Neuro-mesenchymal units control ILC2 and obesity via a brain-adipose circuit.

Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as important regulators of host defence and inflammation1-4. Nevertheless, it is unclear whether neuronal and immune cells co-operate in brain-body axes to orchestrate metabolism and obesity. Here we describe a neuro-mesenchymal unit that controls group 2 innate lymphoid cells (ILC2s), adipose tissue physiology, metabolism and obesity via a brain-adipose circuit. We found that sympathetic nerve terminals act on neighbouring adipose mesenchymal cells via the ß2-adrenergic receptor to control the expression of glial-derived neurotrophic factor (GDNF) and the activity of ILC2s in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to alterations in ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing and chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates ILC2s in gonadal fat and connects to higher-order brain areas, including the paraventricular nucleus of the hypothalamus. Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity.

Author Correction: Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis.

Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism1. ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence2,3. Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut 'postcode receptors' of ILC3s. Strikingly, light-dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis.

Neuronal regulation of type 2 innate lymphoid cells via neuromedin U.

Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis, and are activated by host-derived cytokines and alarmins. Discrete subsets of immune cells integrate nervous system cues, but it remains unclear whether neuron-derived signals control ILC2s. Here we show that neuromedin U (NMU) in mice is a fast and potent regulator of type 2 innate immunity in the context of a functional neuron-ILC2 unit. We found that ILC2s selectively express neuromedin U receptor 1 (Nmur1), and mucosal neurons express NMU. Cell-autonomous activation of ILC2s with NMU resulted in immediate and strong NMUR1-dependent production of innate inflammatory and tissue repair cytokines. NMU controls ILC2s downstream of extracellular signal-regulated kinase and calcium-influx-dependent activation of both calcineurin and nuclear factor of activated T cells (NFAT). NMU treatment in vivo resulted in immediate protective type 2 responses. Accordingly, ILC2-autonomous ablation of Nmur1 led to impaired type 2 responses and poor control of worm infection. Notably, mucosal neurons were found adjacent to ILC2s, and these neurons directly sensed worm products and alarmins to induce NMU and to control innate type 2 cytokines. Our work reveals that neuron-ILC2 cell units confer immediate tissue protection through coordinated neuroimmune sensory responses.

Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence.

Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers. ILC3 development is thought to be programmed, but how ILC3 perceive, integrate and respond to local environmental signals remains unclear. Here we show that ILC3 in mice sense their environment and control gut defence as part of a glial­ILC3­epithelial cell unit orchestrated by neurotrophic factors. We found that enteric ILC3 express the neuroregulatory receptor RET. ILC3-autonomous Ret ablation led to decreased innate interleukin-22 (IL-22), impaired epithelial reactivity, dysbiosis and increased susceptibility to bowel inflammation and infection. Neurotrophic factors directly controlled innate Il22 downstream of the p38 MAPK/ERK-AKT cascade and STAT3 activation. Notably, ILC3 were adjacent to neurotrophic-factor-expressing glial cells that exhibited stellate-shaped projections into ILC3 aggregates. Glial cells sensed microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22. Accordingly, glial-intrinsic Myd88 deletion led to impaired production of ILC3-derived IL-22 and a pronounced propensity towards gut inflammation and infection. Our work sheds light on a novel multi-tissue defence unit, revealing that glial cells are central hubs of neuron and innate immune regulation by neurotrophic factor signals.

The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function.

Haematopoiesis is a developmental cascade that generates all blood cell lineages in health and disease. This process relies on quiescent haematopoietic stem cells capable of differentiating, self renewing and expanding upon physiological demand. However, the mechanisms that regulate haematopoietic stem cell homeostasis and function remain largely unknown. Here we show that the neurotrophic factor receptor RET (rearranged during transfection) drives haematopoietic stem cell survival, expansion and function. We find that haematopoietic stem cells express RET and that its neurotrophic factor partners are produced in the haematopoietic stem cell environment. Ablation of Ret leads to impaired survival and reduced numbers of haematopoietic stem cells with normal differentiation potential, but loss of cell-autonomous stress response and reconstitution potential. Strikingly, RET signals provide haematopoietic stem cells with critical Bcl2 and Bcl2l1 surviving cues, downstream of p38 mitogen-activated protein (MAP) kinase and cyclic-AMP-response element binding protein (CREB) activation. Accordingly, enforced expression of RET downstream targets, Bcl2 or Bcl2l1, is sufficient to restore the activity of Ret null progenitors in vivo. Activation of RET results in improved haematopoietic stem cell survival, expansion and in vivo transplantation efficiency. Remarkably, human cord-blood progenitor expansion and transplantation is also improved by neurotrophic factors, opening the way for exploration of RET agonists in human haematopoietic stem cell transplantation. Our work shows that neurotrophic factors are novel components of the haematopoietic stem cell microenvironment, revealing that haematopoietic stem cells and neurons are regulated by similar signals.

Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity.

The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

Rationale and Study Design for an Individualized Perioperative Open Lung Ventilatory Strategy in Patients on One-Lung Ventilation (iPROVE-OLV).

OBJECTIVE: The aim of this clinical trial is to examine whether it is possible to reduce postoperative complications using an individualized perioperative ventilatory strategy versus using a standard lung-protective ventilation strategy in patients scheduled for thoracic surgery requiring one-lung ventilation. DESIGN: International, multicenter, prospective, randomized controlled clinical trial. SETTING: A network of university hospitals. PARTICIPANTS: The study comprises 1,380 patients scheduled for thoracic surgery. INTERVENTIONS: The individualized group will receive intraoperative recruitment maneuvers followed by individualized positive end-expiratory pressure (open lung approach) during the intraoperative period plus postoperative ventilatory support with high-flow nasal cannula, whereas the control group will be managed with conventional lung-protective ventilation. MEASUREMENTS AND MAIN RESULTS: Individual and total number of postoperative complications, including atelectasis, pneumothorax, pleural effusion, pneumonia, acute lung injury; unplanned readmission and reintubation; length of stay and death in the critical care unit and in the hospital will be analyzed for both groups. The authors hypothesize that the intraoperative application of an open lung approach followed by an individual indication of high-flow nasal cannula in the postoperative period will reduce pulmonary complications and length of hospital stay in high-risk surgical patients.

The neurotrophic factor receptor RET regulates IL-10 production by in vitro polarised T helper 2 cells.

T helper (Th) cells are critical players in the modulation of immune response outcomes. Activation of Th cells gives rise to various subsets of effector cells that are controlled via specialised regulatory T cells or through self-regulation via production of IL-10. However, the environmental factors that regulate IL-10 production by Th cells remain poorly understood. Here, we show that the neurotrophic factor receptor rearranged during transfection (RET) downregulates IL-10 production by Th cells from C57BL/6 mice. We found that effector Th cells express RET and that RET's neurotrophic factor partners are mainly produced by LN stromal cells, allowing context-dependent Th-cell regulation. Despite being dispensable for Th-cell homeostasis, RET controls IL-10 production in Th2 cells: RET-deficient Th cells exhibited increased IL-10 production, while triggering of Th1/2 cells with neurotrophic factors, namely glial-derived neurotrophic factor and neurturin, decreased the expression of IL-10. In agreement, the important IL-10 transcription factor Maf was upregulated in RET-deficient Th2 cells and down-regulated upon RET signalling activation by glial-derived neurotrophic factor family ligands. Thus, our study uncovers neurotrophic factors as novel regulators of Th-cell function, revealing that Th cells and neurons can be regulated by similar signals in tissue-specific responses.

[Pacemaker lead-induced tricuspid stenosis: a report of two cases]. / Estenose tricúspide induzida por eletrocateter de pacemaker: relato de 2 casos clínicos.

Tricuspid stenosis (TS) is an uncommon complication of transvenous ventricular pacemaker implantation, with few cases reported in the literature. The mechanisms described are obstruction of right ventricular inflow by tricuspid vegetations (endocarditis), multiple pacemaker leads and tricuspid valve (TV) fibrosis secondary to perforation or laceration of the TV leaflets, or adherence between redundant portions of the lead and valvular and subvalvular tissue. We report two cases of severe TS, with different etiologies and management: one caused by leaflet perforation, resolved surgically, and the other secondary to fusion between a loop of the pacemaker lead and the subvalvular apparatus, which was treated medically.

[Myocardial infarction after taking zolmitriptan]. / Enfarte agudo do miocárdio após a toma de zolmitriptano.

Zolmitriptan is a drug used in the acute treatment of migraine, which should not be used in high cardiovascular risk individuals because of its potential to induce vasospasm. We report a rare case of myocardial infarction precipitated by taking zolmitriptan.

[Cardiac injury in the context of metastatic hepatocellular carcinoma]. / Lesão cardíaca no contexto de carcinoma hepatocelular metastático.

Hepatocellular carcinoma with extension or metastasis to the right atrium is an uncommon form of cardiac malignancy. The authors report the case of a 51-year-old patient with hepatocellular carcinoma and thrombi in the portal and mesenteric veins, which histopathology revealed to be metastatic. Echocardiography showed a right atrial mass which in this context has to be considered as a possible cardiac metastasis.

[Sequential double vessel myocardial infarction]. / Enfarte agudo do miocárdio duplo sequencial.

Acute myocardial infarction (AMI) involving acute transmural ischemia of two vascular territories at the same time, which is known as double or combined infarction, is a well described phenomenon but rarely reported in most series of patients admitted for AMI. This may be related to the fact that AMI with multiple vessel obstruction often causes extensive myocardial injury and death before the patient arrives at the hospital. It is speculated that double infarction results from the overall prothrombotic and inflammatory conditions associated with AMI.

PT EMT - Portuguese Emergency Medical Team Type 1 Relief Mission in Mozambique.

INTRODUCTION: The tropical cyclone Idai hit Mozambique in the city of Beira on March 15, 2019. During the following days, the Portuguese Emergency Medical Team (PT EMT) and its infrastructure deployed to Mozambique with the mission of helping local people and collaborating with the authorities. METHODS: Data analyzed were collected in the period of the deployment, from April 1-April 30, 2019. All patients admitted to PT EMT were registered through the Clinical Record of PT EMT. RESULTS: In total, 1,662 patients were admitted to PT EMT during the 30-day mission. The five most prevalent diagnoses were: 61.49% classified with "code 29" (which corresponds to "other unspecified diagnoses"), 9.15% of cases of skin disease, 8.90% of minor injuries, 6.74% of acute respiratory infection, and 3.19% of obstetric/genecology complications. DISCUSSION AND CHALLENGES: An important challenge identified was the need for a robust and effective network for transporting patients, allowing transfers between EMTs, enabling a true network response in the provision of care to disaster victims. CONCLUSIONS: The benefit of the deployment of PT EMT in Mozambique after Cyclone Idai was in line with the EMT initiative standards, allowing a direct delivery of care to the affected Mozambican population and support to the local health authorities.

Initial experience with the Presillion stent in an unselected population: immediate and six-month outcomes.

INTRODUCTION: The release of a new bare metal stent (BMS), the Presillion stent, whose main innovative feature is its reduced strut thickness, has created expectations that it may reduce neointimal proliferation and consequently lower the restenosis rate. OBJECTIVE: To evaluate the efficacy and safety profile of Presillion stent implantation in an unselected population referred for coronary revascularization with BMS. METHODS: This was a prospective study of the first 20 consecutive patients undergoing implantation of at least one Presillion stent. We performed a descriptive analysis of the study population in terms of demographics, clinical context, angiographic characteristics of coronary lesions before and after angioplasty, and clinical outcome. After discharge, patients were followed up and assessed clinically at 3 and 6 months for the occurrence of MACE (cardiovascular death, myocardial infarction, stroke or revascularization). The statistical analysis consisted of calculation of means and standard deviation for continuous variables and relative proportions for categorical variables. RESULTS: The study population was predominantly male (65%), with a mean age of 68.8 years. The indication for cardiac catheterization was acute coronary syndrome in 90% and heart failure in 10% of cases. Half the patients had multivessel disease, and 34 stents, of which 26 were Presillion stents, were implanted in 29 coronary lesions. According to the ACC/AHA classification, the coronary lesions treated with Presillion stents were classified as type A in 0% of cases, type B1 in 27% and type B2 or C in 73%; 27% of these had moderate to severe calcification. The percentage of stenosis and minimal luminal diameter (MLD) before and after angioplasty were respectively 88.5 +/- 9.7% (MLD = 0.65 +/- 0.40 mm) and 10.6 +/- 4.3% (MLD = 2.58 +/- 0.36 mm). The success rate of Presillion implantation was 100%, with no significant drop in hemoglobin, additional elevation of cardiac biomarkers or deterioration in renal function after the procedure. No MACE occurred before hospital discharge. At 6-month follow-up all patients were alive, none had had stroke, two patients (10%) had had acute myocardial infarction in territories not dependent on previously treated arteries and two patients had undergone a new revascularization, but not of the target vessel. CONCLUSION: This initial experience with Presillion stents showed a high efficacy rate and an excellent safety profile that was maintained over 6 months of follow-up. Their effectiveness compared to other BMS should be demonstrated in larger-scale comparative studies.

Cardiac troponin I levels in acute pulmonary embolism.

OBJECTIVE: Estimation of individual risk and choice of initial therapeutic approach for patients with pulmonary embolism (PE) remains controversial. The three key components for risk stratification in PE are clinical evaluation, cardiac biomarkers and assessment of right ventricular size and function. The aim of this study was to assess the ability of admission troponin I (TnI) levels to predict short-term mortality and complicated clinical course in patients with PE. METHODS: We performed a retrospective analysis of 100 consecutive patients admitted with a diagnosis of PE between January 2004 and November 2007. Patients in whom the diagnosis was confirmed by spiral computed tomography, ventilation perfusion scan, pulmonary angiography or echocardiography and with serum TnI measurement in the first 24 hours of hospital stay were selected. The study population (n = 62) was divided into two groups according to the presence or absence of elevated TnI levels (TnI > or = 0.10 ng/ml). Clinical characteristics, electrocardiographic and echocardiographic signs of right ventricular dysfunction (RVD), brain natriuretic peptide (BNP) levels, in-hospital mortality and the composite endpoint of complicated PE (defined as the presence of at least one of the following: in-hospital death, cardiogenic shock, need for mechanical ventilation or inotropic support) were compared between groups. RESULTS: Thirty-seven patients (59.7%) had elevated TnI levels (Tpos) and 25 (40.3%) had normal levels (Tneg). The two groups were not significantly different (p = NS) in age (66.2 vs. 71 years), gender (female 70.3 vs. 60.0%), clinical presentation or length of hospital stay (14.7 vs. 18.1 days). Tpos patients had a higher prevalence of electrocardiographic signs of RVD (78.4 vs. 40.0%, p < 0.01). Echocardiographic RVD was also more common in the Tpos group but the difference did not reach statistical significance (56.0% vs. 27.3%, p = NS). Elevated serum TnI was significantly associated with complicated in-hospital clinical course (complicated PE: 29.7% in the Tpos group vs. 4.0% in the Tneg group (adjusted OR = 9.08; 95% CI 1.07-77.4; p = 0.044). In-hospital mortality was 8.1%, with a strong trend for higher mortality in the Tpos group (13.5% vs. 0%, p = 0.055). CONCLUSIONS: Elevated TnI levels are associated with higher risk for in-hospital mortality and complicated clinical course. Additional studies are needed to assess whether troponin levels, alone or in conjunction with other tests, can be used to guide therapeutic strategy and improve the prognosis of patients with PE.

NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors.

Innate lymphoid cells (ILCs) are a family of effectors that originate from a common innate lymphoid cell progenitor. However, the transcriptional program that sets the identity of the ILC lineage remains elusive. Here, we show that NFIL3 is a critical regulator of the common helper-like innate lymphoid cell progenitor (CHILP). Cell-intrinsic Nfil3 ablation led to variably impaired development of fetal and adult ILC subsets. Conditional gene targeting demonstrated that NFIL3 exerted its function prior to ILC subset commitment. Accordingly, NFIL3 ablation resulted in loss of ID2(+) CHILP and PLZF(+) ILC progenitors. Nfil3 expression in lymphoid progenitors was under the control of the mesenchyme-derived hematopoietin IL-7, and NFIL3 exerted its function via direct Id2 regulation in the CHILP. Moreover, ectopic Id2 expression in Nfil3-null precursors rescued defective ILC lineage development in vivo. Our data establish NFIL3 as a key regulator of common helper-like ILC progenitors as they emerge during early lymphopoiesis.

[Giant tumoral lesion in the left atrium: an uncommon case of undifferentiated cardiac sarcoma]. / Lesão tumoral gigante na aurícula esquerda: um caso incomum de sarcoma cardíaco indiferenciado.

Primary cardiac tumors are rare, with an incidence ranging from 0.0001% to 0.030%; 80% are benign, while sarcomas account for 95% of malignant tumors. The authors report the case of a 75-year-old patient with a giant mass in the left atrium. The final diagnosis was of an undifferentiated cardiac sarcoma. This tumor represents a real challenge not only for timely diagnosis, but especially the therapeutic approach to adopt.