Neurohormonal markers in chronic rhinosinusitis.

Chronic rhinosinusitis (CRS), especially with nasal polyps, continues to elude precise pathogenesis and effective treatment. Prior work in our laboratory demonstrated interleukin-33 (IL-33) and Substance P (SP) activation of mast cells, and inhibitory effect of interleukin-37 (IL-37). Our objective is to study the expression of these neurohormonal mediators in mast cell stimulation of nasal polyposis. This was a prospective research study involving collection of nasal lavage fluid and nasal polyp tissue from adult patients with CRS. The study was divided into two arms. First, nasal lavage fluid was collected from normal controls, and patients with allergic rhinitis, CRS, or CRS with nasal polyposis. The second arm was collection of nasal tissue from normal controls undergoing inferior turbinoplasty, or patients with nasal polyposis. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction techniques were used to determine levels in the lavage fluid and relative gene expression in the tissue of SP, IL-33, and IL-37. In total, 70 lavage and 23 tissue specimens were obtained. The level of SP was highest in patients with polyps; however, gene expression was reduced compared to normal controls. The level of IL-33 was reduced in patients with polyps as compared to patients with allergy and sinusitis, and its gene expression was not significantly different from normal controls. IL-37 was elevated in the lavage fluid of patients with nasal polyps and its gene expression was increased in the polyp tissue. Levels of SP and IL-37 were elevated in the lavage fluid of patients with nasal polyps as compared to normal controls and other sinonasal pathologies, and gene expression of IL-37 was significantly increased in the polyp tissue itself. These findings implicate these neurohormonal molecules in the pathophysiology of nasal polyposis and provide possible novel therapeutic targets.

Anaphylaxis is a rare reaction in COVID-19 vaccination.

Anaphylaxis is a severe multisystem reaction that occurs rapidly after the introduction of an antigen that would otherwise be a harmless substance. It is characterized by airway and respiratory problems, cardiovascular collapse, mucosal inflammation, and other complications, all severe symptoms that can cause death. IgE-dependent anaphylaxis involves mast cells (MCs) which are the main sources of biologically active mediators that contribute to the pathological and lethal phenomena that can occur in anaphylaxis. Antibody-mediated anaphylaxis can follow multiple pathways such as that mediated by MCs carrying the FcεRI receptor, which can be activated by very small amounts of antigen including a vaccine antigen and trigger an anaphylactic reaction. In addition, anaphylaxis can also be provoked by high concentrations of IgG antibodies that bind to the FcγR receptor present on basophils, neutrophils, macrophages and MCs. For this reason, the IgG concentration should be kept under control in vaccinations. Activation of MCs is a major cause of anaphylaxis, which requires immediate treatment with epinephrine to arrest severe lethal symptoms. MCs are activated through the antigen binding and cross-linking of IgE with release of mediators such as histamine, proteases, prostaglandins, leukotrienes and inflammatory cytokines. The release of these compounds causes nausea, vomiting, hives, wheezing, flushing, tachycardia, hypotension, laryngeal edema, and cardiovascular collapse. mRNA and viral vector vaccines have been cleared by the United States, Food and Drug Administration (FDA), generating hope of prevention and cure for COVID-19 around the world. Scientists advise against giving the vaccine to individuals who have had a previous history of anaphylaxis. The US Centers for Disease Control and Prevention (CDC) advises people with a previous history of any immediate allergic reaction to remain under observation for approximately 30 minutes after COVID-19 vaccination. To date, vaccines that prevent SARS-CoV-2 infection have not raised major concerns of severe allergic reactions, although, in some cases, pain and redness at the injection site and fever have occurred after administration of the vaccine. These reactions occur in the first 24-48 hours after vaccination. It has been reported that probable forms of anaphylaxis could also occur, especially in women approximately 40 years of age. But after tens of millions of vaccinations, only a few patients had this severe reaction with a low incidence. Anaphylactic and severe allergic reactions can also occur to any component of the vaccine including polysorbates and polyethylene glycol. To date, there is no precise information on allergic reactions to COVID-19 vaccines. Individuals with MCs and complement with higher activation than others may be at greater allergic risk. Moreover, the reactions called anaphylactoids, are those not mediated by IgE because they do not involve this antibody and can also occur in COVID-19 vaccination. These not-IgE-mediated reactions occur through direct activation of MCs and complement with tryptase production, but to a lesser extent than IgE-mediated anaphylaxis. However, at the moment it is not known exactly which component of the vaccine causes the allergic reaction and which vaccine causes the most side effects, including anaphylaxis. Thus, individuals who have a known allergy to any component of the vaccine should not be vaccinated. However, should an anaphylactic reaction occur, this requires immediate treatment with epinephrine to arrest severe lethal symptoms. In conclusion, the purpose of this editorial is to encourage the population to be vaccinated in order to extinguish this global pandemic that is afflicting the world population, and to reassure individuals that anaphylactic reactions do not occur with a higher incidence than other vaccinations.

Be aware of SARS-CoV-2 spike protein: There is more than meets the eye.

The COVID-19 pandemic necessitated the rapid production of vaccines aimed at the production of neutralizing antibodies against the COVID-19 spike protein required for the corona virus binding to target cells. The best well-known vaccines have utilized either mRNA or an adenovirus vector to direct human cells to produce the spike protein against which the body produces mostly neutralizing antibodies. However, recent reports have raised some skepticism as to the biologic actions of the spike protein and the types of antibodies produced. One paper reported that certain antibodies in the blood of infected patients appear to change the shape of the spike protein so as to make it more likely to bind to cells, while other papers showed that the spike protein by itself (without being part of the corona virus) can damage endothelial cells and disrupt the blood-brain barrier. These findings may be even more relevant to the pathogenesis of long-COVID syndrome that may affect as many as 50% of those infected with SARS-CoV-2. In COVID-19, a response to oxidative stress is required by increasing anti-oxidant enzymes. In this regard, it is known that polyphenols are natural anti-oxidants with multiple health effects. Hence, there are even more reasons to intervene with the use of anti-oxidant compounds, such as luteolin, in addition to available vaccines and anti-inflammatory drugs to prevent the harmful actions of the spike protein.

Antibodies for COVID-19 - which, when and how long?

Infection with SARS-CoV2 leads to COVID-19, the severity of which derives from the host's immune response, especially the release of a storm of pro-inflammatory cytokines. This coronavirus infects by first binding to the ectoenzyme Angiotensin Converting Enzyme 2 (ACE2), a serine protease acting as the receptor, while another serine protease is necessary for priming the viral spike "S" protein required for entering the cells. Repurposing existing drugs for potential anti-coronavirus activity have failed. As a result, there were intense efforts to rapidly produce ways of providing prophylactic active immunization (vaccines) or abortive passive (convalescent plasma or monoclonal antibodies) neutralizing antibodies. The availability of vaccines for COVID-19 have been largely successful, but many questions still remain unanswered. In spite of the original enthusiasm, clinical studies using convalescent serum or monoclonal antibodies have shown limited benefit. Moreover, the emergence of Long-COVID syndrome in most infected patients necessitates the development of treatment approaches that may prevent viral entry by blocking both serine proteases involved, as with a liposomal blend of the natural flavonoids luteolin and quercetin.

Monoclonal antibody therapy in COVID-19.

Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) which is associated with inflammation, thrombosis edema, hemorrhage, intra-alveolar fibrin deposition, and vascular and pulmonary damage. In COVID-19, the coronavirus activates macrophages by inducing the generation of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18 and TNF] that can damage endothelial cells, activate platelets and neutrophils to produce thromboxane A2 (TxA2), and mediate thrombus generation. In severe cases, all these phenomena can lead to patient death. The binding of SARS-CoV-2 to the Toll Like Receptor (TLR) results in the release of pro-IL-1ß that is cleaved by caspase-1, followed by the production of active mature IL-1ß which is the most important cytokine in causing fever and inflammation. Its activation in COVID-19 can cause a "cytokine storm" with serious biological and clinical consequences. Blockade of IL-1 with inhibitory and anti-inflammatory cytokines represents a new therapeutic strategy also for COVID-19. Recently, very rare allergic reactions to vaccines have been reported, with phenomena of pulmonary thrombosis. These side effects have raised substantial concern in the population. Highly allergic subjects should therefore be vaccinated under strict medical supervision. COVID-19 has accelerated vaccine therapy but also the use of drugs and monoclonal antibodies (mABs) which have been used in COVID-19 therapy. They are primarily adopted to treat high-risk mild-to-moderate non-hospitalized patients, and it has been noted that the administration of two mABs gave better results. mABs, other than polyclonal plasma antibodies from infected subjects with SARS-CoV-2, are produced in the laboratory and are intended to fight SARS-CoV-2. They bind specifically to the antigenic determinant of the spike protein, inhibiting the pathogenicity of the virus. The most suitable individuals for mAB therapy are people at particular risk, such as the elderly and those with serious chronic diseases including diabetics, hypertension and obesity, including subjects suffering from cardiovascular diseases. These antibodies have a well-predetermined target, they bind mainly to the protein S (formed by the S1A, B, C and D subtypes), located on the viral surface, and to the S2 protein that acts as a fuser between the virus and the cell membrane. Since mABs are derived from a single splenic immune cell, they are identical and form a cell clone which can neutralize SARS-CoV-2 by binding to the epitope of the virus. However, this COVID-19 therapy may cause several side effects such as mild pain, bleeding, bruising of the skin, soreness, swelling, thrombotic-type episodes, arterial hypertension, changes in heart activity, slowed bone marrow activity, impaired renal function, diarrhea, fatigue, nausea, vomiting, allergic reaction, fever, and possible subsequent infection may occur at the site of injection. In conclusion, the studies promoting mAB therapy in COVID-19 are very promising but the results are not yet definitive and more investigations are needed to certify both their good neutralizing effects of SARS-CoV-2, and to eliminate, or at least mitigate, the harmful side effects.

The clock drawing test as a cognitive screening tool for assessment of hypertension-mediated brain damage.

INTRODUCTION: Hypertension (HTN) is the most frequent cause of subcortical vascular brain injury (VBI) and its cognitive consequences. The aims were to show the usefulness of the Clock Drawing Test (CDT) to detect cognitive impairment in hypertensive patients and to compare it with the Mini-Mental Test (MMSE). METHODS: A subset of hypertensive patients of the Heart-Brain Study in Argentina was included. Demographic characteristics, vascular risk factors, blood pressure (BP) and schooling level were recorded. The MMSE and CDT tests were used for neurocognitive assessment and Hospital Anxiety Depression scale (HAD) for mood disorder evaluation. RESULTS: 1414 hypertensive patients (age 59.7±13.8 years, female (62.3%). The prevalence of cognitive impairment was 20.7% (using MMSE) and 36.1% (using CDT). Among hypertensive patients with normal MMSE (>24) 29.3% had cognitive impairment (abnormal CDT). The CDT was associated with level of education but not with age or mood status. CONCLUSIONS: The CDT is a useful screening tool to detect hypertension-mediated brain damage earlier (especially in midlife) and is more sensitive than MMSE.

The British variant of the new coronavirus-19 (Sars-Cov-2) should not create a vaccine problem.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious virus that infects humans and a number of animal species causing coronavirus disease-19 (COVID-19), a respiratory distress syndrome which has provoked a global pandemic and a serious health crisis in most countries across our planet. COVID-19 inflammation is mediated by IL-1, a disease that can cause symptoms such as fever, cough, lung inflammation, thrombosis, stroke, renal failure and headache, to name a few. Strategies that inhibit IL-1 are certainly helpful in COVID-19 and can represent one of the therapeutic options. However, until now, COVID-19 therapy has been scarce and, in many cases, ineffective, since there are no specific drugs other than the vaccine that can solve this serious health problem. Messenger RNA (mRNA) vaccines which are the newest approach, are already available and will certainly meet the many expectations that the population is waiting for. mRNA vaccines, coated with protected soft fatty lipids, use genetic mRNA (plus various inactive excipients) to make a piece of the coronavirus spike protein, which will instruct the immune system to produce specific antibodies. The soft fatty lipids allow the entry of mRNA into cells where it is absorbed into the cytoplasm and initiates the synthesis of the spike protein. In addition, vaccination also activates T cells that help the immune system respond to further exposure to the coronavirus. mRNA induces the synthesis of antigens of SARS-CoV-2 virus which stimulate the antibody response of the vaccinated person with the production of neutralizing antibodies. The new variant of the coronavirus-19 has been detected in the UK where, at the moment, the London government has imposed a lockdown with restrictions on international movements. The virus variant had already infected 1/4 of the total cases and in December 2020, it reached 2/3 of those infected in the UK. It has been noted that the spreading rate of the British variant could be greater than 70% of cases compared to the normal SARS-CoV-2 virus, with an R index growth of 0.4. Recent studies suggest that coronavirus-19 variation occurs at the level N501Y of the spike protein and involves 23 separate mutations on the spike, 17 of which are linked to the virus proteins, thus giving specific characteristics to the virus. In general, coronaviruses undergo many mutations that are often not decisive for their biological behavior and does not significantly alter the structure and the components of the virus. This phenomenon also occurs in SARS-CoV-2. It is highly probable that the variants recently described in the UK will not hinder vaccine-induced immunity. In fact, the variant will not break the vaccine although it may have some chance of making it a little less effective. Therefore, it is pertinent to think that the vaccine will work against the SARS-CoV-2 variant as well. In today's pandemic, the D614G mutation of the amino acid of corronavirus-19, which emerged in Europe in February 2020 is the most frequent form and causes high viral growth. The previously infrequent D614G mutation is now globally dominant. This variant, which is being tested by many international laboratories, is rapidly spreading across the countries and a series of vaccinated subjects are testing to see if their antibodies can neutralize the new variant of SARS-CoV-2. This variant has a very high viral growth and is less detectable with the RT-PCR technique in the laboratory. It has been reported that the British variant that increases viral load does not cause more severe effects in the respiratory tract and lung disease, therefore, it is certain that the variant is growing rapidly and must be kept under control; for this reason, laboratory data is expected impatiently. The study on the many variants that coronavirus-19 presents is very interesting and complete and clearer data on this topic will be ready in the near future. In addition, it is still unclear whether the different variants discovered in many countries, including Africa, share the same spike protein mutation and therefore, this is another study to elaborate on. In order to be certain and to not have unexpected surprises, we need to reduce the spread and the transmission speed of viral variants that could appear around the world, creating new pandemics. For this reason, the scientific community is on the alert since laboratory tests on serum antibodies from COVID-19 survivors have been reported to be less effective in attacking the variant. In light of the above, the scientific community must be on the alert as larger variants of the spike protein could escape vaccine-induced antibodies, which for now are of great help to the community and can save millions of lives. Deepening the study of spike protein mutations will help to better understand how to combat coronavirus-19 and its variants.

COVID-19 and Multisystem Inflammatory Syndrome, or is it Mast Cell Activation Syndrome?

COVID-19 derives from infection with Coronavirus [severe acute respiratory syndrome (SARS)-CoV-2] and is associated with high morbidity and mortality due to release of a storm of pro-inflammatory cytokines and thrombogenic agents resulting in destruction of the lungs. Many reports indicate that a considerable number of patients who are positive for SARS-CoV-2 are asymptomatic or have mild symptoms. However, increasing evidence suggests that many such patients who either recovered from or had mild symptoms after COVID-19 exhibit diffuse, multiorgan, symptoms months after the infection. These symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms that were originally reported in children and named Multisystem Inflammatory Syndrome (MIS-C). Now the US Center for Disease Control (CDC) announced the recognition of a similar condition in adults, named Multisystem Inflammatory Syndrome (MIS-A). The symptoms characterizing these conditions are very similar to those associated with Mast Cell Activation Syndrome (MCAS, US ICD-110 code D89.42-idiopathic mast cell activation syndrome). Hence, the possibility of MCAS should be evaluated in any patient with MIS and/or multisystem inflammatory symptoms. In either case, these syndromes should be addressed with liposomal formulation (in olive pomace oil) of the flavone luteolin (e.g. PureLut® or FibroProtek®) together with the antihistamine rupatadine, which also has anti-platelet activating factor (PAF) activity and inhibits mast cells that have been implicated in the pathogenesis of cytokine storms in COVID-19.

Coronavirus-19 (SARS-CoV-2) induces acute severe lung inflammation via IL-1 causing cytokine storm in COVID-19: a promising inhibitory strategy.

SARS-Cov-2 infection causes local and systemic inflammation mediated by pro-inflammatory cytokines and COX-2 eicosanoid products with metabolic dysfunction and tissue damage that can lead to patient death. These effects are primarily induced by IL-1 cytokines, which are involved in the elevation of hepatic acute phase proteins and fever. IL-1 has a broad spectrum of biological activities and participates in both innate and acquired immunity. In infections, IL-1 induces gene expression and synthesis of several cytokines/chemokines in both macrophages and mast cells (MCs). The activation of MCs triggers the secretion of mediators stored in the granules, and the de novo synthesis of pro-inflammatory cytokines. In microorganism infections, the release of IL-1 macrophage acts on adhesion molecules and endothelial cells leading to hypotension and septic shock syndrome. IL-1 activated by SARS-CoV-2 stimulates the secretion of TNF, IL-6 and other cytokines, a pro-inflammatory complex that can lead to cytokine storm and be deleterious in both lung and systemically. In SARS-CoV-2 septic shock, severe metabolic cellular abnormalities occur which can lead to death. Here, we report that SARS-CoV-2 induces IL-1 in macrophages and MCs causing the induction of gene expression and activation of other pro-inflammatory cytokines. Since IL-1 is toxic, its production from ubiquitous MCs and macrophages activated by SARS-CoV-2 can also provokes both gastrointestinal and brain disorders. Furthermore, in these immune cells, IL-1 also elevates nitric oxide, and the release of inflammatory arachidonic acid products such as prostaglndins and thromboxane A2. All together these effects can generate cytokine storm and be the primary cause of severe inflammation with respiratory distress and death. Although, IL-1 administered in low doses may be protective; when it is produced in high doses in infectious diseases can be detrimental, therefore, IL-1 blockade has been studied in many human diseases including sepsis, resulting that blocking it is absolutely necessary. This definitely nurtures hope for a new effective therapeutic treatment. Recently, two interesting anti-IL-1 cytokines have been widely described: IL-37 and IL-1Ra. IL-37, by blocking IL-1, has been observed to have anti-inflammatory action in rodents in vivo and in transfected cells. It has been reported that IL-37 is a very powerful protein which inhibits inflammation and its inhibition can be a valid therapeutic strategy. IL-37 is a natural suppressor of inflammation that is generated through a caspase-1 that cleaves pro-IL-37 into mature IL-37 which translocates to the nucleus and inhibits the transcription of pro-inflammatory genes; while IL-1Ra inhibits inflammation by binding IL-1 to its IL-1R (receptor). We firmly believe that blocking IL-1 with an anti-inflammatory cytokine such as IL-37 and/or IL-1Ra is an effective valid therapy in a wide spectrum of inflammatory disorders including SARS-CoV-2-induced COVID-19. Here, we propose for the first time that IL-37, by blocking IL-1, may have an important role in the therapy of COVID-19.

Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19.

SARS-CoV-2 virus is an infectious agent commonly found in certain mammalian animal species and today also in humans. SARS-CoV-2, can cause a pandemic infection with severe acute lung injury respiratory distress syndrome in patients with COVID-19, that can lead to patient death across all ages. The pathology associated with pandemic infection is linked to an over-response of immune cells, including virus-activated macrophages and mast cells (MCs). The local inflammatory response in the lung that occurs after exposure to SARS-CoV-2 is due to a complex network of activated inflammatory innate immune cells and structural lung cells such as bronchial epithelial cells, endothelial cells and fibroblasts. Bronchial epithelial cells and fibroblasts activated by SARS-CoV-2 can result in the up-regulation of pro-inflammatory cytokines and induction of MC differentiation. In addition, endothelial cells which control leukocyte traffic through the expression of adhesion molecules are also able to amplify leukocyte activation by generating interleukin (IL)-1, IL-6 and CXC chemokines. In this pathologic environment, the activation of mast cells (MCs) causes the release of histamine, proteases, cytokines, chemokines and arachidonic acid compounds, such as prostaglandin D2 and leukotrienes, all of which are involved in the inflammatory network. Histamine is stored endogenously within the secretory granules of MCs and is released into the vessels after cell stimulation. Histamine is involved in the expression of chemokine IL-8 and cytokine IL-6, an effect that can be inhibited by histamine receptor antagonists. IL-1 is a pleiotropic cytokine that is mainly active in inflammation and immunity. Alveolar macrophages activated by SARS-CoV-2 through the TLR produce IL-1 which stimulates MCs to produce IL-6. IL-1 in combination with IL-6 leads to excessive inflammation which can be lethal. In an interesting study published several years ago (by E. Vannier et al., 1993), it was found that histamine as well as IL-1 are implicated in the pathogenesis of pulmonary inflammatory reaction, after micorganism immune cell activation. IL-1 in combination with histamine can cause a strong increase of IL-1 levels and, consequently, a higher degree of inflammation. However, it has been reported that histamine alone has no effect on IL-1 production. Furthermore, histamine enhances IL-1-induced IL-6 gene expression and protein synthesis via H2 receptors in peripheral monocytes. Therefore, since MCs are large producers of histamine in inflammatory reactions, this vasoactive amine, by increasing the production of IL-1, can amplify the inflammatory process in the lung infected with SARS-CoV-2. Here, we have proposed for the first time an emerging role for histamine released by MCs which in combination with IL-1 can cause an increase in lung inflammation induced by the viral infection SARS-CoV-2.

IL-1 induces throboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL-1 receptor antagonist (IL-1Ra).

IL-1 induces a significant number of metabolic and hematological changes. In experimental animals, IL-1 treatments cause hypotension due to rapid reduction of systemic blood pressure, reduced vascular resistance, increased heart rate and leukocyte aggregations. IL-1 causes endothelial dysfunction, the triggering factor of which may be of a different nature including pathogen infection. This dysfunction, which includes macrophage intervention and increased protein permeability, can be mediated by several factors including cytokines and arachidonic acid products. These effects are caused by the induction of IL-1 in various pathologies, including those caused by pathogenic viral infections, including SARS-CoV-2 which provokes COVID-19. Activation of macrophages by coronavirus-19 leads to the release of pro-inflammatory cytokines, metalloproteinases and other proteolytic enzymes that can cause thrombi formation and severe respiratory dysfunction. Patients with COVID-19, seriously ill and hospitalized in intensive care, present systemic inflammation, intravascular coagulopathy with high risk of thrombotic complications, and venous thromboembolism, effects mostly mediated by IL-1. In these patients the lungs are the most critical target organ as it can present an increase in the degradation products of fibrin, fibrinogen and D-dimer, with organ lesions and respiratory failure. It is well known that IL-1 induces itself and another very important pro-inflammatory cytokine, TNF, which also participates in hemodynamic states, including shock syndrome in COVID-19. Both IL-1 and TNF cause pulmonary edema, thrombosis and bleeding. In addition to hypotension and resistance of systemic blood pressure, IL-1 causes leukopenia and thrombocytopenia. The formation of thrombi is the main complication of the circulatory system and functionality of the organ, and represents an important cause of morbidity and mortality. IL-1 causes platelet vascular thrombogenicity also on non-endothelial cells by stimulating the formation of thromboxane A2 which is released into the inflamed environment. IL-1 is the most important immune molecule in inducing fever, since it is involved in the metabolism of arachidonic acid which increases from vascular endothelial organs of the hypothalamus. The pathogenesis of thrombosis, vascular inflammation and angigenesis involves the mediation of the activation of the prostanoid thromboxane A2 receptor. In 1986, in an interesting article (Conti P, Reale M, Fiore S, Cancelli A, Angeletti PU, Dinarello CA. In vitro enhanced thromboxane B2 release by polymorphonuclear leukocytes and macrophages after treatment with human recombinant interleukin 1. Prostaglandins. 1986 Jul;32(1):111-5), we reported for the first time that IL-1 induces thromboxane B2 (TxB2) releases in activated neutrophils and macrophages. An increase in thromboxane can induce leukocyte aggregation and systemic inflammation, which would account for the dramatic thrombi formation and organ dysfunction. Hence, IL-1 stimulates endothelial cell-leukocyte adhesion, and TxB2 production. All these events are supported by the large increase in neutrophils that adhere to the lung and the decrease in lymphocytes. Therefore, ecosanoids such as TxA2 (detected as TxB2) have a powerful action on vascular inflammation and platelet aggregation, mediating the formation of thrombi. The thrombogenesis that occurs in COVID-19 includes platelet and cell aggregation with clotting abnormalities, and anti-clotting inhibitor agents are used in the prevention and therapy of thrombotic diseases. Prevention of or induction of TxA2 avoids thrombi formation induced by IL-1. However, in some serious vascular events where TxA2 increases significantly, it is difficult to inhibit, therefore, it would be much better to prevent its induction and generation by blocking its inductors including IL-1. The inhibition or lack of formation of IL-1 avoids all the above pathological events which can lead to death of the patient. The treatment of innate immune cells producing IL-1 with IL-1 receptor antagonist (IL-1Ra) can avoid hemodynamic changes, septic shock and organ inflammation by carrying out a new therapeutic efficacy on COVID-19 induced by SARS-CoV-2.

IL-1 Superfamily Members and Periodontal Diseases.

Periodontitis is a complex, multifactorial chronic disease involving continuous interactions among bacteria, host immune/inflammatory responses, and modifying genetic and environmental factors. More than any other cytokine family, the interleukin (IL)-1 family includes key signaling molecules that trigger and perpetuate periodontal inflammation. Over the years, the IL-1 family expanded to include 11 members of cytokines, some with agonist activity (IL-1α, IL-1ß, IL-18, IL-33, IL-36α, IL-36ß, and IL-36γ), receptor antagonists (IL-1Ra, IL-36Ra), and 2 anti-inflammatory cytokines (IL-37, IL-38). The IL-1 receptor antagonist (IL-1Ra) has emerged as a pivotal player in the defense against periodontitis. IL-33 primarily induces the production of Th2-associated cytokines but acts as an "alarmin" via stimulation of mast cells. The IL-36 subclass of cytokines may be important in regulating mucosal inflammation and homeostasis. IL-37 suppresses innate and acquired immune responses. IL-38 is the most recent member of the IL-1 superfamily and has anti-inflammatory properties similar to those of IL-37 but through different receptors. However, limited evidence exists regarding the role of IL-37 and IL-38 in periodontitis. Despite the development of IL-1 blocking agents, therapeutic blockade of select IL-1 family members for periodontitis has only been partially investigated in preclinical and clinical research, while the development of IL-37 and IL-38 as novel anti-inflammatory drugs has not been considered adequately. Here, we review the key properties of the IL-1 family members and provide insights into targeting or promoting select cytokines as new therapeutic agents.

SARS-CoV-2, which induces COVID-19, causes kawasaki-like disease in children: role of pro-inflammatory and anti-inflammatory cytokines.

Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a global pandemic coronavirus disease 2019 (COVID-19). In humans, SARS-CoV-2 infection leads to acute respiratory distress syndrome which presents edema, hemorrhage, intra-alveolar fibrin deposition, and vascular changes characterized by thrombus formation, micro-angiopathy and thrombosis. These clinical signs are mediated by pro-inflammatory cytokines. In recent studies it has been noted that COVID-19 pandemic can affect patients of all ages, including children (even if less severely) who were initially thought to be immune. Kawasaki disease is an autoimmune acute febrile inflammatory condition, which primarily affects young children. The disease can present immunodeficiency with the inability of the immune system to fight inflammatory pathogens and leads to fever, rash, alterations of the mucous membranes, conjunctiva infection, pharyngeal erythema, adenopathy, and inflammation. In the COVID-19 period, virus infection aggravates the condition of Kawasaki disease, but it has also been noted that children affected by SARS-V-2 may develop a disease similar to Kawasaki's illness. However, it is uncertain whether the virus alone can give Kawasaki disease-like forms. As in COVID-19, Kawasaki disease and its similar forms are mediated by pro-inflammatory cytokines produced by innate immunity cells such as macrophages and mast cells (MCs). In light of the above, it is therefore pertinent to think that by blocking pro-inflammatory cytokines with new anti-inflammatory cytokines, such as IL-37 and IL-38, it is possible to alleviate the symptoms of the disease and have a new available therapeutic tool. However, since Kawasaki and Kawasaki-like diseases present immunodeficiency, treatment with anti-inflammatory/immunosuppressant molecules must be applied very carefully.

Dexamethasone for COVID-19? Not so fast.

Recent announcements indicated, without sharing any distinct published set of results, that the corticosteroid dexamethasone may reduce mortality of severe COVID-19 patients only. The recent Coronavirus [severe acute respiratory syndrome (SARS)-CoV-2]-associated multiorgan disease, called COVID-19, has high morbidity and mortality due to autoimmune destruction of the lungs stemming from the release of a storm of pro-inflammatory cytokines. Defense against this Corona virus requires activated T cells and specific antibodies. Instead, cytokines are responsible for the serious sequelae of COVID-19 that damage the lungs. Dexamethasone is a synthetic corticosteroid approved by the FDA 1958 as a broad-spectrum immunosuppressor and it is about 30 times as active and with longer duration of action (2-3 days) than cortisone. Dexamethasone would limit the production of and damaging effect of the cytokines, but will also inhibit the protective function of T cells and block B cells from making antibodies, potentially leading to increased plasma viral load that will persist after a patient survives SARS. Moreover, dexamethasone would block macrophages from clearing secondary, nosocomial, infections. Hence, dexamethasone may be useful for the short-term in severe, intubated, COVID-19 patients, but could be outright dangerous during recovery since the virus will not only persist, but the body will be prevented from generating protective antibodies. Instead, a pulse of intravenous dexamethasone may be followed by administration of nebulized triamcinolone (6 times as active as cortisone) to concentrate in the lungs only. These corticosteroids could be given together with the natural flavonoid luteolin because of its antiviral and anti-inflammatory properties, especially its ability to inhibit mast cells, which are the main source of cytokines in the lungs. At the end, we should remember that "The good physician treats the disease; the great physician treats the patient who has the disease" [Sir William Osler's (1849-1919)].

Coronavirus COV-19/SARS-CoV-2 affects women less than men: clinical response to viral infection.

CoV-19/SARS-CoV-2 is a highly pathogenic virus that causes coronavirus-19 disease (COVID-19) an acute respiratory distress syndrome which provokes serious problems for global health. Studies suggest that there are many differences between men and women in the immune response to CoV-19 infection and inflammatory diseases. Women, compared to men, are less susceptible to viral infections based on a different innate immunity, steroid hormones and factors related to sex chromosomes. The presence of two X chromosomes in women emphasize the immune system even if one is inactive. The immune regulatory genes encoded by X chromosome in female gender causes lower viral load levels, and less inflammation than in man, while CD4+ T cells are higher with better immune response. In addition, women generally produce higher levels of antibodies which remain in the circulation longer. The levels of activation of the immune cells are higher in women than in men, and it is correlated with the trigger of TLR7 and the production of IFN. TLR7 is higher in women than in men and its biallelic expression leads to higher immune responses and increases the resistance to viral infections. TLR7 is expressed in innate immune cells which recognizes single strand RNA virus by promoting the production of antibodies against the virus and the generation of pro-inflammatory cytokines including IL-6 and IL-1 family members. Moreover, in women the production of inflammatory IL-6 after viral infection is lower than in males and is often correlated with a better longevity. In addition, on the X chromosome there are loci that code for the genes involved in the regulation of immune cells such as FOXP3, and transcription factor for Treg involved in virus pathogenesis. The X chromosome influences the immune system by acting on many other proteins, including TLR8, CD40L and CXCR3 which can be over-expressed in women, and influence the response to viral infections and vaccinations. However, the biallelic expression of the X-linked genes can promote harmful autoimmune and inflammatory responses. Cardiovascular diseases are more frequent in males and subjects without cardiovascular dysfunctions infected by CoV-19 have a better prognosis, but these effects are still under study. It is hoped that certain drugs, such as CoV-19 receptor blockers, anti-inflammatories (against rheumatic diseases), monoclonal antibodies, anti-IL-1 and anti-IL-6, the remdesevir drug (analogue adenosine, effective against ebola), hydroxychloroquine (for the treatment of malaria) and vaccines, will open up new strategies and new therapeutic ways to combat this terrible virus.

How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1.

SARS-CoV-2, also referred to as CoV-19, is an RNA virus which can cause severe acute respiratory diseases (COVID-19), with serious infection of the lower respiratory tract followed by bronchitis, pneumonia and fibrosis. The severity of the disease depends on the efficiency of the immune system which, if it is weak, cannot stem the infection and its symptoms. The new CoV-19 spreads in the population at a rate of 0.8-3% more than normal flu and mostly affects men, since immune genes are more expressed on the X chromosome. If CoV-19 would spread with a higher incidence rate (over 10%), and affect the people who live in closed communities such as islands, it would cause many more deaths. Moreover, people from the poorest classes are most at risk because of lack of health care and should be given more assistance by the competent authorities. To avoid the aggravation of CoV-19 infection, and the collapse of the health system, individuals should remain at home in quarantine for a period of approximately one month in order to limit viral transmission. In the case of a pandemic, the severe shortage of respirators and protective clothing, due to the enormous demand and insufficient production, could lead the CoV-19 to kill a large number of individuals. At present, there is no drug capable of treating CoV-19 flu, the only therapeutic remedies are those aimed at the side effects caused by the virus, such as inflammation and pulmonary fibrosis, recognized as the first causes of death. One of the COVID-19 treatments involves inhaling a mixture of gaseous hydrogen and oxygen, obtaining better results than with oxygen alone. It was also noted that individuals vaccinated for viral and/or bacterial infectious diseases were less likely to become infected. In addition, germicidal UV radiation "breaks down" the oxygen O2 which then aggregate into O3 (ozone) molecules creating the ozone layer, capable of inhibiting viral replication and improving lung respiration. All these precautions should be taken into consideration to lower the risk of infection by CoV-19. New anti-viral therapies with new drugs should also be taken into consideration. For example, microbes are known to bind TLR, inducing IL-1, a pleiotropic cytokine, highly inflammatory, mediator of fever and fibrosis. Therefore, drugs that suppress IL-1 or IL-1R, also used for the treatment of rheumatoid arthritis are to be taken into consideration to treat COVID-19. We strongly believe that all these devices described above can lead to greater survival and. therefore, reduction in mortality in patients infected with CoV-19.

A Single-Center Experience on Below-The-Knee Endovascular Treatment in Diabetic Patients.

Diabetic ulceration of the foot is a major global medical, social and economic problem and is the most frequent end-point of diabetic complications. A retrospective analysis from February 2017 to May 2019 of diabetic patients presenting below-the-knee artery disease (PAD) was carried out. Only patients treated with endovascular techniques as first choice treatment were evaluated. Outcome measured was perioperative mortality and morbidity. Freedom from occlusion, secondary patency and amputation rate were all registered. Additional maneuvers including stenting or angioplasty with drug eluting balloon (DEB) were reported. A total of 167 (101 male/66 female) patients with a mean age of 71 years were included in the study. A Rutherford 3, 4, 5 and 6 categories were reported in 5, 7, 110 and 45 patients, respectively. No perioperative mortality was reported. Morbidity occurred in 4 (4.4%) cases and consisted of pseudoaneurysm. Additional stenting during first procedure was required in 7 (4%) patients, drug eluting balloon was needed in 56 (33%) patients. At 1-year follow-up, estimated freedom from occlusion and secondary patency was 70% and 80% respectively. Major amputation rate was 2.4%, minor amputation rate was 41.9%. In our experience, extreme revascularization in search of distal direct flow reduce the rate of amputations with an increase in ulcer healing. New materials and techniques such as drug eluting technology, used properly, can improve outcome.

Endovascular Treatment with Drug-Eluting Balloon for Severe Subclavian Artery Stenosis Involving the Origin of the Vertebral Artery.

The first line approach for subclavian steal syndrome is PTA-stenting of subclavian artery. When the ipsilateral vertebral artery origin is involved or in closed proximity of the atherosclerotic lesion in the subclavian artery PTA-stenting is at risk of ipsilateral vertebral artery coverage. Herein we report our experience with DEB to address lesions involving the subclavian artery and the origin of the ipsilateral vertebral artery. From January 2017 to February 2019, patients presenting subclavian artery lesion involving the origin of the ipsilateral vertebral artery and treated using primary DEB, were included. Three patients, with left subclavian steal syndrome, were identified. The perioperative mortality and morbidity were outcomes evaluated. Freedom from occlusion, secondary patency, amputation rate was registered. A total of 3 (2 female) patients were included in the study. No complication, symptoms recurrence, restenosis or occlusion were reported at duplex scan during 12-month follow-up. Indication for stenting was arterial dissection. In our limited experience, the use of DEB in association to embolic protection device in the treatment of atherosclerotic subclavian lesion involving the origin of the vertebral artery was safe and technically feasible.

Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies.

Coronavirus-19 (COVI-19) involves humans as well as animals and may cause serious damage to the respiratory tract, including the lung: coronavirus disease (COVID-19). This pathogenic virus has been identified in swabs performed on the throat and nose of patients who suffer from or are suspected of the disease. When COVI-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1ß and IL-6. The binding of COVI-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1ß which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1ß which is a mediator of lung inflammation, fever and fibrosis. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. Cytokine IL-37 has the ability to suppress innate and acquired immune response and also has the capacity to inhibit inflammation by acting on IL-18Rα receptor. IL-37 performs its immunosuppressive activity by acting on mTOR and increasing the adenosine monophosphate (AMP) kinase. This cytokine inhibits class II histocompatibility complex (MHC) molecules and inflammation in inflammatory diseases by suppressing MyD88 and subsequently IL-1ß, IL-6, TNF and CCL2. The suppression of IL-1ß by IL-37 in inflammatory state induced by coronavirus-19 can have a new therapeutic effect previously unknown. Another inhibitory cytokine is IL-38, the newest cytokine of the IL-1 family members, produced by several immune cells including B cells and macrophages. IL-38 is also a suppressor cytokine which inhibits IL-1ß and other pro-inflammatory IL-family members. IL-38 is a potential therapeutic cytokine which inhibits inflammation in viral infections including that caused by coronavirus-19, providing a new relevant strategy.

Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy.

Coronavirus can cause respiratory syndrome which to date has affected about twelve thousand individuals, especially in China. Coronavirus is interspecies and can also be transmitted from man to man, with an incubation ranging from 1 to 14 days. Human coronavirus infections can induce not only mild to severe respiratory diseases, but also inflammation, high fever, cough, acute respiratory tract infection and dysfunction of internal organs that may lead to death. Coronavirus infection (regardless of the various types of corona virus) is primarily attacked by immune cells including mast cells (MCs), which are located in the submucosa of the respiratory tract and in the nasal cavity and represent a barrier of protection against microorganisms. Viral activate MCs release early inflammatory chemical copounds including histamine and protease; while late activation provoke the generation of pro-inflammatory IL-1 family members including IL-1, IL-6 and IL-33. Here, we propose for the first time that inflammation by coronavirus maybe inhibited by anti-inflammatory cytokines belonging to the IL-1 family members.