Pyrogens[edit]
A pyrogen is a substance that induces fever.[66] In the presence of an infectious agent, such as bacteria, viruses, viroids, etc., the immune response of the body is to inhibit their growth and eliminate them. The most common pyrogens are endotoxins, which are lipopolysaccharides (LPS) produced by Gram-negative bacteria such as E. coli. But pyrogens include non-endotoxic substances (derived from microorganisms other than gram-negative-bacteria or from chemical substances) as well.[67] The types of pyrogens include internal (endogenous) and external (exogenous) to the body.[citation needed]
The "pyrogenicity" of given pyrogens varies: in extreme cases, bacterial pyrogens can act as superantigens and cause rapid and dangerous fevers.[68]
Endogenous[edit]
Endogenous pyrogens are cytokines released from monocytes (which are part of the immune system).[69] In general, they stimulate chemical responses, often in the presence of an antigen, leading to a fever. Whilst they can be a product of external factors like exogenous pyrogens, they can also be induced by internal factors like damage associated from molecular patterns such as cases like rheumatoid arthritis or lupus.[70]
Major endogenous pyrogens are interleukin 1 (α and β)[71]:1237–1248 and interleukin 6 (IL-6).[72] Minor endogenous pyrogens include interleukin-8, tumor necrosis factor-β, macrophage inflammatory protein-α and macrophage inflammatory protein-β as well as interferon-α, interferon-β, and interferon-γ.[71]:1237–1248 Tumor necrosis factor-α (TNF) also acts as a pyrogen, mediated by interleukin 1 (IL-1) release.[73] These cytokine factors are released into general circulation, where they migrate to the brain's circumventricular organs where they are more easily absorbed than in areas protected by the blood–brain barrier.[citation needed] The cytokines then bind to endothelial receptors on vessel walls to receptors on microglial cells, resulting in activation of the arachidonic acid pathway.[citation needed]
Of these, IL-1β, TNF, and IL-6 are able to raise the temperature setpoint of an organism and cause fever. These proteins produce a cyclooxygenasewhich induces the hypothalamic production of PGE2 which then stimulates the release of neurotransmitters such as cyclic adenosine monophosphate and increases body temperature.[74]
Exogenous[edit]
Exogenous pyrogens are external to the body and are of microbial origin. In general, these pyrogens, including bacterial cell wall products, may act on Toll-like receptors in the hypothalamus and elevate the thermoregulatory setpoint.[75]
An example of a class of exogenous pyrogens are bacterial lipopolysaccharides (LPS) present in the cell wall of gram-negative bacteria. According to one mechanism of pyrogen action, an immune system protein, lipopolysaccharide-binding protein (LBP), binds to LPS, and the LBP–LPS complex then binds to a CD14 receptor on a macrophage. The LBP-LPS binding to CD14 results in cellular synthesis and release of various endogenous cytokines, e.g., interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNFα). A further downstream event is activation of the arachidonic acid pathway.[76]
https://en.wikipedia.org/wiki/Fever
Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system.[1] Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells.[2] Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens (and can activate up to 100% of T cells).
The large number of activated T-cells generates a massive immune response which is not specific to any particular epitope on the SAg thus undermining one of the fundamental strengths of the adaptive immune system, that is, its ability to target antigens with high specificity. More importantly, the large number of activated T-cells secrete large amounts of cytokines, the most important of which is Interferon gamma. This excess amount of IFN-gamma in turn activates the macrophages. The activated macrophages, in turn, over-produce proinflammatory cytokines such as IL-1, IL-6 and TNF-alpha. TNF-alpha is particularly important as a part of the body's inflammatory response. In normal circumstances it is released locally in low levels and helps the immune system defeat pathogens. However, when it is systemically released in the blood and in high levels (due to mass T-cell activation resulting from the SAg binding), it can cause severe and life-threatening symptoms, including shock and multiple organ failure.
https://en.wikipedia.org/wiki/Superantigen
For instance, some species of grasshopper will thermoregulate to achieve body temperatures that are 2–5 °C higher than normal in order to inhibit the growth of fungal pathogens such as Beauveria bassiana and Metarhizium acridum.[103] Honeybee colonies are also able to induce a fever in response to a fungal parasite Ascosphaera apis.[103]
https://en.wikipedia.org/wiki/Fever
| Glomerular disease | |
|---|---|
| Tubules | |
| Interstitium | |
| Vascular | |
| General syndromes | |
| Other | |
https://en.wikipedia.org/wiki/Acute_tubular_necrosis
Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis.[1] They are called bisphosphonates because they have two phosphonate (PO(OH)
2) groups. They are thus also called diphosphonates (bis- or di- + phosphonate).
Evidence shows that they reduce the risk of fracture in post-menopausal women with osteoporosis.[2][3][4][5][6]
Bone tissue undergoes constant remodeling and is kept in balance (homeostasis) by osteoblasts creating bone and osteoclasts destroying bone. Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis, or cell death, thereby slowing bone loss.[7]
The uses of bisphosphonates include the prevention and treatment of osteoporosis, Paget's disease of bone, bone metastasis (with or without hypercalcemia), multiple myeloma, primary hyperparathyroidism, osteogenesis imperfecta, fibrous dysplasia, and other conditions that exhibit bone fragility.
https://en.wikipedia.org/wiki/Bisphosphonate
Ethylene glycol (IUPAC name: ethane-1,2-diol) is an organic compound with the formula (CH2OH)2. It is mainly used for two purposes, as a raw material in the manufacture of polyester fibers and for antifreezeformulations. It is an odorless, colorless, sweet-tasting, viscous liquid.
https://en.wikipedia.org/wiki/Ethylene_glycol
Cisplatin is a chemotherapy medication used to treat a number of cancers.[2] These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors and neuroblastoma.[2] It is given by injection into a vein.[2]
Common side effects include bone marrow suppression, hearing problems, kidney damage, and vomiting.[2][3] Other serious side effects include numbness, trouble walking, allergic reactions, electrolyte problems, and heart disease.[2] Use during pregnancy can cause harm to the baby.[1][2] Cisplatin is in the platinum-based antineoplastic family of medications.[2] It works in part by binding to DNA and inhibiting its replication.[2]
Cisplatin was discovered in 1845 and licensed for medical use in 1978 and 1979.[4][2] It is on the World Health Organization's List of Essential Medicines.[5]
https://en.wikipedia.org/wiki/Cisplatin
Plasmodium malariae is a parasitic protozoan that causes malaria in humans. It is one of several species of Plasmodium parasites that infect other organisms as pathogens, also including Plasmodium falciparum and Plasmodium vivax, responsible for most malarial infection. Found worldwide, it causes a so-called "benign malaria", not nearly as dangerous as that produced by P. falciparum or P. vivax. The signs include fevers that recur at approximately three-day intervals – a quartan fever or quartan malaria – longer than the two-day (tertian) intervals of the other malarial parasites.
https://en.wikipedia.org/wiki/Plasmodium_malariae
Brucellosis[2][3] is a highly contagious zoonosis caused by ingestion of unpasteurized milk or undercooked meat from infected animals, or close contact with their secretions.[4] It is also known as undulant fever, Malta fever, and Mediterranean fever.[5]
Brucella species are small, Gram-negative, nonmotile, nonspore-forming, rod-shaped (coccobacilli) bacteria. They function as facultative intracellular parasites, causing chronic disease, which usually persists for life. Four species infect humans: B. abortus, B. canis, B. melitensis, and B. suis. B. abortus is less virulent than B. melitensis and is primarily a disease of cattle. B. canis affects dogs. B. melitensis is the most virulent and invasive species; it usually infects goats and occasionally sheep. B. suis is of intermediate virulence and chiefly infects pigs. Symptoms include profuse sweating and joint and muscle pain. Brucellosis has been recognized in animals and humans since the early 20th century.[citation needed]
https://en.wikipedia.org/wiki/Brucellosis
Human type I interferons (IFNs) are a large subgroup of interferon proteins that help regulate the activity of the immune system.
Interferons bind to interferon receptors. All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains.
Type I IFNs are found in all mammals, and homologous (similar) molecules have been found in birds, reptiles, amphibians and fish species.[1][2]
https://en.wikipedia.org/wiki/Interferon_type_I#IFN-β
Necrosis (from Ancient Greek νέκρωσις, nékrōsis, "death") is a form of cell injury which results in the premature death of cells in living tissue by autolysis.[1] Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal.[2]
Cellular death due to necrosis does not follow the apoptotic signal transduction pathway, but rather various receptors are activated and result in the loss of cell membrane integrity[3]and an uncontrolled release of products of cell death into the extracellular space.[1] This initiates in the surrounding tissue an inflammatory response, which attracts leukocytes and nearby phagocytes which eliminate the dead cells by phagocytosis. However, microbial damaging substances released by leukocytes would create collateral damage to surrounding tissues.[4] This excess collateral damage inhibits the healing process. Thus, untreated necrosis results in a build-up of decomposing dead tissue and cell debris at or near the site of the cell death. A classic example is gangrene. For this reason, it is often necessary to remove necrotic tissue surgically, a procedure known as debridement.
https://en.wikipedia.org/wiki/Necrosis
| Principles of pathology | |
|---|---|
| Anatomical pathology | |
| Clinical pathology | |
https://en.wikipedia.org/wiki/Necrosis
Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disorder that exhibits an unexplained, chronic (> 6 months) elevation in large granular lymphocytes (LGLs) in the peripheral blood.[1]
It is divided in two main categories: T-cell LGL leukemia (T-LGLL) and natural-killer (NK)-cell LGL leukemia (NK-LGLL). As the name suggests, T-cell large granular lymphocyte leukemia is characterized by involvement of cytotoxic-T cells).[2]
In a study based in the US, the average age of diagnosis was 66.5 years[3] whereas in a French study the median age at diagnosis was 59 years (with an age range of 12-87 years old).[4] In the French study, only 26% of patients were younger than 50 years which suggests that this disorder is associated with older age at diagnosis.[4] Due to lack of presenting symptoms, the disorder is likely to be underdiagnosed in the general population.[5]
https://en.wikipedia.org/wiki/Large_granular_lymphocytic_leukemia
Necroptosis is a programmed form of necrosis, or inflammatory cell death.[1] Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication.[2] In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.[3][4]
The signaling pathway responsible for carrying out necroptosis is generally understood. TNFα leads to stimulation of its receptor TNFR1. TNFR1 binding protein TNFR-associated death protein TRADD and TNF receptor-associated factor 2 TRAF2 signals to RIPK1 which recruits RIPK3 forming the necrosome also named ripoptosome.[2] Phosphorylation of MLKLby the ripoptosome drives oligomerization of MLKL, allowing MLKL to insert into and permeabilize plasma membranes and organelles.[5][6] Integration of MLKL leads to the inflammatory phenotype and release of damage-associated molecular patterns (DAMPs), which elicit immune responses.
https://en.wikipedia.org/wiki/Necroptosis
Avascular necrosis (AVN), also called osteonecrosis or bone infarction, is death of bone tissue due to interruption of the blood supply.[1] Early on, there may be no symptoms.[1] Gradually joint pain may develop which may limit the ability to move.[1] Complications may include collapse of the bone or nearby joint surface.[1]
Risk factors include bone fractures, joint dislocations, alcoholism, and the use of high-dose steroids.[1] The condition may also occur without any clear reason.[1] The most commonly affected bone is the femur.[1] Other relatively common sites include the upper arm bone, knee, shoulder, and ankle.[1] Diagnosis is typically by medical imaging such as X-ray, CT scan, or MRI.[1] Rarely biopsymay be used.[1]
Treatments may include medication, not walking on the affected leg, stretching, and surgery.[1] Most of the time surgery is eventually required and may include core decompression, osteotomy, bone grafts, or joint replacement.[1] About 15,000 cases occur per year in the United States.[4] People 30 to 50 years old are most commonly affected.[3] Males are more commonly affected than females.[4]
https://en.wikipedia.org/wiki/Avascular_necrosis
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