scholarly journals Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Biomedicines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 82 ◽  
Author(s):  
János Szebeni ◽  
Raj Bawa
Keyword(s):  
Disease Model ◽  
Large Body ◽  
Safety Evaluation ◽  
Toxicity Screening ◽  
Global Response ◽  
Highly Sensitive ◽  
Regulatory Bodies ◽  
Infusion Reactions ◽  
Normal Human ◽  
Pulmonary Intravascular Macrophages

Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views challenging the human relevance of the model and its utility in preclinical safety evaluation of nanomedicines. The argument challenging the model refers to the “global response” of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, preventing the distinction of reactogenic from non-reactogenic particles, therefore overestimating the risk of HSRs relative to its occurrence in the normal human population. The goal of this review is to present the large body of experimental and clinical evidence negating the “global response” claim, while also showing the concordance of symptoms caused by different reactogenic nanoparticles in pigs and hypersensitive man. Contrary to the model’s demotion, we propose that the above features, together with the high reproducibility of quantifiable physiological endpoints, validate the porcine “complement activation-related pseudoallergy” (CARPA) model for safety evaluations. However, it needs to be kept in mind that the model is a disease model in the context of hypersensitivity to certain nanomedicines. Rather than toxicity screening, its main purpose is specific identification of HSR hazard, also enabling studies on the mechanism and mitigation of potentially serious HSRs.

Autonomous Vehicles’ Car-Following Drivability Evaluation Based on Driving Behavior Spectrum Reference Model

2021 ◽  
pp. 036119812199485
Author(s):  
Xiao Qi ◽  
Ying Ni ◽  
Yiming Xu ◽  
Ye Tian ◽  
Junhua Wang ◽  
...  
Keyword(s):  
Autonomous Vehicles ◽  
Reference Model ◽  
Numerical Test ◽  
Safety Evaluation ◽  
Driving Behavior ◽  
Car Following ◽  
Driving Behaviors ◽  
Human Driver ◽  
Normal Human ◽  
Naturalistic Driving

A large portion of the accidents involving autonomous vehicles (AVs) are not caused by the functionality of AV, but rather because of human intervention, since AVs’ driving behavior was not properly understood by human drivers. Such misunderstanding leads to dangerous situations during interaction between AV and human-driven vehicle (HV). However, few researches considered HV-AV interaction safety in AV safety evaluation processes. One of the solutions is to let AV mimic a normal HV’s driving behavior so as to avoid misunderstanding to the most extent. Therefore, to evaluate the differences of driving behaviors between existing AV and HV is necessary. DRIVABILITY is defined in this study to characterize the similarity between AV’s driving behaviors and expected behaviors by human drivers. A driving behavior spectrum reference model built based on human drivers’ behaviors is proposed to evaluate AVs’ car-following drivability. The indicator of the desired reaction time (DRT) is proposed to characterize the car-following drivability. Relative entropy between the DRT distribution of AV and that of the entire human driver population are used to quantify the differences between driving behaviors. A human driver behavior spectrum was configured based on naturalistic driving data by human drivers collected in Shanghai, China. It is observed in the numerical test that amongst all three types of preset AVs in the well-received simulation package VTD, the brisk AV emulates a normal human driver to the most extent (ranking at 55th percentile), while the default AV and the comfortable AV rank at 35th and 8th percentile, respectively.

Depletion of pulmonary intravascular macrophages inhibits acute lung inflammation

2004 ◽  
Vol 286 (2) ◽  
pp. L363-L372 ◽  
Author(s):  
Baljit Singh ◽  
Jacqueline W. Pearce ◽  
Lakshman N. Gamage ◽  
Kyathanahalli Janardhan ◽  
Sarah Caldwell
Keyword(s):  
Lung Inflammation ◽  
Acute Inflammation ◽  
Inflammatory Cells ◽  
Acute Lung Inflammation ◽  
Tnf Α ◽  
Highly Sensitive ◽  
In Vitro Exposure ◽  
Pulmonary Intravascular Macrophages

Pulmonary intravascular macrophages (PIMs) are present in ruminants and horses. These species are highly sensitive to acute lung inflammation compared with non-PIM-containing species such as rats and humans. There is evidence that rats and humans may also recruit PIMs under certain conditions. We investigated precise contributions of PIMs to acute lung inflammation in a calf model. First, PIMs were recognized with a combination of in vivo phagocytic tracer Monastral blue and postembedding immunohistology with anti-CD68 monoclonal antibody. Second, gadolinium chloride depleted PIMs within 48 h of treatment ( P < 0.05). Finally, PIMs contain TNF-α, and their depletion reduces cells positive for IL-8 ( P < 0.05) and TNF-α ( P < 0.05) and histopathological signs of acute lung inflammation in calves infected with Mannheimia hemolytica. The majority of IL-8-positive inflammatory cells in lung septa of infected calves were platelets. Platelets from normal cattle contained preformed IL-8 that was released upon in vitro exposure to thrombin ( P < 0.05). These novel data show that PIMs, as the source of TNF-α, promote recruitment of inflammatory cells including IL-8-containing platelets to stimulate acute inflammation and pathology in lungs. These data may also be relevant to humans due to our ability to recruit PIMs.

scholarly journals Pulmonary intravascular macrophages: prime suspects as cellular mediators of porcine CARPA

2015 ◽  
Vol 7 (1) ◽  
Author(s):  
Domokos Csukás ◽  
Rudolf Urbanics ◽  
György Wéber ◽  
László Rosivall ◽  
János Szebeni
Keyword(s):  
Blood Stream ◽  
In Vivo Model ◽  
Coated Nanoparticles ◽  
Pulmonary Vasoconstriction ◽  
Vasoactive Mediators ◽  
Highly Sensitive ◽  
Cellular Mediators ◽  
Pulmonary Arterial ◽  
Pulmonary Intravascular Macrophages

AbstractPigs provide a highly sensitive and quantitative in vivo model for complement (C) activation-related pseudoallergy (CARPA), a hypersensitivity reaction caused by some state-of-art nanomedicines. In an effort to understand the mechanism of the pigs’ unique sensitivity for CARPA, this review focuses on pulmonary intravascular macrophages (PIMs), which are abundantly present in the lung of pigs. These cells represent a macrophage subpopulation whose unique qualities explain the characteristic symptoms of CARPA in this species, most importantly the rapidly (within minutes) developing pulmonary vasoconstriction, leading to elevation of pulmonary arterial pressure. The unique qualities of PIM cells include the following; 1) they are strongly adhered to the capillary walls via desmosome-like intercellular adhesion plaques, which secure stable and lasting direct exposition of the bulk of these cells to the blood stream; 2) their ruffled surface engaged in intense phagocytic activity ensures efficient binding and phagocytosis of nanoparticles; 3) PIM cells express anaphylatoxin receptors, this way C activation can trigger these cells, 4) they also express pattern recognition molecules on their surface, whose engagement with certain coated nanoparticles may also activate these cells or act in synergy with anaphylatoxins and, finally 5) their high metabolic activity and capability for immediate secretion of vasoactive mediators upon stimulation explain the circulatory blockage and other robust physiological effects that their stimulation may cause. These qualities taken together with reports on liposome uptake by PIM cells during CARPA and the possible presence of these cells in human lung suggests that PIM cells may be a potential therapeutic target against CARPA.

scholarly journals hiPSC-Derived Cardiac Tissue for Disease Modeling and Drug Discovery

2020 ◽  
Vol 21 (23) ◽  
pp. 8893
Author(s):  
Junjun Li ◽  
Ying Hua ◽  
Shigeru Miyagawa ◽  
Jingbo Zhang ◽  
Lingjun Li ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cardiac Tissue ◽  
Disease Modeling ◽  
Disease Model ◽  
Induced Pluripotent Stem Cell ◽  
Model Systems ◽  
Toxicity Screening ◽  
The Difference ◽  
Induced Pluripotent ◽  
Novel Drug

Relevant, predictive normal, or disease model systems are of vital importance for drug development. The difference between nonhuman models and humans could contribute to clinical trial failures despite ideal nonhuman results. As a potential substitute for animal models, human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) provide a powerful tool for drug toxicity screening, modeling cardiovascular diseases, and drug discovery. Here, we review recent hiPSC-CM disease models and discuss the features of hiPSC-CMs, including subtype and maturation and the tissue engineering technologies for drug assessment. Updates from the international multisite collaborators/administrations for development of novel drug discovery paradigms are also summarized.

Ultrastructural study of uptake of monastral blue by the pulmonary intravascular macrophages of sheep in the presence and absence of surface coat

1992 ◽  
Vol 50 (1) ◽  
pp. 702-703
Author(s):  
B. Singh ◽  
D. S. Jassal ◽  
O. S. Atwal ◽  
K. Minhas
Keyword(s):  
Tannic Acid ◽  
Animal Species ◽  
Ultrastructural Level ◽  
Mononuclear Phagocyte ◽  
Surface Coat ◽  
Cell Periphery ◽  
Highly Sensitive ◽  
Pulmonary Intravascular Macrophages

Pulmonary intravascular macrophage (PIM) is an important mononuclear phagocyte of some animal species. In sheep these cells are actively involved in the clearance of microbes and endotoxins. By treating the tissue with tannic acid we have identified at the ultrastructural level a unique globular surface coat, arranged at a distance of 30-40 nm from the cell periphery, This coat is hypothesized to be lipoprotein in nature as tannic acid complexes with the globules to enhance their electron density. This surface coat is highly sensitive to in vitro lipolytic lipase digestion and in vivo heparin treatment.

Serum-Induced Endocytic Vacuole in the Nonphagocytic Tetrahymena Pyriformis Strain NP1

1977 ◽  
Vol 35 ◽  
pp. 644-645
Author(s):  
L. J. Brenner ◽  
D. G. Osborne ◽  
B. L. Schumaker
Keyword(s):  
Electron Microscopy ◽  
Large Body ◽  
Tetrahymena Pyriformis ◽  
Metal Salts ◽  
Proteose Peptone ◽  
Transmission Electron ◽  
Food Vacuoles ◽  
Heavy Metal Salts ◽  
Normal Human ◽  
Peptone Medium

Tetrahymena pyriformis strains WH6, W, HSM, and GLC, after exposure to normal human serum, give rise to large membrane-bounded endocytic vacuoles, as visualized by transmission electron microscopy (TEM). These vacuoles do not resemble ordinary food vacuoles formed in the oral apparatus. Nor do they appear to be vacuoles containing protein concentrated from the serum: Albumin solutions induce a different type of vacuole (Brenner et al., 1976). The large bodies take a stain (PAS) that indicates the presence of polysaccharide. TEM micrographs show the presence of lipid in some of the large bodies. It is not yet known if these large body vacuoles are formed in the oral apparatus like food vacuoles or result from the fusion of pinocytic vacuoles.Although the mutant T. pyriformis strain, NP1, is unable to form a functional oral apparatus at 37° C and cannot form food vacuoles (Rasmussen and Orias, 1975), it multiplies in 2% proteose peptone medium supplemented with vitamins and heavy metal salts.

Clinical and Research Utility of the Highly Sensitive Person Scale

2019 ◽  
Vol 41 (3) ◽  
pp. 221-241
Author(s):  
Heather L. Smith ◽  
Julie Sriken ◽  
Bradley T. Erford
Keyword(s):  
Mental Health ◽  
Sensory Processing ◽  
Mental Health Disorders ◽  
Mental Health Counselors ◽  
Highly Sensitive ◽  
Normal Human ◽  
Health Disorders ◽  
Regular Practice ◽  
Three Factor ◽  
Sensitive Person

This psychometric synthesis reviewed all 29 articles meeting criteria and possessing psychometric results from the 20-year history (1997 to 2017) of the Highly Sensitive Person Scale (HSPS). Aggregated internal consistency (coefficient alpha) was .874. Convergent comparisons were provided between the HSPS total score and 12 measures of constructs similar to the sensory processing sensitivity construct. Structural validity primarily supported both the original one- and three-factor models, as did the pattern of high intra-subscale and total scale correlations, but a unidimensional interpretation is suggested given the low reliabilities for subscale scores. The HSPS performed adequately for a screening-level instrument. Mental health counselors are well suited to use the HSPS within their regular practice of assessing and valuing normal human development in addition to diagnosing and treating mental health disorders.

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