Work Stress in the Nursing Profession : An Evaluation of Organizational Causal Attribution

The goal of this study was to examine the role of organizational causal attribution in understanding the relation of work stressors (work-role overload, excessive role responsibility, and unpleasant physical environment) and personal resources (social support and cognitive coping) to such organizational-attitudinal outcomes as work engagement, turnover intention, and organizational identification. In some analyses, cognitive coping was also treated as an organizational outcome. Causal attribution was conceptualized in terms of four dimensions: internality-externality, attributing the cause of one’s successes and failures to oneself, as opposed to external factors, stability (thinking that the cause of one’s successes and failures is stable over time), globality (perceiving the cause to be operative on many areas of one’s life), and controllability (believing that one can control the causes of one’s successes and failures). Several hypotheses were derived from Karasek’s (1989) Job Demands–Control (JD-C) model and from the Job Demands–Resources (JD-R) model (Demerouti, Bakker, Nachreiner & Schaufeli, 2001). Based on the JD-C model, a number of moderation effects were predicted, stating that the strength of the association of work stressors with the outcome variables (e.g. turnover intentions) varies as a function of the causal attribution; for example, unpleasant work environment is more strongly associated with turnover intention among those with an external locus of causality than among those with an internal locuse of causality. From the JD-R model, a number of hypotheses on the mediation model were derived. They were based on two processes posited by the model: an energy-draining process in which work stressors along with a mediating effect of causal attribution for failures deplete the nurses’ energy, leading to turnover intention, and a motivational process in which personal resources along with a mediating effect of causal attribution for successes foster the nurses’ engagement in their work, leading to higher organizational identification and to decreased intention to leave the nursing job. For instance, it was expected that the relationship between work stressors and turnover intention could be explained (mediated) by a tendency to attribute one’s work failures to stable causes. The data were collected from among Finnish hospital nurses using e-questionnaires. Overall 934 nurses responded the questionnaires. Work stressors and personal resources were measured by five scales derived from the Occupational Stress Inventory-Revised (Osipow, 1998). Causal attribution was measured using the Occupational Attributional Style Questionnaire (Furnham, 2004). Work engagement was assessed through the Utrecht Work Engagement Scale (Schaufeli & al., 2002), turnover intention by the Van Veldhoven & Meijman (1994) scale, and organizational identification by the Mael & Ashforth (1992) measure. The results provided support for the function of causal attribution in the overall work stress process. Findings related to the moderation model can be divided into three main findings. First, external locus of causality along with job level moderated the relationship between work overload and cognitive coping. Hence, this interaction was evidenced only among nurses in non-supervisory positions. Second, external locus of causality and job level together moderated the relationship between physical environment and turnover intention. An opposite pattern of interaction was found for this interaction: among nurses, externality exacerbated the effect of perceived unpleasantness of the physical environment on turnover intention, whereas among supervisors internality produced the same effect. Third, job level also disclosed a moderation effect for controllability attribution over the relationship between physical environment and cognitive coping. Findings related to the mediation model for the energetic process indicated that the partial model in which work stressors have also a direct effect on turnover intention fitted the data better. In the mediation model for the motivational process, an intermediate mediation effect in which the effects of personal resources on turnover intention went through two mediators (e.g., causal dimensions and organizational identification) fitted the data better. All dimensions of causal attribution appeared to follow a somewhat unique pattern of mediation effect not only for energetic but also for motivational processes. Overall findings on mediation models partly supported the two simultaneous underlying processes proposed by the JD-R model. While in the energetic process the dimension of externality mediated the relationship between stressors and turnover partially, all the dimensions of causal attribution appeared to entail significant mediator effects in the motivational process. The general findings supported the moderation effect and the mediation effect of causal attribution in the work stress process. The study contributes to several research traditions, including the interaction approach, the JD-C, and the JD-R models. However, many potential functions of organizational causal attribution are yet to be evaluated by relevant academic and organizational research. Keywords: organizational causal attribution, optimistic / pessimistic attributional style, work stressors, organisational stress process, stressors in nursing profession, hospital nursing, JD-R model, personal resources, turnover intention, work engagement, organizational identification.

Screening for partner violence among family mediation clients: Differentiating types of abuse

Family mediation is mandated in Australia for couples in dispute over separation and parenting as a first step in dispute resolution, except where there is a history of intimate partner violence. However, validation of effective well-differentiated partner violence screening instruments suitable for mediation settings is at an early phase of development. This study contributes to calls for better violence screening instruments in the mediation context to detect a differentiated range of abusive behaviors by examining the reliability and validity of both established scales, and newly developed scales that measured intimate partner violence by partner and by self. The study also aimed to examine relationships between types of abuse, and between gender and types of abuse. A third aim was to examine associations between types of abuse and other relationship indicators such as acrimony and parenting alliance. The data reported here are part of a larger mixed method, naturalistic longitudinal study of clients attending nine family mediation centers in Victoria, Australia. The current analyses on baseline cross-sectional screening data confirmed the reliability of three subscales of the Conflict Tactics Scale (CTS2), and the reliability and validity of three new scales measuring intimidation, controlling and jealous behavior, and financial control. Most clients disclosed a history of at least one type of violence by partner: 95% reported psychological aggression, 72% controlling and jealous behavior, 50% financial control, and 35% physical assault. Higher rates of abuse perpetration were reported by partner versus by self, and gender differences were identified. There were strong associations between certain patterns of psychologically abusive behavior and both acrimony and parenting alliance. The implications for family mediation services and future research are discussed.

Nainen, mies, rakkaus, seksi : Heterosuhteen kulku, kulttuurinen malli ja sitä selittävät diskurssit kahden omaelämäkerta-aineiston valossa

The subject matter of this study is the cultural knowledge concerning romantic male-female relationships in autobiographies written by so called ordinary Finnish men and women born between 1901 and 1965. The research data (98 autobiographies) is selected from two collections by the Finnish Literature Society s folklore archives in the early 1990 s. Autobiographies are cultural representations where negotiation of shared cultural models and personal meanings given to hetero-relationship is evident in an interesting manner. In this research I analyze autobiographies as a written folklore genre. Information concerning male-female relationships is being analyzed using theoretically informed close readings thematic analysis, intertextual reading and reflexive reading. Theoretical implications stem from cognitive anthropology (the idea of cultural models) and an adaptation of discourse theory inspired by Michel Foucault. The structure of the analysis follows the structure of the shared knowledge concerning romantic male-female relationship: the first phase of analysis presents the script of a hetero-relationship and then moves into the actual structure, the cultural model of a relationship. The components of the model of relationship are, as mentioned in the title of the research, woman, man, love and sex. The research shows that all the writers share this basic knowledge concerning a heterosexual relationship despite their age, background or gender. Also the conflicts described and experienced in the relationships of the writers were similar throughout the timespan of the early 1900 s to 1990 s: lack of love, inability to reconcile sexual desires, housework, sharing the responsibility of childcare and financial problems. The research claims that the conflicts in relationships are a major cause for the binary view on gender. When relationships are harmonious, there seems to be no need to see men and women as opposites. The research names five important discourses present in the meaning giving processes of autobiographers. In doing so, the stabile cultural model of male-female relationship widens to show the complexity and variation in data. In this way it is possible to detect some age and gender specific shifts and emphasis. The discourses give meaning to the components of the cultural model and determine the contents of womanhood, manhood, sexuality and love. The way these discourses are spread and their authority are different: the romantic discourse evident in the autobiographies appeal to the authority of love supreme love is the purpose of male-female relationship and it justifies sexuality. In this discourse sex can be the place for confluence of genders. The ideas of romantic love are widely spread in popular culture. Popular scientific discourse defines a relationship as a site to become a man and a woman either from a psychological or a biological point of view. Genders are seen as opposites. These ideas are often presented in media and their authority in science which is seen as infallible. The Christian discourse defines men and women: both should work for the benefit of the nuclear family under the undisputed authority of God. Marital love is based on Christian virtues and within marriage sexuality is acceptable. The discourse I ve named folk tradition defines women and men as guardians of home and offspring. The authority of folk tradition comes from universal truth based in experience and truths known to the mediators of this discourse grandparents, parents and other elders or peers. Societal discourse defines the hetero relationship as the mainstay of society. The authority in societal discourse stems from the laws and regulations that control relationship practices.

ICT and the Shaping of Society: Exploring Human -ICT Relationships in Everyday Life (summary section only)

This thesis explores the relationship between humans and ICTs (information and communication technologies). As ICTs are increasingly penetrating all spheres of social life, their role as mediators – between people, between people and information, and even between people and the natural world – is expanding, and they are increasingly shaping social life. Yet, we still know little of how our life is affected by their growing role. Our understanding of the actors and forces driving the accelerating adoption of new ICTs in all areas of life is also fairly limited. This thesis addresses these problems by interpretively exploring the link between ICTs and the shaping of society at home, in the office, and in the community. The thesis builds on empirical material gathered in three research projects, presented in four separate essays. The first project explores computerized office work through a case study. The second is a regional development project aiming at increasing ICT knowledge and use in 50 small-town families. In the third, the second project is compared to three other longitudinal development projects funded by the European Union. Using theories that consider the human-ICT relationship as intertwined, the thesis provides a multifaceted description of life with ICTs in contemporary information society. By oscillating between empirical and theoretical investigations and balancing between determinist and constructivist conceptualisations of the human-ICT relationship, I construct a dialectical theoretical framework that can be used for studying socio-technical contexts in society. This framework helps us see how societal change stems from the complex social processes that surround routine everyday actions. For example, interacting with and through ICTs may change individuals’ perceptions of time and space, social roles, and the proper ways to communicate – changes which at some point in time result in societal change in terms of, for example, new ways of acting and knowing things.

Identification of TGFβ signaling, p53, and actin stress fibers as targets of LKB1 tumor suppressor activity

Tumorigenesis is a consequence of inactivating mutations of tumor suppressor genes and activating mutations of proto-oncogenes. Most of the mutations compromise cell autonomous and non-autonomous restrains on cell proliferation by modulating kinase signal transduction pathways. LKB1 is a tumor suppressor kinase whose sporadic mutations are frequently found in non-small cell lung cancer and cervical cancer. Germ-line mutations in the LKB1 gene lead to Peutz-Jeghers syndrome with an increased risk of cancer and development of benign gastrointestinal hamartomatous polyps consisting of hyperproliferative epithelia and prominent stromal stalk composed of smooth muscle cell lineage cells. The tumor suppressive function of LKB1 is possibly mediated by 14 identified LKB1 substrate kinases, whose activation is dependent on the LKB1 kinase complex. The aim of my thesis was to identify cell signaling pathways crucial for tumor suppression by LKB1. Re-introduction of LKB1 expression in the melanoma cell line G361 induces cell cycle arrest. Here we demonstrated that restoring the cytoplasmic LKB1 was sufficient to induce the cell cycle arrest in a tumor suppressor p53 dependent manner. To address the role of LKB1 in gastrointestinal tumor suppression, Lkb1 was deleted specifically in SMC lineage in vivo, which was sufficient to cause Peutz-Jeghers syndrome type polyposis. Studies on primary myofibroblasts lacking Lkb1 suggest that the regulation of TGFβ signaling, actin stress fibers and smooth muscle cell lineage differentiation are candidate mechanisms for tumor suppression by LKB1 in the gastrointestinal stroma. Further studies with LKB1 substrate kinase NUAK2 in HeLa cells indicate that NUAK2 is part of a positive feedback loop by which NUAK2 expression promotes actin stress fiber formation and, reciprocally the induction of actin stress fibers promote NUAK2 expression. Findings in this thesis suggest that p53 and TGFβ signaling pathways are potential mediators of tumor suppression by LKB1. An indication of NUAK2 in the promotion of actin stress fibers suggests that NUAK2 is one possible mediator of LKB1 dependent TGFβ signaling and smooth muscle cell lineage differentiation.

The role of inflammation and matrix proteins in airway remodelling

Asthma is a chronic inflammatory disorder of the airways. Remodelling in asthma is defined as the structural changes seen in the airways of asthmatics in comparison to healthy controls. Progressive loss of lung function also seen in asthma might be caused by remodelling. The research aims of this thesis were to investigate inflammation and remodelling in the airways of different types of asthmatics and smokers. The association between inflammation and remodelling was also examined in a mouse model of allergic airway inflammation. Healthy smokers showed increased numbers of macrophages in the BAL with no changes in the inflammatory cells in biopsies. Macrophages seemed to be quite quiescent, since mRNA expression for a wide variety of inflammatory mediators, especially chemokines CCL3, CCL4, CCL5 and CCL20, secreted by macrophages was significantly lower than in healthy non-smokers. Attenuated macrophage activity in the airway lumen may render smokers more susceptible to airway infections and have an impact on the development of other airway pathology. Patients with diisocyanate-induced asthma (DIA) on inhaled corticosteroids (ICS) who still had non-specific bronchial hyperreactivity (NSBHR) at the end of the follow-up showed increased expression of TNF-α, IL-6 and IL-15 mRNA in BAL cells compared to those without NSBHR. In addition to being markers for poor prognosis and possible slight glucocorticoid resistance, these cytokines might aid in guiding the treatment of DIA. The increase in the thickness of tenascin-C layer in the bronchial basement membrane (BM) was much less than usually seen in other types of asthma, which might not make tenascin-C a good marker for DIA. OVA-induced tenascin-C expression in the lung was attenuated in STAT4-/- mice with impaired Th1-type immunity compared to WT mice. Interestingly, STAT6-/- mice with impaired Th2-type immunity showed tenascin-C expression levels similar to those of WT mice. The clearest difference between these two knockout strains in response to OVA was that STAT4-/- mice exhibited no upregulation of IFN-γ and TNF-α mRNA expression. Thus, tenascin-C expression was unexpectedly more related to Th1 type reactions. In vitro studies confirmed the results. Human fibroblasts stimulated by TNF-α and IFN-γ showed increased expression of tenascin-C. Patients with newly diagnosed asthma showed increased expression of laminin α2 in the bronchial BM in comparison to patients with asthma symptoms only and healthy controls. Both patients with asthma and those with only asthma symptoms showed increased expression of the laminin β2 chain in comparison to controls. Thus, laminin α2 expression differentiated patients with clinical asthma from patients with symptoms only. Furthermore, the expression of laminin α2 and β2 was associated with NSBHR, linking very specific remodelling events to clinical findings.

Identification of collagenolytic MMP networks as potential biomarkers in progressive chronic periodontitis subjects and MMP-8 null allele model

Chronic periodontitis results from a complex aetiology, including the formation of a subgingival biofilm and the elicitation of the host s immune and inflammatory response. The hallmark of chronic periodontitis is alveolar bone loss and soft periodontal tissue destruction. Evidence supports that periodontitis progresses in dynamic states of exacerbation and remission or quiescence. The major clinical approach to identify disease progression is the tolerance method, based on sequential probing. Collagen degradation is one of the key events in periodontal destructive lesions. Matrix metalloproteinase (MMP)-8 and MMP-13 are the primary collagenolytic MMPs that are associated with the severity of periodontal inflammation and disease, either by a direct breakdown of the collagenised matrix or by the processing of non-matrix bioactive substrates. Despite the numerous host mediators that have been proposed as potential biomarkers for chronic periodontitis, they reflect inflammation rather than the loss of periodontal attachment. The aim of the present study was to determine the key molecular MMP-8 and -13 interactions in gingival crevicular fluid (GCF) and gingival tissue from progressive periodontitis lesions and MMP-8 null allele mouse model. In study (I), GCF and gingival biopsies from active and inactive sites of chronic periodontitis patients, which were determined clinically by the tolerance method, and healthy GCF were analysed for MMP-13 and tissue inhibitor of matrix metalloproteinases (TIMP)-1. Chronic periodontitis was characterised by increased MMP-13 levels and the active sites showed a tendency of decreased TIMP-1 levels associated with increments of MMP-13 and total protein concentration compared to inactive sites. In study (II), we investigated whether MMP-13 activity was associated with TIMP-1, bone collagen breakdown through ICTP levels, as well as the activation rate of MMP-9 in destructive lesions. The active sites demonstrated increased GCF ICTP levels as well as lowered TIMP-1 detection along with elevated MMP-13 activity. MMP-9 activation rate was enhanced by MMP-13 in diseased gingival tissue. In study (III), we analysed the potential association between the levels, molecular forms, isoenzyme distribution and degree of activation of MMP-8, MMP-14, MPO and the inhibitor TIMP-1 in GCF from periodontitis progressive patients at baseline and after periodontal therapy. A positive correlation was found for MPO/MMP-8 and their levels associated with progression episodes and treatment response. Because MMP-8 is activated by hypochlorous acid in vitro, our results suggested an interaction between the MPO oxidative pathway and MMP-8 activation in GCF. Finally, in study (IV), on the basis of the previous finding that MMP-8-deficient mice showed impaired neutrophil responses and severe alveolar bone loss, we aimed to characterise the detection patterns of LIX/CXCL5, SDF-1/CXCL12 and RANKL in P. gingivalis-induced experimental periodontitis and in the MMP-8-/- murine model. The detection of neutrophil-chemoattractant LIX/CXCL5 was restricted to the oral-periodontal interface and its levels were reduced in infected MMP-8 null mice vs. wild type mice, whereas the detection of SDF-1/CXCL12 and RANKL in periodontal tissues increased in experimentally-induced periodontitis, irrespectively from the genotype. Accordingly, MMP-8 might regulate LIX/CXCL5 levels by undetermined mechanisms, and SDF-1/CXCL12 and RANKL might promote the development and/or progression of periodontitis.

Organophotocatalysis in nanostructured soft gel materials as tunable reaction vessels: comparison with homogeneous and micellar solutions

Riboflavin tetraacetate-catalyzed aerobic photooxidation of 1-(4-methoxyphenyl)ethanol was investigated as a model reaction under blue visible light in different soft gel materials, aiming to establish their potential as reaction vessels for photochemical transformations. Three strategies involving different degrees of organization of the catalyst within the gel network were explored, and the results compared to those obtained in homogeneous and micellar solutions. In general, physical entrapment of both the catalyst and the substrate under optimized concentrations into several hydrogel matrices (including low-molecular-weight and biopolymer-based gels) allowed the photooxidation with conversions between 55 and 100% within 120 min (TOF similar to 0.045-0.08 min(-1); k(obs) similar to 0.011-0.028 min(-1)), albeit with first-order rates ca. 1-3-fold lower than in solution under comparable non-stirred conditions. Remarkably, the organogel made of a cyclohexane-based bisamide gelator in CH3CN not only prevented the photodegradation of the catalyst but also afforded full conversion in less than 60 min (TOF similar to 0.167 min(-1); k(obs) similar to 0.073 min(-1)) without the need of additional proton transfer mediators (e. g., thiourea) as it occurs in CH3CN solutions. In general, the gelators could be recycled without detriment to their gelation ability and reaction rates. Moreover, kinetics could be fine-tuned according to the characteristics of the gel media. For instance, entangled fibrillar networks with relatively high mechanical strength were usually associated with lower reaction rates, whereas wrinkled laminated morphologies seemed to favor the reaction. In addition, the kinetics results showed in most cases a good correlation with the aeration efficiency of the gel media.

Sex and physiological state influence the rate of resource acquisition and monopolisation in urban free-ranging dogs, Canis familiaris

In animal populations, the constraints of energy and time can cause intraspecific variation in foraging behaviour. The proximate developmental mediators of such variation are often the mechanisms underlying perception and associative learning. Here, experience-dependent changes in foraging behaviour and their consequences were investigated in an urban population of free-ranging dogs, Canis familiaris by continually challenging them with the task of food extraction from specially crafted packets. Typically, males and pregnant/lactating (PL) females extracted food using the sophisticated `gap widening' technique, whereas non-pregnant/non-lactating (NPNL) females, the relatively underdeveloped `rip opening' technique. In contrast to most males and PL females (and a few NPNL females) that repeatedly used the gap widening technique and improved their performance in food extraction with experience, most NPNL females (and a few males and PL females) non-preferentially used the two extraction techniques and did not improve over successive trials. Furthermore, the ability of dogs to sophisticatedly extract food was positively related to their ability to improve their performance with experience. Collectively, these findings demonstrate that factors such as sex and physiological state can cause differences among individuals in the likelihood of learning new information and hence, in the rate of resource acquisition and monopolization.

The Modified Selenenyl Amide, M-hydroxy Ebselen, Attenuates Diabetic Nephropathy and Diabetes-Associated Atherosclerosis in ApoE/GPx1 Double Knockout Mice

Seleno-organic glutathione peroxidase (GPx) mimetics, including ebselen (Eb), have been tested in in vitro studies for their ability to scavenge reactive oxygen and nitrogen species, including hydrogen peroxide and peroxynitrite. In this study, we investigated the efficacies of two Eb analogues, m-hydroxy ebselen (ME) and ethanol-ebselen (EtE) and compared these with Eb in cell based assays. We found that ME is superior in attenuating the activation of hydrogen peroxide-induced pro-inflammatory mediators, ERK and P38 in human aortic endothelial cells. Consequently, we investigated the effects of ME in an in vivo model of diabetes, the ApoE/GPx1 double knockout (dKO) mouse. We found that ME attenuates plaque formation in the aorta and lesion deposition within the aortic sinus of diabetic dKO mice. Oxidative stress as assessed by 8-OHdG in urine and nitrotyrosine immunostaining in the aortic sinus and kidney tubules, was reduced by ME in diabetic dKO mice. ME also attenuated diabetes-associated renal injury which included tubulointerstitial fibrosis and glomerulosclerosis. Furthermore, the bioactivity of the pro-fibrotic cytokine transforming growth factor-beta (TGF-beta) as assessed by phospho-Smad2/3 immunostaining was attenuated after treatment with ME. TGF-beta-stimulated increases in collagen I and IV gene expression and protein levels were attenuated by ME in rat kidney tubular cells. However, in contrast to the superior activity of ME in in vitro and cell based assays, ME did not further augment the attenuation of diabetes-associated atherosclerosis and renal injury in our in vivo model when compared with Eb. In conclusion, this study strengthens the notion that bolstering GPx-like activity using synthetic mimetics may be a useful therapeutic strategy in lessening the burden of diabetic complications. However, these studies highlight the importance of in vivo analyses to test the efficacies of novel Eb analogues, as in vitro and cell based assays are only partly predictive of the in vivo situation.

Common recognition principles across diverse sequence and structural families of sialic acid binding proteins

Sialic acids form a large family of 9-carbon monosaccharides and are integral components of glycoconjugates. They are known to bind to a wide range of receptors belonging to diverse sequence families and fold classes and are key mediators in a plethora of cellular processes. Thus, it is of great interest to understand the features that give rise to such a recognition capability. Structural analyses using a non-redundant data set of known sialic acid binding proteins was carried out, which included exhaustive binding site comparisons and site alignments using in-house algorithms, followed by clustering and tree computation, which has led to derivation of sialic acid recognition principles. Although the proteins in the data set belong to several sequence and structure families, their binding sites could be grouped into only six types. Structural comparison of the binding sites indicates that all sites contain one or more different combinations of key structural features over a common scaffold. The six binding site types thus serve as structural motifs for recognizing sialic acid. Scanning the motifs against a non-redundant set of binding sites from PDB indicated the motifs to be specific for sialic acid recognition. Knowledge of determinants obtained from this study will be useful for detecting function in unknown proteins. As an example analysis, a genome-wide scan for the motifs in structures of Mycobacterium tuberculosis proteome identified 17 hits that contain combinations of the features, suggesting a possible function of sialic acid binding by these proteins.

Novel multimeric IL-1 receptor antagonist for the treatment of rheumatoid arthritis

Protein therapeutics targeting inflammatory mediators have shown great promise for the treatment of autoimmunities such as rheumatoid arthritis (RA). However, a significant challenge in this area has been their low in vivo stability and consequently their severely compromised therapeutic efficacy. One such therapeutic molecule IL-1 receptor antagonist (IL-1ra), used in the treatment of rheumatoid arthritis, has displayed only modest efficacy in human clinical trials owing to its short biological half-life. Herein, we report a novel approach to conglomerate individual protein entities into a drug depot by incorporation of an amyloidogenic motif Lys-Phe-Phe-Glu (KFFE) thereby dramatically improving their systemic persistence and in turn their therapeutic efficacy in a mice model of autoimmune arthritis. (C) 2014 Elsevier Ltd. All rights reserved.

Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology

Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific staphylococcal exotoxins in tissue pathology associated with severe pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing pneumonia or lung empyema, or to purified toxins. The necrotizing pneumonia strains secreted high levels of alpha-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of alpha-toxin, and triggered limited tissue damage. alpha-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure alpha-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of alpha-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with staphylococcal pneumonia revealed that strains producing high levels of alpha-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against alpha-toxin and PVL. This study introduces a novel model system for study of staphylococcal pneumonia in a human setting. The results reveal that the combination and levels of alpha-toxin and PVL correlate with tissue pathology and clinical outcome associated with pneumonia.

Sonic hedgehog-responsive lipoxygenases and cyclooxygenase-2 modulate Dectin-1-induced inflammatory cytokines

Immune responses during fungal infections are predominately mediated by 5/15-lipoxygenases (LO)-or cyclooxygenase (COX)-2-catalysed bioactive eicosanoid metabolites like leukotrienes, lipoxins and prostaglandins. Although few host mediators of fungi-triggered eicosanoid production have been established, the molecular mechanism of expression and regulation of 5-LO, 15-LO and COX-2 are not well-defined. Here, we demonstrate that, macrophages infected with representative fungi Candida albicans, Aspergillus flavus or Aspergillus fumigatus or those treated with Curdlan, a selective agonist of pattern recognition receptor for fungi Dectin-1, displays increased expression of 5-LO, 15-LO and COX-2. Interestingly, Dectin-1-responsive Syk pathway activates mTOR-sonic hedgehog (SHH) signaling cascade to stimulate the expression of these lipid metabolizing enzymes. Loss-of-function analysis of the identified intermediaries indicates that while Syk-mTOR-SHH pathway-induced 5-LO and 15-LO suppressed the Dectin-l-responsive pro-inflammatory signature cytokines like TNE-alpha, IL-1 beta and IL-12, Syk-mTOR-SHH-induced COX-2 positively regulated these cytokines. Dectin-1-stimulated IL-6, however, is dependent on 5-LO, 15-LO and COX-2 activity. Together, the current study establishes Dectin-1-arbitrated host mediators that direct the differential regulation of immune responses during fungal infections and thus are potential candidates of therapeutic intervention. (C) 2015 Elsevier Ltd. All rights reserved.

Prognostic Role of Host Cyclooxygenase and Cytokine Genotypes in a Caucasian Cohort of Patients with Gastric Adenocarcinoma

11 p.