Regulation of neutrophilic inflammation by proteinase-activated receptor 1 during bacterial pulmonary infection

Neutrophils are key effector cells of the innate immune response to pathogenic bacteria, but excessive neutrophilic inflammation can be associated with bystander tissue damage. The mechanisms responsible for neutrophil recruitment to the lungs during bacterial pneumonia are poorly defined. In this study, we focus on the potential role of the major high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR-1), during the development of pneumonia to the common lung pathogen Streptococcus pneumoniae. Our studies demonstrate that neutrophils were indispensable for controlling S. pneumoniae outgrowth but contributed to alveolar barrier disruption. We further report that intra-alveolar coagulation (bronchoalveolar lavage fluid thrombin-antithrombin complex levels) and PAR-1 immunostaining were increased in this model of bacterial lung infection. Functional studies using the most clinically advanced PAR-1 antagonist, SCH530348, revealed a key contribution for PAR-1 signaling in influencing neutrophil recruitment to lung airspaces in response to both an invasive and noninvasive strain of S. pneumoniae (D39 and EF3030) but that PAR-1 antagonism did not impair the ability of the host to control bacterial outgrowth. PAR-1 antagonist treatment significantly decreased pulmonary levels of IL-1β, CXCL1, CCL2, and CCL7 and attenuated alveolar leak. Ab neutralization studies further demonstrated a nonredundant role for IL-1β, CXCL1, and CCL7 in mediating neutrophil recruitment in response to S. pneumoniae infection. Taken together, these data demonstrate a key role for PAR-1 during S. pneumoniae lung infection that is mediated, at least in part, by influencing multiple downstream inflammatory mediators

LMO2 and IL2RG synergize in thymocytes to mimic the evolution of SCID-X1 gene therapy-associated T-cell leukaemia

The SCID-X1 disease occurs in males that lack a functional X-linked gene encoding the interleukin 2 receptor subunit gamma (IL2RG) and thus are immuno-deficient (reviewed in Rochman et al.). Gene therapy has been a success in curing SCID-X1 in patients receiving autologous CD34+-bone marrow cells infected with retroviruses expressing IL2RG. This treatment protocol has, however, produced adverse T-cell effects where clonal T-cell leukaemias arose, and four have insertional mutagenesis of the T-cell oncogene LMO2. LMO2 is a T-cell oncogene first discovered via chromosomal translocations in T-cell acute leukaemia (T-ALL) (reviewed in Chambers and Rabbitts). It is unclear if the T-cell neoplasias in the SCID-X1 patients are simply due to insertional activation of the LMO2 gene or reflect synergy between LMO2 and IL2RG. Further, the recurrent involvement of LMO2 in SCID-X1 leukaemias is puzzling as other T-cell oncogenes (for example, TAL1/SCL, HOX11 and LYL1) might equally have been targets. This suggests that specific properties of LMO2 per se are required in these adverse events. The oncogenic potential of IL2RG itself also remains controversial. Although it causes T-cell lymphomas in mice transplanted with virally transduced haematopoetic stem cells, other studies have indicated that IL2RG is not an oncogene. Here we provide evidence that synergy is required between LMO2 and IL2RG proteins specifically in the T-cell lineage to elicit neoplasias and that additional mutations are required such as Notch1 mutations like those in human T-ALL

The ins and outs of participation in a weather information system

In this paper our aim is to show even though access to technology, information or data holds the potential for improved participation, participation is wired into a larger network of actors, artefacts and information practices. We draw on a case study of a weather information system developed and implemented by a non-profit organisation to both describe the configuration of participation, but also critically assess inclusion and exclusion. We present a set of four questions - a basic, practical toolkit - by which we together with the organisation made sense of and evaluated participation in the system

Depression and Prostate Cancer: Examining Comorbidity and Male-Specific Symptoms

© The Author(s) 2018. Depression in men with prostate cancer is a significant and complex issue that can challenge clinicians’ diagnostic efforts. The objective of the current study was to evaluate prototypic and male-specific depression symptoms and suicidal ideation in men with a diagnosis of prostate cancer relative to those with and without comorbidity. The Patient Health Questionnaire-9 (PHQ-9) and Male Depression Risk Scale-22 (MDRS-22) were completed online along with demographic and background variables by 100 men with a diagnosis of prostate cancer (n = 54 prostatectomy, n = 33 receiving active treatment). Hierarchical logistic regression was used to examine recent (past 2 weeks) suicide ideation. Over one-third of the sample (38%) reported a comorbidity, and this group had significantly higher total depression scores on the PHQ-9 (Cohen’s d = 0.65), MDRS-22 emotion suppression (d = 0.35), and drug use subscales (d = 0.38) compared to respondents without comorbidity. A total of 14% reported recent suicidal ideation, of which 71.4% of cases were identified by the PHQ-9 “moderate” cut-off, and 85.7% of cases were identified by the MDRS-22 “elevated” cut-off. After control variables, MDRS-22 subscales accounted for 45.1% of variance in recent suicidal ideation. While limited by the exclusive use of self-report data, findings point to the potential benefits of evaluating male-specific symptoms as part of depression and suicide risk screening in men with prostate cancer and the need to be mindful of the heightened risk for depression among men with prostate cancer who have comorbidity

The Anxiety Depression Pathway Among Men Following a Prostate Cancer Diagnosis: Cross-Sectional Interactions Between Anger Responses and Loneliness.

Anger has been a largely neglected emotion in prostate cancer research and intervention. This paper highlights the role of anger in the anxiety depression pathway among men with prostate cancer, and whether its impact is dependent on loneliness. Data are presented from a sample of men with prostate cancer (N = 105, M = 69.12 years, prostatectomy = 63.8%) and analysed using conditional process analysis. Dimensions of anger were evaluated as parallel mediators in bi-directional anxiety and depression pathways. Loneliness was evaluated as a conditional moderator of identified significant mediation relationships. Moderate severity depression (16.5%) was endorsed more frequently than moderate severity anxiety (8.6%, p = .008), with 19.1% of the sample reporting past two-week suicide ideation. Consistent with hypotheses, anger-related social interference (but not other dimensions of anger) significantly mediated the anxiety-depression pathway, but not the reverse depression-anxiety pathway. This indirect effect was conditional on men experiencing loneliness. Sensitivity analyses indicated the observed moderated mediation effect occurred for affective, but not somatic symptoms of depression. Findings support anger-related social interference (as opposed to anger frequency, intensity, duration or antagonism) as key to explaining the previously established anxiety-depression pathway. Results underscore the need for enhanced psychosocial supports for men with prostate cancer, with a particular focus on relational aspects. Supporting men with prostate cancer to adaptively process and manage their anger in ways that ameliorate negative social consequences will likely enhance their perceived social support quality, which may in turn better facilitate post-diagnosis recovery and emotional adjustment

Digital literacy linked to engagement and psychological benefits among breast cancer survivors in Internet-based peer support groups

© 2019 John Wiley & Sons Ltd Objective: Internet-based peer support groups (ISGs) represent an innovative, scalable approach to addressing information and support needs of cancer survivors. However, this innovation may not benefit survivors equally due to population variance in digital literacy. This study examined how digital literacy influences level of engagement in and psychological benefits from participating in ISGs for breast cancer (N = 183). Methods: Secondary analysis of data from a randomised trial of ISGs that included behavioural measures of engagement, subjective ratings and psychological distress symptoms. Results: Digital literacy was positively related to education level (p =.005). Relative to women with high digital literacy, those with lower digital literacy were more likely to report difficulties using the ISG and to value the user's guide and facilitator assistance (all p's <.05). Digital literacy was negatively correlated with computer anxiety pre-intervention, distress before and after online chat during the intervention and post-intervention depressive symptoms (all p's <.05). Conclusion: Low digital literacy is associated with computer anxiety and barriers to ISG use, as well as distress during and after ISG use. Digital literacy must be taken into account when designing or delivering innovative digital interventions for cancer survivors

Coronary heart disease in Indian Asians.

The Indian Asian population accounts for a fifth of all global deaths from coronary heart disease (CHD). CHD deaths on the Indian subcontinent have doubled since 1990, and are predicted to rise a further 50% by 2030. Reasons underlying the increased CHD mortality among Indian Asians remain unknown. Although conventional cardiovascular risk factors contribute to CHD in Indian Asians as in other populations, these do not account for their increased risk. Type-2 diabetes, insulin resistance and related metabolic disturbances are more prevalent amongst Indian Asians than Europeans, and have been proposed as major determinants of higher CHD risk among Indian Asians. However, this view is not supported by prospective data. Genome-wide association studies have not identified differences in allele frequencies or effect sizes in known loci to explain the increased CHD risk in Indian Asians. Limited knowledge of mechanisms underlying higher CHD risk amongst Indian Asians presents a major obstacle to reducing the burden of CHD in this population. Systems biology approaches such as genomics, epigenomics, metabolomics and transcriptomics, provide a non-biased approach for discovery of novel biomarkers and disease pathways underlying CHD. Incorporation of these omic approaches in prospective Indian Asian cohorts such as the London Life Sciences Population Study (LOLIPOP) provide an exciting opportunity for the identification of new risk factors underlying CHD in this high risk population

Extremely red radio galaxies

At least half the radio galaxies at z>1 in the 7C Redshift Survey have extremely red colours (R-K>5), consistent with stellar populations which formed at high redshift (z>5). We discuss the implications of this for the evolution of massive galaxies in general and for the fraction of near-IR-selected EROs which host AGN, a result which is now being tested by deep, hard X-ray surveys. The conclusion is that many massive galaxies undergo at least two active phases: one at z~5 when the black hole and stellar bulge formed and another at z~1-2 when activity is triggered by an event such as an interaction or merger.Comment: 6 pages, 2 figures, to appear in the proceedings of the workshop on "QSO hosts and their environments", IAA, Granada, 10-12 Jan 2001, Ed. I. Marque

Selecting Forecasting Methods

I examined six ways of selecting forecasting methods: Convenience, “what’s easy,” is inexpensive, but risky. Market popularity, “what others do,” sounds appealing but is unlikely to be of value because popularity and success may not be related and because it overlooks some methods. Structured judgment, “what experts advise,” which is to rate methods against prespecified criteria, is promising. Statistical criteria, “what should work,” are widely used and valuable, but risky if applied narrowly. Relative track records, “what has worked in this situation,” are expensive because they depend on conducting evaluation studies. Guidelines from prior research, “what works in this type of situation,” relies on published research and offers a low-cost, effective approach to selection. Using a systematic review of prior research, I developed a flow chart to guide forecasters in selecting among ten forecasting methods. Some key findings: Given enough data, quantitative methods are more accurate than judgmental methods. When large changes are expected, causal methods are more accurate than naive methods. Simple methods are preferable to complex methods; they are easier to understand, less expensive, and seldom less accurate. To select a judgmental method, determine whether there are large changes, frequent forecasts, conflicts among decision makers, and policy considerations. To select a quantitative method, consider the level of knowledge about relationships, the amount of change involved, the type of data, the need for policy analysis, and the extent of domain knowledge. When selection is difficult, combine forecasts from different methods