Heterogeneous induction of microglia M2a phenotype by central administration of interleukin-4.

BACKGROUND: Acquisition of the M1 or M2 phenotypes by microglia has been shown to occur during the development of pathological conditions, with M1 activation being widely involved in neurotoxicity in relation with the anatomical localization and the reactivity of subtypes of microglia cells. On the contrary, little is known on the ability of microglia to undergo M2 polarization by interleukin-4 (IL4), the typical M2a polarization signal for peripheral macrophages. METHODS: Recombinant mouse IL4 was injected in the third cerebral ventricle of mice to induce brain alternative polarization. The mRNA levels of Fizz1, Arg1, and Ym1 genes, known to be up-regulated by IL4 in peripheral macrophages, together with additional polarization markers, were evaluated in the striatum and frontal cortex at different time intervals after central administration of IL4; in parallel, M2a protein expression was evaluated in tissue extracts and at the cellular level. RESULTS: Our results show that the potency and temporal profile of IL4-mediated M2a gene induction vary depending on the gene analyzed and according to the specific brain area analyzed, with the striatum showing a reduced M2a response compared with the frontal cortex, as further substantiated by assays of polarization protein levels. Of notice, Fizz1 mRNA induction reached 100-fold level, underscoring the potency of this specific IL4 signaling pathway in the brain. In addition, immunochemistry assays demonstrated the localization of the M2 response specifically to microglia cells and, more interestingly, the existence of a subpopulation of microglia cells amenable to undergoing M2a polarization in the healthy mouse brain. CONCLUSIONS: These results show that the responsiveness of brain macrophages to centrally administered IL4 may vary depending on the gene and brain area analyzed, and that M2a polarization can be ascribed to a subpopulation of IL4-responsive microglia cells. The biochemical pathways that enable microglia to undergo M2a activation represent key aspects for understanding the physiopathology of neuroinflammation and for developing novel therapeutic and diagnostic agents.

Residual Adrenal Function After Multivisceral Resection With Adrenalectomy in Adult Patients.

Importance: The risk of developing adrenal insufficiency (AI) following adrenalectomy has been insufficiently studied in the context of multivisceral resection (MVR). Objective: To evaluate the incidence of AI in patients undergoing MVR with en bloc adrenalectomy. Design, Setting, and Participants: Prospective observational longitudinal study in a single referral center including 56 consecutive adult patients undergoing retroperitoneal sarcoma surgery from June 2019 to August 2020. Those who were candidates for MVR with en bloc adrenalectomy and had no preexisting adrenal impairment were considered eligible. Of these, 4 individuals were excluded because they did not receive adrenalectomy at the time of surgery and 2 because they were not considered evaluable for the main end point. Follow-up was set at 4 months after surgery, and 49 patients completed follow-up. Data were analyzed from October 2020 to September 2021. Exposures: Diagnosis of AI was determined by low-dose (1 µg) adrenocorticotropic hormone (ACTH) stimulation test with a threshold of 20 µg/dL in blood samples retrieved 30 and 60 minutes after stimulation. ACTH test was repeated on postoperative days 1 and 10 and at 4 months' follow-up. Main Outcome and Measures: The primary end point was incidence and relevance of AI after MVR. Secondary end points were associations with patient- and tumor-related factors, impact on perioperative hemodynamic management, and association with postoperative morbidity and mortality. Results: Fifty patients (26 female; median [IQR] age, 59 [46-67] years) were evaluable. Incidence of AI was 64% (32 of 50 patients) in the early postoperative period and 38.5% (15 of 39 patients) at follow-up. Patients with AI showed lower postoperative cortisol values. Factors associated with risk of AI at univariate analysis were high American Society of Anesthesiologists score (odds ratio [OR], 0.31; 95% CI, 0.14-0.48) and high malignancy grade (OR, 0.35; 95% CI, 0.24-0.46). Clinical outcomes not associated with AI included morbidity, mortality, reoperation rate, admission to intensive care unit, length of intensive care unit stay, total hospital stay, and long-term quality of life. Conclusions and Relevance: In this study, AI after MVR with en bloc adrenalectomy was frequent, even in patients with adequate preoperative adrenal function. Despite this, adrenalectomy can be safely performed. Patients at risk should be monitored in the long term to exclude underrated impairment of adrenal function.

Comparison Between Swan-Ganz Catheter and Minimally Invasive Hemodynamic Monitoring During Liver Transplantation: Report of a Monocentric Case Series.

INTRODUCTION: The aim of the present investigation was to retrospectively evaluate the utilization of Swan-Ganz catheter during orthotopic liver transplantation as opposed to FloTrac/Vigileo in selected cases, comparing a number of clinical outcomes across postoperative hospitalization. MATERIALS AND METHODS: Before 2015 all recipients received pulmonary artery catheter (Swan-Ganz group, n = 109). After 2015 Swan-Ganz was used only if coronary artery disease or high-grade portal hypertension or Child-Pugh C were present; the remaining recipients were assigned to FloTrac/Vigileo monitoring (Mini group, n =100). A number of clinical outcomes were considered. RESULTS: Donor's Risk Index was similar between groups (median value 1.7, P = .27). Anthropometric characteristics of the recipients were similar in the 2 groups. There were no significant differences in the proportion of patients with Child-Pugh C (P = .873), coronary artery disease (P = .18), and grade of portal hypertension (P = .733). The Model for End-Stage Liver Disease score was slightly higher in the Mini group: (9 [7-11] vs 9 [8-12], Swan-Ganz vs Mini, respectively, P < .035). Swan-Ganz utilization decreased over time (92% vs 26%, Swan-Ganz vs Mini, P < .001). Upon admission to the intensive care unit, patients of the Mini group presented a higher SAPS II score with similar values of Sequential Organ Failure Assessment score. Days on mechanical ventilation were similar between groups. The incidence of graft failure was similar between groups (2% vs 5%, Swan-Ganz and Mini group respectively, P = .376). Recipients' hospital length of stay was similar (13 days [11-19] vs 14 [11-20], P < .083). CONCLUSIONS: Our data suggest that the intraoperative utilization of FloTrac/Vigileo for oncologic patients with low grade end stage liver disease is reasonably safe.

A standardized model of brain death, donor treatment, and lung transplantation for studies on organ preservation and reconditioning.

BACKGROUND: We set a model of brain death, donor management, and lung transplantation for studies on lung preservation and reconditioning before transplantation. METHODS: Ten pigs (39.7 ± 5.9 Kg) were investigated. Five animals underwent brain death and were treated as organ donors; the lungs were then procured and cold stored (Ischemia). Five recipients underwent left lung transplantation and post-reperfusion follow-up (Graft). Cardiorespiratory and metabolic parameters were collected. Lung gene expression of cytokines (tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interferon gamma (IFNγ), high mobility group box-1 (HMGB-1)), chemokines (chemokine CC motif ligand-2 (CCL2-MCP-1), chemokine CXC motif ligand-10 (CXCL-10), interleukin-8 (IL-8)), and endothelial activation markers (endothelin-1 (EDN-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), selectin-E (SELE)) was assessed by real-time polymerase chain reaction (PCR). RESULTS: Tachycardia and hypertension occurred during brain death induction; cardiac output rose, systemic vascular resistance dropped (P < 0.05), and diabetes insipidus occurred. Lung-protective ventilation strategy was applied: 9 h after brain death induction, PaO2 was 192 ± 12 mmHg at positive end-expiratory pressure (PEEP) 8.0 ± 1.8 cmH2O and FiO2 of 40%; wet-to-dry ratio (W/D) was 5.8 ± 0.5, and extravascular lung water (EVLW) was 359 ± 80 mL. Procured lungs were cold-stored for 471 ± 24 min (Ischemia) at the end of which W/D was 6.1 ± 0.9. Left lungs were transplanted and reperfused (warm ischemia 98 ± 14 min). Six hours after controlled reperfusion, PaO2 was 192 ± 23 mmHg (PEEP 8.7 ± 1.5 cmH2O, FiO2 40%), W/D was 5.6 ± 0.4, and EVLW was 366 ± 117 mL. Levels of IL-8 rose at the end of donor management (BD, P < 0.05); CCL2-MCP-1, IL-8, HMGB-1, and SELE were significantly altered after reperfusion (Graft, P < 0.05). CONCLUSIONS: We have set a standardized, reproducible pig model resembling the entire process of organ donation that may be used as a platform to test in vivo and ex vivo strategies of donor lung optimization before transplantation.