Government says no elective surgery
One clinical trial ongoing in China with high dose IV infusions through Sep 2020
"Among patients with sepsis and ARDS, patients in the high-dose vitamin C group did not show a better prognosis and other clinical outcomes. There are still some confounding factors in the existing research, and the conclusions are different.
Therefore, during the current epidemic of SARI, it is necessary to study the clinical efficacy and safety of vitamin C for viral pneumonia through randomized controlled trials."
Chloroquine as mast cell stabilizer. I had to take it once deployed for malaria and some other things. One pill a week. Not by any means a pleasurable experience.
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Chloroquine as mast cell stabilizer. I had to take it once deployed for malaria and some other things. One pill a week. Not by any means a pleasurable experience.
DEFINE_ME
Reposting:
Mast Cell-Induced Lung Injury in Mice Infected with H5N1 Influenza Virus
(Effects of Ketotofin and Oseltamivir in reducing lung damage)
Yanxin Hu, Yi Jin, et.al.
In the present study, we investigated whether mast cells play a role in the initial process of influenza virus infection and what contributions mast cells make to the pathological consequences of influenza viruses.
We show that mast cells actively participate in the first-line immunological responses to infection.
Through release of tryptase, histamine, and gamma interferon (IFN-Îł), mast cells could aggravate pathological injury of the infected tissues by directly inducing apoptosis or inflammatory cytokines and mediators.
To investigate whether mast cells were activated by H5N1 virus (A/chicken/Henan/1/2004) infection, we used the mast cell inhibitor ketotifen. Mice were given ketotifen (1 mg/kg body weight) once daily for 3 days by oral gavage, and all mice were challenged with 5 LD50 of H5N1 virus at 4 h after the first dose of ketotifen.
Remarkably, we found that ketotifen treatment significantly reduced the lung lesions (Fig. 3A).
Mice without ketotifen treatment showed severe bronchiolitis, peribronchiolitis, and bronchopneumonia, which were characterized by dropout and necrosis of mucous epithelial cells in the bronchioles; infiltration of various inflammatory cells, including lymphocytes, neutrophils, and plasmacytes near the small blood vessels; interstitial edema; thickening of the alveolar walls; and alveolar lumen flooding with dropout of alveolar cells, erythrocytes, and inflammatory cells in the lung.
In comparison, the lungs of the mice with ketotifen treatment demonstrated only mild pathological lesions, such as mild bronchiolitis, which was characterized by dropout and necrosis of mucous epithelial cells in the bronchioles and inflammatory cell infiltration around the bronchioles and small blood vessels.
Here, we found that inhibition of mast cell degranulation effectively protected mice from death after H5N1 infection, probably by reducing the lung lesions and by inhibition of apoptosis, which was evidenced by a decreased level of IFN-Îł in ketotifen-treated groups.
The results suggest that the mast cell degranulation inhibitor is a potent antiviral agent against influenza virus. We found that a combination of ketotifen (10 mg/kg) and oseltamivir (10 mg/kg) protected 100% of the mice from death caused by H5N1 infection, which offers an alternative strategy for controlling a potential pandemic influenza outbreak.
Reposting:
Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry
Wenjiao Wu, Richan Li, et.al
"The result revealed that quercetin reduced HA mRNA transcription in influenza-virus-infected cells in a dose-dependent manner (Figure 1C,D).
To further confirm that quercetin also impairs viral protein expressions, MDCK cells were infected with the influenza A/Puerto Rico/8/34 (H1N1) virus at 100 TCID50 in the presence of various concentrations of quercetin. At 24 h post-infection, cells were analyzed for virus nucleoprotein (NP) localization by an indirect immunofluorescence assay. As the data shown (Figure 2), quercetin showed significant inhibition on viral NP protein synthesis in a dose-dependent way in MDCK cells.
All the data above adequately illustrated quercetin could effectively inhibit influenza virus infections and inspired us to further detect the mechanism of quercetin inhibiting influenza virus infections.
In the initial study, we found that quercetin displayed antiviral activity against different influenza virus strains, including H1N1and H3N2, which impelled us to investigate the mechanism of its anti-influenza activity.
Surprisingly, we found that the inhibitory effect of quercetin was enhanced when the virus was pre-incubated with quercetin, or the cell was infected with the virus in the presence of quercetin. The time of the additional assay indicated that quercetin effectively inhibited virus infection when it was added during virus entry stage, while the inhibitory effects of other stages were less clear.
On the basis of the above results, we wondered whether quercetin targeted the virion or the cell.
Through three different modes of treatment, namely co-treatment, pre-treatment of cells and pre-treatment of virus, we found that quercetin targeted influenza viral particles instead of the host cell.
Our study demonstrates quercetin is a novel antiviral agent, which may be used as an effective, safe and affordable chemoprophylaxis or treatment of influenza infection. Importantly, quercetin targeting to the HA2 subunit of influenza hemagglutinin provides new insights for the development of a class of anti-influenza fusion inhibitors."
Reposting
The therapeutic effects of sodium cromoglycate against influenza A virus H5N1 in mice
Deping Han, et.al
"Our previous study revealed that mast cells play roles in the pathogenesis of lung injury after H5N1 virus infection by producing proinflammatory mediators including tryptase, histamine, and interferonâÎł (IFNâÎł). In addition, the resulting lung injury was improved by treatment with ketotifen, which inhibits mast cell activation.19
Sodium cromoglycate (SCG) can inhibit degranulation and the release of histamine and inflammatory mediators from mast cells. It is used to treat allergic asthma, allergic rhinitis, small intestine ischemia/reperfusion, allergic conjunctivitis, and contact dermatitis;20, 21, 22, 23, 24 however, its role in the pathogenesis of H5N1 virus infection is unclear.
In this study, we investigated whether SCG has protective effects during the initial process of influenza virus infection and the possible mechanism behind any such effects.
We show that SCG can improve the mouse survival and respiratory pathological changes. Although viral replication was not inhibited, SCG could regulate the expressions of ILâ6, TNFâα, TLR3, and TRIF to alleviate the pathological injury to the nose, trachea, and lungs by reducing the inflammatory response.
Analysis of the respiratory pathological changes after H5N1 infection revealed that there was significant inflammatory cell infiltration in H5N1 virusâinfected mice, whereas fewer pathological changes were observed in SCGâtreated mice.
This suggests that SCG could stabilize mast cells to reduce the release of cytokines and chemokines and alleviate inflammatory cell infiltration in the lungs.
These results further suggest that mast cells are involved in the pathogenesis of H5N1 virus infection and that preventing aberrant inflammation could protect the mice from mortality.
Previous studies reported that cytokine dysregulation contributed to the severity of influenza H5N1 virus infection.
In summary, SCG protected mice effectively from death after H5N1 infection by alleviating inflammatory injury via its function as an inhibitor of mast cell degranulation. These data provide a novel approach for combating highly pathogenic influenza virus infection."
Movie Night
Cryogenic Electron Microscope 3D reconstruction movies of SARS CoV-2 virus protein spike that infects the target cell.
UT Austin, Jason S. McLellan
https://science.sciencemag.org/content/367/6483/1260
https://science.sciencemag.org/content/367/6483/1260/tab-figures-data
Movie S1 CryoSPARC 3D variability analysis side-view. 2019-nCoV S trimer viewed from the side, along the viral membrane.
https://science.sciencemag.org/content/sci/suppl/2020/02/18/science.abb2507.DC1/abb2507s1.mov
Movie S2 CryoSPARC 3D variability analysis top-view. 2019-nCoV S trimer viewed from the top, toward the viral membrane
https://science.sciencemag.org/content/sci/suppl/2020/02/18/science.abb2507.DC1/abb2507s2.mov
Historic Perspective 1918
Repost
Mast cell profile in appendicitis
Saini Kr. Seemant
Introduction: Today appendicitis remains the most common indication for emergency laparotomy, especially in the young. Mast cell is one of the most important cells of inflammation and acute appendicitis is triggered by Type-1 hypersensitivity reaction and infection is later consequence. Materials and Method ï· In the present study mast cell number & distribution in surgically resected appendix were studied to see variation in normal & inflamed appendix, in Department of pathology Mahadevappa Rampure Medical College, Kalaburagi. ï· 180 appendicectomy specimen received from Oct 2015 to Oct 2016.Routine Hematoxylin & Eosin section for histopathology and 1% aqueous toluidine blue was used to study mast cells. ï· These cases were divided into two groups, Group A: Acute appendicitis showing neutrophilic infiltration-Group A1, with eosinophilic infiltrate-Group A2 Group B: Chronic appendicitis showing lympho mononuclear infiltrate and fibrosis. ï· Mast cells were counted in 10 consecutive high power fields and number were assessed and recorded semi-quantitatively. Results: There is variation in mast cell counts in appendicitis as observed in present study. In acute appendicitis, mucosal and sub mucosal mast cell counts were decreased. Eosinophilic appendicitis showed increased number of eosinophils in mucosal and sub mucosal layer but mean mast cell counts were decreased. In chronic appendicitis was excessive lympho mononuclear infiltrate in mucosal and sub mucosal layer & mean mast cell counts were highest. Conclusion: Our study concluded that acute appendicitis is IgE mediated type 1 hypersensitivity reaction and mast cells count showed variations in different form of appendicitis
Mast Cell Responses to Viruses and Pathogen Products
Jean S. Marshall, Liliana Portales-Cervantes, and Edwin Leong
Mast cells are well accepted as important sentinel cells for host defence against selected pathogens. Their location at mucosal surfaces and ability to mobilize multiple aspects of early immune responses makes them critical contributors to effective immunity in several experimental settings. However, the interactions of mast cells with viruses and pathogen products are complex and can have both detrimental and positive impacts. There is substantial evidence for mast cell mobilization and activation of effector cells and mobilization of dendritic cells following viral challenge. These cells are a major and under-appreciated local source of type I and III interferons following viral challenge. However, mast cells have also been implicated in inappropriate inflammatory responses, long term fibrosis, and vascular leakage associated with viral infections. Progress in combating infection and boosting effective immunity requires a better understanding of mast cell responses to viral infection and the pathogen products and receptors we can employ to modify such responses. In this review, we outline some of the key known responses of mast cells to viral infection and their major responses to pathogen products. We have placed an emphasis on data obtained from human mast cells and aim to provide a framework for considering the complex interactions between mast cells and pathogens with a view to exploiting this knowledge therapeutically. Long-lived resident mast cells and their responses to viruses and pathogen products provide excellent opportunities to modify local immune responses that remain to be fully exploited in cancer immunotherapy, vaccination, and treatment of infectious diseases.
The Significance of Mast Cells and Eosinophils Counts in Surgically Resected Appendix
Objectives: The mast cell remains an enigmatic cell, found resident in tissues throughout the body particularly in association with structures such as blood vessels and nerves. Various inflammatory disorders of the intestines, joints and lungs appear to be associated with an increase in mast cell numbers. The study was conducted on vermiform appendix. The present study was undertaken (1) to compare the mast cell and eosinophil counts in various layers of the appendix in various histopathological groups, and (2) to establish the relationship between the numbers of eosinophils and mast cells in the inflamed appendix. Materials and Methods: The material for study consisted of appendix specimens received for histopathological examination in the Department of pathology. A 5 year study was conducted, 3 years retrospective and 2 years prospective. Results: Out of 777 cases studied the incidence of appendicitis is high, in the first and second decades of life and slightly higher in females. Recurrent appendicitis was more common when compared to other inflamed appendices. Conclusions: Eosinophil counts in all the layers were very high in acute eosinophilic appendicitis compared to normal appendices. A higher mast cell count was seen in acute eosinophilic appendicitis and recurrent appendicitis. No correlation was found between mast cell and eosinophilic density. Our observations support the allergic theory of appendicitis rather than the obstructive theory
The Effect of Bacterial, Viral and Fungal Infection on Mast Cell Reactivity in the Allergic Setting
Sarah M. McAlpine, et.al.
Mast cells are one of our more evolutionary conserved
inflammatory cell types, found even in simple organisms
such as tunicates [1] . They act as surveillance cells, recognizing intruders or cell injury and rapidly respond by releasing mediators causing vascular effects, recruiting and
activating other inflammatory cells, and by modulating
an adaptive immune response. Depending on the nature
of the receptor-ligand engagement, there will be a differentially regulated mast cell reaction to the insult, and
thus, induction of diverse responses dictated by the specific trigger. In allergy, mast cells are infamous for their
role as effector cells that cause a harmful reaction through
the release of histamine, lipid mediators and cytokines. It
is less familiar that mast cells appear to have an important role in host defence to pathogens [2] . Many types of
parasites, bacteria, viruses and fungi are recognized by
mast cells. This recognition takes place through 2 major
ways: either via direct binding to the so-called pattern
recognition receptors (PRRs) or via binding of antibody
or complement coated bacteria by Fc receptors or complement receptors on the mast cell surface, respectively. The anti-microbial protective effects of mast cells are, at least
in part, mediated by their fast release of proteases and
cytokines that induce a rapid recruitment of neutrophils
to the site of infection [2] . In addition, mast cells might
also release antibacterial peptides, such as LL-37 [3] , and
the formation of extracellular traps [4] that can directly
inhibit bacterial growth.
Mast cells in human airways: the culprit?
Jonas S. ErjefÀlt
European Respiratory Review 2014 23: 299-307; DOI: 10.1183/09059180.00005014
"By virtue of their undisputed role in allergy, the study of airway mast cells has focused on nasal and bronchial mast cells and their involvement in allergic rhinitis and asthma. However, recent mechanistic and human studies suggest that peripheral mast cells also have an important role in asthma, as well as chronic obstructive pulmonary disease, respiratory infections and lung fibrosis. Pathogenic roles include immune-modulatory, pro-inflammatory and pro-fibrotic activities. Importantly, mast cells also actively downregulate inflammation and participate in the defence against respiratory infections. Another complicating factor is the notorious mast cell heterogeneity, where each anatomical compartment of the lung harbours site-specific mast cell populations.
Alveolar mast cells stand out as they lack the cardinal expression of the high affinity IgE receptor. Supporting the emerging concept of alveolar inflammation in asthma, alveolar mast cells shift to a highly FcϔRI-expressing phenotype in uncontrolled asthma. Site-specific and disease-associated mast cell changes have also recently been described in most other inflammatory conditions of the lung. Thus, in the exploration of new anti-mast cell treatment strategies the search has widened to include the lung periphery and the delicate task of identifying which of the countless potential roles are the critical disease modifying ones in a given clinical situation.
Apart from the acute airway constriction, one hugely important tissue reaction is plasma extravasation [15, 16]. Within seconds, released histamine and serotonin evoke endothelial gap formation in post-capillary venules and extravasation of bulk plasma into the airway wall and lumen, resulting in airway oedema and increased luminal plug formation [15]. Another important, but often neglected, aspect of plasma extravasation is its profound immunological effect. During the immediate extravasation the extracellular matrix and extracellular epithelial spaces will be soaked with plasma proteins that have potent immunological and cytokine-modulating properties, which will greatly facilitate the subsequent leukocyte recruitment and development of a cellular inflammation [15, 16].
The immediate mast cell degranulation is followed by a fast (20â40 min) de novo production of potent leukotrienes and prostaglandins that further aggravate the response. Apart from the classical anaphylactic mediators and proteases, mast cell degranulation also liberates a large number of pre-stored or de novo synthetised cytokines (e.g. tumour necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-13 and IL-17) [2, 14]. These cytokines can contribute to both the initiation of the subsequent late phase reaction as well as maintaining chronic inflammation,
With an ever-present abundance and vast multifunctional capacity, mast cells are most probably involved in most, if not all, types of inflammatory conditions of the respiratory tract. Currently there is rapid progression in the delicate matter of dissecting out and defining the relative importance of the good and bad roles of mast cells in relevant clinical settings. Together with a better understanding of mast cell heterogeneity at the microenvironmental level, this will most likely lead to new treatment strategies for both allergic and nonallergic respiratory diseases."
Role of Pulmonary Mast Cells in Influenza Virus Pathology
Influenza A virus (IAV) is a major cause of seasonal viral respiratory infections. Not only do IAV-induced illnesses have a significant economic impact, but there are also ~36,000 deaths and ~1.7 million hospitalizations each year in the United States alone. Moreover, IAV has the potential to cause global pandemics, which have significantly greater morbidity and mortality. Morbidity and mortality associated with IAV infections is thought be the result of significant immunopathology. It is well defined that IAV strains vary in the severity of lung disease they induce. Thus, the long-term goal of our laboratory is to understand the fine balance between protection and host damage caused by immune responses to IAV infection.
Lung histology stained with Toluidine Blue to identify mast cells (purple granules) identifying intact mast cells (left) or a degranulating mast cell (right) during IAV infection.
Our data demonstrate that mast cells are critical for initiating the inflammatory immunopathology induced by influenza virus in a virus strain-specific manner. Thus the goal of is project is to elucidate the molecular mechanisms responsible for mast cell activation, recruitment, and activity during IAV infection. Importantly, we hope to elucidate the factor(s) which mast cells produce that drives pathological lung damage and systemic disease in hopes of discovering novel therapeutic targets. These studies will offer novel insights into the mechanisms of mast cell activation and function during respiratory viral infection and could help us understand why certain human populations (i.e. asthmatic individuals) may develop more severe IAV-induced disease.
Mast cells in human airways: the culprit?
Jonas S. ErjefÀlt
European Respiratory Review 2014 23: 299-307; DOI: 10.1183/09059180.00005014
"By virtue of their undisputed role in allergy, the study of airway mast cells has focused on nasal and bronchial mast cells and their involvement in allergic rhinitis and asthma. However, recent mechanistic and human studies suggest that peripheral mast cells also have an important role in asthma, as well as chronic obstructive pulmonary disease, respiratory infections and lung fibrosis. Pathogenic roles include immune-modulatory, pro-inflammatory and pro-fibrotic activities. Importantly, mast cells also actively downregulate inflammation and participate in the defence against respiratory infections. Another complicating factor is the notorious mast cell heterogeneity, where each anatomical compartment of the lung harbours site-specific mast cell populations.
Alveolar mast cells stand out as they lack the cardinal expression of the high affinity IgE receptor. Supporting the emerging concept of alveolar inflammation in asthma, alveolar mast cells shift to a highly FcϔRI-expressing phenotype in uncontrolled asthma. Site-specific and disease-associated mast cell changes have also recently been described in most other inflammatory conditions of the lung. Thus, in the exploration of new anti-mast cell treatment strategies the search has widened to include the lung periphery and the delicate task of identifying which of the countless potential roles are the critical disease modifying ones in a given clinical situation.
Apart from the acute airway constriction, one hugely important tissue reaction is plasma extravasation [15, 16]. Within seconds, released histamine and serotonin evoke endothelial gap formation in post-capillary venules and extravasation of bulk plasma into the airway wall and lumen, resulting in airway oedema and increased luminal plug formation [15]. Another important, but often neglected, aspect of plasma extravasation is its profound immunological effect. During the immediate extravasation the extracellular matrix and extracellular epithelial spaces will be soaked with plasma proteins that have potent immunological and cytokine-modulating properties, which will greatly facilitate the subsequent leukocyte recruitment and development of a cellular inflammation [15, 16].
The immediate mast cell degranulation is followed by a fast (20â40 min) de novo production of potent leukotrienes and prostaglandins that further aggravate the response. Apart from the classical anaphylactic mediators and proteases, mast cell degranulation also liberates a large number of pre-stored or de novo synthetised cytokines (e.g. tumour necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-13 and IL-17) [2, 14]. These cytokines can contribute to both the initiation of the subsequent late phase reaction as well as maintaining chronic inflammation,
With an ever-present abundance and vast multifunctional capacity, mast cells are most probably involved in most, if not all, types of inflammatory conditions of the respiratory tract. Currently there is rapid progression in the delicate matter of dissecting out and defining the relative importance of the good and bad roles of mast cells in relevant clinical settings. Together with a better understanding of mast cell heterogeneity at the microenvironmental level, this will most likely lead to new treatment strategies for both allergic and nonallergic respiratory diseases."
One effective approach to Social Distancing, particularly when the other now Extinct Dinosaurs tended to gather in Herds and couldnât or didnât Wash their Hands!
They couldnât really tap them on the shoulders either with their tiny little arms now, could they?
Those who just canât hunker down and stay home (oh and the news media as a given)
Considering mean viral particle diameters are 0.3 nanometers freaking amazing. #cryoEM. #physicsrules #youronlyasgoodasthereachofyourtools