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Minimally invasive strabismus surgery (MISS) is a technique in strabismus surgery that uses smaller incisions than the classical surgical approach to correct the condition, thus minimizing tissue disruption. The technique was introduced by Swiss ophthalmologist Daniel Mojon around 2007, after the Belgian ophthalmologist Marc Gobin described the idea in 1994 in a French-language textbook. == Indications == MISS is a technique that can be employed for all major types of strabismus surgery like rectus muscle recessions, resections, plications, reoperations, transpositions, oblique muscle recessions, or plications, and adjustable sutures, even in the presence of restricted motility. The smaller openings and the less traumatic procedure are in general associated with faster postoperative rehabilitation and less swelling and discomfort for the patient immediately after the procedure. It is supposed that the technique can be performed as an outpatient intervention in many patients (mainly adults) who would otherwise be hospitalized. A study published in 2017 documented fewer conjunctival and eyelid swelling complications in the immediate postoperative period after MISS than after conventional strabismus surgery with long-term results being similar between both groups. Another advantage is that MISS technique may decrease the risk of anterior segment ischemia in some patients, particularly those suffering from Graves' ophthalmopathy. == Principle == In MISS the operating microscope rather than magnifying glasses should be used by the surgeon. Instead of one large opening of the conjunctiva as is done in conventional strabismus surgery, several small cuts are placed where the main surgical steps, usually suturing, have to be performed. Openings are placed as far away from the corneal limbus as possible to minimize postoperative discomfort. Between two of these incisions, called keyhole openings, there is a "tunnel" used by the surgeon to insert the instrument for the treatment of the eye muscles. At the end of the operation, the keyhole openings are closed with resorbable sutures. These mini-incisions are postoperatively covered by the eyelid. MISS openings markedly reduce the frequency and severity of corneal complications like, for example, dry eye syndrome and dellen formation, and will allow wearing contact lenses earlier. Long-term benefits are avoidance of an increase in redness of the visible conjunctiva and a decreased scarring of the perimuscular tissue, which will facilitate reoperations - if those should become necessary. == Clinical results == The results after MISS regarding postoperative ocular alignment are widely described in the so far still limited literature on the technique to be about the same as in classical strabismus surgery. This was documented, for instance, in comparing 40 children; the group that had undergone the minimally invasive procedure, however, did show less swelling of the conjunctiva and the eyelids after surgery. Lesser rates of complications and faster reconvalescence have been widely established as the main advantages of MISS. The technique's efficacy has been shown for surgery of the rectus muscles as well as for the surgery of the oblique muscles. A group from India reported on the successful performance of MISS in patients with Graves' orbitopathy. == Disadvantages and potential complications == MISS is more time-consuming than conventional surgery. Operating on the muscles through the tunnel is more demanding on the surgeon. The keyhole cuts may tear in older patients. If the tear involves Tenon's capsule, a visible scar may result. An excessive bleeding that cannot be stopped makes an enlargement of the cuts necessary to cauterize the vessel. Usually, a conversion to a limbal opening as in classical strabismus surgery can be avoided. There are few reports, though, on complications that are unique to MISS. == References ==	Wikipedia/Minimally_invasive_strabismus_surgery
Scleral reinforcement is a surgical procedure used to reduce or stop further macular damage caused by high myopia, which can be degenerative. == High myopia == Myopia is one of the leading causes of blindness in the world. It is caused by both genetic and environmental factors, such as mechanical stretching, excessive eye work and accommodation, as well as an elevated intraocular pressure. It affects both children and adults. In many cases, myopia will stabilize once the growth process has been completed, but in more severe chronic cases, loss of vision can occur. Degenerative myopia, also known as malignant, pathological, or progressive myopia, is characterized by posterior sclera elongation and thinning (at least 25.5 mm to 26.5 mm) and high refractive errors of at least -5 to -7.5 diopters with an increase per year. There may also be changes in the fundus, including posterior staphyloma, caused by the eye growing posteriorly and losing its spherical shape. Since enlargement of the eye does not progress at a uniform rate, abnormal protrusions of uveal tissue may occur through weak points in the eye. Staphyloma is marked by a thinning of sclera collagen bundles and decreased number of collagen striations. It correlates with a large posterior temporal bulge. Curtin described five varieties, based on size, shape, and change in appearance of the optic nerve and retinal vessels, but the posterior pole type is the most common. As the posterior staphyloma enlarges, choroidal tissue becomes thin and Bruch's membrane begins to break, creating lesions called lacquer cracks. Neovascularization may occur, causing blood vessels to protrude through the cracks and leak in the space underneath the photoreceptor cell layer. This hemorrhaging can lead to scarring and macular degeneration, causing vision to gradually deteriorate. If left untreated, high myopia can cause retinal detachment, glaucoma, and a higher risk of cataracts. == History == The condition of posterior staphyloma in high myopia was first described by Scarpa in the 1800s. Speculation about reinforcement of the eye began in the 19th century, when Rubin noted that sclera reinforcement “is probably the only one of all the surgical techniques [for myopia] which attempts to correct a cause, rather than an effect”. Procedures in early literature aimed at shortening the length of the eyeball by resecting a ring of sclera from the equator of the eye. Later procedures focused on modifying the axial length of the eye, by preventing elongation and staphyloma progression by placing grafts over the posterior part of the eye. In 1930, Shevelev proposed the idea of transplantation of fascia lata for sclera reinforcement. Curtin promoted the use of donor-sclera grafting for reinforcement. In 1976, Momose first introduced Lyodura, a material derived from processed cadaver dura mater. At this point, many different surgeons made alterations to existing techniques. Snyder and Thompson modified reinforcement techniques and had positive outcomes, while others, like Curtin and Whitmore, expressed dissatisfaction with their negative conclusions. == Purpose == The surgery aims to cover the thinning posterior pole with a supportive material to withstand intraocular pressure and prevent further progression of the posterior staphyloma. The strain is reduced, although damage from the pathological process cannot be reversed. By stopping the progression of the disease, vision may be maintained or improved. == Methods of surgery == There are three basic techniques, referred to as X-shaped, Y-shaped, and single strip support. In X-shaped and Y-shaped, the arms run the risk of the being pulled medially, which would press on the optic nerve and could result in optic nerve atrophy. In single strip support, the material covers the posterior pole vertically between the optic nerve and insertion of the inferior oblique muscle. Often, this method is preferred, since it is the easiest method for placement, provides the widest area of support, and reduces the risk of optic nerve interference. == Materials == Many different materials have been used in the past, including fascia lata, Lyodura (lyophilized human dura), Gore-Tex, Zenoderm (porcine skin dermis), animal tendons, and donor's or cadaver’s sclera. Human sclera is thought to offer the best support, as well as Lyodura, which is biologically compatible with the eyeball and has sufficient tensile strength. Artificial materials, such as nylon or silicone, are not suggested. Sclera from cadaver’s or animal tendons run the risk of being rejected. == Procedure == While there have been many modifications, Thompson’s procedure has often been used as a basis. First, the conjunctiva and Tenon's capsule are incised about 6 mm from the corneal limbus. The lateral, superior, and inferior recti muscles are separated using a strabismus hook. The connecting tissue is then separated from the posterior pole, as well as the inferior oblique muscle. The strip of material is passed under the separated muscles, and pushed down deeply towards the posterior pole. Both ends of the material strip are crossed over the medial rectus muscle and sutured to the sclera on the medial side of the superior and inferior recti muscles. The conjunctiva and Tenon's capsule are then closed together. == Complications == Long-term complication rates are usually low, but short-term complications may include chemosis, choroidal edema or hemorrhage, damage to the vortex vein, and transient motility problems. == Controversy == Scleral reinforcement surgery is not presently popular in the United States, and there has been a scarcity of published clinical studies. Donor sclera material is also difficult to acquire and store, and artificial materials are still being tested. This procedure is much more popular in other countries, such as the former Soviet Union and Japan. There is also controversy regarding in what developmental stage this procedure should be performed. Some feel efforts should be made as soon as possible to arrest progression in children. Others feel that the procedure should only be done in cases where high myopia is indicated with macular changes. Furthermore, different surgeons have particular criteria that must be met by patients in order to receive surgery. == References ==	Wikipedia/Scleral_reinforcement_surgery
Refractive surgery is an optional eye surgery used to improve the refractive state of the eye and decrease or eliminate dependency on glasses or contact lenses. This can include various methods of surgical remodeling of the cornea (keratomileusis), lens implantation or lens replacement. The most common methods today use excimer lasers to reshape the curvature of the cornea. Refractive eye surgeries are used to treat common vision disorders such as myopia, hyperopia, presbyopia and astigmatism. == History == The first theoretical work on the potential of refractive surgery was published in 1885 by Hjalmar August Schiøtz, an ophthalmologist from Norway. In 1930, the Japanese ophthalmologist Tsutomu Sato made the first attempts at performing this kind of surgery, hoping to correct the vision of military pilots. His approach was to make radial cuts in the cornea, correcting effects by up to 6 diopters. The procedure unfortunately produced a high rate of corneal degeneration, however, and was soon rejected by the medical community. The first proficient refractive surgery technique was developed in the Barraquer ophthalmologic clinic (Bogotá, Colombia), in 1963, by Jose Barraquer. His technique, called keratomileusis, meaning corneal reshaping (from Greek κέρας (kéras: horn) and σμίλευσις (smileusis: carving)), enabled the correction, not only of myopia, but also of hyperopia. It involves removing a corneal layer, freezing it so that it could be manually sculpted into the required shape, and finally reimplanting the reshaped layer into the eye. In 1980, Swinger performed first keratomileusis surgery in US. In 1985, Krumeich and Swinger introduced non-freeze keratomileusis technique, it remained a relatively imprecise technique. In 1974 a refractive procedure called Radial Keratotomy (RK) was developed in the USSR by Svyatoslav Fyodorov and later introduced to the United States. RK involves making a number of cuts in the cornea to change its shape and correct refractive errors. The incisions are made with a diamond knife. Following the introduction of RK, doctors routinely corrected nearsightedness, farsightedness, and astigmatism using various applications of incisions on the cornea. Meanwhile, experiments in 1970 using a xenon dimer and in 1975 using noble gas halides resulted in the invention of a type of laser called an excimer laser. While excimer lasers were initially used for industrial purposes, in 1980, Rangaswamy Srinivasan, a scientist of IBM who was using an excimer laser to make microscopic circuits in microchips for informatics equipment, discovered that the excimer could also be used to cut organic tissues with high accuracy without significant thermal damage. The discovery of an effective biological cutting laser, along with the development of computers to control it, enabled the development of new refractive surgery techniques. In 1983, Stephen Trokel, a scientist at Columbia University, in collaboration with Theo Seiler and Srinivasan, performed the first Photorefractive Keratectomy (PRK), or keratomileusis in situ (without separation of corneal layer) in Germany. The first patent for this approach, which later became known as LASIK surgery, was granted by the US Patent Office to Gholam Ali. Peyman, MD on June 20, 1989. It involves cutting a flap in the cornea and pulling it back to expose the corneal bed, then using an excimer laser to ablate the exposed surface to the desired shape, and then replacing the flap. The name LASIK was coined in 1991 by University of Crete and the Vardinoyannion Eye. The patents related to so-called broad-beam LASIK and PRK technologies were granted to US companies including Visx and Summit during 1990–1995 based on the fundamental US patent issued to IBM (1983) which claimed the use of UV laser for the ablation of organic tissues. In 1991, J.T. Lin, Ph.D. (a Chinese Physicist) was granted a US patent for a new technology using a flying-spot for customized LASIK currently used worldwide. The first US patent using an eye-tracking device to prevent decentration in LASIK procedures was granted to another Chinese Physicist, Dr. S. Lai in 1993. == Techniques == === Flap procedures === Excimer laser ablation is done under a partial-thickness lamellar corneal flap. Automated lamellar keratoplasty (ALK): The surgeon uses an instrument called a microkeratome to cut a thin flap of the corneal tissue. The flap is lifted like a hinged door, targeted tissue is removed from the corneal stroma, again with the microkeratome, and then the flap is replaced. Laser-assisted in situ keratomileusis (LASIK): The surgeon uses either a microkeratome or a femtosecond laser to cut a flap of the corneal tissue (usually with a thickness of 100–180 micrometres). The flap is lifted like a hinged door, but in contrast to ALK, the targeted tissue is removed from the corneal stroma with an excimer laser. The flap is subsequently replaced. When the flap is created using an IntraLase brand femtosecond laser, the method is called IntraLASIK; other femtosecond lasers such as the Ziemer create a flap similarly. Femtosecond lasers have numerous advantages over mechanical microkeratome based procedure. Microkeratome related flap complications like incomplete flaps, buttonholes or epithelial erosion are eliminated with femtosecond laser procedure. Absence of microscopic metal fragments from the blade will reduce the risk of lamellar keratitis also. Customized aspheric treatment zone (CATz) is a topography-guided LASIK treatment developed by NIDEK Co. Ltd which ablates the cornea based on patient-specific geometry to address certain disadvantages in conventional wavefront spherocylindrical ablation. The treatment is effective for myopia with astigmatism or otherwise irregular corneas, and reduces symptoms such as glare, halos, and night driving difficulty. Refractive Lenticule Extraction (ReLEx): ReLEx "FLEx" (Femtosecond Lenticule Extraction): A femtosecond laser cuts a disc-shaped piece of corneal tissue called a "lenticule" within the corneal stroma. Subsequently, a LASIK-like flap is cut which can be lifted to access the lenticule. This is removed through manual dissection using a blunt spatula and forceps. ReLEx "SMILE" (Small Incision Lenticule Extraction): A newer technique without a flap, a femtosecond laser cuts a lenticule within the corneal stroma. The same laser is used to cut a small incision along the periphery of the lenticule about 1/5th the size of a standard LASIK flap incision. The surgeon then uses a specially designed instrument to separate and remove the lenticule through the incision, leaving the anterior lamellae of the cornea intact. No excimer laser is used in the "ReLEx-procedures". === Surface procedures === The excimer laser is used to ablate the most anterior portion of the corneal stroma. These procedures do not require a partial thickness cut into the stroma. Surface ablation methods differ only in the way the epithelial layer is handled. Photorefractive keratectomy (PRK) is an outpatient procedure generally performed with local anesthetic eye drops (as with LASIK/LASEK). It is a type of refractive surgery which reshapes the cornea by removing microscopic amounts of tissue from the corneal stroma, using a computer-controlled beam of light (excimer laser). The difference from LASIK is that the top layer of the epithelium is removed (and a bandage contact lens is used), so no flap is created. Recovery time is longer with PRK than with LASIK, though the outcome (after 3 months) is about the same (very good). More recently, customized ablation has been performed with LASIK, LASEK, and PRK. Transepithelial photorefractive keratectomy (TransPRK) is a laser-assisted eye surgery to correct refraction errors of human eye corneas. It uses an excimer laser to ablate the outer layer of the cornea, the epithelium, as well as its connective tissue, the stroma, to correct the eye's optical power. Laser Assisted Sub-Epithelium Keratomileusis (LASEK) is also a procedure that changes the shape of the cornea using an excimer laser to ablate the tissue from the corneal stroma, under the corneal epithelium, which is kept mostly intact to act as a natural bandage. The surgeon uses an alcohol solution to loosen then lift a thin layer of the epithelium (usually with a thickness of 50 micrometres) with a trephine blade. During the weeks following LASEK, the epithelium heals, leaving no permanent flap in the cornea. This healing process can involve discomfort comparable to that with PRK. EPI-LASIK is a new technique similar to LASEK that uses an epi-keratome (rather than a trephine blade and alcohol), to remove the top layer of the epithelium (usually with thickness of 50 micrometres), which is subsequently replaced. For some people it can provide better results than regular LASEK in that it avoids the possibility of negative effects from the alcohol, and recovery may involve less discomfort. Customized Transepithelial No-touch (C-TEN) is an innovative strategy for corneal surgery that avoids any corneal manipulation via a complete laser-assisted trans-epithelial approach. Since C-TEN is planned on the morphology of each individual eye, it can treat a large variety of corneal pathologies from refractive to therapeutic. C-TEN is sometimes referred to as Advanced Surface Ablation (ASA) === Corneal incision procedures === Radial keratotomy (RK), developed by Russian ophthalmologist Svyatoslav Fyodorov in 1974, uses spoke-shaped incisions, always made with a diamond knife, to alter the shape of the cornea and reduce myopia or astigmatism; this technique is, in medium to high diopters, usually replaced by other refractive methods. Arcuate keratotomy (AK), also known as Astigmatic keratotomy, uses curvilinear incisions at the periphery of the cornea to correct high levels of non-pathological astigmatism, up to 13 diopters. AK is often used for the correction of high post-keratoplasty astigmatism or post-cataract surgery astigmatism. Limbal relaxing incisions (LRI) are incisions near the outer edge of the iris, used to correct minor astigmatism (typically less than 2 diopters). This is often performed in conjunction with the implantation of intraocular lenses. === Refractive lens exchange === Clear lens extraction or refractive lens exchange is effectively the same procedure as cataract surgery used to replace a natural lens with high refractive error when other methods are not effective. It can be done in patients with severe refractive error and/or presbyopia who wish to avoid spectacles. In addition to the common complications of cataract surgery, clear lens extraction may also cause premature posterior vitreous detachment and retinal detachment. In some people with very high myopia, the eye may be left aphakic, without intraocular lens implantation. A related procedure is the implantation of phakic intraocular lenses in series with the natural lens to correct vision in cases of high refractive errors. === Other procedures === Radial Keratocoagulation, also known as Radial Thermokeratoplasty, was invented in 1985 by Svyatoslav Fyodorov and is used to correct hyperopia by putting a ring of 8 or 16 small burns surrounding the pupil, and steepen the cornea with a ring of collagen constriction. It can also be used to treat selected types of astigmatism. It is now generally replaced by laser thermal keratoplasty/laser thermokeratoplasty. Laser thermal keratoplasty (LTK) is a non-touch thermal keratoplasty performed with a Holmium laser, while conductive keratoplasty (CK) is thermal keratoplasty performed with a high-frequency electric probe. Thermal keratoplasty can also be used to improve presbyopia or reading vision after age 40. Intrastromal corneal ring segments (Intacs) are approved by FDA for treatment of low degrees of myopia. Phakic intraocular lens (PIOL) implantation inside the eye can also be used to change refractive errors. The newest type of intervention is a type of PIOL called the implantable collamer lens (ICL) which uses a biocompatible flexible lens which can be inserted in the eye via a 3 mm incision. The ICL is used to correct myopia ranging from −0.5 to −18 diopters, and +0.5 cylinder power to +6.0 for the Toric ICL models. Generally refractive surgery can be broadly divided into: corneal surgery, scleral surgery, lens related surgery (including phakic IOL implantation, clear lens extraction, photophacoreduction and photophacomodulation for correction of presbyopia) For presbyopia correction, a corneal inlay consisting of a porous black ring surrounding a small clear aperture was originally developed by D. Miller, H. Grey PhD and a group at Acufocus. The inlay is placed under a LASIK flap or in a stromal pocket. Using mid-IR and UV lasers for the treatment of presbyopia by scleral tissue ablation was first proposed and patented by J.T. Lin, Ph.D. in US patents #6,258,082 (in 2001) and #6,824,540 (in 2004). == Expectations == Research conducted by the Magill Research Center for Vision Correction, Medical University of South Carolina, showed that the overall patient satisfaction rate after primary LASIK surgery was 95.4%. They further differentiated between myopic LASIK (95.3%) and hyperopic LASIK (96.3%). They concluded that the vast majority (95.4%) of patients were satisfied with their outcome after LASIK surgery. Ophthalmologists use various approaches to analyze the results of refractive surgery, and alter their techniques to provide better results in the future. Some of these approaches are programmed into the devices ophthalmologists use to measure the refraction of the eye and the shape of the cornea, such as corneal topography. == Risks == While refractive surgery is becoming more affordable and safe, it may not be recommended for everybody. People with certain eye diseases involving the cornea or retina, pregnant women, and patients who have medical conditions such as glaucoma, diabetes, uncontrolled vascular disease, or autoimmune disease are not good candidates for refractive surgery. Keratoconus, a progressive thinning of the cornea, is a common corneal disorder. Keratoconus occurring after refractive surgery is called Corneal Ectasia. It is believed that additional thinning of the cornea via refractive surgery may contribute to advancement of the disease that may lead to the need for a corneal transplant. Therefore, keratoconus is a contraindication to refractive surgery. Corneal topography and pachymetry are used to screen for abnormal corneas. Furthermore, some people's eye shape may not permit effective refractive surgery without removing excessive amounts of corneal tissue. Those considering laser eye surgery should have a full eye examination. Although the risk of complications is decreasing compared to the early days of refractive surgery, there is still a small chance for serious problems. These include vision problems such as ghosting, halos, starbursts, double-vision, and dry-eye syndrome. With procedures that create a permanent flap in the cornea (such as LASIK), there is also the possibility of accidental traumatic flap displacement years after the surgery, with potentially disastrous results if not given prompt medical attention. For patients with strabismus, risks of complications such as diplopia and/or increased strabismus angle need to be evaluated carefully. In case both refractive surgery and strabismus surgery are to be performed, it is recommended that the refractive surgery be done first. == Children == Pediatric refractive surgery involves other risks than refractive surgery on adults, yet it may be indicated especially for children whose cognitive or visual development is failing due to refractive error, in particular in cases of bilateral high refractive error, anisometropia, anisometric amblyopia or accommodative esotropia. Interventions on young children may require general anaesthesia in order to avoid risks due to involuntary movement, and children have a higher risk of rubbing or manipulating their eyes post-surgically. Changes to refractive error occurring during normal age development need to be accounted for, and children have a higher risk of developing postoperative corneal haze. This risk is particularly relevant with relation to myopic children. One study evaluated the outcome of LASEK interventions on 53 children aged 10 months to 16 years who had anisometropic amblyopia. The choice of LASEK was made as it was felt it would give fewer complications than LASIK and less post-operative pain than PRK. In the intervention, which was performed under general anaesthesia, the refractive error in the weaker eye was corrected to balance the refractive error of the other eye. Strabismus surgery was performed later if required. After one year, over 60% had improved in best corrected visual acuity (BCVA) in the weaker eye. Notably, over 80% showed stereopsis post-operatively whereas less than 40% had shown stereopsis before. In addition to corneal refractive procedures (LASIK, PRK and LASEK), intraocular refractive procedures (phakic intraocular lenses, refractive lens exchange and clear lens extraction) are also performed on children. == See also == Orthokeratology – contact lenses worn only at night to reshape the eye. == References == == External links == DJO\|Digital Journal of Ophthalmology	Wikipedia/Refractive_surgery
Optical coherence tomography angiography (OCTA) is a non-invasive imaging technique based on optical coherence tomography (OCT) developed to visualize vascular networks in the human retina, choroid, skin and various animal models. OCTA may make use of speckle variance optical coherence tomography. OCTA uses motion contrast between cross-sectional OCT scans (B-frames) to differentiate blood flow from static tissue, enabling imaging of vascular anatomy. To correct for patient movement during scanning, bulk tissue changes in the axial direction are eliminated, ensuring that all detected changes are due to red blood cell movement. This form of OCT requires a very high sampling density in order to achieve the resolution needed to detect the tiny capillaries found in the retina. This has allowed OCTA to obtain detailed images of retinal vasculature in the human retina and become widely used clinically to diagnose a variety of eye diseases, such as age related macular degeneration (AMD), diabetic retinopathy (DR), artery and vein occlusions, and glaucoma. == Medical uses == While conventional dye-based angiography is still the common gold standard, OCTA has been evaluated and used across many diseases. OCTA was first introduced in clinical eyecare in 2014. OCTA has applications in several diseases, including leading causes of blindness such as glaucoma and age-related macular degeneration. In diabetic retinopathy (DR), OCTA was shown to resolve previously established markers of severe disease (i.e., vitreous proliferation). Moreover, OCTA was shown to provide a plethora of additional biomarkers including subclinical loss of vessel density. Thus, OCTA may offer in future the potential to monitor the progression of DR at an earlier, pre-clinical state. Similarly, OCTA was shown to provide more refined information compared to dye-based angiography in other vascular occlusive diseases such as central (or branch) retinal vein occlusion. == How it works == OCTA detects moving particles (red blood cells) by comparing sequential B-scans at the same cross-sectional location. To simply put it, the backscattered light reflected back from static samples would remain the same over multiple B-scans while the backscattered light reflected back from moving samples would fluctuate. Multiple algorithms have been proposed and utilized to contrast such motion signals from static signals in various biological tissues. === Calculating blood flow === An algorithm developed by Jia et al. is used to determine blood flow in the retina. The split-spectrum amplitude decorrelation angiography (SSADA) algorithm calculates the decorrelation in the reflected light that is detected by the OCT device. The blood vessels are where the most decorrelation occurs allowing them to be visualized, while static tissue has low decorrelation values. The equation takes into account fluctuations of the received signal amplitude or intensity over time. Greater fluctuations receive a greater decorrelation value and indicate more movement. A significant challenge when trying to image the eye is patient movement and saccadic movement of the eye. Movement introduces a lot of noise into the signal making tiny vessels impossible to distinguish. One approach to decreasing the influence of movement on signal detection is to shorten the scanning time. A short scan time prevents too much patient movement during signal acquisition. With the development of Fourier-domain OCT, spectral-domain OCT, and swept source signal acquisition time was greatly improved making OCTA possible. OCTA scan time is now around three seconds, however, saccadic eye movement still causes a low signal-to-noise ratio. This is where SSADA proves to be very advantageous as it is able to greatly improve SNR by averaging the decorrelation across the number of B-scans, making the microvasculature of the retina visible. == History == Initial efforts to measure blood flow using OCT utilized the Doppler effect. By comparing the phase of successive A-mode scans, the velocity of blood flow can be determined via the Doppler equation. This was deemed Optical Doppler Tomography; the development of spectral domain OCT (SD-OCT) and swept-source OCT (SS-OCT) greatly improved scan times since this phase information was readily accessible. Still, Doppler techniques were fundamentally limited by bulk eye motion artefacts, especially as longer scan times became important for increasing sensitivity. In the mid-2000s systems began compensating for bulk eye motion, which significantly reduced motion artefacts. Systems also began to measure the variance and power of the Doppler phase between successive A-mode and B-mode scans; later it was shown that successive B-mode scans must be corrected for motion and the phase variance data must be thresholded to remove bulk eye motion distortion. By 2012, split spectrum amplitude decorrelation was shown to be effective at increasing SNR and decreasing motion artefacts. Commercial OCT-A devices also emerged around this time, beginning with the OptoVue AngioVue in 2014 (SD-OCT) and the Topcon Atlantis/Triton soon after (SS-OCT). == Other angiography techniques == The most common angiographic techniques were fluorescein (FA) or indocyanine green angiography (ICGA), which both involve the use of an injectable dye. Intravenous dye injection is time-consuming and can have adverse side effects. Furthermore, the edges of the capillaries can become blurred due to dye leakage and imaging of the retina can only be 2D when using this method. With OCTA, dye injection is not needed making the imaging process faster and more comfortable while at the same time improving the quality of the image. The current gold standards of angiography, fluorescein angiography (FA) and indocyanine green angiography (ICGA), both require dye to be injected. OCTA does not need dye but is susceptible to motion artefacts. The dyes used in FA and ICGA can cause nausea, vomiting, and general discomfort, and only have an effective lifetime on the order of a few minutes. From a physics perspective, both dye-based methods utilize the phenomenon of fluorescence. For FA, this corresponds to an excitation wavelength of blue (around 470 nm) and an emission wavelength near yellow (520 nm). For IGCA, the newer method, the excitation wavelength is between 750 and 800 nm while emission occurs above 800 nm. == References ==	Wikipedia/Optical_coherence_tomography_angiography
Strabismus surgery (also: extraocular muscle surgery, eye muscle surgery, or eye alignment surgery) is surgery on the extraocular muscles to correct strabismus, the misalignment of the eyes. Strabismus surgery is a one-day procedure that is usually performed under general anesthesia most commonly by either a neuro- or pediatric ophthalmologist. The patient spends only a few hours in the hospital with minimal preoperative preparation. After surgery, the patient should expect soreness and redness but is generally free to return home. == History == The earliest successful strabismus surgery intervention is known to have been performed on 26 October 1839 by Johann Friedrich Dieffenbach on a 7-year-old esotropic child; a few earlier attempts had been performed in 1818 by William Gibson of Baltimore, a general surgeon and professor at the University of Maryland. The idea of treating strabismus by cutting some of the extraocular muscle fibers was published in American newspapers by New York oculist John Scudder in 1837. == Indications == Strabismus surgery is one of many options used to treat any misalignment of the eyes, called strabismus. This misalignment or "crossing" of the eyes can be caused by a variety of issues. Surgery is indicated when other, less invasive methods have been unable to treat the misalignment or when the procedure will significantly improve quality of life and/or visual function. The type of surgery for a given patient depends on the type of strabismus they are experiencing. Exodeviations are when the misalignment of the eyes is divergent ("crossing out") and esodeviations are when the misalignment is convergent ("crossing in"). These conditions are further categorized based on when the misalignment is present. If it is latent the condition is called a "-phoria" and if it is present all the time it is a "-tropia". Esotropias measuring more than 15 prism diopters (PD) and exotropias more than 20 PD that have not responded to refractive correction can be considered candidates for surgery. == Techniques == The goal of strabismus surgery is to correct misalignment of the eyes. This is achieved by loosening or tightening the extraocular muscles in order to weaken or strengthen them, respectively. There are two main types of extraocular muscles - rectus muscles and oblique muscles - which have specific procedures to achieve the desired results. The amount of weakening or strengthening required is determined through in-office measurements of the eye misalignment. Measured in PD, the size of the deviation is used along with established formulas and tables to inform the surgeon how the muscle must be manipulated in surgery. === Rectus muscle procedures === The main procedure used to weaken a rectus muscle is called a recession. This involves detaching the muscle from its original insertion on the eye and moving it towards the back of the eye a specific amount. If after a recession the muscle requires more weakening a marginal myotomy can be performed, where a cut is made part way across the muscle. The procedures used to strengthen rectus muscles include resections and plications. A resection is when a portion of the muscle is cut away and the new shortened muscle is reattached to the same insertion point. A plication on the other hand is when the muscle is folded and secured to the outer white portion of the eye, known as the sclera. Plication has the advantages of being a quicker procedure that involves less trauma than a resection and preserves the anterior ciliary arteries - the latter of which minimizes the risk of blood loss to the front of the eye allowing for operation on multiple muscles at one time. Studies on horizontal rectus muscle surgeries have shown that both procedures have similar success rates and no difference in post-operative exodrift or overcorrection rate was discovered. However, further investigation is required to determine if there is any difference in long term effects from the two procedures. Because of the antagonistic pairings of the rectus muscles and the fact that strabismus can be a binocular problem, in certain cases surgeons have the option of operating on either one eye or both eyes. For example, a recent study compared the outcomes of bilateral lateral rectus recession and unilateral recession/resection of the later/medial recti for intermittent exotropia. This study showed that the unilateral procedure had higher success rates and lower recurrence rates for this specific condition. This is not necessarily true for all types of strabismus and further investigation is required to reach a consensus on this particular aspect of the surgery. === Oblique muscle procedures === There are two oblique muscles attached to the eye - the superior oblique and the inferior oblique - which each have their respective procedures. ==== Inferior oblique ==== The inferior oblique is weakened through a recession and anteriorization where the muscle is detached from the eye and reinserted at a spot anterior to the original insertion. Some surgeons will alternatively perform a myotomy or myectomy, where a muscle is either cut or has a portion of it removed, respectively. The inferior oblique muscle is rarely tightened due to the technical difficulty of the procedure and the possibility of damage to the macula, which is responsible for central vision. ==== Superior oblique ==== The superior oblique is weakened through either a tenotomy or tenectomy, where part of the muscle tendon is either cut across or removed, respectively. The superior oblique is strengthened by folding and securing the tendon to reduce its length, which is called a tuck. === Adjustable sutures === A technique that is more commonly used for more complicated cases of strabismus is that of adjustable suture surgery. This technique allows for the adjustment of sutures after the initial procedure in order to theoretically achieve a better and more individualized result. This often requires dedicated and specific training in this uncommon procedure that has been reported to be performed in only 7.42% of all strabismus cases. Studies have not shown any significant advantage to performing this type of surgery on most forms of simple strabismus. However, its use in some complex cases such as reoperations, strabismus with large or unstable angle, or strabismus in high myopia has been indicated. The specific circumstances in which this technique is considered to be superior to non-adjustable suture surgery require further investigation. === Minimally invasive strabismus surgery === A relatively new method, primarily devised by Swiss ophthalmologist Daniel Mojon, is minimally invasive strabismus surgery (MISS) which has the potential to reduce the risk of complications and lead to faster visual rehabilitation and wound healing. Done under the operating microscope, the incisions into the conjunctiva are much smaller than in conventional strabismus surgery. A study published in 2017 documented fewer conjunctival and eyelid swelling complications in the immediate postoperative period after MISS with long-term results being similar between both groups. MISS can be used to perform all types of strabismus surgery, namely rectus muscle recessions, resections, transpositions, and plications even in the presence of limited motility. == Outcomes == A strabismus surgery is considered a success when the overall deviation has been corrected 60% or more or if the deviation is under 10 PD 6 weeks after the surgery. === Unsatisfactory alignment === Surgical intervention can result in the eyes being entirely aligned (orthophoria) or nearly so, or it can result in an alignment that is not the desired result. There are many possible types of misalignment that can occur after the surgery including undercorrection, overcorrection, and torsional misalignment. Treating a case of unsatisfactory alignment often involves prisms, botulinum toxin injections, or more surgery. The likelihood that the eyes will stay misaligned over the longer term is higher if the patient is able to achieve some degree of binocular fusion after surgery than if not. There is tentative evidence that children with infantile esotropia achieve better binocular vision post-operatively if the surgical treatment is performed early (see: Infantile esotropia). A recent study reported the reoperation rate in a sample of over 6000 patients being 8.5%. === Psychosocial outcomes === Strabismus has been shown to have a variety of negative psychosocial effects on affected patients. Patients are often more fearful, anxious, have lower self-esteem, and increased interpersonal-sensitivity. These negative impacts often start in childhood and then progress throughout childhood and adolescence if the misalignment is not corrected quickly. There is also data to suggest that society sees this condition as one that negatively affects many qualities important to self-sufficient function such as responsibility, leadership ability, communication, and even intelligence. However, much of this critical mental health burden has been shown to be relieved by corrective surgery. Significant increases in self confidence and self-esteem as well as a reduction in general as well as social anxiety was observed. Overall, strabismus surgery has been shown to successfully improve upon many of the negative impacts strabismus can have on one's mental health. == Complications == Complications that occur rarely or very rarely following surgery include: eye infection, hemorrhage in case of scleral perforation, muscle slip or detachment, or even loss of vision. Eye infection occurs at a rate between 1 in 1100 and 1 in 1900 and can lead to permanent loss of vision if not properly treated. Surgeons take many measures to prevent infection such as careful surgical draping, using povidone iodine as both drops and a solution to soak the sutures in, as well as a post-op course of steroids and antibiotics. There is generally minimal bleeding during strabismus surgery, but medications such as anti-platelet agents and anticoagulants can lead to vision threatening complications retrobulbar hemorrhage. === Diplopia === Diplopia, or double vision, occurs commonly after strabismus surgery. Although the surgery can be used to treat some types of double vision, it can instead end up making existing symptoms worse or create a new type of double vision. The type of double vision can be horizontal, vertical, torsional, or a combination. Treatment of the double vision depends on both the type of double vision and the ability of two eyes to work together, also called binocular function. Diplopia with normal binocular function is treated with prism glasses, botulinum injections into the muscles, or repeated surgery. If binocular function is not normal, a more individualized approach is necessary to best suit the patient's needs. === Scarring === Eye muscle surgery gives rise to scarring (fibrosis) as a result of the trauma caused to the ocular tissues. The goal of surgery is to produce a thin line of firm scar tissue where the muscle is reattached to the sclera. However, the process of surgery can also result in the formation of scar tissue on other parts of eye. These adhesions can, in rare cases, affect the motion of the eye and the desired alignment. If scarring is extensive, it may be seen as raised and red tissue on the white of the eye. Fibrosis reducing measures such as cryopreserved amniotic membrane and mitomycin C have been shown to have some utility during surgery. === Oculocardiac reflex === Very rarely, potentially life-threatening complications may occur during strabismus surgery due to the oculocardiac reflex. This is a physiologic reflex that is described as a reduction in heart rate due to pressure on the globe or traction on the extraocular muscles. It involves activation of the trigeminal nerve leading to activation of the vagus nerve due to the internuclear communication. Although the most common arrhythmia is sinus bradycardia, asystole can be seen in its severe form. The reflex can also have non cardiac effects such as postoperative nausea and vomiting, which is an extremely common consequence of strabismus surgery in children. == See also == Eye surgery Orthoptist Stereopsis recovery == References == == Further reading == == External links == Strabismus Surgery, Horizontal on EyeWiki from the American Academy of Ophthalmology Strabismus Surgery Complications on EyeWiki from the American Academy of Ophthalmology	Wikipedia/Strabismus_surgery
Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects. Activated CD4+ T cells primarily exhibit its ligand CD40L/CD154 to antigen-presenting cells including dendritic cells (DCs), B cells, macrophages, classical and non-classical monocytes, on a variety of non-immune cells including platelets and endothelial cells, and on several types of tumor cells. Mutations affecting this gene are the cause of autosomal recessive hyper-IgM immunodeficiency. == Discovery == Between the late 1950s and the mid-1980s, several immunology laboratories started to use the new hybridoma technology to develop monoclonal antibodies (mAbs) and define receptors expressed at different stages of hematopoietic cell differentiation. The goal of these experiments was to identify differentiation antigens that could be used to describe the stages of lymphocyte differentiation and various functional cell subsets. While doing these experiments, several mAbs were developed against a protein called CD40, a surface receptor of B cells that can be polyclonally activated by a binding ligand. Over time, many features and purposes of the CD40 signaling pathway were discovered, including the discovery of CD40 ligand (CD154/CD40L), a T cell surface molecule which is capable of induction of contact dependent differentiation of B cells. == Function == The protein receptor encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. == Specific effects on cells == In the macrophage, the primary signal for activation is IFN-γ from Th1 type CD4 T cells. The secondary signal is CD40L (CD154) on the Th1 cell which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface which helps increase the level of activation. The increase in activation results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbe. The B cell can present antigens to helper T cells. If an activated T cell recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40 receptor, causing B cell activation. The T cell also produces IL-2, which directly influences B cells. As a result of this net stimulation, the B cell can undergo division, antibody isotype switching, and differentiation to plasma cells. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target. Early evidence for these effects were that in CD40 or CD40L deficient mice, there is little class switching or germinal centre formation, and immune responses are severely inhibited. The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including dendritic cells, B cells and macrophages. It can also be expressed by endothelial cells, smooth muscle cells, fibroblasts and epithelial cells. Consistent with its widespread expression on normal cells, CD40 is also expressed on a wide range of tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, myeloma and some carcinomas including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD40L interactions may play a role in the control of B cell haematopoiesis. == Interactions == CD40 (protein) has been shown to interact with TRAF2, TRAF3, TRAF6, TRAF5 and TTRAP. The remaining member of TRAF4 family, namely TRAF4, positively regulates CD40 signalling, but interacts with CD40 indirectly. CD40 also interacts with CD40L, due to the role of CD40 in stimulating immune synapses when this interaction happens with CD40L activates dendritic cells to activate antigen specific T cells. This occurs through the upregulation of major histocompatibility complex molecules increased expression of the co-stimulatory molecules CD86/CD80, and upregulation of TNF superfamily ligands on the dendritic cells surface, along with secretion of interleukin-12 (IL-12), which promotes CD8+ T cell activation. Moreover CD40/CD40L interactions provoke antitumor immune responses by increasing tumor cell immunogenic cell death (ICD), APC activation, tumor immunogenicity through upregulation of major histocompatibility complex (MHC) molecules, proinflammatory factor production, co-stimulation of CD4+ and CD8+ T cells, and tumor cell susceptibility to T-cell lysis. In addition the CD40/CD40LG axis is important for immune cell turnover and homeostasis under normal conditions. This is hypothesized because the closest association of cell proliferation is with CD40LG and the pro-apoptotic marker BAX also this axis plays a crucial role in promoting B cell activation and proliferation, the B-T cell immune synapses among with antigen presentation == CD40 as a drug target in cancer == The CD40 molecule is a potential target for cancer immunotherapy. Anti-CD40 monoclonal antibodies may help promote the killing of cancer cells by effector cells. Similarly, ligation of CD40 may lead to cell death in some tumor cells, as it is expressed in all lymphoid malignancies and in a number of carcinomas. There are a number of completed and ongoing clinical trials using agonistic anti-CD40 monoclonal antibodies to elicit an anti-tumor T-cell response via dendritic cell activation. Over the past 20 years, numerous human CD40 monoclonal antibodies have been developed and evaluated in clinical trials due to encouraging variability in cancer animal models. Agonistic anti CD -40-Abs are designed to mimic CD40L by cross-linking CD40 and in this way promoting the maturation of DCs and enhancing their antigen presentation ability. This leads to an increase in tumor antigen-specific cytotoxic T cells, which may result in tumor eradication. On the other hand, the preclinical efficacy has not yet been tested in the clinical setting, and none of these monoclonal antibodies have progressed beyond early testing phases. Because of toxicity, the use of CD40 monoclonal antibodies has been limited to suboptimal doses, resulting in inadequate immune activation and antitumor activity. More recently, agonistic CD40 therapy has been shown to decrease T cell cytotoxicity in preclinical glioma models, and in fact affect the efficacy of immune checkpoint blockade. This is likely due to the high mutational burden most of these models display, which causes them to respond better to immune checkpoint blockade than human glioma, but is nonetheless relevant information for research in immunomodulatory therapies. CD40 is expressed on B-cell acute lymphoblastic leukemia (B-ALL) cases and a study on patient-derived xenograft mice suggested that CD40 agonists are promising immunotherapeutic candidates for pediatric B-ALL. == Hyper Ig-M immunodeficiency and CD40 == Hyper-IgM syndrome is a primary immunodeficiency disorder characterized by increased serum levels of immunoglobulin (Ig) M and decreased levels of IgG, IgA, and IgE. CD40 is involved in the development of hyper-IgM syndrome in that it serves as a co-stimulatory molecule in the activation differentiation of B cells, which play a key role in producing immunoglobulins. In hyper-IgM syndrome, mutations in genes involved in CD40 signaling result in impaired B cell activation and differentiation, leading to increased production of IgM and decreased production of other immunoglobulins. As a result, individuals with hyper-IgM syndrome are susceptible to a wide range of infections and have an increased risk of autoimmune diseases and cancer. Currently, treatment for hyper-IgM syndrome involves the replacement of missing immunoglobulins, as well as other therapies to boost the immune system and prevent infections. Research is ongoing to better understand the role of CD40 in hyper-IgM syndrome and to develop new treatments for this disorder. == CD40 and drug development == CD40 is a promising target for the development of drugs to treat a variety of diseases, including cancer, autoimmune diseases, and chronic inflammation. By targeting CD40, it is possible to modulate the immune response and enhance the ability of the body to fight against diseases. For example, drugs that block CD40 signaling have shown promise in treating autoimmune diseases, such as rheumatoid arthritis, by suppressing the overactive immune response. On the other hand, drugs that activate CD40 signaling have shown efficacy in treating cancer by boosting the immune response against tumor cells. CD40 also plays a role in the development of chronic inflammation, and targeting CD40 with drugs has the potential to treat diseases such as Crohn's disease and ulcerative colitis. Overall, CD40 represents a promising target for the development of drugs to treat a wide range of diseases. A study on patient-derived xenograft mice suggested that CD40 agonists antibodies are promising immunotherapeutic candidates for pediatric B-ALL. == References == == External links == Human CD40 genome location and CD40 gene details page in the UCSC Genome Browser. PDBe-KB provides an overview of all the structure information available in the PDB for Human Tumor necrosis factor receptor superfamily member 5 (CD40) == Further reading ==	Wikipedia/CD40_(protein)
The dendritic cell-based cancer vaccine is an innovation in therapeutic strategy for cancer patients. Dendritic cells (DCs) are antigen presenting cells for the induction of antigen specific T cell response. DC-based immunotherapy is safe and can promote antitumor immune responses and prolonged survival of cancer patients. == Human DC subsets == === Immature dendritic cells === Non-activated (immature) DCs are usually located in the peripheral non-lymphoid tissues and they can present self-antigens to T cells, that leads to immune tolerance either through T cell deletion or through the differentiation of regulatory T cells. === Mature dendritic cells === Mature DCs have ability to present antigens in the lymphoid tissues, and to prime, activate, and expand immune effector cells with unique functions and cytokine profiles. === Myeloid dendritic cells (cDCs) === Myeloid or conventional DCs (cDCs) are derived from myeloid progenitor cells in the bone marrow and are characterized by expression of CD11c. cDCs can be subdivided into 3 groups: monocyte-derived DCs, CD1a- interstitial DCs, and CD1a+ Langerhans cells. === Plasmacytoid dendritic cells (pDCs) === Plasmacytoid dendritic cells (pDCs) differentiate from lymphoid progenitor cells in the lymphoid tissues. They express CD123 and product high levels of type I interferon. pDCs also contribute to inflammatory responses in the steady state and in pathology. During inflammatory response, inflammatory DCs (iDCs) are generated from monocytes. == Function of cancer therapeutic vaccines == The main goal of the therapeutic vaccines is to elicit cellular immunity. They should prime naïve T cell, and induce transition from chronically activated non-protective CD8+ T cells to healthy CD8+ T cells that can produce cytotoxic T lymphocytes (CTLs), which recognize and eliminate cancer cells by recognizing specific antigens. This process also creates long-lived memory CD8+ T cells that will act to prevent relapse. The most critical step in vaccination is the effective presentation of cancer antigens to T cells, and because of DCs are the most efficient antigen presenting cells, they are the promising option for improvement of therapeutic vaccines. == Methods for exploiting dendritic cells in cancer therapeutic vaccines == DC-based immunotherapy approach can be employed in two ways: === Direct targeting/stimulating of the DCs in vivo to accentuate their anticancer phenotype === Many trials evaluating in vivo DC stimulation with synthetic peptides failed because of inability of effective stimulation of CD4+ cellular responses and stimulation of Th2 type cytokines. The solution showing clinical responses was pre-treatment with single-dose cyclophosphamide as well as vaccination with tumor associated antigens (TAAs) and granulocyte macrophage colony stimulating factor (GM-CSF). === Stimulation of the DCs ex vivo and infusing them back into the host for carrying out anticancer effector function === In this way, DCs’ precursors are isolated from the patient through leukapheresis and after maturation/stimulation of these precursors ex vivo, fully mature DCs are injected back into the patient. There are different ways applied to generate cancer cells-specific DCs. We can used specific TAAs, tumor lysates, created DC-cancer cell fusions, electroporation/transfection of DCs with total cancer cell-mRNA or tumor derived exosomes (TDEs) by the stimulation. There is also the possibility of additional co-stimulating with cytokine “cocktails” to assure strong maturation. == Dendritic cell vaccine against brain tumor == The most well-known source of antigens used for vaccines in Glioblastoma (Aggressive type of brain tumor) investigations were whole tumor lysate, CMV antigen RNA and tumor associated peptides for instance EGFRvIII. The initial studies showed that patients developed immune responses as measured by Interferon-gamma expression in the peripheral blood, systemic cytokine responses, or CD8+ antigen specific T cell expansion. Clinical response rates were not as vigorous as the immune response rates. Overall survival (OS) and progression free survival (PFS) varied in different studies but were enhanced compared to historical controls. == Dendritic cell vaccine against COVID-19 == Autologous dendritic cells previously loaded ex-vivo with SARS-CoV-2 spike protein. Subjects eligible for treatment will be those who at baseline, are not actively infected with SARS-CoV-2, have no evidence of prior infection with SARS-CoV-2 based on serologic testing, and give informed consent for a vaccination with AV-COVID-19. The patient population will include the elderly and others at higher risk for poor outcomes after COVID-19 infection. For this reason, individuals will not be excluded solely on the basis of age, body mass index, history of hypertension, diabetes, cancer, or autoimmune disease. == Sipuleucel-T == Sipuleucel-T is the first DCs- based cancer vaccine for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC), approved by the US Food and Drug Administration (FDA) . It is an active cellular immunotherapy, which involves obtaining antigen-presenting autologous dendritic cells from the patient following a leukapheresis procedure. The cells are incubated ex vivo in the presence of a recombinant fusion protein PA2024 containing a prostate antigen, prostate acid phosphatase and GM-CSF, an immune-cell activator. The cells are then returned to the patient to generate an immune response. == References ==	Wikipedia/Dendritic_cells-_based_cancer_vaccines
Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies (such as insect bites) and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergens in an attempt to change the immune system's response. Meta-analyses have found that injections of allergens under the skin are effective in the treatment of allergic rhinitis in children and in asthma. The benefits may last for years after treatment is stopped. It is generally safe and effective for allergic rhinitis, allergic conjunctivitis, allergic forms of asthma, and stinging insects. The evidence also supports the use of sublingual immunotherapy against rhinitis and asthma, but it is less strong. In this form the allergen is given under the tongue and people often prefer it to injections. Immunotherapy is not recommended as a stand-alone treatment for asthma. Side effects during sublingual immunotherapy treatment are usually local and mild and can often be eliminated by adjusting the dosage. Anaphylaxis during sublingual immunotherapy treatment has occurred on rare occasions. Potential side effects related to subcutaneous immunotherapy treatment for asthma and allergic rhinoconjunctivitis include mild or moderate skin or respiratory reactions. Severe side effects such as anaphylaxis during subcutaneous immunotherapy treatment are relatively uncommon. Discovered by Leonard Noon and John Freeman in 1911, allergen immunotherapy is the only medicine known to tackle not only the symptoms but also the causes of respiratory allergies. A detailed diagnosis is necessary to identify the allergens involved. == Methods of desensitization == === Subcutaneous === Subcutaneous immunotherapy (SCIT), also known as allergy shots, is the historical route of administration and consists of injections of allergen extract, which must be performed by a medical professional. Subcutaneous immunotherapy protocols generally involve weekly injections during a build-up phase, followed by a monthly maintenance phase that consists of injections for a period of 3–5 years. The build-up phase involves the patient being administered injections which contain increasing amounts of allergens about one to two times per week. The length of the build-up phase is dependent upon how often injections are administered, but normally ranges from three to six months. After the effective dose is reached, the maintenance phase is implemented, which varies depending upon an individual's response to the build-up phase. SCIT can be used for desensitizations to airborne allergens and insect venoms. Common airborne allergens targeted in SCIT include pollens (of grasses, trees, and weeds), animal danders, molds, and cockroach allergens. Venoms from bees and wasps are often the target of SCIT in patients with severe insect venom allergies. When accounting for a person's age, type of allergen, and severity of allergy, there is a high probability that subcutaneous allergen immunotherapy may provide greater clinical and immunological responses than sublingual allergen immunotherapy. Compared to sublingual allergen immunotherapy, there are no significant differences observed in quality of life. It is possible, but rare (1/2.5 million), that people undergoing subcutaneous allergen immunotherapy may experience a fatal anaphylactic event. Subcutaneous allergen immunotherapy adverse events vary significantly depending on different allergenic extracts and the application of different allergen immunotherapy schedules. Allergen immunotherapy schedules include the "cluster" approach, which involves administering several doses sequentially in a single day; a "conventional" approach, which involves incrementally increasing the dose over approximately 15 weeks; and the "rush" approach, which involves administering incremental doses at intervals of 15–60 minutes over 1–3 days. It is challenging to perform an adequate risk assessment on the use of subcutaneous allergen immunotherapy compared to other forms of allergen immunotherapy administration due to the variability of immunotherapy schedules and further research is required. === Sublingual === Sublingual immunotherapy involves putting drops or a tablet of allergen extracts under the tongue, which are then absorbed through the lining of the mouth. Sublingual immunotherapy has been demonstrated to be effective against rhinoconjunctivitis and asthma symptoms. This effectiveness, however, varies depending on the type of allergen. The strongest evidence for the efficacy of sublingual immunotherapy comes from studies that used grass allergens or mite allergens to alleviate allergic rhinitis symptoms; the evidence shows modest improvement. Sublingual immunotherapy is used to treat allergic rhinitis, often from seasonal allergies, and is typically given in several doses over a 12-week period. It works best when given 12 weeks before the start of the pollen season. The first dose is given by a physician to monitor for any rare reactions or anaphylaxis. Subsequent doses can be taken at home which makes this a convenient alternative to subcutaneous immunotherapy. While a number of side effects have been associated with sublingual immunotherapy, serious adverse effects are very rare (about 1.4/100,000 doses), and there has not been a reported fatality. There have been a small number of reports of anaphylaxis. The majority of side effects are 'local' and usually resolve within a few days. They include swelling of the mouth, tongue or lip, throat irritation, nausea, abdominal pain, vomiting, diarrhea, heartburn, and uvular edema. It is not yet clear if there are any risk factors that might increase a person's susceptibility to these adverse effects. Sublingual immunotherapy appears to be better tolerated than subcutaneous immunotherapy and causes fewer side effects. The safety of sublingual immunotherapy has not been studied extensively in people with chronic immunodeficiency or autoimmune disorders. === Oral === Oral immunotherapy (OIT) involves feeding an allergic individual increasing amounts of a food allergen in order to raise the threshold which triggers a reaction. Long-term, many study participants still experienced mild allergic reactions or needed to regularly consume the allergen to maintain desensitivity. Additionally, oral immunotherapy is known to have an increased risk in the probability of needing epinephrine in patients who take it. Currently, the U.S. Food and Drug Administration has not approved any oral immunotherapy agents for asthma. In January 2020, the FDA approved Palforzia for mitigating "allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanuts." It is the first drug approved for peanut allergies. It will not allow allergic people able to eat normal amounts of peanuts, but helps prevent allergies due to accidental eating. === Intralymphatic === Intralymphatic allergen immunotherapy (ILIT) involves administration of immunotherapy directly into the lymphatic system, which is done by ultrasound guided injections into lymph nodes. Compared to SCIT and SLIT, ILIT is completed faster, over the course of eight weeks, and only involves a total of three injections. This form of immunotherapy is newer than SCIT and SLIT. Despite this, multiple clinical trials and systematic reviews have demonstrated that ILIT is safe and effective in reducing symptoms of allergic rhinitis and medication use. As of January 2025, ILIT is not an FDA-approved method of allergen immunotherapy and is not widely available as a form of allergen immunotherapy. Currently, ILIT is most commonly offered at academic medical centers, such as The Ohio State University Wexner Medical Center and Washington University School of Medicine in St. Louis. === Rapid desensitization === Rapid desensitization, also called acute desensitization, is used to quickly and temporarily induce a state of tolerance to an allergen. This method is most often used for critically ill patients with an allergy to a life-saving medication which there are no feasible alternate agents, most commonly antibiotics, insulin, and chemotherapeutic agents. Small doses of the drug are introduced (either orally or intravenously, depending on the drug) and increased every 20-30 minutes until a therapeutic dose is reached. Patients who undergo acute desensitization commonly experience mild allergic side effects such as itching, hives, and wheezing. Around 10% of patients will experience a moderate to severe allergic reaction during the course of rapid desensitization, and allergic symptoms that occur during the course of desensitization are treated with medication. === Transdermal === Transdermal immunotherapy (TDIT) involves skin-induced suppression via epicutaneous (EC) application of an antigen in order to raise the threshold which triggers a reaction. == Mechanism of action == === SCIT === Subcutaneous allergen immunotherapy involves subcutaneous injections of escalating doses of allergen over time. Allergen immunotherapy improves allergic symptoms via an early and late effects on the immune system. Early effects of allergen immunotherapy primarily involve suppression of mast cells and basophils, which increases the threshold of anaphylaxis. Later effects of allergen immunotherapy aim to induce or restore tolerance to the allergen by changing the antibody response from a largely IgE response to one predominated by an IgG subclass, mostly IgG4. Gradually introducing escalating doses of allergen encourages a tolerance response by the immune system via induction of allergen-specific regulatory T cells (Tregs) that produce IL-10 and/or TGF-beta; this cytokine milieu shifts the antibody response from an IgE-predominant to an IgG4-predominant response. === OIT === Oral immunotherapy also creates an increase in allergen-specific IgG4 antibodies and a decrease in allergen-specific IgE antibodies, as well as diminished mast cells and basophils, two cell types that are large contributors to allergic reaction. === Rapid desensitization === The mechanism of action of acute desensitization is thought to be similar to that of the immune system's early response to SCIT. This procedure is thought to lead to subclinical activation of mast cells and basophils that have been sensitized with IgE against the drug, inducing them to gradually release their intracellular mediators at a rate that does not cause severe symptoms; eventually all of the cell-bound IgE is consumed by this process, leaving insufficient IgE available to cause an allergic reaction when subsequent therapeutic doses are administered. In order to maintain the desensitized state, the patient must have consistent therapeutic levels of the drug. If treatment is interrupted, then newly formed mast cells and basophils can be charged with newly secreted drug-specific IgE and can accumulate at levels sufficient to yield a new anaphylactic reaction. == Protocol == Reactivity is tested using oral food challenges or with skin prick tests. Phases 1 & 2 of sublingual immunotherapy are conducted in a supervised clinical setting. However, phase 3 can be done at home. == History == In the late 19th century and early 20th century, allergic conditions were increasingly attracting both medical attention (as an emerging public health problem) and scientific interest (aided by progress in biochemical techniques and the development of molecular and pathogenic theories). However, the many and varied treatment approaches were very unscientific. The British physicians Noon and Freeman were the first researchers to test pollen allergen immunotherapy in humans. Noon and Freeman, researchers at the Department of Therapeutic Inoculation at St. Mary's Hospital in London, published their findings in The Lancet in 1911. Building on the observations of his predecessors Bostock, Blackley and Dunbar, Noon noted that people with hay fever "sometimes become cured" and that this was possibly because they "have had the good fortune to develop an active immunity against the toxin." He hypothesized that by injecting people with hay fever with small amounts of a pollen "toxin", a state of immunity could be achieved. Allergen immunotherapy was part of mainstream medical practice for hay fever treatment in the 1930s. == Society and culture == Sublingual immunotherapy drops are currently commercialized and used in most European and South American countries, and in Australia and Asian countries. In most European countries, national regulations allow marketing of allergen products as "named patient preparations" (NPPs). In the United States, drop formulations have not yet received FDA approval, though off-label prescription is becoming common. In 2014, the FDA approved a once-daily sublingual tablet containing allergen extracts for the treatment of "hay fever" (allergic rhinitis with or without conjunctivitis). === Recognition by international agencies === The use of subcutaneous immunotherapy for treatment of environmental-based allergies and asthma is well supported by the majority of national and international allergy groups such as the World Allergy Organization, Canadian Society of Allergy and Immunology, European Academy of Allergy and Clinical Immunology, and the American Academy of Allergy, Asthma and Immunology. The use of sublingual immunotherapy is supported by few allergy agencies in order to allow for more investigation to occur on its practical use. Oral immunotherapy is generally not recommended, however the EAACI recommends that this treatment only be administered at specialized centres with expert professionals. Subcutaneous immunotherapy is both approved and regulated by the American Food and Drug Administration (FDA) and the European Medicinal Agency (EMEA). The FDA currently allows individual allergists to create the formula for each dosage, whereas the EMEA requires treatment extracts to be prepared at manufacturing sites. The FDA has approved sublingual therapy through the use of tablets, but has not approved specific formulation. The EMEA has also approved sublingual therapy through both tablets and solution, and this administration now accounts for 45% of immunotherapy treatments. The FDA advisory board has supported the use of AR101, an oral immunotherapy, for patients with peanut allergies in 2019. === Science communication === Allergen immunotherapy is viewed as a beneficial way to curb allergies in the perspective of the media. It is seen where it can be covered by insurance and offer a more permanent solution than antihistamines or nasal steroids that treat symptoms, not the body's reaction. Communication about allergen immunotherapy is not described very often in the news media; it is usually only communicated by the science community. The scientific community describes allergen immunotherapy as a scientific solution that helps not only patients with allergies but also positively impacts the quality of life of them and others around them. As temperatures increase due to changing climates, pollen levels also increase. Allergies are becoming a more common problem among the public, which is why the science community advocates for allergen immunotherapy. Subcutaneous allergen immunotherapy, according to the scientific community, is an effective solution to allergies due to numerous positive studies. == Research == === Oral immunotherapy === As of 2015, oral immunotherapy's balance of risk to benefit for food allergies was not well studied. As of 2011, OIT was under investigation as a treatment for a variety of common food allergies including peanuts, milk, and eggs. Studies involving OIT have shown desensitization towards the allergen. However, there are still questions about longevity of tolerance after the study has ended. However, almost every study has excluded people with severe allergen-induced anaphylaxis. One approach being studied is in altering the protein structure of the allergen to decrease immune response but still induce tolerance. Extensive heating of some foods can change the conformation of epitopes recognized by IgE antibodies. In fact, studies show that regular consumption of heated food allergens can speed up allergy resolution. In one study, subjects allergic to milk were 16x more likely to develop complete milk tolerance compared to complete milk avoidance. Another approach regarding changes in protein is to change specific amino acids in the protein to decrease recognition of the allergen by allergen-specific antibodies. Another approach to improving oral immunotherapy is to change the immune environment to prevent TH2 cells from responding to the allergens during treatment. For example, drugs that inhibit IgE-mediated signaling pathways can be used in addition to OIT to reduce immune response. In 1 trial, the monoclonal antibody omalizumab was combined with high-dose milk oral immunotherapy and saw positive results. Several other trials are also currently being done combining omalizumab with OIT for a variety of food allergens. FAHF-2, a Chinese herbal mixture, has shown positive effects on the immune system and has been shown to protect mice from peanut-induced anaphylaxis. FAHF-2 was also well tolerated in a phase I study. While it is possible that omalizumab, FAHF-2 or other immunomodulatory agents alone might be able to treat dangerous allergies, combining these with OIT may be more effective and synergistic, warranting further investigation. In addition, various adjuvants (nanoparticles) is a field of development that can be used for OIT. With the potential to modulate antigen release, it may one day be possible to take a pill containing nanoparticles that will modulate dosing, requiring fewer office visits. Studies have also been done to determine the efficacy of OIT for multiple allergens simultaneously. One study concluded that multi-OIT would be possible and relatively, though larger studies would be necessary. == References == == External links == "American Academy of Allergy, Asthma, and Immunology" information and articles of interest. "American College of Allergy, Asthma, and Immunology" information and articles of interest. "American Board of Allergy and Immunology" American Board of Allergy and Immunology	Wikipedia/Allergen_immunotherapy
Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies (such as insect bites) and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergens in an attempt to change the immune system's response. Meta-analyses have found that injections of allergens under the skin are effective in the treatment of allergic rhinitis in children and in asthma. The benefits may last for years after treatment is stopped. It is generally safe and effective for allergic rhinitis, allergic conjunctivitis, allergic forms of asthma, and stinging insects. The evidence also supports the use of sublingual immunotherapy against rhinitis and asthma, but it is less strong. In this form the allergen is given under the tongue and people often prefer it to injections. Immunotherapy is not recommended as a stand-alone treatment for asthma. Side effects during sublingual immunotherapy treatment are usually local and mild and can often be eliminated by adjusting the dosage. Anaphylaxis during sublingual immunotherapy treatment has occurred on rare occasions. Potential side effects related to subcutaneous immunotherapy treatment for asthma and allergic rhinoconjunctivitis include mild or moderate skin or respiratory reactions. Severe side effects such as anaphylaxis during subcutaneous immunotherapy treatment are relatively uncommon. Discovered by Leonard Noon and John Freeman in 1911, allergen immunotherapy is the only medicine known to tackle not only the symptoms but also the causes of respiratory allergies. A detailed diagnosis is necessary to identify the allergens involved. == Methods of desensitization == === Subcutaneous === Subcutaneous immunotherapy (SCIT), also known as allergy shots, is the historical route of administration and consists of injections of allergen extract, which must be performed by a medical professional. Subcutaneous immunotherapy protocols generally involve weekly injections during a build-up phase, followed by a monthly maintenance phase that consists of injections for a period of 3–5 years. The build-up phase involves the patient being administered injections which contain increasing amounts of allergens about one to two times per week. The length of the build-up phase is dependent upon how often injections are administered, but normally ranges from three to six months. After the effective dose is reached, the maintenance phase is implemented, which varies depending upon an individual's response to the build-up phase. SCIT can be used for desensitizations to airborne allergens and insect venoms. Common airborne allergens targeted in SCIT include pollens (of grasses, trees, and weeds), animal danders, molds, and cockroach allergens. Venoms from bees and wasps are often the target of SCIT in patients with severe insect venom allergies. When accounting for a person's age, type of allergen, and severity of allergy, there is a high probability that subcutaneous allergen immunotherapy may provide greater clinical and immunological responses than sublingual allergen immunotherapy. Compared to sublingual allergen immunotherapy, there are no significant differences observed in quality of life. It is possible, but rare (1/2.5 million), that people undergoing subcutaneous allergen immunotherapy may experience a fatal anaphylactic event. Subcutaneous allergen immunotherapy adverse events vary significantly depending on different allergenic extracts and the application of different allergen immunotherapy schedules. Allergen immunotherapy schedules include the "cluster" approach, which involves administering several doses sequentially in a single day; a "conventional" approach, which involves incrementally increasing the dose over approximately 15 weeks; and the "rush" approach, which involves administering incremental doses at intervals of 15–60 minutes over 1–3 days. It is challenging to perform an adequate risk assessment on the use of subcutaneous allergen immunotherapy compared to other forms of allergen immunotherapy administration due to the variability of immunotherapy schedules and further research is required. === Sublingual === Sublingual immunotherapy involves putting drops or a tablet of allergen extracts under the tongue, which are then absorbed through the lining of the mouth. Sublingual immunotherapy has been demonstrated to be effective against rhinoconjunctivitis and asthma symptoms. This effectiveness, however, varies depending on the type of allergen. The strongest evidence for the efficacy of sublingual immunotherapy comes from studies that used grass allergens or mite allergens to alleviate allergic rhinitis symptoms; the evidence shows modest improvement. Sublingual immunotherapy is used to treat allergic rhinitis, often from seasonal allergies, and is typically given in several doses over a 12-week period. It works best when given 12 weeks before the start of the pollen season. The first dose is given by a physician to monitor for any rare reactions or anaphylaxis. Subsequent doses can be taken at home which makes this a convenient alternative to subcutaneous immunotherapy. While a number of side effects have been associated with sublingual immunotherapy, serious adverse effects are very rare (about 1.4/100,000 doses), and there has not been a reported fatality. There have been a small number of reports of anaphylaxis. The majority of side effects are 'local' and usually resolve within a few days. They include swelling of the mouth, tongue or lip, throat irritation, nausea, abdominal pain, vomiting, diarrhea, heartburn, and uvular edema. It is not yet clear if there are any risk factors that might increase a person's susceptibility to these adverse effects. Sublingual immunotherapy appears to be better tolerated than subcutaneous immunotherapy and causes fewer side effects. The safety of sublingual immunotherapy has not been studied extensively in people with chronic immunodeficiency or autoimmune disorders. === Oral === Oral immunotherapy (OIT) involves feeding an allergic individual increasing amounts of a food allergen in order to raise the threshold which triggers a reaction. Long-term, many study participants still experienced mild allergic reactions or needed to regularly consume the allergen to maintain desensitivity. Additionally, oral immunotherapy is known to have an increased risk in the probability of needing epinephrine in patients who take it. Currently, the U.S. Food and Drug Administration has not approved any oral immunotherapy agents for asthma. In January 2020, the FDA approved Palforzia for mitigating "allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanuts." It is the first drug approved for peanut allergies. It will not allow allergic people able to eat normal amounts of peanuts, but helps prevent allergies due to accidental eating. === Intralymphatic === Intralymphatic allergen immunotherapy (ILIT) involves administration of immunotherapy directly into the lymphatic system, which is done by ultrasound guided injections into lymph nodes. Compared to SCIT and SLIT, ILIT is completed faster, over the course of eight weeks, and only involves a total of three injections. This form of immunotherapy is newer than SCIT and SLIT. Despite this, multiple clinical trials and systematic reviews have demonstrated that ILIT is safe and effective in reducing symptoms of allergic rhinitis and medication use. As of January 2025, ILIT is not an FDA-approved method of allergen immunotherapy and is not widely available as a form of allergen immunotherapy. Currently, ILIT is most commonly offered at academic medical centers, such as The Ohio State University Wexner Medical Center and Washington University School of Medicine in St. Louis. === Rapid desensitization === Rapid desensitization, also called acute desensitization, is used to quickly and temporarily induce a state of tolerance to an allergen. This method is most often used for critically ill patients with an allergy to a life-saving medication which there are no feasible alternate agents, most commonly antibiotics, insulin, and chemotherapeutic agents. Small doses of the drug are introduced (either orally or intravenously, depending on the drug) and increased every 20-30 minutes until a therapeutic dose is reached. Patients who undergo acute desensitization commonly experience mild allergic side effects such as itching, hives, and wheezing. Around 10% of patients will experience a moderate to severe allergic reaction during the course of rapid desensitization, and allergic symptoms that occur during the course of desensitization are treated with medication. === Transdermal === Transdermal immunotherapy (TDIT) involves skin-induced suppression via epicutaneous (EC) application of an antigen in order to raise the threshold which triggers a reaction. == Mechanism of action == === SCIT === Subcutaneous allergen immunotherapy involves subcutaneous injections of escalating doses of allergen over time. Allergen immunotherapy improves allergic symptoms via an early and late effects on the immune system. Early effects of allergen immunotherapy primarily involve suppression of mast cells and basophils, which increases the threshold of anaphylaxis. Later effects of allergen immunotherapy aim to induce or restore tolerance to the allergen by changing the antibody response from a largely IgE response to one predominated by an IgG subclass, mostly IgG4. Gradually introducing escalating doses of allergen encourages a tolerance response by the immune system via induction of allergen-specific regulatory T cells (Tregs) that produce IL-10 and/or TGF-beta; this cytokine milieu shifts the antibody response from an IgE-predominant to an IgG4-predominant response. === OIT === Oral immunotherapy also creates an increase in allergen-specific IgG4 antibodies and a decrease in allergen-specific IgE antibodies, as well as diminished mast cells and basophils, two cell types that are large contributors to allergic reaction. === Rapid desensitization === The mechanism of action of acute desensitization is thought to be similar to that of the immune system's early response to SCIT. This procedure is thought to lead to subclinical activation of mast cells and basophils that have been sensitized with IgE against the drug, inducing them to gradually release their intracellular mediators at a rate that does not cause severe symptoms; eventually all of the cell-bound IgE is consumed by this process, leaving insufficient IgE available to cause an allergic reaction when subsequent therapeutic doses are administered. In order to maintain the desensitized state, the patient must have consistent therapeutic levels of the drug. If treatment is interrupted, then newly formed mast cells and basophils can be charged with newly secreted drug-specific IgE and can accumulate at levels sufficient to yield a new anaphylactic reaction. == Protocol == Reactivity is tested using oral food challenges or with skin prick tests. Phases 1 & 2 of sublingual immunotherapy are conducted in a supervised clinical setting. However, phase 3 can be done at home. == History == In the late 19th century and early 20th century, allergic conditions were increasingly attracting both medical attention (as an emerging public health problem) and scientific interest (aided by progress in biochemical techniques and the development of molecular and pathogenic theories). However, the many and varied treatment approaches were very unscientific. The British physicians Noon and Freeman were the first researchers to test pollen allergen immunotherapy in humans. Noon and Freeman, researchers at the Department of Therapeutic Inoculation at St. Mary's Hospital in London, published their findings in The Lancet in 1911. Building on the observations of his predecessors Bostock, Blackley and Dunbar, Noon noted that people with hay fever "sometimes become cured" and that this was possibly because they "have had the good fortune to develop an active immunity against the toxin." He hypothesized that by injecting people with hay fever with small amounts of a pollen "toxin", a state of immunity could be achieved. Allergen immunotherapy was part of mainstream medical practice for hay fever treatment in the 1930s. == Society and culture == Sublingual immunotherapy drops are currently commercialized and used in most European and South American countries, and in Australia and Asian countries. In most European countries, national regulations allow marketing of allergen products as "named patient preparations" (NPPs). In the United States, drop formulations have not yet received FDA approval, though off-label prescription is becoming common. In 2014, the FDA approved a once-daily sublingual tablet containing allergen extracts for the treatment of "hay fever" (allergic rhinitis with or without conjunctivitis). === Recognition by international agencies === The use of subcutaneous immunotherapy for treatment of environmental-based allergies and asthma is well supported by the majority of national and international allergy groups such as the World Allergy Organization, Canadian Society of Allergy and Immunology, European Academy of Allergy and Clinical Immunology, and the American Academy of Allergy, Asthma and Immunology. The use of sublingual immunotherapy is supported by few allergy agencies in order to allow for more investigation to occur on its practical use. Oral immunotherapy is generally not recommended, however the EAACI recommends that this treatment only be administered at specialized centres with expert professionals. Subcutaneous immunotherapy is both approved and regulated by the American Food and Drug Administration (FDA) and the European Medicinal Agency (EMEA). The FDA currently allows individual allergists to create the formula for each dosage, whereas the EMEA requires treatment extracts to be prepared at manufacturing sites. The FDA has approved sublingual therapy through the use of tablets, but has not approved specific formulation. The EMEA has also approved sublingual therapy through both tablets and solution, and this administration now accounts for 45% of immunotherapy treatments. The FDA advisory board has supported the use of AR101, an oral immunotherapy, for patients with peanut allergies in 2019. === Science communication === Allergen immunotherapy is viewed as a beneficial way to curb allergies in the perspective of the media. It is seen where it can be covered by insurance and offer a more permanent solution than antihistamines or nasal steroids that treat symptoms, not the body's reaction. Communication about allergen immunotherapy is not described very often in the news media; it is usually only communicated by the science community. The scientific community describes allergen immunotherapy as a scientific solution that helps not only patients with allergies but also positively impacts the quality of life of them and others around them. As temperatures increase due to changing climates, pollen levels also increase. Allergies are becoming a more common problem among the public, which is why the science community advocates for allergen immunotherapy. Subcutaneous allergen immunotherapy, according to the scientific community, is an effective solution to allergies due to numerous positive studies. == Research == === Oral immunotherapy === As of 2015, oral immunotherapy's balance of risk to benefit for food allergies was not well studied. As of 2011, OIT was under investigation as a treatment for a variety of common food allergies including peanuts, milk, and eggs. Studies involving OIT have shown desensitization towards the allergen. However, there are still questions about longevity of tolerance after the study has ended. However, almost every study has excluded people with severe allergen-induced anaphylaxis. One approach being studied is in altering the protein structure of the allergen to decrease immune response but still induce tolerance. Extensive heating of some foods can change the conformation of epitopes recognized by IgE antibodies. In fact, studies show that regular consumption of heated food allergens can speed up allergy resolution. In one study, subjects allergic to milk were 16x more likely to develop complete milk tolerance compared to complete milk avoidance. Another approach regarding changes in protein is to change specific amino acids in the protein to decrease recognition of the allergen by allergen-specific antibodies. Another approach to improving oral immunotherapy is to change the immune environment to prevent TH2 cells from responding to the allergens during treatment. For example, drugs that inhibit IgE-mediated signaling pathways can be used in addition to OIT to reduce immune response. In 1 trial, the monoclonal antibody omalizumab was combined with high-dose milk oral immunotherapy and saw positive results. Several other trials are also currently being done combining omalizumab with OIT for a variety of food allergens. FAHF-2, a Chinese herbal mixture, has shown positive effects on the immune system and has been shown to protect mice from peanut-induced anaphylaxis. FAHF-2 was also well tolerated in a phase I study. While it is possible that omalizumab, FAHF-2 or other immunomodulatory agents alone might be able to treat dangerous allergies, combining these with OIT may be more effective and synergistic, warranting further investigation. In addition, various adjuvants (nanoparticles) is a field of development that can be used for OIT. With the potential to modulate antigen release, it may one day be possible to take a pill containing nanoparticles that will modulate dosing, requiring fewer office visits. Studies have also been done to determine the efficacy of OIT for multiple allergens simultaneously. One study concluded that multi-OIT would be possible and relatively, though larger studies would be necessary. == References == == External links == "American Academy of Allergy, Asthma, and Immunology" information and articles of interest. "American College of Allergy, Asthma, and Immunology" information and articles of interest. "American Board of Allergy and Immunology" American Board of Allergy and Immunology	Wikipedia/Oral_immunotherapy
Interleukin-2 (IL-2) is an interleukin, which is a type of cytokine signaling molecule forming part of the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection, and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes. The major sources of IL-2 are activated CD4+ T cells and activated CD8+ T cells. Put shortly the function of IL-2 is to stimulate the growth of helper, cytotoxic and regulatory T cells. == IL-2 receptor == IL-2 is a member of a specific family of cytokines, each member of which has a four alpha helix bundle; this cytokine family also includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through a IL-2 receptor, a complex consisting of three chains, termed alpha (CD25), beta (CD122) and gamma (CD132). The gamma chain is common to all family members. The IL-2 receptor (IL-2R) α subunit binds IL-2 with low affinity (Kd~ 10−8 M). Interaction of IL-2 and CD25 alone does not lead to signal transduction due to its short intracellular chain but has the ability (when bound to the β and γ subunit) to increase the IL-2R affinity 100-fold. Heterodimerization of the β and γ subunits of IL-2R is essential for signalling in T cells. IL-2 can signalize either via intermediate-affinity dimeric CD122/CD132 IL-2R (Kd~ 10−9 M) or high-affinity trimeric CD25/CD122/CD132 IL-2R (Kd~ 10−11 M). Dimeric IL-2R is expressed by memory CD8+ T cells and NK cells, whereas regulatory T cells and activated T cells express high levels of trimeric IL-2R. == IL-2 signaling pathways and regulation == Instructions to express proteins in response to an IL-2 signal (called IL-2 transduction) can take place via 3 different signaling pathways; they are: (1) the JAK-STAT pathway, (2) the PI3K/Akt/mTOR pathway and (3) the MAPK/ERK pathway. The signalling is commenced by IL-2 binding to its receptor, following which cytoplasmatic domains of CD122 and CD132 heterodimerize. This leads to the activation of Janus kinases JAK1 and JAK3 which subsequently phosphorylate T338 on CD122. This phosphorylation recruits STAT transcription factors, predominantly STAT5, which dimerize and migrate to the cell nucleus where they bind to DNA. with an "express other proteins" signal. The proteins expressed by means of the three pathways include bcl-6 (the PI3K/Akt/mTOR pathway), CD25 & prdm-1 (the JAK-STAT pathway) and certain cyclins (the MAPK/ERK pathway). Gene expression regulation for IL-2 can be on multiple levels or by different ways. One of the checkpoints (in other words one of the things which needs to be done before IL-2 is expressed) is that there must be signaling through a conjunction of a T Cell Receptor (a TCR) and an HLA-peptide complex. As a result of that conjunction a signalling pathway (signalling a cell's protein making machinery to express or 'make' IL-2), a PhosphoLipase-C (PLC) dependent pathway, is set up. PLC activates 3 major transcription factors and their pathways: NFAT, NFkB and AP-1. In addition and after costimulation from CD28 the optimal activation of expression of IL-2 and these pathways is induced. In summary therefore before a cell will make IL-2 in accordance with this pathway there have to be two reactions: TCR+HLA and protein complex on the one hand and CD28 costimulation on the other indeed mere IL-2 ligation to its receptor is too low affinity to enable pathway. At the same time Oct-1 is expressed. It helps the activation. Oct1 is expressed in T-lymphocytes and Oct2 is induced after cell activation. NFAT has multiple family members, all of them are located in cytoplasm and signaling goes through calcineurin, NFAT is dephosphorylated and therefore translocated to the nucleus. AP-1 is a dimer and is composed of c-Jun and c-Fos proteins. It cooperates with other transcription factors including NFkB and Oct. NFkB is translocated to the nucleus after costimulation through CD28. NFkB is a heterodimer and there are two binding sites on the IL-2 promoter. == Function == IL-2 has essential roles in key functions of the immune system, tolerance and immunity, primarily via its direct effects on T cells. In the thymus, where T cells mature, it prevents autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells, which suppress other T cells that are otherwise primed to attack normal healthy cells in the body. IL-2 enhances activation-induced cell death (AICD). IL-2 also promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cell is also stimulated by an antigen, thus helping the body fight off infections. Together with other polarizing cytokines, IL-2 stimulates naive CD4+ T cell differentiation into Th1 and Th2 lymphocytes while it impedes differentiation into Th17 and folicular Th lymphocytes. IL-2 increases the cell killing activity of both natural killer cells and cytotoxic T cells. Its expression and secretion is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting and dampening immune responses. Through its role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, it plays a key role in enduring cell-mediated immunity. == Evolution == IL-2 has been discovered in all classes of jawed vertebrates, including sharks, at a similar genomic location. In fish, IL-2 shares a single receptor alpha chain with its related cytokines IL-15 and IL-15-like (IL-15L). This "IL-15Rα" receptor chain is similar to mammalian IL-15Rα, and in tetrapod evolution a duplication of its coding gene plus further diversification created mammalian IL-2Rα. Sequences, and structural analysis of grass carp IL-2, suggest that fish IL-2 binds IL-15Rα in a manner reminiscent of how mammalian IL-15 binds to IL-15Rα. Despite fish IL-2 and IL-15 sharing the same IL-15Rα chain, the stability of fish IL-2 is independent of it whereas IL-15 and especially IL-15L depend on binding to (co-presentation with) IL-15Rα for their stability and function. This suggests that, like in mammals, fish IL-2, in contrast to fish IL-15 and IL-15L, is not relying on "in trans" presentation by its receptor alpha chain. As a free cytokine, mammalian IL-2 that is secreted by activated T cells is important for a negative feedback loop by the stimulation of regulatory T cells, the latter being the cells with the highest constitutive IL-2Rα (aka CD25) expression. Besides this negative feedback loop, mammalian IL-2 also participates in a positive feedback loop because activated T cells enhance their own IL-2Rα expression. As in mammals, fish IL-2 also stimulates T cell proliferation and appears to preferentially stimulate regulatory T cells. Fish IL-2 induces the expression of cytokines of both type 1 (Th1) and type 2 (Th2) immunity. As has been found in some studies on mammalian IL-2, data suggest that fish IL-2 can form homodimers and that this is an ancient property of the IL-2/15/15L-family cytokines. Homologues of IL-2 have not been reported for jawless fish (hagfish and lamprey) or invertebrates. == Role in disease == While the causes of itchiness are poorly understood, some evidence indicates that IL-2 is involved in itchy psoriasis. == Medical use == === Pharmaceutical analogues === Aldesleukin is a form of recombinant interleukin-2. It is manufactured using recombinant DNA technology and is marketed as a protein therapeutic and branded as Proleukin. It has been approved by the Food and Drug Administration (FDA) with a black box warning and in several European countries for the treatment of cancers (malignant melanoma, renal cell cancer) in large intermittent doses and has been extensively used in continuous doses. Interking is a recombinant IL-2 with a serine at residue 125, sold by Shenzhen Neptunus. Neoleukin 2/15 is a computationally designed mimic of IL-2 that was designed to avoid common side effects. However, clinical trials into this candidate were discontinued. ==== Dosage ==== Various dosages of IL-2 across the United States and across the world are used. The efficacy and side effects of different dosages is often a point of disagreement. The commercial interest in local IL-2 therapy has been very low. Because only a very low dose IL-2 is used, treatment of a patient would cost about $500 commercial value of the patented IL-2. The commercial return on investment is too low to stimulate additional clinical studies for the registration of intratumoral IL-2 therapy. ===== United States ===== Usually, in the U.S., the higher dosage option is used, affected by cancer type, response to treatment and general patient health. Patients are typically treated for five consecutive days, three times a day, for fifteen minutes. The following approximately 10 days help the patient to recover between treatments. IL-2 is delivered intravenously on an inpatient basis to enable proper monitoring of side effects. A lower dose regimen involves injection of IL-2 under the skin typically on an outpatient basis. It may alternatively be given on an inpatient basis over 1–3 days, similar to and often including the delivery of chemotherapy. Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate. ==== Local application ==== In preclinical and early clinical studies, local application of IL-2 in the tumor has been shown to be clinically more effective in anticancer therapy than systemic IL-2 therapy, over a broad range of doses, without serious side effects. Tumour blood vessels are more vulnerable than normal blood vessels to the actions of IL-2. When injected inside a tumor, i.e. local application, a process mechanistically similar to the vascular leakage syndrome, occurs in tumor tissue only. Disruption of the blood flow inside of the tumor effectively destroys tumor tissue. In local application, the systemic dose of IL-2 is too low to cause side effects, since the total dose is about 100 to 1000 fold lower. Clinical studies showed painful injections at the site of radiation as the most important side effect, reported by patients. In the case of irradiation of nasopharyngeal carcinoma the five-year disease-free survival increased from 8% to 63% by local IL-2 therapy ==== Toxicity ==== Systemic IL-2 has a narrow therapeutic window, and the level of dosing usually determines the severity of the side effects. In the case of local IL-2 application, the therapeutic window spans several orders of magnitude. Some common side effects: flu-like symptoms (fever, headache, muscle and joint pain, fatigue) nausea/vomiting dry, itchy skin or rash weakness or shortness of breath diarrhea low blood pressure drowsiness or confusion loss of appetite More serious and dangerous side effects sometimes are seen, such as breathing problems, serious infections, seizures, allergic reactions, heart problems, kidney failure or a variety of other possible complications. The most common adverse effect of high-dose IL-2 therapy is vascular leak syndrome (VLS; also termed capillary leak syndrome). It is caused by lung endothelial cells expressing high-affinity IL-2R. These cells, as a result of IL-2 binding, causes increased vascular permeability. Thus, intravascular fluid extravasate into organs, predominantly lungs, which leads to life-threatening pulmonary or brain oedema. Other drawbacks of IL-2 cancer immunotherapy are its short half-life in circulation and its ability to predominantly expand regulatory T cells at high doses. Intralesional IL-2 used to treat in-transit melanoma metastases is generally well tolerated. This is also the case for intralesional IL-2 in other forms of cancer, like nasopharyngeal carcinoma. === Pharmaceutical derivative === Eisai markets a drug called denileukin diftitox (trade name Ontak), which is a recombinant fusion protein of the human IL-2 ligand and the diphtheria toxin. This drug binds to IL-2 receptors and introduces the diphtheria toxin into cells that express those receptors, killing the cells. In some leukemias and lymphomas, malignant cells express the IL-2 receptor, so denileukin diftitox can kill them. In 1999 Ontak was approved by the U.S. Food and Drug Administration (FDA) for treatment of cutaneous T cell lymphoma (CTCL). == Preclinical research == IL-2 does not follow the classical dose-response curve of chemotherapeutics. The immunological activity of high and low dose IL-2 show sharp contrast. This might be related to different distribution of IL-2 receptors (CD25, CD122, CD132) on different cell populations, resulting in different cells that are activated by high and low dose IL-2. In general high doses are immune suppressive, while low doses can stimulate type 1 immunity. Low-dose IL-2 has been reported to reduce hepatitis C and B infection. IL-2 has been used in clinical trials for the treatment of chronic viral infections and as a booster (adjuvant) for vaccines. The use of large doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, was found to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials published in 2009. More recently low dose IL-2 has shown early success in modulating the immune system in disease like type 1 diabetes and vasculitis. There are also promising studies looking to use low dose IL-2 in ischaemic heart disease. === IL-2/anti-IL-2 mAb immune complexes (IL-2 ic) === IL-2 cannot accomplish its role as a promising immunotherapeutic agent due to significant drawbacks which are listed above. Some of the issues can be overcome using IL-2 ic. They are composed of IL-2 and some of its monoclonal antibody (mAb) and can potentiate biologic activity of IL-2 in vivo. The main mechanism of this phenomenon in vivo is due to the prolongation of the cytokine half-life in circulation. Depending on the clone of IL-2 mAb, IL-2 ic can selectively stimulate either CD25high (IL-2/JES6-1 complexes), or CD122high cells (IL-2/S4B6). IL-2/S4B6 immune complexes have high stimulatory activity for NK cells and memory CD8+ T cells and they could thus replace the conventional IL-2 in cancer immunotherapy. On the other hand, IL-2/JES6-1 highly selectively stimulate regulatory T cells and they could be potentially useful for transplantations and in treatment of autoimmune diseases. == History == According to an immunology textbook: "IL-2 is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to the growth factors being studied by endocrinologists and biochemists".: 712 In the mid-1960s, studies reported "activities" in leukocyte-conditioned media that promoted lymphocyte proliferation.: 16 In the mid-1970s, it was discovered that T-cells could be selectively proliferated when normal human bone marrow cells were cultured in conditioned medium obtained from phytohemagglutinin-stimulated normal human lymphocytes.: 712 The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980. The gene for human IL-2 was cloned in 1982 after an intense competition.: 76 Commercial activity to bring an IL-2 drug to market was intense in the 1980s and 1990s. By 1983, Cetus Corporation had created a proprietary recombinant version of IL-2 (Aldesleukin, later branded as Proleukin), with the alanine removed from its N-terminal and residue 125 replaced with serine.: 76–77 : 201 Amgen later entered the field with its own proprietary, mutated, recombinant protein and Cetus and Amgen were soon competing scientifically and in the courts; Cetus won the legal battles and forced Amgen out of the field.: 151 By 1990 Cetus had gotten aldesleukin approved in nine European countries but in that year, the U.S. Food and Drug Administration (FDA) refused to approve Cetus' application to market IL-2. The failure led to the collapse of Cetus, and in 1991 the company was sold to Chiron Corporation. Chiron continued the development of IL-2, which was finally approved by the FDA as Proleukin for metastatic renal carcinoma in 1992. By 1993 aldesleukin was the only approved version of IL-2, but Roche was also developing a proprietary, modified, recombinant IL-2 called teceleukin, with a methionine added at is N-terminal, and Glaxo was developing a version called bioleukin, with a methionine added at is N-terminal and residue 125 replaced with alanine. Dozens of clinical trials had been conducted of recombinant or purified IL-2, alone, in combination with other drugs, or using cell therapies, in which cells were taken from patients, activated with IL-2, then reinfused. Novartis acquired Chiron in 2006 and licensed the US aldesleukin business to Prometheus Laboratories in 2010 before global rights to Proleukin were subsequently acquired by Clinigen in 2018 and 2019. == References == == External links == Proleukin website IL-2 Signaling Pathway Archived 2020-01-11 at the Wayback Machine Rosenberg SA (June 2014). "IL-2: the first effective immunotherapy for human cancer". Journal of Immunology. 192 (12): 5451–8. doi:10.4049/jimmunol.1490019. PMC 6293462. PMID 24907378. Overview of all the structural information available in the PDB for UniProt: P60568 (Interleukin-2) at the PDBe-KB.	Wikipedia/Interleukin-2_immunotherapy
Autologous immune enhancement therapy (AIET) is a treatment method in which immune cells are taken out from the patient's body which are cultured and processed to activate them until their resistance to cancer is strengthened and then the cells are put back in the body. The cells, antibodies, and organs of the immune system work to protect and defend the body against not only tumor cells but also bacteria or viruses. Cell division in any living organism is an integral part of life, as worn out cells have to be replaced by newly generated cells. This process of generating new cells varies between organs and the mechanisms involved are highly complex which include the nature and capability of the underlying stem cells, their environment, metabolism, physical and allied biological factors the organ or tissue is subjected to etc., Aberrant cell division takes place that ends up in a cancer cell and such aberrance may be due to faulty stem cell, abnormal genetic components or any other factor such as radiation or a constant irritation. Cancer is still a leading cause of death in the world yet much is still not known about its mechanisms of establishment and destruction. While surgery and/or chemo- and radiotherapies are various treatment modalities available, still in many cases they don't offer a permanent cure. Another major point to be addressed about this killer disease is the relapse rate which is very high. Researchers have found that these cells mainly target the cancer cells and not the healthy cells whereas in chemotherapy and radiotherapy the healthy cells are also getting destroyed. == Mechanism of action == Cancer cells are formed in our body almost every day but we are not affected by them. This is because they are immediately destroyed by the body's immune system. The immune system is a complex network of cells and organs comprising lymphocytes, macrophages, Dendritic cells, Natural Killer cells (NK Cell), Cytotoxic T Lymphocytes (CTL), etc., that work together to defend the body against attacks by "foreign" or "non-self" invaders including cancer cells. Immediately after a cancer cell is recognized, the Lymphocytes and/or the NK cells attack the cancer cell to kill it. When the immune system is weaker then cancer evolves as a disease and starts growing. Each type of cancer needs a specific combination of treatments aimed at that particular kind of cancer. When the extent of spread of cancer is deep, total removal of the cancer growth by surgery may not be possible. At times, after surgical removal of a part of the cancer, radiotherapy and/or chemotherapy may be necessary to treat the remnant portion of cancer. It is widely known that Chemotherapy has profound toxic side effects and has limitations in efficacy. Radiotherapy is also a very effective mode of treatment in certain types of cancer, but it has its own adverse effects as well. These two modalities affect not only the cancer affected cells, but also the normal cells Now in AIET, specific types of cells mainly the NK cells and T lymphocytes are isolated from the peripheral blood of the cancer patients (during remission in patients who undergo chemotherapy) by proven methods, expanded to 25–30 fold and activated and then reinfused back into the patient's body. These cells act against the cancer cells effectively and recharge the immune system. Upon encountering a tumor cell, the activated NK cell attaches to the membrane of the cancer cell and injects toxic granules which dissolve the target cell. In less than five minutes, the cancer cell dies and the NK cell moves on to its next target cancer cell. A single NK cell can destroy up to 27 cancer cells within its lifespan. This is the mechanism by which AIET is effective in cancer therapy. == History == Adoptive Immuno cell therapy of cancer was first introduced by Steven Rosenberg and his colleagues of National Institute of Health USA. In the late 80s, they published an article in which they reported a low tumor regression rate (2.6–3.3%) in 1205 patients with metastatic cancer who underwent different types of active specific immunotherapy (ASI), and they suggest that AIET with specific chemotherapy or radiotherapy as the future of cancer immunotherapy. In the beginning Immunotherapy treatments involved administration of cytokines such as Interleukin. with an aim of inducing the lymphocytes which will carry their activity of destroying the tumour cells. Thereafter the adverse effects of such intravenously administered cytokines lead to the extraction of the lymphocytes from the blood and culture-expand them in the lab and then to inject the cells alone enable them destroy the cancer cells. Till date different kinds of autologous and allogenic immune cells such as lymphokine-activated killer(LAK)cells, Natural killer (NK) cells, Activated Cytotoxic T lymphocytes(CTLs), Dendritic cells(DCs), Gene manipulated autologous and allogenic Immune cells have been used in clinical applications of Immunotherapy. The present technology of AIET was developed by Japanese scientists and it is being widely practised in several Asian countries which uses autologous natural killer (NK) cells and activated T lymphocytes to treat various cancers. This treatment modality has been in practice since early 90s and has several random clinical trials in lung cancer, gastric cancer, Ovarian cancer and Liver cancer. which has been published with significant disease free survival rates. One of the largest studies in 1400 patients. has proven that the cell based immunotherapy when combined with conventional treatment the efficacy improves by 20–30%. A recent finding published about a relapsed stage IV ovarian cancer treated successfully with this methodology has found its place in the Global medical discovery. == Status of immunotherapy worldwide == Though the concept of this treatment started in the US in 1980s, full-fledged clinical treatments on a routine basis have been in practice in Japan since 1990. Randomized controlled studies in different cancers with significant increase in survival and disease free period have been reported. In India immunotherapy has shown positive results in patients with advanced cancer including acute myeloid leukaemia, pancreatic cancer, cervical cancer, ovarian cancer, Breast Cancer and Philadelphia chromosome Positive Acute Lymphoblastic Leukemia. == Relevance to Auto-Immune Diseases == Auto-Immune diseases like the Auto-Immune Hemolytic Anemia (AIHA) have been known to be associated with malignancies. In general lower Natural Killer (NK) profile has been associated with development of cancers by earlier studies. Recently an article has been published in which it has been described that the in vitro expansion of NK cells is decreased in cancer patients who have concomitant Auto-immune Diseases like the AIHA. This study also throws questions on whether AIHA is a complication of malignancies, due to the lower NK cell profile in cancer which would have given rise to the AIHA due to some common antibody between NK cells and Red Blood Cells (RBCs) or whether the AIHA lowers the NK cell profile which in turn causes the cancer. This warrants further investigations into the identification of common antibodies between NK cells & RBCs and also finding new Immuno- therapeutic strategies which can tackle both cancer and auto-immunity == References == == External links == AIET in NCRM Immunotherapy in Malaysia AIET experience by Nilai Cancer Centre, Malaysia A patient blog: AIET help cure sarcoma, NISCELL, Malaysia experience Press release on Advanced Ovarian Cancer treated with AIET Personal opinion of a patient who underwent autologous immune enhancement therapy, NISCELL, Malaysia Autologous Immune Enhancement Therapy – a brief explanation A review on sources of NK cells, the methods for their in vitro expansion and their potential in treating cancer & viral infections Immune Cell Therapy Program takes shape in Vietnam through Indo-Japan Collaboration Archived 24 January 2018 at the Wayback Machine	Wikipedia/Autologous_immune_enhancement_therapy
Cereblon E3 ligase modulators, also known as immunomodulatory imide drugs (IMiDs), are a class of immunomodulatory drugs (drugs that adjust immune responses) containing an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, mezigdomide and iberdomide). These drugs may also be referred to as 'Cereblon modulators'. Cereblon (CRBN) is the protein targeted by this class of drugs. The name "IMiD" alludes to both "IMD" for "immunomodulatory drug" and the forms imide, imido-, imid-, and imid. The development of analogs of thalidomide was precipitated by the discovery of the anti-angiogenic and anti-inflammatory properties of the drug yielding a new way of fighting cancer as well as some inflammatory diseases after it had been banned in 1961. The problems with thalidomide included teratogenic side effects, high incidence of other adverse reactions, poor solubility in water and poor absorption from the intestines. In 1998 thalidomide was approved by the U.S. Food and Drug Administration (FDA) for use in newly diagnosed multiple myeloma (MM) under strict regulations. This has led to the development of a number of analogs with fewer side effects and increased potency which include lenalidomide and pomalidomide, which are currently marketed and manufactured by Celgene. == History == Thalidomide was originally released in the Federal Republic of Germany (West Germany) under the label of Contergan on October 1, 1957, by Chemie Grünenthal (now Grünenthal). The drug was primarily prescribed as a sedative or hypnotic, but it was also used as an antiemetic for morning sickness in pregnant women. The drug was banned in 1961 after its teratogenic properties were observed. The problems with thalidomide were, aside from the teratogenic side effects, both high incidence of other adverse reactions along with poor solubility in water and absorption from the intestines. Adverse reactions include peripheral neuropathy in large majority of patients, constipation, thromboembolism along with dermatological complications. Four years after thalidomide was withdrawn from the market for its ability to induce severe birth defects, its anti-inflammatory properties were discovered when patients with erythema nodosum leprosum (ENL) used thalidomide as a sedative and it reduced both the clinical signs and symptoms of the disease. Thalidomide was discovered to inhibit tumour necrosis factor-alpha (TNF-α) in 1991 (5a Sampaio, Sarno, Galilly Cohn and Kaplan, JEM 173 (3) 699–703, 1991) . TNF-α is a cytokine produced by macrophages of the immune system, and also a mediator of inflammatory response. Thus the drug is effective against some inflammatory diseases such as ENL (6a Sampaio, Kaplan, Miranda, Nery..... JID 168 (2) 408-414 2008). In 1994 Thalidomide was found to have anti-angiogenic activity and anti-tumor activity which propelled the initiation of clinical trials for cancer including multiple myeloma. The discovery of the anti-inflammatory, anti-angiogenic and anti-tumor activities of thalidomide increased the interest of further research and synthesis of safer analogs. Lenalidomide is the first analog of thalidomide which is marketed. It is considerably more potent than its parent drug with only two differences at a molecular level, with an added amino group at position 4 of the phthaloyl ring and removal of a carbonyl group from the phthaloyl ring. Development of lenalidomide began in the late 1990s and clinical trials of lenalidomide began in 2000. In October 2001 lenalidomide was granted orphan status for the treatment of MM. In mid-2002 it entered phase II and by early 2003 phase III. In February 2003 FDA granted fast-track status to lenalidomide for the treatment of relapsed or refractory MM. In 2006 it was approved for the treatment of MM along with dexamethasone and in 2007 by European Medicines Agency (EMA). In 2008, phase II trial observed efficacy in treating Non-Hodgkin's lymphoma. Pomalidomide (3-aminothalidomide) was the second thalidomide analog to enter the clinic being more potent than both of its predecessors. First reported in 2001, pomalidomide was noted to directly inhibit myeloma cell proliferation and thus inhibiting MM both on the tumor and vascular compartments. This dual activity of pomalidomide makes it more efficacious than thalidomide both in vitro and in vivo. This effect is not related to TNF-α inhibition since potent TNF-α inhibitors such as rolipram and pentoxifylline did not inhibit myeloma cell growth nor angiogenesis. Upregulation of interferon gamma, IL-2 and IL-10 have been reported for pomalidomide and may contribute to its anti-angiogenic and anti-myeloma activities. == Development == The thalidomide molecule is a synthetic derivative of glutamic acid and consists of a glutarimide ring and a phthaloyl ring (Figure 5). Its IUPAC name is 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione and it has one chiral center After thalidomide's selective inhibition of TNF-α had been reported, a renewed effort was put in thalidomide's clinical development. The clinical development led to the discovery of new analogs which strived to have improved activities and decreased side effects. Clinically, thalidomide has always been used as a racemate. Generally the S-isomer is associated with the infamous teratogenic effects of thalidomide and the R-isomer is devoid of the teratogenic properties but conveys the sedative effects, however this view is highly debated and it has been argued that the animal model that these different R- and S-effects were seen in was not sensitive to the thalidomide teratogenic effects. Later reports in rabbits, which is a sensitive species, unveiled teratogenic effects from both isomers. Moreover, thalidomide enantiomers have been shown to be interconversed in vivo due to the acidic chiral hydrogen in the asymmetric center (shown, for the EM-12 analog, in Figure 3), so the plan to administer a purified single enantiomer to avoid the teratogenic effects will most likely be in vain. === Development of lenalidomide and pomalidomide === One of the analogs of interest was made by isoindolinone replacement of the phthaloyl ring. It was given the name EM-12 (Figure 3). This replacement was thought to increase the bioavailability of the substance because of increased stability. The molecule had been reported to be an even more potent teratogenic agent than thalidomide in rats, rabbits and monkeys. Additionally, these analogs are more potent inhibitors of angiogenesis than thalidomide. As well, the amino-thalidomide and amino-EM-12 were potent inhibitors of TNF-α. These two analogs later got the name lenalidomide, which is the EM-12 amino analog, and pomalidomide, the thalidomide amino analog. == Medical use == The primary use of IMiDs in medicine is in the treatment of cancers and autoimmune diseases (including one that is a response to the infection leprosy). Indications for these agents that have received regulatory approval include: Myelodysplastic syndrome, a precursor condition to acute myeloid leukaemia Erythema nodosum, a complication of leprosy Multiple myeloma Off-label indications for which they seem promising treatments include: Hodgkin's lymphoma Light chain-associated (AL) amyloidosis Primary myelofibrosis (PMF) Acute myeloid leukaemia (AML) Prostate cancer Metastatic renal cell carcinoma (mRCC) === Thalidomide === Thalidomide has been approved by the FDA for ENL and MM in combination with dexamethasone. EMA has also approved it to treat MM in combination with prednisone and/or melphalan. Orphan indications by the FDA include graft-versus-host disease, mycobacterial infection, recurrent aphthous ulcers, severe recurrent aphthous stomatitis, primary brain malignancies, AIDS-associated wasting syndrome, Crohn's disease, Kaposi's sarcoma, myelodysplastic syndrome and hematopoietic stem cell transplantation. === Lenalidomide === Lenalidomide is approved in nearly 70 countries, in combination with dexamethasone for the treatment of patients with MM who have received at least one prior therapy. Orphan indications include diffuse large B-cell lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma. Lenalidomide is also approved for transfusion-dependent anemia due to low or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities in the U.S., Canada, Switzerland, Australia, New Zealand, Malaysia, Israel and several Latin American countries, while marketing authorization application is currently being evaluated in a number of other countries. Numerous clinical trials are already in the pipeline or being conducted to explore further use for lenalidomide, alone or in combination with other drugs. Some of these indications include acute myeloid leukemia, follicular lymphoma, MALT lymphoma, Waldenström macroglobulinemia, lupus erythematosus, Hodgkin's lymphoma, myelodysplastic syndrome and more. === Pomalidomide === Pomalidomide was submitted for FDA approval on April 26, 2012 and on 21 June it was announced that the drug would get standard FDA review. A marketing authorization application was filed to EMA 21 June 2012, where a decision could come as soon as early 2013. EMA has already granted pomalidomide an orphan designation for primary myelofibrosis, MM, systemic sclerosis, post-polycythaemia and post-essential thrombocythaemia myelofibrosis. == Adverse effects == The major toxicities of approved IMiDs are peripheral neuropathy, thrombocytopenia, anaemia and venous thromboembolism. There may be an increased risk of secondary malignancies, especially acute myeloid leukaemia in those receiving IMiDs. === Teratogenicity === Thalidomide's teratogenicity has been a subject of much debate and over the years numerous hypotheses have been proposed. Two of the best-known have been the anti-angiogenesis hypothesis and oxidative stress model hypothesis, with considerable experimental evidence supporting these two hypotheses regarding thalidomide's teratogenicity. Recently, new findings have emerged that suggest a novel mechanism of teratogenicity. Cereblon is a 51 kDa protein localized in the cytoplasm, nucleus and peripheral membrane of cells in numerous parts of the body. It acts as a component of the E3 ubiquitin ligase, regulating various developmental processes, including embryogenesis, carcinogenesis and cell cycle regulation, through degradation (ubiquitination) of unknown substrates. Thalidomide has been shown to bind to cereblon, inhibiting the activity of the E3 ubiquitin ligase, resulting in accumulation of the ligase substrates and downregulation of fibroblast growth factor 8 (FGF8) and FGF10. This disrupts the positive feedback loop between the two growth factors, possibly causing both multiple birth defects and anti-myeloma effects. Findings also support the hypothesis that an increase in the expression of cereblon is an essential element of the anti-myeloma effect of both lenalidomide and pomalidomide. Cereblon expression was three times higher in responding patients compared to non-responders and higher cereblon expression was also associated with partial or full response while lower expression was associated with stable or progressive disease. == Mechanism of action == Their mechanism of action is not entirely clear, but it is known that they inhibit the production of tumour necrosis factor, interleukin 6 and immunoglobulin G and VEGF (which leads to its anti-angiogenic effects), co-stimulates T cells and NK cells and increases interferon gamma and interleukin 2 production. Their teratogenic effects appear to be mediated by binding to cereblon. Thalidomide and its analogs, lenalidomide and pomalidomide, are believed to act in a similar fashion even though their exact mechanism of action is not yet fully understood. It is believed that they work through different mechanisms in various diseases. The net effect is probably due to different mechanisms combined. Mechanism of action will be explained in light of today's knowledge. === Thalidomide, lenalidomide and pomalidomide === ==== Altering cytokine production ==== Thalidomide and its immune-modulating analogs alter the production of the inflammatory cytokines TNF-α, IL-1, IL-6, IL-12 and anti-inflammatory cytokine IL-10. The analogs are believed to inhibit the production of TNF-α, where the analogs are up to 50.000 times more potent in vitro than the parent drug thalidomide. The mechanism is believed to be through enhanced degradation of TNF-α mRNA, resulting in diminished amounts of this pro-inflammatory cytokine secreted. This explains the effect of thalidomide when given to ENL patients, as they commonly have high levels of TNF-α in their blood and in dermatological lesions. In contrast, in vitro assay demonstrated that TNF-α is actually enhanced in T-cell activation, where CD4+ and CD8+ T lymphocytes were stimulated by anti-CD3 which was later confirmed in an early phase trials involving solid tumors and inflammatory dermatologic diseases. IL-12 is another cytokine both suppressed and enhanced by thalidomide and its analogs. When monocytes are stimulated by lipopolysaccharides, IL-12 production is suppressed but during T-cell stimulation the production is enhanced. Lenalidomide is believed to be about 1000 times more potent in vitro than thalidomide in anti-inflammatory properties and pomalidomide about 10 times more potent than lenalidomide. It is worth noticing however that, when comparing lenalidomide and pomalidomide, clinical relevance of higher in vitro potency is unclear since maximum tolerated dose of pomalidomide is 2 mg daily compared to 25 mg for lenalidomide, leading to 10-100 times lower plasma drug concentration of pomalidomide. ==== T-cell activation ==== Thalidomide and its analogs help with the co-stimulation of T-cells through the B7-CD28 complex by phosphorylating tyrosine on the CD28 receptor. In vitro data suggests this co-stimulation leads to increased Th1 type cytokine release of IFN-γ and IL-2 that further stimulates clonal T cell proliferation and natural killer cell proliferation and activity. This enhances natural and antibody dependent cellular cytotoxicity. Lenalidomide and pomalidomide are about 100-1000 times more potent in stimulating T-cell clonal proliferation than thalidomide. In addition, in vitro data suggests pomalidomide reverts Th2 cells into Th1 by enhancing transcription factor T-bet. ==== Anti-angiogenesis ==== Angiogenesis or the growth of new blood vessels has been reported to correspond with MM progression where vascular endothelial growth factor (VEGF) and its receptor, bFGF and IL-6 appear to be required for endothelial cell migration during angiogenesis. Thalidomide and its analogs are believed to suppress angiogenesis through modulation of the above-mentioned factors where potency in anti-angiogenic activity for lenalidomide and pomalidomide was 2-3 times higher than for thalidomide in various in vivo assays, Thalidomide has also been shown to block NF-κB activity through the blocking of IL-6, and NF-κB has been shown to be involved in angiogenesis. Inhibition of TNF-α is not the mechanism of thalidomide's inhibition of angiogenesis since numerous other TNF-α inhibitors do not inhibit angiogenesis. ==== Anti-tumor activity ==== In vivo anti-tumor activity of thalidomide is believed to be due to the potent anti-angiogenic effect and also through changes in cytokine expression. In vitro assays on apoptosis in MM cells have been shown, when treated with thalidomide and its analogs, to upregulate the activity of caspase-8. This causes cross talking of apoptotic signaling between caspase-8 and caspase-9 leading to indirect upregulation of caspase-9 activity. Further anti-tumor activity is mediated through the inhibition of apoptosis protein-2 and pro-survival effects of IGF-1, increasing sensitivity to FAS mediated cell death and enhancement of TNF-related apoptosis inducing ligand. They have also been shown to cause dose dependent G0/G1 cell cycle arrest in leukemia cell lines where the analogs showed 100 times more potency than thalidomide. ==== Bone marrow environment ==== The role of angiogenesis in the support of myeloma was first discovered by Vacca in 1994. They discovered increased bone marrow angiogenesis correlates with myeloma growth and supporting stromal cells are a significant source for angiogenic molecules in myeloma. This is believed to be a main component of the mechanism in vivo by which thalidomide inhibits multiple myeloma. Additionally, inflammatory responses within the bone marrow are believed to foster many hematological diseases. The secretion of IL-6 by bone marrow stromal cells (BMSC) and the secretion of the adhesion molecules VCAM-1, ICAM-1 and LFA, is induced in the presence of TNF-α and the adhesion of MM cells to BMSC. In vitro proliferation of MM cell lines and inhibition of Fas-mediated apoptosis is promoted by IL-6. Thalidomide and its analogs directly decrease the up-regulation of IL-6 and indirectly through TNF-α, thereby reducing the secretion of adhesion molecules leading to fewer MM cells adhering to BMSC. Osteoclasts become highly active during MM, leading to bone resorption and secretion of various MM survival factors. They decrease the levels of adhesion molecules paramount to osteoclast activation, decrease the formation of the cells that form osteoclasts and downregulate cathepsin K, an important cysteine protease expressed in osteoclasts. == Structure-activity relationship == Since the mechanism of action of thalidomide and its analogs is not fully clear and the bioreceptor for these substances has not been identified, the insight into the relationship between the structure and activity of thalidomide and its analogs are mostly derived from molecular modelling and continued research investigation. The information on SAR of thalidomide and its analogs is still in process so any trends detailed here are observed during individual studies. Research has mainly focused on improving the TNF-α and PDE4 inhibition of thalidomide, as well as the anti-angiogenesis activity. === TNF-α inhibitors (not via PDE4) === Research indicated that a substitution at the phthaloyl ring would increase TNF-α inhibition activity (Figure 5). An amino group substitution was tested at various locations on the phthaloyl ring (C4, C5, C6, C7) of thalidomide and EM-12 (previously described). Amino addition at the C4 location on both thalidomide and EM-12 resulted in much more potent inhibition of TNF-α. This also revealed that the amino group needed to be directly opposite the carbonyl group on the isoindolinone ring system for the most potent activity. These analogs do not inhibit PDE4 and therefore do not act by PDE4 inhibition. Other additions of longer and bigger groups at the C4 and C5 position of the phthaloyl ring system of thalidomide, some with an olefin functionality, have been tested with various results. Increased inhibitory effect, compared to thalidomide, was noticed with the groups that had an oxygen atom attached directly to the C5 or C4 olefin. Iodine and bromine addition at C4 or C5 resulted in equal or decreased activity compared to thalidomide. These groups were not compared with lenalidomide or pomalidomide. === PDE4 inhibitors === The common structure for analogs that inhibit TNF-α via inhibition of PDE4 is prepared on the basis of hydrolysing the glutarimide ring of thalidomide. These analogs do not have an acidic chiral hydrogen, unlike thalidomide, and would therefore be expected to be chirally stable. On the phenyl ring, a 3,4-dialkoxyphenyl moiety (Figure 6) is a known pharmacophore in PDE4 inhibitors such as rolipram. Optimal activity is achieved with a methoxy group at the 4-position (X2) and a bigger group, such as cyclopentoxy at the 3-position carbon (X3). However the thalidomide PDE4 inhibitory analogs do not follow the SAR of rolipram analogs directly. For thalidomide analogs, an ethoxy group at X3 and a methoxy group at X2, with X1 being just a hydrogen, gave the highest PDE4 and TNF-α inhibition. Substitutes larger than diethoxy at the X2–X3 position had decreased activity. The effects of these substitutions seem to be mediated by steric effects. For the Y-position, a number of groups have been explored. Substituted amides that were larger than methylamide (CONHCH3) decrease PDE4 inhibition activity. Using a carboxylic acid as a starting point, an amide group has similar PDE4 inhibition activity but both groups were shown to be a considerably less potent than a methyl ester group, which had about six-fold increase in PDE4 inhibitory activity. Sulfone group had similar PDE4 inhibition as the methyl ester group. The best PDE4 inhibition was observed when a nitrile group was attached, which has 32 times more PDE4 inhibitory activity than the carboxyl acid. Substituents at Y leading to increasing PDE4 inhibitory activity thus followed the order: COOH ≤ CONH2 ≤ COOCH3 ≤ SO2CH3 < CN Substitutions on the phthaloyl ring have been explored and it was noticed that nitro groups at the C4 or C5 location decreased activity but C4 or C5 amino substitution increased it dramatically. When the substitution at the 4 (Z) location on the phthaloyl ring was examined, hydroxyl and methoxy groups seem to make the analog a less potent PDE4 inhibitor. An increase in activity was observed with amino and dimethylamino to a similar extent but a methyl group improved the activity further than the aforementioned groups. A 4-N-acetylamino group had slightly lower PDE4 inhibitory activity, compared with the methyl group, but increased the compound's TNF-α inhibitory activity to a further extent. Substituents at Z leading to increasing PDE4 inhibitory activity thus followed the order: N(CH3)2 ≤ NH2 < NHC(O)CH3 < CH3 === Angiogenesis inhibition === For angiogenesis inhibition activity, an intact glutarimide ring seems to be required. Different groups were tested in the R position. The substances that had nitrogen salts as the R group showed good activity. The improved angiogenesis inhibitory activity could be due to increased solubility or that the positively charged nitrogen has added interaction with the active site. Tetrafluorination of the phthaloyl ring seems to increase the angiogenesis inhibition. == Synthesis == Described below are schemes for synthesizing thalidomide, lenalidomide, and pomalidomide, as reported from prominent primary literature. Note that these synthesis schemes do not necessarily reflect the organic synthesis strategies used to synthesize these single chemical entities. === Thalidomide === Synthesis of thalidomide has usually been performed as seen in scheme 1. This synthesis is a reasonably simplistic three step process. The downside of this process however is that the last step requires a high-temperature melt reaction which demands multiple recrystallizations and is not compliant with standard equipment. Scheme 2 is the newer synthesis route which was designed to make the reaction more direct and to produce better yields. This route uses L-glutamine rather than L-glutamic acid as a starting material and by letting it react with N-carbethoxyphthalimide gives N-phthaloyl-L-glutamine (4), with 50–70% yield. The substance 4 is then stirred in a mixture with carbonyldiimidazole (CDI) with enough 4-dimethylaminopyridine (DMAP) in tetrahydrofuran (THF) to catalyze the reaction and heated to reflux for 15–18 hours. During the reflux thalidomide crystallizes out of the mixture. The final step gives 85–93% yield of thalidomide, bringing the total yield to 43–63%. === Lenalidomide and pomalidomide === Both of the amino analogs are prepared from the condensation of 3-aminopiperidine-2,6-dione hydrochloride (Compound 3) which is synthesized in a two step reaction from commercially available Cbz-L-glutamine. The Cbz-L-glutamine is treated with CDI in refluxing THF to yield Cbz-aminoglutarimide. To remove the Cbz protecting group hydrogenolysis, under 50–60 psi of hydrogen with 10% Pd/C mixed with ethyl acetate and HCl, was performed. The formulated hydrochloride (Compound 3 in Scheme 3) was then reacted with 3-nitrophthalic anhydride in refluxing acetic acid to yield the 4-nitro substituted thalidomide analog and the nitro group then reduced with hydrogenation to give pomalidomide. Lenalidomide is synthesized in a similar way using compound 3 (3-aminopiperidine-2,6-dione) treated with a nitro-substituted methyl 2-(bromomethyl) benzoate, and hydrogenation of the nitro group. == Pharmacokinetics == === Thalidomide === === Lenalidomide === === Pomalidomide === == See also == == References ==	Wikipedia/Immunomodulatory_imide_drug
Photoimmunotherapy (PIT) is an oncological treatment that combines photodynamic therapy of tumor with immunotherapy treatment. Combining photodynamic therapy with immunotherapy enhances the immunostimulating response and has synergistic effects for metastatic cancer treatment. PIT is type of molecular targeted cancer therapy, which allows the selective destruction of cancer cells without any damage to normal tissues. It is a light-based cancer therapy, which was developed and pioneered by Professor Julia Levy and colleagues at the University of British Columbia, Canada, in 1983. Professor Julia Levy's research has also been pivotal in the clinical approval of Visudyne and Photofrin. Over the last 35 years, PIT has been studied extensively in vitro and in vivo by numerous research teams all over the world. More recently, significant strides in PIT have been made by Professor Kobayashi and his colleagues at National Cancer Institute, Bethesda, Maryland. Conventional photodynamic therapy (PDT) uses a non-specific photosensitizer which can be activated by a non-ionizing light to kill cancer cells. Photosensitizers are molecules that rapidly destroy cells though the production of reactive oxygen species (ROS) when exposed to light at specific wavelength. However, this PDT treatment results in serious side effects because non-targeted photosensitizers are also taken up by normal tissues. PIT treatment avoids the side effects problem through the creation of a targeted-photosensitizer, which involves two components: a monoclonal antibody (mAb) which recognizes specific proteins on the surface of cancer cells, and a non-targeted photosensitizer. Even though the new mAb-based photosensitizers are distributed throughout the body, it can be activated by light for targeted PIT only when bound to specific proteins on cancer cellular membrane. PIT has been previously published using a vast number of photosensitizers, such as porphyrins, chlorins and phthalocyanine dyes. The research team at Professor Kobayashi's lab coupled anti-tumor antibodies targeting human epidermal growth factor receptors to a water soluble phthalocyanine dye, IRDye 700DX, which is activated by near-infrared light. IRDye 700DX was chosen for its hydrophilicity and strong cytotoxicity induced upon association with the cellular membrane and subsequent activation. A variety of cancers, such as breast and pancreatic cancers over-express epidermal growth factor receptors. This new photosensitizing compound utilizing IRDye 700DX NHS Ester was referred to as "mAb-IR700 conjugates". In Vitro studies showed that mAb-IR700 killed tumor cells seconds after the near-infrared light irradiation. There was also a positive correlation between the intensity of excitation light and percentage of cell death. Infrared light alone or mAb-IR700 conjugate alone did not cause any damage to normal cells. When tumor-xenografted mice were treated with mAb-IR700 and near-infrared light, significant tumor shrinkage was observed. With fractionated administration of mAB–IR700 conjugate followed by systematic repeated NIR light irradiation to the tumor, 80 percent of tumor cells were eradicated and the mice's survival were significantly prolonged. Based on the current hypothesis, cell death induced by PIT was caused by rapid expansion of local water upon the formation of holes in the membrane. Another desirable feature of PIT using mAb-IR700 conjugate is that it also emits fluorescence light upon activation. Therefore before PIT, mAb-IR700 can be administered at a lower dosage to guide the application of excitation light to tumor tissues, further minimizing unnecessary light exposure to surrounding tissues. PIT is a promising highly selective and clinically feasible therapeutic method for treatment of mAb-binding tumors with minimal off-target effects. For future directions, researchers are trying to conjugate a variety of other monoclonal antibodies to phthalocyanine, creating a highly flexible therapeutic platform. == See also == Combinatorial ablation and immunotherapy Cryoimmunotherapy == References == == Bibliography == Kobayashi, Hisataka. "Illuminating the cancer-targeting potential of near-infrared photoimmunotherapy." Sato, Kazuhide; et al. (May 2014). "Photoimmunotherapy: comparative effectiveness of two monoclonal antibodies targeting the epidermal growth factor receptor". Molecular Oncology. 8 (3): 620–632. doi:10.1016/j.molonc.2014.01.006. PMC 4004687. PMID 24508062. == External links == Technical information on IRDye 700DX NIR Dye Hisataka Kobayashi, M.D., Ph.D.	Wikipedia/Photoimmunotherapy
Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to autoantigens implicated in autoimmune diseases. Research using animal models in transplantation and autoimmune diseases has led to early-phase human trials of tolerogenic therapy for autoimmune conditions like Type 1 Diabetes. == Dendritic cells in tolerogenic therapy == Tolerogenic therapies employ the inbuilt tolerance mechanisms of a class of immune cells called dendritic cells. Dendritic cells are divided into two main subsets: Mature dendritic cells are immunogenic. Their physiological role is to bridge innate and adaptive immune responses by presenting antigens to T-lymphocytes. In the presence of an inflammatory environment, which usually accompanies infection or tissue ‘danger’ signals, dendritic cells are activated (mature) and present foreign antigens to the T cells, initiating an appropriate immune response. Semi-mature dendritic cells are tolerogenic. Conditions including the absence of an inflammatory environment result in the incomplete maturation of dendritic cells. Their influence on T-lymphocytes follows a different mechanism which induces tolerance, rather than immunogenicity. Tolerogenic therapies are based on the principle that inducing the semi-mature phenotype in dendritic cells and then exposing them to the target antigen should allow antigen-specific induction of T-cell tolerance. Tolerogenic dendritic cells induce tolerance through several mechanisms. Once stimulated, the dendritic cells migrate to the draining lymph node and present antigens to T cells via interaction of MHC class II-antigen complexes. This can induce T cell clonal deletion, T cell anergy or the proliferation of regulatory T cells (Tregs). Collectively, these mechanisms produce tolerance to specific antigens, which should help to prevent autoimmunity, but could therefore also be used as a therapy to induce tolerance to specific antigens implicated in autoimmune disease, or donor antigens in transplant patients. == Mechanisms of therapy == Several methods of inducing tolerance based on this approach are currently being explored. Ex vivo tolerogenic dendritic cells can be induced through the addition of cytokines, pharmacological agents or genetic engineering techniques after their extraction from the patient. The DCs are then pulsed with the specific antigen to which tolerance is desired and these, now tolerogenic, cells can be injected back into the patient. Alternative methods include the direct injection of an inducing agent to induce semi-mature DCs in vivo. == Animal models == Studies have suggested a role for tolerogenic dendritic cells in the treatment of diseases like type 1 diabetes mellitus and multiple sclerosis. In animal models of Diabetes mellitus (NOD mice), GM-CSF induces resistance by increasing the frequency of regulatory T cells which can suppress T cell proliferation through their T-cell receptors. GM-CSF treated mice were found to have a semi-mature phenotype of dendritic cells which were inefficient at inducing antigen specific cytotoxic T cells compared to controls. In multiple sclerosis research, EAE mice were completely protected from symptoms when injected with dendritic cells matured with TNF-α and antigen specific peptide compared to controls. T regulatory cells of mice treated with TNF-α produced IL-10, a cytokine which is able to inhibit the Th1 response therefore protecting against the Th1 dependent autoimmune EAE. Mouse models of autoimmune thyroiditis showed that a semi-mature phenotype of dendritic cells is maintained after mouse thyroglobulin immunization in GM-CSF treated but not control mice. IL-10 produced by T regulatory cells was important in suppressing the mouse thyroglobulin specific T cell response and therefore protecting against Experimental autoimmune thyroiditis in mice. Phase I studies into the safety and efficacy of tolerogenic DC therapy in humans have demonstrated the appropriateness of the therapy for further research. Future research will consider the effectiveness of tolerogenic therapies in a number of planned clinical trials into autoimmune diseases. == See also == Short course immune induction therapy == References ==	Wikipedia/Tolerogenic_therapy
Helminthic therapy, an experimental type of immunotherapy, is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth or with the eggs of a helminth. Helminths are parasitic worms such as hookworms, whipworms, and threadworms that have evolved to live within a host organism on which they rely for nutrients. The theory behind helminth therapy is that these worms reduce negative immune responses due to their TH2 immune response that downregulates the abnormal T-cell responses recently associated with autoimmune disorders. This therapy ties to the Hygiene hypothesis in that the lack of exposure to bacteria and parasites such as helminths can cause a weaker immune system leading to being more susceptible to autoimmune disease. Helminth worms are members of two phyla: nematodes, which are primarily used in human helminthic therapy, and flat worms (trematodes). Helminthic therapy consists primarily of the inoculation of the patient with specific parasitic intestinal nematodes (or other helminths). A number of such organisms are currently being investigated for their use as treatment, including: Trichuris suis ova, commonly known as pig whipworm eggs; Necator americanus, commonly known as hookworms; Trichuris trichiura ova, commonly referred to as human whipworm eggs; and Hymenolepis diminuta, commonly known as rat tapeworm. While the latter four species may be considered to be mutualists – providing benefit to their host without causing long term harm – there are other helminth species that have demonstrated therapeutic uses, but these have a potential to cause harmful side effects, and therefore do not share the ideal characteristics for a therapeutic helminth. These include Ascaris lumbricoides, commonly known as human giant roundworm; Strongyloides stercoralis, commonly known as human roundworm; Enterobius vermicularis, commonly known as pinworm or threadworm; and Hymenolepis nana, also known as dwarf tapeworm. Current research targets Crohn's disease, ulcerative colitis, inflammatory bowel disease, coeliac disease, multiple sclerosis and asthma. Helminth infection has emerged as one possible explanation for the low incidence of autoimmune diseases and allergies in less developed countries, while reduced infection rates have been linked with the significant and sustained increase in autoimmune diseases seen in industrialized countries. == Incidence of autoimmune diseases and parasitic infestation == While it is recognized that there is probably a genetic disposition in certain individuals for the development of autoimmune diseases, the rate of increase in incidence of autoimmune diseases is not a result of genetic changes in humans; the increased rate of autoimmune-related diseases in the industrialized world is occurring in too short a time to be explained in this way. There is evidence that one of the primary reasons for the increase in autoimmune diseases in industrialized nations is the significant change in environmental factors over the last century. It is posited that the absence of exposure to certain parasites, bacteria, and viruses is playing a significant role in the development of autoimmune diseases in the more sanitized and industrialized Western nations. Lack of exposure to naturally occurring pathogens and parasites may result in an increased incidence of autoimmune diseases. Correlational data has shown the prevalence of helminthic infections to be greatest south of the equator where the rates of autoimmune diseases such as multiple sclerosis are low. This is consistent with the hygiene hypothesis which suggests that helminthic infections protect individuals from developing auto-immune diseases rather than being an agent responsible for inducing them. A complete explanation of how environmental factors play a role in autoimmune diseases has still not been proposed. Epidemiological studies such as the meta-analysis by Leonardi-Bee et al., however, have helped to establish the link between parasitic infestation and their protective role in autoimmune disease development. == Hypotheses == Although the mechanisms of autoimmune disease development are not fully understood, there is broad agreement that the majority of autoimmune diseases are caused by inappropriate immunological responses to innocuous antigens; these are generally called the hygiene hypothesis, but exist in several variants. One version proposes that the dysfunction is driven by a branch of the immune system known as the T helper cells (Th or TH). Two other refinements to the hygiene hypothesis exist: The "old friends" hypothesis, and the "microbiome depletion" hypothesis. === TH1 vs. TH2 response regulation === Extra-cellular antigens primarily trigger the TH2 response, as observed with allergies, while intracellular antigens trigger a TH1 response. Th cells can be divided into subtypes based on the characteristic cytokines they secrete. TH2 immune responses result in the release of cytokines associated with inflammation reduction such as interleukin 4, interleukin 5, and interleukin 10. These cytokines are thought to reduce the symptoms of many autoimmune disorders. Conversely, TH1 immune responses are characterized by the cytokines interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα), both of which are thought to increase inflammation and worsen the progression of autoimmune diseases and their symptoms. The antagonism between these two types of immune response is a central theme of one proposal for the biological basis of the hygiene hypothesis, which suggests that there is a regulatory action between the two types of response. The observation that allergies and autoimmune response are increasing at a similar rate in industrialized nations appears to undermine this explanation of hygiene hypothesis. === Learned appropriate response === The hygiene hypothesis proposes that appropriate immune response is in part learned by exposure to micro-organisms and parasites, and in part regulated by their presence. In industrialized nations, humans are exposed to somewhat lower levels of these organisms, potentially resulting in unbalanced immune systems. The development of vaccines, hygienic practices, and effective medical care have diminished or eliminated the prevalence and impact of many parasitic organisms, as well as bacterial and viral infections. This has been of obvious benefit with the effective eradication of many diseases that have plagued human beings. However, while many severe diseases have been eradicated, humans' exposure to benign and apparently beneficial parasites has also been reduced commensurately. The central thrust of the hypothesis is, therefore, that correct development of regulatory T cells in individuals may depend on exposure to organisms such as lactobacilli, various mycobacteria, and helminths. Lack of exposure to sufficient benign antigens, particularly during childhood, is sometimes suggested as a cause of the increase in autoimmune diseases and diseases for which chronic inflammation is a major component in the industrialized world. === Old friends hypothesis === The old friends hypothesis modifies the hygiene hypothesis by proposing that regulatory T cells can only become fully effective if they are stimulated by exposure to microorganisms and parasites that have low levels of pathogenicity and that have coexisted universally with human beings throughout our evolutionary history. This hypothesis has recently been given more credibility by a study demonstrating the impact of infectious organisms, and helminths in particular, upon genes responsible for the production of various cytokines, some involved in the regulation of inflammation, in particular those associated with the development of Crohn's disease, ulcerative colitis, and celiac disease. === Microbiome depletion hypothesis === The microbiome depletion hypothesis posits that the absence of an entire class of organisms from the human inner ecology is a profound evolutionary mismatch that destabilizes the immune system, resulting in disease: The microbiome is "depleted". The way to correct the dysregulation is to "reconstitute", or replenish, keystone species in healthy individuals prior to the development of human diseases of modern living. As keystone organisms, helminths are central to correcting immune dysregulation, and their replenishment may prevent disease. The biome depletion hypothesis departs from a drug model approach, which remains the current focus of helminthic therapy as evidenced by numerous clinical trials now underway for existing disease states. == Proposed mechanism of action == Experimental data support the hypothesis that clinically induced helminthic infections have the ability to alleviate or mitigate immune responses. Most autoimmune disorders are believed to involve hyperactive TH1 or TH17 immune responses that are down-regulated by the promotion of a TH2 response by helminths. Helminths secrete immunoregulatory molecules that promote the induction of regulatory T cells while inhibiting the function of antigen presenting cells and other T cells. As such, helminthic therapy attempts to restore homeostasis by shifting a hyperactive TH1 pro-inflammatory response to a TH2 response with reduced inflammation. Human and animal studies have provided evidence of decreased TH1 and TH17 immune responses with a shift to TH2 cytokine production resulting in significantly decreased levels of interleukin 12 and IFNy with simultaneous increases in the regulatory T cells, interleukin 4, interleukin 5 and interleukin 10 of test subjects. These observations indicate that helminth therapy can provide protection against autoimmune disease not only through prevention, since helminths can be present before autoimmune disease develops, but also after autoimmune responses are initiated. Furthermore, responses of type-2 T helper cells rarely kill the parasitic worms. Rather, the TH2 response limits the infection by reducing the viability and reproductive capacity of the parasite. Given the down regulation of TH1 and TH17 immune responses with helminthic therapy, immune responses to other pathogens and allergens may be suppressed. Consequently, unmonitored and uncontrolled helminthic infections may be associated with suppressed immunity to the viruses and bacteria that normally trigger TH1 and TH17 immune responses required for protection against them, leading to illness or disease. == Research == Evidence in support of the idea that helminthic infections reduce the severity of autoimmune diseases is primarily derived from animal models. Studies conducted on mice and rat models of colitis, multiple sclerosis, type 1 diabetes, and asthma have shown helminth-infected subjects to display protection from the disease. The first clinical studies of helminthic therapy on humans started in 2003 with the use of Trichirus suis. While helminths are often considered a homogenous group, considerable differences exist between species and the species used in clinical research varies between human and animal trials. As such, caution must be exercised when interpreting the results from animal models. Helminthic therapy is currently being studied as a treatment for several (non-viral) autoimmune diseases in humans including celiac disease, Crohn's disease, multiple sclerosis, ulcerative colitis, and atherosclerosis. It is currently unknown which clinical dose or species of helminth is the most effective method of treatment. Hookworms have been linked to reduced risk of developing asthma, while Ascaris lumbricoides (roundworm infection) was associated with an increased risk of asthma. Similarly, Hymenolepis nana, Trichuris trichiura, Ascaris lumbricoides, Strongyloides stercoralis, Enterobius vermicularis, and Trichuris suis ova have all been found to lower the number of symptom exacerbations, reduce the number of symptom relapses, and decrease the number of new or enlarging brain lesions in patients with multiple sclerosis at doses ranging from 1,180 to 9,340 eggs per gram. However, Ascaris lumbricoides, Strongyloides stercoralis and Enterobius vermicularis are not considered suitable for therapeutic use in humans because they do not meet the criteria for a therapeutic helminth. Trichuris suis ova has been used in most cases to treat autoimmune disorders because it is thought to be non-pathogenic in humans and therefore has been presumed safe. The use of Trichuris suis ova has been granted by the USA Food and Drug Administration as an investigational medicinal product (IMP). A patient will ingest the eggs so the worms can colonize the caecum and colon of the human gut for a short period of time and provide treatment. The beneficial effect is temporary because the worms only live for a few weeks. Because of this short life span, treatments need to be repeated at intervals. Trichirus suis removes any wider public health issues due to species-specificity and lack of chronic infection. The hookworm Necator americanus has been granted an IMP license by the Medicines and Healthcare Regulatory Authority in the U.K. Necator americanus larvae are administered percutaneously and migrate through the vasculature and lungs to the small intestine. They feed on the blood from the mucosa. This hookworm is likely to be relatively safe, although it can cause temporary gastrointestinal side effects, especially following the initial inoculation, or with increased doses. High doses can also cause anemia. The general ideal characteristics for a therapeutic helminth are as follows: Little or no pathogenic potential Can complete whole life cycle in host Does not multiply in the host Cannot be directly spread to close contacts Produces a self-limited colonization in humans Produces an asymptomatic colonization in humans Does not alter behavior in patients with depressed immunity Is not affected by most commonly used medications Can be eradicated with an anti-helminthic drug Can be isolated free of other potential pathogens Can be isolated or produced in large numbers Can be made stable for transport and storage Easy to administer While the research is still rudimentary and the treatment is still being studied, helminthic therapy is a viable option as of current due to its lowered cost and seemingly high effectiveness in comparison to other treatments. == Potential side effects == Helminths are extremely successful parasites capable of establishing long-lasting infections within a host. During this time, helminths compete with the host organism's cells for nutrient resources and thus possess the potential to cause harm. However, the number of organisms hosted by individuals undergoing helminthic therapy is very small and any side effects are typically only encountered in the first three months of infection. In the long term, the vast majority of clinically infected individuals are asymptomatic, with no significant nutrient loss. In fact, nutrient uptake can be enhanced in some subjects who are hosting a small number of helminths. If the side effects from helminthic therapy were to become unmanageable, they can be alleviated by the use of anti-helminthic medications. The most common clinical symptoms which may be encountered while undergoing helminthic therapy can include: Fatigue Gastrointestinal discomfort Anemia Fever Abdominal pain Weight loss Anorexia Diarrhea General malaise Tissue Invasion Tumor promotion Outside of these initial symptoms that can arise, there are other worries attached to using live helminth parasites as treatment including: Ethical perspective: using living things as treatment Symptoms re-occurring post treatment Worm adaption if in a colitis host == Self-Administration == Social media has brought helminth therapy to the forefront of treatment discussion with many false claims and misinformation. Due to this increased online discussion on Helminth therapy, many people struggling with autoimmune diseases have turned to self-administering parasites to treat themselves. Patients have begun to travel or look in the black market to purchase helminths, as the treatment is still in testing stages and generally discouraged by most medical professionals. == See also == Anthelmintics Diseases of affluence Effects of parasitic worms on the immune system Gut flora Ichthyotherapy Malariotherapy Medical leech Trematodes Hygiene Hypothesis Autoimmune disease Tapeworm diet == References == == Bibliography == Velasquez-Manoff, Moises (2013). An Epidemic of Absence: A new way of understanding allergies and autoimmune diseases. Scribner. ISBN 978-1439199398. Dunn, Rob (2011). The Wild Life of Our Bodies: Predators, parasites, and partners that shape who we are today. Harper. ISBN 978-0061806483. Lorimer, Jamie (2020). The Probiotic Planet: Using Life to Manage Life. University of Minnesota Press. ISBN 978-1-5179-0920-8. == External links == Helminthic Therapy Wiki	Wikipedia/Helminthic_therapy
The British Armed Forces are the unified military forces responsible for the defence of the United Kingdom, its Overseas Territories and the Crown Dependencies. They also promote the UK's wider interests, support international peacekeeping efforts and provide humanitarian aid. The force is also known as His Majesty's Armed Forces. Since the formation of the united Kingdom of Great Britain in 1707 (later succeeded by the United Kingdom of Great Britain and Ireland, and finally by the United Kingdom of Great Britain and Northern Ireland), the British Armed Forces have seen action in most major wars involving the world's great powers, including the Seven Years' War, the American War of Independence, the Napoleonic Wars, the Crimean War, the First World War and the Second World War. Britain's victories in most of these wars allowed it to influence world events and establish itself as one of the world's leading military and economic powers. The British Armed Forces consist of: the Royal Navy, a blue-water navy with a fleet of 62 commissioned and active ships, together with the Royal Marines, a highly specialised amphibious light infantry force; the British Army, the UK's principal land warfare branch; and the Royal Air Force, a technologically sophisticated air force with a diverse operational fleet consisting of both fixed-wing and rotary aircraft. The British Armed Forces include standing forces, Regular Reserve, Volunteer Reserves and Sponsored Reserves. King Charles III, sovereign of the United Kingdom, is the commander-in-chief and is styled as Head of the Armed Forces, with officers and personnel swearing allegiance to him. Long-standing constitutional convention, however, has vested de facto executive authority, by the exercise of royal prerogative, in the Prime Minister and the secretary of state for defence. The Prime Minister (acting with the Cabinet) makes the key decisions on the use of the armed forces. The UK Parliament approves the continued existence of the British Army by passing an Armed Forces Act at least once every five years, as required by the Bill of Rights 1689. Only a "standing army" requires reapproval by Parliament; the Royal Navy, Royal Air Force and the Royal Marines and any other forces are not included in the requirement. The armed forces are managed by the Defence Council. The United Kingdom is one of five recognised nuclear powers, a permanent member on the United Nations Security Council, a founding and leading member of NATO and party to the AUKUS security pact and the Five Power Defence Arrangements. Overseas garrisons and training facilities are maintained at Ascension Island, Bahrain, Belize, Bermuda, British Indian Ocean Territory, Brunei, Canada, Cyprus, the Falkland Islands, Germany, Gibraltar, Kenya, Montserrat, Nepal, Qatar, Singapore and the United States. == History == === Organisation === With the Acts of Union 1707, the armed forces of England and Scotland were merged into the armed forces of the Kingdom of Great Britain. There were originally several naval and several military regular and reserve forces, although most of these were consolidated into the Royal Navy or the British Army during the 19th and 20th Centuries (the Royal Naval Air Service and the Royal Flying Corps of the British Army, by contrast, were separated from their parent forces in 1918 and amalgamated to form a new force, the Royal Air Force, which would have complete responsibility for naval, military and strategic aviation until the Second World War). Naval forces included the Royal Navy, the Waterguard, later renamed the HM Coastguard, and Sea Fencibles and River Fencibles formed as and when required for the duration of emergencies. The Merchant Navy and offshore fishing boat crews were also important manpower reserves to the armed naval forces. Any seaman was liable to impressment, with many so conscripted especially during the two decades of conflict from the French Revolution until the end of the Napoleonic Wars, and from 1835 registered on the Register of Seamen to identify them as a potential resource, and many of their seamen would serve part time in the Royal Navy Reserve, created under the Naval Reserve Act 1859, and Royal Naval Volunteer Reserve, created in 1903. The British military (those parts of the British Armed Forces tasked with land warfare, as opposed to the naval forces) historically was divided into a number of military forces, of which the British Army (also referred to historically as the 'Regular Army' and the 'Regular Force') was only one. The oldest of these organisations was the Militia Force (also referred to as the Constitutional Force), which (in the Kingdom of England) was originally the main military defensive force (there otherwise were originally only royal bodyguards, including the Yeomen Warders and the Yeomen of the Guard, with armies raised only temporarily for expeditions overseas), made up of civilians embodied for annual training or emergencies, and had used various schemes of compulsory service during different periods of its long existence. The Militia was originally an all infantry force, organised at the city or county level, and members were not required to serve outside of their recruitment area, although the area within which militia units in Britain could be posted was increased to anywhere in the Britain during the 18th century, and Militia coastal artillery, field artillery, and engineers units were introduced from the 1850s. The Yeomanry was a mounted force that could be mobilised in times of war or emergency. Volunteer Force units were also frequently raised during wartime, which did not rely on compulsory service and hence attracted recruits keen to avoid the Militia. These were seen as a useful way to add to military strength economically during wartime, but otherwise as a drain on the Militia and so were not normally maintained in peacetime, although in Bermuda prominent propertied men were still appointed Captains of Forts, taking charge of maintaining and commanding fortified coastal artillery batteries and manned by volunteers (reinforced in wartime by embodied militiamen), defending the colony's coast from the 17th century to the 19th century (when all of the batteries were taken over by the regular Royal Artillery). The militia system was extended to a number of English (subsequently British) colonies, beginning with Virginia and Bermuda. In some colonies, Troops of Horse or other mounted units similar to the Yeomanry were also created. The militia and volunteer units of a colony were generally considered to be separate forces from the Home Militia Force and Volunteer Force in the United Kingdom, and from the militia forces and volunteer forces of other colonies. Where a colony had more than one militia or volunteer unit, they would be grouped as a militia or volunteer force for that colony, such as the Jamaica Volunteer Defence Force, which comprised the St. Andrew Rifle Corps, or Kingston Infantry Volunteers, the Jamaica Corps of Scouts, and the Jamaica Reserve Regiment, but not the Jamaica Militia Artillery. In smaller colonies with a single militia or volunteer unit, that single unit would still be considered to be listed within a force, or in some case might be named a force rather than a regiment or corps, such as is the case for the Falkland Islands Defence Force and the Royal Montserrat Defence Force. The militia, yeomanry and volunteer forces collectively were known as the reserve forces, auxiliary forces, or local forces. Officers of these forces could not sit on courts martial of regular forces personnel. The Mutiny Act did not apply to members of the Reserve Forces. The other regular military force that existed alongside the British Army was the Board of Ordnance, which included the Ordnance Military Corps (made up of the Royal Artillery, Royal Engineers, and the Royal Sappers and Miners), as well as the originally-civilian Commissariat Stores and transport departments, as well as barracks departments, ordnance factories and various other functions supporting the various naval and military forces. The English Army, subsequently the British Army once Scottish regiments were moved onto its establishment following the Union of the Kingdoms of Scotland and England, was originally a separate force from these, but absorbed the Ordnance Military Corps and various previously civilian departments after the Board of Ordnance was abolished in 1855. The Reserve Forces (which referred to the Home Yeomanry, Militia and Volunteer Forces before the 1859 creation of the British Army Regular Reserve by Secretary of State for War Sidney Herbert, and re-organised under the Reserve Force Act 1867) were increasingly integrated with the British Army through a succession of reforms over the last two decades of the 19th century (in 1871, command of the Auxiliary Forces in the British Isles was taken from the Lords-Lieutenant of counties and transferred to the War Office, though colonial governors retained control of their militia and volunteer forces, and by the end of the century, at the latest, any unit wholly or partly funded from Army funds was considered part of the British Army) and the early years of the 20th century, whereby the Reserve Forces units mostly lost their own identities and became numbered Territorial Force sub-units of regular British Army corps or regiments (the Home Militia had followed this path, with the Militia Infantry units becoming numbered battalions of British Army regiments, and the Militia Artillery integrating within Royal Artillery territorial divisions in 1882 and 1889, and becoming parts of the Royal Field Artillery or Royal Garrison Artillery in 1902 (though retaining their traditional corps names), but was not merged into the Territorial Force when it was created in 1908 (by the merger of the Yeomanry and Volunteer Force). The Militia was instead renamed the Special Reserve, and was permanently suspended after the First World War (although a handful of Militia units survived in the United Kingdom, its colonies, and the Crown Dependencies). Unlike the Home, Imperial Fortress and Crown Dependency Militia and Volunteer units and forces that continued to exist after the First World War, although parts of the British military, most were not considered parts of the British Army unless they received Army funds, as was the case for the Bermuda Militia Artillery and the Bermuda Volunteer Rifle Corps, which was generally only the case for those in the Channel Islands or the Imperial Fortress colonies (Nova Scotia, before Canadian confederation, Bermuda, Gibraltar, and Malta). Today, the British Army is the only Home British military force (unless the Army Cadet Force and the Combined Cadet Force are considered), including both the regular army and the forces it absorbed, though British military units organised on Territorial lines remain in British Overseas Territories that are still not considered formally part of the British Army, with only the Royal Gibraltar Regiment and the Royal Bermuda Regiment (an amalgam of the old Bermuda Militia Artillery and Bermuda Volunteer Rifle Corps) appearing on the British Army order of precedence and in the Army List. Confusingly, and similarly to the dual meaning of the word Corps in the British Army. As an example, the 1st Battalion of the King's Royal Rifle Corps was in 1914 part of the 6th Brigade that was part of the 2nd Infantry Division, which was itself part of 1st Army Corps), the British Army sometimes also used the term expeditionary force or field force to describe a body made up of British Army units, most notably the British Expeditionary Force, or of a mixture of British Army, Indian Army, or Imperial auxiliary units, such as the Malakand Field Force (this is similarly to the naval use of the term task force). In this usage, force is used to describe a self-reliant body able to act without external support, at least within the parameters of the task or objective for which it is employed. === British Empire === During the later half of the 17th century, and in particular, throughout the 18th century, British foreign policy sought to contain the expansion of rival European powers through military, diplomatic and commercial means, especially of its chief competitors Spain, the Netherlands, and France. This saw Britain engage in a number of intense conflicts over colonial possessions and world trade, including a long string of Anglo-Spanish and Anglo-Dutch wars, as well as a series of "world wars" with France, such as; the Seven Years' War (1756–1763), the French Revolutionary Wars (1792–1802) and the Napoleonic Wars (1803–1815). During the Napoleonic wars, the Royal Navy victory at Trafalgar (1805) under the command of Horatio Nelson (aboard HMS Victory) marked the culmination of British maritime supremacy, and left the Navy in a position of uncontested hegemony at sea. By 1815 and the conclusion of the Napoleonic Wars, Britain had risen to become the world's dominant great power and the British Empire subsequently presided over a period of relative peace, known as Pax Britannica. With Britain's old rivals no-longer a threat, the 19th century saw the emergence of a new rival, the Russian Empire, and a strategic competition in what became known as The Great Game for supremacy in Central Asia. Britain feared that Russian expansionism in the region would eventually threaten the Empire in India. In response, Britain undertook a number of pre-emptive actions against perceived Russian ambitions, including the First Anglo-Afghan War (1839–1842), the Second Anglo-Afghan War (1878–1880) and the British expedition to Tibet (1903–1904). During this period, Britain also sought to maintain the balance of power in Europe, particularly against Russian expansionism, who at the expense of the waning Ottoman Empire had ambitions to "carve up the European part of Turkey". This ultimately led to British involvement in the Crimean War (1854–1856) against the Russian Empire. === First World War === The beginning of the 20th century served to reduce tensions between Britain and the Russian Empire, partly due to the emergence of a unified German Empire. The era brought about an Anglo-German naval arms race, which encouraged significant advancements in maritime technology, including Dreadnoughts, torpedoes, submarines), and, in 1906, Britain determined that its only likely naval enemy was Germany. The accumulated tensions in European relations finally broke out into the hostilities of the First World War (1914–1918), in what is recognised today, as the most devastating war in British military history, with nearly 800,000 men killed and over 2 million wounded. Allied victory resulted in the defeat of the Central Powers, the end of the German Empire, the Treaty of Versailles and the establishment of the League of Nations. === Second World War === Germany was defeated in the First World War, but by 1933 fascism had given rise to Nazi Germany, which under the leadership of Adolf Hitler re-militarised in defiance of the Treaty of Versailles. Once again tensions accumulated in European relations, and following Germany's invasion of Poland in September 1939, the Second World War began (1939–1945). The conflict was the most widespread in British history, with British Empire and Commonwealth troops engaged in military campaigns in Europe, North Africa, the Middle East, and the Far East. Approximately 390,000 British Empire and Commonwealth troops died. Allied victory resulted in the defeat of the Axis powers and the establishment of the United Nations, replacing the League of nations. === Cold War === Post–Second World War economic and political decline, as well as changing attitudes in British society and government, were reflected by the armed forces' contracting global role, and later epitomised by its political defeat during the Suez Crisis (1956). Reflecting Britain's new role in the world and the escalation of the Cold War (1947–1991), the country became a founding member of the NATO military alliance in 1949. Defence Reviews, such as those in 1957 and 1966, announced significant reductions in conventional forces, the pursuement of a doctrine based on nuclear deterrence, and a permanent military withdrawal east of Suez. By the mid-1970s, the armed forces had reconfigured to focus on the responsibilities allocated to them by NATO. The British Army of the Rhine and RAF Germany consequently represented the largest and most important overseas commitments that the armed forces had during this period, while the Royal Navy developed an anti-submarine warfare specialisation, with a particular focus on countering Soviet submarines in the Eastern Atlantic and North Sea. While NATO obligations took increased prominence, Britain nonetheless found itself engaged in a number of low-intensity conflicts, including a spate of insurgencies against colonial occupation. However the Dhofar Rebellion (1962–1976) and The Troubles (1969–1998) emerged as the primary operational concerns of the armed forces. Perhaps the most important conflict during the Cold War, at least in the context of British defence policy, was the Falklands War (1982). Since the end of the Cold War, an increasingly international role for the armed forces has been pursued, with re-structuring to deliver a greater focus on expeditionary warfare and power projection. This entailed the armed forces often constituting a major component in peacekeeping and humanitarian missions under the auspices of the United Nations, NATO, and other multinational operations, including: peacekeeping responsibilities in the Balkans and Cyprus, the 2000 intervention in Sierra Leone and participation in the UN-mandated no-fly zone over Libya (2011). Post-9/11, the armed forces became heavily committed to the War on Terror (2001–present), with lengthy campaigns in Afghanistan (2001–2021) and Iraq (2003–2009), and more recently as part of the Military intervention against ISIL (2014–present). Britain's military intervention against Islamic State was expanded following a parliamentary vote to launch a bombing campaign over Syria; an extension of the bombing campaign requested by the Iraqi government against the same group. In addition to the aerial campaign, the British Army has trained and supplied allies on the ground and the Special Air Service, the Special Boat Service, and the Special Reconnaissance Regiment (British special forces) has carried out various missions on the ground in both Syria and Iraq. The armed forces have also been called upon to assist with national emergencies through the provisions of the military aid to the civil authorities (MACA) mechanism. This has seen the armed forces assist government departments and civil authorities responding to flooding, food shortages, wildfires, terrorist attacks and the COVID-19 pandemic; the armed forces' support to the latter falls under Operation Rescript, described as the UK's "biggest ever homeland military operation in peacetime" by the Ministry of Defence. Figures released by the Ministry of Defence on 31 March 2016 show that 7,185 British Armed Forces personnel have lost their lives in medal earning theatres since the end of the Second World War. == Today == === Command === King Charles III, sovereign of the United Kingdom, is the Head of the Armed Forces, with officers and personnel swearing allegiance to him. Long-standing constitutional convention, however, has de facto vested military authority and associated royal prerogative powers in the prime minister and the secretary of state for defence, with the former (acting with the support of the Cabinet) making the key decisions on the use of the armed forces. As the prime minister is not the formal head of the armed forces, the chief of the defence staff could refuse a direction by them to use the UK's nuclear arsenal. The Ministry of Defence is the government department charged with formulating and executing defence policy. It currently employs 56,860 civilian staff members as of 1 October 2015. The department is administered by the secretary of state for defence who is assisted by the Minister of State for the Armed Forces, Minister for Defence Procurement, and Minister for Veterans' Affairs. Responsibility for the management of the forces is delegated to a number of committees: the Defence Council, Chiefs of Staff Committee, Defence Management Board and three single-service boards. The Defence Council, composed of senior representatives of the services and the Ministry of Defence, provides the "formal legal basis for the conduct of defence". The three constituent single-service committees (Admiralty Board, Army Board and Air Force Board) are chaired by the secretary of state for defence. The chief of the defence staff (CDS) is the senior-most officer of the armed forces and is an appointment that can be held by an admiral, air chief marshal or general. Before the practice was discontinued in the 1990s, those who were appointed to the position of CDS had been elevated to the most senior rank in their respective service. The CDS, along with the permanent under secretary, are the principal military advisers to the secretary of state. All three services have their own respective professional chiefs; the First Sea Lord for the Royal Navy, the chief of the general staff for the Army and the chief of the air staff for the Royal Air Force. === Personnel === As of 1 July 2023 the British Armed Forces are a professional force with a total strength of 185,980 personnel, consisting of 140,300 UK Regulars and 4,140 Gurkhas, 33,210 Volunteer Reserves and 8,330 "Other Personnel". As a percentage breakdown of UK Service Personnel, 77.1% are UK Regulars and Gurkhas, 18.8% are Volunteer Reserves and 4.1% are composed of Other Personnel. In addition, all ex-Regular personnel retain a "statutory liability for service" and are liable to be recalled (under Section 52 of the Reserve Forces Act (RFA) 1996) for duty during wartime, which is known as the Regular Reserve. MoD publications since April 2013 no longer report the entire strength of the Regular Reserve, instead they only give a figure for Regular Reserves who serve under a fixed-term reserve contract. These contracts are similar in nature to those of the Volunteer Reserve. The distribution of personnel between the services and categories of service on 1 July 2023 was as follows: On 1 April 2024, most personnel in the UK Regular Forces were stationed in the United Kingdom (around 96%). Of the 5,700 personnel stationed overseas, around two thirds were in Europe (66%), while 14% were stationed in North America, 6% in North Africa and the Middle East, 6% in Asia and 5% in Sub-Saharan Africa. 1,230 personnel were distributed across several regions in Germany, primarily North Rhine-Westphalia as part of British Army Germany. However, up to 750 of these were Locally Engaged Civilians. === Defence expenditure === According to the Stockholm International Peace Research Institute, the United Kingdom is in sixth place in the world's military spending list in 2023. For comparison: Great Britain spends more in absolute terms than Germany, Ukraine, France or Japan, similar to Saudi Arabia, but less than India, Russia, China or the United States. In September 2011, according to Professor Malcolm Chalmers of the Royal United Services Institute, current "planned levels of defence spending should be enough for the United Kingdom to maintain its position as one of the world's top military powers, as well as being one of NATO-Europe's top military powers. Its edge – not least its qualitative edge – in relation to rising Asian powers seems set to erode, but will remain significant well into the 2020s, and possibly beyond." The Strategic Defence and Security Review 2015 committed to spending 2% of GDP on defence and announced a £178 billion investment over ten years in new equipment and capabilities. On 8 March 2023 Prime Minister Rishi Sunak announced a further £5bn in defence spending with a long-term goal of an increased spending to 2.5% of GDP. === Nuclear weapons === The United Kingdom is one of five recognised nuclear weapon states under the Non-Proliferation Treaty and maintains an independent nuclear deterrent, currently consisting of four Vanguard-class ballistic missile submarines, UGM-133 Trident II submarine-launched ballistic missiles, and 160 operational thermonuclear warheads. This is known as Trident in both public and political discourse (with nomenclature taken after the UGM-133 Trident II ballistic missile). Trident is operated by the Royal Navy Submarine Service, charged with delivering a 'Continuous At-Sea Deterrent' (CASD) capability, whereby one of the Vanguard-class strategic submarines is always on patrol. According to the British Government, since the introduction of Polaris (Trident's predecessor) in the 1960s, from April 1969 "the Royal Navy's ballistic missile boats have not missed a single day on patrol", giving what the Defence Council described in 1980 as a deterrent "effectively invulnerable to pre-emptive attack". As of 2015, it has been British Government policy for the Vanguard-class strategic submarines to carry no more than 40 nuclear warheads, delivered by eight UGM-133 Trident II ballistic missiles. In contrast with the other recognised nuclear weapon states, the United Kingdom operates only a submarine-based delivery system, having decommissioned its tactical WE.177 free-fall bombs in 1998. The House of Commons voted on 18 July 2016 in favour of replacing the Vanguard-class submarines with a new generation of Dreadnought-class submarines. The programme will also contribute to extending the life of the UGM-133 Trident II ballistic missiles and modernise the infrastructure associated with the CASD. Former weapons of mass destruction possessed by the United Kingdom include both biological and chemical weapons. These were renounced in 1956 and subsequently destroyed. === Overseas military installations === The British Armed Forces historically relied on four Imperial fortress colonies (Bermuda, Gibraltar, Halifax and its environs in Nova Scotia, and Malta), where dockyards were established, naval squadrons based, soldiers garrisoned, and naval and military stores stockpiled. These acted as lynchpins in maintaining British naval supremacy on the Atlantic and its connected seas. As, until the end of the First World War, it was presumed the only navies that might prove a threat were all of countries on, or off, the Atlantic, no Imperial fortress was established in the Pacific or Indian Oceans, to which power would be extended from Bermuda and Malta following the completion of the Panama and Suez canals. Local-service military reserve units were raised in some of the Imperial fortresses (notably Bermuda and Malta), which could be embodied for full time service in war time to reinforce the regular garrisons, and these were funded by the War Office as part of the British Army. After the First World War, the growing belligerence and naval power of the Japanese Empire led to the construction of the Singapore Naval Base. The regular British Armed Forces otherwise were distributed around the world where required to guard against invasion or rebellion, reinforced in some colonies by locally raised reserve forces. In colonies where there was no strategic requirement, regular forces were rarely stationed, with local governments encouraged to maintain and fund military reserve units as contributions to their own defence (although these units were ultimately under the control of the national, i.e. British, Government via the colonial Governors as defence is not a competency that has been delegated to local governments). Under the North Atlantic Treaty Organisation alliance, and with the steady reduction of both the British Empire and the British Armed Forces over the decades that followed the Second World War, the significance of the three remaining Imperial fortresses (military control of Halifax having passed to the new Dominion government following the 1867 Confederation of Canada, and naval control transferred in 1905 to what was to become the Royal Canadian Navy) rapidly faded. The Bermuda-based North America and West Indies Station was abolished in 1956, and the last regular army units removed from the Bermuda Command in 1957 (leaving only two part-time reserve units), with the naval dockyard in Bermuda reduced to a base, without repair or refit capabilities, in 1951 and finally closed in 1995, following the Cold War (United States and Canadian bases in Bermuda closed in the same period), leaving only the Royal Bermuda Regiment and the Bermuda Sea Cadet Corps there today. Malta became independent in 1964, and the last British armed forces personnel were removed from the former colony in 1979. Gibraltar continues to be used by the regular British Armed Forces, though the naval and military establishment in the colony (now termed a British Overseas Territory) has been reduced to several Royal Naval patrol craft, the locally raised Royal Gibraltar Regiment, and a Royal Air Force Station without aircraft based on it. The British Armed Forces today maintain a number of overseas garrisons and military facilities which enable the country to conduct operations worldwide. The majority of Britain's permanent military installations are located on British Overseas Territories (BOTs) or former colonies which retain close diplomatic ties with the United Kingdom, and located in areas of strategic importance. The most significant of these are the "Permanent Joint Operating Bases" (PJOBs), located on the four overseas territories of Cyprus (British Forces Cyprus), Gibraltar (British Forces Gibraltar), the Falkland Islands (British Forces South Atlantic Islands) and Diego Garcia (British Forces British Indian Ocean Territories). While not a PJOB, Ascension Island (another BOT) is home to the airbase RAF Ascension Island, notable for use as a staging post during the 1982 Falklands War, the territory is also the site of a joint UK-US signals intelligence facility. Qatar is home to RAF Al Udeid, a Royal Air Force outpost at Al Udeid Air Base which serves as the operational headquarters for No. 83 Expeditionary Air Group and its operations across the Middle East. A large Royal Navy Naval Support Facility (NSF) is located in Bahrain, established in 2016 it marks the British return East of Suez. In support of the Five Power Defence Arrangements (FPDA), the United Kingdom retains a naval repair and logistics support facility at Sembawang wharf, Singapore. Other overseas military installations include; British Forces Brunei, British Forces Germany, the British Army Training Unit Kenya, British Army Training Unit Suffield in Canada, British Army Training and Support Unit Belize, and British Gurkhas Nepal. Some British Overseas Territories also maintain locally raised units and regiments; The Royal Bermuda Regiment, the Falkland Islands Defence Force, the Royal Gibraltar Regiment, the Royal Montserrat Defence Force, the Cayman Islands Regiment, and the Turks and Caicos Regiment. Though their primary mission is "home defence", individuals have volunteered for operational duties. The Royal Bermuda Regiment is an amalgam of the Bermuda Militia Artillery (which had been part of the Royal Regiment of Artillery) and the Bermuda Volunteer Rifle Corps, raised in the 1890s as Imperial forces funded by the War Office as part of the British Army, and both antecedent units sent contingents to the Western Front during the First World War. They also sent contingents that served in North-Western Europe, and Italy and North Africa during the Second World War. The Royal Gibraltar Regiment mobilised section-sized units for attachment to British regiments deployed during the Iraq War. The Isle of Man, a Crown dependency hosts a multi-capability recruiting and training unit of the British Army Reserve. Since 1969 Britain has had a military satellite communications system, Skynet, initially in large part to support East of Suez bases and deployments. Since 2015 Skynet has offered near global coverage. === Expeditionary forces === The British Armed Forces place significant importance in the ability to conduct expeditionary warfare. While the armed forces are expeditionary in nature, it maintains a core of "high readiness" forces trained and equipped to deploy at very short notice, these include; the Joint Expeditionary Force (Maritime) (Royal Navy), UK Commando Force (Royal Marines), and 16 Air Assault Brigade (British Army). Frequently, these forces will act as part of a larger tri-service effort, under the direction of Permanent Joint Headquarters, or along with like-minded allies under the Joint Expeditionary Force. Similarly, under the auspices of NATO, such expeditionary forces are designed to meet Britain's obligations to the Allied Rapid Reaction Corps and other NATO operations. In 2010, the governments of the United Kingdom and France signed the Lancaster House Treaties which committed both governments to the creation of a Franco-British Combined Joint Expeditionary Force. It is envisaged as a deployable joint force, for use in a wide range of crisis scenarios, up to and including high intensity combat operations. As a joint force it involves all three armed Services: a land component composed of formations at national brigade level, maritime and air components with their associated Headquarters, together with logistics and support functions. == The Armed Forces == === Royal Navy === The Royal Navy is a technologically sophisticated naval force, and as of December 2024 consists of 62 commissioned ships with an additional 11 support vessels of various types operated by the Royal Fleet Auxiliary. Command of deployable assets is exercised by the Fleet Commander of the Naval Service. Personnel matters are the responsibility of the Second Sea Lord/Commander-in-Chief Naval Home Command, an appointment usually held by a vice-admiral. The Surface Fleet consists of aircraft carriers, destroyers, frigates, patrol vessels, mine-countermeasure vessels, and other miscellaneous vessels. The Surface Fleet has been structured around a single fleet since the abolition of the Eastern and Western fleets in 1971. The recently built Type 45 destroyers are stealthy and technologically advanced air-defence destroyers. The Royal Navy has commissioned two Queen Elizabeth-class aircraft carriers, embarking an air-group including the advanced fifth-generation multi-role fighter, the F-35B Lightning. A submarine service has existed within the Royal Navy for more than 100 years. The Submarine Service's four Vanguard-class nuclear-powered submarines carry Trident II ballistic missiles, forming the United Kingdom's nuclear deterrent. Seven Astute-class nuclear-powered fleet (attack) submarines have been ordered, with five completed and two under construction. The Astute class are the most advanced and largest fleet submarines ever built for the Royal Navy and will maintain Britain's nuclear-powered submarine fleet capabilities for decades to come. ==== Royal Marines ==== The Royal Marines are the Royal Navy's amphibious troops. Consisting of a single manoeuvre brigade (UK Commando Force) and various independent units, the Royal Marines specialise in amphibious, arctic, and mountain warfare. Contained within UK Commando Force are three attached army units; 383 Commando Petroleum Troop RLC, 29th Commando Regiment Royal Artillery, a field artillery regiment based in Plymouth, and 24 Commando Regiment Royal Engineers. The Commando Logistic Regiment consists of personnel from the Army, Royal Marines, and Royal Navy. === British Army === The British Army is the land force of the British Armed Forces, and is made up of the Regular Army and the part-time Army Reserve. The Army is commanded by the Chief of the General Staff, a four-star general within Army Headquarters, based at Andover. Deployable combat formations are; 1st (UK) Division, consisting of 16 Air Assault Brigade Combat Team and four other Light or Light Mechanised Brigade Combat Teams, with supporting engineering, logistic, intelligence and signals units. 3rd (UK) Division, consisting of 1st Deep Recce Strike Brigade Combat Team, 7 Air Defence Group, and two Armoured Brigade Combat Teams, with supporting engineering, logistic, intelligence and signals units. Field Army Troops, consisting of the new Ranger Regiment, in Army Special Operations Brigade; Security Force Assistance Brigade and 77 Brigade, a psychological operations unit. The Infantry of the British Army has a strength of 48 battalions (32 regular and 16 reserve), structured under 17 unique regiments. These battalions are trained and equipped for specific roles within their respective Brigade Combat Teams (BCT); Light Infantry, such as the famous 1st Battalion Grenadier Guards, within the 4th Light Brigade Combat Team, fight on foot without armoured vehicles; Light Mechanised Infantry, such as the 1st Battalion Royal Yorkshire Regiment, within the 7th Light Mechanised Brigade Combat Team, operate the Foxhound protected mobility vehicle; Armoured Infantry (to become Heavy Mechanised Infantry under Future Soldier), such as the 1st Battalion Royal Regiment of Fusiliers, within the 20th Armoured Infantry Brigade Combat Team, operate the Warrior infantry fighting vehicle (IFV), but will be equipped with the new Boxer mechanised infantry vehicle from 2024. The four battalions of the Parachute Regiment, forming 16 Air Assault Brigade Combat Team and part of Special Forces Support Group, are the British Army's elite airborne infanteers, held at high readiness and specialising in rapid deployment by parachute and helicopter, widely regarded as the "fittest, most aggressive, resilient and disciplined regiment in the British Army." The Royal Armoured Corps provides the armoured capability of the British Army. The Royal Tank Regiment, Queen's Royal Hussars and Royal Wessex Yeomanry (of the Army Reserve) operate Challenger 2 main battle tanks, which are being upgraded to Challenger 3, and are part of 3rd (UK) Division's Armoured Brigade Combat Teams. Armoured Cavalry regiments, such as the Royal Dragoon Guards, currently operate the Warrior IFV on an interim basis, until Ajax reaches full operating capability. There are six Light Cavalry regiments (three Regular + three Reserve) equipped with the Jackal 2 and Coyote TSV, tasked with providing reconnaissance and fire support. The Household Cavalry, made up of the Life Guards and the Blues and Royals, operate in a dual role of Armoured Cavalry and Mounted Ceremonial on Horse Guards in London, and for state occasions. === Royal Air Force === The Royal Air Force has a large operational fleet that fulfils various roles, consisting of both fixed-wing and rotary aircraft. Frontline aircraft are controlled by Air Command, which is organised into five groups defined by function: 1 Group (Air Combat), 2 Group (Air Support), 11 Group (Air and Space operations), 22 Group (training aircraft and ground facilities) and 38 Group (Royal Air Force's Engineering, Logistics, Communications and Medical Operations units). In addition 83 Expeditionary Air Group directs formations in the Middle East and the 38 Group combines the expeditionary combat support and combat service support units of the RAF. Deployable formations consist of Expeditionary Air Wings and squadrons—the basic unit of the Air Force. Independent flights are deployed to facilities in Brunei, the Falkland Islands, Iraq, and the United States. The Royal Air Force operates multi-role and single-role fighters, reconnaissance and patrol aircraft, tankers, transports, helicopters, unmanned aerial vehicles, and various types of training aircraft. Ground units are also maintained by the Royal Air Force, most prominently the RAF Police and the Royal Air Force Regiment (RAF Regt). The Royal Air Force Regiment essentially functions as the ground defence force of the RAF, optimised for the specialist role of fighting on and around forward airfields, which are densely packed with operationally vital aircraft, equipment, infrastructure and personnel. The Regiment contains nine regular squadrons, supported by five squadrons of the Royal Auxiliary Air Force Regiment. In addition, it provides Forward Air Controllers to defence as well as a contribution to the Special Forces Support Group. == Ministry of Defence == The Ministry of Defence maintains a number of civilian agencies in support of the British Armed Forces. Although they are civilian, they play a vital role in supporting Armed Forces operations, and in certain circumstances are under military discipline: The Royal Fleet Auxiliary (RFA) operates 11 ships which primarily serve to replenish Royal Navy warships at sea, and also provides an amphibious warfare capability through its three Bay-class landing ship dock vessels and the aviation support ship RFA Argus. It is manned by 1,750 civilian personnel and is funded and run by the Ministry of Defence. The Ministry of Defence Police (MDP) has an established strength of 2,700 police officers which provide armed security, counter terrorism, uniformed policing and investigative services to Ministry of Defence property, personnel, and installations throughout the United Kingdom. The Defence Equipment and Support (DE&S) is the merged procurement and support organisation within the UK Ministry of Defence (United Kingdom). It came into being on 2 April 2007, bringing together the MoD's Defence Procurement Agency and the Defence Logistics Organisation under the leadership of General Sir Kevin O'Donoghue as the first Chief of Defence Materiel. As of 2012 it has a civilian and military workforce of approx. 20,000 personnel. DE&S is overseen by the Minister for Defence Equipment, Support and Technology. The UK Hydrographic Office (UKHO) is an organisation within the UK government responsible for providing navigational and other hydrographic information for national, civil and defence requirements. The UKHO is located in Taunton, Somerset, on Admiralty Way and has a workforce of approximately 1,000 staff. == Recruitment == All three services of the British Armed Forces recruit primarily from within the United Kingdom, although citizens from the Commonwealth of Nations and the Republic of Ireland are equally eligible to join. The minimum recruitment age is 16 years (although personnel may not serve on armed operations below 18 years, and if under 18 must also have parental consent to join); the maximum recruitment age depends whether the application is for a regular or reserve role; there are further variations in age limit for different corps/regiments. The normal term of engagement is 22 years; however, the minimum service required before resignation is 4 years, plus, in the case of the Army, any service person below the age of 18. A note to add is that in the United Kingdom, people may join the "Cadet Forces" such as the army cadets, Royal Air Force Air Cadets or the sea and Royal Marine Cadets. Young people may join these organisations which are either funded or affiliated with the MOD from the age of 13-18, there is no obligation to then join the armed forces however it teaches key skills in both civilian and military life and is a key recruitment drive for the armed forces. At present, the yearly intake into the armed forces is 11,880 (per the 12 months to 31 March 2014). Excluding the Brigade of Gurkhas and the Royal Irish Regiment, as of 1 April 2014 there are approximately 11,200 Black and Minority Ethnic (BME) persons serving as Regulars across the three service branches; of those, 6,610 were recruited from outside the United Kingdom. In total, Black and Minority Ethnic persons represent 7.1% of all service personnel, an increase from 6.6% in 2010. Since the year 2000, sexual orientation has not been a factor considered in recruitment, and homosexuals can serve openly in the armed forces. All branches of the forces have actively recruited at Gay Pride events. The forces keep no formal figures concerning the number of gay and lesbian serving soldiers, saying that the sexual orientation of personnel is considered irrelevant and not monitored. === Role of women === Women have been part of the armed forces, on and off, for centuries, more fully integrated since the early 1990s, including flying fast jets and commanding warships or artillery batteries. As of 1 April 2014, there were approximately 15,840 women serving in the armed forces, representing 9.9% of all service personnel. The first female military pilot was Flight Lieutenant Julie Ann Gibson while Flight Lieutenant Jo Salter was the first fast-jet pilot, the latter flying a Tornado GR1 on missions patrolling the then Northern Iraqi No-Fly Zone. Flight Lieutenant Juliette Fleming and Squadron Leader Nikki Thomas recently were the first Tornado GR4 crew. While enforcing the Libyan No-Fly Zone, Flight Lieutenant Helen Seymour was identified as the first female Eurofighter Typhoon pilot. In August 2011, it was announced that a female lieutenant commander, Sarah West, was to command the frigate HMS Portland. In July 2016, it was announced that women would be allowed to serve in close combat, starting with the Royal Armoured Corps. In July 2017, the Secretary of Defence announced that women would be allowed to enlist in the RAF Regiment from September 2017, a year ahead of schedule. In 2018, women were allowed to apply for all roles in the British military, including the special forces. As of 10 June 2024, the most senior serving woman is four-star General Dame Sharon Nesmith. == March == == See also == Armed Forces Day (United Kingdom) List of military equipment of the United Kingdom Atholl Highlanders – The only legal private army in Europe under the command of the Duke of Atholl in Scotland Banknotes of the British Armed Forces British Forces Broadcasting Service Community Cadet Forces Military Covenant – The mutual obligations between the nation and its Armed Forces. Network-enabled capability – British military concept of achieving enhanced military effect through the better use of information systems. Similar to the US concept of network-centric warfare. The Championships, Wimbledon#Services stewards Uniforms of the British Armed Forces Military history of Scotland Armed forces in Scotland Armed forces in Wales == Notes == == References == == External links == British Ministry of Defence (gov.uk) Defence Academy of the United Kingdom (.da.mod.uk) Royal Navy official website (royalnavy.mod.uk) Royal Marines official webpage (royalnavy.mod.uk) British Army official website (army.mod.uk) Royal Air Force official website (raf.mod.uk)	Wikipedia/British_Armed_Forces
Ethnic plastic surgery, or ethnic modification, refers to the types of plastic surgery performed frequently due to certain racial or ethnic traits, or with the intention of making one's appearance more similar or less similar to people of a particular race or ethnicity. Popular procedures which may have an ethnically motivated component are rhinoplasties (nose jobs) and blepharoplasties (double eyelid surgeries). Michael Jackson's plastic surgery has been discussed in the context of ethnic plastic surgery. In her book, Venus Envy: A History of Cosmetic Surgery, Elizabeth Haiken devotes a chapter to "The Michael Jackson Factor" presenting "Black, Asian, and Jewish women who seek WASP noses and Playboy breasts. They are caught in the vexed immigrants' dilemma of struggling not only to keep up with the Joneses but to look like them, too." == Ethical considerations == Plastic surgeons Chuma J. Chike-Obi, M.D., Kofi Boahene, M.D., and Anthony E. Brissett, M.D., F.A.C.S. distinguish between motivations of aesthetics and racial transformation for patients of African descent seeking plastic surgery. In their opinion, "Patients whose desired surgical outcomes result in racial transformation should be educated about the potential risks of this objective, and these requests should generally be discouraged." Feminist scholars have split views on the subject. Christine Overall, professor of philosophy at Queen's University at Kingston, has written that personal racial transformation, or as she puts it "transracialism", belongs to a larger class of personal surgical interventions. This larger class includes transsexual identity change, body art, cosmetic surgery, Munchhausen syndrome, and labiaplasty. Her basic thesis is that the arguments against the ethical nature of racial transformation (e.g. "it's not possible", "betrayal of group identity", "reinforces oppression", etc.) stand or fall with the ethical arguments related to transsexual change. Cressida Heyes, professor of Philosophy of Gender and Sexuality at the University of Alberta, disagrees with Overall's schema. Heyes feels that racial transformation is fundamentally different from gender transformation since race is also determined by ancestry, personal cultural history and societal definitions. Hence ethical considerations of transracial surgery are different from ethical considerations in transsexual surgery. == In popular culture == In the South Park episode "Mr. Garrison's Fancy New Vagina" Kyle undergoes an ethnic plastic surgery called "negroplasty" to qualify for the basketball team. In the 2008 movie Tropic Thunder, Kirk Lazarus goes through a controversial surgery to make his skin darker to play an African-American soldier. == See also == Allophilia Good hair Health and appearance of Michael Jackson Martina Big Oli London The Operated Jew Passing (racial identity) Skin whitening Transracial (identity) == References ==	Wikipedia/Ethnic_plastic_surgery
Plastic Surgery (formerly Canadian Journal of Plastic Surgery) is a peer-reviewed medical journal dealing with plastic surgery. It is the official journal of several national Canadian societies: the Canadian Society of Plastic Surgeons, the Canadian Society for Aesthetic (Cosmetic) Plastic Surgery, the Groupe pour l'Avancement de la Microchirurgie Canada, and the Canadian Society for Surgery of the Hand (Manus Canada). The journal covers both research and material dealing with continuing medical education and society guidelines. It was published by the Pulsus Group, which was placed on Jeffrey Beall's list of "Potential, possible, or probable" predatory open-access publishers following its sale to OMICS Publishing Group. The journal subsequently switched publishers and is now published by SAGE Publications. == Abstracting and indexing == The journal is abstracted and indexed in EBSCO databases and the Science Citation Index Expanded. According to the Journal Citation Reports, the journal has a 2020 impact factor of 0.947. == References == == External links == Official website	Wikipedia/Plastic_Surgery_(journal)
Prison plastic surgery is plastic surgery or cosmetic surgery (often the terms are used interchangeably) offered and performed to people who are incarcerated, as a means of social rehabilitation. These services were normally provided as part of a larger package of care that may include work training, psychological services, and more. Popular surgeries included rhinoplasties, blepharoplasty, facelifts, scar removal and tattoo removal. These programs began in the early 20th century and were commonplace up till the early 1990s. They took place across the US (in 42+ states), the UK, Canada, and Mexico. "Incarceration itself is famously hard on the body," reports journalist and author Zara Stone in her book, Killer Looks: The Forgotten History of Plastic Surgery In Prisons; in 2017, facial injuries accounted for 33% of all inmate hospitalizations in New York City, compared to 0.7 percent of the general population. "The existence of prison plastic surgery programs is America’s dirty little secret." In San Quentin prison, California, the prison's chief medical doctor Dr. Leo L. Stanley was one of the first people to develop a prison plastic surgery practice, focused on reforming the faces of convicts. "Considerable plastic surgery has been done, particularly that done for deformed noses,” Dr. Leo Stanley wrote in his 1918 report to the warden. “This work has been of benefit in that it has improved the appearance of many of the men and removed a deforming feature. Some work has been done on ears which were very prominent." Stanley reported long waiting lists, noted researcher Ethan Blue. Dr. Stanley's "typical prison malingerer," had a fractured nose or scarred face, and was treated with crude methods: for nose surgery, a six-inch length of broomstick was placed against the nose and hit with a mallet. "The physician of the future will be an increasing powerful antagonist in the war against crime," Stanley wrote. New York was an early adopter, with attention to prisoner beautification baked in from the early 1900s. In 1915, NYC police commissioner Arthur Woods referred to a 15-year-old inmate's appearance in relation to his crime. “He was an inferior looking lad, small and flabby...mild acne on the face...forehead broad, nose small, eyes rather sly…chin pointed and receding,” wrote Woods. Prison plastic surgery became more prevalent throughout the 20th century. In 1954 the American Correctional Association added prisoner plastic surgery to its manual, stating: “elective surgery…[for] especially repulsive facial disfigurements has a definite place in the rehabilitation of prisoners.” Many states followed suit, including Texas, North Carolina, and Hawaii. Some of these early surgeries fell in the eugenics bracket, the idea that criminality could be seen and displayed on the face, reports social Psychologist Ray Bull and Nichola Rumsey. An examination of some of the mid-20th century prison programs suggested that by and large, plastic surgeries did reduce recidivism—in some cases, dropping it from 76% to 33%. Some findings: Plastic surgery is effective in enhancing the outcome for non-addict prisoners. In 1970, the former director of the Federal Bureau of Prisons from 1937 to 1964, James Van Benschoten Bennett, analyzed these programs. "One of the more fruitful areas of research now under way in the federal prisons concerns plastic surgery: the way to rehabilitate a misshapen prisoner." "Discriminatory practices based on physical appearance perpetuate social inequalities and hinder individuals' opportunities for reintegration into society," noted author Zara Stone, in a Rockefeller research paper. == Ethical considerations == The scholar and feminist critic Jessica Mitford was one of the first to question the ethics of performing plastic surgery on prisoners, and if in such a circumstance the prisoners could really consent to such treatment. In her book, Kind and Usual Punishment, she wrote that one doctor told her that inmates had become “our companions in medical science.. . . . This has been a rewarding experience both for the physician and for the subjects.” This was in regards to a scurvy experiment where inmates suffered hemorrhages in the skin and whites of the eyes, excessive loss of hair, mental depressions, and abnormal emotional responses... at a time when scurvy was already curable and treatable." The writer Allen M. Hornblum explored the issue of consent in his book, Acres Of Skin, where he reported of strips of skin being flayed off the back of inmates that participated in dermatological trials in the Eastern Penitentiary, Pennsylvania. Ostensibly, they were volunteers, but a payment incentive was the reason for their volunteerism and abuse. == In popular culture == In the movie Dark Passage, Humphrey Bogart plays the role of Vincent Parry, a man sentenced for murder. Parry escapes San Quentin and undergoes plastic surgery to change his appearance and hide from the law while he tries to clear his name. In the 1996 movie A Face to Die For, Yasmine Bleeth plays the part of a scarred young woman that is conned into participating in a crime. In prison she gets plastic surgery as part of a reform program, and when released sets out to seek her revenge. == See also == Allophilia Passing (racial identity) Skin whitening Transracial (identity) Prison reform Prison healthcare – Medical treatment in prisons, jails, and other penal institutions == References ==	Wikipedia/Prison_plastic_surgery
Flap surgery is a technique in plastic and reconstructive surgery where tissue with an intact blood supply is lifted from a donor site and moved to a recipient site. Flaps are distinct from grafts, which do not have an intact blood supply and relies on the growth of new blood vessels. Flaps are done to fill a defect such as a wound resulting from injury or surgery when the remaining tissue is unable to support a graft, wound contraction is to be avoided or to rebuild more complex anatomic structures like breasts or jaws. Flaps may also carry with them tissues such as muscle and bone that may be useful in the ultimate reconstruction. == Uses == Flap surgery is a technique essential to plastic and reconstructive surgery. A flap is defined as tissue that can be moved to another site and has its own blood supply. This is in comparison to a skin graft which does not have its own blood supply and relies on vascularization from the recipient site. Flaps have many uses in wound healing and are used when wounds are large, complex, or need tissue of various types and bulk for successful closure and function. == Anatomy == Flaps can contain many different combination of layers of tissue, from skin to bone (see § Classification). The main goal of a flap is to maintain blood flow to tissue to maintain survival, and understanding the anatomy in flap design is key to a successful flap surgery. === Skin anatomy === Flaps may include skin in their construction. Skin is important for many reasons, but namely its role in thermoregulation, immune function, and blood supply aid in flap survival. The skin can be divided into three main layers: the epidermis, dermis, and subcutaneous tissue. Blood is mainly supplied to the skin by two networks of blood vessels. The deep network lies between the dermis and the subcutaneous tissue, while the shallow network lies within the papillary layer of the dermis. The epidermis is supplied by diffusion from this shallow network and both networks are supplied by collaterals, and by perforating arteries that bring blood from deeper layers either between muscles (septocutaneous perforators) or through muscles (musculocutaneous perforators). This robust and redundant blood supply is important in flap surgery, because flaps are cut off from other blood vessels when it is raised and removed from its surrounding native tissue. The remaining blood supply must then keep the tissue alive until additional blood supply can be formed through angiogenesis. === Angiosome === The angiosome is a concept first coined by Ian Taylor in 1987. It is a three-dimensional region of tissue that is supplied by a single artery and can include skin, soft tissue, and bone. Adjacent angiosomes are connected by narrower choke vessels, and multiple angiosomes can be supplied by a single artery. Knowledge of these supply arteries and their associated angiosomes is useful in planning the location, size, and shape of a flap. == Classification == Flaps can be fundamentally classified by their mechanism of movement, the types of tissues present, or by their blood supply. The surgeon generally chooses the least complex type that will achieve the desired effect via a concept known as the reconstructive ladder. === Mechanism of movement === Local flaps are created by freeing a layer of tissue and then stretching the freed layer to fill a defect. This is the least complex type of flap and includes advancement flaps, rotation flaps, and transposition flaps, in order from least to most complex. With an advancement flap, incisions are extended out parallel from the wound, creating a rectangle with one edge remaining intact. This rectangle is freed from the deeper tissues and then stretched (or advanced) forward to cover the wound. The flap is disconnected from the body except for the uncut edge which contains the blood supply which feeds in horizontally. A rotation flap is similar except instead of being stretched in a straight line, the flap is stretched in an arc. The more complex transposition flap involves rotating an adjacent piece of tissue, resulting in the creation of a new defect that must then be closed. Regional or interpolation flaps are not immediately adjacent to the defect. Instead, the freed tissue "island" is moved over or underneath normal tissue to reach the defect to be filled, with the blood supply still connected to the donor site via a pedicle. The pedicle can be removed after a new blood supply has formed. Examples: pectoralis major myocutaneous flap and deltopectoral flap for head and neck defects, and latissimus dorsi flap and traverse rectus abdominal muscle (TRAM) flap for breast reconstruction. Distant flaps are used when the donor site is far from the defect. These are the most complex class of flap. Direct or tubed flaps involve having the flap connected to both the donor and recipient sites simultaneously, forming a bridge. This allows blood to be supplied by the donor site while a new blood supply from the recipient site is formed. Once this happens, the bridge can be disconnected from the donor site if necessary, completing the transfer. A free flap has the blood supply cut and then reattached microsurgically to a new blood supply at the recipient site. === Tissue type === Flaps can be classified by the content of the tissue within them. Cutaneous flaps contain the full thickness of the skin, fat, and superficial fascia and are used to fill small defects. These are typically supplied by a random blood supply. Examples include Z-plasty, deep inferior epigastric perforator (DIEP) flaps, and V-Y advancement flaps. Fasciocutaneous flaps contain subcutaneous tissue and deep fascia, resulting in a more robust blood supply and ability to fill a larger defect. The Cormack and Lamberty classification is used for the vascular supply of faciocutaneous flaps. Examples: temporoparietal and anterolateral thigh fascocutaneous flap, lateral fasciocutaneous flap, posterior fasciocutaneous flap. Musculocutaneous and muscle flaps contain a layer of muscle to provide bulk that can fill a deeper defect. If skin cover is needed, a skin graft can be placed over top of it. Examples: gastrocnemius flap, latissimus dorsi flap, TRAM flap, and transverse upper gracillis flap. Bone flaps contain bone and are used when structural support is needed such as in jaw reconstruction. Example: fibula flap. Omental flaps can be used in chest wall defects, and intestinal flaps can be used to reconstruct tubular structures like the esophagus. === Vascular supply === Classification based on blood supply to the flap: Axial flaps are supplied by a named artery and vein. This allows for a larger area to be freed from surrounding and underlying tissue, leaving only a small pedicle containing the vessels. Reverse-flow flaps are a type of axial flap in which the supply artery is cut on one end and blood is supplied by backwards flow from the other direction. Random flaps are simpler and have no named blood supply; they are supplied by the subdermal plexus. Pedicled flaps remain attached to the donor site via a pedicle that contains the blood supply, in contrast to a free flap, where the vessels are cut and anastomosed to another blood supply. == Contraindications == Anyone who is unstable for surgery should not undergo flap surgery. As with most surgeries, people who are sicker may have more difficulties with wound healing, which include individuals with comorbidities such as diabetes, smoking, immunosuppression, and vascular disease. == Risks or complications == The risks of flap surgery include infection, wound breakdown, fluid accumulation, bleeding, damage to nearby structures, and scarring. The most notable risk in this procedure is flap death, where the flap loses blood supply. The loss of blood can be due to many reasons, but is commonly due to tension on the vascular supply and insufficient blood flow to the end segments of the flap. This can sometimes be fixed with another surgery or using additional methods of healing in the reconstructive ladder. == Recovery == As with healing of any wound, healing of a flap maintains the same process of wound healing. There are four stages to wound healing: hemostasis, inflammation, proliferation, and remodeling, all of which can take up to a year to complete. Following flap surgery, the biggest risk in recovery is flap death. Flap failure is an uncommon occurrence but does happen. The reported flap failure rate in free flaps is less than 5%. The most commonly cause is by venous insufficiency consisting of 54% of all causes. Venous insufficiency is commonly caused by a venous thrombus within the first 2 days following surgery. After the immediate postoperative risk, the flap will continue to heal adhering to the stages of normal wound healing and will take over 3 months for an incision to be at 80% tensile strength compared to normal tissue. == History == Skin flaps are an essential part of a surgeon's toolbox in plastic surgery. It is part of the reconstructive ladder. The first known reports of surgical flaps originated in 600 BC in India by Sushruta where the tilemakers' caste would reconstruct noses using regional flaps due to the practice of nose amputations as a form of legal punishment. The next description of flap surgery comes from Celsus, an ancient Roman who described the advancement of skin flaps from 25 BC to 50 AD. In the 15th century, Gaspare Tagliacozzi, an Italian surgeon, helped develop the "Italian method" for nasal reconstruction, a delayed pedicle skin graft, where the skin from the arm would be attached to the nose for many months to create the reconstruction, first printed in the 1597 book De Curtorum Chirurgia per Insitionem. The Italian method was rediscovered in 1800 by German surgeon Carl Ferdinand von Graefe. Major advancements in modern plastic surgery are mostly attributed to Harold Gillies, who pioneered facial reconstruction during World War I using pedicled tube flaps on patients like Walter Yeo, and the development of the walking-stalk skin flap by Gilles' cousin Archibald McIndoe in 1930. Advancements continued in flap surgery. With the introduction of the operating microscope, microvascular surgery advancements allowed for the anastomosis of blood vessels. This led to the ability of free tissue transfers, and in 1958 Bernard Seidenberg transferred a part of the jejunum to the esophagus to remove a cancer. Modern advancements in flap surgeries have continued since this time and are now commonly used in many procedures. == See also == Breast reconstruction DIEP flap Hand surgery List of plastic surgery flaps Perforator flaps Rhinoplasty Rotation flap Skin cancer Z-plasty == References == == External links == Flap surgery at eMedicine	Wikipedia/Flap_surgery
The British Armed Forces are the unified military forces responsible for the defence of the United Kingdom, its Overseas Territories and the Crown Dependencies. They also promote the UK's wider interests, support international peacekeeping efforts and provide humanitarian aid. The force is also known as His Majesty's Armed Forces. Since the formation of the united Kingdom of Great Britain in 1707 (later succeeded by the United Kingdom of Great Britain and Ireland, and finally by the United Kingdom of Great Britain and Northern Ireland), the British Armed Forces have seen action in most major wars involving the world's great powers, including the Seven Years' War, the American War of Independence, the Napoleonic Wars, the Crimean War, the First World War and the Second World War. Britain's victories in most of these wars allowed it to influence world events and establish itself as one of the world's leading military and economic powers. The British Armed Forces consist of: the Royal Navy, a blue-water navy with a fleet of 62 commissioned and active ships, together with the Royal Marines, a highly specialised amphibious light infantry force; the British Army, the UK's principal land warfare branch; and the Royal Air Force, a technologically sophisticated air force with a diverse operational fleet consisting of both fixed-wing and rotary aircraft. The British Armed Forces include standing forces, Regular Reserve, Volunteer Reserves and Sponsored Reserves. King Charles III, sovereign of the United Kingdom, is the commander-in-chief and is styled as Head of the Armed Forces, with officers and personnel swearing allegiance to him. Long-standing constitutional convention, however, has vested de facto executive authority, by the exercise of royal prerogative, in the Prime Minister and the secretary of state for defence. The Prime Minister (acting with the Cabinet) makes the key decisions on the use of the armed forces. The UK Parliament approves the continued existence of the British Army by passing an Armed Forces Act at least once every five years, as required by the Bill of Rights 1689. Only a "standing army" requires reapproval by Parliament; the Royal Navy, Royal Air Force and the Royal Marines and any other forces are not included in the requirement. The armed forces are managed by the Defence Council. The United Kingdom is one of five recognised nuclear powers, a permanent member on the United Nations Security Council, a founding and leading member of NATO and party to the AUKUS security pact and the Five Power Defence Arrangements. Overseas garrisons and training facilities are maintained at Ascension Island, Bahrain, Belize, Bermuda, British Indian Ocean Territory, Brunei, Canada, Cyprus, the Falkland Islands, Germany, Gibraltar, Kenya, Montserrat, Nepal, Qatar, Singapore and the United States. == History == === Organisation === With the Acts of Union 1707, the armed forces of England and Scotland were merged into the armed forces of the Kingdom of Great Britain. There were originally several naval and several military regular and reserve forces, although most of these were consolidated into the Royal Navy or the British Army during the 19th and 20th Centuries (the Royal Naval Air Service and the Royal Flying Corps of the British Army, by contrast, were separated from their parent forces in 1918 and amalgamated to form a new force, the Royal Air Force, which would have complete responsibility for naval, military and strategic aviation until the Second World War). Naval forces included the Royal Navy, the Waterguard, later renamed the HM Coastguard, and Sea Fencibles and River Fencibles formed as and when required for the duration of emergencies. The Merchant Navy and offshore fishing boat crews were also important manpower reserves to the armed naval forces. Any seaman was liable to impressment, with many so conscripted especially during the two decades of conflict from the French Revolution until the end of the Napoleonic Wars, and from 1835 registered on the Register of Seamen to identify them as a potential resource, and many of their seamen would serve part time in the Royal Navy Reserve, created under the Naval Reserve Act 1859, and Royal Naval Volunteer Reserve, created in 1903. The British military (those parts of the British Armed Forces tasked with land warfare, as opposed to the naval forces) historically was divided into a number of military forces, of which the British Army (also referred to historically as the 'Regular Army' and the 'Regular Force') was only one. The oldest of these organisations was the Militia Force (also referred to as the Constitutional Force), which (in the Kingdom of England) was originally the main military defensive force (there otherwise were originally only royal bodyguards, including the Yeomen Warders and the Yeomen of the Guard, with armies raised only temporarily for expeditions overseas), made up of civilians embodied for annual training or emergencies, and had used various schemes of compulsory service during different periods of its long existence. The Militia was originally an all infantry force, organised at the city or county level, and members were not required to serve outside of their recruitment area, although the area within which militia units in Britain could be posted was increased to anywhere in the Britain during the 18th century, and Militia coastal artillery, field artillery, and engineers units were introduced from the 1850s. The Yeomanry was a mounted force that could be mobilised in times of war or emergency. Volunteer Force units were also frequently raised during wartime, which did not rely on compulsory service and hence attracted recruits keen to avoid the Militia. These were seen as a useful way to add to military strength economically during wartime, but otherwise as a drain on the Militia and so were not normally maintained in peacetime, although in Bermuda prominent propertied men were still appointed Captains of Forts, taking charge of maintaining and commanding fortified coastal artillery batteries and manned by volunteers (reinforced in wartime by embodied militiamen), defending the colony's coast from the 17th century to the 19th century (when all of the batteries were taken over by the regular Royal Artillery). The militia system was extended to a number of English (subsequently British) colonies, beginning with Virginia and Bermuda. In some colonies, Troops of Horse or other mounted units similar to the Yeomanry were also created. The militia and volunteer units of a colony were generally considered to be separate forces from the Home Militia Force and Volunteer Force in the United Kingdom, and from the militia forces and volunteer forces of other colonies. Where a colony had more than one militia or volunteer unit, they would be grouped as a militia or volunteer force for that colony, such as the Jamaica Volunteer Defence Force, which comprised the St. Andrew Rifle Corps, or Kingston Infantry Volunteers, the Jamaica Corps of Scouts, and the Jamaica Reserve Regiment, but not the Jamaica Militia Artillery. In smaller colonies with a single militia or volunteer unit, that single unit would still be considered to be listed within a force, or in some case might be named a force rather than a regiment or corps, such as is the case for the Falkland Islands Defence Force and the Royal Montserrat Defence Force. The militia, yeomanry and volunteer forces collectively were known as the reserve forces, auxiliary forces, or local forces. Officers of these forces could not sit on courts martial of regular forces personnel. The Mutiny Act did not apply to members of the Reserve Forces. The other regular military force that existed alongside the British Army was the Board of Ordnance, which included the Ordnance Military Corps (made up of the Royal Artillery, Royal Engineers, and the Royal Sappers and Miners), as well as the originally-civilian Commissariat Stores and transport departments, as well as barracks departments, ordnance factories and various other functions supporting the various naval and military forces. The English Army, subsequently the British Army once Scottish regiments were moved onto its establishment following the Union of the Kingdoms of Scotland and England, was originally a separate force from these, but absorbed the Ordnance Military Corps and various previously civilian departments after the Board of Ordnance was abolished in 1855. The Reserve Forces (which referred to the Home Yeomanry, Militia and Volunteer Forces before the 1859 creation of the British Army Regular Reserve by Secretary of State for War Sidney Herbert, and re-organised under the Reserve Force Act 1867) were increasingly integrated with the British Army through a succession of reforms over the last two decades of the 19th century (in 1871, command of the Auxiliary Forces in the British Isles was taken from the Lords-Lieutenant of counties and transferred to the War Office, though colonial governors retained control of their militia and volunteer forces, and by the end of the century, at the latest, any unit wholly or partly funded from Army funds was considered part of the British Army) and the early years of the 20th century, whereby the Reserve Forces units mostly lost their own identities and became numbered Territorial Force sub-units of regular British Army corps or regiments (the Home Militia had followed this path, with the Militia Infantry units becoming numbered battalions of British Army regiments, and the Militia Artillery integrating within Royal Artillery territorial divisions in 1882 and 1889, and becoming parts of the Royal Field Artillery or Royal Garrison Artillery in 1902 (though retaining their traditional corps names), but was not merged into the Territorial Force when it was created in 1908 (by the merger of the Yeomanry and Volunteer Force). The Militia was instead renamed the Special Reserve, and was permanently suspended after the First World War (although a handful of Militia units survived in the United Kingdom, its colonies, and the Crown Dependencies). Unlike the Home, Imperial Fortress and Crown Dependency Militia and Volunteer units and forces that continued to exist after the First World War, although parts of the British military, most were not considered parts of the British Army unless they received Army funds, as was the case for the Bermuda Militia Artillery and the Bermuda Volunteer Rifle Corps, which was generally only the case for those in the Channel Islands or the Imperial Fortress colonies (Nova Scotia, before Canadian confederation, Bermuda, Gibraltar, and Malta). Today, the British Army is the only Home British military force (unless the Army Cadet Force and the Combined Cadet Force are considered), including both the regular army and the forces it absorbed, though British military units organised on Territorial lines remain in British Overseas Territories that are still not considered formally part of the British Army, with only the Royal Gibraltar Regiment and the Royal Bermuda Regiment (an amalgam of the old Bermuda Militia Artillery and Bermuda Volunteer Rifle Corps) appearing on the British Army order of precedence and in the Army List. Confusingly, and similarly to the dual meaning of the word Corps in the British Army. As an example, the 1st Battalion of the King's Royal Rifle Corps was in 1914 part of the 6th Brigade that was part of the 2nd Infantry Division, which was itself part of 1st Army Corps), the British Army sometimes also used the term expeditionary force or field force to describe a body made up of British Army units, most notably the British Expeditionary Force, or of a mixture of British Army, Indian Army, or Imperial auxiliary units, such as the Malakand Field Force (this is similarly to the naval use of the term task force). In this usage, force is used to describe a self-reliant body able to act without external support, at least within the parameters of the task or objective for which it is employed. === British Empire === During the later half of the 17th century, and in particular, throughout the 18th century, British foreign policy sought to contain the expansion of rival European powers through military, diplomatic and commercial means, especially of its chief competitors Spain, the Netherlands, and France. This saw Britain engage in a number of intense conflicts over colonial possessions and world trade, including a long string of Anglo-Spanish and Anglo-Dutch wars, as well as a series of "world wars" with France, such as; the Seven Years' War (1756–1763), the French Revolutionary Wars (1792–1802) and the Napoleonic Wars (1803–1815). During the Napoleonic wars, the Royal Navy victory at Trafalgar (1805) under the command of Horatio Nelson (aboard HMS Victory) marked the culmination of British maritime supremacy, and left the Navy in a position of uncontested hegemony at sea. By 1815 and the conclusion of the Napoleonic Wars, Britain had risen to become the world's dominant great power and the British Empire subsequently presided over a period of relative peace, known as Pax Britannica. With Britain's old rivals no-longer a threat, the 19th century saw the emergence of a new rival, the Russian Empire, and a strategic competition in what became known as The Great Game for supremacy in Central Asia. Britain feared that Russian expansionism in the region would eventually threaten the Empire in India. In response, Britain undertook a number of pre-emptive actions against perceived Russian ambitions, including the First Anglo-Afghan War (1839–1842), the Second Anglo-Afghan War (1878–1880) and the British expedition to Tibet (1903–1904). During this period, Britain also sought to maintain the balance of power in Europe, particularly against Russian expansionism, who at the expense of the waning Ottoman Empire had ambitions to "carve up the European part of Turkey". This ultimately led to British involvement in the Crimean War (1854–1856) against the Russian Empire. === First World War === The beginning of the 20th century served to reduce tensions between Britain and the Russian Empire, partly due to the emergence of a unified German Empire. The era brought about an Anglo-German naval arms race, which encouraged significant advancements in maritime technology, including Dreadnoughts, torpedoes, submarines), and, in 1906, Britain determined that its only likely naval enemy was Germany. The accumulated tensions in European relations finally broke out into the hostilities of the First World War (1914–1918), in what is recognised today, as the most devastating war in British military history, with nearly 800,000 men killed and over 2 million wounded. Allied victory resulted in the defeat of the Central Powers, the end of the German Empire, the Treaty of Versailles and the establishment of the League of Nations. === Second World War === Germany was defeated in the First World War, but by 1933 fascism had given rise to Nazi Germany, which under the leadership of Adolf Hitler re-militarised in defiance of the Treaty of Versailles. Once again tensions accumulated in European relations, and following Germany's invasion of Poland in September 1939, the Second World War began (1939–1945). The conflict was the most widespread in British history, with British Empire and Commonwealth troops engaged in military campaigns in Europe, North Africa, the Middle East, and the Far East. Approximately 390,000 British Empire and Commonwealth troops died. Allied victory resulted in the defeat of the Axis powers and the establishment of the United Nations, replacing the League of nations. === Cold War === Post–Second World War economic and political decline, as well as changing attitudes in British society and government, were reflected by the armed forces' contracting global role, and later epitomised by its political defeat during the Suez Crisis (1956). Reflecting Britain's new role in the world and the escalation of the Cold War (1947–1991), the country became a founding member of the NATO military alliance in 1949. Defence Reviews, such as those in 1957 and 1966, announced significant reductions in conventional forces, the pursuement of a doctrine based on nuclear deterrence, and a permanent military withdrawal east of Suez. By the mid-1970s, the armed forces had reconfigured to focus on the responsibilities allocated to them by NATO. The British Army of the Rhine and RAF Germany consequently represented the largest and most important overseas commitments that the armed forces had during this period, while the Royal Navy developed an anti-submarine warfare specialisation, with a particular focus on countering Soviet submarines in the Eastern Atlantic and North Sea. While NATO obligations took increased prominence, Britain nonetheless found itself engaged in a number of low-intensity conflicts, including a spate of insurgencies against colonial occupation. However the Dhofar Rebellion (1962–1976) and The Troubles (1969–1998) emerged as the primary operational concerns of the armed forces. Perhaps the most important conflict during the Cold War, at least in the context of British defence policy, was the Falklands War (1982). Since the end of the Cold War, an increasingly international role for the armed forces has been pursued, with re-structuring to deliver a greater focus on expeditionary warfare and power projection. This entailed the armed forces often constituting a major component in peacekeeping and humanitarian missions under the auspices of the United Nations, NATO, and other multinational operations, including: peacekeeping responsibilities in the Balkans and Cyprus, the 2000 intervention in Sierra Leone and participation in the UN-mandated no-fly zone over Libya (2011). Post-9/11, the armed forces became heavily committed to the War on Terror (2001–present), with lengthy campaigns in Afghanistan (2001–2021) and Iraq (2003–2009), and more recently as part of the Military intervention against ISIL (2014–present). Britain's military intervention against Islamic State was expanded following a parliamentary vote to launch a bombing campaign over Syria; an extension of the bombing campaign requested by the Iraqi government against the same group. In addition to the aerial campaign, the British Army has trained and supplied allies on the ground and the Special Air Service, the Special Boat Service, and the Special Reconnaissance Regiment (British special forces) has carried out various missions on the ground in both Syria and Iraq. The armed forces have also been called upon to assist with national emergencies through the provisions of the military aid to the civil authorities (MACA) mechanism. This has seen the armed forces assist government departments and civil authorities responding to flooding, food shortages, wildfires, terrorist attacks and the COVID-19 pandemic; the armed forces' support to the latter falls under Operation Rescript, described as the UK's "biggest ever homeland military operation in peacetime" by the Ministry of Defence. Figures released by the Ministry of Defence on 31 March 2016 show that 7,185 British Armed Forces personnel have lost their lives in medal earning theatres since the end of the Second World War. == Today == === Command === King Charles III, sovereign of the United Kingdom, is the Head of the Armed Forces, with officers and personnel swearing allegiance to him. Long-standing constitutional convention, however, has de facto vested military authority and associated royal prerogative powers in the prime minister and the secretary of state for defence, with the former (acting with the support of the Cabinet) making the key decisions on the use of the armed forces. As the prime minister is not the formal head of the armed forces, the chief of the defence staff could refuse a direction by them to use the UK's nuclear arsenal. The Ministry of Defence is the government department charged with formulating and executing defence policy. It currently employs 56,860 civilian staff members as of 1 October 2015. The department is administered by the secretary of state for defence who is assisted by the Minister of State for the Armed Forces, Minister for Defence Procurement, and Minister for Veterans' Affairs. Responsibility for the management of the forces is delegated to a number of committees: the Defence Council, Chiefs of Staff Committee, Defence Management Board and three single-service boards. The Defence Council, composed of senior representatives of the services and the Ministry of Defence, provides the "formal legal basis for the conduct of defence". The three constituent single-service committees (Admiralty Board, Army Board and Air Force Board) are chaired by the secretary of state for defence. The chief of the defence staff (CDS) is the senior-most officer of the armed forces and is an appointment that can be held by an admiral, air chief marshal or general. Before the practice was discontinued in the 1990s, those who were appointed to the position of CDS had been elevated to the most senior rank in their respective service. The CDS, along with the permanent under secretary, are the principal military advisers to the secretary of state. All three services have their own respective professional chiefs; the First Sea Lord for the Royal Navy, the chief of the general staff for the Army and the chief of the air staff for the Royal Air Force. === Personnel === As of 1 July 2023 the British Armed Forces are a professional force with a total strength of 185,980 personnel, consisting of 140,300 UK Regulars and 4,140 Gurkhas, 33,210 Volunteer Reserves and 8,330 "Other Personnel". As a percentage breakdown of UK Service Personnel, 77.1% are UK Regulars and Gurkhas, 18.8% are Volunteer Reserves and 4.1% are composed of Other Personnel. In addition, all ex-Regular personnel retain a "statutory liability for service" and are liable to be recalled (under Section 52 of the Reserve Forces Act (RFA) 1996) for duty during wartime, which is known as the Regular Reserve. MoD publications since April 2013 no longer report the entire strength of the Regular Reserve, instead they only give a figure for Regular Reserves who serve under a fixed-term reserve contract. These contracts are similar in nature to those of the Volunteer Reserve. The distribution of personnel between the services and categories of service on 1 July 2023 was as follows: On 1 April 2024, most personnel in the UK Regular Forces were stationed in the United Kingdom (around 96%). Of the 5,700 personnel stationed overseas, around two thirds were in Europe (66%), while 14% were stationed in North America, 6% in North Africa and the Middle East, 6% in Asia and 5% in Sub-Saharan Africa. 1,230 personnel were distributed across several regions in Germany, primarily North Rhine-Westphalia as part of British Army Germany. However, up to 750 of these were Locally Engaged Civilians. === Defence expenditure === According to the Stockholm International Peace Research Institute, the United Kingdom is in sixth place in the world's military spending list in 2023. For comparison: Great Britain spends more in absolute terms than Germany, Ukraine, France or Japan, similar to Saudi Arabia, but less than India, Russia, China or the United States. In September 2011, according to Professor Malcolm Chalmers of the Royal United Services Institute, current "planned levels of defence spending should be enough for the United Kingdom to maintain its position as one of the world's top military powers, as well as being one of NATO-Europe's top military powers. Its edge – not least its qualitative edge – in relation to rising Asian powers seems set to erode, but will remain significant well into the 2020s, and possibly beyond." The Strategic Defence and Security Review 2015 committed to spending 2% of GDP on defence and announced a £178 billion investment over ten years in new equipment and capabilities. On 8 March 2023 Prime Minister Rishi Sunak announced a further £5bn in defence spending with a long-term goal of an increased spending to 2.5% of GDP. === Nuclear weapons === The United Kingdom is one of five recognised nuclear weapon states under the Non-Proliferation Treaty and maintains an independent nuclear deterrent, currently consisting of four Vanguard-class ballistic missile submarines, UGM-133 Trident II submarine-launched ballistic missiles, and 160 operational thermonuclear warheads. This is known as Trident in both public and political discourse (with nomenclature taken after the UGM-133 Trident II ballistic missile). Trident is operated by the Royal Navy Submarine Service, charged with delivering a 'Continuous At-Sea Deterrent' (CASD) capability, whereby one of the Vanguard-class strategic submarines is always on patrol. According to the British Government, since the introduction of Polaris (Trident's predecessor) in the 1960s, from April 1969 "the Royal Navy's ballistic missile boats have not missed a single day on patrol", giving what the Defence Council described in 1980 as a deterrent "effectively invulnerable to pre-emptive attack". As of 2015, it has been British Government policy for the Vanguard-class strategic submarines to carry no more than 40 nuclear warheads, delivered by eight UGM-133 Trident II ballistic missiles. In contrast with the other recognised nuclear weapon states, the United Kingdom operates only a submarine-based delivery system, having decommissioned its tactical WE.177 free-fall bombs in 1998. The House of Commons voted on 18 July 2016 in favour of replacing the Vanguard-class submarines with a new generation of Dreadnought-class submarines. The programme will also contribute to extending the life of the UGM-133 Trident II ballistic missiles and modernise the infrastructure associated with the CASD. Former weapons of mass destruction possessed by the United Kingdom include both biological and chemical weapons. These were renounced in 1956 and subsequently destroyed. === Overseas military installations === The British Armed Forces historically relied on four Imperial fortress colonies (Bermuda, Gibraltar, Halifax and its environs in Nova Scotia, and Malta), where dockyards were established, naval squadrons based, soldiers garrisoned, and naval and military stores stockpiled. These acted as lynchpins in maintaining British naval supremacy on the Atlantic and its connected seas. As, until the end of the First World War, it was presumed the only navies that might prove a threat were all of countries on, or off, the Atlantic, no Imperial fortress was established in the Pacific or Indian Oceans, to which power would be extended from Bermuda and Malta following the completion of the Panama and Suez canals. Local-service military reserve units were raised in some of the Imperial fortresses (notably Bermuda and Malta), which could be embodied for full time service in war time to reinforce the regular garrisons, and these were funded by the War Office as part of the British Army. After the First World War, the growing belligerence and naval power of the Japanese Empire led to the construction of the Singapore Naval Base. The regular British Armed Forces otherwise were distributed around the world where required to guard against invasion or rebellion, reinforced in some colonies by locally raised reserve forces. In colonies where there was no strategic requirement, regular forces were rarely stationed, with local governments encouraged to maintain and fund military reserve units as contributions to their own defence (although these units were ultimately under the control of the national, i.e. British, Government via the colonial Governors as defence is not a competency that has been delegated to local governments). Under the North Atlantic Treaty Organisation alliance, and with the steady reduction of both the British Empire and the British Armed Forces over the decades that followed the Second World War, the significance of the three remaining Imperial fortresses (military control of Halifax having passed to the new Dominion government following the 1867 Confederation of Canada, and naval control transferred in 1905 to what was to become the Royal Canadian Navy) rapidly faded. The Bermuda-based North America and West Indies Station was abolished in 1956, and the last regular army units removed from the Bermuda Command in 1957 (leaving only two part-time reserve units), with the naval dockyard in Bermuda reduced to a base, without repair or refit capabilities, in 1951 and finally closed in 1995, following the Cold War (United States and Canadian bases in Bermuda closed in the same period), leaving only the Royal Bermuda Regiment and the Bermuda Sea Cadet Corps there today. Malta became independent in 1964, and the last British armed forces personnel were removed from the former colony in 1979. Gibraltar continues to be used by the regular British Armed Forces, though the naval and military establishment in the colony (now termed a British Overseas Territory) has been reduced to several Royal Naval patrol craft, the locally raised Royal Gibraltar Regiment, and a Royal Air Force Station without aircraft based on it. The British Armed Forces today maintain a number of overseas garrisons and military facilities which enable the country to conduct operations worldwide. The majority of Britain's permanent military installations are located on British Overseas Territories (BOTs) or former colonies which retain close diplomatic ties with the United Kingdom, and located in areas of strategic importance. The most significant of these are the "Permanent Joint Operating Bases" (PJOBs), located on the four overseas territories of Cyprus (British Forces Cyprus), Gibraltar (British Forces Gibraltar), the Falkland Islands (British Forces South Atlantic Islands) and Diego Garcia (British Forces British Indian Ocean Territories). While not a PJOB, Ascension Island (another BOT) is home to the airbase RAF Ascension Island, notable for use as a staging post during the 1982 Falklands War, the territory is also the site of a joint UK-US signals intelligence facility. Qatar is home to RAF Al Udeid, a Royal Air Force outpost at Al Udeid Air Base which serves as the operational headquarters for No. 83 Expeditionary Air Group and its operations across the Middle East. A large Royal Navy Naval Support Facility (NSF) is located in Bahrain, established in 2016 it marks the British return East of Suez. In support of the Five Power Defence Arrangements (FPDA), the United Kingdom retains a naval repair and logistics support facility at Sembawang wharf, Singapore. Other overseas military installations include; British Forces Brunei, British Forces Germany, the British Army Training Unit Kenya, British Army Training Unit Suffield in Canada, British Army Training and Support Unit Belize, and British Gurkhas Nepal. Some British Overseas Territories also maintain locally raised units and regiments; The Royal Bermuda Regiment, the Falkland Islands Defence Force, the Royal Gibraltar Regiment, the Royal Montserrat Defence Force, the Cayman Islands Regiment, and the Turks and Caicos Regiment. Though their primary mission is "home defence", individuals have volunteered for operational duties. The Royal Bermuda Regiment is an amalgam of the Bermuda Militia Artillery (which had been part of the Royal Regiment of Artillery) and the Bermuda Volunteer Rifle Corps, raised in the 1890s as Imperial forces funded by the War Office as part of the British Army, and both antecedent units sent contingents to the Western Front during the First World War. They also sent contingents that served in North-Western Europe, and Italy and North Africa during the Second World War. The Royal Gibraltar Regiment mobilised section-sized units for attachment to British regiments deployed during the Iraq War. The Isle of Man, a Crown dependency hosts a multi-capability recruiting and training unit of the British Army Reserve. Since 1969 Britain has had a military satellite communications system, Skynet, initially in large part to support East of Suez bases and deployments. Since 2015 Skynet has offered near global coverage. === Expeditionary forces === The British Armed Forces place significant importance in the ability to conduct expeditionary warfare. While the armed forces are expeditionary in nature, it maintains a core of "high readiness" forces trained and equipped to deploy at very short notice, these include; the Joint Expeditionary Force (Maritime) (Royal Navy), UK Commando Force (Royal Marines), and 16 Air Assault Brigade (British Army). Frequently, these forces will act as part of a larger tri-service effort, under the direction of Permanent Joint Headquarters, or along with like-minded allies under the Joint Expeditionary Force. Similarly, under the auspices of NATO, such expeditionary forces are designed to meet Britain's obligations to the Allied Rapid Reaction Corps and other NATO operations. In 2010, the governments of the United Kingdom and France signed the Lancaster House Treaties which committed both governments to the creation of a Franco-British Combined Joint Expeditionary Force. It is envisaged as a deployable joint force, for use in a wide range of crisis scenarios, up to and including high intensity combat operations. As a joint force it involves all three armed Services: a land component composed of formations at national brigade level, maritime and air components with their associated Headquarters, together with logistics and support functions. == The Armed Forces == === Royal Navy === The Royal Navy is a technologically sophisticated naval force, and as of December 2024 consists of 62 commissioned ships with an additional 11 support vessels of various types operated by the Royal Fleet Auxiliary. Command of deployable assets is exercised by the Fleet Commander of the Naval Service. Personnel matters are the responsibility of the Second Sea Lord/Commander-in-Chief Naval Home Command, an appointment usually held by a vice-admiral. The Surface Fleet consists of aircraft carriers, destroyers, frigates, patrol vessels, mine-countermeasure vessels, and other miscellaneous vessels. The Surface Fleet has been structured around a single fleet since the abolition of the Eastern and Western fleets in 1971. The recently built Type 45 destroyers are stealthy and technologically advanced air-defence destroyers. The Royal Navy has commissioned two Queen Elizabeth-class aircraft carriers, embarking an air-group including the advanced fifth-generation multi-role fighter, the F-35B Lightning. A submarine service has existed within the Royal Navy for more than 100 years. The Submarine Service's four Vanguard-class nuclear-powered submarines carry Trident II ballistic missiles, forming the United Kingdom's nuclear deterrent. Seven Astute-class nuclear-powered fleet (attack) submarines have been ordered, with five completed and two under construction. The Astute class are the most advanced and largest fleet submarines ever built for the Royal Navy and will maintain Britain's nuclear-powered submarine fleet capabilities for decades to come. ==== Royal Marines ==== The Royal Marines are the Royal Navy's amphibious troops. Consisting of a single manoeuvre brigade (UK Commando Force) and various independent units, the Royal Marines specialise in amphibious, arctic, and mountain warfare. Contained within UK Commando Force are three attached army units; 383 Commando Petroleum Troop RLC, 29th Commando Regiment Royal Artillery, a field artillery regiment based in Plymouth, and 24 Commando Regiment Royal Engineers. The Commando Logistic Regiment consists of personnel from the Army, Royal Marines, and Royal Navy. === British Army === The British Army is the land force of the British Armed Forces, and is made up of the Regular Army and the part-time Army Reserve. The Army is commanded by the Chief of the General Staff, a four-star general within Army Headquarters, based at Andover. Deployable combat formations are; 1st (UK) Division, consisting of 16 Air Assault Brigade Combat Team and four other Light or Light Mechanised Brigade Combat Teams, with supporting engineering, logistic, intelligence and signals units. 3rd (UK) Division, consisting of 1st Deep Recce Strike Brigade Combat Team, 7 Air Defence Group, and two Armoured Brigade Combat Teams, with supporting engineering, logistic, intelligence and signals units. Field Army Troops, consisting of the new Ranger Regiment, in Army Special Operations Brigade; Security Force Assistance Brigade and 77 Brigade, a psychological operations unit. The Infantry of the British Army has a strength of 48 battalions (32 regular and 16 reserve), structured under 17 unique regiments. These battalions are trained and equipped for specific roles within their respective Brigade Combat Teams (BCT); Light Infantry, such as the famous 1st Battalion Grenadier Guards, within the 4th Light Brigade Combat Team, fight on foot without armoured vehicles; Light Mechanised Infantry, such as the 1st Battalion Royal Yorkshire Regiment, within the 7th Light Mechanised Brigade Combat Team, operate the Foxhound protected mobility vehicle; Armoured Infantry (to become Heavy Mechanised Infantry under Future Soldier), such as the 1st Battalion Royal Regiment of Fusiliers, within the 20th Armoured Infantry Brigade Combat Team, operate the Warrior infantry fighting vehicle (IFV), but will be equipped with the new Boxer mechanised infantry vehicle from 2024. The four battalions of the Parachute Regiment, forming 16 Air Assault Brigade Combat Team and part of Special Forces Support Group, are the British Army's elite airborne infanteers, held at high readiness and specialising in rapid deployment by parachute and helicopter, widely regarded as the "fittest, most aggressive, resilient and disciplined regiment in the British Army." The Royal Armoured Corps provides the armoured capability of the British Army. The Royal Tank Regiment, Queen's Royal Hussars and Royal Wessex Yeomanry (of the Army Reserve) operate Challenger 2 main battle tanks, which are being upgraded to Challenger 3, and are part of 3rd (UK) Division's Armoured Brigade Combat Teams. Armoured Cavalry regiments, such as the Royal Dragoon Guards, currently operate the Warrior IFV on an interim basis, until Ajax reaches full operating capability. There are six Light Cavalry regiments (three Regular + three Reserve) equipped with the Jackal 2 and Coyote TSV, tasked with providing reconnaissance and fire support. The Household Cavalry, made up of the Life Guards and the Blues and Royals, operate in a dual role of Armoured Cavalry and Mounted Ceremonial on Horse Guards in London, and for state occasions. === Royal Air Force === The Royal Air Force has a large operational fleet that fulfils various roles, consisting of both fixed-wing and rotary aircraft. Frontline aircraft are controlled by Air Command, which is organised into five groups defined by function: 1 Group (Air Combat), 2 Group (Air Support), 11 Group (Air and Space operations), 22 Group (training aircraft and ground facilities) and 38 Group (Royal Air Force's Engineering, Logistics, Communications and Medical Operations units). In addition 83 Expeditionary Air Group directs formations in the Middle East and the 38 Group combines the expeditionary combat support and combat service support units of the RAF. Deployable formations consist of Expeditionary Air Wings and squadrons—the basic unit of the Air Force. Independent flights are deployed to facilities in Brunei, the Falkland Islands, Iraq, and the United States. The Royal Air Force operates multi-role and single-role fighters, reconnaissance and patrol aircraft, tankers, transports, helicopters, unmanned aerial vehicles, and various types of training aircraft. Ground units are also maintained by the Royal Air Force, most prominently the RAF Police and the Royal Air Force Regiment (RAF Regt). The Royal Air Force Regiment essentially functions as the ground defence force of the RAF, optimised for the specialist role of fighting on and around forward airfields, which are densely packed with operationally vital aircraft, equipment, infrastructure and personnel. The Regiment contains nine regular squadrons, supported by five squadrons of the Royal Auxiliary Air Force Regiment. In addition, it provides Forward Air Controllers to defence as well as a contribution to the Special Forces Support Group. == Ministry of Defence == The Ministry of Defence maintains a number of civilian agencies in support of the British Armed Forces. Although they are civilian, they play a vital role in supporting Armed Forces operations, and in certain circumstances are under military discipline: The Royal Fleet Auxiliary (RFA) operates 11 ships which primarily serve to replenish Royal Navy warships at sea, and also provides an amphibious warfare capability through its three Bay-class landing ship dock vessels and the aviation support ship RFA Argus. It is manned by 1,750 civilian personnel and is funded and run by the Ministry of Defence. The Ministry of Defence Police (MDP) has an established strength of 2,700 police officers which provide armed security, counter terrorism, uniformed policing and investigative services to Ministry of Defence property, personnel, and installations throughout the United Kingdom. The Defence Equipment and Support (DE&S) is the merged procurement and support organisation within the UK Ministry of Defence (United Kingdom). It came into being on 2 April 2007, bringing together the MoD's Defence Procurement Agency and the Defence Logistics Organisation under the leadership of General Sir Kevin O'Donoghue as the first Chief of Defence Materiel. As of 2012 it has a civilian and military workforce of approx. 20,000 personnel. DE&S is overseen by the Minister for Defence Equipment, Support and Technology. The UK Hydrographic Office (UKHO) is an organisation within the UK government responsible for providing navigational and other hydrographic information for national, civil and defence requirements. The UKHO is located in Taunton, Somerset, on Admiralty Way and has a workforce of approximately 1,000 staff. == Recruitment == All three services of the British Armed Forces recruit primarily from within the United Kingdom, although citizens from the Commonwealth of Nations and the Republic of Ireland are equally eligible to join. The minimum recruitment age is 16 years (although personnel may not serve on armed operations below 18 years, and if under 18 must also have parental consent to join); the maximum recruitment age depends whether the application is for a regular or reserve role; there are further variations in age limit for different corps/regiments. The normal term of engagement is 22 years; however, the minimum service required before resignation is 4 years, plus, in the case of the Army, any service person below the age of 18. A note to add is that in the United Kingdom, people may join the "Cadet Forces" such as the army cadets, Royal Air Force Air Cadets or the sea and Royal Marine Cadets. Young people may join these organisations which are either funded or affiliated with the MOD from the age of 13-18, there is no obligation to then join the armed forces however it teaches key skills in both civilian and military life and is a key recruitment drive for the armed forces. At present, the yearly intake into the armed forces is 11,880 (per the 12 months to 31 March 2014). Excluding the Brigade of Gurkhas and the Royal Irish Regiment, as of 1 April 2014 there are approximately 11,200 Black and Minority Ethnic (BME) persons serving as Regulars across the three service branches; of those, 6,610 were recruited from outside the United Kingdom. In total, Black and Minority Ethnic persons represent 7.1% of all service personnel, an increase from 6.6% in 2010. Since the year 2000, sexual orientation has not been a factor considered in recruitment, and homosexuals can serve openly in the armed forces. All branches of the forces have actively recruited at Gay Pride events. The forces keep no formal figures concerning the number of gay and lesbian serving soldiers, saying that the sexual orientation of personnel is considered irrelevant and not monitored. === Role of women === Women have been part of the armed forces, on and off, for centuries, more fully integrated since the early 1990s, including flying fast jets and commanding warships or artillery batteries. As of 1 April 2014, there were approximately 15,840 women serving in the armed forces, representing 9.9% of all service personnel. The first female military pilot was Flight Lieutenant Julie Ann Gibson while Flight Lieutenant Jo Salter was the first fast-jet pilot, the latter flying a Tornado GR1 on missions patrolling the then Northern Iraqi No-Fly Zone. Flight Lieutenant Juliette Fleming and Squadron Leader Nikki Thomas recently were the first Tornado GR4 crew. While enforcing the Libyan No-Fly Zone, Flight Lieutenant Helen Seymour was identified as the first female Eurofighter Typhoon pilot. In August 2011, it was announced that a female lieutenant commander, Sarah West, was to command the frigate HMS Portland. In July 2016, it was announced that women would be allowed to serve in close combat, starting with the Royal Armoured Corps. In July 2017, the Secretary of Defence announced that women would be allowed to enlist in the RAF Regiment from September 2017, a year ahead of schedule. In 2018, women were allowed to apply for all roles in the British military, including the special forces. As of 10 June 2024, the most senior serving woman is four-star General Dame Sharon Nesmith. == March == == See also == Armed Forces Day (United Kingdom) List of military equipment of the United Kingdom Atholl Highlanders – The only legal private army in Europe under the command of the Duke of Atholl in Scotland Banknotes of the British Armed Forces British Forces Broadcasting Service Community Cadet Forces Military Covenant – The mutual obligations between the nation and its Armed Forces. Network-enabled capability – British military concept of achieving enhanced military effect through the better use of information systems. Similar to the US concept of network-centric warfare. The Championships, Wimbledon#Services stewards Uniforms of the British Armed Forces Military history of Scotland Armed forces in Scotland Armed forces in Wales == Notes == == References == == External links == British Ministry of Defence (gov.uk) Defence Academy of the United Kingdom (.da.mod.uk) Royal Navy official website (royalnavy.mod.uk) Royal Marines official webpage (royalnavy.mod.uk) British Army official website (army.mod.uk) Royal Air Force official website (raf.mod.uk)	Wikipedia/British_armed_forces
Cosmetic electrotherapy is a range of beauty treatments that uses low electric currents passed through the skin to produce several therapeutic effects such as muscle toning in the body: 226 and micro-lifting of the face. In rehabilitation medicine, electrotherapy has been widely utilized and studied; however, its use on healthy muscles, particularly in cosmetic and non-clinical settings, remains controversial. Some studies have questioned its effectiveness in these contexts, citing a lack of sufficient scientific evidence to support its claimed benefits.". The use of electricity in cosmetics goes back to the end of the 19th century, almost a hundred years after Luigi Galvani discovered that electricity can make the muscle in a frog's leg twitch (see galvanism). In the 20th century, researchers such as Robert O. Becker, Björn Nordenström, and Thomas Wingmade significant contributions to the development of microcurrent devices. Becker's work focused on bioelectric phenomena and their role in tissue regeneration; Nordenström proposed the potential therapeutic applications of endogenous electric currents in disease treatment; and Wing developed some of the earliest microcurrent stimulation devices for use in both clinical and cosmetic settings. == Treatments == There are four main types of treatment, that differ in the type of current they use (see Comparison table, below), including: Galvanic treatment Neuromuscular electrical stimulation (NMES) (also known as Faradic treatment) Micro-current electrical neuromuscular stimulation (MENS) High-frequency treatment === Galvanic treatment === Galvanic treatment in the beauty industry has been described since at least the 1970s and earlier. Sometimes called galvanism, the treatment aims to improve the skin in two ways: (1) cleansing: a process called desincrustation, and (2) nourishing the skin condition, through an electro-chemical process called iontophoresis (also called ionisation). It is used to improve various skin conditions, including signs of aging, hyperpigmentation, and acne. This is achieved by the application of a small, constant, direct current. The treatment works on the principle that charged ions in the skin are either attracted or repelled from the electrodes, resulting in certain chemical effects. "Galvanism works by penetrating active substances into the subcutaneous tissues, where they act on the ineffective circulation to bring about an improvement in the vascular and lymphatic interchange in the area. This is completed in a natural and harmless way, and is aided by the actual effect of the galvanic current on the tissues. This improves the function of the cellular membrane, and allows the trapped fluid and fat to be dispersed and eliminated." Galvanic treatment are often used on the face (facial galvanic treatment) and on the body to treat cellulite (galvanic cellulite treatments). === Faradic treatment === Faradic treatment has also been described in the beauty industry since the 1970s and earlier. The treatment tones the muscles by repeatedly contracting them with the electric current, resulting in their firming and toning, and an increase in muscular metabolism aims to remove waste products more readily. Faradic treatments are generally used on the face and body, and work by contracting muscles with a short pulse of interrupted direct current. The treatment is also called neuromuscular electrical stimulation (NMES), and some of the manufactures who produce the equipment use their own terms, for example, Slendertone calls it electronic muscle stimulation, or the treatment is called after the name of the manufacturer, such as Ultratone or Slim Master.: 264 === Microcurrent treatment === Microcurrent treatments (MENS) have been around since the 1970s in medical applications and are distinguished by their use of micro-ampere currents (i.e. millionths of an amp) which are hardly perceptible, but mimic the body's own bio-electric currents.: 272 The treatment is designed to soften wrinkles and rejuvenate skin, including skin damaged by sunburn, acne, stretch marks, cellulite and scarring. This increased ATP also energizes the facial muscles, similar to how exercise energizes the muscles of our bodies. Unlike anywhere else on the body, the facial muscles are directly connected to the skin, so the result of energizing the muscle is often an improved, lifted appearance. When used on the face, the treatment has become known as a "non-surgical facelift" and "facial lifting".: 273 Microcurrent treatment works by passing a very small direct current through muscle tissue to stimulate the Golgi tendon organ. It encourages production of ATP (Adenosine triphosphate) which leads to the creation and stimulation of structural proteins like elastin and collagen. Different microcurrent characteristics, particular the frequency and shape of the changing voltage (waveform), have different effects on the tissue.: 273 Microcurrent devices have been in the beauty industry for over a decade, the most known being the CACI device. Modern professional and personal use microcurrent devices combine waves of multiple shape and vary in frequencies used. Since microcurrent treatment uses a low-grade electrical current, there has been health concerns over safety of its use. People with pacemakers or any kind of heart condition should avoid it. Moreover, pregnant women are advised against it as well. It is always recommended to individually consult with doctor or aesthetician before using microcurrent. === High-frequency treatment === High-frequency treatment uses low-current high-frequency alternating currents, delivered via a glass electrode. Glass electrodes are often filled with either Neon gas which produces pink, orange, or red light or they are filled with Argon or rarefied gas which produces violet light. Because of the color of light that is produced when electricity is passed through the gas, they are inaccurately called ultraviolet or infra-red, however no UV rays or infra-red rays are produced, just visible light. High frequency does current convert some of the oxygen in the air surrounding the electrodes into ozone, the treatment has a germicidal action, and is also drying and warming. Consequently, the treatment is used to aid healing and also to help desquamation (the skin's natural exfoliation) and stimulate sweat and sebaceous glands. Sparking may occur when the electrode is close to the skin and then pulled away repeatedly. Some electrodes may contain a metal coil that produces a mechanical vibration, as well as sparking energy that can be felt indirectly when held in one person's hand while another person uses their hands directly on the skin. Because the effect may be pleasurable, similar devices are used in erotic electrostimulation. == Treatment and current == The characteristics of the treatment current include: (a) whether it is (direct or alternating), (b) current frequency, (c) size of the current (all very small), and (d) the duration and shape of any pulses. === Comparison === Notes Desincrustation – A skin cleansing process that softens and emulsifies hardened follicle sebum. 1 Amp = 1,000 milliAmps (mA) = 1,000,000 microAmps (μA) 1,000 Hz (cycles per second) = 1 kHz == Terminology == The origins of the terms "galvanic" and "Faradism" are described in the medical journal, The Lancet, in 1851. A note reads: "We should not omit to state that Dr Duchenne closes a paper (Archives, May 1851) on the subject by these words: 'As it will be useful to create a word which should exactly point out electricity by induction, as well as its application, may it not be allowable to use the name of the philosopher who has discovered this kind of electricity? Thus, in the same way as 'Galvani' has given his name to the electricity by contact, so can we like-wise give to the electricity by induction the name of 'Faraday.' This electricity would then be called 'Faradism,' and its application 'Faradization.' Such names would establish a clear distinction between the electricity by contact and that by induction, whilst they, at the same time, render due honour to a philosopher to whom medical science owes a discovery far more valuable in a therapeutic point of view than that of Galvani.'" It is noted that: "Some terms such as galvanic current and faradic stimulation are unique to physiotherapy. Their definitions given in the literature are far from universal. ... The Clinical Electrophysiology Section of the American Physical Therapy Association established a unified terminology for clinical electrical currents—that is, (a) direct current (b) alternating current (c) pulsed current (Kloth and Cummings, 1991) ... However, this terminology does not appear to have been widely adopted and inconsistencies remain in the literature". == See also == Bio-electric stimulation therapy (BEST) Electrotherapy – the use of electricity as a medical treatment Electrical muscle stimulation (neuromuscular electrical stimulation (NMES)) Erotic electrostimulation Microcurrent electrical neuromuscular stimulator (MENS) Transcutaneous electrical nerve stimulation (TENS) – the use of electric current to stimulate the nerves for therapeutic purposes == References == == Bibliography == Lorraine Nordmann, Professional Beauty Therapy: The Official Guide to Level 3, 4th Edition, Publisher Cengage Learning EMEA, 2010, ISBN 1-4080-1928-0 ISBN 9781408019283, 496 pages. Chapter 8: "Electrical treatments" Dawn Mernagh-Ward, Jennifer Cartwright, Health and beauty therapy: a practical approach for NVQ level 3 Edition 3, Publisher Nelson Thornes, 2004, ISBN 0-7487-9035-7, ISBN 978-0-7487-9035-7, 420 pages. Chapter 5. "Facial and Body Electrotherapy Treatments" John Low, Ann Reed, Ann Reed (SRP.), Electrotherapy explained: principles and practice, 4th Edition, Publisher Elsevier Health Sciences, 2000, ISBN 978-0-7506-8843-7. 564 pages. Basanta Kumar Nanda, Electrotherapy Simplified, Publisher Jaypee Brothers Publishers (2008), ISBN 81-8448-261-2, ISBN 978-81-8448-261-4. 548 pages == External links == BABTAC, British Association of Beauty Therapy and Cosmetology website: Galvanic Treatments \| "Galvanic Cellulite Treatments" Electrotherapy Museum website	Wikipedia/Electrotherapy_(cosmetic)
Self-surgery is the act of performing a surgical procedure on oneself. It can be an act taken in extreme circumstances out of necessity, an attempt to avoid embarrassment, legal action, or financial costs, or a rare manifestation of a psychological disorder. == Genitals == These surgeries are generally the least life-threatening. Sometimes people resort to self-surgery in the form of castration in an attempt to control their sexual urges, or due to gender dysphoria. Boston Corbett, the soldier who killed Abraham Lincoln's assassin John Wilkes Booth, had performed self-surgery earlier in life. He castrated himself with a pair of scissors in order to avoid the temptation of prostitutes. Afterwards, he went to a prayer meeting and ate a meal before going for medical treatment. == Abdominal == Successful abdominal self-surgery is extremely rare. A few well-publicized cases have found their way into the medical literature. On February 15, 1921, Evan O'Neill Kane carried out his own appendectomy in an attempt to prove the efficacy of local anesthesia for such operations. He is believed to have been the first surgeon to have done so. However, Kane previously performed appendectomies (on others) with local anesthetic. In 1932, he performed an even more risky self-operation of repairing his inguinal hernia at the age of 70. In August of 1944, Jock McLaren, an Australian Army officer, conducted an appendectomy on himself without anaesthesia of any kind, using only a pocket knife and a mirror. He then proceeded to suture himself with what he had on hand - "jungle fibre". Though not qualified in human medicine or surgery, McLaren had considerable knowledge of veterinary medicine. On April 30, 1961, Leonid Rogozov removed his own infected appendix at the Soviet Novolazarevskaja Research Station in Antarctica, as he was the only physician on staff. The operation lasted one hour and 45 minutes. Rogozov later reported on the surgery in the Information Bulletin of the Soviet Antarctic Expedition. A student who had already performed a self-castration was the subject of a 1979 case report by Kalin. The student, some time after the self-castration, also attempted to reduce the activity of his adrenal glands with an injection of bovine serum albumin, luteinizing hormone-releasing hormone and Freund's adjuvant. When this produced an abscess at the injection site, the student resorted to self-surgery. His psychiatrist reported: At four o'clock on the morning of his surgery, he disinfected his dormitory room with spray disinfectant and alcohol and draped an area with sheets that he had previously sterilized. For anesthesia, he took oral barbiturates. He also took hydrocortisone and prepared a canister of vaporized adrenalin, readying himself for a possible shock syndrome. He performed the procedure wearing sterile gloves and a surgical mask. Lying supine and looking into strategically placed mirrors to obtain an optimum view, he began by cleansing his abdomen with alcohol. The incision was made with a scalpel, exposure obtained by retractors, and the dissection carried out with surgical instruments. For local anesthesia, he injected lidocaine hydrochloride into each successive tissue layer during the opening. He controlled bleeding with locally applied gelatin powder, while sterilized cotton thread ligatures were used for the larger vessels. After eight hours he had had minimal blood loss but was unable to obtain adequate exposure to enter the retroperitoneal space because of the unexpected pain in retracting his liver. Exhausted, he bandaged his wound, cleaned up his room, and called the police for transport to the hospital because of a "rupture". In 2000, a Mexican woman, Inés Ramírez, was forced to resort to self-surgery – a "self-inflicted caesarean section" – because of lack of medical assistance during a difficult labour: "She took three small glasses of hard liquor and, using a kitchen knife, sliced her abdomen in 3 attempts ... cut the uterus itself longitudinally, and delivered a male infant. Both mother and child reportedly survived and are now well." == Medically supervised == Jerri Nielsen was the sole physician on duty at the U.S. National Science Foundation Amundsen–Scott Antarctic research station in 1999 when she found a lump on her breast. She was forced to biopsy the lump herself. Her experience made international news and was the basis for her autobiography, Ice Bound. The lump was found to be cancerous, so she self-administered chemotherapeutic agents. She remained cancer-free for several years but died in 2009 after her cancer reappeared and spread to her brain. == Self-trepanation == Trepanation involves drilling a hole in the skull. The most famous instances of self-trepanation are those of Amanda Feilding, Joey Mellen (Feilding's domestic partner), and Bart Huges (who influenced Mellen and Feilding). In 2023, Michael Raduga performed self-neurosurgery that included electrical stimulation of the motor cortex. == Amputation of trapped limbs == In 1993, Donald Wyman amputated his leg with his pocketknife after it was pinned by a tree. In 1993, Bill Jeracki was fishing near St. Mary's Glacier in Colorado, when a boulder pinned his left leg. Snow was forecast and without a jacket or pack, Jeracki did not believe he would survive the night. Fashioning a tourniquet out of his flannel shirt and using his bait knife, he cut his leg off at the knee joint, using hemostats from his fishing kit to clamp the bleeding arteries. In 2000, British Special Air Service veteran and adventurer, Sir Ranulph Fiennes received severe frostbite on his left hand in a failed solo North Pole expedition. After abandoning the trip and while waiting in England for further medical care, the pain of the necrotized tissue became unbearable. Fiennes retired to his garden shed and amputated his own digits with a power saw after clamping them in a vise. He survived and went on to other expeditions, including summitting Mount Everest and an abandoned Antarctic traverse. In 2002, Doug Goodale cut off one of his arms at the elbow in order to survive an accident at sea. In 2003, Aron Ralston was on a canyoneering trip in Bluejohn Canyon (near Moab, Utah), when a boulder fell and pinned his right forearm down, crushing it. First he tried to chip away the rock around his hand with his pocket knife, but gave up the attempt after two days. Next he tried to lift and move the boulder with a simple pulley system made with rope and gear, but that failed too. On the sixth day, which he did not expect to live to see upon falling asleep the night earlier, a dehydrated and delirious Ralston had a vision of himself as a one-armed man playing with his future son. Upon a subsequent fit of rage he discovered that he could bow his arm against the chockstone far enough to snap the radius and ulna bones. Using the dull blade on his multi-use tool, he cut the soft tissue around the break. He then used the tool's pliers to tear at the tougher tendons. He was careful not to sever the arteries before attaching an improvised tourniquet. After he cut the main bundle of nerves, leading to agonizing pain, he cut through the last piece of skin and was free. In bad physical shape, and having lost more than a litre of blood, he managed to rappel 70 feet down and hike another 8 miles, when he ran into a Dutch family who offered help and guided him to a rescue helicopter which happened to be nearby looking for Ralston and took him to a hospital. His story was dramatized in the film 127 Hours (2010). In 2003, an Australian coal miner trapped three kilometres underground by an overturned tractor cut off his own arm with a box-cutting knife. The 44-year-old man, who was not identified by police, was working late at the Hunter Valley mine when the tractor tipped over, crushing his arm and trapping him. == Mouth == During 1992-1993 Vendée Globe, a solo race around the world, sailor Bertrand de Broc who had been hit full in the face by a rope, had to sew his tongue himself after a doctor telexed instructions on how to sew stitches into the wound. == See also == Self-inflicted caesarean section Self-medication == References == === Citations === === Sources === Morton WA (1991). Scrotum self-repair. Med Aspects Human Sexuality Jul 1991:15. == Further reading == Michell J (1984). Eccentric Lives & Peculiar Notions ISBN 0-15-127358-8. Reprinted 2002. == External links == A reference to the Morton article on the Urban Legends Reference Page. Google Answers: SELF SURGERY ON ARMS	Wikipedia/Self-surgery
Fetal surgery, also known as antenatal surgery or prenatal surgery, is a growing branch of maternal-fetal medicine that covers any of a broad range of surgical techniques that are used to treat congenital abnormalities in fetuses who are still in the pregnant uterus. There are three main types: open fetal surgery, which involves completely opening the uterus to operate on the fetus; minimally invasive fetoscopic surgery, which uses small incisions and is guided by fetoscopy and sonography; and percutaneous fetal therapy, which involves placing a catheter under continuous ultrasound guidance. Fetal intervention is relatively new. Advancing technologies allow earlier and more accurate diagnosis of diseases and congenital problems in a fetus. Fetal surgery draws principally from the fields of surgery, obstetrics and gynecology, and pediatrics- especially the sub-specialties of neonatology (care of newborns), maternal-fetal medicine (care of high-risk pregnancies), and pediatric surgery. It often involves training in obstetrics, pediatrics, and mastery of both invasive and non-invasive surgical techniques. Because of the very high risk and technical complexity of fetal surgery, the procedure is usually performed at specialist centers. Fetal intervention involves risk to fetus and pregnant patient alike. In addition to the general risks associated with any surgery, there is also a risk that scarring of the uterus will lead to difficulties with future pregnancies. This risk is higher than for a typical Cesarean section, for several reasons: the incision is usually a classical vertical one, with a greater risk of complications in subsequent pregnancies; the longer duration of the surgery, while the fetal intervention is performed; a second surgery is required days or weeks later – a Caesarean section to deliver the baby, which brings its own set of risks. == Types == === Open fetal surgery === ==== Technique ==== Tocolytics are generally given to prevent labor; however, these should not be given if the risk is higher for the fetus inside the womb than if delivered, such as may be the case in intrauterine infection, unexplained vaginal bleeding and fetal distress. An H2 antagonist is usually given for anaesthesia the evening before and the morning of the operation, and an antacid is usually given before induction to reduce the risk of acid aspiration. Rapid sequence induction is often used for sedation and intubation. Open fetal surgery is similar in many respects to a normal cesarean section performed under general anesthesia, except that the fetus remains dependent on the placenta and is returned to the uterus. A hysterotomy is performed on the pregnant woman, and once the uterus is open and the fetus is exposed, the fetal surgery begins. Typically, this surgery consists of an interim procedure intended to allow the fetus to remain in utero until it has matured enough to survive delivery and neonatal surgical procedures. Upon completion of the fetal surgery, the fetus is put back inside the uterus and the uterus and abdominal wall are closed up. Before the last stitch is made in the uterine wall, the amniotic fluid is replaced. The mother remains in the hospital for 3–7 days for monitoring. Often babies who have been operated on in this manner are born pre-term. ==== Safety and complications ==== The main priority is maternal safety, avoiding preterm labor and achieving the aims of the surgery. The risk of premature labor is increased by concomitant risk factors such as multiple gestation, a history of maternal smoking, and very young or old maternal age. Risks of fetal surgery, specifically prenatal spina bifida repair, include premature rupture of membranes, uterine rupture in future pregnancies, premature birth and intraspinal inclusion cysts or a tethered cord in the fetus or newborn baby. Open fetal surgery has proven to be reasonably safe for the mother. For the fetus, safety and effectiveness are variable, and depend on the specific procedure, the reasons for the procedure, and the gestational age and condition of the fetus. The overall perinatal mortality after open surgery has been estimated to be approximately 6%, according to a study in the United States 2003. All future pregnancies for the mother require cesarean delivery because of the hysterotomy. Fetal surgery is not thought to decrease maternal fertility. ==== Indications ==== Neural tube defects (NTD), which begin to become observable at the 28th day of pregnancy, occur when the embryonic neural tube fails to close properly, the developing brain and spinal cord are openly exposed to amniotic fluid. After birth, exposure of the spinal cord to the outside environment (myelomeningocele or spina bifida) is associated with several morbidities including weakness or sensory deficits in the lower extremities, bladder dysfunction, fluid buildup in the brain and Type 2 Chiari malformations (herniation of the cerebellar vermis and medulla from the brain into the spinal canal. Prenatal repair of spina bifida is available in specialty centers. Fetuses treated with prenatal fetal repair have significantly improved outcomes compared to children whose defects are repaired shortly after birth. Specifically, fetal repair reduces the rate of hydrocephalus, ventriculoperitoneal shunt dependence, and Chiari malformation. Prenatal repair also shows improved motor skills at 30 months and improved mobility, neuropsychological function, and independent functioning between the ages of 5 and 10. Other conditions that potentially are treated by open fetal surgery include: Congenital diaphragmatic hernia (if indicated at all, it is now more likely to be treated by endoscopic fetal surgery) Congenital cystic adenomatoid malformation Congenital heart disease Pulmonary sequestration Sacrococcygeal teratoma === Minimally invasive fetal surgery === Minimally-invasive fetoscopic surgery has proven to be useful for some fetal conditions. Twin-twin transfusion syndrome – Laser Ablation of Vessels Spina bifida – Fetoscopic closure of the malformation. Prenatal repair of the spina bifida lesion through this approach has been purported to result in less complications to the mother, whilst affording benefit to the baby. == History == Fetal surgical techniques were first developed at the University of California, San Francisco, in 1980 using animal models. On April 26, 1981, the first successful human open fetal surgery in the world was performed at University of California, San Francisco, under the direction of Dr. Michael Harrison. The fetus in question had a congenital hydronephrosis, a blockage in the urinary tract that caused the kidney to dangerously extend. To correct this a vesicostomy was performed by placing a catheter in the fetus to allow the urine to be released normally. The blockage itself was removed surgically after birth. Further advances have been made in the years since this first operation. New techniques have allowed additional defects to be treated and for less invasive forms of fetal surgical intervention. The first two percutaneous ultrasound-guided fetal balloon valvuloplasties, a type of fetal surgery for severe aortic valve obstruction in the heart, were reported in 1991. Among the first dozen reported attempts at this repair in the 1990s, only two children survived long-term. Dr. Oluyinka Olutoye, alongside Darrell Cass, from the Texas Children's Fetal Centre, removed a 23-week-old fetus from her mother's womb in order to perform surgery upon a spinal tumor she had. The girl was placed back in the womb after a five-hour surgery and was born without complications. == See also == Fetoscopy EXIT procedure Maternal-fetal medicine, a discipline of high-risk obstetrics and gynecology; most fetal surgeons were previously trained in OB-GYN and maternal-fetal medicine before their fetal surgical training Neonatology and neonatal surgery, related to high risk OB-GYN and maternal-fetal medicine and fetal surgery, are branches of pediatrics and pediatric surgery that focus on the treatment of newborn infants (less than one month of age) Pediatric surgery, a related but distinct discipline of surgery and pediatrics, involving surgery on infants, toddlers, and children and adolescents MOMS Trial Spina bifida NAFTNet Samuel Armas == References == == Further reading == Sutton LN (February 2008). "Fetal surgery for neural tube defects". Best Pract Res Clin Obstet Gynaecol. 22 (1): 175–88. doi:10.1016/j.bpobgyn.2007.07.004. PMC 2293328. PMID 17714997.	Wikipedia/Fetal_surgery
Hirschsprung's disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Most children develop signs and symptoms shortly after birth. However, others may be diagnosed later in infancy or early childhood. About half of all children with Hirschsprung's disease are diagnosed in the first year of life. Complications may include enterocolitis, megacolon, bowel obstruction and intestinal perforation. The disorder may occur by itself or in association with other genetic disorders such as Down syndrome or Waardenburg syndrome. About half of isolated cases are linked to a specific genetic mutation, and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. If otherwise normal parents have one child with the condition, the next child has a 4% risk of being affected. The condition is divided into two main types, short-segment and long-segment, depending on how much of the bowel is affected. Rarely, the small bowel may be affected, as well. Diagnosis is based on symptoms and confirmed by biopsy. Treatment is generally by surgery to remove the affected section of bowel. The surgical procedure most often carried out is known as a "pull through". Occasionally, an intestinal transplantation may be recommended. Hirschsprung's disease occurs in about one in 5,000 of newborns. Males are more often affected than females. The condition is believed to have first been described in 1691 by Dutch anatomist Frederik Ruysch and is named after Danish physician Harald Hirschsprung following his description in 1888. == Signs and symptoms == Typically, Hirschsprung disease is diagnosed shortly after birth, although it may develop well into adulthood, because of the presence of megacolon, or because the baby fails to pass the first stool (meconium) within 48 hours of delivery. Normally, 90% of babies pass their first meconium within 24 hours, and 99% within 48 hours. Some other signs and symptoms in newborns include a swollen belly, vomiting (green or brown vomit), and flatulence. In older children, some other signs and symptoms include chronic constipation, flatulence, swollen belly, fatigue, and failure to thrive. Other symptoms include symptoms of bowel perforation such as vomiting, constipation, poor feeding, lethargy, and diarrhea. Symptoms of bowel obstruction would include vomiting of bile and abdominal distension. Those who do not pass stools after 36 to 48 hours after birth should raise suspicion of Hirschsprung disease. Such suspicion can also be risen if there is only passage of stools after suppository, rectal exam, or enema. Children who do not respond to constipation treatment for six months should also raise suspicion of such disease. Enterocolitis, an acute complication of Hirschsprung disease, is characterised by sudden onset of fever, abdominal distension, vomiting, passage of bloody stools or release of explosive gas or stools after rectal examination. Some cases are diagnosed later, into childhood, but usually before age 10. The child may experience fecal retention, constipation, or abdominal distention. === Associated syndromes === Hirschsprung's disease can also present as part of multi system disorders, such as: Bardet–Biedl syndrome Cartilage–hair hypoplasia Congenital central hypoventilation syndrome MEN2 Mowat–Wilson syndrome Smith–Lemli–Opitz syndrome Trisomy 21 (Down syndrome) Some forms of Waardenburg syndrome == Cause == The disorder may occur by itself or in association with other genetic disorders such as Down syndrome. About half of isolated cases are linked to a specific genetic mutation and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. If otherwise normal parents have one child with the condition, the next child has a 4% risk of being affected. === Genetics === Several genes and specific regions on chromosomes (loci) have been shown or suggested to be associated with Hirschsprung's disease The RET proto-oncogene accounts for the highest proportion of both familial and sporadic cases, with a wide range of mutations scattered along its entire coding region. A proto-oncogene can cause cancer if it is mutated or overexpressed. === RET proto-oncogene === RET is a gene that codes for proteins that assist cells of the neural crest in their movement through the digestive tract during the development of the embryo. Those neural crest cells eventually form bundles of nerve cells called ganglions. EDNRB codes for proteins that connect these nerve cells to the digestive tract. Thus, mutations in these two genes could directly lead to the absence of certain nerve fibers in the colon. Research suggests that several genes are associated with Hirschsprung's disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung's disease than previously thought. RET can mutate in many ways and is associated with Down syndrome. Since Down syndrome is comorbid in 2% of Hirschsprung's cases, a likelihood exists that RET is involved heavily in both Hirschsprung's disease and Down syndrome. RET is also associated with medullary thyroid cancer and neuroblastoma, which is a type of cancer common in children. Both of these disorders are more common in Hirschsprung's patients than in the general population. One function that RET controls is the travel of the neural crest cells through the intestines in the developing fetus. The earlier the RET mutation occurs in Hirschsprung's disease, the more severe the disorder becomes. === Other genes === Common and rare DNA variations in the neuregulin 1 (NRG1) and NRG3 (NRG3) were first shown to be associated with the disease in Chinese patients through a Genome Wide Association Study by the Hong Kong team in 2009 and 2012, respectively Subsequent studies in both Asian and Caucasian patients confirmed the initial findings by the University of Hong Kong. Both rare and common variants in these two genes have been identified in additional Chinese, Thai, Korean, Indonesian, and Spanish patients. These two genes are known to play a role in the formation of the enteric nervous system; thus, they are likely to be involved in the pathology of Hirschsprung's disease, at least in some cases. Another gene associated with this condition is NADPH oxidase, EF-hand calcium binding domain 5 (NOX5). This gene is located on the long arm of chromosome 15 (15q23). == Pathophysiology == During normal prenatal development, cells from the neural crest migrate into the large intestine (colon) to form the networks of nerves called the myenteric plexus (Auerbach plexus) (between the smooth muscle layers of the gastrointestinal tract wall) and the submucosal plexus (Meissner plexus) (within the submucosa of the gastrointestinal tract wall). In Hirschsprung disease, the migration is not complete and part of the colon lacks these nerve bodies that regulate the activity of the colon. The affected segment of the colon cannot relax and pass stool through the colon, creating an obstruction. The most accepted theory of the cause of Hirschsprung is a defect in the craniocaudal migration of neuroblasts originating from the neural crest that occurs during the first 12 weeks of gestation. Defects in the differentiation of neuroblasts into ganglion cells and accelerated ganglion cell destruction within the intestine may also contribute to the disorder. This lack of ganglion cells in the myenteric and submucosal plexus is well documented in Hirschsprung's disease. With Hirschsprung's disease, the segment lacking neurons (aganglionic) becomes constricted, causing the normal, proximal section of bowel to become distended with feces. This narrowing of the distal colon and the failure of relaxation in the aganglionic segment are thought to be caused by the lack of neurons containing nitric oxide synthase. The most cited feature is absence of ganglion cells: notably in males, 75% have none in the end of the colon (rectosigmoid) and 8% lack ganglion cells in the entire colon. The enlarged section of the bowel is found proximally, while the narrowed, aganglionic section is found distally, closer to the end of the bowel. The absence of ganglion cells results in a persistent overstimulation of nerves in the affected region, resulting in contraction. The equivalent disease in horses is lethal white syndrome. == Diagnosis == Definitive diagnosis is made by suction biopsy of the distally narrowed segment. A histologic examination of the tissue would show a lack of ganglionic nerve cells. Diagnostic techniques involve anorectal manometry, barium enema, and rectal biopsy. The suction rectal biopsy is considered the current international gold standard in the diagnosis of Hirschsprung's disease. Radiologic findings may also assist with diagnosis. An abdominal x-ray can reveal a lack of stool in the large intestine or a bulging caused by blocked stool. Cineanography (fluoroscopy of contrast medium passing anorectal region) assists in determining the level of the affected intestines. == Treatment == Treatment of Hirschsprung's disease consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis. === Colostomy === The first stage of treatment used to be a reversible colostomy. In this approach, the healthy end of the large intestine is cut and attached to an opening created on the front of the abdomen. The contents of the bowel are discharged through the hole in the abdomen and into a bag. Later, when the patient's weight, age, and condition are right, the "new" functional end of the bowel is connected with the anus. The first surgical treatment involving surgical resection followed by reanastomosis without a colostomy occurred as early as 1933 by Doctor Baird in Birmingham on a one-year-old boy. === Other procedures === The Swedish-American surgeon Orvar Swenson (1909–2012), who discovered the cause of Hirschsprung's, first performed its surgical treatment, the pull-through surgery, in 1948. The pull-through procedure repairs the colon by connecting the functioning portion of the bowel to the anus. The pull-through procedure is the typical method for treating Hirschsprung's in younger patients. Swenson devised the original procedure, and the pull-through surgery has been modified many times.' Currently, several different surgical approaches are used, which include the Swenson, Soave, Duhamel, and Boley procedures. The Swenson procedure leaves a small portion of the diseased bowel. The Soave procedure, named after the Italian pediatric surgeon, Franco Soave (1917–1984), leaves the outer wall of the colon unaltered. The Boley procedure, pioneered by the American surgeon, Scott Boley (born 1941), is a small modification of the Soave procedure, so the term "Soave-Boley" procedure is sometimes used. The Duhamel procedure, named for the French pediatric surgeon Bernard Duhamel (1917–1996), uses a surgical stapler to connect the good and bad bowel. For the 15% of children who do not obtain full bowel control, other treatments are available. Constipation may be remedied by laxatives or a high-fiber diet. In those patients, serious dehydration can play a major factor in their lifestyles. A lack of bowel control may be addressed by an ileostomy – similar to a colostomy, but uses the end of the small intestine rather than the colon. The Malone antegrade colonic enema (ACE) is also an option. In a Malone ACE, a tube goes through the abdominal wall to the appendix, or if available, to the colon. The bowel is then flushed daily. Children as young as 6 years of age may administer this daily flush on their own. If the affected portion of the lower intestine is restricted to the lower portion of the rectum, other surgical procedures may be performed, such as a posterior rectal myectomy. The prognosis is good in 70% of cases. Chronic postoperative constipation is present in 7 to 8% of the operated cases. Postoperative enterocolitis, a severe manifestation, is present in the 10–20% of operated patients. == Epidemiology == According to a 1984 study conducted in Maryland, Hirschsprung's disease appears in 18.6 per 100,000 live births. In Japan, it occurs at a similar rate of about one in 5,000 births (20 per 100,000). It is more common in male than female (4.32:1) and in white rather than nonwhite. Nine percent of the Hirschsprung cases were also diagnosed as having Down syndrome. Most cases are diagnosed before the patient is 10 years of age. == History == The first report of Hirschsprung's disease dates to 1691, when it was described by Dutch anatomist Frederik Ruysch. However, the disease is named after Harald Hirschsprung, the Danish physician who first described two infants who died of this disorder in 1888. Hirschsprung's disease is a congenital disorder of the colon in which certain nerve cells, known as ganglion cells, are absent, causing chronic constipation. In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. A barium enema is the mainstay of diagnosis of Hirschsprung's, though a rectal biopsy showing the lack of ganglion cells is the only certain method of diagnosis. The first publication on an important genetic discovery of the disease was from Martucciello Giuseppe et al. in 1992. The authors described a case of a patient with total colonic aganglionosis associated with a 46, XX, del 10 (q11.21 q21.2) karyotype. The major gene of Hirschsprung disease was identified in this chromosomal 10 region, it was the RET proto-oncogene. The usual treatment is "pull-through" surgery where the portion of the colon that does have nerve cells is pulled through and sewn over the part that lacks nerve cells. For a long time, Hirschsprung's was considered a multifactorial disorder, where a combination of nature and nurture was considered to be the cause. However, in August 1993, two articles by independent groups in Nature Genetics said that Hirschsprung's disease could be mapped to a stretch of chromosome 10. == See also == Achalasia Ileus, failure of peristaltic muscle activity in the gut Intestinal neuronal dysplasia Intestinal hypoganglionosis Hirschsprung's disease-type D brachydactyly syndrome == References == == External links ==	Wikipedia/Hirschsprung's_disease
Damage control surgery is surgical intervention to keep the patient alive rather than correct the anatomy. It addresses the "lethal triad" for critically ill patients with severe hemorrhage affecting homeostasis leading to metabolic acidosis, hypothermia, and increased coagulopathy. This lifesaving method has significantly decreased the morbidity and mortality of critically ill patients, though complications can result. It stabilizes patients for clinicians to subsequently reverse the physiologic insult prior to completing a definitive repair. While the temptation to perform a definitive operation exists, surgeons should avoid this practice because the deleterious effects on patients can result in them succumbing to the physiologic effects of the injury, despite the anatomical correction. The leading cause of death among trauma patients remains uncontrolled hemorrhage and accounts for approximately 30–40% of trauma-related deaths. While typically trauma surgeons are heavily involved in treating such patients, the concept has evolved to other sub-specialty services. A multi-disciplinary group of individuals is required: nurses, respiratory therapist, surgical-medicine intensivists, blood bank personnel and others. == Technique == Damage control surgery can be divided into the following three phases: Initial laparotomy, Intensive Care Unit (ICU) resuscitation, and definitive reconstruction. Each of these phases has defined timing and objectives to ensure best outcomes. The following goes through the different phases to illustrate, step by step, how one might approach this. There are clearly different approaches throughout the country, and no one way is necessarily correct. However, the ability to evaluate objectively the differences and then choose the one that fits your team is important. === Initial laparotomy === This is the first part of the damage control process whereby there are some clear-cut goals surgeons should achieve. The first is controlling hemorrhage followed by contamination control, abdominal packing, and placement of a temporary closure device. Minimizing the length of time spent in this phase is essential. For groups (i.e., trauma centers) to be effective in damage control surgery, a multi-disciplinary team is critical. The approach to caring for such critically ill patients is dependent on nurses, surgeons, critical care physicians, operating room staff, blood bank personnel, and administrative support. In addition to having the right team in place is having a prepared team. The more facile the team is enhances the ability for centers to effectively implement damage control surgery. This is referred to by some as damage control ground zero (DC0). The ability to mobilize personnel, equipment, and other resources is bolstered by preparation; however, standardized protocols ensure that team members from various entities within the health care system are all speaking the same language. This has been seen during implementation of complex processes such as the massive transfusion protocol (MTP). Controlling of hemorrhage as discussed above is the most important step in this phase. Eviscerating the intra-abdominal small bowel and packing all four abdominal quadrants usually helps surgeons establish initial hemorrhagic control. Depending up on the source of hemorrhage a number of different maneuvers might need to be performed allowing for control of aortic inflow. Solid organ injury (i.e., spleen, kidney) should be dealt with by resection. When dealing with hepatic hemorrhage a number of different options exist such as performing a Pringle maneuver that would allow for control of hepatic inflow. Surgeons can also apply manual pressure, perform hepatic packing, or even plugging penetrating wounds. Certain situations might require leaving the liver packed and taking the patient for angio-embolization or if operating in a hybrid operating room having perform an on table angio-embolization. Vessels that are able to be ligated should, and one should consider shunting other vessels that do not fall into this category. This has been described by Reilly and colleagues when they shunted the superior mesenteric artery to decrease the length of time in the operating room. Once hemorrhage control is achieved one should quickly proceed to controlling intra-abdominal contamination from hollow-viscus organs. The perception might be that one could quickly perform an anastomosis. This should not be attempted in the damage control setting. The key is to simply prevent continued intra-abdominal contamination, and to leave patients in discontinuity. A number of different techniques can be employed such as using staplers to come across the bowel, or primary suture closure in small perforations. Once this is complete the abdomen should be packed. Many of these patients become coagulopathic and can develop diffuse oozing. It is important to not only pack areas of injury but also pack areas of surgical dissection. There are various methods that can be used to pack the abdomen. Packing with radiopaque laparotomy pads allow for the benefit of being able to detect them via x-ray prior to definitive closure. As a rule abdomens should not be definitively closed until there has been radiologic confirmation that no retained objects are present in the abdomen. The final step of this phase is applying a temporary closure device. Numerous methods of temporary closure exist, with the most common technique being a negative-vacuum type device. Regardless of which method one decides to use it is important that the abdominal fascia is not reapproximated. The ability to develop abdominal compartment syndrome is a real concern and described by Schwab. === ICU resuscitation === On completion of the initial phase of damage control, the key is to reverse the physiologic insult that took place. This specifically relates to factors such as acidosis, coagulopathy, and hypothermia (lethal triad) that many of these critically ill patients develop. When developing a strategy to best care for these patients, the same principles of having a multi-disciplinary team that work together in parallel for the same result apply. The intensivist is critical in working with the staff to ensure that the physiologic abnormalities are treated. This typically requires close monitoring in the intensive care unit, ventilator support, laboratory monitoring of resuscitation parameters (i.e., lactate). In using a number of different resuscitation parameters, the critical care team can have a better idea as to which direction is progressing. The first 24 hours often require a significant amount of resources (i.e., blood products) and investment of time from personnel within the critical care team. In many circumstances, especially trauma patients, require that other specialties address a variety of injuries. Moving the patient early on, unless absolutely necessary, can be detrimental. Certain circumstances might require this, and the patients should continue to receive care from the critical care team during the entire transport period. As the literature begins to grow within the field of damage control surgery, the medical community is continuously learning how to improve the process. Certain pitfalls have also become evident, one of which is the potential to develop abdominal compartment syndrome. In some cases, temporary abdominal closure itself or underlying conditions may contribute to abdominal compartment syndrome, causing increased intraabdominal pressure and compromising organ perfusion. Temporary abdominal dressings with high negative pressures can be a cause of recurrent abdominal compartment syndrome and one should not hesitate to turn off the dressing's suction when evaluating a patient with signs of recurrent abdominal compartment syndrome. While it might sound counterintuitive since the fascia is left open during the placement of these temporary closure devices, they can create a similar type process that leads to abdominal compartment syndrome. If this occurs the temporary closure device should be taken down immediately. === Definitive reconstruction === The third step in damage control surgery is addressing closure of the abdomen. Definitive reconstruction occurs only when the patient is improving. At this point in process the critical care team has been able to correct the physiologic derangements. The optimization typically takes 24 to 48 hours, depending on how severe the initial insult is. Prior to being taken back to the operating room it is paramount that the resolution of acidosis, hypothermia, and coagulopathy has occurred. The first step after removing the temporary closure device is to ensure that all abdominal packs are removed. Typically the number of packs has been documented in the initial laparotomy; however, an abdominal radiograph should be taken prior to definitive closure of the fascia to ensure that no retained sponges are left in the abdomen. Once the abdominal packs are removed the next step is to re-explore the abdomen allowing for the identification of potentially missed injuries during the initial laparotomy and re-evaluating the prior injuries. Attention is then turned to performing the necessary bowel anastomosis or other definitive repairs (i.e., vascular injuries). An attempt should be made to close the abdominal fascia at the first take back, to prevent complications that can result from having an open abdomen. The concern for early closure of the abdomen with development of compartment syndrome is a real one. A method to pre-emptively evaluate whether fascial closure is appropriate would be to determine the difference in peak airway pressure (PAP) prior to closure and the right after closure. An increase of over 10 would suggest that the abdomen be left open. As mentioned above, it is important to obtain an abdominal radiograph to ensure that no retained sponges are left intra-operatively. Considering that not all patients can undergo definitive reconstruction at first return, there are other options that surgeons can consider. Data would suggest that the longer the abdomen is left open from initial laparotomy the higher the rate of complications. After about one week, if surgeons can't close the abdomen, they should consider placing a Vicryl mesh to cover the abdominal contents. This lets granulation occur over a few weeks, with the subsequent ability to place a split-thickness skin graft (STSG) on top for coverage. These patients clearly have a hernia that must be fixed 9 to 12 months later. == Resuscitation == Damage control resuscitation has had a dramatic impact on how care for critically ill patients is administered.. The core principles of resuscitation involve permissive hypotension, transfusion ratios, and massive transfusion protocol. The resuscitation period lets any physiologic derangements be reversed to give the best outcome for patient care. === Permissive hypotension === Typical resuscitation strategies have used an approach where aggressive crystalloid and/or blood product resuscitation is performed to restore blood volume. The term permissive hypotension refers to maintaining a low blood pressure to mitigate hemorrhage; however, continue providing adequate end-organ perfusion [Duchesene, 2010]. The key is to prevent exacerbation of hemorrhaging until definitive vascular control can be achieved, the theory being that if clots have formed within a vessel then increasing the patient's blood pressure might dislodge those established clots resulting in more significant bleeding. Permissive hypotension is not a new concept, and had been described in penetrating thoracic trauma patients during World War I by Bickell and colleagues demonstrating an improvement in both survival and complications. Subsequent animal studies have shown equivalent outcomes with no real benefit in mortality Recently there has been further data in trauma patients that has demonstrated increased survival rates [Morrison, 2011]. Cotton and colleagues found that the use of a permissive hypotension resuscitation strategy resulted in better outcomes (increased 30-day survival) in those undergoing damage control laparotomy. This would not be used in situations where patients might have injuries such as a traumatic brain injury considering that such patients are excluded from the studies. === Transfusion ratios === For over a century the casualties of war have provided valuable lessons that can be applied within the civilian sector. Specifically the past decade has seen a paradigm shift in early resuscitation of critically injured patients. Instead of replacing blood volume with high volumes of crystalloid and packed red blood cells with the sporadic use of fresh frozen plasma and platelets, we have now learned that maintaining a transfusion ratio of 1:1:1 of plasma to red blood cells to platelets in patients requiring massive transfusion results in improved outcomes [Borgman 2007] While this was initially demonstrated in the military setting, Holcomb and colleagues extrapolated this to the civilian trauma center showing improved results as well Broad implementation across both the military and civilian sector has demonstrated a decreased mortality in critically injured patients. Debate has gone back and forth as to the correct ratio that should be used; however, recently Holcomb and colleagues published the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) Study. They compared administration a higher ratio of plasma and platelets (1:1:1) compared to a lower ratio (1:1:2). The patients that received a higher ratio had an associated three to four-fold decrease in mortality. To help mitigate confounding variables a randomized control trial called the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) has been performed to evaluate the transfusion requirement. There was no difference in 24 hour or 30 day mortality between the 1:1:1 group and the 1:1:2 group - https://jamanetwork.com/journals/jama/fullarticle/2107789. === Massive transfusion protocol === Initial resuscitation of trauma patients continues to evolve. Massive transfusion (defined as receiving greater than or equal to 10 units of packed red blood cells with a 24-hour period) is required in up to 5% of civilian trauma patients that arrive severely injured. Patients who are arriving severely injured to trauma centers can be coagulopathic. Data suggests that around 25% of patients arrive with coagulopathy. New ways of measuring coagulopathy such at thromboelastography and rotational thromboelastometry have allowed for a more robust assessment of the coagulation cascade compared to traditional methods of measuring international normalized ratio allowing clinicians to better target areas of deficiency. For trauma teams to systematically and efficiently deliver blood products institutions have created protocols that allow for this. The protocols allow for clear communication between the trauma center, blood bank, nurses, and other ancillary staff. They also allow for the quick delivery of certain set of blood products depending upon the institution. One example might be that a “cooler” would contain 10 units of packed red blood cells, 10 units of plasma, and 2 packs of platelets. The idea is that the coolers would continue to be delivered to the location where the patient is being treated until the trauma team leader (typically the trauma surgeon) would discontinue the order. Systolic blood pressure <90 mmHg, hemoglobin <11 g/dL, temperature <35.5oC, international normalized ratio > 1.5, base deficit ≥6 mEq/L, heart rate ≥120 bpm, presence of penetrating trauma, and Focused Abdominal Sonography Trauma exam have been evaluated to determine their predictive ability in patients arriving at trauma centers. All were be predictive of the need of massive transfusion protocol except for temperature. == History == Surgeons have used the concept of damage control surgery for years, and controlling hemorrhage with packing is over a century old. Pringle described this technique in patients with substantial hepatic trauma in the early twentieth century. The U.S. military did not encourage this technique during World War II and the Vietnam War. Lucas and Ledgerwood described the principle in a series of patients. Subsequent studies were repeated by Feliciano and colleagues, and they found that hepatic packing increased survival by 90%. This technique was then specifically linked to patients who were hemorrhaging, hypothermic, and coagulopathic. This extrapolation allowed for the first article in 1993 by Rotondo and Schwab specifically adapting the term “damage control”. This term was taken from the United States Navy who initially used the term as “the capacity of a ship to absorb damage and maintain mission integrity” (DOD 1996). This was the first article that brought together the concept of limiting operative time in these critically ill patients to allow for reversal of physiologic insults to improve survival. In addition, the description illustrated how the three phases of damage control surgery can be implemented. Since this description the development of this concept has grown both within the trauma community and beyond. == Outcomes == The data that have been published regarding definitive laparotomy versus damage control surgery demonstrate a decrease in mortality when performed in the critically ill patient. Subsequent studies by Rotondo and colleagues in a group of 961 patients that had undergone damage control surgery demonstrate an overall mortality of 50% and a 40% morbidity rate. There are four main complications. The first is development of an intra-abdominal abscess. This has been reported as high as 83%. Next is the development of an entero-atmospheric fistula, which ranges from 2 to 25%. The third is abdominal compartment syndrome that has been reported anywhere from 10 to 40% of the time. Finally fascial dehiscence has been shown to result in 9–25% of patients that have undergone damage control surgery. == References == == Bibliography == Feliciano, David V.; Mattox, Kenneth L.; Moore, Ernest J (2012). Trauma, Seventh Edition (Trauma (Moore)). McGraw-Hill Professional. ISBN 978-0-07-166351-9. Wang, Chih-Hung; Hsieh, Wen-Han; Chou, Hao-Chang; Huang, Yu-Sheng; Shen, Jen-Hsiang; Yeo, Yee Hui; Chang, Huai-En; Chen, Shyr-Chyr; Lee, Chien-Chang (April 2014). "Liberal Versus Restricted Fluid Resuscitation Strategies in Trauma Patients". Critical Care Medicine. 42 (4): 954–961. doi:10.1097/CCM.0000000000000050. PMID 24335443. S2CID 44411659. Garner, Glen B; Ware, Drue N; Cocanour, Christine S; Duke, James H; McKinley, Bruce A; Kozar, Rosemary A; Moore, Frederick A (December 2001). "Vacuum-assisted wound closure provides early fascial reapproximation in trauma patients with open abdomens". The American Journal of Surgery. 182 (6): 630–638. doi:10.1016/S0002-9610(01)00786-3. PMID 11839329. Abikhaled, JA; Granchi, TS; Wall, MJ; Hirshberg, A; Mattox, KL (December 1997). "Prolonged abdominal packing for trauma is associated with increased morbidity and mortality". The American Surgeon. 63 (12): 1109–12, discussion 1112–3. PMID 9393261. Burch, JM; Ortiz, VB; Richardson, RJ; Martin, RR; Mattox, KL; Jordan GL, Jr (May 1992). "Abbreviated laparotomy and planned reoperation for critically injured patients". Annals of Surgery. 215 (5): 476–83, discussion 483–4. doi:10.1097/00000658-199205000-00010. PMC 1242479. PMID 1616384. Surface Ship Survivability. Naval War Publications 3-20.31. Washington, DC: Department of Defense; 1996. Teixeira, PG; Inaba, K; Salim, A; Brown, C; Rhee, P; Browder, T; Belzberg, H; Demetriades, D (October 2007). "Retained foreign bodies after emergent trauma surgery: incidence after 2526 cavitary explorations". The American Surgeon. 73 (10): 1031–4. doi:10.1177/000313480707301024. PMID 17983075. S2CID 28811296. Trauma.org - Damage Control Surgery overview Archived 2013-08-25 at the Wayback Machine	Wikipedia/Damage_control_surgery
Endovenous laser treatment (ELT) is a minimally invasive ultrasound-guided technique used for treating varicose veins using laser energy commonly performed by a phlebologist, interventional radiologist or vascular surgeon. == Methods == Endovenous laser treatment treats varicose veins using an optical fiber that is inserted into the vein to be treated, and laser light, normally in the infrared portion of the spectrum, shines into the interior of the vein. This causes the vein to contract, and the optical fiber is slowly withdrawn. Some minor complications can occur, including thrombophlebitis, pain, hematoma, edema and infection, which can lead to cellulitis. EVLT has the same meaning as ELT, but it is a trademark name owned by Diomed and used as the name for their 910 nm laser treatment unit for ELT. The 810 nm laser is the original laser fiber wavelength as pioneered by Dr. Luis Navarro, Dr. Carlos Bone and Dr. Robert Min, at the Vein Treatment Center in New York, New York. Subsequently, various other fibers with different wavelengths have become available. The varying wavelength each aim to maximize local damage to a component of the varicose vein or the blood contained in it while minimizing damage to adjacent tissues. During the procedure, a catheter bearing a laser fiber is inserted under ultrasound guidance into the great saphenous vein (GSV) or small saphenous vein (SSV) through a small puncture. The catheter is then advanced, also under ultrasound guidance, to the level of the groin or knee crease. Dilute local anesthesia is injected around and along the vein (perivascular infiltration) using ultrasound imaging to place the local anesthetic solution around the vein, mostly in a sub-facial location. This technique derives from the tumescent local anesthesia (TLA) method long used and proven safe and effective for some methods of liposuction. The laser is activated whilst the catheter or laser fiber is slowly withdrawn, resulting in obliteration of the saphenous vein along its entire length. The treatment, which is performed without sedation, usually takes between 1 and two hours, and the patient walks out under his or her own power. The leg is bandaged and/or placed in a stocking that the patient wears for up to three weeks afterwards. Foam sclerotherapy or ambulatory phlebectomy is often performed at the time of the procedure or within the first 1–2 weeks to treat branch varicose veins. However, some physicians do not perform these procedures at the time of the ELT because the varicose veins can improve on their own as a result of reduced reflux from the great saphenous vein. == Complications == Complications of endovenous laser treatment can be categorized as minor, or serious. Minor complications include bruising (51%), hematoma (2.3%), temporary numbness (3.8%), phlebitis (7.4%), induration (46.7%), and a sensation of tightness (24.8%). More serious complications include skin burns (0.5%), deep venous thrombosis (0.4%), pulmonary embolism (0.1%), and nerve injury (0.8%). These rates of complications are derived from the Australian MSAC review of all available literature on the procedure. Retinal damage is a serious but very rare complication (<1%) that can occur during the use of lasers. If the fiber breaks or if the laser is activated when the laser is outside of the body, reflected laser light may cause a focal permanent retinal deficit or "blind spot" or scotoma. The nominal hazard zone (NHZ) or space within which the level of direct, scattered, or reflected laser radiation exceeds the maximum permissible exposure (MPE), varies by the wavelength of the laser and is shorter (17 inches) with the newer 1470 nm laser. Use of appropriate protective eyeware specific to the wavelength laser being used prevents accidental injury. == Clinical evaluations == A 2005 report from one practice, summarising results of 1,000 limbs treated over a 5-year period with EVLT showed that 98% of the treated vessels at up to 60 months follow-up remained closed, with complications and side effects such as temporary paresthesia and DVTs below 0.5%. The Australian Medical Services Advisory Committee (MSAC) in 2008 has determined that endovenous laser treatment for varicose veins "appears to be more effective in the short term, and at least as effective overall, as the comparative procedure of junction ligation and vein stripping for the treatment of varicose veins." It also found in its assessment of available literature, that "occurrence rates of more severe complications such as DVT, nerve injury and paresthesia, post-operative infections and hematomas, appears to be greater after ligation and stripping than after EVLT". A study of 516 treated veins over 69 months by Elmore and Lackey reported a success rate of 98.1%. Endovenous thermal ablation (EVTA) by radiofrequency or laser is a safe and effective treatment of refluxing great saphenous veins (GSVs) and has replaced traditional high ligation and stripping in official recommendations of various leading Vascular Societies in the United States and the United Kingdom. == Postoperative instructions == Patients are usually fitted with Class 3 (30-40mmHg) graduated compression stockings and/or bandages for up to 12 hours weeks. Duplex ultrasound is used during follow-up to assess the success of treatment, if there is a need for additional sclerotherapy or any deep vein thrombosis that has formed as an EHIT secondary to procedure. == See also == Interventional radiology == References == == External links == American College of Phlebology Vascular Web - Varicose Veins	Wikipedia/Endovenous_laser_treatment
Renal replacement therapy (RRT) is therapy that replaces the normal blood-filtering function of the kidneys. It is used when the kidneys are not working well, which is called kidney failure and includes acute kidney injury and chronic kidney disease. Renal replacement therapy includes dialysis (hemodialysis or peritoneal dialysis), hemofiltration, and hemodiafiltration, which are various ways of filtration of blood with or without machines. Renal replacement therapy also includes kidney transplantation, which is the ultimate form of replacement in that the old kidney is replaced by a donor kidney. These treatments are not truly cures for kidney disease. In the context of chronic kidney disease, they are more accurately viewed as life-extending treatments, although if chronic kidney disease is managed well with dialysis and a compatible graft is found early and is successfully transplanted, the clinical course can be quite favorable, with life expectancy of many years. Likewise, in certain acute illnesses or trauma resulting in acute kidney injury, a person could very well survive for many years, with relatively good kidney function, before needing intervention again, as long as they had good response to dialysis, they got a kidney transplant fairly quickly if needed, their body did not reject the transplanted kidney, and they had no other significant health problems. Early dialysis (and, if indicated, early renal transplant) in acute kidney failure usually brings more favorable outcomes. == Types == Hemodialysis, hemofiltration, and hemodiafiltration can be continuous or intermittent and can use an arteriovenous route (in which blood leaves from an artery and returns via a vein) or a venovenous route (in which blood leaves from a vein and returns via a vein). This results in various types of RRT, as follows: continuous renal replacement therapy (CRRT) — continuous renal replacement therapy (CRRT) is a form of dialysis therapy used in critical care settings. The benefit of CRRT for critically ill patients is that it runs slowly (generally over 24 hours to several days) allowing for removal of excess fluid and uremic toxins with less risk of hypotensive complications. continuous hemodialysis (CHD) continuous arteriovenous hemodialysis (CAVHD) continuous venovenous hemodialysis (CVVHD) continuous hemofiltration (CHF) continuous arteriovenous hemofiltration (CAVH or CAVHF) continuous venovenous hemofiltration (CVVH or CVVHF) continuous hemodiafiltration (CHDF) continuous arteriovenous hemodiafiltration (CAVHDF) continuous venovenous hemodiafiltration (CVVHDF) intermittent renal replacement therapy (IRRT) intermittent hemodialysis (IHD) intermittent venovenous hemodialysis (IVVHD) intermittent hemofiltration (IHF) intermittent venovenous hemofiltration (IVVH or IVVHF) intermittent hemodiafiltration (IHDF) intermittent venovenous hemodiafiltration (IVVHDF) == History of Continuous Renal Replacement Therapy == Before implementing continuous renal replacement therapy (CRRT), acute renal failure (ARF) in critically ill, multiple organ failure patients was managed by intermittent hemodialysis and the mortality rate was very high. Hemodialysis is effective in clearance and ultrafiltration, but it has deleterious effects on hemodynamic stability. In 1971, Lee Henderson described the basis for convective transport in blood purification techniques. Subsequently, in 1974 he described hemodiafiltration combining convection and diffusion. These seminal papers represented the basis for the development of chronic hemodiafiltration by Leber and continuous arteriovenous hemofiltration (CAVH) by Peter Kramer. With his team, Peter Kramer (Died unexpectedly in 1984), had actually first reported the use of continuous hemofiltration in Germany in 1977. Peter Kramer in ASAIO presented a paper describing the use of arteriovenous hemofiltration in the management of ARF. Kramer tried that as a mean of managing diuretic-resistant fluid overload. Kramer described his experience of attaching a microporous hemofilter to the femoral artery and vein, and flowing blood through it at around 100 ml/minute. Liters of plasma filtrate poured out. He replaced it with an infusion of electrolyte solution. Kramer explained that this could be done continuously, avoiding the volume shifts and other problems of intermittent hemodialysis. For those in the audience who cared for patients with anuric ARF, this was an epiphany of thunderbolt proportions. He used a hollow fiber “haemofilter” that originally designed as an alternative to HD for chronic renal failure and produced 300-600 ml/hour of ultrafiltrate by convection. The simple, pumpless system made use of temporary dialysis catheters sited in the patient’s femoral artery and vein and could be rapidly established in critically ill patients. Using an isotonic salt solution for fluid replacement, continuous arteriovenous hemofiltration (CAVH) was soon extended to the management of ARF. In 1982, Kramer presented his experience with its use in more than 150 intensive care patients at a meeting of the American Society for Artificial Internal Organs(ASAIO). Before that, Henderson et al and Knopp, had studied hemofiltration in animals and as an alternative to dialysis in chronic renal failure, but it was really Peter Kramer’s report in ASAIO meeting in 1982 that stimulated many of nephrologists and intensivists to undertake the serious evaluation of CAVH in ARF in the ICU. At first, in CAVH, the prescribed ultrafiltration rate was achieved manually by arranging the filtrate bag at the right height, thereby changing the negative pressure caused by the filtrate column. The replacement fluid was also regulated manually. Few years later, CAVH was developed in several centers for managing ARF in critically ill patients with multiple organ failure. In 1986, it has been reported that CAVH improve the patient survival from 9% to 38% with full nutrition in ARF. Moreover, a workshop presented at ASAIO in 1988 summarized the development and role of continuous hemofiltration. Since late 1980s, continuous renal replacement therapy (CRRT) has been studied extensively. In 1982, the use of CAVH in Vicenza was extended for the first time to a neonate with the application of specific minifilters . Two years later, CAVH began to be used to treat septic patients, burn patients and patients after transplantation and cardiac surgery, even with regional citrate anticoagulation. In 1986, the term continuous renal replacement therapy was applied to all these continuous approaches. The technology and terminology were expanded to include slow continuous ultrafiltration for fluid removal without replacement, continuous arteriovenous hemodialysis (CAVHD), and continuous arteriovenous hemodiafiltration. Meanwhile, clinical and technical limitations of CAVH spurred new research and the discovery of new treatments, leading to the development of continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis (CVVHD) and continuous veno-venous hemodiafiltration (CVVHDF). The low depurative efficiency was overcome by applying filters with two ports in the dialysate/filtrate compartment and through the use of counter-current dialysate flow, allowing the addition of diffusion and the birth of continuous arteriovenous hemodiafiltration or hemodialysis (CAVHDF or CAVHD). Development of double-lumen venous catheters and peristaltic blood pumps was invented in the mid-1980s, when CVVH was proposed. The presence of a pump that generated negative pressure in part of the circuit made it necessary to add a device to detect the presence of air and a sensor to monitor the pressure in the circuit, to avoid, respectively, air embolisms and circuit explosion in case of coagulation or obstruction of the venous line. Later, ultrafiltrate and replacement pumps and a heater were added to the circuit. The development of CVVH allows to increase the exchange volumes, and subsequently, the depurative efficiency. The use of counter-current dialysate flow led to further improvements and the birth of CVVHD and CVVHDF. Now Continuous renal replacement therapy has become the mainstay of management of renal failure for multiple organ failure patients in the ICU. Information technology and precision medicine have recently furthered the evolution of CRRT, providing the possibility of collecting data in large databases and evaluating policies and practice patterns. The application of artificial intelligence and enhanced human intelligence programs to the analysis of big data has further moved the front of research ahead, providing the possibility of creating silica-trials and finding answers to patients’ unmet clinical needs. The opportunity to evaluate the endophenotype of the patient makes it possible to adjust treatments and techniques by implementing the concept of precision CRRT. This allows clinicians to normalize outcomes and results among different populations or individuals and establish optimal and personalized care == Ethical discussions == Accountability for reasonableness is often used as a theory of ethics to understand the decision-making process behind renal replacement therapy. == See also == Artificial kidney == References == == External links == Media related to Renal replacement therapy at Wikimedia Commons	Wikipedia/Renal_replacement_therapy
Adventitial cystic disease (also known as cystic adventitial disease CAD) is a rare type of non-atherosclerotic peripheral artery disease. It can present as claudication, critical limb ischemia or acute limb ischemia. The most commonly affected vessel is the popliteal artery. The cause is unknown. == Diagnosis == The definitive diagnosis comes from pathological evaluation of the affected vessel, however adventitial cystic disease can be suspected based on imaging of the affected vessel using CT scan, MRI or angiography. If suspected at the time of angiography, intravascular ultrasound is of use in making the diagnosis. == Treatment == Definitive treatment is resection with or without reconstruction of the affected vessel. Symptoms can be temporarily improved by cyst aspiration. == References ==	Wikipedia/Adventitial_cystic_disease
Spinal disease refers to a condition impairing the backbone. These include various diseases of the back or spine ("dorso-"), such as kyphosis. Dorsalgia refers to back pain. Some other spinal diseases include spinal muscular atrophy, ankylosing spondylitis, scoliosis, lumbar spinal stenosis, spina bifida, spinal tumors, osteoporosis and cauda equina syndrome. == Types == There are many recognized spinal diseases, some more common than others. Spinal disease also includes cervical spine diseases, which are diseases in the vertebrae of the neck. A lot of flexibility exists within the cervical spine and because of that, it is common for an individual to damage that area, especially over a long period of time. Some of the common cervical spine diseases include degenerative disc disease, cervical stenosis, and cervical disc herniation. Degenerative disc disease occurs over time when the discs within each vertebra in the neck begin to fall apart and begin to disintegrate. Because each vertebra can cause pain in different areas of the body, the pain from the disease can be sensed in the back, leg, neck area, or even the arms. When the spinal canal begins to lose its gap and gets thinner, it can cause pain in the neck, which can also cause a numb feeling in the arms and hands. Those are symptoms of cervical stenosis disease. The discs between each vertebra have fibers that can begin to deteriorate, and this can occur in cervical disc herniation. This disease is less common in younger people as it is usually a function of aging. === Spinal muscular atrophy (SMA) === ==== SMA types ==== SMA is a category of spinal disease that in linked with genetic disorders. More specifically, it is caused by an autosomal recessive disorder due to a homozygous mutation of a motor neuron gene. There are different types of SMA. Type 0 is diagnosed to newborns who have muscle weakness, and little to no "fetal movements." Those who have type 0 also have other health issues, most of which are respiratory-related. SMA type 1 is diagnosed to infants with symptoms similar to that of type 0. Those who have type 1 are more likely to have trouble swallowing, controlling the tongue, and sitting up on their own. Moreover, infants with type 1 are likely to develop respiratory issues. Additionally, their thinking and comprehension is unaffected and they are conscientiousness. SMA type 2 is diagnosed to young children. Unlike those with type 1, these children can sit without assistance, but are unable to walk. This type mostly concerns the legs and arms. Some other problems that SMA type 2 patients might encounter are orthopedic, bone, and joint complications. SMA type 3 is typically diagnosed to kids and adults. Those with SMA 3 might be able to walk, and are more likely to experience weakness in the legs compared to the arms. Type 3 patients are most likely to have symptoms of scoliosis with little to no respiratory issues. Unlike types 0, 1, and 2, those with type 3 do not have to worry about comprehension and learning. Lastly, SMA type 4 is diagnosed to elderly individuals, and is the most uncommon version of SMA next to type 0. SMA type 4 is the least severe, and is sort of similar to type 3, but most common in adults. ==== Diagnosing SMA ==== Molecular genetic testing is the tool used to assess SMA. However, this test might not be needed if signs such as hypotonia are present. MRI scans and muscle biopsies used to be the standard testing method, but molecular testing is much more efficient. There are advanced forms of SMA that require other testing concerning the peripheral nervous system. On another note, SMA is due to the malfunctioning SMN1 gene. Patients who have SMA that is caused by the SMN gene is likely due to the compound heterozygotes with only one of the SMN1 genes being mutated. SMA is diagnosed by the deletion of the homozygous SMN1, while the severity is based on the SMN2 gene. Medical screenings, such as scans, should only be used for patients who "are negative for both SMN1 deletion and SMN1 mutation testing." ==== Management ==== As of right now, there are no successful treatments. However, many patients opt to go into physical and rehabilitation therapy designed to help with specific needs, similar to Schroth therapy. The most important and best way to manage SMA is to come up with a plan that both the medical team and patient agrees with. As mentioned before, patients with SMA also suffer from respiratory issues, which is the number one issue that must be prevented. Treating patients while they actively have the issues is not as effective as planning beforehand. It is also important for SMA patients to consider vaccinations as that could aid in the prevention of developing harmful respiratory problems. Some patients choose to use ventilation and other pulmonary-related tools. Taking care of gastrointestinal health is also important, as such issues are also common with SMA patients. Additionally, SMA patients might use G-tubes, also known as gastronomy tubes for feeding. Overall, the best treatment method is to find a plan that works with both the doctors and the patient to ensure that future problems are prevented and handled properly before becoming too severe. === Scoliosis === Scoliosis is a common spinal disease in which the spine has a curvature usually in the shape of the letter "C" or "S". This is most common in girls, but there is no specific cause for scoliosis. Only a few symptoms occur for one with this disease, which include feeling tired in the spinal region or backaches. Generally, if the hips or shoulders are uneven, or if the spine curves, it is due to scoliosis and should be seen by a doctor. When assessing scoliosis, it is important for the physician to assess for neurological issues. Anything from weakness, difficulty with balance and coordination, and bladder and bowel problems should be considered. Curvature advancement is largely dependent "on remaining spinal growth," as well as signs of puberty, indicating the beginning of early adulthood. ==== Diagnosis ==== Physicians must perform physical and neurological examinations, which includes looking at height, asymmetry in the back, chest, ribs, and other areas of the torso, balance and coordination, and even pain. In addition to physical examinations, physicians may order X-ray or MRI scans. These tests will verify any concerns. ==== Management ==== Depending on the level of curvature, there are different treatment options. For those who have curves less than 10 degrees, there is no need to get into treatment. Curves between 10–25 degrees must keep a close eye on it by having X-rays to maintain it. However, those who have curves greater than 25 degrees, but less than 40 to 45 might choose to get bracing. Braces, also known as corsets, hold the spine in a specific position from the outside. These devices are tight, and can get even tighter with the straps. Whether bracing is effective or not is still studied today. In addition to bracing, many patients choose to partake in hydrotherapy. Studies show that water environment positively affects the curvature of different types, and increases mobility as well as flexibility in the shoulders and bending. There are also other physical therapy methods to improving curvature through Schroth therapy. Some experiments have been conducted to determine whether or not this strategy is useful. One study done shows that the Schroth group had improved posture, while the control worsened. Another double-blind experiment was conducted, which did not show outstanding results. The very last treatment option is surgery. There are certain goals that surgery aims to reach. For children, the point of the operation is to stop the curve from getting worse and minimize spinal deformity. On the other hand, adults usually have this surgery due to nerve damage, or if they have serious bladder and bowel issues. Surgery is only recommended to those who have curves greater than 40–50 degrees. There have been some experiments done to determine which surgical method is the most beneficial. One study shows that those who have short segment decompression/ fusion are least likely to suffer from postoperative complications. Moreover, short segment patients had a shorter hospital stay compared to long segment. However, the short segment group did lose more blood, resulting in less blood volume after their operation. === Lumbar spinal stenosis === Lumbar spinal stenosis is classified as a narrowing of the spinal canal in the lumbar region of the vertebrae. This may lead to compression of the nerve root of the spinal cord and result in pain of the lower back and lower extremities. Other symptoms include impaired walking and a slightly stooped posture due to loss of disc height and bulging of the disc. Lumbar spinal stenosis is very prevalent with 9.3% of the general population producing symptoms and the number is continuing to rise in patients older than 60. It's generally an indication for spinal surgery in patients older than 65 years of age. However, there is a myth and fear among most patients that only surgery is the cure for such conditions and spine surgery is very risky. There are many non-surgical treatments available to prevent, halt and even reverse many spine diseases. Also, some surgery patients can be operated on in a daycare procedure or with minimum length of stay in hospital, with statistically good outcomes. === Spina bifida === Spina bifida is the most common defect impacting the Central Nervous System (CNS). The most common and most severe form of Spina Bifida is Myelomeningocele. Individuals with Myelomeningocele are born with an incompletely fused spine, and therefore exposing the spinal cord through an opening in the back. In general, the higher the spinal lesion, the greater the functional impairment to the individual. Symptoms may include bowel and bladder problems, weakness and/or loss of sensation below the level of the lesion, paralysis, or orthopedic issues. Severity of symptoms can vary per situation. === Cauda equina syndrome === Cauda equina syndrome is a rare syndrome that affects the spinal nerves in the region of the lower back called the cauda equine (Latin for "horses tail"). Injury to the cauda equina can have long lasting ramifications for the individual. Symptoms include lower back pain, bladder disturbances, bowel dysfunction, and anesthesia or paresthesia between the thighs. In order to prevent progressive neurological changes surgery can be a viable option. CT scans, myelograms, and MRIs are used to diagnose cauda equina. ==== Management ==== Surgery is the best treatment option for those who have CES. If left untreated, patients might develop paralysis and bladder incontinence. Moreover, the timing of the surgery is crucial, but it is unknown as to when the best time to have it done is. When it comes to timing, it really depends on when the patients' symptoms first arise. Most patients start considering surgery when the symptoms such as bladder incontinence, bowel movement issues, limb weakness, and pain first begin. The most common surgical procedure is a laminectomy, with microdiscectomies and discectomies also being options. With the lack of research regarding this spinal disorder, however, it is unclear as to when the best time have the operation is. One study shows that overnight versus daytime lumbar decompression surgery does not have much significance in terms of complications. However, those who do have overnight surgery are more likely to suffer from complications. === Tumors === A spinal tumor is when unusual tissue begins growing and spreading in the spinal columns or spinal cords. The unusual tissue builds up from abnormal cells that multiply quickly in a specific region. Tumors generally are broken down into categories known as benign, meaning non-cancerous, or malignant, meaning cancerous, and also primary or secondary. Primary spinal tumors begin in either the spinal cord or spinal column, whereas secondary spinal tumors begin elsewhere and spread to the spinal region. Symptoms for spinal tumors may vary due to factors such as the type of tumor, the region of the spine, and the health of the patient. Back pain is the most common symptom and it can be a problem if the pain is severe, has a time frame that lasts longer than it would for a normal injury, and becomes worse while laying down or at rest. Other symptoms, excluding back pains, are loss of muscle function, loss of bowel or bladder function, pain in the legs, scoliosis, or even unusual sensations in the legs. The primary tumor has no known cause, although there are possible answers that scientists have researched. Cancer may be linked to genes because research shows that in certain families, the incidents of spinal tumors are higher. Two of the genetic disorders that may affect spinal tumors, include Von Hippel-Lindau disease and Neurofibromatosis 2. Von Hippel-Lindau disease is a non-cancerous tumor of blood vessels that occur in the brain, spinal cord, or even tumors in the kidneys. The Neurofibromatosis 2 is a non-cancerous tumor that usually affects the nerves for hearing. Loss of hearing in one or both ears, is a common effect of this genetic disorder. == References == == External links ==	Wikipedia/Spinal_disease
Reduction is a medical procedure to restore the correct anatomical alignment of a fracture or dislocation. When an injury results in a fracture, or broken bone, the bone segments can sometimes become misaligned. This is referred to as a displaced fracture which requires the medical procedure called reduction. Some providers may refer to this as 'setting the bone'. When an injury results in a dislocation of a joint, or the misalignment of two connecting bones, a similar process of reduction must be performed to relocate the joint back into normal anatomical positioning. In the case of both displaced fractures and joint dislocation reduction is required for effective healing. == Fracture Reduction == There are two main categories of fracture reductions, closed reductions and open reductions. Both procedures require confirmatory imaging, such as x-ray, before the reduction to confirm the misalignment of bones and after the reduction procedure to confirm successful achievement of anatomical positioning. === Closed Reduction === Closed reduction is when bone alignment is achieved from external manipulation of the bone without having to open the skin. This is not a surgical procedure and is often performed in the emergency department with local anesthetic for pain management. A distal radial fracture (wrist) is a common injury that requires a closed reduction. === Open Reduction === Open reduction is a surgical procedure in which bone alignment is achieved from internal manipulation of the bone when the skin is open. After reduction of the fractured site it is common that fixed hardware is put in place to maintain anatomical alignment during bone healing, this process is called fixation. While many open reductions require either internal (ORIF) or external fixation (OREF) there are some fractures that, after open reduction, do not require fixation. == Dislocation Reduction == Reductions for dislocations are dependent on the joint they involve. Common dislocations include the shoulder, finger, hip, knee and patella. In children the elbow is also a common dislocation and referred to as nursemaid's elbow. There are many techniques but the same tenets are generally applied to all dislocation reductions. Traction, or sustained pulling pressure, is applied to the distal bone of the dislocated joint to relax the surrounding musculature and create space for the bone to move back into anatomical position. Traction can be applied either by human strength or with a system of pulleys and weights. Surrounding muscles, nerves and vasculature can be disrupted during the initial injury which can result in further surgical requirements even if proper bone alignment is achieved. == Procedural Medications == Open reductions are done under general anesthesia administered by anesthesiologists in the operating room. Closed reductions are most often done with the aid of multimodal pain medications, sedatives and/or local anesthesia. Commonly a state of moderate sedation, or conscious sedation, is desired to reduce patient stress from the experience and relax the patient to improve in the manipulation during reduction. Ketamine and Midazolam are common choices for pediatric conscious sedations and are often given in conjunction with a short acting opiate like fentanyl. In adults propofol, midazolam and etomidate are frequently used for conscious sedation with a short acting opiate like fentanyl. Local hematoma blocks are also commonly employed for the reduction of forearm fractures. Hematoma blocks are when a local anesthetic like lidocaine is injected into the fracture site under the guidance of ultrasound to allow for fracture manipulation and reduction without pain or the need for systemic medications. NSAIDs and acetaminophen continue to be mainstays of pain management due to their efficacy and safety == Procedural Risks and Complications == Risks and complications from reductions include but are not limited to further damage to the fracture or dislocation, damage to surrounding structures and tissues such as nerves, muscles, and blood vessels. There is also a risk of an unsuccessful reduction which might require multiple attempts and prolonged need for medication administration or switching to a surgical intervention, in the case of dislocations and closed fractures. The medications administered during the procedure such as medications to block pain (local or general anesthetic) also have side effect profiles and risks of administration. Open reductions carry the risks of any orthopedic surgery, including but not limited to infection, hardware failures, damage to surrounding structures, and adverse reactions to general anesthesia. == Recovery and rehabilitation == After a closed reduction, pain is expected for 2–3 weeks and potentially milder pain for up to 6 weeks. == References == "Closed reduction of a fractured bone". Medline Plus. 11 June 2008. Retrieved 26 September 2014. Vinson DR, Hoehn CL (2013). "Sedation-assisted Orthopedic Reduction in Emergency Medicine". Western J Emerg Med. 14 (1): 47–54. doi:10.5811/westjem.2012.4.12455. PMC 3582522. PMID 23447756. (primary source) Mercier LR (2008). "2". Practical Orthopedics (6th ed.). Mosby. ISBN 978-0-323-03618-4.	Wikipedia/Reduction_(orthopedic_surgery)
Articular cartilage, most notably that which is found in the knee joint, is generally characterized by very low friction, high wear resistance, and poor regenerative qualities. It is responsible for much of the compressive resistance and load bearing qualities of the knee joint and, without it, walking is painful to impossible. Osteoarthritis is a common condition of cartilage failure that can lead to limited range of motion, bone damage and invariably, pain. Due to a combination of acute stress and chronic fatigue, osteoarthritis directly manifests itself in a wearing away of the articular surface and, in extreme cases, bone can be exposed in the joint. Some additional examples of cartilage failure mechanisms include cellular matrix linkage rupture, chondrocyte protein synthesis inhibition, and chondrocyte apoptosis. There are several different repair options available for cartilage damage or failure. "Maci" or autologous cultured chondrocytes on porcine collagen membrane, is a treatment to correct cartilage defects in the knee. This treatment has been approved by the Food and Drug Administration in 2016 for adult treatment only. == Autologous matrix-induced chondrogenesis == Autologous matrix-induced chondrogenesis, which is also known as AMIC, is a biological treatment option for articular cartilage damage bone marrow stimulating technique in combination with a collagen membrane. It is based on the microfracture surgery with the application of a bi-layer collagen I/III membrane. The AMIC technique was developed to improve some of the shortfalls of microfracture surgery such as variable repair cartilage volume and functional deterioration over time. The collagen membrane protects and stabilizes the MSCs released through microfracture and enhances their chondrogenic differentiation. The AMIC surgery is a single-step procedure. Once cartilage damage is assessed there are two methods to access the joint to proceed with the AMIC surgery. First is to perform a mini arthrotomy. Second is an all-arthroscopic procedure. == Autologous chondrocyte implantation == The human body's own cartilage is still the best material for lining knee joints. This drives efforts to develop ways of using a person's own cells to grow, or re-grow cartilage tissue to replace missing or damaged cartilage. One cell-based replacement technique is called autologous chondrocyte implantation (ACI) or autologous chondrocyte transplantation (ACT). A review evaluating autologous chondrocyte implantation was published in 2010. The conclusions are that it is an effective treatment for full thickness chondral defects. The evidence does not suggest ACI is superior to other treatments. One ACI treatment, called MACI (autologous cultured chondrocytes on a porcine collagen matrix), is indicated for healthy patients 18–55 with medium to large sized damage to their cartilage. It is not applicable to osteoarthritis patients. The patient's chondrocytes are removed arthroscopically from a non load-bearing area from either the intercondylar notch or the superior ridge of the medial or lateral femoral condyles. 10,000 cells are harvested and grown in vitro for approximately six weeks until the population reaches 10-12 million cells. Then these cells are seeded onto a film that is implanted into the area of cartilage damage and absorbed back into the tissue into the patient. The implanted chondrocytes then divide and integrate with surrounding tissue and potentially generate hyaline-like cartilage. Another ACI technique, using "chondospheres", uses only chondrocytes and no matrix material. The cells grow in self-organized spheroid matrices which are implanted via injected fluid or inserted tissue matrix. Techniques such as the EELS-TALC to enhance ACI and MACI with enabling chondrocytes to be tissue engineered with long term native knee cartilage phenotype maintenance in vitro and in vivo, with the engineered tissue construct containing stem cell progenitors along with those expressing pluripotency markers and with added advantage of enriched hyaluronic acid (HA) expression by the cells have been reported which will contribute to improvised regenerative therapies for cartilage damage. == Autologous mesenchymal stem cell transplantation == Because mesenchymal stem cells may regenerate cartilage, cartilage growth in human knees using autologous cultured mesenchymal stem cells is under research and preliminary clinical use, and appears to be safe as of 2016. An advantage to this approach is that a person's own stem cells are used, avoiding tissue rejection by the immune system. Stem cells enable surgeons to grow replacement cartilage, which gives the new tissue greater growth potential. While there are few long-term studies as of 2018, a history of knee problems and body weight are factors for how well the procedure will work. == Microdrilling augmented with peripheral blood stem cells == A 2011 study reported histologically confirmed hyaline cartilage regrowth in the knee. The successful protocol involved arthroscopic microdrilling/ microfracture surgery followed by postoperative injections of autologous peripheral blood progenitor cells (PBPCs) and hyaluronic acid. The procedure creates a blood clot scaffold on which injected PBPCs can be recruited and enhance chondrogenesis at the site of the contained lesion. == See also == Meniscal cartilage replacement therapy Meniscus transplant Spheroids of human autologous matrix-associated chondrocytes == References == == External links == Minimally Invasive Total Knee Replacement. American Academy of Orthopaedic Surgeons. February 2005. Osteochondral Grafting of Articular Cartilage Injury at eMedicine	Wikipedia/Knee_cartilage_replacement_therapy
In writing and typography, a ligature occurs where two or more graphemes or letters are joined to form a single glyph. Examples are the characters ⟨æ⟩ and ⟨œ⟩ used in English and French, in which the letters ⟨a⟩ and ⟨e⟩ are joined for the first ligature and the letters ⟨o⟩ and ⟨e⟩ are joined for the second ligature. For stylistic and legibility reasons, ⟨f⟩ and ⟨i⟩ are often merged to create ⟨ﬁ⟩ (where the tittle on the ⟨i⟩ merges with the hood of the ⟨f⟩); the same is true of ⟨s⟩ and ⟨t⟩ to create ⟨ﬆ⟩. The common ampersand, ⟨&⟩, developed from a ligature in which the handwritten Latin letters ⟨e⟩ and ⟨t⟩ (spelling et, Latin for 'and') were combined. == History == The earliest known script Sumerian cuneiform and Egyptian hieratic both include many cases of character combinations that gradually evolve from ligatures into separately recognizable characters. Other notable ligatures, such as the Brahmic abugidas and the Germanic bind rune, figure prominently throughout ancient manuscripts. These new glyphs emerge alongside the proliferation of writing with a stylus, whether on paper or clay, and often for a practical reason: faster handwriting. Merchants especially needed a way to speed up the process of written communication and found that conjoining letters and abbreviating words for lay use was more convenient for record keeping and transaction than the bulky long forms. Around the 9th and 10th centuries, monasteries became a fountainhead for these type of script modifications. Medieval scribes who wrote in Latin increased their writing speed by combining characters and by introducing notational abbreviations. Others conjoined letters for aesthetic purposes. For example, in blackletter, letters with right-facing bowls (⟨b⟩, ⟨o⟩, and ⟨p⟩) and those with left-facing bowls (⟨c⟩, ⟨e⟩, ⟨o⟩, ⟨d⟩, ⟨g⟩ and ⟨q⟩) were written with the facing edges of the bowls superimposed. In many script forms, characters such as ⟨h⟩, ⟨m⟩, and ⟨n⟩ had their vertical strokes superimposed. Scribes also used notational abbreviations to avoid having to write a whole character in one stroke. Manuscripts in the fourteenth century employed hundreds of such abbreviations. In handwriting, a ligature is made by joining two or more characters in an atypical fashion by merging their parts, or by writing one above or inside the other. In printing, a ligature is a group of characters that is typeset as a unit, so the characters do not have to be joined. For example, in some cases the ⟨fi⟩ ligature prints the letters ⟨f⟩ and ⟨i⟩ with a greater separation than when they are typeset as separate letters. When printing with movable type was invented around 1450, typefaces included many ligatures and additional letters, as they were based on handwriting. Ligatures made printing with movable type easier because one sort would replace frequent combinations of letters and also allowed more complex and interesting character designs which would otherwise collide with one another. Because of their complexity, ligatures began to fall out of use in the 20th century. Sans serif typefaces, increasingly used for body text, generally avoid ligatures, though notable exceptions include Gill Sans and Futura. Inexpensive phototypesetting machines in the 1970s (which did not require journeyman knowledge or training to operate) also generally avoid them. A few, however, became characters in their own right, see below the sections about German ß, various Latin accented letters, & et al. The trend against digraph use was further strengthened by the desktop publishing revolution. Early computer software in particular had no way to allow for ligature substitution (the automatic use of ligatures where appropriate), while most new digital typefaces did not include ligatures. As most of the early PC development was designed for the English language (which already treated ligatures as optional at best) dependence on ligatures did not carry over to digital. Ligature use fell as the number of traditional hand compositors and hot metal typesetting machine operators dropped because of the mass production of the IBM Selectric brand of electric typewriter in 1961. A designer active in the period commented: "some of the world's greatest typefaces were quickly becoming some of the world's worst fonts." Ligatures have grown in popularity in the 21st century because of an increasing interest in creating typesetting systems that evoke arcane designs and classical scripts. One of the first computer typesetting programs to take advantage of computer-driven typesetting (and later laser printers) was Donald Knuth's TeX program. Now the standard method of mathematical typesetting, its default fonts are explicitly based on nineteenth-century styles. Many new fonts feature extensive ligature sets; these include FF Scala, Seria and others by Martin Majoor and Hoefler Text by Jonathan Hoefler. Mrs Eaves by Zuzana Licko contains a particularly large set to allow designers to create dramatic display text with a feel of antiquity. A parallel use of ligatures is seen in the creation of script fonts that join letterforms to simulate handwriting effectively. This trend is caused in part by the increased support for other languages and alphabets in modern computing, many of which use ligatures somewhat extensively. This has caused the development of new digital typesetting techniques such as OpenType, and the incorporation of ligature support into the text display systems of macOS, Windows, and applications like Microsoft Office. An increasing modern trend is to use a "Th" ligature which reduces spacing between these letters to make it easier to read, a trait infrequent in metal type. Today, modern font programming divides ligatures into three groups, which can be activated separately: standard, contextual and historical. Standard ligatures are needed to allow the font to display without errors such as character collision. Designers sometimes find contextual and historic ligatures desirable for creating effects or to evoke an old-fashioned print look. == Latin alphabet == === Stylistic ligatures === Many ligatures combine ⟨f⟩ with the following letter. A particularly prominent example is ⟨ﬁ⟩ (or ⟨f‌i⟩, rendered with two normal letters). The tittle of the ⟨i⟩ in many typefaces collides with the hood of the ⟨f⟩ when placed beside each other in a word, and are combined into a single glyph with the tittle absorbed into the ⟨f⟩. Other ligatures with the letter f include ⟨fj⟩, ⟨f‌l⟩ (⟨ﬂ⟩), ⟨f‌f⟩ (⟨ﬀ⟩), ⟨f‌f‌i⟩ (⟨ﬃ⟩), and ⟨f‌f‌l⟩ (⟨ﬄ⟩). In Linotype, ligature matrices for ⟨fa⟩, ⟨fe⟩, ⟨fo⟩, ⟨fr⟩, ⟨fs⟩, ⟨ft⟩, ⟨fb⟩, ⟨fh⟩, ⟨fu⟩, ⟨fy⟩, and for ⟨f⟩ followed by a full stop, comma, or hyphen are optional in many typefaces, as well as the equivalent set for the doubled ⟨ff⟩, as a method to overcome the machine's physical restrictions. These arose because with the usual type sort for lowercase ⟨f⟩, the end of its hood is on a kern, which would be damaged by collision with raised parts of the next letter. Ligatures crossing the morpheme boundary of a composite word are sometimes considered incorrect, especially in official German orthography as outlined in the Duden. An English example of this would be ⟨ff⟩ in shelf‌ful; a German example would be Schiff‌fahrt ("boat trip"). Some computer programs (such as TeX) provide a setting to disable ligatures for German, while some users have also written macros to identify which ligatures to disable. Turkish distinguishes dotted and dotless "I". If a ligature with f were to be used in words such as fırın [oven] and fikir [idea], this contrast would be obscured. The ⟨fi⟩ ligature, at least in the form typical to other languages, is therefore not used in Turkish typography. Remnants of the ligatures ⟨ſʒ⟩ /⟨ſz⟩ ("sharp s", eszett) and ⟨tʒ⟩/⟨tz⟩ ("sharp t", tezett) from Fraktur, a family of German blackletter typefaces, originally mandatory in Fraktur but now employed only stylistically, can be seen to this day on street signs for city squares whose name contains Platz or ends in -platz. Instead, the "sz" ligature has merged into a single character, the German ß – see below. Sometimes, ligatures for ⟨st⟩ (ﬆ), ⟨ſt⟩ (ﬅ), ⟨ch⟩, ⟨ck⟩, ⟨ct⟩, ⟨Qu⟩ and ⟨Th⟩ are used (e.g. in the typeface Linux Libertine). Besides conventional ligatures, in the metal type era some newspapers commissioned custom condensed single sorts for the names of common long names that might appear in news headings, such as "Eisenhower", "Chamberlain". In these cases the characters did not appear combined, just more tightly spaced than if printed conventionally. === German ß === The German letter ⟨ß⟩ (Eszett, also called the scharfes S, meaning sharp s) is an official letter of the alphabet in Germany and Austria. A recognizable ligature representing the ⟨sz⟩ digraph develops in handwriting in the early 14th century. Its name Es-zett (meaning S-Z) suggests a connection of "long s and z" (ſʒ) but the Latin script also knows a ligature of "long s over round s" (ſs). Since German was mostly set in blackletter typefaces until the 1940s, and those typefaces were rarely set in uppercase, a capital version of the Eszett never came into common use, even though its creation has been discussed since the end of the 19th century. Therefore, the common replacement in uppercase typesetting was originally SZ (Maße "measure" → MAS‌ZE, different from Mas‌se "mass" → MAS‌SE) and later SS (Maße → MAS‌SE). Until 2017, the SS replacement was the only valid spelling according to the official orthography in Germany and Austria. In Switzerland, the ß is omitted altogether in favour of ss. The capital version (ẞ) of the Eszett character was occasionally used since 1905/06, has been part of Unicode since 2008, and has appeared in more and more typefaces. Since the end of 2010, the Ständiger Ausschuss für geographische Namen (StAGN) has suggested the new upper case character for "ß" rather than replacing it with "SS" or "SZ" for geographical names. A new standardized German keyboard layout (DIN 2137-T2) has included the capital ß since 2012. The new character entered the official orthographic rules in June 2017. === Massachusett ꝏ === A prominent feature of the colonial orthography created by John Eliot (later used in the first Bible printed in the Americas, the Massachusett-language Mamusse Wunneetupanatamwe Up-Biblum God, published in 1663) was the use of the double-o ligature ⟨ꝏ⟩ to represent the /u/ of food as opposed to the /ʊ/ of hook (although Eliot himself used ⟨oo⟩ and ⟨ꝏ⟩ interchangeably). In the orthography in use since 2000 in the Wampanoag communities participating in the Wôpanâak Language Reclamation Project (WLRP), the ligature was replaced with the numeral ⟨8⟩, partly because of its ease in typesetting and display as well as its similarity to the o-u ligature ⟨Ȣ⟩ used in Abenaki. For example, compare the colonial-era spelling seepꝏash with the modern Wôpanâak Language Reclamation Project (WLRP) spelling seep8ash. === Letter W === As the letter ⟨W⟩ is an addition to the Latin alphabet that originated in the seventh century, the phoneme it represents was formerly written in various ways. In Old English, the runic letter wynn ⟨Ƿ⟩) was used, but Norman influence forced wynn out of use. By the 14th century, the "new" letter ⟨W⟩, originated as two ⟨V⟩ glyphs or ⟨U⟩ glyphs joined, developed into a legitimate letter with its own position in the alphabet. Because of its relative youth compared to other letters of the alphabet, only a few European languages (English, Dutch, German, Polish, Welsh, Maltese, and Walloon) use the letter in native words. === Æ and Œ === The character ⟨Æ⟩ (lower case ⟨æ⟩; in ancient times named æsc) when used in Danish, Norwegian, Icelandic, or Old English is not a typographic ligature. It is a distinct letter — a vowel — and when collated, may be given a different place in the alphabetical order than Ae. In modern English orthography, ⟨Æ⟩ is not considered an independent letter but a spelling variant, for example: "encyclopædia" versus "encyclopaedia" or "encyclopedia". In this use, ⟨Æ⟩ comes from Medieval Latin, where it was an optional ligature in some specific words that had been transliterated and borrowed from Ancient Greek, for example, "Æneas". It is still found as a variant in English and French words descended or borrowed from Medieval Latin, but the trend has recently been towards printing the ⟨A⟩ and ⟨E⟩ separately. Similarly, ⟨Œ⟩ and ⟨œ⟩, while normally printed as ligatures in French, are replaced by component letters if technical restrictions require it. === Umlaut === In German orthography, the umlauted vowels ⟨ä⟩, ⟨ö⟩, and ⟨ü⟩ historically arose from ⟨ae⟩, ⟨oe⟩, ⟨ue⟩ ligatures (strictly, from these vowels with a small letter ⟨e⟩ written as a diacritic, for example ⟨aͤ⟩, ⟨oͤ⟩, ⟨uͤ⟩). It is common practice to replace them with ⟨ae⟩, ⟨oe⟩, ⟨ue⟩ digraphs when the diacritics are unavailable, for example in electronic conversation. Phone books treat umlauted vowels as equivalent to the relevant digraph (so that a name Müller will appear at the same place as if it were spelled Mueller; German surnames have a strongly fixed orthography, either a name is spelled with ⟨ü⟩ or with ⟨ue⟩); however, the alphabetic order used in other books treats them as equivalent to the simple letters ⟨a⟩, ⟨o⟩ and ⟨u⟩. The convention in Scandinavian languages and Finnish is different: there the umlaut vowels are treated as independent letters with positions at the end of the alphabet. === Middle English === In Middle English, the word the (written þe) was frequently abbreviated as ⟨þͤ⟩, a ⟨þ⟩ (thorn) with a small ⟨e⟩ written as a diacritic. Similarly, the word that was abbreviated to ⟨þͭ⟩, a ⟨þ⟩ with a small ⟨t⟩ written as a diacritic. During the latter Middle English and Early Modern English periods, the thorn in its common script, or cursive, form came to resemble a ⟨y⟩ shape. With the arrival of movable type printing, the substitution of ⟨y⟩ for ⟨Þ⟩ became ubiquitous, leading to the common "ye", as in 'Ye Olde Curiositie Shoppe'. One major reason for this was that ⟨y⟩ existed in the printer's types that William Caxton and his contemporaries imported from Belgium and the Netherlands, while ⟨Þ⟩ did not. === Ring === The ring diacritic used in vowels such as ⟨å⟩ likewise originated as an ⟨o⟩ -ligature. Before the replacement of the older "aa" with "å" became a de facto practice, an "a" with another "a" on top (aͣ) could sometimes be used, for example in Johannes Bureus's, Runa: ABC-Boken (1611). The ⟨uo⟩ ligature ů in particular saw use in Early Modern High German, but it merged in later Germanic languages with ⟨u⟩ (e.g. MHG fuosz, ENHG fuͦß, Modern German Fuß "foot"). It survives in Czech, where it is called kroužek. === Hwair === The letter hwair (ƕ), used only in transliteration of the Gothic language, resembles a ⟨hw⟩ ligature. It was introduced by philologists around 1900 to replace the digraph ⟨hv⟩ formerly used to express the phoneme in question, e.g. by Migne in the 1860s (Patrologia Latina vol. 18). === Byzantine Ȣ === The Byzantines had a unique o-u ligature ⟨Ȣ⟩ that, while originally based on the Greek alphabet's ο-υ, carried over into Latin alphabets as well. This ligature is still seen today on icon artwork in Greek Orthodox churches, and sometimes in graffiti or other forms of informal or decorative writing. === Gha (OI) === Gha ⟨ƣ⟩ (File:Latin small letter Reversed thorn.svg), a rarely used letter based on Q and G, was misconstrued by the ISO to be an OI ligature because of its appearance, and is thus known (to the ISO and, in turn, Unicode) as "Oi". Historically, it was used in many Latin-based orthographies of Turkic (e.g., Azerbaijani) and other central Asian languages. === International Phonetic Alphabet === The International Phonetic Alphabet formerly used ligatures to represent affricate consonants, of which six are encoded in Unicode: ʣ, ʤ, ʥ, ʦ, ʧ and ʨ. One fricative consonant is still represented with a ligature: ɮ, and the extensions to the IPA contain three more: ʩ, ʪ and ʫ. === Initial Teaching Alphabet === The Initial Teaching Alphabet, a short-lived alphabet intended for young children, used a number of ligatures to represent long vowels: ⟨ꜷ⟩, ⟨æ⟩, ⟨œ⟩, ⟨ᵫ⟩, ⟨ꭡ⟩, and ligatures for ⟨ee⟩, ⟨ou⟩ and ⟨oi⟩ that are not encoded in Unicode. Ligatures for consonants also existed, including ligatures of ⟨ʃh⟩, ⟨ʈh⟩, ⟨wh⟩, ⟨ʗh⟩, ⟨ng⟩ and a reversed ⟨t⟩ with ⟨h⟩ (neither the reversed t nor any of the consonant ligatures are in Unicode). === Rare ligatures === Rarer ligatures also exist, including ⟨ꜳ⟩; ⟨ꜵ⟩; ⟨ꜷ⟩; ⟨ꜹ⟩; ⟨ꜻ⟩ (barred ⟨av⟩); ⟨ꜽ⟩; ⟨ꝏ⟩, which is used in medieval Nordic languages for /oː/ (a long close-mid back rounded vowel), as well as in some orthographies of the Massachusett language to represent uː (a long close back rounded vowel); ᵺ; ỻ, which was used in Medieval Welsh to represent ɬ (the voiceless lateral fricative); ꜩ; ᴂ; ᴔ; and ꭣ have Unicode codepoints (in code block Latin Extended-E for characters used in German dialectology (Teuthonista), the Anthropos alphabet, Sakha and Americanist usage). === Symbols originating as ligatures === The most common ligature in modern usage is the ampersand ⟨&⟩ . This was originally a ligature of ⟨E⟩ and ⟨t⟩ , forming the Latin: et, meaning and. It has exactly the same use in French and in English. The ampersand comes in many different forms. Because of its ubiquity, it is generally no longer considered a ligature, but a logogram. Like many other ligatures, it has at times been considered a letter (e.g., in early Modern English); in English it is pronounced and, not et, except in the case of &c, pronounced et cetera. In most typefaces, it does not immediately resemble the two letters used to form it, although certain typefaces use designs in the form of a ligature (examples include the original versions of Futura and Univers, Trebuchet MS, and Civilité, known in modern times as the italic of Garamond). Similarly, the number sign ⟨#⟩ originated as a stylized abbreviation of the Roman term libra pondo, written as ℔. Over time, the number sign was simplified to how it is seen today, with two horizontal strokes across two slash-like strokes. Now a logogram, the symbol is used mainly to denote (in the US) numbers, and weight in pounds. It has also been used popularly on push-button telephones and as the hashtag indicator. The at sign ⟨@⟩ is possibly a ligature, but there are many different theories about the origin. One theory says that the French word à (meaning at), was simplified by scribes who, instead of lifting the pen to write the grave accent, drew an arc around the ⟨a⟩. Another states that it is short for the Latin word for toward, ad, with the ⟨d⟩ being represented by the arc. Another says it is short for an abbreviation of the term each at, with the ⟨e⟩ encasing the ⟨a⟩. Around the 18th century, it started being used in commerce to indicate price per unit, as "15 units @ $1". After the popularization of Email, this fairly unpopular character became widely known, used to tag specific users. Lately, it has been used to de-gender nouns in Spanish with no agreed pronunciation. The dollar sign ⟨$⟩ possibly originated as a ligature (for "pesos", although there are other theories as well) but is now a logogram. At least once, the United States dollar used a symbol resembling an overlapping U-S ligature, with the right vertical bar of the U intersecting through the middle of the S ( US ) to resemble the modern dollar sign. The Spanish peseta was sometimes abbreviated by a ligature ⟨₧⟩ (from Pts). The ligature ⟨₣⟩ (F-with-bar) was proposed in 1968 by Édouard Balladur, Minister of Economy. as a symbol for French franc but was never adopted and has never been officially used. In astronomy, the planetary symbol for Mercury (☿) may be a ligature of Mercury's caduceus and a cross (which was added in the 16th century to Christianize the pagan symbol), though other sources disagree; the symbol for Venus ♀ may be a ligature of the Greek letters ⟨ϕ⟩ (phi) and ⟨κ⟩ (kappa). The symbol for Jupiter (♃) descends from a Greek zeta with a horizontal stroke, ⟨Ƶ⟩, as an abbreviation for Zeus. Saturn's astronomical symbol (♄) has been traced back to the Greek Oxyrhynchus Papyri, where it can be seen to be a Greek kappa-rho with a horizontal stroke, as an abbreviation for Κρονος (Cronus), the Greek name for the planet. It later came to look like a lower-case Greek eta, with the cross added at the top in the 16th century to Christianize it. The dwarf planet Pluto is symbolized by a PL ligature, ♇. A different PL ligature, ⅊, represents the property line in surveying. In engineering diagrams, a CL ligature, ℄, represents the center line of an object. The interrobang ⟨‽⟩ is an unconventional punctuation meant to combine the interrogation point (or the question mark) and the bang (printer's slang for exclamation mark) into one symbol, used to denote a sentence which is both a question and is exclaimed. For example, the sentence "Is that actually true‽" shows that the speaker is surprised while asking their question. Alchemy used a set of mostly standardized symbols, many of which were ligatures: 🜇 (AR, for aqua regia); 🜈 (S inside a V, for aqua vitae); 🝫 (MB, for balneum Mariae [Mary's bath], a double boiler); 🝬 (VB, for balneum vaporis, a steam bath); and 🝛 (aaa with overline, for amalgam). Composer Arnold Schoenberg introduced two ligatures as musical symbols to denote melody and countermelody. The symbols are ligatures of HT and NT, 𝆦 and 𝆧, from the German for hauptstimme and nebenstimme respectively. === Digraphs === Digraphs, such as ⟨ll⟩ in Spanish or Welsh, are not ligatures in the general case as the two letters are displayed as separate glyphs: although written together, when they are joined in handwriting or italic fonts the base form of the letters is not changed and the individual glyphs remain separate. Like some ligatures discussed above, these digraphs may or may not be considered individual letters in their respective languages. Until the 1994 spelling reform, the digraphs ⟨ch⟩ and ⟨ll⟩ were considered separate letters in Spanish for collation purposes. Catalan makes a difference between "Spanish ll" or palatalized l, written ll as in llei (law), and "French ll" or geminated l, written l·l as in col·lega (colleague). The difference can be illustrated with the French digraph œu, which is composed of the ligature œ and the simplex letter u. === Dutch IJ === In Dutch, ⟨ĳ⟩ can be considered a digraph, a ligature, or a letter in itself, depending on the standard used. Its uppercase and lowercase forms are often available as a single glyph with a distinctive ligature in several professional typefaces (e.g. Zapfino). Sans serif uppercase ⟨Ĳ⟩ glyphs, popular in the Netherlands, typically use a ligature resembling a ⟨U⟩ with a broken left-hand stroke. Adding to the confusion, Dutch handwriting can render ⟨y⟩ (which is not found in native Dutch words, but occurs in words borrowed from other languages) as a ⟨ĳ⟩-glyph without the dots in its lowercase form and the ⟨Ĳ⟩ in its uppercase form looking virtually identical (only slightly bigger). When written as two separate letters, both should be capitalized – or both not – to form a correctly spelled word, like IJs or ijs (ice). == Non-Latin alphabets == Ligatures are not limited to Latin script: The Armenian alphabet has the following ligatures: և (ե+ւ), ﬔ (մ+ե), ﬕ (մ+ի), ﬓ (մ+ն), ﬗ (մ+խ), ﬖ (վ+ն) Most Brahmic abugidas make frequent use of ligatures in consonant clusters. The number of ligatures employed is language-dependent; thus many more ligatures are conventionally used in Devanagari when writing Sanskrit than when writing Hindi. Having 37 consonants in total, the total number of ligatures that can be formed in Devanagari using only two letters is 1369, though few fonts are able to render all of them. In particular, Mangal, which is included with Microsoft Windows' Indic support, does not correctly handle ligatures with consonants attached to the right of the characters द, ट, ठ, ड, and ढ, leaving the virama attached to them and displaying the following consonant in its standard form. The Georgian script includes უ (uni), which is a combination of ო (oni) and the former letter ჳ (vie). A number of ligatures have been employed in the Greek alphabet, in particular a combination of omicron (Ο) and upsilon (Υ), which later gave rise to a letter of the Cyrillic script—see Ou (letter). Among the ancient Greek acrophonic numerals, ligatures were common (in fact, the ligature of a short-legged capital pi was a key feature of the acrophonic numeral system). Cyrillic ligatures: Љ, Њ, Ы, Ѿ. Iotated Cyrillic letters are ligatures of the early Cyrillic decimal I and another vowel: Ꙗ, Ѥ, Ѩ, Ѭ, Ю (sometimes also spelled ЮУ). In Serbian Cyrillic alphabet, the letters lje and nje (љ, њ), were developed as ligatures of Cyrillic used in Serbian Language, being El and En (л, н) with the soft sign (ь). They were invented by Vuk Stefanović Karadžić for use in his 1818 dictionary, replacing the earlier digraphs ⟨ль⟩ and ⟨нь⟩. The Yae, a ligature of ya (Я) and e also exists: Ԙԙ, as do Dzze (Ꚉꚉ ← Д + З) and Zhwe (Ꚅꚅ ← З + Ж). Some forms of the Glagolitic script, used from Middle Ages to the 19th century to write some Slavic languages, have a box-like shape that lends itself to more frequent use of ligatures. In the Hebrew alphabet, the letters aleph (א‎) and lamed (ל‎) can form a ligature, ﭏ‎. The ligature appears in some pre-modern texts (mainly religious), or in Judeo-Arabic texts, where that combination is very frequent, since [ʔ] [a]l- (written aleph plus lamed, in the Hebrew script) is the definite article in Arabic. For example, the word Allah (אַללַּהּ‎) can be written with this ligature: ﭏלה‎. In the Arabic alphabet, historically a cursive derived from the Nabataean alphabet, most letters' shapes depend on whether they are followed (word-initial), preceded (word-final) or both (medial) by other letters. For example, Arabic mīm, isolated م, tripled (mmm, rendering as initial, medial and final): ممم. Notable are the shapes taken by lām + ʼalif isolated: ﻻ, and lām + ʼalif medial or final: ﻼ. Besides the obligatory lām + ʼalif ligature, Arabic script grammar requires numerous stylistic ligatures. Syriac, a semitic alphabet derived from the Aramaic alphabet, has three different scripts that all use ligatures. Like Arabic, some letters change their form depending on their position in relation to other letters, and this can also change how ligatures look. A popular ligature all three scripts use is Lamadh ܠ‎/ܠ‎ + Alap ܐ‎/ܐ‎ isolated and final: (Serto) ܠܐ‎, (Madnhaya) ܠܐ‎. Another popular one is Taw ܬ‎/ܬ‎ + Alap ܐ‎/ܐ‎, resulting in (Serto) ܬܐ‎, (Madhnhaya) ـܬܐ‎. All three scripts use ligatures, but not in an equal spread or always with the same letters. Serto, being a flexible script, especially has many ligatures. For a wider, but not complete, list of Syriac ligatures, see Contextual forms of letters. Urdu (one of the main languages of South Asia), which uses a calligraphic version of the Arabic-based Nastaʿlīq script, requires a great number of ligatures in digital typography. InPage, a widely used desktop publishing tool for Urdu, uses Nastaliq fonts with over 20,000 ligatures. In American Sign Language a ligature of the American manual alphabet is used to sign "I love you", from the English initialism ILY. It consists of the little finger of the letter I plus the thumb and forefinger of the letter L. The letter Y (little finger and thumb) overlaps with the other two letters. The Japanese language has a number of obsolete kana ligatures. Of these, only two are widely available ones on computers: one for hiragana, ゟ, which is a vertical writing ligature of the characters よ and り; and one for katakana, ヿ, which is a vertical writing ligature of the characters コ and ト. Lao uses three ligatures, all comprising the letter ຫ (h). As a tonal language, most consonant sounds in Lao are represented by two consonants, which will govern the tone of the syllable. Five consonant sounds are only represented by a single consonant letter (ງ (ŋ), ນ (m), ມ (n), ລ (l), ວ (w)), meaning that one cannot render all the tones for words beginning with these sounds. A silent ຫ indicates that the syllable should be read with the tone rules for ຫ, rather than those of the following consonant. Three consonants can form ligatures with the letter ຫ. ຫ+ນ=ໜ (n), ຫ+ມ=ໝ (m) and ຫ+ລ=ຫຼ (l). ງ (ŋ) and ວ (w) just form clusters: ຫງ (ŋ) and ຫວ (w). ລ (l) can also be used written in a cluster rather than as a ligature: ຫລ (l). In many runic texts ligatures are common. Such ligatures are known as bind-runes and were optional. === Chinese ligatures === Written Chinese has a long history of creating new characters by merging parts or wholes of other Chinese characters. However, a few of these combinations do not represent morphemes but retain the original multi-character (multiple morpheme) reading and are therefore not considered true characters themselves. In Chinese, these ligatures are called héwén (合文) or héshū (合書); see polysyllabic Chinese characters for more. One popular ligature used on chūntiē decorations used for Chinese Lunar New Year is a combination of the four characters for zhāocái jìnbǎo (招財進寶), meaning "ushering in wealth and fortune" and used as a popular New Year's greeting. In 1924, Du Dingyou (杜定友; 1898–1967) created the ligature 圕 from two of the three characters 圖書館 (túshūguǎn), meaning "library". Although it does have an assigned pronunciation of tuān and appears in many dictionaries, it is not a morpheme and cannot be used as such in Chinese. Instead, it is usually considered a graphic representation of túshūguǎn. In recent years, a Chinese internet meme, the Grass Mud Horse, has had such a ligature associated with it combining the three relevant Chinese characters 草, 泥, and 马 (Cǎonímǎ). Similar to the ligatures were several "two-syllable Chinese characters" (雙音節漢字) created in the 19th century as Chinese characters for SI units. In Chinese these units are disyllabic and standardly written with two characters, as 厘米 límǐ "centimeter" (厘 centi-, 米 meter) or 千瓦 qiānwǎ "kilowatt". However, in the 19th century these were often written via compound characters, pronounced disyllabically, such as 瓩 for 千瓦 or 糎 for 厘米 – some of these characters were also used in Japan, where they were pronounced with borrowed European readings instead. These have now fallen out of general use, but are occasionally seen. === Japanese ligatures === The CJK Compatibility Unicode block features characters that have been combined into one square character in legacy character set so that it matches Japanese text. For example, the Japanese equivalent of "stock company", 株式会社 (kabushiki gaisha) can be represented in 1 Unicode character ⟨㍿⟩. Its romanized abbreviation K.K. can also be 1 character ⟨㏍⟩. There are other Latin abbreviations such as kg for "kilogram" that can be ligated into 1 square character ⟨㎏⟩. == Computer typesetting == The OpenType font format includes features for associating multiple glyphs to a single character, used for ligature substitution. Typesetting software may or may not implement this feature, even if it is explicitly present in the font's metadata. XeTeX is a TeX typesetting engine designed to make the most of such advanced features. This type of substitution used to be needed mainly for typesetting Arabic texts, but ligature lookups and substitutions are being put into all kinds of Western Latin OpenType fonts. In OpenType, there are standard liga, historical hlig, contextual clig, discretionary dlig and required rlig ligatures. === TeX === Opinion is divided over whether it is the job of writers or typesetters to decide where to use ligatures. TeX is an example of a computer typesetting system that makes use of ligatures automatically. The Computer Modern Roman typeface provided with TeX includes the five common ligatures ⟨ff⟩ , ⟨fi⟩ , ⟨fl⟩ , ⟨ffi⟩ , and ⟨ffl⟩ . When TeX finds these combinations in a text, it substitutes the appropriate ligature, unless overridden by the typesetter. === CSS === CSS3 provides control over these properties using font-feature-settings, though the CSS Fonts Module Level 4 draft standard indicates that authors should prefer several other properties. Those include font-variant-ligatures, common-ligatures, discretionary-ligatures, historical-ligatures, and contextual. === Ligatures in Unicode (Latin alphabets) === This table below shows discrete letter pairs on the left, the corresponding Unicode ligature in the middle column, and the Unicode code point on the right. Provided you are using an operating system and browser that can handle Unicode, and have the correct Unicode fonts installed, some or all of these will display correctly. See also the provided graphic. Unicode maintains that ligaturing is a presentation issue rather than a character definition issue, and that, for example, "if a modern font is asked to display 'h' followed by 'r', and the font has an 'hr' ligature in it, it can display the ligature." Accordingly, the use of the special Unicode ligature characters is "discouraged", and "no more will be encoded in any circumstances". (Unicode has continued to add ligatures, but only in such cases that the ligatures were used as distinct letters in a language or could be interpreted as standalone symbols. For example, ligatures such as æ and œ are not used to replace arbitrary "ae" or "oe" sequences; it is generally considered incorrect to write "does" as "dœs".) Microsoft Word disables ligature substitution by default, largely for backward compatibility when editing documents created in earlier versions of Word. Users can enable automatic ligature substitution on the Advanced tab of the Font dialog box. LibreOffice Writer enables standard ligature substitution by default for OpenType fonts, user can enable or disable any ligature substitution on the Features dialog box, which is accessible via the Features button of the Character dialog box, or alternatively, input a syntax with font name and feature into the Font Name input box, for example: Noto Sans:liga=0. There are separate code points for the digraph DZ, the Dutch digraph IJ, and for the Serbo-Croatian digraphs DŽ, LJ, and NJ. Although similar, these are digraphs, not ligatures. See Digraphs in Unicode. ==== Ligatures used only in phonetic transcription ==== Four "ligature ornaments" are included from U+1F670 to U+1F673 in the Ornamental Dingbats block: regular and bold variants of ℯT (script e and T) and of ɛT (open E and T). == Contemporary art == Typographic ligatures are used in a form of contemporary art, as can be illustrated by Chinese artist Xu Bing's work in which he combines Latin letters to form characters that resemble Chinese. Croatian designer Maja Škripelj also created a ligature that combined Glagolitic letters ⰘⰓ for euro coins. == See also == Complex text layout – Neighbour-dependent grapheme positioning Digraph (orthography) – Pair of characters used to write one phoneme (the unfused pairing of graphemes) Kerning – Process in typography (optimization of spacing between adjacent letters). Letter spacing – Physical spacing of characters in text List of English words that may be spelled with a ligature Monogram – Motif made by overlapping two or more letters Scribal abbreviation – Abbreviations used by ancient and medieval scribes Unicode equivalence – Aspect of the Unicode standard Greek ligatures – Ligatures used in Greek writing Text shaping – Process of converting text to glyph indices and positions == Notes == == References == == External links == Examples of CSS ligatures	Wikipedia/Typographic_ligature
Shoulder surgery is a means of treating injured shoulders. Many surgeries have been developed to repair the muscles, connective tissue, or damaged joints that can arise from traumatic or overuse injuries to the shoulder. == Dislocated shoulder == A dislocated shoulder can be treated with: arthroscopic repairs repair of the glenoid labrum (anterior or posterior) In some cases, arthroscopic surgery is not enough to fix the injured shoulder. When the shoulder dislocates too many times and is worn down, the ball and socket are not lined up correctly. The socket is worn down and the ball will never sit in it the same. After many dislocations the shoulder bones will begin to wear down and chip away. When this occurs, another operation must be done. The operation is called the Latarjet surgery. The procedure involves transfer of the coracoid with its attached muscles to the deficient area over the front of the glenoid. This replaces the missing bone and the transferred muscle also acts as an additional muscular strut preventing further dislocations. It is an open surgery and requires an overnight hospital stay and usually a 4-6 month recovery. The recovery depends upon many factors, including where the tear was located, how severe it was, and how good the surgical repair was. It is believed that it takes at least four to six weeks for the labrum to re-attach itself to the scapula bone (shoulder blade), and probably another four to six weeks to get strong. The labrum is a ring of cartilage on the rim of a shallow socket in the scapula into which the head of the upper arm bone normally fits and rotates. Once the labrum has healed to the rim of the shoulder blade, it should see stress very gradually so that it can gather strength. It is important that it is not re-injured while healing. How much motion and strengthening of the arm is allowed after surgery also depends upon many factors, and it is up to the surgeon to let the patient know their limitations and how fast to progress. Because of the variability in the injury and the type of repair done, it is difficult to predict how soon someone can to return to activities and to sports after the repair. The type of sport also is important, since contact sports have a greater chance of injuring the labrum repair. However, a vast majority of patients have full function of the shoulder after labrum repair, and most patients can return to their previous level of sports with no or few restrictions. repair of the capsular ligaments (Bankart repair) repair of the biceps long head anchor or SLAP lesion tightening of the shoulder capsule (capsulorrhaphy or capsular shift) open repairs (for dislocations with fractures, etc.) biceps tenodesis surgery Surgical treatment of the shoulder due to potential biceps tendonitis or a tear of the labrum otherwise known as a SLAP tear. The long head of the biceps passes through the shoulder joint and attaches to the labrum. During a biceps tenodesis procedure, the surgeon cuts the attachment of the biceps tendon from the labrum and reattaches it to the humerus bone by tacks. By doing this, pressure is relieved from the labrum significantly reducing pain. This surgery is performed to alleviate biceps inflammation and can be implemented in correspondence to a SLAP lesion surgery. Recovery is approximately 4–8 months depending on the individual and requires physical therapy. == Separated shoulder == A separated shoulder can be treated with: Weaver–Dunn procedure Weaver–Dunn with various additional fixations (sutures, suture anchors, tendon autograft) to replace the coracoclavicular ligaments. Note: various methods have been utilized to anchor the clavicle in place while the surgery heals. This includes Dacron graft/loop Bosworth screw Kirschner wires Hook plate Anatomic repair, or any repair using tendon allograft without sacrificing the coracoacromial ligament. Arthroscopic Weaver–Dunn Transfer of conjoined tendon and distal end of coracoid process to the clavicle == Sternoclavicular separation == Sternoclavicular separation can be treated. == Tendinitis, bursitis, and impingement syndrome == The rotator cuff can cause pain in many different ways including tendonitis, bursitis, calcific tendonitis, partial thickness tears, full thickness tears or mechanical impingement. Tendinitis, bursitis, and impingement syndrome can be treated with tendon repair and the Mumford procedure or acromioplasty. == Rotator cuff tear == A rotator cuff tear can be treated with arthroscopic rotator cuff repair. == Fracture == A shoulder fracture can be treated with open reduction internal fixation (ORIF). == Arthritis of the shoulder (glenohumeral joint) == Arthritis of the shoulder can be treated with total shoulder replacement, hemiarthroplasty (half a replacement), or a reverse shoulder implant (for arthritis with large rotator cuff tear). == Arthritis or osteolysis of the acromioclavicular joint == Arthritis or osteolysis of the acromioclavicular joint can be treated with the Mumford procedure (open or arthroscopic). == Scapular winging == Scapular winging due to serratus anterior muscle (long thoracic nerve) palsy can be treated with a pectoralis major transfer. Scapular winging due to trapezius muscle (spinal accessory nerve) palsy can be treated with an Eden–Lange procedure. Scapular winging due to facioscapulohumeral muscular dystrophy can be treated with a scapulopexy or scapulothoracic fusion. == See also == Shoulder problem Separated shoulder Clavicle fracture Arthroscopy Arthritis Capsule of the glenohumeral joint (shoulder joint) Glenoid cavity Glenoid labrum Snapping scapula syndrome == References ==	Wikipedia/Shoulder_surgery
Foot and ankle surgery is a sub-specialty of orthopedics and podiatry that deals with the treatment, diagnosis and prevention of disorders of the foot and ankle. Orthopaedic surgeons are medically qualified, having been through four years of college, followed by 4 years of medical school or osteopathic medical school to obtain an M.D. or D.O. followed by specialist training as a resident in orthopaedics, and only then do they sub-specialise in foot and ankle surgery. Training for a podiatric foot and ankle surgeon consists of four years of college, four years of podiatric medical school (D.P.M.), 3–4 years of a surgical residency and an optional 1 year fellowship. The distinction between a podiatric and orthopedic foot and ankle surgeon is: an orthopedic surgeon has a Doctor of Medicine or Doctor of Osteopathic Medicine medical degree or osteopathic medical degree and training that encompasses both orthopedic residency and an optional 6-month to one year of fellowship training specific in techniques of foot and ankle surgery, while the training of a Doctor of Podiatric Medicine consist of a podiatric medical degree and three to four-year residency training specific to foot and ankle medicine and surgery, with an optional additional 1-year fellowship in foot and ankle trauma, reconstruction, or diabetic limb salvage. In the UK much controversy exists on the scope of podiatrists practicing surgery and the British Orthopaedic Association, and the British Orthopaedic Foot and Ankle Society produced a position statement on the importance of training and ongoing regulation of podiatrists practising podiatric forefoot surgery after certification and recommended that this should be to the same standard as that of medically qualified trauma and orthopaedic surgeons operating on the foot and ankle. == Clinical scope == Foot and ankle surgeons are trained to treat all disorders of the foot and ankle, both surgical and non-surgical. Additionally, the surgeons are also trained to understand the complex connections between disorders and deformities of the foot, ankle, knee, hip, and the spine. Therefore, the surgeon will typically see cases that vary from trauma (such as malleolar fractures, tibial pilon fractures, calcaneus fractures, navicular and midfoot injuries and metatarsal and phalangeal fractures.) Arthritis care (primarily surgical) of the ankle joint and the joints of the hindfoot (tarsals), midfoot (metatarsals) and forefoot (phalanges) also plays a rather significant role. Congenital and acquired deformities include adult acquired flatfoot, non-neuromuscular foot deformity, diabetic foot disorders, hallux valgus and several common pediatric foot and ankle conditions (such as clubfoot, flat feet, tarsal coalitions, etc.) Patients may also be referred to a foot and ankle surgeon for proper diagnosis and treatment of heel pain (such as a consequence from plantar heel fasciitis), nerve disorders (such as tarsal tunnel syndrome) and tumors of the foot and ankle. Amputation and ankle arthroscopy (the use of a laparoscope in foot and ankle surgical procedures) have emerged as prominent tools in foot and ankle care. In addition, more applications for laser surgery are being found in the treatment of foot and ankle disorders, including treatment for bunions and soft tissue lesions. A patient may also be referred to a foot and ankle surgeon for the surgical care of nail problems and phalangeal deformities (such as bunions and bunionettes.) == Non-surgical treatments == The vast majority of foot and ankle conditions do not require surgical intervention. For example, several phalangeal conditions may be traced to the type of foot box used in a shoe, and a change of a shoe or shoe box may be sufficient to treat the condition. For inflammatory processes such as rheumatoid arthritis, non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDS) may be used to manage or slow down the process. Orthotics, or an externally applied device used to modify the structural or functional characteristics of the neuromusculoskeletal system specifically for the foot and ankle, may be used as inserts into shoes to displace regions of the foot for more balanced, comfortable or therapeutic placements of the foot. Physical therapy may also be used to alleviate symptoms, strengthening muscles such as the gastrocnemius muscle (which in turn will pull on the heel, which will then pull on the plantar fascia, thus changing the structure and shape of the foot). == Surgical treatments == Surgery is considered to be a last option when more conservative approaches fail to alleviate symptoms. Techniques such as bunionectomies may be used to surgically remove bunions and other foot and ankle deformalities, arthrodesis (or fusion of joint spaces) for inflammatory processes, and surgical reconstruction (i.e. invasive measures of manipulating neuromusculoskeletal structures) to treat other deformalities. Orthotics, physical therapy, NSAIDs, DMARDs and a change of shoe may act as a complement to surgical intervention, and in most cases will be required for optimal recovery. == Publications == The last 50 years has shown high quality research into the etiology and management of foot and ankle deformities. Several publications have been made to act as forums for such research: Journal of the American Podiatric Medical Association - a peer reviewed indexed medical journal The Journal of Foot & Ankle Surgery - a surgical journal operated by the American College of Foot and Ankle Surgeons Foot and Ankle International - a surgical journal operated by the American Orthopaedic Foot and Ankle Society (AOFAS). Techniques in Foot & Ankle Surgery The Foot & Ankle Journal - the first open access journal for podiatry and foot & ankle orthopaedics. == See also == American College of Foot and Ankle Surgeons Podiatry American Podiatric Medical Association == External links == American Board of Foot and Ankle Surgery Total Ankle Replacement Total Ankle Institute American Orthopaedic Foot & Ankle Society == References == Foot and Ankle: Core Knowledge in Orthopedics 2007 Elsevier Mosby Current Diagnosis and Treatment: Rheumatology 2nd ed. The McGraw-Hill Companies, Inc.	Wikipedia/Foot_and_ankle_surgery
Clinical Orthopaedics and Related Research is a peer-reviewed medical journal. It was established in 1953 as Clinical Orthopaedics by the Association of Bone and Joint Surgeons as an alternative to the Journal of Bone and Joint Surgery, which was the only American orthopaedic journal at the time. The journal obtained its current title in 1963 and its mission is to disseminate knowledge about all aspects of musculoskeletal research, diagnoses, and treatment. The journal was established by Anthony F. DePalma, who was also its editor-in-chief from 1953 to 1966. In conjunction with Clinical Orthopaedics and Related Research, the Association of Bone and Joint Surgeons presents three awards annually including the Nicolas Andry Award. == References == == External links == Official website	Wikipedia/Clinical_Orthopaedics_and_Related_Research
Advances in Therapy is a monthly peer-reviewed medical journal covering clinical medicine, especially research on pharmaceuticals. The Managing Editor is Clare Shepherd. The journal publishes original clinical research papers and review articles. The journal was established in 1984 and published by Health Communications. Since 2008 it has been published by Springer Science+Business Media. == Abstracting and indexing == The journal is abstracted and indexed in CINAHL, Current Contents/Clinical Medicine, EMBASE, International Pharmaceutical Abstracts, PsycINFO, PubMed/MEDLINE, Science Citation Index, and Scopus. According to the Journal Citation Reports, the journal has a 2020 impact factor of 3.847. == References == == External links == Official website	Wikipedia/Advances_in_Therapy
Microfracture surgery is an articular cartilage repair surgical technique that works by creating tiny fractures in the underlying bone. This causes new cartilage to develop from a so-called super-clot. The surgery is quick (typically lasting between 30 and 90 minutes), minimally invasive, and can have a significantly shorter recovery time than an arthroplasty (knee replacement). Chronic articular cartilage defects do not heal spontaneously. However, acute traumatic osteochondral lesions or surgically created lesions extending into subchondral bone, e.g. by Pridie drilling, spongialization abrasion or microfracture causing the release of multipotent mesenchymal stem cells from the bone marrow, may heal with repair tissue consisting of fibrous tissue, fibrocartilage or hyaline-like cartilage. The quality of the repair tissue after these "bone marrow stimulating techniques" depends on various factors including the species and age of the individual, the size and localization of the articular cartilage defect, the surgical technique, e.g., how the subchondral bone plate is treated, and the postoperative rehabilitation protocol. According to a 2017 article in the Journal of Orthopaedics, "Studies have shown that microfracture techniques do not fill in the chondral defect fully, and it forms fibro cartilage rather than hyaline cartilage. The microfracture techniques became controversial due to a lack of favourable reports on the long-term effects." == History == The surgery was developed in the late 1980s and early 1990s by Dr. Richard Steadman of the Steadman-Hawkins clinic in Vail, Colorado. Steadman slowly refined the procedure through research (including tests on horses). The surgery was called "controversial" by many sportswriters, due to a lack of studies on the long-term effects and the fact that an unsuccessful surgery could end an athlete's career. Steadman has also adapted the surgery into a treatment to help reattach torn ligaments (a technique he calls the "healing response"). == Procedure == The surgery is performed by arthroscopy, after the joint is cleaned of calcified cartilage. Through use of an awl, the surgeon creates tiny fractures in the subchondral bone plate. Blood and bone marrow (which contains stem cells) seep out of the fractures, creating a blood clot that releases cartilage-building cells. The microfractures are treated as an injury by the body, which is why the surgery results in new, replacement cartilage. The procedure is less effective in treating older patients, overweight patients, or a cartilage lesion larger than 2.5 cm. Further on, chances are high that after only 1 or 2 years of the surgery symptoms start to return as the fibrocartilage wears away, forcing the patient to reengage in articular cartilage repair. The effectiveness of cartilage growth after microfracture surgery is thought to be dependent on the patient's bone marrow stem cell population and some think increasing the number of stem cells increases the chances of success. A couple of physicians are promoting an alternative treatment implanting autologous mesenchymal stem cells directly into the cartilage defect, without having to penetrate the subchondral bone. == Microfracture reports == Studies have shown that microfracture techniques do not fill in the chondral defect fully, forming fibrocartilage rather than hyaline cartilage. Fibrocartilage is not as mechanically sound as hyaline cartilage; it is much denser and unable to withstand the demands of everyday activities as well as the original cartilage and is thus at higher risk of breaking down. The blood clot is very delicate after surgery and needs to be protected. In terms of time, the clot takes about 8 to 15 weeks for conversion to fibrous tissue and is usually fibrocartilage by about four months post surgery, holding implications for the rehabilitation. Chondrocyte implantation procedures (CCI), a cell-based articular cartilage repair procedure that aims to provide complete hyaline repair tissues for articular cartilage repair, have been posed by some as an alternative to microfracture surgery. In February 2008, Saris et al. published a large-scale study claiming that CCI results in better structural repair for symptomatic cartilage defects of the knee than microfracture surgery. According to the study, one year after treatment, the regenerated tissue associated with CCI is of better quality than that of microfracture surgery. == Use in professional sports == Many notable professional athletes have undergone the procedure. Partially because of the high level of stress placed on the knees by these athletes, the surgery is not a panacea and results have been mixed. Many players' careers effectively end despite the surgery. However, some players such as Jason Kidd, Steve Yzerman, John Stockton, Kenyon Martin and Zach Randolph have been able to return at or near their pre-surgery form while players Ron Harper, Brian Grant, Chris Webber, Allan Houston, Penny Hardaway, and the late Derek Smith never regained their old form. Others such as Jamal Mashburn and Terrell Brandon never recovered and retired. Portland Trail Blazers rookie Greg Oden underwent the procedure on his right knee in early September 2007 and missed the entire 2007–2008 NBA season. At only 19 at the time of the surgery, doctors were confident that he would return to at or near his full strength by the 2008–2009 season; he had a second microfracture surgery, this time on his left knee, in November 2010. Subsequently, Oden did not play in the NBA for over four years, missing the entirety of the 2011–2012 and 2012–2013 NBA seasons. The former San Antonio Spurs and Houston Rockets player, Tracy McGrady also underwent microfracture surgery; doctors were confident that the two-time scoring champion would return to full strength. As of 2012 he has not had the same speed and jumping ability he formerly did. McGrady retired in 2013, never regaining his previous form after the surgery. In October 2005, young star Amar'e Stoudemire of the NBA's Phoenix Suns underwent one of the highest-profile microfracture surgeries to date. He returned to the court in March 2006 and initially appeared to have made a full recovery, but subsequently started feeling stiffness in both knees (his right knee had been overcompensating for the injured left knee). He and the team doctor decided he needed more time to rehab and he did not return until the 2006–2007 NBA season. During the 2006–2007 season, Stoudemire returned to form, averaging 20.4 points and 9.6 rebounds per game while playing in all 82 regular-season games and the 2007 NBA All-Star Game. His success brought positive publicity to the procedure, further distancing it from a previous reputation as a possible "career death sentence" in the sports world, though he was one of the youngest of the aforementioned players to undergo the surgery. In June 2010, Grady Sizemore of the Cleveland Indians underwent microfracture surgery after injuring his left knee while diving back to first base earlier in the season. Sizemore was re-activated as the Indians center fielder in April 2011, ending an 11-month stretch of being disabled due to his injury. In his first game back on April 17, 2011, Sizemore showed no signs of slowing down as he had two hits in four AB which included a double and home run. Currently, Sizemore is the only player in MLB history to come back from knee microfracture surgery and play center field. Terrell Davis is one of the only notable football players that have the procedure done as well. [2] == Recovery == One study has shown a success rate of 75 to 80 percent among patients 45 years of age or younger. It is an outpatient procedure and causes only small discomfort. The harder part is the restrictions that are placed on the patient during the post-operative recovery period. This can be a major challenge for many patients. For optimal re-growth of joint surface, the patients need to be very patient and also extremely cooperative. They usually need to be on crutches for four to six weeks (sometimes longer). Sometimes a brace is needed. This all depends on the size and/or location of the joint surface defect that is being repaired or regenerated. The patients are encouraged to spend approximately 6–8 hours a day on a CPM (continuous passive motion) machine that helps with optimal re-growth of joint surface. The procedure can be painless for some patients to the extent that the patients avoid these critically important steps and expose the knee to physical activity before the joint fully heals. However, with other patients the procedure can be very painful for weeks even months. Pain medication may be required to manage pain levels in those patients. Steadman cites the significance of a patient's natural joint alignment in addition to disciplined rehabilitation in recovery from the procedure. == References == == External links == MedlinePlus Encyclopedia: Knee microfracture surgery	Wikipedia/Microfracture_surgery
This is a list of digraphs used in various Latin alphabets. In the list, letters with diacritics are arranged in alphabetical order according to their base, e.g. ⟨å⟩ is alphabetised with ⟨a⟩, not at the end of the alphabet, as it would be in Danish, Norwegian and Swedish. Substantially-modified letters, such as ⟨ſ⟩ (a variant of ⟨s⟩) and ⟨ɔ⟩ (based on ⟨o⟩), are placed at the end. Capitalisation only involves the first letter (⟨ch⟩ becomes ⟨Ch⟩) unless otherwise stated (⟨ij⟩ becomes ⟨IJ⟩ in Dutch, and digraphs marking eclipsis in Irish, are capitalised on the second letter, i.e. ⟨mb⟩ becomes ⟨mB⟩). == Apostrophe == Source: ⟨ʼb⟩ (capital ⟨ʼB⟩) is used in Bari for /ɓ/. ⟨ʼd⟩ (capital ⟨ʼD⟩) is used in Bari for /ɗ/. ⟨ʼm⟩ is used in the Wu MiniDict Romanisation for dark or yin tone /m/. It is also often written as /ʔm/. ⟨ʼn⟩ is used in the Wu MiniDict Romanisation for dark /n/. ⟨ʼng⟩ is used in the Wu MiniDict Romanisation for dark /ŋ/. ⟨ʼny⟩ is used in the Wu MiniDict Romanisation for dark /ȵ/. ⟨ʼy⟩ (capital ⟨ʼY⟩) is used in Bari and Hausa (in Nigeria) for /ʔʲ/, but in Niger, Hausa ⟨ʼy⟩ is replaced with ⟨ƴ ⟩. == A == ⟨aʼ⟩ is used in Taa for the glottalized or creaky-voiced vowel /a̰/. ⟨aa⟩ is used in Dutch, Finnish and other languages with phonemic long vowels for /aː/. It was formerly used in Danish and Norwegian (and still is in some proper names) for [ɔ] or [ʌ] (in Danish), until it was replaced with ⟨å⟩. There is a ligature ⟨Ꜳ⟩. In Cantonese romanisations such as Jyutping or Yale, it is used for /aː/, contrasting with ⟨a⟩ /ɐ/. ⟨ae⟩ is used in Irish for /eː/ between two "broad" (velarized) consonants, e.g. Gael /ɡeːlˠ/ "a Gael". In Latin, ⟨ae⟩ originally represented the diphthong /ae/, before it was monophthongized in the Vulgar Latin period to /ɛ/; in medieval manuscripts, the digraph was frequently replaced by the ligature ⟨æ⟩. In Modern English, Latin loanwords with ⟨ae⟩ are generally pronounced with /iː/ (e.g. Caesar), prompting Noah Webster to shorten this to ⟨e⟩ in his 1806 spelling reform for American English. In German, ⟨ae⟩ is a variant of ⟨ä⟩ found in some proper names or in contexts where ⟨ä⟩ is unavailable. In Dutch, ⟨ae⟩ is an old spelling variant of ⟨aa⟩ but now only occurs in names of people or (less often) places and in a few loanwords from Greek and Latin. In Zhuang, ⟨ae⟩ represents /a/ (⟨a⟩ represents /aː/). In Revised Romanization of Korean, ⟨ae⟩ represents /ɛ/. ⟨ãe⟩ is used in Portuguese for /ɐ̃ĩ̯/. ⟨ah⟩ is used in Taa for breathy or murmured /a̤/. In German and English it typically represents a long vowel /ɑː/. ⟨ai⟩ is used in many languages, typically representing the diphthong /aɪ/. In English, due to the Great Vowel Shift, it represents /eɪ/ as in pain and rain, while in unstressed syllables it may represent /ə/, e.g. bargain and certain(ly). In French, it represents /ɛ/. In Irish and it represents /a/ between a broad and a slender consonant. In Scottish Gaelic, it represents /a/ or /ɛ/ between a broad and a slender consonant, except when preceding word-final or pre-consonant ⟨ll, m, nn⟩ (e.g. cainnt /kʰaiɲtʲ/, or pre-consonant ⟨bh, mh⟩ (e.g. aimhreit /ˈaivɾʲɪtʲ/. In the Kernowek Standard orthography of Cornish, it represents /eː/, mostly in loanwords from English such as paint. ⟨aí⟩ is used in Irish for /iː/ between a broad and a slender consonant. ⟨aî⟩ is used in French for /ɛː/, as in aînesse /ɛːnɛs/ or maître /mɛːtʁ/. ⟨ái⟩ is used in Irish for /aː/ between a broad and a slender consonant. ⟨ài⟩ is used in Scottish Gaelic for /aː/ or sometimes /ɛː/, between a broad and a slender consonant. ⟨ãi⟩ is used in Portuguese for /ɐ̃ĩ̯/, usually spelt ⟨ãe⟩. ⟨am⟩ is used in Portuguese for /ɐ̃ũ̯/ word finally, /ɐ̃/ before a consonant, and /am/ before a vowel. In French, it represents /ɑ̃/ in lieu of ⟨an⟩ before ⟨b, m, p⟩. ⟨âm⟩ is used in Portuguese for a stressed /ɐ̃/ before a consonant. ⟨an⟩ is used in many languages to write a nasal vowel. In Portuguese it is used for /ɐ̃/ before a consonant. In French it represents /ɑ̃/ (/an/ before a vowel). In Breton it represents /ɑ̃n/. ⟨aⁿ⟩ is used in Hokkien Pe̍h-ōe-jī for /ã/. ⟨ân⟩ is used in Portuguese for a stressed /ɐ̃/ before a consonant. ⟨än⟩ is used in Tibetan Pinyin for /ɛ̃/. It is alternately written ⟨ain⟩. ⟨ån⟩ is used in Walloon, for the nasal vowel /ɔ̃/. ⟨aŋ⟩ is used in Lakhota for the nasal vowel /ã/ ⟨ao⟩ is used in many languages, such as Piedmontese and Mandarin Pinyin, to represent /au̯/. In Irish, it represents /iː/ (/eː/ in Munster) between broad consonants. In Scottish Gaelic, it represents /ɯː/ between broad consonants. In French, it is found in a few words such as paon representing /ɑ̃/ and as paonne representing /a/. In Malagasy, it represents /o/. In Wymysorys, it represents /œʏ̯/. ⟨ão⟩ is used in Portuguese for /ɐ̃ũ̯/. ⟨aq⟩ is used in Taa, for the pharyngealized vowel /aˤ/. ⟨au⟩ is used in English for /ɔː/. It occasionally represents /aʊ/, as in flautist. Other pronunciations are /æ/ or /ɑː/ (depending on dialect) in aunt and laugh, /eɪ/ in gauge, /oʊ/ in gauche and chauffeur, and /ə/ as in meerschaum and restaurant. In German and Dutch, it represents /au/ and /ʌu/, respectively (/au/ in some northern and /ɔu/ in some southern Dutch and some Flemish dialects). In French, it represents /o/ or sometimes /ɔ/. In Icelandic and Norwegian it represents /œy/ and /æʉ/, respectively. In several Romanizations of Wu Chinese, it represents /ɔ/. In the Cornish Kernowek Standard, it is used for /ɔ(ː)/, as in caul "cabbage" or dauncya "to dance". ⟨äu⟩ is used in German for the diphthong /ɔɪ/ in declension of native words with ⟨au⟩; elsewhere, /ɔɪ/ is written as ⟨eu⟩. In words, mostly of Latin origin, where ⟨ä⟩ and ⟨u⟩ are separated by a syllable boundary, it represents /ɛ.ʊ/, e.g. Matthäus (a German form for Matthew). ⟨aw⟩ is used in English in ways that parallel English ⟨au⟩, though it appears more often at the end of a word. In Cornish, it represents /aʊ/ or /æʊ/. In Welsh, it represents /au/. ⟨ay⟩ is used in English in ways that parallel ⟨ai⟩, though it appears more often at the end of a word. In French, it represents /ɛj/ before a vowel (as in ayant) and /ɛ.i/ before a consonant (as in pays). In Cornish, it represents /aɪ/, /əɪ/, /ɛː/, or /eː/. ⟨a_e⟩ (a split digraph) is used in English for /eɪ/. == B == ⟨bb⟩ is used in Pinyin for /b/ in languages such as Yi, where ⟨b⟩ stands for /p/. It was used in Portuguese until 1947. It had the same sound as ⟨b⟩. Was used only for etymological purposes. In Hungarian, it represents geminated /bː/. In English, doubling a letter indicates that the previous vowel is short (so ⟨bb⟩ represents /b/). In ISO romanized Korean, it is used for the fortis sound /p͈/, otherwise spelled ⟨pp⟩; e.g. hobbang. In Hadza it represents the ejective /pʼ/. In several African languages it is implosive /ɓ/. In Cypriot Arabic it is /bʱ/. ⟨bd⟩ is used in English for /d/ in a few words of Greek origin, such as bdellatomy. When not initial, it represents /bd/, as in abdicate. ⟨bf⟩ is used in Bavarian and several African languages for the /b̪͡v/. ⟨bh⟩ is used in transcriptions of Indo-Aryan languages for a murmured voiced bilabial plosive (/bʱ/), and for equivalent sounds in other languages. In Juǀʼhoan, it's used for the similar prevoiced aspirated plosive /b͡pʰ/. It is used in Irish to represent /w/ (beside ⟨a, o, u⟩) and /vʲ/ (beside ⟨e, i⟩), word-initially it marks the lenition of ⟨b⟩, e.g. mo bhád /mˠə waːd̪ˠ/ "my boat", bheadh /vʲɛx/ "would be". In Scottish Gaelic, it represents /v/, or in a few contexts as /w/~/u/ between a broad vowel and a broad consonant or between two broad vowels, as in labhair /l̪ˠau.ɪɾʲ/. In the orthography used in Guinea before 1985, ⟨bh⟩ was used in Pular (a Fula language) for the voiced bilabial implosive /ɓ/, whereas in Xhosa, Zulu, and Shona, ⟨b⟩ represents the implosive and ⟨bh⟩ represents the plosive /b/. In some orthographies of Dan, ⟨b⟩ is /b/ and ⟨bh⟩ is /ɓ/. ⟨bm⟩ is used in Cornish for an optionally pre-occluded /m/; that is, it represents either /m/ or /mː/ (in any position); /ᵇm/ (before a consonant or finally); or /bm/ (before a vowel); examples are mabm ('mother') or hebma ('this'). ⟨bp⟩ is used in Sandawe and romanized Thai for /p/. ⟨bp⟩ (capital ⟨bP⟩) is used in Irish, as the eclipsis of ⟨p⟩, to represent /bˠ/ (beside ⟨a, o, u⟩) and /bʲ/ (beside ⟨e, i⟩). ⟨bv⟩ is used in the General Alphabet of Cameroon Languages for the voiced labiodental affricate /b̪͡v/. ⟨bz⟩ is used in Shona for a whistled sibilant cluster /bz͎/. == C == ⟨cc⟩ was formerly used in Spanish-based spelling systems for Quechua and Aymara for the sound /q/, as in Ccozcco (modern Qusqu) ('Cuzco'). In Italian, ⟨cc⟩ before a front vowel represents a geminated /tʃ/, as in lacci /ˈlat.tʃi/. In Piedmontese and Lombard, ⟨cc⟩ represents the /tʃ/ sound at the end of a word. In Hadza it is the glottalized click /ᵑǀˀ/. In English crip slang, ⟨cc⟩ can sometimes replace the letters ⟨ck⟩ or ⟨ct⟩ at the ends of words, such as with thicc, protecc, succ and fucc. ⟨cg⟩ was used for [ddʒ] or [gg] in Old English (ecg in Old English sounded like 'edge' in Modern English, while frocga sounded like 'froga'), where both are long consonants. It is used for the click /ǀχ/ in Naro, and in the Tindall orthography of Khoekhoe for the voiceless dental click /ǀ/. ⟨ch⟩ is used in several languages. In English, it can represent /tʃ/, /k/, /ʃ/, /x/ or /h/. See article. ⟨çh⟩ is used in Manx for /tʃ/, such as in the word çhengey, meaning speech, as a distinction from ⟨ch⟩ which is used for /x/. ⟨čh⟩ is used in Romani and the Chechen Latin alphabet for /tʃʰ/. In the Ossete Latin alphabet, it was used for /tʃʼ/. ⟨ci⟩ is used in the Italian for /tʃ/ before the non-front vowel letters ⟨a, o, u⟩. In English, it usually represents /ʃ/ whenever it precedes any vowel other than ⟨i⟩. In Polish, it represents /t͡ɕ/ whenever it precedes a vowel, and /t͡ɕi/ whenever it precedes a consonant (or in the end of the word), and is considered a graphic variant of ⟨ć⟩ appearing in other situations. In Romanian, it represents /tʃ/. The digraph is found at the end of a word (deci, atunci, copaci) or before the letters a, o, or u (ciorba, ciuleandra); the /tʃ/ sound made by the letter c in front of the letters e or i becomes /k/ in front of the three aforementioned vowels, making the addition of the letter i necessary. ⟨cj⟩ is used in Friulian for /c/ such as in words cjocolate /cokoˈlate/. It's also used in local orthographies of Lombard to represent /tʃ/ derived from Latin ⟨cl⟩. ⟨ck⟩ is used in many Germanic languages in lieu of ⟨kk⟩ or ⟨cc⟩ to indicate either a geminated /kː/, or a /k/ with a preceding (historically) short vowel. The latter is the case with English tack, deck, pick, lock, and buck (compare backer with baker). In German, ⟨ck⟩ indicates that the preceding vowel is short. Prior to the German spelling reform of 1996, it was replaced by ⟨k-k⟩ for syllabification. The new spelling rules allow only syllabification of the ⟨ck⟩ as a whole: Old spelling: Säcke: Säk-ke ('sacks') New spelling: Säcke: Sä-cke Among the modern Germanic languages, ⟨ck⟩ is used mainly in Alsatian, English, German, Luxembourgish, Scots, Swedish, and other West Germanic languages in Austria, Germany and Switzerland. Similarly, ⟨kk⟩ is used for the same purpose in Afrikaans, Danish, Dutch, Icelandic, Norwegian, and other West Germanic languages in the Netherlands and Belgium. Compare the word nickel, which is the same in many of these languages except for the customary ⟨ck⟩ or ⟨kk⟩ spelling. The word is nickel in English and Swedish, Nickel in German, and nikkel in Afrikaans, Danish, Dutch, Icelandic and Norwegian. It was also used in the Tindall orthography of Khoekhoe for the voiceless dental click /ǀ/ (equivalent to ⟨cg⟩). It is also used in Cornish for /k/ at the end of a syllable after a short vowel; only in loanwords (mostly from English) in the Standard Written Form (SWF), more widely in Kernowek Standard. ⟨cn⟩ is used in English for /n/ in a few words of Greek origin, such as cnidarian. When not initial, it represents /kn/, as in acne. It is used in Scottish Gaelic for /kʰr/, and nasalises the following vowel, as in cneap /kʰrʲɛ̃hb/. ⟨cö⟩ is used in Seri for a labialized velar plosive, /kʷ/. It is placed between ⟨c⟩ and ⟨d⟩ in alphabetical order. ⟨cr⟩ is used in the General Alphabet of Cameroon Languages for /ʈʂ/. ⟨cs⟩ is used in the Hungarian for a voiceless postalveolar affricate, /tʃ/. It is considered a distinct letter, named csé, and is placed between ⟨c⟩ and ⟨d⟩ in alphabetical order. Examples of words with ⟨cs⟩ include csak ('only'), csésze ('cup'), cső ('pipe'), csípős ('peppery'). ⟨ct⟩ is used in English for /t/ in a few words of Greek origin, such as ctenoid. When not initial, it represents /kt/, as in act. Is used in Portuguese for /t/ in some words, e.g. retrospecto but not in tacto. ⟨cu⟩ is used in languages such as Nahuatl (that is, based on Spanish or Portuguese orthography) for /kʷ/. In Nahuatl, ⟨cu⟩ is used before a vowel, whereas ⟨uc⟩ is used after a vowel. ⟨cw⟩ is used in modern scholarly editions of Old English for the sound /kw/, which was spelled ⟨cƿ⟩, ⟨cuu⟩ or ⟨cu⟩ in manuscripts. In Middle English these were all replaced by Latin ⟨qu⟩. ⟨cx⟩ is used in Esperanto as an unofficial surrogate of ⟨ĉ⟩, which represents /tʃ/. ⟨cz⟩ is used in Polish for /ʈ͡ʂ/ as in ('hello'). In Kashubian, ⟨cz⟩ represents /tʃ/. In French and Catalan, historical ⟨cz⟩ contracted to the ligature ⟨ç⟩, which represents /s/ when followed by ⟨a, o, u⟩. In Hungarian, it was formerly used for the sound /ts/, which is now written ⟨c⟩. In English, ⟨cz⟩ is used to represent in the loanwords Czech, and Czechia. == D == ⟨dc⟩ is used in Naro for the click /ᶢǀ/, and in Juǀʼhoan for the prevoiced ejective /d͡tʃʼ/. ⟨dd⟩ is used in English to indicate a /d/ with a preceding (historically) short vowel (e.g. jaded /ˈdʒeɪdɨd/ has a "long a" while ladder /ˈlædər/ has a "short a"). In Welsh, ⟨dd⟩ represents a voiced dental fricative /ð/. It is treated as a distinct letter, named èdd, and placed between ⟨D⟩ and ⟨E⟩ in alphabetical order. In the ISO romanization of Korean, it is used for the fortis sound /t͈/, otherwise spelled ⟨tt⟩; examples are ddeokbokki and bindaeddeok. In Basque, it represents a voiced palatal plosive /ɟ/, as in onddo "mushroom". In several African languages it is implosive /ɗ/. Latin delta (ẟ, lowercase only) is represented by "dd" in Modern Welsh. ⟨dg⟩ is used in English for /dʒ/ in certain contexts, such as with judgement and hedge ⟨dh⟩ is used in the Albanian, Swahili, and revived Cornish for the voiced dental fricative /ð/. The first examples of this digraph are from the Oaths of Strasbourg, the earliest French text, where it denotes the same sound /ð/ developed mainly from intervocalic Latin -t-. In early traditional Cornish ⟨ȝ⟩ (yogh), and later ⟨th⟩, were used for this purpose. Edward Lhuyd is credited for introducing the grapheme to Cornish orthography in 1707 in his Archaeologia Britannica. In Irish it represents /ɣ/ (beside ⟨a, o, u⟩) or /j/ (beside ⟨e, i⟩); at the beginning of a word it shows the lenition of ⟨d⟩, e.g. mo dhoras /mˠə ɣɔɾˠəsˠ/ "my door" (cf. doras /d̪ˠɔɾˠəsˠ/ "door"). In Scottish Gaelic it represents /ɣ/ (beside ⟨a, o, u⟩) or /ʝ/ or /j/ (beside ⟨e, i⟩). In the pre-1985 orthography of Guinea, ⟨dh⟩ was used for the voiced alveolar implosive /ɗ/ in Pular. It is currently written ⟨ɗ⟩. In the orthography of Shona it is the opposite: ⟨dh⟩ represents /d/, and ⟨d⟩ /ɗ/. In the transcription of Australian Aboriginal languages, ⟨dh⟩ represents a dental stop, /t̪/. In addition, ⟨dh⟩ is used in various romanization systems. In transcriptions of Indo-Aryan languages, for example, it represents the murmured voiced dental plosive /d̪ʱ/, and for equivalent sounds in other languages. In Juǀʼhoan, it's used for the similar prevoiced aspirated plosive /d͡tʰ/. In the romanization of Arabic, it denotes ⟨ﺫ⟩, which represents /ð/ in Modern Standard Arabic. Represents /ɖ/ in Javanese and Somali. ⟨dj⟩ is used in Faroese, Portuguese, French and many French-based orthographies for /dʒ/. In the transcription of Australian Aboriginal languages such as Warlpiri, Arrernte, and Pitjantjatjara, it represents a postalveolar stop such as /ṯ/ or /ḏ/; this sound is also written ⟨dy⟩, ⟨tj⟩, ⟨ty⟩, or ⟨c⟩. It is also formerly used in Indonesian as /d͡ʒ/. ⟨dl⟩ is used in Hmong’s Romanized Popular Alphabet for /tˡ/. In Navajo, it represents /tɬ/, and in Xhosa it represents /ɮ̈/. In Hadza it is ejective /cʎʼ/. ⟨dł⟩ is used in Tlingit for /tɬ/ (in Alaska, ⟨dl⟩ is used instead). ⟨dm⟩ is used in Yélî Dnye for doubly articulated and nasally released /t͡pn͡m/. ⟨dn⟩ is used in Yélî Dnye for nasally released /tn/. In Cornish, it is used for an optionally pre-occluded /n/; that is, it is pronounced either /n/ or /nː/ (in any position); /ᵈn/ (before a consonant or finally); or /dn/ (before a vowel); examples are pedn ('head') or pednow ('heads'). ⟨dp⟩ is used in Yélî Dnye for doubly articulated /t͡p/. ⟨dq⟩ is used for the click /ᶢǃ/ in Naro. ⟨dr⟩ is used in Malagasy for /ɖʐ/. See ⟨tr⟩. It is used in Fijian for 'ndr' nasalized (/ɳɖr/). In some Amerindian languages it represents /ʈʂ/ as in Gwichʼin and sporatically /ɖ/ everywhere as in Paiwan and Maba ⟨ds⟩ is used in Juǀʼhoan for the prevoiced ejective /d͡tsʼ/. ⟨dt⟩ is used in German, Swedish, and Sandawe orthography as well as the romanization of Thai for /t/. ⟨dt⟩ (capital ⟨dT⟩) is used in Irish, as the eclipsis of ⟨t⟩, to represent /d̪ˠ/ (beside ⟨a, o, u⟩) and /tʲ/ (beside ⟨e, i⟩). ⟨dv⟩ is used in the General Alphabet of Cameroon Languages for the voiced dental affricate /d͡ð/. ⟨dx⟩ is used in some Zapotecan languages for a voiced postalveolar fricative /ʒ/. (It is placed between ⟨D⟩ and ⟨E⟩ in alphabetical order.) In Juǀʼhoan it is used for the prevoiced uvularized plosive /d͡tᵡ/. ⟨dy⟩ is used in Xhosa for /dʲʱ/. In Shona, it represents /dʒɡ/. In Tagalog it is used for /dʒ/. In the transcription of Australian Aboriginal languages such as Warlpiri, Arrernte, and Pitjantjatjara, it represents a postalveolar stop such as /ṯ/ or /ḏ/. This sound is also written ⟨tj⟩, ⟨dj⟩, ⟨ty⟩, ⟨c⟩, or ⟨j⟩. ⟨dz⟩ is used in several languages, often to represent /d͡z/. See article. ⟨dź⟩ is used in the Polish and Sorbian alphabets for /d͡ʑ/, the voiced alveolo-palatal affricate, as in dźwięk /d͡ʑvʲɛŋk/. ⟨dź⟩ is never written before a vowel (⟨dzi⟩ is used instead, as in dziecko /d͡ʑɛt͡skɔ/ 'child'). ⟨dż⟩ is used in the Polish for a voiced retroflex affricate /ɖ͡ʐ/ (e.g. 'jam'). ⟨dž⟩ is used in Serbo-Croatian, Slovak, Lithuanian, and Latvian to represent /d͡ʒ/. See article. == E == ⟨e′⟩ is used in Taa, where it represents the glottalised or creaky vowel /ḛ/. ⟨ea⟩ is used in many languages. In English, ⟨ea⟩ usually represents the monophthong /iː/ as in meat; due to a sound change that happened in Middle English, it also often represents the vowel /ɛ/ as in sweat. Rare pronunciations occur, like /eɪ/ in break, great, steak, and yea, and /ɔː/ in the archaic ealdorman. When followed by ⟨r⟩, it can represent the standard outcomes of the previously mentioned three vowels in this environment: /ɪər/ as in beard, /ɜːr/ as in heard, and /ɛər/ as in bear, respectively; as another exception, /ɑr/ occurs in the words hearken, heart, and hearth. It often represents two independent vowels, like /eɪ.ɑː/ (seance), /i.æ/ (reality), /i.eɪ/ (create), and /i.ɪ/ or /i.ə/ (lineage). Unstressed, it may represent /jə/ (ocean) and /ɪ/ or /ə/ (Eleanor). In Romanian, it represents the diphthong /e̯a/ as in beată ('drunk female'). In Irish, ⟨ea⟩ represents /a/ between a slender and a broad consonant. In Scottish Gaelic, ⟨ea⟩ represents /ʲa/, /ɛ/ or /e/ between a slender and a broad context, depending on context or dialect. In Old English, it represents the diphthong /æɑ̯/. ⟨Ea⟩ is also the transliteration of the ⟨ᛠ⟩ rune of the Anglo-Frisian Futhorc. ⟨eá⟩ is used in Irish for /aː/ between a slender and a broad consonant. ⟨eà⟩ is used in Scottish Gaelic for /ʲaː/ between a slender and a broad consonant. ⟨éa⟩ is used in Irish for /eː/ between a slender and a broad consonant. ⟨èa⟩ is used in Scottish Gaelic for /ia/ between a slender and a broad consonant, unless the broad consonant is m, mh, or p, in which case it represents /ɛ/. ⟨ee⟩ represents a long mid vowel in a number of languages. In English, ⟨ee⟩ represents /iː/ as in teen. In Dutch and German, ⟨ee⟩ represents /eː/ (though it is pronounced [eɪ] in majority of northern Dutch dialects). In the Cantonese Romanisation, it represents /iː/ as in English, or /ei/ for characters which might be pronounced as /iː/ in other dialects. In Bouyei, ⟨ee⟩ is used for plain /e/, as ⟨e⟩ stands for /ɯ/. ⟨eh⟩ is used in Taa for the murmured vowel /e̤/. In the Wade-Giles transliteration of Mandarin Chinese, it is used for /ɛ/ after a consonant, as in yeh /jɛ/. In German, ⟨eh⟩ represents /eː/, as in Reh. ⟨ei⟩ This digraph was taken over from Middle High German, where it represented /eɪ/. It usually represents a diphthong. In Modern German, ⟨ei⟩ is predominant in representing /aɪ/, as in Einstein, while the equivalent digraph ⟨ai⟩ appears in only a few words. In English, ⟨ei⟩ can represent many sounds, including /eɪ/, as in vein, /i/ as in seize, /aɪ/ as in heist, /ɛ/ as in heifer, /æ/ as in enceinte, and /ɪ/ or /ə/ as in forfeit. See also I before e except after c. In southern and western Faroese dialects, it represents the diphthong /aɪ/, while in northern and eastern dialects, it represents the diphthong /ɔɪ/. In Portuguese, ⟨ei⟩ represents /ɐj/ in Greater Lisbon, so do ⟨éi⟩ and ⟨êi⟩, but /ej ~ e/ or /ɛj/ in Brazil, East Timor, Macau, rest of Portugal, and Portuguese-speaking African countries, In Welsh, ⟨ei⟩ represents /əi/. In Irish and Scottish Gaelic, it represents /ɛ/ or /e/, or /ɪ/ when unstressed, before a slender consonant. In Dutch and Afrikaans, ⟨ei⟩ represents /ɛi/. In French, ⟨ei⟩ represents /ɛ/, as in seiche. In Hepburn romanization of the Japanese language it is used to transcribe the sound /eː/. ⟨eî⟩ is used in French for /ɛː/, as in reître /ʁɛːtʁ/. ⟨éi⟩ is used in Irish for /eː/ between slender consonants. ⟨èi⟩ is used in Scottish Gaelic for /ɛː/ or /eː/ between slender consonants. ⟨ej⟩ is used in Swedish in some short words, such as leja /leːja/ or nej /nɛj/. ⟨em⟩ is used in Portuguese for /ɐĩ̯ ~ ẽĩ̯/ at the end of a word and /ẽ/ before a consonant. In French orthography, it represents a /ɑ̃/ when it is followed by ⟨b⟩ or ⟨p⟩. ⟨ẽm⟩ is used in Portuguese for /ẽĩ/ at the end of a word. ⟨ém⟩ is used in Portuguese for /ɐĩ̯ ~ ẽĩ̯/ at the end of a word. ⟨êm⟩ is used in Portuguese for /ɐĩ̯ ~ ẽĩ̯/ at the end of a word and /ẽ/ before a consonant. ⟨en⟩ is used in Portuguese for /ɐĩ̯ ~ ẽĩ̯/ at the end of a word followed or not by an /s/ as in hífen or hifens; and for /ẽ/ before a consonant within a word. In French, it represents /ɑ̃/ or /ɛ̃/. ⟨én⟩ is used in Portuguese for /ɐĩ̯ ~ ẽĩ̯/ before a consonant. ⟨ên⟩ is used in Portuguese for /ẽ/ before a consonant. ⟨eo⟩ is used in Irish for /oː/ (/ɔ/ in 4 words) between a slender and a broad consonant. In Scottish Gaelic it is used for /ʲɔ/ between a slender and a broad consonant. In the Jyutping romanization of Cantonese, it represents /ɵ/, an allophone of /œː/, while in the Cantonese Romanisation, it represents /œː/. In the Revised Romanization of Korean, ⟨eo⟩ represents the open-mid back unrounded vowel /ʌ/, and in Piedmontese it is /ɛu̯/. In English ⟨eo⟩ is a rare digraph without a single pronunciation, representing /ɛ/ in feoff, jeopardy, leopard and the given names Geoffrey and Leonard, /iː/ in people, /oʊ/ in yeoman and /juː/ in the archaic feodary, while in the originally Gaelic name MacLeod it represents /aʊ/. However, usually it represents two vowels, like /iː.ə/ in leotard and galleon, /iː.oʊ/ in stereo and, /iː.ɒ/ in geodesy, and, uniquely, /uː.iː/ in geoduck. ⟨eò⟩ is used in Scottish Gaelic for /jɔː/ word-initially, and /ɔː/ elsewhere. ⟨eq⟩ is used in Taa for the pharyngealized vowel /eˤ/. ⟨eu⟩ is found in many languages, most commonly for the diphthong /eu/. Additionally, in English, ⟨eu⟩ represents /juː/ as in neuter (/uː/ in yod-dropping accents); however, the ⟨eu⟩ in "maneuver/manoeuvre" always represents /uː/ even in most non yod-dropping accents. In German, it represents /ɔʏ/ as in Deutsch; and in French, Dutch, Breton, and Piedmontese, it represents /ø/. In Cornish, it represents either long /øː ~ œː/ and short /œ/ or long /eː/ and short /ɛ/. In Scottish Gaelic it normally represents /ia/, as in beul /pial̪ˠ/, except when preceding ⟨m⟩ (e.g. leum /ʎeːm/) and usually ⟨b, mh, bh⟩, or in certain high-register words such as treun /t̪ʰɾeːn/ where it represents /eː/, and in southern dialects it is /eː/ in most contexts. In Yale romanization of Cantonese it represents /ɵ ~ œː/, while in the Cantonese Romanisation, it represents /œː/. In romanization of Wu Chinese, it represents /ø/, depending on the lect. In Sundanese and Acehnese, it represents /ɤ/ as in beureum ('red'). In the Revised Romanization of Korean, it represents /ɯ/. ⟨eû⟩ is used in French for /ø/, as in jeûne /ʒøn/. ⟨ew⟩ is used in English for /juː/ as in few and flew. An exception is the pronunciation /oʊ/ in sew, leading to the heteronym sewer,(/ˈsuːər/, 'drain') vs sewer (/ˈsoʊər/, 'one who sews'). In Cornish, it stands for /ɛʊ/. ⟨êw⟩ is used in the Kernowek Standard orthography of Cornish to refer to a sound that can be either /ɛʊ/ or /oʊ/. This distribution can also be written ⟨ôw⟩. ⟨ey⟩ is used in English for a variety of sounds, including /eɪ/ in they, /iː/ in key, and /aɪ/ in geyser. In Faroese, it represents the diphthong /ɛɪ/. In Cornish, it represents the diphthong /ɛɪ/ or /əɪ/. ⟨e_e⟩ (a split digraph) indicates an English 'long e', historically /e:/ but now most commonly realised as /i:/. ⟨eⁿ⟩ is used for /ẽ/ in Hokkien Pe̍h-ōe-jī. == F == ⟨ff⟩, which may be written as the typographic ligature ⟨ﬀ⟩, is used in English and Cornish for the same sound as single ⟨f⟩, /f/. The doubling is used to indicate that the preceding vowel is (historically) short, or for etymological reasons, in latinisms. Very rarely, ⟨ff⟩ may be found word-initially in English, such as in proper names (e.g., Rose ffrench, Jasper Fforde). In Welsh, ⟨ff⟩ represents /f/, while ⟨f⟩ represents /v/. In Welsh, ⟨ff⟩ is considered a distinct letter, and placed between ⟨f⟩ and ⟨g⟩ in alphabetical order. In medieval Breton, vowel nasalisation was represented by a following ⟨ff⟩. This notation was reformed during the 18th century, though proper names retain the former convention, which leads to occasional mispronunciation. ⟨fh⟩ is used in Irish and Scottish Gaelic for the lenition of ⟨f⟩. This happens to be silent, so that ⟨fh⟩ in Gaelic corresponds to no sound at all, e.g. the Irish phrase cá fhad /kaː ˈad̪ˠ/ "how long", where fhad is the lenited form of fad /fˠad̪ˠ/ "long". However, in three Scottish Gaelic words, fhèin, fhuair, and fhathast, it is pronounced as /h/. ⟨fx⟩ is used in Nambikwara for a glottalized /ɸʔ/. == G == ⟨gʻ⟩ is used in Uzbek to represent /ɣ/. ⟨gb⟩ is used in some African languages for a voiced labial-velar plosive, /ɡ͡b/. ⟨gc⟩ is used in languages, such as Xhosa and Zulu, for the click /ᶢǀ/. ⟨gc⟩ (capital ⟨gC⟩) is used in Irish, as the eclipsis of ⟨c⟩, to represent /g/ (beside ⟨a, o, u⟩) and /ɟ/ (beside ⟨e, i⟩). ⟨ge⟩ is used in French for /ʒ/ before ⟨e, i⟩ as in geôle /ʒol/. ⟨gg⟩ is used in English for /ɡ/ before ⟨y⟩, ⟨i⟩ and ⟨e⟩ (e.g. doggy). It is also used in Pinyin for /ɡ/ in languages such as Yi. In Central Alaskan Yup'ik, it represents /x/. In Greenlandic, it represents /çː/. In the ISO romanization of Korean, it is used for the fortis sound /k͈/, otherwise spelled ⟨kk⟩ (e.g. ggakdugi). In Hadza it is ejective /kxʼ/. In Italian, ⟨gg⟩ before a front vowel represents a geminated /dʒ/, as in legge /ˈled.dʒe/. In Piedmontese and Lombard, ⟨gg⟩ is an etymological spelling representing an /tʃ/ at the end of a word which is the unvoicing of an ancient /dʒ/. ⟨gh⟩ is used in several languages. In English, it can be silent or represent /ɡ/ or /f/. See article. ⟨gi⟩ is used in Vietnamese for /z/ in northern dialects and /j/ in the southern ones. In Italian, it represents /dʒ/ before the non-front vowel letters ⟨a o u⟩. In Romansh it represents /dʑ/ before ⟨a o u⟩ (written ⟨g⟩ before front vowels). ⟨gj⟩ is used in Albanian for the voiced palatal plosive /ɟ/, though for Gheg speakers it represents /dʒ/. In the Arbëresh dialect, it represents the voiced velar plosive /ɡʲ/. In Norwegian and Swedish ⟨gj⟩ represents /j/ in words like gjorde ('did'). In Faroese, it represents /dʒ/. It is also used in the Romanization of Macedonian as a Latin equivalent of Cyrillic ⟨Ѓ⟩. Also, it's used in Friulian to represent /ɟ/ (whilst /dʒ/ is one of the pronunciations of the letter ⟨z⟩). It can be found in some local orthographies of Lombard to represent /dʒ/ derived from Latin ⟨gl⟩. Before the letter Đ was introduced into Gaj's Latin alphabet in 1878, the digraph ⟨gj⟩ had been used instead; and it remained in use till the beginning of the 20th century. ⟨gk⟩ is used in Sandawe and the romanization of Thai for /k/; in Limburgish it represents /ɡ/. Modern Greek uses the equivalent digraph γκ for /g/, as γ is used for /ɣ/ ~ /ʝ/. ⟨gl⟩ is used in Italian and some African languages for /ʎ/. ⟨gm⟩ is used in English for /m/ in a few words of Greek origin, such as phlegm and paradigm. Between vowels, it simply represents /ɡm/, as in paradigmatic. ⟨gn⟩ is used in Latin, where it represented /ŋn/ in the classical period. Latin velar-coronal sequences like this (and also ⟨cl cr ct gd gl gr x⟩) underwent a palatal mutation to varying degrees in most Italo-Western Romance languages. For most languages that preserve the ⟨gn⟩ spelling (such as Italian and French), it represents a palatal nasal /ɲ/ (or more precisely /ɲː/ in Italian), and is similarly used in Romanization schemes such as Wugniu for /ȵ/. This was not the case in Dalmatian and the Eastern Romance languages where a different mutation changed the velar component to a labial consonant as well as the spelling to ⟨mn⟩. In Portuguese, ⟨gn⟩ represents /n/, as if there was no ⟨g⟩, e.g. assignatura, signal, impregnado and plurissignificação. It is used in Scottish Gaelic for /kr/, and nasalises the following vowel, as in gnè /krʲɛ̃ː/. In English, ⟨gn⟩ represents /n/ initially (see /gn/ reduction) and finally (i.e. gnome, gnu, benign, sign). When it appears between two syllables, it represents /ɡn/ (e.g. signal). In Norwegian and Swedish, ⟨gn⟩ represents /ŋn/ in monosyllabic words like agn, and between two syllables, tegne. Initially, it represents /ɡn/, e.g. Swedish gnista /ˈɡnɪsta/. ⟨gñ⟩ was used in several Spanish-derived orthographies of the Pacific for /ŋ/. It is one of several variants of the digraph ⟨ñg⟩, and is preserved in the name of the town of Sagñay, Philippines. ⟨go⟩ is used in Piedmontese for /ɡw/ (like the “gu” in Guatemala). ⟨gq⟩ is used in languages, such as Xhosa and Zulu, for the click /ᶢǃ/. In the Taa language, it represents /ɢ/. ⟨gr⟩ is used in Xhosa for /ɣ̈/. ⟨gu⟩ is used in English, Spanish, French, Portuguese and Catalan for /ɡ/ before front vowels ⟨i e⟩ (⟨i e y⟩ in English and French) where a "soft g" pronunciation (English /dʒ/; Spanish /x/; French, Portuguese and Catalan /ʒ/) would otherwise occur. In English, it can also be used to represent /ɡw/. In the Ossete Latin alphabet, it is used for /ɡʷ/. ⟨gü⟩ is used in Spanish, Catalan and formely Portuguese for /ɡw/ before front vowels ⟨i e⟩ where the digraph ⟨gu⟩ would otherwise represent /ɡ/. ⟨gv⟩ is used for /kʷ/ in Standard Zhuang and in Bouyei. In the General Alphabet of Cameroon Languages it is used for the labialized fricative /ɣʷ/. ⟨gw⟩ is used in various languages for /ɡʷ/, and in Dene Suline it represents /kʷ/. ⟨ǥw⟩, capital ⟨Ǥw⟩ (or ⟨G̱w⟩), is used in Tlingit for /qʷ/ (in Alaska); in Canada, this sound is represented by ⟨ghw⟩. ⟨gx⟩ is used in languages, such as Xhosa and Zulu, for the click /ᶢǁ/. In Esperanto, it is an unofficial surrogate of ⟨ĝ⟩, which represents /dʒ/. ⟨gy⟩ is used in Hungarian for a voiced palatal plosive /ɟ/. In Hungarian, the letter's name is gyé. It is considered a single letter, and acronyms keep the digraph intact. The letter appears frequently in Hungarian words, such as the word for "Hungarian" itself: magyar. In the old orthography of Bouyei, it was used for /tɕ/. It is also commonly used in Burmese romanization schemes to represent /dʒ/. ⟨gǃ⟩ is used in Juǀʼhoan for the voiced alveolar click /ᶢǃ/. ⟨gǀ⟩ is used in Juǀʼhoan for the voiced dental click /ᶢǀ/. ⟨gǁ⟩ is used in Juǀʼhoan for the voiced lateral click /ᶢǁ/. ⟨gǂ⟩ is used in Juǀʼhoan for the voiced palatal click /ᶢǂ/. == H == ⟨hh⟩ is used in Xhosa to write the murmured glottal fricative /ɦ̤/, though this is often written ⟨h⟩. In the Iraqw language, ⟨hh⟩ is the voiceless epiglottal fricative /ʜ/, and in Chipewyan it is a velar/uvular /χ/. In Esperanto orthography, it is an official surrogate of ⟨ĥ⟩, which represents /x/. ⟨hj⟩ is used in the Italian dialect of Albanian for /xʲ/. In Faroese, it represents either /tʃ/ or /j/, and in Swedish, Danish and Norwegian, it represents /j/. In Icelandic it is used to denote /ç/. ⟨hl⟩ is used for /ɬ/ or /l̥/ in various alphabets, such as the Romanized Popular Alphabet used to write Hmong (/ɬ/) and Icelandic (/l̥/). See also reduction of Old English /hl/. ⟨hm⟩ is used in the Romanized Popular Alphabet used to write Hmong, where it represents the sound /m̥/. ⟨hn⟩ is used in the Romanized Popular Alphabet used to write Hmong, where it represents the sound /n̥/. It is also used in Icelandic to denote the same phoneme. See also reduction of Old English /hn/. ⟨hr⟩ is used for /ɣ/ in Bouyei. In Icelandic it is used for /r̥/. See also reduction of Old English /hr/. ⟨hs⟩ is used in the Wade-Giles transcription of Mandarin Chinese for the sound /ɕ/, equivalent to Pinyin ⟨x⟩. ⟨hu⟩ is used primarily in the Classical Nahuatl language, in which it represents the /w/ sound before a vowel; for example, Wikipedia in Nahuatl is written Huiquipedia. After a vowel, ⟨uh⟩ is used. In the Ossete Latin alphabet, ⟨hu⟩ was used for /ʁʷ/, similar to French roi. The sequence ⟨hu⟩ is also found in Spanish words such as huevo or hueso; however, in Spanish this is not a digraph but a simple sequence of silent ⟨h⟩ and the vowel ⟨u⟩. ⟨hv⟩ is used Faroese and Icelandic for /kv/ (often /kf/), generally in wh-words, but also in other words, such as Faroese hvonn. In the General Alphabet of Cameroon Languages it is used for the supposed fricative /ɣ͜β/. ⟨hw⟩ is used in modern editions of Old English for /hw/, originally spelled ⟨huu⟩ or ⟨hƿ⟩ (the latter with the wynn letter). In its descendants in modern English, it is now spelled ⟨wh⟩ (see there for more details). It is used in some orthographies of Cornish for /ʍ/. ⟨hx⟩ is used in Pinyin for /h/ in languages such as Yi (⟨h⟩ alone represents the fricative /x/), and in Nambikwara it is a glottalized /hʔ/. In Esperanto orthography, it is an unofficial surrogate of ⟨ĥ⟩, which represents /x/. ⟨hy⟩ is used in Hepburn romanization of the Japanese language to transcribe the sound /ç/, which is the syllable hi before a y-vowel, such as hya, hyu, and hyo, which appear in Chinese loanwords. Was also used in Portuguese until 1947. It appeared in words like: Hydroginástica and Hypóthese. == I == ⟨i′⟩ is used in Taa to represent the glottalized or creaky vowel /ḭ/. ⟨ia⟩ is used in Irish and Scottish Gaelic for the diphthong /iə/. ⟨ie⟩ is used in English, where it usually represents the /aɪ/ sound as in pries and allied or the /iː/ sound as in priest and rallied. Followed by an ⟨r⟩, these vowels follow the standard changes to /aɪə/ and /ɪə/, as in brier and bier. Unique pronunciations are /ɪ/ in sieve, /ɛ/ in friend, and /eɪ/ in lingerie. Unstressed it can represent /jə/, as in spaniel and conscience, or /ɪ/ or /ə/ as in mischief and hurriedly. It also can represent many vowel combinations, including /aɪə/ in diet and client, /aɪɛ/ in diester and quiescent, /iːə/ in alien and skier, /iːɛ/ in oriental and hygienic, and /iː.iː/ in British medieval. In Dutch and Afrikaans, ⟨ie⟩ represents the tense vowel /i/. In German, it may represent the lengthened vowel /iː/ as in Liebe (love) as well as the vowel combination /iə/ as in Belgien (Belgium). In Latvian and Lithuanian, ⟨ie⟩ is considered two letters for all purposes and represents /iæ̯/, commonly (although less precisely) transcribed as /i̯e/. In Maltese, ⟨ie⟩ is a distinct letter and represents a long close front unrounded vowel, /iː/ or /iɛ/. In Pinyin it is used to write the vowel /e/ in languages such as Yi, where ⟨e⟩ stands for /ɛ/. In Old English ⟨ie⟩ was one of the common diphthongs, the umlauted version of ⟨ea⟩ and ⟨eo⟩. Its value is not entirely clear, and in Middle English it had become /e/. ⟨îe⟩ is used in Afrikaans for /əːə/. ⟨ig⟩ is used in Catalan for /t͡ʃ/ (ch as in cheese) in the coda. ⟨ih⟩, is used in Taa to represent the breathy or murmured vowel /i̤/. It is also used in Tongyong Pinyin and Wade-Giles transcription for the fricative vowels of Mandarin Chinese, which are spelled ⟨i⟩ in Hanyu Pinyin. ⟨ii⟩ is used in many languages such as Portuguese (e.g. Aniilar, Sacerdócii) and Finnish (e.g. Riikka, Niinistö, Siitala, Riikkeli), Italian (e.g. Riina), Estonian (e.g. Riik), Scots (e.g. Auld Nii, Iisay), with phonemic long vowels for /iː/. ⟨ií⟩ is used in Portuguese for /iji/. In Portuguese, when forming the superlative absolute synthetic form of adjectives that end in "-io," they often end up with "ii" in the spelling. This happens because the "-íssimo(a)" suffix is added directly to the adjective (e.g. feio(a) -> feiíssimo(a), sério(a) -> seriíssimo(a)). ⟨ij⟩ is used in Dutch for /ɛi/. See article. ⟨il⟩ is used in French for /j/, historically /ʎ/, as in ail /aj/ (approximately eye in English) "garlic". Can also be written as ⟨ille⟩ as in vieille /vjɛj/. ⟨im⟩ is used in Portuguese for /ĩ/. ⟨ím⟩ is used in Portuguese for /ĩ/ before a consonant. ⟨ĩm⟩ is used in Portuguese for the diphthong /ĩə/. ⟨in⟩ is used in many languages to write a nasal vowel. In Portuguese before a consonant, and in many West African languages, it is /ĩ/, while in French it is /ɛ̃/. ⟨ín⟩ is used in Portuguese for /ĩ/ before a consonant. ⟨în⟩ is used in French to write a vowel sound /ɛ̃/ that was once followed by a historical ⟨s⟩, as in vous vîntes /vu vɛ̃t/ "you came". ⟨iŋ⟩ is used in Lakota for the nasal vowel /ĩ/. ⟨io⟩ is used in Irish for /ɪ/, /ʊ/, and /iː/ between a slender and a broad consonant. In Scottish Gaelic it is used for /i/ and sometimes /(j)ũ(ː)/ between a slender and a broad consonant. ⟨ío⟩ is used in Irish for /iː/ between a slender and a broad consonant. ⟨ìo⟩ is used in Scottish Gaelic for /iː/ and /iə/ between a slender and a broad consonant. ⟨iq⟩ is used in Taa to represent the pharyngealized vowel /iˤ/. ⟨iu⟩ is used in Irish for /ʊ/ between a slender and a broad consonant. In Scottish Gaelic, it is used for /(j)u/ between a slender and a broad consonant. In Mandarin pinyin, it is /i̯ou̯/ after a consonant. (In initial position, this is spelled ⟨you⟩). ⟨iú⟩ is used in Irish for /uː/ between a slender and a broad consonant. ⟨iù⟩ is used in Scottish Gaelic for /(j)uː/ between a slender and a broad consonant. ⟨iw⟩ is used in Welsh and Cornish for the diphthong /iʊ/ or /ɪʊ/. ⟨ix⟩ is used in Catalan for /ʃ/ (Eastern Catalan) or /jʃ/ (Western Catalan) after a vowel. ⟨i_e⟩ (a split digraph) indicates an English 'long i', historically /iː/ but now most commonly realised as /aɪ/. == J == ⟨jh⟩ is used in Walloon to write a consonant that is variously /h/, /ʒ/ or /ç/, depending on the dialect. In Tongyong pinyin, it represents /tʂ/, written ⟨zh⟩ in standard pinyin. ⟨jh⟩ is also the standard transliteration for the Devanāgarī letter झ /dʒʱ/. In Esperanto, it is an official surrogate of ⟨ĵ⟩, which represents /ʒ/. In Latin American Spanish, it is sometimes used in first names (like Jhon and Jhordan) to represent /ɟʝ/ and distinguish it from the typical sound of ⟨j⟩ in Spanish, /x/. ⟨jj⟩ is used in Pinyin for /dʑ/ in languages such as Yi. In romanized Korean, it represents the fortis sound /tɕ͈/. In Hadza it is ejective /tʃʼ/. ⟨jö⟩ is used as a letter of the Seri alphabet, where it represents a labialized velar fricative, /xʷ/. It is placed between J and L in alphabetical order. ⟨jr⟩ is used in the General Alphabet of Cameroon Languages for /ɖʐ/. ⟨jx⟩ is used in Esperanto as an unofficial surrogate of ⟨ĵ⟩, which represents /ʒ/. == K == ⟨k'⟩ is used in Nuxalk for /kʼ/. ⟨kg⟩ is used for /kχ/ in southern African languages such as Setswana and Sotho. For instance, the Kalahari is spelled Kgalagadi /kχalaχadi/ in Setswana. ⟨kh⟩, in transcriptions of Indo-Aryan and Dravidian languages, represents the aspirated voiceless velar plosive (/kʰ/). For most other languages, it represents the voiceless velar fricative /x/, for example in transcriptions of the letter ḫāʾ (خ) in standard Arabic, standard Persian, and Urdu, Cyrillic Х, х (kha), Spanish ⟨j⟩, as well as the Hebrew letter kaf (כ‎) in instances when it is lenited. When used for transcription of the letter ḥet (ח‎) in Sephardic Hebrew, it represents the voiceless pharyngeal fricative /ħ/. In Canadian Tlingit it represents /qʰ/, which in Alaska is written k. In the Ossete Latin alphabet, it was used for /kʼ/. ⟨kj⟩ is used Swedish and Norwegian for /ɕ/ or /ç/. See also ⟨tj⟩. In Faroese, it represents /tʃ/. In the romanization of Macedonian, it represents /c/. ⟨kk⟩ is used in romanized Korean for the fortis sound /k͈/, in Haida (Bringhurst orthography) for ejective /kʼ/, and in Cypriot Arabic for /kʰː/. ⟨kl⟩ is used in Zulu to write a sound variously realized as /kʟ̥ʼ/ or /kxʼ/. ⟨km⟩ is used in Yélî Dnye doubly articulated and nasally released /k͡pŋ͡m/. ⟨kn⟩ is used in English to write the word-initial sound /n/ (formerly pronounced /kn/) in some words of Germanic origin, such as knee and knife. It is used in Yélî Dnye for nasally released /kŋ/. ⟨kp⟩ is used as a letter in some African languages, where it represents a voiceless labial-velar plosive /k͡p/. ⟨kr⟩ is used in Xhosa for /kxʼ/. ⟨ks⟩ is used in Cornish for either /ks/ or /ɡz/. ⟨ku⟩ is used in Purépecha for /kʷ/. It also had that value in the Ossete Latin alphabet. ⟨kv⟩ is used for /kwh/ in some dialects of Zhuang. ⟨kw⟩ is used in various languages for the labialized velar consonant /kʷ/, and in Dene Suline (Chipewyan) for /kwh/. Used informally in English for phonemic spelling of qu, as in kwik (from quick), ultimately from Proto-Indo-European /ɡʷ/. ⟨ḵw⟩ is used in Alaskan Tlingit for /qwh/, which in Canada is written ⟨khw⟩. ⟨kx⟩ in used in Nambikwara for a glottalized /kʔ/, and in Juǀʼhoan for the ejective /kxʼ/. ⟨ky⟩ is used in Tibetan Pinyin for /tʃʰ/. It is commonly used in Burmese romanization schemes to represent /tʃ/ (⟨ch⟩ is already used to represent aspirated /tʃʰ/). == L == ⟨lh⟩, in Occitan, Gallo, and Portuguese, represents a palatal lateral approximant /ʎ/. In many Indigenous languages of the Americas it represents a voiceless alveolar lateral fricative /ɬ/. In the transcription of Australian Aboriginal languages it represents a dental lateral, /l̪/. In the Gwoyeu Romatzyh romanization of Mandarin Chinese, initial ⟨lh⟩ indicates an even tone on a syllable beginning in /l/, which is otherwise spelled ⟨l⟩. In Middle Welsh it was sometimes used to represent the sound /ɬ/ as well as ⟨ll⟩, in modern Welsh it has been replaced by ⟨ll⟩. In Tibetan, it represents the voiceless alveolar lateral approximant /ɬ/, as in Lhasa. ⟨lj⟩ is a letter in some Slavic languages, such as the Latin orthographies of Serbo-Croatian, where it represents a palatal lateral approximant /ʎ/. For example, the word ljiljan is pronounced /ʎiʎan/. Ljudevit Gaj first used the digraph ⟨lj⟩ in 1830; he devised it by analogy with a Cyrillic digraph, which developed into the ligature ⟨љ⟩. In Swedish, it represents /j/ in initial position e.g. ljus. The sound /ʎ/ is written ⟨gl⟩ in Italian, in Castilian Spanish and Catalan as ⟨ll⟩, in Portuguese as ⟨lh⟩, in some Hungarian dialects as ⟨lly⟩, and in Latvian as ⟨ļ⟩. In Czech and Slovak, it is often transcribed as ⟨ľ⟩; it is used more frequently in the latter language. While there are dedicated Unicode codepoints, U+01C7 (Ǉ), U+01C8 (ǈ) and U+01C9 (ǉ), these are included for backwards compatibility (with legacy encodings for Serbo-Croatian which kept a one-to-one correspondence with Cyrillic Љљ) and modern texts use a sequence of Basic Latin characters. ⟨ll⟩ and ⟨l·l⟩ are used in several languages. See article. ⟨ḷḷ⟩ is used in Asturian for a sound that was historically /ʎ/ but which is now an affricate, [t͡s], [t͡ʃ], [d͡ʒ]. ⟨lr⟩ is used in the General Alphabet of Cameroon Languages for /ɭ /. ⟨lv⟩ is used in Yélî Dnye for doubly articulated /l͜β/. ⟨lw⟩ is used for /lʷ/ in Arrernte. ⟨lx⟩ in used in Nambikwara for a glottalized /ˀl/. ⟨ly⟩ is used in Hungarian. See article. == M == ⟨mb⟩, in many African languages, represents /mb/ or /ᵐb/. In English, it represents /m/ when final, as in lamb (see reduction of /mb/). In Standard Zhuang and in Bouyei, ⟨mb⟩ is used for /ɓ/. ⟨mb⟩ (capital ⟨mB⟩) is used word initially in Irish, as the eclipsis of ⟨b⟩, to represent /mˠ/ (beside ⟨a, o, u⟩) and /mʲ/ (beside ⟨e, i⟩); e.g. ár mbád /aːɾˠ mˠaːd̪ˠ/ "our boat" (cf. /bˠaːd̪ˠ/ "boat"), i mBaile Átha Cliath "in Dublin". ⟨md⟩ is used in Yélî Dnye for doubly articulated and prenasalized /n͡mt͡p/. ⟨mf⟩, in many African languages, represents /mf/ or /ᵐf/. ⟨mg⟩ is used in Pinyin for /ŋɡ/ in languages such as Yi, where the more common digraph ⟨ng⟩ is restricted to /ŋ/. It is used in Yélî Dnye for doubly articulated and prenasalized /ŋ͡mk͡p/. ⟨mh⟩ is used in Irish, as the lenition of ⟨m⟩, to represent /w/ (beside ⟨a, o, u⟩) and /vʲ/ (beside ⟨e, i⟩), e.g. mo mháthair /mˠə ˈwaːhəɾʲ/ "my mother" (cf. máthair /ˈmˠaːhəɾʲ/ 'mother'). In Scottish Gaelic, it represents /v/, or in a few contexts as /w/~/u/ between a broad vowel and a broad consonant or between two broad vowels, as in reamhar /rˠɛ̃ũ.əɾ/.. In Welsh it stands for the nasal mutation of ⟨p⟩ and represents the voiceless /m̥/; for example fy mhen /və m̥ɛn/ 'my head' (cf. pen /pɛn/ 'head'). In both languages it is considered a sequence of the two letters ⟨m⟩ and ⟨h⟩ for purposes of alphabetization. In Shona, Juǀʼhoan and several other languages, it is used for a murmured /m̤/. In the Gwoyeu Romatzyh romanization of Mandarin Chinese, initial ⟨mh⟩- indicates an even tone on a syllable beginning in /m/, which is otherwise spelled ⟨m⟩-. In several languages, such as Gogo, it's a voiceless /m̥/. ⟨ml⟩ is used in the Romanized Popular Alphabet used to write Hmong, where it represents the sound /mˡ/. ⟨mm⟩ is used in Haida (Bringhurst orthography) for glottalized /ˀm/. It is used in Cornish for an optionally pre-occluded /m/; that is, it is pronounced either /m/ or /mː/ (in any position); /ᵇm/ (before a consonant or finally); or /bm/ (before a vowel); examples are mamm ('mother') or hemma ('this'). ⟨mn⟩ is used in English to write the word-initial sound /n/ in a few words of Greek origin, such as mnemonic. When final, it represents /m/, as in damn or /im/ as in hymn, and between vowels it represents /m/ as in damning, or /mn/ as in damnation (see /mn/-reduction). In French it represents /n/, as in automne and condamner. ⟨mp⟩, in many African languages, represents /mp/ or /ᵐp/. Modern Greek uses the equivalent digraph μπ for /b/, as β is used for /v/. In Mpumpong of Cameroon, ⟨mp⟩ is a plain /p/. ⟨mq⟩ is used in Juǀʼhoan for a pharyngealized or perhaps creaky /m̰/. ⟨mt⟩ is used in Yélî Dnye for doubly articulated and prenasalized /n̪͡mt̪͡p/. ⟨mv⟩, in many African languages, represents /mv/ or /ᵐv/. ⟨mw⟩ is used for /mʷ/ in Arrernte. ⟨mx⟩ is used in Nambikwara for a glottalized /ˀm/. == N == ⟨nʼ⟩ is used in Xhosa and Shona for /ŋ/. Since ⟨ʼ⟩ is not a letter in either language, ⟨nʼ⟩ is not technically a digraph. ⟨nb⟩ is used in Pinyin for /mb/ in languages such as Yi. It is also used in Fula in Guinea for /ᵐb/ (written as ⟨mb⟩ in other countries). ⟨nc⟩ is used in various alphabets. In the Romanized Popular Alphabet used to write Hmong, it represents the sound /ɲɟ/. In Tharaka it is /ntʃ/. In Xhosa and Zulu it represents the click /ᵑǀ/. ⟨nd⟩ (capital ⟨Nd⟩) is used in many African languages to represent /nd/ or /ⁿd/. In Standard Zhuang and Bouyei, itrepresents /ɗ/. ⟨nd⟩ (capital ⟨nD⟩) is used word initially in Irish, as the eclipsis of ⟨d⟩, to represent /n̪ˠ/ (beside ⟨a, o, u⟩) and /n̠ʲ/ (beside ⟨e, i⟩), e.g. ár ndoras /aːɾˠ ˈn̪ˠɔɾˠəsˠ/ "our door" (cf. doras /ˈd̪ˠɔɾˠəsˠ/ "door"), i nDoire "in Derry". ⟨nf⟩, equivalent to ⟨mf⟩ for /mf/ or /ᵐf/. In Rangi ⟨nf⟩ is /ᵐf/ while ⟨mf⟩ is /m.f/. ⟨ng⟩, in Sino-Tibetan languages, as in English and several other European and derived orthographies (for example Vietnamese), generally represents the velar nasal /ŋ/. It is considered a single letter in many Austronesian languages (Māori, Tagalog, Tongan, Gilbertese, Tuvaluan, Indonesian, Chamorro), Welsh, and Rheinische Dokumenta, for velar nasal /ŋ/; and in some African languages (Lingala, Bambara, Wolof) for prenasalized /ɡ/ (/ⁿɡ/). For the development of the pronunciation of this digraph in English, see NG-coalescence and G-dropping. Finnish uses ⟨ng⟩ to represent the phonemically long velar nasal /ŋː/ in contrast to ⟨nk⟩ /ŋk/, which is its "strong" form under consonant gradation, a type of lenition. Weakening /k/ produces an archiphonemic "velar fricative", which, as a velar fricative does not exist in Standard Finnish, is assimilated to the preceding /ŋ/, producing /ŋː/. (No /ɡ/ is involved at any point, despite the spelling ⟨ng⟩). The digraph ⟨ng⟩ is not an independent letter, but it is an exception to the phonemic principle, one of the few in standard Finnish. ⟨ng⟩ (capital ⟨nG⟩) is used word-initially in Irish, as the eclipsis of ⟨g⟩, to represent /ŋ/ (beside ⟨a, o, u⟩) or /ɲ/ (beside ⟨e, i⟩), e.g. ár ngalar /aːɾˠ ˈŋalˠəɾˠ/ "our illness" (cf. /ˈɡalˠəɾˠ/), i nGaillimh "in Galway". In Tagalog and other Philippine languages, ⟨ng⟩ represented the prenasalized sequence /ŋɡ/ during the Spanish era. The velar nasal, /ŋ/, was written in a variety of ways, namely "n͠g", "ñg", "gñ" (as in Sagñay), and—after a vowel—at times "g̃". During the standardization of Tagalog in the early part of the 20th century, ⟨ng⟩ became used for the velar nasal /ŋ/, while prenasalized /ŋɡ/ came to be written ⟨ngg⟩. Furthermore, ⟨ng⟩ is also used for a common genitive particle pronounced /naŋ/, to differentiate it from an adverbial particle nang. In Uzbek, it is considered as a separate letter, being the last (twenty-ninth) letter of the Uzbek alphabet. It is followed by the apostrophe (tutuq belgisi). ⟨ńg⟩ is used in Central Alaskan Yup'ik to write the voiceless nasal sound /ŋ̊/. ⟨ñg⟩, or more precisely ⟨n͠g⟩, was a digraph in several Spanish-derived orthographies of the Pacific, such as Tagalog and Chamorro, where it represented the sound /ŋ/, as opposed to ⟨ng⟩, which originally represented /ŋɡ/. An example is Chamorro agan͠gñáijon (modern agangñaihon) "to declare". Besides ⟨ñg⟩, variants of ⟨n͠g⟩ include ⟨gñ⟩ (as in Sagñay), ⟨ng̃⟩, and a ⟨g̃⟩, that is preceded by a vowel (but not a consonant). It has since been replaced by the trigraph ⟨ngg⟩ or ⟨ng⟩ (see above). ⟨ngʼ⟩ is used for /ŋ/ in Swahili and languages with Swahili-based orthographies. Since ⟨ʼ⟩ is not a letter in Swahili, ⟨ngʼ⟩ is technically a digraph, not a trigraph. ⟨nh⟩ is used in several languages. See article. ⟨ni⟩ in Polish, it usually represents ɲ whenever it precedes a vowel, and ɲi whenever it precedes a consonant (or in the end of the word), and is considered a graphic variant of ń appearing in other situations. (In some cases it may represent also ɲj before a vowel; for a better description, when, see the relevant section in the article on Polish orthography). ⟨nj⟩ is a letter in the Latin orthographies of Albanian, Slovenian and Serbo-Croatian. Ljudevit Gaj, a Croat, first used this digraph in 1830. In all of these languages, it represents the palatal nasal /ɲ/. For example, the Croatian and Serbian word konj "horse" is pronounced /koɲ/. The digraph was created in the 19th century by analogy with a digraph of Cyrillic, which developed into the ligature ⟨њ⟩. While there are dedicated Unicode codepoints, U+01CA (Ǌ), U+01CB (ǋ) and U+01CC (ǌ), these are included for backwards compatibility (with legacy encodings for Serbo-Croatian which kept a one-to-one correspondence with Cyrillic Њњ) and modern texts use a sequence of Basic Latin characters. In Faroese, it generally represents /ɲ/, although in some words it represent /nj/, like in banjo. It is also used in some languages of Africa and Oceania where it represents a prenazalized voiced postalveolar affricate or fricative, /ⁿdʒ/ or /ⁿʒ/. In Malagasy, it represents /ⁿdz/. Other letters and digraphs of the Latin alphabet used for spelling this sound are ⟨ń⟩ (in Polish), ⟨ň⟩ (in Czech and Slovakian), ⟨ñ⟩ (in Spanish), ⟨nh⟩ (in Portuguese and Occitan), ⟨gn⟩ (in Italian and French), and ⟨ny⟩ (in Hungarian, among others). ⟨nk⟩ is used in many Bantu languages like Lingala, Tshiluba, and Kikongo, for /ŋk/ or /ᵑk/. In the transcription of Australian Aboriginal languages such as Warlpiri, Arrernte, and Pitjantjatjara, it distinguishes a prenasalized velar stop, /ŋ͡k ~ ŋ͡ɡ/, from the nasal /ŋ/. ⟨nm⟩ is used in Yélî Dnye for doubly articulated /n͡m/. ⟨ńm⟩ is used in Yélî Dnye for doubly articulated /n̪͡m/. ⟨nn⟩ is used in Irish to represent the fortis nasals /n̪ˠ/ (beside ⟨a, o, u⟩) and /n̠ʲ/ (beside ⟨e, i⟩). It is used in Scottish Gaelic to represent /n̪ˠ/ beside ⟨a, o, u⟩ and /ɲ/ beside ⟨e, i⟩. In Spanish historical ⟨nn⟩ has contracted to the ligature ⟨ñ⟩ and represents the sound /ɲ/. In the Gwoyeu Romatzyh romanization of Mandarin Chinese, final -nn indicates a falling tone on a syllable ending in /n/, which is otherwise spelled -n. It is used in Haida (Bringhurst orthography) for glottalized /ˀn/. In Piedmontese, it is /ŋn/ in the middle of a word, and /n/ at the end. In Cornish, it is used for an optionally pre-occluded /n/; that is, it is pronounced either /n/ or /nː/ (in any position); /ᵈn/ (before a consonant or finally); or /dn/ (before a vowel); examples are penn ('head') or pennow ('heads'). ⟨np⟩ is used in the Romanized Popular Alphabet used to write Hmong, where it represents the sound /mb/. ⟨nq⟩ is used in various alphabets. In the Romanized Popular Alphabet used to write Hmong, it represents the sound /ɴɢ/. In Xhosa and Zulu it represents the click /ᵑǃ/. In the Gwoyeu Romatzyh romanization of Mandarin Chinese, final -nq indicates a falling tone on a syllable ending in /ŋ/, which is otherwise spelled -ng. ⟨nr⟩ is used in the Romanized Popular Alphabet used to write Hmong, where it represents the sound /ɳɖ/. In the General Alphabet of Cameroon Languages it is /ɳ /. ⟨ns⟩, in many African languages, represents /ns/ or /ⁿs/. ⟨nt⟩ is a letter present in many African languages where it represents /nt/ or /ⁿt/. Modern Greek uses the equivalent digraph ντ for /d/, as δ is used for /ð/. ⟨nv⟩, equivalent to ⟨mv⟩ for /mv/ or /ᵐv/. ⟨nw⟩ is used in Igbo for /ŋʷ/, and in Arrernte for /nʷ/. ⟨nx⟩ is used for the click /ᵑǁ/ in Xhosa and Zulu, and in Nambikwara for a glottalized /ˀn/. ⟨ny⟩ is used in several languages for /ɲ/. See article. ⟨nz⟩, in many African languages, represents /nz/ ~ /ⁿz/, /ndz/ ~ /ⁿdz/, /nʒ/ ~ /ⁿʒ/, or /ndʒ/ ~ /ⁿdʒ/. ⟨nǃ⟩ is used in Juǀʼhoan for the alveolar nasal click /ᵑǃ/. ⟨nǀ⟩ is used in Juǀʼhoan for the dental nasal click /ᵑǀ/. ⟨nǁ⟩ is used in Juǀʼhoan for the lateral nasal click /ᵑǁ/. ⟨nǂ⟩ is used in Juǀʼhoan for the palatal nasal click /ᵑǂ/. ⟨n-⟩ is used for medial /ŋ/ in Piedmontese. == O == ⟨o′⟩ is used for /o/ and /ø/ in Uzbek, with the preferred typographical form being ⟨oʻ⟩ (Cyrillic ⟨ў⟩). Technically it is not a digraph in Uzbek, since ⟨ʻ⟩ is not a letter of the Uzbek alphabet, but rather a typographic convention for a diacritic. In handwriting the letter is written as ⟨õ⟩. It is also used in Taa, for the glottalized or creaky vowel /o̰/. ⟨oa⟩ is used in English, where it commonly represents the /oʊ/ sound as in road, coal, boast, coaxing, etc. In Middle English, where the digraph originated, it represented /ɔː/, a pronunciation retained in the word broad and derivatives, and when the digraph is followed by an "r", as in soar and bezoar. The letters also represent two vowels, as in koala /oʊ.ɑː/, boas /oʊ.ə/, coaxial /oʊ.æ/, oasis /oʊ.eɪ/, and doable /uː.ə/. In Malagasy, it is occasionally used for /o/. ⟨oe⟩ is found in many languages. In English, it represents the /oʊ/ sound as in hoe and sometimes the /uː/ sound as in shoe. It may also represent the /ɛ/ sound in AmE pronunciation of Oedipus, (o)esophagus (also in BrE), and (o)estrogen, /eɪ/ in boehmite (AmE) and surnames like Boehner and Groening (as if spelled Bayner and Gray/Greyning respectively), and /iː/ in foetus (BrE and CoE) and some speakers' pronunciation of Oedipus and oestrogen. ⟨oe⟩ represents /u/ in Afrikaans and Dutch, e.g. doen; it also represented the same phoneme in the Indonesian language before the 1972 spelling reform. Ligatured to ⟨œ⟩ in French, it stands for the vowels /œ/ (as in œil /œj/) and /e/ (as in œsophage /ezɔfaʒ ~ øzɔfaʒ/). It is an alternative way to write ⟨ö⟩ or ⟨ø⟩ in German or Scandinavian languages when this character is unavailable. In romanization of Wu Chinese and in Royal Thai General System of Transcription, it represents /ɤ/. In the ILE romanization of Cantonese it represents the vowel /ɵ ~ œː/, while in the Jyutping romanisation of Cantonese it represents /œː/, and in Zhuang it is used for /o/ (⟨o⟩ is used for /oː/). In Piedmontese, it is /wɛ/. In the Kernewek Kemmyn orthography of Cornish, it is used for a phoneme which is [oː] long, [oˑ] mid-length, and [ɤ] short. ⟨oê⟩ is used in French to write the vowel sound /wa/ in a few words before what had historically been an ⟨s⟩, mostly in words derived from poêle /pwal/ "stove". The diacriticless variant, ⟨oe⟩, rarely represents this sound except in words related to moelle /mwal/ (rarely spelt moëlle). ⟨ôe⟩ is used in Afrikaans for the vowel /ɔː/. ⟨õe⟩ is used in Portuguese for /õĩ̯/. It is used in plural forms of some words ended in ⟨ão⟩, such as anão–anões and campeão–campeões. ⟨oh⟩ is used in Taa, for the breathy or murmured vowel /o̤/. ⟨oi⟩ is used in various languages. In English, it represents the /ɔɪ̯/ sound as in coin and join. In French, it represents /wa/, which was historically – and still is in some cases – written ⟨oy⟩. In Irish it is used for /ɛ/, /ɔ/, /ɪ/, /əi̯/, /iː/, /oː/ between a broad and a slender consonant. In Scottish Gaelic it is used for /ɔ/, /ɤ/, except before ⟨ll, m, nn⟩ word-finally or pre-consonant, where it is /əi/. In Piedmontese, it is /ui̯/. ⟨oí⟩ is used in Irish for /iː/ between a broad and a slender consonant. ⟨oî⟩ is used in French to write /wa/ before what had historically been an ⟨s⟩, as in boîtier or cloître. ⟨ói⟩ is used in Irish for /oː/ between a broad and a slender consonant. It is also used in Portuguese. ⟨òi⟩ is used in Piedmontese for /oi̯/. It is used in Scottish Gaelic for /oː/ or /ɔː/ ⟨om⟩ is used in Portuguese for /õ/, and in French to write /ɔ̃/. ⟨ôm⟩ is used in Brazilian Portuguese for /õ/ before a consonant. ⟨on⟩ is used in Portuguese for /õ/ before a consonant, and in French to write /ɔ̃/. ⟨ôn⟩ is used in Portuguese for /õ/ before a consonant. ⟨ön⟩ is used in Tibetan Pinyin for /ø̃/. It is alternately written oin. ⟨oo⟩ is used in many languages. In English, it generally represents sounds which historically descend from the Middle English pronunciation /oː/. After the Great Vowel Shift, this came to typically represent /uː/ as in "moon" and "food". Subsequently, in a handful of common words like "good" and "flood" the vowel was shortened to ⟨/u/⟩, and after the Middle English FOOT–STRUT split, these became /ʊ/ and /ʌ/ respectively. Like in Middle English, the digraph's pronunciation is /oː/ in most other languages. In German and Dutch, the digraph represents /oː/. In Cornish, it represents either /oː/ or /uː/. In Tâi-lô orthography for Taiwanese Hokkien, it represents /ɔ/. ⟨oq⟩ Is used in Taa, for the pharyngealized vowel /oˤ/. ⟨or⟩, in Daighi tongiong pingim, represents mid central vowel /ə/ or close-mid back rounded vowel /o/ in Taiwanese Hokkien. ⟨ou⟩ is used in English for the diphthong /aʊ/, as in out /aʊt/. This spelling is generally used before consonants, with ⟨ow⟩ being used instead before vowels and at the ends of words. Occasionally ⟨ou⟩ may also represent other vowels – /ʌ/ as in trouble, /oʊ/ as in soul, /ʊ/ as in would, /uː/ as in group, or /juː/ as in the alternate American pronunciation of coupon. The ⟨ou⟩ in out originally represented /uː/, as in French, and its pronunciation has mostly changed as part of the Great Vowel Shift. However, the /uː/ sound was kept before ⟨p⟩. In Dutch ⟨ou⟩ represents /ʌu/ in the Netherlands or /oʊ/ in Flanders. In Cornish, it represents [uː], [u], or [ʊ]. In French, it represents the vowel /u/, as in vous /vu/ "you", or the approximant consonant /w/, as in oui /wi/ "yes". In Portuguese this digraph stands for the close-mid back rounded vowel /o/ or for the falling diphthong /ou/, according to dialect. ⟨ou⟩ is used In Hepburn romanization of the Japanese language to transcribe the sound /oː/. ⟨oû⟩ is used in French to write the vowel sound /u/ before what had historically been an ⟨s⟩, as in soûl /su/ "drunk" (also spelt soul). ⟨ow⟩, in English, usually represents the /aʊ/ sound as in coward, sundowner, and now or the /oʊ/ sound, as in froward, landowner, and know. An exceptional pronunciation is /ɒ/ in knowledge and rowlock. There are many English heteronyms distinguished only by the pronunciation of this digraph, like: bow (front of ship or weapon), bower (a dwelling or string player), lower (to frown or drop), mow (to grimace or cut), row (a dispute or line-up), shower (rain or presenter), sow (a pig or to seed), tower (a building or towboat). In Cornish, this represents the diphthong /ɔʊ/ or /oʊ/; before vowels, it can also represent /uː/. ⟨ôw⟩ is used in the Kernowek Standard orthography of Cornish to refer to a sound that can be either /ɛʊ/ or /oʊ/. This distribution can also be written ⟨êw⟩. ⟨oy⟩ is found in many languages. In English and Faroese, ⟨oy⟩ represents the diphthong /ɔɪ/. Examples in English include toy and annoy. In Cornish, it represents the diphthong /oɪ/~/ɔɪ/; in the words oy ('egg') and moy ('much'), it can also be pronounced /uɪ/~/ʊɪ/. ⟨oŷ⟩ is an obsolete digraph once used in French. ⟨øy⟩ is used in Norwegian for /øʏ/. ⟨o_e⟩ (a split digraph) indicates an English 'long o', historically /ɔ:/ but now most commonly realised as /oʊ/. == P == ⟨p'⟩ is used in Nuxalk for /pʼ/. ⟨pf⟩ is used in German for /pf/, e.g. Pferd "horse", Apfel "apple", and Knopf "button". In English, usually in recent loan words from German, it generally represents /f/, such as in Pfizer. ⟨ph⟩ in used in English and French for /f/, mostly in words derived from Greek, but also some words derived from Vietnamese. In Irish, Scottish Gaelic and Welsh it represents the lenition/Aspirate mutation of ⟨p⟩. It represents /f/ in Vietnamese, where ⟨f⟩ is not used. ⟨pl⟩ is used in the Romanized Popular Alphabet used to write Hmong, for /pˡ/. ⟨pm⟩ is used for /ᵖm/ in Arrernte. ⟨pn⟩ is used in English for /n/ initially in words of Greek origin such as pneumatic. ⟨pp⟩ is used in romanized Korean for the fortis sound /p͈/, and in Cypriot Arabic for /pʰː/. It was used in Portuguese until 1947, e.g. guardanappo, appa and mappelido. ⟨ps⟩ is used in English and Portuguese for /s/ initially in words of Greek origin such as psyche (English) and Psychòtico (Portuguese). In Shona it represents a whistled sibilant cluster /ps͎/. ⟨pt⟩ is used in several languages for /t/ in words of Greek origin, where it was /pt/, e.g. in English pterosaur /ˈtɛrəsɔːr/. ⟨pw⟩ is used in Arrernte for /pʷ/. ⟨py⟩ is used in Cypriot Arabic for /pc/. == Q == ⟨q'⟩ is used in Nuxalk for /qʼ/. ⟨qg⟩ is used in Naro for the click /ǃχ/. It was used in the Tindall orthography of Khoekhoe for the voiceless alveolar click /ǃ/. ⟨qh⟩ is used in various alphabets. In Quechua and the Romanized Popular Alphabet used to write Hmong, it represents /qʰ/. In Xhosa, it represents the click /ǃʰ/. ⟨qk⟩ was used in the Tindall orthography of Khoekhoe for the voiceless alveolar click /ǃ/ (equivalent to ⟨qg⟩). ⟨qq⟩ is used in Haida (Bringhurst orthography) for ejective /qʼ/. In Hadza it represents the glottalized click /ᵑǃˀ/. ⟨qu⟩ is used in Aragonese, Asturian, Catalan, French, Galician, Mirandese, Occitan, Portuguese and Spanish for /k/ before ⟨e, i⟩, where ⟨c⟩ represents /θ/ (Castilian Spanish, Asturian, Aragonese and most of Galicia) or /s/ (Catalan, French, American Spanish, Occitan and Portuguese). In French, ⟨qu⟩ is also usually /k/ before ⟨a, o⟩. This dates to Latin ⟨qu⟩, and ultimately the Proto-Indo-European labialized velar consonant /kʷ/; in English this sound instead became written primarily as ⟨wh⟩, due to Grimm's law changing kʷ > xʷ (written ⟨hw⟩), and Middle English spelling change switching ⟨hw⟩ to ⟨wh⟩. In English, it represents /k/ in words derived from those languages (e.g., quiche), and /kw/ in other words, including borrowings from Latin (e.g., quantity). In German, it represents /kv/. In the Ossetian Latin alphabet, it was used for /qʷ/. In Vietnamese it is used to represent /kw/ or /w/. In Cornish, it represents /kw/. ⟨qü⟩ is used in French and formely Portuguese for /kw/ before ⟨e, i⟩. ⟨qv⟩ is used in Bouyei for /ˀw/. ⟨qw⟩ is used in some languages for /qʷ/. In Mi'kmaq it represents /xʷ/. In the Kernowek Standard and Standard Written Form orthographies for Revived Cornish, it represents /kw/. ⟨qy⟩ is used in Bouyei for glottalized /ˀj/. == R == ⟨rd⟩ is used in the transcription of Australian Aboriginal languages such as Warlpiri, Arrernte, and Pitjantjatjara for a retroflex stop, /ʈ/. In Norwegian and Swedish it represents voiced retroflex plosive, [ɖ]. In Scottish Gaelic it sometimes represents /rˠʃt̪/ when broad, or /rˠʃtʲ/ when slender, though this epenthetic consonant is not found in all dialects. ⟨rh⟩ is used in English for Greek words transliterated through Latin. Examples include "rhapsody", "rhetoric" and "rhythm". These were pronounced in Ancient Greek with a voiceless "r" sound, /r̥/, as in Old English ⟨hr⟩. The digraph may also be found within words, but always at the start of a word component, e.g., "polyrhythmic". German, French, and Interlingua use ⟨rh⟩ in the same way. ⟨Rh⟩ is also found in Welsh where it represents a voiceless alveolar trill (r̥), that is a voiceless "r" sound. It can be found anywhere; the most common occurrence in English from Welsh is in the slightly respelled given name "Rhonda". In Wade-Giles transliteration, ⟨rh⟩ is used for the syllable-final rhotic of Mandarin Chinese. In the Gwoyeu Romatzyh romanization of Mandarin Chinese, initial ⟨rh⟩- indicates an even tone on a syllable beginning in /ʐ/, which is otherwise spelled ⟨r⟩-. In Purépecha, it is a retroflex flap, /ɽ/. ⟨rl⟩ is used in the transcription of Australian Aboriginal languages such as Warlpiri, Arrernte, and Pitjantjatjara, as well in Norwegian and Swedish, for a retroflex lateral, written /ɭ/ in the IPA. In Greenlandic, it represents /ɬː/ as the result of an assimilation of a consonant cluster with a uvular consonant as the first component. ⟨rm⟩ is used in Inuktitut for /ɴm/. ⟨rn⟩ represents the retroflex nasal /ɳ/ in Warlpiri, Arrernte, and Pitjantjatjara (see transcription of Australian Aboriginal languages), as well in Norwegian and Swedish. In Greenlandic, it represents /ɴ/. In Inuktitut, it represents /ɴn/. ⟨rp⟩ is used in Greenlandic for /pː/ as the result of an assimilation of a consonant cluster with a uvular consonant as the first component. ⟨rr⟩ is used in English for ⟨r⟩. It normally appears in words of Latin or Romance origin, and ⟨rrh⟩ in words of ancient Greek origin. It is quite a common digraph. Some words with ⟨rr⟩ are relatively recent loanwords from other languages; examples include burro from Spanish. It is often used in impromptu pronunciation guides to denote either an alveolar tap or an alveolar trill. It is a letter in the Albanian alphabet. In several European languages, such as Catalan, Spanish, Portuguese, Basque or Albanian, "rr" represents the alveolar trill /r/ (or the voiced uvular fricative /ʁ/ in Portuguese) and contrasts with the single "r", which represents the alveolar tap /ɾ/ (in Catalan and Spanish a single "r" also represents the alveolar trill at the beginning of words or syllables). In Italian and Finnish, "rr" is a geminated (long) consonant /rː/. In Central Alaskan Yup'ik it is used for /χ/. In Cornish, it can represent either /rː/, /ɾʰ/, or /ɹ/. In Scottish Gaelic, it represents /rˠ/. ⟨rs⟩ was equivalent to ⟨rz⟩ and stood for /r̝/ (modern ř) in medieval Czech. In Greenlandic, it represents /sː/ as the result of an assimilation of a consonant cluster with a uvular consonant as the first component. In Norwegian and Swedish, it represents the voiceless retroflex fricative, [ʂ]. ⟨rt⟩ is used in Australian Aboriginal languages such as Warlpiri, Arrernte, and Pitjantjatjara, as well in Norwegian and Swedish, for a retroflex stop /ʈ/. In Scottish Gaelic it often represents /rˠʃt̪/ when broad, or /rˠʃtʲ/ when slender, though this epenthetic consonant is not found in all dialects. ⟨rw⟩ is used for /ɻʷ/ in Arrernte. ⟨rz⟩ is used in Polish and Kashubian for a voiced retroflex fricative /ʐ/, similar to English ⟨zh⟩ as in Zhivago. Examples from Polish are marzec /ˈma.ʐɛt͡s/ "March" and rzeka /ˈʐɛ.ka/ "river". ⟨rz⟩ represents the same sound as ⟨ż⟩, but they have a different origin. ⟨rz⟩ used to be pronounced the same way as Czech ⟨ř⟩ (/r̝/) in older Polish, but the sounds merged, and the orthography still follows etymology. When preceded by a voiceless consonant (⟨ch, k, p, t⟩) or end of a word, ⟨rz⟩ devoices to [ʂ], as in przed /ˈpʂɛt/ "before". == S == ⟨sc⟩ is used in Italian for /ʃː/ before the front vowel letters ⟨e, i⟩. It is used for /s/ in Catalan, Latin American Spanish, French, English, Occitan and Brazilian Portuguese (e.g. French/English reminiscence, Spanish reminiscencia, Brazilian Portuguese reminiscência, Catalan reminiscència, Occitan reminiscéncia); in European Portuguese this changed to /ʃ/ in the early 20th century, although in careful speech it can be /ʃs/. However, it represents /z/ in modern pronunciations of crescent in British and non-Canadian Commonwealth English. In Old English it usually represented /ʃ/. ⟨sç⟩ is used in French for /s/ in a few verb forms such as simple past acquiesça /akjɛsa/. It is also used in Portuguese as in the imperative/conjunctive form of verbs ending with ⟨scer⟩: crescer cresça. Still pronounced /s/ in Brazilian Portuguese, in European Portuguese this changed to /ʃ/ in the early 20th century, although in careful speech it can be /ʃs/. ⟨sg⟩ is used in Piedmontese and Corsican for /ʒ/. ⟨sh⟩ is used in several languages. In English, it represents /ʃ/. See separate article. See also ⟨ſh⟩ below, which has the capitalized forms SH and ŞH. ⟨si⟩ is used in English for /ʒ/ in words such as fusion (see yod-coalescence). In Polish, it represents /ɕ/ whenever it precedes a vowel, and /ɕi/ whenever it precedes a consonant (or at the end of the word), and is considered a graphic variant of ⟨ś⟩ appearing in other situations. In Welsh ⟨si⟩ is used for the sound /ʃ/ as in siocled /ʃɔklɛd/ ('chocolate'). ⟨sj⟩ is used Swedish to write the sje sound /ɧ/ (see also ⟨sk⟩) and in Faroese, Danish, Norwegian and Dutch to write Voiceless postalveolar fricative /ʃ/. ⟨sk⟩ is used in Swedish to write the sje sound /ɧ/. It takes by rule this sound value before the front vowels (⟨e, i, y, ä, ö⟩) word or root initially (as in sked (spoon)), while normally representing /sk/ in other positions. In Norwegian and Faroese, it is used to write voiceless postalveolar fricative /ʃ/ (only in front of ⟨i, y, ei, øy/oy⟩). ⟨sl⟩ is used in Iraqw and Bouyei to write the lateral fricative /ɬ/. (⟨sl⟩ is used in the French tradition to transcribe /ɬ/ in other languages as well, as in the General Alphabet of Cameroon Languages.) ⟨sp⟩ is used in German for /ʃp/ as in Spaß /ʃpaːs/ instead of using ⟨schp⟩. ⟨sr⟩ is used in Kosraean for /ʂ/. In northern dialects of Scottish Gaelic it represents /s̪t̪ɾ/, as in sràid /s̪t̪ɾaːtʲ/. ⟨ss⟩ is used in Pinyin for /z/ in languages such as Yi. For its use in the Wade–Giles system of Romanization of Chinese, see Wade–Giles → Syllabic consonants. In English, ⟨ss⟩ typically represents /z/ in the first ⟨ss⟩ of possess and its derivatives possessed, possesses, possession, possessive and possessor, brassiere, dessert, dissolution and its derivatives dissolved, dissolves and dissolving, Missoula (County), Missouri(an), scissors, and pronunciations of Aussie outside the United States; otherwise, it represents /s/. In other languages, such as Catalan, Cornish, French, German, Italian, Occitan, Portuguese and Central Alaskan Yup'ik, where ⟨s⟩ transcribes /z/ between vowels (and elsewhere in the case of Yup'ik), ⟨ss⟩ is used for /s/ in that position (/sː/ in Italian and also in some cases in Cornish); English sometimes also follows this convention. In romanized Korean, it represents the fortis sound /s͈/. In Cypriot Arabic it is used for /sʰː/. Also to note, there are spellings of words with ⟨ss⟩ as opposed to them with just one ⟨s⟩, varied in different types of English. For the word focus, in British English the 3rd person singular, the past participle and the present participle are spelled with ⟨ss⟩ (i.e. focusses, focussed and focussing) whereas in American English and usually Canadian and Australian English they are spelled with one ⟨s⟩ (i.e. focuses, focused and focusing). ⟨st⟩ is used in German for /ʃt/ as in Stadt /ʃtat/ instead of using ⟨scht⟩ (or ⟨cht⟩). In some parts of northern Germany, the pronunciation /st/ (as in English) is still quite common in the local dialect. ⟨sv⟩ is used in Shona to write the whistled sibilant /s͎/. This was written ⟨ȿ⟩ from 1931 to 1955. ⟨sx⟩ is used in Nambikwara for a glottalized /sʔ/, and in Esperanto orthography it is an unofficial surrogate of ⟨ŝ⟩, that represents /ʃ/. ⟨sy⟩ represents /ʃ/ in Malay and Tagalog. ⟨sz⟩ is used in several languages. See article. ⟨s-c⟩ and ⟨s-cc⟩ are used in Piedmontese for the sequence /stʃ/. ⟨s-g⟩ and ⟨s-gg⟩ are used in Piedmontese for the sequence /zdʒ/. == T == ⟨t'⟩ is used in Nuxalk for /tʼ/. ⟨tc⟩ is used for the palatal click /ǂ/ in Naro, and to write the affricate /tʃ/ in Sandawe, Hadza and Juǀʼhoan. ⟨tf⟩ is used in the General Alphabet of Cameroon Languages for the voiceless dental affricate /t͡θ/ ⟨tg⟩ is used for /tχ/ in Naro. In Catalan, it represents /d͡ʒ/. In Romansh orthographies it represents the Alveolo-palatal consonant /tɕ/. ⟨th⟩ is used in several languages. In English, it can represent /ð/, /θ/ or /t/. See article. See also: Pronunciation of English th. ⟨ti⟩, before a vowel, is usually pronounced /sj/ in French and /tsj/ in German and is commonly /ʃ/ in English, especially in the suffix -tion. ⟨tj⟩ is used in Norwegian and Faroese words like tjære/tjøra ('tar') for /ç/ (Norwegian) and /tʃ/ (Faroese). In the closely related Swedish alphabet, it represents /ɕ/, as in tjära /ˈɕæːɾa/. It is also the standard written form of the /tʃ/ sound in Dutch and was likewise used in Dutch-based orthographies that used to apply for languages in Indonesia and Surinam. In the transcription of Australian Aboriginal languages such as Warlpiri, Arrernte, and Pitjantjatjara, it represents a postalveolar stop, transcribed in the International Phonetic Alphabet as /ṯ/ or /ḏ/ depending on voicing. This sound is also written ⟨dj⟩, ⟨ty⟩, ⟨dy⟩, ⟨c⟩, or ⟨j⟩. In Catalan it represents /d͡ʒ/. In Juǀʼhoan it is used for the ejective affricate /tʃʼ/. ⟨tk⟩ is used in Juǀʼhoan for the uvularized ejective /tᵡʼ/. ⟨tl⟩ is used in various orthographies for the voiceless alveolar lateral affricate /tɬ/. In Catalan it represents /lː/, although it may be simplify to /l/ in some dialects. ⟨tł⟩ is used in the transcription of Athabascan languages for a lateral affricate /tɬ/ or /tɬʰ/. ⟨tm⟩ is used in Yélî Dnye for doubly articulated and nasally released /t̪͡pn̪͡m/. In Catalan, it is used to represent /mː/, that can result not geminated as well, /m/, as in setmana (pronounced /səˈmːanə/ in standard Catalan and /seˈmana/ in Valencian). ⟨tn⟩ is used for a prestopped nasal /ᵗn/ in Arrernte, and for the similar /t̪n̪/ in Yélî Dnye. In Catalan it represents /nː/, although it may be simplify to /n/ in some dialects. ⟨tp⟩ is used in Yélî Dnye for doubly articulated /t̪͡p/. ⟨tr⟩ generally represents a sound like a retroflex version of English "ch" in areas of German influence, such as Truk lagoon, now spelled ⟨chuuk⟩. For instance, in Malagasy it represents /tʂ/. In southern dialects of Vietnamese, ⟨tr⟩ represents a voiceless retroflex affricate /tʂ/. In the northern dialects, this sound is pronounced /tɕ/, just like what ⟨ch⟩ represents. ⟨tr⟩ was formerly considered a distinct letter of the Vietnamese alphabet, but today is not. ⟨ts⟩ is used in the Basque, where it represents an apical voiceless alveolar affricate /t̺s̺/. It contrasts with ⟨tz⟩, which is laminal /t̻s̻/. It is mainly used to Latinize the letter Tse (Cyrillic) (ц) In Hausa, ⟨ts⟩ represents an alveolar ejective fricative /sʼ/ or affricate /tsʼ/), depending on dialect. It is considered a distinct letter, and placed between ⟨t⟩ and ⟨u⟩ in alphabetical order. It is also used in Catalan for /t͡s/. It is also used in Hausa Boko. In central-western Asturian it's used for /t͡s/. The Wade-Giles and Yale romanizations of Chinese use ⟨ts⟩ for an unaspirated voiceless alveolar affricate /ts/. Wade–Giles also uses ⟨ts'⟩ for the aspirated equivalent /tsʰ/. These are equivalent to Pinyin ⟨z⟩ and ⟨c⟩, respectively. The Hepburn romanization of Japanese uses ⟨ts⟩ for a voiceless alveolar affricate /ts/). In native Japanese words, this sound only occurs before ⟨u⟩, but it may occur before other vowels in loanwords. Other romanization systems write /tsu/ as ⟨tu⟩. ⟨Ts⟩ in Tagalog is used for /tʃ/. The sequence ⟨ts⟩ occurs in English, but it has no special function and simply represents a sequence of ⟨t⟩ and ⟨s⟩. It occurs word-initially only in some loanwords, such as tsunami and tsar. Most English-speakers do not pronounce a /t/ in such words and pronounce them as if they were spelled ⟨sunami⟩ and ⟨sar⟩ or ⟨zar⟩, respectively. ⟨ts̃⟩ was used in medieval Basque and in Azkue's Basque dictionary for a voiceless postalveolar affricate /t͡ʃ/; this is now represented by ⟨tx⟩. ⟨tt⟩ is used in Basque for /c/, and in romanized Kabyle for /ts/. In romanized Korean, it represents the fortis sound /t͈/, in Haida (Bringhurst orthography) it is ejective /tʼ/, and in Cypriot Arabic, it represents /tʰː/. ⟨tw⟩ is used for /tʷ/ in Arrernte. ⟨tx⟩ is used in Basque, Catalan and some indigenous languages of South America, for a voiceless postalveolar affricate /t͡ʃ/. In Nambikwara it represents a glottalized /tʔ/. In Juǀʼhoan it is used for the uvularized-release /tᵡ/. ⟨ty⟩ is used in the Hungarian alphabet for /cç/, a voiceless palatal affricate; in Hungarian, digraphs are considered single letters, and acronyms keep them intact. In Xhosa, ⟨ty⟩ represents /tʲʼ/ and the similar /tʲʼ/ in the Algonquian Massachusett orthography. In Shona, it represents /tʃk/. In Tagalog it represents /tʃ/. In the transcription of Australian Aboriginal languages such as Warlpiri, and Arrernte, it represents a postalveolar stop, either voiceless /ṯ/ or voiced /ḏ/. (This sound is also written ⟨tj⟩, ⟨dj⟩, ⟨dy⟩, ⟨c⟩, and ⟨j⟩). In Cypriot Arabic, it represents /c/. ⟨tz⟩ is used in Basque, German and Nahuatl for the voiceless alveolar affricate /t͡s/). In Basque, this sound is laminal and contrasts with the apical affricate represented by ⟨ts⟩. It is also used in Catalan to represent the voiced alveolar affricate /d͡z/. In Juǀʼhoan it is used for the ejective affricate /tsʼ/. For its use in the Wade–Giles system of Romanization of Chinese, see Wade–Giles → Syllabic consonants. == U == ⟨u′⟩ is used in Taa for the glottalized or creaky vowel /ṵ/. ⟨ua⟩ is used in Irish, Scottish Gaelic, and the Romanized Popular Alphabet used to write Hmong, to represent the diphthong /uə/. ⟨uc⟩ is used in Nahuatl for /kʷ/ before a consonant. Before a vowel, ⟨cu⟩ is used. ⟨ue⟩ is found in many languages. In English, it represents /juː/ or /uː/ as in cue or true, respectively. In German, it is /ʏ/ or /yː/ (equivalent to ⟨ü⟩), appearing mainly in proper nouns. In Cantonese Romanisation, it represents /yː/ in a non-initial position. ⟨ûe⟩ is used in Afrikaans to represent /œː/. ⟨ug⟩ is used in Central Alaskan Yup'ik for /ɣʷ/. ⟨uh⟩ is used in Taa for the breathy or murmured vowel /ṳ/. In Nahuatl, it is used for /w/ before a consonant. Before a vowel, ⟨hu⟩ is used. ⟨ui⟩ is used in Dutch for the diphthong /œy/. In Irish, it is /ɪ/ after a broad (velarized) consonant. In Scottish Gaelic it normally represents /u/, however before ⟨m, n, ng, s⟩ or before ⟨ll, m, nn⟩ preceding a vowel, it represents /ɯ/, and before ⟨dh⟩ or before ⟨ll, m, nn⟩ word-finally or pre-consonant, it represents /ɯi/. In German, it represents the diphthong /ʊɪ̯/, which appears only in interjections such as 'pfui!'. In Mandarin pinyin, it is used for /wei̯/ after a consonant (spelt ⟨wei⟩ in the initial position). In Cantonese Romanisation, it represents /uːy/ or /ɵy/. In Scots it represents /ø/, e.g. bluid "blood", duin "done", muin "moon" and spuin "spoon". In English, when used as a digraph, it represents /uː/ in fruit, juice, suit and pursuit. However, after ⟨g⟩, the ⟨u⟩ functions as a modifier (marking ⟨g⟩ as /ɡ/ rather than /dʒ/), e.g. guild, guilty, sanguine, Guinea, guide etc.), it is also used for other sounds, in cases of unusual etymological spelling, e.g. circuit, biscuit, build. In Portuguese, it represents the diphthong /ui̯/, as in intuito "intention" or cuidar "to care", but in a very small selective group of words that come from Latin multus "much", it represents a nasalized /ũĩ̯/, as in muito "very" or "much". ⟨ũi⟩ was used in old Portuguese for /ũĩ̯/, which in some dialects gets reduced to /ũː/ ⟨uĩ⟩ was used in old Portuguese for /wĩː/ ⟨uí⟩ is used in Irish for /iː/ between a broad and a slender consonant. ⟨úi⟩ is used in Irish for /uː/ between a broad and a slender consonant. ⟨ùi⟩ is used in Scottish Gaelic for /uː/ between a broad and a slender consonant. ⟨um⟩ is used in Portuguese for /ũ/, and in French to write /œ̃/ (only before a consonant and at the end of a word). ⟨úm⟩ is used in Portuguese for /ũ/ before a consonant. ⟨un⟩ is used in many languages for a nasal vowel. In Portuguese before a consonant, and in many West African languages, it is /ũ/, while in French it is /œ̃/, or among the younger generation /ɛ̃/. In pinyin, /u̯ən/ is spelled ⟨un⟩ after a consonant, ⟨wen⟩ initially. ⟨ún⟩ is used in Portuguese for /ũ/ before a consonant. ⟨ün⟩ is used in Tibetan Pinyin for /ỹ/. ⟨uŋ⟩ is used in Lakhota for the nasal vowel /ũ/. ⟨uo⟩ is used in Pinyin for /o/ in languages such as Yi, where ⟨o⟩ stands for /ɔ/. ⟨uq⟩ is used in Taa, for the pharyngealized vowel /uˤ/. ⟨ur⟩ is used in Central Alaskan Yup'ik for /ʁʷ/, and in Pinyin to write the trilled vowel /ʙ̝/ in languages such as Yi. ⟨uu⟩ is used in many languages with phonemic long vowels, for /uː/. In Dutch, it is used for /y/. ⟨uw⟩ is used in Dutch for /yu̯/, e.g. uw "yours", duwen "to push". In Cornish it is used for /iʊ/ or /yʊ/. ⟨uy⟩ is used in Afrikaans for /œy/. ⟨ux⟩ is unofficially used in Esperanto, instead of ⟨ŭ⟩, for /u̯/. ⟨u_e⟩ (a split digraph) is used in English for /juː/ or /uː/. == V == ⟨vb⟩ is used in the General Alphabet of Cameroon Languages for the labiodental flap /ⱱ/. ⟨vg⟩ was used in the Tindall orthography of Khoekhoe for the voiceless palatal click /ǂ/. ⟨vh⟩ represents /v̤/ in Shona. It was also used in the Tindall orthography of Khoekhoe for the aspirated palatal click /ǂʰ/. ⟨vk⟩ was used in the Tindall orthography of Khoekhoe for the voiceless palatal click /ǂ/ (equivalent to ⟨vg⟩). ⟨vn⟩ was used in the Tindall orthography of Khoekhoe for the palatal nasal click /ᵑǂ/. ⟨vv⟩ is used in Central Alaskan Yup'ik for /f/. ⟨vr⟩ is used in Quechua. == W == ⟨wh⟩ is used in English to represent Proto-Germanic /hw/, the continuation of the PIE labiovelar */kʷ/ (which became ⟨qu⟩ in Latin and the Romance languages). Most English question words begin with this digraph, hence the terms wh-word and wh-question. In Old English, /hw/ was spelled ⟨huu⟩ or ⟨hƿ⟩, and only the former was retained during the Middle English period, becoming ⟨hw⟩ during the gradual development of the letter ⟨w⟩ during the 14th-17th centuries. In most dialects it is now pronounced /w/, but a distinct pronunciation realized as a voiceless w sound, [ʍ], is retained in some areas: Scotland, central and southern Ireland, southeastern United States, and (mostly among older speakers) in New Zealand. In a few words (who, whose, etc.) the pronunciation used among almost all speakers regardless of geography is /h/. For details, see Pronunciation of English ⟨wh⟩. In Māori, ⟨wh⟩ represents /ɸ/ or more commonly /f/, with some regional variations approaching /h/ or /hw/. In the Taranaki region, for some speakers, this represents a glottalized /wʼ/. In Xhosa, it represents /w̤/, a murmured variant of /w/ found in loan words. In Cornish, it represents /ʍ/. ⟨wr⟩ is used in English for words which formerly began /wr/, now reduced to /r/ in virtually all dialects. ⟨wu⟩ is used in Mandarin pinyin to write the vowel /u/ in initial position, as in the name Wuhan. It is sometimes found with this value in Romanized Korean as well, as in hanwu. In Cantonese Romanisation, it is used to represent /wuː/ in an initial position or /uː/ in a non-initial position. ⟨ww⟩ is used in Haida (Bringhurst orthography) for glottalized /ˀw/. ⟨wx⟩ is used in Nambikwara for a glottalized /ˀw/. == X == ⟨xc⟩ is used in the Portuguese for /s/ before the front vowel letters ⟨e, i⟩. ⟨xf⟩ is used in the General Alphabet of Cameroon Languages for the labialized fricative /xʷ/. ⟨xg⟩ is used to write the click /ǁχ/ in Naro. It was used in the Tindall orthography of Khoekhoe for the voiceless lateral click /ǁ/. ⟨xh⟩ is used in Albanian to write the voiced postalveolar affricate /dʒ/, as in the surname Hoxha /ˈhɔdʒa/. In Zulu and Xhosa it represents the voiceless aspirated alveolar lateral click /kǁʰ/, e.g. Xhosa /ˈkǁʰoːsa/. In Walloon it represents a consonant that is variously /h/, /ʃ/, /ç ~ x/, depending on the dialect. In Canadian Tlingit it represents /χ/, which is represented by ⟨x̱⟩ in Alaska. ⟨xi⟩ is used in English for /kʃ/ in words such as flexion. (It is equivalent to ⟨c⟩ plus the digraph ⟨ti⟩, as in action.) ⟨xk⟩ was used in the Tindall orthography of Khoekhoe for the voiceless lateral click /ǁ/ (equivalent to ⟨xg⟩). ⟨xö⟩ is used as a letter of the Seri alphabet, where it represents a labialized uvular fricative, /χʷ/. It is placed between ⟨x⟩ and ⟨y⟩ in alphabetical order. ⟨xs⟩ is used in Portuguese in the word exsudar /ˌe.su.ˈda(ʁ)/ in Brazilian Portuguese. In European Portuguese this digraph changed to /ʃs/ in the early 20th century and the word came to be pronounced as /ɐjʃ.su.ˈðaɾ/ ⟨xu⟩ was used in the Ossete Latin alphabet for /χʷ/. ⟨xw⟩ is used in the Kurdish and the Tlingit language for /xʷ/. ⟨x̱w⟩ is used in Alaskan Tlingit for /χʷ/, which in Canada is written ⟨xhw⟩. ⟨xx⟩ is used in Hadza for the glottalized click /ᵑǁˀ/, and in Cypriot Arabic for /χː/. ⟨xy⟩ is used in the Hmong Romanized Popular Alphabet to write /ç/. == Y == ⟨ye⟩ used in various languages. In English it represents /aɪ/ word finally, e.g. bye or dye. ⟨yh⟩ was used in the pre-1985 orthography of Guinea, for the "ejective y" or palatalized glottal stop (/ʔʲ/) in Pular (a Fula language) and in Hausa to represent a creaky voiced palatal approximant [j̰]. In the current orthography it is now written ⟨ƴ⟩. In Xhosa it represents /j̤/. In a handful of Australian languages, it represents a "dental semivowel". ⟨yi⟩ is used in Mandarin pinyin to write /i/ when it forms an entire syllable. ⟨yk⟩ is used in Yanyuwa for a pre-velar stop, /ɡ̟ ~ k̟/. ⟨ym⟩ is used in French to write /ɛ̃/ (/im/ before another vowel), as in thym /tɛ̃/ "thyme". ⟨yn⟩ is used in French to write /ɛ̃/ in some words of Greek origin, such as syncope /sɛ̃kɔp/ "syncope". ⟨yr⟩ is used in Pinyin to write the trilled vowel /r̝/ in languages such as Yi. ⟨yu⟩ is used in romanized Chinese to write the vowel /y/. In Mandarin pinyin it is used for /y/ in initial position, whereas in Cantonese Jyutping it is used for /yː/ in non-initial position. In the Yale romanization of Cantonese and Cantonese Romanisation, it represents /jyː/ in an initial position and /yː/ in a non-initial position. ⟨yw⟩ is used for /jʷ/ in Arrernte and for doubly articulated /ɥ/ in Yélî Dnye. It is used in Cornish for the diphthongs /iʊ/, /ɪʊ/, or /ɛʊ/. ⟨yx⟩ in used in Nambikwara for a glottalized /ˀj/. ⟨yy⟩ is used in some languages such as Finnish to write the long vowel /yː/. In Haida (Bringhurst orthography) it is represents glottalized /ˀj/. Used in some Asturian dialects to represent /ɟ͡ʝ/. ⟨y_e⟩ (a split digraph) indicates an English 'long y' (equivalent to ⟨i...e⟩). == Z == ⟨zh⟩ represents the voiced postalveolar fricative (/ʒ/), like the ⟨s⟩ in pleasure, in Albanian and in Native American orthographies such as Navajo. It is used for the same sound in some English-language dictionaries, as well as to transliterate the sound when represented by Cyrillic ⟨ж⟩ and Persian ⟨ژ⟩ into English, but is rarely seen in English words, appearing primarily in foreign borrowings (e.g. muzhik) and slang (e.g. zhoosh). ⟨zh⟩ as a digraph is rare in European languages using the Latin alphabet; in addition to Albanian it is found in Breton in words that are pronounced with /z/ in some dialects and /h/ in others. In Hanyu Pinyin, ⟨zh⟩ represents the voiceless retroflex affricate /tʂ/. When Malayalam and Tamil are transliterated into the Latin script, ⟨zh⟩ represents a retroflex approximant (Malayalam ഴ and Tamil ழ ⟨ḻ⟩ [ɻ]). ⟨zi⟩ in Polish represents /ʑ/ whenever it precedes a vowel, and /ʑi/ whenever it precedes a consonant (or in the end of the word), and is considered a graphic variant of ⟨ź⟩ appearing in other situations. ⟨zl⟩ is used in the General Alphabet of Cameroon Languages for the voiced lateral fricative /ɮ/ ⟨zr⟩ is used in the General Alphabet of Cameroon Languages for /ʐ/. ⟨zs⟩ is the last (forty-fourth) letter of the Hungarian alphabet. Its name is zsé [ʒeː] and represents /ʒ/, a voiced postalveolar fricative, similar to ⟨j⟩ in Jacques and beside ⟨s⟩ in vision. A few examples are rózsa "rose" and zsír "fat". ⟨zv⟩ is used in Shona to write the whistled sibilant /z͎/. This was written ⟨ɀ⟩ from 1931 to 1955. ⟨zz⟩ is used in Pinyin for /dz/ in languages such as Yi. It is also used with that value in romanized Kabyle. In medieval Czech, it stood for /s/. In Hadza it is ejective /tsʼ/. == Other == ⟨ɛn⟩, capital ⟨Ɛn⟩, is used in many West African languages for the nasal vowel /ɛ̃/. ⟨ɛ⟩ is an "open e". ⟨ɔn⟩, capital ⟨Ɔn⟩, is used in many West African languages for the nasal vowel /ɔ̃/. ⟨ɔ⟩ is an "open o". ⟨œu⟩, capital ⟨Œu⟩, is used in French for the vowels /œ/ and /ø/. The first element of the digraph, ⟨œ⟩, is itself is a ligature of ⟨o⟩ and ⟨e⟩, and ⟨œu⟩ may also be written as the trigraph ⟨oeu⟩. ⟨ŋg⟩ is used in the General Alphabet of Cameroon Languages for /ᵑɡ/. ⟨ŋk⟩ is used in the General Alphabet of Cameroon Languages for /ᵑk/. ⟨ŋm⟩ is used in the General Alphabet of Cameroon Languages for the labial-velar nasal /ŋ͡m/. ⟨ŋv⟩, capital ⟨Ŋv⟩, was used for /ŋʷ/ in the old orthography of Zhuang and Bouyei; this is now spelled with the trigraph ⟨ngv⟩. ⟨ŋʼ⟩ is used in Adzera for the prenasalized glottal stop /ⁿʔ/. ⟨ſh⟩, capital ⟨SH⟩ or sometimes ⟨ŞH⟩, was a digraph used in the Slovene Bohorič alphabet for /ʃ/. The first element, ⟨ſ⟩, the long s, is an archaic non-final form of the letter ⟨s⟩. ⟨ǃʼ⟩ ⟨ǀʼ⟩ ⟨ǁʼ⟩ ⟨ǂʼ⟩ are used in Juǀʼhoan for its four glottalized nasal clicks, /ᵑǃˀ, ᵑǀˀ, ᵑǁˀ, ᵑǂˀ/. ⟨ǃg⟩ ⟨ǀg⟩ ⟨ǁg⟩ ⟨ǂg⟩ are used in Khoekhoe for its four tenuis clicks, /ǃ, ǀ, ǁ, ǂ/. ⟨ǃh⟩ ⟨ǀh⟩ ⟨ǁh⟩ ⟨ǂh⟩ are used in Khoekhoe for its four aspirated nasal clicks, /ᵑ̊ǃʰ, ᵑ̊ǀʰ, ᵑ̊ǁʰ, ᵑ̊ǂʰ/, and in Juǀʼhoan for its plain aspirated clicks, /ǃʰ, ǀʰ, ǁʰ, ǂʰ/. ⟨ǃk⟩ ⟨ǀk⟩ ⟨ǁk⟩ ⟨ǂk⟩ are used in Juǀʼhoan for its four affricate ejective-contour clicks, /ǃ͡χʼ, ǀ͡χʼ, ǁ͡χʼ, ǂ͡χʼ/. ⟨ǃn⟩ ⟨ǀn⟩ ⟨ǁn⟩ ⟨ǂn⟩ are used in Khoekhoe for its four plain nasal clicks, /ᵑǃ, ᵑǀ, ᵑǁ, ᵑǂ/. ⟨ǃx⟩ ⟨ǀx⟩ ⟨ǁx⟩ ⟨ǂx⟩ are used in Juǀʼhoan for its four affricate pulmonic-contour clicks, /ǃ͡χ, ǀ͡χ, ǁ͡χ, ǂ͡χ/. ⟨ьj⟩ was used in Yañalif and some Turkic languages for the diphthong /ɤj/. == See also == Trigraph List of Latin-script trigraphs Tetragraph List of Latin-script tetragraphs Pentagraph List of Latin-script pentagraphs Hexagraph Heptagraph List of Latin letters List of Cyrillic digraphs == References ==	Wikipedia/Ae_(digraph)
Affinity chromatography is a method of separating a biomolecule from a mixture, based on a highly specific macromolecular binding interaction between the biomolecule and another substance. The specific type of binding interaction depends on the biomolecule of interest; antigen and antibody, enzyme and substrate, receptor and ligand, or protein and nucleic acid binding interactions are frequently exploited for isolation of various biomolecules. Affinity chromatography is useful for its high selectivity and resolution of separation, compared to other chromatographic methods. == Principle == Affinity chromatography has the advantage of specific binding interactions between the analyte of interest (normally dissolved in the mobile phase), and a binding partner or ligand (immobilized on the stationary phase). In a typical affinity chromatography experiment, the ligand is attached to a solid, insoluble matrix—usually a polymer such as agarose or polyacrylamide—chemically modified to introduce reactive functional groups with which the ligand can react, forming stable covalent bonds. The stationary phase is first loaded into a column to which the mobile phase is introduced. Molecules that bind to the ligand will remain associated with the stationary phase. A wash buffer is then applied to remove non-target biomolecules by disrupting their weaker interactions with the stationary phase, while the biomolecules of interest will remain bound. Target biomolecules may then be removed by applying a so-called elution buffer, which disrupts interactions between the bound target biomolecules and the ligand. The target molecule is thus recovered in the eluting solution. Affinity chromatography does not require the molecular weight, charge, hydrophobicity, or other physical properties of the analyte of interest to be known, although knowledge of its binding properties is useful in the design of a separation protocol. Types of binding interactions commonly exploited in affinity chromatography procedures are summarized in the table below. == Batch and column setups == Binding to the solid phase may be achieved by column chromatography whereby the solid medium is packed onto a column, the initial mixture run through the column to allow settling, a wash buffer run through the column and the elution buffer subsequently applied to the column and collected. These steps are usually done at ambient pressure. Alternatively, binding may be achieved using a batch treatment, for example, by adding the initial mixture to the solid phase in a vessel, mixing, separating the solid phase, removing the liquid phase, washing, re-centrifuging, adding the elution buffer, re-centrifuging and removing the elute. Sometimes a hybrid method is employed such that the binding is done by the batch method, but the solid phase with the target molecule bound is packed onto a column and washing and elution are done on the column. The ligands used in affinity chromatography are obtained from both organic and inorganic sources. Examples of biological sources are serum proteins, lectins and antibodies. Inorganic sources are moronic acid, metal chelates and triazine dyes. A third method, expanded bed absorption, which combines the advantages of the two methods mentioned above, has also been developed. The solid phase particles are placed in a column where liquid phase is pumped in from the bottom and exits at the top. The gravity of the particles ensure that the solid phase does not exit the column with the liquid phase. Affinity columns can be eluted by changing salt concentrations, pH, pI, charge and ionic strength directly or through a gradient to resolve the particles of interest. More recently, setups employing more than one column in series have been developed. The advantage compared to single column setups is that the resin material can be fully loaded since non-binding product is directly passed on to a consecutive column with fresh column material. These chromatographic processes are known as periodic counter-current chromatography (PCC). The resin costs per amount of produced product can thus be drastically reduced. Since one column can always be eluted and regenerated while the other column is loaded, already two columns are sufficient to make full use of the advantages. Additional columns can give additional flexibility for elution and regeneration times, at the cost of additional equipment and resin costs. == Specific uses == Affinity chromatography can be used in a number of applications, including nucleic acid purification, protein purification from cell free extracts, and purification from blood. By using affinity chromatography, one can separate proteins that bind to a certain fragment from proteins that do not bind that specific fragment. Because this technique of purification relies on the biological properties of the protein needed, it is a useful technique and proteins can be purified many folds in one step. === Various affinity media === Many different affinity media exist for a variety of possible uses. Briefly, they are (generalized) activated/functionalized that work as a functional spacer, support matrix, and eliminates handling of toxic reagents. Amino acid media is used with a variety of serum proteins, proteins, peptides, and enzymes, as well as rRNA and dsDNA. Avidin biotin media is used in the purification process of biotin/avidin and their derivatives. Carbohydrate bonding is most often used with glycoproteins or any other carbohydrate-containing substance; carbohydrate is used with lectins, glycoproteins, or any other carbohydrate metabolite protein. Dye ligand media is nonspecific but mimics biological substrates and proteins. Glutathione is useful for separation of GST tagged recombinant proteins. Heparin is a generalized affinity ligand, and it is most useful for separation of plasma coagulation proteins, along with nucleic acid enzymes and lipases Hydrophobic interaction media are most commonly used to target free carboxyl groups and proteins. Immunoaffinity media (detailed below) utilizes antigens' and antibodies' high specificity to separate; immobilized metal affinity chromatography is detailed further below and uses interactions between metal ions and proteins (usually specially tagged) to separate; nucleotide/coenzyme that works to separate dehydrogenases, kinases, and transaminases. Nucleic acids function to trap mRNA, DNA, rRNA, and other nucleic acids/oligonucleotides. Protein A/G method is used to purify immunoglobulins. Speciality media are designed for a specific class or type of protein/co enzyme; this type of media will only work to separate a specific protein or coenzyme. === Immunoaffinity === Another use for the procedure is the affinity purification of antibodies from blood serum. If the serum is known to contain antibodies against a specific antigen (for example if the serum comes from an organism immunized against the antigen concerned) then it can be used for the affinity purification of that antigen. This is also known as Immunoaffinity Chromatography. For example, if an organism is immunised against a GST-fusion protein it will produce antibodies against the fusion-protein, and possibly antibodies against the GST tag as well. The protein can then be covalently coupled to a solid support such as agarose and used as an affinity ligand in purifications of antibody from immune serum. For thoroughness, the GST protein and the GST-fusion protein can each be coupled separately. The serum is initially allowed to bind to the GST affinity matrix. This will remove antibodies against the GST part of the fusion protein. The serum is then separated from the solid support and allowed to bind to the GST-fusion protein matrix. This allows any antibodies that recognize the antigen to be captured on the solid support. Elution of the antibodies of interest is most often achieved using a low pH buffer such as glycine pH 2.8. The eluate is collected into a neutral tris or phosphate buffer, to neutralize the low pH elution buffer and halt any degradation of the antibody's activity. This is a nice example as affinity purification is used to purify the initial GST-fusion protein, to remove the undesirable anti-GST antibodies from the serum and to purify the target antibody. Monoclonal antibodies can also be selected to bind proteins with great specificity, where protein is released under fairly gentle conditions. This can become of use for further research in the future. A simplified strategy is often employed to purify antibodies generated against peptide antigens. When the peptide antigens are produced synthetically, a terminal cysteine residue is added at either the N- or C-terminus of the peptide. This cysteine residue contains a sulfhydryl functional group which allows the peptide to be easily conjugated to a carrier protein (e.g. Keyhole limpet hemocyanin (KLH)). The same cysteine-containing peptide is also immobilized onto an agarose resin through the cysteine residue and is then used to purify the antibody. Most monoclonal antibodies have been purified using affinity chromatography based on immunoglobulin-specific Protein A or Protein G, derived from bacteria. Immunoaffinity chromatography with monoclonal antibodies immobilized on monolithic column has been successfully used to capture extracellular vesicles (e.g., exosomes and exomeres) from human blood plasma by targeting tetraspanins and integrins found on the surface of the EVs. Immunoaffinity chromatography is also the basis for immunochromatographic test (ICT) strips, which provide a rapid means of diagnosis in patient care. Using ICT, a technician can make a determination at a patient's bedside, without the need for a laboratory. ICT detection is highly specific to the microbe causing an infection. === Immobilized metal ion affinity chromatography === Immobilized metal ion affinity chromatography (IMAC) is based on the specific coordinate covalent bond of amino acids, particularly histidine, to metals. This technique works by allowing proteins with an affinity for metal ions to be retained in a column containing immobilized metal ions, such as cobalt, nickel, or copper for the purification of histidine-containing proteins or peptides, iron, zinc or gallium for the purification of phosphorylated proteins or peptides. Many naturally occurring proteins do not have an affinity for metal ions, therefore recombinant DNA technology can be used to introduce such a protein tag into the relevant gene. Methods used to elute the protein of interest include changing the pH, or adding a competitive molecule, such as imidazole. === Recombinant proteins === Possibly the most common use of affinity chromatography is for the purification of recombinant proteins. Proteins with a known affinity are protein tagged in order to aid their purification. The protein may have been genetically modified so as to allow it to be selected for affinity binding; this is known as a fusion protein. Protein tags include hexahistidine (His), glutathione-S-transferase (GST), maltose binding protein (MBP), and the Colicin E7 variant CL7 tag. Histidine tags have an affinity for nickel, cobalt, zinc, copper and iron ions which have been immobilized by forming coordinate covalent bonds with a chelator incorporated in the stationary phase. For elution, an excess amount of a compound able to act as a metal ion ligand, such as imidazole, is used. GST has an affinity for glutathione which is commercially available immobilized as glutathione agarose. During elution, excess glutathione is used to displace the tagged protein. CL7 has an affinity and specificity for Immunity Protein 7 (Im7) which is commercially available immobilized as Im7 agarose resin. For elution, an active and site-specific protease is applied to the Im7 resin to release the tag-free protein. === Lectins === Lectin affinity chromatography is a form of affinity chromatography where lectins are used to separate components within the sample. Lectins, such as concanavalin A are proteins which can bind specific alpha-D-mannose and alpha-D-glucose carbohydrate molecules. Some common carbohydrate molecules that is used in lectin affinity chromatography are Con A-Sepharose and WGA-agarose. Another example of a lectin is wheat germ agglutinin which binds D-N-acetyl-glucosamine. The most common application is to separate glycoproteins from non-glycosylated proteins, or one glycoform from another glycoform. Although there are various ways to perform lectin affinity chromatography, the goal is extract a sugar ligand of the desired protein. === Specialty === Another use for affinity chromatography is the purification of specific proteins using a gel matrix that is unique to a specific protein. For example, the purification of E. coli β-galactosidase is accomplished by affinity chromatography using p-aminobenyl-1-thio-β-D-galactopyranosyl agarose as the affinity matrix. p-aminobenyl-1-thio-β-D-galactopyranosyl agarose is used as the affinity matrix because it contains a galactopyranosyl group, which serves as a good substrate analog for E. coli β-Galactosidase. This property allows the enzyme to bind to the stationary phase of the affinity matrix and β-Galactosidase is eluted by adding increasing concentrations of salt to the column. ==== Alkaline phosphatase ==== Alkaline phosphatase from E. coli can be purified using a DEAE-Cellulose matrix. A. phosphatase has a slight negative charge, allowing it to weakly bind to the positively charged amine groups in the matrix. The enzyme can then be eluted out by adding buffer with higher salt concentrations. ==== Boronate affinity chromatography ==== Boronate affinity chromatography consists of using boronic acid or boronates to elute and quantify amounts of glycoproteins. Clinical adaptations have applied this type of chromatography for use in determining long term assessment of diabetic patients through analysis of their glycated hemoglobin. === Serum albumin purification === Affinity purification of albumin and macroglobulin contamination is helpful in removing excess albumin and α2-macroglobulin contamination, when performing mass spectrometry. In affinity purification of serum albumin, the stationary used for collecting or attracting serum proteins can be Cibacron Blue-Sepharose. Then the serum proteins can be eluted from the adsorbent with a buffer containing thiocyanate (SCN−). == Weak affinity chromatography == Weak affinity chromatography (WAC) is an affinity chromatography technique for affinity screening in drug development. WAC is an affinity-based liquid chromatographic technique that separates chemical compounds based on their different weak affinities to an immobilized target. The higher affinity a compound has towards the target, the longer it remains in the separation unit, and this will be expressed as a longer retention time. The affinity measure and ranking of affinity can be achieved by processing the obtained retention times of analyzed compounds. Affinity chromatography is part of a larger suite of techniques used in chemoproteomics based drug target identification. The WAC technology is demonstrated against a number of different protein targets – proteases, kinases, chaperones and protein–protein interaction (PPI) targets. WAC has been shown to be more effective than established methods for fragment based screening. == History == Affinity chromatography was conceived and first developed by Pedro Cuatrecasas and Meir Wilchek. == References == == External links == "Affinity Chromatography Principle, Procedure And Advance Detailed Note – 2020". "What is affinity chromatography"	Wikipedia/Lectin_affinity_chromatography
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane proteins can be classified as IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a significant fraction of the proteins encoded in an organism's genome. Proteins that cross the membrane are surrounded by annular lipids, which are defined as lipids that are in direct contact with a membrane protein. Such proteins can only be separated from the membranes by using detergents, nonpolar solvents, or sometimes denaturing agents. Proteins that adhere only temporarily to cellular membranes are known as peripheral membrane proteins. These proteins can either associate with integral membrane proteins, or independently insert in the lipid bilayer in several ways. == Structure == Three-dimensional structures of ~160 different integral membrane proteins have been determined at atomic resolution by X-ray crystallography or nuclear magnetic resonance spectroscopy. They are challenging subjects for study owing to the difficulties associated with extraction and crystallization. In addition, structures of many water-soluble protein domains of IMPs are available in the Protein Data Bank. Their membrane-anchoring α-helices have been removed to facilitate the extraction and crystallization. Search integral membrane proteins in the PDB (based on gene ontology classification) IMPs can be divided into two groups: Integral polytopic proteins (Transmembrane proteins) Integral monotopic proteins === Integral polytopic protein === The most common type of IMP is the transmembrane protein, which spans the entire biological membrane. Single-pass membrane proteins cross the membrane only once, while multi-pass membrane proteins weave in and out, crossing the membrane several times. Single pass membrane proteins can be categorized as Type I, which are positioned such that their carboxyl-terminus is towards the cytosol, or Type II, which have their amino-terminus towards the cytosol. Type III proteins have multiple transmembrane domains in a single polypeptide, while type IV consists of several different polypeptides assembled together in a channel through the membrane. Type V proteins are anchored to the lipid bilayer through covalently linked lipids. Finally Type VI proteins have both transmembrane domains and lipid anchors. === Integral monotopic proteins === Integral monotopic proteins are permanently attached to the cell membrane from one side. Three-dimensional structures of the following integral monotopic proteins have been determined: prostaglandin H2 syntheses 1 and 2 (cyclooxygenases) lanosterol synthase and squalene-hopene cyclase microsomal prostaglandin E synthase carnitine O-palmitoyltransferase 2 Phosphoglycosyl transferase C There are also structures of integral monotopic domains of transmembrane proteins: monoamine oxidases A and B fatty acid amide hydrolase mammalian cytochrome P450 oxidases corticosteroid 11-beta-dehydrogenases === Extraction === Many challenges facing the study of integral membrane proteins are attributed to the extraction of those proteins from the phospholipid bilayer. Since integral proteins span the width of the phospholipid bilayer, their extraction involves disrupting the phospholipids surrounding them, without causing any damage that would interrupt the function or structure of the proteins. Several successful methods are available for performing the extraction including the uses of "detergents, low ionic salt (salting out), shearing force, and rapid pressure change". === Determination of protein structure === The Protein Structure Initiative (PSI), funded by the U.S. National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health (NIH), has among its aim to determine three-dimensional protein structures and to develop techniques for use in structural biology, including for membrane proteins. Homology modeling can be used to construct an atomic-resolution model of the "target" integral protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein. This procedure has been extensively used for ligand-G protein–coupled receptors (GPCR) and their complexes. == Function == IMPs include transporters, linkers, channels, receptors, enzymes, structural membrane-anchoring domains, proteins involved in accumulation and transduction of energy, and proteins responsible for cell adhesion. Classification of transporters can be found in Transporter Classification Database. As an example of the relationship between the IMP (in this case the bacterial phototrapping pigment, bacteriorhodopsin) and the membrane formed by the phospholipid bilayer is illustrated below. In this case the integral membrane protein spans the phospholipid bilayer seven times. The part of the protein that is embedded in the hydrophobic regions of the bilayer are alpha helical and composed of predominantly hydrophobic amino acids. The C terminal end of the protein is in the cytosol while the N terminal region is in the outside of the cell. A membrane that contains this particular protein is able to function in photosynthesis. == Examples == Examples of integral membrane proteins: Insulin receptor Some types of cell adhesion proteins or cell adhesion molecules (CAMs) such as integrins, cadherins, NCAMs, or selectins Some types of receptor proteins Glycophorin Rhodopsin Band 3 CD36 Glucose Permease Ion channels and Gates Gap junction Proteins G protein coupled receptors (e.g., Beta-adrenergic receptor) Seipin Photosystem I == See also == Membrane protein Transmembrane protein Peripheral membrane protein Annular lipid shell Hydrophilicity plot Inner nuclear membrane protein == References ==	Wikipedia/Integral_membrane_proteins
A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides. Secretory proteins are synthesized in the endoplasmic reticulum. == Production == The production of a secretory protein starts like any other protein. The mRNA is produced and transported to the cytosol where it interacts with a free cytosolic ribosome. The part that is produced first, the N-terminal, contains a signal sequence consisting of 6 to 12 amino acids with hydrophobic side chains. This sequence is recognised by a cytosolic protein, SRP (Signal Recognition Particle), which stops the translation and aids in the transport of the mRNA-ribosome complex to an SRP receptor found in the membrane of the endoplasmic reticulum. When it arrives at the ER, the signal sequence is transferred to the translocon, a protein-conducting channel in the membrane that allows the newly synthesized polypeptide to be translocated to the ER lumen. The dissociation of SRP from the ribosome restores the translation of the secretory protein. The signal sequence is removed and the translation continues while the produced chain moves through the translocon (cotranslational translocation). == Modification == After the production of the protein is completed, it interacts with several other proteins to gain its final state. === Endoplasmic reticulum === After translation, proteins within the ER make sure that the protein is folded correctly. If after a first attempt the folding is unsuccessful, a second folding is attempted. If this fails too the protein is exported to the cytosol and labelled for destruction. Aside from the folding, there is also a sugar chain added to the protein. After these changes, the protein is transported to the Golgi apparatus by a coated vesicle using coating protein COPII. === Golgi apparatus === In the Golgi apparatus, the sugar chains are modified by adding or removing certain sugars. The secretory protein leaves the Golgi apparatus by an uncoated vesicle. == Secretion == Membrane proteins with functional areas on the cytosolic side of both the vesicle and cell membrane make sure the vesicle associates with the membrane. The vesicle membrane fuses with the cell membrane and so the protein leaves the cell. Some vesicles don't fuse immediately and await a signal before starting the fusing. This is seen in vesicles carrying neurotransmitter in presynaptic cells. This process constitutes an effective cell-cell signaling mechanism via membrane vesicle trafficking from secretory cell to the target cells in human or animal body. The process has been extended to the host–pathogen interface, wherein, gram negative bacteria secrete outer membrane vesicles containing fully conformed signal proteins and virulence factors via exocytosis of nano-sized vesicles, in order to control host or target cell activities and exploit their environment. == Sequence data and related databases == Effective, database (2010) UniProt contains manually curated secretory proteins. There are also computationally predicted secretory protein databases, these databases are listed in the secretome section. == See also == Bacterial outer membrane vesicles Exocytosis Host–pathogen interaction Membrane vesicle trafficking Secretion Secretome Secretomics == References == == External links == "Localization: Secreted". Orientations of Proteins in Membranes (OPM) database.	Wikipedia/Secretory_protein
A sialoglycoprotein is a combination of sialic acid and glycoprotein, which is, itself, a combination of sugar and protein. These proteins often contain one or more sialyl oligosaccharides that are covalently bound to the rest of the molecule. Glycophorin C is one common sialoglycoprotein. Podocalyxin is another sialoglycoprotein found in the foot processes of the podocyte cells of the glomerulus in kidneys. Podocalyxin is negatively charged and therefore repels other negatively charged molecules, thus contributing to the minimal filtration of negatively charged molecules by the kidney. Its molecular weight is 46 kDa. == References == == External links == Sialoglycoproteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)	Wikipedia/Sialoglycoprotein
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 six months, failure to thrive and developmental delays are obvious signs of this disorder. Some physical signs, such as abnormal skeletal development, coarse facial features (e.g. bulging scaphocephalic head, flat nose), 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. Consequently, lysosomes lack the requisite hydrolytic enzymes needed for catabolism of cellular debris, so this debris accumulates within them and forms the characteristic intracellular inclusions (hence the name of the disorder). Hydrolases secreted into the blood stream cause little problem as they are inactivate at the near neutral pH of blood (7.4). It can be associated with N-acetylglucosamine-1-phosphate transferase (GNPTA). In a case report, I-cell disease was complicated by severe dilative cardiomyopathy (DCM). Though rare, a deficiency of phosphodiesterase which would cleave GlcNAc from the mannose-6-phosphate tag will also cause I-cell disease. The presence of lipids, glycosaminoglycans (GAG's) and carbohydrates in the blood provide for the distinguishing characteristic to separate I-cell from Hurler Syndrome. In Hurler's, only glycosaminoglycans would be present. == Diagnosis == Diagnostic measures can include the following: Before birth: Abnormally low concentrations of UDP-N-acetylglucosamine-1-phosphotransferase enzyme activity in amniotic fluid cells or chorionic villi In infants: Elevated plasma lysosomal enzyme concentrations Decreased concentration of lysosomal enzymes in cultured fibroblasts and increased in the surrounding medium Presence of inclusion bodies in peripheral blood lymphocytes Low concentrations of UDP-N-acetylglucosamine-1-phosphotransferase enzyme activity as measured in white blood cells == Treatment == There is no cure for I-cell disease/Mucolipidosis II disease; treatment is limited to controlling or reducing symptoms. Nutritional supplements, particularly iron and vitamin B12, are often recommended. Physical therapy to improve motor delays and speech therapy to improve language acquisition are treatment options. Surgery can remove the thin layer of corneal clouding to temporarily improve the complication. It is possible that bone marrow transplant may be helpful in delaying or correcting the neurological deterioration that occurs with I-Cell disease. The Yash Gandhi Foundation is a US non-profit organization which funds research for I-Cell disease. == References == == External links == lipid-storage-diseases at NINDS I cell disease at NIH's Office of Rare Diseases GeneReview/NIH/UW entry on Mucolipidosis II	Wikipedia/I-cell_disease
Protein S (also known as PROS) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene. Protein S plays a role in coagulation. == History == Protein S is named for Seattle, Washington, where it was originally discovered and purified by Earl Davie's group in 1977. == Structure == Protein S is partly homologous to other vitamin K-dependent plasma coagulation proteins, such as protein C and factors VII, IX, and X. Similar to them, it has a Gla domain and several EGF-like domains (four rather than two), but no serine protease domain. Instead, there is a large C-terminus domain that is homologous to plasma steroid hormone-binding proteins such as sex hormone-binding globulin and corticosteroid-binding globulin. It may play a role in the protein functions as either a cofactor for activated protein C (APC) or in binding C4BP. Additionally, protein S has a peptide between the Gla domain and the EGF-like domain, that is cleaved by thrombin. The Gla and EGF-like domains stay connected after the cleavage by a disulfide bond. However, protein S loses its function as an APC cofactor following either this cleavage or binding C4BP. == Function == The best characterized function of Protein S is its role in the anti coagulation pathway, where it functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. Only the free form has cofactor activity. Protein S binds to negatively charged phospholipids via the carboxylated Gla domain. This property allows Protein S to facilitate the removal of cells that are undergoing apoptosis, a form of structured cell death used by the body to remove unwanted or damaged cells. In healthy cells, an ATP (adenosine triphosphate)-dependent enzyme removes negatively charged phospholipids such as phosphatidyl serine from the outer leaflet of the cell membrane. An apoptotic cell (that is, one undergoing apoptosis) no longer actively manages the distribution of phospholipids in its outer membrane and hence begins to display negatively charged phospholipids on its exterior surface. These negatively charged phospholipids are recognized by phagocytes such as macrophages. Protein S binds to the negatively charged phospholipids and functions as a bridge between the apoptotic cell and the phagocyte. This bridging expedites phagocytosis and allows the cell to be removed without giving rise to inflammation or other signs of tissue damage. Protein S does not bind to the nascent complement complex C5,6,7 to prevents it from inserting into a membrane. This is a different complement protein S AKA vitronectin made by the VTN gene, not to be confused with the coagulation protein S made by the PROS gene which this wiki page concerns. == Pathology == Mutations in the PROS1 gene can lead to Protein S deficiency which is a rare blood disorder which can lead to an increased risk of thrombosis. The SARS-CoV-2 papain-like protease (PLpro) was shown to cleave a sequence (LRGG*KIEVQL) in PROS1. The cleavage of PROS1 may lead to a transient deficiency in PROS1 during or after infection and may be associated with COVID coagulopathy. == Interactions == Protein S has been shown to interact with Factor V. A sequence in PROS1 can be cut by the papain-like protease of SARS-CoV-2. == See also == Hemostasis == References == == Further reading ==	Wikipedia/Protein_S
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density lipoproteins (VLDL) or chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride. == Genetics == The CETP gene is located on chromosome 16 (16q21). == Protein fold == The crystal structure of CETP is that of dimer of two TUbular LIPid (TULIP) binding domains. Each domain consists of a core of 6 elements: 4 beta-sheets forming an extended superhelix; 2 flanking elements that tend to include some alpha helix. The sheets wrap around the helices to produce a cylinder 6 x 2.5 x 2.5 nm. CETP contains two of these domains that interact head-to-head via an interface made of 6 beta-sheets, 3 from each protomer. The same fold is shared by Bacterial Permeability Inducing proteins (examples: BPIFP1 BPIFP2 BPIFA3 and BPIFB4), phospholipid transfer protein (PLTP), and long-Palate Lung, and Nasal Epithelium protein (L-PLUNC). The fold is similar to intracellular SMP domains, and originated in bacteria. The crystal structure of CETP has been obtained with bound CETP inhibitors. However, this has not resolved the doubt over whether CETP function as a lipid tube or shuttle. == Role in disease == Rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis. In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity and to metabolic response to nutritional intervention. However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia. The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease. Elaidic acid, a major component of trans fat, increases CETP activity. == Pharmacology == As HDL can alleviate atherosclerosis and other cardiovascular diseases, and certain disease states such as the metabolic syndrome feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels. To be specific, in a 2004 study, the small molecular agent torcetrapib was shown to increase HDL levels, alone and with a statin, and lower LDL when co-administered with a statin. Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in lipid levels, most reported an increase in blood pressure, no change in atherosclerosis, and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality. A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also studied, but trials have ceased. It increases HDL levels by 30%, as compared to 60% by torcetrapib. Two CETP inhibitors were previously under development. One was Merck's MK-0859 anacetrapib, which in initial studies did not increase blood pressure. In 2017, its development was abandoned by Merck. The other was Eli Lilly's evacetrapib, which failed in Phase 3 trials. == Interactive pathway map == Click on genes, proteins and metabolites below to link to respective articles. == References == == Further reading == == External links == Cholesterol+ester+transfer+proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)	Wikipedia/Cholesterylester_transfer_protein
Salla disease (SD) or mild Free Sialic Acid Storage Disease (FSASD) is an autosomal recessive lysosomal storage disease characterized by early physical impairment and intellectual disability. Salla disease (also referred to as Finnish-type sialuria, OMIM#604369) was first reported as a lysosomal storage disorder in a family from northern Finland. Salla refers to the area where the affected family resided. It was first described in 1979, after Salla, a municipality in Finnish Lapland and is one of 40 Finnish heritage diseases. The term Salla disease is now used in the literature not only for FSASD cases with the Finnish founder variant in SLC17A5, but also for any mild FSASD cases, independent of the mutation or region of origin. FSASD (Salla and Infantile Free Sialic Acid Storage Disease) affects males and females in equal numbers. The worldwide prevalence of FSASD is estimated at less than 1 per 1,000,000 individuals. Higher estimated prevalence rates occur in the Salla region of Finland and other Scandinavian countries. == Signs and symptoms == Affected infants appear normal at birth but may develop symptoms during the first year of life. Individuals with Salla disease may present with nystagmus as well as hypotonia, and may have difficulty coordinating voluntary movements (ataxia), reduced muscle tone and strength, and cognitive impairment. The most severely impaired children do not walk or acquire language, but the typical patient learns to walk and speak and has normal life expectancy. The MRI shows arrested or delayed myelination. Approximately two-thirds of children with mild FSASD eventually learn to walk. Some degree of speech impairment is usually present. Affected infants may learn single words or small sentences, but this ability may be lost as they age. The ability to produce speech is affected more severely than the ability to understand speech. Affected children exhibit some degree of cognitive impairment as well. FSASD (Salla and Infantile Free Sialic Acid Storage Disease) affects males and females in equal numbers. The worldwide prevalence of FSASD is estimated at less than 1 per 1,000,000 individuals. Higher estimated prevalence rates occur in the Salla region of Finland and other Scandinavian countries. Approximately ~300 individuals with FSASD have been reported in the literature, of which the majority (> 160 cases) are of Finnish or Swedish ancestry. Individuals with FSASD may be misdiagnosed or undiagnosed, making it difficult to determine the true frequency of the disease in the general population. == Genetics == SD is caused by a mutation in the SLC17A5 gene, located at human chromosome 6q14-15. This gene codes for sialin, a lysosomal membrane protein that transports the charged sugar, N-acetylneuraminic acid (sialic acid), out of lysosomes. The mutation causes sialic acid to build up in the cells. The disease is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome (chromosome 6 is an autosome), and two copies of the defective gene (one inherited from each parent) are required to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. == Diagnosis == A diagnosis of this disorder can be made by measuring urine to look for elevated levels of free sialic acid. Prenatal testing is also available for known carriers of this disorder. The diagnosis is ultimately confirmed by identifying genetic mutation(s) in the SLC17A5 gene by molecular genetic testing. This testing is available on a clinical basis. == Treatment == There is no cure for Salla disease. Treatment is limited to controlling the symptoms of this disorder. Anti-convulsant medication may control seizure episodes. Physical therapists can assist an affected individual in building muscle strength and coordination. Genetic counseling is recommended for affected individuals and their families. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website. == Prognosis == Some individuals with mild FSASD may not develop symptoms until later in childhood when a variety of neurological findings become apparent. These include seizures, involuntary muscle spasms that result in slow, stiff movements of the legs (spasticity), and repetitive, involuntary, writhing movements of the arms and legs (athetosis). Some individuals who previously developed the ability to walk or talk may lose these skills (regression). Some individuals may experience a gradual coarsening of facial features. == See also == Infantile free sialic acid storage disease (ISSD) == References == == External links == GeneReview/NIH/UW entry on Free Sialic Acid Storage Disorders	Wikipedia/Salla_disease
Antifreeze proteins (AFPs) or ice structuring proteins refer to a class of polypeptides produced by certain animals, plants, fungi and bacteria that permit their survival in temperatures below the freezing point of water. AFPs bind to small ice crystals to inhibit the growth and recrystallization of ice that would otherwise be fatal. There is also increasing evidence that AFPs interact with mammalian cell membranes to protect them from cold damage. This work suggests the involvement of AFPs in cold acclimatization. == Non-colligative properties == Unlike the widely used automotive antifreeze, ethylene glycol, AFPs do not lower freezing point in proportion to concentration. Rather, they work in a noncolligative manner. This phenomenon allows them to act as an antifreeze at concentrations 1/300th to 1/500th of those of other dissolved solutes. Their low concentration minimizes their effect on osmotic pressure. The unusual properties of AFPs are attributed to their selective affinity for specific crystalline ice forms and the resulting blockade of the ice-nucleation process. == Thermal hysteresis == AFPs create a difference between the melting point and freezing point (busting temperature of AFP bound ice crystal) known as thermal hysteresis. The addition of AFPs at the interface between solid ice and liquid water inhibits the thermodynamically favored growth of the ice crystal. Ice growth is kinetically inhibited by the AFPs covering the water-accessible surfaces of ice. Thermal hysteresis is easily measured in the lab with a nanolitre osmometer. Organisms differ in their values of thermal hysteresis. The maximum level of thermal hysteresis shown by fish AFP is approximately −3.5 °C (Sheikh Mahatabuddin et al., SciRep)(29.3 °F). In contrast, aquatic organisms are exposed only to −1 to −2 °C below freezing. During the extreme winter months, the spruce budworm resists freezing at temperatures approaching −30 °C. The rate of cooling can influence the thermal hysteresis value of AFPs. Rapid cooling can substantially decrease the nonequilibrium freezing point, and hence the thermal hysteresis value. Consequently, organisms cannot necessarily adapt to their subzero environment if the temperature drops abruptly. == Freeze tolerance versus freeze avoidance == Species containing AFPs may be classified as Freeze avoidant: These species are able to prevent their body fluids from freezing altogether. Generally, the AFP function may be overcome at extremely cold temperatures, leading to rapid ice growth and death. Freeze tolerant: These species are able to survive body fluid freezing. Some freeze tolerant species are thought to use AFPs as cryoprotectants to prevent the damage of freezing, but not freezing altogether. The exact mechanism is still unknown. However, it is thought AFPs may inhibit recrystallization and stabilize cell membranes to prevent damage by ice. They may work in conjunction with ice nucleating proteins (INPs) to control the rate of ice propagation following freezing. == Diversity == There are many known nonhomologous types of AFPs. === Fish AFPs === Antifreeze glycoproteins or AFGPs are found in Antarctic notothenioids and northern cod. They are 2.6-3.3 kD. AFGPs evolved separately in notothenioids and northern cod. In notothenioids, the AFGP gene arose from an ancestral trypsinogen-like serine protease gene. Type I AFP is found in winter flounder, longhorn sculpin and shorthorn sculpin. It is the best documented AFP because it was the first to have its three-dimensional structure determined. Type I AFP consists of a single, long, amphipathic alpha helix, about 3.3-4.5 kD in size. There are three faces to the 3D structure: the hydrophobic, hydrophilic, and Thr-Asx face. Type I-hyp AFP (where hyp stands for hyperactive) are found in several righteye flounders. It is approximately 32 kD (two 17 kD dimeric molecules). The protein was isolated from the blood plasma of winter flounder. It is considerably better at depressing freezing temperature than most fish AFPs. The ability is partially derived from its many repeats of the Type I ice-binding site. Type II AFPs (e.g. P05140) are found in sea raven, smelt and herring. They are cysteine-rich globular proteins containing five disulfide bonds. Type II AFPs likely evolved from calcium dependent (c-type) lectins. Sea ravens, smelt, and herring are quite divergent lineages of teleost. If the AFP gene were present in the most recent common ancestor of these lineages, it is peculiar that the gene is scattered throughout those lineages, present in some orders and absent in others. It has been suggested that lateral gene transfer could be attributed to this discrepancy, such that the smelt acquired the type II AFP gene from the herring. Type III AFPs are found in Antarctic eelpout. They exhibit similar overall hydrophobicity at ice binding surfaces to type I AFPs. They are approximately 6kD in size. Type III AFPs likely evolved from a sialic acid synthase (SAS) gene present in Antarctic eelpout. Through a gene duplication event, this gene—which has been shown to exhibit some ice-binding activity of its own—evolved into an effective AFP gene by loss of the N-terminal part. Type IV AFPs (P80961) are found in longhorn sculpins. They are alpha helical proteins rich in glutamate and glutamine. This protein is approximately 12KDa in size and consists of a 4-helix bundle. Its only posttranslational modification is a pyroglutamate residue, a cyclized glutamine residue at its N-terminus. === Plant AFPs === The classification of AFPs became more complicated when antifreeze proteins from plants were discovered. Plant AFPs are rather different from the other AFPs in the following aspects: They have much weaker thermal hysteresis activity when compared to other AFPs. Their physiological function is likely in inhibiting the recrystallization of ice rather than in preventing ice formation. Most of them are evolved pathogenesis-related proteins, sometimes retaining antifungal properties. === Insect AFPs === There are a number of AFPs found in insects, including those from Dendroides, Tenebrio and Rhagium beetles, spruce budworm and pale beauty moths, and midges (same order as flies). Insect AFPs share certain similarities, with most having higher activity (i.e. greater thermal hysteresis value, termed hyperactive) and a repetitive structure with a flat ice-binding surface. Those from the closely related Tenebrio and Dendroides beetles are homologous and each 12–13 amino-acid repeat is stabilized by an internal disulfide bond. Isoforms have between 6 and 10 of these repeats that form a coil, or beta-solenoid. One side of the solenoid has a flat ice-binding surface that consists of a double row of threonine residues. Other beetles (genus Rhagium) have longer repeats without internal disulfide bonds that form a compressed beta-solenoid (beta sandwich) with four rows of threonine residus, and this AFP is structurally similar to that modelled for the non-homologous AFP from the pale beauty moth. In contrast, the AFP from the spruce budworm moth is a solenoid that superficially resembles the Tenebrio protein, with a similar ice-binding surface, but it has a triangular cross-section, with longer repeats that lack the internal disulfide bonds. The AFP from midges is structurally similar to those from Tenebrio and Dendroides, but the disulfide-braced beta-solenoid is formed from shorter 10 amino-acids repeats, and instead of threonine, the ice-binding surface consists of a single row of tyrosine residues. Springtails (Collembola) are not insects, but like insects, they are arthropods with six legs. A species found in Canada, which is often called a "snow flea", produces hyperactive AFPs. Although they are also repetitive and have a flat ice-binding surface, the similarity ends there. Around 50% of the residues are glycine (Gly), with repeats of Gly-Gly- X or Gly-X-X, where X is any amino acid. Each 3-amino-acid repeat forms one turn of a polyproline type II helix. The helices then fold together, to form a bundle that is two helices thick, with an ice-binding face dominated by small hydrophobic residues like alanine, rather than threonine. Other insects, such as an Alaskan beetle, produce hyperactive antifreezes that are even less similar, as they are polymers of sugars (xylomannan) rather than polymers of amino acids (proteins). Taken together, this suggests that most of the AFPs and antifreezes arose after the lineages that gave rise to these various insects diverged. The similarities they do share are the result of convergent evolution. === Sea ice organism AFPs === Many microorganisms living in sea ice possess AFPs that belong to a single family. The diatoms Fragilariopsis cylindrus and F. curta play a key role in polar sea ice communities, dominating the assemblages of both platelet layer and within pack ice. AFPs are widespread in these species, and the presence of AFP genes as a multigene family indicates the importance of this group for the genus Fragilariopsis. AFPs identified in F. cylindrus belong to an AFP family which is represented in different taxa and can be found in other organisms related to sea ice (Colwellia spp., Navicula glaciei, Chaetoceros neogracile and Stephos longipes and Leucosporidium antarcticum) and Antarctic inland ice bacteria (Flavobacteriaceae), as well as in cold-tolerant fungi (Typhula ishikariensis, Lentinula edodes and Flammulina populicola). Several structures for sea ice AFPs have been solved. This family of proteins fold into a beta helix that form a flat ice-binding surface. Unlike the other AFPs, there is not a singular sequence motif for the ice-binding site. AFP found from the metagenome of the ciliate Euplotes focardii and psychrophilic bacteria has an efficient ice re-crystallization inhibition ability. 1 μM of Euplotes focardii consortium ice-binding protein (EfcIBP) is enough for the total inhibition of ice re-crystallization in –7.4 °C temperature. This ice-recrystallization inhibition ability helps bacteria to tolerate ice rather than preventing the formation of ice. EfcIBP produces also thermal hysteresis gap, but this ability is not as efficient as the ice-recrystallization inhibition ability. EfcIBP helps to protect both purified proteins and whole bacterial cells in freezing temperatures. Green fluorescent protein is functional after several cycles of freezing and melting when incubated with EfcIBP. Escherichia coli survives longer periods in 0 °C temperature when the efcIBP gene was inserted to E. coli genome. EfcIBP has a typical AFP structure consisting of multiple beta-sheets and an alpha-helix. Also, all the ice-binding polar residues are at the same site of the protein. == Evolution == The remarkable diversity and distribution of AFPs suggest the different types evolved recently in response to sea level glaciation occurring 1–2 million years ago in the Northern hemisphere and 10-30 million years ago in Antarctica. Data collected from deep sea ocean drilling has revealed that the development of the Antarctic Circumpolar Current was formed over 30 million years ago. The cooling of Antarctic imposed from this current caused a mass extinction of teleost species that were unable to withstand freezing temperatures. Notothenioids species with the antifreeze glycoprotein were able to survive the glaciation event and diversify into new niches. This independent development of similar adaptations is referred to as convergent evolution. Evidence for convergent evolution in Northern cod (Gadidae) and Notothenioids is supported by the findings of different spacer sequences and different organization of introns and exons as well as unmatching AFGP tripeptide sequences, which emerged from duplications of short ancestral sequences which were differently permuted (for the same tripeptide) by each group. These groups diverged approximately 7-15 million years ago. Shortly after (5-15 mya), the AFGP gene evolved from an ancestral pancreatic trypsinogen gene in Notothenioids. AFGP and trypsinogen genes split via a sequence divergence - an adaptation which occurred alongside the cooling and eventual freezing of the Antarctic Ocean. The evolution of the AFGP gene in Northern cod occurred more recently (~3.2 mya) and emerged from a noncoding sequence via tandem duplications in a Thr-Ala-Ala unit. Antarctic notothenioid fish and arctic cod, Boreogadus saida, are part of two distinct orders and have very similar antifreeze glycoproteins. Although the two fish orders have similar antifreeze proteins, cod species contain arginine in AFG, while Antarctic notothenioid do not. The role of arginine as an enhancer has been investigated in Dendroides canadensis antifreeze protein (DAFP-1) by observing the effect of a chemical modification using 1-2 cyclohexanedione. Previous research has found various enhancers of this bettles' antifreeze protein including a thaumatin-like protein and polycarboxylates. Modifications of DAFP-1 with the arginine specific reagent resulted in the partial and complete loss of thermal hysteresis in DAFP-1, indicating that arginine plays a crucial role in enhancing its ability. Different enhancer molecules of DAFP-1 have distinct thermal hysteresis activity. Amornwittawat et al. 2008 found that the number of carboxylate groups in a molecules influence the enhancing ability of DAFP-1. Optimum activity in TH is correlated with high concentration of enhancer molecules. Li et al. 1998 investigated the effects of pH and solute on thermal hysteresis in Antifreeze proteins from Dendrioides canadensis. TH activity of DAFP-4 was not affected by pH unless the there was a low solute concentration (pH 1) in which TH decreased. The effect of five solutes; succinate, citrate, malate, malonate, and acetate, on TH activity was reported. Among the five solutes, citrate was shown to have the greatest enhancing effect. This is an example of a proto-ORF model, a rare occurrence where new genes pre exist as a formed open reading frame before the existence of the regulatory element needed to activate them. In fishes, horizontal gene transfer is responsible for the presence of Type II AFP proteins in some groups without a recently shared phylogeny. In Herring and smelt, up to 98% of introns for this gene are shared; the method of transfer is assumed to occur during mating via sperm cells exposed to foreign DNA. The direction of transfer is known to be from herring to smelt as herring have 8 times the copies of AFP gene as smelt (1) and the segments of the gene in smelt house transposable elements which are otherwise characteristic of and common in herring but not found in other fishes. There are two reasons why many types of AFPs are able to carry out the same function despite their diversity: Although ice is uniformly composed of water molecules, it has many different surfaces exposed for binding. Different types of AFPs may interact with different surfaces. Although the five types of AFPs differ in their primary structure of amino acids, when each folds into a functioning protein they may share similarities in their three-dimensional or tertiary structure that facilitates the same interactions with ice. Antifreeze glycoprotein activity has been observed across several ray-finned species including eelpouts, sculpins, and cod species. Fish species that possess the antifreeze glycoprotein express different levels of protein activity. Polar cod (Boreogadus saida) exhibit similar protein activity and properties to the Antarctic species, T. borchgrevinki. Both species have higher protein activity than saffron cod (Eleginus gracilis). Ice antifreeze proteins have been reported in diatom species to help decrease the freezing point of organism's proteins. Bayer-Giraldi et al. 2010 found 30 species from distinct taxa with homologues of ice antifreeze proteins. The diversity is consistent with previous research that has observed the presence of these genes in crustaceans, insects, bacteria, and fungi. Horizontal gene transfer is responsible for the presence of ice antifreeze proteins in two sea diatom species, F. cylindrus and F. curta. == Mechanisms of action == AFPs are thought to inhibit ice growth by an adsorption–inhibition mechanism. They adsorb to nonbasal planes of ice, inhibiting thermodynamically-favored ice growth. The presence of a flat, rigid surface in some AFPs seems to facilitate its interaction with ice via Van der Waals force surface complementarity. == Binding to ice == Normally, ice crystals grown in solution only exhibit the basal (0001) and prism faces (1010), and appear as round and flat discs. However, it appears the presence of AFPs exposes other faces. It now appears the ice surface 2021 is the preferred binding surface, at least for AFP type I. Through studies on type I AFP, ice and AFP were initially thought to interact through hydrogen bonding (Raymond and DeVries, 1977). However, when parts of the protein thought to facilitate this hydrogen bonding were mutated, the hypothesized decrease in antifreeze activity was not observed. Recent data suggest hydrophobic interactions could be the main contributor. It is difficult to discern the exact mechanism of binding because of the complex water-ice interface. Currently, attempts to uncover the precise mechanism are being made through use of molecular modelling programs (molecular dynamics or the Monte Carlo method). == Binding mechanism and antifreeze function == According to the structure and function study on the antifreeze protein from Pseudopleuronectes americanus, the antifreeze mechanism of the type-I AFP molecule was shown to be due to the binding to an ice nucleation structure in a zipper-like fashion through hydrogen bonding of the hydroxyl groups of its four Thr residues to the oxygens along the [ 01 1 ¯ 2 ] {\displaystyle [01{\overline {1}}2]} direction in ice lattice, subsequently stopping or retarding the growth of ice pyramidal planes so as to depress the freeze point. The above mechanism can be used to elucidate the structure-function relationship of other antifreeze proteins with the following two common features: recurrence of a Thr residue (or any other polar amino acid residue whose side-chain can form a hydrogen bond with water) in an 11-amino-acid period along the sequence concerned, and a high percentage of an Ala residue component therein. == History == In the 1950s, Norwegian scientist Scholander set out to explain how Arctic fish can survive in water colder than the freezing point of their blood. His experiments led him to believe there was “antifreeze” in the blood of Arctic fish. Then in the late 1960s, animal biologist Arthur DeVries was able to isolate the antifreeze protein through his investigation of Antarctic fish. These proteins were later called antifreeze glycoproteins (AFGPs) or antifreeze glycopeptides to distinguish them from newly discovered nonglycoprotein biological antifreeze agents (AFPs). DeVries worked with Robert Feeney (1970) to characterize the chemical and physical properties of antifreeze proteins. In 1992, Griffith et al. documented their discovery of AFP in winter rye leaves. Around the same time, Urrutia, Duman and Knight (1992) documented thermal hysteresis protein in angiosperms. The next year, Duman and Olsen noted AFPs had also been discovered in over 23 species of angiosperms, including ones eaten by humans. They reported their presence in fungi and bacteria as well. == Name change == Recent attempts have been made to relabel antifreeze proteins as ice structuring proteins to more accurately represent their function and to dispose of any assumed negative relation between AFPs and automotive antifreeze, ethylene glycol. These two things are completely separate entities, and show loose similarity only in their function. == Commercial and medical applications == Numerous fields would be able to benefit from the protection of tissue damage by freezing. Businesses are currently investigating the use of these proteins in: Increasing freeze tolerance of crop plants and extending the harvest season in cooler climates Improving farm fish production in cooler climates Lengthening shelf life of frozen foods Improving cryosurgery Enhancing preservation of tissues for transplant or transfusion in medicine Therapy for hypothermia Human Cryopreservation (Cryonics) Unilever has obtained UK, US, EU, Mexico, China, Philippines, Australia and New Zealand approval to use a genetically modified yeast to produce antifreeze proteins from fish for use in ice cream production. They are labeled "ISP" or ice structuring protein on the label, instead of AFP or antifreeze protein. == Recent news == One recent, successful business endeavor has been the introduction of AFPs into ice cream and yogurt products. This ingredient, labelled ice-structuring protein, has been approved by the Food and Drug Administration. The proteins are isolated from fish and replicated, on a larger scale, in genetically modified yeast. There is concern from organizations opposed to genetically modified organisms (GMOs) who believe that antifreeze proteins may cause inflammation. Intake of AFPs in diet is likely substantial in most northerly and temperate regions already. Given the known historic consumption of AFPs, it is safe to conclude their functional properties do not impart any toxicologic or allergenic effects in humans. As well, the transgenic process of ice structuring proteins production is widely used in society. Insulin and rennet are produced using this technology. The process does not impact the product; it merely makes production more efficient and prevents the death of fish that would otherwise be killed to extract the protein. Currently, Unilever incorporates AFPs into some of its American products, including some Popsicle ice pops and a new line of Breyers Light Double Churned ice cream bars. In ice cream, AFPs allow the production of very creamy, dense, reduced fat ice cream with fewer additives. They control ice crystal growth brought on by thawing on the loading dock or kitchen table, which reduces texture quality. In November 2009, the Proceedings of the National Academy of Sciences published the discovery of a molecule in an Alaskan beetle that behaves like AFPs, but is composed of saccharides and fatty acids. A 2010 study demonstrated the stability of superheated water ice crystals in an AFP solution, showing that while the proteins can inhibit freezing, they can also inhibit melting. In 2021, EPFL and Warwick scientists have found an artificial imitation of antifreeze proteins. == References == == Further reading == == External links == Cold, Hard Fact: Fish Antifreeze Produced in Pancreas Antifreeze Proteins: Molecule of the Month Archived 2015-11-04 at the Wayback Machine, by David Goodsell, RCSB Protein Data Bank Overview of all the structural information available in the PDB for UniProt: Q9GTP0 (Thermal hysteresis or Antifreeze protein) at the PDBe-KB.	Wikipedia/Antifreeze_protein
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV,: 6822 is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease since it contains a residue of serine in its active site.: 35 In humans, protein C is encoded by the PROC gene, which is found on chromosome 2. The zymogenic form of protein C is a vitamin K-dependent glycoprotein that circulates in blood plasma. Its structure is that of a two-chain polypeptide consisting of a light chain and a heavy chain connected by a disulfide bond.: 4673 The protein C zymogen is activated when it binds to thrombin, another protein heavily involved in coagulation, and protein C's activation is greatly promoted by the presence of thrombomodulin and endothelial protein C receptors (EPCRs). Because of EPCR's role, activated protein C is found primarily near endothelial cells (i.e., those that make up the walls of blood vessels), and it is these cells and leukocytes (white blood cells) that APC affects.: 34 : 3162 Because of the crucial role that protein C plays as an anticoagulant, those with deficiencies in protein C, or some kind of resistance to APC, suffer from a significantly increased risk of forming dangerous blood clots (thrombosis). Research into the clinical use of a recombinant form of human Activated Protein C (rhAPC) known as Drotrecogin alfa-activated, branded Xigris by Eli Lilly and Company, has been surrounded by controversy. Eli Lilly ran an aggressive marketing campaign to promote its use for people with severe sepsis and septic shock and sponsored the 2004 Surviving Sepsis Campaign Guidelines. However, a 2012 Cochrane review found that its use cannot be recommended since it does not improve survival and increases bleeding risk. In October 2011, Xigris was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. == History == Protein C's anticoagulant role in the human body was first noted by Seegers et al. in 1960, who gave protein C its original name, autoprothrombin II-a.: 6822 Protein C was first isolated by Johan Stenflo from bovine plasma in 1976, and Stenflo determined it to be a vitamin K-dependent protein. He named it protein C because it was the third protein ("peak C") that eluted from a DEAE-Sepharose ion-exchange chromotograph. Seegers was, at the time, searching for vitamin K-dependent coagulation factors undetected by clotting assays, which measure global clotting function. Soon after this, Seegers recognised Stenflo's discovery was identical with his own.: 6822 Activated protein C was discovered later that year, and in 1977 it was first recognised that APC inactivates Factor Va.: 2382 In 1980, Vehar and Davie discovered that APC also inactivates Factor VIIIa, and soon after, Protein S was recognised as a cofactor by Walker. In 1982, a family study by Griffin et al. first associated protein C deficiency with symptoms of venous thrombosis. Homozygous protein C deficiency and the consequent serious health effects were described in 1984 by several scientists.: 1214 cDNA cloning of protein C was first performed in 1984 by Beckmann et al. which produced a map of the gene responsible for producing protein C in the liver. In 1987 a seminal experiment was performed (Taylor et al.) whereby it was demonstrated that activated protein C prevented coagulopathy and death in baboons infused with lethal concentrations of E. coli.: 2382 In 1993, a heritable resistance to APC was detected by Dahlbäck et al. and associated with familial thrombophilia. In 1994, the relatively common genetic mutation that produces Factor VLeiden was noted (Bertina et al.). Two years later, Gla-domainless APC was imaged at a resolution of 2.8 Ångströms. Beginning with the PROWESS clinical trial of 2001, it was recognised that many of the symptoms of sepsis may be ameliorated by infusion of APC, and mortality rates of septic patients may be significantly decreased.: 3161, 6 Near the end of that year, Drotrecogin alfa (activated), a recombinant human activated protein C, became the first drug approved by the U.S. FDA for treating severe sepsis. In 2002, Science published an article that first showed protein C activates protease-activated receptor-1 (PAR-1) and this process accounts for the protein's modulation of the immune system.: 2382 == Genetics == The biologic instructions for synthesising protein C in humans are encoded in the gene officially named "protein C (inactivator of coagulation factors Va and VIIIa)". The gene's symbol approved by the HUGO Gene Nomenclature Committee is "PROC" from "protein C". It is located on the second chromosome (2q13-q14) and comprises nine exons.: 2383 The nucleotide sequence that codes for human protein C is approximately 11,000 bases long.: 4675 == Structure and processing == Human protein C is a vitamin K-dependent glycoprotein structurally similar to other vitamin K-dependent proteins affecting blood clotting, such as prothrombin, Factor VII, Factor IX and Factor X.: 1215 Protein C synthesis occurs in the liver and begins with a single-chain precursor molecule: a 32 amino acid N-terminus signal peptide preceding a propeptide.: S11 Protein C is formed when a dipeptide of Lys198 and Arg199 is removed; this causes the transformation into a heterodimer with N-linked carbohydrates on each chain. The protein has one light chain (21 kDa) and one heavy chain (41 kDa) connected by a disulfide bond between Cys183 and Cys319. Inactive protein C comprises 419 amino acids in multiple domains:: 2383 one Gla domain (residues 43–88); a helical aromatic segment (89–96); two epidermal growth factor (EGF)-like domains (97–132 and 136–176); an activation peptide (200–211); and a trypsin-like serine protease domain (212–450). The light chain contains the Gla- and EGF-like domains and the aromatic segment. The heavy chain contains the protease domain and the activation petide. It is in this form that 85–90% of protein C circulates in the plasma as a zymogen, waiting to be activated.: 6822 The remaining protein C zymogen comprises slightly modified forms of the protein. Activation of the enzyme occurs when a thrombin molecule cleaves away the activation peptide from the N-terminus of the heavy chain.: 4673 : S11 The active site contains a catalytic triad typical of serine proteases (His253, Asp299 and Ser402).: 2833 The Gla domain is particularly useful for binding to negatively charged phospholipids for anticoagulation and to EPCR for cytoprotection. One particular exosite augments protein C's ability to inactivate Factor Va efficiently. Another is necessary for interacting with thrombomodulin.: 2833 Post-translational modifications. Human Protein C has at least five types of post-translational modifications: (1) gamma-carboxylation on the first nine glutamic acid residues in the protein sequence. This modification event is performed by a vitamin K-dependent microsomal carboxylase. The full complement of Gla is required to give full activity to protein C. (2) beta-Hydroxylation of Asp71 in one of the two EGF-like domains to give erythro-L-beta-hydroxy-aspartate (bHA). The modification is required for functional activity as was demonstrated by mutating Asp71 to Glu. (3) N-linked glycosylation at three possible glycosylation sites. Plasma human Protein C has been reported to be 23% carbohydrate by weight. (4) Disulfide formation. (5) Multiple proteolytic cleavages of the polypeptide backbone to remove an 18 amino acid signal peptide, a 24 amino acid propeptide and then cleavages at amino acids 155-156 and 157-158 to yield the two-chain structure of the circulating zymogen. == Physiology == The activation of protein C is strongly promoted by thrombomodulin and endothelial protein C receptor (EPCR), the latter of which is found primarily on endothelial cells (cells on the inside of blood vessels). The presence of thrombomodulin accelerates activation by several orders of magnitude,: 34 and EPCR speeds up activation by a factor of 20. If either of these two proteins is absent in murine specimens, the mouse dies from excessive blood-clotting while still in an embryonic state.: 1983 : 43335 On the endothelium, APC performs a major role in regulating blood clotting, inflammation, and cell death (apoptosis).: 28S Because of the accelerating effect of thrombomodulin on the activation of protein C, the protein may be said to be activated not by thrombin but the thrombin–thrombomodulin (or even thrombin–thrombomodulin–EPCR) complex.: 2381 Once in active form, APC may or may not remain bound to EPCR, to which it has approximately the same affinity as the protein zymogen.: 3162 Protein C in zymogen form is present in normal adult human blood plasma at concentrations between 65 and 135 IU/dL. Activated protein C is found at levels approximately 2000 times lower than this.: 3161 Mild protein C deficiency corresponds to plasma levels above 20 IU/dL, but below the normal range. Moderately severe deficiencies describe blood concentrations between 1 and 20 IU/dL; severe deficiencies yield levels of protein C that are below 1 IU/dL or are undetectable. Protein C levels in a healthy term infant average 40 IU/dL. The concentration of protein C increases until six months, when the mean level is 60 IU/dL; the level stays low through childhood until it reaches adult levels after adolescence.: 1216 The half-life of activated protein C is around 15 minutes.: 6823 == Pathways == The protein C pathways are the specific chemical reactions that control the level of expression of APC and its activity in the body.: 34 Protein C is pleiotropic, with two main classes of functions: anticoagulation and cytoprotection (its direct effect on cells). Which function protein C performs depends on whether or not APC remains bound to EPCR after it is activated; the anticoagulative effects of APC occur when it does not. In this case, protein C functions as an anticoagulant by irreversibly proteolytically inactivating Factor Va and Factor VIIIa, turning them into Factor Vi and Factor VIIIi respectively. When still bound to EPCR, activated protein C performs its cytoprotective effects, acting on the effector substrate PAR-1, protease-activated receptor-1. To a degree, APC's anticoagulant properties are independent of its cytoprotective ones, in that expression of one pathway is not affected by the existence of the other.: 3162 : 26S The activity of protein C may be down-regulated by reducing the amount either of available thrombomodulin or of EPCR. This may be done by inflammatory cytokines, such as interleukin-1β (IL-1β ) and tumor necrosis factor-α (TNF-α). Activated leukocytes release these inflammatory mediators during inflammation, inhibiting the creation of both thrombomodulin and EPCR, and inducing their shedding from the endothelial surface. Both of these actions down-regulate protein C activation. Thrombin itself may also have an effect on the levels of EPCR. In addition, proteins released from cells can impede protein C activation, for example eosinophil, which may explain thrombosis in hypereosinophilic heart disease. Protein C may be up-regulated by platelet factor 4. This cytokine is conjectured to improve activation of protein C by forming an electrostatic bridge from protein C's Gla domain to the glycosaminoglycan (GAG) domain of thrombomodulin, reducing the Michaelis constant (KM) for their reaction.: 2386 : 29S In addition, Protein C is inhibited by protein C inhibitor.: 369 === Anticoagulative effects === Protein C is a major component in anticoagulation in the human body. It acts as a serine protease zymogen: APC proteolyses peptide bonds in activated Factor V and Factor VIII (Factor Va and Factor VIIIa), and one of the amino acids in the bond is serine.: 2381 These proteins that APC inactivates, Factor Va and Factor VIIIa, are highly procoagulant cofactors in the generation of thrombin, which is a crucial element in blood clotting; together they are part of the prothrombinase complex.: 26S Cofactors in the inactivation of Factor Va and Factor VIIIa include protein S, Factor V, high-density lipoprotein, anionic phospholipids and glycosphingolipids.: 3161 Factor Va binds to prothrombin and Factor Xa, increasing the rate at which thrombin is produced by four orders of magnitude (10,000x). Inactivation of Factor Va thus practically halts the production of thrombin. Factor VIII, on the other hand, is a cofactor in production of activated Factor X, which in turn converts prothrombin into thrombin. Factor VIIIa augments Factor X activation by a factor of around 200,000. Because of its importance in clotting, Factor VIII is also known as anti-haemophilic factor, and deficiencies of Factor VIII cause haemophilia A.: 2382, 3 APC inactivates Factor Va by making three cleavages (Arg306, Arg506, Arg679). The cleavages at both Arg306 and Arg506 diminish the molecule's attraction to Factor Xa, and though the first of these sites is slow to be cleaved, it is entirely necessary to the functioning of Factor V. Protein S aids this process by catalysing the proteolysis at Arg306, in which the A2 domain of Factor V is dissociated from the rest of the protein. Protein S also binds to Factor Xa, inhibiting the latter from diminishing APC's inactivation of Factor Va.: 2386 The inactivation of Factor VIIIa is not as well understood. The half-life of Factor VIIIa is only around two minutes unless Factor IXa is present to stabilise it. Some have questioned the significance of APC's inactivation of Factor VIIIa, and it is unknown to what degree Factor V and protein S are cofactors in its proteolysis. It is known that APC works on Factor VIIIa by cleaving at two sites, Arg336 and Arg562, either of which is sufficient to disable Factor VIIIa and convert it to Factor VIIIi.: 2387 === Cytoprotective effects === When APC is bound to EPCR, it performs a number of important cytoprotective (i.e. cell-protecting) functions, most of which are known to require EPCR and PAR-1. These include regulating gene expression, anti-inflammatory effects, antiapoptotic effects and protecting endothelial barrier function.: 3162 Treatment of cells with APC demonstrates that its gene expression modulation effectively controls major pathways for inflammatory and apoptotic behaviour. There are about 20 genes that are up-regulated by protein C, and 20 genes that are down-regulated: the former are generally anti-inflammatory and antiapoptotic pathways, while the latter tend to be proinflammatory and proapoptotic. APC's mechanisms for altering gene expression profiles are not well understood, but it is believed that they at least partly involve an inhibitory effect on transcription factor activity.: 3162, 4 Important proteins that APC up-regulates include Bcl-2, eNOS and IAP. APC effects significant down-regulation of p53 and Bax.: 2388 APC has anti-inflammatory effects on endothelial cells and leukocytes. APC affects endothelial cells by inhibiting inflammatory mediator release and down-regulating vascular adhesion molecules. This reduces leukocyte adhesion and infiltration into tissues, while also limiting damage to underlying tissue. APC supports endothelial barrier function and reduces chemotaxis. APC inhibits the release of inflammatory-response mediators in leukocytes as well as endothelial cells, by reducing cytokine response, and maybe diminishing systemic inflammatory response, such as is seen in sepsis. Studies on both rats and humans have demonstrated that APC reduces endotoxin-induced pulmonary injury and inflammation.: 3164 Scientists recognise activated protein C's antiapoptotic effects, but are unclear as to the exact mechanisms by which apoptosis is inhibited. It is known that APC is neuroprotective. Antiapoptosis is achieved with diminished activation of caspase 3 and caspase 8, improved Bax/Bcl-2 ratio and down-regulation of p53.: 2388 Activated protein C also provides much protection of endothelial barrier function. Endothelial barrier breakdown, and the corresponding increase in endothelial permeability, are associated with swelling, hypotension and inflammation, all problems of sepsis. APC protects endothelial barrier function by inducing PAR-1 dependent sphingosine kinase-1 activation and up-regulating sphingosine-1-phosphate with sphingosine kinase.: 3165 Several studies have indicated that the proteolytic activity of APC contributes to the observed cytoprotective properties of APC, but variants that are proteolytically inactive also are able to regulate formation of PAR-activators thrombin and factor Xa and express cytoprotective properties in vitro and in vivo. == Role in disease == A genetic protein C deficiency, in its mild form associated with simple heterozygosity, causes a significantly increased risk of venous thrombosis in adults. If a fetus is homozygous or compound heterozygous for the deficiency, there may be a presentation of purpura fulminans, severe disseminated intravascular coagulation and simultaneous venous thromboembolism in the womb;: 1214 this is very severe and usually fatal.: 211s Deletion of the protein C gene in mice causes fetal death around the time of birth. Fetal mice with no protein C develop normally at first, but experience severe bleeding, coagulopathy, deposition of fibrin and necrosis of the liver.: 3161 The frequency of protein C deficiency among asymptomatic individuals is between 1 in 200 and 1 in 500. In contrast, significant symptoms of the deficiency are detectable in 1 in 20,000 individuals. No racial nor ethnic biases have been detected.: 1215 At least 177 disease-causing mutations in this gene have been discovered. Activated protein C resistance occurs when APC is unable to perform its functions. This disease has similar symptoms to protein C deficiency. The most common mutation leading to activated protein C resistance among Caucasians is at the cleavage site in Factor V for APC. There, Arg506 is replaced with Gln, producing Factor V Leiden. This mutation is also called a R506Q.: 2382 The mutation leading to the loss of this cleavage site actually stops APC from effectively inactivating both Factor Va and Factor VIIIa. Thus, the person's blood clots too readily, and he is perpetually at an increased risk for thrombosis.: 3 Individuals heterozygous for the Factor VLeiden mutation carry a risk of venous thrombosis 5–7 times higher than in the general population. Homozygous subjects have a risk 80 times higher.: 40 This mutation is also the most common hereditary risk for venous thrombosis among Caucasians.: 2382 Around 5% of APC resistance are not associated with the above mutation and Factor VLeiden. Other genetic mutations cause APC resistance, but none to the extent that Factor VLeiden does. These mutations include various other versions of Factor V, spontaneous generation of autoantibodies targeting Factor V, and dysfunction of any of APC's cofactors.: 2387 Also, some acquired conditions may reduce the efficacy of APC in performing its anticoagulative functions.: 33 Studies suggest that between 20% and 60% of thrombophilic patients suffer from some form of APC resistance.: 37 Warfarin necrosis is an acquired protein C deficiency due to treatment with warfarin, which is a vitamin K antagonist and an anticoagulant itself. However, warfarin treatment may produce paradoxical skin lesions similar to those seen in purpura fulminans. A variant of this response presents as venous limb gangrene when warfarin is used to treat deep vein thrombosis associated with cancer. In these situations, warfarin may be restarted at a low dosage to ensure that the protein C deficiency does not present before the vitamin K coagulation factors II, IX and X are suppressed.: 211s Activated protein C cleaves Plasmodium falciparum histones which are released during infection: cleavage of these histones eliminates their pro inflammatory effects. == Role in medicine == In November 2001, the Food and Drug Administration approved Drotrecogin alfa-activated (DrotAA) for the clinical treatment of adults suffering from severe sepsis and with a high risk of death.: 1332 Drotrecogin alfa-activated is a recombinant form of human activated protein C (rhAPC). It is marketed as Xigris by Eli Lilly and Company,: 224 Drotrecogin alfa-activated was the subject of significant controversy while it was approved for clinical use as it was found to increase bleeding and not to reduce mortality. In October 2011 rhAPC (Xigris) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. APC has been studied as way of treating lung injury, after studies showed that in patients with lung injury, reduced APC levels in specific parts of the lungs correlated with worse outcomes.: 3167, 8 APC also has been considered for use in improving patient outcome in cases of ischemic stroke, a medical emergency in which arterial blockage deprives a region of brain of oxygen, causing tissue death. Promising studies suggest that APC could be coupled with the only currently approved treatment, tissue plasminogen activator (tPA), to protect the brain from tPA's very harmful side effects, in addition to preventing cell death from lack of oxygen (hypoxia).: 211 Clinical use of APC has also been proposed for improving the outcome of pancreatic islet transplantation in treating type I diabetes.: 2392 Ceprotin was approved for medical used in the European Union in July 2001. Ceprotin is indicated in purpura fulminans and coumarin-induced skin necrosis in people with severe congenital protein C deficiency. == See also == Activated protein C–protein C inhibitor == Notes == ^ α: GLA-domainless protein C is produced by selective proteolysis between residues 82 and 83 to remove the N-terminal portion of the protein that includes essentially all of the GLA domain (residues 47–88). The N-terminus was removed in order to make crystallization of the protein easier.: 5548 ^ β: In hypereosinophilia, excess eosinophil-specific granule proteins (such as major basic protein, erythropoietin and eosinophil cationic protein) on the endothelial surface bind to thrombomodulin and inhibit its participation in the activation of protein C by electrostatic interaction on the surface of thrombomodulin.: 1728 == References == == External links == The MEROPS online database for peptidases and their inhibitors: S01.218 Archived 2007-09-16 at the Wayback Machine Overview of all the structural information available in the PDB for UniProt: P04070 (Vitamin K-dependent protein C) at the PDBe-KB.	Wikipedia/Protein_C
β2-glycoprotein 1, also known as beta-2 glycoprotein 1 and Apolipoprotein H (Apo-H), is a 38 kDa multifunctional plasma protein that in humans is encoded by the APOH gene. One of its functions is to bind cardiolipin. When bound, the structure of cardiolipin and β2-GP1 both undergo large changes in structure. Within the structure of Apo-H is a stretch of positively charged amino acids (protein sequence positions 282-287), Lys-Asn-Lys-Glu-Lys-Lys, are involved in phospholipid binding (see image on right). β2-GP1 has a complex involvement in agglutination. It appears to alter adenosine diphosphate (ADP)-mediated agglutination of platelets. Normally, β2-GP1 assumes an anticoagulation activity in serum (by inhibiting coagulation factors); however, changes in blood factors can result in a reversal of that activity. Although previously referred to as apolipoprotein H, it is not present in appreciable quantities in the lipoprotein fractions, so ApoH is therefore thought to be a misnomer. == Inhibitory activities == β2-GP1 appears to completely inhibit serotonin release by the platelets and prevents subsequent waves of the ADP-induced aggregation. The activity of β2-GP1 appears to involve the binding of agglutinating, negatively charged compounds, and inhibits agglutination by the contact activation of the intrinsic blood coagulation pathway. β2-GP1 causes a reduction of the prothrombinase binding sites on platelets and reduces the activation caused by collagen when thrombin is present at physiological serum concentrations of β2-GP1 suggesting a regulatory role of β2-GP1 in coagulation. β2-GP1 also inhibits the generation of factor Xa in the presence of platelets. β2-GP1 also inhibits that activation of factor XIIa. In addition, β2-GP1 inhibits the activation of protein C blocking its activity on phosphatidylserine:phosphatidylcholine vesicles however once protein C is activated, Apo-H fails to inhibit activity. Since protein C is involved in factor Va degradation Apo-H indirectly inhibits the degradation of factor Va. This inhibitory activity is diminished by adding phospholipids suggesting the Apo-H inhibition of protein C is phospholipid competitive. This indicates that under certain conditions Apo-H takes on procoagulation properties. == Pathology == Anti-β2-GP1 antibodies are found in both infectious and some systemic autoimmune diseases (eg. systemic lupus erythematosus (SLE)). Positivity for anti-cardiolipin antibodies in diagnostic tests for autoimmune antiphospholipid syndrome requires the presence of β2-GP1in the cardiolipin extract. Anti-β2-GP1 antibodies are strongly associated with thrombotic forms of lupus. == Sushi 2 protein domain == In molecular biology, the protein domain Sushi 2 is also known as the fifth protein domain of beta-2 glycoprotein 1 (β2-GP1). This protein domain is only found in eukaryotes. The first four domains found in Apolipoprotein H resemble each other, however the fifth one appears to be different. === Structure === This protein domain is composed of four well-defined anti-parallel beta-strands and two short alpha-helices, as well as a long highly flexible loop. Additionally, the fifth protein domain appears to resemble the other four in Apolipoprotein with the exception of three internal disulfide bonds and an extra C-terminal loop. === Function === Its exact function remains to be fully elucidated; however it is known to play an important role in the binding of β2-GP1 to negatively charged compounds and subsequent capture for binding of anti-β2-GP1 antibodies. Development of antibodies against β2-GP1 can lead to Antiphospholipid syndrome which often leads to pregnancy complications. == References == == External links == Apolipoprotein+H at the U.S. National Library of Medicine Medical Subject Headings (MeSH) Apolipoprotein H and Applied Research Human APOH genome location and APOH gene details page in the UCSC Genome Browser. PDBe-KB provides an overview of all the structure information available in the PDB for Human Apolipoprotein H (B2G1)	Wikipedia/Apolipoprotein_H
Variant surface glycoprotein (VSG) is a ~60kDa protein which densely packs the cell surface of protozoan parasites belonging to the genus Trypanosoma. This genus is notable for their cell surface proteins. They were first isolated from Trypanosoma brucei in 1975 by George Cross. VSG allows the trypanosomatid parasites to evade the mammalian host's immune system by extensive antigenic variation. They form a 12–15 nm surface coat. VSG dimers make up ~90% of all cell surface protein and ~10% of total cell protein. For this reason, these proteins are highly immunogenic and an immune response raised against a specific VSG coat will rapidly kill trypanosomes expressing this variant. However, with each cell division there is a possibility that the progeny will switch expression to change the VSG that is being expressed. VSG has no prescribed biochemical activity. The parasite has a large cellular repertoire of antigenically distinct VSGs (~1500/2000 complete and partial (pseudogenes)) located in telomeric and subtelomeric arrays (on megabase chromosomes or minichromosomes). VSGs are expressed from a bloodstream expression site (BES, ES) in a polycistron by RNA polymerase I (recruited to a ribosomal-type promoter) with other ES-associated genes (ESAGs), of which transferrin receptor (Tfr: ESAG6, ESAG7) is one. Only one VSG gene is expressed at a time, as only one of the ~15 ES are active in a cell. VSG expression is 'switched' by homologous recombination of a silent basic copy gene from an array (directed by homology) into the active telomerically-located expression site. During this transition, trypanosomes simultaneously display both pre- and post-switch VSGs on their surface. This coat replacement process is critical for the survival of recently switched cells because initial VSGs remain targets for the escalating host Ab response. Mosaic VSG genes can be created by homologous recombination of a partial VSG gene from an array. This partial gene may replace any portion of the residing VSG gene, creating a new mosaic VSG. VSG half-life measurements suggest that initial VSGs may persist on the surface of genetically switched trypanosomes for several days. It remains unclear whether the regulation of VSG switching is purely stochastic or whether environmental stimuli affect switching frequency. The fact that switching occurs in vitro suggests that there is at least some host-independent, stochastic element to the process. The antigenic variation causes cyclical waves of parasitemia, which is one of the characteristics of human African trypanosomiasis. The cyclical process take 5–8 days. This occurs because a diverse range of coats expressed by the trypanosome population means that the immune system is always one step behind: it takes several days for an immune response against a given VSG to develop, giving the population time to diversify as individuals undergo further switching events. The repetition of this process prevents the extinction of the infecting trypanosome population, allowing chronic persistence of parasites in the host and enhancing opportunities for transmission. == In Trypanosoma brucei == In Trypanosoma brucei, the cell surface is covered by a dense coat of ~5 x 106 VSG dimers, ~90% of all cell surface protein and ~10% of total cell protein. The properties of the VSG coat that enable immune evasion are: Shielding – the dense nature of the VSG coat (VSG proteins pack shoulder-to-shoulder) prevents the immune system of the mammalian host from accessing the plasma membrane or any other parasitic invariant surface epitopes (such as ion channels, transporters, receptors etc.). The coat is uniform, made up of millions of copies of the same molecule; therefore, VSG is the only part of the trypanosome that the immune system can recognize. Periodic antigenic variation – the VSG coat undergoes frequent stochastic genetic modification—'switching'—allowing variants expressing a new VSG coat to escape the specific immune response raised against the previous coat. This antigenic variation creates cyclical waves of parasitemia characteristic of Human African Trypanosomiasis. Antigen 'cleaning' and VSG recycling—VSG is efficiently recycled through the trypanosome flagellar pocket, allowing antibodies to be 'cleaned' from VSG before re-incorporation back into the cellular membrane. Importantly, VSGs recognized and bound by antibodies are selectively pushed toward the flagellar pocket at a quicker rate than unidentified VSG; in this scenario, the antibody acts as a 'sail', which quickens the process of VSG being brought to the area of recycling. The VSGs from T. brucei are attached to the plasma membrane via a covalent attachment to two glycosyl-phosphatidylinositol (GPI) anchors (one per monomer), which directs its forward-trafficking from the ER to the flagellar pocket for incorporation into the membrane, as predicted by the GPI valence hypothesis. VSGs are replaced by an equally dense coat of procyclins when the parasite differentiates into the procyclic form in the tsetse fly midgut. There is a very fast inhibition of VSG gene transcription which occurs as soon as the temperature is lowered. === Expression === The source of VSG variability during infection is a large 'archive' of VSG genes present in the T. brucei genome. Some of these are full-length, intact genes; others are pseudogenes (typically with frameshift mutations, premature stop codons, or fragmentation). Expression of an antigenically different VSG can occur by simply switching to a different full-length VSG gene by Expression Site switching (switching which ES is active). In addition, chimeric or 'mosaic' VSG genes can be generated by combining segments from more than one silent VSG gene. The formation of mosaic VSGs allows the (partial) expression of pseudogene VSGs, which can constitute the major portion of the VSG archive, and can contribute directly to antigenic variation, vastly increasing the trypanosome's capacity for immune evasion and posing a major problem for vaccine development. VSG genes can be kept silent and switched on at any given time. The expressed VSG is always located in an Expression Site (ES), which are specialised expression loci found at the telomeres of some of the large and intermediate chromosomes. Each ES is a polycistronic unit, containing a number of Expression Site-Associated Genes (ESAGs) all expressed along with the active VSG. While multiple ES exist, only a single one is ever active at one time. A number of mechanisms appear to be involved in this process, but the exact nature of the silencing is still unclear. The expressed VSG can be switched either by activating a different expression site (and thus changing to express the VSG in that site), or by changing the VSG gene in the active site to a different variant. The genome contains many copies of VSG genes, both on minichromosomes and in repeated sections in the interior of the chromosomes. These are generally silent, typically with omitted sections or premature stop codons, but are important in the evolution of new VSG genes. It is estimated up to 10% of the T.brucei genome may be made up of VSG genes or pseudogenes. Any of these genes can be moved into the active site by recombination for expression. Again, the exact mechanisms that control this are unclear, but the process seems to rely on DNA repair machinery and a process of homologous recombination. The bloodstream expression site (BES), or telomeric expression site, is used for exchanging variant surface glycoproteins when in host's blood stream to escape the complement system. BESs are polymorphic in size and structure but reveal a surprisingly conserved architecture in the context of extensive recombination. Very small BESs do exist and many functioning BESs do not contain the full complement of expression site associated genes (ESAGs). There is a collection of an estimated 20-30 sites, each being active at a time. Active VSG expression sites are depleted of nucleosomes. The gene repertoires in T. brucei have diverged to become strain-specific. The variant surface glycoprotein genes of T. brucei have been classified into two groups depending upon whether or not duplication of the genes is observed when they are expressed. === Secretory trafficking === Trypanosoma have a simple, polarized membrane transport system consisting of a single ER, lysosome, and Golgi apparatus. VSG is first transcribed as a polycistron and then undergoes trypanosomatid-specific poly-adenylation and trans-splicing directed by polypyrimidine tracts. Because there is no transcriptional control, the VSG 3'UTR is important for its RNA stability (most importantly, the 8mer and 14mer). VSG is then transcribed on membrane-bound polysomes, and the appearance of the N-terminal signal sequence directs VSG to the ER. VSG is thereby co-translationally transported into the ER lumen, rapidly N-glycosylated (on asn-x-ser/thr sites) and GPI anchored at the ω site by a transamination reaction (removing of the C-term hydrophobic 17 or 23 aa GPI anchoring sequence). The ω site is always Ser (usually in 17 aa signal sequence peptides), Asp (usually in 23 aa signal sequence peptides), or Asn. Also, the number of N-glycosylation sites per VSG may vary (usually 1-3 N-glycans). VSG MITat.1.5 is glycosylated at all three potential N-glycosylation sites. VSG then undergoes the calreticulin/calnexin folding cycle (calnexin is absent in Trypanosoma brucei), where it is transiently monoglucosylated and deglucosylated, and interacts with various ER chaperone proteins, such as BiP, in order to fold correctly. VSG efficiently folds and dimerizes (suggesting intrinsically favorable folding) and is transported through the Golgi to the flagellar pocket for incorporation into the cell membrane. Importantly, following incorporation into the cellular membrane, VSG may later be recycled through the flagellar pocket and sorted back to the cell surface. VSG is not turned over by lysosomal or proteasomal canonical degradation pathways, but is instead lost from the cell by specific cleavage of its GPI anchor by GPI-specific PLC. === Structure === VSG genes are hugely variable at the sequence (primary) level, but variants are thought to have strongly conserved structural (tertiary) features, based on two determined 3-dimensional structures and conservation of 2-dimensional sequence motifs (descending and ascending alpha-helices that make up the dimerization interface), allowing them to perform a similar shielding function. VSGs are made up of N terminal domain of around 300–350 amino acids with low sequence homology (13–30% identity), and a more conserved C terminal domain of ~100 amino acids. N-terminal domains are grouped into classes A-C depending on their cysteine patterns. C-term domains are grouped by sequence homology into classes I-III, with apparently no restriction on which N-term classes they can pair with to form a full VSG. To dimerize, VSG N-terminal domains form a bundle of four alpha helices directed by hydrophobic interactions, around which hang smaller structural features (five smaller helices and three beta-sheets). VSG is anchored to the cell membrane via a glycophosphatidylinositol (GPI) anchor—a noncovalent linkage from the C-terminus which directs its forward trafficking from the ER to the membrane. This GPI anchor is specifically cleaved by GPI Phospholipase C, cleaving the membrane-form VSG, and allowing VSG protein and portion of the GPI anchor to be lost into the extracellular milieu as soluble VSG (sVSG, which is can be recognized as Cross-Reacting Determinant, or CRD), while retaining the two 1,2-dimyristolglycerol chains in the membrane. === Antigenic variation === VSG is highly immunogenic, and an immune response raised against a specific VSG coat will rapidly kill trypanosomes expressing this variant. Antibody-mediated trypanosome killing can also be observed in vitro by a complement-mediated lysis assay. However, with each cell division there is a possibility that one or both of the progeny will switch expression to change the VSG that is being expressed. The frequency of VSG switching has been measured to be approximately 0.1% per division, though switching rates do differ in culture vs. in vivo. As T. brucei populations can peak at a size of 1011 within a host this rapid rate of switching ensures that the parasite population is constantly diverse. A diverse range of coats expressed by the trypanosome population means that the immune system is always one step behind: it takes several days for an immune response against a given VSG to develop, giving the population time to diversify as individuals undergo further switching events. Reiteration of this process prevents extinction of the infecting trypanosome population, allowing chronic persistence of parasites in the host, enhancing opportunities for transmission. The clinical effect of this cycle is successive 'waves' of parasitaemia (trypanosomes in the blood). == In other trypanosomes == Variable surface glycoproteins are also found in other Trypanosoma species. In Trypanosoma equiperdum, a parasite causing the covering sickness in horses, these proteins allow the parasite to efficiently evade the host animal's immune system. These VSGs allow the organism to constantly manipulate and change the surface structure of its proteins, which means it is constantly being presented to the immune system as a new foreign organism and this prevents the body from mounting a large enough immune response to eradicate the disease. In this sense, Trypanosoma equiperdum is a very efficient organism; it may infect fewer species than other diseases, but it infects and survives very efficiently within its specified hosts. The VSG proteins in T. equiperdum are also phosphorylated. A VSG gene from Trypanosoma evansi, a parasite that causes a form of surra in animals, has been cloned in Escherichia coli. The expressed protein is immunoreactive with all the sera combinations. The animals immunized with whole cell lysate or recombinant protein show similar antibody reactions in ELISA (enzyme-linked immunosorbent assay) and CATT (card agglutination test for trypanosomiasis). The variable surface glycoprotein RoTat 1.2 PCR can be used as a specific diagnostic tool for the detection of T. evansi infections. The smallest VSG protein (40 kDa in size) to date (1996) has been found in Trypanosoma vivax, which bears little carbohydrate. In Trypanosoma congolense, in vitro analyses of the incorporated sugars after hydrolysis of the glycoprotein showed that glucosamine and mannose are utilized in the biosynthesis of the carbohydrate moiety directly whereas galactose was converted possibly to other intermediates before being incorporated into the antigen. The unglycosylated VSG with a molecular weight of 47 kDa had completely lost its size heterogeneity. == See also == Amastin, another surface (trans-membrane) glycoprotein in trypanosomatid parasites Coat protein (disambiguation) Glycocalyx List of MeSH codes (D23) List of MeSH codes (D12.776.395) List of MeSH codes (D12.776.543) == References == == External links == Variant Surface Glycoproteins, Trypanosoma at the U.S. National Library of Medicine Medical Subject Headings (MeSH) www.icp.ucl.ac.be	Wikipedia/Variable_surface_glycoprotein
Schindler disease, also known as Kanzaki disease and alpha-N-acetylgalactosaminidase deficiency, is a rare disease found in humans. This lysosomal storage disorder is caused by a deficiency in the enzyme alpha-NAGA (alpha-N-acetylgalactosaminidase), attributable to mutations in the NAGA gene on chromosome 22, which leads to excessive lysosomal accumulation of glycoproteins. A deficiency of the alpha-NAGA enzyme leads to an accumulation of glycosphingolipids throughout the body. This accumulation of sugars gives rise to the clinical features associated with this disorder. Schindler disease is an autosomal recessive disorder, meaning that one must inherit an abnormal allele from both parents in order to have the disease. == Types == There are three main types of the disease each with its own distinctive symptoms. Type I: infantile form, infants will develop normally until about a year old. At this time, the affected infant will begin to lose previously acquired skills involving the coordination of physical and mental behaviors. Additional neurological and neuromuscular symptoms such as diminished muscle tone, weakness, involuntary rapid eye movements, vision loss, and seizures may become present. With time, the symptoms worsen and children affected with this disorder will experience a decreased ability to move certain muscles due to muscle rigidity. The ability to respond to external stimuli will also decrease. Other symptoms include neuroaxonal dystrophy from birth, discoloration of skin, and telangiectasia or widening of blood vessels. Type II: adult form, symptoms are milder and may not appear until the individual is in his or her 30s. Angiokeratomas, an increased coarsening of facial features, and mild intellectual impairment are likely symptoms. Type III: is considered an intermediate disorder. Symptoms vary and can include to be more severe with seizures and intellectual disability, or less severe with delayed speech, a mild autistic-like presentation, and/or behavioral problems. == Cause == == Diagnosis == Amniocentesis or chorionic villus sampling can be used to screen for the disease before birth. After birth, urine tests, along with blood tests and skin biopsies can be used to diagnose Schindler disease. Genetic testing is also always an option, since different forms of Schindler disease have been mapped to the same gene on chromosome 22; though different changes (mutations) of this gene are responsible for the infantile- and adult-onset forms of the disease. The Genetic Testing Registry can be used to acquire information about the genetics tests for this condition. == Management == Infants with Schindler disease tend to die within four years of birth; therefore, treatment for this form of the disease is mostly palliative. However, Type II Schindler disease, with its late onset of symptoms, is not characterized by neurological degeneration. There is no known cure for Schindler disease, but bone marrow transplants have been trialed, as they have been successful in curing other glycoprotein disorders. == History == Schindler disease was named after Detlev Schindler (born 1946) M.D., the first author of a 1988 paper detailing the disease. It is also named after the Japanese biochemist and physician, Hiro Kanzaki (born 1949), who further studied it and released papers detailing the disease in 2006. == See also == List of cutaneous conditions == References == == Further reading == Reference, Genetics Home. "Schindler disease". Genetics Home Reference. Retrieved 27 December 2016. == External links ==	Wikipedia/Schindler_disease
ADAMs (short for a disintegrin and metalloproteinase) are a family of single-pass transmembrane and secreted metalloendopeptidases. All ADAMs are characterized by a particular domain organization featuring a pro-domain, a metalloprotease, a disintegrin, a cysteine-rich, an epidermal-growth factor like and a transmembrane domain, as well as a C-terminal cytoplasmic tail. Nonetheless, not all human ADAMs have a functional protease domain, which indicates that their biological function mainly depends on protein–protein interactions. Those ADAMs which are active proteases are classified as sheddases because they cut off or shed extracellular portions of transmembrane proteins. For example, ADAM10 can cut off part of the HER2 receptor, thereby activating it. ADAM genes are found in animals, choanoflagellates, fungi and some groups of green algae. Most green algae and all land plants probably had ADAM proteins but lost them. ADAMs are categorized under the EC 3.4.24.46 enzyme group, and in the MEROPS peptidase family M12B. The terms adamalysin and MDC family (metalloproteinase-like, disintegrin-like, cysteine rich) have been used to refer to this family historically. == ADAM family members == == Medicine == Therapeutic ADAM inhibitors might potentiate anti-cancer therapy. == See also == ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) family Ectodomain shedding == References == == External links == ADAM+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) http://www.healthvalue.net/sheddase.html Archived 19 June 2019 at the Wayback Machine	Wikipedia/A_disintegrin_and_metalloproteinase
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it. Lysosomal storage disorders are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins (sugar-containing proteins), or mucopolysaccharides. Individually, lysosomal storage diseases occur with incidences of less than 1:100,000; however, as a group, the incidence is about 1:5,000 – 1:10,000. Most of these disorders are autosomal recessively inherited such as Niemann–Pick disease, type C, but a few are X-linked recessively inherited, such as Fabry disease and Hunter syndrome (MPS II). The lysosome is commonly referred to as the cell's recycling center because it processes unwanted material into substances that the cell can use. Lysosomes break down this unwanted matter by enzymes, highly specialized proteins essential for survival. Lysosomal disorders are usually triggered when a particular enzyme exists in too small an amount or is missing altogether. When this happens, substances accumulate in the cell. In other words, when the lysosome does not function normally, excess products destined for breakdown and recycling are stored in the cell. Like other genetic disorders, individuals inherit lysosomal storage diseases from their parents. Although each disorder results from different gene mutations that translate into a deficiency in enzyme activity, they all share a common biochemical characteristic – all lysosomal disorders originate from an abnormal accumulation of substances inside the lysosome. Lysosomal storage diseases affect mostly children and they often die at a young age, many within a few months or years of birth. == Classification == === Standard classification === The lysosomal storage diseases are generally classified by the nature of the primary stored material involved, and can be broadly broken into the following: (ICD-10 codes are provided where available) (E75) Lipid storage disorders Gangliosidoses (including Tay–Sachs disease (E75.0-E75.1) - they are a subtype of sphingolipidoses Sphingolipidoses that are not gangliosidoses, including Gaucher's and Niemann–Pick diseases (E75.2-E75.3) Leukodystrophies (E76.0) Mucopolysaccharidoses, including Hunter syndrome and Hurler disease (E77) Glycoprotein storage disorders (E77.0-E77.1, E75.11) Mucolipidoses; Mucolipidosis IV is a gangliosidosis Also, glycogen storage disease type II (Pompe disease) is a defect in lysosomal metabolism as well, although it is otherwise classified into E74.0 in ICD-10. Cystinosis is an lysosomal storage disease characterized by the abnormal accumulation of the amino acid cystine. === By type of defect protein === Alternatively to the protein targets, lysosomal storage diseases may be classified by the type of protein that is deficient and is causing buildup. === Lysosomal storage disorders === Lysosomal storage diseases include: == Signs and symptoms == The symptoms of lysosomal storage diseases vary depending on the particular disorder and other variables such as the age of onset, and can be mild to severe. They can include developmental delay, movement disorders, seizures, dementia, deafness, and/or blindness. Some people with lysosomal storage diseases have enlarged livers or spleens, pulmonary and cardiac problems, and bones that grow abnormally. == Diagnosis == The majority of patients are initially screened by enzyme assay, which is the most efficient method to arrive at a definitive diagnosis. In some families where the disease-causing mutations are known, and in certain genetic isolates, mutation analysis may be performed. In addition, after a diagnosis is made by biochemical means, mutation analysis may be performed for certain disorders. == Treatment == No cures for lysosomal storage diseases are known, and treatment is mostly symptomatic, although bone marrow transplantation and enzyme replacement therapy (ERT) have been tried with some success. ERT can minimize symptoms and prevent permanent damage to the body. In addition, umbilical cord blood transplantation is being performed at specialized centers for a number of these diseases. In addition, substrate reduction therapy, a method used to decrease the production of storage material, is currently being evaluated for some of these diseases. Furthermore, chaperone therapy, a technique used to stabilize the defective enzymes produced by patients, is being examined for certain of these disorders. The experimental technique of gene therapy may offer cures in the future. Ambroxol has recently been shown to increase activity of the lysosomal enzyme glucocerebrosidase, so it may be a useful therapeutic agent for both Gaucher disease and Parkinson's disease. Ambroxol triggers the secretion of lysosomes from cells by inducing a pH-dependent calcium release from acidic calcium stores. Hence, relieving the cell from accumulating degradation products is a proposed mechanism by which this drug may help. == History == Tay–Sachs disease was the first of these disorders to be described, in 1881, followed by Gaucher disease in 1882. In the late 1950s and early 1960s, de Duve and colleagues, using cell fractionation techniques, cytological studies, and biochemical analyses, identified and characterized the lysosome as a cellular organelle responsible for intracellular digestion and recycling of macromolecules. This was the scientific breakthrough that would lead to the understanding of the physiological basis of the lysosomal storage diseases. Pompe disease was the first disease to be identified as an lysosomal storage disease in 1963, with L. Hers reporting the cause as a deficiency of α-glucosidase. Hers also suggested that other diseases, such as the mucopolysaccharidosis, might be due to enzyme deficiencies. == See also == Mannosidosis Molecular chaperone therapy == References == == External links ==	Wikipedia/Lysosomal_storage_disease
Alpha-fetoprotein (AFP, α-fetoprotein; also sometimes called alpha-1-fetoprotein, alpha-fetoglobulin, or alpha fetal protein) is a protein that in humans is encoded by the AFP gene. The AFP gene is located on the q arm of chromosome 4 (4q13.3). Maternal AFP serum level is used to screen for Down syndrome, neural tube defects, and other chromosomal abnormalities. AFP is a major plasma protein produced by the yolk sac and the fetal liver during fetal development. It is thought to be the fetal analog of serum albumin. AFP binds to copper, nickel, fatty acids and bilirubin and is found in monomeric, dimeric and trimeric forms. == Structure == AFP is a glycoprotein of 591 amino acids and a carbohydrate moiety. == Function == The function of AFP in adult humans is unknown. AFP is the most abundant plasma protein found in the human fetus. In the fetus, AFP is produced by both the liver and the yolk sac. It is believed to function as a carrier protein (similar to albumin) that transports materials such as fatty acids to cells. Maternal plasma levels peak near the end of the first trimester, and begin decreasing prenatally at that time, then decrease rapidly after birth. Normal adult levels in the newborn are usually reached by the age of 8 to 12 months. While the function in humans is unknown, in rodents it binds estradiol to prevent the transport of this hormone across the placenta to the fetus. The main function of this is to prevent the virilization of female fetuses. As human AFP does not bind estrogen, its function in humans is less clear. In human liver cancer, AFP is found to bind glypican-3 (GPC3), another oncofetal antigen. The rodent AFP system can be overridden with massive injections of estrogen, which overwhelm the AFP system and will masculinize the fetus. The masculinizing effect of estrogens may seem counter-intuitive since estrogens are critical for the proper development of female secondary characteristics during puberty. However, this is not the case prenatally. Gonadal hormones from the testes, such as testosterone and anti-Müllerian hormone, are required to cause development of a phenotypic male. Without these hormones, the fetus will develop into a phenotypic female even if genetically XY. The conversion of testosterone into estradiol by aromatase in many tissues may be an important step in masculinization of that tissue. Masculinization of the brain is thought to occur both by conversion of testosterone into estradiol by aromatase, but also by de novo synthesis of estrogens within the brain. Thus, AFP may protect the fetus from maternal estradiol that would otherwise have a masculinizing effect on the fetus, but its exact role is still controversial. == Serum levels == === Maternal === In pregnant women, fetal AFP levels can be monitored in the urine of the pregnant woman. Since AFP is quickly cleared from the mother's serum via her kidneys, maternal urine AFP correlates with fetal serum levels, although the maternal urine level is much lower than the fetal serum level. AFP levels rise until about week 32. Maternal serum alpha-fetoprotein (MSAFP) screening is performed at 16 to 18 weeks of gestation. If MSAFP levels indicate an anomaly, amniocentesis may be offered to the patient. === Infants === The normal range of AFP for adults and children is variously reported as under 50, under 10, or under 5 ng/mL. At birth, normal infants have AFP levels four or more orders of magnitude above this normal range, that decreases to a normal range over the first year of life. During this time, the normal range of AFP levels spans approximately two orders of magnitude. Correct evaluation of abnormal AFP levels in infants must take into account these normal patterns. Very high AFP levels may be subject to hooking (see Tumor marker), which results in the level being reported significantly lower than the actual concentration. This is important for analysis of a series of AFP tumor marker tests, e.g. in the context of post-treatment early surveillance of cancer survivors, where the rate of decrease of AFP has diagnostic value. == Clinical significance == Measurement of AFP is generally used in two clinical contexts. First, it is measured in pregnant women through the analysis of maternal blood or amniotic fluid as a screening test for certain developmental abnormalities, such as aneuploidy. Second, serum AFP level is elevated in people with certain tumors, and so it is used as a biomarker to follow these diseases. Some of these diseases are listed below: Developmental birth defects associated with elevated AFP Omphalocele Gastroschisis Neural tube defects: ↑ α-fetoprotein in amniotic fluid and maternal serum Tumors associated with elevated AFP Hepatocellular carcinoma Metastatic disease affecting the liver Nonseminomatous germ cell tumors Yolk sac tumor Other conditions associated with elevated AFP Ataxia telangiectasia: elevated AFP is used as one factor in diagnosis A peptide derived from AFP that is referred to as AFPep is claimed to possess anti-cancer properties. In the treatment of testicular cancer it is paramount to differentiate seminomatous and nonseminomatous tumors. This is typically done pathologically after removal of the testicle and confirmed by tumor markers. However, if the pathology is pure seminoma but the AFP is elevated, the tumor is treated as a nonseminomatous tumor because it contains yolk sac (nonseminomatous) components. == See also == Tumor marker AFP-L3 Triple test Advanced maternal age == References == == Further reading == == External links == alpha-Fetoproteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) Overview of all the structural information available in the PDB for UniProt: P02771 (Alpha-fetoprotein) at the PDBe-KB. This article incorporates text from the United States National Library of Medicine, which is in the public domain.	Wikipedia/Alpha-fetoprotein
A mucoprotein is a glycoprotein composed primarily of mucopolysaccharides. Mucoproteins can be found throughout the body, including the gastrointestinal tract, reproductive organs, airways, and the synovial fluid of the knees. They are called mucoproteins because the carbohydrate quantity is more than 4% unlike glycoproteins where the carbohydrate quantity is less than 4%. Mucoprotein is produced in the cecum of the gastrointestinal tract. During gallbladder cancer, mucoprotein is over expressed. Sustaining a brain injury will lead to decreased mucoprotein production. The result is an alteration of gut microbiota as seen in mice. == Function == Mucoproteins are the proteins that are the building blocks of mucus, which is a protective barrier to the epithelia of cells. It is semipermeable, so it acts as a barrier to most bacteria and pathogens, while allowing for the uptake of nutrients, water, and hormones. == Protein Structure == Mucoproteins are composed of o-linked carbohydrates as well as highly glycosylated proteins, which are held together by disulfide bonds. The viscosity of the mucus depends on the strength of the disulfide bonds. When these disulfide bonds are broken, the viscosity of the mucus secretions is reduced. == Clinical Significance == Mucolytic medications will break through the disulfide bonds and lower the viscosity of the mucus, thus allowing the hypersecreted mucus to be more manageable. A hypersectretion of mucus is often a symptom of pulmonary diseases or respiratory infections. There are two subgroups in mycolytic medications and each one works differently to control the hypersecreted mucus. Classic mucolytic medications these medications change the disulfide bond by reducing it to a thiol bond, thus thoroughly breaking down the mucoproteins and making the mucus more manageable. Peptide mucolytic medications these medications depolymerize DNA polymer and F-actin links that are present when the mucus hypersecretes. This preserves the mucins that are helpful to the epithelial tissue of the lungs. == References == == Bibliography == Houlden, A.; Goldrick, M.; Brough, D.; Vizi, E.S.; Lénárt, N.; Martinecz, B.; Roberts, I.S.; Denes, A. (October 2016). "Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production". Brain, Behavior, and Immunity. 57: 10–20. doi:10.1016/j.bbi.2016.04.003. PMC 5021180. PMID 27060191. Aksoy, Murat; Guven, Suleyman; Tosun, Ilknur; Aydın, Faruk; Kart, Cavit (September 2012). "The effect of ethinyl estradiol and drospirenone-containing oral contraceptives upon mucoprotein content of cervical mucus". European Journal of Obstetrics & Gynecology and Reproductive Biology. 164 (1): 40–43. doi:10.1016/j.ejogrb.2012.05.002. PMID 22633169. Aronson, Jeffrey K., ed. (2016). "Acetylcysteine". Meyler's Side Effects of Drugs. pp. 23–25. doi:10.1016/b978-0-444-53717-1.00217-1. ISBN 978-0-444-53716-4. Gupta, Rishab; Wadhwa, Roopma (2024). "Mucolytic Medications". StatPearls. StatPearls Publishing. PMID 32644589. Cone, Richard A. (February 2009). "Barrier properties of mucus". Advanced Drug Delivery Reviews. 61 (2): 75–85. doi:10.1016/j.addr.2008.09.008. PMID 19135107. Kumar, Puneet; Shukla, Priyesh; Kumari, Soni; Dixit, Ruhi; Narayan, Gopeshwar; Dixit, V. K.; Khanna, A. K. (June 2022). "Expression of Mucoproteins in Gallbladder Cancer". Indian Journal of Surgery. 84 (3): 456–462. doi:10.1007/s12262-021-02989-7. == External links == Mucoproteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)	Wikipedia/Mucoprotein
Pelizaeus–Merzbacher disease is an X-linked neurological disorder that damages oligodendrocytes in the central nervous system. It is caused by mutations in proteolipid protein 1 (PLP1), a major myelin protein. It is characterized by a decrease in the amount of insulating myelin surrounding the nerves (hypomyelination) and belongs to a group of genetic diseases referred to as leukodystrophies. == Signs and symptoms == The hallmark signs and symptoms of Pelizaeus–Merzbacher disease include little or no movement in the arms or legs, respiratory difficulties, and characteristic horizontal movements of the eyes left to right. The onset of Pelizaeus–Merzbacher disease is usually in early infancy. The most characteristic early signs are nystagmus (rapid, involuntary, rhythmic motion of the eyes) and low muscle tone. Motor abilities are delayed or never acquired, mostly depending upon the severity of the mutation. Most children with Pelizaeus–Merzbacher disease learn to understand language, and usually have some speech. Other signs may include tremor, lack of coordination, involuntary movements, weakness, unsteady gait, and over time, spasticity in legs and arms. Muscle contractures often occur over time. Mental functions may deteriorate. Some patients may have convulsions and skeletal deformation, such as scoliosis, resulting from abnormal muscular stress on bones. == Cause == Pelizaeus–Merzbacher disease is caused by X-linked recessive mutations in the major myelin protein proteolipid protein 1 (PLP1). This causes hypomyelination in the central nervous system and severe neurological disease. The majority of mutations result in duplications of the entire PLP1 gene. Deletions of PLP1 locus (which are rare) cause a milder form of Pelizaeus–Merzbacher disease than is observed with the typical duplication mutations, which demonstrates the critical importance of gene dosage at this locus for normal CNS function. == Diagnosis == The diagnosis of Pelizaeus–Merzbacher disease is often first suggested after identification by magnetic resonance imaging of abnormal white matter (high T2 signal intensity, i.e. T2 lengthening) throughout the brain, which is typically evident by about 1 year of age, but more subtle abnormalities should be evident during infancy. Unless a family history consistent with sex-linked inheritance exists, the condition is often misdiagnosed as cerebral palsy. Once a PLP1 mutation is identified, prenatal diagnosis or preimplantation genetic diagnostic testing is possible. === Classification === The disease is one in a group of genetic disorders collectively known as leukodystrophies that affect the growth of the myelin sheath, the fatty covering—which acts as an insulator—on nerve fibers in the central nervous system. The several forms of Pelizaeus–Merzbacher disease include classic, congenital, transitional, and adult variants. Pelizaeus–Merzbacher disease is the common name for hypomyelinating leukodystrophies (HLD). There are at least 26 HLD variants cataloged by the National Institutes of Health National Library of Medicine and the Online Mendelian Inheritance in Man (OMIM) compendium of human genes and genetic phenotypes. Milder mutations of the PLP1 gene that mainly cause leg weakness and spasticity, with little or no cerebral involvement, are classified as spastic paraplegia 2 (SPG2). == Treatment == No cure for Pelizaeus–Merzbacher disease has been developed. Outcomes are variable: people with the most severe form of the disease do not usually survive to adolescence, although with milder forms, survival into adulthood is possible. A phase I clinical trial using an antisense oligonucleotide (known as ION356) targeted against PLP1 is expected to begin in early 2024. == Research == In December 2008, StemCells, Inc received clearance in the United States to conduct a phase I clinical trials of human neural stem cell transplantation. The trial did not show meaningful efficacy and the company has since gone bankrupt. In 2019 Paul Tesar, a professor at Case Western Reserve University, used CRISPR and antisense therapy in a mouse model of Pelizaeus–Merzbacher with success. In 2022 Case Western Reserve University entered an exclusive licensing agreement with Ionis Pharmaceuticals to develop a human treatment for the disorder. == See also == The Myelin Project The Stennis Foundation Friedrich Christoph Pelizaeus Ludwig Merzbacher == References == == Further reading == Uhlenberg, Birgit; Schuelke, Markus; Rüschendorf, Franz; Ruf, Nico; Kaindl, Angela M.; Henneke, Marco; Thiele, Holger; Stoltenburg-Didinger, Gisela; Aksu, Fuat; Topaloğlu, Haluk; Nürnberg, Peter; Hübner, Christoph; Weschke, Bernhard; Gärtner, Jutta (August 2004). "Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46.6) Cause Pelizaeus-Merzbacher–Like Disease". The American Journal of Human Genetics. 75 (2): 251–260. doi:10.1086/422763. PMC 1216059. PMID 15192806. == External links == Pelizaeus-Merzbacher Disease - PMD Foundation Pelizaeus-Merzbacher Disease Archived 2008-10-07 at the Wayback Machine. NINDS/National Health Institutes. pmd at NIH/UW GeneTests	Wikipedia/Pelizaeus–Merzbacher_disease
The Diseases Database is a free website that provides information about the relationships between medical conditions, symptoms, and medications. The database is run by Medical Object Oriented Software Enterprises Ltd, a company based in London. The site's stated aim is "education, background reading and general interest" with an intended audience "physicians, other clinical healthcare workers and students of these professions". The editor of the site is stated as Malcolm H Duncan, a UK qualified medical doctor. == Organization == The Diseases Database is based on a collection of about 8,500 concepts, called "items", related to human medicine including diseases, drugs, symptoms, physical signs and abnormal laboratory results. In order to link items to both each other and external information resources three sets of metadata are modelled within the database. Items are assigned various relationships e.g. diabetes mellitus type 2 is labelled "a risk factor for" ischaemic heart disease. More formally the database employs an entity-attribute-value model with items populating both entity and value slots. Relationships may be read in either direction e.g. the assertion "myocardial infarction {may cause} chest pain" has the corollary "chest pain {may be caused by} myocardial infarction". Such relationships aggregate within the database and allow lists to be retrieved - e.g. a list of items which may cause chest pain, and a list of items which may be caused by myocardial infarction. Most items are assigned topic specific hyperlinks to Web resources which include Online Mendelian Inheritance in Man, eMedicine and Wikipedia. Most items are mapped to concepts within the Unified Medical Language System (UMLS). UMLS links enable the display of short text definitions or Medical Subject Heading (MeSH) scope notes for the majority of items on the database. The UMLS map also enables links to and from other medical classifications and terminologies e.g. ICD-9 and SNOMED. == References == == External links == Official website	Wikipedia/Diseases_Database
Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, brain, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. The genetic mutation that causes Fabry disease interferes with the function of an enzyme that processes biomolecules known as sphingolipids, leading to these substances building up in the walls of blood vessels and other organs. It is inherited in an X-linked manner. Fabry disease is sometimes diagnosed using a blood test that measures the activity of the affected enzyme called alpha-galactosidase, but genetic testing is also sometimes used, particularly in females. The treatment for Fabry disease varies depending on the organs affected by the condition, and the underlying cause can be addressed by replacing the enzyme that is lacking. The first descriptions of the condition were made simultaneously by dermatologist Johannes Fabry and the surgeon William Anderson in 1898. == Signs and symptoms == Symptoms are typically first experienced in early childhood and can be very difficult to diagnose; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses. Manifestations of the disease usually increase in number and severity as an individual ages. === Pain === Full-body or localized pain to the extremities (known as acroparesthesia) or gastrointestinal (GI) tract is common in patients with Fabry disease. This pain can increase over time. This acroparesthesia is believed to be related to the damage of peripheral nerve fibers that transmit pain. Gastrointestinal tract pain is likely caused by the accumulation of lipids in the small vasculature of the GI tract, which obstructs blood flow and causes pain. === Kidney === Kidney complications are common and serious effects of the disease; chronic kidney disease and kidney failure may worsen throughout life. The presence of protein in the urine (which causes foamy urine) is often the first sign of kidney involvement. End-stage kidney failure in those with Fabry disease typically occurs in the third decade of life and is a common cause of death due to the disease. === Heart === Fabry disease can affect the heart in several ways. The accumulation of sphingolipids within heart muscle cells causes an abnormal thickening of the heart muscle or hypertrophy. This hypertrophy can cause the heart muscle to become abnormally stiff and unable to relax, leading to a hypertrophic cardiomyopathy causing shortness of breath. Fabry disease can also affect how the heart conducts electrical impulses, leading to both abnormally slow heart rhythms such as complete heart block, and abnormally rapid heart rhythms such as ventricular tachycardia. These abnormal heart rhythms can cause blackouts, palpitations, or even sudden cardiac death. Sphingolipids can also build up within the heart valves, thickening the valves and affecting the way they open and close. If severe, this can cause the valves to leak (regurgitation) or restrict the forward flow of blood (stenosis). The aortic and mitral valves are more commonly affected than the valves on the right side of the heart. === Skin === Angiokeratomas (tiny, painless papules that can appear on any region of the body, but are predominant on the thighs, around the navel, buttocks, lower abdomen, and groin) are common. Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating). Additionally, patients can exhibit Raynaud's disease-like symptoms with neuropathy (in particular, burning extremity pain). Ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy), i.e. clouding of the corneas. Keratopathy may be the presenting feature in asymptomatic patients and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea). This clouding does not affect vision. Other ocular findings can include conjunctival and retinal vascular abnormalities and anterior/posterior spoke-like cataracts. Visual reduction from these manifestations is uncommon. === Other manifestations === Fatigue, neuropathy (in particular, burning extremity pain, red hands and feet on and off), cerebrovascular effects leading to an increased risk of stroke - early strokes, mostly vertebrobasilar system tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical imbalances, and diarrhea are other common symptoms. == Causes == Fabry disease is caused by a DNA sequence (gene) that is not functioning as it should. A person who inherits this gene does not have enough of a functioning enzyme known as alpha-galactosidase A. The lack of alpha-galactosidase leads to Fabry disease. A deficiency of alpha-galactosidase A (a-GAL A, encoded by GLA) due to mutation causes a glycolipid known as globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, other tissues, and organs. This accumulation leads to an impairment of their proper functions. At least 443 disease-causing mutations in the GLA gene have been discovered. The DNA mutations that cause the disease are X-linked recessive with incomplete penetrance in heterozygous females. The condition affects hemizygous males (i.e. all non-intersex males), as well as homozygous, and in many cases heterozygous females. While males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms. Research suggests many women experience severe symptoms ranging from early cataracts or strokes to hypertrophic left ventricular heart problems and kidney failure. This variability is thought to be due to X-inactivation patterns during embryonic development of the female. == Mechanism == Fabry disease is an inherited lysosomal storage disorder that is caused by a deficiency of alpha-galactosidase A. This enzyme deficiency is a result of an accumulation of glycosphingolipids found in the lysosomes and most cell types and tissues, which leads it to be considered a multisystem disease. Indications include painful crisis, angiokeratomas, corneal dystrophy, and hypohidrosis. In severe cases there is renal, cerebrovascular, and cardiac involvement and it is predominately responsible for premature mortality in Fabry patients. Fabry disease is X-linked and manifests mostly in homozygous males but also in heterozygous females. Cardiac involvement is recurrent in Fabry patients. Patients have developed hypertrophic cardiomyopathy, arrhythmias, conduction abnormalities, and valvular abnormalities. Deficient activity of lysosomal alpha-galactosidase results in progressive accumulation of globotriaosylceramide (GL-3) within lysosomes, that is believed to trigger a cascade of cellular events. The demonstration of marked alpha-galactosidase deficiency is the conclusive method for the diagnosis in homozygous males. It may be detected in heterozygous females, but it is often inconclusive due to random X-chromosomal inactivation, so molecular testing (genotyping) of females is mandatory. == Diagnosis == Fabry disease is suspected based on the individual's clinical presentation and can be diagnosed by an enzyme assay (usually done on leukocytes) to measure the level of alpha-galactosidase activity. An enzyme assay is not reliable for the diagnosis of disease in females due to the random nature of X-inactivation. Molecular genetic analysis of the GLA gene is the most accurate method of diagnosis in females, particularly if the mutations have already been identified in male family members. Many disease-causing mutations have been noted. Kidney biopsy may also be suggestive of Fabry disease if excessive lipid buildup is noted. Pediatricians, as well as internists, commonly misdiagnose Fabry disease. All immediate and extended family members in the same family have the same family mutation, so if one member of a family has a DNA sequence analysis performed, other members of the family can be diagnosed by performing a targeted sequence analysis instead of testing the entire gene. Targeted sequencing is quicker and less expensive to perform. One study reported that for every first diagnosis in a family, on average five more family members (immediate and extended) are also diagnosed. MRI is accurate in accessing left ventricular mass and thickness and hypertrophy. Late gadolinium enhancement shows an increased signal of the mid wall at the inferolateral wall of the base of the left ventricle, usually in the non-hypertrophic ventricle. T1-weighted imaging can show low T1 signal due to sphingolipid storage in the heart even without ventricular hypertrophy in 40% of those affected by the disease. Thus, MRI is a useful way of diagnosing the disease early. T2 signal is increased in inflammation and oedema. == Treatment == The treatments available for Fabry disease can be divided into therapies that aim to correct the underlying problem of decreased activity of the alpha-galactosidase A enzyme and thereby reduce the risk of organ damage, and therapies to improve symptoms and life expectancy once organ damage has already occurred. === Therapies targeting enzyme activity === Enzyme replacement therapy is designed to provide the enzyme the patient is missing as a result of a genetic malfunction. This treatment is not a cure, but can partially prevent disease progression, and potentially reverse some symptoms. As of March 2022, three medical drugs based on enzyme replacement therapy are available for Fabry disease: Agalsidase alfa, sold under the brand name Replagal by the company Takeda (since its acquisition of the company Shire), is a recombinant form of alpha-galactosidase A It received approval in the EU in 2001. FDA approval was applied for the United States. However, Shire withdrew their application for approval in the United States in 2012, citing that the agency will require additional clinical trials before approval. As of March 2022, Replagal has not received FDA approval. Agalsidase beta, sold under the brand name Fabrazyme by the company Sanofi, is another recombinant form of alpha-galactosidase. Like replagal, it received approval in the EU in 2001. In 2003, it was the first treatment for Fabry disease to be approved by the FDA. Pegunigalsidase alfa (Elfabrio) was approved for medical use in the European Union in May 2023. Clinically, agalsidase alfa and agalsidase beta are generally similar in effectiveness and safety, however they have never been compared directly in a randomized trial. Both are given by intravenous infusion every two weeks. They are available in Europe and in many other parts of the world, but treatment costs remain very high. Pharmacological chaperone therapy is another strategy to maintain enzyme activity. It does so by assisting correct folding of alpha-galactosidase despite the mutations that cause Fabry disease. As of March 2022, one medical drug based on pharmacological chaperone therapy is available for Fabry disease: Migalastat, sold under the brand name Galafold by the company Amicus Therapeutics, is a pharmacological chaperone that can stabilize many mutant forms of alpha-galactosidase. It is taken by mouth. In a randomized trial comparing Migalastat with enzyme replacement therapy, the efficacy and safety of both treatments were similar. The US Food and Drug Administration (FDA) granted Galafold orphan drug status in 2004, and the European Commission followed in 2006. The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) granted the drug a marketing approval under the name Galafold in May 2016. FDA approval followed in 2018. Experimental therapies that are not approved for treatment as of March 2022 include the following: A gene therapy treatment that is in early-phase clinical trials, with the technology licensed to AvroBio. The substrate reduction therapy Venglustat (Ibiglustat) under development by Sanofi-Genzyme Bio-better ERT (CDX-6311) under pre-clinical development by the company Codexis A gene therapy (ST-920) under development by the company Sangamo. A nucleoside-modified RNA treatment that has shown efficacy in a mouse model of Fabry disease and in cardiomyocytes derived from induced pluripotent stem cells from individuals with Fabry disease. === Organ-specific treatment === Pain associated with Fabry disease may be partially alleviated by enzyme replacement therapy in some patients, but pain management regimens may also include analgesics, anticonvulsants, and nonsteroidal anti-inflammatory drugs, though the latter are usually best avoided in kidney disease. The kidney failure seen in some of those with Fabry disease sometimes requires haemodialysis. The cardiac complications of Fabry disease include abnormal heart rhythms, which may require a pacemaker or implantable cardioverter-defibrillator, while the restrictive cardiomyopathy often seen may require diuretics. == Prognosis == Life expectancy with Fabry disease for males was 58.2 years, compared with 74.7 years in the general population, and for females 75.4 years compared with 80.0 years in the general population, according to registry data from 2001 to 2008. The most common cause of death was cardiovascular disease, and most of those had received kidney replacements. == Epidemiology == Fabry disease is panethnic, but due to its rarity, determining an accurate disease frequency is difficult. Reported incidences, ranging from 1-5:10,000 in the general population, may largely underestimate the true prevalence. Newborn screening initiatives have found an unexpectedly high prevalence of the disease, as high as one in about 3,100 newborns in Italy, and have identified a surprisingly high frequency of newborn males around one in 1,500 in Taiwan. == Research == Enzyme replacement therapy: Replacement of the missing enzyme to clear the lipids (GL-3) from the cells Substrate synthesis inhibition, also called substrate reduction therapy: Inhibits the production of the lipid (GL-3) that accumulates in the cells Chaperone therapy: Uses small-molecule drugs that bind to the defective enzyme and stabilize it to increase enzyme activity and increase cellular function Gene editing: Technology that can potentially cut and fix a broken gene in a cell Gene therapy: Genetically modifies the affected cells to produce the missing enzyme. == History == Fabry disease was first described by dermatologist Johannes Fabry and surgeon William Anderson independently in 1898. It was recognised to be due to abnormal storage of lipids in 1952. In the 1960s, the inheritance pattern was established as being X-linked, as well as the molecular defect responsible for causing the accumulation of glycolipids. Ken Hashimoto published his classic paper on his electron microscopic findings in Fabry disease in 1965. The first specific treatment for Fabry disease was approved in 2001. == Society and culture == House ("Epic Fail", season six, episode three) centers on a patient with Fabry disease. Scrubs ("My Catalyst", season three, episode 12) features a Fabry disease diagnosis. Crossing Jordan ("There's No Place Like Home", season two, episode one) features a patient who died from Fabry disease. The Village (Korean drama): "Achiara's Secret" features daughters of a serial rapist who find each other because they share Fabry disease. Doctor John (Korean drama): In episode two, a prisoner is diagnosed with Fabry disease. In Lincoln Rhyme: Hunt for the Bone Collector, a copycat of the titular Bone Collector has Fabry disease and takes Galafold, which allows the detectives to learn his identity. Partners for Justice 2 (Korean drama), features Doctor K, who had Fabry disease. Doc (Italian drama): Series two features an episode with a tennis player who is diagnosed with Fabry disease == References == == Further reading == == External links == Fabry Disease Information Page Archived 2 December 2016 at the Wayback Machine at NINDS Fabry disease at NLM Genetics Home Reference https://www.orpha.net/en/disease/detail/324?name=Fabry%20disease&mode=name	Wikipedia/Fabry_disease
Dent's disease (or Dent disease) is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure. "Dent's disease" is often used to describe an entire group of familial disorders, including X-linked recessive nephrolithiasis with kidney failure, X-linked recessive hypophosphatemic rickets, and both Japanese and idiopathic low-molecular-weight proteinuria. About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the OCRL1 gene (Dent 2). == Signs and symptoms == Dent's disease often produces the following signs and symptoms: Extreme thirst combined with dehydration, which leads to frequent urination Nephrolithiasis (kidney stones) Hypercalciuria (high urine calcium - >300 mg/d or >4 mg/kg per d with normal levels blood/serum calcium) Aminoaciduria (amino acids in urine) Phosphaturia (phosphate in urine) Glycosuria (glucose in urine) Kaliuresis (potassium in urine) Hyperuricosuria (excessive amounts of uric acid in the urine) Impaired urinary acidification Rickets In a study of 25 patients with Dent's disease, 9 of 15 men, and one of 10 women had end-stage kidney disease by the age of 47. == Genetics == === Dent disease 1 === Dent's disease is a X-linked recessive disorder. The males are prone to manifesting symptoms in early adulthood with symptoms of calculi, rickets or even with kidney failure in more severe cases. In humans, gene CLCN5 is located on chromosome Xp11.22, and has a 2238-bp coding sequence that consists of 11 exons that span 25 to 30 kb of genomic DNA and encode a 746-amino-acid protein. CLCN5 belongs to the family of voltage-gated chloride channel genes (CLCN1-CLCN7, CLCKa and CLCKb) that have about 12 transmembrane domains. These chloride channels have an important role in the control of membrane excitability, transepithelial transport, and possibly cell volume. The mechanisms by which CLC-5 dysfunction results in hypercalciuria and the other features of Dent's disease remain to be elucidated. The identification of additional CLCN5 mutations may help in these studies. === Dent disease 2 === Dent disease 2 (nephrolithiasis type 2) is associated with the OCRL gene. Both Lowe syndrome (oculocerebrorenal syndrome) and Dent disease can be caused by truncating or missense mutations in OCRL. == Diagnosis == Diagnosis is based on genetic study of CLCN5 gene. == Treatment == As of today, no agreed-upon treatment of Dent's disease is known and no therapy has been formally accepted. Most treatment measures are supportive in nature: Thiazide diuretics (i.e. hydrochlorothiazide) have been used with success in reducing the calcium output in urine, but they are also known to cause hypokalemia. In rats with diabetes insipidus, thiazide diuretics inhibit the NaCl cotransporter in the renal distal convoluted tubule, leading indirectly to less water and solutes being delivered to the distal tubule. The impairment of Na transport in the distal convoluted tubule induces natriuresis and water loss, while increasing the reabsorption of calcium in this segment in a manner unrelated to sodium transport. Amiloride also increases distal tubular calcium reabsorption and has been used as a therapy for idiopathic hypercalciuria. A combination of 25 mg of chlorthalidone plus 5 mg of amiloride daily led to a substantial reduction in urine calcium in Dent's patients, but urine pH was "significantly higher in patients with Dent's disease than in those with idiopathic hypercalciuria (P < 0.03), and supersaturation for uric acid was consequently lower (P < 0.03)." For patients with osteomalacia, vitamin D or derivatives have been employed, apparently with success. Some lab tests on mice with CLC-5-related tubular damage showed a high-citrate diet preserved kidney function and delayed progress of kidney disease. == History == Dent's disease was first described by Charles Enrique Dent and M. Friedman in 1964, when they reported two unrelated British boys with rickets associated with renal tubular damage characterized by hypercalciuria, hyperphosphaturia, proteinuria, and aminoaciduria. This set of symptoms was not given a name until 30 years later, when the nephrologist Oliver Wrong more fully described the disease. Wrong had studied with Dent and chose to name the disease after his mentor. Dent's disease is a genetic disorder caused by mutations in the gene CLCN5, which encodes a kidney-specific voltage-gated chloride channel, a 746-amino-acid protein (CLC-5) with 12 to 13 transmembrane domains. It manifests itself through low-molecular-weight proteinuria, hypercalciuria, aminoaciduria and hypophosphataemia. Because of its rather rare occurrence, Dent's disease is often diagnosed as idiopathic hypercalciuria, i.e., excess calcium in urine with undetermined causes. == References == == External links == Genetic Hypercalciuria Dent disease on Orphanet Archived 2007-12-15 at the Wayback Machine	Wikipedia/Dent's_disease
Norrie disease is a rare X-linked recessive genetic disorder that primarily affects the eyes and almost always leads to blindness. It is caused by mutations in the Norrin cystine knot growth factor gene, also referred to as Norrie Disease Pseudoglioma (NDP) gene. Norrie disease manifests with vision impairment either at birth, or within a few weeks of life, following an ocular event like retinal detachment and is progressive through childhood and adolescence. It generally begins with retinal degeneration, which occurs before birth and results in blindness at birth (congenital) or early infancy, usually by 3 months of age. Patients with Norrie disease may develop cataracts, leukocoria (where the pupils appear white when light is shone on them), along with other developmental issues in the eye, such as shrinking of the globe and the wasting away of the iris. In addition to the congenital ocular symptoms, the majority of individuals afflicted by this disease develop progressive hearing loss caused by vascular abnormalities in the cochlea. Hearing loss usually begins in early childhood and may be mild at first before becoming more progressive by the third or forth decade of life. Roughly 30–50% of those affected by the disease might encounter cognitive challenges, learning difficulties, incoordination of movements or behavioral abnormalities. These developmental delays often surpass those expected from their visual impairment alone. Additionally, behavioral issues such as psychosis, aggression, and cognitive decline may manifest in patients. Intellectual disabilities have been observed in 20–30% of cases, while dementia, though uncommon, can emerge in late adulthood. About 15% of patients are estimated to develop all the features of the disease. Due to the X-linked recessive pattern of inheritance, Norrie disease affects almost entirely males. Only in very rare cases, females have been diagnosed with Norrie disease; cases of symptomatic female carriers have been reported. It is a very rare disorder that is not associated with any specific ethnic or racial groups, with cases reported worldwide (including cases in North America, South America, Europe, Asia and Australasia). While more than 400 cases have been described, the prevalence and incidence of the disease still remains unknown. == Presentation == The most prominent symptoms initially observed in Norrie disease are ocular. Initial characteristics are usually identified at birth or in early infancy, with parents often noticing abnormal eye features or that their child fails to show a response to light. The first visible finding is leukocoria, a grayish-yellow pupillary reflection that originates from a mass of disorganized tissue behind the lens. This material, which possibly includes an already detached retina, may be confused with a tumor and thus is termed pseudoglioma. However, an affected baby may have a normally sized eye globe and unremarkable iris, anterior chamber, cornea and intraocular pressure. Over the first few months of life, complete or partial retinal detachment evolves. From infancy through childhood, the patient may undergo progressive changes in the disease. Disease progression often includes vitreoretinal hemorrhages, the formation of cataracts, deterioration of the iris with adhesions forming between the iris and the lens or the cornea, and shallowing of the anterior chamber which may increase intraocular pressure, causing eye pain. As the situation worsens, there is corneal opacification, where the cornea becomes opaque, and band keratopathy. Intraocular pressure is lost and the globe shrinks. In the last stage of Norrie disease, the globes appear small and sunken in (phthisis bulbi) and the cornea appears to be milky. Auditory symptoms are common with Norrie disease. Progressive hearing loss has been reported to occur in 85–90% of patients and onset is generally in childhood and before the patient reaches their mid-20s. Early hearing loss is sensorineural, mild and asymmetric. By adolescence, high-frequency hearing loss begins to appear. Hearing loss is severe, symmetric, and broad-spectrum by the age of 35 years. However, studies show that while hearing deteriorates, the ability to speak well is highly preserved. The slowly progressing hearing loss is more problematic to adjust to than the congenital blindness for most people with Norrie disease. === Additional characteristics === Individuals with Norrie disease can also have cognitive and behavioral symptoms. Developmental delay or learning difficulties are present in about 30 to 50% of males who have Norrie disease. Psycho-social disturbances and poorly characterized behavior abnormalities may also be present. In a study reporting extraocular manifestations in 56 patients with Norrie disease, conditions reported included cognitive impairment (28% of patients), behavioral issues, for example autism spectrum disorder (27% of patients presented with autism or autism-like disorders), neurological features, including seizure disorders and epilepsy (16% of patients reported seizures or seizure history), and peripheral vascular disease (38% of patients). Additionally, children with visual impairment have been shown to struggle establishing regular sleep/wake cycles due to reduced light perception impacting on their understanding of night and day; this can impact on the individual's behavior, mood and cognitive ability. Consistent with this, some case reports of Norrie disease patients have reported the presence of sleep disorders. Peripheral vascular disease (PVD) has also been associated with Norrie disease. In a study of 56 patients with Norrie disease, 21 patients (38%) reported PVD (including varicose veins, peripheral venous stasis ulcers and erectile dysfunction). Due to the known role of the protein norrin in the vascular development of the eye and inner ear, as well as the association with PVD, norrin is thought to have an important angiogenic role in the body. == Genetics == Norrie disease is a rare genetic disorder caused by mutations in the NDP gene, located on Xp11.4 (GeneID: 4693). It is inherited in an X-linked recessive manner. This means that almost only males are affected. Sons of affected men will not have the mutation, while all of their daughters will be genetic carriers of the mutation. Female carriers usually show no clinical symptoms, but will pass the mutation to 50% of their offspring. Daughters with the mutated gene will also be, like their mother, asymptomatic carriers, but 50% of their sons will express clinical symptoms. Females are very unlikely to express clinical signs. However, there have been a few rare cases where females have shown symptoms associated with Norrie disease such as retinal abnormalities and mild hearing loss. Additionally, cases of symptomatic female carriers have been reported. One possible scenario that could lead to a female case of Norrie disease is if both of their copies of the NDP gene bear mutations, which could be the case in consanguineous families or due to a spontaneous somatic mutation. Another explanation for affected females could be skewed X-chromosome inactivation. In this latter case, carrier females with one mutated NDP allele could have a higher proportion of defective norrin being expressed, leading to the presentation of symptoms of Norrie disease. === The NDP gene === Norrie disease is caused by a mutation in the Norrin cystine knot growth factor gene, also known as the Norrie disease (pseudoglioma) gene or NDP gene. Mutations could include splicing or mis-sense mutations, as well as partial or full gene deletion. The normal function of the NDP gene is to produce the instructions for creating a protein called norrin. For the normal development of the eye and other body systems, norrin is believed to be crucial. Norrin also appears to be crucial in the specialization of the cells of the retina and the establishment of a blood supply to the inner ear and the tissues of the retina. The role of norrin in the specialization of retinal cells for their unique sensory function is impeded by the mutation of NDP. This results in an accumulation of immature retinal cells in the back of the eye. When norrin's role in the establishment of blood vessels supplying the eye is disrupted, the tissues cannot develop properly. Norrin is not only important in the development of the eye. The mutation of the NDP gene can affect other systems of the body as well. The most severe problems are caused by chromosomal deletions in the region of the NDP gene, causing the prevention of the gene product, or even that of the neighboring MAO genes. When the mutations simply change a single amino acid in norrin, the effects are less widespread and severe. However, the location and type of the NDP mutation does not necessarily determine the degree of severity of the disease, since highly varying clinical signs have been diagnosed in patients carrying exactly the same mutation. Therefore, the involvement of other modifying genes is very likely. On the other hand, if certain structurally important amino acids are changed (e.g. the cysteines forming the putative cystine knot), the clinical outcome has been shown to be more serious. == Diagnosis == Norrie disease and other NDP related diseases are diagnosed with the combination of clinical findings and molecular genetic testing. Molecular genetic testing identifies the mutations that cause the disease in about 95% of affected males. Clinical diagnoses rely on ocular findings. Norrie disease is diagnosed when grayish-yellow fibrovascular masses are found behind the eye from birth through three months. Doctors also look for progression of the disease from three months through 8–10 years of age. Some of these progressions include cataracts, iris atrophy, shallowing of anterior chamber, and shrinking of the globe. Children with the condition either have only light perception or no vision at all. In addition to its use for initial diagnosis, molecular genetic testing is used to confirm diagnostic testing (such as diagnosis by ocular examination), for carrier testing females, prenatal diagnosis, and preimplantation genetic diagnosis. There are three types of clinical molecular genetic testing. In approximately 95% of males, mis-sense and splice mutations of the NDP gene and partial or whole gene deletions are detected using sequence analysis. Deletion/duplication analysis can be used to detect the 15% of mutations that are submicroscopic deletions. This is also used when testing for carrier females. The last testing used is linkage analysis, which is used when the first two types are unavailable. Linkage analysis is also recommended for those families who have more than one member affected by the disease. MRI is often used to diagnose the retinal dysplasia that occurs with the Norrie disease. However, the retinal dysplasia can be indistinguishable on MRI from persistent fetal vasculature, or the dysplasia of trisomy 13 and Walker–Warburg syndrome. For families with an existing history of Norrie disease, genetic counselling and in utero diagnosis of Norrie disease may be considered. In utero diagnosis has been reported to include genetic testing by amniocentesis and ultrasonography to examine fetal eyes. Confirmation of diagnosis on the first day of life by ophthalmological examination under anesthesia has also been reported in some cases. == Management == Ocular, auditory and behavioral management are the most common areas of intervention and treatment for patients with Norrie disease. For ocular (eye) management, often patients already have complete retinal detachment at birth, or by the time of diagnosis, so surgical intervention is often not offered. However, there is some evidence for the benefit of early surgery or laser therapy for cases where retinal detachment is incomplete. Surgery may also be used to treat increased intraocular pressure and in rare cases enucleation (removal) of the eye is considered to control pain. A high proportion (85–90%) of individuals with Norrie disease experience progressive hearing loss in their second decade of life. In most cases, use of hearing aids has been shown to be effective into middle or late adulthood. For more significantly impaired hearing, cochlear implants may also be considered. 30–50% of individuals with Norrie disease have been reported to present with developmental delay or cognitive impairment. Additionally, behavioral issues have also been reported. Supportive intervention and therapy, for example working with speech and language therapists and occupational therapists, can be used to maximize educational opportunities for these individuals. Furthermore, training of teachers and school counselors on how to best support children with vision and hearing impairment can be extremely beneficial. Routine monitoring of individuals with Norrie disease is recommended to best manage the disease. This includes regular follow-up with an ophthalmologist, even when vision is severely compromised. Additionally, due to the high proportion of individuals with Norrie disease who develop hearing loss, regular monitoring of hearing loss is beneficial to allow any hearing loss to be detected early and then correctly managed. More recently, the use of dual sensory clinics has been proposed to provide improved care to patients living with conditions such as Norrie disease. For example, Great Ormond Street Hospital (GOSH), London are building a new Sight and Sound center, with the aim of improving the patient experience for individuals with conditions such as Norrie disease. The benefits of dual sensory clinics include improved communication between the different health care professionals (HCPs) involved in management of Norrie disease (e.g. ophthalmologists and audiologists) as well as allowing more consistent training of staff on best practices for managing and interacting with individuals with sensory impairment. Individuals with Norrie disease can often feel isolated from society due to difficulties in communication. In cases where hearing loss is also experienced, this psychological burden has been shown to increase. For example, a number of Norrie disease patients have been reported to experience transient depression correlating with the onset of hearing loss. Because of this, the provision of emotional support to individuals with Norrie disease can be as important as clinical treatment strategies in terms of improving their quality of life and reducing disease burden. == Research == Research into understanding Norrie disease and how to improve the lives of those with Norrie disease is ongoing. For example, research is taking place at Great Ormond Street Institute of Child Health, University College London (UCL GOSICH) to study the developmental changes in the ear and eye in Norrie disease, with the hope to understand how to improve current treatment strategies. The group at UCL GOSICH is focusing particularly on the hearing loss aspect of the disease, and whether it might be possible to treat by gene therapy. == History == In 1961, a Danish ophthalmologist named Mette Warburg reported on a Danish family that showed seven cases of a hereditary degenerative disease throughout seven generations. The first member of the family to be thoroughly studied was a 12-month-old boy. At the child's examination at three months, it was noticed that he was normal except that his lens appeared to be opaque and his irises were deteriorating. The area behind his lens was filled with a growing yellowish mass. Five months later, his left eye was removed due to suspicion of retinoblastoma, a cancerous tumor on the retina. A histologic examination showed a hemorrhagic necrotic mass in the posterior chamber, surrounded by undifferentiated (immature, undeveloped) glial tissue. The diagnosis included a pseudotumor of the retina, hyperplasia of retinal, ciliary, and iris pigment epithelium, hypoplasia and necrosis of the inner layer of the retina, cataract, and phthisis bulbi. The physician had suspected a tumor, although it emerged that it was a developmental defect that led to the malformation of inner parts of the eye. Because the eye was not functional, cells had already begun to die (necrosis) and the eye globe began to shrink due to its dysfunction (phthisi bulbi). In this Danish family, five of the seven people in these cases developed deafness later in life. Also, in four of the seven, mental capacity was determined to be low. After Warburg researched literature under various medical categories, she discovered 48 similar cases which she believed were caused by this disease as well. She then suggested this disease be named after another famous Danish ophthalmologist, Gordon Norrie (1855–1941). Norrie was greatly recognized for his work with the blind and for being a surgeon at the Danish Institute for the Blind for 35 years. The NDP gene was previously named the "Norrie disease (pseudoglioma)" gene, which is still used widely when referring to NDP. However, the current approved name for NDP is "Norrin cystine knot growth factor". == Culture == There are two patient organizations for people affected by Norrie disease. The Norrie Disease Association (NDA) was founded in 1994 and is a US-based non-profit organization aiming to provide information and support to people living with Norrie disease and their families. The NDA holds a conference on Norrie disease every three years in Boston, US. The Norrie Disease Foundation (NDF) is a UK-based charity established in 2016. The main aims of NDF are to provide support for families and promote pioneering research into Norrie disease. They organize two family days a year where families with Norrie disease can come together to share experiences, meet each other and build relationships and supportive networks. The websites for both patient organizations contain useful information for patients and their families about the disease. == References == == External links == NCBI Genetic Testing Registry	Wikipedia/Norrie_disease
Danon disease (or glycogen storage disease Type IIb) is a metabolic disorder. Danon disease is an X-linked lysosomal and glycogen storage disorder associated with hypertrophic cardiomyopathy, skeletal muscle weakness, and intellectual disability. It is inherited in an X-linked dominant pattern. == Signs and symptoms == Males In males, the symptoms of Danon disease are more severe. Features of Danon disease in males are: An early age of onset of muscle weakness and heart disease (onset in childhood or adolescence) Some learning problems or intellectual disability can be present Muscle weakness can be severe and can affect endurance and the ability to walk Heart disease (cardiomyopathy) can be severe and can lead to a need for medications. It usually progresses to heart failure, commonly complicated by atrial fibrillation and embolic strokes with severe neurological disability, leading to death unless a heart transplant is performed. Cardiac conduction abnormalities can occur. Wolff–Parkinson–White syndrome is a common conduction pattern in Danon disease. Symptoms are usually gradually progressive Some individuals may have visual disturbances, and/or retinal pigment abnormalities Danon Disease is rare and unfamiliar to most physicians. It can be mistaken for other forms of heart disease and/or muscular dystrophies, including Pompe disease. Females In females, the symptoms of Danon disease are less severe. Common symptoms of Danon disease in females are: A later age of onset of symptoms. Many females will not have obvious symptoms until late adolescence or even adulthood. Learning problems and intellectual disability are usually absent. Muscle weakness is often absent or subtle. Some females will tire easily with exercise Cardiomyopathy is often absent in childhood. Some women will develop this in adulthood. Cardiomyopathy can be associated with atrial fibrillation and embolic strokes. Cardiac conduction abnormalities can occur. Wolff–Parkinson–White syndrome is a common conduction pattern in Danon disease. Symptoms in females progress more slowly than in males. Some females may have visual disturbances, and/or retinal pigment abnormalities Danon Disease is rare and unfamiliar to most physicians. The milder and more subtle symptoms in females can make it more difficult to diagnose females with Danon Disease == Causes == Although the genetic cause of Danon disease is known, the mechanism of the disease is not well understood. Danon disease involves a genetic defect (mutation) in a gene called LAMP2, which results in a change to the normal protein structure. While the function of the LAMP2 gene is not well understood, it is known that LAMP2 protein is primarily located in small structures within cells called lysosomes. == Genetics == It is associated with LAMP2. The status of this condition as a GSD has been disputed. == Diagnosis == Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person's medical history, symptoms, physical exam, and laboratory test results to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional. Testing Resources The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is healthcare providers and researchers. Patients and consumers with specific questions about a genetic test should contact a healthcare provider or a genetics professional. Orphanet lists international laboratories offering diagnostic testing for this condition. == Treatment == RP-A501 is an AAV-based gene therapy aimed to restore the LAMP-2 gene which is defective in male patients with Danon Disease and how to cure it. Cardiac transplantation has been performed as a treatment; however, most patients die early in life. == History == Danon disease was characterized by Moris Danon in 1981. Dr. Danon first described the disease in 2 boys with heart and skeletal muscle disease (muscle weakness), and intellectual disability. The first case of Danon disease reported in the Middle East was a family diagnosed in the eastern region of United Arab Emirates with a new LAMP2 mutation; discovered by the Egyptian cardiologist Dr. Mahmoud Ramadan the associate professor of Cardiology in Mansoura University (Egypt) after doing genetic analysis for all the family members in Bergamo, Italy, where 6 males were diagnosed as Danon disease patients and 5 female were diagnosed as carriers; as published in Al-Bayan newspaper on 20 February 2016 making this family the largest one with patients and carriers of Danon disease. Danon disease has overlapping symptoms with another rare genetic condition called 'Pompe' disease. Microscopically, muscles from Danon disease patients appear similar to muscles from Pompe disease patients. However, intellectual disability is rarely, if ever, a symptom of Pompe disease. Negative enzymatic or molecular genetic testing for Pompe disease can help rule out this disorder as a differential diagnosis. == See also == Autophagic vacuolar myopathy Glycogen storage disease GSD-II (Pompe disease, formerly GSD-IIa) Inborn errors of carbohydrate metabolism Lysosomal storage disease Metabolic myopathies == References == == External links == AGSD - Association of Glycogen Storage Disease in the United States AGSD-UK - Association of Glycogen Storage Disease in the UK IamGSD - International Association for Muscle Glycogen Storage Disease	Wikipedia/Danon_disease
X-linked lymphoproliferative disease (also known as Duncan disease: 86 or Purtilo syndrome and abbreviated as XLP) is a lymphoproliferative disorder, usually caused by SH2DIA gene mutations in males. XLP-positive individuals experience immune system deficiencies that render them unable to effectively respond to the Epstein-Barr virus (EBV), a common virus in humans that typically induces mild symptoms or infectious mononucleosis (IM) in patients. There are two currently known variations of the disorder, known as XLP1 (XLP Type 1) and XLP2. XLP1 is estimated to occur in approximately one in every million males, while XLP2 is rarer, estimated to occur in one of every five million males. Due to therapies such as chemotherapy and stem cell transplants, the survival rate of XLP1 has increased dramatically since its discovery in the 1970s. == Presentation == In boys with X-linked lymphoproliferative disorder, the inability to mount an immune response to EBV may lead to death via hemophagocytic lymphohistiocytosis (HLH). Patients may also develop dysgammaglobulinemia and malignant non-Hodgkin lymphoma, even without exposure to EBV. Other observed symptoms of XLP include aplastic anemia, vasculitis, chronic gastritis, and skin lesions, as well as IM. Nearly half of XLP patients express humoral immune anomalies, which can include diminished responses to vaccines and low levels of immunoglobulin G (IgG). Patients produce insufficient numbers of CD27 memory B cells. == Cause == === XLP1 === XLP1 is caused by mutations in the SH2D1A gene, which is located at position Xq25 on the X-chromosome. This gene codes for an SH2 domain on a signal transducing protein called signaling lymphocyte activation molecule (SLAM)-associated protein, or SAP. A variety of mutations have been implicated in XLP1 expression, including deletions, single nucleotide changes, and incorrect splicing, although a correlation between the type of mutation and the severity of the disorder has not been established. These defects in SAP fundamentally change the function of two SLAM receptors, 2B4 (CD244) and NTB-A (SLAMF6). Typically, after the receptors bind to their associated ligands, the immunoreceptor tyrosine-based switch motifs (ITSMs) in their cytoplasms are phosphorylated, which activates cell-activating signaling pathways. In an XLP patient, the defects in SAP cause these receptors to induce an inhibitory, rather than activating effect. Ligand binding thus fails to activate natural killer (NK) and cytotoxic T cells that typically eliminate EBV infection, leading to cytokine overproduction and tissue damage. The term "SH2" domain stands for src-homology 2 domain, which is a three-dimensional domain structure of about 100 amino acid residues. These domains are present in many signalling proteins because they permit specific, non-covalent bonding to proteins that contain phosphotyrosines. The amino acid residues adjacent to the phosphotyrosine on the target protein are what determine the unique binding specificity. === XLP2 === Any instance of XLP caused by a mutation not in SHD21A is categorized as XLP2, although the variation is typically caused by mutations in the XIAP (X-linked inhibitor of apoptosis, also known as BIRC4) gene. XLP2 patients express different features from those typically found in XLP1 patients, such as splenomegaly and colitis. This variation is closely associated with HLH, so much so that some sources recommend classifying this condition as "X-linked familial hemophagocytic lymphohistiocytosis" instead of X-linked lymphoproliferative disease. Mutations in XIAP inhibit the expression of the gene, which usually regulates the rate of lymphocyte apoptosis during an immune response. Nonfunctional XIAP is unable to prevent lymphocytes from undergoing apoptosis in response to stimuli, which include the formation of the T-cell receptor (TCR)-CD3 complex, the binding the CD95 death receptor, and the activation TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). This leads to higher rates of lymphocyte apoptosis during a normal immune response. XIAP-deficient individuals also produce low numbers of natural killer cells, a feature shared with XLP1 patients, which leads to a similarly inefficient response to EBV infection. == Treatment == Chemotherapy and hematopoietic stem-cell transplantation (HSCT) therapies have shown great success in treating XLP. The development of the two therapies, alongside more efficient monitoring techniques and supportive care, has reduced the overall mortality of the disease from 75% to 29%. Care differs depending on the phenotype of XLP expressed, with treatments varying between those experiencing HLH or lymphoma, and whether or not they have been infected with EBV. Still, a bone marrow transplant that includes CD34+ hematopoietic stem cells is the only known treatment for the disorder as a whole. Patients who cannot find a bone marrow donor have a survival rate of less than 20%. In addition to the typical restrictions imposed on donor-recipient matches, XLP1 patients who have been infected with EBV typically receive transplants from EBV-positive donors. == Eponym == XLP is also known as Duncan disease, after 6 of 18 males in the Duncan family died of lymphoproliferative disease, including fulminant infectious mononucleosis and lymphoma. It is also called "Purtilo's syndrome", after David Theodore Purtilo (1939–1992), a pioneering pathologist and immunologist at the American Army Center for Pathology in Washington, who discovered it in the early 1970s. A native of Duluth, Minnesota, he pioneered the research for this condition after discovering it in one of his patients. In the late 1980s, he resided in Omaha, Nebraska and died on September 28, 1992, in Florida, following a stroke before he could deliver a speech to a forum. == References == == External links == GeneReview/NIH/UW entry on Lymphoproliferative Disease, X-Linked	Wikipedia/X-linked_lymphoproliferative_disease
Bachelor of Ayurvedic Medicine and Surgery (B.A.M.S.) is a professional degree focused on Ayurveda offered in India, Nepal, Bangladesh, and Sri Lanka. Ayurveda is a type of alternative medicine, and the study of Ayurveda is scientific while the practice can be classified as scientific. == About == A 2001 report from the World Health Organization noted that Ayurveda was widely practiced in India, Nepal, Bangladesh, and Sri Lanka, the four corresponding nations that offer the BAMS degree. Ayurveda was generally not integrated with the national health system of nations outside of the Indian subcontinent. === India === In India, the curriculum includes the study of Ayurveda and corresponding Ayurvedic subjects such as Rachana Sharira, Kriya Sharira, Dravyuaguna, Svasthavritta and Yoga, Roga Nidana and Vikriti Vijnana, Kaya Chikitsa, Kaumara Bhritya, Prasuti Tantra, Shalya Tantra, Shalakya Tantra etc. along with human anatomy, physiology, pathology & diagnostic procedures, principles of medicine, pharmacology, toxicology, forensic medicine, E.N.T, gynecology & obstetrics, ophthalmology and principles of surgery from modern medicine. The syllabus also includes ancient and medieval classics, sometimes in the Sanskrit language. Institutions in India that offer the degree include the National Institute of Ayurveda and All India Institute of Ayurveda, Delhi. In India, a student can go on to earn a master's degree in the form of MD (Ayurveda) and MS (Ayurveda), a PhD, and clinical doctorate degrees in traditional and complementary medicine at the university level. There are also opportunities to perform research, work in hospital and healthcare administration, and in health supervision. In a report from 2020, the World Health Organization stated there was "a history of combining allopathic and traditional medicine systems in India, including through medical education." The WHO described AYUSH and conventional medical systems as "separate and parallel at the levels of governance, organisation, education and service delivery." A nation-wide survey conducted by the researchers of the Banaras Hindu University in 2009, which included a total of 1022 students and teachers of Ayurveda, revealed that the graduates possessing a BAMS degree generally lack required exposure to essential clinical skills. In another paper derived from the same study, the authors have identified multiple global challenges being faced by the Ayurveda education sector. ==== Permission to practice medicine ==== BAMS graduates have been permitted to practice medicine in the state of Maharashtra. In the state of Karnataka, BAMS doctors appointed in primary health centres in rural areas can practice modern-medicine in case of "emergencies". == References == == External links == Central Council of Indian Medicine (CCIM), the apex body in India which regulates education and practice of BAMS doctors	Wikipedia/Bachelor_of_Ayurveda,_Medicine_and_Surgery
A Doctor of Science (Latin: Scientiae Doctor; most commonly abbreviated DSc or ScD) is a science doctorate awarded in a number of countries throughout the world. == Africa == === Algeria and Morocco === In Algeria, Morocco, Libya and Tunisia, all universities accredited by the state award a "Doctorate" in all fields of science and humanities, equivalent to a PhD in the United Kingdom or United States. Some universities in these four North African countries award a "Doctorate of the State" in some fields of study and science. A "Doctorate of the State" is slightly higher in esteem than a regular doctorate, and is awarded after performing additional in-depth post-doctorate research or achievement. == Asia == === Japan === Similarly to in the US and most of Europe, Japanese universities offer both the PhD and the ScD as initial doctorates in science. === India === In India only a few prestigious universities offer ScD/DSc in science which is obtained in Graduate School after satisfactory evaluation of knowledge, research accomplishment, and a doctoral defence. The oldest institute to award a DSc degree in India is Rajabazar Science College, University of Calcutta. === Thailand === Higher education institutes in Thailand generally grant PhD as a doctoral research degree, some universities including Chulalongkorn University award DSc. In exception, Mahidol University can grant both PhD and DSc. Doctoral students in Faculty of Science are always awarded PhD, but some other programs award DSc. === Uzbekistan === DSc or PhD degrees are awarded after dissertation and fulfilling the required publication number. In order to qualify for DSc, one is required to have attained a PhD. The higher education institutes in Uzbekistan also grant DSc degrees. As an example, the National University of Uzbekistan and the Uzbekistan Academy of Sciences offer DSc in various fields. == Europe == === Austria, Germany, and Switzerland === In Germany, Austria, and the German-speaking region of Switzerland, common doctoral degrees in science are the following: Dr. techn.: Doctor technicae, awarded by Austrian technical universities. In German: "Doktor der technischen Wissenschaften" which translates to Doctor of Engineering Sciences, or Doctor of Science, or Doctor of Technical Sciences, or Doctor of Technology. Dr.techn. title is also awarded in Denmark. Dr. rer. nat.: Doctor rerum naturalium, literally "Doctor of the things of nature" Dr. rer. medic.: Doctor rerum medicarum, Doctor of medical sciences Dr. sc. med.: Doctor scientiarum medicarum, Doctor of science in medicine Dr. sc. nat.: Doktor der Naturwissenschaften, Doctor of Natural Sciences Dr. sc. ETH: Doktor der Naturwissenschaften ETH, Doctor of Natural Sciences, awarded by ETH Zurich, Switzerland. Dr. phil. nat.: Doctor philosophiae naturalis, used only by Goethe University Frankfurt instead of Dr rer. nat; Doctor of Natural Sciences, awarded by Swiss universities. Dr.-Ing.: Doktor der Ingenieurwissenschaften (Doctor of Engineering), awarded by German universities in areas of technology and engineering. Dr. mont.: Doctor rerum montanarum, awarded by the University of Leoben instead of Dr. techn. Dr. nat. techn.: Doctor rerum naturalium technicarum, awarded by the University of Natural Resources and Life Sciences, Vienna instead of Dr. techn. In these countries there are some related doctoral degrees with very similar names, these are the: Dr. sc. agr.: Doctor scientiarum agrariarum, Doctor of Agricultural science Dr. sc. hum.: Doctor scientiarum humanarum, Doctor of Humanistic Sciences Dr. sc. inf.: Doctor scientiarum informaticarum, Doctor of Science in Informatics Dr. sc. inf. med.: Doctor scientiarum informaticarum medicæ, Doctor of Science in Medical Informatics Dr. sc. inf. biomed.: Doctor scientiarum informaticarum biomedicæ, Doctor of Science in Biomedical Informatics Dr. sc. math.: Doctor scientiarum mathematicarum, Doctor of Mathematics Dr. scient. med.: Doctor scientiæ medicæ, Doctor of Medical Sciences Dr. sc. mus.: Doctor scientiae musicae, Doctor of Musicology Dr. sc. oec.: Doctor scientiarum oeconomicarum, Doctor of Economics Dr. sc. pol.: Doctor scientiarum politicarum, Doctor of Political Sciences Dr. rer. pol.: Doctor rerum politicarum, Doctor of economics, business administration, or political science Dr. sc. soc.: Doctor scientiae socialis, Doctor of Social Sciences All of these doctoral degrees are equivalent to the PhD or ScD of the American system. Until German Reunification, universities in East Germany also awarded the Dr Sc. However, the East German Dr Sc was not equivalent to the PhD since it was adopted to replace the German Habilitation and therefore was equivalent to this higher-level qualification. After reunification the Habilitation was reintroduced at universities in Eastern Germany. The procedure of habilitation is normally required to receive officially the "venia docendi", which entitles the candidate to lecture at universities (Privatdozent, for men, or Privatdozentin, for women). The academic degree after the successful habilitation is e.g. Dr. rer. nat. habil., by adding the suffix "habil." to the earlier received Doctors degree. In Switzerland, the Dr sc. is a doctoral degree awarded only by the two Swiss Federal Institutes of Technology (EPFL and ETHZ), the University of Fribourg and the Department of Informatics of the University of Zurich. The Swiss Dr sc., like the DSc in the US, is equivalent to the PhD. It is earned with the approval of a committee on the basis of original research, publications, and extensive applied professional contributions and is awarded in doctoral level science and technology programs. Since 2004 the Dr sc. is the only doctoral degree awarded by the ETH Zurich. The École polytechnique fédérale de Lausanne awards the degree Docteur ès sciences, abbreviated Dr ès sc.and translated into English as PhD. === Poland === In Poland higher doctorate is Habilitation (habilitated doctor, doctor with habilitation) (doktor habilitowany or dr hab. in Polish) is the degree higher than PhD and it is awarded for substantial accomplishments in academic teaching, research and service after getting the PhD degree (usually up to 8 years of original research and multiple publications in peer reviewed scientific journals and monograph, habilitation dissertation after PhD). It is similar to habilitation degree in Germany and Austria. It is also similar (in terms of requirements) to associate professor with tenure. After achieving high degrees and rich research or artistic achievements, including as an academic teacher, lecturer, one can apply to become a professor. The President of Poland awards a scientist also in engineering (engineer) or artist the scientific title of professor (tytuł naukowy profesora) and the title of professor of art (tytuł profesora sztuki), respectively, in recognition of their scientific achievements and contributions to science, technology, and respectively their achievements in art and contributions to art. These titles are not academic/scientific or art degrees. However, possession of high degrees is required to receive the title. Habilitation has been a mandatory requirement for many years to apply for professorship in Poland. === United Kingdom, Ireland, India, Pakistan and the Commonwealth === In Ireland, the United Kingdom and the countries of the Commonwealth, such as Australia and India (in the Indian Institute of Technology, Bombay), the degree of Doctor of Science (DSc or ScD) is one of the Higher Doctorates. In some older universities it typically has precedence after Divinity, Laws or Civil Law, Medicine, and Letters, and above Music. The degree is conferred on a member of the university who has a proven record of internationally recognised scholarship. A candidate for the degree will usually be required to submit a selection of their publications that follow a consistent theme to the board of the appropriate faculty, which will decide if the candidate merits this accolade. Quite often they will need to be a doctoral graduate of at least ten years' standing and have a substantial research association with the awarding university. The first University to admit an individual to this degree was the University of London in 1860. In 1893 Maria Gordon (née Ogilvie) was the first woman to receive this degree. In former times the doctorate in science was regarded as a greater distinction than a professorial chair and hence a professor who was also a DSc would be known as Doctor. The Doctor of Science may also be awarded as an honorary degree, that is, given to individuals who have made extensive contributions to a particular field and not for specific academic accomplishments. It is usual to signify this by adding DSc h.c. (for honoris causa). === Other European Union countries === In the Czech Republic and Slovakia "Doctor of Sciences" (DrSc behind the name), established in 1953, is equivalent to the degree of Doctor of Science in the sense in which the DSc is used in the Commonwealth. It is the highest academic qualification, different from both PhD and PhDr. titles. In the Czech Republic, DrSc has not been awarded since 2001; instead, since 2006, a "Doctor of Sciences" degree (DSc behind the name) has been awarded, not by universities but by the Czech Academy of Sciences mostly for research in the field of natural or formal science. In Slovakia, "Doctor of Sciences" (DrSc) is awarded by the Slovak Academy of Sciences. In Hungary, "Doctor of Sciences" (DSc) is a higher doctorate degree and it is awarded by the Hungarian Academy of Sciences. In Finland, most doctoral degrees awarded in the fields of natural sciences, technology and economics are termed DSc degrees in English, with a suffix indicating the field of study. However, there is no translation of the term Doctor of Science to Finnish. For example, the proper translation for the doctorate in technology (tekniikan tohtori) would be DSc (Tech), whereas a doctorate in economics and business administration (kauppatieteiden tohtori) would be translated as DSc (Econ). When conversing or writing in English, the prefix Dr may be used to address a holder of a doctoral degree awarded in Finland. The degrees are equivalent to filosofian tohtori (FT, English: PhD), but FT is usually awarded only in general sciences, not in specializations like engineering, economics or medicine. In France, the Doctor of Sciences degree (doctorat en sciences also called doctorat d'État) was a higher doctorate in the fields of experimental and natural sciences, superseded in 1984 by the habilitation. In Denmark, Dr Scient. is a higher doctorate. In Bulgaria, "Doctor" (PhD) is the highest education level and first science degree. Doctor of Sciences (DrSc) is the second and the highest science degree. === Russia and other post-communist states === In Russia, the status of Russian Doktor Nauk (literally 'Doctor of Sciences') is considered a higher scientific degree. The equivalent to PhD is "Candidat Nauk" === Other European countries === In the former Yugoslavia, (Croatia, Serbia, Bosnia and Herzegovina, Montenegro, Slovenia, North Macedonia), title doktor nauka or doktor znanosti (literally "doctor of science") is used in a much broader sense than DSc, simply referring to a field of academic study – from art history (doktor znanosti/nauka povijesti umjetnosti), philosophy (doktor znanosti/nauka filozofije), and literary studies (doktor znanosti/nauka književnosti) to hard sciences such as molecular biology (doktor znanosti/nauka molekularne biologije). It is therefore formally recognized as a PhD degree. Starting in 2016, in Ukraine Doctor of Philosophy (PhD, Ukrainian: Доктор філософії) is the highest education level and first science degree. "Doctor of Sciences" (DSc Ukrainian: Доктор наук) is the second and the highest science degree, awarded in recognition of a substantial contribution to scientific knowledge, origination of new directions and visions in science. Since 2016, a PhD degree is one of the prerequisites for heading a university department in Ukraine. In Belarus "Doctor of Sciences" (DSc, Belarusian: Доктар навук) is the highest level of education that follows a PhD. Is awarded by The Higher Attestation Commission under the aegis of the President of the Republic of Belarus. == North America == === United States === In the United States, the formally recognized traditional Doctor of Science is an academic research doctoral degree awarded by research universities. The academic research ScD (or DSc) is not higher than a PhD as is the case in some European countries. The first North American ScD was inaugurated by Harvard University in 1872, when graduate studies first began at Harvard, and where the PhD and ScD degrees were introduced in the same year. The Doctor of Science research degree is earned with the formal dissertation defense and approval of a committee on the basis of original research and publications, and it is awarded predominantly in doctoral-level science programs, such as engineering, medical and health sciences, and health economics. Although rarer than the Doctor of Philosophy, the Doctor of Science is awarded by institutions including: Harvard University Columbia University Chapman University Middle Georgia State University Johns Hopkins University Massachusetts Institute of Technology, Capitol Technology University Bowie State University Towson University Tulane University University of Baltimore Marymount University Rocky Mountain University of Health Professions Aspen University in Computer Science University of Massachusetts Lowell in public health (epidemiology) Jacksonville State University in emergency management Spertus Institute for Jewish Learning and Leadership in Jewish studies. The George Washington University (although as of 2011 the university decided to offer only the more widely recognized PhD degree) A few university doctoral research programs offer both the Doctor of Science and Doctor of Philosophy degrees in the same academic field, such as Johns Hopkins University and Massachusetts Institute of Technology, with identical requirements for obtaining either. Research programs that offer the formal research ScD but not the PhD degree for a given field include several doctoral programs at Harvard University, Boston University, Capitol Technology University, and Texas Tech University Health Sciences Center. The University of Baltimore, School of Information Arts and Technologies offers a DSc degree in Information and Interaction Design, a program focused on usable design/user experience (UX) and Human Computer Interaction (HCI). There are programs where the Doctor of Science and Doctor of Philosophy have different degree requirements, though the two degrees are officially considered equivalent. The Engineering school at Washington University in St. Louis, for example, requires four more graduate courses in the DSc program, which can be completed in one year in conjunction with research duties, while the PhD requires teaching assistance services. The Johns Hopkins University also offers both PhD and ScD in certain programs, with only minor differences in university administration of the degrees. In some institutions, the ScD has been converted to the PhD. For instance, the doctoral degree in biostatistics at Harvard recently converted from ScD to PhD, even though the doctoral degree structure and requirements have remained identical. === Mexico === In Mexico the PhD level is considered a doctoral degree (level 8) similar to the doctorate degrees in Canada and the United States. The Doctor of Sciences degree is instead recognized as a Higher Degree (Grado Propio). === Costa Rica === In Costa Rica, doctorates are the highest academic degrees awarded by a university. They are focused on research and accessible only after the study of an academic Master's degree (as opposed to a professional Master's degree, intended for practical subjects). The University of Costa Rica, for example, offers a general Doctor of Sciences degree for students of all natural and exact sciences, a Doctor of Engineering degree for students of Engineering (in cooperation with the Costa Rica Institute of Technology), and a few other doctorate programs on applied sciences (for example, in Agricultural Sciences or Informatics). == South America == === Argentina === In Argentina the formal title Doctor of Science would be attributed to different fields of the hard or soft sciences. To get into an Argentine PhD program the applicant must have experience in research and at least an Engineering, Licentiate or master's degree: ==== Applied sciences ==== Doctorate of Agronomic Sciences (University of Buenos Aires, NU of LP, NU of C, NU of R, NU of MP, NU of the S) Doctorate of Sciences in Lacteal Technology (NU of the L) Doctorate of Sciences in Material Technology (NU of the S, NU of MP) Doctorate of Computer Sciences (University of Buenos Aires, NU of C, NU of SL, NU of the S) Doctorate of Engineering Sciences (NU of C, NU of Cu, NU of RC, NU of the S, ITBA) Doctorate of Geological Sciences (NU of C, NU of Cu, NU of SJ, NU of SL, NU of the S) Doctorate of Informatics Sciences (NU of LP) Doctorate of Basic Sciences Applied (NU of Q) Doctorate of Science and Technology (NU of GS) Doctorate of Geological Sciences (University of Buenos Aires) Doctorate of Molecular Biology and Biotechnology (NU of SAM) Doctorate of Systems Control (NU of the S) Doctorate of Economics Sciences (NU of LM) Doctorate of Economy (NU of LP, NU of the S) Doctorate of Geography (NU of the S) Doctorate of History (NU of the S) Doctorate of Chemical Engineering (NU of the S) ==== Basic sciences ==== Doctorate of Biological Sciences (U of BA, NU of LP, NU of C, NU of R, NU of the L, NU of Cu, NU of RC, NU of MP, NU of the S) Doctorate of Biological Chemistry Sciences (U of BA, NU of the S) Doctorate of Molecular Biology Sciences (U of BA) Doctorate of Mathematics Sciences (U of BA, NU of LP, NU of SL, NU of the S) Doctorate of Chemistry Sciences (NU of LP, NU of R, NU of C, NU of RC, NU of MP, NU of the S) Doctorate of Physics Sciences (U of BA, NU of LP, NU of MP, NU of SAM, NU of the S) Doctorate of Natural Sciences (U of BA, NU of LP) Doctorate of Philosophy (NU of the S) === Brazil === In Brazil only the Doctor in Sciences (DSc) category is recognized as a higher doctorate, generally followed by the concentration area (program field). This kind of doctorate is obtained in Graduate School after satisfactory evaluation of knowledge, research accomplishment, and thesis defense. This doctorate is comparable to a PhD program found in other countries. In the state of São Paulo, the doctorate title is the second highest academic title given by the state's universities (University of São Paulo (USP), State University of Campinas (UNICAMP) and São Paulo State University (UNESP)) and most Federal Universities, such as the Federal University of São Paulo (UNIFESP). The highest academic title is the Portuguese: Livre-Docência, which is not equivalent to the German Habilitation, since Portuguese: Livre-Docência is not a requisite to be a professor in Brazilian universities, and German Habilitation is a requisite to be a professor in German universities. However, Portuguese: Livre-Docência is a requisite to be promoted to Associate Professor / "full" Professor (Portuguese: Professor Titular) at several of those public research Universities. == References ==	Wikipedia/Doctor_of_Science
A Bachelor of Medical Sciences (BMedSci, BMedSc, BSc(Med), BMSc) is an undergraduate academic degree involving study of a variety of disciplines related to human health leading to an in depth understanding of human biology and associated research skills such as study design, statistics and laboratory techniques. Such disciplines include biochemistry, cell biology, physiology, pharmacology or psychosocial aspects of health. It is an equivalent level qualification to the more commonly awarded Bachelor of Science (BSc). Graduates may enter a diverse range of roles including post-graduate study, higher education, the biotechnology industry, the pharmaceutical industry, consultancy roles, scientific communication, education or unrelated disciplines which make use of the broad range of transferable skills gained through this degree. == Australia == In Australia, the Bachelor of Medical Sciences (BMedSc) degree is offered by The University of Adelaide, Griffith University, University of New South Wales, University of Sydney, Monash University, Australian National University, University of Western Sydney, University of Newcastle, Flinders University, Charles Sturt University, Macquarie University , Central Queensland University and The University of the Sunshine Coast. == Canada == At the University of Western Ontario, BMSc is a four-year degree offered by the Schulich School of Medicine & Dentistry. It is differentiated from a BSc due to the advanced medical sciences orientation of the courses offered such as Anatomy and Pharmacology. The University of Alberta offers a BMSc to Faculty of Medicine and Dentistry students who did not complete a bachelor's degree prior to entry into the program. == India == In India, BMSc is an undergraduate degree offered by top universities like Panjab University, Punjabi University, Indian Institutes of Technology and the R. G. Kar Medical College and Hospital. == United Kingdom == In the United Kingdom, the Bachelor of Medical Sciences degree can be awarded in four situations; firstly as a standalone 3-year first degree, secondly, as a consequence of taking an extra year during a medical or dental course (termed intercalating), thirdly as an additional part of a medical degree but without any additional years of study, and fourthly as an exit award if a student wishes to leave their primary medical or dental undergraduate course. When the degree is obtained without any additional years of study, it may not be viewed as an equivalent qualification. For example, the UK Foundation Programme Office (the British body which manages first jobs for new medical graduates) places less value on a BMedSc degree if an additional year of study has not been undertaken. Regardless of the way in which the degree is obtained, a research project typically forms a large component of the degree as well as formal teaching in medical science related disciplines. Bachelor of Medical Sciences degrees are awarded as a standalone 3-year course by the University of Chester, University of Exeter, University of Birmingham, the University of Sheffield, Bangor University, Oxford Brookes University, De Montfort University, and the University of St Andrews. Medical schools which award an intercalated Bachelor of Medical Sciences after an additional year of study are Barts and The London School of Medicine and Dentistry, the University of Birmingham, the University of Dundee, the University of Edinburgh the University of Aberdeen and the University of Sheffield. The University of Nottingham and the University of Southampton award the degree as a standard part of their undergraduate medicine courses without an additional year of study (students must undertake a research project). == Egypt == In Egypt, the bachelor of medical sciences is awarded after four years of study in addition to an internship year in which interns are trained in multiple public and university hospitals. The degree is offered in five universities in Egypt: October 6 University, Misr University for Science and Technology, Pharos University in Alexandria, Beni-Suef University and Menoufia University. Faculties of applied medical sciences offer various disciplines for students to choose from, including medical laboratories, radiology and medical imaging, therapeutic nutrition, and biomedical equipment. In 2015, the Central Authority For Organization and Administration (CAOA) granted the holders of the bachelor of medical sciences the title of "specialist" in the corresponding specialty. == Israel == BSc.Med is granted by all six medical schools in Israel: the Hebrew University, Tel Aviv University, Ben-Gurion University, the Technion, Bar-Ilan University and Ariel University. The full M.D. program consists of six years of studies and an additional year of internship. The first part of the program consists of three years of basic science (pre-clinical) studies, culminating in the award of a BSc.Med degree in medical sciences. == References ==	Wikipedia/Bachelor_of_Medical_Science
The University of Auckland Faculty of Medical and Health Sciences (FMHS; Māori: Mātauranga Hauora) was established in 1968 as The University of Auckland School of Medicine at its present site in Grafton, Auckland. Prior to this, the University of Otago had taught some students from the final years of its medical course in Auckland through a branch faculty of the Dunedin School of Medicine. == Research == FMHS has 7 research centres: the Aotearoa–New Zealand National Eye Centre (ANZ–NEC), Auckland Cancer Society Research Centre (ACSRC), Centre for Addiction Research, Centre for Medical Imaging, Eisdell Moore Centre, Manaaki Mānawa – The Centre for Heart Research, and Surgical and Translational Research (STaR) Centre. The faculty also possesses the only brain bank in New Zealand. This brain bank contains over 400 brains bequeathed to the medical school. These include brains donated by people who died with neurological diseases such as Huntington's disease and Parkinson's disease. The University of Auckland welcomed the commitment by New Zealand and Australian prime ministers to fund NZ $3 million over 2 years for a trans-Tasman project to investigate potential vaccines against Rheumatic fever. Rheumatic fever is a major health concern in NZ and Australia, particularly in Maori, Pacifica and Aboriginal communities, which have the highest rates in the world. It is a result of an immune reaction to infection by group A streptococcus. This vaccine project complements ongoing public health programs which contribute to high rates of disease in New Zealand and Australia. The University has considerable expertise in both the basic science of group A streptococcus infection and public health approaches required to take high rates of rheumatic fever as per Professor John Fraser, former Dean of the Faculty of Medical and Health Sciences. == Schools and departments == FMHS consists of 6 schools and 1 department, all of which are based on the Grafton Campus. It is made up of School of Medical Sciences School of Medicine School of Nursing School of Optometry and Vision Sciences School of Pharmacy School of Population Health Te Kupenga Hauora Māori The Philson Library in the School of Medicine is named after Thomas Moore Philson, a notable doctor and medical superintendent of Auckland Hospital, who set up a trust fund to found a medical library for students. == References == == External links == Faculty homepage Auckland University Medical Students' Association website New Zealand Medical Students' Association website	Wikipedia/University_of_Auckland_Faculty_of_Medical_and_Health_Sciences
Clinical clerkships encompass a period of medical education in which students – medical, dental, veterinary, nursing or otherwise – practice medicine under the supervision of a health practitioner. == Medical clerkships == In medical education, a clerkship, or rotation, refers to the practice of medicine by medical students (M.D., D.O., D.P.M) during their final year(s) of study. Traditionally, the first half of medical school trains students in the classroom setting, and the second half takes place in a teaching hospital. Clerkships give students experience in all parts of the hospital setting, including the operating room, emergency department, and various other departments that allow learning by viewing and doing. Students are required to undergo a pre-clerkship course, which include introduction to clinical medicine, clinical skills, and clinical reasoning. A performance assessment such as the Objective Structured Clinical Examination (OSCE) is conducted at the end of this period. During the clerkship training, students are required to rotate through different medical specialties and treat patients under the supervision of physicians. Students elicit patient histories, complete physical examinations, write progress notes, and assist in surgeries and medical procedures. They are also actively involved in the diagnoses and treatment of patients under the supervision of a resident or faculty. Students undergoing two-year clerkships spend their first year in patient care environment in month-long rotations with limited patient workloads. In their final year, when they are sometimes referred to as sub-interns or externs, they are given more patient care responsibilities in a variety or elective rotations. The work hours are that of a full-time job, generally similar to that of residents. Students may also be required to work on weekends and to be on call. For medical students, clerkships occur after the basic science curriculum, and are supervised by medical specialists at a teaching hospital or medical school. Typically, certain clerkships are required to obtain the Doctor of Medicine degree or the Doctor of Osteopathic Medicine degree in the United States (e.g., internal medicine, surgery, pediatrics), while others are elective (e.g., dermatology, pathology, and neurology). The intent of the clinical clerkship is to teach the medical student the fundamentals of clinical examination, evaluation, and care provision, and to enable the student to select the course of further study. Another purpose of the clerkship is for the student to determine if they really want to pursue a career in the field of medicine. During the clinical clerkship, the medical student will interact with real patients much as a physician does, but their evaluation and recommendations will be reviewed and approved by more senior physicians. The expectation is that the students will not only master the knowledge in successfully treating patients but they are also expected to assume the physician's role. === United States === In the United States, medical school typically lasts four years. Medical students spend the first part of this third and fourth years rotating through a combination of required clerkship and electives. Most medical schools require rotations in internal medicine, surgery, pediatrics, psychiatry, obstetrics and gynecology, family medicine, and neurology. Some schools may additionally require emergency medicine, anesthesiology, radiology, ambulatory medicine, or intensive-care medicine. Furthermore, a common graduation requirement is to complete a sub-internship in a specialty, where the medical student acts as an intern. === Australia === ==== New South Wales ==== In the 2010s, the New South Wales administration partnered with the University of Wollongong to enroll its senior medical students in a year-long integrated experience of longitudinal clinical clerkship. Students were sent in regional, rural or remote areas of the NSW and worked in interprofessional hospitals and community teams in which a supervisor or a review gave them first access to acute and chronic care patients. Active and experiential learning were based on multi-professional general practices, primary health care clinics, hospital emergency, ward-based patient care and concerns of surgery. Care and supervision had been modelled on the previous Cambridge community-based clinical course and on the Parallel Rural Community Curriculum introduced by South Australia in 2007. == Nursing and Physician Assistant programs == In nursing education, a clerkship refers to the clinical courses conducted by students during their final year of studies. The student satisfaction with the clerkship is a determinant factor in selection of nursing field. Physician assistant programs in the United States used the term in the same manner. == References ==	Wikipedia/Clinical_clerkship
Bachelor of Eastern Medicine and Surgery (BEMS) or Bachelor of Unani Medicine and Surgery (BUMS) is a bachelor's degree in Unani medicine and surgery awarded upon graduation from medical school by universities in Pakistan, India, Bangladesh, Sri Lanka and in South Africa as BCM Complementary Medicine: Unani Tibb. == In Pakistan == It is a form of Oriental medicine launched for the first time at the Hamdard University and then in Islamia University in Pakistan. Admission to 5-yearly BEMS degree/classified program/course is purely based on FSC (Pre-Medical). Internship Bachelor of Eastern Medicine and Surgery: After completing the degree program and one-yearly house internship, NCT licensed graduates can practice Eastern medicine as registered Unani physician according to the UAH Act 2002-1965. Qualified graduates can be enrolled in Higher Education Commission registered private and public universities. They can also be enrolled for Eastern Medicine curriculum to receive M.Phil. And Ph.D. degrees inside and abroad. In 2020, National Council for Tibb (NCT) announced that BEMS graduate will be regarded as "Doctor of Natural Medicine". == References ==	Wikipedia/Bachelor_of_Unani_Medicine_and_Surgery
Licentiate in Medicine and Surgery (also known as Licentiate in Medical Practice in some instances) is a medical degree of historical importance in India. During the British rule of India some universities conferred this qualification. The qualification was conferred on a candidate who, having completed a five-year course, passed the required examination. This was in contrast with the MB degree which was of same duration but the curriculum was larger. Bhore committee, a committee for public health improvement strategies, in 1946 decided to stop the LMS (or, LMP) degree, and recommended a single qualification for all doctors (MBBS). The qualification was known by some other names in some of the states/universities, such as Licentiate of Medical Faculty (LMF). The L.M.S. was also previously conferred in other former British colonies such as Ceylon, Malaysia and Singapore. The name of the degree has been adopted to Finland, where physicians usually hold the L.M. instead of M.D. == References ==	Wikipedia/Licentiate_in_Medicine_and_Surgery
Occupational therapy (OT), also known as ergotherapy, is a healthcare profession. Ergotherapy is derived from the Greek ergon which is allied to work, to act and to be active. Occupational therapy is based on the assumption that engaging in meaningful activities, also referred to as occupations, is a basic human need and that purposeful activity has a health-promoting and therapeutic effect. Occupational science the study of humans as 'doers' or 'occupational beings' was developed by inter-disciplinary scholars, including occupational therapists, in the 1980s. The World Federation of Occupational Therapists (WFOT) defines occupational therapy as ‘a client-centred health profession concerned with promoting health and wellbeing through occupation. The primary goal of occupational therapy is to enable people to participate in the activities of everyday life. Occupational therapists achieve this outcome by working with people and communities to enhance their ability to engage in the occupations they want to, need to, or are expected to do, or by modifying the occupation or the environment to better support their occupational engagement'. Many of the Member Organisations of WFOT have agreed a national definition of occupational therapy. In New Zealand occupational therapy is translated into Maori as 'whakaora ngangahau'. 'Whakaora' means ‘to restore to health' and 'ngangahau' is an adjective meaning 'active, spirited, zealous'. Education programmes leading to entry to practice as an occupational therapist can be at diploma, baccalaureate, bachelors, masters or doctoral level. Information about entry level education programmes, currently or previously approved by WFOT, is available on the WFOT website Occupational therapy is an allied health profession. In England, allied health professions (AHPs) are the third largest clinical workforce in health and care. Fifteen professions, with 352,593 registrants are regulated by the Health and Care Professions Council in the United Kingdom. == History == The earliest evidence of using occupations as a method of therapy can be found in ancient times. In c. 100 BCE, Greek physician Asclepiades treated patients with a mental illness humanely using therapeutic baths, massage, exercise, and music. Later, the Roman Celsus prescribed music, travel, conversation and exercise to his patients. However, by medieval times the use of these interventions with people with mental illness was rare, if not nonexistent. === Moral treatment and graded activity === In late 18th-century Europe, doctors such as Philippe Pinel and Johann Christian Reil reformed the mental asylum system. Their institutions used rigorous work and leisure activities. This became part of what was known as moral treatment. Although it was thriving in Europe, interest in the reform movement fluctuated in the United States throughout the 19th century. In the late 19th and early 20th centuries, the establishment of public health measures to control infectious diseases included the building of fever hospitals. Patients with tuberculosis were recommended to have a regime of prolonged bed rest followed by a gradual increase in exercise. This was a time in which the rising incidence of disability related to industrial accidents, tuberculosis, and mental illness brought about an increasing social awareness of the issues involved. The Arts and Crafts movement that took place between 1860 and 1910 also impacted occupational therapy. The movement emerged against the monotony and lost autonomy of factory work in the developed world. Arts and crafts were used to promote learning through doing, provided a creative outlet, and served as a way to avoid boredom during long hospital stays. From the late 1870's, Scottish tuberculosis doctor Robert William Philip prescribed graded activity from complete rest through to gentle exercise and eventually to activities such as digging, sawing, carpentry and window cleaning. During this period a farm colony near Edinburgh and a village settlement near Papworth in England were established, both of which aimed to employ people in appropriate long-term work prior to their return to open employment. === Development into a health profession === In the United States, the health profession of occupational therapy was conceived in the early 1910s as a reflection of the Progressive Era. Early professionals merged highly valued ideals, such as having a strong work ethic and the importance of crafting with one's own hands with scientific and medical principles. American social worker Eleanor Clarke Slagle (1870-1942) is considered to be the "mother" of occupational therapy. Slagle proposed habit training as a primary occupational therapy model of treatment. Based on the philosophy that engagement in meaningful routines shape a person's wellbeing, habit training focused on creating structure and balance between work, rest and leisure. In 1912, she became director of a department of occupational therapy at The Henry Phipps Psychiatric Clinic in Baltimore. === World War I === In 1915, Slagle worked at the first occupational therapy training program, the Henry B. Favill School of Occupations at Hull House in Chicago. British-Canadian teacher and architect Thomas B. Kidner was appointed vocational secretary of the Canadian Military Hospitals Commission in January 1916. He was given the duty of preparing soldiers returning from World War I to return to their former vocational duties or retrain soldiers no longer able to perform their previous duties. He developed a program that engaged soldiers recovering from wartime injuries or tuberculosis in occupations even while they were still bedridden. Once the soldiers were sufficiently recovered they would work in a curative workshop and eventually progress to an industrial workshop before being placed in an appropriate work setting. He used occupations (daily activities) as a medium for manual training and helping injured individuals to return to productive duties such as work.The entry of the United States into World War I in April 1917 was a crucial event in the history of the profession. Up until this time, occupational therapy was not formalised into a profession. U.S. involvement in the war led to an escalating number of injured and disabled soldiers, which presented a daunting challenge to those in command. The inaugural meeting of the National Society for the Promotion of Occupational Therapy (NSPOT) was held in Clifton Springs, New York, 15-17 March 1917. The meeting was attended by six founders: George Edward Barton, William Rush Dunton, Eleanor Clarke Slagle, Thomas B Kidner, Susan Cox Johnson and Isabel Gladwin Newton Barton. Susan E. Tracy and Herbert James Hall, did not attend but are considered near founders of the Society. The military enlisted the assistance of NSPOT to recruit and train over 1,200 "reconstruction aides" to help with the rehabilitation of those wounded in the war. Dunton's 1918 article "The Principles of Occupational Therapy" appeared in the journal Public Health, and laid the foundation for the textbook he published in 1919 entitled Reconstruction Therapy. Dunton struggled with "the cumbersomeness of the term occupational therapy", as he thought it lacked the "exactness of meaning which is possessed by scientific terms". Other titles such as "work-cure", "ergo therapy" (ergo being the Greek root for "work"), and "creative occupations" were discussed as substitutes, but ultimately, none possessed the broad meaning that the practice of occupational therapy demanded in order to capture the many forms of treatment that existed from the beginning. NSPOT formally adopted the name "occupational therapy" for the field in 1921. === Inter-war period === There was a struggle to keep people in the profession during the post-war years. Emphasis shifted from the altruistic war-time mentality to the financial, professional, and personal satisfaction that comes with being a therapist. To make the profession more appealing, practice was standardized, as was the curriculum. Entry and exit criteria were established, and the American Occupational Therapy Association advocated for steady employment, decent wages, and fair working conditions. Via these methods, occupational therapy sought and obtained medical legitimacy in the 1920s. The emergence of occupational therapy challenged the views of mainstream scientific medicine. Instead of focusing purely on the medical model, occupational therapists argued that a complex combination of social, economic, and biological reasons cause dysfunction. Principles and techniques were borrowed from many disciplines—including but not limited to physical therapy, nursing, psychiatry, rehabilitation, self-help, orthopedics, and social work—to enrich the profession's scope. The 1920s and 1930s were a time of establishing standards of education and laying the foundation of the profession and its organization. Eleanor Clarke Slagle proposed a 12-month course of training in 1922, and these standards were adopted in 1923. In 1928, William Denton published another textbook, Prescribing Occupational Therapy. Educational standards were expanded to a total training time of 18 months in 1930 to place the requirements for professional entry on par with those of other professions. By the early 1930s, AOTA had established educational guidelines and accreditation procedures. Margaret Barr Fulton became the first US qualified occupational therapist to work in the United Kingdom in 1925. She qualified at the Philadelphia School in the United States and was appointed to the Aberdeen Royal Hospital for mental patients where she worked until her retirement in 1963. US-style OT was introduced into England by Dr Elizabeth Casson who had visited similar establishments in America. (Casson had also earlier worked under the transformative English social reformer Octavia Hill.) In 1929 she established her own residential clinic in Bristol, Dorset House, for "women with mental disorders", and worked as its medical director. It was here in 1930 that she founded the first school of occupational therapy in the UK. The Scottish Association of Occupational Therapists was founded in 1932. The profession was served in the rest of the UK by the Association of Occupational Therapists from 1936. (The two later merged to form what is today the Royal College of Occupational Therapists in 1974.) === World War II === With the US entry into World War II and the ensuing skyrocketing demand for occupational therapists to treat those injured in the war, the field of occupational therapy underwent dramatic growth and change. Occupational therapists needed to be skilled not only in the use of constructive activities such as crafts, but also increasingly in the use of activities of daily living. The body that is now Occupational Therapy Australia began in 1944. === Post-World War II === Another textbook was published in the United States for occupational therapy in 1947, edited by Helen S. Willard and Clare S. Spackman. The profession continued to grow and redefine itself in the 1950s. In 1954, AOTA created the Eleanor Clarke Slagle Lectureship Award in its namesake's honor. Each year, this award recognizes a member of AOTA "who has creatively contributed to the development of the body of knowledge of the profession through research, education, or clinical practice." The profession also began to assess the potential for the use of trained assistants in the attempt to address the ongoing shortage of qualified therapists, and educational standards for occupational therapy assistants were implemented in 1960. The 1960s and 1970s were a time of ongoing change and growth for the profession as it struggled to incorporate new knowledge and cope with the recent and rapid growth of the profession in the previous decades. New developments in the areas of neurobehavioral research led to new conceptualizations and new treatment approaches, possibly the most groundbreaking being the sensory integrative approach developed by A. Jean Ayres. The profession has continued to grow and expand its scope and settings of practice. Occupational science, the study of occupation, was founded in 1989 by Elizabeth Yerxa at the University of Southern California as an academic discipline to provide foundational research on occupation to support and advance the practice of occupation-based occupational therapy, as well as offer a basic science to study topics surrounding "occupation". In addition, occupational therapy practitioner's roles have expanded to include political advocacy (from a grassroots base to higher legislation); for example, in 2010 PL 111-148 titled the Patient Protection and Affordable Care Act had a habilitation clause that was passed in large part due to AOTA's political efforts. Furthermore, occupational therapy practitioners have been striving personally and professionally toward concepts of occupational justice and other human rights issues that have both local and global impacts. The World Federation of Occupational Therapist's Resource Centre has many position statements on occupational therapy's roles regarding their participation in human rights issues. In 2021, U.S. News & World Report ranked occupational therapy as #19 of their list of '100 Best Jobs'. == Practice frameworks == An occupational therapist works systematically with a client through a sequence of actions called an "occupational therapy process." There are several versions of this process. All practice frameworks include the components of evaluation (or assessment), intervention, and outcomes. This process provides a framework through which occupational therapists assist and contribute to promoting health and ensures structure and consistency among therapists. === Occupational Therapy Practice Framework (OTPF, United States) === The Occupational Therapy Practice Framework (OTPF) is the core competency of occupational therapy in the United States. The OTPF is divided into two sections: domain and process. The domain includes environment, client factors, such as the individual's motivation, health status, and status of performing occupational tasks. The domain looks at the contextual picture to help the occupational therapist understand how to diagnose and treat the patient. The process is the actions taken by the therapist to implement a plan and strategy to treat the patient. === Canadian Practice Process Framework === The Canadian Model of Client Centered Enablement (CMCE) embraces occupational enablement as the core competency of occupational therapy and the Canadian Practice Process Framework (CPPF) as the core process of occupational enablement in Canada. The Canadian Practice Process Framework (CPPF) has eight action points and three contextual element which are: set the stage, evaluate, agree on objective plan, implement plan, monitor/modify, and evaluate outcome. A central element of this process model is the focus on identifying both client and therapists strengths and resources prior to developing the outcomes and action plan. === International Classification of Functioning, Disability and Health (ICF) === The International Classification of Functioning, Disability and Health (ICF) is the World Health Organisation's framework to measure health and ability by illustrating how these components impact one's function. This relates very closely to the Occupational Therapy Practice Framework, as it is stated that "the profession's core beliefs are in the positive relationship between occupation and health and its view of people as occupational beings". The ICF is built into the 2nd edition of the practice framework. Activities and participation examples from the ICF overlap Areas of Occupation, Performance Skills, and Performance Patterns in the framework. The ICF also includes contextual factors (environmental and personal factors) that relate to the framework's context. In addition, body functions and structures classified within the ICF help describe the client factors described in the Occupational Therapy Practice Framework. Further exploration of the relationship between occupational therapy and the components of the ICIDH-2 (revision of the original International Classification of Impairments, Disabilities, and Handicaps (ICIDH), which later became the ICF) was conducted by McLaughlin Gray. It is noted in the literature that occupational therapists should use specific occupational therapy vocabulary along with the ICF in order to ensure correct communication about specific concepts. The ICF might lack certain categories to describe what occupational therapists need to communicate to clients and colleagues. It also may not be possible to exactly match the connotations of the ICF categories to occupational therapy terms. The ICF is not an assessment and specialized occupational therapy terminology should not be replaced with ICF terminology. The ICF is an overarching framework for current therapy practices. == Occupations == According to the American Occupational Therapy Association's (AOTA) Occupational Therapy Practice Framework: Domain and Process, 4th Edition (OTPF-4), occupations are defined as "everyday activities that people do as individuals, and families, and with communities to occupy time and bring meaning and purpose to life. Occupations include things people need to, want to and are expected to do". Occupations are central to a client's (person's, group's, or population's) health, identity, and sense of competence and have particular meaning and value to that client. Occupations include activities of daily living (ADLs), instrumental activities of daily living (IADLs), education, work, play, leisure, social participation, rest and sleep. == Practice settings == According to the 2019 Salary and Workforce Survey by the American Occupational Therapy Association, occupational therapists work in a wide-variety of practice settings including: hospitals (28.6%), schools (18.8%), long-term care facilities/skilled nursing facilities (14.5%), free-standing outpatient (13.3%), home health (7.3%), academia (6.9%), early intervention (4.4%), mental health (2.2%), community (2.4%), and other (1.6%). According to the AOTA, the most common primary work setting for occupational therapists is in hospitals. Also according to the survey, 46% of occupational therapists work in urban areas, 39% work in suburban areas and the remaining 15% work in rural areas. The Canadian Institute for Health Information (CIHI) found that as of 2020 nearly half (46.1%) of occupational therapists worked in hospitals, 43.2% worked in community health, 3.6% work in long-term care (LTC) and 7.1% work in "other", including government, industry, manufacturing, and commercial settings. The CIHI also found that 68% of occupational therapists in Canada work in urban settings and only 3.7% work in rural settings. == Areas of practice in the United States == === Children and youth === Occupational therapists work with infants, toddlers, children, youth, and their families in a variety of settings, including schools, clinics, homes, hospitals, and the community. Evaluation assesses the child's ability to engage in daily, meaningful occupations, the underlying skills (or performance components) which may be physical, cognitive, or emotional in nature, and the fit between the client's skills and the environments and contexts in which the client functions. OT intervention and involves evaluating a young person's occupational performance in areas of feeding, playing, socializing which aligns with their neurodiversity, daily living skills, or attending school. In planning treatment, occupational therapists work in collaboration with the children and teens themselves, parents, caregivers, and teachers in order to develop functional goals within a variety of occupations meaningful to the young client. Early intervention addresses daily functioning of a child between the ages of birth to three years old. OTs who practice in early intervention support a family's ability to care for their child with special needs and promote his or her function and participation in the most natural environment. Each child is required to have an Individualized Family Service Plan (IFSP) that focuses on the family's goals for the child. It's possible for an OT to serve as the family's service coordinator and facilitate the team process for creating an IFSP for each eligible child. Objectives that an occupational therapist addresses with children and youth may take a variety of forms. Examples are as follows: Providing rehabilitation activities to children with neuromuscular disabilities such as cerebral palsy Supporting self-regulation within neurodivergent children whose neurobiology does not align with the sensory environment or the contexts in which they function Facilitating coping skills to a child with generalized anxiety disorder. Consulting with teachers, psychologists, social workers, parents/caregivers, and other professionals who work with children regarding modifications, accommodations and supports in a variety of areas, such as sensory processing, motor planning, visual processing, and executive function skills. Providing individualized treatment for sensory processing differences. Providing splinting and caregiver education in a hospital burn unit. Instructing caregivers in regard to mealtime intervention for autistic children who have feeding challenges. Facilitating handwriting development through providing intervention to develop fine motor and writing readiness skills in school-aged children. In the United States, pediatric occupational therapists work in the school setting as a "related service" for children with an Individual Education Plan (IEP). Every student who receives special education and related services in the public school system is required by law to have an IEP, which is a very individualized plan designed for each specific student (U.S. Department of Education, 2007). Related services are "developmental, corrective, and other supportive services as are required to assist a child with a disability to benefit from special education," and include a variety of professions such as speech–language pathology and audiology services, interpreting services, psychological services, and physical and occupational therapy. As a related service, occupational therapists work with children with varying disabilities to address those skills needed to access the special education program and support academic achievement and social participation throughout the school day (AOTA, n.d.-b). In doing so, occupational therapists help children fulfill their role as students and prepare them to transition to post-secondary education, career and community integration (AOTA, n.d.-b). Occupational therapists have specific knowledge to increase participation in school routines throughout the day, including: Modification of the school environment to allow physical access for children with disabilities Provide assistive technology to support student success Helping to plan instructional activities for implementation in the classroom Support the needs of students with significant challenges such as helping to determine methods for alternate assessment of learning Helping students develop the skills necessary to transition to post-high school employment, independent living or further education (AOTA). Other settings, such as homes, hospitals, and the community are important environments where occupational therapists work with children and teens to promote their independence in meaningful, daily activities. Outpatient clinics offer a growing OT intervention referred to as "Sensory Integration Treatment". This therapy, provided by experienced and knowledgeable pediatric occupational therapists, was originally developed by A. Jean Ayres, an occupational therapist. Sensory integration therapy is an evidence-based practice which enables children to better process and integrate sensory input from the child's body and from the environment, thus improving his or her emotional regulation, ability to learn, behavior, and functional participation in meaningful daily activities. Recognition of occupational therapy programs and services for children and youth is increasing worldwide. Occupational therapy for both children and adults is now recognized by the United Nations as a human right which is linked to the social determinants of health. As of 2018, there are over 500,000 occupational therapists working worldwide (many of whom work with children) and 778 academic institutions providing occupational therapy instruction. === Health and wellness === According to the American Occupational Therapy Association's (AOTA) Occupational Therapy Practice Framework, 3rd Edition, the domain of occupational therapy is described as "Achieving health, well-being, and participation in life through engagement in occupation". Occupational therapy practitioners have a distinct value in their ability to utilize daily occupations to achieve optimal health and well-being. By examining an individual's roles, routines, environment, and occupations, occupational therapists can identify the barriers in achieving overall health, well-being and participation. Occupational therapy practitioners can intervene at primary, secondary and tertiary levels of intervention to promote health and wellness. It can be addressed in all practice settings to prevent disease and injuries, and adapt healthy lifestyle practices for those with chronic diseases. Two of the occupational therapy programs that have emerged targeting health and wellness are the Lifestyle Redesign Program and the REAL Diabetes Program. Occupational therapy interventions for health and wellness vary in each setting: ==== School ==== Occupational therapy practitioners target school-wide advocacy for health and wellness including: bullying prevention, backpack awareness, recess promotion, school lunches, and PE inclusion. They also heavily work with students with learning disabilities such as those on the autism spectrum. A study conducted in Switzerland showed that a large majority of occupational therapists collaborate with schools, half of them providing direct services within mainstream school settings. The results also show that services were mainly provided to children with medical diagnoses, focusing on the school environment rather than the child's disability. ==== Outpatient ==== Occupational therapy practitioners conduct 1:1 treatment sessions and group interventions to address: leisure, health literacy and education, modified physical activity, stress/anger management, healthy meal preparation, and medication management. ==== Acute care ==== Occupational therapy practitioners in acute care assess whether a patient has the cognitive, emotional and physical ability as well as the social supports needed to live independently and care for themselves after discharge from the hospital. Occupational therapists are uniquely positioned to support patients in acute care as they focus on both clinical and social determinants of health. Services delivered by occupational therapists in acute care include: Direct rehabilitation interventions, individually or in group settings to address physical, emotional and cognitive skills that are required for the patient to perform self-care and other important activities. Caregiver training to assist patients after discharge. Recommendations for adaptive equipment for increased safety and independence with activities of daily living (e.g. aids for getting dressed, shower chairs for bathing, and medication organizers for self-administering medications). They also perform home safety assessments to suggest modifications for improved safety and function after discharge. Occupational therapists use a variety of models, including the Model of Human Occupation, Person, Environment and Occupation, and Canadian Occupational Performance Model to adopt a client centered approach used for discharge planning. Hospital spending on occupational therapy services in acute care was found to be the single most significant spending category in reducing the risk of readmission to the hospital for heart failure, pneumonia, and acute myocardial infarction. ==== Community-based ==== Occupational therapy practitioners develop and implement community wide programs to assist in prevention of diseases and encourage healthy lifestyles by: conducting education classes for prevention, facilitating gardening, offering ergonomic assessments, and offering pleasurable leisure and physical activity programs. === Mental health === Mental Health Occupational therapy's foundation in mental health is deeply rooted in the moral treatment movement, which sought to replace the harsh treatment of mental disorders with the establishment of healthy routines and engagement in meaningful activities. This movement significantly influenced the development of occupational therapy, particularly through the contributions of early 20th-century practitioners and theorists like Adolph Meyer, who emphasized a holistic approach to mental health care (Christiansen & Haertl, 2014). According to the American Occupational Therapy Association (AOTA), occupational therapy is based on the principle that "active engagement in occupation promotes, facilitates, supports, and maintains health and participation" (AOTA, 2017). Occupations refer to individuals' activities to structure their time and provide meaning. The primary goals of occupational therapy include promoting physical and mental health and well-being and establishing, restoring, maintaining, and improving function and quality of life for individuals at risk of or affected by physical or mental health disorders (AOTA, 2017). Education and Professional Qualifications Occupational therapists require a master's degree or clinical doctorate, while occupational therapy assistants need at least an associate's degree. Their education encompasses extensive mental health-related topics, including biological, physical, social, and behavioral sciences, and supervised clinical experiences culminating in full-time internships. Both must pass national examinations and meet state licensure requirements. Occupational therapists apply mental and physical health knowledge, focusing on participation and occupation, using performance-based assessments to understand the relationship between occupational participation and well-being. Their education covers various aspects of mental health, including neurophysiological changes, human development, historical and contemporary perspectives on mental health, and current diagnostic criteria. This comprehensive training prepares occupational therapy practitioners to address the complex interplay of client variables, activity demands, and environmental factors in promoting health and managing health challenges (Bazyk & Downing, 2017). Occupational therapy role in mental health practice Occupational therapy practitioners play a critical role in mental health by using therapeutic activities to promote mental health and support full participation in life for individuals at risk of or experiencing psychiatric, behavioral, and substance use disorders. They work across the lifespan and in various settings, including homes, schools, workplaces, community environments, hospitals, outpatient clinics, and residential facilities (AOTA,2017). Occupational therapists and occupational therapy assistants assume diverse roles, such as case managers, care coordinators, group facilitators, community mental health providers, consultants, program developers, and advocates. Their interventions aim to facilitate engagement in meaningful occupations, enhance role performance, and improve overall well-being. This involves analyzing, adapting, and modifying tasks and environments to support clients' goals and optimal engagement in daily activities (AOTA, 2017). Occupational therapy practitioners utilize clinical reasoning, informed by various theoretical perspectives and evidence-based approaches, to guide evaluation and intervention. They are skilled in analyzing the complex interplay among client variables, activity demands, and the environments where participation occurs. For individuals experiencing any mental health issues, his or her ability to participate in occupations actively may be hindered. For example, an individual diagnosed with depression or anxiety may experience interruptions in sleep, difficulty completing self-care tasks, decreased motivation to participate in leisure activities, decreased concentration for school or job-related work, and avoidance of social interactions. Occupational therapy utilizes the public health approach to mental health (WHO, 2001) which emphasizes the promotion of mental health as well as the prevention of, and intervention for, mental illness. This model highlights the distinct value of occupational therapists in mental health promotion, prevention, and intensive interventions across the lifespan (Miles et al., 2010). Below are the three major levels of service: ==== Tier 3: intensive interventions ==== Intensive interventions are provided for individuals with identified mental, emotional, or behavioral disorders that limit daily functioning, interpersonal relationships, feelings of emotional well-being, and the ability to cope with challenges in daily life. Occupational therapy practitioners are committed to the recovery model which focuses on enabling persons with mental health challenges through a client-centered process to live a meaningful life in the community and reach their potential (Champagne & Gray, 2011). The focus of intensive interventions (direct–individual or group, consultation) is engagement in occupation to foster recovery or "reclaiming mental health" resulting in optimal levels of community participation, daily functioning, and quality of life; functional assessment and intervention (skills training, accommodations, compensatory strategies) (Brown, 2012); identification and implementation of healthy habits, rituals, and routines to support wellness. ==== Tier 2: targeted services ==== Targeted services are designed to prevent mental health problems in persons who are at risk of developing mental health challenges, such as those who have emotional experiences (e.g., trauma, abuse), situational stressors (e.g., physical disability, bullying, social isolation, obesity) or genetic factors (e.g., family history of mental illness). Occupational therapy practitioners are committed to early identification of and intervention for mental health challenges in all settings. The focus of targeted services (small groups, consultation, accommodations, education) is engagement in occupations to promote mental health and diminish early symptoms; small, therapeutic groups (Olson, 2011); environmental modifications to enhance participation (e.g., create Sensory friendly classrooms, home, or work environments) ==== Tier 1: universal services ==== Universal services are provided to all individuals with or without mental health or behavioral problems, including those with disabilities and illnesses (Barry & Jenkins, 2007). Occupational therapy services focus on mental health promotion and prevention for all: encouraging participation in health-promoting occupations (e.g., enjoyable activities, healthy eating, exercise, adequate sleep); fostering self-regulation and coping strategies (e.g., mindfulness, yoga); promoting mental health literacy (e.g., knowing how to take care of one's mental health and what to do when experiencing symptoms associated with ill mental health). Occupational therapy practitioners develop universal programs and embed strategies to promote mental health and well-being in a variety of settings, from schools to the workplace. The focus of universal services (individual, group, school-wide, employee/organizational level) is universal programs to help all individuals successfully participate in occupations that promote positive mental health (Bazyk, 2011); educational and coaching strategies with a wide range of relevant stakeholders focusing on mental health promotion and prevention; the development of coping strategies and resilience; environmental modifications and supports to foster participation in health-promoting occupations. === Productive aging === Occupational therapists work with older adults to maintain independence, participate in meaningful activities, and live fulfilling lives. Some examples of areas that occupational therapists address with older adults are driving, aging in place, low vision, and dementia or Alzheimer's disease (AD). When addressing driving, driver evaluations are administered to determine if drivers are safe behind the wheel. To enable independence of older adults at home, occupational therapists perform falls risk assessments, assess clients functioning in their homes, and recommend specific home modifications. When addressing low vision, occupational therapists modify tasks and the environment. While working with individuals with AD, occupational therapists focus on maintaining quality of life, ensuring safety, and promoting independence. === Geriatrics/productive aging === Occupational therapists address all aspects of aging from health promotion to treatment of various disease processes. The goal of occupational therapy for older adults is to ensure that older adults can maintain independence and reduce health care costs associated with hospitalization and institutionalization. In the community, occupational therapists can assess an older adults ability to drive and if they are safe to do so. If it is found that an individual is not safe to drive the occupational therapist can assist with finding alternate transit options. Occupational therapists also work with older adults in their home as part of home care. In the home, an occupational therapist can work on such things as fall prevention, maximizing independence with activities of daily living, ensuring safety and being able to stay in the home for as long as the person wants. An occupational therapist can also recommend home modifications to ensure safety in the home. Many older adults have chronic conditions such as diabetes, arthritis, and cardiopulmonary conditions. Occupational therapists can help manage these conditions by offering education on energy conservation strategies or coping strategies. Not only do occupational therapists work with older adults in their homes, they also work with older adults in hospitals, nursing homes and post-acute rehabilitation. In nursing homes, the role of the occupational therapist is to work with clients and caregivers on education for safe care, modifying the environment, positioning needs and enhancing IADL skills to name a few. In post-acute rehabilitation, occupational therapists work with clients to get them back home and to their prior level of function after a hospitalization for an illness or accident. Occupational therapists also play a unique role for those with dementia. The therapist may assist with modifying the environment to ensure safety as the disease progresses along with caregiver education to prevent burnout. Occupational therapists also play a role in palliative and hospice care. The goal at this stage of life is to ensure that the roles and occupations that the individual finds meaningful continue to be meaningful. If the person is no longer able to perform these activities, the occupational therapist can offer new ways to complete these tasks while taking into consideration the environment along with psychosocial and physical needs. Not only do occupational therapists work with older adults in traditional settings, they also work in senior centre's and ALFs. === Visual impairment === Visual impairment is one of the top 10 disabilities among American adults. Occupational therapists work with other professions, such as optometrists, ophthalmologists, and certified low vision therapists, to maximize the independence of persons with a visual impairment by using their remaining vision as efficiently as possible. AOTA's promotional goal of "Living Life to Its Fullest" speaks to who people are and learning about what they want to do, particularly when promoting the participation in meaningful activities, regardless of a visual impairment. Populations that may benefit from occupational therapy includes older adults, persons with traumatic brain injury, adults with potential to return to driving, and children with visual impairments. Visual impairments addressed by occupational therapists may be characterized into two types including low vision or a neurological visual impairment. An example of a neurological impairment is a cortical visual impairment (CVI) which is defined as "...abnormal or inefficient vision resulting from a problem or disorder affecting the parts of brain that provide sight". The following section will discuss the role of occupational therapy when working with the visually impaired. Occupational therapy for older adults with low vision includes task analysis, environmental evaluation, and modification of tasks or the environment as needed. Many occupational therapy practitioners work closely with optometrists and ophthalmologists to address visual deficits in acuity, visual field, and eye movement in people with traumatic brain injury, including providing education on compensatory strategies to complete daily tasks safely and efficiently. Adults with a stable visual impairment may benefit from occupational therapy for the provision of a driving assessment and an evaluation of the potential to return to driving. Lastly, occupational therapy practitioners enable children with visual impairments to complete self care tasks and participate in classroom activities using compensatory strategies. === Adult rehabilitation === Occupational therapists address the need for rehabilitation following an injury or impairment. When planning treatment, occupational therapists address the physical, cognitive, psychosocial, and environmental needs involved in adult populations across a variety of settings. Occupational therapy in adult rehabilitation may take a variety of forms: Working with adults with autism at day rehabilitation programs to promote successful relationships and community participation through instruction on social skills Increasing the quality of life for an individual with cancer by engaging them in occupations that are meaningful, providing anxiety and stress reduction methods, and suggesting fatigue management strategies Coaching individuals with hand amputations how to put on and take off a myoelectrically controlled limb as well as training for functional use of the limb Pressure sore prevention for those with sensation loss such as in spinal cord injuries. Using and implementing new technology such as speech to text software and Nintendo Wii video games Communicating via telehealth methods as a service delivery model for clients who live in rural areas Working with adults who have had a stroke to regain their activities of daily living === Assistive technology === Occupational therapy practitioners, or occupational therapists (OTs), are uniquely poised to educate, recommend, and promote the use of assistive technology to improve the quality of life for their clients. OTs are able to understand the unique needs of the individual in regards to occupational performance and have a strong background in activity analysis to focus on helping clients achieve goals. Thus, the use of varied and diverse assistive technology is strongly supported within occupational therapy practice models. === Travel occupational therapy === Because of the rising need for occupational therapy practitioners in the U.S., many facilities are opting for travel occupational therapy practitioners—who are willing to travel, often out of state, to work temporarily in a facility. Assignments can range from 8 weeks to 9 months, but typically last 13–26 weeks in length. Travel therapists work in many different settings, but the highest need for therapists are in home health and skilled nursing facility settings. There are no further educational requirements needed to be a travel occupational therapy practitioner; however, there may be different state licensure guidelines and practice acts that must be followed. According to Zip Recruiter, as of July 2019, the national average salary for a full-time travel therapist is $86,475 with a range between $62,500 to $100,000 across the United States. Most commonly (43%), travel occupational therapists enter the industry between the ages of 21–30. === Occupational justice === The practice area of occupational justice relates to the "benefits, privileges and harms associated with participation in occupations" and the effects related to access or denial of opportunities to participate in occupations. This theory brings attention to the relationship between occupations, health, well-being, and quality of life. Occupational justice can be approached individually and collectively. The individual path includes disease, disability, and functional restrictions. The collective way consists of public health, gender and sexual identity, social inclusion, migration, and environment. The skills of occupational therapy practitioners enable them to serve as advocates for systemic change, impacting institutions, policy, individuals, communities, and entire populations. Examples of populations that experience occupational injustice include refugees, prisoners, homeless persons, survivors of natural disasters, individuals at the end of their life, people with disabilities, elderly living in residential homes, individuals experiencing poverty, children, immigrants, and LGBTQI+ individuals. For example, the role of an occupational therapist working to promote occupational justice may include: Analyzing task, modifying activities and environments to minimize barriers to participation in meaningful activities of daily living. Addressing physical and mental aspects that may hinder a person's functional ability. Provide intervention that is relevant to the client, family, and social context. Contribute to global health by advocating for individuals with disabilities to participate in meaningful activities on a global level. Occupation therapists are involved with the World Health Organization (WHO), non-governmental organizations and community groups and policymaking to influence the health and well-being of individuals with disabilities worldwide Occupational therapy practitioners' role in occupational justice is not only to align with perceptions of procedural and social justice but to advocate for the inherent need of meaningful occupation and how it promotes a just society, well-being, and quality of life among people relevant to their context. It is recommended to the clinicians to consider occupational justice in their everyday practice to promote the intention of helping people participate in tasks that they want and need to do. === Occupational injustice === In contrast, occupational injustice relates to conditions wherein people are deprived, excluded or denied of opportunities that are meaningful to them. Types of occupational injustices and examples within the OT practice include: Occupational deprivation: The exclusion from meaningful occupations due to external factors that are beyond the person's control. For example, a person with difficulties with functional mobility may find it challenging to reintegrate into the community due to transportation barriers. OTs can help in raising awareness and bringing communities together to reduce occupational deprivation OTs can recommend the removal of environmental barriers to facilitate occupation, whilst designing programs that enable engagement. Advocacy by providing information to policy to prevent possible unintended occupational deprivation and increase social cohesion and inclusion Occupational apartheid: The exclusion of a person in chosen occupations due to personal characteristics such as age, gender, race, nationality, or socioeconomic status. An example can be seen in children with developmental disabilities from low socioeconomic backgrounds whose families would opt out of therapy due to financial constraints. OTs providing interventions within a segregated population must focus on increasing occupational engagement through large-scale environmental modification and occupational exploration. OTs can address occupational engagement through group and individual skill-building opportunities, as well as community-based experiences that explore free and local resources Occupational marginalization: Relates to how implicit norms of behavior or societal expectations prevent a person from engaging in a chosen occupation. As an example, a child with physical impairments may only be offered table-top leisure activities instead of sports as an extracurricular activity due to the functional limitations caused by his physical impairments. OTs can design, develop, and/or provide programs that mitigate the negative impacts of occupational marginalization and enhance optimal levels of performance and wellbeing that enable participation Occupational imbalance: The limited participation in a meaningful occupation brought about by another role in a different occupation. This can be seen in the situation of a caregiver of a person with a disability who also has to fulfill other roles such as being a parent to other children, a student, or a worker. OTs can advocate fostering for supportive environments for participation in occupations that promote individuals' well-being and in advocating for building healthy public policy Occupational alienation: The imposition of an occupation that does not hold meaning for that person. In the OT profession, this manifests in the provision of rote activities that do not really relate to the goals or the client's interests. OTs can develop individualized activities tailored to the interests of the individual to maximize their potential. OTs can design, develop and promote programs that can be inclusive and provide a variety of choices that the individual can engage in. Within occupational therapy practice, injustice may ensue in situations wherein professional dominance, standardized treatments, laws and political conditions create a negative impact on the occupational engagement of our clients. Awareness of these injustices will enable the therapist to reflect on his own practice and think of ways in approaching their client's problems while promoting occupational justice. === Community-based therapy === As occupational therapy (OT) has grown and developed, community-based practice has blossomed from an emerging area of practice to a fundamental part of occupational therapy practice (Scaffa & Reitz, 2013). Community-based practice allows for OTs to work with clients and other stakeholders such as families, schools, employers, agencies, service providers, stores, day treatment and day care and others who may influence the degree of success the client will have in participating. It also allows the therapist to see what is actually happening in the context and design interventions relevant to what might support the client in participating and what is impeding her or him from participating. Community-based practice crosses all of the categories within which OTs practice from physical to cognitive, mental health to spiritual, all types of clients may be seen in community-based settings. The role of the OT also may vary, from advocate to consultant, direct care provider to program designer, adjunctive services to therapeutic leader. === Nature-based therapy === Nature-based interventions and outdoor activities may be incorporated into occupational therapy practice as they can provide therapeutic benefits in various ways. Examples include therapeutic gardening, animal-assisted therapy (AAT), and adventure therapy. For instance, parents reported improvement in the emotional regulation and social engagement of their children with autism spectrum disorder (ASD) in a study of parental perceptions regarding the outcomes of AAT conducted with trained dogs. They also observed reductions in problematic behaviors. A source cited in the study found similar results with AAT employing horses and llamas. Gardening in a group setting may serve as a complementary intervention in stroke rehabilitation; in addition to being mentally restful and conducive to social connection, it helps patients master skills and can remind them of experiences from their past. Royal Rehab's Productive Garden Project in Australia, managed by a horticultural therapist, allows patients and practitioners to participate in meaningful activity outside the usual healthcare settings. Thus, tending a garden helps facilitate experiential activities, perhaps attaining a better balance between clinical and real-life pursuits during rehabilitation, in lieu of mainly relying on clinical interventions. For adults with acquired brain injury, nature-based therapy has been found to improve motor abilities, cognitive function, and general quality of life. Contributing to a theoretical understanding of such successes in nature-based approaches are: nature's positive impact on problem solving and the refocusing of attention; an innate human connection with, and positive response to, the natural world; an increased sense of well-being when in contact with nature; and the emotional, nonverbal, and cognitive aspects of human-environment interaction. == Education == Worldwide, there is a range of qualifications required to practice as an occupational therapist or occupational therapy assistant. Depending on the country and expected level of practice, degree options include associate degree, Bachelor's degree, entry-level master's degree, post-professional master's degree, entry-level Doctorate (OTD), post-professional Doctorate (DrOT or OTD), Doctor of Clinical Science in OT (CScD), Doctor of Philosophy in Occupational Therapy (PhD), and combined OTD/PhD degrees. Both occupational therapist and occupational therapy assistant roles exist internationally. Currently in the United States, dual points of entry exist for both OT and OTA programs. For OT, that is entry-level Master's or entry-level Doctorate. For OTA, that is associate degree or bachelor's degree. The World Federation of Occupational Therapists (WFOT) has minimum standards for the education of OTs, which was revised in 2016. All of the educational programs around the world need to meet these minimum standards. These standards are subsumed by and can be supplemented with academic standards set by a country's national accreditation organization. As part of the minimum standards, all programs must have a curriculum that includes practice placements (fieldwork). Examples of fieldwork settings include: acute care, inpatient hospital, outpatient hospital, skilled nursing facilities, schools, group homes, early intervention, home health, and community settings. The profession of occupational therapy is based on a wide theoretical and evidence based background. The OT curriculum focuses on the theoretical basis of occupation through multiple facets of science, including occupational science, anatomy, physiology, biomechanics, and neurology. In addition, this scientific foundation is integrated with knowledge from psychology, sociology and more. In the United States, Canada, and other countries around the world, there is a licensure requirement. In order to obtain an OT or OTA license, one must graduate from an accredited program, complete fieldwork requirements, and pass a national certification examination. == Philosophical underpinnings == The philosophy of occupational therapy has evolved over the history of the profession. The philosophy articulated by the founders owed much to the ideals of romanticism, pragmatism and humanism, which are collectively considered the fundamental ideologies of the past century. One of the most widely cited early papers about the philosophy of occupational therapy was presented by Adolf Meyer, a psychiatrist who had emigrated to the United States from Switzerland in the late 19th century and who was invited to present his views to a gathering of the new Occupational Therapy Society in 1922. At the time, Dr. Meyer was one of the leading psychiatrists in the United States and head of the new psychiatry department and Phipps Clinic at Johns Hopkins University in Baltimore, Maryland. William Rush Dunton, a supporter of the National Society for the Promotion of Occupational Therapy, now the American Occupational Therapy Association, sought to promote the ideas that occupation is a basic human need, and that occupation is therapeutic. From his statements came some of the basic assumptions of occupational therapy, which include: Occupation has a positive effect on health and well-being. Occupation creates structure and organizes time. Occupation brings meaning to life, culturally and personally. Occupations are individual. People value different occupations. These assumptions have been developed over time and are the basis of the values that underpin the Codes of Ethics issued by the national associations. The relevance of occupation to health and well-being remains the central theme. In the 1950s, criticism from medicine and the multitude of disabled World War II veterans resulted in the emergence of a more reductionistic philosophy. While this approach led to developments in technical knowledge about occupational performance, clinicians became increasingly disillusioned and re-considered these beliefs. As a result, client centeredness and occupation have re-emerged as dominant themes in the profession. Over the past century, the underlying philosophy of occupational therapy has evolved from being a diversion from illness, to treatment, to enablement through meaningful occupation. Three commonly mentioned philosophical precepts of occupational therapy are that occupation is necessary for health, that its theories are based on holism and that its central components are people, their occupations (activities), and the environments in which those activities take place. However, there have been some dissenting voices. Mocellin, in particular, advocated abandoning the notion of health through occupation as he proclaimed it obsolete in the modern world. As well, he questioned the appropriateness of advocating holism when practice rarely supports it. Some values formulated by the American Occupational Therapy Association have been critiqued as being therapist-centric and do not reflect the modern reality of multicultural practice. In recent times occupational therapy practitioners have challenged themselves to think more broadly about the potential scope of the profession, and expanded it to include working with groups experiencing occupational injustice stemming from sources other than disability. Examples of new and emerging practice areas would include therapists working with refugees, children experiencing obesity, and people experiencing homelessness. == Theoretical frameworks == A distinguishing facet of occupational therapy is that therapists often espouse the use theoretical frameworks to frame their practice. Many have argued that the use of theory complicates everyday clinical care and is not necessary to provide patient-driven care. Note that terminology differs between scholars. An incomplete list of theoretical bases for framing a human and their occupations include the following: === Generic models === Generic models are the overarching title given to a collation of compatible knowledge, research and theories that form conceptual practice. More generally they are defined as "those aspects which influence our perceptions, decisions and practice". The Person Environment Occupation Performance model (PEOP) was originally published in 1991 (Charles Christiansen & M. Carolyn Baum) and describes an individual's performance based on four elements including: environment, person, performance and occupation. The model focuses on the interplay of these components and how this interaction works to inhibit or promote successful engagement in occupation. Occupation-focused practice models Occupational Therapy Intervention Process Model (OTIPM) (Anne Fisher and others) Occupational Performance Process Model (OPPM) Model of Human Occupation (MOHO) (Gary Kielhofner and others) MOHO was first published in 1980. It explains how people select, organise and undertake occupations within their environment. The model is supported with evidence generated over thirty years and has been successfully applied throughout the world. Canadian Model of Occupational Performance and Engagement (CMOP-E) This framework was originated in 1997 by the Canadian Association of Occupational Therapists (CAOT) as the Canadian Model of Occupational Performance (CMOP). It was expanded in 2007 by Palatjko, Townsend and Craik to add engagement. This framework upholds the view that three components—the person, environment and occupation- are related. Engagement was added to encompass occupational performance. A visual model is depicted with the person located at the center of the model as a triangle. The triangles three points represent cognitive, affective, and physical components with a spiritual center. The person triangle is surrounded by an outer ring symbolizing the context of environment with an inner ring symbolizing the context of occupation. Occupational Performances Model – Australia (OPM-A) (Chris Chapparo & Judy Ranka) The OPM(A) was conceptualized in 1986 with its current form launched in 2006. The OPM(A) illustrates the complexity of occupational performance, the scope of occupational therapy practice, and provides a framework for occupational therapy education. Kawa (River) Model (Michael Iwama) Biopsychosocial models Engel's biopsychosocial model takes into account how disease and illness can be impacted by social, environmental, psychological and body functions. The biopsychosocial model is unique in that it takes the client's subjective experience and the client-provider relationship as factors to wellness. This model also factors in cultural diversity as many countries have different societal norms and beliefs. This is a multifactorial and multi-dimensional model to understand not only the cause of disease but also a person-centered approach that the provider has more of a participatory and reflective role. Other models which incorporate biology (body and brain), psychology (mind), and social (relational, attachment) elements influencing human health include interpersonal neurobiology (IPNB), polyvagal theory (PVT), and the dynamic-maturational model of attachment and adaptation (DMM). The latter two in particular provide detail about the source, mechanism and function of somatic symptoms. Kasia Kozlowska describes how she uses these models to better connect with clients, to understand complex human illness, and how she includes occupational therapists as part of a team to address functional somatic symptoms. Her research indicates children with functional neurological disorders (FND) utilize higher, or more challenging, DMM self-protective attachment strategies to cope with their family environments, and how those impact functional somatic symptoms. Pamela Meredith and colleagues have been exploring the relationship between the attachment system and psychological and neurobiological systems with implications for how occupational therapists can improve their approach and techniques. They have found correlations between attachment and adult sensory processing, distress, and pain perception. In a literature review, Meredith identified a number of ways that occupational therapists can effectively apply an attachment perspective, sometimes uniquely. === Frames of reference === Frames of reference are an additional knowledge base for the occupational therapist to develop their treatment or assessment of a patient or client group. Though there are conceptual models (listed above) that allow the therapist to conceptualise the occupational roles of the patient, it is often important to use further reference to embed clinical reasoning. Therefore, many occupational therapists will use additional frames of reference to both assess and then develop therapy goals for their patients or service users. Biomechanical frame of reference The biomechanical frame of reference is primarily concerned with motion during occupation. It is used with individuals who experience limitations in movement, inadequate muscle strength or loss of endurance in occupations. The frame of reference was not originally compiled by occupational therapists, and therapists should translate it to the occupational therapy perspective, to avoid the risk of movement or exercise becoming the main focus. Rehabilitative (compensatory) Neurofunctional (Gordon Muir Giles and Clark-Wilson) Dynamic systems theory Client-centered frame of reference This frame of reference is developed from the work of Carl Rogers. It views the client as the center of all therapeutic activity, and the client's needs and goals direct the delivery of the occupational therapy process. Cognitive-behavioural frame of reference Ecology of human performance model The recovery model Sensory integration Sensory integration framework is commonly implemented in clinical, community, and school-based occupational therapy practice. It is most frequently used with children with developmental delays and developmental disabilities such as autism spectrum disorder, Sensory processing disorder and dyspraxia. Core features of sensory integration in treatment include providing opportunities for the client to experience and integrate feedback using multiple sensory systems, providing therapeutic challenges to the client's skills, integrating the client's interests into therapy, organizing of the environment to support the client's engagement, facilitating a physically safe and emotionally supportive environment, modifying activities to support the client's strengths and weaknesses, and creating sensory opportunities within the context of play to develop intrinsic motivation. While sensory integration is traditionally implemented in pediatric practice, there is emerging evidence for the benefits of sensory integration strategies for adults. == See also == Busy work Occupational apartheid Occupational therapy and substance use disorder Occupational therapy in the management of cerebral palsy Occupational therapy in Greece Occupational therapy in the United Kingdom == References == American Occupational Therapy Association (2014c). Occupational therapy practice framework: Domain and process (3rd ed.). American Journal of Occupational Therapy, 68(Suppl. 1), S1–S48. https://doi.org/10.5014/ajot.2014.682006 American Occupational Therapy Association (2017). Mental Health Promotion, Prevention, and Intervention in Occupational Therapy Practice. The American Journal of Occupational Therapy. 71(Suppl. 2). https://doi.org/10.5014/ajot.2017.716S03 Christiansen, C. H., & Haertl, K. (2014). A contextual history of occupational therapy. In B. A. B. Schell, G. Gillen, & M. E. Scaffa (Eds.), Willard and Spackman's occupational therapy (12th ed., pp. 9–34).Philadelphia: Lippincott Williams & Wilkins. == External links == World Federation of Occupational Therapists	Wikipedia/Occupational_Therapy
The Bachelor of Science in Clinical Medicine and community health/ Bachelor of Science in clinical medicine/ Bachelor of Science in clinical medicine, surgery and community health/ Bachelor of clinical medicine and community health (Kampala International University) is an academic dual/triple degree awarded to Clinical officers by universities in East Africa. In Kenya, it is currently offered by Great Lakes University of Kisumu, Kabarak university, Mount Kenya University, Kenya Methodist University, University of Kabianga and Meru University of Science and Technology (MUST), Masinde Muliro University of Science and Technology (MMUST) Jomo Kenyatta University of Technology (JKUAT) Kaimosi Friends University (KAFU) Egerton University, Kisii University, Kirinyaga University and Uzima University. In Uganda and Tanzania, it is offered at Kampala International University. In Rwanda, it is offered at the University of Rwanda., Bachelor of Science in clinical medicine/ Bachelor of Science in clinical sciences is also offered in Zambia in various universities such as Eden University, Copperbelt University. The graduates of this course are referred to as Bsc Clinical Officers in Kenya. However, in Zambia, their designation was changed from clinical officers to medical licentiates. In Tanzania, their designation was changed from clinical officers/assistant medical officers to Medical Officers and are given the title of a doctor to their name and allowed to practice and specialize as doctors in that country and even abroad. Duration of study: The degree takes four years to complete plus one year paid internship for a high school graduate while it takes three years for a diploma graduate in clinical medicine. Curriculum: The current curriculum for Bachelor of Science degree in clinical medicine, (surgery) and community health has been derived from the Bachelor of Medicine and Bachelor of Surgery (MBBS) version hence it is a crashed program of MBBS. It takes four and half years to train MBBS in India and four years in USA, UK, Cuba and other countries for accelerated programs for high school leavers and those who have a prior Bachelor of Science degrees and diplomas and degrees in health related fields. Specialization: There are various specialization that the graduates can embark on, for instance Masters in clinical medicine ( Paediatrics and Child Health, Reproductive Health, Oncology) offered at Kirinyaga University, Masters of clinical medicine (Oncology) offered at Jomo Kenyatta University of Science and Technology, Masters of clinical medicine ;Coroner and forensic medicine, Family medicine, Emergency medicine) offered at Mount Kenya University. Other graduates undertake the masters of medicine (Radiology, Internal medicine) like in the case of Tanzania and others pursue Master of science degrees in overseas countries. == See also == Bachelor of Clinical Medical Practice	Wikipedia/Bachelor_of_Clinical_Medicine_and_Community_Health
The University of Health and Allied Sciences (UHAS) is a public university located at Ho in the Volta Region of Ghana. UHAS is one of the youngest public universities in Ghana. Its operation started in September 2012, when the first batch of 154 students were admitted. == History == The university was established by an Act of Parliament (Act 828), which received presidential approval in December 2011. It however, started admitting students in 2012. The university is devoted to teaching, research, and service in the health sciences. The university was formed with an Interim University Council that governs the affairs of the school, chaired by professor Kofi Anyidoho. The Foundation Vice-Chancellor was professor Fred Newton Binka, who served from March 2012 to July 2016. In August 2017, a new council was inaugurated with Justice Jones Victor Mawulorm Dotse as the chairman. Other members of the council are professor John Owusu Gyapong (Vice-Chancellor, UHAS); professor Victor Gadzekpo (Member), Sylvia Ayeley Deganus (Member), Nana Owusu-Afari (Member), Richard K. Adjei (Member), Mark Amexo (Member), Emmanuel Newman(NCTE), Courage Meteku (Representative of CHASS), professor Harry Kwami Tagbor (representative of Convocation-professorial), Yaa Amankwaa Opuni (representative of Convocation-professorial), Kwesi Aseredum Hagan (Representative of FUSSAG), Joshua Gadasu, (representative of TEWU), Francis Zotor (representative of UTAG), and Derrick Asare (representative of SRC). == Campuses == The university has two main campuses: Ho campus - main and central administrative campus Perm site: Phase 1 and Phase 2 Dave Trafalgar Hohoe campus where the School of Public Health is located == Office of the Vice-Chancellor == Professor Lydia Aziato is the current Vice-Chancellor of the University of Health and Allied Sciences. In a special meeting held on June 3, 2022, the Governing Council of the University of Health and Allied Sciences approved the appointment of Prof. Aziato as the new Vice-Chancellor. Effective August 1, 2022, Prof. Aziato assumes the prestigious position, becoming the first woman and a nurse to hold the role of Vice-Chancellor in the history of the University Health and Allied Sciences. === History of the Office === Professor Lydia Aziato(2022–Present) Vice-Chancellor Professor John Owusu Gyapong (2016-2022) Vice-Chancellor Professor Fred Newton Binka (2012-2016), founding Vice-Chancellor == Schools and institutes == The University of Health and Allied Sciences comprises of 9 Schools and 3 Institutes: === Schools === School of Basic and Biomedical Sciences. School of Allied Health Sciences. School of Nursing and Midwifery. Fred Newton Binka School of Public Health School of Pharmacy. School of Medicine. School of Sports and Exercise Medicine. School of Graduate Studies UHAS Basic School. === Institutes === Institute of Health Research has the following centres: Centre for Health Policy and Implementation Research Centre for Non-Communicable Diseases Research Centre for Malaria Research Centre for Neglected Tropical Diseases Research The Institute of Traditional and Alternative Medicine (ITAM), UHAS is comprised of six departments, namely: Department of Traditional Medicine Department of Complementary & Alternative Medicines Department of Natural Products Sourcing Department of Education and Advocacy Clinical Department Drug Production Department Institute Of Medical Education has the following centres: Center for Health Policy and Implementation Research (CHPIR) Center for Malaria Research (CMR) Center for Neglected Tropical Diseases Research (CNTDR) Center for Non-communicable Diseases Research (CNCDR) Directorates Academic Affairs Finance Human Resources Information Communication Technology Internal Audit International Programmes Library Public Affairs Quality Assurance Works & Physical Development == Research Ethics Committee == The university has a Research Ethics Committee (REC), that is responsible for the oversight of responsibilities with reviewing and approving all research planned to be conducted in the university's facilities and/or involve the staff or students of the university. The goal of the REC is to protect the rights and welfare of human participants in research studies. The REC is made up of seven (7) Scientists/Academics and 8 Non-scientists; including A lawyer, Journalist, Religious Body Representing the larger Community, Sociologist, Educationist, Traditional leader, Public Health Expert and a Medical Doctor The officers of the REC include the chair, Vice Chair and the Administrator. CUT OFF POINTS SCHOOL OF NURSING AND MIDWIFERY (SONAM) SCHOOL OF MEDICINE (SOM) SCHOOL OF PHARMACY (SOP) SCHOOL OF ALLIED HEALTH SCIENCES SCHOOL OF BASIC AND BIOMEDICAL SCIENCES (SBBS) SCHOOL OF PUBLIC HEALTH (SPH) SCHOOL OF SPORTS AND EXERCISE MEDICINE(SSEM) Key: * Non – Science Students , ** Science Students == Postgraduate studies == Department Of Medical Laboratory Sciences Graduate Programmes A. M.PHIL IN MEDICAL LABORATORY SCIENCES PROGRAMME with options in: a. Chemical Pathology b. Haematology and Transfusion Science c. Histopathology and Cytopathology d. Immunology/Vaccinology e. Microbiology (Parasitology, Bacteriology, Virology, Mycology) B. Ph.D IN MEDICAL LABORATORY SCIENCES PROGRAMME with options a. Chemical Pathology b. Histopathology c. Microbiology SCHOOL OF BASIC AND BIOMEDICAL SCIENCES Master Of Biomedical Science, Biomedical Science MASTER OF PHILOSOPHY (MPHIL), BIOMEDICAL SCIENCE DOCTOR OF PHILOSOPHY (PHD), BIOMEDICAL SCIENCE C. SCHOOL OF PUBLIC HEALTH MASTER OF PHILOSOPHY (M.Phil.) IN APPLIED EPIDEMIOLOGY (REGULAR) (Ghanaian and International) MASTER OF PUBLIC HEALTH (MPH) (Ghanaian and International) DOCTOR OF PHILOSOPHY (PHD IN PUBLIC HEALTH) – FULL-TIME (Ghanaian and International) D. SCHOOL OF NURSING AND MIDWIFERY MPhil Nursing Studies and MPhil Midwifery D. SCHOOL OF PHARMACY i) Doctor of Philosophy (Pharmacology) ii) Doctor of Philosophy (Toxicology) iii) Doctor of Philosophy (Pharmacognosy) iv) Doctor of Philosophy (Pharmaceutical Chemistry) Requirements A Master's degree (with research) or its equivalent in Pharmacology, Toxicology, Pharmacognosy, Pharmaceutical Chemistry, Biochemistry, Biomedical Sciences, Molecular and Cell Biology, or any other relevant field of study. i. Master of Philosophy (Pharmacology) ii. Master of Philosophy (Toxicology) iii. Master of Philosophy (Pharmacognosy) iv. Master of Philosophy (Pharmaceutical Chemistry) v. Master of Science (Pharmaceutical Chemistry) Requirements A first degree with a minimum of Second-Class Lower division or equivalent in Pharmacology, Biochemistry, Biomedical Sciences, Molecular and Cell Biology, Toxicology, Pharmacy (BPharm/PharmD) or any other relevant field of study. == Ranks == The University of Health and Allied Sciences (UHAS) was ranked second in Ghana and 36th in Africa in the World Scientist and University Rankings 2021 by AD Scientific Index, beating out KNUST, UCC, and GIMPA, among other universities. UHAS achieved the highest ranking among Ghanaian universities in the Times Higher Education Impact Rankings for the SDG-3 category, recognizing their outstanding efforts in promoting good health and well-being in the 2022. == See also == List of universities in Ghana == External links == National Accreditation Board, Ghana == References ==	Wikipedia/University_of_Health_and_Allied_Sciences
Step 2 Clinical Skills (Step 2 CS) of the United States Medical Licensing Examination (USMLE) was an exam administered to medical students/graduates who wish to become licensed physicians in the U.S. It is similar to the COMLEX-USA Level 2-PE exam, taken by osteopathic medical students/graduates who seek licensure as physicians in the U.S. For US medical students, the exam fee is $1,300 (as of 2020). For medical students at non-US medical schools, the tests cost is higher—currently $1,535. These fees do not include costs associated with travel and lodging to take the test. Historically, US students have taken Step 2 CS late in their senior year, prior to graduation. However, now that more residency programs require students to record a passing score, many US medical schools recommend students take Step 2 CS in the fall of their senior year. On May 26, 2020, in response to the COVID-19 pandemic, the USMLE "suspended Step 2 CS test administrations for the next 12-18 months." On January 26, 2021, the USMLE announced that the work to relaunch a modified form USMLE Step 2 CS had been discontinued citing rapidly evolving medical education and changes in other standardized exams, like computer-based simulations in Step 3, that would supplement medical students' education in place of Step 2 CS. == Structure == The USMLE Step 2CS exam consists of a series of patient encounters in which the examinee must see standardized patients (SPs), take a history, do a physical examination, determine differential diagnoses, and then write a patient note based on their determinations. The topics covered are common outpatient or Emergency Room visits which are encountered in the fields of internal medicine, surgery, psychiatry, pediatrics, and obstetrics and gynecology. Examinees are expected to investigate the simulated patient's chief complaint, as well as obtain a thorough assessment of their past medical history, medications, allergies, social history (including alcohol, tobacco, drug use, sexual practices, etc.), and family history. Usually, examinees have one telephone encounter, speaking to an SP through a microphone during which there is no physical exam component. Examinees are allowed 15 minutes to complete each encounter and 10 minutes for the patient note for a single patient encounter. The patient note is slightly different from a standard SOAP note. For the exam note, the examinees will document the pertinent facts relating to the history of present illness as well as elements of the past medical history, medication history, allergies, social history, family history, and physical exam. The examinees will then state up to 3 differential diagnoses relating to the simulated patient's symptoms, and tests or procedures to investigate the simulated patient's complaints. The examinees should also list pertinent positive and negative findings to support each potential diagnosis. The examinees will not recommend any specific treatments in the note in contrast to a true clinic SOAP note (i.e., IV fluids, antibiotics, or other medications). Over the course of an 8-hour exam day, the examinees complete 12 such encounters. Examinees are required to type patient notes on a computer. USMLE Step 2 CS replaced the former ECFMG Clinical Skills Assessment (CSA) effective June 14, 2004. The last administration of the ECFMG Clinical Skills Assessment (CSA) took place on April 16, 2004. When the CSA first started it was strictly for Foreign Medical Graduates while US graduates were not required to do it. That was considered a double standard in the US medical licensing process. Later the CSA was replaced with the USMLE step 2 CS and became inclusive to all medical graduates. == Grading == The test was graded on a pass/fail basis, without any numerical score associated with it (as opposed to the other parts of the USMLE series). Examinees were scored on three separate subcomponents: Communication and Interpersonal Skills (CIS), Spoken English Proficiency (SEP), and Integrated Clinical Encounter (ICE). Each of the three subcomponents must be passed in a single administration in order to achieve a passing performance on Step 2 CS. Communication and Interpersonal Skills (CIS) - includes assessment of the patient-centered communication skills of fostering the relationship, gathering information, providing information, helping the patient make decisions, and supporting emotions. CIS performance is assessed by the standardized patients, who record these skills using a checklist based on observable behaviors. Spoken English Proficiency (SEP) - includes assessment of clarity of spoken English communication within the context of the doctor-patient encounter (for example, pronunciation, word choice, and minimizing the need to repeat questions or statements). SEP performance is assessed by the standardized patients using a global rating scale, where the rating is based upon the frequency of pronunciation or word choice errors that affect comprehension and the amount of listener effort required to understand the examinee's questions and responses. Integrated Clinical Encounter (ICE) - includes assessments of both data gathering and data interpretation skills. Scoring for this subcomponent consists of a checklist completed by the standardized patients for the physical examination portion of the encounter, and global ratings provided by trained physician raters. The patient note raters provide ratings on the documented summary of the findings of the patient encounter (history and physical examination), diagnostic impressions, justification of the potential diagnoses, and initial patient diagnostic studies. == Exam centers == Before its retirement, the exam could be taken in the U.S. at five Clinical Skills Evaluation Centers (CSEC), located in: Atlanta, Georgia Chicago, Illinois Houston, Texas Los Angeles, California Philadelphia, Pennsylvania == Controversy == The Step 2 CS exam was added to the USMLE series in 2004 by the NBME and FSMB. However, the test garnered criticism for its high exam fee and need to travel to one of five testing sites. Even before the exam was rolled out, the American Medical Association raised serious concerns with the exam, both because it failed to provide students feedback and room for remediation and because there was no proof the exam actually accomplished its mission of protecting the public. Beginning in 2004, the USMLE program undertook a comprehensive review of the USMLE, referred to as the Comprehensive Review of USMLE (CRU). The review was overseen by the committee to Evaluate the USMLE Program (CEUP), which was composed of students, residents, clinicians, and members of the licensing, graduate, and undergraduate education communities. The goal of the committee was to determine if the mission and purpose of USMLE were effectively and efficiently supported by the current design, structure, and format of the USMLE. This process was to be guided, in part, by an analysis of information gathered from stakeholders, and was to result in recommendations to USMLE governance. The CEUP worked from 2006 to early 2008. The CEUP's final report states that "none of the feedback (received from other stakeholders) seemed to indicate that USMLE is broken, but there was considerable interest in enhancing and improving the program." Additionally, the report states that "there appeared to be very strong reactions to Step 2 CS, and CEUP felt that survey and stakeholder meeting data on this component needed to be interpreted in a special way by attempting to separate (but still be attentive to) issues related to the mechanics and costs of Step 2 CS versus the value of what the exam is intended to measure. On the issue of mechanics and costs, CEUP recognized that USMLE must be very attentive to the burden put on examinees by this testing format and that the impact on examinees must be considered when proposing future directions. Concerning the skills measured by Step 2 CS, there seemed to be legitimate concerns about content. Many people wanted to see the exam begin to assess whether the examinee can detect and interpret abnormal findings and handle challenging communication issues. There was a frequently expressed sentiment that this exam was ripe for enhancement and that many of the more advanced communication skills and other competencies could be assessed through this vehicle." In response to the feedback gathered, the CEUP recommended that "the assessment of clinical skills remain a component of USMLE, but that USMLE consider ways to further enhance the testing methods currently used, in order to address additional skills im-portant to medical practice. It is also recommended that the administrative challenges and costs to examinees associated with related testing formats be given substantial weight in the consideration of future changes." In 2013, an article published in the New England Journal of Medicine raised concerns about the value of the exam. The authors calculated that the test fee alone cost students $36 million annually, and that the cost of detecting a single student who failed the exam on back-to-back attempts was $1.1 million. A letter to the editor from the leadership of the NBME and the FSMB in response to the article highlighted the need to view the value of the Step 2 CS in terms other than just cost; specifically, they state that: Although (the authors') interest in cost is consistent with the current climate in health care, the 'value' referenced in their title is a function of quality as well as cost. They fail to fully consider the long-term effect of this assessment program on patient safety and satisfaction, societal expectations, and effective medical education. They also note that inclusion of Step 2 CS in the USMLE "brought the USMLE closer to meeting the expectations of the public that physicians exhibit competence in communicating with and examining patients." In February 2016, a group of students at Harvard Medical School launched a national petition calling for an end to Step 2 CS. Since the petition opened, it has collected over 20,000 signatures from medical students and physicians from all over the country. In May 2016, the Massachusetts Medical Society and the Michigan State Medical Society have passed resolutions calling for the elimination of Step 2 CS. In June 2016, the Arizona Medical Association and the AMA - Medical Student Section passed resolutions also calling for the elimination of Step 2 CS. All four resolutions were introduced to the American Medical Association's 2016 Annual House of Delegates meeting, and were combined and adopted as a substitute, single resolution by a unanimous voice vote on 6/15/2016. The adopted language calls for the AMA to work with the FSMB, NBME, state medical societies, and state medical boards to pursue the transition from the Step 2 CS exam to a school-administered clinical skills exam as a licensure requirement. March 16, 2020, USMLE cancelled all appointments for the USMLE STEP 2 CS exam due to the COVID-19 pandemic. Scheduling functionality for the exam was also cancelled. On May 26, 2020, USMLE has "decided to suspend Step 2 CS test administrations for the next 12-18 months." The USMLE announced on January 26, 2021, that "[they] have decided to discontinue Step 2 CS." == See also == USMLE Step 1 USMLE Step 2 CK USMLE Step 3 COMLEX, the counterpart examination for osteopathic medical students. == References == == External links == Official Webpage of the USMLE about the Step 2CS ECFMG Official Website USMLE Recommended Material	Wikipedia/USMLE_Step_2_Clinical_Skills
USMLE Step 2 CK ("Clinical Knowledge") is a nine-hour-long exam that represents the second part of the United States Medical Licensure Examination. It assesses clinical knowledge through a traditional, multiple-choice examination divided into eight 60-minute blocks, each containing up to 40 questions, as well as an hour of break time. In contrast to USMLE Step 1, which prioritizes knowledge of basic sciences, the focus of Step 2 is on clinical application of medical knowledge, and requires the examinee to apply medical knowledge, skills, and understanding of clinical science essential for the provision of patient care under supervision. The USMLE Step 2 is generally taken during the third or fourth year of medical school by U.S. medical students. Step 2 results are reported numerically on a scale between 1 and 300; this is in contrast to Step 1, which is pass/fail only. == Format == The exam is administered in a 9-hour single-day computer-based session. The session is divided into eight one-hour blocks of questions, a 15 minute tutorial and a 45 minute break. The 15-minute tutorial at the beginning of the exam is optional. The 45 minutes allowed for breaks can only be taken between sections at the discretion of the test taker. Both the unused tutorial time and time saved from finishing a test block early is added to the break time. The test is administered at the Prometric testing sites. Prior to 2020, the Step 2 exam consisted of both the CK ("Clinical Knowledge") portion, as well as a CS ("Clinical Skills") exam. However, the CS exam was put on hold in May 2020, and permanently discontinued in January 2021. == Topics == Step 2 CK includes test items in the following content areas: internal medicine, obstetrics and gynecology, pediatrics, preventive medicine, psychiatry, surgery, other areas relevant to provision of care under supervision. Most Step 2 CK test items describe clinical situations and require that you provide one or more of the following: diagnosis, a prognosis, an indication of underlying mechanisms of disease, the next step in medical care, including preventive measures. Step 2 CK is an integrated examination that frequently requires the interpretation of tables and laboratory data, imaging studies, photographs of gross and microscopic pathologic specimens, and results of other diagnostic studies. Step 2 CK tests the aspiring physician's knowledge of medicine putting special emphasis on the principles and mechanisms underlying disease, and the therapies needed to address them. == Scoring == The Step 2CK scores are reported in a 3 digit format with a range between 1 and 300. As of July 1, 2022, the passing score is 214. As of academic year 2020-2021, the mean CK score was 246 with a standard deviation of 15 for first-time takers from accredited medical schools in the United States and Canada. Approximately once every four years, the USMLE decides whether to change the recommended minimum passing score. At its May 2014 meeting, the Step 2 Committee conducted a review for USMLE Step 2 Clinical Knowledge (CK) and decided to raise the Step 2 minimum passing score to 209 for students taking the test after July 1, 2014. In 2022, the passing score was increased to 214, with an implementation date of July 1, 2022. USMLE provides each test taker with a score report that includes information on their performance on various physician tasks, disciplines and systems. == Effect on residency matching == The USMLE Step 2 CK score is one of many factors considered by residency programs in selecting applicants. Along with the USMLE Step 1, this test is a standardized measure of all applicants. The median USMLE Step 2 scores for graduates of U.S. Medical Schools for various residencies is published periodically by the NRMP in their "Charting Outcomes in the Match" documents USMLE Step 1’s pass/fail status in 2022 is likely to enhance the effect of USMLE Step 2 CK on residency matching, since it will remain as the sole standardized factor in the residency application process. == See also == USMLE Step 1 USMLE Step 2 Clinical Skills USMLE Step 3 == References == == External links ==	Wikipedia/USMLE_Step_2_Clinical_Knowledge
A didactic method (from Greek: διδάσκειν didáskein, "to teach") is a teaching method that follows a consistent scientific approach or educational style to present information to students. The didactic method of instruction is often contrasted with dialectics and the Socratic method; the term can also be used to refer to a specific didactic method, as for instance constructivist didactics. == Overview == Didactics is a theory of teaching, and in a wider sense, a theory and practical application of teaching and learning. In demarcation from "mathetics" (the science of learning), didactics refers only to the science of teaching. This theory might be contrasted with open learning, also known as experiential learning, in which people can learn by themselves, in an unstructured manner (or in an unusually structured manner) as in experiential education, on topics of interest. It can also be contrasted with autodidactic learning, in which one instructs oneself, often from existing books or curricula. The theory of didactic learning methods focuses on the baseline knowledge students possess and seeks to improve upon and convey this information. It also refers to the foundation or starting point in a lesson plan, where the overall goal is knowledge. A teacher or educator functions in this role as an authoritative figure, but also as both a guide and a resource for students. Didactics or the didactic method have different connotations in continental Europe and English-speaking countries. Didacticism was indeed the cultural origin of the didactic method but refers within its narrow context usually pejoratively to the use of language to a doctrinal end. The interpretation of these opposing views are theorised to be the result of a differential cultural development in the 19th century when Great Britain and its former colonies went through a renewal and increased cultural distancing from continental Europe. It was particularly the later appearance of Romanticism and Aestheticism in the Anglo-Saxon world which offered these negative and limiting views of the didactic method. On the other hand, in continental Europe those moralising aspects of didactics were removed earlier by cultural representatives of the Age of Enlightenment, such as Voltaire, Rousseau, and later specifically related to teaching by Johann Heinrich Pestalozzi. The consequences of these cultural differences then created two main didactic traditions: The Anglo-Saxon tradition of curriculum studies on one side and the Continental and North European tradition of didactics on the other. Still today, the science of didactics carries much less weight in much of the English-speaking world.. With the advent of globalisation at the beginning of the 20th century, however, the arguments for such relative philosophical aspects in the methods of teaching started to diminish somewhat. It is therefore possible to categorise didactics and pedagogy as a general analytic theory on three levels: a theoretical or research level (denoting a field of study) a practical level (summaries of curricular activities) a discursive level (implying a frame of reference for professional dialogs) == Nature of didactics and difference with pedagogy == The discipline of didactics is interested in both theoretical knowledge and practical activities related to teaching, learning and their conditions. It is concerned with the content of teaching (the "what"), the method of teaching (the "how") and the historical, cultural and social justifications of curricular choices (the "why"). It focuses on the individual learner, their cognitive characteristics and functioning when they learn a given content and become a knowing subject. The perspective of educational reality in didactics is drawn extensively from cognitive psychology and the theory of teaching, and sometimes from social psychology. Didactics is descriptive and diachronic ("what is" and "what was"), as opposed to pedagogy, the other discipline related to educational theorizing, which is normative or prescriptive and synchronic ("what should or ought to be") in nature. Didactics can be said to provide the descriptive foundation for pedagogy, which is more concerned with educational goal-setting and with the learner's becoming a social subject and their future role in society. In continental Europe, as opposed to English-speaking research cultures, pedagogy and didactics are distinct areas of study. Didactics is a knowledge-based discipline concerned with the descriptive and rational study of all teaching-related activities before, during and after the teaching of content in the classroom, which includes the "planning, control and regulation of the teaching context" and its objective is to analyze how teaching leads to learning. On the other hand, pedagogy is a practice-oriented discipline concerned with the normative study of the applied aspects of teaching in real teaching contexts, i.e., inside the classroom. Pedagogy draws from didactic research and can be seen as an applied component of didactics. === Didactic transposition === In France, didactics refers to the science that takes the teaching of disciplined knowledge as its object of study. In other words, didactics is concerned with the teaching of specific disciplines to students. One of the central concepts studied in didactics of a specific discipline in France is the concept of "didactic transposition" (La transposition didactique in French). French philosopher and sociologist Michel Verret introduced this concept in 1975, which was borrowed and elaborated further in the 1980s by the French didactician of Mathematics Yves Chevallard. Although Chevallard initially presented this concept regarding the didactics of mathematics, it has since been generalized for other disciplines as well. Didactic transposition is composed of multiple steps. The first step, called the "external transposition" (transposition externe), is about how the "scholarly knowledge" (savoir savant) produced by the scholars, scientists or specialists of a certain discipline in a research context, i.e., at universities and other academic institutions is transformed into "knowledge to teach" (savoir à enseigner) by precisely selecting, rearranging and defining the knowledge which will be taught (the official curriculum for each discipline) and how it will be taught, so that it becomes an object of learning accessible to the learner. This external didactic transposition is a socio-political construction made possible by different actors working within various educational institutions: education specialists, political authorities, teachers and their associations define the issues of teaching and choose what should be taught under which form. Chevallard called this socio-political context of institutional organization the “noosphere”, which defines the limits, redefines and reorganizes the knowledge in socially, historically or culturally determined contexts.[1] The second step, called the "internal transposition" (transposition interne) is about how the knowledge to teach is transformed into "taught knowledge" (savoir enseigné), which is the knowledge actually taught through the day-to-day concrete practices of a teacher in a teaching context, e.g. in a classroom, and which depends on their students and the constraints imposed on them (time, exams, conformity to prevailing school rules, etc.).[2] In the third and final step, the taught knowledge is transformed into "acquired knowledge" (savoir acquis), which is the knowledge as it is actually acquired by students in a learning context. The acquired knowledge can be used as a feedback to the didactic system. Didactic research has to account for all the aforementioned steps of didactic transposition. == Didactic teaching == Didactic method provides students with the required theoretical knowledge. It is an effective method used to teach students who are unable to organize their work and depend on the teachers for instructions. It is also used to teach basic skills of reading and writing. The teacher or the literate is the source of knowledge and the knowledge is transmitted to the students through didactic method. === Limitations === Though the didactic method has been given importance in several schools, it does not satisfy the needs and interests of all students. It can be tedious for students to listen to the possible lectures. There is minimum interaction between the students and the teachers. Learning which also involves motivating the students to develop an interest towards the subject may not be satisfied through this teaching method. It may be a monologue process and experience of the students may not have a significant role in learning. == See also == Guy Brousseau == References == == External links == Media related to Didactic method at Wikimedia Commons The dictionary definition of didactic at Wiktionary	Wikipedia/Didactic_method
Physical therapy (PT), also known as physiotherapy, is a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease prevention, and health promotion. Physical therapist is the term used for such professionals in the United States, and physiotherapist is the term used in many other countries. The career has many specialties including musculoskeletal, orthopedics, cardiopulmonary, neurology, endocrinology, sports medicine, geriatrics, pediatrics, women's health, wound care and electromyography. PTs practice in many settings, both public and private. In addition to clinical practice, other aspects of physical therapy practice include research, education, consultation, and health administration. Physical therapy is provided as a primary care treatment or alongside, or in conjunction with, other medical services. In some jurisdictions, such as the United Kingdom, physical therapists may have the authority to prescribe medication. == Overview == Physical therapy addresses the illnesses or injuries that limit a person's abilities to move and perform functional activities in their daily lives. PTs use an individual's history and physical examination to arrive at a diagnosis and establish a management plan and, when necessary, incorporate the results of laboratory and imaging studies like X-rays, CT-scan, or MRI findings. Physical therapists can use sonography to diagnose and manage common musculoskeletal, nerve, and pulmonary conditions. Electrodiagnostic testing (e.g., electromyograms and nerve conduction velocity testing) may also be used. PT management commonly includes prescription of or assistance with specific exercises, manual therapy, and manipulation, mechanical devices such as traction, education, electrophysical modalities which include heat, cold, electricity, sound waves, radiation, assistive devices, prostheses, orthoses, and other interventions. In addition, PTs work with individuals to prevent the loss of mobility before it occurs by developing fitness and wellness-oriented programs for healthier and more active lifestyles, providing services to individuals and populations to develop, maintain, and restore maximum movement and functional ability throughout the lifespan. This includes providing treatment in circumstances where movement and function are threatened by aging, injury, disease, or environmental factors. Functional movement is central to what it means to be healthy. Physical therapy is a professional career that has many specialties including musculoskeletal, orthopedics, cardiopulmonary, neurology, endocrinology, sports medicine, geriatrics, pediatrics, women's health, wound care and electromyography. Neurological rehabilitation is, in particular, a rapidly emerging field. PTs practice in many settings, such as privately-owned physical therapy clinics, outpatient clinics or offices, health and wellness clinics, rehabilitation hospital facilities, skilled nursing facilities, extended care facilities, private homes, education and research centers, schools, hospices, industrial and these workplaces or other occupational environments, fitness centers and sports training facilities. Physical therapists also practice in non-patient care roles such as health policy, health insurance, health care administration and as health care executives. Physical therapists are involved in the medical-legal field serving as experts, performing peer review and independent medical examinations. Education varies greatly by country. The span of education ranges from some countries having little formal education to others having doctoral degrees and post-doctoral residencies and fellowships. Regarding its relationship to other healthcare professions, physiotherapy is one of the allied health professions. World Physiotherapy has signed a "memorandum of understanding" with the four other members of the World Health Professions Alliance "to enhance their joint collaboration on protecting and investing in the health workforce to provide safe, quality and equitable care in all settings". == History == Physicians like Hippocrates and later Galen are believed to have been the first practitioners of physical therapy, advocating massage, manual therapy techniques and hydrotherapy to treat people in 460 BC. After the development of orthopedics in the eighteenth century, machines like the Gymnasticon were developed to treat gout and similar diseases by systematic exercise of the joints, similar to later developments in physical therapy. The earliest documented origins of actual physical therapy as a professional group date back to Per Henrik Ling, "Father of Swedish Gymnastics," who founded the Royal Central Institute of Gymnastics (RCIG) in 1813 for manipulation, and exercise. Up until 2014, the Swedish word for a physical therapist was sjukgymnast = someone involved in gymnastics for those who are ill, but the title was then changed to fysioterapeut (physiotherapist), the word used in the other Scandinavian countries. In 1887, PTs were given official registration by Sweden's National Board of Health and Welfare. Other countries soon followed. In 1894, four nurses in Great Britain formed the Chartered Society of Physiotherapy. The School of Physiotherapy at the University of Otago in New Zealand in 1913, and the United States 1914 Reed College in Portland, Oregon, which graduated "reconstruction aides." Since the profession's inception, spinal manipulative therapy has been a component of the physical therapist practice. Modern physical therapy was established towards the end of the 19th century due to events that affected on a global scale, which called for rapid advances in physical therapy. Following this, American orthopedic surgeons began treating children with disabilities and employed women trained in physical education, and remedial exercise. These treatments were further applied and promoted during the Polio outbreak of 1916. During the First World War, women were recruited to work with and restore physical function to injured soldiers, and the field of physical therapy was institutionalized. In 1918 the term "Reconstruction Aide" was used to refer to individuals practicing physical therapy. The first school of physical therapy was established at Walter Reed Army Hospital in Washington, D.C., following the outbreak of World War I. Treatment through the 1940s primarily consisted of exercise, massage, and traction. Manipulative procedures to the spine and extremity joints began to be practiced, especially in the British Commonwealth countries, in the early 1950s. Around the time polio vaccines were developed, physical therapists became a normal occurrence in hospitals throughout North America and Europe. In the late 1950s, physical therapists started to move beyond hospital-based practice to outpatient orthopedic clinics, public schools, colleges/universities health-centres, geriatric settings (skilled nursing facilities), rehabilitation centers and medical centers. Specialization in physical therapy in the U.S. occurred in 1974, with the Orthopaedic Section of the APTA being formed for those physical therapists specializing in orthopedics. In the same year, the International Federation of Orthopaedic Manipulative Physical Therapists was formed, which has ever since played an important role in advancing manual therapy worldwide. An international organization for the profession is the World Confederation for Physical Therapy (WCPT). It was founded in 1951 and has operated under the brand name World Physiotherapy since 2020. == Education == Educational criteria for physical therapy providers vary from state to state, country to country, and among various levels of professional responsibility. Most U.S. states have physical therapy practice acts that recognize both physical therapists (PT) and physical therapist assistants (PTA) and some jurisdictions also recognize physical therapy technicians (PT Techs) or aides. Most countries have licensing bodies that require physical therapists to be member of before they can start practicing as independent professionals. === Canada === The Canadian Alliance of Physiotherapy Regulators (CAPR) offers eligible program graduates to apply for the national Physiotherapy Competency Examination (PCE). Passing the PCE is one of the requirements in most provinces and territories to work as a licensed physiotherapist in Canada. CAPR has members which are physiotherapy regulatory organizations recognized in their respective provinces and territories: Government of Yukon, Consumer Services College of Physical Therapists of British Columbia College of Physiotherapists of Alberta Saskatchewan College of Physical Therapists College of Physiotherapists of Manitoba College of Physiotherapists of Ontario Ordre professionnel de la physiothérapie du Québec College of Physiotherapists of New Brunswick/Collège des physiothérapeutes du Nouveau-Brunswick Nova Scotia College of Physiotherapists Prince Edward Island College of Physiotherapists Newfoundland & Labrador College of Physiotherapists Physiotherapy programs are offered at fifteen universities, often through the university's respective college of medicine. Each of Canada's physical therapy schools has transitioned from three-year Bachelor of Science in Physical Therapy (BScPT) programs that required two years of prerequisite university courses (five-year bachelor's degree) to two-year Master's of Physical Therapy (MPT) programs that require prerequisite bachelor's degrees. The last Canadian university to follow suit was the University of Manitoba, which transitioned to the MPT program in 2012, making the MPT credential the new entry to practice standard across Canada. Existing practitioners with BScPT credentials are not required to upgrade their qualifications. In the province of Quebec, prospective physiotherapists are required to have completed a college diploma in either health sciences, which lasts on average two years, or physical rehabilitation technology, which lasts at least three years, to apply to a physiotherapy program or program in university. Following admission, physical therapy students work on a bachelor of science with a major in physical therapy and rehabilitation. The B.Sc. usually requires three years to complete. Students must then enter graduate school to complete a master's degree in physical therapy, which normally requires one and a half to two years of study. Graduates who obtain their M.Sc. must successfully pass the membership examination to become members of the Ordre Professionnel de la physiothérapie du Québec (PPQ). Physiotherapists can pursue their education in such fields as rehabilitation sciences, sports medicine, kinesiology, and physiology. In the province of Quebec, physical rehabilitation therapists are health care professionals who are required to complete a four-year college diploma program in physical rehabilitation therapy and be members of the Ordre Professionnel de la physiothérapie du Québec (OPPQ) to practice legally in the country according to specialist De Van Gerard. Most physical rehabilitation therapists complete their college diploma at Collège Montmorency, Dawson College, or Cégep Marie-Victorin, all situated in and around the Montreal area. After completing their technical college diploma, graduates have the opportunity to pursue their studies at the university level to perhaps obtain a bachelor's degree in physiotherapy, kinesiology, exercise science, or occupational therapy. The Université de Montréal, the Université Laval and the Université de Sherbrooke are among the Québécois universities that admit physical rehabilitation therapists in their programs of study related to health sciences and rehabilitation to credit courses that were completed in college. To date, there are no bridging programs available to facilitate upgrading from the BScPT to the MPT credential. However, research Master's of Science (MSc) and Doctor of Philosophy (Ph.D.) programs are available at every university. Aside from academic research, practitioners can upgrade their skills and qualifications through continuing education courses and curriculums. Continuing education is a requirement of the provincial regulatory bodies. The Canadian Physiotherapy Association offers a curriculum of continuing education courses in orthopedics and manual therapy. The program consists of 5 levels (7 courses) of training with ongoing mentorship and evaluation at each level. The orthopedic curriculum and examinations take a minimum of 4 years to complete. However, upon completion of level 2, physiotherapists can apply to a unique 1-year course-based Master's program in advanced orthopedics and manipulation at the University of Western Ontario to complete their training. This program accepts only 16 physiotherapists annually since 2007. Successful completion of either of these education streams and their respective examinations allows physiotherapists the opportunity to apply to the Canadian Academy of Manipulative Physiotherapy (CAMPT) for fellowship. Fellows of the Canadian Academy of manipulative Physiotherapists (FCAMPT) are considered leaders in the field, having extensive post-graduate education in orthopedics and manual therapy. FCAMPT is an internationally recognized credential, as CAMPT is a member of the International Federation of Manipulative Physiotherapists (IFOMPT), a branch of World Physiotherapy (formerly World Confederation of Physical Therapy (WCPT)) and the World Health Organization (WHO). === Scotland === Physiotherapy degrees are offered at four universities: Edinburgh Napier University in Edinburgh, Robert Gordon University in Aberdeen, Glasgow Caledonian University in Glasgow, and Queen Margaret University in Edinburgh. Students can qualify as physiotherapists by completing a four-year Bachelor of Science degree or a two-year master's degree (if they already have an undergraduate degree in a related field). To use the title 'Physiotherapist', a student must register with the Health and Care Professions Council, a UK-wide regulatory body, on qualifying. Many physiotherapists are also members of the Chartered Society of Physiotherapy (CSP), which provides insurance and professional support. === United States === The primary physical therapy practitioner is the Physical Therapist (PT) who is trained and licensed to examine, evaluate, diagnose and treat impairment, functional limitations, and disabilities in patients or clients. Physical therapist education curricula in the United States culminate in a Doctor of Physical Therapy (DPT) degree, with some practicing PTs holding a Master of Physical Therapy degree, and some with a Bachelor's degree. The Master of Physical Therapy and Master of Science in Physical Therapy degrees are no longer offered, and the entry-level degree is the Doctor of Physical Therapy degree, which typically takes 3 years after completing a bachelor's degree. PTs who hold a Masters or bachelors in PT are encouraged to get their DPT because APTA's goal is for all PT's to be on a doctoral level. WCPT recommends physical therapist entry-level educational programs be based on university or university-level studies, of a minimum of four years, independently validated and accredited. Curricula in the United States are accredited by the Commission on Accreditation in Physical Therapy Education (CAPTE). According to CAPTE, as of 2022 there are 37,306 students currently enrolled in 294 accredited PT programs in the United States while 10,096 PTA students are currently enrolled in 396 PTA programs in the United States. The physical therapist professional curriculum includes content in the clinical sciences (e.g., content about the cardiovascular, pulmonary, endocrine, metabolic, gastrointestinal, genitourinary, integumentary, musculoskeletal, and neuromuscular systems and the medical and surgical conditions frequently seen by physical therapists). Current training is specifically aimed to enable physical therapists to appropriately recognize and refer non-musculoskeletal diagnoses that may present similarly to those caused by systems not appropriate for physical therapy intervention, which has resulted in direct access to physical therapists in many states. Post-doctoral residency and fellowship education prevalence is increasing steadily with 219 residency, and 42 fellowship programs accredited in 2016. Residencies are aimed to train physical therapists in a specialty such as acute care, cardiovascular & pulmonary, clinical electrophysiology, faculty, geriatrics, neurology, orthopaedics, pediatrics, sports, women's health, and wound care, whereas fellowships train specialists in a subspecialty (e.g. critical care, hand therapy, and division 1 sports), similar to the medical model. Residency programs offer eligibility to sit for the specialist certification in their respective area of practice. For example, completion of an orthopedic physical therapy residency, allows its graduates to apply and sit for the clinical specialist examination in orthopedics, achieving the OCS designation upon passing the examination. Board certification of physical therapy specialists is aimed to recognize individuals with advanced clinical knowledge and skill training in their respective area of practice, and exemplifies the trend toward greater education to optimally treat individuals with movement dysfunction. Physical therapist assistants may deliver treatment and physical interventions for patients and clients under a care plan established by and under the supervision of a physical therapist. Physical therapist assistants in the United States are currently trained under associate of applied sciences curricula specific to the profession, as outlined and accredited by CAPTE. As of December 2022, there were 396 accredited two-year (Associate degree) programs for physical therapist assistants In the United States of America. == Employment == Physical therapy–related jobs in North America have shown rapid growth in recent years, but employment rates and average wages may vary significantly between different countries, states, provinces, or regions. A study from 2013 states that 56.4% of physical therapists were globally satisfied with their jobs. Salary, interest in work, and fulfillment in a job are important predictors of job satisfaction. In a Polish study, job burnout among the physical therapists was manifested by increased emotional exhaustion and decreased sense of personal achievement. Emotional exhaustion is significantly higher among physical therapists working with adults and employed in hospitals. Other factors that increased burnout include working in a hospital setting and having seniority from 15 to 19 years. === United States === According to the United States Department of Labor's Bureau of Labor Statistics, there were approximately 210,900 physical therapists employed in the United States in 2014, earning an average of $84,020 annually in 2015, or $40.40 per hour, with 34% growth in employment projected by 2024. The Bureau of Labor Statistics also reports that there were approximately 128,700 Physical Therapist Assistants and Aides employed in the United States in 2014, earning an average $42,980 annually, or $20.66 per hour, with 40% growth in employment projected by 2024. To meet their needs, many healthcare and physical therapy facilities hire "travel physical therapists", who work temporary assignments between 8 and 26 weeks for much higher wages; about $113,500 a year." Bureau of Labor Statistics data on PTAs and techs can be difficult to decipher, due to their tendency to report data on these job fields collectively rather than separately. O-Net reports that in 2015, PTAs in the United States earned a median wage of $55,170 annually or $26.52 hourly and that Aides/Techs earned a median wage of $25,120 annually or $12.08 hourly in 2015. The American Physical Therapy Association reports vacancy rates for physical therapists as 11.2% in outpatient private practice, 10% in acute care settings, and 12.1% in skilled nursing facilities. The APTA also reports turnover rates for physical therapists as 10.7% in outpatient private practice, 11.9% in acute care settings, 27.6% in skilled nursing facilities. Definitions and licensing requirements in the United States vary among jurisdictions, as each state has enacted its own physical therapy practice act defining the profession within its jurisdiction, but the Federation of State Boards of Physical Therapy has also drafted a model definition to limit this variation. The Commission on Accreditation in Physical Therapy Education (CAPTE) is responsible for accrediting physical therapy education curricula throughout the United States of America. === United Kingdom === The title of Physiotherapist is a protected professional title in the United Kingdom. Anyone using this title must be registered with the Health & Care Professions Council (HCPC). Physiotherapists must complete the necessary qualifications, usually an undergraduate physiotherapy degree (at university or as an intern), a master rehabilitation degree, or a doctoral degree in physiotherapy. This is typically followed by supervised professional experience lasting two to three years. All professionals on the HCPC register must comply with continuing professional development and can be audited for this evidence at intervals. == Specialty areas == The body of knowledge of physical therapy is large, and therefore physical therapists may specialize in a specific clinical area. While there are many different types of physical therapy, the American Board of Physical Therapy Specialties lists ten current specialist certifications. Most Physical Therapists practicing in a specialty will have undergone further training, such as an accredited residency program, although individuals are currently able to sit for their specialist examination after 2,000 hours of focused practice in their respective specialty population, in addition to requirements set by each respective specialty board. === Cardiovascular and pulmonary === Cardiovascular and pulmonary rehabilitation respiratory practitioners and physical therapists offer therapy for a wide variety of cardiopulmonary disorders or pre and post cardiac or pulmonary surgery. An example of cardiac surgery is coronary bypass surgery. The primary goals of this specialty include increasing endurance and functional independence. Manual therapy is used in this field to assist in clearing lung secretions experienced with cystic fibrosis. Pulmonary disorders, heart attacks, post coronary bypass surgery, chronic obstructive pulmonary disease, and pulmonary fibrosis, treatments can benefit from cardiovascular and pulmonary specialized physical therapists. === Clinical electrophysiology === This specialty area includes electrotherapy/physical agents, electrophysiological evaluation (EMG/NCV), physical agents, and wound management. === Geriatric === Geriatric physical therapy covers a wide area of issues concerning people as they go through normal adult aging but is usually focused on the older adult. There are many conditions that affect many people as they grow older and include but are not limited to the following: arthritis, osteoporosis, cancer, Alzheimer's disease, hip and joint replacement, balance disorders, incontinence, etc. Geriatric physical therapists specialize in providing therapy for such conditions in older adults. Physical rehabilitation can prevent deterioration in health and activities of daily living among care home residents. The current evidence suggests benefits to physical health from participating in different types of physical rehabilitation to improve daily living, strength, flexibility, balance, mood, memory, exercise tolerance, fear of falling, injuries, and death. It may be both safe and effective in improving physical and possibly mental state, while reducing disability with few adverse events. The current body of evidence suggests that physical rehabilitation may be effective for long-term care residents in reducing disability with few adverse events. However, there is insufficient to conclude whether the beneficial effects are sustainable and cost-effective. The findings are based on moderate quality evidence. === Wound management === Wound management physical therapy includes the treatment of conditions involving the skin and all its related organs. Common conditions managed include wounds and burns. Physical therapists may utilize surgical instruments, wound irrigations, dressings, and topical agents to remove the damaged or contaminated tissue and promote tissue healing. Other commonly used interventions include exercise, edema control, splinting, and compression garments. The work done by physical therapists in the integumentary specialty does work similar to what would be done by medical doctors or nurses in the emergency room or triage. === Neurology === Neurological physical therapy is a field focused on working with individuals who have a neurological disorder or disease. These can include stroke, chronic back pain, Alzheimer's disease, Charcot-Marie-Tooth disease (CMT), ALS, brain injury, cerebral palsy, multiple sclerosis, Parkinson's disease, facial palsy and spinal cord injury. Common impairments associated with neurologic conditions include impairments of vision, balance, ambulation, activities of daily living, movement, muscle strength and loss of functional independence. The techniques involve in neurological physical therapy are wide-ranging and often require specialized training. Neurological physiotherapy is also called neurophysiotherapy or neurological rehabilitation. It is recommended for neurophysiotherapists to collaborate with psychologists when providing physical treatment of movement disorders. This is especially important because combining physical therapy and psychotherapy can improve neurological status of the patients. === Orthopaedics === Orthopedic physical therapists diagnose, manage, and treat disorders and injuries of the musculoskeletal system including rehabilitation after orthopedic surgery, acute trauma such as sprains, strains, injuries of insidious onset such as tendinopathy, bursitis, and deformities like scoliosis. This specialty of physical therapy is most often found in the outpatient clinical setting. Orthopedic therapists are trained in the treatment of post-operative orthopedic procedures, fractures, acute sports injuries, arthritis, sprains, strains, back and neck pain, spinal conditions, and amputations. Joint and spine mobilization/manipulation, dry needling (similar to acupuncture), therapeutic exercise, neuromuscular techniques, muscle reeducation, hot/cold packs, and electrical muscle stimulation (e.g., cryotherapy, iontophoresis, electrotherapy) are modalities employed to expedite recovery in the orthopedic setting. Additionally, an emerging adjunct to diagnosis and treatment is the use of sonography for diagnosis and to guide treatments such as muscle retraining. Those with injury or disease affecting the muscles, bones, ligaments, or tendons will benefit from assessment by a physical therapist specialized in orthopedics. === Pediatrics === Pediatric physical therapy assists in the early detection of health problems and uses a variety of modalities to provide physical therapy for disorders in the pediatric population. These therapists are specialized in the diagnosis, treatment, and management of infants, children, and adolescents with a variety of congenital, developmental, neuromuscular, skeletal, or acquired disorders/diseases. Treatments focus mainly on improving gross and fine motor skills, balance and coordination, strength and endurance as well as cognitive and sensory processing/integration. === Sports === Physical therapists are closely involved in the care and wellbeing of athletes including recreational, semi-professional (paid), and professional (full-time employment) participants. This area of practice encompasses athletic injury management under 5 main categories: acute care – assessment and diagnosis of an initial injury; treatment – application of specialist advice and techniques to encourage healing; rehabilitation – progressive management for full return to sport; prevention – identification and address of deficiencies known to directly result in, or act as precursors to injury, such as movement assessment education – sharing of specialist knowledge to individual athletes, teams, or clubs to assist in prevention or management of injury Physical therapists who work for professional sports teams often have a specialized sports certification issued through their national registering organization. Most Physical therapists who practice in a sporting environment are also active in collaborative sports medicine programs too (See also: athletic trainers). === Women's health === Women's health or pelvic floor physical therapy mostly addresses women's issues related to the female reproductive system, child birth, and post-partum. These conditions include lymphedema, osteoporosis, pelvic pain, prenatal and post-partum periods, and urinary incontinence. It also addresses incontinence, pelvic pain, pelvic organ prolapse and other disorders associated with pelvic floor dysfunction. Manual physical therapy has been demonstrated in multiple studies to increase rates of conception in women with infertility. === Oncology === Physical therapy in the field of oncology and palliative care is a continuously evolving and developing specialty, both in malignant and non-malignant diseases. Physical therapy for both groups of patients is now recognized as an essential part of the clinical pathway, as early diagnoses and new treatments are enabling patients to live longer. it is generally accepted that patients should have access to an appropriate level of rehabilitation, so that they can function at a minimum level of dependency and optimize their quality of life, regardless of their life expectancy. == Physical therapist–patient collaborative relationship == People with brain injury, musculoskeletal conditions, cardiac conditions, or multiple pathologies benefit from a positive alliance between patient and therapist. Outcomes include the ability to perform activities of daily living, manage pain, complete specific physical function tasks, depression, global assessment of physical health, treatment adherence, and treatment satisfaction. Studies have explored four themes that may influence patient-therapist interactions: interpersonal and communication skills, practical skills, individualized patient-centered care, and organizational and environmental factors. Physical therapists need to be able to effectively communicate with their patients on a variety of levels. Patients have varying levels of health literacy so physical therapists need to take that into account when discussing the patient's ailments as well as planned treatment. Research has shown that using communication tools tailored to the patient's health literacy leads to improved engagement with their practitioner and their clinical care. In addition, patients reported that shared decision-making will yield a positive relationship. Practical skills such as the ability to educate patients about their conditions, and professional expertise are perceived as valuable factors inpatient care. Patients value the ability of a clinician to provide clear and simple explanations about their problems. Furthermore, patients value when physical therapists possess excellent technical skills that improve the patient effectively. Environmental factors such as the location, equipment used, and parking are less important to the patient than the physical therapy clinical encounter itself. Based on the current understanding, the most important factors that contribute to the patient-therapist interactions include that the physical therapist: spends an adequate amount of time with the patient, possesses strong listening and communication skills, treats the patient with respect, provides clear explanations of the treatment, and allows the patient to be involved in the treatment decisions. == Effectiveness == Physical therapy has been found to be effective for improving outcomes, both in terms of pain and function, in multiple musculoskeletal conditions. Spinal manipulation by physical therapists is a safe option to improve outcomes for lower back pain. Several studies have suggested that physical therapy, particularly manual therapy techniques focused on the neck and the median nerve, combined with stretching exercises, may be equivalent or even preferable to surgery for carpal tunnel syndrome. While spine manipulation and therapeutic massage are effective interventions for neck pain, electroacupuncture, strain-counterstrain, relaxation massage, heat therapy, and ultrasound therapy are not as effective, and thus not recommended. Studies also show physical therapy is effective for patients with other conditions. Physiotherapy treatment may improve quality of life, promote cardiopulmonary fitness and inspiratory pressure, as well as reduce symptoms and medication use by people with asthma. Physical therapy is sometimes provided to patients in the ICU, as early mobilization can help reduce ICU and hospital length of stay and improve long-term functional ability. Early progressive mobilization for adult, intubated ICU patients on mechanical ventilation is safe and effective. Psychologically informed physical therapy (PIPT), in which a physical therapist treats patients while other members of a multidisciplinary care team help in preoperative planning for patient management of pain and quality of life, helps improve patient outcomes, especially before and after spine, hip, or knee surgery. However, in the United States, there are obstacles affecting the effectiveness of physical therapy, such as racial disparities among patients. Studies have shown that patients who identified as black experiences were below standard compared to the white patients. Physical therapy has been experiencing disparities with Hispanic patients like many other medical fields. Whether not receiving a referral for inpatient Hispanic patients to follow-up with their care, despite insurance status. Another being limited access to physical therapy as a reason. Raising awareness of these racial disparities in physical therapy is crucial to improving treatment effectiveness across all demographics. == Telehealth == Telehealth (or telerehabilitation) is a developing form of physical therapy in response to the increasing demand for physical therapy treatment. Telehealth is online communication between the clinician and patient, either live or in pre-recorded sessions with mixed reviews when compared to usual, in-person care. The benefits of telehealth include improved accessibility in remote areas, cost efficiency, and improved convenience for people who are bedridden and home-restricted, or physically disabled. Some considerations for telehealth include: limited evidence to prove effectiveness and compliance more than in-person therapy, licensing and payment policy issues, and compromised privacy. Studies are controversial as to the effectiveness of telehealth in patients with more serious conditions, such as stroke, multiple sclerosis, and lower back pain. The interstate compact, enacted in March 2018, allows patients to participate in Telehealth appointments with medical practices located in different states. During the COVID-19 pandemic, the need for telehealth came to the fore as patients were less able to safely attend in-person, particularly if they were elderly or had chronic diseases. Telehealth was considered to be a proactive step to prevent decline in individuals that could not attend classes. Physical decline in at risk groups is difficult to address or undo later. The platform licensing or development are found to be the most substantial cost in telehealth. Telehealth does not remove the need for the physical therapist as they still need to oversee the program. == See also == == References == == External links == Europe: Regulated professions database – Physiotherapist, European Commission	Wikipedia/Physical_Therapy
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine, as well as the mouth, esophagus, stomach and the anus, whereas UC primarily affects the colon and the rectum. == Signs and symptoms == In spite of Crohn's and UC being very different diseases, both may present with any of the following symptoms: abdominal pain, diarrhea, rectal bleeding, severe internal cramps/muscle spasms in the region of the pelvis and weight loss. Anemia is the most prevalent extraintestinal complication of inflammatory bowel disease (IBD). Associated complaints or diseases include arthritis, pyoderma gangrenosum, primary sclerosing cholangitis, and non-thyroidal illness syndrome (NTIS). Associations with deep vein thrombosis (DVT) and bronchiolitis obliterans organizing pneumonia (BOOP) have also been reported. Diagnosis is generally by assessment of inflammatory markers in stool followed by colonoscopy with biopsy of pathological lesions. == Causes == IBD is a complex disease which arises as a result of the interaction of environmental and genetic factors leading to immunological responses and inflammation in the intestine. === Diet === People living with IBD are very interested in diet, but little is known about the impact of diet on these patients. Recent reviews underlined the important role of nutritional counselling in IBD patients. Patients should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. A 2022 study found that diets with increased intake of fruits and vegetables, reduction of processed meats and refined carbohydrates, and preference of water for hydration were associated with lower risk of active symptoms with IBD, although increased intake of fruits and vegetables alone did not reduce risk of symptoms with Crohn's disease. A 2022 scientific review also found generally positive outcomes for IBD patients who adhered to the Mediterranean diet (high fruit and vegetable intake). Dietary patterns are associated with a risk for ulcerative colitis. In particular, subjects who were in the highest tertile of the healthy dietary pattern had a 79% lower risk of ulcerative colitis. Gluten sensitivity is common in IBD and associated with having flareups. Gluten sensitivity was reported in 23.6% and 27.3% of Crohn's disease and ulcerative colitis patients, respectively. A diet high in protein, particularly animal protein, and/or high in sugar may be associated with increased risk of IBD and relapses. === Bile acids === Emerging evidence indicates that bile acids are important etiological agents in IBD pathogenesis. IBD patients have a consistent pattern of an increased abundance of primary bile acids such as cholic acid and chenodeoxycholic acid (and their conjugated forms), and a decreased abundance of secondary bile acids such as lithocholic acid and deoxycholic acid. === Microbiota === The human microbiota consists of 10–100 trillion microorganisms. Several studies have confirmed that the microbiota composition is different in patients with IBD compared to healthy individuals. This difference is more pronounced in patients with Crohn's disease than in those with ulcerative colitis. In IBD patients, there is a decrease or absence of beneficial bacteria such as Bifidobacterium longum, Eubacterium rectale, Faecalibacterium prausnitzii, and Roseburia intestinalis, while harmful species like Bacteroides fragilis, Ruminococcus torques, and Ruminococcus are more abundant. The activation of reactive oxygen species and reactive nitrogen species leads to oxidative stress for both host cells and the gut microbiome. Consequently, in IBD, there is a microbial imbalance, known as dysbiosis, characterized by an increase in functional pathways involved in the microbial response to oxidative stress. This oxidative stress can promote the growth of certain species such as R. gnavus. Another opportunistic bacterium called A. muciniphila contributes to IBD development and is more prevalent in individuals lacking NOD-like receptor 6 (NLRP6). Both R. gnavus and A. muciniphila are bacterial species that are more abundant in IBD. Patients with IBD often exhibit stronger antibody and T-cell responses to microbial antigens. The gut microbiome employs various approaches to interact with the host immune system. For instance, B. fragilis, which is symbiotic in humans, can transfer immune regulatory molecules to immune cells through the secretion of outer membrane vesicles. This mechanism plays a protective role in IBD by activating the non-classical autophagy pathway, dependent on Atg16L1 and NOD2 genes. B. thetaiotaomicron induces the differentiation of T regulatory cells (Tregs) to modulate gut immunity, thus increasing the expression of Gata3 and FoxP3 genes. The colonization of Clostridium spp. can enhance the aggregation of RORγT+ FOXP3 Treg cells, which inhibit the development of Th2 and Th17 cells. Ultimately, this colonization could decrease the response of colonic Th2 and Th17 cells. Also F. prausnitzii attracts CD4 and CD8a (DP8α) regulatory T cells. E. coli Nissle 1917 has the capability to inhibit the growth of Salmonella and other harmful bacteria. It prevents these pathogens from adhering to and invading intestinal epithelial cells, which significantly reduces the likelihood of inflammation in the gut and may also prevent the onset of IBD. === Breach of intestinal barrier === Loss of integrity of the intestinal epithelium plays a key pathogenic role in IBD. Dysfunction of the innate immune system as a result of abnormal signaling through immune receptors called toll-like receptors (TLRs)—which activates an immune response to molecules that are broadly shared by multiple pathogens—contributes to acute and chronic inflammatory processes in IBD colitis and associated cancer. Changes in the composition of the intestinal microbiota are an important environmental factor in the development of IBD. Detrimental changes in the intestinal microbiota induce an inappropriate (uncontrolled) immune response that results in damage to the intestinal epithelium. Breaches in this critical barrier (the intestinal epithelium) allow further infiltration of microbiota that, in turn, elicit further immune responses. IBD is a multifactorial disease that is nonetheless driven in part by an exaggerated immune response to gut microbiota that causes defects in epithelial barrier function. === Oxidative stress and DNA damage === Oxidative stress and DNA damage likely have a role in the pathophysiology of IBD. Oxidative DNA damage as measured by 8-OHdG levels was found to be significantly increased in people with IBD compared to healthy controls, and in inflamed mucosa compared with noninflamed mucosa. Antioxidant capacity as measured by the total action of all antioxidants detected in blood plasma or body fluids was found to be significantly decreased in people with IBD compared to healthy controls, and in inflamed mucosa compared with noninflamed mucosa. == Genetics == A genetic component to IBD has been recognized for over a century. Research that has contributed to understanding of the genetics include studies of ethnic groups (e.g., Ashkenazi Jews, Irish), familial clustering, epidemiological studies, and twin studies. With the advent of molecular genetics, understanding of the genetic basis has expanded considerably, particularly in the past decade. The first gene linked to IBD was NOD2 in 2001. Genome-wide association studies have since added to understanding of the genomics and pathogenesis of the disease. More than 200 single nucleotide polymorphisms (SNPs or "snips") are now known to be associated with susceptibility to IBD. One of the largest genetic studies of IBD was published in 2012. The analysis explained more of the variance in Crohn's disease and ulcerative colitis than previously reported. The results suggested that commensal microbiota are altered in such a way that they act as pathogens in inflammatory bowel diseases. Other studies show that mutations in IBD-associated genes might interfere with the cellular activity and interactions with the microbiome that promote normal immune responses. Many studies identified that microRNAs dysregulation involved in IBD and to promote colorectal cancer. By 2020, single-cell RNA sequencing analysis was launched by a small consortium using IBD patient biopsy material in a search for therapeutic targets. According to an article published on Nature, ETS2 gene plays a vital role in the development of the disease. == Diagnosis == The diagnosis is usually confirmed by biopsies on colonoscopy. Fecal calprotectin is useful as an initial investigation, which may suggest the possibility of IBD, as this test is sensitive but not specific for IBD. === Classification === Inflammatory bowel diseases are autoimmune diseases, in which the body's own immune system attacks elements of the digestive system. The chief types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Several other conditions are variously referred to either as being inflammatory bowel diseases or as being similar to but distinct from inflammatory bowel diseases. These conditions include: Microscopic colitis with subtypes Collagenous colitis Lymphocytic colitis Diversion colitis Behçet's disease === Differential diagnosis === Crohn's disease and ulcerative colitis are both common differential diagnoses for the other, and confidently diagnosing a patient with one of the two diseases may sometimes not be possible. No disease specific markers are currently known in the blood that would enable the reliable separation of patients with Crohn's disease and ulcerative colitis. Physicians tell the difference between Crohn's disease and UC by the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the full thickness of the bowel wall ("transmural lesions"). Lastly, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions. In 10–15% of cases, a definitive diagnosis neither of Crohn's disease nor of ulcerative colitis can be made because of idiosyncrasies in the presentation. In these cases, a diagnosis of indeterminate colitis may be made. Irritable bowel syndrome can present with similar symptoms as either disease, as can nonsteroidal anti-inflammatory drug (NSAID) enteritis and intestinal tuberculosis. Conditions that can be mistaken particularly for Crohn's disease include Behçet's disease and coeliac disease, while conditions that can be symptomatically similar to ulcerative colitis in particular include acute self-limiting colitis, amebic colitis, schistosomiasis and colon cancer. Other diseases may cause an increased excretion of fecal calprotectin, such as infectious diarrhea, untreated celiac disease, necrotizing enterocolitis, intestinal cystic fibrosis and neoplastic pediatric tumor cells. Liver function tests are often elevated in IBD, and are often mild and generally return spontaneously to normal levels. The most relevant mechanisms of elevated liver functions tests in IBD are drug-induced hepatotoxicity and fatty liver. == Treatment == === Surgery === CD and UC are chronic inflammatory diseases, and are not medically curable. However, ulcerative colitis can in most cases be cured by proctocolectomy, although this may not eliminate extra-intestinal symptoms. An ileostomy will collect feces in a bag. Alternatively, a pouch can be created from the small intestine; this serves as the rectum and prevents the need for a permanent ileostomy. Between one-quarter and one-half of patients with ileo-anal pouches do have to manage occasional or chronic pouchitis. Surgery cannot cure Crohn's disease but may be needed to treat complications such as abscesses, strictures or fistulae. Severe cases may require surgery, such as bowel resection, strictureplasty or a temporary or permanent colostomy or ileostomy. In Crohn's disease, surgery involves removing the worst inflamed segments of the intestine and connecting the healthy regions, but unfortunately, it does not cure Crohn's or eliminate the disease. At some point after the first surgery, Crohn's disease can recur in the healthy parts of the intestine, usually at the resection site. (For example, if a patient with Crohn's disease has an ileocecal anastomosis, in which the caecum and terminal ileum are removed and the ileum is joined to the ascending colon, their Crohn's will nearly always flare-up near the anastomosis or in the rest of the ascending colon). === Medical therapies === Medical treatment of IBD is individualised to each patient. The choice of which drugs to use and by which route to administer them (oral, rectal, injection, infusion) depends on factors including the type, distribution, and severity of the patient's disease, as well as other historical and biochemical prognostic factors, and patient preferences. For example, mesalazine is more useful in ulcerative colitis than in Crohn's disease. Generally, depending on the level of severity, IBD may require immunosuppression to control the symptoms, with drugs such as prednisone, tumor necrosis factor inhibitors (TNF inhibitors), azathioprine, methotrexate, or 6-mercaptopurine. Steroids, such as the glucocorticoid prednisone, are frequently used to control disease flares and were once acceptable as a maintenance drug. Biological therapy for inflammatory bowel disease, especially the TNF inhibitors, are used in people with more severe or resistant Crohn's disease and sometimes in ulcerative colitis. Treatment is usually started by administering drugs with high anti-inflammatory effects, such as prednisone. Once the inflammation is successfully controlled, another drug to keep the disease in remission, such as mesalazine in UC, is the main treatment. If further treatment is required, a combination of an immunosuppressive drug (such as azathioprine) with mesalazine (which may also have an anti-inflammatory effect) may be needed, depending on the patient. Controlled release budesonide is used for mild ileal Crohn's disease. === Nutritional and dietetic therapies === Exclusive enteral nutrition is a first-line therapy in pediatric Crohn's disease with weaker data in adults.: 331 Evidence supporting exclusive enteral nutrition in ulcerative colitis is lacking.: 333 Nutritional deficiencies play a prominent role in IBD. Malabsorption, diarrhea, and GI blood loss are common features of IBD. Deficiencies of B vitamins, fat-soluble vitamins, essential fatty acids, and key minerals such as magnesium, zinc, and selenium are extremely common and benefit from replacement therapy. Dietary interventions, including certain exclusion diets like the specific carbohydrate diet (SCD) can be beneficial for symptom management. Dietary fiber interventions, such as psyillium supplementation (a mixture of soluble and insoluble fibers), may relieve symptoms as well as induce/maintain remission by altering the microbiome composition of the GI tract, thereby improving regulation of immune function, reducing inflammation, and helping to restore the intestinal mucosal lining. Low serum levels of alanine transaminase can be a marker of sarcopenia which is underdiagnosed in patients with IBD and associated with a higher disease activity. Anemia is commonly present in both ulcerative colitis and Crohn's disease. Due to raised levels of inflammatory cytokines which lead to the increased expression of hepcidin, parenteral iron is the preferred treatment option as it bypasses the gastrointestinal system, has lower incidence of adverse events and enables quicker treatment. Hepcidin itself is also an anti-inflammatory agent. In the murine model very low levels of iron restrict hepcidin synthesis, worsening the inflammation that is present. Enteral nutrition has been found to be efficient to improve hemoglobin level in patients with IBD, especially combined with erythropoietin. Gastrointestinal bleeding, occurring especially during ulcerative colitis relapse, can contribute to anemia when chronic, and may be life-threatening when acute. To limit the possible risk of dietary intake disturbing hemostasis in acute gastrointestinal bleeding, temporary fasting is often considered necessary in hospital settings. The effectiveness of this approach is unknown; a Cochrane review in 2016 found no published clinical trials including children. Low levels of vitamin D are associated with crohn's disease and ulcerative colitis and people with more severe cases of inflammatory bowel disease often have lower vitamin D levels. It is not clear if vitamin D deficiency causes inflammatory bowel disease or is a symptom of the disease. There is some evidence that vitamin D supplementation therapy may be associated with improvements in scores for clinical inflammatory bowel disease activity and biochemical markers. Vitamin D treatment may be associated with less inflammatory bowel disease reoccurrence of symptoms (relapse). It is not clear if this treatment improves the person's quality of life or what the clinical response to vitamin D treatment. The ideal treatment regime and dose of vitamin D therapy has not been well enough studied. === Microbiome === There is preliminary evidence of an infectious contribution to IBD in some patients that may benefit from antibiotic therapy, such as with rifaximin. The evidence for a benefit of rifaximin is mostly limited to Crohn's disease with less convincing evidence supporting use in ulcerative colitis. The use of oral probiotic supplements to modify the composition and behaviour of the microbiome has been considered as a possible therapy for both induction and maintenance of remission in people with Crohn's disease and ulcerative colitis. A Cochrane review in 2020 did not find clear evidence of improved remission likelihood, nor lower adverse events, in people with Crohn's disease, following probiotic treatment. For ulcerative colitis, there is low-certainty evidence that probiotic supplements may increase the probability of clinical remission. People receiving probiotics were 73% more likely to experience disease remission and over 2x as likely to report improvement in symptoms compared to those receiving a placebo, with no clear difference in minor or serious adverse effects. Although there was no clear evidence of greater remission when probiotic supplements were compared with 5‐aminosalicylic acid treatment as a monotherapy, the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy. Whereas in people who are already in remission, it is unclear whether probiotics help to prevent future relapse, either as a monotherapy or combination therapy. Fecal microbiota transplant is a relatively new treatment option for IBD which has attracted attention since 2010. Some preliminary studies have suggested benefits similar to those in Clostridioides difficile infection but a review of use in IBD shows that FMT is safe, but of variable efficacy. Systematic reviews showed that 33% of ulcerative colitis, and 50% of Crohn's disease patients reach clinical remission after fecal microbiota transplant. === Alternative medicine === Complementary and alternative medicine approaches have been used in inflammatory bowel disorders. Evidence from controlled studies of these therapies has been reviewed; risk of bias was quite heterogeneous. The best supportive evidence was found for herbal therapy, with Plantago ovata and curcumin in UC maintenance therapy, wormwood in CD, mind/body therapy and self-intervention in UC, and acupuncture in UC and CD. === Novel approaches === Stem cell therapy is undergoing research as a possible treatment for IBD. A review of studies suggests a promising role, although there are substantial challenges, including cost and characterization of effects, which limit the current use in clinical practice. === Psychological interventions === Patients with IBD have a higher prevalence of depressive and anxiety disorders compared to the general population, women with IBD are more likely than men to develop affective disorders since up to 65% of them may have depression and anxiety disorder. Currently, there is no evidence to recommend psychological treatment, such as psychotherapy, stress management and patient's education, to all adults with IBD in general. These treatments had no effect on quality of life, emotional well-being and disease activity. The need for these approaches should be individually assessed and further researched to identify subgroups and determine type of therapy that may benefit individuals with IBD. In adolescents population such treatments may be beneficial on quality of life and depression, although only short-term effects have been found, which also imposes the need for further research. A meta analysis of interventions to improve mood (including talking therapy, antidepressants, and exercise) in people with IBD found that they reduced inflammatory markers such as C-reactive protein and faecal calprotectin. Psychological therapies reduced inflammation more than antidepressants or exercise. == Treatment standards == Crohn's and Colitis Australia, the peak body for IBD in Australia, where prevalence is one of the highest in the world, reviewed the quality of care for patients admitted to Australian hospitals. They found that only one hospital met accepted standards for multidisciplinary care, but that care was improved with the availability of even minimal specialised services. == Prognosis == While IBD can limit quality of life because of pain, vomiting, and diarrhea, it is rarely fatal on its own. Fatalities due to complications such as toxic megacolon, bowel perforation and surgical complications are also rare. Fatigue is a common symptom of IBD and can be a burden. Around one-third of individuals with IBD experience persistent gastrointestinal symptoms similar to irritable bowel syndrome (IBS) in the absence of objective evidence of disease activity. Despite enduring the side-effects of long-term therapies, this cohort has a quality of life that is not significantly different to that of individuals with uncontrolled, objectively active disease, and escalation of therapy to biological agents is typically ineffective in resolving their symptoms. The cause of these IBS-like symptoms is unclear, but it has been suggested that changes in the gut-brain axis, epithelial barrier dysfunction, and the gut flora may be partially responsible. While patients of IBD do have an increased risk of colorectal cancer, this is usually caught much earlier than the general population in routine surveillance of the colon by colonoscopy, and therefore patients are much more likely to survive. New evidence suggests that patients with IBD may have an elevated risk of endothelial dysfunction and coronary artery disease. The goal of treatment is toward achieving remission, after which the patient is usually switched to a lighter drug with fewer potential side effects. Every so often, an acute resurgence of the original symptoms may appear; this is known as a "flare-up". Depending on the circumstances, it may go away on its own or require medication. The time between flare-ups may be anywhere from weeks to years, and varies wildly between patients – a few have never experienced a flare-up. Life with IBD can be challenging; however, many with the condition lead relatively normal lives. IBD carries a psychological burden due to stigmatization of being diagnosed, leading to high levels of anxiety, depression, and a general reduction in the quality of life. Although living with IBD can be difficult, there are numerous resources available to help families navigate the ins and out of IBD, such as the Crohn's and Colitis Foundation of America (CCFA). == Epidemiology == IBD resulted in a global total of 51,000 deaths in 2013 and 55,000 deaths in 1990. The increased incidence of IBD since World War II has been correlated to the increase in meat consumption worldwide, supporting the claim that animal protein intake is associated with IBD. However, there are many environmental risk factors that have been linked to the increased and decreased risk of IBD, such as smoking, air pollution and greenspace, urbanization and Westernization. Inflammatory bowel diseases are increasing in Europe. Incidence and prevalence of IBD has risen steadily for the last decades in Asia, which could be related changes in diet and other environmental factors. Around 0.8% of people in the UK have IBD. Similarly, around 270,000 (0.7%) of people in Canada have IBD, with that number expected to rise to 400,000 (1%) by 2030. == Research == The following treatment strategies are not used routinely, but appear promising in some forms of IBD. Initial reports suggest that helminthic therapy may not only prevent but even control IBD: a drink with roughly 2,500 ova of the Trichuris suis helminth taken twice monthly decreased symptoms markedly in many patients. It is even speculated that an effective "immunization" procedure could be developed—by ingesting the cocktail at an early age. Prebiotics and probiotics are focusing increasing interest as treatments for IBD. Currently, there is evidence to support the use of certain probiotics in addition to standard treatments in people with ulcerative colitis but there is no sufficient data to recommend probiotics in people with Crohn's disease. Both single strain and multi-strain probiotics have been researched for mild to moderate cases of ulcerative colitis. The most clinically researched multi-strain probiotic with over 70 human trials is the De Simone Formulation. Further research is required to identify specific probiotic strains or their combinations and prebiotic substances for therapies of intestinal inflammation. Currently, the probiotic strain, frequency, dose and duration of the probiotic therapy are not established. In severely ill people with IBD there is a risk of the passage of viable bacteria from the gastrointestinal tract to the internal organs (bacterial translocation) and subsequent bacteremia, which can cause serious adverse health consequences. Live bacteria might not be essential because of beneficial effects of probiotics seems to be mediated by their DNA and by secreted soluble factors, and their therapeutic effects may be obtained by systemic administration rather than oral administration. In 2005 New Scientist published a joint study by Bristol University and the University of Bath on the apparent healing power of cannabis on IBD. Reports that cannabis eased IBD symptoms indicated the possible existence of cannabinoid receptors in the intestinal lining, which respond to molecules in the plant-derived chemicals. CB1 cannabinoid receptors – which are known to be present in the brain – exist in the endothelial cells which line the gut, it is thought that they are involved in repairing the lining of the gut when damaged. The team deliberately damaged the cells to cause inflammation of the gut lining and then added synthetically produced cannabinoids; the result was that gut started to heal: the broken cells were repaired and brought back closer together to mend the tears. It is believed that in a healthy gut, natural endogenous cannabinoids are released from endothelial cells when they are injured, which then bind to the CB1 receptors. The process appears to set off a wound-healing reaction, and when people use cannabis, the cannabinoids bind to these receptors in the same way. Previous studies have shown that CB1 receptors located on the nerve cells in the gut respond to cannabinoids by slowing gut motility, therefore reducing the painful muscle contractions associated with diarrhea. CB2, another cannabinoid receptor predominantly expressed by immune cells, was detected in the gut of people with IBD at a higher concentration. These receptors, which also respond to chemicals in cannabis, appear to be associated with apoptosis – programmed cell death – and may have a role in suppressing the overactive immune system and reducing inflammation by mopping up excess cells. Activation of the endocannabinoid system was found efficient in ameliorating colitis and increasing the survival rate of mice, and reducing remote organ changes induced by colitis, further suggest that modulation of this system is a potential therapeutic approach for IBDs and the associated remote organ lesions. Alicaforsen is a first generation antisense oligodeoxynucleotide designed to bind specifically to the human ICAM-1 messenger RNA through Watson-Crick base pair interactions in order to subdue expression of ICAM-1. ICAM-1 propagates an inflammatory response promoting the extravasation and activation of leukocytes (white blood cells) into inflamed tissue. Increased expression of ICAM-1 has been observed within the inflamed intestinal mucosa of people with ulcerative colitis, pouchitis and Crohn's, where ICAM-1 over production correlated with disease activity. This suggests that ICAM-1 is a potential therapeutic target in the treatment of these diseases. Cannabinoid CB2 receptor agonists are found to decrease the induction of ICAM-1 and VCAM-1 surface expression in human brain tissues and primary human brain endothelial cells (BMVEC) exposed to various pro-inflammatory mediators. In 2014, an alliance among the Broad Institute, Amgen and Massachusetts General Hospital formed with the intention to "collect and analyze patient DNA samples to identify and further validate genetic targets." In 2015, a meta-analysis on 938 IBD patients and 953 controls, IBD was significantly associated with having higher odds of vitamin D deficiency. Gram-positive bacteria present in the lumen could be associated with extending the time of relapse for ulcerative colitis. Bidirectional pathways between depression and IBD have been suggested and psychological processes have been demonstrated to influence self-perceived physical and psychological health over time. IBD-disease activity may impact quality of life and over time may significantly affect individual's mental well-being, which may be related to the increased risk to develop anxiety and/or depression. On the other hand, psychological distress may also influence IBD activity. Higher rates of anxiety and depression are observed among those with IBD compared to healthy individuals, which correlated with disease severity. Part of this phenotypic correlation is due to a shared genetic overlap between IBD and psychiatric comorbidities. Moreover, anxiety and depression rates increase during active disease compared with inactive phases. Flu vaccines are recommended for people with IBD in the UK; however, research suggests that vaccine uptake is low. Researchers analysed data on 13,631 adults with IBD on immune-suppressing drugs during the 2018 – 2019 flu season. Only half of this population received a vaccine during this period and few (32%) were vaccinated before the flu circulated in the community. This could be due to the belief that flu vaccines cause IBD flares; however, the same study did not find a link between vaccination and IBD flares. == In other species == IBD also occurs in dogs and is thought to arise from a combination of host genetics, intestinal microenvironment, environmental components and the immune system. There is an ongoing discussion, however, that the term "chronic enteropathy" might be better to use than "inflammatory bowel disease" in dogs because it differs from IBD in humans in how the dogs respond to treatment. For example, many dogs respond to only dietary changes compared to humans with IBD, who often need immunosuppressive treatment. Some dogs may also need immunosuppressant or antibiotic treatment when dietary changes are not enough. After having excluded other diseases that can lead to vomiting, diarrhea, and abdominal pain in dogs, intestinal biopsies are often performed to investigate what kind of inflammation is occurring (lymphoplasmacytic, eosinophilic, or granulomatous). In dogs, low levels of cobalamin in the blood have been shown to be a risk factor for negative outcome. == See also == Inflammatory bowel disease-22 World Inflammatory Bowel Disease Day == References == == External links == Media related to Inflammatory bowel diseases at Wikimedia Commons	Wikipedia/Inflammatory_bowel_diseases
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease. The term non-steroidal, common from around 1960, distinguishes these drugs from corticosteroids, another class of anti-inflammatory drugs, which during the 1950s had acquired a bad reputation due to overuse and side-effect problems after their introduction in 1948. NSAIDs work by inhibiting the activity of cyclooxygenase enzymes (the COX-1 and COX-2 isoenzymes). In cells, these enzymes are involved in the synthesis of key biological mediators, namely prostaglandins, which are involved in inflammation, and thromboxanes, which are involved in blood clotting. There are two general types of NSAIDs available: non-selective and COX-2 selective. Most NSAIDs are non-selective, and inhibit the activity of both COX-1 and COX-2. These NSAIDs, while reducing inflammation, also inhibit platelet aggregation and increase the risk of gastrointestinal ulcers and bleeds. COX-2 selective inhibitors have fewer gastrointestinal side effects, but promote thrombosis, and some of these agents substantially increase the risk of heart attack. As a result, certain COX-2 selective inhibitors—such as rofecoxib—are no longer used due to the high risk of undiagnosed vascular disease. These differential effects are due to the different roles and tissue localisations of each COX isoenzyme. By inhibiting physiological COX activity, NSAIDs may cause deleterious effects on kidney function, and, perhaps as a result of water and sodium retention and decreases in renal blood flow, may lead to heart problems. In addition, NSAIDs can blunt the production of erythropoietin, resulting in anaemia, since haemoglobin needs this hormone to be produced. The most prominent NSAIDs are aspirin, ibuprofen, diclofenac and naproxen; all available over the counter (OTC) in most countries. Paracetamol (acetaminophen) is generally not considered an NSAID because it has only minor anti-inflammatory activity. Paracetamol treats pain mainly by blocking COX-2 and inhibiting endocannabinoid reuptake almost exclusively within the brain, and only minimally in the rest of the body. == Medical uses == NSAIDs are often suggested for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs are generally used for the symptomatic relief of the following conditions: === Chronic pain and cancer-related pain === The effectiveness of NSAIDs for treating non-cancer chronic pain and cancer-related pain in children and adolescents is not clear. There have not been sufficient numbers of high-quality randomised controlled trials conducted. === Inflammation === Differences in anti-inflammatory activity between the various individual NSAIDs are small, but there is considerable variation among individual patients in therapeutic response and tolerance to these drugs. About 60% of patients will respond to any NSAID; of the others, those who do not respond to one may well respond to another. Pain relief starts soon after taking the first dose, and a full analgesic effect should normally be obtained within a week, whereas an anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to three weeks. If appropriate responses are not obtained within these times, another NSAID should be tried. === Surgical pain === Pain following surgery can be significant, and many people require strong pain medications such as opioids. There is some low-certainty evidence that starting NSAID painkiller medications in adults early, before surgery, may help reduce post-operative pain, and also reduce the dose or quantity of opioid medications required after surgery. Any increase risk of surgical bleeding, bleeding in the gastrointestinal system, myocardial infarctions, or injury to the kidneys has not been well studied. When used in combination with paracetamol, the analgesic effect on post-operative pain may be improved. === Aspirin === Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for antithrombosis through inhibition of platelet aggregation. This is useful for the management of arterial thrombosis, and prevention of adverse cardiovascular events like heart attacks. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane A2. === Dentistry === NSAIDs are useful in the management of post-operative dental pain following invasive dental procedures such as dental extraction. When not contra-indicated, they are favoured over the use of paracetamol alone due to the anti-inflammatory effect they provide. There is weak evidence suggesting that taking pre-operative analgesia can reduce the length of post operative pain associated with placing orthodontic spacers under local anaesthetic. === Alzheimer's disease === Based on observational studies and randomized controlled trials, NSAID use is not effective for the treatment or prevention of Alzheimer's disease. == Contraindications == NSAIDs may be used with caution by people with the following conditions: Persons who are over age 50, and who have a family history of gastrointestinal (GI) problems Persons who have had previous gastrointestinal problems from NSAID use NSAIDs should usually be avoided by people with the following conditions: == Adverse effects == The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly common. Use of NSAIDs increases risk of a range of gastrointestinal (GI) problems, kidney disease and adverse cardiovascular events. As commonly used for post-operative pain, there is evidence of increased risk of kidney complications. Their use following gastrointestinal surgery remains controversial, given mixed evidence of increased risk of leakage from any bowel anastomosis created. An estimated 10–20% of people taking NSAIDs experience indigestion. In the 1990s, high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding. NSAIDs, like all medications, may interact with other medications. For example, concurrent use of NSAIDs and quinolone antibiotics may increase the risk of quinolones' adverse central nervous system effects, including seizure. There is an argument over the benefits and risks of NSAIDs for treating chronic musculoskeletal pain. Each drug has a benefit-risk profile and balancing the risk of no treatment with the competing potential risks of various therapies should be considered. For people over the age of 65 years old, the balance between the benefits of pain-relief medications such as NSAIDS and the potential for adverse effects has not been well determined. There is some evidence suggesting that, for some people, use of NSAIDs (or other anti-inflammatories) may contribute to the initiation of chronic pain. Side effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10–20% of NSAID patients experience dyspepsia, and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits. Aspirin should not be taken by people who have salicylate intolerance or a more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitated bronchospasm. Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcers, mild diabetes, or gastritis seek medical advice before using aspirin. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. People with kidney disease, hyperuricemia, or gout should not take aspirin because it inhibits the kidneys' ability to excrete uric acid, and thus may exacerbate these conditions. === Combinational risk === If a COX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time. Rofecoxib (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions (ADRs) compared with naproxen. The study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs (COX-2 inhibitors). A statistically significant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a statistically significant relative risk of cardiovascular events of 1.97 versus placebo—which caused a worldwide withdrawal of rofecoxib in October 2004. Use of methotrexate together with NSAIDs in rheumatoid arthritis is safe, if adequate monitoring is done. === Cardiovascular === NSAIDs, aside from aspirin, increase the risk of myocardial infarction and stroke. This occurs at least within a week of use. They are not recommended in those who have had a previous heart attack as they increase the risk of death or recurrent MI. Evidence indicates that naproxen may be the least harmful out of these. NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of heart failure in people without a history of cardiac disease. In people with such a history, use of NSAIDs (aside from low-dose aspirin) was associated with a more than 10-fold increase in heart failure. If this link is proven causal, researchers estimate that NSAIDs would be responsible for up to 20 percent of hospital admissions for congestive heart failure. In people with heart failure, NSAIDs increase mortality risk (hazard ratio) by approximately 1.2–1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2.1 for diclofenac. On 9 July 2015, the Food and Drug Administration (FDA) toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin. === Possible erectile dysfunction risk === A 2005 Finnish survey study found an association between long term (over three months) use of NSAIDs and erectile dysfunction. A 2011 publication in The Journal of Urology received widespread publicity. According to the study, men who used NSAIDs regularly were at significantly increased risk of erectile dysfunction. A link between NSAID use and erectile dysfunction still existed after controlling for several conditions. However, the study was observational and not controlled, with low original participation rate, potential participation bias, and other uncontrolled factors. The authors warned against drawing any conclusion regarding cause. === Gastrointestinal === The main adverse drug reactions (ADRs) associated with NSAID use relate to direct and indirect irritation of the gastrointestinal (GI) tract. NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic effects on the epithelial mucosa. Common gastrointestinal side effects include: Nausea or vomiting Indigestion Gastric ulceration or bleeding Diarrhea Clinical NSAID ulcers are related to the systemic effects of NSAID administration. Such damage occurs irrespective of the route of administration of the NSAID (e.g., oral, rectal, or parenteral) and can occur even in people who have achlorhydria. Ulceration risk increases with therapy duration, and with higher doses. To minimize GI side effects, it is prudent to use the lowest effective dose for the shortest period of time—a practice that studies show is often not followed. Over 50% of patients who take NSAIDs have sustained some mucosal damage to their small intestine. The risk and rate of gastric adverse effects is different depending on the type of NSAID medication a person is taking. Indomethacin, ketoprofen, and piroxicam use appear to lead to the highest rate of gastric adverse effects, while ibuprofen (lower doses) and diclofenac appear to have lower rates. Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations that manufacturers claim reduce the incidence of gastrointestinal ADRs. Similarly, some believe that rectal formulations may reduce gastrointestinal ADRs. However, consistent with the systemic mechanism of such ADRs, and in clinical practice, these formulations have not demonstrated a reduced risk of GI ulceration. Numerous "gastro-protective" drugs have been developed with the goal of preventing gastrointestinal toxicity in people who need to take NSAIDs on a regular basis. Gastric adverse effects may be reduced by taking medications that suppress acid production such as proton pump inhibitors (e.g.: omeprazole and esomeprazole), or by treatment with a drug that mimics prostaglandin in order to restore the lining of the GI tract (e.g.: a prostaglandin analog misoprostol). Diarrhea is a common side effect of misoprostol; however, higher doses of misoprostol have been shown to reduce the risk of a person having a complication related to a gastric ulcer while taking NSAIDs. While these techniques may be effective, they are expensive for maintenance therapy. Hydrogen sulfide NSAID hybrids prevent the gastric ulceration/bleeding associated with taking the NSAIDs alone. Hydrogen sulfide is known to have a protective effect on the cardiovascular and gastrointestinal system. === Inflammatory bowel disease === NSAIDs should be used with caution in individuals with inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) due to their tendency to cause gastric bleeding and form ulceration in the gastric lining. === Renal === NSAIDs are also associated with a fairly high incidence of adverse drug reactions (ADRs) on the kidney and over time can lead to chronic kidney disease. The mechanism of these kidney ADRs is due to changes in kidney blood flow. Prostaglandins normally dilate the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of kidney function. This is particularly important in kidney failure where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent arteriole into the glomerulus in addition to the efferent arteriole it normally constricts. Since NSAIDs block this prostaglandin-mediated effect of afferent arteriole dilation, particularly in kidney failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased RPF (renal perfusion flow) and GFR. Common ADRs associated with altered kidney function include: Sodium and fluid retention Hypertension (high blood pressure) These agents may also cause kidney impairment, especially in combination with other nephrotoxic agents. Kidney failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor (which removes angiotensin II's vasoconstriction of the efferent arteriole) and a diuretic (which drops plasma volume, and thereby RPF)—the so-called "triple whammy" effect. In rarer instances NSAIDs may also cause more severe kidney conditions: Interstitial nephritis Nephrotic syndrome Acute kidney injury Acute tubular necrosis Renal papillary necrosis NSAIDs in combination with excessive use of phenacetin or paracetamol (acetaminophen) may lead to analgesic nephropathy. === Photosensitivity === Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. The 2-arylpropionic acids are the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac, and benzydamine. Benoxaprofen, since withdrawn due to its liver toxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. === During pregnancy === While NSAIDs as a class are not direct teratogens, use of NSAIDs in late pregnancy can cause premature closure of the fetal ductus arteriosus and kidney ADRs in the fetus. Thus, NSAIDs are not recommended during the third trimester of pregnancy because of the increased risk of premature constriction of the ductus arteriosus. Additionally, they are linked with premature birth and miscarriage. Aspirin, however, is used together with heparin in pregnant women with antiphospholipid syndrome. Additionally, indomethacin can be used in pregnancy to treat polyhydramnios by reducing fetal urine production via inhibiting fetal renal blood flow. In contrast, paracetamol (acetaminophen) is regarded as being safe and well tolerated during pregnancy, but Leffers et al. released a study in 2010, indicating that there may be associated male infertility in the unborn. Doses should be taken as prescribed, due to risk of liver toxicity with overdoses. In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy. In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications, to describe the risk of kidney problems in unborn babies which can then lead to low amniotic fluid levels, as a result of the use of NSAIDs. They are recommending avoiding the use of NSAIDs by pregnant women at 20 weeks or later in pregnancy. === Allergy and allergy-like hypersensitivity reactions === A variety of allergic or allergic-like NSAID hypersensitivity reactions follow the ingestion of NSAIDs. These hypersensitivity reactions differ from the other adverse reactions listed here which are toxicity reactions, i.e. unwanted reactions that result from the pharmacological action of a drug, are dose-related, and can occur in any treated individual; hypersensitivity reactions are idiosyncratic reactions to a drug. Some NSAID hypersensitivity reactions are truly allergic in origin: 1) repetitive IgE-mediated urticarial skin eruptions, angioedema, and anaphylaxis following immediately to hours after ingesting one structural type of NSAID but not after ingesting structurally unrelated NSAIDs; and 2) Comparatively mild to moderately severe T cell-mediated delayed onset (usually more than 24 hour), skin reactions such as maculopapular rash, fixed drug eruptions, photosensitivity reactions, delayed urticaria, and contact dermatitis; or 3) far more severe and potentially life-threatening t-cell-mediated delayed systemic reactions such as the DRESS syndrome, acute generalized exanthematous pustulosis, the Stevens–Johnson syndrome, and toxic epidermal necrolysis. Other NSAID hypersensitivity reactions are allergy-like symptoms but do not involve true allergic mechanisms; rather, they appear due to the ability of NSAIDs to alter the metabolism of arachidonic acid in favor of forming metabolites that promote allergic symptoms. Affected individuals may be abnormally sensitive to these provocative metabolites or overproduce them and typically are susceptible to a wide range of structurally dissimilar NSAIDs, particularly those that inhibit COX1. Symptoms, which develop immediately to hours after ingesting any of various NSAIDs that inhibit COX-1, are: 1) exacerbations of asthmatic and rhinitis (see aspirin-exacerbated respiratory disease) symptoms in individuals with a history of asthma or rhinitis and 2) exacerbation or first-time development of wheals or angioedema in individuals with or without a history of chronic urticarial lesions or angioedema. === Possible effects on bone and soft tissue healing === It has been hypothesized that NSAIDs may delay healing from bone and soft-tissue injuries by inhibiting inflammation. On the other hand, it has also been hypothesized that NSAIDs might speed recovery from soft tissue injuries by preventing inflammatory processes from damaging adjacent, non-injured muscles. There is moderate evidence that they delay bone healing. Their overall effect on soft-tissue healing is unclear. === Ototoxicity === Long-term use of NSAID analgesics and paracetamol is associated with an increased risk of hearing loss. === Other === The use of NSAIDs for analgesia following gastrointestinal surgery remains controversial, given mixed evidence of an increased risk of leakage from any bowel anastomosis created. This risk may vary according to the class of NSAID prescribed. Common adverse drug reactions (ADR), other than listed above, include: raised liver enzymes, headache, dizziness. Uncommon ADRs include an abnormally high level of potassium in the blood, confusion, spasm of the airways, and rash. Ibuprofen may also rarely cause irritable bowel syndrome symptoms. NSAIDs are also implicated in some cases of Stevens–Johnson syndrome. Most NSAIDs penetrate poorly into the central nervous system (CNS). However, the COX enzymes are expressed constitutively in some areas of the CNS, meaning that even limited penetration may cause adverse effects such as somnolence and dizziness. NSAIDs may increase the risk of bleeding in patients with Dengue fever For this reason, NSAIDs are only available with a prescription in India. In very rare cases, ibuprofen can cause aseptic meningitis. As with other drugs, allergies to NSAIDs might exist. While many allergies are specific to one NSAID, up to 1 in 5 people may have unpredictable cross-reactive allergic responses to other NSAIDs as well. === Immune response === Although small doses generally have little to no effect on the immune system, large doses of NSAIDs significantly suppress the production of immune cells. As NSAIDs affect prostaglandins, they affect the production of most fast growing cells. This includes immune cells. Unlike corticosteroids, they do not directly suppress the immune system and so their effect on the immune system is not immediately obvious. They suppress the production of new immune cells, but leave existing immune cells functional. Large doses slowly reduce the immune response as the immune cells are renewed at a much lower rate. Causing a gradual reduction of the immune system, much slower and less noticeable than the immediate effect of Corticosteroids. The effect significantly increases with dosage, in a nearly exponential rate. Doubling of dose reduced cells by nearly four times. Increasing dose by five times reduced cell counts to only a few percent of normal levels. This is likely why the effect was not immediately obvious in low dose trials, as the effect is not apparent until much higher dosages are tested. == Interactions == NSAIDs reduce kidney blood flow and thereby decrease the efficacy of diuretics, and inhibit the elimination of lithium and methotrexate. NSAIDs cause decreased ability to form blood clots, which can increase the risk of bleeding when combined with other drugs that also decrease blood clotting, such as warfarin. NSAIDs may aggravate hypertension (high blood pressure) and thereby antagonize the effect of antihypertensives, such as ACE inhibitors. NSAIDs may interfere and reduce effectiveness of SSRI antidepressants through inhibiting TNFα and IFNγ, both of which are cytokine derivatives. NSAIDs, when used in combination with SSRIs, increase the risk of adverse gastrointestinal effects. NSAIDs, when used in combination with SSRIs, increase the risk of internal bleeding and brain hemorrhages. Various widely used NSAIDs enhance endocannabinoid signaling by blocking the anandamide-degrading membrane enzyme fatty acid amide hydrolase (FAAH). NSAIDs may reduce the effectiveness of antibiotics. An in-vitro study on cultured bacteria found that adding NSAIDs to antibiotics reduced their effectiveness by around 20%. The concomitant use of NSAIDs with alcohol and/or tobacco products significantly increases the already elevated risk of peptic ulcers during NSAID therapy. == Mechanism of action == Most NSAIDs act as nonselective inhibitors of the cyclooxygenase (COX) enzymes, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. This inhibition is competitively reversible (albeit at varying degrees of reversibility), as opposed to the mechanism of aspirin, which is irreversible inhibition. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated in 1970 by John Vane (1927–2004), who received a Nobel Prize for his work (see Mechanism of action of aspirin). COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs. When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum and internal bleeding can result. The discovery of COX-2 led to research to the development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs. NSAIDs have been studied in various assays to understand how they affect each of these enzymes. While the assays reveal differences, unfortunately, different assays provide differing ratios. Paracetamol (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body. However, many aspects of the mechanism of action of NSAIDs remain unexplained, and for this reason, further COX pathways are hypothesized. The COX-3 pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed. NSAIDs interact with the endocannabinoid system and its endocannabinoids, as COX2 have been shown to utilize endocannabinoids as substrates, and may have a key role in both the therapeutic effects and adverse effects of NSAIDs, as well as in NSAID-induced placebo responses. NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase. === Antipyretic activity === NSAIDs have antipyretic activity and can be used to treat fever. Fever is caused by elevated levels of prostaglandin E2 (PGE2), which alters the firing rate of neurons within the hypothalamus that control thermoregulation. Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus. PGE2 signals to the hypothalamus to increase the body's thermal setpoint. Ibuprofen has been shown more effective as an antipyretic than paracetamol (acetaminophen). Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D, and E. == Classification == NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action. === Salicylates === === Propionic acid derivatives === === Acetic acid derivatives === === Enolic acid (oxicam) derivatives === === Anthranilic acid derivatives (Fenamates) === The following NSAIDs are derived from fenamic acid, which is a derivative of anthranilic acid,: 235 which in turn is a nitrogen isostere of salicylic acid, which is the active metabolite of aspirin.: 235 : 17 === Selective COX-2 inhibitors (Coxibs) === === Sulfonanilides === Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity) === Others === Benzydamine (commonly branded as Tantum Verde or Difflam) is an indazole derivative with local anaesthetic and analgesic properties Clonixin Licofelone acts by inhibiting LOX (lipooxygenase) and COX and hence known as 5-LOX/COX inhibitor H-harpagide in figwort or devil's claw Some NSAIDs are also given intravenously, such as Ketorolac and Diclofenac sodium. === Chirality === Most NSAIDs are chiral molecules; diclofenac and the oxicams are exceptions. However, the majority are prepared as racemic mixtures. Typically, only a single enantiomer is pharmacologically active. For some drugs (typically profens), an isomerase enzyme in vivo converts the inactive enantiomer into the active form, although its activity varies widely in individuals. This phenomenon is likely responsible for the poor correlation between NSAID efficacy and plasma concentration observed in older studies when specific analysis of the active enantiomer was not performed. Ibuprofen and ketoprofen are now available in single-enantiomer preparations (dexibuprofen and dexketoprofen), which purport to offer quicker onset and an improved side-effect profile. Naproxen has always been marketed as the single active enantiomer. === Main practical differences === NSAIDs within a group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. Rather, differences among compounds usually relate to dosing regimens (related to the compound's elimination half-life), route of administration, and tolerability profile. Regarding adverse effects, selective COX-2 inhibitors have lower risk of gastrointestinal bleeding. With the exception of naproxen, nonselective NSAIDs increase the risk of having a heart attack. Some data also supports that the partially selective nabumetone is less likely to cause gastrointestinal events. A consumer report noted that ibuprofen, naproxen, and salsalate are less expensive than other NSAIDs, and essentially as effective and safe when used appropriately to treat osteoarthritis and pain. == Pharmacokinetics == Most nonsteroidal anti-inflammatory drugs are weak acids, with a pKa of 3–5. They are absorbed well from the stomach and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually to albumin, so that their volume of distribution typically approximates to plasma volume. Most NSAIDs are metabolized in the liver by oxidation and conjugation to inactive metabolites that typically are excreted in the urine, though some drugs are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage. NSAIDs can also be divided into short-acting (plasma half-life less than 6 h) such as aspirin, diclofenac and ibuprofen and long-acting (half-life approximately greater than 10 h) such as naproxen, celecoxib. == History == It is widely believed that naturally occurring salicin in willow trees and other plants was used by the ancients as a form of analgesic or anti-inflammatory drug, but this story, although compelling, is not entirely true. Hippocrates does not mention willow at all. Dioscorides's De materia medica was arguably the most influential herbal from Roman to Medieval times but, if he mentions willow at all (there is doubt about the identity of 'Itea'), then he used the ashes, steeped in vinegar, as a treatment for corns, which corresponds well with modern uses of salicylic acid. Willow bark (from trees of the Salix genus) was widely known to be used as a medicine by multiple First Nations communities. The bark would be chewed or steeped in water for its pain relieving and antipyretic effects. The effects are a result of the bark's salicin content. Meadowsweet, another plant to contain salicin, has strong roots in British folk medicine for the same maladies. Willow bark was first reported in Western science by Edward Stone in 1763 as a treatment for ague (fever) according to the pseudoscientific doctrine of signatures. In the body, salicin is turned into salicylic acid, which produces the antipyretic and analgesic effects that the plants are known for. Salicin was first isolated by Johann Andreas Buchner in 1827. By 1829, French chemist Henri Leroux had improved the extraction process to obtain about 30g of purified salicin from 1.5 kg of willow bark. By hydrolysis, salicin releases glucose and salicyl alcohol which can be converted into salicylic acid, both in vivo and through chemical methods. In 1869, Hermann Kolbe synthesised salicylic acid, although it was too acidic for the gastric mucosa. The reaction used to synthesise aromatic acid from a phenol in the presence of CO2 is known as the Kolbe-Schmitt reaction. By 1897, the German chemist Felix Hoffmann and the Bayer company prompted a new age of pharmacology by converting salicylic acid into acetylsalicylic acid—named aspirin by Heinrich Dreser. Other NSAIDs like ibuprofen were developed from the 1950s forward. In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States. == Veterinary use == Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning and castration of calves. The best effect is obtained by combining a short-term local anesthetic such as lidocaine with an NSAID acting as a longer term analgesic. However, as different species have varying reactions to different medications in the NSAID family, little of the existing research data can be extrapolated to animal species other than those specifically studied, and the relevant government agency in one area sometimes prohibits uses approved in other jurisdictions. In the United States, meloxicam is approved for use only in canines, whereas (due to concerns about liver damage) it carries warnings against its use in cats except for one-time use during surgery. In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species. In other countries, for example The European Union (EU), there is a label claim for use in cats. == See also == Discovery and development of cyclooxygenase 2 inhibitors == References == == External links == "Nonsteroidal Anti-inflammatory Drugs (NSAIDs)". U.S. Food and Drug Administration (FDA). 30 December 2020. Archived from the original on 12 June 2019.	Wikipedia/Nonsteroidal_anti-inflammatory_drugs
Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adrenal glands (adrenal cortex), causing adrenal insufficiency. Symptoms generally develop slowly and insidiously and may include abdominal pain and gastrointestinal abnormalities, weakness, and weight loss. Darkening of the skin in certain areas may also occur. Under certain circumstances, an adrenal crisis may occur with low blood pressure, vomiting, lower back pain, and loss of consciousness. Mood changes may also occur. Rapid onset of symptoms indicates acute adrenal failure, which is a clinical emergency. An adrenal crisis can be triggered by stress, such as from an injury, surgery, or infection. Addison's disease arises when the adrenal gland does not produce sufficient amounts of the steroid hormones cortisol and (sometimes) aldosterone. It is an autoimmune disease which affects some genetically predisposed people in whom the body's own immune system has started to target the adrenal glands. In many adult cases it is unclear what has triggered the onset of this disease, though it sometimes follows tuberculosis. Causes can include certain medications, sepsis, and bleeding into both adrenal glands. Addison's disease is generally diagnosed by blood tests, urine tests, and medical imaging. Treatment involves replacing the absent or low hormones. This involves taking a synthetic corticosteroid, such as hydrocortisone or fludrocortisone. These medications are typically taken orally. Lifelong, continuous steroid replacement therapy is required, with regular follow-up treatment and monitoring for other health problems which may occur. A high-salt diet may also be useful in some people. If symptoms worsen, an injection of corticosteroid is recommended (people need to carry a dose with them at all times). Often, large amounts of intravenous fluids with the sugar dextrose are also required. With appropriate treatment, the overall outcome is generally favorable, and most people are able to lead a reasonably normal life. Without treatment, an adrenal crisis can result in death. Addison's disease affects about 9 to 14 per 100,000 people in the developed world. It occurs most frequently in middle-aged females. The disease is named after Thomas Addison, a graduate of the University of Edinburgh Medical School, who first described the condition in 1855. == Signs and symptoms == The symptoms of Addison's disease can develop over several months and resemble other medical conditions. Most common symptoms are caused by low levels of hormones that would normally be produced by the adrenal glands. Low blood cortisol can cause a variety of symptoms, including fatigue, malaise, muscle and joint pain, reduced appetite, weight loss, and increased sensitivity to cold. Gastrointestinal symptoms such as nausea, abdominal pain, and vomiting are particularly common. Low aldosterone can cause affected people to crave salty foods, as well as develop low blood pressure that leads to dizziness upon standing. In women, low dehydroepiandrosterone (DHEA) can result in dry and itchy skin, loss of armpit and pubic hair, and reduced sexual drive. Young children with Addison's disease may have insufficient weight gain and recurrent infections. Low cortisol also interferes with adrenocorticotropic hormone (ACTH) regulation, sometimes resulting in the darkening of the skin and mucous membranes, particularly in areas exposed to sun or regular friction. Blood tests in people with Addison's disease often reveal low blood sodium. Many also have high blood potassium and/or high thyroid-stimulating hormone (TSH). Most people with Addison's disease develop or have a preexisting autoimmune disease. Particularly common comorbid conditions are autoimmune thyroid disease (40% of people with Addison's), premature ovarian failure (up to 16% of people with Addison's), type 1 diabetes (11%), pernicious anemia (10%), vitiligo (6%) and celiac disease (2%). The combination of Addison's disease in addition to mucocutaneous candidiasis, hypoparathyroidism, or both, is called autoimmune polyendocrine syndrome type 1. The presence of Addison's in addition to autoimmune thyroid disease, type 1 diabetes, or both, is called autoimmune polyendocrine syndrome type 2. === Adrenal crisis === An "adrenal crisis" or "Addisonian crisis" is a constellation of symptoms that indicates severe adrenal insufficiency. This may be the result of either previously undiagnosed Addison's disease, a disease process suddenly affecting adrenal function (such as adrenal hemorrhage), or an intercurrent problem (e.g., infection, trauma) in someone known to have Addison's disease. It is a medical emergency and potentially life-threatening situation requiring immediate emergency treatment. Characteristic symptoms are: Sudden penetrating pain in the legs, lower back, or abdomen Severe vomiting and diarrhea, resulting in dehydration Low blood pressure Syncope (loss of consciousness and ability to stand) Hypoglycemia (reduced level of blood glucose) Confusion, psychosis, slurred speech Severe lethargy Hyponatremia (low sodium level in the blood) Hyperkalemia (elevated potassium level in the blood) Hypercalcemia (elevated calcium level in the blood) Convulsions Fever == Causes == Causes of adrenal insufficiency can be categorized by the mechanism through which they cause the adrenal glands to produce insufficient cortisol. This can be due to damage or destruction of the adrenal cortex. These deficiencies include glucocorticoid and mineralocorticoid hormones as well. These are adrenal dysgenesis (the gland has not formed adequately during development), impaired steroidogenesis (the gland is present but is biochemically unable to produce cortisol), or adrenal destruction (disease processes leading to glandular damage). Darkening (hyperpigmentation) of the skin, including areas not exposed to the sun – characteristic sites of darkening are skin creases (e.g., of the hands), nipple, and the inside of the cheek (buccal mucosa); also, old scars may darken. This occurs because melanocyte-stimulating hormone (MSH) and ACTH share the same precursor molecule, pro-opiomelanocortin (POMC). After production in the anterior pituitary gland, POMC gets cleaved into gamma-MSH, ACTH, and beta-lipotropin. The subunit ACTH undergoes further cleavage to produce alpha-MSH, the most important MSH for skin pigmentation. In secondary and tertiary forms of adrenal insufficiency, skin darkening does not occur, as ACTH is not overproduced. === Adrenal destruction === Autoimmune adrenalitis is the most common cause of Addison's disease in the industrialized world as it represents between 68% and 94% of cases. Autoimmune destruction of the adrenal cortex is caused by an immune reaction against the enzyme 21-hydroxylase (a phenomenon first described in 1992). This may be isolated or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2), in which other hormone-producing organs, such as the thyroid and pancreas, may also be affected. Adrenal destruction is also a feature of adrenoleukodystrophy, and when the adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body, especially lung), hemorrhage (e.g., in Waterhouse–Friderichsen syndrome or antiphospholipid syndrome), particular infections (tuberculosis, histoplasmosis, coccidioidomycosis), or the deposition of abnormal protein in amyloidosis. === Adrenal dysgenesis === All causes in this category are genetic, and generally very rare. These include mutations to the SF1 transcription factor, congenital adrenal hypoplasia due to DAX-1 gene mutations and mutations to the ACTH receptor gene (or related genes, such as in the Triple-A or Allgrove syndrome). DAX-1 mutations may cluster in a syndrome with glycerol kinase deficiency with a number of other symptoms when DAX-1 is deleted together with a number of other genes. === Impaired steroidogenesis === To form cortisol, the adrenal gland requires cholesterol, which is then converted biochemically into steroid hormones. Interruptions in the delivery of cholesterol include Smith–Lemli–Opitz syndrome and abetalipoproteinemia. Of the synthesis problems, congenital adrenal hyperplasia is the most common (in various forms: 21-hydroxylase, 17α-hydroxylase, 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase), lipoid CAH due to deficiency of StAR and mitochondrial DNA mutations. Some medications interfere with steroid synthesis enzymes (e.g., ketoconazole), while others accelerate the normal breakdown of hormones by the liver (e.g., rifampicin, phenytoin). == Diagnosis == === Suggestive features === Routine laboratory investigations may show: Low blood sugar (worse in children due to loss of glucocorticoid's glucogenic effects) Low blood sodium, due to loss of production of the hormone aldosterone, to the kidney's inability to excrete free water in the absence of sufficient cortisol, and also the effect of corticotropin-releasing hormone to stimulate secretion of ADH. High blood potassium, due to loss of production of the hormone aldosterone. Eosinophilia and lymphocytosis (increased number of eosinophils or lymphocytes, two types of white blood cells) Metabolic acidosis (increased blood acidity), also is due to loss of the hormone aldosterone because sodium reabsorption in the distal tubule is linked with acid/hydrogen ion (H+) secretion. Absent or insufficient levels of aldosterone stimulation of the renal distal tubule lead to sodium wasting in the urine and H+ retention in the serum. === Testing === In suspected cases of Addison's disease, demonstration of low adrenal hormone levels even after appropriate stimulation (called the ACTH stimulation test or synacthen test) with synthetic pituitary ACTH hormone tetracosactide is needed for the diagnosis. Two tests are performed, the short and the long test. Dexamethasone does not cross-react with the assay and can be administered concomitantly during testing. The short test compares blood cortisol levels before and after 250 micrograms of tetracosactide (intramuscular or intravenous) is given. If one hour later, plasma cortisol exceeds 170 nmol/L and has risen by at least 330 nmol/L to at least 690 nmol/L, adrenal failure is excluded. If the short test is abnormal, the long test is used to differentiate between primary adrenal insufficiency and secondary adrenocortical insufficiency. The long test uses 1 mg tetracosactide (intramuscular). Blood is taken 1, 4, 8, and 24 hours later. Normal plasma cortisol level should reach 1,000 nmol/L by 4 hours. In primary Addison's disease, the cortisol level is reduced at all stages, whereas in secondary corticoadrenal insufficiency, a delayed but normal response is seen. Other tests may be performed to distinguish between various causes of hypoadrenalism, including renin and adrenocorticotropic hormone levels, as well as medical imaging – usually in the form of ultrasound, computed tomography or magnetic resonance imaging. Adrenoleukodystrophy, and the milder form, adrenomyeloneuropathy, cause adrenal insufficiency combined with neurological symptoms. These diseases are estimated to be the cause of adrenal insufficiency in about 35% of diagnosed males with idiopathic Addison's disease and should be considered in the differential diagnosis of any male with adrenal insufficiency. Diagnosis is made by a blood test to detect very long-chain fatty acids. == Treatment == === Maintenance === Treatment for Addison's disease involves replacing the missing cortisol, sometimes in the form of hydrocortisone tablets, or prednisone tablets in a dosing regimen that mimics the physiological concentrations of cortisol. Alternatively, one-quarter as much prednisolone may be used for equal glucocorticoid effect as hydrocortisone. Treatment is usually lifelong. In addition, many people require fludrocortisone as a replacement for the missing aldosterone. People with Addison's are often advised to carry information on them (e.g., in the form of a MedicAlert bracelet or information card) for the attention of emergency medical services personnel who might need to attend to their needs. A needle, syringe, and injectable form of cortisol are also recommended to be carried for emergencies. People with Addison's disease are advised to increase their medication during periods of illness or when undergoing surgery or dental treatment. Immediate medical attention is needed when severe infections, vomiting, or diarrhea occur, as these conditions can precipitate an Addisonian crisis. A person who is vomiting may require injections of hydrocortisone, instead. Those with low aldosterone levels may also benefit from a high-sodium diet. It may also be beneficial for the people with Addison's disease to increase their dietary intake of calcium and vitamin D. High dosages of corticosteroids are linked to osteoporosis so these may be necessary for bone health. Sources of calcium include dairy products, leafy greens, and fortified flours among many others. Vitamin D can be obtained through the sun, oily fish, red meat, and egg yolks among many others. Though there are many sources to obtain vitamin D through diet, supplements are also an option. === Crisis === Standard therapy involves intravenous injections of glucocorticoids and large volumes of intravenous saline solution with dextrose (glucose). This treatment usually brings rapid improvement. If intravenous access is not immediately available, intramuscular injection of glucocorticoids can be used. When the person is capable of swallowing fluids and medications by mouth, the amount of glucocorticoids is decreased until a maintenance dose is reached. If aldosterone is deficient, maintenance therapy also includes oral doses of fludrocortisone acetate. == Prognosis == Outcomes are typically good when treated. Most people can expect to live relatively normal lives. Someone with the disease should be observant of symptoms of an "Addison's crisis" while the body is strained, as in rigorous exercise or being sick, the latter often needing emergency treatment with intravenous injections to treat the crisis. Individuals with Addison's disease have more than a doubled mortality rate. Furthermore, individuals with Addison's disease and diabetes mellitus have an almost four-fold increase in mortality compared to individuals with only diabetes. The risk ratio for cause mortality in males and females is 2.19 and 2.86, respectively. Death for individuals with Addison's disease often occurs due to cardiovascular disease, infectious disease, and malignant tumors, among other possibilities. Recent studies indicate that individuals with Addison’s disease may have an increased risk of osteoporotic fractures and higher rates of work loss, including sick leave and disability pension. == Epidemiology == The frequency rate of Addison's disease in the human population is sometimes estimated at one in 100,000. Some put the number closer to 40–144 cases per million population (1/25,000–1/7,000). Addison's can affect persons of any age, sex, or ethnicity, but it typically presents in adults between 30 and 50 years of age. Research has shown no significant predispositions based on ethnicity. About 70% of Addison's disease diagnoses occur due to autoimmune reactions, which cause damage to the adrenal cortex. == History == Addison's disease is named after Thomas Addison, the British physician who first described the condition in On the Constitutional and Local Effects of Disease of the Suprarenal Capsules (1855). He originally described it as "melasma suprarenale", but later physicians gave it the medical eponym "Addison's disease" in recognition of Addison's discovery. While the six patients examined by Addison in 1855 all had adrenal tuberculosis, the term "Addison's disease" does not imply an underlying disease process. The condition was initially considered a form of anemia associated with the adrenal glands. Because little was known at the time about the adrenal glands (then called "Supra-Renal Capsules"), Addison's monograph describing the condition was an isolated insight. As the adrenal function became better known, Addison's monograph became known as an important medical contribution and a classic example of careful medical observation. Tuberculosis used to be a major cause of Addison's disease and acute adrenal failure worldwide. It remains a leading cause in developing countries today. US president John F. Kennedy (1917–1963) suffered from complications of Addison's disease throughout his life, including during his presidency, resulting in fatigue and hyperpigmentation of the face. He is possibly the most famous known case. == Other animals == Hypoadrenocorticism is uncommon in dogs, and rare in cats, with less than 40 known feline cases worldwide, since first documented in 1983. Individual cases have been reported in a grey seal, a red panda, a flying fox, and a sloth. In dogs, hypoadrenocorticism has been diagnosed in many breeds. Vague symptoms, which wax and wane, can cause delay in recognition of the presence of the disease. Female dogs appear more affected than male dogs, though this may not be the case in all breeds. The disease is most often diagnosed in dogs that are young to middle-aged, but it can occur at any age from 4 months to 14 years. Treatment of hypoadrenocorticism must replace the hormones (cortisol and aldosterone) which the dog cannot produce itself. This is achieved either by daily treatment with fludrocortisone, or monthly injections with desoxycorticosterone pivalate (DOCP) and daily treatment with a glucocorticoid, such as prednisone. Several follow-up blood tests are required so the dose can be adjusted until the dog is receiving the correct amount of treatment, because the medications used in the therapy of hypoadrenocorticism can cause excessive thirst and urination if not prescribed at the lowest effective dose. In anticipation of stressful situations, such as staying in a boarding kennel, dogs require an increased dose of prednisone. Lifelong treatment is required, but the prognosis for dogs with hypoadrenocorticism is very good. Michigan State University has conducted a study that explores the process of getting to the lowest effective dose safely. This must be done slowly overtime, so that crisis does not occur. Medications should never be suddenly stopped, as this will cause severe medical issues quickly. Hypoadrenocorticism can also occur in cats but is extremely rare. It is usually caused by an immune reaction, resulting in adrenal insufficiency. An ACTH stimulation test is used to diagnosis the condition. == References == == External links ==	Wikipedia/Addison's_disease
C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via C1q. CRP is synthesized by the liver in response to factors released by macrophages, T cells and fat cells (adipocytes). It is a member of the pentraxin family of proteins. It is not related to C-peptide (insulin) or protein C (blood coagulation). C-reactive protein was the first pattern recognition receptor (PRR) to be identified. == History and etymology == Discovered by Tillett and Francis in 1930, it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including cancer. The later discovery of hepatic synthesis (made in the liver) demonstrated that it is a native protein. Initially, CRP was measured using the quellung reaction which gave a positive or a negative result. More precise methods nowadays use dynamic light scattering after reaction with CRP-specific antibodies. CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the cell wall polysaccharide (C-polysaccharide) of pneumococcus. == Genetics and structure == It is a member of the small pentraxins family (also known as short pentraxins). The polypeptide encoded by this gene has 224 amino acids. The full-length polypeptide is not present in the body in significant quantities due to signal peptide, which is removed by signal peptidase before translation is completed. The complete protein, composed of five monomers, has a total mass of approximately 120,000 Da. In serum, it assembles into stable pentameric structure with a discoid shape. == Function == CRP binds to the phosphocholine expressed on the surface of bacterial cells such as pneumococcus bacteria. This activates the complement system, promoting phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria. With this mechanism, CRP also binds to ischemic/hypoxic cells, which could regenerate with more time. However, the binding of CRP causes them to be disposed of prematurely. CRP binds to the Fc-gamma receptor IIa, to which IgG isotype antibodies also bind. In addition, CRP activates the classical complement pathway via C1q binding. CRP thus forms immune complexes in the same way as IgG antibodies. This so-called acute phase response occurs as a result of increasing concentrations of interleukin-6 (IL-6), which is produced by macrophages as well as adipocytes in response to a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury and necrosis. These conditions cause release of IL-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver. CRP binds to phosphocholine on micro-organisms. It is thought to assist in complement binding to foreign and damaged cells and enhances phagocytosis by macrophages (opsonin-mediated phagocytosis), which express a receptor for CRP. It plays a role in innate immunity as an early defense system against infections. == Serum levels == === Measurement methods === Traditional CRP measurement only detected CRP in the range of 10 to 1,000 mg/L, whereas high sensitivity CRP (hs-CRP) detects CRP in the range of 0.5 to 10 mg/L. hs-CRP can detect cardiovascular disease risk when in excess of 3 mg/L, whereas below 1 mg/L would be low risk. Traditional CRP measurement is faster and less costly than hs-CRP, and can be adequate for some applications, such as monitoring hemodialysis patients. Current immunoassay methods for CRP have similar precision to hsCRP performed by nephelometry and could probably replace hsCRP for cardiovascular risk assessment, however, in the United States this would represent off-label use, making it a laboratory-developed test under FDA regulations. === Normal === In healthy adults, the normal concentrations of CRP varies between 0.8 mg/L and 3.0 mg/L. However, some healthy adults show elevated CRP at 10 mg/L. CRP concentrations also increase with age, possibly due to subclinical conditions. There are also no seasonal variations of CRP concentrations. Gene polymorphism of interleukin-1 family, interleukin 6, and polymorphic GT repeat of the CRP gene do affect the usual CRP concentrations when a person does not have any medical illnesses. === Acute inflammation === When there is a stimulus, the CRP level can increase 10,000-fold from less than 50 μg/L to more than 500 mg/L. Its concentration can increase to 5 mg/L by 6 hours and peak at 48 hours. The plasma half-life of CRP is 19 hours, and is constant in all medical conditions. Therefore, the only factor that affects the blood CRP concentration is its production rate, which increases with inflammation, infection, trauma, necrosis, malignancy, and allergic reactions. Other inflammatory mediators that can increase CRP are TGF beta 1, and tumor necrosis factor alpha. In acute inflammation, CRP can increase as much as 50 to 100 mg/L within 4 to 6 hours in mild to moderate inflammation or an insult such as skin infection, cystitis, or bronchitis. It can double every 8 hours and reaches its peak at 36 to 50 hours following injury or inflammation. CRP between 100 and 500 mg/L is considered highly predictive of inflammation due to bacterial infection. Once inflammation subsides, CRP level falls quickly because of its relatively short half-life. === Metabolic inflammation === CRP concentrations between 2 and 10 mg/L are considered as metabolic inflammation: metabolic pathways that cause arteriosclerosis and type II diabetes mellitus. == Clinical significance == === Diagnostic use === CRP is used mainly as an inflammation marker. Apart from liver failure, there are few known factors that interfere with CRP production. Interferon alpha inhibits CRP production from liver cells which may explain the relatively low levels of CRP found during viral infections compared to bacterial infections Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. ELISA and radial immunodiffusion methods are available for research use, while immunoturbidimetry is used clinically for CRP and nephelometry is typically used for hsCRP. Cutoffs for cardiovascular risk assessment have included: low: hs-CRP level under 1.0 mg/L average: between 1.0 and 3.0 mg/L high: above 3.0 mg/L Normal levels increase with aging. Higher levels are found in late pregnant women, mild inflammation and viral infections (10–40 mg/L), active inflammation, bacterial infection (40–200 mg/L), severe bacterial infections and burns (>200 mg/L). CRP cut-off levels indicating bacterial from non-bacterial illness can vary due to co-morbidities such as malaria, HIV and malnutrition and the stage of disease presentation. In patients presenting to the emergency department with suspected sepsis, a CRP/albumin ratio of less than 32 has a negative predictive value of 89% for ruling out sepsis. CRP is a more sensitive and accurate reflection of the acute phase response than the ESR (erythrocyte sedimentation rate). ESR may be normal while CRP is elevated. CRP returns to normal more quickly than ESR in response to therapy. === Cardiovascular disease === Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of diabetes, hypertension and cardiovascular disease. A study of over 700 nurses showed that those in the highest quartile of trans fat consumption had blood levels of CRP that were 73% higher than those in the lowest quartile. Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease, this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time, which may have attenuated the association between CRP and future outcomes. Others have shown that CRP can exacerbate ischemic necrosis in a complement-dependent fashion and that CRP inhibition can be a safe and effective therapy for myocardial and cerebral infarcts; this has been demonstrated in animal models and humans. It has been hypothesized that patients with high CRP levels might benefit from use of statins. This is based on the JUPITER trial that found that elevated CRP levels without hyperlipidemia benefited. Statins were selected because they have been proven to reduce levels of CRP. Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins. A subsequent trial however failed to find that CRP was useful for determining statin benefit. In a meta-analysis of 20 studies involving 1,466 patients with coronary artery disease, CRP levels were found to be reduced after exercise interventions. Among those studies, higher CRP concentrations or poorer lipid profiles before beginning exercise were associated with greater reductions in CRP. To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP. A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets. === Coronary heart disease risk === Arterial damage results from white blood cell invasion and inflammation within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very specific prognostic indicator. Nevertheless, a level above 2.4 mg/L has been associated with a doubled risk of a coronary event compared to levels below 1 mg/L; however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear. Currently, C-reactive protein is not recommended as a cardiovascular disease screening test for average-risk adults without symptoms. The American Heart Association and U.S. Centers for Disease Control and Prevention have defined risk groups as follows: Low Risk: less than 1.0 mg/L Average risk: 1.0 to 3.0 mg/L High risk: above 3.0 mg/L But hs-CRP is not to be used alone and should be combined with elevated levels of cholesterol, LDL-C, triglycerides, and glucose level. Smoking, hypertension and diabetes also increase the risk level of cardiovascular disease. === Fibrosis and inflammation === Scleroderma, polymyositis, and dermatomyositis elicit little or no CRP response. CRP levels also tend to remain low despite inflammatory activity in systemic lupus erythematosus (SLE) unless serositis or synovitis is present. This may be explained by increased levels of type I IFN in SLE, since type I IFN (i.e IFN alpha) inhibits hepatic CRP production. A polymorphisms of the CRP gene which cause lower CRP levels is also more frequent in SLE patients compared with controls. Elevations of CRP in the absence of clinically significant inflammation can occur in kidney failure. CRP level is an independent risk factor for atherosclerotic disease. Patients with high CRP concentrations are more likely to develop stroke, myocardial infarction, and severe peripheral vascular disease. Elevated level of CRP can also be observed in inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. High levels of CRP has been associated to point mutation Cys130Arg in the APOE gene, coding for apolipoprotein E, establishing a link between lipid values and inflammatory markers modulation. === Cancer === The role of inflammation in cancer is not well understood. Some organs of the body show greater risk of cancer when they are chronically inflamed. While there is an association between increased levels of C-reactive protein and risk of developing cancer, there is no association between genetic polymorphisms influencing circulating levels of CRP and cancer risk. In a 2004 prospective cohort study on colon cancer risk associated with CRP levels, people with colon cancer had higher average CRP concentrations than people without colon cancer. It can be noted that the average CRP levels in both groups were well within the range of CRP levels usually found in healthy people. However, these findings may suggest that low inflammation level can be associated with a lower risk of colon cancer, concurring with previous studies that indicate anti-inflammatory drugs could lower colon cancer risk. === Obstructive sleep apnea === C-reactive protein (CRP), a marker of systemic inflammation, is also increased in obstructive sleep apnea (OSA). CRP and interleukin-6 (IL-6) levels were significantly higher in patients with OSA compared to obese control subjects. Patients with OSA have higher plasma CRP concentrations that increased corresponding to the severity of their apnea-hypopnea index score. Treatment of OSA with CPAP (continuous positive airway pressure) significantly alleviated the effect of OSA on CRP and IL-6 levels. === Rheumatoid arthritis === In the context of rheumatoid arthritis (RA), CRP is one of the acute phase reactants, whose assessment is defined as part of the joint 2010 ACR/EULAR classification criteria for RA with abnormal levels accounting for a single point within the criteria. Higher levels of CRP are associated with more severe disease and a higher likelihood of radiographic progression. Rheumatoid arthritis associated antibodies together with 14-3-3η YWHAH have been reported to complement CRP in predicting clinical and radiographic outcomes in patients with recent onset inflammatory polyarthritis. Elevated levels of CRP appear to be associated with common comorbidities including cardiovascular disease, metabolic syndrome, diabetes and interstitial lung (pulmonary) disease. Mechanistically, CRP also appears to influence osteoclast activity leading to bone resorption and also stimulates RANKL expression in peripheral blood monocytes. It has previously been speculated that single-nucleotide polymorphisms in the CRP gene may affect clinical decision-making based on CRP in rheumatoid arthritis, e.g. DAS28 (Disease Activity Score 28 joints). A recent study showed that CRP genotype and haplotype were only marginally associated with serum CRP levels and without any association to the DAS28 score. Thus, that DAS28, which is the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants. === Viral infections === Increased blood CRP levels were higher in people with avian flu H7N9 compared to those with H1N1 (more common) influenza, with a review reporting that severe H1N1 influenza had elevated CRP. In 2020, people infected with COVID-19 in Wuhan, China, had elevated CRP. == Additional images == == References == == External links == MedlinePlus Encyclopedia: C-reactive protein Inflammation, Heart Disease and Stroke: The Role of C-Reactive Protein (American Heart Association) C-Reactive+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH) CRP: analyte monograph - The Association for Clinical Biochemistry and Laboratory Medicine George Vrousgos, N.D. - Southern Cross University Archived 2020-02-18 at the Wayback Machine Human CRP genome location and CRP gene details page in the UCSC Genome Browser. Overview of all the structural information available in the PDB for UniProt: P02741 (C-reactive protein) at the PDBe-KB.	Wikipedia/C-Reactive_Protein
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine, as well as the mouth, esophagus, stomach and the anus, whereas UC primarily affects the colon and the rectum. == Signs and symptoms == In spite of Crohn's and UC being very different diseases, both may present with any of the following symptoms: abdominal pain, diarrhea, rectal bleeding, severe internal cramps/muscle spasms in the region of the pelvis and weight loss. Anemia is the most prevalent extraintestinal complication of inflammatory bowel disease (IBD). Associated complaints or diseases include arthritis, pyoderma gangrenosum, primary sclerosing cholangitis, and non-thyroidal illness syndrome (NTIS). Associations with deep vein thrombosis (DVT) and bronchiolitis obliterans organizing pneumonia (BOOP) have also been reported. Diagnosis is generally by assessment of inflammatory markers in stool followed by colonoscopy with biopsy of pathological lesions. == Causes == IBD is a complex disease which arises as a result of the interaction of environmental and genetic factors leading to immunological responses and inflammation in the intestine. === Diet === People living with IBD are very interested in diet, but little is known about the impact of diet on these patients. Recent reviews underlined the important role of nutritional counselling in IBD patients. Patients should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. A 2022 study found that diets with increased intake of fruits and vegetables, reduction of processed meats and refined carbohydrates, and preference of water for hydration were associated with lower risk of active symptoms with IBD, although increased intake of fruits and vegetables alone did not reduce risk of symptoms with Crohn's disease. A 2022 scientific review also found generally positive outcomes for IBD patients who adhered to the Mediterranean diet (high fruit and vegetable intake). Dietary patterns are associated with a risk for ulcerative colitis. In particular, subjects who were in the highest tertile of the healthy dietary pattern had a 79% lower risk of ulcerative colitis. Gluten sensitivity is common in IBD and associated with having flareups. Gluten sensitivity was reported in 23.6% and 27.3% of Crohn's disease and ulcerative colitis patients, respectively. A diet high in protein, particularly animal protein, and/or high in sugar may be associated with increased risk of IBD and relapses. === Bile acids === Emerging evidence indicates that bile acids are important etiological agents in IBD pathogenesis. IBD patients have a consistent pattern of an increased abundance of primary bile acids such as cholic acid and chenodeoxycholic acid (and their conjugated forms), and a decreased abundance of secondary bile acids such as lithocholic acid and deoxycholic acid. === Microbiota === The human microbiota consists of 10–100 trillion microorganisms. Several studies have confirmed that the microbiota composition is different in patients with IBD compared to healthy individuals. This difference is more pronounced in patients with Crohn's disease than in those with ulcerative colitis. In IBD patients, there is a decrease or absence of beneficial bacteria such as Bifidobacterium longum, Eubacterium rectale, Faecalibacterium prausnitzii, and Roseburia intestinalis, while harmful species like Bacteroides fragilis, Ruminococcus torques, and Ruminococcus are more abundant. The activation of reactive oxygen species and reactive nitrogen species leads to oxidative stress for both host cells and the gut microbiome. Consequently, in IBD, there is a microbial imbalance, known as dysbiosis, characterized by an increase in functional pathways involved in the microbial response to oxidative stress. This oxidative stress can promote the growth of certain species such as R. gnavus. Another opportunistic bacterium called A. muciniphila contributes to IBD development and is more prevalent in individuals lacking NOD-like receptor 6 (NLRP6). Both R. gnavus and A. muciniphila are bacterial species that are more abundant in IBD. Patients with IBD often exhibit stronger antibody and T-cell responses to microbial antigens. The gut microbiome employs various approaches to interact with the host immune system. For instance, B. fragilis, which is symbiotic in humans, can transfer immune regulatory molecules to immune cells through the secretion of outer membrane vesicles. This mechanism plays a protective role in IBD by activating the non-classical autophagy pathway, dependent on Atg16L1 and NOD2 genes. B. thetaiotaomicron induces the differentiation of T regulatory cells (Tregs) to modulate gut immunity, thus increasing the expression of Gata3 and FoxP3 genes. The colonization of Clostridium spp. can enhance the aggregation of RORγT+ FOXP3 Treg cells, which inhibit the development of Th2 and Th17 cells. Ultimately, this colonization could decrease the response of colonic Th2 and Th17 cells. Also F. prausnitzii attracts CD4 and CD8a (DP8α) regulatory T cells. E. coli Nissle 1917 has the capability to inhibit the growth of Salmonella and other harmful bacteria. It prevents these pathogens from adhering to and invading intestinal epithelial cells, which significantly reduces the likelihood of inflammation in the gut and may also prevent the onset of IBD. === Breach of intestinal barrier === Loss of integrity of the intestinal epithelium plays a key pathogenic role in IBD. Dysfunction of the innate immune system as a result of abnormal signaling through immune receptors called toll-like receptors (TLRs)—which activates an immune response to molecules that are broadly shared by multiple pathogens—contributes to acute and chronic inflammatory processes in IBD colitis and associated cancer. Changes in the composition of the intestinal microbiota are an important environmental factor in the development of IBD. Detrimental changes in the intestinal microbiota induce an inappropriate (uncontrolled) immune response that results in damage to the intestinal epithelium. Breaches in this critical barrier (the intestinal epithelium) allow further infiltration of microbiota that, in turn, elicit further immune responses. IBD is a multifactorial disease that is nonetheless driven in part by an exaggerated immune response to gut microbiota that causes defects in epithelial barrier function. === Oxidative stress and DNA damage === Oxidative stress and DNA damage likely have a role in the pathophysiology of IBD. Oxidative DNA damage as measured by 8-OHdG levels was found to be significantly increased in people with IBD compared to healthy controls, and in inflamed mucosa compared with noninflamed mucosa. Antioxidant capacity as measured by the total action of all antioxidants detected in blood plasma or body fluids was found to be significantly decreased in people with IBD compared to healthy controls, and in inflamed mucosa compared with noninflamed mucosa. == Genetics == A genetic component to IBD has been recognized for over a century. Research that has contributed to understanding of the genetics include studies of ethnic groups (e.g., Ashkenazi Jews, Irish), familial clustering, epidemiological studies, and twin studies. With the advent of molecular genetics, understanding of the genetic basis has expanded considerably, particularly in the past decade. The first gene linked to IBD was NOD2 in 2001. Genome-wide association studies have since added to understanding of the genomics and pathogenesis of the disease. More than 200 single nucleotide polymorphisms (SNPs or "snips") are now known to be associated with susceptibility to IBD. One of the largest genetic studies of IBD was published in 2012. The analysis explained more of the variance in Crohn's disease and ulcerative colitis than previously reported. The results suggested that commensal microbiota are altered in such a way that they act as pathogens in inflammatory bowel diseases. Other studies show that mutations in IBD-associated genes might interfere with the cellular activity and interactions with the microbiome that promote normal immune responses. Many studies identified that microRNAs dysregulation involved in IBD and to promote colorectal cancer. By 2020, single-cell RNA sequencing analysis was launched by a small consortium using IBD patient biopsy material in a search for therapeutic targets. According to an article published on Nature, ETS2 gene plays a vital role in the development of the disease. == Diagnosis == The diagnosis is usually confirmed by biopsies on colonoscopy. Fecal calprotectin is useful as an initial investigation, which may suggest the possibility of IBD, as this test is sensitive but not specific for IBD. === Classification === Inflammatory bowel diseases are autoimmune diseases, in which the body's own immune system attacks elements of the digestive system. The chief types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Several other conditions are variously referred to either as being inflammatory bowel diseases or as being similar to but distinct from inflammatory bowel diseases. These conditions include: Microscopic colitis with subtypes Collagenous colitis Lymphocytic colitis Diversion colitis Behçet's disease === Differential diagnosis === Crohn's disease and ulcerative colitis are both common differential diagnoses for the other, and confidently diagnosing a patient with one of the two diseases may sometimes not be possible. No disease specific markers are currently known in the blood that would enable the reliable separation of patients with Crohn's disease and ulcerative colitis. Physicians tell the difference between Crohn's disease and UC by the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the full thickness of the bowel wall ("transmural lesions"). Lastly, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions. In 10–15% of cases, a definitive diagnosis neither of Crohn's disease nor of ulcerative colitis can be made because of idiosyncrasies in the presentation. In these cases, a diagnosis of indeterminate colitis may be made. Irritable bowel syndrome can present with similar symptoms as either disease, as can nonsteroidal anti-inflammatory drug (NSAID) enteritis and intestinal tuberculosis. Conditions that can be mistaken particularly for Crohn's disease include Behçet's disease and coeliac disease, while conditions that can be symptomatically similar to ulcerative colitis in particular include acute self-limiting colitis, amebic colitis, schistosomiasis and colon cancer. Other diseases may cause an increased excretion of fecal calprotectin, such as infectious diarrhea, untreated celiac disease, necrotizing enterocolitis, intestinal cystic fibrosis and neoplastic pediatric tumor cells. Liver function tests are often elevated in IBD, and are often mild and generally return spontaneously to normal levels. The most relevant mechanisms of elevated liver functions tests in IBD are drug-induced hepatotoxicity and fatty liver. == Treatment == === Surgery === CD and UC are chronic inflammatory diseases, and are not medically curable. However, ulcerative colitis can in most cases be cured by proctocolectomy, although this may not eliminate extra-intestinal symptoms. An ileostomy will collect feces in a bag. Alternatively, a pouch can be created from the small intestine; this serves as the rectum and prevents the need for a permanent ileostomy. Between one-quarter and one-half of patients with ileo-anal pouches do have to manage occasional or chronic pouchitis. Surgery cannot cure Crohn's disease but may be needed to treat complications such as abscesses, strictures or fistulae. Severe cases may require surgery, such as bowel resection, strictureplasty or a temporary or permanent colostomy or ileostomy. In Crohn's disease, surgery involves removing the worst inflamed segments of the intestine and connecting the healthy regions, but unfortunately, it does not cure Crohn's or eliminate the disease. At some point after the first surgery, Crohn's disease can recur in the healthy parts of the intestine, usually at the resection site. (For example, if a patient with Crohn's disease has an ileocecal anastomosis, in which the caecum and terminal ileum are removed and the ileum is joined to the ascending colon, their Crohn's will nearly always flare-up near the anastomosis or in the rest of the ascending colon). === Medical therapies === Medical treatment of IBD is individualised to each patient. The choice of which drugs to use and by which route to administer them (oral, rectal, injection, infusion) depends on factors including the type, distribution, and severity of the patient's disease, as well as other historical and biochemical prognostic factors, and patient preferences. For example, mesalazine is more useful in ulcerative colitis than in Crohn's disease. Generally, depending on the level of severity, IBD may require immunosuppression to control the symptoms, with drugs such as prednisone, tumor necrosis factor inhibitors (TNF inhibitors), azathioprine, methotrexate, or 6-mercaptopurine. Steroids, such as the glucocorticoid prednisone, are frequently used to control disease flares and were once acceptable as a maintenance drug. Biological therapy for inflammatory bowel disease, especially the TNF inhibitors, are used in people with more severe or resistant Crohn's disease and sometimes in ulcerative colitis. Treatment is usually started by administering drugs with high anti-inflammatory effects, such as prednisone. Once the inflammation is successfully controlled, another drug to keep the disease in remission, such as mesalazine in UC, is the main treatment. If further treatment is required, a combination of an immunosuppressive drug (such as azathioprine) with mesalazine (which may also have an anti-inflammatory effect) may be needed, depending on the patient. Controlled release budesonide is used for mild ileal Crohn's disease. === Nutritional and dietetic therapies === Exclusive enteral nutrition is a first-line therapy in pediatric Crohn's disease with weaker data in adults.: 331 Evidence supporting exclusive enteral nutrition in ulcerative colitis is lacking.: 333 Nutritional deficiencies play a prominent role in IBD. Malabsorption, diarrhea, and GI blood loss are common features of IBD. Deficiencies of B vitamins, fat-soluble vitamins, essential fatty acids, and key minerals such as magnesium, zinc, and selenium are extremely common and benefit from replacement therapy. Dietary interventions, including certain exclusion diets like the specific carbohydrate diet (SCD) can be beneficial for symptom management. Dietary fiber interventions, such as psyillium supplementation (a mixture of soluble and insoluble fibers), may relieve symptoms as well as induce/maintain remission by altering the microbiome composition of the GI tract, thereby improving regulation of immune function, reducing inflammation, and helping to restore the intestinal mucosal lining. Low serum levels of alanine transaminase can be a marker of sarcopenia which is underdiagnosed in patients with IBD and associated with a higher disease activity. Anemia is commonly present in both ulcerative colitis and Crohn's disease. Due to raised levels of inflammatory cytokines which lead to the increased expression of hepcidin, parenteral iron is the preferred treatment option as it bypasses the gastrointestinal system, has lower incidence of adverse events and enables quicker treatment. Hepcidin itself is also an anti-inflammatory agent. In the murine model very low levels of iron restrict hepcidin synthesis, worsening the inflammation that is present. Enteral nutrition has been found to be efficient to improve hemoglobin level in patients with IBD, especially combined with erythropoietin. Gastrointestinal bleeding, occurring especially during ulcerative colitis relapse, can contribute to anemia when chronic, and may be life-threatening when acute. To limit the possible risk of dietary intake disturbing hemostasis in acute gastrointestinal bleeding, temporary fasting is often considered necessary in hospital settings. The effectiveness of this approach is unknown; a Cochrane review in 2016 found no published clinical trials including children. Low levels of vitamin D are associated with crohn's disease and ulcerative colitis and people with more severe cases of inflammatory bowel disease often have lower vitamin D levels. It is not clear if vitamin D deficiency causes inflammatory bowel disease or is a symptom of the disease. There is some evidence that vitamin D supplementation therapy may be associated with improvements in scores for clinical inflammatory bowel disease activity and biochemical markers. Vitamin D treatment may be associated with less inflammatory bowel disease reoccurrence of symptoms (relapse). It is not clear if this treatment improves the person's quality of life or what the clinical response to vitamin D treatment. The ideal treatment regime and dose of vitamin D therapy has not been well enough studied. === Microbiome === There is preliminary evidence of an infectious contribution to IBD in some patients that may benefit from antibiotic therapy, such as with rifaximin. The evidence for a benefit of rifaximin is mostly limited to Crohn's disease with less convincing evidence supporting use in ulcerative colitis. The use of oral probiotic supplements to modify the composition and behaviour of the microbiome has been considered as a possible therapy for both induction and maintenance of remission in people with Crohn's disease and ulcerative colitis. A Cochrane review in 2020 did not find clear evidence of improved remission likelihood, nor lower adverse events, in people with Crohn's disease, following probiotic treatment. For ulcerative colitis, there is low-certainty evidence that probiotic supplements may increase the probability of clinical remission. People receiving probiotics were 73% more likely to experience disease remission and over 2x as likely to report improvement in symptoms compared to those receiving a placebo, with no clear difference in minor or serious adverse effects. Although there was no clear evidence of greater remission when probiotic supplements were compared with 5‐aminosalicylic acid treatment as a monotherapy, the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy. Whereas in people who are already in remission, it is unclear whether probiotics help to prevent future relapse, either as a monotherapy or combination therapy. Fecal microbiota transplant is a relatively new treatment option for IBD which has attracted attention since 2010. Some preliminary studies have suggested benefits similar to those in Clostridioides difficile infection but a review of use in IBD shows that FMT is safe, but of variable efficacy. Systematic reviews showed that 33% of ulcerative colitis, and 50% of Crohn's disease patients reach clinical remission after fecal microbiota transplant. === Alternative medicine === Complementary and alternative medicine approaches have been used in inflammatory bowel disorders. Evidence from controlled studies of these therapies has been reviewed; risk of bias was quite heterogeneous. The best supportive evidence was found for herbal therapy, with Plantago ovata and curcumin in UC maintenance therapy, wormwood in CD, mind/body therapy and self-intervention in UC, and acupuncture in UC and CD. === Novel approaches === Stem cell therapy is undergoing research as a possible treatment for IBD. A review of studies suggests a promising role, although there are substantial challenges, including cost and characterization of effects, which limit the current use in clinical practice. === Psychological interventions === Patients with IBD have a higher prevalence of depressive and anxiety disorders compared to the general population, women with IBD are more likely than men to develop affective disorders since up to 65% of them may have depression and anxiety disorder. Currently, there is no evidence to recommend psychological treatment, such as psychotherapy, stress management and patient's education, to all adults with IBD in general. These treatments had no effect on quality of life, emotional well-being and disease activity. The need for these approaches should be individually assessed and further researched to identify subgroups and determine type of therapy that may benefit individuals with IBD. In adolescents population such treatments may be beneficial on quality of life and depression, although only short-term effects have been found, which also imposes the need for further research. A meta analysis of interventions to improve mood (including talking therapy, antidepressants, and exercise) in people with IBD found that they reduced inflammatory markers such as C-reactive protein and faecal calprotectin. Psychological therapies reduced inflammation more than antidepressants or exercise. == Treatment standards == Crohn's and Colitis Australia, the peak body for IBD in Australia, where prevalence is one of the highest in the world, reviewed the quality of care for patients admitted to Australian hospitals. They found that only one hospital met accepted standards for multidisciplinary care, but that care was improved with the availability of even minimal specialised services. == Prognosis == While IBD can limit quality of life because of pain, vomiting, and diarrhea, it is rarely fatal on its own. Fatalities due to complications such as toxic megacolon, bowel perforation and surgical complications are also rare. Fatigue is a common symptom of IBD and can be a burden. Around one-third of individuals with IBD experience persistent gastrointestinal symptoms similar to irritable bowel syndrome (IBS) in the absence of objective evidence of disease activity. Despite enduring the side-effects of long-term therapies, this cohort has a quality of life that is not significantly different to that of individuals with uncontrolled, objectively active disease, and escalation of therapy to biological agents is typically ineffective in resolving their symptoms. The cause of these IBS-like symptoms is unclear, but it has been suggested that changes in the gut-brain axis, epithelial barrier dysfunction, and the gut flora may be partially responsible. While patients of IBD do have an increased risk of colorectal cancer, this is usually caught much earlier than the general population in routine surveillance of the colon by colonoscopy, and therefore patients are much more likely to survive. New evidence suggests that patients with IBD may have an elevated risk of endothelial dysfunction and coronary artery disease. The goal of treatment is toward achieving remission, after which the patient is usually switched to a lighter drug with fewer potential side effects. Every so often, an acute resurgence of the original symptoms may appear; this is known as a "flare-up". Depending on the circumstances, it may go away on its own or require medication. The time between flare-ups may be anywhere from weeks to years, and varies wildly between patients – a few have never experienced a flare-up. Life with IBD can be challenging; however, many with the condition lead relatively normal lives. IBD carries a psychological burden due to stigmatization of being diagnosed, leading to high levels of anxiety, depression, and a general reduction in the quality of life. Although living with IBD can be difficult, there are numerous resources available to help families navigate the ins and out of IBD, such as the Crohn's and Colitis Foundation of America (CCFA). == Epidemiology == IBD resulted in a global total of 51,000 deaths in 2013 and 55,000 deaths in 1990. The increased incidence of IBD since World War II has been correlated to the increase in meat consumption worldwide, supporting the claim that animal protein intake is associated with IBD. However, there are many environmental risk factors that have been linked to the increased and decreased risk of IBD, such as smoking, air pollution and greenspace, urbanization and Westernization. Inflammatory bowel diseases are increasing in Europe. Incidence and prevalence of IBD has risen steadily for the last decades in Asia, which could be related changes in diet and other environmental factors. Around 0.8% of people in the UK have IBD. Similarly, around 270,000 (0.7%) of people in Canada have IBD, with that number expected to rise to 400,000 (1%) by 2030. == Research == The following treatment strategies are not used routinely, but appear promising in some forms of IBD. Initial reports suggest that helminthic therapy may not only prevent but even control IBD: a drink with roughly 2,500 ova of the Trichuris suis helminth taken twice monthly decreased symptoms markedly in many patients. It is even speculated that an effective "immunization" procedure could be developed—by ingesting the cocktail at an early age. Prebiotics and probiotics are focusing increasing interest as treatments for IBD. Currently, there is evidence to support the use of certain probiotics in addition to standard treatments in people with ulcerative colitis but there is no sufficient data to recommend probiotics in people with Crohn's disease. Both single strain and multi-strain probiotics have been researched for mild to moderate cases of ulcerative colitis. The most clinically researched multi-strain probiotic with over 70 human trials is the De Simone Formulation. Further research is required to identify specific probiotic strains or their combinations and prebiotic substances for therapies of intestinal inflammation. Currently, the probiotic strain, frequency, dose and duration of the probiotic therapy are not established. In severely ill people with IBD there is a risk of the passage of viable bacteria from the gastrointestinal tract to the internal organs (bacterial translocation) and subsequent bacteremia, which can cause serious adverse health consequences. Live bacteria might not be essential because of beneficial effects of probiotics seems to be mediated by their DNA and by secreted soluble factors, and their therapeutic effects may be obtained by systemic administration rather than oral administration. In 2005 New Scientist published a joint study by Bristol University and the University of Bath on the apparent healing power of cannabis on IBD. Reports that cannabis eased IBD symptoms indicated the possible existence of cannabinoid receptors in the intestinal lining, which respond to molecules in the plant-derived chemicals. CB1 cannabinoid receptors – which are known to be present in the brain – exist in the endothelial cells which line the gut, it is thought that they are involved in repairing the lining of the gut when damaged. The team deliberately damaged the cells to cause inflammation of the gut lining and then added synthetically produced cannabinoids; the result was that gut started to heal: the broken cells were repaired and brought back closer together to mend the tears. It is believed that in a healthy gut, natural endogenous cannabinoids are released from endothelial cells when they are injured, which then bind to the CB1 receptors. The process appears to set off a wound-healing reaction, and when people use cannabis, the cannabinoids bind to these receptors in the same way. Previous studies have shown that CB1 receptors located on the nerve cells in the gut respond to cannabinoids by slowing gut motility, therefore reducing the painful muscle contractions associated with diarrhea. CB2, another cannabinoid receptor predominantly expressed by immune cells, was detected in the gut of people with IBD at a higher concentration. These receptors, which also respond to chemicals in cannabis, appear to be associated with apoptosis – programmed cell death – and may have a role in suppressing the overactive immune system and reducing inflammation by mopping up excess cells. Activation of the endocannabinoid system was found efficient in ameliorating colitis and increasing the survival rate of mice, and reducing remote organ changes induced by colitis, further suggest that modulation of this system is a potential therapeutic approach for IBDs and the associated remote organ lesions. Alicaforsen is a first generation antisense oligodeoxynucleotide designed to bind specifically to the human ICAM-1 messenger RNA through Watson-Crick base pair interactions in order to subdue expression of ICAM-1. ICAM-1 propagates an inflammatory response promoting the extravasation and activation of leukocytes (white blood cells) into inflamed tissue. Increased expression of ICAM-1 has been observed within the inflamed intestinal mucosa of people with ulcerative colitis, pouchitis and Crohn's, where ICAM-1 over production correlated with disease activity. This suggests that ICAM-1 is a potential therapeutic target in the treatment of these diseases. Cannabinoid CB2 receptor agonists are found to decrease the induction of ICAM-1 and VCAM-1 surface expression in human brain tissues and primary human brain endothelial cells (BMVEC) exposed to various pro-inflammatory mediators. In 2014, an alliance among the Broad Institute, Amgen and Massachusetts General Hospital formed with the intention to "collect and analyze patient DNA samples to identify and further validate genetic targets." In 2015, a meta-analysis on 938 IBD patients and 953 controls, IBD was significantly associated with having higher odds of vitamin D deficiency. Gram-positive bacteria present in the lumen could be associated with extending the time of relapse for ulcerative colitis. Bidirectional pathways between depression and IBD have been suggested and psychological processes have been demonstrated to influence self-perceived physical and psychological health over time. IBD-disease activity may impact quality of life and over time may significantly affect individual's mental well-being, which may be related to the increased risk to develop anxiety and/or depression. On the other hand, psychological distress may also influence IBD activity. Higher rates of anxiety and depression are observed among those with IBD compared to healthy individuals, which correlated with disease severity. Part of this phenotypic correlation is due to a shared genetic overlap between IBD and psychiatric comorbidities. Moreover, anxiety and depression rates increase during active disease compared with inactive phases. Flu vaccines are recommended for people with IBD in the UK; however, research suggests that vaccine uptake is low. Researchers analysed data on 13,631 adults with IBD on immune-suppressing drugs during the 2018 – 2019 flu season. Only half of this population received a vaccine during this period and few (32%) were vaccinated before the flu circulated in the community. This could be due to the belief that flu vaccines cause IBD flares; however, the same study did not find a link between vaccination and IBD flares. == In other species == IBD also occurs in dogs and is thought to arise from a combination of host genetics, intestinal microenvironment, environmental components and the immune system. There is an ongoing discussion, however, that the term "chronic enteropathy" might be better to use than "inflammatory bowel disease" in dogs because it differs from IBD in humans in how the dogs respond to treatment. For example, many dogs respond to only dietary changes compared to humans with IBD, who often need immunosuppressive treatment. Some dogs may also need immunosuppressant or antibiotic treatment when dietary changes are not enough. After having excluded other diseases that can lead to vomiting, diarrhea, and abdominal pain in dogs, intestinal biopsies are often performed to investigate what kind of inflammation is occurring (lymphoplasmacytic, eosinophilic, or granulomatous). In dogs, low levels of cobalamin in the blood have been shown to be a risk factor for negative outcome. == See also == Inflammatory bowel disease-22 World Inflammatory Bowel Disease Day == References == == External links == Media related to Inflammatory bowel diseases at Wikimedia Commons	Wikipedia/Inflammatory_bowel_disease
Autoimmunity refers to a pathological immune response of the body's immune system against itself. Autoimmune disease is widely recognized to be significantly more common in women than in men, and often presents differently between the sexes. The reasons for these disparities are still under investigation, but may in part involve the presence of an additional X chromosome in women (given that several genes on the X chromosome are associated with immune system development), as well as the higher presence of female sex hormones such as estrogen (which increases immune system response). The risk, incidence, and character of autoimmune disease in women may also be associated with female-specific physiological changes, such as hormonal shifts during menses, pregnancy, and menopause. Common autoimmune symptoms experienced by both sexes include rashes, fevers, fatigue, and joint pain. Symptoms which are specific to women include irregular menses, pelvic pain, or vaginal dryness, depending on the given disease. Some diseases such as Graves' disease, rheumatoid arthritis, and multiple sclerosis may improve during pregnancy, whereas others such as lupus may worsen. Currently it is not possible to cure autoimmune disease, but many treatments are available. Treatment of autoimmune disease can be broadly classified into anti-inflammatory, immunosuppressive, and palliative – i.e., correcting a functional disturbance related to the condition. Some medications used to treat autoimmune diseases might not be safe to use during pregnancy. == Common diseases == There are over 100 autoimmune conditions described, of which the majority are more prevalent in women than in men. Approximately 80% of all patients with autoimmune disease are women. Autoimmune diseases which overwhelmingly affect women include those which affect the thyroid gland (Hashimoto's thyroiditis, Graves' disease), rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and Sjögren syndrome), hepatobiliary diseases (primary biliary cholangitis, autoimmune hepatitis), and neurological diseases (myasthenia gravis, neuromyelitis optica spectrum disorders (NMOSD), and multiple sclerosis). For men who may develop these conditions, epidemiological and symptomological differences may still exist. For example, when multiple sclerosis and rheumatoid arthritis do occur in men, they tend to develop later in life for men (around age 30–40) than for women, when incidence rises after puberty. Some autoimmune diseases affect both sexes at roughly equal rates, or have only a slight female predominance. These conditions include inflammatory bowel disease (ulcerative colitis, Crohn's disease), immune thrombocytopenic purpura (ITP), and MOG antibody disease, among others. Although the lifetime incidence of these diseases may be similar, they may still exist a difference in disease onset, course, complications, and prognosis which vary based on sex. For example, men are more likely to develop Crohn's disease in the upper GI tract compared to women. Males and females are equally as likely to be affected by Crohn's disease until around age 25, when women become overrepresented as Crohn's disease patients. Women and men are equally likely to develop ulcerative colitis until age 45, after which this shifts to a significant male predominance. Very few autoimmune diseases are thought to be more common in men than in women. Examples of these may include ankylosing spondylitis, primary sclerosing cholangitis, type 1 diabetes, and certain vasculitides including anti-GBM disease (Goodpasture syndrome) and Behçet's disease (though whether this represents an autoimmune disease vs autoinflammatory disease remains unclear.) On closer inspection, some diseases initially thought to be overrepresented in men have trended towards sex neutrality over time. For example, early studies of ankylosing spondylitis reported a ratio of 10:1 male to female patients, but more recent reports have indicated this is closer to 3:1. This may reflect a true increased incidence in women over time, or may be due to improvements in diagnostic testing. Additionally, sex ratios of affected patients can vary widely between geographic regions. For instance, Crohn's disease is slightly more common in women in Western countries, whereas it is slightly more common in men in Asian countries. Behçet's disease is more common in males in regions along the historic Silk Road, but is more common in women in the United States. This suggests that the risks of developing autoimmune disease are multifactorial, and may vary based on race and environment as well as sex. == Signs and symptoms == Autoimmune diseases can result in systemic or localized symptoms, depending on the given disease. Typical systemic symptoms include fevers, fatigue, muscle aches, joint pain, and rashes; these can be seen in diseases such as lupus or rheumatoid arthritis. Other autoimmune diseases have localized effects on specific organ or tissue types. For instance, alopecia areata presents with patchy baldness due to autoimmune destruction of hair follicles, whereas multiple sclerosis presents with neurological symptoms due to autoimmune demyelination of the central nervous system. Both systemic and localized disease can present with symptoms which are exclusive to women. Women with Sjögren syndrome (an autoimmune disease characterized by destruction and inflammation of the salivary and lacrimal glands) are 2–3 times more likely to report vaginal dryness than other postmenopausal women. == Causes == The causes of autoimmunity are still the subject of extensive research, and include genetic as well as environmental factors. However, the clear overrepresentation of women as persons with autoimmune disease suggests that sex-specific factors are highly instrumental in the development of these conditions. Posited reasons for this disparity include the differential effects of sex hormones (especially estrogen) on immune response, X-chromosome inactivation, changes associated with pregnancy, and evolutionary pressures that affect the sexes differently. Due to biological development, many of these elements are inextricably linked, and it can be difficult to isolate the individual effects of each factor. === X chromosome inactivation === Many genes involved in the immune response reside on the X chromosome, of which most women have two copies, whereas men typically only have one. During cell division in embryological development, one of the two X chromosomes is inactivated at random, in a process called lyonization. This ensures that the expression of X chromosome genes is randomly suppressed on one of the two copies in females in order to compensate for the extra copy of these genes. Incomplete suppression of the extra copies of these genes may lead to overexpression of some genes involved in the immune response resulting in a more robust immune response and an increased risk of developing autoimmune diseases. Additional support for this hypothesis can be illustrated by the higher rates of autoimmune disease in men with Klinefelter syndrome (47,XXY). Like women, males with Klinefelter syndrome also have two copies of the X chromosome, which may predispose them to increased risk of autoimmune disease through the same mechanism. This risk is highest in autoimmune diseases which are female-predominant (e.g., Addison's disease, multiple sclerosis, Sjögren syndrome). With the exception of Type 1 diabetes, which affects both sexes at roughly equal rates, Klinefelter syndrome was not correlated with increased risk of autoimmune diseases which occur in males with greater or equal frequency (e.g., ankylosing spondylitis, psoriasis.) Despite having only one copy of the X chromosome, women with Turner syndrome (45,XO) are still twice as likely as the general female population to develop autoimmune diseases. Interestingly, the autoimmune diseases for which Turner syndrome patients are at greater risk include inflammatory bowel disease, type 1 diabetes, alopecia areata, and several other autoimmune disorders which tend to affect the sexes at roughly equal rates. This suggests that the development of autoimmune disease is not solely mediated by differential expression of genes on the X chromosome. === Sex hormones === Sex hormones are instrumental in nearly every aspect of human biology, including the development and response of the adaptive immune system. Sex hormones such as estrogen, progesterone, and testosterone are all present in healthy men and women, albeit at different levels. Estrogen and progesterone are considered primary female sex hormones, while testosterone is the primary male sex hormone. Broadly speaking, estrogen is understood to be immune-activating, while testosterone is considered to be immune-suppressing. The ideal immune system response must be alert enough to recognize and destroy foreign antigens, while also being selective enough to avoid attacking the self. There exists a necessary trade-off between immune system hyperactivity (autoimmunity) versus hypoactivity (immune deficiency). Since men and women have different levels of these sex hormones, they necessarily incur unequal risk for developing these conditions. Very broadly speaking, men are more predisposed to infectious disease, but are less likely to develop autoimmune disease. Women conversely are at higher risk for developing autoimmune disease, but are more protected from infectious disease than men. Women have a greater number of circulating antibodies than do men, which has implications for their development of autoimmune disease, as well as their increased resistance to infectious disease. ==== Estrogen ==== Estrogen has significant effects on the response of the adaptive immune system. Higher levels of estrogen are correlated with higher levels of circulating antibodies, which are responsible for mounting an immune response. In addition to short-term changes, the immune system may also be influenced by longer-term changes, such as total lifetime exposure. The course of disease may also be related to hormonal fluctuations, especially those of puberty, pregnancy, and menopause. ==== Testosterone ==== The immunocompetence handicap hypothesis proposes that testosterone may have utility as a secondary sexual characteristic which signals fitness to prospective mates. As males have higher levels of testosterone, which suppresses immune system activity, signaling fitness in spite of this handicap is a demonstration of mate quality in spite of this handicap. Additional proof-of-concept can be demonstrated through testosterone supplementation. Men with Klinefelter syndrome (47,XXY) naturally make very little testosterone; androgen supplementation has been shown to decrease serum levels of all immunoglobulins in these men. === Pregnancy === Pregnancy has both short- and long-term effects on the immune system, and these changes may persist even after the completion of pregnancy. These effects on the course of autoimmune diseases vary widely, and are dependent on the specific disease, as well as the individual patient. Conditions such as rheumatoid arthritis often improve over the course of pregnancy, especially in the second and third trimesters; however, women often relapse within three months of giving birth. Other conditions, such as lupus, often become much worse over the course of pregnancy. During pregnancy, the hormone estrogen spikes; additionally, hormonal fluctuations may continue long after childbirth. These changes could trigger, improve or even worsen an autoimmune disease. In addition to estrogen, other hormones like progesterone and prolactin may trigger these illnesses. The mother's immune system tends to be suppressed during pregnancy, to prevent fetal rejection from foreign antibodies in the fetus. As stated before, pregnancy causes an increase of estrogen in the female body. The increase of this hormone weakens the functioning of immune cells, thus debilitating the mother's immune system. In addition, it is possible that fetal cells continue to circulate in the mother's body for years after childbirth, making it a possible trigger for autoimmune disease. == Diagnosis == Diagnosis of autoimmune disease is based upon clinical and laboratory evidence. In order to diagnose autoimmune disease, typical symptoms of a given disorder must be present, along with laboratory evidence of autoantibodies. Autoantibodies develop throughout the course of autoimmune disease, as the immune system mistakenly forms specific antibodies to its own tissues, resulting in inflammation. The presence of autoantibodies alone is not sufficient for diagnosis, as autoantibodies may arise for a variety of other reasons, including malignancy, infection, or injury, and may be present even in persons who are completely healthy. However, it is possible for persons to have detectable autoantibody levels prior to clinical development autoimmune disease; this state may be characterized as pre-autoimmunity. Additionally, it is possible to display clinical signs of autoimmune disease before autoantibody levels are detectable. Most autoantibody assays are more sensitive than they are specific; that is, a negative autoantibody test is better at excluding a given disease, than a positive autoantibody test is at diagnosing a disease. Generally, autoantibody results are reported in the form of titers, with higher titers (e.g., 1:160) indicating greater autoantibody concentration than lower titers (e.g., 1:8). Different autoantibody assays will have different criteria for determining whether a given test is positive, negative, or indeterminate. Other laboratories ordered in the workup of autoimmune disease may include a white blood cell count (WBC), CRP (C-reactive protein), ESR (erythrocyte sedimentation rate), and C3/C4 (complement levels), among others. Additional circumstantial evidence to indicate likely autoimmune disease include family history and clustering of autoimmune diseases within a given family, presence of HLA haplotypes associated with a given disease, sex bias, and proof-of-concept through response to immunosuppressive therapy. == Treatment == Currently, it is not possible to fully cure any autoimmune disease. However, treatments exist which can improve the course of a given disease and/or result in long periods of remission. Pharmacological treatment of autoimmune disease can be broadly classified into anti-inflammatory, immunosuppressive, and palliative – e.g., correcting a functional disturbance related to the condition. The overall goals of such treatment are to limit the severity of flare-ups of disease, as well as to limit the total number of flares – that is, to extend periods of disease remission. === Anti-inflammatory === Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used to reduce inflammation associated with flares of autoimmune illness. NSAIDs work by inhibiting COX-1 and COX-2 enzymes, which are responsible for generating prostaglandins which cause inflammation. They additionally may inhibit chemotaxis, stop neutrophil aggregation, and decrease levels of pro-inflammatory cytokines. They are not considered immunosuppressive agents, as they do not directly target immune cells. Examples of NSAIDs include ibuprofen, naproxen, and diclofenac. These drugs are not recommended past the 20th week of pregnancy, as they may have adverse effects on development of the fetal circulatory system and kidneys. === Corticosteroids === Corticosteroids also have both anti-inflammatory and immunosuppressive effects, and are used widely in the treatment of autoimmune disease. They work through promoting the synthesis of multiple proteins such as lipocortin-1 and annexin A1, which stop the downstream production of prostaglandins and leukotrienes which promote inflammation. Examples of corticosteroids used in autoimmune disease include prednisone and methylprednisolone. There are no robust randomized controlled studies in humans regarding the safety of corticosteroid use in pregnancy. Corticosteroid use may be associated with cleft palate formation in the 1st trimester, but the data on this is limited. There is little evidence to suggest that material corticosteroid use is associated with early delivery, low birth weight, or preeclampsia. Prednisone and methylprednisolone have been classed as pregnancy category C, in that they should only be used in the maternal benefits outweigh potential risks to the fetus. === Immunosuppressive === Optimal treatment of autoimmune disease addition to quelling the generalized inflammation which may occur with autoimmune disease, treatment is also focused on specifically targeting the adaptive immune system. The goal of direct immunosuppression is to treat flares as well as extend the period of remission between episodes. Immunosuppressive drugs are categorized into DMARDs (disease-modifying anti-rheumatic drugs), as well as ==== DMARDs (Disease-Modifying Anti-Rheumatic Drugs) ==== DMARDs can be further classified into conventional-synthetic, targeted-synthetic, and biologic agents. === Palliative === Some autoimmune diseases with targeted effects on endocrine organs can result in an inability to produce hormones necessary to maintain normal physiology. Palliative treatment of autoimmune disease involves treating the secondary condition, by replacing vital hormones which are no longer being produced. Examples of this include the treatment of type-1 diabetes with exogenous insulin. Though this does not cure the primary autoimmune disease, it effectively treats the lack of hormone caused by it. === Non-pharmacological === Non-pharmacological treatments are effective in treating autoimmune disease and contribute to a sense of well-being. Women can: Eat healthy, well-balanced meals. A healthy diet limits saturated fat, trans fat, cholesterol, salt, and added sugars. People may alleviate symptoms of inflammation by following the Autoimmune Protocol Diet, which focuses on eliminating food that may trigger inflammation. Those with autoimmune diseases should focus on consuming foods that are very fresh and nutritious. Engage in regular physical activity without overdoing it. Patients should speak with a clinician about what types of physical activity is appropriate. A gradual and gentle exercise program often works well for people with long-lasting muscle and joint pain. For example, yoga or tai chi may be helpful. Get enough rest. Rest allows body tissues and joints the time they need to repair. Sleeping is a great way to maintain health of the mind and body. Lack of sleep, along with elevated stress levels may cause symptoms to worsen. Without proper rest, the body's immune defense remains inadequate. Many people need at least seven to nine hours of sleep each day to feel well-rested. Reduce stress. Stress and anxiety can trigger symptoms to flare up with some autoimmune diseases. Simplifying daily stressors will help alleviate symptoms and contribute to a sense of well-being. Meditation, self-hypnosis, and guided imagery, may be effective in reducing stress, pain, and boost people's ability to cope with other effects of autoimmune diseases. Instructional materials can guide people in learning these activities. Some include self-help books, audio sources, tapes, or consulting with an instructor. Joining a support group or talking with a counselor might also help manage stress and cope with the disease. === Complementary === Some complementary treatments may be effective and include: Listening to music Taking time to relax in a comfortable position Using imagery throughout the day Imagining confronting the pain and watching it be destroyed. Journaling and daily affirmations Traditional herbal medicine == During pregnancy == Concerns about fertility and pregnancy are present in women with autoimmune diseases. Talking with a health care provider before becoming pregnant is recommended. They may suggest to wait until the disease is in remission or suggest a change in medication before becoming pregnant. There are endocrinologists that specialize in treating women with high-risk pregnancies. Some women with autoimmune diseases may have problems getting pregnant. This can happen for many reasons such as medication types or even disease types. Tests can tell if fertility problems are caused by an autoimmune disease or an unrelated reason. Fertility treatments are able to help some women with autoimmune disease become pregnant. Changes in the severity of the disease seem to vary depending on the type of disease. There is an observable trend in pregnant women with rheumatoid arthritis, where the condition seems to improve during pregnancy. Differently, expecting mothers with systemic lupus erythematosus (SLE) may be more likely to have worsened symptoms through pregnancy; however, this is difficult to predict. Medications have an influence on female fertility a well; furthermore, fertility has an impact on pregnancy. There are certain medications that can hinder women's ability to get pregnant, such as cyclophosphamide or corticosteroids. For this reason, it may be extremely helpful for women with autoimmune diseases to seek treatment when conceiving. == References == == External links == American Thyroid Association National Endocrine and Metabolic Diseases Information Service, NIDDK, NIH, DHHS	Wikipedia/Autoimmune_disease_in_women
Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which remain within the donated tissue (the graft) recognize the recipient (the host) as foreign (non-self). The white blood cells present within the transplanted tissue then attack the recipient's body's cells, which leads to GvHD. This should not be confused with a transplant rejection, which occurs when the immune system of the transplant recipient rejects the transplanted tissue; GvHD occurs when the donor's immune system's white blood cells reject the recipient. The underlying principle (alloimmunity) is the same, but the details and course may differ. GvHD can also occur after a blood transfusion, known as Transfusion-associated graft-versus-host disease or TA-GvHD if the blood products used have not been gamma irradiated or treated with an approved leukocyte reduction system. In contrast to organ/tissue transplant associated GvHD, the incidence of TA-GvHD is increased with HLA matching (first-degree or close relatives). == Types == In the clinical setting, graft-versus-host disease is divided into acute and chronic forms, and scored or graded on the basis of the tissue affected and the severity of the reaction. In the classical sense, acute graft-versus-host disease is characterized by selective damage to the liver, skin (rash), mucosa, and the gastrointestinal tract. Newer research indicates that other graft-versus-host disease target organs include the immune system (the hematopoietic system, e.g., the bone marrow and the thymus) itself, and the lungs in the form of immune-mediated pneumonitis. Biomarkers can be used to identify specific causes of GvHD, such as elafin in the skin. Chronic graft-versus-host disease also attacks the above organs, but over its long-term course can also cause damage to the connective tissue and exocrine glands. Mucosal damage to the vagina can result in severe pain and scarring, and appears in both acute and chronic GvHD. This can result in an inability to have sexual intercourse. === Acute === The acute or fulminant form of the disease (aGvHD) is normally observed within the first 10 to 100 days post-transplant, and is a major challenge to transplants owing to associated morbidity and mortality. About one-third to one-half of allogeneic transplant recipients will develop acute GvHD. It is less common in younger patients and in those with closer human leukocyte antigens (HLA) matches between donor and the patient. The first signs are usually a rash, burning, and redness of the skin on the palms and soles. This can spread over the entire body. Other symptoms can include nausea, vomiting, stomach cramps, diarrhea (watery and sometimes bloody), loss of appetite, jaundice, abdominal pain, and weight loss. Acute GvHD of the GI tract can result in severe intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting. This is typically diagnosed via intestinal biopsy. Liver GvHD is measured by the bilirubin level in acute patients. Skin GvHD results in a diffuse red maculopapular rash, sometimes in a lacy pattern. Acute GvHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GvHD usually have a poor prognosis. If the GvHD is severe and requires intense immunosuppression involving steroids and additional agents to get under control, the patient may develop severe infections as a result of the immunosuppression and may die of infection. However, a 2016 study found that the prognosis for patients with grade IV GvHD has improved in recent years. === Chronic === The chronic form of graft-versus-host disease (cGvHD) normally begins 90 to 600 days post-transplant. The appearance of moderate to severe cases of cGVHD adversely influences long-term survival. The first symptom of cGvHD is commonly a rash on the palms of the hands or the soles of the feet, and the rash can spread and is usually itchy and dry. In severe cases, the skin may blister and peel, like a bad sunburn. A fever may also develop. Other symptoms of chronic GVHD can include: Decreased appetite Diarrhea Abdominal cramps Weight loss Yellowing of the skin and eyes (jaundice) Enlarged liver Bloated abdomen Pain in the upper right part of the abdomen Increased levels of liver enzymes in the blood (seen on blood tests) Skin that feels tight Dry, burning eyes Dryness or painful sores in the mouth Burning sensations when eating acidic foods Bacterial infections Blockages in the smaller airways of the lungs In the oral cavity, chronic graft-versus-host disease manifests as lichen planus with a higher risk of malignant transformation to oral squamous cell carcinoma in comparison to the classical oral lichen planus. Oral cancer associated with graft-versus-host disease may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-hematopoietic stem cell transplantation patients. == Causes == Three criteria, known as the Billingham criteria, must be met in order for GvHD to occur. An immuno-competent graft is administered, with viable and functional immune cells. The recipient is immunologically different from the donor – histo-incompatible. The recipient is immunocompromised and therefore cannot destroy or inactivate the transplanted cells. In particular, it involves an inability of the recipient's cell-mediated immunity to destroy or inactivate viable lymphocytes from the donor. After bone marrow transplantation, T cells present in the graft, either as contaminants or intentionally introduced into the host, attack the tissues of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of cytokines, including TNF-α and interferon-gamma (IFNγ). A wide range of host antigens can initiate graft-versus-host disease, among them the human leukocyte antigens (HLA). However, graft-versus-host disease can occur even when HLA-identical siblings are the donors. HLA-identical siblings or HLA-identical unrelated donors often have genetically different proteins (called minor histocompatibility antigens) that can be presented by major histocompatibility complex (MHC) molecules to the donor's T-cells, which see these antigens as foreign and so mount an immune response. Antigens most responsible for graft loss are HLA-DR (first six months), HLA-B (first two years), and HLA-A (long-term survival). While donor T-cells are undesirable as effector cells of graft-versus-host disease, they are valuable for engraftment by preventing the recipient's residual immune system from rejecting the bone marrow graft (host-versus-graft). In addition, as bone marrow transplantation is frequently used to treat cancer, mainly leukemias, donor T-cells have proven to have a valuable graft-versus-tumor effect. A great deal of current research on allogeneic bone marrow transplantation involves attempts to separate the undesirable graft-vs-host disease aspects of T-cell physiology from the desirable graft-versus-tumor effect. === Transfusion-associated GvHD === This type of GvHD is associated with transfusion of un-irradiated blood to immunocompromised recipients. It can also occur in situations in which the blood donor is homozygous and the recipient is heterozygous for an HLA haplotype. It is associated with higher mortality (80–90%) due to involvement of bone marrow lymphoid tissue, however the clinical manifestations are similar to GVHD resulting from bone marrow transplantation. Transfusion-associated GvHD is rare in modern medicine. It is almost entirely preventable by controlled irradiation of blood products to inactivate the white blood cells (including lymphocytes) within. === Thymus transplantation === Thymus transplantation may be said to be able to cause a special type of GvHD because the recipient's thymocytes would use the donor thymus cells as models when going through the negative selection to recognize self-antigens, and could therefore still mistake own structures in the rest of the body for being non-self. This is a rather indirect GvHD because it is not directly cells in the graft itself that causes it but cells in the graft that make the recipient's T cells act like donor T cells. It can be seen as a multiple-organ autoimmunity in xenotransplantation experiments of the thymus between different species. Autoimmune disease is a frequent complication after human allogeneic thymus transplantation, found in 42% of subjects over one year post-transplantation. However, this is partially explained by the fact that the indication itself, that is, complete DiGeorge syndrome, increases the risk of autoimmune disease. === Thymoma-associated multiorgan autoimmunity (TAMA) === A GvHD-like disease called thymoma-associated multiorgan autoimmunity (TAMA) can occur in patients with thymoma. In these patients rather than a donor being a source of pathogenic T cells, the patient's own malignant thymus produces self-directed T cells. This is because the malignant thymus is incapable of appropriately educating developing thymocytes to eliminate self-reactive T cells. The result is a disease virtually indistinguishable from GvHD. == Mechanism == The pathophysiology of GvHD includes three phases: The afferent phase: activation of APC (antigen presenting cells) The efferent phase: activation, proliferation, differentiation and migration of effector cells The effector phase: target tissue destruction Activation of APC occurs in the first stage of GvHD. Prior to haematopoietic stem cell transplantation, radiation or chemotherapy results in damage and activation of host tissues, especially intestinal mucosa. This allows the microbial products to enter and stimulate pro-inflammatory cytokines such as IL-1 and TNF-α. These proinflammatory cytokines increase the expression of MHC and adhesion molecules on APCs, thereby increasing the ability of APC to present antigen. The second phase is characterized by the activation of effector cells. Activation of donor T-cells further enhances the expression of MHC and adhesion molecules, chemokines and the expansion of CD8 + and CD4 + T-cells and guest B-cells. In the final phase, these effector cells migrate to target organs and mediate tissue damage, resulting in multiorgan failure. == Prevention == DNA-based tissue typing allows for more precise HLA matching between donors and transplant patients, which has been proven to reduce the incidence and severity of GvHD and to increase long-term survival. The T-cells of umbilical cord blood (UCB) have an inherent immunological immaturity, and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GvHD. Methotrexate, cyclosporin and tacrolimus are common drugs used for GvHD prophylaxis. Further research is necessary to evaluate whether mesenchymal stromal cells can also be used for the prophylaxis. Graft-versus-host disease can largely be avoided by performing a T-cell-depleted bone marrow transplant. However, these types of transplants come at a cost of diminished graft-versus-tumor effect, greater risk of engraftment failure, or cancer relapse, and general immunodeficiency, resulting in a patient more susceptible to viral, bacterial, and fungal infection. In a multi-center study, disease-free survival at three years was not different between T cell-depleted and T cell-replete transplants. == Treatment == === Glucocorticoids === Intravenously administered glucocorticoids, such as prednisone, are the standard of care in acute GvHD and chronic GVHD. The use of these glucocorticoids is designed to suppress the T-cell-mediated immune onslaught on the host tissues; however, in high doses, this immune-suppression raises the risk of infections and cancer relapse. Therefore, it is desirable to taper off the post-transplant high-level steroid doses to lower levels, at which point the appearance of mild GVHD may be welcome, especially in HLA mis-matched patients, as it is typically associated with a graft-versus-tumor effect..While glucocorticoids remain the first line of treatment for acute GVHD, only about 50% of patients respond to treatment, otherwise having steroid-refractory GVHD (SR-GVHD). An increasing number of recent treatment options for SR-GVHD have been investigated, such as extracorporeal photopheresis (ECP), mesenchymal stem cell (MSCs), fecal microbial transplantation (FMT), and the medication Ruxolitinib. === Steroid-sparing immunosuppression/immunomodulation === Cyclosporine and tacrolimus are calcineurin inhibitors. The substances are structurally different but have the same mechanism of action. Cyclosporine binds to the cytosolic protein peptidyl-prolyl cis-trans isomerase A (known as cyclophilin), while tacrolimus binds to the cytosolic protein peptidyl-prolyl cis-trans isomerase FKBP12. These complexes inhibit calcineurin, block dephosphorylation of the transcription factor NFAT of activated T-cells and its translocation into the nucleus. Standard prophylaxis involves the use of cyclosporine for six months with methotrexate. Cyclosporin levels should be maintained above 200 ng/ml. Other substances that have been studied for GvHD treatment include, for example: sirolimus, pentostatin, etanercept, and alemtuzumab. In August 2017, the US FDA approved ibrutinib to treat chronic GvHD after failure of one or more other systemic treatments. Axatilimab (Niktimvo) was approved for medical use in the United States in August 2024. === Cell therapy === Remestemcel (Ryoncil) was approved for medical use in the United States in December 2024. === Non-pharmacological treatment === Given the complex systemic condition and immunosuppression of the chronic GVHD patients, non-drug therapies are a significant advancement, and may be preferred whenever possible. Examples are photobiomodulation for GVHD-related oral mucosal ulcers, and electrostimulation for GVHD-related xerostomia. == Clinical research == There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention. On 17 May 2012, Osiris Therapeutics announced that Canadian health regulators approved Prochymal, its drug for acute graft-versus-host disease in children who have failed to respond to steroid treatment. Prochymal is the first stem cell drug to be approved for a systemic disease. In January 2016, Mesoblast released results of a phase 2 clinical trial on 241 children with acute Graft-versus-host disease, that was not responsive to steroids. The trial was of a mesenchymal stem cell therapy known as remestemcel-L or MSC-100-IV. Survival rate was 82% (vs 39% of controls) for those who showed some improvement after one month, and in the long term 72% (vs 18% of controls) for those that showed little effect after one month. == HIV elimination == Graft-versus-host disease has been implicated in eliminating several cases of HIV, including The Berlin Patient and six others in Spain. == See also == Graft-versus-tumor effect Immunosuppression Transplant rejection == References == == Further reading == Ferrara JLM, Deeg HJ, Burakoff SJ. Graft-Vs.-Host Disease: Immunology, Pathophysiology, and Treatment. Marcel Dekker, 1990 ISBN 0-8247-9728-0 Polsdorfer, JR Gale Encyclopedia of Medicine: Graft-vs.-host disease == External links ==	Wikipedia/Graft-versus-host_disease
Transfusion-associated graft-versus-host disease (TA-GvHD) is a rare complication of blood transfusion, in which the immunologically competent donor T lymphocytes mount an immune response against the recipient's lymphoid tissue. These donor lymphocytes engraft, recognize recipient cells as foreign and mount an immune response against recipient tissues. Donor lymphocytes are usually identified as foreign and destroyed by the recipient's immune system. However, in situations where the recipient is severely immunocompromised, or when the donor and recipient HLA type is similar (as can occur in directed donations from first-degree relatives), the recipient's immune system is not able to destroy the donor lymphocytes. This can result in transfusion associated graft-versus-host disease. This is in contrast with organ/tissue transplant associated GvHD, where matching HLA reduces the incident of the complication. == Signs and symptoms == The clinical presentation is the same as GvHD occurring in other settings, such as bone marrow transplantation. TA-GvHD can develop two days to six weeks after the transfusion. Typical symptoms include: fever erythematous maculopapular rash, which can progress to generalised erythroderma toxic epidermal necrolysis in extreme cases hepatomegaly diarrhea Other symptoms can include cough, abdominal pain, dyspnea and vomiting. == Diagnosis == Laboratory findings include pancytopenia, marrow aplasia, abnormal liver enzymes, and electrolyte imbalance (when diarrhea is present). TA-GvHD can be suspected from a biopsy of the affected skin or liver, and established by HLA analysis of the circulating lymphocytes. This testing can identify circulating lymphocytes with a different HLA type than the tissue cells of the host. In 2023, the first case of fetal-induced GvHD was reported in the New England Journal of Medicine. == Prevention == Prevention includes gamma irradiation of the lymphocyte-containing blood components such as red blood cells, platelets and granulocytes. Irradiated blood components should be issued in the following situations: Intrauterine transfusions Prematurity, low birthweight, or erythroblastosis fetalis in newborns Congenital immunodeficiencies Certain hematologic malignancies (e.g. Hodgkin lymphoma) Patients undergoing hematopoietic stem cell transplantation Components that are HLA matched, or directed donations from a family member Patients receiving fludarabine therapy Patients receiving granulocyte transfusions == Treatment == Treatment is supportive. No available form of therapy has proven effective in treating TA-GvHD and it is fatal in more than 90% of cases. == Epidemiology == The incidence of TA-GvHD in immunocompromised patients receiving blood transfusions is estimated to be 0.1–1.0%, and mortality around 80–90%. Mortality is higher in TA-GvHD than in GvHD associated with bone marrow transplantation, where the engrafted lymphoid cells in the bone marrow are of donor origin (in autotransplant) and therefore the immune reaction is not directed against them. The most common causes of death in TA-GvHD are infections and hemorrhages secondary to pancytopenia and liver dysfunction. == References == == Further reading ==	Wikipedia/Transfusion-associated_graft-versus-host_disease
The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of inflammation. To perform the test, anticoagulated blood is traditionally placed in an upright tube, known as a Westergren tube, and the distance which the red blood cells fall is measured and reported in millimetres at the end of one hour. Since the introduction of automated analyzers into the clinical laboratory, the ESR test has been automatically performed. The ESR is influenced by the aggregation of red blood cells: blood plasma proteins, mainly fibrinogen, promote the formation of red cell clusters called rouleaux or larger structures (interconnected rouleaux, irregular clusters). As according to Stokes' law the sedimentation velocity varies like the square of the object's diameter, larger aggregates settle faster. While aggregation already takes place at normal physiological fibrinogen levels, these tend to increase when an inflammatory process is present, leading to increased ESR. The ESR is increased in inflammation, pregnancy, anemia, autoimmune disorders (such as rheumatoid arthritis and lupus), infections, some kidney diseases and some cancers (such as lymphoma and multiple myeloma). The ESR is decreased in polycythemia, hyperviscosity, sickle cell anemia, leukemia, chronic fatigue syndrome, low plasma protein (due to liver or kidney disease) and congestive heart failure. Although increases in immunoglobulins usually increase the ESR, very high levels can reduce it again due to hyperviscosity of the plasma. This is especially likely with IgM-class paraproteins, and to a lesser extent, IgA-class. The basal ESR is slightly higher in females. == Stages == Erythrocyte sedimentation rate (ESR) is the measure of ability of erythrocytes (red blood cell) to fall through the blood plasma and accumulate together at the base of container in one hour. There are three stages in erythrocyte sedimentation: Rouleaux formation Sedimentation or settling stage Packing stage - 10 minutes (sedimentation slows and cells start to pack at the bottom of the tube) In normal conditions, the red blood cells are negatively charged and therefore repel each other rather than stacking. ESR is also reduced by high blood viscosity, which slows the rate of fall. == Causes of elevation == The rate of erythrocyte sedimentation is affected by both inflammatory and non-inflammatory conditions. === Inflammation === In inflammatory conditions, fibrinogen, other clotting proteins, and alpha globulin are positively charged, thus increasing the ESR. ESR begins to rise at 24 to 48 hours after the onset of acute self-limited inflammation, decreases slowly as inflammation resolves, and can take weeks to months to return to normal levels. For ESR values more than 100 mm/hour, there is a 90% probability that an underlying cause would be found upon investigation. === Non-inflammatory conditions === In non-inflammatory conditions, plasma albumin concentration, size, shape, and number of red blood cells, and the concentration of immunoglobulin can affect the ESR. Non-inflammatory conditions that can cause raised ESR include anemia, kidney failure, obesity, ageing, and female sex. ESR is also higher in women during menstruation and pregnancy. The value of ESR does not change whether dialysis is performed or not. Therefore, ESR is not a reliable measure of inflammation in those with kidney injuries as the ESR value is already elevated. == Causes of reduction == An increased number of red blood cells (polycythemia) causes reduced ESR as blood viscosity increases. Hemoglobinopathy such as sickle-cell disease can have low ESR due to an improper shape of red blood cells that impairs stacking. == Medical uses == === Diagnosis === ESR can sometimes be useful in diagnosing diseases, such as multiple myeloma, temporal arteritis, polymyalgia rheumatica, various autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and chronic kidney diseases. In many of these cases, the ESR may exceed 100 mm/hour. It is commonly used for a differential diagnosis for Kawasaki's disease (from Takayasu's arteritis; which would have a markedly elevated ESR) and it may be increased in some chronic infective conditions like tuberculosis and infective endocarditis. It is also elevated in subacute thyroiditis also known as DeQuervain's. In markedly increased ESR of over 100 mm/h, infection is the most common cause (33% of cases in an American study), followed by cancer (17%), kidney disease (17%) and noninfectious inflammatory disorders (14%). Yet, in pneumonia the ESR stays under 100. The usefulness of the ESR in current practice has been questioned by some, as it is a relatively imprecise and non-specific test compared to other available diagnostic tests. Current literature suggests that an ESR should be "obtained on all patients over the age of 50" who have an intense headache. === Disease severity === It is a component of the PCDAI (pediatric Crohn's disease activity index), an index for assessment of the severity of inflammatory bowel disease in children. === Monitoring response to therapy === The clinical usefulness of ESR is limited to monitoring the response to therapy in certain inflammatory diseases such as temporal arteritis, polymyalgia rheumatica and rheumatoid arthritis. It can also be used as a crude measure of response in Hodgkin's lymphoma. Additionally, ESR levels are used to define one of the several possible adverse prognostic factors in the staging of Hodgkin's lymphoma. == Normal values == Note: mm/h. = millimeters per hour. Westergren's original normal values (men 3 mm/h and women 7 mm/h) made no allowance for a person's age. Later studies from 1967 confirmed that ESR values tend to rise with age and to be generally higher in women. Values of the ESR also appear to be slightly higher in normal populations of African-Americans than Caucasians of both genders. Values also appear to be higher in anemic individuals than non-anemic individuals. === Adults === The widely used rule calculating normal maximum ESR values in adults (98% confidence limit) is given by a formula devised in 1983 from a study of ≈1000 individuals over the age of 20: The normal values of ESR in men is age (in years) divided by 2; for women, the normal value is age (in years) plus 10, divided by 2. E S R ( m m / h ) ≤ A g e ( i n y e a r s ) + 10 ( i f f e m a l e ) 2 {\displaystyle {\rm {ESR}}\ (mm/h)\leq {\frac {{\rm {Age}}\ ({\it {in\ years}})+10\ ({\it {if\ female}})}{2}}} Other studies confirm a dependence of ESR on age and gender, as seen in the following: ESR reference ranges from a large 1996 study of 3,910 healthy adults (NB. these use 95% confidence intervals rather than the 98% intervals used in the study used to derive the formula above, and because of the skewness of the data, these values appear to be less than expected from the above formula): === Children === Normal values of ESR have been quoted as 1 to 2 mm/h at birth, rising to 4 mm/h 8 days after delivery, and then to 17 mm/h by day 14. Typical normal ranges quoted are: Newborn: 0 to 2 mm/h Neonatal to puberty: 3 to 13 mm/h, but other laboratories place an upper limit of 20. == Relation to C-reactive protein == C-reactive protein (CRP) is an acute phase protein. Therefore, it is a better marker for acute phase reaction than ESR. While ESR and CRP generally together correlate with the degree of inflammation, this is not always the case and results may be discordant in 12.5% of the cases. Cases with raised CRP but normal ESR may demonstrate a combination of infection and some other tissue damage such as myocardial infarction, and venous thromboembolism. Such inflammation may not be enough to raise the level of ESR. Those with high ESR usually do not have demonstrable inflammation. However, in cases of low grade bacterial infections of bone and joints such as coagulase negative staphylococcus (CoNS), and systemic lupus erythematosus (SLE), ESR can be a good marker for the inflammatory process. This may be due to the production of Interferon type I that inhibits the CRP production in liver cells during SLE. CRP is a better marker for other autoimmune diseases such as polymyalgia rheumatica, giant cell arteritis, post-operative sepsis, and neonatal sepsis. ESR may be reduced in those who are taking statins and non-steroidal anti-inflammatory drugs (NSAIDs). == History == The test was invented in 1897 by the Polish pathologist Edmund Biernacki. In some parts of the world the test continues to be referred to as Biernacki's Reaction (Polish: odczyn Biernackiego, OB). In 1918, Dr Robert Fåhræus noted that ESR differed only during pregnancy. Therefore, he suggested that ESR could be used as an indicator of pregnancy. In 1921, Dr Alf Vilhelm Albertsson Westergren used ESR to measure the disease outcome of tuberculosis. He defined the measurement standards of ESR which is still being used today. Robert Fåhræus and Alf Vilhelm Albertsson Westergren are eponymously remembered for the 'Fahraeus-Westergren test' (abbreviated as FW test; in the UK, usually termed Westergren test), which uses sodium citrate-anti-coagulated specimens. == Research == According to a study released in 2015, a stop gain mutation in HBB gene (p. Gln40stop) was shown to be associated with ESR values in Sardinian population. The red blood cell count, whose values are inversely related to ESR, is affected in carriers of this SNP. This mutation is almost exclusive of the inhabitants of Sardinia and is a common cause of beta thalassemia. According to a 2010 study, there is a reverse correlation between ESR and general intelligence (IQ) in Swedish males aged 18–20. == References == == External links == Mediscuss on ESR Brigden ML (October 1999). "Clinical utility of the erythrocyte sedimentation rate". American Family Physician. 60 (5): 1443–50. PMID 10524488. ESR at Lab Tests Online	Wikipedia/Erythrocyte_Sedimentation_Rate
Undifferentiated connective tissue disease (UCTD) (also known as latent lupus or incomplete lupus) is a disease in which the connective tissues are targeted by the immune system. It is a serological and clinical manifestation of an autoimmune disease. When there is proof of an autoimmune disease, but the disease does not correspond to any specific autoimmune disease (such as systemic lupus erythematosus (SLE), scleroderma, mixed connective tissue disease, Sjögren syndrome, systemic sclerosis, polymyositis, dermatomyositis, or rheumatoid arthritis), it will be diagnosed as UCTD. This is also the case of major rheumatic diseases whose early phase was defined by LeRoy et al in 1980 as undifferentiated connective tissue disease. The term is sometimes used interchangeably with mixed connective tissue disease (MCTD), as it is an overlap syndrome. However, some researchers believe that MCTD is a clinically distinct entity and is strongly associated with the presence of titer high in antibodies Ribonucleoproteins (RNP). It is estimated that up to 25% of people with systemic autoimmune disease could be considered to have UCTD. There are many people who have features of connective tissue disease, such as blood test results and external characteristics, but do not fulfill the diagnostic criteria established for any one disease. These people are considered to have undifferentiated connective tissue disease (UCTD). == Classification == UCTD is not specifically included in the WHOs ICD-11 disease classification system, but may be included in the 'diseases of the immune system' group. == Signs and symptoms == The presentation of the disease varies considerably from one patient to another. Generally, the symptoms include nonspecific symptoms common to connective tissue diseases such as fatigue – this is common in autoimmune diseases, and is the patient's primary concern malaise fever These can be the initial presentation for some patients. Other symptoms associated with UCTD include : joint pain – the most common symptom, occurring in up to 86% of patients. The pain is often an aching or arthritis-like pain in the elbows, wrists, hands, and knees, in a symmetrical pattern. dry eyes dry mouth hair loss joint inflammation mouth ulcers Raynaud's phenomenon sun-sensitive rash Clinical presentation in some people diagnosed with UCTD may show : positive antinuclear antibody (ANA) test. Patients with UCTD usually have positive ANA. a decrease in the number of white blood cells anemia abnormal nerve sensations in the extremities inflammation of the lining of the heart and/or lungs a decrease in platelet count Pulmonary involvement, such as nonspecific interstitial pneumonia, can be a complication of the disease. == Mechanism == UCTD is caused by genetic and environmental factors. It may be triggered by factors such as: Exposure to harmful products such as cigarette smoke. Exposure to an atmospheric pollutant, primary air pollutants (nitrogen oxides [NOx], sulfur dioxide [SO2], volatile organic compounds [VOCs], hydrocarbons and certain metals [such as lead or cadmium]) or secondary (created in the atmosphere through chemical reactions between pollutants). Exposure to UV light. === T-cell hypothesis === Populations of regulatory T cells are believed to be responsible for the onset of the disease. When there is a decline of these cells, manifestations of diseases begin to appear, giving an idea of the vital role of these cells in the prevention of autoimmune diseases. Moreover, an additional decrease could unfortunately worsen the pathological state and lead to the differentiation of an undifferentiated connective tissue disease into a differentiated connective tissue disease with a poorer prognosis. Due to the wide range of variation in the inclusion criteria of the disease, up to 50% of patients diagnosed with connective tissue disease may have undifferentiated disease of the underlying connective tissue. == Diagnosis and research inclusion == === Diagnosis === There are no formal diagnostic criteria for UCTD. It is determined by a differential diagnosis. Diagnostic tests are undertaken to determine whether a patient has a disease assured or undifferentiated of the connective tissues. Patients with UCTD usually have positive ANA (antinuclear antibody), and raised ESR (erythrocyte sedimentation rate) values, without typical autoantibody specificities. Some 20% of the general population, and up to 15% of completely healthy people, test positive for ANA, but nonetheless this is regarded by some as almost always a sign of an autoimmune disorder. If more specific types of ANAs or other proteins are present, other autoimmune conditions (not UCTD) are implied. Other mechanisms that may be used are tests for Anti-histone antibodies, Chromatin and vitamin D, and chest X-ray to show signs of pericardial effusion. === Classification criteria === Patients may be included for UCTD research if they have: Signs and symptoms which (a) are suggestive of a connective tissue disease, but (b) do not meet the criteria of any defined connective tissue diseases, and (c) have lasted for at least three years. (Note if less than three years may be regarded as early UCTD). Positive ANA test on two different occasions. == Treatment == UCTD is normally managed primarily as an outpatient. Meds can be used to manage aspects of the disease. Treatment depends largely on the progression of the individual disease and the nature of the symptoms presented. Antimalarial medications, corticosteroids and other medications may be prescribed, as the treating physician considers appropriate: Nonsteroidal anti-inflammatory drugs for pain. Anti-inflammatory corticosteroids In severe cases, immunosuppressive drugs may be used. Antimalarial medications (like hydroxychloroquine) can inhibit chemotaxis of neutrophil and eosinophil. Calcium channel blockers can be used to relax smooth muscles and decrease the resistance of the peripheral vascular system. This can help in managing Raynaud's phenomenon. === Possible complications === Complications are present with an affected or injured system, such as the lesions and long-term inflammation in the pulmonary system, interstitial lung disease (in 88% of cases, severe interstitial lung disease) or pulmonary fibrosis. If the heart is affected, hypertrophy can occur, leading to cardiomegaly. Organs can also be affected (neurological or renal manifestations) and life-threatening conditions can occur. Affected pregnant women follow careful clinical observation because they are more likely to see disease progression. Those with the disease at the beginning of pregnancy will keep the disease undifferentiated against 25% who progress to a defined disease at the end of pregnancy. In addition, 45% of pregnancies with the disease end in preterm birth. === Prevention and patient education === Early recognition and knowledge of the onset of UCTD can help patients manage and control their disease. Patients should be informed of common agents and triggers to help manage symptoms to shorten the duration of the disease and prevent complications. === Improving health care team outcomes === Undifferentiated connective tissue disease occurs for various reasons; underlying factors may affect several organs depending on individual sensitivity. Coordination of care between primary clinicians and experts (like rheumatologists) can help achieve optimal patient outcomes. == Outlook == === Progression === 30–40% of UCTD cases may develop into a defined connective tissue disease as more diagnostic criteria are progressively met. This generally happens within five years of onset. Several factors may help predict progression: the presence of cytopenia at the time of diagnosis. the degree of modification of the capillaroscopy test (skin blood vessel study technique) of nail fold during follow-up. the presence of antinuclear antibodies. young age. severe vitamin D deficiency. the presence of anti-dsDNA, anti-Sm and anti-cardiolipin autoantibodies correlates with the development of systemic lupus erythematosus in particular. The rate of progression is higher in the first five years following the onset of the disease and tends to decrease over time. Patients progressing to a defined disease seem to see a slight progression of the disease with a mitigated risk of developing complications. === Remaining undifferentiated === Most UCTD cases will remain undifferentiated. UCTD itself usually has a mild clinical course, particularly if there is low organ involvement. Most patients who remain undifferentiated tend to not experience major organ involvement. Up to 10–20% of patients diagnosed with UCTD will never progress to a defined disease and their symptoms will decrease or disappear. About 12% of patients will go into remission. === Particular studies === In a Bulgarian study, after five years, 34% had developed into a defined connective tissue disease (with the highest probability of development being within the first two years after onset of symptoms), 54% continued undifferentiated and 12% were in remission. In a US study, after 10 years, 37% had developed into a defined connective tissue disease, 43% continued undifferentiated and 20% were in remission. In a Spanish study, after a mean follow-up of 11±3 years, 14% had developed a definite CTD, 62% continued undifferentiated, and 24% were in remission. In an Italian study (in which 58% had ANA abnormalities), after five years, 6% had developed a defined autoimmune disease. The remaining 94% saw clinical and serological features little changed in the period and quite stable. 11% of these were and remained asymptomatic. == Epidemiology == Up to 90% of UCTD cases are females between 32 and 44 years old. In the United States up to 78% of patients were female, against 93 to 95% in Italy and 94% in Hungary. Higher female prevalence is common in autoimmune diseases. In the United States, up to 72% of patients diagnosed with UCTD had white skin. Prevalence of UCTD has been estimated at 2 people per 100,000 people per year. Annual incidence has been estimated as varying from 41 to 149 per 100,000 adults. It has also been suggested that UCTD is a relatively common condition seen in rheumatology practice, making up 10–20% of referrals to tertiary care clinics. Classical epidemiological data for UCTD are not available due to the limited literature exploring the disease. Also, differences in patient selection criteria in existing studies make comparisons between them difficult. == History == The term was first suggested in 1980, as connective tissue disease in patients whose features did not meet other classification criteria. In 1999 a study noted, "In recent years there has been growing concern regarding the diagnosis of incomplete forms of the autoimmune diseases" and the first classification criteria were proposed in that year. Historically the condition was sometimes called undifferentiated connective tissue syndrome, latent lupus or incomplete lupus. == References ==	Wikipedia/Undifferentiated_connective_tissue_disease
Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy, Kawasaki disease, certain cases of HIV/AIDS and measles, Guillain–Barré syndrome, and certain other infections when a more specific immunoglobulin is not available. Depending on the formulation it can be given by injection into muscle, a vein, or under the skin. The effects last a few weeks. Common side effects include pain at the site of injection, muscle pain, and allergic reactions. Other severe side effects include kidney problems, anaphylaxis, blood clots, and red blood cell breakdown. Use is not recommended in people with some types of IgA deficiency. Use appears to be relatively safe during pregnancy. Human immunoglobulin is made from human blood plasma. It contains antibodies against many viruses. Human immunoglobulin therapy first occurred in the 1930s and a formulation for injection into a vein was approved for medical use in the United States in 1981. It is on the World Health Organization's List of Essential Medicines. Each formulation of the product is somewhat different. A number of specific immunoglobulin formulations are also available including for hepatitis B, rabies, tetanus, varicella infection, and Rh positive blood exposure. == Medical uses == Immunoglobulin therapy is used in a variety of conditions, many of which involve decreased or abolished antibody production capabilities, which range from a complete absence of multiple types of antibodies, to IgG subclass deficiencies (usually involving IgG2 or IgG3), to other disorders in which antibodies are within a normal quantitative range, but lacking in quality – unable to respond to antigens as they normally should – resulting in an increased rate or increased severity of infections. In these situations, immunoglobulin infusions confer passive resistance to infection on their recipients by increasing the quantity/quality of IgG they possess. Immunoglobulin therapy is also used for a number of other conditions, including in many autoimmune disorders such as dermatomyositis in an attempt to decrease the severity of symptoms. Immunoglobulin therapy is also used in some treatment protocols for secondary immunodeficiencies such as human immunodeficiency virus (HIV), some autoimmune disorders (such as immune thrombocytopenia and Kawasaki disease), some neurological diseases (multifocal motor neuropathy, stiff person syndrome, multiple sclerosis and myasthenia gravis) some acute infections and some complications of organ transplantation. Immunoglobulin therapy is especially useful in some acute infection cases such as pediatric HIV infection and is also considered the standard of treatment for some autoimmune disorders such as Guillain–Barré syndrome. The high demand which coupled with the difficulty of producing immunoglobulin in large quantities has resulted in increasing global shortages, usage limitations and rationing of immunoglobulin. === Australia === The Australian Red Cross Blood Service developed their own guidelines for the appropriate use of immunoglobulin therapy in 1997. Immunoglobulin is funded under the National Blood Supply and indications are classified as either an established or emerging therapeutic role or conditions for which immunoglobulin use is in exceptional circumstances only. Subcutaneous immunoglobulin access programs have been developed to facilitate hospital based programs. Human normal immunoglobulin (human immunoglobulin G) (Cutaquig) was approved for medical use in Australia in May 2021. === Canada === The National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services have also developed their own separate set of guidelines for the appropriate use of immunoglobulin therapy, which strongly support the use of immunoglobulin therapy in primary immunodeficiencies and some complications of HIV, while remaining silent on the issues of sepsis, multiple sclerosis, and chronic fatigue syndrome. === European Union === Brands include HyQvia (human normal immunoglobulin), Privigen (human normal immunoglobulin (IVIg)), Hizentra (human normal immunoglobulin (SCIg)), Kiovig (human normal immunoglobulin), and Flebogamma DIF (human normal immunoglobulin). In the EU human normal immunoglobulin (SCIg) (Hizentra) is used in people whose blood does not contain enough antibodies (proteins that help the body to fight infections and other diseases), also known as immunoglobulins. It is used to treat the following conditions: primary immunodeficiency syndromes (PID, when people are born with an inability to produce enough antibodies); low levels of antibodies in the blood in people with chronic lymphocytic leukaemia (a cancer of a type of white blood cell) or myeloma (a cancer of another type of white blood cell) and who have frequent infections; low levels of antibodies in the blood in people before or after allogeneic haematopoietic stem cell transplantation (a procedure where the patient's bone marrow is cleared of cells and replaced by stem cells from a donor); chronic inflammatory demyelinating polyneuropathy (CIDP). In this rare disease, the immune system (the body's defence system) works abnormally and destroys the protective covering over the nerves. It is indicated for replacement therapy in adults and children in primary immunodeficiency syndromes such as: congenital agammaglobulinaemia and hypogammaglobulinaemia (low levels of antibodies); common variable immunodeficiency; severe combined immunodeficiency; immunoglobulin-G-subclass deficiencies with recurrent infections; replacement therapy in myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections. Flebogamma DIF is indicated for the replacement therapy in adults, children and adolescents (0–18 years) in: primary immunodeficiency syndromes with impaired antibody production; hypogammaglobulinaemia (low levels of antibodies) and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (a cancer of a type of white blood cell), in whom prophylactic antibiotics have failed; hypogammaglobulinaemia (low levels of antibodies) and recurrent bacterial infections in plateau-phase-multiple-myeloma (another cancer of a type of white blood cell) patients who failed to respond to pneumococcal immunisation; hypogammaglobulinaemia (low levels of antibodies) in patients after allogenic haematopoietic-stem-cell transplantation (HSCT) (when the patient receives stem cells from a matched donor to help restore the bone marrow); congenital acquired immune deficiency syndrome (AIDS) with recurrent bacterial infections. and for the immunomodulation in adults, children and adolescents (0–18 years) in: primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count; Guillain–Barré syndrome, which causes multiple inflammations of the nerves in the body; Kawasaki disease, which causes multiple inflammation of several organs in the body. In February 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Deqsiga, intended for replacement therapy in people with primary or secondary immunodeficiencies and immunomodulation in people with certain autoimmune diseases. The applicant for this medicinal product is Takeda Manufacturing Austria AG. Deqsiga is a duplicate of Kiovig (human normal immunoglobulin), which was authorized in the EU in January 2006. Deqsiga and Kiovig have the same pharmaceutical form, active substance and indications, but Deqsiga contains lower levels of immunoglobulin A (IgA) and may therefore be more suitable for people with IgA deficiency who have a higher risk of hypersensitivity to immunoglobulin products that contain higher levels of IgA. === United Kingdom === The United Kingdom's National Health Service recommends the routine use of immunoglobulin for a variety of conditions including primary immunodeficiencies and a number of other conditions, but recommends against the use of immunoglobulin in sepsis (unless a specific toxin has been identified), multiple sclerosis, neonatal sepsis, and pediatric HIV/AIDS. === United States === The American Academy of Allergy, Asthma, and Immunology supports the use of immunoglobulin for primary immunodeficiencies, while noting that such usage actually accounts for a minority of usage and acknowledging that immunoglobulin supplementation can be appropriately used for a number of other conditions, including neonatal sepsis (citing a sixfold decrease in mortality), considered in cases of HIV (including pediatric HIV), considered as a second line treatment in relapsing-remitting multiple sclerosis, but recommending against its use in such conditions as chronic fatigue syndrome, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) until further evidence to support its use is found (though noting that it may be useful in PANDAS patients with an autoimmune component), cystic fibrosis, and a number of other conditions. Brands include: Alyglo (immune globulin intravenous human-stwk) Anthrasil (anthrax immune globulin- human liquid) Asceniv (immune globulin intravenous, human – slra) Bivigam (immune globulin intravenous – human 10% liquid) Gamunex-C, (immune globulin injection human) Hizentra (immune globulin subcutaneous human) Hyqvia (immune globulin 10 percent – human with recombinant human hyaluronidase) Octagam (immune globulin intravenous, human) Panzyga (immune globulin intravenous, human – ifas) Xembify (immune globulin subcutaneous, human – klhw) Yimmugo (immune globulin intravenous, human-dira) == Side effects == Although immunoglobulin is frequently used for long periods of time and is generally considered safe, immunoglobulin therapy can have severe adverse effects, both localized and systemic. Subcutaneous administration of immunoglobulin is associated with a lower risk of both systemic and localized risk when compared to intravenous administration (hyaluronidase-assisted subcutaneous administration is associated with a greater frequency of adverse effects than traditional subcutaneous administration but still a lower frequency of adverse effects when compared to intravenous administration). Patients who are receiving immunoglobulin and experience adverse events are sometimes recommended to take acetaminophen and diphenhydramine before their infusions to reduce the rate of adverse effects. Additional premedication may be required in some instances (especially when first getting accustomed to a new dosage), prednisone or another oral steroid. Local side effects of immunoglobulin infusions most frequently include an injection site reaction (reddening of the skin around the injection site), itching, rash, and hives. Less serious systemic side effects to immunoglobulin infusions include an increased heart rate, hyper or hypotension, an increased body temperature, diarrhea, nausea, abdominal pain, vomiting, arthralgia or myalgia, dizziness, headache, fatigue, fever, and pain. Serious side effects of immunoglobulin infusions in infants, children, and adults include chest discomfort or pain, myocardial infarction, tachycardia, hyponatremia, hemolysis, hemolytic anemia, thrombosis, hepatitis, anaphylaxis, backache, aseptic meningitis, acute kidney injury, hypokalemic nephropathy, pulmonary embolism, and transfusion related acute lung injury. There is also a small chance that even given the precautions taken in preparing immunoglobulin preparations, an immunoglobulin infusion may pass a virus to its recipient. Some immunoglobulin solutions also contain isohemagglutinins, which in rare circumstances can cause hemolysis by the isohemagglutinins triggering phagocytosis. IVIG has long been known to induce a decrease in peripheral blood neutrophil count, or neutropenia in neonates, and in patients with Idiopathic Thrombocytopenic Purpura, resolving spontaneously and without complications within 48 h. Possible pathomechanisms include apoptosis/cell death due to antineutrophil antibodies with or without neutrophil migration into a storage pool outside the blood circulation. Immunoglobulin therapy interferes with the ability of the body to produce a normal immune response to an attenuated live-virus vaccine (like MMR) for up to a year, can result in falsely elevated blood glucose levels, and can interfere with many of the IgG-based assays often used to diagnose a patient with a particular infection. == Routes of administration == === 1950s – intramuscular === After immunoglobulin therapy's discovery in 1952, weekly intramuscular injections of immunoglobulin (IMIg) were the norm until intravenous formulations (IVIg) began to be introduced in the 1980s. During the mid and late 1950s, one-time IMIg injections were a common public health response to outbreaks of polio before the widespread availability of vaccines. Intramuscular injections were extremely poorly tolerated due to their extreme pain and poor efficacy – rarely could intramuscular injections alone raise plasma immunoglobulin levels enough to make a clinically meaningful difference. === 1980s – intravenous === Intravenous formulations began to be approved in the 1980s, which represented a significant improvement over intramuscular injections, as they allowed for a sufficient amount of immunoglobulin to be injected to reach clinical efficacy, although they still had a fairly high rate of adverse effects (though the addition of stabilizing agents reduced this further). === 1990s – subcutaneous === The first description of a subcutaneous route of administration for immunoglobulin therapy dates back to 1980, but for many years subcutaneous administration was considered to be a secondary choice, only to be considered when peripheral venous access was no longer possible or tolerable. During the late 1980s and early 1990s, it became obvious that for at least a subset of patients the systemic adverse events associated with intravenous therapy were still not easily tolerable, and more doctors began to experiment with subcutaneous immunoglobulin administration, culminating in an ad hoc clinical trial in Sweden of 3000 subcutaneous injections administered to 25 adults (most of whom had previously experienced systemic adverse effects with IMIg or IVIg), where no infusion in the ad hoc trial resulted in a severe systemic adverse reaction, and most subcutaneous injections were able to be administered in non-hospital settings, allowing for considerably more freedom for the people involved. In the later 1990s, large-scale trials began in Europe to test the feasibility of subcutaneous immunoglobulin administration, although it was not until 2006 that the first subcutaneous-specific preparation of immunoglobulin was approved by a major regulatory agency (Vivaglobin, which was voluntarily discontinued in 2011). A number of other brand names of subcutaneous immunoglobulin have since been approved, although some small-scale studies have indicated that a particular cohort of patients with common variable immunodeficiency (CVID) may develop intolerable side effects with subcutaneous immunoglobulin (SCIg) that they do not with intravenous immunoglobulin (IVIg). Although intravenous was the preferred route for immunoglobulin therapy for many years, in 2006, the US Food and Drug Administration (FDA) approved the first preparation of immunoglobulin that was designed exclusively for subcutaneous use. == Mechanism of action == The precise mechanism by which immunoglobulin therapy suppresses harmful inflammation is likely multifactorial. For example, it has been reported that immunoglobulin therapy can block Fas-mediated cell death. Perhaps a more popular theory is that the immunosuppressive effects of immunoglobulin therapy are mediated through IgG's Fc glycosylation. By binding to receptors on antigen presenting cells, IVIG can increase the expression of the inhibitory Fc receptor, FcgRIIB, and shorten the half-life of auto-reactive antibodies. The ability of immunoglobulin therapy to suppress pathogenic immune responses by this mechanism is dependent on the presence of a sialylated glycan at position CH2-84.4 of IgG. Specifically, de-sialylated preparations of immunoglobulin lose their therapeutic activity and the anti-inflammatory effects of IVIG can be recapitulated by administration of recombinant sialylated IgG1 Fc. Sialylated-Fc-dependent mechanism was not reproduced in other experimental models suggesting that this mechanism is functional under a particular disease or experimental settings. On the other hand, several other mechanisms of action and the actual primary targets of immunoglobulin therapy have been reported. In particular, F(ab')2-dependent action of immunoglobulin to inhibit activation of human dendritic cells, induction of autophagy, induction of COX-2-dependent PGE-2 in human dendritic cells leading to expansion of regulatory T cells, inhibition of pathogenic Th17 responses, and induction of human basophil activation and IL-4 induction via anti-IgE autoantibodies. Some believe that immunoglobulin therapy may work via a multi-step model where the injected immunoglobulin first forms a type of immune complex in the patient. Once these immune complexes are formed, they can interact with Fc receptors on dendritic cells, which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state. Other proposed mechanisms include the possibility that donor antibodies may bind directly with the abnormal host antibodies, stimulating their removal; the possibility that IgG stimulates the host's complement system, leading to enhanced removal of all antibodies, including the harmful ones; and the ability of immunoglobulin to block the antibody receptors on immune cells (macrophages), leading to decreased damage by these cells, or regulation of macrophage phagocytosis. Indeed, it is becoming more clear that immunoglobulin can bind to a number of membrane receptors on T cells, B cells, and monocytes that are pertinent to autoreactivity and induction of tolerance to self. A report stated that immunoglobulin application to activated T cells leads to their decreased ability to engage microglia. As a result of immunoglobulin treatment of T cells, the findings showed reduced levels of tumor necrosis factor-alpha and interleukin-10 in T cell-microglia co-culture. The results add to the understanding of how immunoglobulin may affect inflammation of the central nervous system in autoimmune inflammatory diseases. == Hyperimmune globulin == Hyperimmune globulins are a class of immunoglobulins prepared in a similar way as for normal human immunoglobulin, except that the donor has high titers of antibody against a specific organism or antigen in their plasma. Some agents against which hyperimmune globulins are available include hepatitis B, rabies, tetanus toxin, varicella-zoster, etc. Administration of hyperimmune globulin provides "passive" immunity to the patient against an agent. This is in contrast to vaccines that provide "active" immunity. However, vaccines take much longer to achieve that purpose while hyperimmune globulin provides instant "passive" short-lived immunity. Hyperimmune globulin may have serious side effects, thus usage is taken very seriously. Hyperimmune serum and plasma contain high amounts of an antibody, as a consequence of disease convalescence or of repeated immunization. Hyperimmune plasma is used in veterinary medicine, and hyperimmune plasma derivatives are used to treat snakebite. It has been hypothesized that hyperimmune serum may be an effective therapy for persons infected with the Ebola virus. == Society and culture == === Economics === In the United Kingdom a dose cost the NHS between £11.20 and £1,200.00 depending on the type and amount. In the United States, antivenoms may cost thousands of dollars per dose because of markups that occur after manufacturing. === Brand names === As biologicals, various brand names of immunoglobulin products are not necessarily interchangeable, and care must be exercised when changing between them. Brand names of intravenous immunoglobulin formulations include Flebogamma, Gamunex, Privigen, Octagam, and Gammagard, while brand names of subcutaneous formulations include Cutaquig, Cuvitru, HyQvia, Hizentra, Gamunex-C, and Gammaked. === Supply issues === The United States is one of a handful of countries that allow plasma donors to be paid, meaning that the US supplies much of the plasma-derived medicinal products (including immunoglobulin) used across the world, including more than 50% of the European Union's supply. The Council of Europe has officially endorsed the idea of not paying for plasma donations for both ethical reasons and reasons of safety, but studies have found that relying on entirely voluntary plasma donation leads to shortages of immunoglobulin and forces member countries to import immunoglobulin from countries that do compensate donors. In Australia, blood donation is voluntary and therefore to cope with increasing demand and to reduce the shortages of locally produced immunoglobulin, several programs have been undertaken including adopting plasma for first time blood donors, better processes for donation, plasma donor centres and encouraging current blood donors to consider plasma only donation. == Research == Experimental results from a small clinical trial in humans suggested protection against the progression of Alzheimer's disease, but no such benefit was found in a subsequent phase III clinical trial. In May 2020, the US approved a phase three clinical trial on the efficacy and safety of high-concentration intravenous immune globulin therapy in severe COVID-19. Efficacy of heterologous immunoglobulin derivatives has been demonstrated in clinical trials of antivenoms for scorpion sting and for snakebite. == References ==	Wikipedia/Immunoglobulin_therapy
Graves' disease, also known as toxic diffuse goiter or Basedow’s disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems. The exact cause of the disease is unclear, but symptoms are a result of antibodies binding to receptors on the thyroid causing over-expression of thyroid hormone. Persons are more likely to be affected if they have a family member with the disease. If one monozygotic twin is affected, a 30% chance exists that the other twin will also have the disease. The onset of disease may be triggered by physical or emotional stress, infection, or giving birth. Those with other autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, are more likely to be affected. Smoking increases the risk of disease and may worsen eye problems. The disorder results from an antibody, called thyroid-stimulating immunoglobulin (TSI), that has a similar effect to thyroid stimulating hormone (TSH). These TSI antibodies cause the thyroid gland to produce excess thyroid hormones. The diagnosis may be suspected based on symptoms and confirmed with blood tests and radioiodine uptake. Typically, blood tests show a raised T3 and T4, low TSH, increased radioiodine uptake in all areas of the thyroid, and TSI antibodies. The three treatment options are radioiodine therapy, medications, and thyroid surgery. Radioiodine therapy involves taking iodine-131 by mouth, which is then concentrated in the thyroid and destroys it over weeks to months. The resulting hypothyroidism is treated with synthetic thyroid hormones. Medications such as beta blockers may control some of the symptoms, and antithyroid medications such as methimazole may temporarily help people, while other treatments are having effect. Surgery to remove the thyroid is another option. Eye problems may require additional treatments. Graves disease develops in about 0.5% of males and 3.0% of females. It occurs about 7.5 times more often in women than in men. Often, it starts between the ages of 40 and 60, but can begin at any age. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases). The condition is named after Irish surgeon Robert Graves, who described it in 1835. A number of prior descriptions also exist. == Signs and symptoms == The signs and symptoms of Graves disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions being Graves ophthalmopathy, goiter, and pretibial myxedema (which are caused by the autoimmune processes of the disease). Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, oligomenorrhea, itching, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, periodic partial muscle weakness or paralysis in those especially of Asian descent, and skin warmth and moistness. Further signs that may be seen on physical examination are most commonly a diffusely enlarged (usually symmetric), nontender thyroid, lid lag, excessive lacrimation due to Graves' ophthalmopathy, arrhythmias of the heart, such as sinus tachycardia, atrial fibrillation, and premature ventricular contractions, and hypertension. == Cause == The exact cause is unclear, but it is believed to involve a combination of genetic and environmental factors. While a theoretical mechanism occurs by which exposure to severe stressors and high levels of subsequent distress such as post-traumatic stress disorder could increase the risk of immune disease and cause an aggravation of the autoimmune response that leads to Graves disease, more robust clinical data are needed for a firm conclusion. === Genetics === A genetic predisposition for Graves' disease is seen, with some people more prone to develop TSH receptor-activating antibodies due to a genetic cause. Human leukocyte antigen DR (especially DR3) appears to play a role. To date, no clear genetic defect has been found to point to a single-gene cause. Genes believed to be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), and cytotoxic T-lymphocyte–associated antigen 4, among others. === Infectious trigger === Since Graves disease is an autoimmune disease that appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies, which cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry. The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals. In the 1990s, Y. enterocolitica was suggested to be possibly associated with Graves' disease. More recently, the role for Y. enterocolitica has been disputed. Epstein–Barr virus is another potential trigger. == Mechanism == Thyroid-stimulating immunoglobulins recognize and bind to the TSH receptor, which stimulates the secretion of thyroxine (T4) and triiodothyronine (T3). Thyroxine receptors in the pituitary gland are activated by the surplus hormone, suppressing additional release of TSH in a negative feedback loop. The result is very high levels of circulating thyroid hormones and a low TSH level. === Pathophysiology === Graves' disease is an autoimmune disorder, in which the body produces antibodies that are specific to a self-protein - the receptor for thyroid-stimulating hormone. (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.) These antibodies cause hyperthyroidism because they bind to the TSHr and chronically stimulate it. The TSHr is expressed on the thyroid follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This, in turn, causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter. The infiltrative exophthalmos frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen, which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball. The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques. The three types of autoantibodies to the TSH receptor are: Thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as long-acting thyroid stimulants (LATS), activating the cells through a slower and more drawn out process compared to TSH, leading to an elevated production of thyroid hormone. Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles. Thyrotrophin binding-inhibiting immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. Some actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but prevent TSI and TSH from binding to and stimulating the receptor. Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early. Thyrotoxicosis can also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function. == Diagnosis == Graves disease may present clinically with one or more of these characteristic signs: Rapid heartbeat (80%) Diffuse palpable goiter with audible bruit (70%) Tremor (40%) Exophthalmos (protuberance of one or both eyes), periorbital edema (25%) Fatigue (70%), weight loss (60%) with increased appetite in young people and poor appetite in the elderly, and other symptoms of hyperthyroidism/thyrotoxicosis Heat intolerance (55%) Tremulousness (55%) Palpitations (50%) Two signs are truly diagnostic of Graves' disease (i.e., not seen in other hyperthyroid conditions): exophthalmos and non-pitting edema (pretibial myxedema). Goiter is an enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). Diffuse goiter may be seen with other causes of hyperthyroidism, although Graves' disease is the most common cause of diffuse goiter. A large goiter will be visible to the naked eye, but a small one (mild enlargement of the gland) may be detectable only by physical examination. Occasionally, goiter is not clinically detectable, but may be seen only with computed tomography or ultrasound examination of the thyroid. Another sign of Graves' disease is hyperthyroidism, that is, overproduction of the thyroid hormones T3 and T4. Normal thyroid levels are also seen, and occasionally also hypothyroidism, which may assist in causing goiter (though it is not the cause of the Graves' disease). Hyperthyroidism in Graves' disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free (unbound) T4. Other useful laboratory measurements in Graves disease include thyroid-stimulating hormone (TSH, usually undetectable in Graves' disease due to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated). Serologically detected thyroid-stimulating antibodies, radioactive iodine uptake, or thyroid ultrasound with Doppler all can independently confirm a diagnosis of Graves' disease. Biopsy to obtain histiological testing is not normally required, but may be obtained if thyroidectomy is performed. The goiter in Graves' disease is often not nodular, but thyroid nodules are also common. Differentiating common forms of hyperthyroidism such as Graves' disease, single thyroid adenoma, and toxic multinodular goiter is important to determine proper treatment. The differentiation among these entities has advanced, as imaging and biochemical tests have improved. Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study. === Eye disease === Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease (TED), is the most common extrathyroidal manifestation of Graves' disease. It is a form of idiopathic lymphocytic orbital inflammation, and although its pathogenesis is not completely understood, autoimmune activation of orbital fibroblasts, which in TAO express the TSH receptor, is thought to play a central role. Hypertrophy of the extraocular muscles, adipogenesis, and deposition of nonsulfated glycosaminoglycans and hyaluronate, causes expansion of the orbital fat and muscle compartments, which within the confines of the bony orbit may lead to dysthyroid optic neuropathy, increased intraocular pressures, proptosis, venous congestion leading to chemosis and periorbital edema, and progressive remodeling of the orbital walls. Other distinctive features of TAO include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, and exposure keratopathy. Severity of eye disease may be classified by the mnemonic: "NO SPECS": Class 0: No signs or symptoms Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag) Class 2: Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc.) Class 3: Proptosis Class 4: Extraocular muscle involvement (usually with diplopia) Class 5: Corneal involvement (primarily due to lagophthalmos) Class 6: Sight loss (due to optic nerve involvement) Typically, the natural history of TAO follows Rundle's curve, which describes a rapid worsening during an initial phase, up to a peak of maximum severity, and then improvement to a static plateau without, however, resolving back to a normal condition. == Management == Treatment of Graves disease includes antithyroid drugs that reduce the production of thyroid hormone, radioiodine (radioactive iodine I-131) and thyroidectomy (surgical excision of the gland). As operating on a hyperthyroid patient is dangerous, prior to thyroidectomy, preoperative treatment with antithyroid drugs is given to render the patient euthyroid. Each of these treatments has advantages and disadvantages, and no single treatment approach is considered the best for everyone. Treatment with antithyroid medications must be administered for six months to two years to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. The risk of recurrence is about 40–50%, and lifelong treatment with antithyroid drugs carries some side effects such as agranulocytosis and liver disease. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells. Therapy with radioiodine is the most common treatment in the United States, while antithyroid drugs and/or thyroidectomy are used more often in Europe, Japan, and most of the rest of the world. β-Blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia and nausea until antithyroid treatments start to take effect. Pure β-blockers do not inhibit lid retraction in the eyes, which is mediated by alpha adrenergic receptors. === Antithyroid drugs === The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil/PTU. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side effect is agranulocytosis (1/250, more in PTU). Others include granulocytopenia (dose-dependent, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk. Lugol's iodine may be used to block hormone synthesis before surgery. A randomized control trial testing single-dose treatment for Graves found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups). No difference in outcome was shown for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However, two markers were found that can help predict the risk of recurrence. These two markers are a positive TSHr antibody (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), and a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab. === Radioiodine === Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are failed medical therapy or surgery and where medical or surgical therapy are contraindicated. Hypothyroidism may be a complication of this therapy, but may be treated with thyroid hormones if it appears. The rationale for radioactive iodine is that it accumulates in the thyroid and irradiates the gland with its beta and gamma radiations, about 90% of the total radiation being emitted by the beta (electron) particles. The most common method of iodine-131 treatment is to administer a specified amount in microcuries per gram of thyroid gland based on palpation or radiodiagnostic imaging of the gland over 24 hours. Patients who receive the therapy must be monitored regularly with thyroid blood tests to ensure they are treated with thyroid hormone before they become symptomatically hypothyroid. Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitary nodules. Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring eventual thyroid hormone supplementation in the form of a daily pill(s). The radioiodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves' disease–associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered. In rare cases, radiation induced thyroiditis has been linked to this treatment. === Surgery === This modality is suitable for young people and pregnant females. Indications for thyroidectomy can be separated into absolute indications or relative indications. These indications aid in deciding which people would benefit most from surgery. The absolute indications are a large goiter (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid), and people with ophthalmopathy and additionally if it is the person's preferred method of treatment or if refusing to undergo radioactive iodine treatment. Pregnancy is advised to be delayed for six months after radioactive iodine treatment. Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on one side and partial lobectomy on other side) are possible. Advantages are immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea), relapse following medical treatment, infections (less common), and scarring. The increase in the risk of nerve injury can be due to the increased vascularity of the thyroid parenchyma and the development of links between the thyroid capsule and the surrounding tissues. Reportedly, a 1% incidence exists of permanent recurrent laryngeal nerve paralysis after complete thyroidectomy. Risks related to anesthesia are many, thus coordination with the anesthesiologist and patient optimization for surgery preoperatively are essential. Removal of the gland enables complete biopsy to be performed to have definite evidence of cancer anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of the thyroid). No further treatment of the thyroid is required, unless cancer is detected. Radioiodine uptake study may be done after surgery, to ensure all remaining (potentially cancerous) thyroid cells (i.e., near the nerves to the vocal cords) are destroyed. Besides this, the only remaining treatment will be levothyroxine, or thyroid replacement pills to be taken for the rest of the patient's life. A 2013 review article concludes that surgery appears to be the most successful in the management of Graves' disease, with total thyroidectomy being the preferred surgical option. === Eyes === Mild cases are treated with lubricant eye drops or nonsteroidal anti-inflammatory drops. Severe cases threatening vision (corneal exposure or optic nerve compression) are treated with steroids or orbital decompression. In all cases, cessation of smoking is essential. Double vision can be corrected with prism glasses and surgery (the latter only when the process has been stable for a while). Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full, deep sleep. Orbital decompression can be performed to enable bulging eyes to retreat back into the head. Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty tissue to fall back into the skull. For management of clinically active Graves disease, orbitopathy (clinical activity score >2) with at least mild to moderate severity, intravenous glucocorticoids are the treatment of choice, usually administered in the form of pulse intravenous methylprednisolone. Studies have consistently shown that pulse intravenous methylprednisolone is superior to oral glucocorticoids both in terms of efficacy and decreased side effects for managing Graves' orbitopathy. == Prognosis == If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, bone mineral loss and, in extreme cases, death (e.g. indirectly through complications, or through a thyroid storm event). Graves' disease is often accompanied by an increase in heart rate, which may lead to further heart complications, including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. If the eyes are proptotic (bulging) enough that the lids do not close completely at night, dryness will occur – with the risk of a secondary corneal infection, which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss, as well. Prolonged untreated hyperthyroidism can lead to bone loss, which may resolve when treated. == Epidemiology == Graves' disease occurs in about 0.5% of people. Graves' disease data has shown that the lifetime risk for women is around 3% and 0.5% for men. It occurs about 7.5 times more often in women than in men and often starts between the ages of 40 and 60. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases). == History == Graves disease owes its name to the Anglo-Irish doctor Robert James Graves, who described a case of goiter with exophthalmos in 1835. (Medical eponyms are often styled nonpossessively; thus Graves' disease and Graves disease are variant stylings of the same term.) The German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, on the European continent, the terms "Basedow syndrome", "Basedow disease", or "Morbus Basedow" are more common than "Graves' disease". Graves disease has also been called exophthalmic goiter. Less commonly, it has been known as Parry disease, Begbie disease, Flajan disease, Flajani–Basedow syndrome, and Marsh disease. These names for the disease were derived from Caleb Hillier Parry, James Begbie, Giuseppe Flajani, and Henry Marsh. Early reports, not widely circulated, of cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810, respectively. Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th century (and a friend of Edward Miller-Gallus), described a case in 1786. This case was not published until 1825 - ten years ahead of Graves. However, fair credit for the first description of Graves disease goes to the 12th-century Persian physician Sayyid Ismail al-Jurjani, who noted the association of goiter and exophthalmos in his Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time. == Society and culture == === Notable cases === Ayaka, Japanese singer, was diagnosed with Graves disease in 2007. After going public with her diagnosis in 2009, she took a two-year hiatus from music to focus on treatment. Susan Elizabeth Blow, American educator and founder of the first publicly funded kindergarten in the United States, was forced to retire and seek treatment for Graves disease in 1884. George H. W. Bush, former U.S. president, developed new atrial fibrillation and was diagnosed in 1991 with hyperthyroidism due to the disease and treated with radioactive iodine. The president's wife, Barbara Bush, also developed the disease around the same time, which, in her case, produced severe infiltrative exophthalmos. Rodney Dangerfield, American comedian and actor Gail Devers, American sprinter: A doctor considered amputating her feet after she developed blistering and swelling following radiation treatment for Graves' disease, but she went on to recover and win Olympic medals. Missy Elliott, American hip-hop artist Marty Feldman, British comedy writer, comedian and actor Sia, Australian singer and songwriter Sammy Gravano, Italian-American former underboss of the Gambino crime family Jim Hamilton, Scottish rugby player, discovered he had Graves' disease shortly after retiring from the sport in 2017. Heino, German folk singer, whose dark sunglasses (worn to hide his symptoms) became part of his trademark look Herbert Howells, British composer; the first person to be treated with radium injections Vybz Kartel, Jamaican dancehall musician; contracted disease while incarcerated Yayoi Kusama, Japanese artist Nadezhda Krupskaya, Russian Communist and wife of Vladimir Lenin Umm Kulthum was an Egyptian singer, songwriter, and film actress active from the 1920s to the 1970s. Barbara Leigh, an American former actress and fashion model, now spokeswoman for the National Graves' Disease Foundation Keiko Masuda, Japanese singer and one-half of the duo Pink Lady. Yūko Miyamura, Japanese voice actress Lord Monckton, former UKIP and Conservative politician; notorious promoter of climate change denial Sophia Parnok, Russian poet Sir Cecil Spring Rice, British ambassador to the United States during World War I, died suddenly of the disease in 1918. Daisy Ridley, British actress Christina Rossetti, English Victorian-era poet Dame Maggie Smith, British actress Mary Webb, British novelist and poet Wendy Williams, American TV show host Act Yasukawa, Japanese professional wrestler === Literature === In Italo Svevo's novel Zeno's Conscience, character Ada develops the disease. Ern Malley was an acclaimed Australian poet whose work was not published until after his death from Graves' disease in 1943. However, Malley's existence and entire biography was actually later revealed to be a literary hoax. == Research == Agents that act as antagonists at thyroid stimulating hormone receptors are under investigation as a possible treatment for Graves' disease. == References == == External links == "Graves' disease". Genetics Home Reference. U.S. National Library of Medicine. Graves disease on ncbi	Wikipedia/Graves'_disease
Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection. ADCC is independent of the immune complement system that also lyses targets but does not require any other cell. ADCC requires an effector cell which classically is known to be natural killer (NK) cells that typically interact with immunoglobulin G (IgG) antibodies. However, macrophages, neutrophils and eosinophils can also mediate ADCC, such as eosinophils killing certain parasitic worms known as helminths via IgE antibodies. In general, ADCC has typically been described as the immune response to antibody-coated cells leading ultimately to the lysing of the infected or non-host cell. In recent literature, its importance in regards to treatment of cancerous cells and deeper insight into its deceptively complex pathways have been topics of increasing interest to medical researchers. == NK cells == The typical ADCC involves activation of NK cells by antibodies in a multi-tiered progression of immune control. A NK cell expresses Fcγ receptors. These receptors recognize and bind to the reciprocal portion of an antibody, such as IgG, which binds to the surface of a pathogen-infected target cell. The most common of these Fc receptors on the surface of an NK cell is CD16 or FcγRIII. Once the Fc receptor binds to the Fc region of the antibody, the NK cell releases cytotoxic factors that cause the death of the target cell. During replication of a virus, some of the viral proteins are expressed on the cell surface membrane of the infected cell. Antibodies can then bind to these viral proteins. Next, the NK cells which have reciprocal Fcγ receptors will bind to that antibody, inducing the NK cell to release proteins such as perforin and proteases known as granzymes, which causes the lysis of the infected cell to hinder the spread of the virus. == Eosinophils == Large parasites like helminths are too big to be engulfed and killed by phagocytosis. They also have an external structure or integument that is resistant to attack by substances released by neutrophils and macrophages. After IgE coat these parasites, the Fc receptor (FcɛRI) of an eosinophil will recognize IgE. Subsequently, interaction between FcεRI and the Fc portion of helminth-bound IgE signals the eosinophil to degranulate. == In vitro assays == Several laboratory methods exist for determining the efficacy of antibodies or effector cells in eliciting ADCC. Usually, a target cell line expressing a certain surface-exposed antigen is incubated with antibody specific for that antigen. After washing, effector cells expressing Fc receptor CD16 are co-incubated with the antibody-labelled target cells. Effector cells are typically PBMCs (peripheral blood mononuclear cell), of which a small percentage are NK cells (natural killer cell); less often they are purified NK cells themselves. Over the course of a few hours a complex forms between the antibody, target cell, and effector cell which leads to lysis of the cell membrane of the target. If the target cell was pre-loaded with a label of some sort, that label is released in proportion to the amount of cell lysis. Cytotoxicity can be quantified by measuring the amount of label in solution compared to the amount of label that remains within healthy, intact cells. The classical method of detecting this is the chromium-51 [51Cr] release assay; the sulfur-35 [35S] release assay is a little used radioisotope-based alternative. Target cell lysis is determined by measuring the amount of radiolabel released into the cell culture medium by means of a gamma counter or scintillation counter. A variety of non-radioactive methods are now in widespread use. Fluorescence-based methods include such things as direct labelling with a fluorescent dye like calcein or labelling with europium that becomes fluorescent when released Eu3+ binds to a chelator. Fluorescence can be measured by means of multi-well fluorometers or by flow cytometry methods. There are also enzymatic-based assays in which the contents of the lysed cells includes cellular enzymes like GAPDH that remain active; supplying a substrate for that enzyme can catalyze a reaction whose product can be detected by luminescence or by absorbance. == Medical applications == NK cells are involved in killing tumor cells and other cells that may lack MHC I on their surface, indicating a non-self cell. NK cells have been shown to behave similarly to memory cells due to their ability to react to destroy non-host cells only after interacting with a host cell. As NK cells are not themselves specific to certain pathways of immune control, they are utilized a majority of the time in ADCC as a less discriminate cell destroyer than antibody-specific apoptosis mechanisms. The ability of activated ex vivo NK cells has been a topic of interest for the treatment of tumors. After early clinical trials involving activation through cytokines produced poor results and severe toxicological side effects, more recent studies have produced success in regulating metastatic tumors using interleukin proteins to activate the NK cell. The effects against solid tumors of trastuzumab and rituximab monoclonal antibodies have been shown in experiments with mice to involve ADCC as an important mechanism of therapeutic action. In the clinic, the FcgRIII 158V/F polymorphism interfere with the ability to generate ADCC responses in vitro during trastuzumab treatment. Multiple myeloma can be treated with daratumumab (Darzalex) monoclonal antibody. Studies with in vitro materials and patient materials indicate that ADCC is an important mechanism, along with CDC (complement-dependent cytotoxicity). ADCC as used in immune control is typically more useful for viral infections than bacterial infections due to IgG antibodies binding to virus-related antigens over prokaryotic cells. Instead of ADCC removing outside toxins, immunoglobulins neutralize products of infecting bacteria and encase infected host cells that have had bacterial toxins directly inserted through the cell membrane. ADCC is also important in the use of vaccines, as creation of antibodies and the destruction of antigens introduced to the host body are crucial to building immunity through small exposure to viral and bacterial proteins. Examples of this include vaccines targeting repeats in toxins (RTX) that are structurally crucial to a wide variety of erythrocyte-lysing bacteria, described as hemolysins. These bacteria target the CD18 portion of leukocytes, which has historically been shown to impact ADCC in adhesion-deficient cells. == See also == Afucosylated monoclonal antibodies == References == == Further reading == Janeway CA Jr.; et al. (2001). Immunobiology (5th ed.). Garland Publishing. ISBN 0-8153-3642-X. (electronic full text via NCBI Bookshelf). Pier GB, Lyczak JB, Wetzler LM (2004). Immunology, Infection, and Immunity. ASM Press. ISBN 1-55581-246-5. == External links == University of Leicester, Virus Immunopathology Notes Antibody-Dependent+Cell+Cytotoxicity at the U.S. National Library of Medicine Medical Subject Headings (MeSH)	Wikipedia/Antibody-dependent_cellular_cytotoxicity
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spelt and barley. Classic symptoms include gastrointestinal problems such as chronic diarrhoea, abdominal distention, malabsorption, loss of appetite, and among children failure to grow normally. Non-classic symptoms are more common, especially in people older than two years. There may be mild or absent gastrointestinal symptoms, a wide number of symptoms involving any part of the body, or no obvious symptoms. Due to the frequency of these symptoms, coeliac disease is often considered a systemic disease, rather than a gastrointestinal condition. Coeliac disease was first described as a disease which initially presents during childhood; however, it may develop at any age. It is associated with other autoimmune diseases, such as Type 1 diabetes mellitus and Hashimoto's thyroiditis, among others. Coeliac disease is caused by a reaction to gluten, a group of various proteins found in wheat and in other grains such as barley and rye. Moderate quantities of oats, free of contamination with other gluten-containing grains, are usually tolerated. The occurrence of problems may depend on the variety of oat. It occurs more often in people who are genetically predisposed. Upon exposure to gluten, an abnormal immune response may lead to the production of several different autoantibodies that can affect a number of different organs. In the small bowel, this causes an inflammatory reaction and may produce shortening of the villi lining the small intestine (villous atrophy). This affects the absorption of nutrients, frequently leading to anaemia. Diagnosis is typically made by a combination of blood antibody tests and intestinal biopsies, helped by specific genetic testing. Making the diagnosis is not always straightforward. About 10% of the time, the autoantibodies in the blood are negative, and many people have only minor intestinal changes with normal villi. People may have severe symptoms and they may be investigated for years before a diagnosis is achieved. As a result of screening, the diagnosis is increasingly being made in people who have no symptoms. Evidence regarding the effects of screening, however, is currently insufficient to determine its usefulness. While the disease is caused by a permanent intolerance to gluten proteins, it is distinct from wheat allergy, which is much more rare. The only known effective treatment is a strict lifelong gluten-free diet, which leads to recovery of the intestinal lining (mucous membrane), improves symptoms, and reduces the risk of developing complications in most people. If untreated, it may result in cancers such as intestinal lymphoma, and a slightly increased risk of early death. Rates vary between different regions of the world, from as few as 1 in 300 to as many as 1 in 40, with an average of between 1 in 100 and 1 in 170 people. It is estimated that 80% of cases remain undiagnosed, usually because of minimal or absent gastrointestinal complaints and lack of knowledge of symptoms and diagnostic criteria. Coeliac disease is slightly more common in women than in men. == Signs and symptoms == The classic symptoms of untreated coeliac disease include diarrhea, steatorrhoea, iron-deficiency anemia, and weight loss or failure to gain weight. Other common symptoms may be subtle or primarily occur in organs other than the bowel itself. It is also possible to have coeliac disease without any of the classic symptoms at all. This has been shown to comprise at least 43% of presentations in children. Further, many adults with subtle disease may only present with fatigue, anaemia or low bone mass. Many undiagnosed individuals who consider themselves asymptomatic are in fact not, but rather have become accustomed to living in a state of chronically compromised health. Indeed, after starting a gluten-free diet and subsequent improvement becomes evident, such individuals are often able to retrospectively recall and recognise prior symptoms of their untreated disease that they had mistakenly ignored. === Gastrointestinal === Diarrhoea that is characteristic of coeliac disease is chronic, sometimes pale, of large volume, and abnormally foul in odor. Abdominal pain, cramping, bloating with abdominal distension (thought to be the result of fermentative production of bowel gas), and mouth ulcers may be present. As the bowel becomes more damaged, a degree of lactose intolerance may develop. This is because in addition to damage in the intestines, coeliac disease can cause a lactase deficiency, which is the enzyme that is responsible for breaking down lactose. Frequently, the symptoms are ascribed to irritable bowel syndrome (IBS), only later to be recognised as coeliac disease. In populations of people with symptoms of IBS, a diagnosis of coeliac disease can be made in about 3.3% of cases, or four times more likely than in general. Screening them for coeliac disease is recommended by the National Institute for Health and Clinical Excellence (NICE), the British Society of Gastroenterology and the American College of Gastroenterology, but is of unclear benefit in North America. Coeliac disease leads to an increased risk of both adenocarcinoma and lymphoma of the small bowel (enteropathy-associated T-cell lymphoma (EATL) or other non-Hodgkin lymphomas). This risk is also higher in first-degree relatives such as siblings, parents and children. Whether a gluten-free diet brings this risk back to baseline is not clear. Long-standing and untreated disease may lead to other complications, such as ulcerative jejunitis (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring with obstruction of the bowel). === Malabsorption-related === The changes in the bowel reduce its ability to absorb nutrients, minerals, and the fat-soluble vitamins A, D, E, and K. Malabsorption of carbohydrates and fats may cause weight loss (or failure to thrive or stunted growth in children) and fatigue or lack of energy. Anaemia may develop in several ways: iron malabsorption may cause iron deficiency anaemia, and folic acid and vitamin B12 malabsorption may give rise to megaloblastic anaemia. Calcium and vitamin D malabsorption (and compensatory secondary hyperparathyroidism) may cause osteopenia (decreased mineral content of the bone) or osteoporosis (bone weakening and risk of fragility fractures). Selenium malabsorption in coeliac disease, combined with low selenium content in many gluten-free foods, confers a risk of selenium deficiency. Copper and zinc deficiencies have also been associated with coeliac disease. A small proportion of people have abnormal coagulation because of vitamin K deficiency and are at a slight risk of abnormal bleeding. === Miscellaneous === Coeliac disease has been linked with many conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition. IgA deficiency is present in 2.3% of people with coeliac disease, and is itself associated with a tenfold increased risk of coeliac disease. Other features of this condition are an increased risk of infections and autoimmune disease. Dermatitis herpetiformis, an itchy cutaneous condition that has been linked to a transglutaminase enzyme in the skin, features small-bowel changes identical to those in coeliac disease and may respond to gluten withdrawal even if no gastrointestinal symptoms are present. Growth failure and/or pubertal delay in later childhood can occur even without obvious bowel symptoms or severe malnutrition. Evaluation of growth failure often includes coeliac screening. Pregnancy complications can occur if coeliac disease is pre-existing or later acquired, with significant outcomes including miscarriage, intrauterine growth restriction, low birthweight and preterm birth. Hyposplenism (a small and underactive spleen) occurs in about a third of cases and may predispose to infection given the role of the spleen in protecting against harmful bacteria. Abnormal liver function tests (randomly detected on blood tests) may be seen. Depression, anxiety and other mental health disorders Coeliac disease is associated with several other medical conditions, many of which are autoimmune disorders: diabetes mellitus type 1, hypothyroidism, primary biliary cholangitis, microscopic colitis, gluten ataxia, psoriasis, vitiligo, autoimmune hepatitis, primary sclerosing cholangitis, and more. == Causes == Coeliac disease is caused by an inflammatory reaction to gliadins and glutenins (gluten proteins) found in wheat and to similar proteins found in the crops of the tribe Triticeae (which includes other common grains such as barley and rye) and to the tribe Aveneae (oats). Wheat subspecies (such as spelt, durum, and Kamut) and wheat hybrids (such as triticale) also cause symptoms of coeliac disease. A small number of people with coeliac disease react to oats. Oat toxicity in coeliac people depends on the oat cultivar consumed because the prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins are different in different oat varieties. Also, oats are frequently cross-contaminated with other grains containing gluten. The term "pure oats" refers to oats uncontaminated with other gluten-containing cereals. The long-term effects of pure oat consumption are still unclear, and further studies identifying the cultivars used are needed before making final recommendations on their inclusion in a gluten-free diet. Coeliac people who choose to consume oats need a more rigorous lifelong follow-up, possibly including periodic intestinal biopsies. === Other grains === Other cereals such as corn, millet, sorghum, teff, rice, and wild rice are safe for people with coeliac disease to consume, as well as non-cereals such as amaranth, quinoa, and buckwheat. Noncereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms. === Risk modifiers === There are various theories as to what determines whether a genetically susceptible individual will go on to develop coeliac disease. Major theories include surgery, pregnancy, infection and emotional stress. The eating of gluten early in a baby's life does not appear to increase the risk of coeliac disease but later introduction after six months may increase it. There is uncertainty whether being breastfed reduces risk. Prolonging breastfeeding until the introduction of gluten-containing grains into the diet appears to be associated with a 50% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear. These factors may just influence the timing of onset. == Mechanism == Coeliac disease appears to be multifactorial, both in that more than one genetic factor can cause the disease and in that more than one factor is necessary for the disease to manifest in a person. Almost all people (95%) with coeliac disease have either the variant HLA-DQ2 allele or (less commonly) the HLA-DQ8 allele. However, about 20–30% of people without coeliac disease have also inherited either of these alleles. This suggests that additional factors are needed for coeliac disease to develop; that is, the predisposing HLA risk allele is necessary but not sufficient to develop coeliac disease. Furthermore, around 5% of those people who do develop coeliac disease do not have typical HLA-DQ2 or HLA-DQ8 alleles (see below). === Genetics === The vast majority of people with coeliac have one of two types (out of seven) of the HLA-DQ protein. HLA-DQ is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. The two subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and HLA-DQB1 genes, located on the short arm of chromosome 6. There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of people with coeliac have the isoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process. Most people with coeliac bear a two-gene HLA-DQ2 haplotype referred to as DQ2.5 haplotype. This haplotype is composed of two adjacent gene alleles, DQA10501 and DQB10201, which encode the two subunits, DQ α5 and DQ β2. In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents (DQ2.5cis). Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from both parents; the latter are especially at risk for coeliac disease as well as being more susceptible to severe complications. Some individuals inherit DQ2.5 from one parent and an additional portion of the haplotype (either DQB102 or DQA105) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA105 allele from one parent and the DQB102 from the other parent (DQ2.5trans) (called a trans-haplotype association), and these individuals are at similar risk for coeliac disease as those with a single DQ2.5-bearing chromosome 6, but in this instance, the disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA103:DQB10302), 4% have the DQ2.2 isoform, and the remaining 2% lack DQ2 or DQ8. The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe (Basque Country and Ireland with highest frequencies) and portions of Africa and is associated with disease in India, but it is not found along portions of the West Pacific rim. DQ8 has a wider global distribution than DQ2.5 and is particularly common in South and Central America; up to 90% of individuals in certain Amerindian populations carry DQ8 and thus may display the coeliac phenotype. Other genetic factors have been repeatedly reported in coeliac disease; however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population. Many of the loci detected have been found in association with other autoimmune diseases. One locus, the LPP or lipoma-preferred partner gene, is involved in the adhesion of extracellular matrix to the cell surface, and a minor variant (SNP=rs1464510) increases the risk of disease by approximately 30%. This gene strongly associates with coeliac disease (p < 10−39) in samples taken from a broad area of Europe and the US. The prevalence of coeliac disease genotypes in the modern population is not completely understood. Given the characteristics of the disease and its apparent strong heritability, it would normally be expected that the genotypes would undergo negative selection and to be absent in societies where agriculture has been practised the longest (compare with a similar condition, lactose intolerance, which has been negatively selected so strongly that its prevalence went from ~100% in ancestral populations to less than 5% in some European countries). This expectation was first proposed by Simoons (1981). By now, however, it is apparent that this is not the case; on the contrary, there is evidence of positive selection in coeliac disease genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections. === Prolamins === The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. These are storage proteins rich in proline (prol-) and glutamine (-amin) that dissolve in alcohols and are resistant to proteases and peptidases of the gut. Prolamins are found in cereal grains with different grains having different but related prolamins: wheat (gliadin), barley (hordein), rye (secalin) and oats (avenin). One region of α-gliadin stimulates membrane cells, enterocytes, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than three amino acids to enter the intestinal lining. Membrane leaking permits peptides of gliadin that stimulate two levels of the immune response: the innate response, and the adaptive (T-helper cell-mediated) response. One protease-resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. This innate response to gliadin results in immune-system signalling that attracts inflammatory cells and increases the release of inflammatory chemicals. The strongest and most common adaptive response to gliadin is directed toward an α2-gliadin fragment of 33 amino acids in length. The response to the 33mer occurs in most coeliacs who have a DQ2 isoform. This peptide, when altered by intestinal transglutaminase, has a high density of overlapping T-cell epitopes. This increases the likelihood that the DQ2 isoform will bind, and stay bound to, peptide when recognised by T-cells. Gliadin in wheat is the best-understood member of this family, but other prolamins exist, and hordein (from barley), secalin (from rye), and avenin (from oats) may contribute to coeliac disease. Avenin's toxicity in people with coeliac disease depends on the oat cultivar consumed, as prolamin genes, protein amino acid sequences, and the immunoreactivities of toxic prolamins vary among oat varieties. === Tissue transglutaminase === Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in the blood of the majority of people with classic symptoms and complete villous atrophy, but only in 70% of the cases with partial villous atrophy and 30% of the cases with minor mucosal lesions. Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively. These peptides are modified by tTG in two ways, deamidation or transamidation. Deamidation is the reaction by which a glutamate residue is formed by cleavage of the epsilon-amino group of a glutamine side chain. Transamidation, which occurs three times more often than deamidation, is the cross-linking of a glutamine residue from the gliadin peptide to a lysine residue of tTg in a reaction that is catalysed by the transglutaminase. Crosslinking may occur either within or outside the active site of the enzyme. The latter case yields a permanently covalently linked complex between the gliadin and the tTg. This results in the formation of new epitopes believed to trigger the primary immune response by which the autoantibodies against tTg develop. Stored biopsies from people with suspected coeliac disease have revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in people who present with other autoimmune diseases, anaemia, or malabsorption phenomena at a much increased rate over the normal population. Endomysial components of antibodies (EMA) to tTG are believed to be directed toward cell-surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative people with coeliac tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms, including autoimmune disease. In this study, the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with work showing that gliadin has an innate response component, suggest that gliadin may be more responsible for the primary manifestations of coeliac disease, whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases. In a large percentage of people with coeliac, the anti-tTG antibodies also recognise a rotavirus protein called VP7. These antibodies stimulate monocyte proliferation, and rotavirus infection might explain some early steps in the cascade of immune cell proliferation. Indeed, earlier studies of rotavirus damage in the gut showed this causes villous atrophy. This suggests that viral proteins may take part in the initial flattening and stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin-mediated tTG presentation provides a second source of crossreactive antibodies. Other intestinal disorders may have biopsy that look like coeliac disease including lesions caused by Candida. === Villous atrophy and malabsorption === The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel's mucosal lining and causes malabsorption as it impairs the body's ability to absorb nutrients, minerals, and fat-soluble vitamins A, D, E, and K from food. Lactose intolerance may be present due to the decreased bowel surface and reduced production of lactase but typically resolves once the coeliac disease is under control. Rarely, lactose intolerance may be the only noticeable symptom of underlying coeliac disease. Alternative causes of this tissue damage have been proposed and involve the release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of enterocytes by lymphocytes in the epithelium. The villous atrophy seen on biopsy may also be due to unrelated causes, such as tropical sprue, giardiasis and radiation enteritis. While positive serology and typical biopsy are highly suggestive of coeliac disease, lack of response to the diet may require these alternative diagnoses to be considered. == Diagnosis == Diagnosis is often difficult and as of 2019, there continues to be a lack of awareness among physicians about the variability of presentations of coeliac disease and the diagnostic criteria, such that most cases are diagnosed with great delay. It can take up to 12 years to receive a diagnosis from the onset of symptoms and the majority of those affected in most countries never receive it. Several tests can be used. The level of symptoms may determine the order of the tests, but all tests lose their usefulness if the person is already eating a gluten-free diet. Intestinal damage begins to heal within weeks of gluten being removed from the diet, and antibody levels decline over months. For those who have already started on a gluten-free diet, it may be necessary to perform a rechallenge with some gluten-containing food in one meal a day over six weeks before repeating the investigations. === Blood tests === Serological blood tests are the first-line investigation required to make a diagnosis of coeliac disease. Its sensitivity correlates with the degree of histological lesions. People who present with minor damage to the small intestine may have seronegative findings so many patients with coeliac disease often are missed. In patients with villous atrophy, anti-endomysial (EMA) antibodies of the immunoglobulin A (IgA) type can detect coeliac disease with a sensitivity and specificity of 90% and 99%, respectively. Serology for anti-transglutaminase antibodies (anti-tTG) was initially reported to have a higher sensitivity (99%) and specificity (>90%). However, it is now thought to have similar characteristics to anti-endomysial antibodies. Both anti-transglutaminase and anti-endomysial antibodies have high sensitivity to diagnose people with classic symptoms and complete villous atrophy, but they are only found in 30–89% of the cases with partial villous atrophy and in less than 50% of the people who have minor mucosal lesions (duodenal lymphocytosis) with normal villi. Tissue transglutaminase (abbreviated as tTG or TG2) modifies gluten peptides into a form that may stimulate the immune system more effectively. These peptides are modified by tTG in two ways, deamidation or transamidation. Modern anti-tTG assays rely on a human recombinant protein as an antigen. tTG testing should be done first as it is an easier test to perform. An equivocal result on tTG testing should be followed by anti-endomysial antibodies. Guidelines recommend that a total serum IgA level is checked in parallel, as people with coeliac with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false negative"). In those people, IgG antibodies against transglutaminase (IgG-tTG) may be diagnostic. If all these antibodies are negative, then anti-DGP antibodies (antibodies against deamidated gliadin peptides) should be determined. IgG class anti-DGP antibodies may be useful in people with IgA deficiency. In children younger than two years, anti-DGP antibodies perform better than anti-endomysial and anti-transglutaminase antibodies tests. Because of the major implications of a diagnosis of coeliac disease, professional guidelines recommend that a positive blood test is still followed by an endoscopy/gastroscopy and biopsy. A negative serology test may still be followed by a recommendation for endoscopy and duodenal biopsy if clinical suspicion remains high. Historically three other antibodies were measured: anti-reticulin (ARA), anti-gliadin (AGA) and anti-endomysial (EMA) antibodies. ARA testing, however, is not accurate enough for routine diagnostic use. Serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five. Serology tests are based on indirect immunofluorescence (reticulin, gliadin and endomysium) or ELISA (gliadin or tissue transglutaminase, tTG). Other antibodies such as anti–Saccharomyces cerevisiae antibodies occur in some people with coeliac disease but also occur in other autoimmune disorders and about 5% of those who donate blood. Antibody testing may be combined with HLA testing if the diagnosis is unclear. TGA and EMA testing are the most sensitive serum antibody tests, but as a negative HLA-DQ type excludes the diagnosis of coeliac disease, testing also for HLA-DQ2 or DQ8 maximises sensitivity and negative predictive values. In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) does not (as of 2015) recommend the use of HLA typing to rule out coeliac disease outside of a specialist setting, for example, in children who are not having a biopsy, or in patients who already have limited gluten ingestion and opt not to have a gluten challenge. === Endoscopy === An upper endoscopy with biopsy of the duodenum (beyond the duodenal bulb) or jejunum is performed to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative. Even in the same bioptic fragment, different degrees of damage may be present. Most people with coeliac disease have a small intestine that appears to be normal on endoscopy before the biopsies are examined. However, five findings have been associated with high specificity for coeliac disease: scalloping of the small bowel folds (pictured), paucity in the folds, a mosaic pattern to the mucosa (described as a "cracked-mud" appearance), prominence of the submucosa blood vessels, and a nodular pattern to the mucosa. European guidelines suggest that in children and adolescents with symptoms compatible with coeliac disease, the diagnosis can be made without the need for intestinal biopsy if anti-tTG antibodies titres are very high (10 times the upper limit of normal). Until the 1970s, biopsies were obtained using metal capsules attached to a suction device. The capsule was swallowed and allowed to pass into the small intestine. After x-ray verification of its position, suction was applied to collect part of the intestinal wall inside the capsule. Often-utilised capsule systems were the Watson capsule and the Crosby–Kugler capsule. This method has now been largely replaced by fibre-optic endoscopy, which carries a higher sensitivity and a lower frequency of errors. Capsule endoscopy (CE) allows identification of typical mucosal changes observed in coeliac disease but has a lower sensitivity compared to regular endoscopy and histology. CE is therefore not the primary diagnostic tool for coeliac disease. However, CE can be used for diagnosing T-cell lymphoma, ulcerative jejunoileitis, and adenocarcinoma in refractory or complicated coeliac disease. === Pathology === The classic pathology changes of coeliac disease in the small bowel are categorised by the "Marsh classification": Marsh stage 0: normal mucosa Marsh stage 1: increased number of intra-epithelial lymphocytes (IELs), usually exceeding 20 per 100 enterocytes Marsh stage 2: a proliferation of the crypts of Lieberkühn Marsh stage 3: partial or complete villous atrophy and crypt hyperplasia Marsh stage 4: hypoplasia of the small intestine architecture Marsh's classification, introduced in 1992, was subsequently modified in 1999 to six stages, where the previous stage 3 was split in three substages. Further studies demonstrated that this system was not always reliable and that the changes observed in coeliac disease could be described in one of three stages: A representing lymphocytic infiltration with normal villous appearance; B1 describing partial villous atrophy; and B2 describing complete villous atrophy. The changes classically improve or reverse after gluten is removed from the diet. However, most guidelines do not recommend a repeat biopsy unless there is no improvement in the symptoms on diet. In some cases, a deliberate gluten challenge, followed by a biopsy, may be conducted to confirm or refute the diagnosis. A normal biopsy and normal serology after challenge indicates the diagnosis may have been incorrect. In untreated coeliac disease, villous atrophy is more common in children younger than three years, but in older children and adults, it is common to find minor intestinal lesions (duodenal lymphocytosis) with normal intestinal villi. === Other diagnostic tests === At the time of diagnosis, further investigations may be performed to identify complications, such as iron deficiency (by full blood count and iron studies), folic acid and vitamin B12 deficiency and hypocalcaemia (low calcium levels, often due to decreased vitamin D levels). Thyroid function tests may be requested during blood tests to identify hypothyroidism, which is more common in people with coeliac disease. Osteopenia and osteoporosis, mildly and severely reduced bone mineral density, are often present in people with coeliac disease, and investigations to measure bone density may be performed at diagnosis, such as dual-energy X-ray absorptiometry (DXA) scanning, to identify the risk of fracture and need for bone protection medication. === Gluten withdrawal === Although blood antibody tests, biopsies, and genetic tests usually provide a clear diagnosis, occasionally the response to gluten withdrawal on a gluten-free diet is needed to support the diagnosis. Currently, gluten challenge is no longer required to confirm the diagnosis in patients with intestinal lesions compatible with coeliac disease and a positive response to a gluten-free diet. Nevertheless, in some cases, a gluten challenge with a subsequent biopsy may be useful to support the diagnosis, for example in people with a high suspicion for coeliac disease, without a biopsy confirmation, who have negative blood antibodies and are already on a gluten-free diet. Gluten challenge is discouraged before the age of 5 years and during pubertal growth. The alternative diagnosis of non-coeliac gluten sensitivity may be made where there is only symptomatic evidence of gluten sensitivity. Gastrointestinal and extraintestinal symptoms of people with non-coeliac gluten sensitivity can be similar to those of coeliac disease, and improve when gluten is removed from the diet, after coeliac disease and wheat allergy are reasonably excluded. Up to 30% of people often continue having or redeveloping symptoms after starting a gluten-free diet. A careful interpretation of the symptomatic response is needed, as a lack of response in a person with coeliac disease may be due to continued ingestion of small amounts of gluten, either voluntary or inadvertent, or be due to other commonly associated conditions such as small intestinal bacterial overgrowth (SIBO), lactose intolerance, fructose, sucrose, and sorbitol malabsorption, exocrine pancreatic insufficiency, and microscopic colitis, among others. In untreated coeliac disease, these are often transient conditions derived from the intestinal damage. They normally revert or improve several months after starting a gluten-free diet, but may need temporary interventions such as supplementation with pancreatic enzymes, dietary restrictions of lactose, fructose, sucrose or sorbitol containing foods, or treatment with oral antibiotics in the case of associated bacterial overgrowth. In addition to gluten withdrawal, some people need to follow a low-FODMAPs diet or avoid consumption of commercial gluten-free products, which are usually rich in preservatives and additives (such as sulfites, glutamates, nitrates and benzoates) and might have a role in triggering functional gastrointestinal symptoms. == Screening == There is debate as to the benefits of screening. As of 2017, the United States Preventive Services Task Force found insufficient evidence to make a recommendation among those without symptoms. In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) recommend testing for coeliac disease in first-degree relatives of those with the disease already confirmed, in people with persistent fatigue, abdominal or gastrointestinal symptoms, faltering growth, unexplained weight loss or iron, vitamin B12 or folate deficiency, severe mouth ulcers, and with diagnoses of type 1 diabetes, autoimmune thyroid disease, and with newly diagnosed chronic fatigue syndrome and irritable bowel syndrome. Dermatitis herpetiformis is included in other recommendations. The NICE also recommend offering serological testing for coeliac disease in people with metabolic bone disease (reduced bone mineral density or osteomalacia), unexplained neurological disorders (such as peripheral neuropathy and ataxia), fertility problems or recurrent miscarriage, persistently raised liver enzymes with unknown cause, dental enamel defects and with diagnose of Down syndrome or Turner syndrome. Some evidence has found that early detection may decrease the risk of developing health complications, such as osteoporosis, anaemia, and certain types of cancer, neurological disorders, cardiovascular diseases, and reproductive problems. They thus recommend screening in people with certain health problems. Serology has been proposed as a screening measure, because the presence of antibodies would detect some previously undiagnosed cases of coeliac disease and prevent its complications in those people. However, serologic tests have high sensitivity only in people with total villous atrophy and have a very low ability to detect cases with partial villous atrophy or minor intestinal lesions. Testing for coeliac disease may be offered to those with commonly associated conditions. == Treatment == === Diet === At present, the only effective treatment is a lifelong gluten-free diet. No medication exists that prevents damage or prevents the body from attacking the gut when gluten is present. Strict adherence to the diet helps the intestines heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer and in some cases sterility. Compliance to a strict gluten-free diet is difficult for the patient, but evidence has accumulated that a strict gluten-free diet can result in resolution of diarrhea, weight gain and normalization of nutrient malabsorption, with normalization of biopsies in 6 months to 2 years on a gluten-free diet. Dietitian input is generally requested to ensure the person is aware which foods contain gluten, which foods are safe, and how to have a balanced diet despite the limitations. In many countries, gluten-free products are available on prescription and may be reimbursed by health insurance plans. Gluten-free products are usually more expensive and harder to find than common gluten-containing foods. Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch. The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence. The exact level at which gluten is harmless is uncertain and controversial. A recent systematic review tentatively concluded that consumption of less than 10 mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done. Regulation of the label "gluten-free" varies. In the European Union, the European Commission issued regulations in 2009 limiting the use of "gluten-free" labels for food products to those with less than 20 mg/kg of gluten, and "very low gluten" labels for those with less than 100 mg/kg. In the United States, the FDA issued regulations in 2013 limiting the use of "gluten-free" labels for food products to those with less than 20 ppm of gluten. The current international Codex Alimentarius standard allows for 20 ppm of gluten in so-called "gluten-free" foods. Gluten-free diet improves healthcare-related quality of life, and strict adherence to the diet gives more benefit than incomplete adherence. Nevertheless, gluten-free diet does not completely normalise the quality of life. === Vaccination === Even though it is unclear if coeliac patients have a generally increased risk of infectious diseases, they should generally be encouraged to receive all common vaccines against vaccine preventable diseases (VPDs) as the general population. Moreover, some pathogens could be harmful to coeliac patients. According to the European Society for the Study of Coeliac Disease (ESsCD), coeliac disease can be associated with hyposplenism or functional asplenia, which could result in impaired immunity to encapsulated bacteria, with an increased risk of such infections. For this reason, patients who are known to be hyposplenic should be offered at least the pneumococcal vaccine. However, the ESsCD states that it is not clear whether vaccination with the conjugated vaccine is preferable in this setting and whether additional vaccination against Haemophilus, meningococcus, and influenza should be considered if not previously given. However, Mårild et al. suggested considering additional vaccination against influenza because of an observed increased risk of hospital admission for this infection in coeliac patients. === Refractory disease === Between 0.3% and 10% of affected people have refractory disease, which means that they have persistent villous atrophy on a gluten-free diet despite the lack of gluten exposure for more than 12 months. Nevertheless, inadvertent exposure to gluten is the main cause of persistent villous atrophy, and must be ruled out before a diagnosis of refractory disease is made. People with poor basic education and understanding of gluten-free diet often believe that they are strictly following the diet, but are making regular errors. Also, a lack of symptoms is not a reliable indicator of intestinal recuperation. If alternative causes of villous atrophy have been eliminated, steroids or immunosuppressants (such as azathioprine) may be considered in this scenario. Refractory coeliac disease should not be confused with the persistence of symptoms despite gluten withdrawal caused by transient conditions derived from the intestinal damage, which generally revert or improve several months after starting a gluten-free diet, such as small intestinal bacterial overgrowth, lactose intolerance, fructose, sucrose, and sorbitol malabsorption, exocrine pancreatic insufficiency, and microscopic colitis among others. Refractory coeliac disease can be divided into types I and II. A recent studied compared patients with type I and II. Refractory coeliac disease type I more frequently exhibits diarrhea, anemia, hypoalbuminemia, parenteral nutrition need, ulcerative jejuno-ileitis, and extended small intestinal atrophy. Among patients with refractory coeliac disease type II is more common to develop lymphoma. Among these patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality. == Epidemiology == Globally coeliac disease affects between 1 in 100 and 1 in 170 people. Rates, however, vary between different regions of the world from as few as 1 in 300 to as many as 1 in 40. In the United States it is thought to affect between 1 in 1,750 (defined as clinical disease including dermatitis herpetiformis with limited digestive tract symptoms) to 1 in 105 (defined by presence of IgA TG in blood donors). Due to variable signs and symptoms it is believed that about 85% of people affected are undiagnosed. The percentage of people with clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, India, South America, Australasia and the USA (using serology and biopsy) indicate that the percentage of people with the disease may be between 0.33 and 1.06% in children (but 5.66% in one study of children of the predisposed Sahrawi people) and 0.18–1.2% in adults. Among those in primary care populations who report gastrointestinal symptoms, the rate of coeliac disease is about 3%. In Australia, approximately 1 in 70 people have the disease. The rate amongst adult blood donors in Iran, Israel, Syria and Turkey is 0.60%, 0.64%, 1.61% and 1.15%, respectively. People of African, Japanese and Chinese descent are rarely diagnosed; this reflects a much lower prevalence of the genetic risk factors, such as HLA-B8. People of Indian ancestry seem to have a similar risk to those of Western Caucasian ancestry. Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due, in part, to many clinicians being unfamiliar with the condition and also due to the fact it can be asymptomatic. Coeliac disease is slightly more common in women than in men. A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic people, 2.6% in second-degree relatives (like grandparents, aunt or uncle, grandchildren, etc.) of a person with coeliac disease and 4.5% in first-degree relatives (siblings, parents or children). This profile is similar to the prevalence in Europe. Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with Down and Turner syndromes, type 1 diabetes, and autoimmune thyroid disease, including both hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid). Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%, which is approximately 1 50 {\textstyle {\frac {1}{50}}} of more recent estimates of prevalence. The reason for the recent increases in the number of reported cases is unclear. It may be at least in part due to changes in diagnostic practice. There also appears to be an approximately 4.5 fold true increase that may be due to less exposure to bacteria and other pathogens in Western environments. In the United States, the median age at diagnosis is 38 years. Roughly 20 percent of individuals with coeliac disease are diagnosed after 60 years of age. == Immune Therapy == In 2025, researchers demonstrated the potential of engineered regulatory T cells (eTregs) as a cell-based therapy for celiac disease. By orthotopically inserting T cell receptors (TCRs) specific to immunodominant gluten epitopes into human Tregs, the team created gluten-reactive eTregs that suppressed pathogenic T cell responses in HLA-DQ2.5 transgenic mouse models. These eTregs showed the ability to exert bystander suppression—not only inhibiting T cells with the same antigen specificity, but also suppressing responses to distinct gluten peptides—thus addressing the polyclonal nature of the autoimmune response in celiac disease. The data support the clinical potential of antigen-specific eTreg therapies for autoimmune diseases beyond current applications. == History == The term coeliac comes from Greek κοιλιακός (koiliakós) 'abdominal' and was introduced in the 19th century in a translation of what is generally regarded as an Ancient Greek description of the disease by Aretaeus of Cappadocia. Humans first started to cultivate grains in the Neolithic period (beginning about 9500 BCE) in the Fertile Crescent in Western Asia, and, likely, coeliac disease did not occur before this time. Aretaeus of Cappadocia, living in the second century in the same area, recorded a malabsorptive syndrome with chronic diarrhoea, causing a debilitation of the whole body. A 15th-century medical prescription from Mamluk Cairo, attributed to Shams al-Din ibn al-'Afif, the personal physician to Sultan Barsbay and director of the Qalawun complex hospital, describes a treatment for symptoms consistent with coeliac disease. Found in Fustat and now held in the Museum of Islamic Art in Cairo, the remedy combines herbs and plant waters for patients intolerant to wheat. Aretaeus of Cappadocia's "Cœliac Affection" gained the attention of Western medicine when Francis Adams presented a translation of Aretaeus's work at the Sydenham Society in 1856. The patient described in Aretaeus' work had stomach pain and was atrophied, pale, feeble, and incapable of work. The diarrhoea manifested as loose stools that were white, malodorous, and flatulent, and the disease was intractable and liable to periodic return. The problem, Aretaeus believed, was a lack of heat in the stomach necessary to digest the food and a reduced ability to distribute the digestive products throughout the body, this incomplete digestion resulting in diarrhoea. He regarded this as an affliction of the old and more commonly affecting women, explicitly excluding children. The cause, according to Aretaeus, was sometimes either another chronic disease or even consuming "a copious draught of cold water." The paediatrician Samuel Gee gave the first modern-day description of the condition in children in a lecture at Hospital for Sick Children, Great Ormond Street, London, in 1887. Gee acknowledged earlier descriptions and terms for the disease and adopted the same term as Aretaeus (coeliac disease). He perceptively stated: "If the patient can be cured at all, it must be by means of diet." Gee recognised that milk intolerance is a problem with coeliac children and that highly starched foods should be avoided. However, he forbade rice, sago, fruit, and vegetables, which all would have been safe to eat, and he recommended raw meat as well as thin slices of toasted bread. Gee highlighted particular success with a child "who was fed upon a quart of the best Dutch mussels daily." However, the child could not bear this diet for more than one season. Christian Archibald Herter, an American physician, wrote a book in 1908 on children with coeliac disease, which he called "intestinal infantilism". He noted their growth was retarded and that fat was better tolerated than carbohydrate. The eponym Gee-Herter disease was sometimes used to acknowledge both contributions. Sidney V. Haas, an American paediatrician, reported positive effects of a diet of bananas in 1924. This diet remained in vogue until the actual cause of coeliac disease was determined. While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatrician Willem Karel Dicke. It is likely that clinical improvement of his patients during the Dutch famine of 1944–1945 (during which flour was scarce) may have contributed to his discovery. Dicke noticed that the shortage of bread led to a significant drop in the death rate among children affected by coeliac disease from greater than 35% to essentially zero. He also reported that once wheat was again available after the conflict, the mortality rate soared to previous levels. The link with the gluten component of wheat was made in 1952 by a team from Birmingham, England. Villous atrophy was described by British physician John W. Paulley in 1954 on samples taken at surgery. This paved the way for biopsy samples taken by endoscopy. Throughout the 1960s, other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965. In 1966, dermatitis herpetiformis was linked to gluten sensitivity. == Society and culture == May has been designated as "Coeliac Awareness Month" by several coeliac organisations. === Christian churches and the Eucharist === Speaking generally, the various denominations of Christians celebrate a Eucharist in which a wafer or small piece of sacramental bread from wheat bread is blessed and then eaten. A typical wafer weighs about half a gram. Small communion wafers typically contain 2-5 mg of gliadin if they are not a gluten-free variety, and many people with coeliac disease report altering their religious practices because of coeliac symptoms caused by these wafers. Many Christian churches offer their communicants gluten-free alternatives, usually in the form of a rice-based cracker or gluten-free bread. These include the United Methodist, Christian Reformed, Episcopal, the Anglican Church (Church of England, UK) and Lutheran. Catholics may receive from the chalice alone, or ask for gluten-reduced hosts; gluten-free ones however are not considered still to be wheat bread, and hence are invalid matter. ==== Roman Catholic position ==== Roman Catholic doctrine states that for a valid Eucharist, the bread to be used at Mass must be made from wheat. Low-gluten hosts meet all of the Catholic Church's requirements, but they are not entirely gluten free. Requests to use rice wafers have been denied. The issue is more complex for priests. As a celebrant, a priest is, for the fullness of the sacrifice of the Mass, absolutely required to receive under both species. On 24 July 2003, the Congregation for the Doctrine of the Faith stated, "Given the centrality of the celebration of the Eucharist in the life of a priest, one must proceed with great caution before admitting to Holy Orders those candidates unable to ingest gluten or alcohol without serious harm." By January 2004, extremely low-gluten Church-approved hosts had become available in the United States, Italy and Australia. As of July 2017, the Vatican still outlawed the use of gluten-free bread for Holy Communion. === Passover === The Jewish festival of Pesach (Passover) may present problems with its obligation to eat Matzah, which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye. In addition, many other grains that are normally used as substitutes for people with gluten sensitivity, including rice, are avoided altogether on Passover by Ashkenazi Jews. Many kosher-for-Passover products avoid grains altogether and are therefore gluten-free. Potato starch is the primary starch used to replace the grains. === Spelling === "Coeliac disease" is the preferred spelling in Commonwealth English, while "celiac disease" is typically used in North American English. == Research directions == The search for environmental factors that could be responsible for genetically susceptible people becoming intolerant to gluten has resulted in increasing research activity looking at gastrointestinal infections. Research published in April 2017 suggests that an often-symptomless infection by a common strain of reovirus can increase sensitivity to foods such as gluten. Various treatment approaches are being studied, including some that would reduce the need for dieting. All are still under development, and are not expected to be available to the general public for a while. Three main approaches have been proposed as new therapeutic modalities for coeliac disease: gluten detoxification, modulation of the intestinal permeability, and modulation of the immune response. Using genetically engineered wheat species, or wheat species that have been selectively bred to be minimally immunogenic, may allow the consumption of wheat. This, however, could interfere with the effects that gliadin has on the quality of dough. Alternatively, gluten exposure can be minimised by the ingestion of a combination of enzymes (prolyl endopeptidase and a barley glutamine-specific cysteine endopeptidase (EP-B2)) that degrade the putative 33-mer peptide in the duodenum. Latiglutenase (IMGX003) is a biotheraputic digestive enzyme therapy currently being trialled that aims to degrade gluten proteins and aid gluten digestion. It was shown to mitigate intestinal mucosal damage and reduce the severity and frequency of symptoms in phase 2 clinical trials and is scheduled for phase 3 clinical trials. Other potential approaches to pharmacotherapy include the inhibition of zonulin, an endogenous signalling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system. Other modifiers of other well-understood steps in the pathogenesis of coeliac disease, such as the action of HLA-DQ2 or tissue transglutaminase and the MICA/NKG2D interaction that may be involved in the killing of enterocytes. Attempts to modulate the immune response concerning coeliac disease are mostly still in phase I of clinical testing; one agent (CCX282-B) has been evaluated in a phase II clinical trial based on small-intestinal biopsies taken from people with coeliac disease before and after gluten exposure. == References == == External links ==	Wikipedia/Celiac_disease
Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity. Autoinflammatory diseases are a separate class from autoimmune diseases; however, both are characterized by an immune system malfunction that may cause similar symptoms, such as rash, swelling or fatigue. However, the main source of the diseases are different. A key difference between the two classes of diseases is that while AIDs trigger a malfunction of the innate immune system, autoimmune diseases trigger a malfunction of the adaptive immune system. The boundaries between autoinflammation (overactivity of the innate immunity), autoimmunity (overactivity of the adaptive immunity) and immunodeficiency (decreased activity of the innate or adaptive immunity) are often fluid. Clinical phenotypes associated with these processes are driven by the cell type most affected by a particular mutation or signal. Excessive activation of neutrophils, monocytes/macrophages and dendritic cells leads to auto-inflammatory symptoms, while T cell and B cell dysfunction leads to autoimmunity. Failure of innate and/or adaptive immune cells to appropriately activate, recognize, and clear infectious agents causes immunodeficiency and vulnerability to infection. == Classification == === Clinical classification === Episodic and multisystem AIDs (NLRP12-associated disease, mevalonate kinase deficiency, PFAPA (periodic fever syndrome, aphthous stomatitis, pharyngitis, and cervical adenitis) or TRAPS (tumor necrosis factor (TNF) receptor–associated periodic fever syndrome)) Episodic, affecting the joints (gout) Episodic, affecting bone (chronic recurrent multifocal osteomyelitis (CRMO)) Persistent and multisystemic (Schnitzler syndrome, Crohn's disease, or DIRA) Persistent, affecting the skin (Interleukin-36-receptor antagonist deficiency (DITRA), Sweet syndrome or neutrophilic panniculitis) === Molecular mechanism of the origin === Inflammasome activation (Mevalonate kinase deficiency or Muckle–Wells syndrome) NFκB activation (NLRP12-associated disease, Crohn's disease or Blau syndrome) IL‑1β pathway dysregulation (PFAPA, Schnitzler syndrome, DIRA or DITRA) Impaired efficacy of cytotoxic T lymphocytes with compensatory macrophage activation (Familial hemophagocytic lymphohistiocytosis (HLH)) Inactivation of IL‑10 signaling (Early-onset enterocolitis) Multiple (TRAPS) and Uncharacterized (CRMO or Behçet disease) === Simplified classification by the predominant cytokine or pathway === IL-1 mediated IFN-mediated Mediated by increased NF-κB activation == Mechanisms of the origin == Most proteins known to be involved in hereditary AIDs are involved in the regulation of interleukin-1 β (IL-1β). Their mutations induce increased and/or prolonged secretion of IL-1β, a pro-inflammatory and pyrogenic cytokine. Patients with AIDs often suffer from non-infectious fever and systemic and/or disease-specific organ inflammation. The over-secretion of pro-inflammatory cytokines and chemokines leads to organ damage and can be life-threatening. For such patients, excessive IL-1 signaling, constitutive NF-κB activation, and chronic IFN I signaling are specific. Some AIDs seemingly do not have any specific pivotal pro-inflammatory mediators, being caused by the accumulation of metabolites or triggered by intracellular stress or cell death. === Loss of negative regulators === Loss of negative regulators results in an inability to attenuate pro-inflammatory cytokine responses, causing autoinflammation. Among these negative regulators, antagonists of IL-1 receptor (IL-1Ra) or IL-36 receptor (IL-36Ra) can be concluded. Loss-of-function mutations of IL-1Ra can develop fatal systemic inflammatory response syndrome. Another example is the inability of the anti-inflammatory cytokines, such as IL-10, to signal through its receptor. That, again, can lead to systemic inflammation and severe inflammatory bowel disease (IBD). This shows that even single-cytokine dysregulation can cause autoinflammatory diseases. Some mutations can change the ability of cytotoxic cells to induce cell death, failing to terminate macrophage and dendritic cell activation and causing macrophage activation syndrome. === Inflammasome mediated autoinflammatory disorders === As indicated above, AIDs are caused by abnormal innate immune activation and, in the case of inflammasome disorders, are attributable to activation of an inflammasome complex nucleated by innate immune sensors such as NLRP1 (nucleotide-binding oligomerization domain (NOD)-like receptors), pyrin, or NLRC4 (NOD-like receptors (NLR) Family CARD Domain Containing 4). Inflammasomes are cytoplasmic protein complexes that can generate active, secreted IL-1β and IL-18 from a cell. The sensors of innate immunity help to activate caspase 1 from pro-caspase 1. When activated, caspase 1 cleaves precursors of the pro-inflammatory cytokines pro-IL-1β and pro-IL-18 to their active forms. ==== NLRP1 ==== There have been reports of patients with activating mutations in NLRP1, where arginine is affected. There is a de novo heterozygous Pro1214Arg substitution in some cases, while in others there is a homozygous arginine to tryptophan substitution at position 726 (R726W). It has been shown that the mutation position matters. Pro1214Arg is located in the FIIND (from function to find domain) domain, which is important for NLRP1 activation. R726W is located in the linker region between the NOD and LRR (from leucine rich) domains. All of the patients with such mutations exhibited dyskeratosis, arthritis, recurrent fever episodes, recurrent elevated CRP (from C-reactive protein) levels, and vitamin A deficiency. Among the AIDs caused by the NLRP1 mutation are multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). ==== Pyrin ==== A hereditary disorder driven by pyrin mutation, called PAAND (Pyrin-associated autoinflammation with neutrophilic dermatosis), is characterized by neutrophilic dermatosis, recurrent fever, increased acute-phase reactants, arthralgia, or myalgia. Patients with PAAND have a serine-to-arginine substitution at position 242 in pyrin. This loss of serine at position 242 causes the inability of 14-3-3 to bind to this region and to inhibit pyrin, resulting in spontaneous inflammasome formation by pyrin, increased recruitment of pro-caspase-1 via ASC (from adaptor molecule apoptosis-associated speck-like protein containing a CARD), increased IL-1β secretion, and pyroptosis. The 14-3-3 molecule can bind and inhibit pyrin inflammasome activity due to RhoA activity. RhoA regulates pyrin through the activation of serine-threonine kinases, which phosphorylate the serine of pyrin at S208 and S242 and allow the signaling molecule 14-3-3 to bind pyrin. Already mentioned serine-to-arginine substitution at position 242 in pyrin causes the loss of RhoA activity and thus activation of the pyrin inflammasome. One of the best-known pyrin AIDs is Mevalonate kinase deficiency, which is an enzyme in the cholesterol biosynthesis pathway. This loss/lack of enzyme results in mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS). === Relopathies (NFkBopathies) === It has been proven that NF-κB (nuclear factor κB) is overactivated in cells of the gut mucosa of patients with inflammatory bowel diseases, including Crohn's disease (CD), which is a well known AID. The constitutive activation of NF-κB, not only in CD, is in particular caused by alanine (A20) deficiency. NFκB pathway is tightly regulated through multiple posttranslational mechanisms including ubiquitination. Mutations in these regulatory pathways often cause diseases connected with malfunctions of NF-κB. The loss-of-function mutations in HOIL-1L and HOIP, which are subunits of the linear ubiquitin chain assembly complex (LUBAC), result in phenotypes, characterized by immunodeficiency, multi-organ autoinflammation, and elevated NF-κB signaling. Also the hypomorphic mutations in deubiquitinase enzyme OTULIN (from OTU deubiquitinase with linear linkage specificity), results in elevated NF-κB signaling causing an autoinflammatory syndrome. Similarly, patients with high-penetrance heterozygous mutations in the gene encoding A20 display excessive ubiquitination and increased activity of NFκB. Such patients present with Behçet-like characteristics or an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype. === Interferonpathies === In addition to antivirus and antitumor effects, interferons (IFNs) also have broad immune-modulating functions, including enhancing the antigen-presentation function of dendritic cells, promoting T lymphocyte response and B lymphocyte antibody production, and restraining proinflammatory cytokine production. The production and signaling of IFNs are tightly regulated and dysregulation has been linked to inflammatory diseases, such as systemic lupus erythematosus and a growing number of conditions that clinically present as autoinflammatory diseases. It is very often a mutation that somehow influences the expression/function of IFNs. In the case of Aicardi-Goutieres syndrome 7 (AGS7), the gain-of-function mutation in a sensor molecule in the RNA-sensing pathway leads to both spontaneous and enhanced ligand-induced IFN-β transcription. === Dysregulation of proteasomes === Some AIDs, such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), appear to be associated with dysfunction of the proteasome. This syndrome is caused by a mutation in the gene that encodes subunit β type-8 of the proteasome (PSMB8 gene). Due to this mutation, there is a problem with the proteolysis of proteins and their presentation to the cells of innate immunity. This results in the accumulation of intermediates in the cell and accumulation of the proteins in the tissues. This leads to elevated cell stress, activation of Janus kinase, and production of IFNs. === Persistent macrophage activation === Systemic activation of macrophages is characterized by the accumulation of activated macrophages, which secrete a large number of inflammatory mediators, such as cytokines, chemokines, DAMPs, etc. They can become hemophagocytes. Once considered the diagnostic hallmarks of macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH), they can be abundant in organs of the reticuloendothelial system during systemic inflammation. These inflammatory cytokines cannot be cleared and inflammatory mediators cause fever, cytopenias, coagulopathy, and central nervous system inflammation, which can progress to sepsis-like pathophysiology, shock, and death. The progression of macrophage activation in the context of rheumatic diseases is historically called MAS, and in the context of the familial monogenic defects resulting in impaired NK (natural killer cells) or CD8+ T cell cytotoxicity, it is called HLH. Systemic macrophage activation is also associated with chronic overproduction of IL-18, which may also impair cytotoxicity. Chronic IL-18 exposure may cause impairments in cytotoxicity or NK cell death, thus promoting macrophage activation by priming lymphocyte inflammatory response or disabling/depleting NK cells. IL-18-induced NK cell dysfunction resulting is a defect shared between MAS and cytotoxicity-related HLH. This macrophage activation can be caused by increased activity of intracellular sensor NLRC4 and subsequent constitutive NLRC4 inflammasome activation. The macrophage activation can be due to the loss of the negative regulatory effect of cytotoxicity. == References ==	Wikipedia/Autoinflammatory_diseases
Functional constipation, also known as chronic idiopathic constipation (CIC), is defined by less than three bowel movements per week, hard stools, severe straining, the sensation of anorectal blockage, the feeling of incomplete evacuation, and the need for manual maneuvers during feces, without organic abnormalities. Many illnesses, including endocrine, metabolic, neurological, mental, and gastrointestinal obstructions, can cause constipation as a secondary symptom. When there is no such cause, functional constipation is diagnosed. Functional constipation requires symptoms to be present at least a fourth of the time. Causes include anismus, descending perineum syndrome, inability to control the external anal sphincter, poor diet, unwillingness to defecate, nervous reactions, and deep psychosomatic disorders. Comorbid symptoms such as headache may also be present, especially in children. Functional constipation is diagnosed using the Rome criteria, a consensus of experts. The criteria include over 25% of defecations involving straining, 25% resulting in lumpy or hard stools, 25% requiring partial evacuation, 25% experiencing anorectal blockage or obstruction, and 25% using manual techniques. Less than three weekly spontaneous bowel movements are also considered. A thorough history and physical examination, including a digital rectal exam, is crucial for diagnosing constipation. Additional laboratory testing is typically used in cases of uncertainty or to rule out underlying medical conditions. Functional constipation is a condition that requires nonpharmacological management, including education and lifestyle modifications. It begins with dietary guidelines, focusing on regular fiber and fluid intake. Children with functional constipation should consume a normal intake of fiber, as per ESPGHAN/NASPGHAN criteria. Parents and children should receive counseling about overflow incontinence and withholding behavior. An organized toilet-training program with a reward system can help reduce faecal impaction. Pharmacological treatment for children with functional constipation consists of maintenance therapy and faecal disimpaction. High-dose oral polyethylene glycol (PEG) or enemas containing active substances can induce fecal disimpaction, while maintenance therapy is recommended after successful disimpaction to avoid reoccurring stool buildup. Glycerine or bisacodyl suppositories are also used for both adults and children. Maintenance treatment for functional constipation includes osmotic laxatives, milk of magnesia, and mineral oil. Stimulant laxatives such as senna or bisacodyl are recommended for those with persistent symptoms. == Signs and symptoms == Individuals suffering from functional constipation often exhibit hard or lumpy stools, decreased frequency of bowel movements, a feeling of incomplete evacuation or obstruction, straining, and in some cases, stomach pain and bloating. Generally speaking, symptoms are considered chronic if they have persisted for three months or more. Faecal incontinence, which is the involuntary loss of stools in the underwear during toilet training and is brought on by an overflow of soft stools passing around a solid faecal mass in the rectum (faecal impaction), is a common symptom in children. Urinary symptoms, including urine incontinence and urinary tract infections, are frequently observed in children who suffer from functional constipation. == Causes == To be considered functional constipation, symptoms must be present at least a fourth of the time. Possible causes are: Anismus Descending perineum syndrome Other inability or unwillingness to control the external anal sphincter, which normally is under voluntary control A poor diet An unwillingness to defecate Nervous reactions, including prolonged and/or chronic stress and anxiety, that close the internal anal sphincter, a muscle that is not under voluntary control Deeper psychosomatic disorders which sometimes affect digestion and the absorption of water in the colon There is also possibility of presentation with other comorbid symptoms such as headache, especially in children. == Diagnosis == Functional constipation cannot be diagnosed with particular testing; instead, the Rome criteria, a consensus of experts, is used to make this diagnosis. The Rome IV criteria define functional constipation as meeting at least two of the six requirements given below: Over ¼ (25%) of defecations involve straining. More than ¼ (25%) of defecations result in lumpy or hard stools (Bristol Stool Form Scale 1-2). Sensation of partial evacuation for over ¼ (25%) of the defecations. Sensation of anorectal blockage or obstruction during more than ¼ (25%) of bowel movements. Manual techniques (such as pelvic floor support and digital evacuation) to assist in more than ¼ (25%) of defecations. Less than three weekly spontaneous bowel movements. Loose stools are rarely seen without the use of laxatives. Not enough criteria met to diagnose irritable bowel syndrome. A thorough history and physical examination should be performed while evaluating constipation. Along with push and squeeze maneuvers, a comprehensive digital rectal exam (DRE) is a crucial component of the clinical examination. Generally speaking, additional laboratory testing should be carried out only in cases of uncertainty or to rule out underlying medical conditions such as hypothyroidism or celiac disease. Abdominal radiography, with or without the introduction of radio-opaque markers to determine colonic transit time, and abdominal ultrasonography are frequently employed supplementary tests in the diagnosis of constipation. Chronic idiopathic constipation is similar to constipation-predominant irritable bowel syndrome (IBS-C); however, people with CIC do not have other symptoms of IBS, such as abdominal pain. == Treatment == Treatment for functional constipation begins with nonpharmacological management. This includes education and lifestyle modifications, such as diet changes, consistent exercise, and guidance on proper body position and behavior when using the restroom. The first treatments for constipation are dietary guidelines, which include the requirement for a regular consumption of fiber and fluids. A normal intake of fiber is advocated for children with functional constipation, as per the criteria of ESPGHAN/NASPGHAN. It is not recommended to increase the consumption of fiber above what is considered normal. In order to effectively treat childhood constipation, it is imperative that parents and children receive counseling. This includes teaching them about the concept of overflow incontinence and the significance of withholding behavior. One way to reduce faecal impaction and lower the risk of faecal incontinence is to use an organized toilet-training program with a reward system that instructs the kid to try to defaecate at least twice or three times a day (after each meal). Children with functional constipation can be treated pharmacologically in two stages: maintenance therapy and faecal disimpaction. High-dose oral polyethylene glycol (PEG) or enemas containing active substances such sodium phosphate, sodium lauryl sulfoacetate, or sodium docusate can be used to induce fecal disimpaction. Maintenance therapy is suggested following successful disimpaction in order to avoid reoccurring stool buildup. Adults rarely need faecal disimpaction, although the methods are comparable, and substantial doses of PEG or magnesium citrate are popular oral therapies. For both adults and children, glycerine or bisacodyl suppositories provide an alternative to enemas. The first-choice maintenance treatment advised for functional constipation is osmotic laxatives. Other often used laxatives include milk of magnesia (magnesium hydroxide) and mineral oil, a lubricant. Clinical recommendations advocate using stimulant laxatives, such as senna or bisacodyl, in both adults and children if symptoms are still present. A number of novel therapeutic treatments have been suggested and licensed in recent years for the treatment of functional constipation. Prosecretory drugs including plecanatide, linaclotide, and lubiprostone alter gut epithelial channels, encouraging intestinal fluid secretion and increasing stool volume, which improves GI transit. Functional constipation has been treated with a variety of 5-hydroxytryptamine 4 (5-HT4) agonists. Serotonin (5-HT) is an enteric and central neurotransmitter that binds to the gut's 5-HT4 receptors to boost acetylcholine release, which in turn increases secretion and motility of the gut. Additionally, serotonin promotes motility by stimulating the mucosa's afferent neurons, which in turn triggers the gastrocolic reflex. == Research == A 2014 meta-analysis of three small trials evaluating probiotics showed a slight improvement in management of chronic idiopathic constipation, but well-designed studies are necessary to know the true efficacy of probiotics in treating this condition. Children with functional constipation often claim to lack the sensation of the urge to defecate, and may be conditioned to avoid doing so due to a previous painful experience. One retrospective study showed that these children did indeed have the urge to defecate using colonic manometry, and suggested behavioral modification as a treatment for functional constipation. == See also == Functional symptom Sacral nerve stimulation == References == == Further reading == Serra, Jordi; Pohl, Daniel; Azpiroz, Fernando; Chiarioni, Giuseppe; Ducrotté, Philippe; Gourcerol, Guillaume; Hungin, A. Pali S.; Layer, Peter; Mendive, Juan-Manuel; Pfeifer, Johann; Rogler, Gerhard; Scott, S. Mark; Simrén, Magnus; Whorwell, Peter; The Functional Constipation Guidelines Working Group (2020). "European society of neurogastroenterology and motility guidelines on functional constipation in adults". Neurogastroenterology & Motility. 32 (2): e13762. doi:10.1111/nmo.13762. ISSN 1350-1925. PMID 31756783. Bassotti, Gabrio; Usai Satta, Paolo; Bellini, Massimo (2021). "Chronic Idiopathic Constipation in Adults: A Review on Current Guidelines and Emerging Treatment Options". Clinical and Experimental Gastroenterology. 14. Informa UK Limited: 413–428. doi:10.2147/ceg.s256364. ISSN 1178-7023. PMC 8547593. PMID 34712055. == External links == WebMD The Hospital for Sick Children	Wikipedia/Functional_constipation
Ménétrier disease is a rare, acquired, premalignant disease of the stomach characterized by massive gastric folds, gastric hyperplasia, excessive mucus production with resultant protein loss, and little or no acid production (achlorhydria). The disorder is associated with excessive secretion of transforming growth factor alpha (TGF-α). It is named after French physician Pierre Eugène Ménétrier (1859–1935). == Signs and symptoms == Individuals with the disease present with upper abdominal (epigastric) pain, at times accompanied by nausea, vomiting, loss of appetite, edema, weakness, and weight loss. A small amount of gastrointestinal bleeding may occur, which is typically due to superficial mucosal erosions; large volume bleeding is rare. 20% to 100% of patients, depending on time of presentation, develop a protein-losing gastropathy accompanied by low blood albumin and edema. Symptoms and pathological features of Ménétrier disease in children are similar to those in adults, but disease in children is usually self-limited and often follows respiratory infection. == Cause == The cause of Ménétrier disease is unknown, but it has been associated with HCMV infection in children and H. pylori infections in adults. Additionally, increased TGF-α has been noted in the gastric mucosa of patients with the disease. While the pathophysiology of Ménétrier disease isn't fully understood, it is thought that an increase in EGFR signaling — the effect of increased TGF-alpha production responsible for the inhibition of acid production — gives rise to epithelial cell proliferation of the mucosa, causing a direct impact on malabsorption of nutrients, electrolytes, and vitamins in the bowel. == Pathology == With Ménétrier disease, the stomach is characterized by large, tortuous gastric folds in the fundus and body, with the antrum generally spared, giving the mucosa a cobblestone or cerebriform (brain-like) appearance. Histologically, the most characteristic feature is massive foveolar hyperplasia (hyperplasia of surface and glandular mucous cells). The glands are elongated with a corkscrew-like appearance and cystic dilation is common. Inflammation is usually only modest, although some cases show marked intraepithelial lymphocytosis. Diffuse or patchy glandular atrophy, evident as hypoplasia of parietal and chief cells, is typical. Although ICD-10 classifies it under "Other gastritis" (K29.6), and the lamina propria may contain mild chronic inflammatory infiltrate, Ménétrier disease is not considered a form of gastritis. It is rather considered one of the two most well understood hypertrophic gastropathies; the other being Zollinger–Ellison syndrome. == Diagnosis == The large folds of the stomach, as seen in Ménétrier disease, are easily detected by x-ray imaging following a barium meal or by endoscopic methods. Due to the thickened rugae folds, it is said to have a cerebriform (brain-like) appearance. Endoscopy with deep mucosal biopsy (and cytology) is required to establish the diagnosis and exclude other entities that may present similarly. A non-diagnostic biopsy may lead to a surgically obtained full-thickness biopsy to exclude malignancy. CMV and helicobacter pylori serology should be a part of the evaluation. Twenty-four-hour pH monitoring reveals hypochlorhydria or achlorhydria, and a chromium-labelled albumin test reveals increased GI protein loss. Serum gastrin levels will be within normal limits. Other possible causes (e.g. differential diagnoses) of large folds within the stomach include: Zollinger-Ellison syndrome, cancer, cytomegalovirus infection, histoplasmosis, syphilis, and infiltrative disorders such as sarcoidosis. == Treatment == Cetuximab is the first-line therapy for Ménétrier disease. Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR), and has been shown to be effective in treating Ménétrier disease. Several medications have been used in the treatment of the condition, with variable efficacy. Such medications include: anticholinergic agents, prostaglandins, proton pump inhibitors, prednisone, and H2 receptor antagonists. Anticholinergics decrease protein loss. A high-protein diet should be recommended to replace protein loss in patients with low levels of albumin in the blood (hypoalbuminemia). Any ulcers discovered during the evaluation should be treated in standard fashion. Severe disease with persistent and substantial protein loss despite cetuximab may require total removal of the stomach, especially when the disease is debilitating or irretractable or when there is a high risk for developing gastric cancer. Subtotal gastrectomy is performed by some; it may be associated with higher morbidity and mortality secondary to the difficulty in obtaining a patent and long-lasting anastomosis between normal and hyperplastic tissue. In adults, there is no FDA approved treatment other than gastrectomy and a high-protein diet. Cetuximab is approved for compassionate use in the treatment of the disease. Pediatric cases are normally treated for symptoms with the disease clearing up in weeks to months. == Epidemiology == The average age of onset is 40 to 60 years, and men are affected more often than women. Risk of gastric adenocarcinoma is increased in adults with Ménétrier disease. Less than 1,000 cases have been reported in human history. == References == == External links ==	Wikipedia/Ménétrier's_disease
Sphincter of Oddi dysfunction refers to a group of functional disorders leading to abdominal pain due to dysfunction of the Sphincter of Oddi: functional biliary sphincter of Oddi and functional pancreatic sphincter of Oddi disorder. The sphincter of Oddi is a sphincter muscle, a circular band of muscle at the bottom of the biliary tree which controls the flow of pancreatic juices and bile into the second part of the duodenum. The pathogenesis of this condition is recognized to encompass stenosis or dyskinesia of the sphincter of Oddi (especially after cholecystectomy); consequently the terms biliary dyskinesia, papillary stenosis, and postcholecystectomy syndrome have all been used to describe this condition. Both stenosis and dyskinesia can obstruct flow through the sphincter of Oddi and can therefore cause retention of bile in the biliary tree and pancreatic juice in the pancreatic duct. Individuals with sphincter of Oddi dysfunction present with abdominal pain resembling that of structural or inflammatory disorders of the gallbladder, biliary tree or pancreas. Among other characteristics, the pain is typically in the upper part of the abdomen or in the right upper quadrant of the abdomen, lasts 30 minutes or longer, and is not associated with a structural abnormality that could lead to these symptoms. The disorder is classified into two subtypes: functional biliary sphincter of Oddi disorder, where there is no disturbance in pancreatic enzyme measurements, such as amylase and lipase; and, functional pancreatic sphincter of Oddi disorder, where pancreatic enzyme measurements are elevated. Attacks can be precipitated by opioid analgesics, particularly in patients having undergone a cholecystectomy or bariatric surgery. == Classification == Functional disorders of the gallbladder, bile duct and pancreas have been defined and classified by the Rome criteria for functional gastrointestinal disorders. The criteria outline three variants of functional disorders of the gallbladder, bile duct and pancreas, termed functional gallbladder disorder, functional biliary sphincter of Oddi disorder and functional pancreatic sphincter of Oddi disorder. All of the following criteria need to be met for as part of the definition of a functional disorder of the gallbladder: the pain must be located in the upper part of the abdomen and/or the right upper quadrant of the abdomen episodes of pain must last at least 30 minutes the symptoms must be recurrent, and occur at differing intervals the pain must incrementally increase to a "steady level" the pain must be severe enough the patient's daily activities are affected, or that the patient must attend the emergency department the pain must not be relieved by any of bowel movements, change in posture, or antacids; and, other structural disorders that could explain the symptoms must be excluded. === Functional gallbladder disorder === Individuals are classified as having a functional gallbladder disorder if the above criteria are met, if the gallbladder is present, and if the testing of liver enzymes, conjugated bilirubin, and pancreatic enzymes (amylase and lipase) are normal. === Functional biliary sphincter of Oddi disorder === If all of the above criteria are met, individuals are classified as having a functional biliary sphincter of Oddi disorder, if the testing of pancreatic enzymes (amylase and lipase) is normal. The old Milwaukee classification of biliary sphincter of Oddi dysfunction (SOD) used to divide the condition into three subtypes: but it is no longer in use. Type I included patients with biliary-type abdominal pain, with all of altered liver enzymes on blood testing, dilated biliary ducts on ultrasound or ERCP, and delayed bile clearance on HIDA scan. Type II included patients with biliary-type abdominal pain associated with at least one of the following: altered liver enzymes on blood testing, dilated biliary ducts on imaging tests, and delayed bile clearance on HIDA scan. Biliary-type pain in the absence of any sign of biliary or pancreatic alteration was the so-called Type III biliary SOD. The hypothesis that this pain could be linked to SOD has been studied in a large trial published in JAMA (2014) where patients were randomized to sphincterotomy or sham surgery. Contrary to expectations, patients who were not subjected to sphincterotomy fared better. Overall, the investigators found that only 23% of the patients who underwent sphincterotomy improved versus 37% of the control group. The EPISOD trial has substantiated the ineffectiveness of endoscopic sphincterotomy in patients with these symptoms and SOD Type III is no longer considered to be a clinical entity. == Characteristics == Sphincter of Oddi dysfunction may be suggested by pain which seems to come from a biliary origin, which may or may not be associated with transient increases of liver or pancreatic enzymes. Common bile duct dilation and episodes of pancreatitis are also signs. == Pathophysiology == Two mechanisms are involved in the development of sphincter of Oddi dysfunction, either or both of which may be contributory to the condition: stenosis, or narrowing of the sphincter of Oddi (also termed papillary stenosis), and dyskinesia, or alteration in the function of the sphincter of Oddi (also termed biliary dyskinesia). Individuals with stenosis of the sphincter of Oddi typically have an elevated baseline pressure of the sphincter of Oddi, due to an anatomical problem that leads to narrowing of the sphincter, such as recurrent passage of gallstones through the ampulla of Vater, trauma to the sphincter from procedures such as endoscopic retrograde cholangiopancreatography or biliary surgery, or infections of the common bile duct. In contrast, dyskinesia of the sphincter of Oddi is a purely functional disorder, wherein there is intermittent obstruction of the bile duct due to inappropriate spasms. The reasons for dyskinesia of the sphincter of Oddi are not completely understood, but believed to be due to alteration in local gut hormones and peptides, such as cholecystokinin, which act on the sphincter or to altered neuronal control of the sphincter. == Diagnosis == For diagnosis, measures of liver biochemistry and pancreatic enzymes are performed. Along with ruling out structural abnormalities, normally by performing an abdominal ultrasound and endoscopic retrograde cholangiopancreatography (ERCP). Measurements of bile transit when performing ERCP are taken to help evaluate different treatment options. Sphincter of Oddi dysfunction is best diagnosed using manometry-an internal test done to measure the pressures within surrounding ducts to determine whether or not the muscle is functioning normally. == Treatment == Medication (to prevent spasms) or sphincterotomy (surgical procedure to cut the muscle) are the standard treatments for sphincter of Oddi dysfunction. One or the other may be better based on the classification of the condition. == See also == Stenosis Dyskinesia Bile == References == == External links == http://www.ddc.musc.edu/public/symptomsDiseases/diseases/pancreas/SOD.html	Wikipedia/Sphincter_of_Oddi_dysfunction
Paget's disease of bone (commonly known as Paget's disease or, historically, osteitis deformans) is a condition involving cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone remodeling at the microscopic level, specifically excessive bone breakdown and subsequent disorganized new bone formation. These structural changes cause the bone to weaken, which may result in deformity, pain, fracture or arthritis of associated joints. The exact cause is unknown, although leading theories indicate both genetic and acquired factors (see Causes). Paget's disease may affect any one or several bones of the body (most commonly pelvis, tibia, femur, lumbar vertebrae, and skull), but never the entire skeleton, and does not spread from bone to bone. Rarely, a bone affected by Paget's disease can transform into a malignant bone cancer. As the disease often affects people differently, treatments of Paget's disease can vary. Although there is no cure for Paget's disease, medications (bisphosphonates and calcitonin) can help control the disorder and lessen pain and other symptoms. Medications are often successful in controlling the disorder, especially when started before complications begin. Paget's disease affects from 1.5 to 8.0% of the population, and is most common in those of British descent followed by Northern European and Northern Americans. It is primarily diagnosed in older people and is rare in people less than 55 years of age. Men are more commonly affected than women (3:2). The disease is named after English surgeon Sir James Paget, who described it in 1877. == Signs and symptoms == Mild or early cases of Paget's are asymptomatic, and so most people are diagnosed with Paget's disease incidentally during medical evaluation for another problem. Approximately 35% of patients with Paget's have symptoms related to the disease when they are first diagnosed. Overall, the most common symptom is bone pain. When symptoms do occur, they may be confused with those of arthritis or other disorders, and so diagnosis may be delayed. Paget's may first be noticed as an increasing deformity of a person's bones. Paget's disease affecting the skull may cause frontal bossing, increased hat size, and headaches. Often patients may develop loss of hearing in one or both ears due to auditory foramen narrowing and resultant compression of the nerves in the inner ear. Rarely, skull involvement may lead to compression of the nerves that supply the eye, leading to vision loss. === Associated conditions === Paget's disease is a frequent component of multisystem proteinopathy. Advanced Paget's disease may lead to other medical conditions, including: Osteoarthritis may result from changes in bone shape that alter normal skeletal mechanics. For example, bowing of a femur affected by Paget's may distort overall leg alignment, subjecting the knee to abnormal mechanical forces and accelerating degenerative wear. Heart failure is a rare, reported consequence of severe Paget's disease (i.e. more than 40% skeletal involvement). The abnormal bone formation is associated with recruitment of abnormal blood vessels, forcing the cardiovascular system to work harder (pump more blood) to ensure adequate circulation. Kidney stones are somewhat more common in patients with Paget's disease. Nervous system problems may occur in Paget's disease, resulting from increased pressure on the brain, spinal cord, or nerves, and reduced blood flow to the brain and spinal cord. When Paget's disease affects the facial bones, the teeth may become loose. Disturbance in chewing may occur. Chronic dental problems may lead to infection of the jaw bone. Angioid streaks may develop, possibly as a result of calcification of collagen or other pathological deposition. Paget's disease is not associated with osteoporosis. Although Paget's disease and osteoporosis can occur in the same patient, they are different disorders. Despite their marked differences, several treatments for Paget's disease are also used to treat osteoporosis. == Causes == === Viral === Paget's disease may be caused by a slow virus infection (i.e., paramyxoviridae) present for many years before symptoms appear. Associated viral infections include respiratory syncytial virus, canine distemper virus, and the measles virus. However, recent evidence has cast some doubt upon the measles association. Laboratory contamination may have played a role in past studies linking paramyxovirus (e.g. measles) to Paget's disease. === Genetic === There is a hereditary factor in the development of Paget's disease of bone. Two genes, SQSTM1 and RANK, and specific regions of chromosome 5 and 6 are associated with Paget's disease of bone. Genetic causes may or may not involve a family history of Paget's disease. About 40–50% of people with the inherited version of Paget's disease have a mutation in the gene SQSTM1, which encodes a protein, called p62, that is involved in regulating the function of osteoclasts (bone cells). However, about 10–15 percent of people that develop the disease without any family history also have a mutation in the SQSTM1 gene. Paget's disease of bone is associated with mutations in RANK. Receptor Activator of Nuclear Factor κ B (RANK), which is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding. Additional genetic associations include: == Pathogenesis == The pathogenesis of Paget's disease is described in four stages: Osteoclastic activity Mixed osteoclastic – osteoblastic activity Osteoblastic activity Malignant degeneration Initially, there is a marked increase in the rate of bone resorption in localized areas, caused by large and numerous osteoclasts. Radiographs at this phase show lucency in the affected bone. These localized areas of pathological destruction of bone tissue (osteolysis) are seen radiologically as an advancing lytic wedge in long bones or the skull. When this occurs in the skull, it is called osteoporosis circumscripta. The osteolysis is followed by a compensatory increase in bone formation and increase in alkaline phosphatase levels induced by the bone-forming cells, called osteoblasts, that are recruited to the area. This is associated with accelerated deposition of lamellar bone in a disorganized fashion. Woven bone, rather than lamellar bone, predominates and mineralization occurs at twice the normal rate. This intense cellular activity produces a chaotic picture of trabecular bone ("mosaic" pattern), rather than the normal linear lamellar pattern. The resorbed bone is replaced and the marrow spaces are filled by an excess of fibrous connective tissue with a marked increase in blood vessels, causing the bone to become hypervascular. The bone hypercellularity may then diminish, leaving a dense "pagetic bone", also known as burned-out Paget's disease. A later phase of the disease is characterized by the replacement of normal bone marrow with highly vascular fibrous tissue. Sir James Paget first suggested the disease was due to an inflammatory process. Some evidence suggests that a paramyxovirus infection is the underlying cause of Paget's disease, which may support the possible role of inflammation in the pathogenesis. However, no infectious virus has yet been isolated as a causative agent, and other evidence suggests an intrinsic hyperresponsive reaction to vitamin D and RANK ligand is the cause. Further research is therefore necessary. == Diagnosis == The first clinical manifestation of Paget's disease is usually an elevated alkaline phosphatase in the blood. Paget's disease may be diagnosed using one or more of the following tests: Pagetic bone has a characteristic appearance on X-rays. A skeletal survey is therefore indicated. An elevated level of alkaline phosphatase in the blood in combination with normal calcium, phosphate, and aminotransferase levels in an elderly patient are suggestive of Paget's disease. Markers of bone turnover in urine eg. Pyridinoline Elevated levels of serum and urinary hydroxyproline are also found. Bone scans are useful in determining the extent and activity of the condition. If a bone scan suggests Paget's disease, the affected bone(s) should be X-rayed to confirm the diagnosis. === Differential diagnosis === == Treatment == Although initially diagnosed by a primary care physician, endocrinologists (internal medicine physicians who specialize in hormonal and metabolic disorders), rheumatologists (internal medicine physicians who specialize in joint and muscle disorders), orthopedic surgeons, neurosurgeons, neurologists, oral and maxillofacial surgeons, and otolaryngologists are generally knowledgeable about treating Paget's disease and may be called upon to evaluate specialized symptoms. It can sometimes be difficult to predict whether a person with Paget's disease, who otherwise has no signs or symptoms of the disorder, will develop symptoms or complications (such as a bone fracture) in the future. === Medication === The goal of treatment is to relieve bone pain and prevent the progression of the disease. These medications are usually recommended for people with Paget's disease who: have bone pain, headache, back pain, or a nerve-related symptom (such as "shooting" pains in the leg) that is directly associated with the disease; have elevated levels of serum alkaline phosphatase (ALP) in their blood; display evidence that a bone fracture will occur; require pretreatment therapy for affected bones that require surgery; have active symptoms in the skull, long bones, or vertebrae (spine); have the disease in bones located next to major joints, placing them at risk of developing osteoarthritis; develop hypercalcemia that occurs when a person, with several bones affected by Paget's disease and a high serum alkaline phosphatase level, is immobilized. ==== Bisphosphonates ==== Five bisphosphonates are currently available. In general, the most commonly prescribed are risedronic acid, alendronic acid, and pamidronic acid. Etidronic acid and other bisphosphonates may be appropriate therapies for selected patients but are less commonly used. In one study it was reported that people experienced side effects when taking bisphosphonates for six months, however the quality of evidence was low. None of these drugs should be used by people with severe kidney disease. Neridronate Etidronate disodium The approved regimen is once daily for six months; a higher dose is more commonly used. No food, beverage, or medications should be consumed for two hours before and after taking. The course should not exceed six months, but repeat courses can be given after rest periods, preferably of three to six months duration. Pamidronate disodium in intravenous form: the approved regimen uses an infusion over four hours on each of three consecutive days, but a more commonly used regimen is over two to four hours for two or more consecutive or nonconsecutive days. Alendronate sodium is given as tablets once daily for six months; patients should wait at least 30 minutes after taking before eating any food, drinking anything other than tap water, taking any medication, or lying down (patient may sit). Tiludronate disodium is taken once daily for three months; they may be taken any time of day, as long as there is a period of two hours before and after resuming food, beverages, and medications. Risedronate sodium tablet taken once daily for 2 months is the prescribed regimen; patients should wait at least 30 minutes after taking before eating any food, drinking anything other than tap water, taking any medication, or lying down (patient may sit). Zoledronic acid is given as an intravenous infusion; a single dose is effective for two years. This is recommended for most people at high risk with active disease. ==== Calcitonin ==== Salcatonin, also called calcitonin-salmon is a synthetic copy of a polypeptide hormone secreted by the ultimobranchial gland of salmon. Miacalcin is administered by injection, three times per week or daily, for 6–18 months. Repeat courses can be given after brief rest periods. Miacalcin may be appropriate for certain patients but is seldom used. Calcitonin was putatively linked to increased chance of cancer. The European Medicines Agency (EMA) recommended that calcitonin be used only on a short-term basis for 3 conditions for which it had previously been approved in the European Union: Paget's disease, acute bone loss resulting from sudden immobilization, and hypercalcemia caused by cancer. As a solution for injection or infusion, calcitonin should be administered for no more than 4 weeks to prevent acute bone loss resulting from sudden immobilization, and normally for no more than 3 months to treat Paget's disease, the EMA said. The agency did not specify a time frame for the short-term use of calcitonin for treating hypercalcemia caused by cancer. The EMA based its recommendations on a review of the benefits and risks of calcitonin-containing medicines. Conducted by the agency's Committee for Medicinal Products for Human Use (CHMP), the review encompassed available data from the companies that market these drugs, postmarketing safety data, randomized controlled studies, 2 studies of unlicensed oral calcitonin drugs, and experimental cancer studies, among other sources. In 2014, the FDA noted the risk imbalances in the prescribing information for Miacalcin but declined to label this product with a boxed warning as a causal association was not identified. A more recent meta-analysis determined that a causal link between calcitonin and cancer is both unlikely and antithetical to known biology, although a weak association was not definitively excluded. The available studies for analysis were inconsistent and nonspecific, with one study noting an increased risk of liver cancer and decreased risk of breast cancer. This was not replicated in any other study. Additionally, there is question of the overall efficacy of calcitonin-containing nasal sprays. A phase III trial found no difference between placebo and nasal calcitonin sprays on lumbar bone mineral density in osteoporosis. It did find a significant increase in bone mineral density with oral calcitonin. This result was replicated in another study, but this study found that the bone mineral density increase did not significantly impact fracture risk. However, these studies were only inclusive of osteoporosis. === Surgery === Medical therapy prior to surgery helps to decrease bleeding and other complications. Patients who are having surgery should discuss treatment with their physician. There are generally three major complications of Paget's disease for which surgery may be recommended. Fractures – Surgery may allow fractures to heal in a better position. Severe degenerative arthritis – If disability is severe and medication and physical therapy are no longer helpful, joint replacement of the hips and knees may be considered. Bone deformity – Cutting and realignment of pagetic bone (osteotomy) may help painful weight bearing joints, especially the knees. Complications resulting from enlargement of the skull or spine may injure the nervous system. However, most neurologic symptoms, even those that are moderately severe, can be treated with medication and do not require neurosurgery. === Diet and exercise === In general, patients with Paget's disease should receive 1000–1500 mg of calcium, adequate sunshine, and at least 400 units of vitamin D daily. This is especially important in patients being treated with bisphosphonates; however, taking oral bisphosphonates should be separated from taking calcium by at least two hours, because the calcium can inhibit the absorption of the bisphosphonate. Patients with a history of kidney stones should discuss calcium and vitamin D intake with their physicians. Exercise is very important in maintaining skeletal health, avoiding weight gain, and maintaining joint mobility. Since undue stress on affected bones should be avoided, people with Paget's disease of bone should discuss any exercise program with their physicians or physical therapists before beginning. == Prognosis == The disease is progressive and slowly worsens with time, although people may remain minimally symptomatic. Treatment is aimed at controlling symptoms, but there is no cure. Any bone or bones can be affected, but Paget's disease occurs most frequently in the spine, skull, pelvis, femur, and lower legs. Osteogenic sarcoma, a form of bone cancer, is a rare complication of Paget's disease occurring in less than one percent of those affected. The development of osteosarcoma may be suggested by the sudden onset or worsening pain. == Epidemiology == Paget's disease of bone is the second most common metabolic bone disorder, after osteoporosis. The overall prevalence and severity of Paget's disease are decreasing; the cause for these changes is unclear. Paget's disease is rare in people less than 55 years of age, and the prevalence increases with age. Evidence from studies of autopsy results have demonstrated Paget's disease in about 3 percent of people older than 40 years of age. Paget's disease is more common in males than females. Rates of Paget's disease are about 50 percent higher in men than in women. About 15 percent of people with Paget's disease also have a family member with the disease. In cases where the disease is familial, it is inherited in an autosomal dominant fashion, although not all people that inherit the affected version of the genes will express the disease (incomplete penetrance). The incidence of Paget's disease varies considerably with geographic location. Paget's predominantly affects people of European descent, whereas people of African, Asian, or Indian descent are less commonly affected. Paget's disease is less common in Switzerland and Scandinavia than in the rest of Western Europe. Paget's disease is uncommon in the native populations of North and South America, Africa, Asia, and the Middle East. When an individual from these regions does develop Paget's disease, there is typically some European ancestry present. == History == The condition was initially described by Dr. James Paget. In a paper published in 1877, Paget told of five patients with "a rare disease of bones" which presented with slowly progressive bone deformities in the 4th and 5th decades of age. Strikingly, the first patient was described to have many of the classic complications of the disease, including arthritis related to abnormal bone mechanics, cranial nerve palsies associated with an enlarging skull, and malignant transformation of a tumor of the radius which ultimately proved fatal. Paget's post-mortem autopsy evaluation showed "bones of the vault of this skull were in every part increased to about four times the normal thickness," and microscopic evaluation showed evidence of both bone erosion and abnormal remodeling. Although he incorrectly attributed the findings to a process of chronic inflammation, having ruled out tumor and hypertrophy as alternative etiologies, these prescient observations of a mixed destructive/regenerative process correspond to the modern understanding of the disease. Holding, then, the disease to be an inflammation of bones, I would suggest that, for brief reference, and for the present, it may be called, after its most striking character, Osteitis deformans. A better name may be given when more is known of it. Paget's disease of bone was originally termed osteitis deformans, because it was thought to involve an inflammatory process, which is implied by the suffix -itis. Now, that term is considered technically incorrect, and the preferred term is osteodystrophia deformans. == Society and culture == Viking warrior and poet Egill Skallagrímsson may have had Paget's disease. Ludwig van Beethoven is speculated to have had Paget's disease based on autopsy description, and which may have contributed to his well-known deafness. Retired Boston Red Sox center fielder Dom DiMaggio had Paget's disease and served as a member of the board of directors of the Paget Foundation. American retired boxer Red Burman died of Paget's disease in 1996. == References == == External links == Paget's Disease of Bone Overview - NIH Osteoporosis and Related Bone Diseases ~ National Resource Center	Wikipedia/Paget's_disease_of_bone
Tongue diseases can be congenital or acquired, and are multiple in number. Considered according to a surgical sieve, some example conditions which can involve the tongue are discussed below. Glossitis is a general term for tongue inflammation, which can have various etiologies, e.g. infection. == Congenital == Examples of congenital disorders which affect the tongue include: Aglossia - complete absence of the tongue at birth Ankyloglossia (tongue tie) - where the lingual frenum tethers the tongue to the floor of the mouth. If it interferes with oral hygiene and feeding, frenectomy may be indicated. Hypoglossia - congenitally short tongue Microglossia Macroglossia - an abnormally large tongue, seen in some disorders such as Down syndrome (although macroglossia can be an acquired condition as well). Hamartomata - for example Leiomyomatous hamartoma Glossoptosis Choristomata - For example, osseous choristoma of the tongue, a very rare condition characterized by a nodule on the dorsum of the tongue containing mature lamellar bone without osteoblastic or osteoclastic activity.: 808 Cartilaginous (chondroid), and glial choristomas may also very rarely occur on the tongue. Lingual thyroid Cleft tongue (bifid tongue) - completely cleft tongue is a rare condition caused by a failure of the lateral lingual swellings to merge. More common is an incompletely cleft tongue, appearing as midline fissure. This is normally classed as fissured tongue. == Acquired == === Vascular === Caviar tongue - the veins underneath the tongue can become dilated and prominent, giving the undersurface of the tongue a caviar like appearance. Hemangioma === Infective === Glossitis - some types of glossitis are caused by infections, e.g. median rhomboid glossitis (Candida species), "strawberry tongue" (seen in scarlet fever), and syphilitic glossitis (seen in tertiary syphilis). Oral hairy leukoplakia (seen in people with immunosuppression, caused by Epstein–Barr virus) Oral candidiasis can affect the tongue. Risk factors for oral candidiasis include antibiotic and corticosteroid use, and immunodeficiency (e.g. HIV), or diabetes mellitus). === Traumatic === The tongue may traumatized by mechanical, thermal, electrical or chemical means. A common scenario is where the tongue is bitten accidentally whilst a local anesthetic inferior alveolar nerve block is wearing off. The tongue may develop scalloping on the lateral margins, sometimes termed crenated tongue. This appearance is the result of indentations of the teeth where the tongue is habitually pressed against the teeth ("tongue thrusting", and example of oral parafunction). A lesion similar to morsicatio buccarum can occur on the tongue (sometimes called morsicatio linguarum), caused by chronic chewing on the tongue. The ventral surface (under surface) of the tongue may also be traumatized during oral sexual activity such as cunnilingus ("cunnilingus tongue"). === Autoimmune === Autoimmune conditions such as Sjögren syndrome can cause xerostomia, with resultant glossitis. === Inflammatory === Glossitis Oral lichen planus === Neurological === Hypoglossal nerve weakness can cause atrophy and fasciculation of the tongue. Melkersson–Rosenthal syndrome - a neurological disorder characterized by fissured tongue, facial palsy and orofacial swelling. === Neoplastic === The sides (lateral) and undersurface (ventral) of the tongue are high risk sites for the development of oral cancer, most commonly squamous cell carcinoma. === Degenerative === Motor neuron disease (Lou Gehrig's disease) can cause impaired control of tongue movement, affecting speech and swallowing. === Environmental === Poor diet can cause malnutrition and nutritional deficiencies. Deficiency of iron, B vitamins and folic acid are common causes for atrophic glossitis. Black hairy tongue - some factors thought to cause black hairy tongue are environmental, such as eating a soft diet, poor oral hygiene, smoking and antibiotic use. === Unknown === Geographic tongue (benign migratory glossitis) - a common disorder which occasionally causes a burning sensation but is usually painless. Irregular patches of depapillation form on the tongue giving the appearance of a map. The cause is unknown. Leukoplakia - can affect the tongue Tongue coating - food debris, desquamated epithelial cells and bacteria often form a visible tongue coating. This coating has been identified as a major contributing factor in bad breath (halitosis), which can be managed by brushing the tongue gently with a toothbrush or using special oral hygiene instruments such as tongue scrapers or mouth brushes. Burning mouth syndrome - this chronic pain disorder commonly involves the tongue. In reflection of this, some of the synonyms for the condition include tongue-specific terms such as "glossodynia" or "burning tongue syndrome". Burning mouth syndrome is characterized by chronic burning sensation on the tongue and other oral mucous membranes in the absences of any identifiable signs or causes. === Iatrogenic === Paratrichosis tongue - Real hair implanted on tongue. == Epidemiology == Tongue lesions are very common. For example, in the United States one estimated point prevalence was 15.5% in adults. Tongue lesions are more common in persons who wear dentures and tobacco users. The most common tongue conditions are geographic tongue, followed by fissured tongue and hairy tongue. == History == Hippocrates, Galen and others considered the tongue to be a "barometer" of health, and emphasized the diagnostic and prognostic importance of the tongue. Assessment of the tongue has historically been an important part of a medical examination. The shape and color of the tongue is examined and observed diagnostically in traditional Chinese medicine. For example, scalloping of the tongue is said to indicate qi vacuity. Some modern medical sources still describe the tongue as "the mirror of physical health". This is related to the high rate of turnover of the oral mucosa compared to the skin, which means that systemic conditions may manifest sooner in the mouth than the skin. Physical appearances such as cyanosis are also often more readily apparent in the mouth. == See also == Tooth pathology Tongue Tongue map Oral and maxillofacial pathology == References == == External links ==	Wikipedia/Tongue_disease
Necrotizing periodontal diseases is one of the three categories of periodontitis as defined by the American Academy of Periodontology/European Federation of Periodontology 2017 World Workshop classification system. Necrotizing periodontal diseases are a type of inflammatory periodontal (gum) disease caused by bacteria (notably fusobacteria and spirochaete species). The diseases appear to represent different severities or stages of the same disease process, although this is not completely certain. These diseases usually have a sudden onset. The mildest on the spectrum is necrotizing gingivitis (NG), followed by the successively more severe conditions necrotizing periodontitis (NP), necrotizing stomatitis and finally cancrum oris (noma), which is frequently fatal. == Necrotizing gingivitis == Necrotizing gingivitis, is a common, non-contagious infection of the gums. If improperly treated necrotizing may become chronic and/or recurrent. In developed countries, necrotizing gingivitis occurs mostly in young adults with predisposing factors such as psychological stress, sleep deprivation, poor oral hygiene, smoking, immunosuppression and/or malnutrition. In developing countries, necrotizing gingivitis occurs mostly in malnourished children. Due to shared predisposing factors in a population (e.g. students during a period of examinations, armed forces recruits) necrotizing gingivitis is known to occur in epidemic-type patterns. This has led to the popular belief that necrotizing gingivitis is contagious, but this is not the case. The main features of necrotizing gingivitis are painful, bleeding gums and ulceration and necrosis of the interdental papilla. There may also be intra-oral halitosis, cervical lymphadenitis (swollen lymph nodes in the neck) and malaise. Treatment of the acute disease is by debridement and antibiotics, usually metronidazole. Poor oral hygiene and other predisposing factors may need to be corrected to prevent recurrence. Necrotizing gingivitis is also known as trench mouth, as it was observed to occur in the mouths of front line soldiers during World War I. == Necrotizing periodontitis == Necrotizing periodontitis (NP) is where the infection leads to attachment loss (destruction of the ligaments anchoring teeth in their sockets), but involves only the gingiva, periodontal ligament and alveolar ligament. If attachment loss is present in the disease, it is termed NP, unless the disease has progressed beyond the mucogingival junction. NP may be an extension of NG into the periodontal ligaments, although this is not completely proven. In the meantime, NG, NP, and NS are classified together under the term necrotizing periodontal diseases. == Necrotizing stomatitis == Progression of NP into tissue beyond the mucogingival junction characterizes necrotizing stomatitis. Atypical case reports describe NS development without prior NPD lesions. == Noma == Noma (also termed cancrum oris) is a necrotizing and destructive infection of the mouth and face, and therefore not strictly speaking a periodontal disease. In modern times, this condition usually occurs in malnourished children in developing countries. It may be disfiguring and is frequently fatal. It has been suggested that all cases of noma develop from pre-existing NG, but this is not confirmed. Furthermore, the vast majority of cases of NG and NP will not progress to the more severe forms, even without treatment. == Vincent's angina == Strictly speaking, Vincent's angina is not a necrotizing periodontal disease. However, Vincent's angina is widely confused with necrotizing gingivitis (previously also called "Vincent's gingivitis"). Vincent's angina is tonsillitis and pharyngitis, and does not typically involve the gums. Many publications using the term "Vincent's angina" date from the twentieth century, and the term is not so common in modern times. The condition is named after Jean Hyacinthe Vincent, a French physician who was working at the Paris Pasteur Institute. Vincent described a fusospirochetal infection of the pharynx and palatine tonsils, causing "ulcero-membranous pharyngitis and tonsillitis", which later became known as Vincent's angina. Later in 1904, Vincent described the same pathogenic organisms in "ulceronecrotic gingivitis". == Nomenclature == The necrotizing periodontal diseases used to include the words "acute" and "ulcerative" in their names (e.g., "necrotizing ulcerative gingivitis"). Neither term is included in the AAP/EFP 2017 World Workshop classification on Necrotizing Periodontal Diseases. == References == J Lindhe, NP Lang, T Karring (editors) (2008) "Clinical periodontology and implant dentistry" 5th edition, Blackwell Munksgaard, pp. 413,459 MG Newman, HH. Takei, PR Klokkevold, FA Carranza (editors) (2012) "Carranza's clinical periodontology" 11th edition, Elsevier/Saunders, p. 165	Wikipedia/Necrotizing_periodontal_diseases
The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms. The UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. In this scenario, the UPR has three aims: initially to restore normal function of the cell by halting protein translation, degrading misfolded proteins, and activating the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. If these objectives are not achieved within a certain time span or the disruption is prolonged, the UPR aims towards apoptosis. Sustained overactivation of the UPR has been implicated in prion diseases as well as several other neurodegenerative diseases, and inhibiting the UPR could become a treatment for those diseases. Diseases amenable to UPR inhibition include Creutzfeldt–Jakob disease, Alzheimer's disease, Parkinson's disease, and Huntington's disease. == Protein folding in the endoplasmic reticulum == === Protein synthesis === The term protein folding incorporates all the processes involved in the production of a protein after the nascent polypeptides have become synthesized by the ribosomes. The proteins destined to be secreted or sorted to other cell organelles carry an N-terminal signal sequence that will interact with a signal recognition particle (SRP). The SRP will lead the whole complex (Ribosome, RNA, polypeptide) to the ER membrane. Once the sequence has “docked”, the protein continues translation, with the resultant strand being fed through the polypeptide translocator directly into the ER. Protein folding commences as soon as the polypeptide enters to the luminal environment, even as translation of the remaining polypeptide continues. === Protein folding and quality control === Protein folding steps involve a range of enzymes and molecular chaperones to coordinate and regulate reactions, in addition to a range of substrates required in order for the reactions to take place. The most important of these to note are N-linked glycosylation and disulfide bond formation. N-linked glycosylation occurs as soon as the protein sequence passes into the ER through the translocon, where it is glycosylated with a sugar molecule that forms the key ligand for the lectin molecules calreticulin (CRT; soluble in ER lumen) and calnexin (CNX; membrane bound). Favoured by the highly oxidizing environment of the ER, protein disulfide isomerases facilitate formation of disulfide bonds, which confer structural stability to the protein in order for it to withstand adverse conditions such as extremes of pH and degradative enzymes. The ER is capable of recognizing misfolding proteins without causing disruption to the functioning of the ER. The aforementioned sugar molecule remains the means by which the cell monitors protein folding, as the misfolding protein becomes characteristically devoid of glucose residues, targeting it for identification and re-glycosylation by the enzyme UGGT (UDP-glucose:glycoprotein glucosyltransferase). If this fails to restore the normal folding process, exposed hydrophobic residues of the misfolded protein are bound by the protein glucose regulate protein 78 (Grp78), a heat shock protein 70kDa family member that prevents the protein from further transit and secretion. Where circumstances continue to cause a particular protein to misfold, the protein is recognized as posing a threat to the proper functioning of the ER, as they can aggregate to one another and accumulate. In such circumstances the protein is guided through endoplasmic reticulum-associated degradation (ERAD). The chaperone EDEM guides the retrotranslocation of the misfolded protein back into the cytosol in transient complexes with PDI and Grp78. Here it enters the ubiquitin-proteasome pathway, as it is tagged by multiple ubiquitin molecules, targeting it for degradation by cytosolic proteasomes. Successful protein folding requires a tightly controlled environment of substrates that include glucose to meet the metabolic energy requirements of the functioning molecular chaperones; calcium that is stored bound to resident molecular chaperones; and redox buffers that maintain the oxidizing environment required for disulfide bond formation. Unsuccessful protein folding can be caused by HLA-B27, disturbing balance of important (IL-10 and TNF) signaling proteins. At least some disturbances are reliant on correct HLA-B27 folding. However, where circumstances cause a more global disruption to protein folding that overwhelms the ER's coping mechanisms, the UPR is activated. == Molecular mechanism == === Initiation === The molecular chaperone BiP/Grp78 has a range of functions within the ER. It maintains specific transmembrane receptor proteins involved in initiation of the downstream signalling of the UPR in an inactive state by binding to their luminal domains. An overwhelming load of misfolded proteins or simply the over-expression of proteins (e.g. IgG) requires more of the available BiP/Grp78 to bind to the exposed hydrophobic regions of these proteins, and consequently BiP/Grp78 dissociates from these receptor sites to meet this requirement. Dissociation from the intracellular receptor domains allows them to become active. PERK dimerizes with BiP in resting cells and oligomerizes in ER-stressed cells. Although this is traditionally the accepted model, doubts have been raised over its validity. It has been argued that the genetic and structural evidence supporting the model simply shows BiP dissociation to be merely correlated with Ire1 activation, rather than specifically causing it. An alternative model has been proposed, whereby unfolded proteins interact directly with the ER-lumenal domain of Ire1, causing oligomerization and transautophosphorylation. However these models are not mutually exclusive, it is also possible that both direct interaction of Ire1 with unfolded proteins and dissociation of BiP from IRE1 contribute to the activation of the Ire1 pathway. === Functions === The initial phases of UPR activation have two key roles: Translation Attenuation and Cell Cycle Arrest by the PERK Receptor This occurs within minutes to hours of UPR activation to prevent further translational loading of the ER. PERK (protein kinase RNA-like endoplasmic reticulum kinase) activates itself by oligomerization and autophosphorylation of the free luminal domain. The activated cytosolic domain causes translational attenuation by directly phosphorylating the α subunit of the regulating initiator of the mRNA translation machinery, eIF2. This also produces translational attenuation of the protein machinery involved in running the cell cycle, producing cell cycle arrest in the G1 phase. PERK deficiency may have a significant impact on physiological states associated with ER stress. Increased Production of Proteins Involved in the Functions of the UPR UPR activation also results in upregulation of proteins involved in chaperoning malfolding proteins, protein folding and ERAD, including further production of Grp78. Ultimately this increases the cell's molecular mechanisms by which it can deal with the misfolded protein load. These receptor proteins have been identified as: Inositol-requiring kinase 1, whose free luminal domain activates itself by homodimerisation and transautophosphorylation. The activated domain is able to activate the transcription factor XBP1(Xbox binding protein) mRNA (the mammalian equivalent of the yeast Hac1 mRNA) by cleavage and removal of a 26bp intron. The activated transcription factor upregulates UPR 'stress genes' by directly binding to stress element promoters in the nucleus. ATF6 (activating transcription factor 6) is a basic leucine zipper transcription factor. Upon Grp78 dissociation, the entire 90kDa protein translocates to the Golgi, where it is cleaved by proteases to form an active 50kDa transcription factor that translocates to the nucleus. It binds to stress element promoters upstream of genes that are upregulated in the UPR. The aim of these responses is to remove the accumulated protein load whilst preventing any further addition to the stress, so that normal function of the ER can be restored as soon as possible. If the UPR pathway is activated in an abnormal fashion, such as when obesity triggers chronic ER stress and the pathway is constitutively active, this can lead to insensitivity to insulin signaling and thus insulin resistance. Individuals suffering from obesity have an elevated demand placed on the secretory and synthesis systems of their cells. This activates cellular stress signaling and inflammatory pathways because of the abnormal conditions disrupting ER homeostasis. A downstream effect of the ER stress is a significant decrease in insulin-stimulated phosphorylation of tyrosine residues of insulin receptor substrate (IRS-1), which is the substrate for insulin tyrosine kinase (the insulin receptor). C-Jun N-terminal kinase (JNK) is also activated at high levels by IRE-1α, which itself is phosphorylated to become activated in the presence of ER stress. Subsequently, JNK phosphorylates serine residues of IRS-1, and thus inhibits insulin receptor signaling. IRE-1α also recruits tumor necrosis factor receptor-associated factor 2 (TRAF2). This kinase cascade that is dependent on IRE-1α and JNK mediates ER stress–induced inhibition of insulin action. Obesity provides chronic cellular stimuli for the UPR pathway as a result of the stresses and strains placed upon the ER, and without allowing restoration to normal cellular responsiveness to insulin hormone signaling, an individual becomes very likely to develop type 2 diabetes. Skeletal muscles are sensitive to physiological stress, as exercise can impair ER homeostasis. This causes the expression of ER chaperones to be induced by the UPR in response to the exercise-induced ER stress. Muscular contraction during exercise causes calcium to be released from the sarcoplasmic reticulum (SR), a specialized ER network in skeletal muscles. This calcium then interacts with calcineurin and calcium/calmodulin-dependent kinases that in turn activate transcription factors. These transcription factors then proceed to alter the expression of exercise-regulated muscle genes. PGC-1alpha, a transcriptional coactivator, is a key transcription factor involved in mediating the UPR in a tissue-specific manner in skeletal muscles by coactivating ATF6alpha. Therefore, PGC-1alpha gets expressed in muscles after acute and long-term exercise training. The function of this transcription factor is to increase the number and function of mitochondria, as well as to induce a switch of skeletal fibers to slow oxidative muscle fibers, as these are fatigue-resistant. Therefore, this UPR pathway mediates changes in muscles that have undergone endurance training by making them more resistant to fatigue and protecting them from future stress. === Initiating apoptosis === In conditions of prolonged stress, the goal of the UPR changes from being one that promotes cellular survival to one that commits the cell to a pathway of apoptosis. Proteins downstream of all 3 UPR receptor pathways have been identified as having pro-apoptotic roles. However, the point at which the 'apoptotic switch' is activated has not yet been determined, but it is a logical consideration that this should be beyond a certain time period in which resolution of the stress has not been achieved. The two principal UPR receptors involved are Ire1 and PERK. By binding with the protein TRAF2, Ire1 activates a JNK signaling pathway, at which point human procaspase 4 is believed to cause apoptosis by activating downstream caspases. Although PERK is recognised to produce a translational block, certain genes can bypass this block. An important example is that the proapoptotic protein CHOP (CCAAT/-enhancer-binding protein homologous protein), is upregulated downstream of the bZIP transcription factor ATF4 (activating transcription factor 4) and uniquely responsive to ER stress. CHOP causes downregulation of the anti-apoptotic mitochondrial protein Bcl-2, favouring a pro-apoptotic drive at the mitochondria by proteins that cause mitochondrial damage, cytochrome c release and caspase 3 activation. Diseases Diseases amenable to UPR inhibition include Creutzfeldt–Jakob disease, Alzheimer's disease, Parkinson's disease, and Huntington's disease. Endoplasmic reticulum stress was reported to play a major role in non‐alcoholic fatty liver disease (NAFLD) induction and progression. High fat diet fed rats showed increased ER stress markers CHOP, XBP1, and GRP78. ER stress is known to activate hepatic de novo lipogenesis, inhibit VLDL secretion, promote insulin resistance and inflammatory process, and promote cell apoptosis. Thus it increase the level of fat accumulation and worsens the NAFLD to a more serious hepatic state. Zingiber officinale (ginger) extract and omega‐3 fatty acids were reported to ameliorate endoplasmic reticulum stress in a nonalcoholic fatty liver rat model. As stated above, the UPR can also be activated as a compensatory mechanism in disease states. For instance, the UPR is up-regulated in an inherited form of dilated cardiomyopathy due to a mutation in gene encoding the Phospholamban protein. Further activation proved therapeutic in a human induced pluripotent stem cell model of PLN mutant dilated cardiomyopathy. == Chemical inducers == Brefeldin A is a very common inducer of the unfolded protein response or endoplasmic reticulum stress response (ER stress). thapsigargin leads to ER Ca2+ depletion due to inhibition of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA). A23187 upregulates expression of ER stress proteins 2-deoxyglucose dithiothreitol reduces the disulfide bridges of proteins. The denatured proteins accumulated inside the ER. fenretinide and bortezomib (Velcade), each acting via different cellular mechanisms, induce ER stress, leading to apoptosis in melanoma cells. tunicamycin inhibits N-linked glycosylation. ErSO activates unfolded protein response and has anti cancer activity == Biological inducers == Dengue virus induces PERK dependent ER stress as part of virus induced response in infected cells to favor replication. Influenza virus requires endoplasmic reticulum protein 57-kD (ERp57) for replication and apoptosis induction in infected cells. == See also == Endoplasmic reticulum stress response (ER stress) Mitochondrial unfolded protein response Aggresome PERK inhibitors == References ==	Wikipedia/Unfolded_protein_response
Salivary gland diseases (SGDs) are multiple and varied in cause. There are three paired major salivary glands in humans: the parotid glands, the submandibular glands, and the sublingual glands. There are also about 800–1,000 minor salivary glands in the mucosa of the mouth. The parotid glands are in front of the ears, one on side, and secrete mostly serous saliva, via the parotid ducts (Stenson ducts), into the mouth, usually opening roughly opposite the second upper molars. The submandibular gland is medial to the angle of the mandible, and it drains its mixture of serous and mucous saliva via the submandibular duct (Wharton duct) into the mouth, usually opening in a punctum in the floor of mouth. The sublingual gland is below the tongue, on the floor of the mouth; it drains its mostly mucous saliva into the mouth via about 8–20 ducts, which open along the plica sublingualis, a fold of tissue under the tongue. The function of the salivary glands is to secrete saliva, which has a lubricating function, which protects the mucosa of the mouth during eating and speaking. Saliva also contains digestive enzymes (e.g. salivary amylase), has antimicrobial action, and acts as a buffer. Salivary-gland dysfunction occurs when salivary rates are reduced; this can cause xerostomia (dry mouth). Some disorders affecting the salivary glands are listed below. Some are more common than others, and they are considered according to a surgical sieve; but this list is not exhaustive. Sialadenitis is inflammation of a salivary gland, usually caused by infections, although there are other, less common causes of inflammation, such as irradiation, allergic reactions, and trauma. == Congenital == Congenital disorders of the salivary glands are rare. They include: Aplasia Atresia Ectopic salivary gland tissue Stafne defect - an uncommon condition which some consider to be an anatomic variant rather than a true disease. It is thought to be created by an ectopic portion of salivary gland tissue which causes the bone of the mandible to remodel around the tissue, creating an apparent cyst like radiolucent area on radiographs. Classically, this lesion is discovered as a chance finding, since it causes no symptoms. It appears below the inferior alveolar nerve canal in the posterior region of the mandible. == Acquired == === Dysfunction === Salivary gland dysfunction affects the flow, amount, or quality of saliva produced. A reduced salivation is termed hyposalivation. Hyposalivation often results in a dry mouth condition called xerostomia, and this can cause tooth decay due to the loss of the protective properties of saliva. In addition, The results of a study have suggested that hyposalivation could lead to acute respiratory infection. There are two potential reasons for increasing the incidence rate of this infection. First, reduced saliva secretion may impair the oral and airway mucosal surface as a physical barrier, which consequently enhances the adhesion and colonization of viruses. Second, this reduction may also impair the secretion of antimicrobial proteins and peptides. In saliva, there are many antiviral proteins and peptides, some of which can inhibit replication of viruses, especially coronavirus; these salivary proteins may also protect against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, hyposalivation may be a risk factor for acute respiratory infection, including (COVID-19). However, further investigations are crucial to prove this hypothesis. Hypersalivation is the overproduction of saliva and has many causes. === Vascular === Necrotizing sialometaplasia is a lesion that usually arises from a minor salivary gland on the palate. It is thought to be due to vascular infarction of the salivary gland lobules. It is often mistaken for oral cancer, but the lesion is not neoplastic. === Infective === Infections involving the salivary glands can be viral or bacterial (or rarely fungal). Mumps is the most common viral sialadenitis. It usually occurs in children and involves pain in front of the ear, swelling of the parotid, fever, chills, and headaches. Bacterial sialadenitis is usually caused by ascending organisms from the mouth. Risk factors include reduced salivary flow. Human immunodeficiency virus-associated salivary gland disease (HIV-SGD). === Traumatic === Oral mucoceles are common, and are caused by rupture of a salivary gland duct and spillage of mucin into the surrounding tissues. Usually, they are caused by trauma. Classically, a mucocele is bluish and fluctuant, and most commonly occurs on the lower lip. Ranula is a mucocele under the tongue. Ranulas may be larger than mucoceles at other sites; they are usually associated with the sublingual gland, and less often they arise from the submandibular gland or a minor salivary gland. Rarely, a ranula may descend into the neck rather than the mouth (plunging ranula). If small, the ranula may be left alone; if it is larger and causing symptoms, excision of the sublingual gland may be indicated. Nicotinic stomatitis is whitening of the hard palate by hyperkeratosis caused by the heat from smoking or from drinking hot liquids. This irritation also causes inflammation of the duct openings of the minor salivary glands of the palate, and they become dilated. This manifests as red patches or spots on a white background. === Autoimmune === Sjögren's syndrome Graft-versus-host disease === Inflammatory === Post-irradiation sialadenitis Sarcoidosis—there may be parotitis alone or uveoparotitis (inflammation of both the parotid and the uvea of the eyes), which occurs in Heerfordt's syndrome. Cheilitis glandularis—This is inflammation of the minor salivary glands, usually in the lower lip, eversion and swelling of the lip. Chronic sclerosing sialadenitis is a salivary gland manifestation of IgG4-related disease. === Neurological === Frey's syndrome === Neoplastic === Salivary gland neoplasm === Diverticulum === A salivary diverticulum (plural diverticuli) is a small pouch or out-pocketing of the duct system of a major salivary gland. Such diverticuli typically cause pooling of saliva and recurrent sialadenitis, especially parotitis. A diverticulum may also cause a sialolith to form. The condition can be diagnosed by sialography. Affected individuals may "milk" the salivary gland to encourage flow of saliva through the duct. === Unknown === Sialolithiasis - although several possibly coexisting factors have been suggested to be involved in the formation of salivary stones, including altered acidity of saliva, reduced salivary flow rate, abnormal calcium metabolism and abnormalities in the sphincter mechanism of the duct opening, the exact cause in many cases is unknown. Sialadenosis (sialosis) is an uncommon, non-inflammatory, non-neoplastic, recurrent swelling of the salivary glands. The cause is hypothesized to be abnormalities of neurosecretory control. It may be associated with alcoholism. == References == == External links ==	Wikipedia/Salivary_gland_disease

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