document_title: Inflammation

question_text: what is the first step in the major events of the inflammatory process

question_tokens: what is the first step in the major events of the inflammatory process

root

text: Inflammation

text: Causes[edit]

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tag: table

text:
Burns[3]
Frostbite
Physical injury, blunt or penetrating[4]
Foreign bodies, including splinters, dirt and debris
Trauma[3]
Ionizing radiation

tag: ul

text: Biological:

tag: p

text:
Infection by pathogens[3]
Immune reactions due to hypersensitivity
Stress

text:
Chemical irritants
Toxins
Alcohol

text: Psychological:

text: Types[edit]

text:
Appendicitis
Bursitis
Colitis
Cystitis
Dermatitis
Encephalitis

Meningitis
Phlebitis
RSD/CRPS
Rhinitis
Tendonitis
Tonsillitis
Vasculitis

text:
Comparison between acute and chronic inflammation:

Acute
Chronic

Causative agent
Bacterial pathogens, injured tissues
Persistent acute inflammation due to non-degradable pathogens, viral infection, persistent foreign bodies, or autoimmune reactions

Major cells involved
neutrophils (primarily), basophils (inflammatory response), and eosinophils (response to helminth worms and parasites), mononuclear cells (monocytes, macrophages)
Mononuclear cells (monocytes, macrophages, lymphocytes, plasma cells), fibroblasts

Primary mediators
Vasoactive amines, eicosanoids
IFN-γ and other cytokines, growth factors, reactive oxygen species, hydrolytic enzymes

Onset
Immediate
Delayed

Duration
Few days
Up to many months, or years

Outcomes
Resolution, abscess formation, chronic inflammation
Tissue destruction, fibrosis, necrosis

text: Cardinal signs[edit]

text:
The classic signs and symptoms of acute inflammation:

English
Latin

Redness
Rubor*

Swelling
Tumor*

Heat
Calor*

Pain
Dolor*

Loss of function
Functio laesa**

All the above signs may be observed in specific instances, but no single sign must, as a matter of course, be present.[6]
These are the original, or "cardinal signs" of inflammation.[6]*
Functio laesa is an antiquated notion, as it is not unique to inflammation and is a characteristic of many disease states.[7]**

text: Acute inflammation is a short-term process, usually appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus.[8] It involves a coordinated and systemic mobilization response locally of various immune, endocrine and neurological mediators of acute inflammation. In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and then ceases.[9] It is characterized by five cardinal signs:[10]

text: An acronym that may be used to remember the key symptoms is "PRISH", for pain, redness, immobility (loss of function), swelling and heat.

text: The traditional names for signs of inflammation come from Latin:

text:
Dolor (pain)
Calor (heat)
Rubor (redness)
Tumor (swelling)
Functio laesa (loss of function)[11]

text: The first four (classical signs) were described by Celsus (ca. 30 BC–38 AD),[12] while loss of function was added later by Galen[13] even though the attribution is disputed and the origination of the fifth sign has also been ascribed to Thomas Sydenham[14] and Virchow.[8][10]

text: Redness and heat are due to increased blood flow at body core temperature to the inflamed site; swelling is caused by accumulation of fluid; pain is due to the release of chemicals such as bradykinin and histamine that stimulate nerve endings. Loss of function has multiple causes.[10]

text: Acute inflammation of the lung (usually caused in response to pneumonia) does not cause pain unless the inflammation involves the parietal pleura, which does have pain-sensitive nerve endings.[10]

text: Process of acute inflammation[edit]

text: The process of acute inflammation is initiated by resident immune cells already present in the involved tissue, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells and mast cells. These cells possess surface receptors known as pattern recognition receptors (PRRs), which recognize (i.e., bind) two subclasses of molecules: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs are compounds that are associated with various pathogens, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related injury and cell damage.

text: At the onset of an infection, burn, or other injuries, these cells undergo activation (one of the PRRs recognize a PAMP or DAMP) and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes the redness (rubor) and increased heat (calor). Increased permeability of the blood vessels results in an exudation (leakage) of plasma proteins and fluid into the tissue (edema), which manifests itself as swelling (tumor). Some of the released mediators such as bradykinin increase the sensitivity to pain (hyperalgesia, dolor). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly neutrophils and macrophages, outside of the blood vessels (extravasation) into the tissue. The neutrophils migrate along a chemotactic gradient created by the local cells to reach the site of injury.[8] The loss of function (functio laesa) is probably the result of a neurological reflex in response to pain.

text: In addition to cell-derived mediators, several acellular biochemical cascade systems consisting of preformed plasma proteins act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria and the coagulation and fibrinolysis systems activated by necrosis, e.g. a burn or a trauma.[8]

text: Acute inflammation may be regarded as the first line of defense against injury. Acute inflammatory response requires constant stimulation to be sustained. Inflammatory mediators are short-lived and are quickly degraded in the tissue. Hence, acute inflammation begins to cease once the stimulus has been removed.[8]

text: Vascular component[edit]

text: Vasodilation and increased permeability[edit]

text: As defined, acute inflammation is an immunovascular response to an inflammatory stimulus. This means acute inflammation can be broadly divided into a vascular phase that occurs first, followed by a cellular phase involving immune cells (more specifically myeloid granulocytes in the acute setting). The vascular component of acute inflammation involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue.

text: Upon contact with PAMPs, tissue macrophages and mastocytes release vasoactive amines such as histamine and serotonin, as well as eicosanoids such as prostaglandin E2 and leukotriene B4 to remodel the local vasculature. Macrophages and endothelial cells release nitric oxide. These mediators vasodilate and permeabilize the blood vessels, which results in the net distribution of blood plasma from the vessel into the tissue space. The increased collection of fluid into the tissue causes it to swell (edema). This exuded tissue fluid contain various antimicrobial mediators from the plasma such as complement, lysozyme, antibodies, which can immediately deal damage to microbes, and opsonise the microbes in preparation for the cellular phase. If the inflammatory stimulus is a lacerating wound, exuded platelets, coagulants, plasmin and kinins can clot the wounded area and provide haemostasis in the first instance. These clotting mediators also provide a structural staging framework at the inflammatory tissue site in the form of a fibrin lattice – as would construction scaffolding at a construction site – for the purpose of aiding phagocytic debridement and wound repair later on. Some of the exuded tissue fluid is also funnelled by lymphatics to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the adaptive immune system.

text: Acute inflammation is characterized by marked vascular changes, including vasodilation, increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood – a condition characterized by enlarged vessels packed with cells. Stasis allows leukocytes to marginate (move) along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.

text: Plasma cascade systems[edit]

text:
The complement system, when activated, creates a cascade of chemical reactions that promotes opsonization, chemotaxis, and agglutination, and produces the MAC.
The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.
The coagulation system or clotting cascade, which forms a protective protein mesh over sites of injury.
The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.

text: Plasma-derived mediators[edit]

text: * non-exhaustive list

text:
Name
Produced by
Description

Bradykinin
Kinin system
A vasoactive protein that is able to induce vasodilation, increase vascular permeability, cause smooth muscle contraction, and induce pain.

C3
Complement system
Cleaves to produce C3a and C3b. C3a stimulates histamine release by mast cells, thereby producing vasodilation. C3b is able to bind to bacterial cell walls and act as an opsonin, which marks the invader as a target for phagocytosis.

C5a
Complement system
Stimulates histamine release by mast cells, thereby producing vasodilation. It is also able to act as a chemoattractant to direct cells via chemotaxis to the site of inflammation.

Factor XII (Hageman Factor)
Liver
A protein that circulates inactively, until activated by collagen, platelets, or exposed basement membranes via conformational change. When activated, it in turn is able to activate three plasma systems involved in inflammation: the kinin system, fibrinolysis system, and coagulation system.

Membrane attack complex
Complement system
A complex of the complement proteins C5b, C6, C7, C8, and multiple units of C9. The combination and activation of this range of complement proteins forms the membrane attack complex, which is able to insert into bacterial cell walls and causes cell lysis with ensuing bacterial death.

Plasmin
Fibrinolysis system
Able to break down fibrin clots, cleave complement protein C3, and activate Factor XII.

Thrombin
Coagulation system
Cleaves the soluble plasma protein fibrinogen to produce insoluble fibrin, which aggregates to form a blood clot. Thrombin can also bind to cells via the PAR1 receptor to trigger several other inflammatory responses, such as production of chemokines and nitric oxide.

text: Cellular component[edit]

text: The cellular component involves leukocytes, which normally reside in blood and must move into the inflamed tissue via extravasation to aid in inflammation. Some act as phagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymatic granules that damage pathogenic invaders. Leukocytes also release inflammatory mediators that develop and maintain the inflammatory response. In general, acute inflammation is mediated by granulocytes, whereas chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.

text: Leukocyte extravasation[edit]

text: Various leukocytes, particularly neutrophils, are critically involved in the initiation and maintenance of inflammation. These cells must be able to move to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasation, and can be broadly divided up into a number of steps:

text:
Leukocyte margination and endothelial adhesion: The white blood cells within the vessels which are generally centrally located move peripherally towards the walls of the vessels.[15] Activated macrophages in the tissue release cytokines such as IL-1 and TNFα, which bind to their respective G protein-coupled receptors on the endothelial wall. Signal transduction induces the immediate expression of P-selectin on endothelial cell surfaces. This receptor binds weakly to carbohydrate ligands on the surface of leukocytes and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines from injured cells induce the expression of E-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of integrin ligands such as ICAM-1 and VCAM-1 on endothelial cells, which mediate the adhesion and further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue. Activation increases the affinity of bound integrin receptors for ICAM-1 and VCAM-1 on the endothelial cell surface, firmly binding the leukocytes to the endothelium.
Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between adjacent endothelial cells. The endothelial cells retract and the leukocytes pass through the basement membrane into the surrounding tissue using adhesion molecules such as ICAM-1.[15]
Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrix proteins via expressed integrins and CD44 to prevent them from leaving the site. A variety of molecules behave as chemoattractants, for example, C3a or C5, and cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.

tag: ol

text: Phagocytosis[edit]

text: Extravasated neutrophils in the cellular phase come into contact with microbes at the inflamed tissue. Phagocytes express cell-surface endocytic pattern recognition receptors (PRRs) that have affinity and efficacy against non-specific microbe-associated molecular patterns (PAMPs). Most PAMPs that bind to endocytic PRRs and initiate phagocytosis are cell wall components, including complex carbohydrates such as mannans and β-glucans, lipopolysaccharides (LPS), peptidoglycans, and surface proteins. Endocytic PRRs on phagocytes reflect these molecular patterns, with C-type lectin receptors binding to mannans and β-glucans, and scavenger receptors binding to LPS.

text: Upon endocytic PRR binding, actin-myosin cytoskeletal rearrangement adjacent to the plasma membrane occurs in a way that endocytoses the plasma membrane containing the PRR-PAMP complex, and the microbe. Phosphatidylinositol and Vps34-Vps15-Beclin1 signalling pathways have been implicated to traffic the endocytosed phagosome to intracellular lysosomes, where fusion of the phagosome and the lysosome produces a phagolysosome. The reactive oxygen species, superoxides and hypochlorite bleach within the phagolysosomes then kill microbes inside the phagocyte.

text: Phagocytic efficacy can be enhanced by opsonization. Plasma derived complement C3b and antibodies that exude into the inflamed tissue during the vascular phase bind to and coat the microbial antigens. As well as endocytic PRRs, phagocytes also express opsonin receptors Fc receptor and complement receptor 1 (CR1), which bind to antibodies and C3b, respectively. The co-stimulation of endocytic PRR and opsonin receptor increases the efficacy of the phagocytic process, enhancing the lysosomal elimination of the infective agent.

text: Cell-derived mediators[edit]

text: * non-exhaustive list

text:
Name
Type
Source
Description

Lysosome granules
Enzymes
Granulocytes
These cells contain a large variety of enzymes that perform a number of functions. Granules can be classified as either specific or azurophilic depending upon the contents, and are able to break down a number of substances, some of which may be plasma-derived proteins that allow these enzymes to act as inflammatory mediators.

Histamine
Monoamine
Mast cells and basophils
Stored in preformed granules, histamine is released in response to a number of stimuli. It causes arteriole dilation, increased venous permeability, and a wide variety of organ-specific effects.

IFN-γ
Cytokine
T-cells, NK cells
Antiviral, immunoregulatory, and anti-tumour properties. This interferon was originally called macrophage-activating factor, and is especially important in the maintenance of chronic inflammation.

IL-8
Chemokine
Primarily macrophages
Activation and chemoattraction of neutrophils, with a weak effect on monocytes and eosinophils.

Leukotriene B4
Eicosanoid
Leukocytes, cancer cells
Able to mediate leukocyte adhesion and activation, allowing them to bind to the endothelium and migrate across it. In neutrophils, it is also a potent chemoattractant, and is able to induce the formation of reactive oxygen species and the release of lysosomal enzymes by these cells.

LTC4, LTD4
Eicosanoid
eosinophils, mast cells, macrophages
These three Cysteine-containing leukotrienes contract lung airways, increase micro-vascular permeability, stimulate mucus secretion, and promote eosinophil-based inflammation in the lung, skin, nose, eye, and other tissues.

5-oxo-eicosatetraenoic acid
Eicosanoid
leukocytes, cancer cells
Potent stimulator of neutrophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation; monocyte chemotaxis; and with even greater potency eosinophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation.

5-HETE
Eicosanoid
Leukocytes
Metabolic precursor to 5-Oxo-eicosatetraenoic acid, it is a less potent stimulator of neutrophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation; monocyte chemotaxis; and eosinophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation.

Prostaglandins
Eicosanoid
Mast cells
A group of lipids that can cause vasodilation, fever, and pain.

Nitric oxide
Soluble gas
Macrophages, endothelial cells, some neurons
Potent vasodilator, relaxes smooth muscle, reduces platelet aggregation, aids in leukocyte recruitment, direct antimicrobial activity in high concentrations.

TNF-α and IL-1
Cytokines
Primarily macrophages
Both affect a wide variety of cells to induce many similar inflammatory reactions: fever, production of cytokines, endothelial gene regulation, chemotaxis, leukocyte adherence, activation of fibroblasts. Responsible for the systemic effects of inflammation, such as loss of appetite and increased heart rate. TNF-α inhibits osteoblast differentiation.

Tryptase
Enzymes
Mast Cells
This serine protease is believed to be exclusively stored in mast cells and secreted, along with histamine, during mast cell activation.[16][17][18]

text: Morphologic patterns[edit]

text: Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved.

text:
Granulomatous inflammation: Characterised by the formation of granulomas, they are the result of a limited but diverse number of diseases, which include among others tuberculosis, leprosy, sarcoidosis, and syphilis.
Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows fibrin to pass through the blood vessels. If an appropriate procoagulative stimulus is present, such as cancer cells,[8] a fibrinous exudate is deposited. This is commonly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function. The deposit sometimes forms a pseudomembrane sheet. During inflammation of the intestine (Pseudomembranous colitis), pseudomembranous tubes can be formed.
Purulent inflammation: Inflammation resulting in large amount of pus, which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are called abscesses.
Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may be derived from blood plasma. Skin blisters exemplify this pattern of inflammation.
Ulcerative inflammation: Inflammation occurring near an epithelium can result in the necrotic loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as an ulcer.

text: Inflammatory disorders[edit]

text: Inflammatory abnormalities are a large group of disorders that underlie a vast variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with causal origins in inflammatory processes include cancer, atherosclerosis, and ischemic heart disease.[8]

text: Examples of disorders associated with inflammation include:

text:
Acne vulgaris
Asthma
Autoimmune diseases
Autoinflammatory diseases
Celiac disease
Chronic prostatitis
Colitis
Diverticulitis
Glomerulonephritis
Hidradenitis suppurativa
Hypersensitivities
Inflammatory bowel diseases
Interstitial cystitis
Mast Cell Activation Syndrome
Mastocytosis
Otitis
Pelvic inflammatory disease
Reperfusion injury
Rheumatic fever
Rheumatoid arthritis
Rhinitis
Sarcoidosis
Transplant rejection
Vasculitis

text: Atherosclerosis[edit]

text: Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.[19]

text: Allergy[edit]

text: An allergic reaction, formally known as type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation, vasodilation, and nerve irritation. A common example is hay fever, which is caused by a hypersensitive response by mast cells to allergens. Pre-sensitised mast cells respond by degranulating, releasing vasoactive chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes.[8] Severe inflammatory response may mature into a systemic response known as anaphylaxis.

text: Myopathies[edit]

text: Inflammatory myopathies are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis.[8]

text: Leukocyte defects[edit]

text: Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte functionality often result in a decreased capacity for inflammatory defense with subsequent vulnerability to infection.[8] Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria (Chédiak–Higashi syndrome), or produce microbicides (chronic granulomatous disease). In addition, diseases affecting the bone marrow may result in abnormal or few leukocytes.

text: Pharmacological[edit]

text: Certain drugs or exogenous chemical compounds are known to affect inflammation. Vitamin A deficiency causes an increase in inflammatory responses,[20] and anti-inflammatory drugs work specifically by inhibiting the enzymes that produce inflammatory eicosanoids. Certain illicit drugs such as cocaine and ecstasy may exert some of their detrimental effects by activating transcription factors intimately involved with inflammation (e.g. NF-κB).[21][22]

text: Cancer[edit]

text: Inflammation orchestrates the microenvironment around tumours, contributing to proliferation, survival and migration.[23] Cancer cells use selectins, chemokines and their receptors for invasion, migration and metastasis.[24] On the other hand, many cells of the immune system contribute to cancer immunology, suppressing cancer.[25] Molecular intersection between receptors of steroid hormones, which have important effects on cellular development, and transcription factors that play key roles in inflammation, such as NF-κB, may mediate some of the most critical effects of inflammatory stimuli on cancer cells.[26] This capacity of a mediator of inflammation to influence the effects of steroid hormones in cells, is very likely to affect carcinogenesis on the one hand; on the other hand, due to the modular nature of many steroid hormone receptors, this interaction may offer ways to interfere with cancer progression, through targeting of a specific protein domain in a specific cell type. Such an approach may limit side effects that are unrelated to the tumor of interest, and may help preserve vital homeostatic functions and developmental processes in the organism.

text: According to a review of 2009, recent data suggests that cancer-related inflammation (CRI) may lead to accumulation of random genetic alterations in cancer cells.[27]

text: HIV and AIDS[edit]

text: It has long been recognized that infection with HIV is characterized not only by development of profound immunodeficiency but also by sustained inflammation and immune activation.[28][29][30] A substantial body of evidence implicates chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency.[28][31] Many now regard HIV infection not only as an evolving virus-induced immunodeficiency but also as chronic inflammatory disease.[32] Even after the introduction of effective antiretroviral therapy (ART) and effective suppression of viremia in HIV-infected individuals, chronic inflammation persists. Animal studies also support the relationship between immune activation and progressive cellular immune deficiency: SIVsm infection of its natural nonhuman primate hosts, the sooty mangabey, causes high-level viral replication but limited evidence of disease.[33][34] This lack of pathogenicity is accompanied by a lack of inflammation, immune activation and cellular proliferation. In sharp contrast, experimental SIVsm infection of rhesus macaque produces immune activation and AIDS-like disease with many parallels to human HIV infection.[35]

text: Delineating how CD4 T cells are depleted and how chronic inflammation and immune activation are induced lies at the heart of understanding HIV pathogenesis––one of the top priorities for HIV research by the Office of AIDS Research, National Institutes of Health. Recent studies demonstrated that caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death, drives CD4 T-cell depletion and inflammation by HIV.[36][37][38] These are the two signature events that propel HIV disease progression to AIDS. Pyroptosis appears to create a pathogenic vicious cycle in which dying CD4 T cells and other immune cells (including macrophages and neutrophils) release inflammatory signals that recruit more cells into the infected lymphoid tissues to die. The feed-forward nature of this inflammatory response produces chronic inflammation and tissue injury.[39] Identifying pyroptosis as the predominant mechanism that causes CD4 T-cell depletion and chronic inflammation, provides novel therapeutic opportunities, namely caspase-1 which controls the pyroptotic pathway. In this regard, pyroptosis of CD4 T cells and secretion of pro-inflmammatory cytokines such as IL-1β and IL-18 can be blocked in HIV-infected human lymphoid tissues by addition of the caspase-1 inhibitor VX-765,[36] which has already proven to be safe and well tolerated in phase II human clinical trials.[40] These findings could propel development of an entirely new class of “anti-AIDS” therapies that act by targeting the host rather than the virus. Such agents would almost certainly be used in combination with ART. By promoting “tolerance” of the virus instead of suppressing its replication, VX-765 or related drugs may mimic the evolutionary solutions occurring in multiple monkey hosts (e.g. the sooty mangabey) infected with species-specific lentiviruses that have led to a lack of disease, no decline in CD4 T-cell counts, and no chronic inflammation.

text: Resolution of inflammation[edit]

text: The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues.[8] Failure to do so results in chronic inflammation, and cellular destruction. Resolution of inflammation occurs by different mechanisms in different tissues. Mechanisms that serve to terminate inflammation include:[8][41]

text:
Short half-life of inflammatory mediators in vivo.
Production and release of transforming growth factor (TGF) beta from macrophages[42][43][44]
Production and release of interleukin 10 (IL-10)[45]
Production of anti-inflammatory specialized proresolving mediators, i.e. lipoxins, resolvins, maresins, and neuroprotectins[46][47]
Downregulation of pro-inflammatory molecules, such as leukotrienes.
Upregulation of anti-inflammatory molecules such as the interleukin 1 receptor antagonist or the soluble tumor necrosis factor receptor (TNFR)
Apoptosis of pro-inflammatory cells[48]
Desensitization of receptors.
Increased survival of cells in regions of inflammation due to their interaction with the extracellular matrix (ECM)[49][50]
Downregulation of receptor activity by high concentrations of ligands
Cleavage of chemokines by matrix metalloproteinases (MMPs) might lead to production of anti-inflammatory factors.[51]

text:
“
Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes promote the switch of arachidonic acid–derived prostaglandins and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3 polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. As a consequence, apoptotic neutrophils undergo phagocytosis by macrophages, leading to neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor-β1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics.[52]
”

— Charles Serhan

text: Connection to depression[edit]

text: There is evidence for a link between inflammation and depression.[53] Inflammatory processes can be triggered by negative cognitions or their consequences, such as stress, violence, or deprivation. Thus, negative cognitions can cause inflammation that can, in turn, lead to depression.[54][55][dubious – discuss] In addition there is increasing evidence that inflammation can cause depression because of the increase of cytokines, setting the brain into a "sickness mode".[56] Classical symptoms of being physically sick like lethargy show a large overlap in behaviors that characterize depression. Levels of cytokines tend to increase sharply during depressive episodes in manics and drop off during remission.[57] Furthermore, it has been shown in clinical trials that anti-inflammatory medicines taken in addition to antidepressants not only significantly improves symptoms but also increases the proportion of subjects positively responding to treatment.[58] Inflammations that lead to serious depression could be caused by common infections such as those caused by a virus, bacteria or even parasites.[59]

text: Systemic effects[edit]

text: An infectious organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. When lymph nodes cannot destroy all pathogens, the infection spreads further. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.

text: When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with the terms bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.

text: Acute-phase proteins[edit]

text: Inflammation also induces high systemic levels of acute-phase proteins. In acute inflammation, these proteins prove beneficial; however, in chronic inflammation they can contribute to amyloidosis.[8] These proteins include C-reactive protein, serum amyloid A, and serum amyloid P, which cause a range of systemic effects including:[8]

text:
Fever
Increased blood pressure
Decreased sweating
Malaise
Loss of appetite
Somnolence

text: Leukocyte numbers[edit]

text: Inflammation often affects the numbers of leukocytes present in the body:

text:
Leukocytosis is often seen during inflammation induced by infection, where it results in a large increase in the amount of leukocytes in the blood, especially immature cells. Leukocyte numbers usually increase to between 15 000 and 20 000 cells per microliter, but extreme cases can see it approach 100 000 cells per microliter.[8] Bacterial infection usually results in an increase of neutrophils, creating neutrophilia, whereas diseases such as asthma, hay fever, and parasite infestation result in an increase in eosinophils, creating eosinophilia.[8]
Leukopenia can be induced by certain infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis, and some cancers.[8]

text: Systemic inflammation and obesity[edit]

text: With the discovery of interleukins (IL), the concept of systemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium and other organ systems.

text: Chronic inflammation is widely observed in obesity.[60][61] The obese commonly have many elevated markers of inflammation, including:[62][63]

text: IL-6 (Interleukin-6)[64][65]

text:
IL-8 (Interleukin-8)
IL-18 (Interleukin-18)[64][65]
TNF-α (Tumor necrosis factor-alpha)[64][65]
CRP (C-reactive protein)[64][65]
Insulin[64][65]
Blood glucose[64][65]
Leptin[64][65]

text: Low-grade chronic inflammation is characterized by a two- to threefold increase in the systemic concentrations of cytokines such as TNF-α, IL-6, and CRP.[66] Waist circumference correlates significantly with systemic inflammatory response.[67] A predominant factor in this correlation is due to the autoimmune response triggered by adiposity, whereby immune cells may mistake fatty deposits for intruders. The body attacks fat similar to bacteria and fungi. When expanded fat cells leak or break open, macrophages mobilize to clean up and embed into the adipose tissue. Then macrophages release inflammatory chemicals, including TNF-α and IL-6. TNF's primary role is to regulate the immune cells and induce inflammation. White blood cells then assist by releasing more cytokines. This link between adiposity and inflammation has been shown to produce 10–35% of IL-6 in a resting individual, and this production increases with increasing adiposity.[68]

text: Loss of white adipose tissue reduces levels of inflammation markers.[60] The association of systemic inflammation with insulin resistance and atherosclerosis is the subject of intense research.[69]

text: In the obese mouse models, inflammation and macrophage-specific genes are upregulated in white adipose tissue (WAT). There were also signs of dramatic increase in circulating insulin level, adipocyte lipolysis and formation of multinucleate giant cells.[70] The fat-derived protein called angiopoietin-like protein 2 (Angptl2) elevates in fat tissues. Higher than normal Angptl2 level in fat tissues develop inflammation as well as insulin and leptin resistance. Stored fat secretes Leptin to signal satiety. Leptin resistance plays a role in the process where appetite overrules the message of satiety. Angptl2 then starts an inflammatory cascade causing blood vessels to remodel and attract macrophages. Angptl2 is an adipocyte-derived inflammatory mediator linking obesity to systemic insulin resistance.[71] It is possible that, as an inflammatory marker, leptin responds specifically to adipose-derived inflammatory cytokines.

text: C-reactive protein (CRP) is generated at a higher level in obese people. It raises when there is inflammation throughout the body. Mild elevation in CRP increase risk of heart attacks, strokes, high blood pressure, muscle weakness and fragility.[72][citation needed]

text: Systemic inflammation and overeating[edit]

text: Hyperglycemia induces IL-6 production from endothelial cells and macrophages.[73] Meals high in saturated fat, as well as meals high in calories have been associated with increases in inflammatory markers.[74][75] In addition, interstitial abdominal adiposity (also referred to as accumulated intra-abdominal fat) may be a factor in increasing systemic risk for multiple inflammatory diseases. Although the exact mechanisms are still being investigated, a review published in 2010 suggested that significant growth of adipose tissue in response to overeating can evoke a chronic inflammatory response.[76]

text: Outcomes[edit]

text: The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred and the injurious agent that is causing it. Here are the possible outcomes to inflammation:[8]

text:
Resolution
The complete restoration of the inflamed tissue back to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease, and damaged parenchymal cells regenerate. In situations where limited or short-lived inflammation has occurred this is usually the outcome.
Fibrosis
Large amounts of tissue destruction, or damage in tissues unable to regenerate, cannot be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen. The scar will not contain any specialized structures, such as parenchymal cells, hence functional impairment may occur.
Abscess formation
A cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells.
Chronic inflammation
In acute inflammation, if the injurious agent persists then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a chronic wound. Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release (including reactive oxygen species) are injurious to the organism's own tissues as well as invading agents. As a consequence, chronic inflammation is almost always accompanied by tissue destruction.

text: Examples[edit]

text: Inflammation is usually indicated by adding the suffix "itis", as shown below. However, some conditions such as asthma and pneumonia do not follow this convention. More examples are available at list of types of inflammation.

text:
Acute appendicitis

Acute dermatitis

Acute infective meningitis

Acute tonsillitis

text: Diet and inflammation[edit]

text: The Dietary Inflammatory Index (DII) is a score (number) that describes the potential of diet to modulate systemic inflammation within the body. As stated chronic inflammation is linked to most chronic diseases including arthritis, many types of cancer, cardiovascular diseases, inflammatory bowel diseases, and diabetes.

text: Exercise and inflammation[edit]

text: Exercise-induced acute inflammation[edit]

text: Acute inflammation of the muscle cells, as understood in exercise physiology,[77] can result after induced eccentric and concentric muscle training. Participation in eccentric training and conditioning, including resistance training and activities that emphasize eccentric lengthening of the muscle including downhill running on a moderate to high incline can result in considerable soreness within 24 to 48 hours, even though blood lactate levels, previously thought to cause muscle soreness, were much higher with level running. This delayed onset muscle soreness (DOMS) results from structural damage to the contractile filaments and z-disks, which has been noted especially in marathon runners whose muscle fibers revealed remarkable damage to the muscle fibers after both training and marathon competition [78][citation needed]. The onset and timing of this gradient damage to the muscle parallels the degree of muscle soreness experienced by the runners.

text: Z-disks are the point of contact for the contractile proteins. They provide structural support for transmission of force when muscle fibers are activated to shorten. However, in marathon runners and those who subscribe to the overload principle to enhance their muscles, show moderate Z-disk streaming and major disruption of thick and thin filaments in parallel groups of sarcomeres as a result of the force of eccentric actions or stretching of tightened muscle fibers.

text: This disruption of muscle fibers triggers white blood cells to increase following induced muscle soreness, leading to the inflammatory response observation from induced muscle soreness. Elevations in plasma enzymes, myoglobinemia, and abnormal muscle histology and ultrastructure are concluded to be associated with inflammatory response. High tension in the contractile-elastic system of muscle results in structural damage to the muscle fiber and plasmalemma and its epimysium, perimysium, and/or endomysium. The mysium damage disrupts calcium homeostasis in injured fibers and fiber bundles, resulting in necrosis that peaks about 48 hours after exercise. The products of macrophage activity and intracellular contents (such as histamines, kinins, and K+) accumulate outside cells. These substances then stimulate free nerve endings in the muscle; a process that appears accentuated by eccentric exercise, in which large forces are distributed over a relatively small cross-sectional area of the muscle[78][citation needed].

text: Post-inflammatory muscle growth and repair[edit]

text: There is a known relationship between inflammation and muscle growth.[79] For instance, high doses of anti-inflammatory medicines (e.g., NSAIDs) are able to blunt muscle growth.[80][81][original research?] Cold therapy has been shown to negatively affect muscle growth as well. Reducing inflammation results in decreased macrophage activity and lower levels of IGF-1[82] Acute effects of cold therapy on training adaptations show reduced satellite cell proliferation.[83] Long term effects include less muscular hypertrophy and an altered cell structure of muscle fibers.[84]

text: It has been further theorized that the acute localized inflammatory responses to muscular contraction during exercise, as described above, are a necessary precursor to muscle growth.[85] As a response to muscular contractions, the acute inflammatory response initiates the breakdown and removal of damaged muscle tissue.[86] Muscles can synthesize cytokines in response to contractions,[87][88][89] such that the cytokines interleukin-1 beta (IL-1β), TNF-α, and IL-6 are expressed in skeletal muscle up to 5 days after exercise.[86]

text: In particular, the increase in levels of IL-6 (interleukin 6), a myokine, can reach up to one hundred times that of resting levels.[89] Depending on volume, intensity, and other training factors, the IL-6 increase associated with training initiates about 4 hours after resistance training and remains elevated for up to 24 hours.[90][91][92]

text: These acute increases in cytokines, as a response to muscle contractions, help initiate the process of muscle repair and growth by activating satellite cells within the inflamed muscle. Satellite cells are crucial for skeletal muscle adaptation to exercise.[93] They contribute to hypertrophy by providing new myonuclei and repair damaged segments of mature myofibers for successful regeneration following injury- or exercise-induced muscle damage;[94][95][96] high-level powerlifters can have up to 100% more satellite cells than untrained controls.[97][98]

text: A rapid and transient localization of the IL-6 receptor and increased IL-6 expression occurs in satellite cells following contractions.[90] IL-6 has been shown to mediate hypertrophic muscle growth both in vitro and in vivo.[93] Unaccustomed exercise can increase IL-6 by up to sixfold at 5 hours post-exercise and threefold 8 days after exercise.[99] Also telling is the fact that NSAIDs can decrease satellite cell response to exercise,[80] thereby reducing exercise-induced protein synthesis.[81]

text: The increase in cytokines (myokines) after resistance exercise coincides with the decrease in levels of myostatin, a protein that inhibits muscle differentiation and growth.[92] The cytokine response to resistance exercise and moderate-intensity running occur differently, with the latter causing a more prolonged response, especially at the 12–24 hour mark.[92]

text: Developing research has demonstrated that many of the benefits of exercise are mediated through the role of skeletal muscle as an endocrine organ. That is, contracting muscles release multiple substances known as myokines, including but not limited to those cited in the above description, which promote the growth of new tissue, tissue repair, and various anti-inflammatory functions, which in turn reduce the risk of developing various inflammatory diseases. The new view that muscle is an endocrine organ is transforming our understanding of exercise physiology and with it, of the role of inflammation in adaptation to stress.[100]

text: Chronic inflammation and muscle loss[edit]

text: Both chronic and extreme inflammation are associated with disruptions of anabolic signals initiating muscle growth. Chronic inflammation has been implicated as part of the cause of the muscle loss that occurs with aging.[79][101] Increased protein levels of myostatin have been described in patients with diseases characterized by chronic low-grade inflammation.[102] Increased levels of TNF-α can suppress the AKT/mTOR pathway, a crucial pathway for regulating skeletal muscle hypertrophy,[103] thereby increasing muscle catabolism.[104][105][106] Cytokines may antagonize the anabolic effects of insulin-like growth factor 1 (IGF-1).[107][108] In the case of sepsis, an extreme whole body inflammatory state, the synthesis of both myofibrillar and sarcoplasmic proteins are inhibited, with the inhibition taking place preferentially in fast-twitch muscle fibers.[107][109] Sepsis is also able to prevent leucine from stimulating muscle protein synthesis.[87] In animal models, when inflammation is created, mTOR loses its ability to be stimulated by muscle growth.[110]

text: Exercise as a treatment for inflammation[edit]

text: Regular physical activity is reported to decrease markers of inflammation,[111][112][113] although the correlation is imperfect and seems to reveal differing results contingent upon training intensity. For instance, while baseline measurements of circulating inflammatory markers do not seem to differ greatly between healthy trained and untrained adults,[114][115] long-term training may help reduce chronic low-grade inflammation.[116] On the other hand, levels of the anti-inflammatory myokine IL-6 (interleukin 6) remained elevated longer into the recovery period following an acute bout of exercise in patients with inflammatory diseases, relative to the recovery of healthy controls.[116] It may well be that low-intensity training can reduce resting pro-inflammatory markers (CRP, IL-6), while moderate-intensity training has milder and less-established anti-inflammatory benefits.[114][117][118][119] There is a strong relationship between exhaustive exercise and chronic low-grade inflammation.[120] Marathon running may enhance IL-6 levels as much as 100 times over normal and increases total leuckocyte count and neturophil mobilization.[120]

text: Regarding the above, IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage.[121] However, it has become evident that eccentric exercise is not associated with a larger increase in plasma IL-6 than exercise involving concentric “nondamaging” muscle contractions. This finding clearly demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.[122]

text: Recent work has shown that both upstream and downstream signalling pathways for IL-6 differ markedly between myocytes and macrophages. It appears that unlike IL-6 signalling in macrophages, which is dependent upon activation of the NFκB signalling pathway, intramuscular IL-6 expression is regulated by a network of signalling cascades, including the Ca2+/NFAT and glycogen/p38 MAPK pathways. Thus, when IL-6 is signalling in monocytes or macrophages, it creates a pro-inflammatory response, whereas IL-6 activation and signalling in muscle is totally independent of a preceding TNF-response or NFκB activation, and is anti-inflammatory.[123]

text: Several studies show that markers of inflammation are reduced following longer-term behavioural changes involving both reduced energy intake and a regular program of increased physical activity, and that, in particular, IL-6 was miscast as an inflammatory marker. For example, the anti-inflammatory effects of IL-6 have been demonstrated by IL-6 stimulating the production of the classical anti-inflammatory cytokines IL-1ra and IL-10.[123] As such, individuals pursuing exercise as a means to treat the causal factors underlying chronic inflammation are pursuing a course of action strongly supported by current research, as an inactive lifestyle is strongly associated with the development and progression of multiple inflammatory diseases. Note that cautions regarding over-exertion may apply in certain cases, as discussed above, though this concern rarely applies to the general population.

text: Signal-to-noise theory[edit]

text: Given that localized acute inflammation is a necessary component for muscle growth, and that chronic low-grade inflammation is associated with a disruption of anabolic signals initiating muscle growth, it has been theorized that a signal-to-noise model may best describe the relationship between inflammation and muscle growth.[124] By keeping the "noise" of chronic inflammation to a minimum, the localized acute inflammatory response signals a stronger anabolic response than could be achieved with higher levels of chronic inflammation.


document_title: State of the Union

question_text: when is the state of the union held

question_tokens: when is the state of the union held

text: State of the Union

text: Ceremony

text: The practice arises from a duty given to the president in the Constitution of the United States:

text: He shall from time to time give to Congress information of the State of the Union and recommend to their Consideration such measures as he shall judge necessary and expedient.

text: Although the language of this State of the Union Clause[5] of the Constitution is not specific, since the 1930s, the President makes this report annually in late January or early February. Between 1934 and 2013 the date has been as early as January 3,[6] and as late as February 12.[7]

text: While not required to deliver a speech, every president since Woodrow Wilson, with the notable exception of Herbert Hoover,[8] has made at least one State of the Union report as a speech delivered before a joint session of Congress. Before that time, most presidents delivered the State of the Union as a written report.[6]

text: Since Franklin Roosevelt, the State of the Union is given typically each January before a joint session of the United States Congress and is held in the House of Representatives chamber of the United States Capitol. Newly inaugurated presidents generally deliver an address to Congress in February of the first year of their term, but this speech is not officially considered to be a "State of the Union".[6]

text: What began as a communication between president and Congress has become a communication between the president and the people of the United States. Since the advent of radio, and then television, the speech has been broadcast live on most networks, preempting scheduled programming. To reach the largest audience, the speech, once given during the day, is now typically given in the evening, after 9pm ET (UTC-5).

text: History

text: George Washington delivered the first regular annual message before a joint session of Congress on January 8, 1790, in New York City, then the provisional U.S. capital. In 1801, Thomas Jefferson discontinued the practice of delivering the address in person, regarding it as too monarchical (similar to the Speech from the Throne). Instead, the address was written and then sent to Congress to be read by a clerk until 1913 when Woodrow Wilson re-established the practice despite some initial controversy. However, there have been exceptions to this rule. Presidents during the latter half of the 20th century[who?] have sent written State of the Union addresses. The last President to do this was Jimmy Carter in 1981, after his defeat by Ronald Reagan and days before his term ended.[9]

text: For many years, the speech was referred to as "the President's Annual Message to Congress".[10] The actual term "State of the Union" first emerged in 1934 when Franklin D. Roosevelt used the phrase, becoming its generally accepted name since 1947.[10]

text:
Franklin Delano Roosevelt

State of the Union (Four Freedoms) (January 6, 1941)

Franklin Delano Roosevelt's January 6, 1941 State of the Union Address introducing the theme of the Four Freedoms (starting at 32:02)

Problems playing this file? See media help.

text: Prior to 1934, the annual message was delivered at the end of the calendar year, in December. The ratification of the 20th Amendment on January 23, 1933, changed the opening of Congress from early March to early January, affecting the delivery of the annual message. Since 1934, the message or address has been delivered to Congress in January or February.

text: The Twentieth Amendment also established January 20 as the beginning of the presidential term. In years when a new president is inaugurated, the outgoing president may deliver a final State of the Union message, but none has done so since Jimmy Carter sent a written message in 1981. In 1953 and 1961, Congress received both a written State of the Union message from the outgoing president and a separate State of the Union speech by the incoming president. Since 1989, in recognition that the responsibility of reporting the State of the Union formally belongs to the president who held office during the past year, newly inaugurated Presidents have not officially called their first speech before Congress a "State of the Union" message.

text: In 1936, President Roosevelt set a precedent when he delivered the address at night. Only once before—when Woodrow Wilson asked Congress to order the U.S. into World War I—had a sitting president addressed Congress at night.[11]

text: Warren Harding's 1922 speech was the first to be broadcast on radio, albeit to a limited audience,[12] while Calvin Coolidge's 1923 speech was the first to be broadcast across the nation.[2] Harry S. Truman's 1947 address was the first to be broadcast on television. Lyndon B. Johnson's address in 1965 was the first delivered in the evening.[12] Three years later, in 1968, television networks in the United States, for the first time, imposed no time limit for their coverage of a State of the Union address. Delivered by Lyndon B. Johnson, this address was followed by extensive televised commentary by, among others, Daniel Patrick Moynihan and Milton Friedman.[13] Ronald Reagan's 1986 State of the Union Address is the only one to have been postponed. He had planned to deliver it on January 28, 1986 but postponed it for a week after learning of the Space Shuttle Challenger disaster and instead addressed the nation on the day's events.[14][15] Bill Clinton's 1997 address was the first broadcast available live on the World Wide Web.[16]

text: Delivery of the speech

text: A formal invitation is made by the Speaker of the House to the President several weeks before each State of the Union Address.[17][18]

text: Invitations

text: Every member of Congress can bring one guest to the State of the Union address. The President may invite up to 24 guests with the First Lady in her box. The Speaker of the House may invite up to 24 guests in the Speaker’s box. Seating for Congress on the main floor is by a first-in, first-served basis with no reservations. The Cabinet, Supreme Court justices, members of the Diplomatic Corps, and Joint Chiefs have reserved seating.

text: Protocol of entry into House chamber

text: By approximately 8:30 pm on the night of the address, the members of the House have gathered in their seats for the joint session.[19] Then, the Deputy Sergeant at Arms addresses the Speaker and loudly announces the Vice President and members of the Senate, who enter and take the seats assigned for them.[19]

text: The Speaker, and then the Vice President, specify the members of the House and Senate, respectively, who will escort the President into the House chamber.[19] The Deputy Sergeant at Arms addresses the Speaker again and loudly announces, in order, the Dean of the Diplomatic Corps, the Chief Justice of the United States and the Associate Justices, and the Cabinet, each of whom enters and takes their seats when called.[19] The justices take the seats nearest to the Speaker's rostrum and adjacent to the sections reserved for the Cabinet and the members of the Joint Chiefs of Staff.[20]

text: Just after 9 pm, as the President reaches the door to the chamber,[21] the House Sergeant at Arms stands just inside the doors, faces the Speaker, and waits until the President is ready to enter the chamber.[20] When the President is ready, the Sergeant at Arms always announces his entrance, loudly stating the phrase: "Mister Speaker, the President of the United States!"[21]

text: As applause and cheering begins, the President slowly walks toward the Speaker's rostrum, followed by members of his Congressional escort committee.[21] The President's approach is slowed by pausing to shake hands, hug, kiss, and autograph copies of his speech for Members of Congress.[20] After he takes his place at the House Clerk's desk,[21] he hands two manila envelopes, previously placed on the desk and containing copies of the speech, to the Speaker and Vice President.

text: After continuing applause from the attendees has diminished, the Speaker introduces the President to the Representatives and Senators, stating: "Members of Congress, I have the high privilege and distinct honor of presenting to you the President of the United States."[20][21] This leads to a further round of applause and, eventually, the beginning of the address by the President.[21]

text: At close of the ceremony, attendees leave on their own accord. The Sergeants at Arms guides the President out of the Chamber. Some politicians stay to shake hands with and congratulate the President on his way out.

text: Designated survivor and other logistics

text: Customarily, one cabinet member (the designated survivor) does not attend the speech, in order to provide continuity in the line of succession in the event that a catastrophe disables the President, the Vice President, and other succeeding officers gathered in the House chamber. Additionally, since the September 11 attacks in 2001, a few members of Congress have been asked to relocate to undisclosed locations for the duration of the speech to form a rump Congress in the event of a disaster.[22] Since 2003, each chamber of Congress has formally named a separate designated survivor.[23][24]

text: Both the Speaker and the Vice President sit at the Speaker's desk, behind the President for the duration of the speech. If either is unavailable, the next highest-ranking member of the respective house substitutes. Once the chamber settles down from the President's arrival, the Speaker officially presents the President to the joint session of Congress. The President then delivers the speech from the podium at the front of the House Chamber.

text: In the State of the Union the President traditionally outlines the administration's accomplishments over the previous year, as well as the agenda for the coming year, often in upbeat and optimistic terms.[25] Since the 1982 address, it has also become common for the President to honor special guests sitting in the gallery, such as American citizens or visiting heads of state. During that 1982 address, President Ronald Reagan acknowledged Lenny Skutnik for his act of heroism following the crash of Air Florida Flight 90.[26] Since then, the term "Lenny Skutniks" has been used to refer to individuals invited to sit in the gallery, and then cited by the President, during the State of the Union.[27][28]

text: State of the Union speeches usually last a little over an hour, partly because of the large amounts of applause that occur from the audience throughout. The applause is often political in tone, with many portions of the speech being applauded only by members of the President's own party. As non-political officeholders, members of the Supreme Court or the Joint Chiefs of Staff rarely applaud in order to retain the appearance of political impartiality. In recent years, the presiding officers of the House and the Senate, the Speaker and the Vice President, respectively, have departed from the neutrality expected of presiding officers of deliberative bodies, as they, too, stand and applaud in response to the remarks of the President with which they agree.

text: For the 2011 address, Senator Mark Udall of Colorado proposed a break in tradition wherein all members of Congress sit together regardless of party, as well as the avoiding of standing;[29] this was in response to the 2011 Tucson Shooting in which Representative Gabrielle Giffords was shot and wounded in an assassination attempt. This practice was also repeated during the 2012 address and every address after.[30]

text: Opposition response

text: Since 1966,[31] the speech has been followed on television by a response or rebuttal by a member of the major political party opposing the President's party. The response is typically broadcast from a studio with no audience. In 1970, the Democratic Party put together a TV program with their speech to reply to President Nixon, as well as a televised response to Nixon's written speech in 1973.[32] The same was done by Democrats for President Reagan's speeches in 1982 and 1985. The response is not always produced in a studio; in 1997, the Republicans for the first time delivered the response in front of high school students.[33] In 2004, the Democratic Party's response was also delivered in Spanish for the first time, by New Mexico Governor Bill Richardson.[34] In 2011, Minnesota Congresswoman Michele Bachmann also gave a televised response for the Tea Party Express, a first for a political movement.[35]

text: Significance

text: Although much of the pomp and ceremony behind the State of the Union address is governed by tradition rather than law, in modern times, the event is seen as one of the most important in the US political calendar. It is one of the few instances when all three branches of the US government are assembled under one roof: members of both houses of Congress constituting the legislature, the President's Cabinet constituting the executive, and the Chief Justice and Associate Justices of the Supreme Court constituting the judiciary. In addition, the military is represented by the Joint Chiefs of Staff, while foreign governments are represented by the Dean of the Diplomatic Corps. The address has also been used as an opportunity to honor the achievements of some ordinary Americans, who are typically invited by the President to sit with the First Lady.[28]

text: Local versions

text: Certain states have a similar annual address given by the governor. For most of them, it is called the State of the State address. In Iowa, it is called the Condition of the State Address; in Kentucky, Massachusetts, Pennsylvania, and Virginia, the speech is called the State of the Commonwealth address. The mayor of Washington, D.C. gives a State of the District address. American Samoa has a State of the Territory address given by the governor. Puerto Rico has a State Address given by the governor.

text: Some cities or counties also have an annual State of the City Address given by the mayor, county commissioner or board chair, including Sonoma County, California; Orlando, Florida; Cincinnati, Ohio; New Haven, Connecticut; Parma, Ohio; Detroit, Michigan; Seattle, Washington; Birmingham, Alabama; Boston, Massachusetts; Los Angeles, California; Buffalo, New York; Rochester, New York; San Antonio, Texas; McAllen, Texas; and San Diego, California. The Mayor of the Metropolitan Government of Nashville and Davidson County in Nashville, Tennessee gives a speech similar called the State of Metro Address. Some university presidents give a State of the University address at the beginning of every academic term.[36][37] Private companies usually have a "State of the Corporation" or "State of the Company" address given by the respective CEO.[38]

text: The State of the Union model has also been adopted by the European Union,[39] and in France since the presidency of Emmanuel Macron.

text: Historic speeches

text: This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (January 2018) (Learn how and when to remove this template message)

text:
President James Monroe first stated the Monroe Doctrine during his seventh annual State of the Union Address to Congress on December 2, 1823. It became a defining moment in the foreign policy of the United States and one of its longest-standing tenets, and would be invoked by many U.S. statesmen and several U.S. presidents, including Theodore Roosevelt, John F. Kennedy, and Ronald Reagan.
The Four Freedoms were goals first articulated by Franklin D. Roosevelt on January 6, 1941. In an address known as the Four Freedoms speech, he proposed four fundamental freedoms that people "everywhere in the world" ought to enjoy: freedom of speech and expression, freedom of worship, freedom from want, and freedom from fear.
During his State of the Union Address on January 11, 1944, FDR proposed the Second Bill of Rights. Roosevelt's argument was that the "political rights" guaranteed by the constitution and the Bill of Rights had "proved inadequate to assure us equality in the pursuit of happiness".
During his State of the Union address on January 8, 1964, Lyndon B. Johnson introduced legislation that would come to be known as the "War on Poverty". This legislation was proposed by Johnson in response to a national poverty rate of around nineteen percent. The speech led the United States Congress to pass the Economic Opportunity Act, which established the Office of Economic Opportunity (OEO) to administer the local application of federal funds targeted against poverty.
During his State of the Union address on January 15, 1975, Gerald R. Ford very bluntly stated that "the state of the Union is not good: Millions of Americans are out of work... We depend on others for essential energy. Some people question their Government's ability to make hard decisions and stick with them; they expect Washington politics as usual." Ford said he didn't "expect much, if any, applause. The American people want action, and it will take both the Congress and the President to give them what they want. Progress and solutions can be achieved, and they will be achieved."

text: In his 2002 State of the Union Address, President George W. Bush identified North Korea, Iran, and Iraq as representing significant threats to the United States. He said, "States like these and their terrorist allies constitute an axis of evil, arming to threaten the peace of the world". In this speech, he would outline the objectives for the War on Terror.

text: TV ratings

text: Television ratings for recent State of the Union Addresses were:[40][41][42]

text:
Date
President
Viewers,
millions

Households,
millions

Rating
Networks

1/30/2018
Donald Trump
45.551
32.168
26.9
ABC, CBS, FOX, NBC, ESTRELLA, TELEMUNDO, UNIVISION, CNN, FOX BUSINESS, FOXNC, MSNBC, PBS

2/28/2017
Donald Trump
47.741
33.857
28.7
ABC, CBS, FOX, NBC, UNIVISION, PBS, CNN, FOX BUSINESS, FOXNC, MSNBC, NBC UNIVERSO

1/12/2016
Barack Obama
31.334
23.040
19.6
ABC, AL JAZEERA AMERICA, AZTECA, CBS, CNN, FOX, FOX BUSINESS, FOXNC, GALAVISION, MSNBC, NBC, NBC UNIVERSO, UNIVISION**

1/20/2015
Barack Obama
31.710
23.137
19.9
ABC, AL JAZEERA AMERICA, AZTECA, CBS, CNN, FOX, FOX BUSINESS, FOXNC, GALAVISION, MSNBC, MUNDOFOX, NBC, UNIVISION**

1/28/2014
Barack Obama
33.299
23.949
20.7
CBS, ABC, NBC, FOX, AZTECA, FOX BUSINESS, FOXNC, CNN, MSNBC, CNBC, AL JAZEERA AMERICA, GALAVISION, MUN2, UNIVISION**

2/12/2013
Barack Obama
33.497
24.767
21.8
FOX, ABC, CBS, NBC, PBS, AZTECA, UNIVISION, MFX, CNBC, CNN, FOX BUSINESS, FOXNC, MSNBC, CURRENT, CENTRIC, GALAVISION

1/24/2012
Barack Obama
37.752
27.569
24.0
ABC, CBS, FOX, NBC, TELEMUNDO, TF, UNIVISION, CNBC, CNN, FOX BUSINESS, FOXNC, GALAVISION, MSNBC, MUN2

1/25/2011
Barack Obama
42.789
30.871
26.6
ABC, CBS, FOX, NBC, TELEMUNDO, UNIVISION, CNN, CENTRIC, CNBC, FOXNC, MSNBC

1/27/2010
Barack Obama
48.009
34.182
29.8
ABC, CBS, FOX, NBC, TELEMUNDO, UNIVISION, CNN, BET, CNBC, FOXNC, MSNBC

2/24/2009
Barack Obama
52.373
37.185
32.5
ABC, CBS, FOX, NBC, CNBC, CNN, FOXNC, MSNBC, TELEMUNDO, UNIVISION

1/28/2008
George W. Bush
37.515
27.702
24.7
ABC, CBS, FOX, NBC, CNN, FOXNC, MSNBC, TELEMUNDO**, UNIVISION

1/24/2007
George W. Bush
45.486
32.968
29.6
ABC, CBS, FOX, NBC, CNN, FOXNC, MSNBC, TELEMUNDO, UNIVISION

2/01/2006
George W. Bush
43.179
30.528
31.2
ABC, CBS, FOX, NBC, CNN, FOXNC, MSNBC, TELEMUNDO, AZTECA AMERICA, TELFUTURA

2/02/2005
George W. Bush
39.432
28.359
35.3
ABC, CBS, FOX, NBC, CNN, FOXNC, MSNBC, TELEMUNDO, TELEFUTURA

1/20/2004
George W. Bush
43.411
30.286
28.0
ABC, CBS, FOX, NBC, CNN, CNBC, FOXNC, MSNBC

1/28/2003
George W. Bush
62.061
41.447
38.8
ABC, CBS, FOX, NBC, CNN, CNBC, FOXNC, MSNBC

1/29/2002
George W. Bush
51.773
35.547
33.6
ABC, CBS, FOX, NBC, CNN, CNBC, FOXNC, MSNBC

2/27/2001
George W. Bush
39.793
28.201
27.6
ABC, CBS, FOX, NBC, CNN, FOXNC, MSNBC

1/27/2000
Bill Clinton
31.478
22.536
22.4
ABC, CBS, FOX, NBC, CNN, FOXNC, MSNBC

1/19/1999
Bill Clinton
43.500
30.700
31.0
ABC, CBS, FOX, NBC, CNN, FOXNC, MSNBC

1/27/1998
Bill Clinton
53.077
36.513
37.2
ABC, CBS, FOX, NBC, CNN, FOXNC, MSNBC, CNBC

2/04/1997
Bill Clinton
41.100
27.600
28.4
ABC, CBS, FOX, NBC, CNN

1/23/1996
Bill Clinton
40.900
28.400
29.6
ABC, CBS, FOX, NBC, CNN

1/24/1995
Bill Clinton
42.200
28.100
29.5
ABC, CBS, NBC, CNN

1/25/1994
Bill Clinton
45.800
31.000
32.9
ABC, CBS, NBC, CNN

2/17/1993
Bill Clinton
66.900
41.200
44.3
ABC, CBS, NBC, CNN


document_title: List of most streamed artists on Spotify

question_text: second most listened to artist on spotify 2018

text: Monthly[edit]

text:
Rank

Artist

Monthly listeners(millions)

Country

Ref(s)

1.
Drake
60
 CAN
[1]

2.
J Balvin
47
 COL
[2]

3.
Maroon 5
43
 USA
[3]

4.
Calvin Harris
41
 GBR
[4]

5.
Khalid
 USA
[5]

6.
Ed Sheeran
40
 GBR
[6]

7.
Ariana Grande
39
 USA
[7]

8.
Bad Bunny
38
 PRI
[8]

9.
Imagine Dragons
 USA
[9]

10.
Dua Lipa
 GBR
[10]

11.
David Guetta
37
 FRA
[11]

12.
Demi Lovato
 USA
[12]

13.
Post Malone
36
 USA
[13]

14.
Justin Bieber
 CAN
[14]

15.
Cardi B
34
 USA
[15]

16.
DJ Khaled
 USA
[16]

17.
Sia
33
 AUS
[17]

18.
Clean Bandit
32
 GBR
[18]

19.
Nicki Minaj
 TTO
[19]

20.
Camila Cabello
 USA
[20]

As of August 27, 2018

text: On the Spotify Global Top 200[edit]

text: This list enumerates the streams artists' song accrued on the Spotify Global Top 200, which is less than the artist's total streams.[21]

text:
| align="center" | 3. || Justin Bieber || align="center" | 8.73 ||  CAN
|-
| align="center" | 4. || Post Malone || align="center" | 6.00 ||  USA
|-
| align="center" | 5. || The Weeknd || align="center" | 5.83 ||  CAN
|-
| align="center" | 6. || style="background:#DDF4FF " | J Balvin || align="center" | 5.67 ||  COL
|-
| align="center" | 7. || The Chainsmokers || align="center" | 5.21 ||  USA
|-
| align="center" | 8. || style="background:#DDF4FF " | Ozuna || align="center" | 4.67 ||  PRI
|-
| align="center" | 9. || Kendrick Lamar || align="center" | 4.62 ||  USA
|-
| align="center" | 10. || Rihanna || align="center" | 4.49 ||  BAR
|-
| align="center" | 11. || style="background:#DDF4FF | Daddy Yankee || align="center" | 4.44 ||  PRI
|-
| align="center" | 12. || Calvin Harris || align="center" | 4.35 ||  GBR
|-
| align="center" | 13. || style="background:#DDF4FF " | Bad Bunny ||  align="center" | 3.80 || PRI
|-
| align="center" | 14. || Future || align="center" | 3.76 || rowspan="4" |  USA
|-
| align="center" | 15. || Selena Gomez || align="center" | 3.72
|-
| align="center" | 16. || Ariana Grande || align="center" | 3.61
|-
| align="center" | 17. || Khalid || align="center" | 3.60
|-
| align="center" | 18. || Nicki Minaj || align="center" | 3.56 ||  TTO
|-
| align="center" | 19. || Sia || align="center" | 3.48 ||  AUS
|-
| align="center" | 20. || Imagine Dragons || align="center" | 3.45 ||  USA
|-
! colspan="4" style="text-align:center; font-size:8pt;" | As of August 20, 2018
|}

text: All-time[edit]

text: This list enumerates the number of streams artists' albums (LP & EP) have accrued on Spotify.

text:
Rank

Artist

Total streams
(billions)

Country

1.

Francesca Michielin

17.1

 ITA

2.

Justin Bieber

11

 CAN

As of July 27, 2018

text: Most followers[edit]

text: It has been suggested that this section be split out  into another article titled List of most followed artists on Spotify. (Discuss) (July 2018)

text:
Rank

Artist

Followers(millions)

Country

Ref(s)

1.
Ed Sheeran
31.1
 GBR
[6]

2.
Rihanna
26.1
 BAR
[22]

3.
Drake
25.1
 CAN
[23]

4.
Justin Bieber
24.5
 CAN
[24]

5.
Eminem
19.2
 USA
[25]

6.
Ariana Grande
17.7
[7]

7.
Bruno Mars
15.8
 USA
[11]

8.
David Guetta
15.5
 FRA
[11]

9.
Beyoncé
15.1
 USA
[26]

10.
Taylor Swift
14.5
 USA
[27]

11.
Coldplay
13.9
 GBR
[28]

12.
Shakira
13.1
 COL
[29]

13.
Calvin Harris
12.8
 GBR
[5]

14.
Maroon 5
12.6
 USA
[3]

15.
Nicki Minaj
12.2
 TTO
[19]

16.
The Weeknd
11.9
 CAN
[30]

17.
Maluma
11.6
 COL
[31]

18.
Imagine Dragons
11.6
 USA
[9]

19.
Shawn Mendes
11.1
 CAN
[32]

20.
Selena Gomez
11
 USA
[33]

As of August 17, 2018

text: Peak position on chart[edit]

text: Timeline of artists who have held the peak position each month as the most streamed artist since September 2015, when the feature was first made public.[34]

text: Indicates most streamed artist of the year

text:
Year

Month

Artist

Ref(s)

2015
September
The Weeknd
[37]

October

November

December
Justin Bieber
[42]

2016
January

February

March

April
Rihanna
[43]

May
Drake
[44]

June.

July

August

September

October

November

December
The Weeknd

2017
January

February
Ed Sheeran
[48]

March

April

May

June

July

August

September

October

November

December

2018
January
Ed Sheeran

February

March
Drake
[49]

April

May

June
J Balvin
[50]

July
Drake

text: Most streamed artists by year[edit]

text: Spotify's most streamed artist of 2017 was Ed Sheeran with 6.3 billion streams that year. This was his second year topping the list.[51]

text:
Rank

Chg

Artist

Country

1.

Ed Sheeran
 GBR

2.

Drake
 CAN

3.

The Weeknd

4.

Kendrick Lamar
 USA

5.

The Chainsmokers

text: Spotify's most streamed artist of 2016 was Drake with 4.7 billion streams that year. He topped the list for a second year in a row.[52]

text:
Rank

Chg

Artist

Country

1.

Drake
 CAN

2.

Justin Bieber

3.

Rihanna
 BAR

4.

Twenty One Pilots
 USA

5.

Kanye West

text: Spotify's most streamed artist of 2015 was Drake with 1.8 billion streams that year.[53]

text:
Rank

Chg

Artist

Country

1.

Drake
 CAN

2.

Ed Sheeran
 GBR

3.

The Weeknd
 CAN

4.

Maroon 5
 USA

5.

Kanye West

text: Spotify's most streamed artist of 2014 was Ed Sheeran with 860 million streams that year.[54]

text:
Rank

Chg

Artist

Country

1.

Ed Sheeran
 GBR

2.

Eminem
 USA

3.

Coldplay
 GBR

4.

Calvin Harris

5.

Katy Perry
 USA

text: Spotify's most streamed artists of 2013 were Macklemore & Ryan Lewis.[55]

text:
Rank

Artist

Country

1.
Macklemore & Ryan Lewis
 USA

2.
Avicii
 SWE

3.
Daft Punk
 FRA

4.
Eminem
 USA

5.
Imagine Dragons

6.
Jay-Z

7.
Bruno Mars

8.
Rihanna
 BAR

9.
Calvin Harris
 GBR

10.
Drake
 CAN


document_title: Publishers Clearing House

question_text: where does the money from pch come from

question_tokens: where does the money from pch come from

text: Publishers Clearing House

text: History[edit]

text: Early history[edit]

text: Publishers Clearing House was founded in 1953 in Port Washington, New York, by Harold Mertz,[4][5] a former manager of a door-to-door sales team for magazine subscriptions.[6] The company started in Mertz's basement with help from his wife LuEsther and daughter Joyce.[7][8] Its first mailings were of 10,000 envelopes from Mertz's home in Long Island, New York, and offered 20 magazine subscriptions. 100 orders were received. Within a few years the company moved out of Mertz's basement into an office building and started hiring staff. When Publishers Clearing House moved its headquarters in 1969, its prior location was donated to the city and renamed the Harold E. Mertz community center.[8] The company revenue had grown to US$50 million by 1981, and $100 million by 1988.[6]

text: In 1967 Publishers Clearing House started its first sweepstakes as a way to increase subscription sales,[9] based on the sweepstakes held by Reader's Digest.[4] The first prizes ranged from 25 cents to $10 and entrants had a 1 in 10 chance of winning. After the sweepstakes increased response rates to mailings, prizes of[8] $5,000[6] and eventually $250,000 were offered.[10] PCH began advertising the sweepstakes on TV in 1974.[7][11] It was the only major multi-magazine subscription business until 1977. Former client Time Inc. and several other publishers formed American Family Publishers to compete with Publishers Clearing House after the company refused repeated requests by Time for a larger share of sales revenue from magazine subscriptions.[4][8]

text: American Family Publishers and Publishers Clearing House competed for exclusive rights to magazines and for the better promotion and prize ideas. When American Family Publishers increased their jackpot to $1 million,[10] then to $10 million in 1985, Publishers Clearing House raised its prizes to match.[4] $7 million in prizes were distributed by 1979,[12] $40 million by 1991[5] and $137 million by 2000.[9] In 1989 two members of its advertising team, Dave Sayer and Todd Sloane, started the Prize Patrol, a publicized event where winners are surprised with a check at their home. The idea was inspired by the 1950s television series "The Millionaire".[4][13][14]

text: In 1992 thousands of discarded sweepstakes entries from contestants who had not bought magazine subscriptions were found in the trash by city employees,[4][15] reinforcing beliefs that the company favored those who made purchases in selecting a sweepstakes winner.[4] Publishers Clearing House said this was done by a disgruntled employee at their mail processing vendor.[8] A class action ensued, which PCH settled by giving discarded entrants a second chance to win.[4][15][16]

text: Government regulation[edit]

text: In the 1990s Publishers Clearing House and its primary competitor, American Family Publishers, experienced a series of legal troubles due to concerns that their mailings misled consumers about their odds of winning and implied that magazine purchases increased their chances.[4][10] This led to the Deceptive Mail Prevention and Enforcement Act of 2000, which regulates direct mail businesses.[4] At the senate hearings regarding this Act, Publishers Clearing House said most consumers were not confused about their chances of winning or that purchases did not increase their chances. The company said less than five percent of participants spend more than $300.[8] Government officials from California said 5,000 local consumers paid more than $2,500 each in magazine purchases under the false belief that they were increasing their odds of winning the sweepstakes.[17]

text: Industry sources estimated Publishers Clearing House's response rates decreased by 7-12 percent and its sales volume by 22 to 30 percent in response to the bad publicity from the lawsuits.[6][18] In 2000, Publishers Clearing House laid off a quarter of its 800-person work force.[18]

text: Lawsuits[edit]

text: In 1994 Publishers Clearing House sent mailings telling recipients they were all "finalists", which led to[10] a lawsuit involving the attorneys general of 14 US states.[19][20][21] Later that year, Publishers Clearing House denied wrongdoing, but agreed to pay a settlement of $490,000 and to change their practices.[20] Under the agreement, Publishers Clearing House said it would define terms like "finalist" and disclose the chances of winning.[22]

text: In 1997, a contestant of competitor American Family Publishers flew to Tampa, Florida, thinking he had won, though he had not. The resulting publicity caused more lawsuits for both companies.[6] Publishers Clearing House reached a $30 million national settlement in 1999.[8][23] In 2000, another $18 million settlement was reached with 24 states, after the company sent mass mailings that said "You are a winner!" and used mock personalized checks.[17][24] Publishers Clearing House agreed to avoid similar mailings in the future, and add a "sweepstakes fact box" to mailings.[17][24]

text: State attorneys spoke out against the national settlement from 2000 and additional lawsuits were filed by individual states.[8] Another $34 million settlement was reached in 2001 in a lawsuit involving 25 states.[1][25] As part of the settlement, Publishers Clearing House was required to avoid terms like "Guaranteed Winner," add disclaimers to mailings saying that the recipient has not won and that purchasing merchandise won't increase their chances.[26][25][27] Publishers Clearing House reached settlements with all fifty states and agreed to work with a "compliance counsel."[6] Publishers Clearing House apologized in the settlement and said it would contact customers who had spent more than $1,000 on merchandise the prior year".[28]

text: Publishers Clearing House also reached an agreement with Iowa in 2007.[29] In 2010 the company paid $3.5 million to the Attorneys General of 32 states and the District of Columbia to settle possible contempt charges that it had violated the terms of the 2001 agreement. The company denied wrongdoing, but agreed to work with both an ombudsperson and a compliance counsel who would review its mailings quarterly.[30][31][32][33]

text: In April 2014, an investigation by the Senate Special Committee on Aging concluded that Publishers Clearing House had "pushed the limits" of prior agreements and that additional legislation may be needed.[34]

text: Online development[edit]

text: Publishers Clearing House began selling merchandise in 1985[7] with two products. After a Hershey's Chocolate Cookbook and a diet cookbook sold more than other products, the company began expanding into jewelry, media, collectibles, household products and others.[8] The company also shifted its focus online.[1][35] It began selling magazine subscriptions and merchandise on PCH.com in 1996.[36] In 2006, it acquired Blingo Inc., an ad-supported metasearch engine that was later re-branded as PCH Search and Win.[13][37] Publishers Clearing House ran contests on Twitter, Facebook and Myspace. iPhone apps for slot games and trivia were developed. The company created online play-and-win sites like PCH Games (formerly Candystand) and PCHQuiz4Cash, with air-hockey and video poker games.[1]

text: In December 2010, Publishers Clearing House acquired Funtank and its online gaming site Candystand.com.[38] In 2011, Publishers Clearing House promoted a "$5,000 every week for life" sweepstakes in TV ads and the front page of AOL.com.[11][26] The following year the company acquired a mobile marketing company, Liquid Wireless.[39] The company utilized, then stopped then started again utilizing coregistration (through other websites) to expand its customer base.[40]

text: In 2008, a PCH spokesperson said the digital properties were intended to attract younger consumers. By 2013, the internet had become PCH's primary channel of interaction with consumers.[7] The New York Times described the digital transition as "part of an overall effort to collect information on Web users, show them advertisements and use the registration information for PCH’s mailing lists."[1]

text: Products[edit]

text: Publishers Clearing House is a direct-marketing company that sells merchandise, magazine subscriptions and operates several prize-based websites.[11] While best known for the sweepstakes and Prize Patrol it uses to promote its magazine subscriptions,[1][13][36] the majority of the company's revenue now comes from merchandise.[11] The company has been selling books, media, jewelry and other consumer items[4] since the 1980s.[8] Publishers Clearing house operates eight websites, including PCH Search and Win, PCH Lotto, PCH Games, PCH Save and Win, and Candystand.[1][11]

text: The company also sells magazine subscriptions at a discount and advertises subscriptions along with its sweepstakes.[41] It's estimated that companies like Publishers Clearing House keep 75-90 percent of the fees from the original subscription, while publishers use the increased distribution to improve circulation numbers and revenue from renewals.[10][42] Publishers Clearing House popularized the idea of using sweepstakes to sell magazine subscriptions in the direct-marketing market and became known by detractors as a producer of junk-mail for advertising through mass-mailings.[5][41] Documents filed with the New York State Department in 1993 said that year the company mailed 220 million envelopes. Frequent buyers can receive 30-40 mailings a year.[43]

text: Sweepstakes[edit]

text: Although Publishers Clearing House advertises its sweepstakes along with magazine subscriptions, no purchase is necessary to enter or win.[10][43][44] In 1995, Publishers Clearing House began the tradition of announcing winners of its $10 million prize just after the Super Bowl.[45] As of 2012, $225 million in prizes have been distributed.[8] Some of its larger prizes are for $5,000 a week for life,[46] or $10 million.[47] Prizes can also range from $1 Amazon gift cards to $2,500, $1 million or $3 million.[48] The larger cash prizes are paid in installments, typically with a balloon payment at 30 years,[49] reducing the present value of prizes to much less than their nominal values.

text: Sweepstakes scammers often pose as being from Publishers Clearing House and say that a cash payment is needed before they can deliver a prize.[50] According to Chris Irving from Publishers Clearing House "If you are contacted by anyone claiming to represent Publishers Clearing House and they request payment of any amount to collect a prize, do not send any money... You have not heard from the real Publishers Clearing House."[51][52]

text: Odds of Winning[edit]

text: The odds of winning a Publishers Clearing House sweepstakes vary depending on the number of entries and what prize or sweepstakes is involved.[48] According to the official rules, the estimated odds of winning the $1 million a year forever are one in 1.3 billion.[53] As of 2017, the odds of winning $15 million in Giveaway 8800 are 1 in 2.4 billion. [54] Smaller prizes have better odds that may vary from one in 223 to one in 80,000, depending on the prize.[48]

text: Prize Patrol[edit]

text: The Prize Patrol surprises sweepstakes winners at their homes, work or other locations with cash prizes and captures the event on video.[7] Since their introduction in 1989, these reality TV-style videos of prize-winners surprised at their doorstep with checks for $1,000 to $10 million have been used in widely broadcast television commercials, and, more recently, in the company's online acquisition efforts, websites and social media communications.[7][11][55][56] In 2013, a $5 million television campaign modified the traditional prize patrol commercial by digitally altering video from classic sitcoms like The Brady Bunch and Gilligan's Island to show the prize patrol visiting characters in the show.[56]

text: The Prize Patrol has made in-person appearances or delivered prizes on TV programs such as The Oprah Winfrey Show[57] and The Price Is Right.[58][59] Their surprise winning moments have been spoofed by Jay Leno,[60] Conan O'Brien[61] and the cast of Saturday Night Live;[62] woven into the plots of movies such as Let's Go to Prison,[63][64] The Sentinel[65] and Knight and Day;[66][67] and the subject of cartoons.[8]