FLUOXETINE ATTENUATES MAST CELL FUNCTION BY TARGETING PURINERGIC SIGNALING

Mast cells are tissue resident, innate immune cells that provide protection against parasitic and bacterial infections and venom poisoning. Mast cells also play a pathogenic role in atopy and allergic diseases. Atopy and allergic diseases are increasing in the developed world and are predicted to continue to increase at an alarming rate. Current treatment options include corticosteroids, anti-histamines, anti-IgE and avoidance of allergen. These interventions have limitations: some patients are steroid resistant; anti-histamines have low efficacy since they need to be administered early during allergen exposure; and anti-IgE is costly. Thus there is a clinical need for new treatment options. An efficient approach is to re-purpose FDA-approved drugs. Selective serotonin reuptake inhibitors (SSRIs) are a class of anti-depressants used to treat depression and other psychiatric disorders. SSRIs have been shown to possess anti-inflammatory properties, but the mechanism of action is unclear. The possibility to treat allergic diseases with SSRIs has not been studied. Using primary mouse bone marrow derived, ex vivo cultured mouse peritoneal, and primary skin derived human mast cells, we show that the SSRI fluoxetine suppresses IgE-mediated degranulation, cytokine production, and inflammatory lipid secretion. Several other SSRIs showed similar effects on mouse mast cells. Cytokine suppression occurs at a transcriptional level, as evidenced by decreased signaling downstream of the IgE receptor and reduced cytokine mRNA induction. We found that fluoxetine-mediated suppression requires the purinergic receptor, P2X3. Furthermore, we show that IgE stimulation elicits rapid ATP release from mast cells, and that ATP and purinergic signaling is a positive feedback regulator of mast cell activation. Fluoxetine can also suppress ATP-mediated cytokine production, degranulation, and lipid production most likely via NFkb suppression and diminished purinergic receptor expression. Importantly, fluoxetine effects are consistent in an in vivo passive systemic anaphylaxis (PSA) model and in a house dust mite (HDM) airway hyperresponsiveness and lung inflammation model of asthma. In the PSA model, fluoxetine reduced hypothermia and cytokine production. In the asthma model, the drug suppressed bronchoresponsiveness as well as pulmonary mast cell hyperplasia and eosinophilia, and the recruitment of Th2 cells, neutrophils, eosinophils, and lymphocytes to the bronchoalveolar space, as well as cytokine levels in the bronchoalveolar fluid in sensitized mice. Overall, we show that fluoxetine broadly suppresses mast cell activation in vitro and in vivo, most likely by impeding an ATP-P2X3 positive feedback loop

Inhibiting Glycolysis and ATP Production Attenuates IL-33-Mediated Mast Cell Function and Peritonitis

Cellular metabolism and energy sensing pathways are closely linked to inflammation, but there is little understanding of how these pathways affect mast cell function. Mast cells are major effectors of allergy and asthma, and can be activated by the alarmin IL-33, which is linked to allergic disease. Therefore, we investigated the metabolic requirements for IL-33-induced mast cell function, to identify targets for controlling inflammation. We found that IL-33 increases glycolysis, glycolytic protein expression, and oxidative phosphorylation (OX PHOS). Inhibiting OX PHOS had little effect on cytokine production, but antagonizing glycolysis with 2-deoxyglucose or oxamate suppressed inflammatory cytokine production in vitro and in vivo. ATP reversed this suppression. Glycolytic blockade suppressed IL-33 signaling, including ERK phosphorylation, NFκB transcription, and ROS production in vitro, and suppressed IL-33-induced neutrophil recruitment in vivo. To test a clinically relevant way to modulate these pathways, we examined the effects of the FDA-approved drug metformin on IL-33 activation. Metformin activates AMPK, which suppresses glycolysis in immune cells. We found that metformin suppressed cytokine production in vitro and in vivo, effects that were reversed by ATP, mimicking the actions of the glycolytic inhibitors we tested. These data suggest that glycolytic ATP production is important for IL-33-induced mast cell activation, and that targeting this pathway may be useful in allergic disease

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The Role of TGF&beta; and Other Cytokines in Regulating Mast Cell Functions in Allergic Inflammation

Mast cells (MC) are a key effector cell in multiple types of immune responses, including atopic conditions. Allergic diseases have been steadily rising across the globe, creating a growing public health problem. IgE-mediated activation of MCs leads to the release of potent mediators that can have dire clinical consequences. Current therapeutic options to inhibit MC activation and degranulation are limited; thus, a better understanding of the mechanisms that regulate MC effector functions in allergic inflammation are necessary in order to develop effective treatment options with minimal side effects. Several cytokines have been identified that play multifaceted roles in regulating MC activation, including TGF&beta;, IL-10, and IL-33, and others that appear to serve primarily anti-inflammatory functions, including IL-35 and IL-37. Here, we review the literature examining cytokines that regulate MC-mediated allergic immune responses

Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today

Mast cells are tissue resident, innate immune cells with heterogenous phenotypes tuned by cytokines and other microenvironmental stimuli. Playing a protective role in parasitic, bacterial, and viral infections, mast cells are also known for their role in the pathogenesis of allergy, asthma, and autoimmune diseases. Here, we review factors controlling mast cell activation, with a focus on receptor signaling and potential therapies for allergic disease. Specifically, we will discuss our work with FcεRI and FγR signaling, IL-4, IL-10, and TGF-β1 treatment, and Stat5. We conclude with potential therapeutics for allergic disease. Much of these efforts have been influenced by the work of Bill Paul. With many mechanistic targets for mast cell activation and different classes of therapeutics being studied, there is reason to be hopeful for continued clinical progress in this area