Proteomics reveals distinct mechanisms regulating the release of cytokines and alarmins during pyroptosis

A major pathway for proinflammatory protein release by macrophages is inflammasome-mediated pyroptotic cell death. As conventional secretion, unconventional secretion, and cell death are executed simultaneously, however, the cellular mechanisms regulating this complex paracrine program remain incompletely understood. Here, we devise a quantitative proteomics strategy to define the cellular exit route for each protein by pharmacological and genetic dissection of cellular checkpoints regulating protein release. We report the release of hundreds of proteins during pyroptosis, predominantly due to cell lysis. They comprise constitutively expressed and transcriptionally induced proteins derived from the cytoplasm and specific intracellular organelles. Many low-molecular-weight proteins including the cytokine interleukin-1b, alarmins, and lysosomal-cargo proteins exit cells in the absence of cell lysis. Cytokines and alarmins are released in an endoplasmic reticulum (ER)-Golgi-dependent manner as free proteins rather than by extracellular vesicles. Our work provides an experimental framework for the dissection of cellular exit pathways and a resource for pyroptotic protein release

Persistent depression affects adherence to secondary prevention behaviors after acute coronary syndromes

Background: The persistence of depressive symptoms after hospitalization is a strong risk factor for mortality after acute coronary syndromes (ACS). Poor adherence to secondary prevention behaviors may be a mediator of the relationship between depression and increased mortality. Objective: To determine whether rates of adherence to risk reducing behaviors were affected by depressive status during hospitalization and 3 months later. Design: Prospective observational cohort study. Setting: Three university hospitals. Participants: Five hundred and sixty patients were enrolled within 7 days after ACS. Of these, 492 (88%) patients completed 3-month follow-up. Measurements: We used the Beck Depression Inventory (BDI) to assess depressive symptoms in the hospital and 3 months after discharge. We assessed adherence to 5 risk-reducing behaviors by patient self-report at 3 months. We used χ2 analysis to compare differences in adherence among 3 groups: persistently nondepressed (BDI<10 at hospitalization and 3 months); remittent depressed (BDI ≥10 at hospitalization; <10 at 3 months); and persistently depressed patients (BDI ≥10 at hospitalization and 3 months). Results: Compared with persistently nondepressed, persistently depressed patients reported lower rates of adherence to quitting smoking (adjusted odds ratio [OR] 0.23, 95% confidence interval [95% CI] 0.05 to 0.97), taking medications (adjusted OR 0.50, 95% CI 0.27 to 0.95), exercising (adjusted OR 0.57, 95% CI 0.34 to 0.95), and attending cardiac rehabilitation (adjusted OR 0.5, 95% CI 0.27 to 0.91). There were no significant differences between remittent depressed and persistently nondepressed patients. Conclusions: Persistently depressed patients were less likely to adhere to behaviors that reduce the risk of recurrent ACS. Differences in adherence to these behaviors may explain in part why depression predicts mortality after ACS. Key Words: cardiovascular diseases, depression, medication adherence, prevention, self car

Long-term Outcomes of Enhanced Depression Treatment in Patients with Acute Coronary Syndromes

Background: The Coronary Psychosocial Evaluation Studies trial demonstrated promising results for enhanced depression treatment to reduce cardiovascular risk of patients with acute coronary syndrome and comorbid depression, but the long-term effectiveness of this intervention is unclear. Methods: A total of 157 participants with persistent depression after hospitalization for acute coronary syndromes were enrolled in the Coronary Psychosocial Evaluation Studies trial. A total of 80 participants were allocated to 6 months of enhanced depression treatment, and 77 participants were allocated to usual care. We report on an additional 12 months of observational follow-up for the composite outcome of death or first hospitalization for myocardial infarction or unstable angina. Results: Although the intervention was previously shown to have favorable cardiovascular effects during the treatment period, we observed a significant time-by-treatment group interaction during extended follow-up (P = .008). Specifically, during the 6-month treatment period, death or hospitalization for myocardial infarction/unstable angina occurred in 3 participants (4%) in the treatment group compared with 11 participants (14%) in the usual care group (hazard ratio, 0.25; 95% confidence interval, 0.07-0.90; P = .03). In contrast, during 12 months of additional observational follow-up, 11 participants (14%) in the treatment group experienced the composite outcome of death or hospitalization for myocardial infarction/unstable angina compared with 3 participants (4%) in the usual care group (hazard ratio, 2.91; 95% confidence interval, 0.80-10.56; P = .10). Conclusions: Enhanced depression treatment was associated with a reduced risk of death or hospitalization for myocardial infarction/unstable angina during active treatment, but this effect did not persist after treatment ceased. Future research is needed to confirm our findings and to determine the optimal duration of depression treatment in patients with depression after acute coronary syndromes

Interferon β-1a in relapsing multiple sclerosis: four-year extension of the European IFNβ-1a Dose-C omparison Study

Background: Multiple sclerosis (MS) is a chronic disease requiring long-term monitoring of treatment. Objective: To assess the four-year clinical efficacy of intramuscular (IM) IFNb-1a in patients with relapsing MS from the European IFNb-1a Dose-C omparison Study. Methods: Patients who completed 36 months of treatment (Part 1) of the European IFNb-1a Dose-C omparison Study were given the option to continue double-blind treatment with IFNb-1a 30 mcg or 60 mcg IM once weekly (Part 2). Analyses of 48-month data were performed on sustained disability progression, relapses, and neutralizing antibody (NA b) formation. Results: O f 608/802 subjects who completed 36 months of treatment, 493 subjects continued treatment and 446 completed 48 months of treatment and follow-up. IFNb-1a 30 mcg and 60 mcg IM once weekly were equally effective for up to 48 months. There were no significant differences between doses over 48 months on any of the clinical endpoints, including rate of disability progression, cumulative percentage of patients who progressed (48 and 43, respectively), and annual relapse rates; relapses tended to decrease over 48 months. The incidence of patients who were positive for NAbs at any time during the study was low in both treatment groups. Conclusion: C ompared with 60-mcg IM IFNb-1a once weekly, a dose of 30 mcg IM IFNb-1a once weekly maintains the same clinical efficacy over four years

Dimensions of professional competences for interventions towards sustainability

This paper investigates sustainability competences through the eyes of professional practitioners in the field of sustainability and presents empirical data that have been created using an action research approach. The design of the study consists of two workshops, in which professional practitioners in interaction with each other and the facilitators are invited to explore and reflect on the specific knowledge, skills, attitudes and behaviours necessary to conduct change processes successfully towards sustainability in a variety of business and professional contexts. The research focuses on the competences associated with these change processes to devise, propose and conduct appropriate interventions that address sustainability issues. Labelled ‘intervention competence’, this ability comprises an interlocking set of knowledge, skills, attitudes and behaviours that include: appreciating the importance of (trying to) reaching decisions or interventions; being able to learn from lived experience of practice and to connect such learning to one’s own scientific knowledge; being able to engage in political-strategic thinking, deliberations and actions, related to different perspectives; the ability for showing goal-oriented, adequate action; adopting and communicating ethical practices during the intervention process; being able to cope with the degree of complexity, and finally being able to translate stakeholder diversity into collectively produced interventions (actions) towards sustainability. Moreover, this competence has to be practised in contexts of competing values, non-technical interests and power relations. The article concludes with recommendations for future research and practice

Cellular and humoral immune responses and protection against schistosomes induced by a radiation-attenuated vaccine in chimpanzees

The radiation-attenuated Schistosoma mansoni vaccine is highly effective in rodents and primates but has never been tested in humans, primarily for safety reasons. To strengthen its status as a paradigm for a human recombinant antigen vaccine, we have undertaken a small-scale vaccination and challenge experiment in chimpanzees (Pan troglodytes). Immunological, clinical, and parasitological parameters were measured in three animals after multiple vaccinations, together with three controls, during the acute and chronic stages of challenge infection up to chemotherapeutic cure. Vaccination induced a strong in vitro proliferative response and early gamma interferon production, but type 2 cytokines were dominant by the time of challenge. The controls showed little response to challenge infection before the acute stage of the disease, initiated by egg deposition. In contrast, the responses of vaccinated animals were muted throughout the challenge period. Vaccination also induced parasite-specific immunoglobulin M (IgM) and IgG, which reached high levels at the time of challenge, while in control animals levels did not rise markedly before egg deposition. The protective effects of vaccination were manifested as an amelioration of acute disease and overall morbidity, revealed by differences in gamma-glutamyl transferase level, leukocytosis, eosinophilia, and hematocrit. Moreover, vaccinated chimpanzees had a 46% lower level of circulating cathodic antigen and a 38% reduction in fecal egg output, compared to controls, during the chronic phase of infection