Pro-inflammatory monocyte phenotype and cell-specific steroid signaling alterations in unmedicated patients with major depressive disorder

Several lines of evidence have strongly implicated inflammatory processes in the pathobiology of major depressive disorder (MDD). However, the cellular origin of inflammatory signals and their specificity remain unclear. We examined the phenotype and glucocorticoid signaling in key cell populations of the innate immune system (monocytes) vs. adaptive immunity (T cells) in a sample of 35 well-characterized, antidepressant-free patients with MDD and 35 healthy controls individually matched for age, sex, smoking status and body mass index. Monocyte and T cell phenotype was assessed by flow cytometry. Cell-specific steroid signaling was determined by mRNA expression of pre-receptor regulation (11 beta-hydroxysteroid dehydrogenase type 1; 11 beta-HSD1), steroid receptor expression [glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)], and the downstream target glucocorticoid-induced leucine-zipper (GILZ). We also collected salivary cortisol samples (8:00 a.m. and 10:00 p.m.) on two consecutive days. Patients showed a shift toward a pro-inflammatory phenotype characterized by higher frequency and higher absolute numbers of non-classical monocytes. No group differences were observed in major T cell subset frequencies and phenotype. Correspondingly, gene expression indicative of steroid resistance (i.e., lower expression of GR and GILZ) in patients with MDD was specific to monocytes and not observed in T cells. Monocyte phenotype and steroid receptor expression was not related to cortisol levels or serum levels of IL-6, IL-1 beta, or TNF-alpha. Our results thus suggest that in MDD, cells of the innate and adaptive immune system are differentially affected with shifts in monocyte subsets and lower expression of steroid signaling related genes

Pro-inflammatory monocyte phenotype and cell-specific steroid signaling alterations in unmedicated patients with major depressive disorder

Several lines of evidence have strongly implicated inflammatory processes in the pathobiology of major depressive disorder (MDD). However, the cellular origin of inflammatory signals and their specificity remain unclear. We examined the phenotype and glucocorticoid signaling in key cell populations of the innate immune system (monocytes) vs. adaptive immunity (T cells) in a sample of 35 well-characterized, antidepressant-free patients with MDD and 35 healthy controls individually matched for age, sex, smoking status and body mass index. Monocyte and T cell phenotype was assessed by flow cytometry. Cell-specific steroid signaling was determined by mRNA expression of pre-receptor regulation (11 beta-hydroxysteroid dehydrogenase type 1; 11 beta-HSD1), steroid receptor expression [glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)], and the downstream target glucocorticoid-induced leucine-zipper (GILZ). We also collected salivary cortisol samples (8:00 a.m. and 10:00 p.m.) on two consecutive days. Patients showed a shift toward a pro-inflammatory phenotype characterized by higher frequency and higher absolute numbers of non-classical monocytes. No group differences were observed in major T cell subset frequencies and phenotype. Correspondingly, gene expression indicative of steroid resistance (i.e., lower expression of GR and GILZ) in patients with MDD was specific to monocytes and not observed in T cells. Monocyte phenotype and steroid receptor expression was not related to cortisol levels or serum levels of IL-6, IL-1 beta, or TNF-alpha. Our results thus suggest that in MDD, cells of the innate and adaptive immune system are differentially affected with shifts in monocyte subsets and lower expression of steroid signaling related genes

Pro-inflammatory Monocyte Phenotype and Cell-Specific Steroid Signaling Alterations in Unmedicated Patients With Major Depressive Disorder

Several lines of evidence have strongly implicated inflammatory processes in the pathobiology of major depressive disorder (MDD). However, the cellular origin of inflammatory signals and their specificity remain unclear. We examined the phenotype and glucocorticoid signaling in key cell populations of the innate immune system (monocytes) vs. adaptive immunity (T cells) in a sample of 35 well-characterized, antidepressant-free patients with MDD and 35 healthy controls individually matched for age, sex, smoking status and body mass index. Monocyte and T cell phenotype was assessed by flow cytometry. Cell-specific steroid signaling was determined by mRNA expression of pre-receptor regulation (11β-hydroxysteroid dehydrogenase type 1; 11β -HSD1), steroid receptor expression [glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)], and the downstream target glucocorticoid-induced leucine-zipper (GILZ). We also collected salivary cortisol samples (8:00 a.m. and 10:00 p.m.) on two consecutive days. Patients showed a shift toward a pro-inflammatory phenotype characterized by higher frequency and higher absolute numbers of non-classical monocytes. No group differences were observed in major T cell subset frequencies and phenotype. Correspondingly, gene expression indicative of steroid resistance (i.e., lower expression of GR and GILZ) in patients with MDD was specific to monocytes and not observed in T cells. Monocyte phenotype and steroid receptor expression was not related to cortisol levels or serum levels of IL-6, IL-1β, or TNF-α. Our results thus suggest that in MDD, cells of the innate and adaptive immune system are differentially affected with shifts in monocyte subsets and lower expression of steroid signaling related genes

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial

Introduction: Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity. Methods and analysis: This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-angstrom sberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients' self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12. Ethics and dissemination: This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences

Reduced mitochondrial respiration in T cells of patients with major depressive disorder

Converging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA (CPT1a) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology

The politics of evaluation: The case of cultural organizations

Cultural policy always means to decide how to spend money. This is a problem, as there are usually more useful options to use financial means than money available . Hence a sound evaluation of the proposed results and the predicted outcome as well as to some extent also a comparison of different projects is required. We raise the question, if and how the interests of various stakeholders can be considered in the theoretical framework of evaluation in the field of arts and culture. This entails the question, what kind of political processes are hidden behind processes of evaluation in the cultural sector and how the relation between the purpose of evaluation, the evaluators, and the other stakeholders can be understood and explicitly addressed. Hence, this requires a focus on the inherent (political) values and interests as well as their contexts

Cultural Heritage as a trigger for Civic Wealth Creation and Sustainable Urban Development

La rigenerazione urbana si basa su una visione integrata volta a risolvere i problemi urbani e a promuovere lo sviluppo delle comunità interessate. Reiventare lo spazio, valorizzare la cultura per dare nuova vita ai centri storici, è un’esigenza civica crescente e una sfida per i politici e i manager delle città. Questo obiettivo potrebbe essere raggiunto valorizzando il Patrimonio Culturale e i saperi locali per generare nuove opportunità e benessere per i cittadini. Al momento, troppo spesso il Patrimonio Culturale viene apprezzato principalmente a fini turistici. Un fatto che causa anche molteplici problemi: sovraffollamento, gentrificazione, conflitti tra interessi turistici e civici, traffico urbano, generazione di posti di lavoro a basso reddito, per citare solo i più evidenti. Ne deriva che una profonda comprensione della partecipazione civica e democratica nell'accesso, nella conservazione e nello sfruttamento del nostro Patrimonio Culturale è un terreno fertile per il dibattito tra studiosi di varie discipline. I contributi di questo libro cercano di alimentare tale dibattito dal punto di vista degli studiosi di management.Urban regeneration rests on an integrated and comprehensive vision aimed at solving urban problems and promoting the development of the concerned communities. A reinvention of the way space is perceived, building on culture to breathe new life into historic centres, is a rising civic need and a key challenge for policymakers and city managers. This could be achieved by resting on Cultural Heritage, local knowledge and capabilities to generate new opportunities and civic wealth. At present, Cultural Heritage is too often valued mainly for tourism purposes. A fact that also causes multiple problems: overcrowding, gentrification, conflicts between tourist and civic interests, urban traffic, generation of low-income jobs, to name but the most obvious. It follows that a deep understanding of civic and democratic participation in the access, preservation and exploitation of our Cultural Heritage is fertile ground for debate among scholars from various disciplines. The contributions in this book seek to fuel this debate from the perspective of management scholars

The Outreach of Participatory Cultural Initiatives: the Importance of Creating and Exchanging Knowledge

Purpose – This paper investigates Participatory Cultural Initiatves (PCIs) and patterns of learning and knowledge sharing among participating actors. We highlight Participatory Cultural Initiatives (PCIs) and their impact on communities, cities, and regions. PCIs create material and immaterial outcomes through the presence of cultural artefacts and the exchange of ideas, thoughts and feelings among participants. In particular, a participatory approach to cultural and creative initiatives entails civic engagement and strong support for creating and sharing cultural projects, highlighting the subjective relevance of individual contributions and strengthening the feeling of being socially connected among each other. Unfolding participation also activates knowledge sharing and learning processes. Hence, we address the following research questions: First: What role does the exchange of knowledge play in PCIs intended as collective learning organizations? Secondly, we look at the knowledge outcome of PCIs relating to individual and collective knowledge components. Both research questions contribute to a better understanding of the general phenomenon of participatory culture as well as the role of culture in society. Design/methodology/approach – Based on a sound literature review in the field of PCIs, we propose an inductive approach by conducting two connected case studies: Matera as a European Capital of Culture and Rome as a City of Film (within the UNESCO network of creatives cities). The cases were chosen, as both examples have similar selection criteria (referring to UNESCO programs). We selected primary data through personal semi-structured interviews with the key actors of each initiative, as well as secondary data through the analysis of relevant documents, press releases, websites, social media, etc. concerning the initiatives. Originality/value – More and more, citizens and cultural institutions collaborate to develop cultural projects through a participatory approach. This leads to the stratification of knowledge and of learning processes that further enrich the local communities. Notwithstanding a prolific body of knowledge on cultural initiatives, we need more insights on how PCIs as well as the resulting collective knowledge components can contribute to creating value for individuals and society. We propose a comprehensive framework to analyse these new phenomena, highlighting their impact on different stakeholders. Practical implications – The research fosters a deeper understanding of PCIs and their societal impact. It supports professionals, politicians, institutions and citizens who are involved in developing, funding, managing and measuring cultural and creative projects. Finally, this paper contributes to expanding the literature on knowledge generation and participatory culture