From Facebook

General
1092

Neutrophil Defensins Induce Histamine Secretion from Mast Cells: Mechanisms of Action

A. Dean Befus, Connie Mowat, Mark Gilchrist, Jing Hu, Samuel Solomon, and Andrew Bateman

Immunol 1999; 163:947-953; ; http://www.jimmunol.org/content/163/2/947

Defensins are endogenous antimicrobial peptides stored in neutrophil granules. Here we report that a panel of defensins from human, rat, guinea pig, and rabbit neutrophils all have histamine-releasing activity, degranulating rat peritoneal mast cells with EC50 ranging from 70 to 2500 nM, and between 45 and 60% of the total histamine released.

Activation of mast cells by cross-linkage of surface IgE with specific Ag is widely recognized as a major pathway for the induction of inflammatory responses, particularly immediate hypersensitivity reactions (1, 2).

There are other pathways of mast cell activation, (2±4) but, unfortunately, little is known about the significance of these in host defenses or in the pathogenesis of inflammatory diseases. For example, Askenase and co-workers (5) have identifed an Ag-specific, T cell derived factor that can sensitize mouse mast cells and together with Ag selectively induce serotonin release as opposed to histamine secretion.

Several other secretagogues can activate selected mast cell populations, including anaphylatoxins (C3a and C5a), neuropeptides (substance P, neurotensin, vasoactive intestinal peptide, somatostatin, etc.), bee venom peptides, 48/80, polylysine, and polymyxin (2±4, 6±10).

Many of these secretagogues share the characteristic of being polycations. Recent evidence suggests that they act by direct stimulation of G proteins of the Gi subtype following their binding to complementary cell surface sites, not to classical receptors (7, 10±13).

The pathway of activation involved is distinct from that of IgE-dependent mast cell activation.

1093

Fennel Oil in Perfumes and Italian Sausage will put me into anaphylaxsis. But I skin test negative. Beware Skin tests.

https://www.semanticscholar.org/paper/Toothpaste-allergy-diagnosis-and-management.-Zirwas-Otto/2c6337e31a6e2e8e40989fa4cd808d43e2bda123&ved=2ahUKEwjqxIuako7qAhUHRqwKHeMICh0QFjAJegQIBRAI&usg=AOvVaw0WNdeoTwlvEe-9EipEqfl9&cshid=1592578978593

1094

H1‐antihistamines for primary mast cell activation syndromes: a systematic review

U. B. Nurmatov

E. Rhatigan

F. E. R. Simons

A. Sheikh

First published:11 June 2015

https://doi.org/10.1111/all.12672

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12672

1095

Not 100 percent correct but useful reference. Recent aerosol shows over 8 hrs viability.

1096

Antibody Persistence and Cross Reactivity.

Normal HCoV antibodies for 229E and OC43 strains have 6 month to 3 yrs significant persistence depending on the severity of infection.

"Most long-term studies found that IgG waned over time (typically detectable up to at least a year) while others found detectable levels of IgG three years post symptoms onset.

Antibody kinetics varied across the severity gradient with longer durations of detectable antibody associated with more severe symptoms. Human challenge studies with HCoV indicate that serum and mucosal immune responses (serum IgG, IgA, neutralizing titer, mucosal IgA) provide possible correlates of protection from infection and disease.

However, repeat human challenge experiments with single HCoV suggest individuals can be infected with the same HCoV one year after first challenge, but with possible lower severity.

There is cross-reactivity within but minimal reactivity between Alpha- and Beta-CoVs. While endemic HCoVs rarely induce cross-reactive antibodies against emerging HCoVs, SARS-CoV-1 and MERS-CoV stimulate antibodies induced by prior HCoV infections.

Multiple mechanisms for immunopathology have been suggested but no strong causal evidence exists and the extent to which the presence of antibodies affects human disease severity is not known.

Seroprevalence with the four major endemic HCoV strains rose rapidly during childhood and remained high in adults. The median age at first infection with any strain was 4.8 years (95% CI 2.5, 11.2). There was no clear trend in seroincidence with age, and many studies have demonstrated incidence of coronavirus infections in elderly populations.

These results suggest a measurable impact of immunity to coronaviruses on future risk, but this protection may be transient. "

Serology studies by Scripps folks of samples from California patients prior to SARS-COV-2 onset found a 50% level of HCoV Betacorona virus antibodies (229E/OC43) in 50% of the patients.

So half level immunity to CD4+ antibody with cross reactivity.

So the bad corona virus cold Johnny or Suzie dragged home from day care or school last year and shared, may explain the high amount of asymptomatic infections of CoV-2.

That bad cold your toddler child or grandchild brought home from daycare​:+1::+1::+1::heart:.

Cross reactive antibodies to the “benign” cold causing human corona viruses evidently showed up in patients blood BEFORE they were exposed to the new SARS COV-2 Corona Virus.

That may be why so many infected folks may not have had the severe symptoms others have had. They may had some level of antibodies that did some work.

1097

Lot of ignorance out there about effectiveness of face masks. Here is one of the gold standard references. BTW median dry particle diameter for SARS CoV-2 is 125 nanometers, 0.125 microns. Droplets of speech spit ~100 microns.
…
A comparison of facemask and respirator filtration test methods

Samy Rengasamy, Ronald Shaffer, Brandon Williams & Sarah Smit

"…Filtration efficiencies of “N95 Filtering Facepiece Respirators” including six N95 FFR models and three surgical N95 FFR models, and three Surgival Masks (SM) models were measured using the NIOSH NaCl aerosol test method, and FDA required particulate filtration efficiency (PFE) and bacterial filtration efficiency (BFE) methods, and viral filtration efficiency (VFE) method.

Five samples of each model were tested using each method. Both PFE and BFE tests were done using unneutralized particles as per FDA guidance document.

PFE was measured using 0.1 µm size polystyrene latex particles and BFE with ∼3.0 µm size particles containing Staphylococcus aureus bacteria. VFE was obtained using ∼3.0 µm size particles containing phiX 174 as the challenge virus and Escherichia coli as the host.

Results showed that the efficiencies measured by the NIOSH NaCl method for “N95 FFRs” were from 98.15–99.68% compared to 99.74–99.99% for PFE, 99.62–99.9% for BFE, and 99.8–99.9% for VFE methods. Efficiencies by the NIOSH NaCl method were significantly (p = <0.05) lower than the other methods.

SMs showed lower efficiencies (54.72–88.40%) than “N95 FFRs” measured by the NIOSH NaCl method, while PFE, BFE, and VFE methods produced no significant difference." [1]
…

So if we’re both wearing suboptimal cheap Chinese Surgical Masks the worst case is : VFE=0.55

Probability of infection particle transmission is Pvinf=1-0.55=0.45;

So the probability of my viral infected particle droplet exhalation getting through my mask AND your mask is 0.45x0.45=0.2025 => 20% .

Not counting a 6 foot separation reduction of probability to 0.13 (13%). [2]

Just wearing crappy masks reduces probability of you ingesting 1000 virion particles from my infected breath to 20%

Adding distancing: The risk of being infected is estimated to be 13% within 1m, but only 3% beyond that distance.

So taken together:

P(Mask) x P(Separation)= 0.20x0.13=0.026325= 2.6%

<2.6% probability of me infecting you, if we both wear crappy cheap masks and stay 6 feet away.

It’s not politics, it’s just simple math and fluid dynamics for the mathematics and logically challenged.

[1] Samy Rengasamy, Ronald Shaffer, Brandon Williams & Sarah Smit (2017) A comparison of facemask and respirator filtration test methods, Journal of Occupational and Environmental Hygiene, 14:2, 92-103, DOI: 10.1080/15459624.2016.1225157

[2] David Shukman, BBC Science editor
Coronavirus: Could social distancing of less than two metres work?, Redirect Notice

1098

Mast cell activation syndromes

Cem Akin, MD, PhD
DOI:Redirecting

Journal of Allergy and Clinical Immunology

Volume 140, Issue 2, August 2017, Pages 349-355

Emotional stress and other neuropsychological stressors can be a major trigger of inflammatory processes that contribute to mast cell recruitment and triggers.

According to Dr Akin, "Although general statements of avoidance of specific triggers are not appropriate for all patients, emotional stress is a major trigger factor for all groups of mast cell activation syndromes and therefore should be managed appropriately by using pharmacologic or nonpharmacologic methods.

Possible mechanisms of stress-induced mast cell activation can include corticotropin-releasing factor and substance P."

https://www.jacionline.org/article/S0091-6749(17)31025-4/fulltext

1099

The Genius of N95 Masks

Really Cool Physics Hipster You Tube Video and point of this post!!

The physics & engineering of N95 mask design is pretty incredible.

Most people are Acluistic (Websters Unabridged: One without a clue) about how a mask really works. They think it just blocks the particles like a very fine screen (in a crude or simple cloth mask partially true).

But then if that’s true ( and it’s not, how does it block those submicron virus size particles???). Physics of course! It’s thanks to Maxwell, Newton, and van der Waals. So let’s slow it down, bounce it around, suck it up, and zap it in a mosquito zapping kind of way.
H/T: Andrew Huntington

REFERENCES

10X efficiency of electrically charged fibers

“The electrostatic charge of N95 masks is a major contributor to their filtration efficiency, improving it at least 10-fold over uncharged fabric” (Tsai et al., Journal of Electrostatics 2002; Peter Tsai, personal communication). Prakash Lab COVID-19 Response Group Working Draft

Document on N95 masks: https://docs.google.com/document/d/1a… “Electrostatic charge contributes as much as 95% of the filtration efficiency” Molina, A., Vyas, P., Khlystov, N., Kumar, S., Kothari, A., Deriso, D., … & Prakash, M. (2020).

Project 1000 x 1000: Centrifugal melt spinning for distributed manufacturing of N95 filtering facepiece respirators. arXiv preprint arXiv:2004.13494. https://arxiv.org/pdf/2004.13494.pdf Tsai, P. P., Schreuder-Gibson, H., & Gibson, P. (2002).

Different electrostatic methods for making electret filters. Journal of electrostatics, 54(3-4), 333-341. https://www.researchgate.net/profile/… History of Electrets Jefimenko, O. D., & Walker, D. K. (1980). Electrets. The Physics Teacher, 18(9), 651-659. https://aapt.scitation.org/doi/abs/10…

Physics of Air Filtration Hinds, W. C. (1999). Aerosol technology: properties, behavior, and measurement of airborne particles. John Wiley & Sons. https://www.wiley.com/en-us/Aerosol+T…

Scientific consortium for data-driven study of N95: https://www.n95decon.org/

N95 & virus particle sizes Bałazy, A., Toivola, M., Adhikari, A., Sivasubramani, S. K., Reponen, T., & Grinshpun, S. A. (2006). Do N95 respirators provide 95% protection level against airborne viruses, and how adequate are surgical masks?. American journal of infection control, 34(2), 51-57. http://citeseerx.ist.psu.edu/viewdoc/…

Harnish, D. A., Heimbuch, B. K., Husband, M., Lumley, A. E., Kinney, K., Shaffer, R. E., & Wander, J. D. (2013). Challenge of N95 filtering facepiece respirators with viable H1N1 influenza aerosols. Infection Control & Hospital Epidemiology, 34(5), 494-499. https://www.ncbi.nlm.nih.gov/pmc/arti…

Liao, L., Xiao, W., Zhao, M., Yu, X., Wang, H., Wang, Q., … & Cui, Y. (2020). "Can N95 respirators be reused after disinfection? How many times?. ACS nano. https://www.ncbi.nlm.nih.gov/pmc/arti…

Created by Henry Reich

1100

Systemic mastocytosis

Genetic Home Reference NIH https://ghr.nlm.nih.gov/

Systemic mastocytosis is a blood disorder that can affect many different body systems. Individuals with the condition can develop signs and symptoms at any age, but it usually appears after adolescence.

Signs and symptoms of systemic mastocytosis often include extreme tiredness (fatigue), skin redness and warmth (flushing), nausea, abdominal pain, bloating, diarrhea, the backflow of stomach acids into the esophagus (gastroesophageal reflux), nasal congestion, shortness of breath, low blood pressure (hypotension), lightheadedness, and headache. Some affected individuals have attention or memory problems, anxiety, or depression.

Many individuals with systemic mastocytosis develop a skin condition called urticaria pigmentosa, which is characterized by raised patches of brownish skin that sting or itch with contact or changes in temperature.

Nearly half of individuals with systemic mastocytosis will experience severe allergic reactions (anaphylaxis).

There are five subtypes of systemic mastocytosis, which are differentiated by their severity and the signs and symptoms

Mutations in additional genes seem to modify the severity of systemic mastocytosis, often resulting in a more aggressive disease and shorter survival. These genes primarily play roles in controlling the proliferation of cells or regulating the activity of other genes that are important in development.

This condition is generally not inherited but arises from a somatic mutation in the body’s cells that occurs after conception.

Learn more about the genes associated with systemic mastocytosis

ASXL1

DNMT3A

KIT

RUNX1

SRSF2

TET2

1101

Familial Occurrence of Systemic Mast Cell Activation Disease

Gerhard J. Molderings, Britta Haenisch, […], and Markus M. Nöthen

The present study aimed to quantify familial aggregation for MCAD and to investigate the variability of clinical and molecular findings (e.g. somatic mutations in KIT) among affected family members in three selected pedigrees.

Our data suggest that systemic MCAD pedigrees include more systemic MCAD cases than would be expected by chance, i.e., compared with the prevalence of MCAD in the general population.

The prevalence of MCAD suspected by symptom self-report in first-degree relatives of patients with MCAD amounted to approximately 46%, compared to prevalence in the general German population of about 17% (p<0.0001). In three families with a high familial loading of MCAD, the subtype of MCAD and the severity of mediator-related symptoms varied between family members.

In addition, genetic alterations detected in KIT were variable, and included mutations at position 816 of the amino acid sequence. In conclusion, our data provide evidence for common familial occurrence of MCAD. Our findings observed in the three pedigrees together with recent reports in the literature suggest that, in familial cases (i.e., in the majority of MCAD), mutated disease-related operator and/or regulator genes could be responsible for the development of somatic mutations in KIT and other proteins important for the regulation of mast cell activity.

Accordingly, the immunohistochemically different subtypes of MCAD (i.e. mast cell activation syndrome and systemic mastocytosis) should be more accurately regarded as varying presentations of a common generic root process of mast cell dysfunction, than as distinct diseases.

1102

Often seen, rarely recognized: mast cell activation disease – a guide to diagnosis and therapeutic options

Lawrence B. Afrin,Joseph H. Butterfield,Martin Raithel &Gerhard J. Molderings

Recent discoveries show a new view of the realm of mast cell disease is in order, with mastocytosis capping a metaphorical iceberg now termed “MC activation disease” (MCAD, i.e. disease principally manifesting inappropriate MC activation) and with the bulk of the iceberg being comprised of the recently recognized “MC activation syndrome” (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation.

Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme, but diagnostic recognition is challenged by great heterogeneity of clinical presentation which may be due to great underlying mutational heterogeneity in assorted mast cell regulatory elements.

Although few biomarkers predictive of helpful therapy are yet available, most MCAD patients are able to eventually identify significantly helpful therapy by persistently and methodically stepping through trials of the many treatments shown helpful across this patient population.

https://www.tandfonline.com/doi/full/10.3109/07853890.2016.1161231%3Fsrc%3Drecsys

1103

Mast Cell Regulatory Gene Variants Are Common in Mast Cell Activation Syndrome

Lawrence B Afrin, MD,
Frank Cichocki, PhD,
Andrea Hoeschen, M.A.,
Kenneth B Beckman, PhD,
Kalpna Gupta, PhD,
Julia Nguyen, BS,
Kevin A Silverstein, PhD,
Lauren J Mills, PhD

MCAS features aberrant MC reactivity and constitutive MC activation with little MC accumulation [Afrin, Ann Med 48:190-201], distinct from mastocytosis (rare and notable for recurrent KIT codon 816 variants).

Studies at Univ. of Bonn [Molderings, Scand J Gastroenterol 42:1045-53 and Immunogenetics 62:721-7] suggest most MCAS patients (pts) bear in peripheral blood (PB) MCs somatic, likely constitutively activating, non-codon-816 variants, and some splicing variants, in mRNA for KIT, the dominant MC regulatory gene (MCRG).

Other studies show most mastocytosis, too, bears variants in many MCRGs beyond KIT [e.g., Soverini, Blood 126:4085], suggesting the same is likely in MCAS.

Confirmation of MCRG variants in MCAS would spur new direction in research in MCAS and chronic inflammatory diseases (CIDs) possibly born of MCAS [Afrin, Transl Res 174:33-59].

We are studying (UMN IRB-approved protocol 2015NTLS023) mRNA for KIT and other MCRGs in PB MCs from MCAS pts and controls (ctls).

https://ashpublications.org/blood/article/128/22/4878/99575/Mast-Cell-Regulatory-Gene-Variants-Are-Common-in

1104

Molecular Diagnosis of Mast Cell Disorders

Journal of Molecular Diagnostics, Vol. 8, No. 4, September 2006 Copyright © American Society for Investigative Pathology and the Association for Molecular Pathology

DOI: 10.2353/jmoldx.2006.060022

The most common molecular abnormality consistently detected in systemic mastocytosis is a somatic point mutation, AT in nucleotide 2468 of c-kit cDNA, affecting codon 816 with resulting replacement of an aspartic acid by valine (D816V)21 (Figure 3).

Codon 816 is a critical residue contributing to the structure of the activation loop of the tyrosine kinase enzymatic domain of Kit by forming a hydrogen bond with N819. Disruption of this bond by replacement of aspartic acid at codon 816 destabilizes the inactive conformation of the kinase domain and results in ligand-independent constitutive activation and autophosphorylation of Kit.22–24

The D816V c-kit mutation accounts for more than 90% of all mutations described in mastocytosis and has been reported in all categories of disease (Table 1). Replacement of D816 by another residue or mutations in extracellular, transmembrane, or juxtamembrane domains of the molecule have also been described (Figure 3).

Some of these unusual c-kit mutations have been detected in a germline pattern, although familial transmission of mastocytosis is rare and has been shown to occur in less than 5% of pediatric-onset disease in several cohorts.

1105

Hematology

Clonal and non-clonal mast cell activation disorders

K. Frank Austen, Cem Akin

Hematology

Clonal and non-clonal mast cell activation disorders

Clonal and non-clonal mast cell activation disorders

What every physician needs to know:

Mast cell activation disorders are a heterogeneous group in which patients present with signs and symptoms of disease mediated by the synthesis and release of activation products such as reformed vasoactive amines, newly generated arachidonic acid derived mediators, and induced cytokines.

Mast cell activation may occur via immunoglobulin E (IgE) and/or non-IgE mediated mechanisms in the presence of clonal or non-clonally derived mast cells in tissues.

The majority of patients with symptoms due to mast cell activation have non-clonal disorders such as those mediated by specific IgE (for example, against inhalant or food allergens, Hymenoptera venom, or medications), and are cared for by allergists/immunologists.

Occasionally, a patient with episodic, recurrent mast cell activation may have an unremarkable work-up for allergic causes and have no evidence of clonal mast cell disease.

These patients are considered for diagnoses of idiopathic anaphylaxis or idiopathic non-clonal mast cell activation syndrome, depending on the severity of presenting symptoms.

https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/hematology/clonal-and-non-clonal-mast-cell-activation-disorders/

1106

If you are allergic to venomous creatures, this might be interesting.

1107

Does anyone else hear Pac Man music and wockawockawocka…in their heads while watching this…

1108

Walnut Brownies, never again.

1109

Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer’s Disease Pathogenesis

Duraisamy Kempuraj, Govindhasamy P. Selvakumar, et.al.

REVIEW ARTICLE

Front. Neurosci., 12 December 2017 | Frontiers | Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer's Disease Pathogenesis

Mast cells are localized throughout the body and mediate allergic, immune, and inflammatory reactions. They are heterogeneous, tissue-resident, long-lived, and granulated cells.

Mast cells increase their numbers in specific site in the body by proliferation, increased recruitment, increased survival, and increased rate of maturation from its progenitors.

Mast cells are implicated in brain injuries, neuropsychiatric disorders, stress, neuroinflammation, and neurodegeneration. Brain mast cells are the first responders before microglia in the brain injuries since mast cells can release prestored mediators.

Mast cells also can detect amyloid plaque formation during Alzheimer’s disease (AD) pathogenesis. Stress conditions activate mast cells to release prestored and newly synthesized inflammatory mediators and induce increased blood-brain barrier permeability, recruitment of immune and inflammatory cells into the brain and neuroinflammation.

Stress induces the release of corticotropin-releasing hormone (CRH) from paraventricular nucleus of hypothalamus and mast cells. CRH activates glial cells and mast cells through CRH receptors and releases neuroinflammatory mediators.

Stress also increases proinflammatory mediator release in the peripheral systems that can induce and augment neuroinflammation.

1110

Skaper, Stephen & Facci, Laura & Giusti, Pietro. (2014).

Neuroinflammation, Microglia and Mast Cells in the Pathophysiology of Neurocognitive Disorders: A Review.

CNS & neurological disorders drug targets. 13. 10.2174/1871527313666141130224206.

"Cells of the immune system and the central nervous system are capable of interacting with each other. The former cell populations respond to infection, tissue injury and trauma by releasing substances capable of provoking an inflammatory reaction.

Inflammation is a key element in the pathobiology of chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders such as anxiety/depression and schizophrenia.

Neuroinflammation may also raise the brain’s sensitivity to stress, resulting in stress-related neuropsychiatric disorders, such as anxiety or depression.

The cytokine network plays a large part in how immune system cells influence the central nervous system. Further, inflammation resulting from activation of innate immune system cells in the periphery can impact on central nervous system behaviors, such as depression and cognitive performance.

In this review, we will present the reader with the current state of knowledge which implicates both microglia and mast cells, two of the principle innate immune cell populations, in neuroinflammation.

Further, we shall make the case that dysregulation of microglia and mast cells may impact cognitive performance and, even more importantly, how their cell-cell interactions can work to not only promote but also amplify neuroinflammation.

Finally, we will use this information to provide a starting point to propose therapeutic approaches based upon naturally-occurring lipid signaling molecules."

https://www.researchgate.net/profile/Stephen_Skaper2/publication/269189553_Neuroinflammation_Microglia_and_Mast_Cells_in_the_Pathophysiology_of_Neurocognitive_Disorders_A_Review/links/568e536308aef987e567ac26/Neuroinflammation-Microglia-and-Mast-Cells-in-the-Pathophysiology-of-Neurocognitive-Disorders-A-Review.pdf

1111

Stress triggers coronary mast cells leading to cardiac events

Michail Alevizos, MD, Anna Karagkouni, MD; Smaro Panagiotidou, MA; Magdalini Vasiadi, DSc; and Theoharis C. Theoharides, MS, PhD, MD

Annnals of American College of Allergy, Asthma & Immunology. Redirecting

"Mast cells are well known for their role in the pathogenesis of allergic reactions, but MCs are currently considered important in innate and acquired immunity, antigen presentation, and inflammation.

MCs originate from hemopoietic stem cells that differentiate in tissues under the influence of various tissue microenvironmental conditions, including nerve growth factor and mainly stem cell factor.

MCs also are present in the heart, and cardiac MCs have been shown to differ from other connective tissue MCs in that they are not stimulated by morphine.

MCs are present, especially in coronary arteries, during spasm, accumulate in the rupture-prone shoulder region of coronary atheromas (Fig 1), and are associated specifically with plaque erosion and rupture.

Degranulated MCs have been identified in the adventitia of vulnerable and ruptured lesions in patients with MI. MCs can be triggered by many molecules relevant to CAD, such as oxidized low-density lipoprotein (LDL) and complement fragment 5a, which has been implicated in ruptured coronary plaques in MI (Fig 2).

Adventitial MCs are localized close to nerve endings in atherosclerotic coronary arteries and correlate with the number of nerve fibers. Nerve fibers immunoreactive for NTare also present in the heart, and NT can trigger coronary vasoconstriction."

http://citeseerx.ist.psu.edu/viewdoc/download%3Fdoi%3D10.1.1.718.1280%26rep%3Drep1%26type%3Dpdf