A vasculature niche orchestrates stromal cell phenotype through PDGF signaling: Importance in human fibrotic disease.

SignificanceTissue fibrotic diseases, for example of the liver and lung, represent a huge unmet medical need. In this study, using single-cell RNA sequencing, cytometry by time of flight (CyTOF), tissue imaging, and functional assays, we identify a complex vascular niche in Dupuytren's disease (DD), a common localized fibrotic condition of the palm, where early-disease-stage tissue can be accessed readily. We uncover a population of myofibroblast precursors within the pericyte compartment and demonstrate that the endothelium instructs the differentiation of functionally distinct stromal cells, thereby orchestrating discrete microenvironments in the fibrotic milieu. Together, these findings provide a basis for the concept of targeting blood vessel signaling to control the progression of human fibrosis.

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300.

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren's disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1 Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren's nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

The JAK inhibitor baricitinib inhibits oncostatin M induction of proinflammatory mediators in ex-vivo synovial derived cells.

OBJECTIVES: To investigate the ex vivo effect of the JAK1/2 inhibitor baricitinib on expression of pro-inflammatory mediators in rheumatoid arthritis (RA) fibroblast like synoviocytes (FLS) stimulated with TNFα, IL-1ß and oncostatin M (OSM), and in RA synovial membrane cells (SMCs). METHODS: RA and osteoarthritis (OA) SMCs, were isolated from arthroplasty specimens of RA (n=8) and OA (n=8) patients, respectively, using enzymatic digestion followed by cell propagation to obtain RA (n=5) and OA (n=3) FLS. Normal FLS and normal human foreskin fibroblasts (HSF) were purchased from commercial sources. Fibroblasts were stimulated with cytokines with or without baricitinib. RA SMCs were cultured in the presence of baricitinib without stimulation. JAK/STAT activation and levels of mRNA and proteins of the various inflammatory cytokines (IL-6, IL-8, MCP-1, RANTES and IP-10) were determined by qPCR, ELISA and MSD. RESULTS: Baricitinib inhibited OSM-induced JAK signalling in RA synovial fibroblasts and effectively suppressed subsequent expression of the proinflammatory mediators IL-6, MCP-1 and IP-10. However, baricitinib was not effective in altering levels of spontaneously released TNFα, IL-6 and IL-8 in RA SMC. Although both TNFα and IL-1ß signal independently of the JAK/STAT pathway, in HSF, but not in RA FLS, baricitinib significantly inhibited TNFα- and IL-1ß-induced MCP-1 and IP-10 protein levels in a dose dependent manner. Furthermore, baricitinib did not inhibit TNFα- and IL-1ß-induced expression of IL-6, IL-8 and MCP-1 in RA FLS. CONCLUSIONS: These findings are consistent with known signalling pathways employed by OSM, TNFα and IL-1ß, but our data suggest that in HSF, baricitinib may have anti-inflammatory effects via downstream modulation of cytokines and chemokines produced in response to TNFα or IL-1ß.

COVID-19 vaccine hesitancy among health and social care workers during mass vaccination in Scotland.

Health and social care workers (HSCWs) have an essential role in the uptake of the COVID-19 vaccine. Vaccination is an emotionally charged issue and perceptions of risk associated with COVID19 can contribute towards vaccine hesitancy (VH). The aim of this study was to explore the role of emotion and risk perception associated with HSCWs' uptake of the COVID-19 vaccine during the initial mass roll-out of the vaccine in Scotland. A cross-sectional online survey with a correlational design was used. An online survey was conducted with HSCWs (N = 1189) aged 18 to 67 years (M = 44.09 yrs, SD = 11.48) working in Scotland during the third lockdown period (26 December - 31 March 2021) of the COVID-19 pandemic. The survey collected data relating to sociodemographic characteristics, vaccine uptake and VH, emotions associated with the COVID-19 vaccine, and risk perception. Open-ended free text data were also collected on HSCWs' main reasons for VH. Most participants (83.96%) felt positively about the roll-out of the COVID-19 vaccine, stating it would be beneficial for themselves and others to receive it. Nonetheless, 16.04% of HSCWs expressed VH. Occupational group, age, gender and risk perceptions did not affect variance in VH, but positive emotions associated with the COVID-19 vaccine and years of experience did. We emphasise the importance of future interventions to increase COVID-19 vaccine uptake by enhancing positive emotions and reducing ambivalent emotions associated with the COVID-19 vaccine particularly among less experienced HSCWs.

TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis.

The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease status in rheumatoid arthritis (RA), ankylosing spondylitis (AS), and in experimental arthritis. TLR gene expression was measured in whole blood and monocytes, before and after TNF blockade. In RA and osteoarthritis synovia, the expression of TLRs was quantified by standard curve qPCR. In addition, four distinct stages of disease were defined and validated in collagen-induced arthritis (CIA), the gold standard animal model for RA - pre-onset, early disease, late disease and immunised mice that were resistant to the development of disease. TLR expression was measured in spleens, lymph nodes, blood cells, liver and the paws (inflamed and unaffected). In RA whole blood, the expression of TLR1, 4 and 6 was significantly reduced by TNF blockade but the differences in TLR expression profiles between responders and non-responders were less pronounced than the differences between RA and AS patients. In RA non-responders, monocytes had greater TLR2 expression prior to therapy compared to responders. The expression of TLR1, 2, 4 and 8 was higher in RA synovium compared to control OA synovium. Circulating cytokine levels in CIA resistant mice were similar to naïve mice, but anti-collagen antibodies were similar to arthritic mice. Distinct profiles of inflammatory gene expression were mapped in paws and organs with differing disease status. TLR expression in arthritic paws tended to be similar in early and late disease, with TLR1 and 2 moderately higher in late disease. TLR expression in unaffected paws varied according to gene and disease status but was generally lower in resistant paws. Disease status-specific profiles of TLR expression were observed in spleens, lymph nodes, blood cells and the liver. Notably, TLR2 expression rose then fell in the transition from naïve to pre-onset to early arthritis. TLR gene expression profiles are strongly associated with disease status. In particular, increased expression in the blood precedes clinical manifestation.

Bruton's tyrosine kinase regulates TLR7/8-induced TNF transcription via nuclear factor-κB recruitment.

Tumour necrosis factor (TNF) is produced by primary human macrophages in response to stimulation by exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) via Toll-like receptor (TLR) signalling. However, uncontrolled TNF production can be deleterious and hence it is tightly controlled at multiple stages. We have previously shown that Bruton's tyrosine kinase (Btk) regulates TLR4-induced TNF production via p38 MAP Kinase by stabilising TNF messenger RNA. Using both gene over-expression and siRNA-mediated knockdown we have examined the role of Btk in TLR7/8 mediated TNF production. Our data shows that Btk acts in the TLR7/8 pathway and mediates Ser-536 phosphorylation of p65 RelA and subsequent nuclear entry in primary human macrophages. These data show an important role for Btk in TLR7/8 mediated TNF production and reveal distinct differences for Btk in TLR4 versus TLR7/8 signalling.

Effectiveness of interventions to improve the public's antimicrobial resistance awareness and behaviours associated with prudent use of antimicrobials: a systematic review.

Background: A global antimicrobial resistance (AMR) awareness intervention targeting the general public has been prioritized. Objectives: To evaluate the effectiveness of interventions that aim to change AMR awareness and subsequent stewardship behaviours amongst the public. Methods: Five databases were searched between 2000 and 2016 for interventions to change the public's AMR awareness and/or antimicrobial stewardship behaviours. Study designs meeting the Cochrane Effective Practice and Organization of Care (EPOC) criteria, non-controlled before-and-after studies and prospective cohort studies were considered eligible. Participants recruited from healthcare settings and studies measuring stewardship behaviours of healthcare professionals were excluded. Quality of studies was assessed using EPOC risk of bias criteria. Data were extracted and synthesized narratively. Registration: PROSPERO international prospective register of systematic reviews (PROSPERO 2016: CRD42016050343). Results: Twenty studies were included in the review with nine meeting the EPOC criteria. The overall risk of bias was high. Nineteen studies were conducted in high-income countries. Mass media interventions were most common (n = 7), followed by school-based (n = 6) and printed material interventions (n = 6). Seventeen studies demonstrated a significant effect on changing knowledge, attitudes or the public's antimicrobial stewardship behaviours. Analysis showed that interventions targeting schoolchildren and parents have notable potential, but for the general public the picture is less clear. Conclusions: Our work provides an in-depth examination of the effectiveness of AMR interventions for the public. However, the studies were heterogeneous and the quality of evidence was poor. Well-designed, experimental studies on behavioural outcomes of such interventions are required.

The Impact of Alexithymia on Desire for Alcohol during a Social Stress Test.

BACKGROUND: Alexithymia is a personality construct comprising difficulty in identifying and describing emotions and externally oriented thinking. Its role in heavy and problematic alcohol consumption is well documented, together with its relationship with social stress. However, little research has examined whether social stress has any effect on desire for alcohol among alexithymic individuals. OBJECTIVES: In this experimental study, we explored the relationship between alexithymia and desire for alcohol in response to an experimental social stressor. METHODS: One hundred and thirty eight social drinkers completed the Toronto Alexithymia Scale, self-report measures of alcohol consumption and a stress-inducing task. Desire for alcohol was measured at three time points: baseline, stressor and recovery. RESULTS: Correlation analysis demonstrated that alexithymia was associated with significantly higher rates of alcohol consumption and higher levels of desire for alcohol. Mixed measures ANOVA demonstrated a significant main effect of alexithymia and a significant group by time effect of alexithymia on desire for alcohol. Conclusions/Importance: The findings demonstrate increased desire for alcohol before, during and after a social stressor among alexithymic participants. These findings offer an insight into the relationship between alexithymia, social stress and alcohol consumption.

The effects of perceived social norms on handwashing behaviour in students.

Handwashing is widely considered the most effective method of preventing the spread of infectious illness. Exploring the determinants of handwashing is vital to the development of interventions to increase this behaviour. A survey based on Social Norms Theory assessed handwashing frequency and perceptions of peer handwashing in 255 university students. Participants reported their own handwashing frequency, and how often they thought their peers washed their hands in particular circumstances, to determine whether misperceptions around handwashing exist, and whether these influence the behaviour of individuals. Gender was found to be a significant determinant of handwashing frequency as females reported washing their hands significantly more often than males. Participants also believed they washed their hands significantly more frequently than their peers. Perceived peer handwashing frequency was significantly correlated with participants' own behaviour. This effect was seen in overall handwashing and in food, waste and illness-related hand washing. These results suggest perceived social norms around hand washing have a clear association with individual behaviour. Future research might test the effectiveness of a social norms intervention in other settings which carry an increased risk of infection spread.

Assessing the impact of autonomous motivation and psychological need satisfaction in explaining adherence to an exercise referral scheme.

Given the mixed findings concerning self-determination theory in explaining adherence to exercise referral schemes (ERS), the present study attempted to examine whether autonomous motivation and psychological need satisfaction could predict ERS adherence. Participants referred to an 8-week ERS completed self-report measures grounded in self-determination theory and basic needs theory at baseline (N = 124), mid-scheme (N = 58), and at the end of the scheme (N = 40). Logistic regressions were used to analyse the data. Autonomous motivation measured at mid-scheme explained between 12 and 16% of the variance in ERS adherence. Autonomy, relatedness and competence measured at mid-scheme explained between 18 and 26% of the variance in ERS adherence. This model also explained between 18 and 25% when measured at the end of the scheme. The study found limited evidence for the role of autonomous motivation in explaining ERS adherence. Stronger support was found for the satisfaction of the three needs for autonomy, relatedness and competence in predicting ERS adherence. Future research should tap into the satisfaction of all three needs collectively to help foster ERS adherence.

Aspiration, but not injection, decreases cultured equine mesenchymal stromal cell viability.

BACKGROUND: Recently, equine multipotent mesenchymal stromal cells (MSC) have received significant attention as therapy for various conditions due to their proposed regenerative and immune-modulating capacity. MSC are commonly administered to the patient through a hypodermic needle. Currently, little information is available on the effect of such injection has on equine MSC immediate and delayed viability. We hypothesize that viability of equine MSC is not correlated with needle diameter during aspiration and injection. RESULTS: Using a 3 mL syringe, manual injection of equine cord blood (CB) or bone marrow-derived (BM) MSC with no needle and needles ranging in size from 18 to 30 Ga did not affect immediate MSC viability. Similarly, 24 h post-injection, MSC delayed viability was not different between any of the tested needles as determined by a resazurin-based proliferation assay. Using a 3 mL syringe, aspiration of MSC through 20, 25, and 30 Ga needles resulted in significant decreases in immediate viability with no change in delayed viability when compared to aspiration without a needle. BM- and CB-MSC were observed to be of similar size with a diameter ± SD of 19.8 ± 2.7 and 20.4 ± 2.2 µm, respectively. In comparison, the smallest needles, (30 Ga) have an internal diameter of 160 µm. CONCLUSIONS: Following injection, needle diameter did not affect immediate or delayed viability of equine MSC. Following aspiration through needles sizes 20 Ga and smaller, immediate viability, but not delayed viability, decreased. As a result, an 18 Ga or larger needle should be utilized for aspiration of cell suspensions. In contrast, needle selection for MSC injection should be based on clinical preference and experience rather than concerns over decreasing MSC viability.

Spontaneous social distancing in response to a simulated epidemic: a virtual experiment.

BACKGROUND: Studies of social distancing during epidemics have found that the strength of the response can have a decisive impact on the outcome. In previous work we developed a model of social distancing driven by individuals' risk attitude, a parameter which determines the extent to which social contacts are reduced in response to a given infection level. We showed by simulation that a strong response, driven by a highly cautious risk attitude, can quickly suppress an epidemic. However, a moderately cautious risk attitude gives weak control and, by prolonging the epidemic without reducing its impact, may yield a worse outcome than doing nothing. In real societies, social distancing may arise spontaneously from individual choices rather than being imposed centrally. There is little data available about this as opportunistic data collection during epidemics is difficult. Our study uses a simulated epidemic in a computer game setting to measure the social distancing response. METHODS: Two hundred thirty participants played a computer game simulating an epidemic on a spatial network. The player controls one individual in a population of 2500 (with others controlled by computer) and decides how many others to contact each day. To mimic real-world trade-offs, the player is motivated to make contact by being rewarded with points, while simultaneously being deterred by the threat of infection. Participants completed a questionnaire regarding psychological measures of health protection motivation. Finally, simulations were used to compare the experimentally-observed response to epidemics with no response. RESULTS: Participants reduced contacts in response to infection in a manner consistent with our model of social distancing. The experimentally observed response was too weak to halt epidemics quickly, resulting in a somewhat reduced attack rate and a substantially reduced peak attack rate, but longer duration and fewer social contacts, compared to no response. Little correlation was observed between participants' risk attitudes and the psychological measures. CONCLUSIONS: Our cognitive model of social distancing matches responses to a simulated epidemic. If these responses indicate real world behaviour, spontaneous social distancing can be expected to reduce peak attack rates. However, additional measures are needed if it is important to stop an epidemic quickly.

Protection motivation theory and social distancing behaviour in response to a simulated infectious disease epidemic.

Epidemics of respiratory infectious disease remain one of the most serious health risks facing the population. Non-pharmaceutical interventions (e.g. hand-washing or wearing face masks) can have a significant impact on the course of an infectious disease epidemic. The current study investigated whether protection motivation theory (PMT) is a useful framework for understanding social distancing behaviour (i.e. the tendency to reduce social contacts) in response to a simulated infectious disease epidemic. There were 230 participants (109 males, 121 females, mean age 32.4 years) from the general population who completed self-report measures assessing the components of PMT. In addition, participants completed a computer game which simulated an infectious disease epidemic in order to provide a measure of social distancing behaviour. The regression analyses revealed that none of the PMT variables were significant predictors of social distancing behaviour during the simulation task. However, fear (ß = .218, p < .001), response efficacy (ß = .175, p < .01) and self-efficacy (ß = .251, p < .001) were all significant predictors of intention to engage in social distancing behaviour. Overall, the PMT variables (and demographic factors) explain 21.2% of the variance in intention. The findings demonstrated that PMT was a useful framework for understanding intention to engage in social distancing behaviour, but not actual behaviour during the simulated epidemic. These findings may reflect an intention-behaviour gap in relation to social distancing behaviour.

Production of TNF-α in macrophages activated by T cells, compared with lipopolysaccharide, uses distinct IL-10-dependent regulatory mechanism.

Previously, we demonstrated that spontaneous TNF-α production by macrophages in rheumatoid arthritis (RA) synovial tissue is largely driven by contact-dependent activation with T cells in that tissue. Whereas abundant IL-10 is present in these RA synovial cultures, it does not adequately control the production of TNF-α. In this study, we have compared the mechanisms involved in IL-10-mediated TNF-α regulation in LPS-stimulated macrophages with macrophages stimulated with activated T cells. We confirm that in LPS-stimulated macrophages the 3' enhancer region of tnf is essential for tnf transcription, and its regulation by IL-10 is dominated by a STAT3-dependent pathway. However, in contrast, we have found that tnf transcription in macrophages stimulated by activated T cells or by RA synovial T cells does not require the 3' enhancer region of tnf, and that its regulation by IL-10 is subsequently altered and clearly is not mediated by a dominant STAT3 pathway. These observations have very important implications for our understanding as to how IL-10 regulates TNF-α production at sites of chronic inflammation, such as the synovial tissue of patients with RA. Furthermore, these distinct IL-10 mechanisms will have bearing upon the identification of potential therapeutic targets in RA synovial macrophages where the activation stimulus is clearly not LPS.

A qualitative investigation into the role of illness perceptions in endometriosis-related quality of life.

Endometriosis is related to adverse quality of life (QoL) and wellbeing outcomes. The way in which endometriosis is perceived by individuals experiencing the condition has not been directly considered, yet illness perceptions (IPs) are predictors of QoL in several chronic conditions. This research aims to gain an understanding of the IPs held by individuals experiencing endometriosis and their impact on QoL. Semi-structured, one-to-one interviews with 30 UK-based participants sought to gain an understanding of participant experiences and perceptions linked to endometriosis. Three themes were constructed through reflexive thematic analysis: a life disrupted; lost sense of self; and complex emotional responses. Largely negative IPs were held by individuals experiencing endometriosis which, along with endometriosis-specific symptoms, fuelled fears for the future and reduced QoL. IP-based interventions may support the QoL of those experiencing endometriosis whilst effective treatment is sought.

Dupuytren's disease: a localised and accessible human fibrotic disorder.

We review the biology of Dupuytren's disease (DD), a common localised fibrotic disorder of the hand. The disease develops through a complex interplay of genetic and environmental factors, and epigenetic signalling. The early-stage disease nodules comprise a complex milieu of stromal and immune cells which interact to promote disease development. Recently, inhibition of tumour necrosis factor (TNF) locally resulted in softening and a decrease in nodule size, potentially controlling disease progression. Unlike fibrotic disorders of the visceral organs, the easy access to tissue in DD patients enables dissection of the cellular landscape and molecular signalling pathways. In addition, the study of DD may have wider benefits in enhancing our understanding of less-accessible fibrotic tissues.

A Pilot Study of Yoga with Incarcerated Youth Using the Prison Yoga Project Approach.

In recent decades, there has been more significant implementation and research of yoga programs in prisons and correctional facilities. Existing literature suggests that adult and juvenile prison-based yoga programs may improve stress-management and self-regulation skills; reduce depression, anxiety, aggression, and addictive behaviors; and increase prosocial behaviors. However, yoga in juvenile correctional facilities is still understudied compared to adult populations. The Prison Yoga Project (PYP) and Yoga FLAME (Focus, Letting go, Anger management, Mindfulness, and Exhaling negativity) are two frameworks used to structure the implementation of prison-based yoga programs among incarcerated adolescents. The present study aimed to describe trauma-related stress and self-regulation levels in a sample of incarcerated youth and to explore yoga's effects on developing stress-reduction skills. The study collected measures on overall and in-session stress reduction and baseline self-regulation. Because of the COVID-19 pandemic and public-safety restrictions, the present study was prematurely terminated after 5 months. Only pre-assessment measures were collected. Across time, participants reported a 38% mean stress reduction from the beginning to the end of a yoga session. Incarcerated youth with higher initial self-regulation levels showed higher pre- to post-session improvements in stress. The present findings provide valuable evidence that yoga practice using the combined PYP and FLAME framework can deliver practical benefits to juvenile correctional facilities. Furthermore, yoga may be used to foster rehabilitation, enhance skill development, and facilitate greater success in youth transitioning back into the community.

Barriers and enablers to influenza vaccination uptake in adults with chronic respiratory conditions: applying the behaviour change wheel to specify multi-levelled tailored intervention content.

OBJECTIVE: To specify intervention content to enhance influenza vaccination uptake among adults with chronic respiratory conditions using the Behaviour Change Wheel (BCW). DESIGN: Cross-sectional, multi-modal data collection and theory-informed analysis and expert stakeholder engagement. METHODS: Content analysis was used to identify barriers and enablers to influenza vaccination from nine focus groups (n = 38), individual interviews (n = 21) and open-ended survey responses (n = 101). The Theoretical Domains Framework (TDF) and the BCW were used to specify evidence-based and theoretically-informed recommendations. Expert stakeholders refined recommendations using the Acceptability, Practicability, Effectiveness, Affordability, Side-effects, and Equity (APEASE) criteria to yield a range of potentially actionable ideas. RESULTS: TDF analysis identified perceptions of vaccine side effects (beliefs about consequences [BACons]) was the most common barrier to vaccination, followed by time constraints (environmental context and resources [ECR]) and fear of needles (Emotion). Enablers included protection from influenza (BACons), receiving reminders (ECR) and support from others (Social Influences). These factors mapped to seven BCW intervention functions and 22 behaviour change techniques. CONCLUSIONS: Factors affecting vaccine uptake are multifaceted and multileveled. The study suggested a suite of complementary multi-level intervention components to enhance vaccination uptake involving a range of diverse actors, intervention recipients and settings.

Reactive oxygen species and p38 mitogen-activated protein kinase mediate tumor necrosis factor α-converting enzyme (TACE/ADAM-17) activation in primary human monocytes.

Tumor necrosis factor α-converting enzyme (TACE) is responsible for the shedding of cell surface TNF. Studies suggest that reactive oxygen species (ROS) mediate up-regulation of TACE activity by direct oxidization or modification of the protein. However, these investigations have been largely based upon nonphysiological stimulation of promonocytic cell lines which may respond and process TACE differently from primary cells. Furthermore, investigators have relied upon TACE substrate shedding as a surrogate for activity quantification. We addressed these concerns, employing a direct, cell-based fluorometric assay to investigate the regulation of TACE catalytic activity on freshly isolated primary human monocytes during LPS stimulation. We hypothesized that ROS mediate up-regulation of TACE activity indirectly, by activation of intracellular signaling pathways. LPS up-regulated TACE activity rapidly (within 30 min) without changing cell surface TACE expression. Scavenging of ROS or inhibiting their production by flavoprotein oxidoreductases significantly attenuated LPS-induced TACE activity up-regulation. Exogenous ROS (H(2)O(2)) also up-regulated TACE activity with similar kinetics and magnitude as LPS. H(2)O(2)- and LPS-induced TACE activity up-regulation were effectively abolished by a variety of selective p38 MAPK inhibitors. Activation of p38 was redox-sensitive as H(2)O(2) caused p38 phosphorylation, and ROS scavenging significantly reduced LPS-induced phospho-p38 expression. Inhibition of the p38 substrate, MAPK-activated protein kinase 2, completely attenuated TACE activity up-regulation, whereas inhibition of ERK had little effect. Lastly, inhibition of cell surface oxidoreductases prevented TACE activity up-regulation distal to p38 activation. In conclusion, our data indicate that in primary human monocytes, ROS mediate LPS-induced up-regulation of TACE activity indirectly through activation of the p38 signaling pathway.

Predicting psychological responses to influenza A, H1N1 ("swine flu"): the role of illness perceptions.

Previous research on H1N1 ("Swine flu") has demonstrated that although the public reported concern about H1N1, knowledge levels were low, as were reports of behavioural changes aimed at minimising the spread of H1N1. The current study had two main aims; (i) to ascertain levels of state anxiety and knowledge about H1N1, and (ii) to examine if illness perceptions predict anxiety about H1N1, perceived risk of contracting H1N1, and knowledge about H1N1. The study was cross-sectional in design, and involved 235 participants (100 males, 135 females, mean age 22.48 years) completing self-report measures of knowledge, anxiety, and perceived risk about H1N1, and illness perceptions (BIPQ). Analyses revealed low levels of knowledge about H1N1, 37.4% of participants could not identify any of the causes of H1N1. Correlation and multiple regression analyses demonstrated that illness perceptions were associated with responses to H1N1, with negative illness perceptions predicting state anxiety (ß = 0.498, p < 0.01) and perceived risk of contracting H1N1 (ß = 0.346, p < 0.01). In addition, females (M = 10.07, SD = 2.68) were found to have higher levels of knowledge about H1N1, compared to males (M = 8.29, SD = 2.65), t(233) = -5.08, p < 0.001. These findings suggest low levels of knowledge about the causes, symptoms and possible preventive measures associated with H1N1. In addition, the current study points to a key role for illness perceptions in predicting psychological responses to H1N1.