or young adults. A consensus process among the authors was used to establish if each item in each measure assessed withdrawal or compulsion, or if the item tapped other aspects of cigarette smoking including tolerance, harm, triggers for smoking, cigarette use patterns, prioritizing smoking, perceived utility, or attitudes about smoking. Out of 14 measures identified, three (Hooked on Nicotine Checklist, Latency to Withdrawal, Withdrawal Symptom Cluster) measured the core clinical features of ND; six (Autonomy Over Smoking Scale, DSM IV, Dimensions of Tobacco Dependence Scale, ICD-10 Tobacco Dependence, ND/Cravings Symptom Cluster, Nicotine Dependence Syndrome Scale) measured withdrawal/compulsion and other aspects of smoking; and five (Fagerström Test for Nicotine Dependence, Modified Fagerström Tolerance Questionnaire, Nicotine Dependence Scale for Adolescents, Self-Medication Symptom Cluster, Stanford Dependence Index) had few or no withdrawal/compulsion indicators. Existing measures vary widely in the degree to which they assess the known clinical features of ND. Attempts to assess ND indirectly in youth by measuring other aspects of smoking may result in inaccuracy if items are endorsed for reasons other than ND. No existing measure assesses the full spectrum of clinically recognized features of ND.

Seasonality in onset of youth smoking parallels seasonality in cigarette sales

Sun, 06/07/2015 - 9:28pm

Extract: Cigarette sales in the USA peak in the summer months, June through August. This finding prompted examination of data on the onset of youth smoking to determine whether a similar pattern could be discerned. In this letter we report data from the Development and Assessment of Nicotine Dependence in Youth (DANDY) study.

Preventing cancer by controlling youth tobacco use

Sun, 06/07/2015 - 9:28pm

OBJECTIVES: To review the epidemiology and prevention of teen smoking and the risks of smoking among survivors of childhood cancer.

DATA SOURCES: Research articles, government reports, and surveys.

CONCLUSION: Nicotine dependence often begins with the first few cigarettes smoked during adolescence. Teen tobacco use is fueled by the attractive social images that tobacco companies create for their products. Curtailing the sale of tobacco to minors and increasing their price decreases availability. Banning smoking in schools and public places reduces smoking opportunities.

IMPLICATIONS FOR NURSING PRACTICE: Nurses have an important role to play in the battle against tobacco-induced malignancies through collaboration with community efforts or state initiatives.

Screening adolescents for nicotine dependence: the Hooked On Nicotine Checklist

Sun, 06/07/2015 - 9:28pm

PURPOSE: To evaluate the Hooked On Nicotine Checklist's (HONC) internal consistency, reliability over time, correlation with self-described smoking behavior, and to compare the results with previous studies of the onset of nicotine dependence in youths.

METHODS: Ninth-grade students were recruited from a regional school district. Subjects (Ss; n = 371; 91% of the 9th-grade class) were 48.8% male, 97% white, aged 13.8-15.6 years. Ss self-administered a questionnaire on smoking experiences. The HONC was completed by 88 (23.7%) who had puffed on a cigarette at least once; 74 were retested 2 weeks later. Responding "yes" to any of the 10 HONC items indicates nicotine dependence (ND); the number of items endorsed indicates the degree of its severity.

RESULTS: The internal consistency of the HONC is high overall (alpha = 0.90; n = 88), and test-retest reliability for the entire HONC is excellent (intraclass correlation = 0.88, p < .001). Individual items generally showed good to excellent reliability over time (Median Yules' Y = 0.71, range = 0.41-0.82). HONC scores were strongly correlated with self-reported smoking (r = 0.70, p < .001, n = 88).

CONCLUSIONS: Adding the HONC to routine adolescent health examinations, health classes, and prevention programs may make adolescents more aware of their symptoms of ND and enable intervention before ND progresses.

A sensitization-homeostasis model of nicotine craving, withdrawal, and tolerance: integrating the clinical and basic science literature

Sun, 06/07/2015 - 9:28pm

Recent reports suggest that nicotine withdrawal symptoms are common among adolescents after a few weeks of intermittent tobacco use. No current model of nicotine dependence had predicted the rapid development of symptoms of dependence and withdrawal before the development of tolerance. We present a model that integrates neuroscience with clinical observations regarding how nicotine dependence develops, progresses, and resolves in humans. The central tenet of this sensitization-homeostasis model is that nicotine's dependence liability derives from its ability to stimulate neural pathways responsible for the suppression of craving. As a result of sensitization, the craving suppression produced by nicotine is magnified to superphysiological levels. The overinhibition of neurons responsible for craving initiates compensatory homeostatic measures that stimulate the craving pathways and result in craving when nicotine is absent. Separate homeostatic mechanisms are responsible for craving, withdrawal, and tolerance. The sensitization-homeostasis model is unique in its attribution of dependence to craving suppression, its attention to the temporal relationships among clinical features of nicotine dependence, and its extensive integration of clinical observations and basic science. It provides a framework for theory-based research.

Tobacco chippers report diminished autonomy over smoking

Sun, 06/07/2015 - 9:28pm

We assessed tobacco chippers (n=35) for symptoms of diminished autonomy over tobacco use, which begins when symptoms present a barrier to smoking cessation. Although they reported each of the symptoms measured by the Hooked on Nicotine Checklist, chippers' level of autonomy was generally higher than that of regular smokers and their symptom intensity was low. The rank order of symptom prevalence in chippers and regular smokers was similar, and 40% of chippers had failed at least one cessation attempt. Only 23% of chippers reported full autonomy over their smoking. Although chippers may not warrant a dependence diagnosis, they may benefit from help with cessation. Autonomy over smoking may be a more useful basis than cigarette consumption rates for classifying smokers.

Sensitization to nicotine: how the animal literature might inform future human research

Sun, 06/07/2015 - 9:28pm

Despite a rich neuroscience literature on sensitization, this phenomenon has been neglected in clinical nicotine research. This paper offers a primer on the neuroscience of nicotine sensitization for behavioral scientists, identifying key concepts, potential theoretical and clinical implications, and directions for future research. Sensitization to a drug occurs when repeated exposures to the same dose produce greater responses. In animals, sensitization to nicotine, morphine, alcohol, cocaine, amphetamine, and methamphetamine manifests as increased locomotor activity. In animals, sensitization to nicotine begins with the first dose and is maximal within 5-7 days. It involves multiple neurotransmitters, receptors, and brain structures and cannot be attributed to any single alteration. The processes involved in its induction and expression are not identical. The neurologic changes associated with sensitization are not consistent across drugs, suggesting that sensitization is not an accident of neurophysiology but perhaps an exaggerated adaptive response. Sensitization is incorporated into two theories of addiction: incentive-sensitization and sensitization-homeostasis. Whether sensitization occurs in humans and how it is expressed is unclear, as is its role in human addiction.

R-rated film viewing and adolescent smoking

Sun, 06/07/2015 - 9:28pm

OBJECTIVES: As smoking is very common in R-rated films, we sought to determine if viewing R-rated films is associated with adolescent smoking.

METHODS: Three annual cross-sectional surveys conducted of 88,505 Year 10 students of largely European, Maori, Asian or Pacific Islander ethnicity in secondary schools in New Zealand between 2002 and 2004. Outcomes of interest were: intention to smoke among never smokers; past experimentation with smoking among current non-smokers; current smoking status; and current frequency of smoking.

RESULTS: Dose-response relationships were observed between the frequency of viewing R-rated films and all outcome measures controlling for age, gender, ethnicity, peer smoking, parental smoking, socioeconomic status, pocket money and household smoking rules. Compared to never viewing R-rated films, viewing at least weekly nearly tripled the relative risk (2.81; 95% confidence interval 2.57, 3.09) of never smokers being susceptible to smoking, and more than doubled the risk of both past experimentation (2.28; 95% CI 2.12, 2.45) and smoking > /=monthly (2.31; 95% CI 2.10, 2.54). Each of these risks was seen across all ethnic groups.

CONCLUSIONS: Our results extend the association that has been demonstrated between viewing R-rated films and current smoking in American youth by demonstrating the same association in youth of different ethnic and cultural backgrounds in New Zealand.

Diminished autonomy over tobacco can appear with the first cigarettes

Sun, 06/07/2015 - 9:28pm

Individuals have lost full autonomy over their smoking when quitting becomes unpleasant or difficult. We examined autonomy in relation to smoking frequency and lifetime cigarette use. A self-administered questionnaire was completed by three convenience samples of Year 10 students (ages 14-15) in New Zealand between 2002 and 2004 (n=96,156). The Hooked On Nicotine Checklist was used to measure diminished autonomy. Diminished autonomy was reported by 46% of subjects who smoked less often than monthly and by 25%-30% of current smokers who had smoked only one cigarette in total. The prevalence of diminished autonomy increased with increasing frequency of current use and with increasing lifetime use. Symptoms developed earlier among girls than boys. The data confirm previous reports that diminished autonomy appears soon after the onset of intermittent tobacco use and extends this literature by providing the first description of how diminished autonomy develops in relation to the total number of cigarettes smoked. These data suggest that smoking one cigarette in total can prompt a loss of autonomy.

Assessing college students' autonomy over smoking with the Hooked On Nicotine Checklist

Sun, 06/07/2015 - 9:28pm

OBJECTIVE, PARTICIPANTS, AND METHODS: In this study, the authors explored the psychometric properties of the Hooked on Nicotine Checklist (HONC) among 300 college students who were current smokers. The HONC is a 10-item survey instrument designed to measure diminished autonomy over smoking, a key aspect of dependence. Autonomy is diminished when symptoms present a barrier to cessation.

RESULTS: Internal consistency was high (alpha = .89), as was concurrent validity. Students who began smoking earlier and heavier smokers reported more symptoms than did those who started later and smoked less. After controlling for smoking frequency, the HONC was predictive of the likelihood of a failed cessation attempt, with each additional symptom doubling that likelihood.

CONCLUSIONS: College health professionals could use the HONC to help new smokers recognize their symptoms of diminished autonomy. The HONC may serve as a recruiting tool for cessation programs, which could benefit such early-phase smokers.