There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

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2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

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European Position Paper on Rhinosinusitis and Nasal Polyps 2020

Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

A lineage of myeloid cells independent of Myb and hematopoietic stem cells

Prolonged low grade inflammation or smoldering inflammation is a hallmark of cancer. Mast cells form a heterogeneous population of immune cells with differences in their ultra-structure, morphology, mediator content and surface receptors. Mast cells are widely distributed throughout all tissues and are stromal components of the inflammatory microenvironment that modulates tumor initiation and development. Although canonically associated with allergic disorders, mast cells are a major source of protumorigenic (e.g., angiogenic and lymphangiogenic factors) and anti-tumorigenic molecules (e.g., TNF- and IL-9) depending on the milieu. In certain neoplasias (e.g., gastric, thyroid, and Hodgkin’s lymphoma) mast cells play a protumorigenic role, in others (e.g., breast cancer) a protective role, whereas in yet others they are apparently innocent bystanders. These seemingly conflicting results suggest that the role of mast cells and their mediators could be cancer-specific. The microlocalization (e.g., peritumoral vs intratumoral) of mast cells is another important aspect in the initiation/progression of solid and hematologic tumors. Increasing evidence in certain experimental models indicate that targeting mast cells and/or their mediators represent a potential therapeutic target in cancer. Thus, mast cells deserve focused consideration also as therapeutic targets in different types of tumors. There are many unanswered questions that should be addressed before we understand whether mast cells are an ally, adversary or innocent bystanders in human cancers.

/pdf/are-mast-cells-masters-in-cancer-5u3nrifm5k.pdf

Are Mast Cells MASTers in Cancer

Cardiac toxicity after conventional antineoplastic drugs (eg, anthracyclines) has historically been a relevant issue. In addition, targeted therapies and biological molecules can also induce cardiotoxicity. Immune checkpoint inhibitors are a novel class of anticancer drugs, distinct from targeted or tumour type-specific therapies. Cancer immunotherapy with immune checkpoint blockers (ie, monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligand (PD-L1)) has revolutionised the management of a wide variety of malignancies endowed with poor prognosis. These inhibitors unleash antitumour immunity, mediate cancer regression and improve the survival in a percentage of patients with different types of malignancies, but can also produce a wide spectrum of immune-related adverse events. Interestingly, PD-1 and PD-L1 are expressed in rodent and human cardiomyocytes, and early animal studies have demonstrated that CTLA-4 and PD-1 deletion can cause autoimmune myocarditis. Cardiac toxicity has largely been underestimated in recent reviews of toxicity of checkpoint inhibitors, but during the last years several cases of myocarditis and fatal heart failure have been reported in patients treated with checkpoint inhibitors alone and in combination. Here we describe the mechanisms of the most prominent checkpoint inhibitors, specifically ipilimumab (anti-CTLA-4, the godfather of checkpoint inhibitors) patient and monoclonal antibodies targeting PD-1 (eg, nivolumab, pembrolizumab) and PD-L1 (eg, atezolizumab). We also discuss what is known and what needs to be done about cardiotoxicity of checkpoint inhibitors in patients with cancer. Severe cardiovascular effects associated with checkpoint blockade introduce important issues for oncologists, cardiologists and immunologists.

Cardiotoxicity of immune checkpoint inhibitors

Asthma is a high-prevalence disease, still accounting for mortality and high direct and indirect costs. It is now recognized that, despite the implementation of guidelines, a large proportion of cases remain not controlled. Certainly, adherence to therapy and the education of patients remain the primary objective, but the increasingly detailed knowledge about the pathogenic mechanisms and new biotechnologies offer the opportunity to better address and treat the disease. Interleukin (IL)-13 and IL-4 appear as the most suitable targets to treat the T helper 2 (TH2)-mediated forms (endotypes) of asthma. IL-13 and IL-4 partly share the same receptor and signaling pathways and both are deeply involved in immunoglobulin E (IgE) synthesis, eosinophil activation, mucus secretion and airways remodeling. Several anti-IL-13 strategies have been proposed (anrukinzumab, lebrikizunab and tralokinumab), with relevant clinical results reported with lebrikizumab. Such studies facilitate better definition of the possible predictive markers of response to a specific treatment (e.g. eosinophils, total IgE, fraction of exhaled nitric oxide and periostin). In parallel, anti-IL-4 strategies have been attempted (pascolizumab, pitakinra and dupilumab). So far, dupilumab was reported capable of reducing the severity of asthma and the rate of exacerbations. IL-13 and IL-4 are crucial in TH2-mediated inflammation in asthma, but it remains clear that only specific endotypes respond to these treatments. Although the use of anti-IL-14 and anti-IL-13 strategies is promising, the search for appropriate predictive biomarkers is urgently needed to better apply biological treatments.

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A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma

Prolonged low-grade inflammation or smoldering inflammation is a hallmark of a cancer. Eosinophils are components of the immune microenvironment that modulates tumor initiation and progression. Although canonically associated with a detrimental role in allergic disorders, these cells can induce a protective immune response against helminthes, viral and bacterial pathogens. Eosinophils are a source of anti-tumorigenic (e.g., TNF-α, granzyme, cationic proteins, and IL-18) and protumorigenic molecules (e.g., pro-angiogenic factors) depending on the milieu. In several neoplasias (e.g., melanoma, gastric, colorectal, oral and prostate cancer) eosinophils play an anti-tumorigenic role, in others (e.g., Hodgkin's lymphoma, cervical carcinoma) have been linked to poor prognosis, whereas in yet others they are apparently innocent bystanders. These seemingly conflicting results suggest that the role of eosinophils and their mediators could be cancer-dependent. The microlocalization (e.g., peritumoral vs intratumoral) of eosinophils could be another important aspect in the initiation/progression of solid and hematological tumors. Increasing evidence in experimental models indicates that activation/recruitment of eosinophils could represent a new therapeutic strategy for certain tumors (e.g., melanoma). Many unanswered questions should be addressed before we understand whether eosinophils are an ally, adversary or neutral bystanders in different types of human cancers.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1393134

Eosinophils: The unsung heroes in cancer?

Purpose of reviewHuman eosinophils were first identified and named by Paul Ehrlich in 1879 on the basis of the cell's granular uptake of eosin. Although eosinophils represent approximately 1% of peripheral blood leukocytes, they have the propensity to leave the blood stream and migrate into inflamed

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Gilda Varricchi

Papers

Are Mast Cells MASTers in Cancer

Cardiotoxicity of immune checkpoint inhibitors

A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma

Eosinophils: The unsung heroes in cancer?

Interleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs