scholarly journals Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine

2021 ◽  
Vol 22 (22) ◽  
pp. 12345
Author(s):  
Anita Sapoznikov ◽  
Yoav Gal ◽  
Yentl Evgy ◽  
Moshe Aftalion ◽  
Shahaf Katalan ◽  
...  
Keyword(s):  
Ricinus Communis ◽  
Lethal Dose ◽  
Clinical Manifestations ◽  
Dark Field ◽  
Endothelial Glycocalyx ◽  
Microscopy Imaging ◽  
Ricin Toxin ◽  
Side Stream ◽  
Clinical Consequences ◽  
Microcirculation Dysfunction

Ricin toxin isolated from the castor bean (Ricinus communis) is one of the most potent and lethal molecules known. While the pathophysiology and clinical consequences of ricin poisoning by the parenteral route, i.e., intramuscular penetration, have been described recently in various animal models, the preceding mechanism underlying the clinical manifestations of systemic ricin poisoning has not been completely defined. Here, we show that following intramuscular administration, ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages. Increased levels of circulating VEGF and decreased expression of vascular VE-cadherin caused blood vessel impairment, thereby promoting hyperpermeability in various organs. Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication, indicating that the vascular glycocalyx of both mice and swine underwent extensive damage. Finally, by using side-stream dark field intravital microscopy imaging, we determined that ricin poisoning leads to microvasculature malfunctioning, as manifested by aberrant blood flow and a significant decrease in the number of diffused microvessels. These findings, which suggest that glycocalyx shedding and microcirculation dysfunction play a major role in the pathology of systemic ricin poisoning, may serve for the formulation of specifically tailored therapies for treating parenteral ricin intoxication.

PRECLINICAL STUDY OF THE VETERINARY DRUGS TOXICITY

1970 ◽  
pp. 61-64
Author(s):  
E. K. Rakhmatullin ◽  
O. D. Sklyarov
Keyword(s):  
Lethal Dose ◽  
Clinical Manifestations ◽  
Preclinical Study ◽  
Veterinary Drugs ◽  
Toxic Effects ◽  
Laboratory Animals ◽  
Therapeutic Effects ◽  
Significant Information ◽  
Important Indicator ◽  
Organ Systems

Preclinical study of the drugs toxicity was analysed it allows predicting the safety of veterinary drugs in laboratory animals. The fundamental normative instruments in the field of preclinical study of drugs for veterinary medicine and animal husbandry are Order of the Ministry of Agriculture of the Russian Federation dated 06.03.2018 N 101 and GOST 33044-2014 Principles of Good Laboratory Practice. An important indicator of the preclinical study of the veterinary drugs is the determination (calculation) of median lethal dose value (lethal dose for half of the animals tested) or concentration (LD50 or LC50). Existing methods for determining this indicator make it possible at the initial study stage to determine the degree and class the drug of toxicity. Studying the symptoms of intoxication in the analysis of pharmacological substances one obtains significant information about the nature of the action of the future drug. The clinical manifestations of intoxication with damage to various organ systems are presented. As criteria for assessing the toxic effects of veterinary drugs it is recommended to determine LD50, cumulation coefficient, latitude index of therapeutic effects, dose level of toxic effects in the experiment which allows predicting the nature and degree of toxic effects of the drug even at the stage of preclinical veterinary drugs study.

Abstract MP61: Evidence of Impaired Microvascular Function a Decade After Delivery in Women With Placental Malperfusion Lesions

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Alisse Hauspurg ◽  
Judith Brands ◽  
Robin Gandley ◽  
Matthew F Muldoon ◽  
William Tony Parks ◽  
...  
Keyword(s):  
Disease Risk ◽  
Gestational Hypertension ◽  
Boundary Region ◽  
Dark Field ◽  
Endothelial Glycocalyx ◽  
Sidestream Dark Field ◽  
Sublingual Microcirculation ◽  
Dark Field Imaging ◽  
Median Diameter ◽  
History Of

Introduction: Maternal vascular malperfusion (MVM) lesions in the placenta are characterized by incomplete vascular remodeling and vessel features similar to atherosclerosis. MVM lesions indicate a maladaptive maternal vascular response to pregnancy, are often detected in hypertensive disorders of pregnancy (HDP), and may provide a pathologic link to future cardiovascular disease. The endothelial glycocalyx is a glycoprotein-rich layer that is critical for microvascular health and damage may have an important role in the pathophysiology of microcardiovascular disease risk. Hypothesis: We hypothesized that women with malperfusion lesions of the placenta are more likely to evidence microvascular glycocalyx derangement a decade after delivery compared to women without these lesions and that this effect would be most pronounced among women with a history of HDP. Methods: A total of 412 women with placental pathology (N=129 with MVM lesions, N=283 without MVM lesions) were evaluated at 8-10 years postpartum. Placental specimens were reviewed by a blinded perinatal pathologist . HDP (including preeclampsia and gestational hypertension) were abstracted from the medical record. Glycocalyx barrier function was assessed using sublingual sidestream dark field imaging, with reduction defined as deeper penetration of red blood cells (RBCs) into the glycocalyx of the sublingual microcirculation (5-25μm diameter). We compared the median diameter (size) of microvessels, penetration of RBCs into the glycocalyx (perfused boundary region, PBR) and microvascular density (total length of perfused microvessels/mm 2 surface area) in women with and without MVM lesions. Results: Women with placental MVM lesions had smaller-sized sublingual vessels (median 8.59 μM [IQR 8.12, 9.19] vs. 9.01 μM [IQR 8.37, 9.64]; p<0.001), and a lower density of vessels compared to women without lesions. Glycocalyx perfused boundary region was unexpectedly lower in women with MVM lesions (median 2.20 μM [IQR 2.06, 2.43] vs. 2.32 μM [IQR 2.15, 2.50]; p=0.003) in 10-19 μM vessels. Women with HDP and MVM lesions appear to be the most impacted, with the smallest size vessels (median 8.47 [IQR 8.09-9.13]) and the lowest glycocalyx PBR across all vessel sizes. Women with MVM lesions without a HDP similarly had evidence of microvascular glycocalyx derangement whereas women with HDP without placental lesions had a glycocalyx profile similar to women without MVM or a history of HDP. Conclusions: A decade after delivery, women with a history of placental malperfusion lesions had alterations in microvascular perfusion. Women with MVM lesions and a history of HDP appear to be the most severely impacted, which may reflect an underlying maladaptive vascular phenotype detected in the placenta at the time of pregnancy that might provide pathologic insight into future maternal microvascular health.

scholarly journals Effects of high-intensity interval training on microvascular glycocalyx and associated microRNAs

2019 ◽  
Vol 316 (6) ◽  
pp. H1538-H1551 ◽  
Author(s):  
Boris Schmitz ◽  
Hannah Niehues ◽  
Malte Lenders ◽  
Lothar Thorwesten ◽  
Andreas Klose ◽  
...  
Keyword(s):  
High Intensity ◽  
Interval Training ◽  
Dark Field ◽  
Endothelial Glycocalyx ◽  
High Intensity Interval Training ◽  
Sidestream Dark Field ◽  
Sidestream Dark Field Imaging ◽  
High Intensity Interval ◽  
Glycocalyx Thickness

High-intensity interval training (HIIT) has been proposed to exert vasculoprotective effects. This study aimed to evaluate whether HIIT affects the microvasculature, including the endothelial glycocalyx barrier, and to identify associated microRNAs (miRNAs). Fifty healthy participants (23.1 ± 3.0 yr) performed a 4-wk 4 × 30-s all-out running HIIT. Sidestream dark-field imaging was performed at baseline and follow-up to detect changes of the sublingual microvasculature including the endothelial glycocalyx. Exercise parameters were determined by continuous running field test and documentation of high-intensity runs. miRNAs potentially associated with glycocalyx thickness were selected by structured literature search and blood samples for miRNA, and lactate measurements were drawn at baseline and follow-up HIIT. At baseline, a correlation between maximal exercise performance capacity and glycocalyx thickness (determined by perfused boundary region) was detected ( P = 0.045, r = 0.303). Increased exercise performance at follow-up also correlated with glycocalyx thickness ( P = 0.031, r = 0.416), and increased high-intensity sprinting speed was associated with an increased number of perfused vessels ( P = 0.0129, r = 0.449). Literature search identified miR-143, -96-5p, and -24, which were upregulated by HIIT already at baseline and showed an association with peak blood lactate levels after sprints (all P < 0.05). Moreover, increased baseline miR-143 levels predicted increased glycocalyx thickness at follow-up (AUCmiR-143 = 0.92, 95% confidence interval, 0.81–1.0, P = 0.0008). Elevated resting miR-126 levels after the intervention were associated with cell-free versican mRNA levels. We conclude that HIIT induces changes in the endothelial glycocalyx of the microvasculature. Associated miRNAs such as miR-143 may represent a tool for monitoring early vasculoprotective adaptations to physical activity. NEW & NOTEWORTHY High-intensity interval training is known to improve health-related fitness in general and in lifestyle-induced chronic diseases. To visualize microvasculature structure and to detect exercise-induced changes, sublingual sidestream dark-field imaging microscopy was used, and circulating miRNAs were measured. This study shows that exercise-induced changes correlate with associated circulating miRNA, which might be useful for monitoring vasculoprotective effects. Furthermore, sidestream dark-field imaging may represent a sensitive tool for the early detection of exercise-induced systemic vascular changes.

scholarly journals Introduction to the Toxins Special Issue “Ricin Toxins”

Toxins ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 13 ◽  
Author(s):  
Nilgun E. Tumer
Keyword(s):  
Castor Bean ◽  
Ricinus Communis ◽  
Special Issue ◽  
Ricin Toxin

Ricin toxin isolated from the castor bean (Ricinus communis) is one of the most potent and lethal molecules known [...]

scholarly journals Development of a bioassay to quantify the ricin toxin content of castor bean (Ricinus communis L.) seeds

2012 ◽  
Vol 34 (4) ◽  
Author(s):  
Carlos Alberto Rauer Demant ◽  
Dick Auld ◽  
Aline Rodrigues de Mello Demant
Keyword(s):  
Castor Bean ◽  
Ricinus Communis ◽  
Ricin Toxin ◽  
Toxin Content ◽  
Ricinus Communis L

scholarly journals Effect of the Route of Administration of the Vaccinia Virus Strain LIVP to Mice on Its Virulence and Immunogenicity

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 795
Author(s):  
Sergei N. Shchelkunov ◽  
Stanislav N. Yakubitskiy ◽  
Alexander A. Sergeev ◽  
Alexei S. Kabanov ◽  
Tatiana V. Bauer ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Vaccinia Virus ◽  
Vaccination Campaign ◽  
Lethal Dose ◽  
Clinical Manifestations ◽  
Immune Defense ◽  
Smallpox Vaccination ◽  
Laboratory Animals ◽  
Optimal Method ◽  
Clonal Variant

The mass smallpox vaccination campaign has played a crucial role in smallpox eradication. Various strains of the vaccinia virus (VACV) were used as a live smallpox vaccine in different countries, their origin being unknown in most cases. The VACV strains differ in terms of pathogenicity exhibited upon inoculation of laboratory animals and reactogenicity exhibited upon vaccination of humans. Therefore, each generated strain or clonal variant of VACV needs to be thoroughly studied in in vivo systems. The clonal variant 14 of LIVP strain (LIVP-14) was the study object in this work. A comparative analysis of the virulence and immunogenicity of LIVP-14 inoculated intranasally (i.n.), intradermally (i.d.), or subcutaneously (s.c.) to BALB/c mice at doses of 108, 107, and 106 pfu was carried out. Adult mice exhibited the highest sensitivity to the i.n. administered LIVP-14 strain, although the infection was not lethal. The i.n. inoculated LIVP-14 replicated efficiently in the lungs. Furthermore, this virus was accumulated in the brain at relatively high concentrations. Significantly lower levels of LIVP-14 were detected in the liver, kidneys, and spleen of experimental animals. No clinical manifestations of the disease were observed after i.d. or s.c. injection of LIVP-14 to mice. After s.c. inoculation, the virus was detected only at the injection site, while it could disseminate to the liver and lungs when delivered via i.d. administration. A comparative analysis of the production of virus-specific antibodies by ELISA and PRNT revealed that the highest level of antibodies was induced in i.n. inoculated mice; a lower level of antibodies was observed after i.d. administration of the virus and the lowest level after s.c. injection. Even at the lowest studied dose (106 pfu), i.n. or i.d. administered LIVP-14 completely protected mice against infection with the cowpox virus at the lethal dose. Our findings imply that, according to the ratio between such characteristics as pathogenicity/immunogenicity/protectivity, i.d. injection is the optimal method of inoculation with the VACV LIVP-14 strain to ensure the safe formation of immune defense after vaccination against orthopoxviral infections.

scholarly journals Thermostable ricin vaccine protects rhesus macaques against aerosolized ricin: Epitope-specific neutralizing antibodies correlate with protection

2015 ◽  
Vol 112 (12) ◽  
pp. 3782-3787 ◽  
Author(s):  
Chad J. Roy ◽  
Robert N. Brey ◽  
Nicholas J. Mantis ◽  
Kelly Mapes ◽  
Iliodora V. Pop ◽  
...  
Keyword(s):  
Castor Oil ◽  
Mammalian Cells ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Lethal Dose ◽  
Lung Damage ◽  
Ricin Toxin ◽  
A Cell ◽  
A Chain ◽  
Antibody Competition

Ricin toxin (RT) is the second most lethal toxin known; it has been designated by the CDC as a select agent. RT is made by the castor bean plant; an estimated 50,000 tons of RT are produced annually as a by-product of castor oil. RT has two subunits, a ribotoxic A chain (RTA) and galactose-binding B chain (RTB). RT binds to all mammalian cells and once internalized, a single RTA catalytically inactivates all of the ribosomes in a cell. Administered as an aerosol, RT causes rapid lung damage and fibrosis followed by death. There are no Food and Drug Administration-approved vaccines and treatments are only effective in the first few hours after exposure. We have developed a recombinant RTA vaccine that has two mutations V76M/Y80A (RiVax). The protein is expressed in Escherichia coli and is nontoxic and immunogenic in mice, rabbits, and humans. When vaccinated mice are challenged with injected, aerosolized, or orally administered (gavaged) RT, they are completely protected. We have now developed a thermostable, aluminum-adjuvant–containing formulation of RiVax and tested it in rhesus macaques. After three injections, the animals developed antibodies that completely protected them from a lethal dose of aerosolized RT. These antibodies neutralized RT and competed to varying degrees with a panel of neutralizing and nonneutralizing mouse monoclonal antibodies known to recognize specific epitopes on native RTA. The resulting antibody competition profile could represent an immunologic signature of protection. Importantly, the same signature was observed using sera from RiVax-immunized humans.

Progression of carotid near-occlusion to complete occlusion: related factors and clinical implications

2020 ◽  
pp. neurintsurg-2019-015638
Author(s):  
Andrés García-Pastor ◽  
Antonio Gil-Núñez ◽  
José María Ramírez-Moreno ◽  
Noelia González-Nafría ◽  
Javier Tejada ◽  
...  
Keyword(s):  
Collateral Circulation ◽  
Demographic Data ◽  
Clinical Manifestations ◽  
Treatment Modalities ◽  
Clinical Implications ◽  
Related Factors ◽  
Complete Occlusion ◽  
Clinical Consequences ◽  
Near Occlusion

BackgroundThe clinical consequences and factors related to the progression from a carotid near-occlusion (CNO) to a complete occlusion are not well established. Our aim is to describe the rate, predictive factors and clinical implications of the progression to complete carotid occlusion (PCCO) in a population of patients with symptomatic CNO.MethodsWe conducted a multicenter, nationwide, prospective study from January 2010 to May 2016. Patients with angiography-confirmed CNO were included. We collected information on demographic data, clinical manifestations, radiological and hemodynamic findings, and treatment modalities. A 24 month carotid-imaging follow-up of the CNO was performed.Results141 patients were included in the study, and carotid-imaging follow-up was performed in 122 patients. PCCO occurred in 40 patients (32.8%), and was more frequent in medically-treated patients (34 out of 61; 55.7%) compared with patients treated with revascularization (6 out of 61; 9.8%) (p<0.001). 7 of the 40 patients with PCCO (17.5%) suffered ipsilateral symptoms. Factors independently related with PCCO in the multivariate analysis were: age ≥75 years (OR 2.93, 95% CI 1.05 to 8.13), revascularization (OR 0.07, 95% CI 0.02 to 0.20), and collateral circulation through the ipsilateral ophthalmic artery (OR 3.25, 95% CI 1.01 to 10.48).ConclusionsPCCO occurred within 24 months in more than half of the patients under medical treatment. Most episodes of PCCO were not associated with ipsilateral symptoms. Revascularization reduces the risk of PCCO.

scholarly journals Decreased endothelial glycocalyx thickness is an early predictor of mortality in sepsis

2020 ◽  
Vol 48 (3) ◽  
pp. 221-228
Author(s):  
Daniëlle MH Beurskens ◽  
Martine E Bol ◽  
Tammo Delhaas ◽  
Marcel CG van de Poll ◽  
Chris PM Reutelingsperger ◽  
...  
Keyword(s):  
Organ Failure ◽  
Early Stage ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
Dark Field ◽  
Endothelial Glycocalyx ◽  
Pathophysiological Mechanism ◽  
Heparin Binding ◽  
Sidestream Dark Field ◽  
Glycocalyx Thickness

Microcirculatory alterations play an important role in the early phase of sepsis. Shedding of the endothelial glycocalyx is regarded as a central pathophysiological mechanism causing microvascular dysfunction, contributing to multiple organ failure and death in sepsis. The objective of this study was to investigate whether endothelial glycocalyx thickness at an early stage in septic patients relates to clinical outcome. We measured the perfused boundary region (PBR), which is inversely proportional to glycocalyx thickness, of sublingual microvessels (5–25 µm) using sidestream dark field imaging. The PBR in 21 patients with sepsis was measured within 24 h of admission to the intensive care unit (ICU). In addition, we determined plasma markers of microcirculatory dysfunction and studied their correlation with PBR and mortality. Endothelial glycocalyx thickness in sepsis was significantly lower for non-survivors as compared with survivors, indicated by a higher PBR of 1.97 [1.85, 2.19]µm compared with 1.76 [1.59, 1.97] µm, P=0.03. Admission PBR was associated with hospital mortality with an area under the curve of 0.778 based on the receiver operating characteristic curve. Furthermore, PBR correlated positively with angiopoietin-2 (rho=0.532, P=0.03), indicative of impaired barrier function. PBR did not correlate with Acute Physiology and Chronic Health Evaluation IV (APACHE IV), Sequential Organ Failure Assessment score (SOFA score), lactate, syndecan-1, angiopoietin-1 or heparin-binding protein. An increased PBR within the first 24 h after ICU admission is associated with mortality in sepsis. Further research should be aimed at the pathophysiological importance of glycocalyx shedding in the development of multi-organ failure and at therapies attempting to preserve glycocalyx integrity.

New insights into antiphospholipid-related endothelial dysfunction by assessment of vascular glycocalyx layer: results from a preliminary cross-sectional study

Lupus ◽  
2020 ◽  
Vol 29 (2) ◽  
pp. 157-164 ◽  
Author(s):  
S Miranda ◽  
P Billoir ◽  
M Le Besnerais ◽  
R Joannides ◽  
V Richard ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Plasma Level ◽  
Thiobarbituric Acid ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Dark Field ◽  
Endothelial Glycocalyx ◽  
Sidestream Dark Field ◽  
Cross Sectional ◽  
Early Atherosclerosis

Introduction Antiphospholipid syndrome (APS) is associated with greater atherothrombotic risk and endothelial dysfunction, suggesting that endothelial glycocalyx is impaired in this disease. Objectives The aim was to investigate the endothelial glycocalyx and the relationship between glycocalyx markers, endothelial dysfunction parameters and atherosclerotic markers in APS. Methods A total of 15 primary arterial APS patients and healthy controls were included in the study. Glycocalyx was assessed in both groups by sublingual sidestream dark field imaging and syndecan-1 plasma level. Endothelial function was evaluated by brachial artery flow-mediated dilatation (FMD) and early atherosclerosis by carotid intima media thickness (IMT). Thrombotic profile was also performed by measuring the plasma level of the tissue factor (TF). Results APS patients had significantly increased syndecan-1 plasma level 38.6 ± 5.0 pg/ml vs. 19.1 ± 3.5 pg/ml; p < 0.01 and a reduced glycocalyx thickness 0.26 ± 0.03 µm vs. 0.75 ± 0.07 µm; p < 0.01 compared with control. FMD was impaired in APS patients compared with control, 5.68% ± 0.42 vs. 8.29 ± 0.30, p < 0.01, respectively. IMT was significantly increased in APS patients compared with control, 0.52 ± 0.13 mm vs. 0.40 ± 0.06 mm, p < 0.01, respectively. Soluble TF, thiobarbituric acid-reactive substances levels were increased in the sera from APS patients compared with control. Conclusions This preliminary study supports, for the first time, that in APS patients endothelial glycocalyx is impaired, which could lead to thrombosis, endothelial dysfunction and early atherosclerosis.

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