<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Inflammation and can you explain it in depth? [/INST] Inflammation (from Latin: inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.
The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin calor, dolor, rubor, tumor, and functio laesa).  Inflammation is a generic response, and therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. In contrast, too much inflammation, in the form of chronic inflammation, is associated with various diseases, such as hay fever, periodontal disease, atherosclerosis, and osteoarthritis.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli, and is achieved by the increased movement of plasma and leukocytes (in particular granulocytes) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
Inflammation has also been classified as Type 1 and Type 2 based on the type of cytokines and helper T cells (Th1 and Th2) involved.Inflammation is not a synonym for infection. Infection describes the interaction between the action of microbial invasion and the reaction of the bodys inflammatory response—the two components are considered together when discussing an infection, and the word is used to imply a microbial invasive cause for the observed inflammatory reaction. Inflammation, on the other hand, describes purely the bodys immunovascular response—whatever the cause may be. But because of how often the two are correlated, words ending in the suffix -itis (which refers to inflammation) are sometimes informally described as referring to infection. For example, the word urethritis strictly means only "urethral inflammation", but clinical health care providers usually discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis.
However, the inflammation-infection distinction becomes crucial for situations in pathology and medical diagnosis where inflammation is not driven by microbial invasion, such as the cases of atherosclerosis, trauma, ischemia, and autoimmune diseases (including type III hypersensitivity).

Causes
Types
Acute
Acute inflammation occurs immediately upon injury, lasting only a few days. Cytokines and chemokines promote the migration of neutrophils and macrophages to the site of inflammation. Pathogens, allergens, toxins, burns, and frostbite are some of the typical causes of acute inflammation. Toll-like receptors (TLRs) recognize microbial pathogens. Acute inflammation can be a defensive mechanism to protect tissues against injury. Inflammation lasting 2–6 weeks is designated subacute inflammation.

Cardinal signs
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. 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. It is characterized by five cardinal signs:The traditional names for signs of inflammation come from Latin:

Dolor (pain)
Calor (heat)
Rubor (redness)
Tumor (swelling)
Functio laesa (loss of function)The first four (classical signs) were described by Celsus (c. 30 BC–38 AD), while loss of function was probably added later by Galen. However, the addition of this fifth sign has also been ascribed to Thomas Sydenham and Virchow.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.Acute inflammation of the lung (usually as in response to pneumonia) does not cause pain unless the inflammation involves the parietal pleura, which does have pain-sensitive nerve endings.

Acute process
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.
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, to flow out of the blood vessels (extravasation) and into the tissue. The neutrophils migrate along a chemotactic gradient created by the local cells to reach the site of injury. The loss of function (functio laesa) is probably the result of a neurological reflex in response to pain.
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., burn, trauma).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.

Chronic
Chronic inflammation is inflammation that lasts for months or years. Macrophages, lymphocytes, and plasma cells predominate in chronic inflammation, in contrast to the neutrophils that predominate in acute inflammation. Diabetes, cardiovascular disease, allergies, and chronic obstructive pulmonary disease (COPD) are examples of diseases mediated by chronic inflammation. Obesity, smoking, stress and insufficient diet are some of the factors that promote chronic inflammation. A 2014 study reported that 60% of Americans had at least one chronic inflammatory condition, and 42% had more than one.

Cardinal signs
Common signs and symptoms that develop during chronic inflammation are:
Body pain, arthralgia, myalgia
Chronic fatigue and insomnia
Depression, anxiety and mood disorders
Gastrointestinal complications such as constipation, diarrhea, and acid reflux
Weight gain or  loss
Frequent infections

Vascular component
Vasodilation and increased permeability
As defined, acute inflammation is an immunovascular response to inflammatory stimuli. 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.
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 contains 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 funneled by lymphatics to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the adaptive immune system.

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.

Plasma cascade systems
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.

Plasma-derived mediators
* non-exhaustive list

Cellular component
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.

Leukocyte extravasation
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:

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. Activated macrophages in the tissue release cytokines such as IL-1 and TNFα, which in turn leads to production of chemokines that bind to proteoglycans forming gradient in the inflamed tissue and along the endothelial wall. Inflammatory cytokines induce the immediate expression of P-selectin on endothelial cell surfaces and P-selectin 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 released 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 after signal transduction via respective G protein-coupled receptors that activates integrins on the leukocyte surface for firm adhesion. Such 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.
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.

Phagocytosis
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.
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.
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.

Cell-derived mediators
* non-exhaustive list

Morphologic patterns
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.

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, 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.

Disorders
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, as 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.Examples of disorders associated with inflammation include:

Atherosclerosis
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 atherosclerosis from initiation through progression and, ultimately, the thrombotic complications from it. 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, the anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights on inflammation contribute to the etiology of atherosclerosis, and the practical clinical applications in risk stratification and the targeting of therapy for atherosclerosis.

Allergy
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. Severe inflammatory response may mature into a systemic response known as anaphylaxis.

Myopathies
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.

Leukocyte defects
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. 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.

Pharmacological
Certain drugs or exogenous chemical compounds are known to affect inflammation. Vitamin A deficiency, for example, causes an increase in inflammatory responses, and anti-inflammatory drugs work specifically by inhibiting the enzymes that produce inflammatory eicosanoids. Additionally, 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).

Cancer
Inflammation orchestrates the microenvironment around tumours, contributing to proliferation, survival and migration. Cancer cells use selectins, chemokines and their receptors for invasion, migration and metastasis. On the other hand, many cells of the immune system contribute to cancer immunology, suppressing cancer.
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. This capacity of a mediator of inflammation to influence the effects of steroid hormones in cells is very likely to affect carcinogenesis. 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.
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.

Role in cancer
In 1863, Rudolf Virchow hypothesized that the origin of cancer was at sites of chronic inflammation. At present, chronic inflammation is estimated to contribute to approximately 15% to 25% of human cancers.

Mediators and DNA damage in cancer
An inflammatory mediator is a messenger that acts on blood vessels and/or cells to promote an inflammatory response.  Inflammatory mediators that contribute to neoplasia include prostaglandins, inflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-15 and chemokines such as IL-8 and GRO-alpha.  These inflammatory mediators, and others, orchestrate an environment that fosters proliferation and survival.Inflammation also causes DNA damages due to the induction of reactive oxygen species (ROS) by various intracellular inflammatory mediators.  In addition, leukocytes and other phagocytic cells attracted to the site of inflammation induce DNA damages in proliferating cells through their generation of ROS and reactive nitrogen species (RNS).   ROS and RNS are normally produced by these cells to fight infection. ROS, alone, cause more than 20 types of DNA damage. Oxidative DNA damages cause both mutations and epigenetic alterations.  RNS also cause mutagenic DNA damages.A normal cell may undergo carcinogenesis to become a cancer cell if it is frequently subjected to DNA damage during long periods of chronic inflammation. DNA damages may cause genetic mutations due to inaccurate repair. In addition, mistakes in the DNA repair process may cause epigenetic alterations.  Mutations and epigenetic alterations that are replicated and provide a selective advantage during somatic cell proliferation may be carcinogenic.
Genome-wide analyses of human cancer tissues reveal that a single typical cancer cell may possess roughly 100 mutations in coding regions, 10-20 of which are "driver mutations" that contribute to cancer development.  However, chronic inflammation also causes epigenetic changes such as DNA methylations, that are often more common than mutations. Typically, several hundreds to thousands of genes are methylated in a cancer cell (see DNA methylation in cancer). Sites of oxidative damage in chromatin can recruit complexes that contain DNA methyltransferases (DNMTs), a histone deacetylase (SIRT1), and a histone methyltransferase (EZH2), and thus induce DNA methylation. DNA methylation of a CpG island in a promoter region may cause silencing of its downstream gene (see CpG site and regulation of transcription in cancer).   DNA repair genes, in particular, are frequently inactivated by methylation in various cancers (see hypermethylation of DNA repair genes in cancer). A 2018 report evaluated the relative importance of mutations and epigenetic alterations in progression to two different types of cancer. This report showed that epigenetic alterations were much more important than mutations in generating gastric cancers (associated with inflammation). However, mutations and epigenetic alterations were of roughly equal importance in generating esophageal squamous cell cancers (associated with tobacco chemicals and acetaldehyde, a product of alcohol metabolism).

HIV and AIDS
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. A substantial body of evidence implicates chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency. Many now regard HIV infection not only as an evolving virus-induced immunodeficiency, but also as chronic inflammatory disease. 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. 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.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. 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. 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-inflammatory 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, which has already proven to be safe and well tolerated in phase II human clinical trials. 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.

Resolution
The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues.  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:

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.

Connection to depression
There is evidence for a link between inflammation and depression. 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.
In addition, there is increasing evidence that inflammation can cause depression because of the increase of cytokines, setting the brain into a "sickness mode". Classical symptoms of being physically sick, such as lethargy, show a large overlap in behaviors that characterize depression. Levels of cytokines tend to increase sharply during the depressive episodes of people with bipolar disorder and drop off during remission. 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.
Inflammations that lead to serious depression could be caused by common infections such as those caused by a virus, bacteria or even parasites.

Connection to delirium
There is evidence for a link between inflammation and delirium based on the results of a recent longitudinal study investigating CRP in COVID-19 patients.

Systemic effects
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.
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.

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

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

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. 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.
Leukopenia can be induced by certain infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis, and some cancers.

Interleukins and obesity
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.
Chronic inflammation is widely observed in obesity. Obese people commonly have many elevated markers of inflammation, including:
IL-6 (Interleukin-6)
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. Waist circumference correlates significantly with systemic inflammatory response.Loss of white adipose tissue reduces levels of inflammation markers. As of 2017 the association of systemic inflammation with insulin resistance and type 2 diabetes, and with atherosclerosis was under preliminary research, although rigorous clinical trials had not been conducted to confirm such relationships.C-reactive protein (CRP) is generated at a higher level in obese people, and may increase the risk for cardiovascular diseases.

Outcomes
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:
ResolutionThe complete restoration of the inflamed tissue back to a normal status </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hypocholesterolemia and can you explain it in depth? [/INST] Hypocholesterolemia is the presence of abnormally low (hypo-) levels of cholesterol in the blood (-emia) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Nodular fasciitis and can you explain it in depth? [/INST] Nodular fasciitis (NF) is a benign, soft tissue tumor composed of myofibroblasts (i.e. immature cells that contain features of myocytes and fibroblasts) that typically occurs in subcutaneous tissue (i.e. lowermost layer of the skin), fascia (i.e. band  of connective tissue just beneath the skin), and/or muscles. The literature sometimes titles rare NF variants according to their tissue locations. The most frequently used and important of these are: cranial fasciitis (NF variants that occur in the soft and hard tissues of the skull) and intravascular fasciitis (NF variants that involve arteries and/or veins). In 2020, the World Health Organization classified nodular fasciitis as in the category of benign fibroblastic/myofibroblastic tumors. NF is the most common of the benign fibroblastic proliferative tumors of soft tissue and exceeds in frequency any other tumor or tumor-like lesion in this group of tumors.Nodular fasciitis is a rapidly growing, usually self-limiting neoplasm that occurs primarily but not exclusively in adults. Due to its rapid growth, NF has often been misdiagnosed as a malignant tumor, usually a sarcoma.  Indeed, NF was originally termed subcutaneous pseudosarcomatous fibromatosis when first described in 1955 by Konwaler et al. The correct diagnosis of a tumor as NF is pivotal to prevent its overtreatment as a more aggressive and/or malignant growth.NF tumors have long been mentioned as local reactions to traumatic injuries in at least some cases. While it still may be precipitated by such injuries, recent studies indicate that NFs are true neoplasms (i.e. abnormal proliferations of cells even after any precipitating event is removed). This is because up to 92% of NF cases have a specific type of fusion gene in their tumor cells. Fusion genes are abnormal and potentially tumor-inducing genes formed by mergers between parts of two different genes. The fusion gene involved in NF merges part of the USP6 gene to a part of any one of numerous other genes. The USP6 gene is responsible for producing ubiquitin carboxyl-terminal hydrolase 6a, a deubiquitinating enzyme that indirectly regulates various signaling pathways which regulate cell growth and death. All of the USP6-containing fusion genes overproduce a chimeric protein (i.e. an abnormal protein consisting of parts derived from different genes) with uncontrolled deubiquitinating enzyme activity that is thought to contribute to the development of NF.

Presentation
Nodular fasciitis occurs in all age groups but more often affects 20-40 year old individuals. Males and females are equally affected. NF tumors, which may be tender or painful, typically present as rapidly growing solitary lesions that reach a final size (usually of 2–3 cm.) within a few weeks. They are located in the upper limbs (39–54% of cases), trunk (15–20% of cases), lower limbs (16–18% of cases), and head or neck area (20% of cases). (Involvement of the head or neck area is more commonly observed in children.) Rare cases off NF have occurred in the: 1) joints of the knee (18 cases), shoulder (3 cases), hand (3 cases), elbow (2 cases), hip (1 case), ankle (1 case), and temporomandibular joint (1 case); or 2) peripheral nerves of the arm (i.e. ulnar nerve, 2 cases) or median nerve, 1 case), hip/lower limb (i.e. sciatic nerve, 1 case), and lumbar spine/pelvis/thigh (i.e. the obturator nerve, 1 case).  Individual cases of NF have been reported to occur in the lower female genital tract, bladder, prostate, tongue, and parotid gland. In some cases, NF tumors have  regressed after incisional biopsy, i.e. a biopsy that takes a small part of the diseased tissue.The cranial fasciitis variant of NF occurs in the soft and hard cranial tissues of the outer layers of the skull. Patients with this variant are more commonly males than females and almost exclusively between 3 weeks and 6 years of age. They typically present with a tumor in areas of the head that lay directly over the temporal or parietal bones. Individual cases have been reported to occur in the lower jaw, frontonasal region, anterior nasal spine (i.e. nasal process of the maxilla), and the orbit (i.e. eye socket)-maxilla area. Characteristically, the tumor is rapidly enlarging, non-painful, rarely regressing without treatment, and potentially expanding into the skulls interior.In a review of 50 cases, the intravascular fasciitis variant of NF occurred in individuals aged 6 months to 66 years (median age 27 years) with male and females being equally affected (52%:48%). Individuals with this variant commonly presented with a blood vessel-localized tumor of the head and neck area (34% of cases), lower extremity (32% of cases), upper extremity (20% of cases), or trunk (14% of cases). The tumor originates in the small blood vessels of the oral mucosa, eyes, lips, cheeks, tongues, and subcutaneous tissue of the extremities (78% of all cases). About 18% of cases involve major veins i.e. 5 cases involved the common femoral veins and one case each involved the femoral vein, common iliac vein, inferior vena cava, and subclavian vein. Cases involving the ascending aorta have also been reported. The presenting symptoms of these tumors were strictly dependent on their locations and impacts on the involved vasculature. Most cases involving superficial sites presented with a small (mean diameter of 1.5 cm), painless, slowly growing mass. However, tumors growing in deep tissues went unnoticed until they became large (e.g. 15 cm.) enough to obstruct blood flow: two cases involving the ascending aorta presented with the signs and symptoms of acute aortic dissection (e.g. severe pain, congestive heart failure, cardiac arrest, fainting , stroke, ischemic peripheral neuropathy, and/or paraplegia) while 9 cases involving large veins presented with acute swelling, pain, and tissue/organ dysfunctions in the areas drained by the involved veins.

Pathology
The microscopic histopathology of hematoxylin and eosin stained nodular fasciitis tumors (see above and three below figures) consists of spindle-shaped myofibroblastic cells (i.e. cells with features of smooth muscle cells and fibroblasts.). These cells are in a myxoid (i.e. more blue or purple compared to normal connective tissue because of excessive uptake of the hematoxylin stain) or a collagenous (high content of collagen fibers) tissue background. The neoplastic myofibroblasts are arranged in whorls and/or short bundles. These cells may show high rates of replicating as judged by their mitotic index but these mitoses are normal in appearance. The tumor tissues often contain red blood cells, lymphocytes and giant osteoclast-like giant cells and may contain sites of bone-like tissue. NF is sometimes classified into three subtypes based on its predominant histopathological pattern: myxoid or reactive (type I), cellular (type II), and fibrous (type III). These patterns appear related to the duration of the lesion with the myxoid variant tending to have the shortest duration and the cellular and fibrous variants tending to have progressively longer durations.Immunohistochemical analyses indicate that the cells in NF usually express smooth muscle actin, muscle specific actin, and vimentin proteins but generally do not express CD34, S-100 protein, desmin, trypsin, factor VIII, F4/80 (also termed macrophage-specific antigen), or HLA-DR1 proteins. Uncommonly, the cells in NF tumors also express the CD68 (a histiocyte-specific marker) protein.

The histopathology and expressions of marker proteins in cranial fasciitis tumors are similar to NF although its tumors tend to be more organized and have higher levels of inflammatory cell infiltrates, vascularity, and involvements of underlying bone than NF.The histopathology and expressions of marker proteins in intravascular fasciitis tumors are also similar to NF. In comparison to NF, however, its spindle-shaped tumor cells are more often arranged in a storiformed (i.e. whirled) or haphazard pattern and have vesicle-containing nuclei with prominent nucleoli.

Gene abnormalities
Until recently, nodular fasciitis was considered a reaction to trauma or some other unidentified insult at the site where the tumor subsequently developed. However, recent findings indicate that up to 92% of NF tumors involve the self-limiting growth of a clone (i.e. a group of identical cells that share a common ancestry} of neoplastic cells that contain a fusion gene. Fusion genes are abnormal genes consisting of parts from two different genes that form as a result of large scale gene mutations such as chromosomal translocations, interstitial deletions, or inversions. The fusion gene found in NF tumor cells consists of a part of the USP6 gene combined with any one of numerous other genes. Its most common partner gene in NF is the MYH9 (i.e. myosin-9) gene. This USP6-MYH9 fusion gene forms as a result of a translocation of part of the USP6 gene located at band 13.2 on the long (or "q") arm of chromosome 17 with part of the MYH9 gene at band 13.2 on the short (or "p") arm of chromosome 22. Other genes that partner with the USP6 gene to form a fusion gene found in NF include the: RRBP1 (i.e. ribosome binding protein 1) gene, CALU (calumenin) gene, CTNNB1 (catenin beta 1) gene, MIR22HG (produces the MIR22HG long non-coding RNA) gene, SPARC (secreted protein acidic and cysteine rich [also termed osteonectin]) gene, THBS2 (thrombospondin-2) gene, COL6A2 (collagen type VI alpha 2 chain) gene, SEC31A {SEC31 homolog A, COPII coat complex component) gene, EIF5A (eukaryotic translation initiation factor 5A) gene, COL1A1 (collagen type I alpha 1 chain) gene, COL1A2 (collagen type I alpha 2 chain) gene, COL3A1 (collagen type III alpha 1 chain) gene, PAFAH1B1 (platelet activating factor acetylhydrolase 1b regulatory subunit 1) gene, SERPINH1 (serpin family H member 1) gene which produces heat shock protein 47, PDLIM7 (PDZ and LIM domain protein 7) gene, and MYL12A (myosin regulatory light chain 12A) gene. While very few cases have been analyzed to date, USP6-containing fusion genes have been found in the tumor cells of 7 of 15 tested cases of cranial fasciitis and six of  six tested cases of intravascular fasciitis.All of the USP6-containing fusion genes in NF and variants overproduce a chimeric protein containing a part of the USP6 genes product, ubiquitin carboxyl-terminal hydrolase 6a, that has uncontrolled deubiquitinating enzyme activity. This may result in the inappropriate stimulation of  multiple cell signaling pathways including the Wnt signaling pathway, one of the JAK-STAT signaling pathways (i.e. the Jak1-STAT3 pathway), the c-Jun signaling pathway, and the NF-κB signaling pathway. Each of these pathways, when inappropriately activated, has been implicated in promoting the development of various tumors and cancers. Further studies are needed to determine which, if any, of these pathways are overactive in and can be successfully targeted with specific drug therapies to treat NF and its variants.Two cases of NF have tumor cells in which the USP6 gene has fuses with the  PPP6R3 (i.e. protein phosphatase 6 regulatory subunit 3) gene. In both of these cases, the tumors clearly showed malignant behavior.

Diagnosis
NF may resemble and therefore be misdiagnosed as dermatofibrosarcoma protuberans, fibrosarcoma, malignant fibrous histiocytoma, spindle-cell melanoma (a rare form of melanoma,) leiomyosarcoma, and inflammatory myofibroblastic tumor. The diagnosis of NF and its variants depends on a combination of findings no single one of which is definitive. These findings are: the tumors: presentation (particularly its location in the cranium, within blood vessels, or outside of these areas); histopathology (particularly analyses of tumor cell mitoses which if atypical strongly suggest the tumor is not NF); presence of myofibroblasts that typically express muscle-specific actin, SMA, and vimentin and may express CD68 but generally do not express S100, desmin, trypsin, factor VIII, F4/80, or CD34 (lack of Cd34-expressing cells indicates that the tumor is not a sarcoma); and presence of typical neoplastic cells expressing an USP6-containing fusion gene. (USP6-containing fusion genes also occur in the tumor cells of aneurysmal bone cysts, fibroma of tendon sheaths, giant cell reparative granuloma, and myositis ossificans/fibro-osseous pseudotumor of digits.)
While virtually all cases of NF and variants have had excellent prognoses, the two cases of individuals with an USP6-PPP6R3 fusion gene in their NF tumor cells had less favorable prognoses: their tumors were locally invasive, repeatedly relapsed after surgical removal, and grew progressively larger over 2 and 10 years of observations.

Treatment
Some cases of NF have regressed after being partially biopsied suggesting that a watchful waiting approach may be appropriate after biopsy in some cases of these tumors. In all events, the most common and generally accepted first-line treatment for most cases of NF, craniofacial fasciitis, and intravascular fasciitis tumors is surgical removal </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Epidermoid cyst and can you explain it in depth? [/INST] An epidermoid cyst or epidermal inclusion cyst is a benign cyst usually found on the skin. The cyst develops out of ectodermal tissue. Histologically, it is made of a thin layer of squamous epithelium.

Signs and symptoms
The epidermoid cyst may have no symptoms, or it may be painful when touched. It can release macerated keratin. In contrast to pilar cysts, epidermoid cysts are usually present on parts of the body with relatively little hair. An epidermoid cyst is one type of vaginal cysts.Although they are not malignant, there are rare cases of malignant tumors arising from an epidermoid cyst. Epidermal inclusion cysts account for approximately 85–95% of all excised cysts, malignant transformation is exceedingly rare. The incidence of squamous cell carcinoma developing from an epidermal inclusion cyst has been estimated to range from 0.011 to 0.045%.

Diagnosis
Epidermoid cysts are usually diagnosed when a person notices a bump on their skin and seeks medical attention </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Zenkers diverticulum and can you explain it in depth? [/INST] A Zenkers diverticulum, also pharyngeal pouch, is a diverticulum of the mucosa of the human pharynx, just above the cricopharyngeal muscle (i.e. above the upper sphincter of the esophagus). It is a pseudo diverticulum (not involving all layers of the esophageal wall).
It was named in 1877 after German pathologist Friedrich Albert von Zenker.

Signs and symptoms
In simple words, when there is excessive pressure within the lower pharynx, the weakest portion of the pharyngeal wall balloons out, forming a diverticulum which may reach several centimetres in diameter.
More precisely, while traction and pulsion mechanisms have long been deemed the main factors promoting development of a Zenkers diverticulum, current consensus considers occlusive mechanisms to be most important: uncoordinated swallowing, impaired relaxation and spasm of the cricopharyngeus muscle lead to an increase in pressure within the distal pharynx, so that its wall herniates through the point of least resistance (known as Killians triangle, located superior to the cricopharyngeus muscle and inferior to the thyropharyngeus muscle. Thyropharyngeus and cricopharyngeus are the superior and inferior parts of inferior constrictor muscle of pharynx respectively) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is I-cell disease and can you explain it in depth? [/INST] Inclusion-cell (I-cell) disease, also referred to as mucolipidosis II (ML II), is part of the lysosomal storage disease family and results from a defective phosphotransferase (an enzyme of the Golgi apparatus). This enzyme transfers phosphate to mannose residues on specific proteins. Mannose-6-phosphate serves as a marker for proteins to be targeted to lysosomes within the cell.  Without this marker, proteins are instead secreted outside the cell, which is the default pathway for proteins moving through the Golgi apparatus.  Lysosomes cannot function without these proteins, which function as catabolic enzymes for the normal breakdown of substances (e.g. oligosaccharides, lipids, and glycosaminoglycans)  in various tissues throughout the body (i.e. fibroblasts). As a result, a buildup of these substances occurs within lysosomes because they cannot be degraded, resulting in the characteristic I-cells, or "inclusion cells" seen microscopically. In addition, the defective lysosomal enzymes normally found only within lysosomes are instead found in high concentrations in the blood, but they remain inactive at blood pH (around 7.4) because they require the low lysosomal pH 5 to function.

Signs and symptoms
Mucolipidosis II (ML II) is a particularly severe form of ML that has a significant resemblance to another mucopolysaccharidosis called Hurler syndrome. Generally only
laboratory testing can distinguish the two as the presentation is so similar, with high plasma concentrations of lysosomal enzymes, often fatal in childhood. Typically, by the age of 6 months, failure to thrive and developmental delays are obvious signs of this disorder.  Some physical signs, such as abnormal skeletal development, coarse facial features, and restricted joint movement, may be present at birth. Children with ML II usually have enlargement of certain organs, such as the liver (hepatomegaly) or spleen (splenomegaly), and sometimes even the heart valves. Affected children often have stiff claw-shaped hands and fail to grow and develop in the first months of life.  Delays in the development of their motor skills are usually more pronounced than delays in their cognitive (mental processing) skills. Children with ML II eventually develop a clouding on the cornea of their eyes and, because of their lack of growth, develop short-trunk dwarfism (underdeveloped trunk). These young patients are often plagued by recurrent respiratory tract infections, including pneumonia, otitis media (middle ear infections), bronchitis and carpal tunnel syndrome. Children with ML II generally die before their seventh year of life, often as a result of congestive heart failure or recurrent respiratory tract infections.

Pathophysiology
I-cell disease is an autosomal recessive disorder caused by a deficiency of GlcNAc phosphotransferase, which phosphorylates mannose residues to mannose-6-phosphate on N-linked glycoproteins in the Golgi apparatus within cells. Without mannose-6-phosphate to target them to the lysosomes, the enzymes are erroneously transported from the Golgi to the extracellular space </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Factor V and can you explain it in depth? [/INST] Factor V (pronounced factor five) is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations (most notably factor V Leiden) predispose for thrombosis.

Genetics
The gene for factor V is located on the first chromosome (1q24). It is genomically related to the family of multicopper oxidases, and is homologous to coagulation factor VIII. The gene spans 70 kb, consists of 25 exons, and the resulting protein has a relative molecular mass of approximately 330kDa.

Structure
Factor V protein consists of six domains: A1-A2-B-A3-C1-C2.
The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin, and form a triangular as in that protein. A copper ion is bound in the A1-A3 interface, and A3 interacts with the plasma.The C domains belong to the  phospholipid-binding discoidin domain family (unrelated to C2 domain), and the C2 domain mediates membrane binding. The B domain C-terminus acts as a cofactor for the anticoagulant protein C activation by protein S.Activation of factor V to factor Va is done by cleavage and release of the B domain, after which the protein no longer assists in activating protein C. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor Va.

Physiology
Factor V synthesis occurs in the liver, principally. The molecule circulates in plasma as a single-chain molecule with a plasma half-life of 12–36 hours.Factor V is able to bind to activated platelets and is activated by thrombin. On activation, factor V is spliced in two chains (heavy and light chain with molecular masses of 110000 and 73000, respectively) which are noncovalently bound to each other by calcium. The thereby activated factor V (now called FVa) is a cofactor of the prothrombinase complex: The activated factor X (FXa) enzyme requires calcium and activated factor V (FVa) to convert prothrombin to thrombin on the cell surface membrane.
Factor Va is degraded by activated protein C, one of the principal physiological inhibitors of coagulation. In the presence of thrombomodulin, thrombin acts to decrease clotting by activating protein C; therefore, the concentration and action of protein C are  important determinants in the negative feedback loop through which thrombin limits its own activation.

Role in disease
Various hereditary disorders of factor V are known. Deficiency is associated with a rare mild form of hemophilia (termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in an autosomal recessive fashion.
There exists a bleeding tendency associated with the genetic up‐regulation of FV‐short, a minor splicing isoform of FV. This abnormal bleeding tendency occurs in east Texas bleeding disorder, Amsterdam bleeding disorder, and a third and more extreme example described in 2021 by Karen L. Zimowski et al.Other mutations of factor V are associated with venous thrombosis. They are the most common hereditary causes for thrombophilia (a tendency to form blood clots). The most common one of these, factor V Leiden, is due to the replacement of an arginine residue with glutamine at amino acid position 506 (R506Q). All prothrombotic factor V mutations (factor V Leiden, factor V Cambridge, factor V Hong Kong) make it resistant to cleavage by activated protein C ("APC resistance") </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Undifferentiated pleomorphic sarcoma and can you explain it in depth? [/INST] Undifferentiated pleomorphic sarcoma (UPS), also termed pleomorphic myofibrosarcoma, high-grade myofibroblastic sarcoma, and high-grade myofibrosarcoma, is characterized by the World Health Organization (WHO), 2020, as a rare, poorly differentiated neoplasm, i.e. an abnormal growth of cells that have an unclear identity and/or cell of origin. WHO classified it as one of the undifferentiated/unclassified sarcomas in the category of tumors of uncertain differentiation. Sarcomas are cancers known or thought to derive from mesenchymal stem cells that typically develop in bone, muscle, fat, blood vessels, lymphatic vessels, tendons, and ligaments. More than 70 sarcoma subtypes have been described. The UPS subtype of these sarcomas consists of tumor cells that are poorly differentiated and may appear as spindle-shaped cells, histiocytes, and giant cells. UPS is considered a diagnosis that defies formal sub-classification after thorough histologic, immunohistochemical, and ultrastructural examinations fail to identify the type of cells involved.The diagnosis of UPS initially included the malignant fibrous histiocytomas (MFH). MFH are now regarded as a wastebasket category of various sarcoma types including sarcoma-like carcinomas and melanomas. Studies strongly suggest that MFH tumors are not derived from histiocytes (cells descended from blood monocytes), but rather from mesenchymal cells. UPS had also been regarded as a more aggressive and metastasizing form of the low-grade myofibroblastic sarcomas and intermediate‐grade myofibroblasic sarcomas. WHO has combined low- and intermediate-grade myofibroblastic sarcomas into a single entity, low-grade myofibroblastic sarcomas, and categorized it as one type of the intermediate (rarely metastasizing) fibroblastic and myofibroblastic tumors quite distinct from UPS. Because of their low incidence and frequent grouping with what are now considered to be other sarcoma types, past findings on the clinical behaviour, proper treatment, and prognosis of UPS may be revised with further study.The majority of UPS tumors are highly aggressive, often recur after surgical removal, and often metastasize. They are treated with a combination of surgical resection, radiotherapy, and/or chemotherapy. More recently, UPS tumors have been treated with antibody therapy, i.e. antibodies which in the case of UPS bind to specific antigens on the surface of T-cells (a type of lymphocyte) and thereby promote the ability of these T-cells to organizes an attack on UPS tumor cells.

Presentation
UPS commonly presents as a deep-seated, rapidly enlarging, painless mass in individuals aged 50 to 70 years. These masses are rarely superficial lesions and rarely occur in the pediatric population. In a retrospective study of 266 individuals, UPS tumors ranged from 1–55 cm in greatest diameter (average 8.8 cm with 25%, 38%, and 38% having greatest diameters of 0–1, 5–9, and ≥10 cm, respectively). In a study of 205 individuals (median age 59 years) diagnosed with UPS, the tumors were located in the arm or leg (47.3% of cases), abdomen or pelvis (26.8%), thorax (17.6%), and head or neck (8.3%) areas. In rare cases, these tumors have also presented in other sites such as the retroperitoneal space, liver, pleura of the lung, heart, and small intestine. In a retrospective study, distant metastases were detected at the time of initial diagnosis in 6.4% of 266 individuals. Overall, metastases have or will develop in up to 40% of individuals with UPS. These metastases are reported to occur in lung (40% to 55% of cases) and less commonly in other sites such as lymph nodes near the primary tumor, brain, pancreas, and heart.

Neoplastic Fever
A review study conducted in China of 183 individuals with UPS reported that 7 (3.83%) individuals (age 51 to 73 years; median age 62.8 years) had a subtype of the paraneoplastic syndrome termed neoplastic fever, i.e. these individuals suffered continuous, disabling fevers. Their tumors  were located within a thigh muscle (4 cases), the upper arm (2 cases), or the lower leg (1 case). Compared to 89 individuals (median age 59.1 years) with a similar distribution of their UPS tumors, individuals with the neoplastic syndrome had similar tumor recurrence rates (57.14% vs 53.93% for the two respective groups) but a lower metastasis rate (14.29% vs 44.94%) and a higher 3-year survival rate (85.71% vs 59.55%). Fever symptoms disappeared in all patients after surgical removal of their tumors. It is suggested that individuals with UPS and neoplastic fever have a more favorable prognosis than individuals with UPS that do not evidence such fevers.

Pathology
UPS is a diagnosis of exclusion (a diagnosis reached by the process of elimination) because the histopathology of this disorders tumors is non-specific. UPS tumor cells are undifferentiated (i.e. do not resemble any particular cell type) and pleomorphic (i.e. highly variable in size, shape, and/or color) when examined microscopically. Therefore, the diagnosis of UPS is commonly based on detecting a specific set of proteins that are expressed by UPS tumor cells but not by the cells of other undifferentiated and pleomorphic tumors or visa versa (see Diagnosis section).A study of 52 individuals found that their UPS tumor cells expressed on their surface membranes PD-L1 protein (i.e. programmed death-ligand 1 protein) either focally (36.5% of cases) or strongly (9.62% of cases); 48.1% of these individuals had tumor cells which also expressed IDO1 protein (i.e. indoleamine 2,3-dioxygenase protein). Tumor cells that strongly expressed PD-L1 also expressed CMTM6 protein (i.e. CKLF like MARVEL transmembrane domain containing 6 protein). Strong PD‑L1 expression proved to be a poor, while expression of IDO‑1 proved to be a favorable, prognostic factor for disease outcomes. Individuals with tumor cells that strongly expressed CMTM6 protein also had poor prognoses. Increases in the expression of CMTM6 protein were associated in some cases with mutations that increased the number of copies of its gene, i.e. CMTM6. In a later study that examined 83 individuals, 72.8% had UPS tumor cells that expressed PD-L1 with 53%, 35%, and 12% of these cases showing weak, intermediate, and strong PD-L1 expression, respectively. And, in a study of 73 patients with UPS, 39 cases showed no, 23 cases showed low, 10 showed intermediate, and 11 strong  immunoreactivity for AMPD2, i.e. AMP deaminase 2 protein; the gains in AMPD2 protein immunoreactivity were associated with copy number gains in the AMPD2 gene and patients with higher AMPD2 levels had poorer prognoses (5 year survivals for AMPD2 positive versus AMPD2 negative cases were ~38 and 59%, respectively). Other abnormalities found in some or isolated cases of UPS include: 1) Amplification of the Hippo signaling pathway, an intracellular cell signaling pathway that regulates cell proliferation and cell death; this amplification is associated with the overexpression of two proteins, vestigial-like family member 3 protein, a product of the VGLL3 gene, and YAP1, i.e. yes-associated protein 1, a product of the YAP1 gene, in the Hippo signaling pathway; 2) Abnormal activation of notch signaling pathways (this activation has been shown to promote the growth and survival of various types of cancer cells; and 3) Overexpression of DKK1, i.e. Dickkopf-related protein 1 (elevated in the tumor cells of various cancer types).UPS tumors also show gene and chromosome abnormalities that further studies may find contribute to the development and/or progression of UPS. These abnormalities, which have not yet been reported to be helpful in diagnosing UPS, include the following. 1) Deletion and/or inactivation or the RB1 gene that encodes (i.e. is responsible for production of) the retinoblastoma protein that functions as a tumor suppressor protein; 2) deletions and/or mutations in the TP53 gene that encodes tumor protein P53 (a protein which regulates cell proliferation and cell death); 3) mutations in the ATRX gene that encodes transcriptional regulator ATRX protein which contributes to regulating the expression of various genes; 4) mutations in the KMT2C gene which encodes lysine N-methyltransferase 2C protein (the KMT2C gene is mutated in various cancer types); 5) amplification of the IL7R gene which encodes Interleukin-7 receptor-α protein (mutations in the IL7R gene are commonly found in acute lymphoblastic leukemia) and 6) expression of a fusion gene (i.e. a hybrid gene formed from two previously independent genes as a result of a mutation) that merges TRIO with other genes and is often found in other sarcoma subtypes.)

Diagnosis
The diagnosis of UPS depends on finding non-specific, undifferentiated tumor cells that have features suggestive of UPS and not features of other tumor types that also consist of pleomorphic, undifferentiated cells. The features primarily involve the expression of certain proteins by the tumor cells. The identifying proteins for UPS tumor cells are given in the preceding section. Identification proteins for tumors that have been confused with UPS inlclude:
Pleomorphic leimyosarcoma: Desmin and h-caldesmon (i.e. high molecular form of caldesmon.) proteins
Pleomorphic rhabdomyosarcoma: Desmin and myogenin proteins.
Defifferentiated liposarcoma: MDM2 and CDK4 proteins.
Poorly differentiated carcinoma (i.e. grade 3 or 4 carcinoma): MUC1 (also termed EMA), TP63 (also termed p63; which is detected with the p40 antibody), and various members of the keratin family of proteins.
Melanoma: MLANA (i.e. melanoma antigen recognized by T cells 1 protein), S100, and PMEL (a product of the PMEL gene which is detected using an antibody termed HMB-45.) proteinsTwo other tumors that may be confused with UPS have microscopic histopathological and/or other features that help make this distinction. These tumors and features are:
Pleomorphic liposarcoma: At least some tumor cells have features of pleomorphic lipoblasts, i.e. variable shaped immature fat cells.
Malignant peripheral nerve sheath tumor: Typically occurs in young children, often develops in a preexisting inoperable plexiform neurofibroma, and often associated with neural tissue. These tumors typically show undifferentiated, pleomorphic cells that are arranged in whorls, parallel bundles, or rosettes (i.e. circular arrangement resembling leaves in a flowering plant) and often contain large areas of necrosis (i.e. dead or dying cells).

Treatment and prognosis
The most often used treatment for localized (i.e. no metastases) UPS tumors is complete surgical removal with the object of leaving no tumor cells behind as evidenced by microscopic examinations. Adjuvant therapy combining radiotherapy or/and chemotherapy with surgical resection is employed to reduce the risk of developing recurrent and metastatic disease in cases with high-risk disease (e.g. large tumors, tumors deemed highly aggressive based on their pathology and/or local invasiveness, inoperable tumors, and resections that did not remove all tumor cells). A standard chemotherapy two-drug regimen (epirubicin plus ifosfamide) may be used in these cases. In place or combined with surgery and/or radiotherapy, severe and/or metastatic cases of UPS are commonly treated with epirubicin plus ifosfamide; doxorubicin alone or combined with ifosfamide, olaratumab, trabectedin, gemcitabine, or docetaxel;  cyclophosphamide, vincristine, doxorubicin, plus dacarbazine or cisplatin; cyclophosphamide, doxorubicin, plus dacarbazine; high dose methotrexate; or etoposide, ifosfamide, and cisplatin. These treatment regimens have been reported to lower local recurrence rates, prolong disease-free survival rates (i.e. time after treatment when no disease is detected), and increase overall survival rates (i.e. time after treatment to death from any cause). However, other studies report that the addition of radiotherapy and/or chemotherapy to surgical resection does not improve recurrence or overall survival rates; addition of radiotherapy to surgery improves local control of UPS tumors but not disease-free survival rates (i.e. time from treatment to recurrence of disease); and adjuvant chemotherapy and radiotherapy have no significant effects on local recurrence-free survival rates, metastasis-free survival times, and overall survival rates. Further studies are needed to define the best treatments for UPS tumors.In a retrospective study of 176 patients with localized UPS undergoing curative-intent treated with surgical resection or resection plus adjuvant treatment, disease-free survival rates at 120 months for patients with tumors in an extremity (leg or arm), heat/neck area, thorax, and abdomen/pelvis were about 70, 60, 50, and 0%, respectively; overall survival rates at 150 months for disease at these sites were about 90, 80, 75, and 35%, respectively. Patients who received surgery alone or surgery plus adjuvant treatment had disease-free survival rates of about 50 and 40%, respectively. A retrospective analysis of  266 patients with UPS were treated with surgery alone (6% of cases), surgery plus radiotherapy (91% of cases), or surgery plus chemotherapy (3% of cases). Post-treatment local recurrences and metastases were observed in 15% and 38% of cases; 5- and 10-year overall survival rates were 60% and 48%, respectively; Overall median survival time were 10.1 years; and patients with tumors ≥10 cm in longest diameter had an almost 6-fold higher rate of developing metastases than patients with tumors 4 cm or smaller. Poorer prognoses were seen in older patients; in patients with tumors that were large-sized, deep-seated, and/or located in a leg; in patients that presented with metastases; and in patients who had positive surgical margins and/or developed local recurrences after surgery. In another retrospective study, 203 individuals with UPS, 141 of whom had metastatic disease, were treated with regimens selected based on the severity of their disease </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Thrombus and can you explain it in depth? [/INST] A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to stop and prevent further bleeding, but can be harmful in thrombosis, when a clot obstructs blood flow through healthy blood vessels in the circulatory system.
In the microcirculation consisting of the very small and smallest blood vessels the capillaries, tiny thrombi known as microclots can obstruct the flow of blood in the capillaries. This can cause a number of problems particularly affecting the alveoli in the lungs of the respiratory system resulting from reduced oxygen supply. Microclots have been found to be a characteristic feature in severe cases of COVID-19, and in long COVID.Mural thrombi are thrombi that adhere to the wall of a large blood vessel or heart chamber. They are most commonly found in the aorta, the largest artery in the body, more often in the descending aorta, and less often in the aortic arch or abdominal aorta. They can restrict blood flow but usually do not block it entirely.  They appear grey-red with alternating light and dark lines (known as lines of Zahn) which represent bands of white blood cells and red blood cells (darker) entrapped in layers of fibrin.

Classification
Thrombi are classified into two major groups depending on their location and the relative amount of platelets and red blood cells (RBCs). The two major groups are:

Arterial or white thrombi (characterized by predominance of platelets)
Venous or red thrombi (characterized by predominance of red blood cells).

Microclots
In the microcirculation consisting of the very small and smallest blood vessels the capillaries, tiny thrombi known as microclots can obstruct the flow of blood in the capillaries. This can cause a number of problems particularly affecting the alveoli in the lungs of the respiratory system resulting from reduced oxygen supply. Microclots have been found to be a characteristic feature in severe cases of COVID-19, and in long COVID.

Mural thrombi
Mural thrombi are thrombi that adhere to the wall of a large blood vessel or heart chamber. They are most commonly found in the aorta, the largest artery in the body, more often in the descending aorta, and less often in the aortic arch or abdominal aorta. They can restrict blood flow but usually do not block it entirely. Mural thrombi are not usually found in vessels already damaged by atherosclerosis.A mural thrombus can affect any heart chamber. When found in the left ventricle it is often a result of a heart attack complication. The thrombus in this case can separate from the chamber, be carried through arteries and block a blood vessel. They appear grey-red with alternating light and dark lines (known as lines of Zahn) which represent bands of white blood cells and red blood cells (darker) entrapped in layers of fibrin.

Cause
Virchows triad describes the pathogenesis of thrombus formation:
Endothelial injury: Injury to the endothelium (interior surface of blood vessel), causing platelet activation and aggregation;
Common causes include: trauma, smoking, hypertension, atheroma.
Hemodynamic changes (stasis, turbulence):  Blood stasis promotes greater contact between platelets/coagulative factors with vascular endothelium. If rapid blood circulation (e.g., because of tachycardia) occurs within vessels that have endothelial injuries, that creates disordered flow (turbulence) that can lead to the formation of thrombosis;Common causes of stasis include anything that leads to prolonged immobility and reduced blood flow such as: trauma/broken bones and extended air travel.
Hypercoagulability (also called thrombophilia; any disorder of the blood that predisposes to thrombosis);
Common causes include: cancer (leukaemia), factor V mutation (Leiden) - prevents Factor V inactivation leading to increased coagulability.Disseminated intravascular coagulation (DIC) involves widespread microthrombi formation throughout the majority of the blood vessels. This is due to excessive consumption of coagulation factors and subsequent activation of fibrinolysis using all of the bodys available platelets and clotting factors. The result is hemorrhaging and ischemic necrosis of tissue/organs. Causes are septicaemia, acute leukaemia, shock, snake bites, fat emboli from broken bones, or other severe traumas. DIC may also be seen in pregnant females. Treatment involves the use of fresh frozen plasma to restore the level of clotting factors in the blood, as well as platelets and heparin to prevent further thrombi formation.

Pathophysiology
A thrombus occurs when the hemostatic process, which normally occurs in response to injury, becomes activated in an uninjured or slightly injured vessel. A thrombus in a large blood vessel will decrease blood flow through that vessel (termed a mural thrombus).  In a small blood vessel, blood flow may be completely cut off (termed an occlusive thrombus), resulting in death of tissue supplied by that vessel. If a thrombus dislodges and becomes free-floating, it is considered an embolus. If an embolus becomes trapped within a blood vessel, it blocks blood flow and is termed as an embolism. Embolisms, depending on their specific location, can cause more significant effects like strokes, heart attacks, or even death.Some of the conditions which increase the risk of blood clots developing include atrial fibrillation (a form of cardiac arrhythmia), heart valve replacement, a recent heart attack (also known as a myocardial infarction), extended periods of inactivity (see deep venous thrombosis), and genetic or disease-related deficiencies in the bloods clotting abilities.

Formation
Platelet activation occurs through injuries that damage the endothelium of the blood vessels, exposing the enzyme called factor VII, a protein normally circulating within the vessels, to the tissue factor, which is a protein encoded by the F3 gene.
The platelet activation can potentially cause a cascade, eventually leading to the formation of the thrombus. This process is regulated through thromboregulation.

Prevention
Anticoagulants are drugs used to prevent the formation of blood clots, reducing the risk of stroke, heart attack and pulmonary embolism. Heparin and warfarin are used to inhibit the formation and growth of existing thrombi, with the former used for acute anticoagulation while the latter is used for long-term anticoagulation. The mechanism of action of heparin and warfarin are different as they work on different pathways of the coagulation cascade. Heparin works by binding to and activating the enzyme inhibitor antithrombin III, an enzyme that acts by inactivating thrombin and factor Xa. In contrast, warfarin works by inhibiting vitamin K epoxide reductase, an enzyme needed to synthesize vitamin K dependent clotting factors II, VII, IX, and X. Bleeding time with heparin and warfarin therapy can be measured with the partial thromboplastin time (PTT) and prothrombin time (PT), respectively.

Treatment
Once clots have formed, other drugs can be used to promote thrombolysis or clot breakdown. Streptokinase, an enzyme produced by streptococcal bacteria, is one of the oldest thrombolytic drugs. This drug can be administered intravenously to dissolve blood clots in coronary vessels.  However, streptokinase causes systemic fibrinolytic state and can lead to bleeding problems. Tissue plasminogen activator (tPA) is a different enzyme that promotes the degradation of fibrin in clots but not free fibrinogen. This drug is made by transgenic bacteria and converts plasminogen into the clot-dissolving enzyme, plasmin </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Streptococcal intertrigo and can you explain it in depth? [/INST] Streptococcal intertrigo is a skin condition that is secondary to a streptococcal bacterial infection. It is often seen in infants and young children and can be characterized by a fiery-red color of the skin, foul odor with an absence of satellite lesions, and skin softening (due to moisture) in the neck, armpits or folds of the groin.: 262  Newborn children and infants commonly develop intertrigo because of physical features such as deep skin folds, short neck, and flexed posture. Prompt diagnosis by a medical professional and treatment with topical and/or oral antibiotics can effectively relieve symptoms.

Etiology
The main causes of intertrigo are mechanical factors, such as heat and maceration of the skin, and secondary infections, which mostly happens due to moisture build-up in the skin folds, making those areas ideal feeding places for secondary bacterial and fungal infections. A lot of cases of this disease are seen in individuals with diabetes mellitus since they have higher pH levels in their skin folds because of their condition. Given these reasons mentioned above, there have been higher cases of intertrigo in individuals with obesity, diabetes mellitus, immunodeficiency secondary to virus infection, large skin folds, are bedridden, or wear diapers that trap moisture (i.e. babies or older adults using incontinence supplies).

Signs and symptoms
Streptococcal intertrigo commonly presents with a beefy-red, smooth, shiny lesion that has well-defined borders. There are no satellite lesions surrounding the area, and a distinct foul smell is common. The infection may be accompanied by general malaise and a low-grade fever. The folds of the neck are most commonly affected, but other areas with skin folds are also susceptible, including the armpits, groin, and anus.

Complications
Progression of intertrigo is dependent on the strain of streptococcus responsible for the symptoms. Streptococcal intertrigo can lead to complications if not appropriately diagnosed and treated in a timely manner. It has been reported that bacteremia, or a bacterial infection of the circulating blood, can occur which may require intravenous antibiotic therapy. Streptococcus pyogenes is also known to cause other serious diseases such as meningitis, necrotizing fasciitis, toxic shock syndrome, and osteomyelitis. Skin infections caused by Group A Beta-hemolytic streptococci (GABHS) can also be associated with acute glomerulonephritis, furthering the need for prompt diagnosis and treatment.

Cause
Intertrigo is a skin condition often associated with rashes in deep skin folds with increased friction and moisture exposure. There are various causes that can lead to intertrigo including fungal and viral, although the agent would depend on the nature of the infection whether it be candidal or bacterial. In the case of bacterial infections, the main etiological agents are either group A beta hemolytic streptococci or Staphylococcus aureus. Group A streptococci (GAS) are ubiquitous microorganisms found in the surrounding environment and in the normal skin microbiota. Although there are different severities of infections Group A streptococci can affect individuals, broken skin and wounds allow easier access for colonization by the bacteria. The streptococci family has its own factors that aid in its promotion of infection and severity. Group A streptococci have surface molecules of lipoteichoic acid and protein F which aid in the adhesion to host cells. Once adhered, it releases streptolysin and hyaluronidase to further degrade host tissues, enabling a deeper colonization. In addition to attachment and dissemination factors, Group A streptococci are also encapsulated and have other varying protein factors that defend it from host immunity.

Mechanism
The most common symptom associated with streptococcal associated intertrigo is erysipelas, an infection of the upper or superficial layers of the skin. This infection is mostly associated with group A beta-hemolytic streptococcal bacteria (GABHS) since they are normally found in the skin flora. This group of bacteria typically invades and affects the lymphatic vessels, often leading to a localized inflammation. The infection can be recognized by tongue-like or irregular extensions of the rash, accompanied by systemic symptoms such as fever, chills, or a general feeling of discomfort. Once in the lymphatic system of the host, GABHS can easily disseminate systemically to produce effects.

Risk Factors
Streptococcal intertrigo occurs when bacteria penetrates the skin. Having an increased amount of skin folds can increase the risk of skin abrasion and erosion, leading to inflammation. Therefore, individuals with obesity, infants, and other factors that increase ones own skin-to-skin contact have an increased risk of intertrigo. Immunocompromised individuals are also at a greater risk for intertrigo since they are more susceptible to infection from any foreign pathogen. Environmental factors also play a role in increasing the risk of this condition. Living in a humid region increases sweat and the accumulation of moisture, contributing to the aggravation of the skin. Similarly, poor hygiene can exacerbate friction as this brings dirt and other particles to build up, increasing the potential and severity of an inflammatory response. Infants tendency to drool onto their skin folds also puts them at greater risk for infection and intertrigo.

Diagnosis
Streptococcal intertrigo is diagnosed by a medical professional after performing a detailed physical examination and taking an overnight culture of the affected areas. A second sample is tested with a rapid antigen detection test for Group A streptococcus. Upon physical examination, streptococcal intertrigo commonly presents with a marked area of redness of the skin, a distinct, foul smell, and a lack of satellite lesions. The presence of satellite lesions, or lesions smaller and further away from the main affected region, may point to a differential diagnosis of candidal intertrigo, which is a more common cause of these characteristics. Streptococcal intertrigo is frequently underdiagnosed and should be considered as a causative agent when standard therapy for candidal intertrigo fails.Other differential diagnoses which may present similarly include seborrheic dermatitis, atopic dermatitis, irritant contact dermatitis, allergic contact dermatitis, mixed bacterial intertrigo, scabies, erythrasma, and inverse psoriasis.

Prevention
Given the main etiology of streptococcal intertrigo is the warm and moist skin surface, in order to prevent future infection and repeat incident of this kind, it is best to keep the affected area and other skin folds clean and dry of moisture. It is also helpful to expose such areas to air and limit skin-on-skin friction as much as possible. In order to decrease friction as a predisposing factor, weight loss for individuals with obesity or reduction mammoplasty for large breasts is encouraged and recommended. To decrease the chance of worsening symptoms, a drying agent, such as baby powder, can be applied. Application of other barrier agents, such as zinc oxide or petrolatum, aids in the reduction of skin deterioration and alleviates itching and pain.

Treatment
The most common treatment options of intertrigo complicated with secondary bacterial infection such as group A beta-hemolytic streptococcus are topical mupirocin (bactroban), erythromycin, low potency topical steroids like hydrocortisone 1% cream, and oral antibiotics (such as oral penicillin, cephalexin, ceftriaxon, cefazolin, and clindamycin). These broad-spectrum antibiotics are ideal in targeting bacterial agents due to the large number of microbiota on the human skin. Additionally, the low potency steroids aid in the reduction of the reaction, reducing discomfort to the patient. Drying agents, such as aluminum sulfate and talcum powder, may be used alongside other treatments to help the healing process to go faster. Although, if these agents are to be used, it is better to space them few hours apart. A hair drier could also be utilized on the affected area as intertrigo responds well to the removal of moisture.  Age is an important factor to consider when dosing since intertrigo is prevalent amongst young children. Proper identification of etiology is required in order to treat optimally.

Case studies
3-month old infant
A 3-month old infant presented with streptococcal intertrigo after experiencing a rash in their groin area for 3 days. A bright, distinct red coloration was evident in the infants skin folds, which were also moist and wrinkly. A bacterial sample was collected and tested on with antibiotics. The infant was initially treated with oral flucloxacillin which proved to be effective in clearing the bacteria. From the culture, the bacteria was classified as a group A beta-hemolytic streptococci.

5-month old male
A 5-month old infant with a history of eczema presented with a dark red rash on their ear, neck and lower limbs </s>