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Environmental Compliance and Control for Radiopharmaceutical Production
Published in Michael Ljungberg, Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
Ching-Hung Chiu, Ya-Yao Huang, Wen-Yi Chang, Jacek Koziorowski
Bacterial endotoxin is the lipopolysaccharide (LPS) component of the cell wall of gram-negative bacteria. It is pyrogenic, and it is a risk to patients who are administered intravenous and intramuscular preparations [21]. The pathological effects of endotoxin, when injected, are a rapid increase in body temperature followed by extremely rapid and severe shock, often followed by death, before the cause is even diagnosed. The limulus amebocyte lysate (LAL) test is the most widely method used for endotoxin tests [22]. The pharmacopoeia monographs for the LAL test are long-established and relatively comprehensive and have been applied to the testing of parenteral products for bacterial endotoxin since the 1980s. Pyrogens are a concern for pharmaceutical drug products and for many of the ingredients used to formulate them. This is especially for radiopharmaceuticals that have direct contact with human blood. Here, by far the most concerning pyrogen is bacterial endotoxin. In relation to this, the risks of endotoxin to radiopharmaceutical processing and some of the control measures in place to reduce the risk of endotoxin contamination should be considered.
Endotoxin: Historical Perspectives
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Ernst T. Rietschel, Otto Westphal
The very first international conference dedicated primarily to bacterial endotoxin took place in New York in the year 1952. It was organized by Florence Seibert (1897–1991), a pioneer in pyrogen research (Fig. 1), who introduced a sensitive test for pyrogenicity in rabbits (2). In her introductory remarks to the 1952 conference, she said: “The isolation of a pure and stable pyrogen with well defined chemical and biological properties which could be easily reproduced, would furnish a valuable standard for the evaluation of pyrogen use” (3). Obviously, at that time the exact nature of pyrogens was not yet known, but from one of her studies she concluded: “The pyrogen is a filterable product produced by a specific bacterium …” (4). In her attempts to identify the pyrogenic material that contaminated pharmaceutical drugs and infusion fluids, she always ended up with such small amounts of what may have been the pyrogenic substance that a characterization of the material was impossible. Florence Seibert called the elusive bioactive material her “little blue devil,” showing both her affection towards and frustration with the material that would later turn out to be endotoxin. One of her students, Dennis W. Watson, working with her in 1939 in Philadelphia will play, as described later in this chapter, an important role in one of the most exciting chapters of the history of endotoxin research, i.e., the identification of the bioactive principle of endotoxin.
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
The pyrogenic lipopolysaccharide endotoxin is absent in the cell wall of Gram-positive bacteria, and therefore, their fever-inducing action is different. Sufficient doses of Grampositive bacteria produce a biphasic febrile reaction after a delay of 45 to 60 min. This latency is longer than the delayed action of endotoxins (Figure 21). It seems that Grampositive bacteria are pyrogenic by themselves due to their capacity to be phagocytozed and accordingly, they provoke a profound inflammatory reaction at extravascular sites by releasing endogenous pyrogens into the circulation. The nature of pyrogenic factors isolated from Gram-positive bacteria differs from those of Gram-negatives. A primarily intracellular and group-specific pyrogen and several extracellular substances have been isolated from Gram-positive bacteria. These are different from each other in antigen response and also distinct chemically from the endotoxins of Gram-negative bacteria; they are mucopeptides rather than lipopolysaccharides.
Dendritic Cells Therapy with Cytokine-Induced Killer Cells and Activated Cytotoxic T Cells Attenuated Th2 Bias Immune Response
Published in Immunological Investigations, 2020
Changyou Li, Danni Zhu, Yonghui Zhao, Qingming Guo, Weihong Sun, Linxi Li, Daiqing Gao, Peng Zhao
Adherent cells were differentiated into DC in a serum-free medium containing 20 ng/ml IL-4 and 50 ng/ml GM-CSF for 5 days. On the fifth day, they were pulsed with tumor-associated antigens (TAAs) from tumor cell line lysates (Chakraborty et al. 1998). Maturity promoting factors (mPF, Novoprotein, China) were added into the medium for another 24 h. We detected CD11c, CD80, and CD86 as the indicators for the analysis of dendritic cells. CD83 and HLA-DR as the markers of matured DCs were examined by flow cytometry on the eighth day. Preparations were tested as bacteria and pyrogen-free. A portion of the prepared DC was infused into the patients and the remaining DCs were stored at −80℃ until the 17th-day infusion. Non-adherent cells were cultured in serum-free medium supplemented with 100 U/ml IL-2, 300 U/ml IFN-γ, 20 ng/ml CD3 monoclonal antibody. The medium was added moderately according to the growth status of cells. On the 10th day, CIK cells with antibodies against CD3, CD8, and CD56 were examined by flow cytometry. The final number of CIK cells were approximately (2–5)×109 cells. The viability of CIK cells was evaluated by survival cell count, proliferative and killing activity. Cells were then kept in normal saline with 1% albumin and infused into the patients. The rest of the suspension cells were kept in culture for the other two infusions.
Novel mulberry silkworm cocoon-derived carbon dots and their anti-inflammatory properties
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Xiaoke Wang, Yue Zhang, Hui Kong, Jinjun Cheng, Meiling Zhang, Ziwei Sun, Suna Wang, Jiaxing Liu, Huihua Qu, Yan Zhao
LPS-induced sepsis in C57 mice [30] was also performed 1 h after pre-treatment with the test substance. LPS was diluted in pyrogen-free NS and injected i.p. into the mice (0.25 mg/mL, 5 mg/kg). Then, 6 h post injection of LPS, blood was collected into tubes without anticoagulant via retro-orbital bleeding, and the samples were allowed to clot overnight at 4 °C before centrifugation for 10 min at approximately 3000 rpm. The serum levels of tumour necrosis factor (TNF)-α [31] and interleukin (IL)-6 [32], which are primarily involved in promoting inflammatory processes and play an important role in sepsis, were assessed. The enzyme-linked immunosorbent assay kits were calibrated using commercial cytokine standards and used according to the manufacturer's instructions (Cloud-Clone, USA).
Elevated plasma interleukin 34 levels correlate with disease severity-reflecting parameters of patients with haemorrhagic fever with renal syndrome
Published in Infectious Diseases, 2019
Kang Tang, Chunmei Zhang, Yusi Zhang, Yun Zhang, Hong Du, Boquan Jin, Ying Ma
Haemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus is a serious acute infectious disease with great harm to human distributed globally [1]. China is one of the most severe endemic areas of HFRS in the world, and accounts for almost 90% of human cases globally with the highest incidence each year [2,3]. HFRS is pathophysiologically characterized by increased vascular endothelial permeability, thrombocytopenia and acute kidney injury (AKI) [4]. Hantaan virus infection induces activation of immune system leading to uncontrolled cytokine storm, including dramatically increased levels of interleukin 1 (IL-1), IL-6, chemokine (C-C motif) ligand 2 (CCL2), CCL4 and tumour necrosis factor-α (TNF-α) [4,5]. These cytokines might enhance the host defense against Hantaan virus infection, but also induce the reorganization of the endothelial cytoskeleton and junctions, which mediate an increase in endothelial permeability [6,7]. Increased endothelial permeability leads to dysfunction of vascular endothelial barrier, manifested as petechiae, oedema, and hypotension [8]. The cytokine storm may cause dysfunction of the vascular endothelial barrier, thereby being involved in the pathogenesis of HFRS. Additionally, pro-inflammatory cytokines as endogenous pyrogen could induce fever, which is the early clinical manifestation of HFRS [9]. Patients with HFRS show increased thrombopoiesis and platelet activation, which may induce intravascular coagulation and cause thrombocytopenia [10,11]. Moreover, the infiltration of inflammatory cells and pro-inflammatory cytokines in kidney tissue could lead to kidney damage [4].