The macrophage-inducible C-type lectin, Mincle, is an essential component of the innate immune response to Candida albicans

The recognition of carbohydrate moieties by cells of the innate immune system is emerging as an essential element in antifungal immunity, but despite the number and diversity of lectins expressed by innate immune cells, few carbohydrate receptors have been characterized. Mincle, a C-type lectin, is expressed predominantly on macrophages, and is here shown to play a role in macrophage responses to the yeast Candida albicans. After exposure to the yeast in vitro, Mincle localized to the phagocytic cup, but it was not essential for phagocytosis. In the absence of Mincle, production of TNF-_ by macrophages was reduced, both in vivo and in vitro. In addition, mice lacking Mincle showed a significantly increased susceptibility to systemic candidiasis. Thus, Mincle plays a novel and nonredundant role in the induction of inflammatory signaling in response to C. albicans infection.

Syntaxin 6 and Vti1b form a novel SNARE complex, which is upregulated in activated macrophages to facilitate exocytosis of TNF.

A key function of activated macrophages is to secrete proinflammatory cytokines such as TNF; however, the intracellular pathway and machinery responsible for cytokine trafficking and secretion is largely undefined. Here we show that individual SNARE proteins involved in vesicle docking and fusion are regulated at both gene and protein expression upon stimulation with the bacterial cell wall component lipopolysaccharide. Focusing on two intracellular SNARE proteins, Vti1b and syntaxin 6 (Stx6), we show that they are up-regulated in conjunction with increasing cytokine secretion in activated macrophages and that their levels are selectively titrated to accommodate the volume and timing of post-Golgi cytokine trafficking. In macrophages, Vti1b and syntaxin 6 are localized on intracellular membranes and are present on isolated Golgi membranes and on Golgi-derived TNF� vesicles budded in vitro. By immunoprecipitation, we find that Vti1b and syntaxin 6 interact to form a novel intracellular Q-SNARE complex. Functional studies using overexpression of full-length and truncated proteins show that both Vti1b and syntaxin 6 function and have rate-limiting roles in TNF� trafficking and secretion. This study shows how macrophages have uniquely adapted a novel Golgi-associated SNARE complex to accommodate their requirement for increased cytokine secretion.

Is –110°C cold air cryotherapy effective in improving post-exercise recovery in sports people?

Whole body cryotherapy (WBC) involves repeatedly exposing an individual, dressed in minimal clothing, to extremely cold air (–100 to –130°C) for a short period. One specific claim that is often made is that WBC is effective in treating exercise-induced muscle soreness and damage. However, our results suggest that two bouts of WBC were ineffective in improving recovery from eccentric exercise when administered 24 hours after eccentric exercise.

Where the bridge is

Memoir excerpt

Is flapless implant surgery a viable option in posterior maxilla? : a review

This article reviews the literature on the outcome of flapless surgery for dental implants in the posterior maxilla. The literature search was carried out in using the keywords: flapless, dental implants and maxilla. A hand search and Medline search were carried out on studies published between 1971 and 2011. The authors included research involving a minimum of 15 dental implants with a followup period of 1 year, an outcome measurement of implant survival, but excluded studies involving multiple simultaneous interventions, and studies with missing data. The Cochrane approach for cohort studies and Oxford Centre for Evidence- Based Medicine were applied. Of the 56 published papers selected, 14 papers on the flapless technique showed high overall implant survival rates. The prospective studies yielded 97.01% (95% CI: 90.72–99.0) while retrospective studies or case series illustrated 95.08% (95% CI: 91.0–97.93) survival. The average of intraoperative complications was 6.55% using the flapless procedure. The limited data obtained showed that flapless surgery in posterior maxilla areas could be a viable and predictable treatment method for implant placement. Flapless surgery tends to be more applicable in this area of the mouth. Further long-term clinical controlled studies are needed.

Is there an inverted U-shape relationship between job demands and work engagement : the moderating role of social support

Purpose - The purpose of this paper is to examine the possibility of an inverted U-shaped relationship between job demands and work engagement, and whether social support moderates this relationship. Design/methodology/approach – This study uses 307 technical and information technology (IT) managers who responded to an online survey. Multiple regressions are employed to examine linear and curvilinear relationship among variables. Findings – Overall, results support the applicability of the quadratic effect of job demands on employee engagement. However, only supervisor support, not colleague support, moderated the relationship between job demands and work engagement. Originality/value – The paper is the first to shed light on the quadratic effect of job demands on work engagement. The findings have noteworthy implications for managers to design optimal job demands that increase employee engagement.

Dietetic confidence working with clients with depression/anxiety is associated with client-focused practice and advocacy skills

Confidence in a professional role is a key element in the successful transition to competent practice. New graduate dietitians report that whilst they are confident about their general dietetic ability, they are not as confident when working with clients experiencing depression or anxiety. This study aimed to develop and validate a scale which measured confidence about working with clients with depression/anxiety. The 21-item Dietetic Collaborative Practice Scale was developed using research about dietetic practice in mental health (Dowding et al., 2011), coping self-efficacy literature (Chesney et al., 2006) and collaboration with industry experts. A convenience sample of 189 Australian dietitians completed the questionnaire. Exploratory factor analysis suggests that dietetic confidence is best represented by a two-dimensional solution consisting of (a) Client-focused practice (CFP, 50.8% variance); and (b) Advocacy for self and client care (ASC, 9.7% variance). The alpha coefficient of both dimensions (CFP α=.95, ASC α=.84) demonstrates the internal consistency of components. Combined, these two components account for 60.5% of variance. The scale components were not related to years of practice or working with mental health clients but were significantly related to overall dietetic confidence (ODC). Correlation coefficients between ODC and CFP were .501 (p<.01), ODC and ASC were correlated at .465 (p<.01) and CFP and number of years as a dietitian were weakly correlated at 0.24 (p<.05). Results have implications for dietetic training and professional development. Client focus and advocacy for self and client appear to be important factors in overall confidence as a dietitian.

P147 Deprivation is associated with increased healthcare utilisation in patients with chronic obstructive pulmonary disease

Deprivation assessed using the index of multiple deprivation (IMD) has been shown to be an independent risk factor for 1-year mortality in outpatients with chronic obstructive pulmonary disease; COPD (Collins et al, 2010). IMD combines a number of economic and social issues (eg, health, education, employment) into one overall deprivation score, the higher the score the higher an individual's deprivation. Whilst malnutrition in COPD has been linked to increased healthcare use it is not clear if deprivation is also independently associated. This study aimed to investigate the influence of deprivation on 1-year healthcare utilisation in outpatients with COPD. IMD was established in 424 outpatients with COPD according to the geographical location for each patient's address (postcode) and related to their healthcare use in the year post-date screened (Nobel et al, 2008). Patients were routinely screened in outpatient clinics for malnutrition using the ‘Malnutrition Universal Screening Tool’, ‘MUST’ (Elia 2003); mean age 73 (SD 9.9) years; body mass index 25.8 (SD 6.3) kg/m2 with healthcare use collected 1 year from screening (Abstract P147 Table 1). Deprivation assessed using IMD (mean 15.9; SD 11.1) was found to be a significant predictor for the frequency and duration of emergency hospital admissions as well as the duration of elective hospital admission. Deprivation was also linked to reduced secondary care outpatient appointment attendance but not an increase in failure to attend and deprivation was not associated with increased disease severity, as classified by the GOLD criteria (p=0.580). COPD outpatients residing in more deprived areas experience increased hospitalisation rates but decreased outpatient appointment attendance. The underlying reason behind this disparity in healthcare use requires further investigation.

Introduction: Is a General Theory of Violence Possible?

"There once was a man who aspired to be the author of the general theory of holes. When asked ‘What kind of hole—holes dug by children in the sand for amusement, holes dug by gardeners to plant lettuce seedlings, tank traps, holes made by road makers?’ he would reply indignantly that he wished for a general theory that would explain all of these. He rejected ab initio the—as he saw it—pathetically common-sense view that of the digging of different kinds of holes there are quite different kinds of explanations to be given; why then he would ask do we have the concept of a hole? Lacking the explanations to which he originally aspired, he then fell to discovering statistically significant correlations; he found for example that there is a correlation between the aggregate hole-digging achievement of a society as measured, or at least one day to be measured, by econometric techniques, and its degree of techno- logical development. The United States surpasses both Paraguay and Upper Volta in hole-digging; there are more holes in Vietnam than there were. These observations, he would always insist, were neutral and value-free. This man’s achievement has passed totally unnoticed except by me. Had he however turned his talents to political science, had he concerned himself not with holes, but with modernization, urbanization or violence, I find it difficult to believe that he might not have achieved high office in the APSA." (MacIntyre 1971, 260)

Deprivation is an independent predictor of 1-year mortality in outpatients with chronic obstructive pulmonary disease

Deprivation is linked to increased incidence in a number of chronic diseases but its relationship to chronic obstructive pulmonary disease (COPD) is uncertain despite suggestions that the socioeconomic gradient seen in COPD is as great, if not greater, than any other disease (Prescott and Vestbo).1 There is also a need to take into account the confounding effects of malnutrition which have been shown to be independently linked to increased mortality (Collins et al).2 The current study investigated the influence of social deprivation on 1-year survival rates in COPD outpatients, independently of malnutrition. 424 outpatients with COPD were routinely screened for malnutrition risk using the ‘Malnutrition Universal Screening Tool’; ‘MUST’ (Elia),3 between July and May 2009; 222 males and 202 females; mean age 73 (SD 9.9) years; body mass index 25.8 (SD 6.3) kg/m2. Each individual's deprivation was calculated using the index of multiple deprivation (IMD) which was established according to the geographical location of each patient's address (postcode). IMD includes a number of indicators covering economic, housing and social issues (eg, health, education and employment) into a single deprivation score (Nobel et al).4 The lower the IMD score, the lower an individual's deprivation. The IMD was assigned to each outpatient at the time of screening and related to1-year mortality from the date screened. Outpatients who died within 1-year of screening were significantly more likely to reside within a deprived postcode (IMD 19.7±SD 13.1 vs 15.4±SD 10.7; p=0.023, OR 1.03, 95% CI 1.00 to 1.06) than those that did not die. Deprivation remained a significant independent risk factor for 1-year mortality even when adjusted for malnutrition as well as age, gender and disease severity (binary logistic regression; p=0.008, OR 1.04, 95% CI 1.04 to 1.07). Deprivation was not associated with disease-severity (p=0.906) or body mass index, kg/m2 (p=0.921) using ANOVA. This is the first study to show that deprivation, assessed using IMD, is associated with increased 1-year mortality in outpatients with COPD independently of malnutrition, age and disease severity. Deprivation should be considered in the targeted management of these patients.

Clusterin is a critical downstream mediator of stress-induced YB-1 transactivation in prostate cancer

Clusterin is a stress-activated, cytoprotective chaperone that confers broad-spectrum treatment resistance in cancer. However, the molecular mechanisms mediating CLU transcription following anticancer treatment stress remain incompletely defined. We report that Y-box binding protein-1 (YB-1) directly binds to CLU promoter regions to transcriptionally regulate clusterin expression. In response to endoplasmic reticulum stress inducers, including paclitaxel, YB-1 is translocated to the nucleus to transactivate clusterin. Furthermore, higher levels of activated YB-1 and clusterin are seen in taxane-resistant, compared with parental, prostate cancer cells. Knockdown of either YB-1 or clusterin sensitized prostate cancer cells to paclitaxel, whereas their overexpression increased resistance to taxane. Clusterin overexpression rescued cells from increased paclitaxel-induced apoptosis following YB-1 knockdown; in contrast, however, YB-1 overexpression did not rescue cells from increased paclitaxel-induced apoptosis following clusterin knockdown. Collectively, these data indicate that YB-1 transactivation of clusterin in response to stress is a critical mediator of paclitaxel resistance in prostate cancer. Mol Cancer Res; 9(12); 1755–66.