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You are a medical interpreter. Your duty is to translate medical terms into easily digestible information, maintaining accuracy and detail. | I've come across the term 'Functional constipation' in a medical context, but I'm not sure what it means. Can you clarify? | Functional constipation, known as chronic idiopathic constipation (CIC), is constipation that does not have a physical (anatomical) or physiological (hormonal or other body chemistry) cause. It may have a neurological, psychological or psychosomatic cause. A person with functional constipation may be healthy, yet has difficulty defecating.
Symptoms and diagnosis
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. Diagnosing CIC can be difficult as other syndromes must be ruled out as there is no physiological cause for CIC. Doctors will typically look for other symptoms, such as blood in stool, weight loss, low blood count, or other symptoms.
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 colonThere is also possibility of presentation with other comorbid symptoms such as headache, especially in children.
Treatment
Treatment options appear similar and include prucalopride, lubiprostone, linaclotide, tegaserod, velusetrag, elobixibat, bisacodyl, sodium picosulphate, and most recently, plecanatide.
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 == |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | Please help me grasp the concept behind the medical term 'Coccidiosis.' | Coccidiosis is a parasitic disease of the intestinal tract of animals caused by coccidian protozoa. The disease spreads from one animal to another by contact with infected feces or ingestion of infected tissue. Diarrhea, which may become bloody in severe cases, is the primary symptom. Most animals infected with coccidia are asymptomatic, but young or immunocompromised animals may suffer severe symptoms and death.
While coccidia can infect a wide variety of animals, including humans, birds, and livestock, they are usually species-specific. One well-known exception is toxoplasmosis caused by Toxoplasma gondii.Humans may first encounter coccidia when they acquire a dog, cat or bird that is infected. Other than T. gondii, the infectious organisms are canine and feline-specific and are not contagious to humans, unlike the zoonotic diseases.
Coccidia in dogs
Puppies are frequently infected with coccidia from the feces of their mother, and are more likely to develop coccidiosis due to their undeveloped immune systems. Stress can trigger symptoms in susceptible animals.Symptoms in young dogs include diarrhoea with mucus and blood, poor appetite, vomiting, and dehydration. Untreated, the disease can be fatal.
Treatment is routine and effective. Diagnosis is made by low-powered microscopic examination of the feces, which is generally replete with oocysts. Readily available drugs eliminate the protozoa or reduce them enough that the animals immune system can clear the infection. Permanent damage to the gastrointestinal system is rare, and a dog will usually suffer no long-lasting negative effects.
SYMPTOM A VOMITING OF DOGS IS YELLOW AND BLACKISH.
Coccidia in chickens
Coccidiosis is a significant disease for chickens, especially affecting the young chicks. It can be fatal or leave the bird with compromised digestion. There are chick feed mixes that contain a coccidiostat to manage exposure levels and control disease. In an outbreak, coccidiocidal medications are given. Examples are toltrazuril (Baycox) or amprolium. After multiple infections, surviving chickens become resistant to the coccidia.
Coccidia in cattle
Coccidiosis (in cattle also known as Eimeriosis) is one of the most important diseases in calves and youngstock both under housing conditions and when grazing. Symptoms are generally caused by the species Eimeria zuernii and Eimeria bovis and include loss of appetite, fatigue, dehydration, and watery, sometimes bloody, diarrhoea. Outbreaks are known to occur in cattle herds. The parasite can infect all animals on the farm and in some countries the parasite is present on all farms. Coccidiosis affects the growth and sometimes survival of the calves and consequently affect the production and the profitability of cattle livestock production.
Coccidia in goats
Coccidiosis is also present in goats, and is the largest cause of diarrhea in young goats. It can also cause high temperature and loss of appetite.
Genera and species that cause coccidiosis
Genus Isospora is the most common cause of intestinal coccidiosis in dogs and cats. Species of Isospora are host-specific, infecting only one species. Species that infect dogs include I. canis, I. ohioensis, I. burrowsi, and I. neorivolta. Species that infect cats include I. felis and I. rivolta. The most common symptom is diarrhea. Sulfonamides are the most common treatment.
Genus Eimeria affects birds such as poultry and mammals such as cattle and rabbits. Species include E. tenella, E. brunetti, E. necatrix, and E. acervulina. Sulfonamides are effective.
Genus Cryptosporidium contains two species known to cause cryptosporidiosis, C. parvum and C. muris. Cattle are most commonly affected, and their feces may be a source of infection for other mammals, including humans. Recent genetic analyses of Cryptosporidium in humans have identified C. hominis as a human-specific pathogen. Infection occurs most commonly in immunocompromised individuals, such as dogs with canine distemper, cats with feline leukemia, and humans with AIDS.
Genus Hammondia is transmitted by ingestion of cysts found in the tissue of grazing animals and rodents. Dogs and cats are the definitive hosts, with H. heydorni infecting dogs and the H. hammondi and H. pardalis infecting cats. Symptoms do not usually occur.
Genus Besnoitia infects cats that ingest cysts in the tissue of rodents and opossums, but usually do not cause disease.
Genus Sarcocystis infects carnivores that ingest cysts from various intermediate hosts. Sarcocystis may cause disease in dogs and cats.
Genus Toxoplasma has one important species, T. gondii. Cats are the definitive host, but all mammals and some fish, reptiles, and amphibians can be intermediate hosts. Only cat feces will hold infective oocysts, but infection through ingestion of cysts can occur with the tissue of any intermediate host. Toxoplasmosis occurs in humans usually as low-grade fever or muscle pain for a few days. A normal immune system will suppress the infection but the tissue cysts will persist in that animal or human for years or for life. In immunocompromised individuals, dormant cysts can be reactivated and cause lesions in the brain, heart, lungs, eyes, and other tissues. A fetus may be at risk if a pregnant woman without immunity becomes infected. Symptoms in cats include fever, weight loss, diarrhea, vomiting, uveitis, and central nervous system signs. Disease in dogs includes paralysis, tremors, and seizures. Dogs and cats are usually treated with clindamycin.
Genus Neospora has one important species, N. caninum, which affects dogs in a manner similar to toxoplasmosis. Neosporosis is difficult to treat.
Genus Hepatozoon contains one species that causes hepatozoonosis in dogs and cats, H. canis. Animals become infected by ingesting an infected brown dog tick (Rhipicephalus sanguineus). Symptoms include fever, weight loss, and pain in the spine and limbs.The most common medications used to treat coccidian infections are in the sulfonamide antibiotic family.Depending on the pathogen and the condition of the animal, untreated coccidiosis may clear of its own accord, or become severe and damaging, and sometimes cause death.
== References == |
You function as a medical explainer. Your task is to convey the meanings of medical terms in a detailed, yet easy-to-understand manner. | Could you please explain the term 'Berlins edema' in simple language? | Berlins edema (commotio retinae) a common condition caused by blunt injury to the eye. It is characterized by decreased vision in the injured eye a few hours after the injury. Under examination the retina appears opaque and white in colour in the periphery but the blood vessels are normally seen along with "cherry red spot" in the foveal region. This whitening is indicative of cell damage, which occurs in the retinal pigment epithelium and outer segment layer of photoreceptors. Damage to the outer segment often results in photoreceptor death through uncertain mechanisms. Usually there is no leakage of fluid and therefore it is not considered a true edema. The choroidal fluorescence in fluorescent angiography is absent. Visual acuity ranges from 20/20 to 20/400.
The prognosis is excellent except in case of complications of choroidal rupture, hemorrhage or pigment epithelial damage, but damage to the macula will result in poorer recovery. The outcome can be worsened in the case of retinal detachment, atrophy or hyperplasia. Visual field defects can occur. In late cases cystoid macular edema sometimes develops which can further lead to macular destruction.
Commotio retinae is usually self limiting and there is no treatment as such. It usually resolves in 3–4 weeks without any complications and sequelae.
== References == |
You are a medical educator. Your role is to provide detailed and clear explanations for medical terms, suitable for both professionals and laypersons. | The term 'Ocular tilt reaction' keeps coming up in medical discussions. What does it stand for? | The ocular tilt reaction (OTR) comprises skew deviation, head tilt and ocular torsion involving structures of the inner ear responsible for maintenance of balance of the body i.e. the semi-circular canals (SCC), utricle and saccule.
Each anterior semi-circular canals has excitatory projections to the ipsilateral superior rectus muscle and its yoke i.e., the contralateral inferior oblique while simultaneously inhibiting the ipsilateral inferior rectus muscle and its yoke i.e. the contralateral superior oblique. Also, each posterior semi-circular canals has excitatory projections to the ipsilateral superior oblique and its yoke i.e. the contralateral inferior rectus, while simultaneously inhibiting the ipsilateral inferior oblique and its yoke i.e. the contralateral superior rectus. A head tilt causes stimulation of both anterior semi-circular canals and the posterior semi-circular canals resulting in excitation of ipsilateral intorters (superior oblique and superior rectus) and contralateral extorters (inferior oblique and inferior rectus) while their antagonists are simultaneously inhibited. The otoliths (utricle and saccule) probably follow a similar pathway.
Normally, a body tilt (along with the initial head tilt) to the right causes a shift of the subjective visual vertical (SVV) to the left resulting in reflex, compensatory orientation of the head to left to realign the SVV to the true vertical.
The initial head tilt to right will cause stimulation of the right utricle resulting in excitory signals to pass to the SR and SO (right eye), and IO and IR (left eye). Simultaneously, inhibitory signals pass to their antagonists. The stimulated two intorters (right eye) and the two extorters (left eye) have opposite vertical actions i.e., one is an elevator and the other is a depressor. The opposite vertical actions nearly cancel each other and therefore only a small vertical deviation occurs, whereas their identical torsional actions are additive.
In case of any lesion from the utricle to the brainstem, diminished input from the affected vestibular pathway, for example the left vestibular is the same as stimulation of right vestibular pathway, resulting in the erroneous interpretation by the brain that the head is tilted to the right and consequently that the SVV is tilted to the left. This causes reflex rotation of the head to the left, thus realigning the eyes and head to a position that is actually tilted but which the brain interprets as vertical.
Published literature on ocular torsion in physiologic ocular counter-roll are usually not very clear on the type of head tilt inducing the torsion, i.e., initial head tilt causing a tilt in the SVV or the compensatory head tilt to realign SVV with the true vertical. It has been stated that the ocular torsion in physiologic ocular counter-roll appears in the opposite direction as that of the head tilt in contrast to the same direction of ocular torsion as the head tilt in pathologic ocular tilt reaction.
If instead of the actual head tilt (as compared to true vertical), the direction of the head tilt as interpreted by the brain (subjective head tilt) is given importance, then it is seen that the head tilt and ocular torsion are actually in the same direction in both the physiologic ocular counter-roll and the pathologic ocular tilt reaction. The subjective head tilt as interpreted by the brain in the presence of asymmetric signals from the inner ear neural afferents is the principal factor in determining the direction of ocular torsion in ocular tilt reaction.
== References == |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | I'm not familiar with the medical term 'Wart.' Could you provide some insights? | Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the hands and feet, they can also affect other locations. One or many warts may appear. They are not cancerous.Warts are caused by infection with a type of human papillomavirus (HPV). Factors that increase the risk include use of public showers and pools, working with meat, eczema and a weak immune system. The virus is believed to enter the body through skin that has been damaged slightly. A number of types exist, including "common warts", plantar warts, "filiform warts", and genital warts. Genital warts are often sexually transmitted.Without treatment, most types of warts resolve in months to years. A number of treatments may speed resolution, including salicylic acid applied to the skin and cryotherapy. In those who are otherwise healthy, they do not typically result in significant problems. Treatment of genital warts differs from that of other types.Warts are very common, with most people being infected at some point in their lives. The estimated current rate of non-genital warts among the general population is 1–13%. They are more common among young people. Prior to widespread adoption of the HPV vaccine, the estimated rate of genital warts in sexually active women was 12%. Warts have been described at least as far back as 400 BC by Hippocrates.
Types
A range of types of wart have been identified, varying in shape and site affected, as well as the type of human papillomavirus involved. These include:
Common wart (verruca vulgaris), a raised wart with roughened surface, most common on hands, but can grow anywhere on the body. Sometimes known as a Palmer wart or Junior wart.
Flat wart (verruca plana), a small, smooth flattened wart, flesh-coloured, which can occur in large numbers; most common on the face, neck, hands, wrists and knees.
Filiform or digitate wart, a thread- or finger-like wart, most common on the face, especially near the eyelids and lips.
Genital wart (venereal wart, condyloma acuminatum, verruca acuminata), a wart that occurs on the genitalia.
Periungual wart, a cauliflower-like cluster of warts that occurs around the nails.
Plantar wart (verruca, verruca plantaris), a hard, sometimes painful lump, often with multiple black specks in the center; usually only found on pressure points on the soles of the feet.
Mosaic wart, a group of tightly clustered plantar-type warts, commonly on the hands or soles of the feet.
Cause
Warts are caused by the human papilloma virus (HPV). There are about 130 known types of human papilloma viruses. HPV infects the squamous epithelium, usually of the skin or genitals, but each HPV type is typically only able to infect a few specific areas on the body. Many HPV types can produce a benign growth, often called a "wart" or "papilloma", in the area they infect. Many of the more common HPV and wart types are listed below.
Common warts – HPV types 2 and 4 (most common); also types 1, 3, 26, 29, and 57 and others.
Cancers and genital dysplasia – "high-risk" HPV types are associated with cancers, notably cervical cancer, and can also cause some vulvar, vaginal, penile, anal and some oropharyngeal cancers. "Low-risk" types are associated with warts or other conditions.High-risk: 16, 18 (cause the most cervical cancer); also 31, 33, 35, 39, 45, 52, 58, 59, and others.Plantar warts (verruca) – HPV type 1 (most common); also types 2, 3, 4, 27, 28, and 58 and others.
Anogenital warts (condylomata acuminata or venereal warts) – HPV types 6 and 11 (most common); also types 42, 44 and others.Low-risk: 6, 11 (most common); also 13, 44, 40, 43, 42, 54, 61, 72, 81, 89, and others.Verruca plana (flat warts) – HPV types 3, 10, and 28.
Butchers warts – HPV type 7.
Hecks disease (focal epithelial hyperplasia) – HPV types 13 and 32.
Pathophysiology
Common warts have a characteristic appearance under the microscope. They have thickening of the stratum corneum (hyperkeratosis), thickening of the stratum spinosum (acanthosis), thickening of the stratum granulosum, rete ridge elongation, and large blood vessels at the dermoepidermal junction.
Diagnosis
On dermatoscopic examination, warts will commonly have fingerlike or knoblike extensions.
Prevention
Gardasil 6 is an HPV vaccine aimed at preventing cervical cancers and genital warts. Gardasil is designed to prevent infection with HPV types 16, 18, 6, and 11. HPV types 16 and 18 currently cause about 70% of cervical cancer cases, and also cause some vulvar, vaginal, penile and anal cancers. HPV types 6 and 11 are responsible for 90% of documented cases of genital warts.Gardasil 9, approved in 2014 protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.HPV vaccines do not currently protect against the virus strains responsible for plantar warts (verrucae).
Disinfection
The virus is relatively hardy and immune to many common disinfectants. Exposure to 90% ethanol for at least 1 minute, 2% glutaraldehyde, 30% Savlon, and/or 1% sodium hypochlorite can disinfect the pathogen.The virus is resistant to drying and heat, but killed by 100 °C (212 °F) and ultraviolet radiation.
Treatment
There are many treatments and procedures associated with wart removal. A review of various skin wart treatments concluded that topical treatments containing salicylic acid were more effective than placebo. Cryotherapy appears to be as effective as salicylic acid, but there have been fewer trials.
Medication
Salicylic acid can be prescribed by a dermatologist in a higher concentration than that found in over-the-counter products. Several over-the-counter products are readily available at pharmacies and supermarkets of roughly two types: adhesive pads treated with salicylic acid, and bottled concentrated salicylic acid and lactic acid solution.
Fluorouracil — Fluorouracil cream, a chemotherapy agent sometimes used to treat skin cancer, can be used on particularly resistant warts, by blocking viral DNA and RNA production and repair.
Imiquimod is a topical cream that helps the bodys immune system fight the wart virus by encouraging interferon production. It has been approved by the U.S. Food and Drug Administration (FDA) for genital warts.
Cantharidin, found naturally in the bodies of many members of the beetle family Meloidae, causes dermal blistering. It is used either by itself or compounded with podophyllin. Not FDA approved, but available through Canada or select US compounding pharmacies.
Bleomycin — A more potent chemotherapy drug, can be injected into deep warts, destroying the viral DNA or RNA. Bleomycin is notably not US FDA approved for this purpose. Possible side effects include necrosis of the digits, nail loss and Raynaud syndrome. The usual treatment is one or two injections.
Dinitrochlorobenzene (DNCB), like salicylic acid, is applied directly to the wart. Studies show this method is effective with a cure rate of 80%. But DNCB must be used much more cautiously than salicylic acid; the chemical is known to cause genetic mutations, so it must be administered by a physician. This drug induces an allergic immune response, resulting in inflammation that wards off the wart-causing virus.
Cidofovir is an antiviral drug which is injected into HPV lesions within the larynx (laryngeal papillomatosis) as an experimental treatment.
Verrutop verruca treatment is a topical solution made from a combination of organic acids, inorganic acids, and metal ions. This solution causes the production of nitrites, which act to denature viral proteins and mummify the wart tissue. The difference between Verrutop and other acid treatments is that it does not damage the surrounding skin.
Another product available over-the-counter that can aid in wart removal is silver nitrate in the form of a caustic pencil, which is also available at drug stores. In a placebo-controlled study of 70 patients, silver nitrate given over nine days resulted in clearance of all warts in 43% and improvement in warts in 26% one month after treatment compared to 11% and 14%, respectively, in the placebo group. The instructions must be followed to minimize staining of skin and clothing. Occasionally, pigmented scars may develop.
Procedures
Keratolysis, of dead surface skin cells usually using salicylic acid, blistering agents, immune system modifiers ("immunomodulators"), or formaldehyde, often with mechanical paring of the wart with a pumice stone, blade etc.
Electrodesiccation
Cryosurgery or cryotherapy, which involves freezing the wart (generally with liquid nitrogen), creating a blister between the wart and epidermal layer after which the wart and the surrounding dead skin fall off. An average of 3 to 4 treatments are required for warts on thin skin. Warts on calloused skin like plantar warts might take dozens or more treatments.
Surgical curettage of the wart
Laser treatment – often with a pulse dye laser or carbon dioxide (CO2) laser. Pulse dye lasers (wavelength 582 nm) work by selective absorption by blood cells (specifically hemoglobin). CO2 lasers work by selective absorption by water molecules. Pulse dye lasers are less destructive and more likely to heal without scarring. CO2 laser works by vaporizing and destroying tissue and skin. Laser treatments can be painful, expensive (though covered by many insurance plans), and not extensively scarring when used appropriately. CO2 lasers will require local anaesthetic. Pulse dye laser treatment does not need conscious sedation or local anesthetic. It takes 2 to 4 treatments, but can be many more for extreme cases. Typically, 10–14 days are required between treatments. Preventative measures are important.
Infrared coagulator – an intense source of infrared light in a small beam like a laser. This works essentially on the same principle as laser treatment. It is less expensive. Like the laser, it can cause blistering, pain and scarring.
Intralesional immunotherapy with purified candida, MMR, and tuberculin (PPD) protein appears safe and effective.
Duct tape occlusion therapy involves placing a piece of duct tape over the wart. The mechanism of action of this technique still remains unknown. Despite several trials, evidence for the efficacy of duct tape therapy is inconclusive. Despite the mixed evidence for efficacy, the simplicity of the method and its limited side-effects leads some researchers to be reluctant to dismiss it.
No intervention. Spontaneous resolution within a few years can be recommended.
Alternative medicine
Daily application of the latex of Chelidonium majus is a traditional treatment.The acrid yellow sap of Greater Celandine is used as a traditional wart remedy.According to English folk belief, touching toads causes warts; according to a German belief, touching a toad under a full moon cures warts. The most common Northern Hemisphere toads have glands that protrude from their skin that superficially resemble warts. Warts are caused by a virus, and toads do not harbor it. A variety of traditional folk remedies and rituals claim to be able to remove warts.
In The Adventures of Tom Sawyer, Mark Twain has his characters discuss a variety of such remedies. Tom Sawyer proposes "spunk-water" (or "stump-water", the water collecting in the hollow of a tree stump) as a remedy for warts on the hand. You put your hand into the water at midnight and say:
You then "walk away quick, eleven steps, with your eyes shut, and then turn around three times and walk home without speaking to anybody. Because if you speak the charms busted." This is given as an example to Huckleberry Finns planned remedy, which involves throwing a dead cat into a graveyard as a devil or devils comes to collect a recently buried wicked person. Another remedy involved splitting a bean, drawing blood from the wart and putting it on one of the halves, and burying that half at a crossroads at midnight. The theory of operation is that the blood on the buried bean will draw away the wart. Twain is recognized as an early collector and recorder of genuine American folklore.Similar practices are recorded elsewhere. In Louisiana, one remedy for warts involves rubbing the wart with a potato, which is then buried; when the "buried potato dries up, the wart will be cured". Another remedy similar to Twains is reported from Northern Ireland, where water from a specific well on Rathlin Island is credited with the power to cure warts.
History
Surviving ancient medical texts show that warts were a documented disease since at least the time of Hippocrates, who lived c. 460 – c. 370 BC. In the book De Medecia by the Roman physician Aulus Cornelius Celsus, who lived c. 25 BC – c. 50 AD, different types of warts were described. Celsus described myrmecia, today recognized as plantar wart, and categorized acrochordon (a skin tag) as wart. In the 13th century, warts were described in books published by the surgeons William of Saliceto and Lanfranc of Milan. The word verruca to describe a wart was introduced by the physician Daniel Sennert, who described warts in his 1636 book Hypomnemata physicae.But the cause of warts was disputed in the medical profession. In the early 18th century the physician Daniel Turner, who published the first book on dermatology, suggested that warts were caused by damaged nerves close to the skin. In the mid 18th century, the surgeon John Hunter popularized the belief that warts were caused by a bacterial syphilis
infection. The surgeon Benjamin Bell documented that warts were caused by a disease entirely unrelated to syphilis, and established a causal link between warts and cancer. In the 19th century, the chief physician of Verona hospital established a link between warts and cervical cancer. But in 1874 it was noted by the dermatologist Ferdinand Ritter von Hebra that while various theories were advanced by the medical profession, the "influences causing warts are still very obscure".In 1907 the physician Giuseppe Ciuffo was the first to demonstrate that warts were caused by a virus infection. In 1976 the virologist Harald zur Hausen was the first to discover that warts were caused by the human papillomavirus (HPV). His continuous research established the evidence necessary to develop a HPV vaccine, which first became available in 2006.
Other animals
References
External links
Wart photo library, Dermnet |
You are a medical educator. Your role is to provide detailed and clear explanations for medical terms, suitable for both professionals and laypersons. | The term 'Waardenburg Syndrome Type 1' keeps coming up in medical discussions. What does it stand for? | Waardenburg Syndrome Type 1 is a congenital disorder that caused by a mutation in the PAX3 gene that results in abnormal development in the neural crest during early development. Type 1 results in early graying and white forelock and a notable distance between the eyes, noted as dystopia canthorum. Common symptoms of the disease also includes non-progressive hearing loss in majority of patients with Type 1. Patients can display complete or partial heterochromia and hypoplastic blue irides and congenital leukemia.
Presentation
Type 1 of the Waardenburg Syndrome’s notable feature is dystopia canthorum. Along with this feature, some patients eyelids are fused medially, resulting in medial sclerae. Inferior lachrymal is moved laterally, along with punctae opposite of the cornea. Other features include high and broad nasal root and also nasi hypoplasia. A squared jaw is reported in some patients. Others present with spina bifida due to the mutation in the neural crest during early development. Other features include the white forelock and graying that occurs in most patients prior to reaching age thirty. In extremely rare cases, the forelock may even be colored red rather than white. The coloring of the forelock may differ from patient to patient. It can appear at birth, or later in the life of those affected and size may vary. It is usually observed in the midline of the hair, but it can appear in other locations as well. Associated with the hair forelock, skin pigmentation can also appear in different parts of the body and limbs (suspected to be caused by the mutation in KIT). In parts of the body of some patients, congenital leukoderma is observed.Similar to other types of the syndrome, Type 1 displays heterochromia in some patients, sometimes complete or partial. If it happens to be partial, the differently colored iris is separated from the radial segment of the eye. Deficient iris stroma along with hypoplastic blue arises have also been found in some patients with Type 1. Another one of the symptoms is hearing loss, presenting in about 69% of cases. The types of hearing loss reported in patients differ over a great spectrum. Some of which could be bilateral or unilateral, sensorineural sometimes a combination of different ones in each ear. The most common loss types reported for Type 1 are profound and bilateral. Waardenburg Type 1 is estimated to cause 3% of overall congenital deaf children.
Genetics
Type 1 Waardenburg Syndrome is a dominant autosomal disease, with extremely high penetrance of nearly 85% Type 1, as well as type 3, are linked to a mutation in the PAX3 gene located in chromosome 2q35. This gene is responsible for encoding a transaction factor named Drosophila paired (noted as prd) resulting in essential proteins. These proteins are responsible for multiple functions in early human development such as stem cell pluripotency, as well as inhibition of differentiation when needed and cell-lineage specification, migration, and proliferation in the cells . These functions are essential in properly developing the central nervous system, somites, skeletal muscles, and neural crest-derived cells that are present throughout various cell types in the body. PAX3 controls the neural crest development through regulation of c-RET, TGF-b2, and WNT1 which are essential controllers of migration and differentiation.PAX3 in combination with other transcription factors such as MITF and TRP1 can control melanocyte development. This gene also plays a major role in muscle development as it regulated myoD and myf-5, essential transcription factors in muscle development.The structure of the gene and protein are well understood in research, PAX3 consists of 10 exons and results in major proteins that has 479 amino acids. It has also been found that a majority of the mutations that occur on the PAX3 gene is located on the 2-6 exons. Heterozygous mutation is the basis of the majority of Type 1 Waardenburg Syndrome mutations.
Diagnosis
Type 1 Waardenburg Syndrome is sometimes misdiagnosed as Type 2, therefore when measuring dystopia canthorum if present in a certain patient has been set in strict guidelines. There is a biometric index used as well formula to create a discriminant analysis. These measurements are based on three indices, based on the distances of the inner canthal, interpupillary, and outer canthal. This testing of the dystopia canthorum is referred to as the W index. Other features and dysfunctions are used for diagnoses such as hearing loss or pigmentation of the skin and the notable forelock that appears in the hair. A diagnosis can also be provided through genetic testing and identification of the PAX3 mutation in the patient’s genes. Gene analysis can take on a variety of tests such as single-gene testing (focus on PAX3), a multigene panel (PAX3 along with other genes), and a more comprehensive genomic testing when available.A list of major criteria was created to assess patients for Type 1 Waardenburg Syndrome. The list includes similar features as listed above such as congenital sensorineural hearing loss, white forelock, and hair pigmentation, pigmentation abnormality of the iris, dystopia canthorum, and related family members who exhibit the disease.
Management
There is no direct treatment for the patients with Waardenburg Syndrome Type 1, however, there are multiple ways in which the symptoms are managed. There are some options for hearing loss aid depending on the type faced by the patient. In previous cases, cochlea implants were successful to aid the hearing loss. There is also some genetic screening available that can assess whether children can inherit the mutation in the PAX3 gene, but not an overall prediction on the manifestation of the disease in the future generations. Pregnant women who are at risk for children suffering from this disease are recommended Folic acid supplementation to assist with the neural crest development. Further counseling is available with life decisions such as pregnancies and starting families. Since Type 1 is a dominant autosomal disease, any offsprings of those affected are likely to also have the disease.
Medical history
Waardenburg syndrome was first described by Petrus J Waardenburg in 1951 in the American Journal of Human Genetics. It is now commonly thought that the description refers to Waardenburg syndrome Type 1. The description focused on the distinguishing feature of dystopia canthorum, the wide distance between the eyes observed in over 80% of patients with Type 1. Variations in Type 1 and the difference from Type 2 were later described by Arias in 1971. In 1991, Da-Silva in focused on Brazilian children who exhibited the physical characteristics of Type 1 followed by Winship and Beighton in 1992 with 68 children to describe the onset and manifestation of Type 1. Research in 2016 resulted in connecting the hearing loss and other physical features to the syndrome and provided more accurate diagnosis.
== References == |
You function as a medical explainer. Your task is to convey the meanings of medical terms in a detailed, yet easy-to-understand manner. | I've come across the term 'Hepatotoxicity' in a medical context, but I'm not sure what it means. Can you clarify? | Hepatotoxicity (from hepatic toxicity) implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn from the market after approval.
The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses (e.g. paracetamol) and sometimes even when introduced within therapeutic ranges (e.g. halothane), may injure the organ. Other chemical agents, such as those used in laboratories and industries, natural chemicals (e.g., microcystins), and herbal remedies (two prominent examples being kava, mechanism unknown, and comfrey, through its pyrrolizidine alkaloid content) can also induce hepatotoxicity. Chemicals that cause liver injury are called hepatotoxins.
More than 900 drugs have been implicated in causing liver injury (see LiverTox, external link, below) and it is the most common reason for a drug to be withdrawn from the market. Hepatotoxicity and drug-induced liver injury also account for a substantial number of compound failures, highlighting the need for toxicity prediction models (e.g. DTI), and drug screening assays, such as stem cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process. Chemicals often cause subclinical injury to the liver, which manifests only as abnormal liver enzyme tests.
Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures.
Causes
Adverse drug reactions are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic). Type A drug reaction accounts for 80% of all toxicities.Drugs or toxins that have a pharmacological (type A) hepatotoxicity are those that have predictable dose-response curves (higher concentrations cause more liver damage) and well characterized mechanisms of toxicity, such as directly damaging liver tissue or blocking a metabolic process. As in the case of paracetamol overdose, this type of injury occurs shortly after some threshold for toxicity is reached. Carbon tetrachloride is commonly used to induce acute type A liver injury in animal models.
Idiosyncratic (type B) injury occurs without warning, when agents cause non-predictable hepatotoxicity in susceptible individuals, which is not related to dose and has a variable latency period. This type of injury does not have a clear dose-response nor temporal relationship, and most often does not have predictive models. Idiosyncratic hepatotoxicity has led to the withdrawal of several drugs from market even after rigorous clinical testing as part of the FDA approval process; Troglitazone (Rezulin) and trovafloxacin (Trovan) are two prime examples of idiosyncratic hepatotoxins pulled from market.
The herb kava has caused a number of cases of idiosyncratic liver injury, ranging everywhere from asymptomatic to fatal.
Oral use of the antifungal ketoconazole has been associated with hepatic toxicity, including some fatalities; however, such effects appear to be limited to doses taken over a period longer than 7 days.
Paracetamol
Paracetamol also known as acetaminophen, and by the brand names of Tylenol and Panadol, is usually well-tolerated in prescribed dose, but overdose is the most common cause of drug-induced liver disease and acute liver failure worldwide. Damage to the liver is not due to the drug itself but to a toxic metabolite (N-acetyl-p-benzoquinone imine (NAPQI)) produced by cytochrome P-450 enzymes in the liver. In normal circumstances, this metabolite is detoxified by conjugating with glutathione in phase 2 reaction. In an overdose, a large amount of NAPQI is generated, which overwhelms the detoxification process and leads to liver cell damage. Nitric oxide also plays a role in inducing toxicity. The risk of liver injury is influenced by several factors including the dose ingested, concurrent alcohol or other drug intake, interval between ingestion and antidote, etc. The dose toxic to the liver is quite variable from person to person and is often thought to be lower in chronic alcoholics. Measurement of blood level is important in assessing prognosis, higher levels predicting a worse prognosis. Administration of Acetylcysteine, a precursor of glutathione, can limit the severity of the liver damage by capturing the toxic NAPQI. Those that develop acute liver failure can still recover spontaneously, but may require transplantation if poor prognostic signs such as encephalopathy or coagulopathy is present (see Kings College Criteria).
Nonsteroidal anti-inflammatory drugs
Although individual analgesics rarely induce liver damage due to their widespread use, NSAIDs have emerged as a major group of drugs exhibiting hepatotoxicity. Both dose-dependent and idiosyncratic reactions have been documented. Aspirin and phenylbutazone are associated with intrinsic hepatotoxicity; idiosyncratic reaction has been associated with ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin.
Glucocorticoids
Glucocorticoids are so named due to their effect on the carbohydrate mechanism. They promote glycogen storage in the liver. An enlarged liver is a rare side-effect of long-term steroid use in children. The classical effect of prolonged use both in adult and paediatric population is steatosis.
Isoniazid
Isoniazide (INH) is one of the most commonly used drugs for tuberculosis; it is associated with mild elevation of liver enzymes in up to 20% of patients and severe hepatotoxicity in 1-2% of patients.
Other hydrazine derivative drugs
There are also cases where other hydrazine derivative drugs, such as the MAOI antidepressant iproniazid, are associated with liver damage. Phenelzine has been associated with abnormal liver tests. Toxic effects can develop from antibiotics.
Natural products
Examples include alpha-Amanitin containing mushrooms, kava, and aflatoxin producing molds. Pyrrolizidine alkaloids, which occur in some plants, can be toxic. Green tea extract is a growing cause of liver failure due to its inclusion in more products.
Alternative remedies
Examples include: Ackee fruit, Bajiaolian, Camphor, Copaltra, Cycasin, Garcinia, Kava leaves, pyrrolizidine alkaloids, Horse chestnut leaves, Valerian, Comfrey. Chinese herbal remedies: Jin Bu Huan, Ephedra, Shou Wu Pian, Bai Xian Pi.
Industrial toxin
Examples include arsenic, carbon tetrachloride, and vinyl chloride.
Mechanism
Drugs continue to be taken off the market due to late discovery of hepatotoxicity. Due to its unique metabolism and close relationship with the gastrointestinal tract, the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and the spleen via portal veins that bring drugs and xenobiotics in near-undiluted form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process.
Many chemicals damage mitochondria, an intracellular organelle that produces energy. Its dysfunction releases excessive amount of oxidants that, in turn, injure hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as CYP2E1 also lead to oxidative stress. Injury to hepatocyte and bile duct cells lead to accumulation of bile acid inside the liver. This promotes further liver damage. Non-parenchymal cells such as Kupffer cells, collagen-producing stellate cells, and leukocytes (i.e. neutrophil and monocyte) also have a role in the mechanism.
Drug metabolism in liver
The human body subjects most, but not all, compounds to various chemical processes (i.e. metabolism) to make them suitable for elimination. This involves chemical transformations to (a) reduce fat solubility and (b) to change biological activity. Although almost all tissues in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in the liver is the principal "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, proteins) and exogenous substances (e.g., drugs, alcohol). The central role played by liver in the clearance and transformation of chemicals makes it susceptible to drug-induced injury.
Drug metabolism is usually divided into two phases: phase 1 and phase 2. Phase 1 reaction is generally speaking to prepare a drug for phase 2. However, many compounds can be metabolized by phase 2 directly or be excreted without any phase 2 reactions occurring. Phase 1 reaction involves oxidation, reduction, hydrolysis, hydration and many other rare chemical reactions. These processes tend to increase water solubility of the drug and can generate metabolites that are more chemically active and/or potentially toxic. Most of phase 2 reactions take place in cytosol and involve conjugation with endogenous compounds via transferase enzymes. Phase 1 are typically more suitable for elimination.
A group of enzymes located in the endoplasmic reticulum, known as cytochrome P-450, is the most important family of metabolizing enzymes in the liver. Cytochrome P-450 is not a single enzyme, but rather consists of a closely related family of 50 isoforms; six of them metabolize 90% of drugs. There is a tremendous diversity of individual P-450 gene products, and this heterogeneity allows the liver to perform oxidation on a vast array of chemicals (including most drugs) in phase 1. Three important characteristics of the P-450 system have roles in drug-induced toxicity:
1. Genetic diversity:Each of the P-450 proteins is unique and accounts (to some extent) for the variation in drug metabolism between individuals. Genetic variations (polymorphism) in P-450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses. Such polymorphism is also responsible for variable drug response among patients of differing ethnic backgrounds.
2. Change in enzyme activity:Many substances can influence the P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways. Drugs that modify cytochrome P-450 enzyme are referred to as either inhibitors or inducers. Enzyme inhibitors block the metabolic activity of one or several P-450 enzymes. This effect usually occurs immediately. On the other hand, inducers increase P-450 activity by increasing enzyme production, or, in the case of CYP2E1, preventing degradation in the proteasome. There is usually a delay before enzyme activity increases.
3. Competitive inhibition:Some drugs may share the same P-450 specificity and thus competitively block their biotransformation. This may lead to accumulation of drugs metabolized by the enzyme. This type of drug interaction may also reduce the rate of generation of toxic metabolites.
Patterns of injury
Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (e.g. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage. Liver injury is defined as a rise in either (a) ALT level more than three times of upper limit of normal (ULN), (b) ALP level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP. Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed types of injuries are often encountered.
Specific histo-pathological patterns of liver injury from drug-induced damage are discussed below.
Zonal Necrosis
This is the most common type of drug-induced liver cell necrosis where the injury is largely confined to a particular zone of the liver lobule. It may manifest as a very high level of ALT and severe disturbance of liver function leading to acute liver failure.
Causes include:
Paracetamol, carbon tetrachloride
Hepatitis
In this pattern, hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug-induced hepatitis. (A) viral hepatitis is the most common, where histological features are similar to acute viral hepatitis. (B) in focal or non-specific hepatitis, scattered foci of cell necrosis may accompany lymphocytic infiltration. (C) chronic hepatitis is very similar to autoimmune hepatitis clinically, serologically, and histologically.
Causes:
(a) Viral hepatitis: Halothane, isoniazid, phenytoin
(b) Focal hepatitis: Aspirin
(c) Chronic hepatitis: Methyldopa, diclofenac
Cholestasis
Liver injury leads to impairment of bile flow and cases are predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland (without any parenchymal inflammation). On rare occasions, it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (vanishing duct syndrome).
Causes:
(a) Bland: Oral contraceptive pills, anabolic steroid, androgens
(b) Inflammatory: Allopurinol, co-amoxiclav, carbamazepine
(c) Ductal: Chlorpromazine, flucloxacillin
Steatosis
Hepatotoxicity may manifest as triglyceride accumulation, which leads to either small-droplet (microvesicular) or large-droplet (macrovesicular) fatty liver. There is a separate type of steatosis by which phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g., Tay–Sachs disease)
Causes:
(a) Microvesicular: Aspirin (Reyes syndrome), ketoprofen, tetracycline (especially if expired)
(b) Macrovesicular: Acetaminophen, methotrexate
(c) Phospholipidosis: Amiodarone, total parenteral nutrition
(d) Antiviral: nucleoside analogues
(e) Corticosteroid
(f) Hormonal: Tamoxifen
Granuloma
Drug-induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity. More than 50 drugs have been implicated.
Causes:
Allopurinol, phenytoin, isoniazid, quinine, penicillin, quinidine
Vascular lesions
These result from injury to the vascular endothelium.
Causes:
Venoocclusive disease: Chemotherapeutic agents, bush tea
Peliosis hepatis: Anabolic steroids
Hepatic vein thrombosis: Oral contraceptives
Neoplasm
Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma, and liver adenomas are the ones usually reported.
Causes:
Vinyl chloride, combined oral contraceptive pill, anabolic steroid, arsenic, thorotrast
Diagnosis
This remains a challenge in clinical practice due to a lack of reliable markers. Many other conditions lead to similar clinical as well as pathological pictures. To diagnose hepatotoxicity, a causal relationship between the use of the toxin or drug and subsequent liver damage has to be established, but might be difficult, especially when idiosyncratic reaction is suspected. Simultaneous use of multiple drugs may add to the complexity. As in acetaminophen toxicity, well established, dose-dependent, pharmacological hepatotoxicity is easier to spot. Several clinical scales such as CIOMS/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage. CIOMS/RUCAM scale involves a scoring system that categorizes the suspicion into "definite or highly probable" (score > 8), "probable" (score 6–8), "possible" (score 3–5), "unlikely" (score 1–2) and "excluded" (score ≤ 0). In clinical practice, physicians put more emphasis on the presence or absence of similarity between the biochemical profile of the patient and known biochemical profile of the suspected toxicity (e.g., cholestatic damage in amoxycillin-clauvonic acid ).
Treatment
In most cases, liver function will return to normal if the offending drug is stopped early. Additionally, the patient may require supportive treatment. In acetaminophen toxicity, however, the initial insult can be fatal. Fulminant hepatic failure from drug-induced hepatotoxicity may require liver transplantation. In the past, glucocorticoids in allergic features and ursodeoxycholic acid in cholestatic cases had been used, but there is no good evidence to support their effectiveness.
Prognosis
An elevation in serum bilirubin level of more than 2 times ULN with associated transaminase rise is an ominous sign. This indicates severe hepatotoxicity and is likely to lead to mortality in 10% to 15% of patients, especially if the offending drug is not stopped (Hys Law). This is because it requires significant damage to the liver to impair bilirubin excretion, hence minor impairment (in the absence of biliary obstruction or Gilbert syndrome) would not lead to jaundice. Other poor predictors of outcome are old age, female sex, high AST.
Drugs withdrawn
The following therapeutic drugs were withdrawn from the market primarily because of hepatotoxicity: Troglitazone, bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, ximelagatran and pemoline.
See also
Hepatoprotection
Reyes syndrome
Notes
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External links
LiverTox at the United States National Library of Medicine |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | Could you offer a clear explanation of the term 'Laryngitis' as used in the medical field? | Laryngitis is inflammation of the larynx (voice box). Symptoms often include a hoarse voice and may include fever, cough, pain in the front of the neck, and trouble swallowing. Typically, these last under two weeks.Laryngitis is categorised as acute if it lasts less than three weeks and chronic if symptoms last more than three weeks. Acute cases usually occur as part of a viral upper respiratory tract infection, other infections and trauma such as from coughing are other causes. Chronic cases may occur due to smoking, tuberculosis, allergies, acid reflux, rheumatoid arthritis, or sarcoidosis. The underlying mechanism involves irritation of the vocal cords.Concerning signs that may require further investigation include stridor, history of radiation therapy to the neck, trouble swallowing, duration of more than three weeks, and a history of smoking. If concerning signs are present the vocal cords should be examined via laryngoscopy. Other conditions that can produce similar symptoms include epiglottitis, croup, inhaling a foreign body, and laryngeal cancer.The acute form generally resolves without specific treatment. Resting the voice and sufficient fluids may help. Antibiotics generally do not appear to be useful in the acute form. The acute form is common while the chronic form is not. The chronic form occurs most often in middle age and is more common in men than women.
Signs and symptoms
The primary symptom of laryngitis is a hoarse voice.: 108 Because laryngitis can have various causes, other signs and symptoms may vary. They can include
Dry or sore throat
Coughing (both a causal factor and a symptom of laryngitis)
Frequent throat clearing
Increased saliva production
Dysphagia (difficulty swallowing)
Sensation of swelling in the area of the larynx (discomfort in the front of the neck)
Globus pharyngeus (feeling like there is a lump in the throat)
Cold or flu-like symptoms (which, like a cough, may also be a causal factor for laryngitis)
Swollen lymph nodes in the throat, chest, or face
Fever
General muscle pain (myalgia)
Shortness of breath, predominantly in children
Voice quality
Aside from a hoarse-sounding voice, changes to pitch and volume may occur with laryngitis. Speakers may experience a lower or higher pitch than normal, depending on whether their vocal folds are swollen or stiff. They may also have breathier voices, as more air flows through the space between the vocal folds (the glottis), quieter volume and a reduced range.
Causes
Laryngitis can be infectious as well as noninfectious in origin. The resulting inflammation of the vocal folds results in a distortion of the sound produced there. It normally develops in response to either an infection, trauma to the vocal folds, or allergies. Chronic laryngitis may also be caused by more severe problems, such as nerve damage, sores, polyps, or hard and thick lumps (nodules) on the vocal cords.[4]
Acute
Viral
Most acute cases of laryngitis are caused by viral infections, the most common of which tend to be rhinovirus, influenza virus, parainfluenza virus, adenovirus, coronavirus, and RSV. In patients who have a compromised immune system, other viruses such as herpes, HIV may also be potential causes.
Bacterial
This is another major cause of acute laryngitis, and may develop in conjunction with or due to a viral infection. Common bacterial strains are group A streptococcus, Streptococcus pneumoniae, C. diphtheriae, M. catarrhalis, Haemophilus influenzae, Bordetella pertussis, Bacillus anthracis, and M. tuberculosis. In developing countries, more unusual bacterial causes may occur, such as mycobacterial and syphilitic, though these may occur in developed nations as well.
Fungal
Laryngitis caused by fungal infection is common but not frequently diagnosed according to a review by BMJ and can account for up to 10% of acute laryngitis cases. Patients with both functioning and impaired immune systems can develop fungal laryngitis, which may develop as a result of recent antibiotic or inhaled corticosteroids use. Certain strains of fungi that may cause laryngitis include; Histoplasma, Blastomyces, Candida (especially in immunocompromised persons), and Cryptococcus and Coccidioides.
Trauma
Often due to excessive use of the vocal folds such as excessive yelling, screaming, or singing. Though this often results in damage to the outer layers of the vocal folds, the subsequent healing may lead to changes in the physiology of the folds. Another potential cause of inflammation may be overuse of the vocal cords.[5] [6] [7] [8] [9] Laryngeal trauma, including iatrogenic (caused by endotracheal intubation), can also result in inflammation of the vocal cords.
Chronic
Allergies
Findings are unclear as to whether asthma may cause symptoms commonly associated with laryngitis. Some researchers have posited that allergic causes of laryngitis are often misdiagnosed as being the result of acid reflux.
Reflux
One possible explanation of chronic laryngitis is that inflammation is caused by gastro-oesophageal reflux, which causes subsequent irritation of the vocal folds.
Autoimmune disorders
Approximately between 30 and 75% of persons with rheumatoid arthritis report symptoms of laryngitis.
Symptoms of laryngitis are present in only 0.5–5% of people that have sarcoidosis. According to a meta-analysis by Silva et al. (2007), this disease is often an uncommon cause of laryngeal symptoms and is frequently misdiagnosed as another voice disorder.
Diagnosis
Diagnosis of different forms of acute laryngitis
Laryngitis following trauma: This form of laryngitis is usually identified by obtaining a case history providing information on previous phono traumatic experiences, internal trauma caused by recent procedures as well as any previous neck injuries.
Acute viral laryngitis: This form of laryngitis is characterized by lower vocal pitch as well as hoarseness. The symptoms in this form of laryngitis are usually present for less than one week, however they can persist for 3–4 weeks. This form of laryngitis might also be accompanied by upper respiratory tract symptoms such as: sore throat, odynophagia, rhinorrhea, dyspnea, postnasal discharge, and congestion.
Fungal laryngitis: A biopsy and culture of abnormal lesion may help confirm fungal laryngitis.
Visual diagnosis
The larynx itself will often show erythema (reddening) and edema (swelling). This can be seen with laryngoscopy or stroboscopy (method depends on the type of laryngitis).: 108 Stroboscopy may be relatively normal or may reveal asymmetry, aperiodicity, and reduced mucosal wave patterns.Other features of the laryngeal tissues may include
Redness of the laryngeal tissues (acute)
Dilated blood vessels (acute)
Thick, yet dry laryngal tissue (chronic)
Stiff vocal folds
Sticky secretions between the vocal folds and nearby structures (the interarytenoid region)
Referral
Some signs and symptoms indicate the need for early referral. These include
Difficulty swallowing
Vocal stridor
Ear pain
Recent weight loss
History of smoking
Current or recent radiotherapy treatment (in the neck region)
Recent neck surgery or surgery involving endotracheal tubing
Person is a professional voice user (teacher, singer, actor, call center worker, and so on)
Differential diagnosis
Acute epiglottitis: This is more likely in those with stridor, drooling, and painful or trouble swallowing.
Spasmodic dysphonia
Reflux laryngitis
Chronic allergic laryngitis
Neoplasm
Croup: This presents with a barking cough, hoarseness of voice, and inspiratory stridor.
Treatment
Treatment is often supportive in nature, and depends on the severity and type of laryngitis (acute or chronic). General measures to relieve symptoms of laryngitis include behaviour modification, hydration and humidification.Vocal hygiene (care of the voice) is very important to relieve symptoms of laryngitis. Vocal hygiene involves measures such as: resting the voice, drinking sufficient water, reducing caffeine and alcohol intake, stopping smoking and limiting throat clearing.
Acute laryngitis
In general, acute laryngitis treatment involves vocal hygiene, painkillers (analgesics), humidification, and antibiotics.
Viral
The suggested treatment for viral laryngitis involves vocal rest, pain medication, and mucolytics for frequent coughing. Home remedies such as tea and honey may also be helpful. Antibiotics are not used for treatment of viral laryngitis.
Bacterial
Antibiotics may be prescribed for bacterial laryngitis, especially when symptoms of upper respiratory infection are present. However, the use of antibiotics is highly debated for acute laryngitis. This relates to issues of effectiveness, side effects, cost, and possibility of antibiotic resistance patterns. Overall, antibiotics do not appear to be very effective in the treatment of acute laryngitis.In severe cases of bacterial laryngitis, such as supraglottitis or epiglottitis, there is a higher risk of the airway becoming blocked. An urgent referral should be made to manage the airway. Treatment may involve humidification, corticosteroids, intravenous antibiotics, and nebulised adrenaline.
Fungal
Fungal laryngitis can be treated with oral antifungal tablets and antifungal solutions. These are typically used for up to three weeks and treatment may need to be repeated if the fungal infection returns.
Trauma
Laryngitis caused by excessive use or misuse of the voice can be managed though vocal hygiene measures.
Chronic laryngitis
Reflux
Laryngopharyngeal reflux treatment primarily involves behavioural management and medication. Behavioural management involves aspects such as
Wearing loose clothing
Eating smaller, more frequent meals
Avoiding certain foods (e.g. caffeine, alcohol, spicy foods)Anti-reflux medications may be prescribed for patients with signs of chronic laryngitis and hoarse voice. If anti-reflux treatment does not result in a decrease of symptoms, other possible causes should be examined. Over-the-counter medications for neutralizing acids (antacids) and acid suppressants (H-2 blockers) may be used. Antacids are often short-acting and may not be sufficient for treatment. Proton pump inhibitors are an effective type of medication. These should only be prescribed for a set period of time, after which the symptoms should be reviewed. Proton pump inhibitors do not work for everyone. A physical reflux barrier (e.g. Gaviscon Liquid) may be more appropriate for some. Antisecretory medications can have several side-effects.When appropriate, anti-reflux surgery may benefit some individuals.
Inflammatory
When treating allergic laryngitis, topical nasal steroids and immunotherapy have been found to be effective for allergic rhinitis. Antihistamines may also be helpful, but can create a dryness in the larynx. Inhaled steroids that are used for a long period can lead to problems with the larynx and voice.
Autoimmune
Mucous membrane pemphigoid may be managed with medication (cyclophosphamide and prednisolone).
Granulomatous
Sarcoidosis is typically treated with systemic corticosteroids. Less frequently used treatments include intralesional injections or laser resection.
Prognosis
Acute
Acute laryngitis may persist, but will typically resolve on its own within two weeks. Recovery is likely to be quick if the patient follows the treatment plan. In viral laryngitis, symptoms can persist for an extended period, even when upper respiratory tract inflammation has been resolved.
Chronic
Laryngitis that continues for more than three weeks is considered chronic. If laryngeal symptoms last for more than three weeks, a referral should be made for further examination, including direct laryngoscopy. The prognosis for chronic laryngitis varies depending on the cause of the laryngitis.
References
External links
Laryngitis at Curlie
Mayo Clinic |
You are a medical interpreter. Your duty is to translate medical terms into easily digestible information, maintaining accuracy and detail. | Please help me grasp the concept behind the medical term 'Onyongnyong virus.' | The onyongnyong virus (ONNV) was first isolated by researchers at the Uganda Virus Research Institute in Entebbe, Uganda, during a large outbreak of a disease in 1959 that resembled dengue fever. ONNV is a togavirus (family Togaviridae), genus Alphavirus, is closely related to the chikungunya and Igbo Ora viruses, and is a member of the Semliki Forest antigenic complex. The name was given to the disease by the Acholi tribe during the 1959 outbreak. The name comes from the Nilotic language of Uganda and Sudan and means “weakening of the joints". The virus can infect humans and may cause disease.
Signs and symptoms
Common symptoms of infection with the virus are polyarthritis, rash and fever. Other symptoms include eye pain, chest pain, lymphadenitis and lethargy. The disease is self-limiting. No fatalities due to infection are known.
Cause
Strains
ONNV has at least three major subtypes, or strains, the genomic sequences of which are currently available on genome databases.
Transmission
ONNV is transmitted by bites from an infected mosquito. It is the only virus whose primary vectors are anopheline mosquitoes (Anopheles funestus and Anopheles gambiae).
Epidemiology
There have been two epidemics of o’nyong’nyong fever. The first occurred from 1959 to 1962, spreading from Uganda to Kenya, Tanzania, Zaire (Democratic Republic of the Congo), Malawi and Mozambique, and affecting over two million people, one of the largest arbovirus epidemics ever recorded. The first virus isolates were obtained during this outbreak from mosquitoes and human blood samples collected from Gulu in northern Uganda in 1959.The second epidemic in 1996–1997 was confined to Uganda. The 35-year hiatus between the two outbreaks and evidence of an outbreak in 1904–1906 in Uganda indicate a 30–50 year cycle for epidemics.In 2013, ONNV was confirmed as the cause of disease in a 60-year-old German woman who became infected while traveling in East Africa. In 2015–2016 there was a minor outbreak in Uganda with 51 suspected cases.There has been a minor outbreak in Mombasa (Kenya) and the County Government of Mombasa issued a warning.
A 2015 study indicated that ONNV is endemic in coastal East Africa, along with chikungunya virus.
References
== External links == |
You act as a mediator between medical professionals and the public. Provide comprehensive explanations of medical terms, ensuring they are both precise and easily understood. | Can you demystify the medical term 'Trichorrhexis invaginata' for me? | Trichorrhexis invaginata is a distinctive hair shaft abnormality that may occur sporadically, either in normal hair or with other hair shaft abnormalities, or regularly as a marker for Nethertons syndrome.: 638 : 766–7 The primary defect appears to be abnormal keratinization of the hair shaft in the keratogenous zone, allowing for intussusception of the fully keratinized and hard distal shaft into the incompletely keratinized and soft proximal portion of the shaft.: 638
Genetics
"Bamboo hair" is a rare autosomal recessive genodermatosis characterized by congenital ichthyosiform erythroderma, trichorrhexis invaginata, and atopic diathesis with failure to thrive. Chronic skin inflammation results in scaling and exfoliation, predisposing these patients to life-threatening infections, sepsis, and dehydration. The Netherton syndrome Mendelian Inheritance in Man is inherited as an autosomal recessive disorder due to mutations of both copies of the SPINK5 gene (localized to band 5q31-32), which encodes the serine protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). LEKTI is expressed in epithelial and mucosal surfaces and in the thymus. Each SPINK5 mutation leads to a different length of LEKTI protein, resulting in genotype/phenotype correlations in cutaneous severity, susceptibility to atopic dermatitis, growth retardation, skin infection, increased stratum corneum protease activities, and elevated kallikrein levels in the stratum corneum.Trichorrhexis invaginata, or bamboo hair, is a hair shaft abnormality that occurs as a result of an intermittent keratinizing defect of the hair cortex. Incomplete conversion of the sulfhydryl –SH group onto S-S disulfide bonds in the protein of the cortical fibers leads to cortical softness and subsequent invagination of the fully keratinized distal hair shaft into the softer, abnormally keratinized proximal hair shaft. Intussusception of the distal hair shaft into the proximal hair shaft results in a distinctive ball-and-socket hair shaft deformity. The affected hairs are brittle and breakage is common, resulting in short hairs.Migratory lesions of ichthyosis linearis circumflexa may be caused by a dermal influx of inflammatory cells that undergo phagocytosis and digestion by keratinocytes, resulting in disruption of keratinization.Increased transepidermal water loss resulting from the disturbance of corneocyte barrier function in erythroderma may cause profound metabolic abnormalities and hypernatremia, particularly in neonates.
Epidemiology
Approximately 200 cases of trichorrhexis invaginata (bamboo hair) have been reported in the literature, but the true incidence is not known. The incidence of trichorrhexis invaginata (bamboo hair) may be as high as 1 case in 50,000 population. Girls are affected more often by trichorrhexis invaginata (bamboo hair) than boys, but is present in all races.
History
In 1937, Touraine and Solente first noted the association between hair-shaft defects (bamboo node) and ichthyosiform erythroderma. Còme first coined the term ichthyosis linearis circumflexa in 1949, although Rille had previously recorded the distinctive features of ichthyosis linearis circumflexa by 1922. In 1958, Netherton described a young girl with generalized scaly dermatitis and fragile nodular hair-shaft deformities, which he termed trichorrhexis nodosa. Later, this was more appropriately renamed as trichorrhexis invaginata (bamboo hair) for a ball-and-socket–type hair-shaft deformity at the suggestion of Wilkinson et al.
In 1974, Mevorah et al. established the clinical relationship between ichthyosis linearis circumflexa and Netherton syndrome, and an atopic diathesis was found to occur in approximately 75% of patients with Netherton syndrome.
See also
Trichomegaly
List of cutaneous conditions
References
== External links == |
You are a medical advisor. Your role is to break down medical terminology into clear, detailed explanations for a general audience. | I'm trying to expand my medical knowledge. Can you elucidate the term 'Hypodontia'? | Hypodontia is defined as the developmental absence of one or more teeth excluding the third molars. It is one of the most common dental anomalies, and can have a negative impact on function, and also appearance. It rarely occurs in primary teeth (also known as deciduous, milk, first and baby teeth) and the most commonly affected are the adult second premolars and the upper lateral incisors. It usually occurs as part of a syndrome that involves other abnormalities and requires multidisciplinary treatment.
The phenomenon can be subdivided into the following according to the number of teeth concerned:
Hypodontia: one to six missing teeth excluding the third molars
Oligodontia: six or more missing permanent teeth excluding the third molars
Anodontia: complete absence of teeth
Signs and symptoms
Typically, all baby teeth will be present by the age of three. As for all adult teeth, they erupt between the ages 6 to 14, with the exception of the third molar, also known as the wisdom teeth which normally erupt between 17 and 25 years of age. If the tooth has yet to erupt by an appropriate age, panoramic x-rays are taken.
Dental features
Microdontia may be present in one or more of the other teeth. This means that the teeth appear smaller than normal, may be observed in both the primary and permanent dentition. This condition can be genetically-linked and in severe cases, may present themselves in the form of ectodermal dysplasia, cleft lip or palate or Down Syndrome. A delay in tooth development may also serve as an indication, whereby the absence of an adult successor slows down the normal resorption of the roots of the baby teeth, which is the progressive loss of parts of the tooth.
Misplaced (ectopic) positioning of the adult teeth may be discovered upon examination or a radiograph. One of the consequences may be an adult tooth intercepting with a baby tooth, causing premature loss or wrong positioning. This can be due to either the absence of neighboring teeth acting as a guide during eruption or the lack of space in the jaw for them to erupt into because of malocclusion.
Skeletal features
Several studies have discovered that anteriorly missing teeth can accompany retrognathic maxilla, also known as an underbite, prognathic mandible, where the lower jaw protrudes out more than normal, and smaller posterior cranial base length. Occurrence of hypodontia can be associated with reduced anterior lower facial height and lip protrusion. This can be linked to lower maxillary to mandibular plane angles.
A more acute mandibular angle and flatter chin may develop as a result. These characteristics become more prominent as the condition becomes progressively severe, particularly when more than one tooth is missing.
Other dental and radiographic features
Data derived from principal component analysis of radiographic images show that children with mild hypodontia may display significant increase of the interincisal angle and decrease in the maxillary and mandibular incisor angles.
Cephalometric tracing is commonly used to study a patients dentofacial proportions in the craniofacial complex. This can aid in predicting growth changes, allowing dentists, especially orthodontists, to develop a suitable treatment plan. Coupled with that, findings consistent among individuals include:
Anterior hypodontia associated with hyper divergent craniofacial pattern;
A tendency toward a class III malocclusion identified in maxillary hypodontia, and;
Reduced lower posterior facial height in children with posterior and mandibular hypodontia.
Associated anomalies
Reduction in coronal or radical dimensions
Retained primary teeth
Ectopic canine eruption
Abnormal morphology such as peg-shaped maxillary lateral incisors and taurodontism, characterized by an enlarged tooth body and roots that are reduced in size
Extracted teeth
Cause
Several theories regarding the aetiology of hypodontia have been proposed in existing literature. There have been various theories mostly looking into genetic and environmental aspects and how they may both be involved. However, the exact cause remains unclear. The extent of individual influences of genetic and environmental factors is still widely debated.Theories regarding the mechanism through which hypodontia occurs can be categorised into evolutional or anatomical.Preliminary studies focused on an evolutionary approach which suggested shortening of the intermaxillary complex and thus shorter arches may contribute to a decrease in number of teeth. This was also suggested in 1945 by Dahlberg using Butlers Field Theory that focused on evolution and development of mammalian teeth into human dentition in an attempt to analyse different of agenesis. In each jaw, four morphological sites were identified (incisors, canines, premolars and molars). The tooth at the end of each region was less genetically stable and hence more prone to absence. In contrast, the tooth most mesial in each region seemed to be more genetically stable. A subsequent theory hypothesised the teeth at the end of each region were possibly "vestigial bodies" that became obsolete during the evolutionary process. At present, it has been theorised that evolutionary change is working to decrease the human dentition by the loss of an incisor, premolar and molar in each quadrant. According to Vastardis (2000), the size of jaws and number of teeth seem to decrease along with human evolution.Theories focusing on anatomical principle, hypothesised that specific areas of the dental lamina are especially prone to environmental effects during tooth maturation. Svinhufvud et al. (1988) suggested that teeth that were more prone to absence developed in areas of initial fusion of the jaw. For instance, maxillary lateral incisors originate where the lateral maxillae and medial nasal bone processes fuse. In contrast, Kjaer et al. (1994) suggested regions where innervation developed were more sensitive than areas of fusion. Commonly affected regions were found to undergo innervation last, this might imply the developmental relationship between nerve and hard tissue. It is thought to be local nerve development that affects tooth agenesis rather than global development, as brainstem anomalies have not been seen to affect tooth development.Presently, the role of polygenic and environmental factors on hypodontia is recognised in most theories.
Environmental factors
Environmental factors can be classified into two main groups, invasive and non-invasive. These factors act additively or independently, ultimately affecting positioning and physical development of the tooth.Invasive environmental factors potentially affect tooth development and positioning leading to hypodontia and impaction. Examples include jaw fractures, surgical procedures and extraction of the preceding deciduous tooth. Treatment such as irradiation has been shown to have severe effects on developing teeth. In a smaller capacity, chemotherapy was also found to have a similar effect. Thalidomide (N-phthaloylglutamine) was also discovered to have a causative effect on mothers who took the drug during pregnancy, resulting in congenitally missing teeth in their children. A link was found between systemic diseases, endocrine disruption (i.e. idiopathic hypoparathyroidism and pseudohypoparathyroidism) and ectodermal dysplasia. However, a definite etiological relationship has yet to be established. Examples of infections include rubella and candida. Exposure to PCBs (such as dioxin), allergies, and toxic epidermal necrolysis folloeing a drug reaction may also be contributing factors.
In a recent study assessing environmental risk factors for hypodontia, it was established that maternal smoking does play a causative role in hypodontia. Passive smoking and caffeine were also assessed but showed no statistical significance.The Journal of the American Dental Association published preliminary data suggesting a statistical association between hypodontia of the permanent teeth and epithelial ovarian cancer (EOC). The study shows that women with EOC are 8.1 times more likely to have hypodontia than are women without EOC. The suggestion therefore is that hypodontia can serve as a "marker" for potential risk of EOC in women.
Genetics
Genetic causes also involve the genes MSX1 and PAX9.Genetic associations for selective tooth agenesis ("STHAG") include:
Failure of tooth formation due to disturbances during the early stages of development could be the cause of congenital missing teeth; this is also known as tooth agenesis. A variety of studies show that missing teeth are commonly associated with genetic and environmental factors. Some literature also shows that a combination of both factors may contribute to the occurrence of hypodontia.Most craniofacial characteristics are influenced by both genetic and environmental factors through complex interactions. The variable expressivity of traits can be either completely genetically determined, environmentally determined, or both. That genetics plays an important role in hypodontia is shown in many different cases. There are hundreds of genes expressed and involved in regulating tooth morphogenesis. Although a single gene defect may contribute to hypodontia, more studies propose that hypodontia is the result of one or more points of closely linked genetic mutations, or polygenic defects.The pattern of congenitally missing teeth seen in monozygotic twins is different, suggesting an underlying epigenetic factor, which may be due to the simultaneous occurrence of two anomalies. This multifactorial aetiology involves environmental factors which trigger the genetic anomalies, resulting in the occurrence of dental agenesis. Common environmental factors include infection, trauma and drugs which predispose to the condition. In hereditary cases, evidence of dental germ developing after surrounding tissues have closed the space required for development may be a large contributing factor, as well as such genetic disorders as Down syndrome, ectodermal dysplasia, cleidocranial dysplasia, and cleft lip and cleft palate.
MSX1
MSX1 (muscle segment homeobox 1) is involved in condensation of ectomesenchyme in the tooth germ. Among the members of homeobox genes, MSX1 and MSX2 are crucial in mediating direct epithelial-mesenchymal interactions during tooth development by expressing in regions of condensing ectomesenchyme in the tooth germ. MSX1 mutations have been identified as a contributing factor in missing second premolars, third molars, and a small percentage of first molars. MSX1 is less likely to cause anterior agenesis.Heterozygous mutations in PAX9 (paired box gene 9) could arrest tooth morphogenesis as it plays a role of transcription the gene expressed in tooth mesenchyme at the bud stage during tooth development. A study showed that single nucleotide polymorphisms in PAX9 were highly associated with missing upper lateral incisors.
AXIN2
The AXIN2 (AXIS inhibition protein 2) gene is a negative regulator of the Wnt signalling pathway, which is important in regulating cell fate, proliferation, differentiation and apoptosis. Its polymorphic variant may be associated with hypodontia such as missing lower incisors or in a more severe form of agenesis like oligontia (lack of six or more permanent teeth).
EDA
EDA provides instructions for making a protein called ectodysplasin A. It encodes transmembrane protein that is part of TNF (tumour necrosis factor) family of ligands. EDA gene defects cause ectodermal dysplasia, which is also known as X-linked hypohidrotic ectodermal dysplasia. Common dental features of ectodermal dysplasia are multiple missing teeth and microdontia.PAX9 and TGFA are involved in regulating between MSX1 and PAX9, causing hypodontia of the molars.Hypodontia can be found in isolated cases too. The familiar or sporadic type of isolations are more frequently reported than the syndromic type. Isolated cases of autosomal dominant, autosomal recessive, or X-linked inheritance patterns may have an impact on the isolation conditions in expressing variation of both penetration and expressivity of traits. Mutations in MSX, PAX9 and TGFA genes are known to cause congenitally missing teeth in some racial groups.
Research
In the 1960s and 1970s, several studies were conducted sponsored by the U.S. Atomic Energy Commission, with the aim of finding a link between genetics and hypodontia.
Impact
There are numerous studies and research reports on the prevalence, aetiology, and treatment of hypodontia and the dentoskeletal effect of hypodontia. A few studies have investigated Oral Health-related Quality of Life (OHRQoL) in individuals with hypodontia and provided some evidence that hypodotia may have an impact on quality of life.
Psychosocial
Cosmetic dentistry has become more notable and prevalent in modern society. Interpersonal relationships and perceived qualities, such as intelligence, friendliness, social class, and popularity can be affected by dentofacial appearance. Some studies have shown that the extent of complaints made by patients was associated with the severity of the condition and the number of missing permanent teeth.Meta-analyses and theoretical reviews have demonstrated that attractive children are seen by others as more intelligent and exhibit more positive social behaviour and traits, other than receiving much more positive treatment than their less attractive counterparts. Therefore, a divergence from perceived ideal dentofacial aesthetic, particularly in children, might adversely affect self-esteem and self-confidence besides attracting mockery from peers.It is therefore reasonable to theorize that deviations from "normal" or "ideal" dentofacial aesthetic could be destructive to an individuals psychosocial and emotional well-being, which brings upon some psychosocial distress in that individual as a result of their condition.
Functional
Individuals with hypodontia tend to have deeper bites and spaces. Further deepening of the bite can also be seen on individuals with missing posterior teeth. Apart from that, hypodontia may lead to non-working interferences, poor gingival contours and over-eruptions of the opposing teeth.It has been found that individuals with hypodontia experience more difficulty during mastication or functioning movements due to smaller occlusal table available. A recent cross-sectional study showed that hypodontia patients have more difficulties in chewing, especially if the deciduous teeth associated with the missing permanent teeth had been exfoliated. Despite currently limited evidence to support this statement, it is plausible that hypodontia may pose functional limitations, which eventually affect that individuals general well-being and quality of life.Hypodontia can indeed pose limitations on the chewing ability of a patient. The condition can be associated with split in the upper lips – a condition known as oral cleft. Hypodontia can have impacts on speech, aesthetics and function of muscles in the mouth. As a result, hypodontia can have negative impacts on the quality of life, although the condition can be well managed and treated by dentists and orthodontists. To manage the condition, the patient will need to have long-term orthodontic treatment.
Financial
Patient with hypodontia requires careful treatment plan due to complex case in order to ensure the best treatment outcomes. Such treatment plans require multi-disciplinary approach, which usually come at a financial cost to both patient and possibly their family. Due to this reason, a team consists of different dental specialties is involved in the patient care.
Management
Hypodontia is a condition that can present in various ways with differing severities. This results in a wide range of treatment methods available. Those affected should be allowed to consider and select the most suitable option for themselves. Early diagnosis of hypodontia is critical for treatment success. The treatment of hypodontia involves specialists in departments such as oral and maxillofacial surgery, operative dentistry, pediatric dentistry, orthodontics and prosthodontics.Before determining a treatment plan, the following should be determined:
Evaluate the number of teeth missing
The size and number of remaining teeth in both arches
Malocclusion
Facial profile
Bone volume
Age: Definitive treatment for hypodontia only commences once all permanent teeth erupt, or upon the completion of orthodontic treatment
Primary teeth condition
Patients motivation towards treatmentTraditionally, the management of hypodontia has involved replacing missing teeth. By replacing the missing teeth, it can prevent neighbouring teeth tilting or drifting and also prevents the overeruption of opposing teeth which could then impact on occlusion and temporo-mandibular joint dysfunction and impact the patients susceptibility to gum disease, tooth wear and tooth fractures. However, studies have suggested that a stable occlusion can be achieved even with a shortened arch of 10 occluding pairs of teeth. The findings support the concept that a healthy and stable occlusion can exist despite missing teeth as long as an acceptable number of teeth are in occlusion. However, this management technique may not be suitable for those with gum disease, parafunctioning activity (tooth grinding or clenching) or malocclusion.It should also be noted that spaces within the dental arch should be monitored, especially in younger patients, as teeth are more likely to drift, tilt or over-erupt. To do this, study models and clinical photographs could be taken in order to record baseline records. If tooth movement was to occur, another form of management may be required depending on the severity and nature.The following below are the methods used to manage hypodontia:
Accept spacing
This is a method suitable to individuals if the space from a missing tooth is not deemed to be an aesthetic concern. Appearance may not be a problem in some cases, for example, when spacing present behind the canines may not be particularly visible, depending on the individual.
Management of retained primary teeth
When there is a case of hypodontia of the permanent premolar teeth, the primary molar teeth would often remain in the mouth beyond the time they are meant to be lost. Therefore, with a presence of healthy primary teeth in the absence of a permanent successor, retaining the primary teeth can be a feasible management of hypodontia.
The primary molars present also functions as a space maintainer, prevent alveolar bone resorption and delays future prosthodontic space replacement by acting as a semi permanent solution going into adulthood Previous studies also shown a good prognosis of retained primary molars going into adulthood. However, leaving the primary teeth in place may run the risk of tooth infraocclusion where the occlusal surface is below that of adjacent teeth.Despite this, the retention of primary teeth, particularly molars, are more susceptible to occlusal wear, over-eruption of opposing teeth and the loss of inter-occlusal space.
Orthodontic space closure
Orthodontic space closure is a way of using orthodontics in order to close spaces in the mouth where the teeth are missing. The ideal age for definitive orthodontic treatment is early adolescence but it is important to consider the patients age, severity of hypodontia, patient expectations and their commitment to treatment. It can be an option for hypodontia management in the case of missing maxillary lateral incisors through the reshaping, and mesial re-positioning of the adjacent canine. This management is indicated in hypodontia cases of Class I molar relationship with severe crowding in the mandibular anterior region where the extraction of lower premolar leads to a predictable outcome, and Class II molar relationship in the absence of crowding and protrusion of the mandibular anterior dentition.When moving the canine into the space of the lateral incisor, the dimensions of the canine, root position and gingival position differ from a lateral incisor and therefore preparation of the canine is necessary in order for it to mimic the incisor. This may involve:
Reduction of the incisal tip and addition of composite on the incisal edge to create a straight contour and a rounded disto-incisal corner
Reduction of the mesial and distal surfaces to reduce the width of the tooth
Flattening of the labial surface to reduce bulbosity. However, removal of enamel by expose the darker coloured dentine and therefore further restoration may be required.
Preparation of the palatal surface of the canine to reduce its bulk.The use of veneers can also be used instead of composite however, these are more expensive and more time-consuming.
There have been several studies which showed the advantages of orthodontic space closure without prosthodontic space replacements. The main advantage mentioned is the early completion of the treatment during early adolescence and the long lasting result of the treatment outcome. In individuals with a high smile line, the mesial re-positioning of canine maintains the normal soft tissue architecture is important in maintaining the aesthetic appearance. This option also negates the risks and costs that comes with prosthodontic treatment and the impression that there is no missing tooth.Some factors need to be considered when making a decision whether to undergo space closure. These include facial profile, size and dimension of canine, the shade of colour of the teeth and the gingival contour and height. Group function occlusion is usually present as a result of the mesial movement of the canine. In order to maintain the stability of the closed space, direct-bonded lingual retainers are usually required.
Orthodontic space opening prior to prosthodontic treatment
The need for orthodontic space opening prior to prosthodontic management depends on the amount of edentulous space available in relation to adjacent teeth, occlusion and aesthetic concerns. To determine the amount of space needed, three methods in the literature can be used which are the golden proportion, the Bolton Analysis and comparing the edentulous space with the contralateral tooth size if present.Space opening and prosthodontic treatment is indicated where there is a Class I molar relationships in the absence of malocclusion Class III molar relationships presenting with a concave facial profile. However, the alteration in appearance during orthodontic treatment (e.g. creating diastema for placement of prostheses) before the filling up the space, although temporary, can negatively impact the oral health-related quality of life in adolescents.
Removable partial dentures
Removable partial dentures are known to be an effective interim method for maintaining functional and aesthetic demands in a growing patient, where definitive fixed restorations are not suitable yet. Removable dentures act as a space maintainer and also prevent the migration of adjacent or opposing teeth, thereby preserving the face height. They are also easy to adjust or add on to in the event of further tooth eruption. However, it may be difficult for young individuals to adhere with wearing removable dentures, due to their bulk. Some patients also find the idea of dentures functionally and socially unacceptable, making them unwilling to comply. Removable prosthetic devices are also known to cause damage to the remaining teeth if worn over a long period of time.
Conventional crown and bridgework
Fixed restorative options are generally preferred over removable ones.
Resin-bonded bridges: Due to its minimal preparation required, this method of replacing teeth is more suited to young adults. It is a definitive restoration with the ability to fill up one or two tooth spaces. Research has reflected a survival rate of 80% over a period of 6 years or longer, and that cantilever resin-bonded bridges are at least as good as conventional fixed-fixed bridges. Restoring teeth with this method can only be done after orthodontic treatment and will need an element of retention to ensure that tooth contacts are not misplaced.
Conventional bridges: Teeth tend to be prepared for conventional bridgework if there are large restorations present, thus being more commonly done on adult patients with hypodontia. Treatment with conventional bridgework will require significant reduction of tooth structure, which will put the tooth at risk of biological damage i.e. loss of vitality. This risk is especially high in young patients with large pulp chambers.
Tooth autotransplantation
Autotransplantation involves the removal of a tooth from one socket and relocating to another socket in the same individual. If done successfully, it is able to ensure stable alveolar bone volume as there is continuous stimulation of the periodontal ligament.
Implant supported tooth replacement
Placing dental implants has proven to be a predictable and reliable method of treating hypodontia, along with bringing excellent aesthetic results. Implant placement should be delayed until jaw growth in an individual is complete. One limitation of implant placement would be the need for a sufficient amount of bone volume, which if not met, may affect the positioning of the implant. However, bone grafting can be carried out to overcome this.
Epidemiology
Hypodontia is less common in the primary dentition, with reported prevalence rates ranging from 0.5% in the Icelandic population to 2.4% in the Japanese population. In the primary dentition the teeth reported as most likely to be missing are the lateral incisors, both maxillary and mandibular. If a deciduous tooth is missing this will increase the risk of an absent successor.In the permanent dentition third molars are most commonly absent, and one study found prevalence rates of between 20–22%. When third molars are ignored the prevalence rate for each tooth varies from study to study. In Caucasian studies mandibular second premolars and maxillary lateral incisors are most often absent. Several UK studies have found the lower second premolar to be most commonly absent. Studies from Asian populations report that the mandibular incisor is most commonly absent.A higher prevalence of hypodontia in females has been reported. The most extensive studies have been in Caucasian populations and suggest a prevalence of 4–6%.One study looked at 33 previous studies with a sample size of 127,000, and concluded that the prevalence of hypodontia in the permanent dentition varied between continents, racial groups and genders. In the white European population they suggested a prevalence of 4.6% in males and 6.3% in females. In an African-American sample they found this to be 3.2% in males and 4.6% in females. The same study found that in the permanent dentition the most likely teeth to be missing and the frequency of these missing teeth was:
Mandibular second premolar 3%
Maxillary lateral incisor 1.7%
Maxillary second premolar 1.5%
Mandibular central incisor 0.3%
References
== External links == |
You are an expert in medical terminology. Explain medical terms in a way that is both precise and easy to understand for non-medical audiences. | I'm looking for a concise explanation of the medical term 'Cerebellar degeneration.' | Cerebellar degeneration is a condition in which cerebellar cells, otherwise known as neurons, become damaged and progressively weaken in the cerebellum. There are two types of cerebellar degeneration; paraneoplastic cerebellar degeneration, and alcoholic or nutritional cerebellar degeneration. As the cerebellum contributes to the coordination and regulation of motor activities, as well as controlling equilibrium of the human body, any degeneration to this part of the organ can be life-threatening. Cerebellar degeneration can result in disorders in fine movement, posture, and motor learning in humans, due to a disturbance of the vestibular system. This condition may not only cause cerebellar damage on a temporary or permanent basis, but can also affect other tissues of the central nervous system, those including the cerebral cortex, spinal cord and the brainstem (made up of the medulla oblongata, midbrain, and pons).Cerebellar degeneration can be attributed to a plethora of hereditary and non-hereditary conditions. More commonly, cerebellar degeneration can also be classified according to conditions that an individual may acquire during their lifetime, including infectious, metabolic, autoimmune, paraneoplastic, nutritional or toxic triggers.
Signs and symptoms
Patients with cerebellar degeneration experience a progressive loss of nerve cells (Purkinje cells) throughout the cerebellum. As well as this, it is common to incur an elevated blood protein level and a high volume of lymph cells within the cerebrospinal fluid, resulting in swelling and enlargement of the brain. The most characteristic signs and symptoms experienced by patients with cerebellar degeneration include:
muscle weakness
an uncoordinated, staggering walk
quivering of the torso
jerky arm and leg movements
tendency to falling over
dysarthria (difficulty in articulating speech)
dysphagia (difficulty in deglutition/swallowing of solids and liquids)
vertigo (dizziness)
nystagmus (rapid, involuntary eye movements), causing sleep disturbances
ophthalmoplegia (paralysis of extraocular muscles)
diplopia (double vision)Scientific studies have revealed that psychiatric symptoms are also common in patients with cerebellar degeneration, where dementia is a typical psychiatric disorder resulting from cerebellar damage. Approximately 50% of all patients experience dementia as a result of paraneoplastic cerebellar degeneration.
Causes
The root cause of incurring a cerebellar degenerative condition can be due to a range of different inherited or acquired (non-genetic and non-inherited) conditions, including neurological diseases, paraneoplastic disorders, nutritional deficiency, and chronic heavy alcohol use.
Neurological diseases
A neurological disease refers to any ailment of the central nervous system, including abnormalities of the brain, spinal cord and other connecting nerve fibres. Where millions of people are affected by neurological diseases on a worldwide scale, it has been identified that the number of different types of neurological diseases exceeds six hundred, any of which an individual can incur. Some of the most prevalent types include Alzheimers disease, cerebral palsy, epilepsy, Parkinsons disease and stroke. More specifically, the neurological diseases that can cause cerebellar degeneration include:
Inherited
Spinocerebellar ataxia (SCA), which refers to a group of conditions caused by mutations in the genes of a human, and are characterised by degenerative changes to many parts of the central nervous system, inclusive of the cerebellum, brain stem, and spinal cord. If a parent is affected by SCA, each of their children will have a 50% risk of inheriting the mutated gene.
Non-inherited
Multiple sclerosis (MS), a progressive and incurable condition caused by the combination of an individuals genetic influences and environmental circumstances. It occurs when the myelin sheath of the nerve cells becomes damaged. As the myelin sheath is responsible for protecting the nerves and conducting rapid impulses between them, any damage to this lipid-rich layer will result in delayed and interrupted nerve impulses to and from the brain.
Transmissible spongiform encephalopathies (TSEs), which refers to a combination of diseases caused by the subsistence of foreign proteins in the blood, called prions. Prions originate in the bloodstream via ingestion of contaminated foods or through contact with contaminated medical instruments, body fluids, or infected tissue. This causes severe inflammation of the brain, impairing ones memory, personality and muscular coordination.
Acute & haemorrhagic stroke, resulting in the death of neurons in the cerebellum due to a disrupted flow of oxygen to the brain. This disrupted flow may be due to one of two causes; either a narrowing or blocked artery which derives from a build-up of plaque in the inner walls of the coronary arteries, or a ruptured blood vessel, commonly deriving from high blood pressure or head trauma.
Paraneoplastic disorders
Paraneoplastic disorders are a combination of non-inherited conditions that are activated by an individuals autoimmune response to a malignant tumour. These disorders prevail when T-cells (also known as white blood cells) begin to harm familiar cells in the central nervous system rather than the cancerous cells, resulting in degeneration of neurons in the cerebellum. Other signs and symptoms that commonly result from the incursion of a paraneoplastic disorder include an impaired ability to talk, walk, sleep, maintain balance and coordinate muscle activity, as well as experiencing seizures and hallucinations. Paraneoplastic disorders are prevalent among middle-aged individuals, typically those with lung, lymphatic, ovarian or breast cancer.
Nutritional deficiency
Nutritional deficiency relates to an insufficient amount of macronutrients and micronutrients being provided to the body. Nutrient deficiencies are most prevalent among infants, the elderly, the poverty-stricken, and individuals with eating disorders. Alcohol use disorder is the diagnosis of which an individual frequently consumes excessive amounts of alcohol, and thus becomes dependent on the intoxicating substance. Studies show that men of every age group consume more alcohol than women, where the prevalence is higher in some regions of the world than others, such as across Western Europe and Australia. Nutritional deficiency is a non-inherited conditions that lead to impaired absorption or utilisation of the vitamin thiamine (B-1) by the body, thus causing temporary or permanent damage to cerebellar cells. Alcoholic degeneration of cerebellar cells is the most common trigger of spinocerebellar ataxia.
Diagnosis
To select an appropriate and accurate diagnostic test for cerebellar degeneration, it is crucial that a range of factors specific to each patient are taken into consideration. These include; the patients age, acuity of their signs and symptoms, associated neurological conditions, and family history of hereditary forms of cerebellar degeneration. A diagnosis for cerebellar degeneration is regarded after any of the aforementioned signs and symptoms surface. For genetically classified forms of cerebellar degeneration, genetic testing can be carried out in order to confirm or deny the diagnosis, where this form of testing is only possible if the gene responsible for the cause of the condition is recognised. In saying this, for most conditions the genetic cause of cerebellar degeneration is unidentified, hence these patients cannot proceed with genetic testing. In cases where cerebellar degeneration is acquired, a diagnosis can be established using imaging methods such as computerised tomography (CT scans) and magnetic resonance imaging (MRI), necessary to detect brain abnormalities in patients with cerebellar degeneration.
Treatment
Like any other disease, treatment for cerebellar degeneration is contingent on the underlying cause, unique to each patient. As of present time, hereditary forms of cerebellar degeneration are incurable, though they can be managed. Management is centred around coping with symptoms and improving a patients quality of life. In these cases, immediate management of inherited cerebellum damage should involve consultation with a neurologist, followed by specific management approaches based on the signs and symptoms experienced by each unique patient. These management approaches aim to provide supportive care to the patient, consisting of physical therapy to strengthen muscles, occupational therapy, and speech pathology. Long-term management of inherited cerebellar degeneration involves an ongoing commitment to supportive care therapies, as well as a longitudinal relationship with a neurologist. In some instances adjustments need to be made in the patients home, to improve accessibility and mobility in and around their living environment, to optimise safety.For non-hereditary types of cerebellar degeneration, some physical and mental indicators can be reversed by treating the fundamental cause. For instance, the signs and symptoms of paraneoplastic cerebellar degeneration can be managed by initially terminating the underlying cancer with treatments such as surgery, radiation therapy and chemotherapy. In cases of nutritional or alcoholic cerebellar degeneration, symptoms of these conditions can be relieved by initially consuming a balanced diet and discontinuing the consumption of alcohol respectively, followed by dietary supplementation with thiamine.
Prognosis
The long-term prospect for patients with cerebellar degeneration differs according to the underlying cause of the disease. Each inherited or acquired disease that results in cerebellar degeneration has its own specific prognosis, however most are generally poor, progressive and often fatal.
Epidemiology
Cerebellar degeneration continues to carry a considerable burden on the health of the world population, as well as on health agencies and governing bodies across the globe. Cerebellum-related disorders generally transpire in individuals between the ages of 45 to 65 years, however the age of symptomatic onset differs in accordance with the underlying cause of the degenerative disorder. For paraneoplastic cerebellar degeneration, the average age of onset is 50 years, generally affecting a greater population of males than females. Nutritional and alcoholic cerebellar degeneration, being more prevalent than paraneoplastic cerebellar degeneration, affects individuals with a thiamine deficiency and dipsomaniacs, respectively. Recent epidemiological studies on cerebellar degeneration estimated a global prevalence rate of 26 per 100,000 cases of cerebellar degeneration in children.
References
== External links == |
You act as a bridge between medical jargon and everyday language. Explain medical terms in a manner that is comprehensive yet approachable for non-experts. | I'm trying to understand 'Amyotrophic lateral sclerosis' within a medical context. Could you shed some light on it? | Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrigs disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most common type of motor neuron disease. Early symptoms of ALS include stiff muscles, muscle twitches, and gradual increasing weakness and muscle wasting. Limb-onset ALS begins with weakness in the arms or legs, while bulbar-onset ALS begins with difficulty speaking or swallowing. Half of the people with ALS develop at least mild difficulties with thinking and behavior, and about 15% develop frontotemporal dementia. Most people experience pain. The affected muscles are responsible for chewing food, speaking, and walking. Motor neuron loss continues until the ability to eat, speak, move, and finally the ability to breathe is lost. ALS eventually causes paralysis and early death, usually from respiratory failure.Most cases of ALS (about 90% to 95%) have no known cause, and are known as sporadic ALS. However, both genetic and environmental factors are believed to be involved. The remaining 5% to 10% of cases have a genetic cause linked to a history of the disease in the family, and these are known as familial ALS. About half of these genetic cases are due to one of two specific genes. ALS and frontotemporal dementia (FTD) are considered to be part of a common disease continuum (ALS-FTD) because of genetic, clinical, and pathological similarities. The underlying mechanism involves damage to both upper and lower motor neurons; in ALS-FTD, neurons in the frontal and temporal lobes of the brain die as well. The diagnosis is based on a persons signs and symptoms, with testing done to rule out other potential causes.There is no known cure for ALS. The goal of treatment is to improve symptoms. A medication called riluzole may extend life by about two to three months. Non-invasive ventilation may result in both improved quality and length of life. Mechanical ventilation can prolong survival but does not stop disease progression. A feeding tube may help. The disease can affect people of any age, but usually starts around the age of 60 and in inherited cases around the age of 50. The average survival from onset to death is two to four years, though this can vary, and about 10% survive longer than 10 years, and death is usually due to respiratory failure. In Europe, the disease affects about two to three people per 100,000 per year. Rates in much of the world are unclear. In the United States, it most commonly occurs in whites.Descriptions of the disease date back to at least 1824 by Charles Bell. In 1869, the connection between the symptoms and the underlying neurological problems was first described by French neurologist Jean-Martin Charcot, who in 1874 began using the term amyotrophic lateral sclerosis. It became well known in the United States in the 20th century when in 1939 it affected baseball player Lou Gehrig (leading to his death two years later), and later worldwide, following the 1963 diagnosis of then 21 year old cosmologist Stephen Hawking. However, unlike most individuals with ALS, Hawking managed to survive his illness for another 55 years. The first ALS gene was discovered in 1993 while the first animal model was developed in 1994. In 2014, videos of the Ice Bucket Challenge went viral on the Internet and increased public awareness of the condition.
Classification
ALS is a motor neuron disease, also spelled "motor neurone disease", which is a group of neurological disorders that selectively affect motor neurons, the cells that control voluntary muscles of the body. Other motor neuron diseases include primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), progressive bulbar palsy, pseudobulbar palsy, and monomelic amyotrophy (MMA).ALS itself can be classified in a few different ways: by how fast the disease progresses which is related to the age of onset; by whether it is familial or sporadic, and by the region first affected. In about 25% of cases, muscles in the face, mouth, and throat are affected first because motor neurons in the part of the brainstem called the medulla oblongata (formerly called the "bulb") start to die first along with lower motor neurons. This form is called "bulbar-onset ALS". In about 5% of cases, muscles in the trunk of the body are affected first. In most cases the disease spreads and affects other spinal cord regions. A few people with ALS have symptoms that are limited to one spinal cord region for at least 12 to 24 months before spreading to a second region; these regional variants of ALS are associated with a better prognosis.
Classical ALS, PLS, and PMA
ALS can be classified by the types of motor neurons that are affected. Typical or "classical" ALS involves upper motor neurons in the brain and lower motor neurons in the spinal cord. Primary lateral sclerosis (PLS) involves only upper motor neurons, and progressive muscular atrophy (PMA) involves only lower motor neurons. There is debate over whether PLS and PMA are separate diseases or simply variants of ALS.Classic ALS accounts for about 70% of all cases of ALS and can be subdivided into limb-onset ALS (also known as spinal-onset) and bulbar-onset ALS. Limb-onset ALS begins with weakness in the arms and legs and accounts for about two-thirds of all classic ALS cases. Bulbar-onset ALS begins with weakness in the muscles of speech, chewing, and swallowing and accounts for the other one-third of cases. Bulbar onset is associated with a worse prognosis than limb-onset ALS; a population-based study found that bulbar-onset ALS has a median survival of 2.0 years and a 10-year survival rate of 3%, while limb-onset ALS has a median survival of 2.6 years and a 10-year survival rate of 13%. A rare variant is respiratory-onset ALS that accounts for about 3% of all cases of ALS, in which the initial symptoms are difficulty breathing (dyspnea) with exertion, at rest, or while lying down (orthopnea). Spinal and bulbar symptoms tend to be mild or absent at the beginning. It is more common in males. Respiratory-onset ALS has the worst prognosis of any ALS variant; in a population-based study, those with respiratory-onset had a median survival of 1.4 years and 0% survival at 10 years.Primary lateral sclerosis (PLS) accounts for about 5% of all cases of ALS and affects upper motor neurons in the arms and legs. However, more than 75% of people with apparent PLS develop lower motor neuron signs within four years of symptom onset, meaning that a definite diagnosis of PLS cannot be made until then. PLS has a better prognosis than classic ALS, as it progresses slower, results in less functional decline, does not affect the ability to breathe, and causes less severe weight loss.Progressive muscular atrophy (PMA) accounts for about 5% of all cases of ALS and affects lower motor neurons in the arms and legs. While PMA is associated with longer survival on average than classic ALS, it still progresses to other spinal cord regions over time, eventually leading to respiratory failure and death. Upper motor neuron signs can develop late in the course of PMA, in which case the diagnosis might be changed to classic ALS.
Regional variants
Regional variants of ALS have symptoms that are limited to a single spinal cord region for at least a year; they progress more slowly than classic ALS and are associated with longer survival. Examples include flail arm syndrome, flail leg syndrome, and isolated bulbar ALS. Flail arm syndrome and flail leg syndrome are often considered to be regional variants of PMA because they only involve lower motor neurons. Isolated bulbar ALS can involve upper or lower motor neurons. These regional variants of ALS cannot be diagnosed at the onset of symptoms; a failure of the disease to spread to other spinal cord regions for an extended period of time (at least 12 months) must be observed.Flail arm syndrome, also called brachial amyotrophic diplegia, is characterized by lower motor neuron damage in the cervical spinal cord only, leading to gradual onset of weakness in the proximal arm muscles and decreased or absent reflexes. Flail leg syndrome, also called leg amyotrophic diplegia, is characterized by lower motor neuron damage in the lumbosacral spinal cord only, leading to gradual onset of weakness in the legs and decreased or absent reflexes. Isolated bulbar ALS is characterized by upper or lower motor neuron damage in the bulbar region only, leading to gradual onset of difficulty with speech (dysarthria) and swallowing (dysphagia); breathing (respiration) is generally preserved, at least initially. Two small studies have shown that people with isolated bulbar ALS may live longer than people with bulbar-onset ALS.
Age of onset
ALS can also be classified based on the age of onset. While the peak age of onset is 58 to 63 for sporadic ALS and 47 to 52 for familial ALS, about 10% of all cases of ALS begin before age 45 ("young-onset" ALS), and about 1% of all cases begin before age 25 (juvenile ALS). People who develop young-onset ALS are more likely to be male, less likely to have bulbar onset of symptoms, and more likely to have a slower progression of disease. Juvenile ALS is more likely to be familial than adult-onset ALS; genes known to be associated with juvenile ALS include ALS2, SETX, SPG11, FUS, and SIGMAR1. Although most people with juvenile ALS live longer than those with adult-onset ALS, some of them have specific mutations in FUS and SOD1 that are associated with a poor prognosis. Late onset (after age 65) is associated with a more rapid functional decline and shorter survival.
Signs and symptoms
The disorder causes muscle weakness, atrophy, and muscle spasms throughout the body due to the degeneration of the upper motor and lower motor neurons. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel function and the extraocular muscles (the muscles responsible for eye movement) are usually spared until the final stages of the disease.Cognitive or behavioral dysfunction is present in 30–50% of individuals with ALS. Around half of people with ALS will experience mild changes in cognition and behavior, and 10–15% will show signs of frontotemporal dementia (FTD). Most people with ALS who have normal cognition at the time of diagnosis have preserved cognition throughout the course of their disease; the development of cognitive impairment in those with normal cognition at baseline is associated with a worse prognosis. Repeating phrases or gestures, apathy, and loss of inhibition are frequently reported behavioral features of ALS. Language dysfunction, executive dysfunction, and troubles with social cognition and verbal memory are the most commonly reported cognitive symptoms in ALS; a meta-analysis found no relationship between dysfunction and disease severity. However, cognitive and behavioral dysfunctions have been found to correlate with reduced survival in people with ALS and increased caregiver burden; this may be due in part to deficits in social cognition. About half the people who have ALS experience emotional lability, in which they cry or laugh for no reason; it is more common in those with bulbar-onset ALS.Pain is a symptom experienced by most people with ALS and can take the form of neuropathic pain (pain caused by nerve damage), spasticity, muscle cramps, and nociceptive pain caused by reduced mobility and muscle weakness; examples of nociceptive pain in ALS include contractures (permanent shortening of a muscle or joint), neck pain, back pain, shoulder pain, and pressure ulcers.Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS maintain hearing, sight, touch, smell, and taste.
Initial symptoms
The start of ALS may be so subtle that the symptoms are overlooked. The earliest symptoms of ALS are muscle weakness or muscle atrophy. Other presenting symptoms include trouble swallowing or breathing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first.In limb-onset ALS, the first symptoms are in the arms or the legs. If the legs are affected first, people may experience awkwardness, tripping, or stumbling when walking or running; this is often marked by walking with a "dropped foot" that drags gently on the ground. If the arms are affected first, they may experience difficulty with tasks requiring manual dexterity, such as buttoning a shirt, writing, or turning a key in a lock.In bulbar-onset ALS, the first symptoms are difficulty speaking or swallowing. Speech may become slurred, nasal in character, or quieter. There may be difficulty with swallowing and loss of tongue mobility. A smaller proportion of people experience "respiratory-onset" ALS, where the intercostal muscles that support breathing are affected first.Over time, people experience increasing difficulty moving, swallowing (dysphagia), and speaking or forming words (dysarthria). Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia), including an overactive gag reflex. An abnormal reflex commonly called Babinskis sign also indicates upper motor neuron damage. Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin (fasciculations). However, twitching is more of a side effect than a diagnostic symptom; it either occurs after or accompanies weakness and atrophy.
Progression
Although the initial symptoms and rate of progression vary from person to person, the disease eventually spreads to unaffected regions and the affected regions become more affected. Most people eventually are not able to walk or use their hands and arms, lose the ability to speak and swallow food and their own saliva, and begin to lose the ability to cough and to breathe on their own.The rate of progression can be measured using the ALS Functional Rating Scale - Revised (ALSFRS-R), a 12-item instrument survey administered as a clinical interview or self-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability); it is the most commonly used outcome measure in clinical trials and is used by doctors to track disease progression. Though the degree of variability is high and a small percentage of people have a much slower disorder, on average, people with ALS lose about 0.9 FRS points per month. A survey-based study among clinicians showed that they rated a 20% change in the slope of the ALSFRS-R as being clinically meaningful.Disease progression tends to be slower in people who are younger than 40 at onset, are mildly obese,
have symptoms restricted primarily to one limb, and those with primarily upper motor neuron symptoms. Conversely, progression is faster and prognosis poorer in people with bulbar-onset ALS, respiratory-onset ALS and frontotemporal dementia.
Late stages
Difficulties with chewing and swallowing make eating very difficult and increase the risk of choking or of aspirating food into the lungs. In later stages of the disorder, aspiration pneumonia can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. As the diaphragm and intercostal muscles of the rib cage that support breathing weaken, measures of lung function such as vital capacity and inspiratory pressure diminish. In respiratory-onset ALS, this may occur before significant limb weakness is apparent. The most common cause of death among people with ALS are respiratory failure or pneumonia and most people with ALS die in their own home from the former cause, with their breath stopping while they sleep.Although respiratory support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die between two and four years after the diagnosis. Around half of people with ALS die within 30 months of their symptoms beginning, and about 20% of people with ALS live between five and ten years after symptoms begin. Guitarist Jason Becker has lived since 1989 with the disorder, while cosmologist Stephen Hawking lived for 55 more years following his diagnosis, but they are considered unusual cases.
Cause
Though the exact cause of ALS is unknown, genetic and environmental factors are thought to be of roughly equal importance. The genetic factors are better understood than the environmental factors; no specific environmental factor has been definitively shown to cause ALS. A liability threshold model for ALS proposes that cellular damage accumulates over time due to genetic factors present at birth and exposure to environmental risks throughout life.
Genetics
ALS can be classified as familial or sporadic, depending on whether or not there is a family history of the disease. There is no consensus among neurologists on the exact definition of familial ALS. The strictest definition is that a person with ALS must have two or more first-degree relatives (children, siblings, or parents) who also have ALS. A less strict definition is that a person with ALS must have at least one first-degree or second-degree relative (grandparents, grandchildren, aunts, uncles, nephews, nieces or half-siblings) who also has ALS. Familial ALS is usually said to account for 10% of all cases of ALS, though estimates range from 5% to 20%. Higher estimates use a broader definition of familial ALS and examine the family history of people with ALS more thoroughly.In sporadic ALS, there is no family history of the disease. Sporadic ALS and familial ALS appear identical clinically and pathologically and are similar genetically; about 10% of people with sporadic ALS have mutations in genes that are known to cause familial ALS. In light of these parallels, the term "sporadic ALS" has been criticized as misleading because it implies that cases of sporadic ALS are only caused by environmental factors; the term "isolated ALS" has been suggested as a more accurate alternative.More than 20 genes have been associated with familial ALS, of which four account for the majority of familial cases: C9orf72 (40%), SOD1 (20%), FUS (1–5%), and TARDBP (1–5%). The genetics of familial ALS are better understood than the genetics of sporadic ALS; as of 2016, the known ALS genes explained about 70% of familial ALS and about 15% of sporadic ALS. Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS. ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.ALS and frontotemporal dementia (FTD) are now considered to be part of a common disease spectrum (FTD–ALS) because of genetic, clinical, and pathological similarities. Genetically, C9orf72 repeat expansions account for about 40% of familial ALS and 25% of familial FTD. Clinically, 50% of people with ALS have some cognitive or behavioral impairments and 5–15% have FTD, while 40% of people with FTD have some motor neuron symptoms and 12.5% have ALS. Pathologically, abnormal aggregations of TDP-43 protein are seen in up to 97% of ALS patients and up to 50% of FTD patients. In December 2021 a paper found the TDP-43 proteinopathy is in turn caused by defective cyclophilin A which regulates TARDBP gene expression. Other genes known to cause FTD-ALS include CHCHD10, SQSTM1, and TBK1.
Environmental factors
Where no family history of the disease is present – around 90% of cases – no cause is known. Possible associations for which evidence is inconclusive include military service and smoking. Although studies on military history and ALS frequency are inconsistent, there is weak evidence for a positive correlation. Various proposed factors include exposure to environmental toxins (inferred from geographical deployment studies), as well as alcohol and tobacco use during military service.A 2016 review of 16 meta-analyses concluded that there was convincing evidence for an association with chronic occupational exposure to lead; suggestive evidence for farming, exposure to heavy metals other than lead, beta-carotene intake, and head injury; and weak evidence for omega-3 fatty acid intake, exposure to extremely low frequency electromagnetic fields, pesticides, and serum uric acid.In a 2017 study by the United States Centers for Disease Control and Prevention analyzing U.S. deaths from 1985 to 2011, occupations correlated with ALS deaths were white collar, such as in management, financial, architectural, computing, legal, and education jobs. Other potential risk factors remain unconfirmed, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock. There is a tentative association with exposure to various pesticides, including the organochlorine insecticides aldrin, dieldrin, DDT, and toxaphene.
Head injury
A 2015 review found that moderate to severe traumatic brain injury is a risk factor for ALS, but whether mild traumatic brain injury increases rates was unclear. A 2017 meta-analysis found an association between head injuries and ALS; however, this association disappeared when the authors considered the possibility of reverse causation, which is the idea that head injuries are an early symptom of undiagnosed ALS, rather than the cause of ALS.
Physical activity
A number of reviews prior to 2021 found no relationship between the amount of physical activity and the risk of developing ALS. A 2009 review found that the evidence for physical activity as a risk factor for ALS was limited, conflicting, and of insufficient quality to come to a firm conclusion. A 2014 review concluded that physical activity in general is not a risk factor for ALS, that soccer and American football are possibly associated with ALS, and that there was not enough evidence to say whether or not physically demanding occupations are associated with ALS. A 2016 review found the evidence inconclusive and noted that differences in study design make it difficult to compare studies, as they do not use the same measures of physical activity or the same diagnostic criteria for ALS.
However, research published in 2021 suggested that there was a positive causal relationship between ALS and intense physical exercise in those with a risk genotype.
Sports
Both football and American football have been identified as risk factors for ALS in several studies, although this association is based on small numbers of ALS cases. A 2012 retrospective cohort study of 3,439 former NFL players found that their risk of dying from neurodegenerative causes was three times higher than the general US population, and their risk of dying from ALS or Alzheimers disease was four times higher. However, this increased risk was calculated on the basis of two deaths from Alzheimers disease and six deaths from ALS out of 334 deaths total in this cohort, meaning that this study does not definitively prove that playing American football is a risk factor for ALS. Some NFL players thought to have died from ALS may have actually had chronic traumatic encephalopathy (CTE), a neurodegenerative disorder associated with multiple head injuries that can present with symptoms that are very similar to ALS.Football was identified as a possible risk factor for ALS in a retrospective cohort study of 24,000 Italian footballers who played between 1960 and 1996. There were 375 deaths in this group, including eight from ALS. Based on this information and the incidence of ALS, it was calculated that the soccer players were 11 times more likely to die from ALS than the general Italian population. However, this calculation has been criticized for relying on an inappropriately low number of expected cases of ALS in the cohort. When the lifetime risk of developing ALS was used to predict the number of expected cases, soccer players were no more likely to die of ALS than the general population.
Smoking
Smoking is possibly associated with ALS. A 2009 review concluded that smoking was an established risk factor for ALS. A 2010 systematic review and meta-analysis concluded that there was not a strong association between smoking and ALS, but that smoking might be associated with a higher risk of ALS in women. A 2011 meta-analysis concluded that smoking increases the risk of ALS versus never smoking. Among smokers, the younger they started smoking, the more likely they were to get ALS; however, neither the number of years smoked nor the number of cigarettes smoked per day affected their risk of developing ALS.
Risk factor
ALS can strike at any age, but it increases with age. Most people who develop ALS are between the ages of 40 and 70, with an average age of 55 at the time of diagnosis. ALS is 20% more common in men than women, but the difference will disappear after age 70. It has also been suggested that military veterans are about 1.5 to 2 times more likely to develop ALS, though the reason is unclear.
Pathophysiology
Neuropathology
The defining feature of ALS is the death of both upper motor neurons (located in the motor cortex of the brain) and lower motor neurons (located in the brainstem and spinal cord). In ALS with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the brain die as well. The pathological hallmark of ALS is the presence of inclusion bodies (abnormal aggregations of protein) known as Bunina bodies in the cytoplasm of motor neurons. In about 97% of people with ALS, the main component of the inclusion bodies is TDP-43 protein; however, in those with SOD1 or FUS mutations, the main component of the inclusion bodies is SOD1 protein or FUS protein, respectively. The gross pathology of ALS, which are features of the disease that can be seen with the naked eye, include skeletal muscle atrophy, motor cortex atrophy, sclerosis of the corticospinal and corticobulbar tracts, thinning of the hypoglossal nerves (which control the tongue), and thinning of the anterior roots of the spinal cord. Aside from the death of motor neurons, two other characteristics common to most ALS variants are focal initial pathology, meaning that symptoms start in a single spinal cord region, and progressive continuous spread, meaning that symptoms spread to additional regions over time. Prion-like propagation of misfolded proteins from cell to cell may explain why ALS starts in one area and spreads to others. The glymphatic system may also be involved in the pathogenesis of ALS.
Biochemistry
It is still not fully understood why neurons die in ALS, but this neurodegeneration is thought to involve many different cellular and molecular processes. The genes known to be involved in ALS can be grouped into three general categories based on their normal function: protein degradation, the cytoskeleton, and RNA processing. Mutant SOD1 protein forms intracellular aggregations that inhibit protein degradation. Cytoplasmic aggregations of wild-type (normal) SOD1 protein are common in sporadic ALS. It is thought that misfolded mutant SOD1 can cause misfolding and aggregation of wild-type SOD1 in neighboring neurons in a prion-like manner. Other protein degradation genes that can cause ALS when mutated include VCP, OPTN, TBK1, and SQSTM1. Three genes implicated in ALS that are important for maintaining the cytoskeleton and for axonal transport include DCTN1, PFN1, and TUBA4A.There are a number of ALS genes that encode for RNA-binding proteins. The first to be discovered was TDP-43 protein, a nuclear protein that aggregates in the cytoplasm of motor neurons in almost all cases of ALS; however, mutations in TARDBP, the gene that codes for TDP-43, are a rare cause of ALS. FUS codes for FUS, another RNA-binding protein with a similar function to TDP-43, which can cause ALS when mutated. It is thought that mutations in TARDBP and FUS increase the binding affinity of the low-complexity domain, causing their respective proteins to aggregate in the cytoplasm. Once these mutant RNA-binding proteins are misfolded and aggregated, they may be able to misfold normal protein both within and between cells in a prion-like manner. This also leads to decreased levels of RNA-binding protein in the nucleus, which may mean that their target RNA transcripts do not undergo the normal processing. Other RNA metabolism genes associated with ALS include ANG, SETX, and MATR3.C9orf72 is the most commonly mutated gene in ALS and causes motor neuron death through a number of mechanisms. The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over); people with up to 30 repeats are considered normal, while people with hundreds or thousands of repeats can have familial ALS, frontotemporal dementia, or sometimes sporadic ALS. The three mechanisms of disease associated with these C9orf72 repeats are deposition of RNA transcripts in the nucleus, translation of the RNA into toxic dipeptide repeat proteins in the cytoplasm, and decreased levels of the normal C9orf72 protein. Mitochondrial bioenergetic dysfunction leading to dysfunctional motor neuron axonal homeostasis (reduced axonal length and fast axonal transport of mitochondrial cargo) has been shown to occur in C9orf72-ALS using human induced pluripotent stem cell (iPSC) technologies coupled with CRISPR/Cas9 gene-editing, and human post-mortem spinal cord tissue examination.Excitotoxicity, or nerve cell death caused by high levels of intracellular calcium due to excessive stimulation by the excitatory neurotransmitter glutamate, is a mechanism thought to be common to all forms of ALS. Motor neurons are more sensitive to excitotoxicity than other types of neurons because they have a lower calcium-buffering capacity and a type of glutamate receptor (the AMPA receptor) that is more permeable to calcium. In ALS, there are decreased levels of excitatory amino acid transporter 2 (EAAT2), which is the main transporter that removes glutamate from the synapse; this leads to increased synaptic glutamate levels and excitotoxicity. Riluzole, a drug that modestly prolongs survival in ALS, inhibits glutamate release from pre-synaptic neurons; however, it is unclear if this mechanism is responsible for its therapeutic effect.
Diagnosis
No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the person and a series of tests to rule out other diseases. Physicians obtain the persons full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are worsening. A number of biomarkers are being studied for the condition, but so far are not in general medical use.
Diagnostic criteria
The diagnosis of ALS is based on the El Escorial Revised criteria and the Awaji criteria. The original El Escorial criteria had four levels of diagnostic certainty, based on how many of the four spinal cord regions were involved: bulbar, cervical, thoracic, and lumbar. Definite ALS was defined as upper motor neuron (UMN) and lower motor neuron (LMN) signs in three spinal cord regions, probable ALS as UMN and LMN signs in two regions, possible ALS as UMN and LMN signs in only one region, and suspected ALS as LMN signs only. The El Escorial Revised criteria, also known as the Airlie House criteria, dropped the "suspected ALS" category and added a "laboratory-supported probable ALS" category. The Awaji criteria give abnormal EMG tests the same weight as clinical signs of LMN dysfunction in making the diagnosis of ALS, thus making the "laboratory-supported probable ALS" category unnecessary. The only three categories in the Awaji criteria are definite ALS, probable ALS, and possible ALS.The El Escorial Revised criteria are specific for ALS, which means that someone who meets the criteria is very likely to have ALS; however, they are not especially sensitive for ALS, which means that someone who does not meet the criteria can still have ALS. Their sensitivity is particularly poor in the early stages of ALS. The Awaji criteria have better sensitivity than the El Escorial Revised criteria, especially for bulbar-onset ALS. A 2012 meta-analysis found that the El Escorial Revised criteria had a sensitivity of 62.2%, while the Awaji criteria had a sensitivity of 81.1%; both sets of criteria had a specificity of about 98%. The El Escorial criteria were designed to standardize patient groups for clinical trials but are not as useful in clinical practice; possible ALS as described by the El Escorial criteria is almost always clinically ALS.
Differential diagnosis
Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support the diagnosis of ALS. Another common test measures nerve conduction velocity (NCV). Specific abnormalities in the NCV results may suggest, for example, that the person has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. While a magnetic resonance imaging (MRI) is often normal in people with early stage ALS, it can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, a herniated disc in the neck, syringomyelia, or cervical spondylosis.Based on the persons symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases, as well as routine laboratory tests. In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.A number of infectious diseases can sometimes cause ALS-like symptoms, including human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), Lyme disease, and syphilis. Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, spinal muscular atrophy, and spinal and bulbar muscular atrophy can also mimic certain aspects of the disease and should be considered.ALS must be differentiated from the "ALS mimic syndromes", which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants. Because the prognosis of ALS and closely related subtypes of motor neurone disease are generally poor, neurologists may carry out investigations to evaluate and exclude other diagnostic possibilities. Disorders of the neuromuscular junction, such as myasthenia gravis (MG) and Lambert–Eaton myasthenic syndrome, may also mimic ALS, although this rarely presents diagnostic difficulty over time. Benign fasciculation syndrome and cramp fasciculation syndrome may also, occasionally, mimic some of the early symptoms of ALS. Nonetheless, the absence of other neurological features that develop inexorably with ALS means that, over time, the distinction will not present any difficulty to the experienced neurologist; where doubt remains, EMG may be helpful.Most cases of ALS, however, are correctly diagnosed, with the error rate of diagnosis in large ALS clinics being less than 10%. One study examined 190 people who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these people (16%) had their diagnosis completely changed during the clinical observation development period. In the same study, three people had a false negative diagnosis of MG, which can mimic ALS and other neurological disorders, leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.
Management
There is no cure for ALS. Management focuses on treating symptoms and providing supportive care, with the goal of improving quality of life and prolonging survival. This care is best provided by multidisciplinary teams of healthcare professionals; attending a multidisciplinary ALS clinic is associated with longer survival, fewer hospitalizations, and improved quality of life. Riluzole prolongs survival by about 2–3 months. Edaravone slows functional decline slightly in a small number of people with ALS; it is expensive and must be administered by daily IV infusions that may decrease quality of life. Other medications may be used to manage other symptoms.Non-invasive ventilation (NIV) is the main treatment for respiratory failure in ALS. In people with normal bulbar function, it prolongs survival by about seven months and improves quality of life. One study found that NIV is ineffective for people with poor bulbar function while another suggested that it may provide a modest survival benefit. Many people with ALS have difficulty tolerating NIV. Invasive ventilation is an option for people with advanced ALS when NIV is not enough to manage their symptoms. While invasive ventilation prolongs survival, disease progression and functional decline continue. It may decrease the quality of life of people with ALS or their caregivers. Invasive ventilation is more commonly used in Japan than North America or Europe.Physical therapy can promote functional independence through aerobic, range of motion, and stretching exercises. Occupational therapy can assist with activities of daily living through adaptive equipment. Speech therapy can assist people with ALS who have difficulty speaking. Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life. Initially, difficulty swallowing (dysphagia) can be managed by dietary changes and swallowing techniques. A feeding tube should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water. The feeding tube is usually inserted by percutaneous endoscopic gastrostomy (PEG). There is weak evidence that PEG tubes improve survival. PEG insertion is usually performed with the intent of improving quality of life.Palliative care should begin shortly after someone is diagnosed with ALS. Discussion of end-of-life issues gives people with ALS time to reflect on their preferences for end-of-life care and can help avoid unwanted interventions or procedures. Hospice care can improve symptom management at the end of life and increases the likelihood of a peaceful death. In the final days of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety.
Medications
Riluzole has been found to modestly prolong survival by about 2–3 months. It may have a greater survival benefit for those with bulbar-onset ALS. It may work by decreasing release of the excitatory neurotransmitter glutamate from pre-synaptic neurons. The most common side effects are nausea and a lack of energy (asthenia). People with ALS should begin treatment with riluzole as soon as possible following their diagnosis.Edaravone has been shown to modestly slow the decline in function in a small group of people with early-stage ALS. It may work by protecting motor neurons from oxidative stress. The most common side effects are bruising and gait disturbance. Treatment with edaravone is expensive and requires daily hour-long IV infusions for 10 days in a two-week period.Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm. Gabapentin, pregabalin, and tricyclic antidepressants (e.g., amitriptyline) can be used for neuropathic pain, while nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids can be used for nociceptive pain.Depression can be treated with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants, while benzodiazepines can be used for anxiety. There are no medications to treat cognitive impairment/frontotemporal dementia (FTD); however, SSRIs and antipsychotics can help treat some of the symptoms of FTD. Baclofen and tizanidine are the most commonly used oral drugs for treating spasticity; an intrathecal baclofen pump can be used for severe spasticity. Atropine, scopolamine, amitriptyline or glycopyrrolate may be prescribed when people with ALS begin having trouble swallowing their saliva (sialorrhea).A 2017 review concluded that mexiletine was safe and effective for treating cramps in ALS based on a randomized controlled trial from 2016. In a study from 2020, AMX0035, a combination of sodium phenylbutyrate and taurursodiol, was shown to prolong the survival of patients by several months. In March 2022, an independent advisory panel to the FDA voted 6–4 that data was insufficient to show the drug slowed progression of ALS.
Breathing support
Non-invasive ventilation
Non-invasive ventilation (NIV) is the primary treatment for respiratory failure in ALS and was the first treatment shown to improve both survival and quality of life. NIV uses a face or nasal mask connected to a ventilator that provides intermittent positive pressure to support breathing. Continuous positive pressure is not recommended for people with ALS because it makes breathing more difficult. Initially, NIV is used only at night because the first sign of respiratory failure is decreased gas exchange (hypoventilation) during sleep; symptoms associated with this nocturnal hypoventilation include interrupted sleep, anxiety, morning headaches, and daytime fatigue. As the disease progresses, people with ALS develop shortness of breath when lying down, during physical activity or talking, and eventually at rest. Other symptoms include poor concentration, poor memory, confusion, respiratory tract infections, and a weak cough. Respiratory failure is the most common cause of death in ALS.It is important to monitor the respiratory function of people with ALS every three months, because beginning NIV soon after the start of respiratory symptoms is associated with increased survival. This involves asking the person with ALS if they have any respiratory symptoms and measuring their respiratory function. The most commonly used measurement is upright forced vital capacity (FVC), but it is a poor detector of early respiratory failure and is not a good choice for those with bulbar symptoms, as they have difficulty maintaining a tight seal around the mouthpiece. Measuring FVC while the person is lying on their back (supine FVC) is a more accurate measure of diaphragm weakness than upright FVC. Sniff nasal inspiratory pressure (SNIP) is a rapid, convenient test of diaphragm strength that is not affected by bulbar muscle weakness. If someone with ALS has signs and symptoms of respiratory failure, they should undergo daytime blood gas analysis to look for hypoxemia (low oxygen in the blood) and hypercapnia (too much carbon dioxide in the blood). If their daytime blood gas analysis is normal, they should then have nocturnal pulse oximetry to look for hypoxemia during sleep.Non-invasive ventilation prolongs survival longer than riluzole. A 2006 randomized controlled trial found that NIV prolongs survival by about 48 days and improves quality of life; however, it also found that some people with ALS benefit more from this intervention than others. For those with normal or only moderately impaired bulbar function, NIV prolongs survival by about seven months and significantly improves quality of life. For those with poor bulbar function, NIV neither prolongs survival nor improves quality of life, though it does improve some sleep-related symptoms. Despite the clear benefits of NIV, about 25–30% of all people with ALS are unable to tolerate it, especially those with cognitive impairment or bulbar dysfunction. Results from a large 2015 cohort study suggest that NIV may prolong survival in those with bulbar weakness, and so NIV should be offered to all people with ALS, even if it is likely that they will have difficulty tolerating it.
Invasive ventilation
Invasive ventilation bypasses the nose and mouth (the upper airways) by making a cut in the trachea (tracheostomy) and inserting a tube connected to a ventilator. It is an option for people with advanced ALS whose respiratory symptoms are poorly managed despite continuous NIV use. While invasive ventilation prolongs survival, especially for those younger than 60, it does not treat the underlying neurodegenerative process. The person with ALS will continue to lose motor function, making communication increasingly difficult and sometimes leading to locked-in syndrome, in which they are completely paralyzed except for their eye muscles. About half of the people with ALS who choose to undergo invasive ventilation report a decrease in their quality of life but most still consider it to be satisfactory. However, invasive ventilation imposes a heavy burden on caregivers and may decrease their quality of life. Attitudes toward invasive ventilation vary from country to country; about 30% of people with ALS in Japan choose invasive ventilation, versus less than 5% in North America and Europe.
Therapy
Physical therapy plays a large role in rehabilitation for individuals with ALS. Specifically, physical, occupational, and speech therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, improving speech and swallowing, preventing complications, and promoting functional independence.Occupational therapy and special equipment such as assistive technology can also enhance peoples independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercise such as performing activities of daily living, walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help people fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles, because muscle exhaustion can lead to worsening of symptoms associated with ALS, rather than providing help to people with ALS. They can suggest devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help people remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable ALS people to retain as much safety and independence in activities of daily living as possible. Since respiratory insufficiency is the primary cause of mortality, physical therapists can help improve respiratory outcomes in people with ALS by implementing pulmonary physical therapy. This includes inspiratory muscle training, lung volume recruitment training, and manual assisted cough therapy aimed at increasing respiratory muscle strength as well as increasing survival rates.People with ALS who have difficulty speaking or swallowing may benefit from working with a speech-language pathologist. These health professionals can teach people adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use of augmentative and alternative communication such as voice amplifiers, speech-generating devices (or voice output communication devices) or low-tech communication techniques such as head mounted laser pointers, alphabet boards or yes/no signals.In a study published in 2022, a completely locked-in ALS patient was fitted with two 64-bit brain implant microarrays in his motor cortex in 2020. Using audible feedback from his own intentional neural firing rates, he was able to communicate letters to form phrases. This is the first example of communication at length with a fully locked-in ALS patient.
Nutrition
Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life. Weight loss in ALS is caused by muscle wasting due to motor neuron death, increased resting energy expenditure, and decreased food intake. Difficulty swallowing (dysphagia) develops in about 85% of people with ALS at some point over the course of their disease and is a major cause of decreased food intake, leading to malnutrition and weight loss. It is important to regularly assess the weight and swallowing ability of people with ALS. Initially, dysphagia may be managed by dietary changes and modified swallowing techniques. Difficulty swallowing liquids usually develops first and can be managed by switching to thicker liquids like fruit nectar or smoothies, or by adding fluid thickeners to thin fluids like water and coffee. People with ALS should eat soft, moist foods, which tend to be easier to swallow than dry, crumbly, or chewy foods. They should also be instructed on proper head posture during swallowing, which can make swallowing easier. There is tentative evidence that high-calorie diets may prevent further weight loss and improve survival.A feeding tube should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water. This can take the form of a gastrostomy tube, in which a tube is placed through the wall of the abdomen into the stomach, or a nasogastric tube, in which a tube is placed through the nose and down the esophagus into the stomach. A gastrostomy tube is more appropriate for long-term use than a nasogastric tube, which is uncomfortable and can cause esophageal ulcers. The feeding tube is usually inserted by percutaneous endoscopic gastrostomy (PEG). There is some evidence that a PEG tube should be inserted before vital capacity drops below 50% of expected, as a low vital capacity may be associated with a higher risk of complications. However, a large 2015 study showed that PEG insertion is safe in people with advanced ALS and low vital capacities, as long as they are on NIV during the procedure.There is weak evidence that PEG tubes improve survival. PEG insertion is usually performed with the intent of improving quality of life by sustaining nutrition and medication intake. This reduces the risk of weight loss and dehydration, and can decrease anxiety from extended mealtimes and decreased oral food intake.
End-of-life care
Palliative care, which relieves symptoms and improves quality of life without treating the underlying disease, should begin shortly after someone is diagnosed with ALS. Early discussion of end-of-life issues gives people with ALS time to reflect on their preferences for end-of-life care and can help avoid unwanted interventions or procedures. Once they have been fully informed about all aspects of various life-prolonging measures, they can fill out advance directives indicating their attitude toward noninvasive ventilation, invasive ventilation, and feeding tubes. Late in the disease course, difficulty speaking due to muscle weakness (dysarthria) and cognitive dysfunction may impair their ability to communicate their wishes regarding care. Continued failure to solicit the preferences of the person with ALS may lead to unplanned and potentially unwanted emergency interventions, such as invasive ventilation. If people with ALS or their family members are reluctant to discuss end-of-life issues, it may be useful to use the introduction of gastrostomy or noninvasive ventilation as an opportunity to bring up the subject.Hospice care, or palliative care at the end of life, is especially important in ALS because it helps to optimize the management of symptoms and increases the likelihood of a peaceful death. It is unclear exactly when the end-of-life phase begins in ALS, but it is associated with significant difficulty moving, communicating, and, in some cases, thinking. Although many people with ALS fear choking to death (suffocating), they can be reassured that this occurs rarely, about 0–3% of the time. About 90% of people with ALS die peacefully. In the final days of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety.
Epidemiology
ALS is the most common motor neuron disease in adults and the third most common neurodegenerative disease after Alzheimers disease and Parkinsons disease. Worldwide the number of people who develop ALS yearly is estimated to be 1.9 people per 100,000 per year, while the number of people who have ALS at any given time is estimated to be about 4.5 people per 100,000. In Europe, the number of new cases a year is about 2.6 people per 100,000, while the number affected is 7–9 people per 100,000. The lifetime risk of developing ALS is 1:350 for European men and 1:400 for European women. Men have a higher risk mainly because spinal-onset ALS is more common in men than women. The number of those with ALS in the United States in 2015 was 5.2 people per 100,000, and was higher in whites, males, and people over 60 years old. The number of new cases is about 0.8 people per 100,000 per year in east Asia and about 0.7 people per 100,000 per year in south Asia. About 80% of ALS epidemiology studies have been conducted in Europe and the United States, mostly in people of northern European descent. There is not enough information to determine the rates of ALS in much of the world, including Africa, parts of Asia, India, Russia, and South America. There are several geographic clusters in the Western Pacific where the prevalence of ALS was reported to be 50–100 times higher than the rest of the world, including Guam, the Kii Peninsula of Japan, and Western New Guinea. The incidence in these areas has decreased since the 1960s; the cause remains unknown.People of all races and ethnic backgrounds may be affected by ALS, but it is more common in whites than in Africans, Asians, or Hispanics. In the United States in 2015, the prevalence of ALS in whites was 5.4 people per 100,000, while the prevalence in blacks was 2.3 people per 100,000. The Midwest had the highest prevalence of the four US Census regions with 5.5 people per 100,000, followed by the Northeast (5.1), the South (4.7), and the West (4.4). The Midwest and Northeast likely had a higher prevalence of ALS because they have a higher proportion of whites than the South and West. Ethnically mixed populations may be at a lower risk of developing ALS; a study in Cuba found that people of mixed ancestry were less likely to die from ALS than whites or blacks. There are also differences in the genetics of ALS between different ethnic groups; the most common ALS gene in Europe is C9orf72, followed by SOD1, TARDBP, and FUS, while the most common ALS gene in Asia is SOD1, followed by FUS, C9orf72, and TARDBP.
ALS can affect people at any age, but the peak incidence is between 50 and 75 years and decreases dramatically after 80 years. The reason for the decreased incidence in the elderly is unclear. One thought is that people who survive into their 80s may not be genetically susceptible to developing ALS; alternatively, ALS in the elderly might go undiagnosed because of comorbidities (other diseases they have), difficulty seeing a neurologist, or dying quickly from an aggressive form of ALS. In the United States in 2015, the lowest prevalence was in the 18–39 age group, while the highest prevalence was in the 70–79 age group. Sporadic ALS usually starts around the ages of 58 to 63 years, while familial ALS starts earlier, usually around 47 to 52 years. The number of ALS cases worldwide is projected to increase from 222,801 in 2015 to 376,674 in 2040, an increase of 69%. This will largely be due to the aging of the worlds population, especially in developing countries.
History
Descriptions of the disease date back to at least 1824 by Charles Bell. In 1850, François-Amilcar Aran was the first to describe a disorder he named "progressive muscular atrophy", a form of ALS in which only the lower motor neurons are affected. In 1869, the connection between the symptoms and the underlying neurological problems were first described by Jean-Martin Charcot, who initially introduced the term amyotrophic lateral sclerosis in his 1874 paper. Flail arm syndrome, a regional variant of ALS, was first described by Alfred Vulpian in 1886. Flail leg syndrome, another regional variant of ALS, was first described by Pierre Marie and his student Patrikios in 1918.In 1945, American naval doctors reported that ALS was 100 times more prevalent among the Chamorro people of Guam than in the rest of the world. In 1956 the variant of ALS endemic to Guam was named "amyotrophic lateral sclerosis/parkinsonism dementia complex" (ALS/PDC), as it had the typical symptoms of ALS accompanied by parkinsonism-like symptoms; the name in the local language is lytico-bodig disease. Despite a number of genetic and environmental studies, the cause of ALS/PDC remains unknown. Rates peaked in the early 1950s and steadily declined thereafter, and by 1985 the incidence of ALS/PDC in Guam was about the same as the rest of the world.The first gene to be associated with ALS was SOD1, which was identified in 1993. This led to the development of the first animal model of ALS, the transgenic SOD1 mouse, in 1994. In December 1995, riluzole became the first FDA-approved drug for ALS. It was then approved in Europe in 1996 and in Japan in 1998. In 1996, the ALS Functional Rating Scale (ALSFRS) was first published; it was a 10-item questionnaire that measured the ability of people with ALS to perform activities of daily living. In 1999, the scale was changed to give more weight to respiratory symptoms. The resulting ALS Functional Rating Scale - Revised (ALSFRS-R) is a 12-item questionnaire that replaces the single question about breathing with a question each about dyspnea, orthopnea, and respiratory insufficiency.In 2006, it was discovered that the protein TDP-43 is a major component of the inclusion bodies seen in both ALS and frontotemporal dementia (FTD), which provided evidence that ALS and FTD are part of a common disease spectrum. This led to the discovery in 2008 that mutations in TARDBP, the gene that codes for TDP-43, are a cause of familial ALS. In 2011, noncoding repeat expansions in C9orf72 were found to be a major cause of ALS and FTD. Edaravone was approved to treat ALS in Japan and South Korea in 2015 and in the United States in 2017. As of 2017, it has not been approved to treat ALS in Europe.
Diagnostic criteria
In the 1950s, electrodiagnostic testing (EMG and NCV) began to be used to evaluate clinically suspected ALS. In 1969 Edward H. Lambert published the first EMG/NCS diagnostic criteria for ALS, consisting of four findings he considered to strongly support the diagnosis. In 1990, the World Federation of Neurology (WFN) held a meeting at El Escorial, Spain, to come up with precise diagnostic criteria for ALS to help standardize clinical trials; the resulting "El Escorial" criteria were published in 1994. In 1998, the WFN held another meeting to revise the criteria at Airlie House in Warrenton, Virginia; the resulting "Airlie House" or "El Escorial Revised" criteria were published in 2000. In 2006, a meeting was held on Awaji Island in Japan to discuss how to use EMG and NCV tests to help diagnose ALS earlier; the resulting "Awaji" criteria were published in 2008.
Name
Amyotrophic comes from Greek: a- means "no", myo- (from mûs) refers to "muscle", and trophḗ means "nourishment". Therefore, amyotrophy means "muscle malnourishment" or the wasting of muscle tissue. Lateral identifies the areas in a persons spinal cord where the affected motor neurons that control muscle are located. Sclerosis means "scarring" or "hardening" and refers to the death of the motor neurons in the spinal cord.ALS is sometimes referred to as Charcots disease (not to be confused with Charcot–Marie–Tooth disease and Charcot joint disease), because Jean-Martin Charcot was the first to connect the clinical symptoms with the pathology seen at autopsy. The British neurologist Russell Brain coined the term motor neurone disease in 1933 to reflect his belief that ALS, progressive bulbar palsy, and progressive muscular atrophy were all different forms of the same disease, neurone being a historically incorrect form of neuron. In some countries, especially the United States, ALS is called Lou Gehrigs disease after the American baseball player Lou Gehrig who developed ALS in 1938.In the United States and continental Europe, the term ALS (as well as Lou Gehrigs disease in the US) refers to all forms of the disease, including "classical" ALS, progressive bulbar palsy, progressive muscular atrophy, and primary lateral sclerosis. In the United Kingdom and Australia, the term motor neurone disease refers to all forms of the disease while ALS only refers to "classical" ALS, meaning the form with both upper and lower motor neuron involvement.
Society and culture
In August 2014, a challenge went viral online, commonly known as the "ALS Ice Bucket Challenge". Contestants fill a bucket full of ice and water, then state who nominated them to do the challenge, and nominate three other individuals of their choice to take part in it. The contestants then dump the buckets of ice and water onto themselves. However, it can be done in a different order. The contestants then donate at least US$10 (or a similar amount in their local currency) to ALS research at the ALS Association, the ALS Therapy Development Institute, ALS Society of Canada or Motor Neurone Disease Association in the UK. Any contestants who refuse to have the ice and water dumped on them are expected to donate at least US$100 to ALS research. As of July 2015, the Ice Bucket Challenge had raised $115 million for the ALS Association. Many celebrities have taken part in the challenge. The Ice Bucket Challenge was credited with helping to raise funds that contributed to the discovery that the gene NEK1 may potentially contribute to the development for ALS.
Research
Model organisms
Many different organisms are used as models for studying ALS, including Saccharomyces cerevisiae (a species of yeast), Caenorhabditis elegans (a roundworm), Drosophila melanogaster (the common fruit fly), Danio rerio (the zebrafish), Mus musculus (the house mouse), and Rattus norvegicus (the common rat). None of these models perfectly represents ALS in humans, partly because most animal models are based on gene overexpression, meaning that multiple copies of the mutant human gene are inserted into the transgenic model, and partly because the human nervous system is very different from that of other animals.The first animal model for ALS was the SOD1G93A transgenic mouse, which was developed in 1994. It expresses about 20–24 copies of the mutant human SOD1 gene and reproduces most of the clinical and pathological findings seen in ALS. Although there are now over 20 different SOD1 mouse models, the SOD1G93A model remains both the most widely used SOD1 mouse model and the most widely used ALS mouse model overall. Much of the present understanding of ALS pathophysiology came from studying mouse models that overexpress mutant SOD1, especially SOD1G93A mice. However, many drug targets that were shown to be effective in the SOD1G93A transgenic mouse failed in clinical trials in humans; other SOD1 models have had similar problems. Most of these drugs were identified as potentially effective based on a single study in a rodent SOD1 model and then failed in clinical trials in patients who primarily had sporadic ALS. It is thought that these clinical trials failed because SOD1 mutations account for only 2% of all ALS cases and because the pathology of SOD1 ALS is thought to be distinct from all other types of ALS; it lacks the abnormal aggregations of TDP-43 protein or FUS protein seen in nearly all other cases of ALS.As of 2018, there are about 20 TARDBP mouse models, a dozen FUS mouse models, and a number of C9orf72, PFN1, and UBQLN2 mouse models. There are also new methods of developing animal models, including viral transgenesis, in which viruses are used to deliver mutant genes to an animal model, and CRISPR/Cas9, which can be used to give an animal model multiple mutated genes. Both of these methods are faster and cheaper than traditional methods of genetically engineering mice; they also allow scientists to study the effects of a mutation in mice of different genetic backgrounds, which better represents the genetic diversity seen in humans.Cellular models used to study ALS include the yeast Saccharomyces cerevisiae and rat or mouse motor neurons in culture. Small-animal models include the fruit fly, the roundworm C. elegans, and the zebrafish. Of the three, the fruit fly is the most widely used; it has a rapid life-cycle, short lifespan, a sophisticated nervous system, and many genetic tools available. C. elegans has a short life-cycle, is easy to manipulate genetically, and has a simple but well-understood nervous system. The zebrafish has transparent embryos that can be injected with DNA or RNA and has a lifespan of up to two years. Induced pluripotent stem cells (iPSCs) can be used to convert skin fibroblasts into motor neurons. It is now possible to generate iPSCs from people with ALS, which can then be converted into spinal motor neurons, which are useful for studying disease mechanisms and for testing potential drugs for ALS. iPSCs allow sporadic ALS to be modelled, which cannot be done with animal models.
Treatments
From the 1960s until 2014, about 50 drugs for ALS were tested in randomized controlled trials (RCTs); of these, riluzole was the only one that showed a slight benefit in improving survival. Drugs tested and not shown to be effective in clinical trials in humans include antiviral drugs, anti-excitotoxic drugs, growth factors, neurotrophic factors, anti-inflammatory drugs, antioxidants, anti-apoptotic drugs, and drugs to improve mitochondria function.An analysis of 23 large phase II and phase III RCTs that failed between 2004 and 2014 concluded that there were many potential reasons for their lack of success. These trials in humans went ahead on the basis of positive results in SOD1 transgenic mice, which are not a good animal model for sporadic ALS. In most preclinical studies the SOD1 mice were given the drug during the presymptomatic stage, which makes the results less likely to apply to people with ALS, who begin treatment well after their symptoms begin. Positive results in small phase II studies in humans could also be misleading and lead to failure in phase III trials. Other potential issues included the drug not reaching its intended site of action in the central nervous system and drug interactions between the study drug and riluzole.Repetitive transcranial magnetic stimulation had been studied in ALS in small and poorly designed clinical trials; as of 2013, evidence was insufficient to know whether rTMS is safe or effective for ALS. One 2016 review of stem-cell therapy trials found tentative evidence that intraspinal stem cell implantation was relatively safe and possibly effective. A 2019 Cochrane review of cell-based therapies found that there was insufficient evidence to speculate about efficacy. Masitinib has been approved as an orphan drug in Europe and the United States, with studies ongoing as of 2016. Beta-adrenergic agonist drugs have been proposed as a treatment for their effects on muscle growth and neuroprotection, but research in humans is insufficient to determine their efficacy.
Cause
With the discovery that TDP-43, FUS, and C9orf72 can cause ALS as well as related forms of frontotemporal dementia (FTD/ALS) there has been intense effort to understand how these mutations cause disease, and whether other protein dysfunction may be important. As of 2013, it appeared that differences in the methylation of arginine residues in FUS protein may be relevant, and methylation status may be a way to distinguish some forms of FTD from ALS.
See also
Transportin 1
Notes
References
External links
ALS Association Official Website
Amyotrophic lateral sclerosis at Curlie |
You are a medical lexicon. Explain medical terminology with depth and clarity, making sure the information is both accurate and easy to grasp. | I've encountered the term 'Peri-implant mucositis' while reading about medical topics. What does it refer to exactly? | Peri-implant mucositis is defined as an inflammatory lesion of the peri-implant mucosa in the absence of continuing marginal bone loss.The American Academy of Periodontology defines peri‐implant mucositis as a disease in which inflammation of the soft tissues surrounding a dental implant is present without additional bone loss after the initial bone remodeling that may occur during healing following the surgical placement of the implant.Peri-implant mucositis is largely accepted as the precursor of peri-implantitis and corresponds to gingivitis around natural teeth.Important criteria to defining peri-implant mucositis are, the inflammation of mucosa surrounding an endosseous implant and the absence of continuing marginal peri-implant bone loss.
Aetiology
A shift in bacterial biofilm composition, from uninterrupted plaque maturation, and the immune system disintegration causes peri-implant mucosa inflammation to occur.
In peri-implant mucositis, there is an increase in proportion of bacteria from the orange complex: F. nucleatum, P. intermedia and Eubacterium species. A decrease in proportion of Streptococci and Actinomoyces species is also observed.Accumulation of bacteria around osseointegrated dental implants has been proven to be a cause of peri-implant mucositis by demonstrating this under experimental conditions and the development of an inflammatory response due to this has also been shown experimentally. When the surfaces of the implant in the mouth are colonised by pathogenic bacteria, plaque-induced inflammation can go on to cause destruction of the tissues around the implant. The presence of an inflammatory cell infiltrate in the connective tissue lateral to the junctional epithelium has been discovered in this condition, contributing to its development. The bacterial biofilm disrupts the host-microbe homeostasis, creating a dysbiosis which results in an inflammatory lesion. The inflammatory cell infiltrate has been found to increase in size as the peri-implant mucositis develops.Where peri-implant mucositis has been brought about by the accumulation of bacteria and their formation of a biofilm, it has been shown to be eventually reversible once the biofilm has been brought under control by regular cleaning by both patient and dental professional. This has been shown as studies display a clear reduction in redness, swelling and bleeding on probing in lesions of the peri-implant soft tissue after bacterial load has been minimised. This was shown in an experiment where bacteria were encouraged to accumulate for a period of time in which no oral hygiene was undertaken, allowing all of the patients to develop peri-implant mucositis. When oral hygiene was regularly commenced once again, all of the periodontal tissues eventually became healthy once more. However, the best management of peri-implant mucositis is not reversing it but preventing this from occurring in the first instance.The presence of excess luting cement has been demonstrated to contribute to causing peri-implant mucositis. One study gleaned results that suggested that in both patients with and without a history of periodontal problems, implants with extracoronal residual cement developed statistically significantly more cases of peri-implant mucositis as well as other periodontal problems. In this study 85% of implants in patients with previous periodontal conditions went on to develop peri-implant mucositis, which then progressed to peri-implantitis. In the group with no previous history of periodontal issues, 65% of implants still developed peri-implant mucositis, but significantly fewer of these implants then developed peri-implantitis. In contrast, the group with no extracoronal residual cement only had 30% of implants develop peri-implant mucositis. Therefore, cement remnants may be more likely to cause patients to develop peri-implant mucositis.Other causal factors of peri-implant mucositis include radiation and smoking, in addition to accretion of oral bacteria at the site. Other factors that are thought to contribute to the condition include lack of keratinised mucosa and diabetes mellitus, particularly poorly-controlled diabetes which will mean the patient will have a high level of blood glucose over longer periods. Understanding and controlling peri-implant mucositis is essential as it often leads to peri-implantitis.
Signs and Symptoms
Clinical signs and symptoms of peri-implant mucositis involves the localised surrounding gingival tissues (gum tissue) of a dental implant. These include:-
Bleeding on probing with no supporting bone loss.
Localised swelling
Redness/erythema.
Increased shininess of soft tissue surface.
Soreness
Risk Factors
Risk Factors of PIM are categorised into General and Local Risk Factors
General Risk Factors
Smoking
Radiation Therapy
Poorly controlled Diabetes Mellitus (HbA1c >10.1)Local Risk Factors
Oral Hygiene
Poor compliance / access to regular supportive implant therapy
Design of Implant-supported prostheses affecting accessibility for plaque removal
Sub-mucosal restorations
Dimension of Keratinized Peri-implant mucosa
Excess CementPossible Risk Factors:
Some other possible risk factors may include the location the implant is placed, type of implant placed and the age of the subject, as it was found that these factors had significant influences on bleeding on probing (BOP).Although it is uncertain whether increased abutment roughness will cause an increase in plaque accumulation and hence increase the risk of peri-implant mucositis, a 12-month comparative analysis in humans found that “a further reduction of the surface roughness, below a certain "threshold R(a)" (0.2 microns), has no major impact on the supra‐ and subgingival microbial composition.”Implants and abutments made of zirconium dioxide (ZrO2) were claimed to be more bio-compatible compared to those made of titanium but clinical studies show that there were slightly higher BOP scores or no significant difference in BOP scores around ZrO2 compared to titanium abutments.
Diagnosis
In order to diagnose peri-implant mucositis, it is essential to investigate probing parameters and complete a radiographic assessment. Correct diagnosis of peri-implant diseases is essential to allow appropriate management of the condition present. Failure to identify a peri-implant disease can lead to a complete loss of osseointegration and eventual loss of the implant.Though there are clear structural differences between dental implants and natural teeth, peri-implant health shares many common features with periodontal health around natural teeth. This is especially true with respect to their surrounding tissues and biological attachment.The diagnosis of peri-implant mucositis should be based on clinical signs of inflammatory disease, and radiographic assessment should be carried out to exclude bone level changes as this is an indication that peri-implant disease has already progressed to peri-implantitis stage.
Clinical presentations to diagnose peri-implant mucositis include:-- Red, swollen and soft peri-implant tissues
- Bleeding on probing (BoP) and/or suppuration on probing
- Increased probing depths compared to baseline measurements
- Absence of bone loss beyond crestal bone level changes as a result of initial remodelling following implant placement
It has been suggested that the soft tissue cuff surrounding implants are less resistant to probing than the gingiva at adjacent teeth sites. This potentially leads to mechanically induced BoP on dental implants that are clinically healthy, as a result of trauma-induced BoP rather than a sign of biofilm-induced inflammation which represent the presence of peri-implant disease. Increased levels of bleeding on probing was present at 67% of sites where there is peri-implant mucositis as it is indicative of the presence of active disease and inflammation of the peri-implant mucosa. A light probing force of 0.25N should be used to probe the gingival margins so as not to damage the soft periodontal tissues. Bleeding on probing can be used in order to predict future loss of support from surrounding tissues. Microbiological testing was shown to improve the prognostic features compared to recording bleeding on probing alone as this was better for recognising the disease advancement around implants.
Increased probing depths over time is linked to loss of attachment and a reduction in the supporting alveolar bone levels. When bone becomes involved, the disease has progressed to peri-implantitis and this site is no longer diagnosed with peri-implant mucositis. The presence of bleeding on probing, the probing depths measured to the base of any pocketing and suppuration should all be assessed regularly in order to correctly diagnose peri-implant mucositis. Mucosal recession, a draining sinus or fistula and swelling or hyperplasia of the gingivae surrounding the implant can all signify the presence of peri-implant disease and should all prompt further investigations to ascertain whether this is the case.Radiographs are required to distinguish between peri-implant mucositis and peri-implantitis as the supporting alveolar bone levels must be evaluated in order to decide on a diagnosis. Dental Panoramic Tomography or a variety of intra-oral radiographs can be used to monitor marginal bone levels and evaluate interproximal bone loss in particular, but most agree peri-apical radiographs show bone loss more comprehensively. Current radiographs can be compared to previous radiographs and the distance from a fixed point, such as the implant shoulder, used to measure the bone loss in mm over time. If an implant is mobile, this is indicative of a deficiency in osseointegration and at this point the implant should be removed. Therefore, this is not a valuable factor for early diagnosis of peri-implant mucositis.
Alveolar bone loss following implant placement after first year in function should not exceed 2mm as generally between 0.5 – 2 mm of crestal bone height is lost during remodelling/healing process. As such changes ≥ 2mm during or after the first year should be considered as pathologic. Ie Peri-implant disease-induced.
There are currently no biochemical diagnostic tests clinically available, as no sensitive diagnostic test has yet been found that can detect reversible changes before this is clinically visible and detectable. There are many salivary biomarkers and biomarkers in the crevicular fluid surrounding implants that are present in much higher levels when there is peri-implant mucositis or peri-implant disease but all these present after or at the same time as clinical signs and symptoms. Therefore, there is currently no benefit to assessing the peri-implant fluid or analysing the saliva. Research continues in this field, though there is also no biochemical diagnostic test clinically available to detect the progression of gingivitis or periodontitis as of yet.
Prevention and Maintenance
The best management of peri-implant mucositis is preventing it from occurring through maintenance of the implants. This involves regular cleaning from both the patient and a dental professional and antibacterial mouthwashes may help reduce plaque and bleeding around dental implants.
Self-care
Various mechanical ways of removing bacteria from around implants are available to be used by patients in their own homes, including but not limited to nylon-coated interdental brushes, soft-bristled toothbrushes and hard plastic cleaning instruments. These are all designed to prevent damage of the implant abutment, which would roughen the surface and lead to the accumulation of more bacteria on the surface which would contribute to the formation of more biofilms in the area.
However, it was found that there were no statistically significant differences between some types of self administered antimicrobials, as they were all equally successful at maintaining the health of the soft tissues. One study was done comparing hyaluronic acid gel and chlorhexidine gel and another compared amine fluoride/stannous fluoride mouthwash to chlorhexidine mouthwash, but neither study showed either antimicrobial to be more effective at preventing peri-implant mucositis.It was found that there was no statistically significant difference between the effectiveness of using a powered/sonic toothbrush and using a manual toothbrush, although participants reported that they preferred the sonic toothbrush as they felt that it was better at keeping the areas around the implants clean.
Dental Professional
In terms of professionally administered treatment done by a dentist, there was no evidence to suggest that phosphoric acid etching gel is any more clinically advantageous than scaling or mechanical debridement and polishing or that enclosing chlorhexidine in the inner part of an implant is in any way superior to a physiological solution.It was also shown that a topical antibiotic inserted submucosally is no more successful at preventing peri-implant mucositis than a chlorhexidine gel.Debridement with manual curettes, followed by air polishing with glycine powder, and a prophylaxis brush, showed significant differences in BOP and peri-implant pocket depths. The use of manual curettes, sonic-driven scaler, and prophylaxis brush were found to be effective in maintaining the tissues around an implant, preventing inflammation. Applying chlorhexidine varnish in addition to debridement on implant surfaces had no significant additional benefit.
Treatment
When prevention of peri-implant mucositis fails, there are several options available to treat it.
A similar study was conducted to assess if there was a difference between using sonic/powered toothbrushes and using manual toothbrushes in the treatment of peri-implant mucositis and it was found that there is no statistically significant difference between the two in terms of intervention either.Irrigants were also tested as part of a set of interventions administered by dental professionals but it was found that there was no statistically significant difference between chlorhexidine and physiologic solutions when used as irrigants at second state surgery to maintain health of soft tissues.Reduced mean plaque scores and reduced marginal bleeding scores were achieved more effectively from chlorhexidine irrigation than from the use of chlorhexidine mouthwash. Listerine mouthwash was found to be statistically significantly better than a placebo at attaining reduced mean plaque scores and reduced marginal bleeding scores. When Listerine mouthwash was used twice daily for 30 seconds in addition to routine oral hygiene, it was shown that a reduction of 54% in mean plaque and 34% in marginal bleeding compared to a placebo. Chlorhexidine irrigations reduced mean plaque by 20% and marginal bleeding by 35% in comparison to a chlorhexidine mouthwash. Chlorhexidine is the most effective antiplaque agent used in the mouth to date. Reducing the mean plaque scores and the marginal bleeding scores contributes to both the prevention and the treatment of peri-implant mucositis. Initially, the use of mouthwashes was only proposed for patients with physical disabilities which would result in decreased manual dexterity and hence make active cleaning difficult. However, it is now thought that this will lead to less peri-implant mucositis being caused in all implant patients. Despite this, there have been concerns about the link between mouthwashes containing alcohol and the incidence of oral cancer.Some studies looked solely at interventions which contribute to the reversal of peri-implant mucositis. One such study found no statistically significant difference between triclosan dentrifice in comparison to sodium fluoride dentrifice at recovering soft tissue health. There were also two trials conducted where patients with peri-implant mucositis were assessed after different interventions carried out by dental professionals. In these trials mechanical debridement being followed by minocycline or chlorhexidine gel had no statistically significant difference, nor did debridement with titanium curettes compared to an ultrasonic debridement tool.
Nouveau interventions
A double‐blind randomized controlled trial assessing the effect of subgingival ozone (O3, gaseous ozone, HealOzone MK II, KaVo) and/or hydrogen peroxide on the development of peri‐implant mucositis, found that ozone showed significant potential for management of peri-implant mucositis compared to oxygen and saline.Mechanical curettage with adjunct antimicrobial photodynamic therapy is more effective in reducing peri-implant inflammation in smokeless tobacco product users as compared to mechanical curettage alone in the short term (3 months). Further long-term studies will be needed to confirm long term efficacy.Current research found no evidence for use of systemic antibiotics in the treatment of peri-implant mucositis
Further Discussion
There is low quality evidence to suggest the most effective treatments for peri-implant mucositis, with no reliable evidence for which are more beneficial in the long term. All trials so far have had generally short follow-up periods and limited numbers of subjects. It is expected we will learn more about peri-implant mucositis as the number of patients opting to have implants continues to rise.
There is little evidence for the most effective interventions for maintaining health and reversing the effects of peri-implant mucositis on the soft periodontal tissues.
More RCTs should be conducted on implants and their potential failure and the inflammation of the periodontal tissues that can be caused by them, especially long term studies. Such trials will likely be difficult and expensive to carry out but there is definitely a need for them in order to find a definitive answer on how implants should be maintained and treated.
Research is being continued into the investigations of peri-implant crevicular fluid and saliva in an attempt to find biomarkers that are diagnostic and will be indicative of peri-implant mucositis before the disease has started and other clinical signs and symptoms are visible.
There are concerns with metal and ultrasonic instrumentation roughening implant surface and causing increased plaque retention. Studies in vitro have found that special coated scalers and ultrasonic tips (e.g. newly developed metallic tip and plastic hand curettes) were compatible with implant surfaces and caused minimal damage. However, this is yet to be confirmed in vivo. It was also found that plastic-coated scalers left plastic deposits on implant surfaces, hence more research is needed for evaluating their use in debriding implant.
Studies on patient perception on comfort regarding hand scaling compared to ultrasonic scaling will be helpful in order to increase patient compliance, especially in the event that hand and ultrasonic instrumentation were found to be equally effective.
== References == |
You function as a medical informant. Please provide in-depth yet accessible descriptions of medical terms, suitable for a broad audience. | I'm not familiar with the medical term 'Caroli disease.' Could you provide some insights? | Caroli disease (communicating cavernous ectasia, or congenital cystic dilatation of the intrahepatic biliary tree) is a rare inherited disorder characterized by cystic dilatation (or ectasia) of the bile ducts within the liver. There are two patterns of Caroli disease: focal or simple Caroli disease consists of abnormally widened bile ducts affecting an isolated portion of liver. The second form is more diffuse, and when associated with portal hypertension and congenital hepatic fibrosis, is often referred to as "Caroli syndrome". The underlying differences between the two types are not well understood. Caroli disease is also associated with liver failure and polycystic kidney disease. The disease affects about one in 1,000,000 people, with more reported cases of Caroli syndrome than of Caroli disease.Caroli disease is distinct from other diseases that cause ductal dilatation caused by obstruction, in that it is not one of the many choledochal cyst derivatives.
Signs and symptoms
The first symptoms typically include fever, intermittent abdominal pain, and an enlarged liver. Occasionally, yellow discoloration of the skin occurs. Caroli disease usually occurs in the presence of other diseases, such as autosomal recessive polycystic kidney disease, cholangitis, gallstones, biliary abscess, sepsis, liver cirrhosis, kidney failure, and cholangiocarcinoma (7% affected). People with Caroli disease are 100 times more at risk for cholangiocarcinoma than the general population. After recognizing symptoms of related diseases, Caroli disease can be diagnosed.Morbidity is common and is caused by complications of cholangitis, sepsis, choledocholithiasis, and cholangiocarcinoma. These morbid conditions often prompt the diagnosis. Portal hypertension may be present, resulting in other conditions including enlarged spleen, hematemesis, and melena. These problems can severely affect the patients quality of life. In a 10-year period between 1995 and 2005, only 10 patients were surgically treated for Caroli disease, with an average patient age of 45.8 years.After reviewing 46 cases of Caroli disease before 1990, 21.7% of the cases were the result of an intrahepatic cyst or nonobstructive biliary tree dilation, 34.7% were linked with congenital hepatic fibrosis, 13% were isolated choledochal cystic dilation, and the remaining 24.6% had a combination of all three.
Causes
The cause appears to be genetic; the simple form is an autosomal dominant trait, while the complex form is an autosomal recessive trait. Females are more prone to Caroli disease than males. Family history may include kidney and liver disease due to the link between Caroli disease and ARPKD. PKHD1, the gene linked to ARPKD, has been found mutated in patients with Caroli syndrome. PKHD1 is expressed primarily in the kidneys with lower levels in the liver, pancreas, and lungs, a pattern consistent with phenotype of the disease, which primarily affects the liver and kidneys. The genetic basis for the difference between Caroli disease and Caroli syndrome has not been defined.
Diagnosis
Modern imaging techniques allow the diagnosis to be made more easily and without invasive imaging of the biliary tree. Commonly, the disease is limited to the left lobe of the liver. Images taken by CT scan, X-ray, or MRI show enlarged intrahepatic (in the liver) bile ducts due to ectasia. Using an ultrasound, tubular dilation of the bile ducts can be seen. On a CT scan, Caroli disease can be observed by noting the many fluid-filled, tubular structures extending to the liver. A high-contrast CT must be used to distinguish the difference between stones and widened ducts. Bowel gas and digestive habits make it difficult to obtain a clear sonogram, so a CT scan is a good substitution. When the intrahepatic bile duct wall has protrusions, it is clearly seen as central dots or a linear streak. Caroli disease is commonly diagnosed after this “central dot sign” is detected on a CT scan or ultrasound. However, cholangiography is the best, and final, approach to show the enlarged bile ducts as a result of Caroli disease.
Treatment
The treatment depends on clinical features and the location of the biliary abnormality. When the disease is localized to one hepatic lobe, hepatectomy relieves symptoms and appears to remove the risk of malignancy. Good evidence suggests that malignancy complicates Caroli disease in roughly 7% of cases.Antibiotics are used to treat the inflammation of the bile duct, and ursodeoxycholic acid is used for hepatolithiasis. Ursodiol is given to treat cholelithiasis. In diffuse cases of Caroli disease, treatment options include conservative or endoscopic therapy, internal biliary bypass procedures, and liver transplantation in carefully selected cases. Surgical resection has been used successfully in patients with monolobar disease. An orthotopic liver transplant is another option, used only when antibiotics have no effect, in combination with recurring cholangitis. With a liver transplant, cholangiocarcinoma is usually avoided in the long run.Family studies are necessary to determine if Caroli disease is due to inheritable causes. Regular follow-ups, including ultrasounds and liver biopsies, are performed.
Prognosis
Mortality is indirect and caused by complications. After cholangitis occurs, patients typically die within 5–10 years.
Epidemiology
Caroli disease is typically found in Asia, and diagnosed in persons under the age of 22. Cases have also been found in infants and adults. As medical imaging technology improves, diagnostic age decreases.
History
Jacques Caroli, a gastroenterologist, first described a rare congenital condition in 1958 in Paris, France.
He described it as "nonobstructive saccular or fusiform multifocal segmental dilatation of the intrahepatic bile ducts"; basically, he observed cavernous ectasia in the biliary tree causing a chronic, often life-threatening hepatobiliary disease.
Caroli, born in France in 1902, learned and practiced medicine in Angers. After World War II, he was chief of service for 30 years at Saint-Antoine in Paris. Before dying in 1979, he was honored with the rank of commander in the Legion of Honour in 1976.
References
== External links == |
You serve as a medical tutor. Your objective is to demystify medical terms, providing thorough explanations that cater to various levels of medical knowledge. | Please help me grasp the concept behind the medical term 'Spinal 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, 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.
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.
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. Its 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 effects the spinal nerves in the region of the lower back called the cauda equine (Latin for "horses tail"). Injury to the cauda equine 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.
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 Neuroflibromatosis 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 == |
You are an expert in medical terminology. Explain medical terms in a way that is both precise and easy to understand for non-medical audiences. | I've encountered the term 'Alpha-1 antitrypsin' while reading about medical topics. What does it refer to exactly? | Alpha-1 antitrypsin or α1-antitrypsin (A1AT, α1AT, A1A, or AAT) is a protein belonging to the serpin superfamily. It is encoded in humans by the SERPINA1 gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor (A1PI) or alpha1-antiproteinase (A1AP) because it inhibits various proteases (not just trypsin). In older biomedical literature it was sometimes called serum trypsin inhibitor (STI, dated terminology), because its capability as a trypsin inhibitor was a salient feature of its early study. As a type of enzyme inhibitor, it protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and has a reference range in blood of 0.9–2.3 g/L (in the US the reference range is expressed as mg/dL or micromoles), but the concentration can rise manyfold upon acute inflammation.When the blood contains inadequate amounts of A1AT or functionally defective A1AT (such as in alpha-1 antitrypsin deficiency), neutrophil elastase is excessively free to break down elastin, degrading the elasticity of the lungs, which results in respiratory complications, such as chronic obstructive pulmonary disease, in adults. Normally, A1AT leaves its site of origin, the liver, and joins the systemic circulation; defective A1AT can fail to do so, building up in the liver, which results in cirrhosis in either adults or children.
In addition to binding to neutrophil elastase released by inflammatory cells, A1AT also binds to elastase localized on the cell surface in which case elastase does not act as an enzyme, but instead acts to signal cells to undergo locomotion. Besides liver cells, A1PI is produced in bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut.Inactivation of A1AT by enzymes other than elastase due to inflammation/infection causes the migration of T cells to halt precisely at the site where the pathologic insult exists. This suggests a role for α1PI not only in locomotion of lymphocytes through tissue, but as a consequence of infection, a primary role as a sentinel in immune vigilance.A1AT is both an endogenous protease inhibitor and an exogenous one used as medication. The pharmaceutical form is purified from human donor blood and is sold under the nonproprietary name alpha1–proteinase inhibitor (human) and under various trade names (including Aralast NP, Glassia, Prolastin, Prolastin-C, and Zemaira). Recombinant versions are also available but are currently used in medical research more than as medication.
Function
A1AT is a 52-kDa serpin and, in medicine, it is considered the most prominent serpin; the terms α1-antitrypsin and protease inhibitor (Pi) are often used interchangeably.
Most serpins inactivate enzymes by binding to them covalently. These enzymes are released locally in relatively low concentrations where they are immediately cleared by proteins such as A1AT. In the acute phase reaction, a further elevation is required to "limit" the damage caused by activated neutrophil granulocytes and their enzyme elastase, which breaks down the connective tissue fiber elastin.
Besides limiting elastase activity to limit tissue degradation, A1PI also acts to induce locomotion of lymphocytes through tissue including immature T cells through the thymus where immature T cells mature to become immunocompetent T cells that are released into tissue to elevate immune responsiveness.Like all serine protease inhibitors, A1AT has a characteristic secondary structure of beta sheets and alpha helices. Mutations in these areas can lead to non-functional proteins that can polymerise and accumulate in the liver (infantile hepatic cirrhosis).
Role in disease
Disorders of this protein include alpha-1 antitrypsin deficiency, an autosomal co-dominant hereditary disorder in which a deficiency of alpha-1 antitrypsin leads to a chronic uninhibited tissue breakdown. This causes the degradation especially of lung tissue and eventually leads to characteristic manifestations of pulmonary emphysema. Evidence has shown that cigarette smoke can result in oxidation of methionine 358 of α1-antitrypsin (382 in the pre-processed form containing the 24 amino acid signal peptide), a residue essential for binding elastase; this is thought to be one of the primary mechanisms by which cigarette smoking (or second-hand smoke) can lead to emphysema. Because A1AT is expressed in the liver, certain mutations in the gene encoding the protein can cause misfolding and impaired secretion, which can lead to liver cirrhosis.
An extremely rare form of Pi, termed PiPittsburgh, functions as an antithrombin (a related serpin), due to a mutation (Met358Arg). One person with this mutation has been reported to have died of a bleeding diathesis.A liver biopsy will show abundant PAS-positive globules within periportal hepatocytes.
Patients with rheumatoid arthritis (RA) have been found to make autoantibodies toward the carbamylated form of A1AT in the synovial fluid. This suggests that A1AT may play an anti-inflammatory or tissue-protecting role outside the lungs. These antibodies are associated with a more severe disease course, can be observed years before disease onset, and may predict the development of RA in arthralgia patients. Consequently, carbamylated A1AT is currently being developed as an antigenic biomarker for RA.
Nomenclature
The protein was initially named "antitrypsin" because of its ability to bind and irreversibly inactivate the enzyme trypsin in vitro covalently. Trypsin, a type of peptidase, is a digestive enzyme active in the duodenum and elsewhere.
The term alpha-1 refers to the proteins behavior on protein electrophoresis. On electrophoresis, the protein component of the blood is separated by electric current. There are several clusters, the first being albumin, the second being the alpha, the third beta and the fourth gamma (immunoglobulins). The non-albumin proteins are referred to as globulins.
The alpha region can be further divided into two sub-regions, termed "1" and "2". Alpha-1 antitrypsin is the main protein of the alpha-globulin 1 region.
Another name used is alpha-1 proteinase inhibitor (α1-PI).
Genetics
The gene is located on the long arm of chromosome 14 (14q32.1).
Over 100 different variants of α1-antitrypsin have been described in various populations. North-Western Europeans are most at risk for carrying one of the most common mutant forms of A1AT, the Z mutation (Glu342Lys on M1A, rs28929474).
Biochemical properties
A1AT is a single-chain glycoprotein consisting of 394 amino acids in the mature form and exhibits many glycoforms. The three N-linked glycosylations sites are mainly equipped with so-called diantennary N-glycans. However, one particular site shows a considerable amount of heterogeneity since tri- and even tetraantennary N-glycans can be attached to the Asparagine 107 (UniProtKB amino acid nomenclature). These glycans carry different amounts of negatively charged sialic acids; this causes the heterogeneity observed on normal A1AT when analysed by isoelectric focusing. Also, the fucosylated triantennary N-glycans were shown to have the fucose as part of a so-called Sialyl Lewis x epitope, which could confer this protein particular protein-cell recognition properties. The single cysteine residue of A1AT in position 256 (UniProtKB nomenclature) is found to be covalently linked to a free single cysteine by a disulfide bridge.
Analysis
The level of A1AT in serum is most often determined by adding an antibody that binds to A1AT, then using turbidimetry to measure how much A1AT is present. Other detection methods include the use of enzyme-linked-immuno-sorbent-assays and radial immunodiffusion.
Different analytical methods are used to determine A1AT phenotype. As protein electrophoresis is imprecise, the A1AT phenotype is analysed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point or charge in a pH gradient.
Normal A1AT is termed M, as it migrates toward the center of such an IEF gel. Other variants are less functional and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha-1 antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above.
As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although heterozygote with one null mutant that abolishes expression of the gene will only show one band.
In blood test results, the IEF results are notated as in PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that patient.
Alpha-1 antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome, whereas others have a tendency to polymerise, being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:
PiMM: 100% (normal)
PiMS: 80% of normal serum level of A1AT
PiSS: 60% of normal serum level of A1AT
PiMZ: 60% of normal serum level of A1AT
PiSZ: 40% of normal serum level of A1AT
PiZZ: 10-15% (severe alpha-1 antitrypsin deficiency)
PiZ is caused by a glutamate to lysine mutation at position 342 (366 in pre-processed form)
PiS is caused by a glutamate to valine mutation at position 264 (288 in pre-processed form)Other rarer forms have been described; in all, there are over 80 variants.
Medical uses
Alpha-1 antitrypsin concentrates are prepared from the blood plasma of blood donors. The US Food and Drug Administration (FDA) has approved the use of four alpha-1 antitrypsin products derived from a human plasma: Prolastin, Zemaira, Glassia, and Aralast. These products for intravenous augmentation A1AT therapy can cost up to $100,000 per year per patient. They are administered intravenously at a dose of 60 mg/kg once a week; higher doses do not provided additional benefit although they can be used in anticipation of an interruption of weekly administration, such as for a vacation.Alpha1-proteinase inhibitor (Respreeza) was approved for medical use in the European Union in August 2015. It is indicated for maintenance treatment, to slow the progression of emphysema in adults with documented severe alpha1-proteinase inhibitor deficiency (e.g., genotypes PiZZ, PiZ (null), Pi (null, null), PiSZ). People are to be under optimal pharmacologic and non-pharmacologic treatment and show evidence of progressive lung disease (e.g. lower forced expiratory volume per second (FEV1) predicted, impaired walking capacity or increased number of exacerbations) as evaluated by a healthcare professional experienced in the treatment of alpha1-proteinase inhibitor deficiency.The most common side effects include dizziness, headache, dyspnoea (shortness of breath) and nausea. Allergic reactions have been observed during treatment, some of which were severe.Aerosolized-augmented A1AT therapy is under study. This involves inhaling purified human A1AT into the lungs and trapping the A1AT into the lower respiratory tract. However, inhaled A1AT may not reach the elastin fibers in the lung where elastase injury occurs. Further study is currently underway. Recombinant alpha-1 antitrypsin is not yet available for use as a medication but is under development.
History
Axelsson and Laurell first investigated the possibility of allelic variants of A1AT leading to disease in 1965.
See also
Alpha 1-antichymotrypsin, another serpin that is analogous for protecting the body from excessive effects of its own inflammatory proteases
References
Further reading
External links
"Alpha 1-Antitrypsin". Drug Information Portal. U.S. National Library of Medicine.
The MEROPS online database for peptidases and their inhibitors: I04.001
Proteopedia: Alpha-1-antitrypsin
Human SERPINA1 genome location and SERPINA1 gene details page in the UCSC Genome Browser. |
You are a resource for medical understanding. Offer detailed explanations of medical terms, making complex concepts clear and comprehensible. | The term 'Thermal burn' keeps coming up in medical discussions. What does it stand for? | A thermal burn is a type of burn resulting from making contact with heated objects, such as boiling water, steam, hot cooking oil, fire, and hot objects. Scalds are the most common type of thermal burn suffered by children, but for adults thermal burns are most commonly caused by fire. Burns are generally classified from first degree up to fourth degree, but the American Burn Association (ABA) has categorized thermal burns as minor, moderate, and major, based almost solely on the depth and size of the burn.
Causes
Hot liquids and steam
Scalding is a type of thermal burn caused by boiling water and steam, commonly suffered by children. Scalds are commonly caused by accidental spilling of hot liquids, having water temperature too high for baths and showers, steam from boiling water or heated food, or getting splattered by hot cooking oil. Scalding is usually a first- or second-degree burn, and third-degree burn can sometimes result from prolonged contact. Nearly three quarters of all burn injuries suffered by young children are scalds.
Fire
Fire causes about 50% of all cases of thermal burns in the United States. The most frequent event where people get burned by fire is during house fires encountered by firefighters and trapped occupants, where 85% of all fire deaths take place. Fireworks are another notable cause of fire burns, especially among adolescent males on holidays such as Independence Day in the US. The most common cause of injury by fire or flame in children is touching candle flame. In some regions, such as the western United States, wildfires are responsible for an increase in burn injuries. Wildfires can suddenly shift due to changing wind directions, making it harder for firefighters and eyewitnesses to avoid getting burned.
If clothing catches fire, third-degree burn can develop in a matter of just a few seconds.
Hot objects
Solid objects that are hot can also cause contact burns, especially in children, who may intentionally touch things they dont know are too hot to touch. Such burns imprinted on the skin usually form a pattern that resembles the object. Sources of burns from solid objects include ashes and coal, irons, soldering equipment, frying pans and pots, oven containers, light bulbs, and exhaust pipes.
Pathophysiology
There are three (or sometimes four) degrees of burns, in ascending order of severity and depth. For more information, see Signs and symptoms.
According to Jacksons thermal wound theory, there are three zones of major burn injury.
Zone of coagulation is the area that sustained maximum damage from the heat source. Proteins become denaturated, and cell death is imminent due to destruction of blood vessels, resulting in ischemia to the area. Injury at this area is irreversible (coagulative necrosis & gangrene)
Zone of stasis surrounds the coagulation area, where tissue is potentially salvageable. This is the main area of focus when treating burn injuries.
Zone of hyperemia is the area surrounding the zone of stasis. Perfusion is adequate due to patent blood vessels, and erythema occurs due to increased vascular permeability.
Prevention
It is important to teach children how to avoid fire and scalding. Firefighters and community leaders often lead such programs in schools and clinics.Smoke alarms installed in homes can reduce deaths resulting from fire by half. Homeowners should change batteries at least once a year and replace smoke alarms every decade. Before fire occurs, a family should practice evacuating the home, and when fire occurs the family must leave the residence immediately (within two minutes). Sources of flame, like matches, should be kept out of childrens reach. Stoves, ovens, space-heaters, and candles must not be left unattended, and flammable objects must be kept at least 30 cm away from open flames. Fire extinguishers should be stored in the kitchen, where most house fires start.To prevent children from getting burned, water temperature must not be set too high when taking baths or washing hands, nonflammable sleepwear should be worn, back burners should be used when cooking something on the stove, and hot foods, drinks, and irons should be kept away from the edge of counter and table. Oven mitts and potholders must be used in handling hot containers. Care should be taken when taking hot foods out of microwave ovens, and covers should be opened gently to reduce the risk of steam burns.
Treatment
The most important first action is to stop the burning process. The source of the burn should promptly be removed (or the patient removed from the source). If the person is on fire, he/she must be told to stop, drop and roll, or extinguish the fire by covering them with heavy blanket, wool, coat, or rug. Burning clothing should be removed as should all jewelry that could act as a tourniquet as swelling occurs, but burned clothing stuck to the skin must not be removed. Cooling the burn with cold running water has been shown to be beneficial if accomplished within 30 minutes of the injury. The pain or inflammation can then be effectively treated using acetaminophen (paracetamol), or ibuprofen. Ice, butter, cream and ointment cannot be used since they can worsen the burn.Severe burn patients are often treated through trauma resuscitation, airway management, fluid resuscitation, blood transfusion, wound management, and skin grafting, as well as the use of antibiotics.
Outcome
95% of people hospitalized for thermal burns survive. Survival rates have increased steadily over the last half century due to advances in treatment and better burn centers. Patients with uncomplicated burns have a 99.7% survival rate. Three risk factors—patient age above 60, burns covering more than 40% of the body, and inhalation injury—greatly reduce the odds of survival, which decline to 97% with any one of these complications, to 67% with any two, and to only 10% in cases with all three.
Epidemiology
In the United States, over two million people required medical attention for thermal burns every year. About 1 in 30 of those victims (75,000) are hospitalized for thermal burns every year, with a third of those patients staying in the hospital for more than two months. About 14,000 Americans die each year from burns.
Children
Thermal burns are one of the most common early childhood injuries. In the United States, burns are the third most common cause of accidental death among children. Nearly 96,000 children around the world died as a result of thermal burns in 2004, and 61,400 died in 2008 from thermal injuries. Deaths from burns dropped by 55% from 1999 to 2011. Burns are the only mode of unintentional injury which more girls suffer from than boys worldwide, including by fire.
References
External links
Burns at MedlinePlus |
You are a medical advisor. Your role is to break down medical terminology into clear, detailed explanations for a general audience. | What does the medical term 'Esketamine' encompass? | Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the S(+) enantiomer of ketamine, is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand names Spravato (for depression), Ketanest (for anesthesia), among others. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.It is specifically used as a therapy for treatment-resistant depression (TRD) and for major depressive disorder (MDD) with co-occurring suicidal ideation or behavior. Its effectiveness for depression is modest and similar to that of other antidepressants. Esketamine is used by infusion into a vein for anesthesia and under direct medical supervision as a nasal spray once or twice weekly for depression.Adverse effects of esketamine include dissociation, dizziness, sedation, nausea, vomiting, vertigo, numbness, anxiety, lethargy, increased blood pressure, and feelings of drunkenness. Less often, esketamine can cause bladder problems. Esketamine acts primarily as a N-methyl-D-aspartate (NMDA) receptor antagonist but also has other actions.In the form of racemic ketamine, esketamine was first synthesized in 1962 and introduced for medical use as an anesthetic in 1970. Enantiopure esketamine was introduced for medical use as an anesthetic in 1997 and as an antidepressant in 2019. It is used as an anesthetic in the European Union and as an antidepressant in the United States and Canada. Due to misuse liability as a dissociative hallucinogen, esketamine is a controlled substance.
Medical uses
Anesthesia
Esketamine is a general anesthetic and is used for similar indications as ketamine. Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shock, anaphylactic shock, septic shock, severe bronchospasm, severe hepatic insufficiency, cardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks.
Depression
Esketamine is approved under the brand name Spravato in the form of a nasal spray added to a conventional antidepressant as a therapy for treatment-resistant depression (TRD) as well as major depressive disorder (MDD) associated with suicidal ideation or behavior in adults in the United States. In the clinical trials that led to approval of esketamine, TRD was defined as MDD with inadequate response to at least two different conventional antidepressants. The nasal spray formulation of esketamine used for depression delivers two sprays containing a total of 28 mg esketamine and doses of 56 mg (2 devices) to 84 mg (3 devices) are used. The recommended dosage of Spravato is 56 mg on day 1, 56 or 84 mg twice per week during weeks 1 to 4, 56 or 84 mg once per week during weeks 5 to 8, and 56 or 84 mg every 2 weeks or once weekly during week 9 and thereafter. Dosing is individualized to the least frequent dosing necessary to maintain response or remission. Spravato is administered under the supervision of a healthcare provider and patients are monitored for at least 2 hours during each treatment session. Due to concerns about sedation, dissociation, and misuse, esketamine is available for treatment of depression only from certified providers through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Spravato REMS.Five clinical studies of esketamine for TRD (TRANSFORM-1, -2, and -3, and SUSTAIN-1 and -2) were submitted to and evaluated by the FDA when approval of esketamine for treatment of TRD was sought by Janssen Pharmaceuticals. Of these five studies, three were short-term (4-week) efficacy studies (the TRANSFORM studies). Two of these three studies (TRANSFORM-1 and -3) did not find a statistically significant antidepressant effect of esketamine relative to placebo. In the one positive short-term efficacy study (TRANSFORM-2), there was a 4.0-point difference between esketamine and placebo on the Montgomery–Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment (P = 0.020). This scale ranges from 0 to 60 and the average score of the participants at the start of the study was about 37.0 in both the esketamine and placebo groups. The total change in score after 4 weeks was –19.8 points in the esketamine group and –15.8 points in the placebo group. This corresponded to a percentage change in MADRS score from baseline of –53.5% with esketamine and –42.4% with placebo (a difference and reduction of depression score of –11.1% potentially attributable to the pharmacological action of esketamine) in these patient samples. Placebo showed 80.0% of the antidepressant effect of esketamine for TRD in this study and hence approximately 20.0% of the antidepressant response was attributable to esketamine. In the two negative short-term efficacy trials that did not reach statistical significance (TRANSFORM-1 and -3), the differences in MADRS reductions between esketamine and placebo were –3.2 (P = 0.088) and –3.6 (P = 0.059) after 4 weeks of treatment.
The 4.0-point additional reduction in MADRS score with esketamine over placebo in the single positive efficacy trial corresponds to less than "minimal improvement" and has been criticized as being below the threshold for clinically meaningful change. A difference of at least 6.5 points was originally suggested by the trial investigators to be a reasonable threshold for clinical significance. In other literature, MADRS reductions have been interpreted as "very much improved" corresponding to 27–28 points, "much improved" to 16–17 points, and "minimally improved" to 7–9 points. It has additionally been argued that the small advantage in scores with esketamine may have been related to an enhanced placebo response in the esketamine group due to functional unblinding caused by the psychoactive effects of esketamine. In other words, it is argued that the study was not truly a double-blind controlled trial. Dissociation was experienced as a side effect by a majority of participants who received esketamine (61–75% with esketamine and 5–12% with placebo; ~7-fold difference) and "severe" dissociation was experienced by 25%. Deblinding and expectancy confounds are problems with studies of hallucinogens for psychiatric indications in general. The FDA normally requires at least two positive short-term efficacy studies for approval of antidepressants, but this requirement was loosened for esketamine and a relapse-prevention trial was allowed to fill the place of the second efficacy trial instead. This is the first time that the FDA is known to have made such an exception and the decision has been criticized as lowering regulatory standards. In the relapse-prevention trial (SUSTAIN-2), the rate of depression relapse was significantly lower with esketamine continued than with it discontinued and replaced with placebo in esketamine-treated stable responders and remitters (51% rate reduction in remitters and 70% reduction in responders).
Esketamine was approved for the treatment of MDD with co-occurring suicidal ideation or behavior on the basis of two short-term (4-week) phase 3 trials (ASPIRE-1 and -2) of esketamine nasal spray added to a conventional antidepressant. The primary efficacy measure was reduction in MADRS total score after 24 hours following the first dose of esketamine. In both trials, MADRS scores were significantly reduced with esketamine relative to placebo at 24 hours. The mean MADRS scores at baseline were 39.4 to 41.3 in all groups and the MADRS reductions at 24 hours were –15.9 and –16.0 with esketamine and –12.0 and –12.2 with placebo, resulting in mean differences between esketamine and placebo of –3.8 and –3.9. The secondary efficacy measure in the trials was change in Clinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) 24 hours after the first dose of esketamine. The CGI-SS-r is a single-item scale with scores ranging from 0 to 6. Esketamine was not significantly effective in reducing suicidality relative to placebo on this measure either at 24 hours or after 25 days. At 24 hours, CGI-SS-r scores were changed by –1.5 with esketamine and –1.3 with placebo, giving a non-significant mean difference between esketamine and placebo of –0.20. Hence, while efficacious in reducing depressive symptoms in people with depression and suicidality, antisuicidal effects of esketamine in such individuals have not been demonstrated.Expectations were initially very high for ketamine and esketamine for treatment of depression based on early small-scale clinical studies, with discovery of the rapid and ostensibly robust antidepressant effects of ketamine described by some authors as "the most important advance in the field of psychiatry in the past half century". According to a 2018 review, ketamine showed more than double the antidepressant effect size over placebo of conventional antidepressants in the treatment of depression based on the preliminary evidence available at the time (Cohens d = 1.3–1.7 for ketamine, Cohens d = 0.8 for midazolam (active placebo), and Cohens d = 0.53–0.81 for conventional antidepressants). However, the efficacy of ketamine/esketamine for depression declined dramatically as studies became larger and more methodologically rigorous. The effectiveness of esketamine for the indication of TRD is described as "modest" and is similar in magnitude to that of other antidepressants for treatment of MDD. The comparative effectiveness of ketamine and esketamine in the treatment of depression has not been adequately characterized. A January 2021 meta-analysis reported that ketamine was similarly effective to esketamine in terms of antidepressant effect size (SMD for depression score of –1.1 vs. –1.2) but more effective than esketamine in terms of response and remission rates (RR = 3.01 vs. RR = 1.38 for response and RR = 3.70 vs. RR = 1.47 for remission). A September 2021 Cochrane review found that ketamine had an effect size (SMD) for depression at 24 hours of –0.87, with very low certainty, and that esketamine had an effect size (SMD) at 24 hours of –0.31, based on moderate-certainty evidence. However, these meta-analyses have involved largely non-directly-comparative studies with dissimilar research designs and patient populations. Only a single clinical trial has directly compared ketamine and esketamine for depression as of May 2021. This study reported similar antidepressant efficacy as well as tolerability and psychotomimetic effects between the two agents. However, the study was small and underpowered, and more research is still needed to better-characterize the comparative antidepressant effects of ketamine and esketamine. Preliminary research suggests that arketamine, the R(−) enantiomer of ketamine, may also have its own independent antidepressant effects and may contribute to the antidepressant efficacy of racemic ketamine, but more research likewise is needed to evaluate this possibility.In February 2019, an outside panel of experts recommended in a 14–2 vote that the FDA approve the nasal spray version of esketamine for TRD, provided that it be given in a clinical setting, with people remaining on site for at least two hours after. The reasoning for this requirement is that trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness during immediately after. The approval of esketamine for TRD by the FDA was controversial due to limited and mixed evidence of efficacy and safety. In January 2020, esketamine was rejected by the National Health Service (NHS) of Great Britain. The NHS questioned the benefits of the medication for depression and claimed that it was too expensive. People who have been already using esketamine were allowed to complete treatment if their doctors considered this necessary.Spravato debuted to a cost of treatment of US$32,400 per year when it launched in the United States in March 2019. The Institute for Clinical and Economic Review (ICER), which evaluates cost effectiveness of drugs analogously to the National Institute for Health and Care Excellence (NICE) in the United Kingdom, declined to recommend esketamine for depression due to its steep cost and modest efficacy, deeming it not sufficiently cost-effective.Esketamine is the second drug to be approved for TRD by the FDA, following olanzapine/fluoxetine (Symbyax) in 2009. Other agents, like the atypical antipsychotics aripiprazole (Abilify) and quetiapine (Seroquel), have been approved for use in the adjunctive therapy of MDD in people with a partial response to treatment. In a meta-analysis conducted internally by the FDA during its evaluation of esketamine for TRD, the FDA reported a standardized mean difference (SMD) of esketamine for TRD of 0.28 using the three phase 3 short-term efficacy trials conducted by Janssen. This was similar to an SMD of 0.26 for olanzapine/fluoxetine for TRD and lower than SMDs of 0.35 for aripiprazole and 0.40 for quetiapine as adjuncts for MDD. These drugs are less expensive than esketamine and may serve as more affordable alternatives to it for depression with similar effectiveness.
Adverse effects
The most common adverse effects of esketamine for depression (≥5% incidence) include dissociation, dizziness, sedation, nausea, vomiting, vertigo, numbness, anxiety, lethargy, increased blood pressure, and feelings of drunkenness. Long-term use of esketamine has been associated with bladder disease.
Pharmacology
Pharmacodynamics
Esketamine is approximately twice as potent an anesthetic as racemic ketamine.In mice, the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine. The usefulness of arketamine over esketamine has been supported by other researchers.Esketamine inhibits dopamine transporters eight times more than arketamine. This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients. Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly. This is however in contradiction with arketamine being devoid of psychotomimetic side effects.Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in the frontal cortex, while arketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while arketamine is reportedly more relaxing. However, another study found no difference between racemic ketamine and esketamine on the patients level of vigilance. Interpretation of this finding is complicated by the fact that racemic ketamine is 50% esketamine.
Pharmacokinetics
Esketamine is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows the elimination of esketamine.
History
Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries. In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such. Esketamine received a breakthrough designation from the FDA for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016. In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States. Johnson & Johnson filed a Food and Drug Administration (FDA) New Drug Application (NDA) for approval on 4 September 2018; the application was endorsed by an FDA advisory panel on 12 February 2019, and on 5 March 2019, the FDA approved esketamine, in conjunction with an oral antidepressant, for the treatment of depression in adults. In August 2020, it was approved by the U.S. Food and Drug Administration (FDA) with the added indication for the short-term treatment of suicidal thoughts.Since the 1980s, closely associated ketamine has been used as a club drug also known as "Special K" for its trip-inducing side effects.
Society and culture
Names
Esketamine is the generic name of the drug and its INN and BAN, while esketamine hydrochloride is its BANM. It is also known as S(+)-ketamine, (S)-ketamine, or (–)-ketamine ((-)[+] ketamine) as well as by its developmental code name JNJ-54135419.Esketamine is sold under the brand name Spravato for use as an antidepressant and the brand names Eskesia, Ketanest, Ketanest S, Ketanest-S, Keta-S for use as an anesthetic (veterinary), among others.
Availability
Esketamine is marketed as an antidepressant in the United States; and as an anesthetic in the European Union.
Legal status
Esketamine is a Schedule III controlled substance in the United States.
References
External links
"Esketamine". Drug Information Portal. U.S. National Library of Medicine.
"Esketamine hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
You are a medical knowledge base. Your task is to elucidate medical terminology, offering insights into their meanings, origins, and applications. | I'd like to learn more about the medical term 'Median palatal cyst.' Can you provide some details? | The median palatal cyst is a rare cyst that may occur anywhere along the median palatal raphe. It may produce swelling because of infection and is treated by excision or surgical removal.
Some investigators now believe that this cyst represents a more posterior presentation of a nasopalatine duct cyst, rather than a separate cystic degeneration of epithelial rests at the line of fusion of the palatine shelves.
References
Sanjay Saraf (1 December 2008). Textbook of Oral Pathology. Jaypee Brothers Publishers. p. 66. ISBN 978-81-8061-655-6. |
You act as a mediator between medical professionals and the public. Provide comprehensive explanations of medical terms, ensuring they are both precise and easily understood. | I'm trying to expand my medical knowledge. Can you elucidate the term 'Laryngocele'? | A laryngocele is a congenital anomalous air sac communicating with the cavity of the larynx, which may bulge outward on the neck.It may also be acquired, as seen in glassblowers, due to continual forced expiration producing increased pressures in the larynx which leads to dilatation of the laryngeal ventricle (sinus of Morgagni). It is also seen in people with chronic obstructive airway disease.
Additional images
References
== External links == |
You are an expert in medical terminology. Explain medical terms in a way that is both precise and easy to understand for non-medical audiences. | Can you demystify the medical term 'Herpesviridae' for me? | Herpesviridae is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ἕρπειν (herpein to creep), referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster (shingles). In 1971, the International Committee on the Taxonomy of Viruses (ICTV) established Herpesvirus as a genus with 23 viruses among four groups. As of 2020, 115 species are recognized, all but one of which are in one of the three subfamilies. Herpesviruses can cause both latent and lytic infections.
Nine herpesvirus types are known to primarily infect humans, at least five of which – herpes simplex viruses 1 and 2 (HSV-1 and HSV-2, also known as HHV-1 and HHV-2; both of which can cause orolabial herpes and genital herpes), varicella zoster virus (or HHV-3; the cause of chickenpox and shingles), Epstein–Barr virus (EBV or HHV-4; implicated in several diseases, including mononucleosis and some cancers), and human cytomegalovirus (HCMV or HHV-5) – are extremely common among humans. More than 90% of adults have been infected with at least one of these, and a latent form of the virus remains in almost all humans who have been infected. Other human herpesviruses are human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus 7 (HHV-7), and Kaposis sarcoma-associated herpesvirus (KSHV, also known as HHV-8).In total, more than 130 herpesviruses are known, some of them from mammals, birds, fish, reptiles, amphibians, and molluscs. Among the animal herpesviruses are pseudorabies virus, the causative agent of Aujeszkys disease in pigs, and bovine herpesvirus 1, the causative agent of bovine infectious rhinotracheitis and pustular vulvovaginitis.
Taxonomy
Subfamily Alphaherpesvirinae
Iltovirus
Mardivirus
Scutavirus
Simplexvirus
Varicellovirus
Subfamily Betaherpesvirinae
Cytomegalovirus
Muromegalovirus
Proboscivirus
Quwivirus
Roseolovirus
Subfamily Gammaherpesvirinae
Bossavirus
Lymphocryptovirus
Macavirus
Manticavirus
Patagivirus
Percavirus
RhadinovirusAdditionally, the species Iguanid herpesvirus 2 is currently unassigned to a genus and subfamily.See Herpesvirales#Taxonomy for information on taxonomic history, phylogenetic research, and the nomenclatural system.
Structure
All members of the Herpesviridae share a common structure; a relatively large, monopartite, double-stranded, linear DNA genome encoding 100-200 genes encased within an icosahedral protein cage (with T=16 symmetry) called the capsid, which is itself wrapped in a protein layer called the tegument containing both viral proteins and viral mRNAs and a lipid bilayer membrane called the envelope. This whole particle is known as a virion.
The structural components of a typical HSV virion are the Lipid bilayer envelope, Tegument, DNA, Glycoprotein spikes and Nucleocapsid. The four-component Herpes simplex virion encompasses the double-stranded DNA genome into an icosahedral nucleocapsid. There is tegument around. Tegument contains filaments, each 7 nm wide. It is an amorphous layer with some structured regions. Finally, it is covered with a lipoprotein envelope. There are spikes made of glycoprotein protruding from each virion. These can expand the diameter of the virus to 225 nm. The diameters of virions without spikes are around 186 nm. There are at least two unglycosylated membrane proteins in the outer envelope of the virion. There are also 11 glycoproteins. These are gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL and gM. Tegument contains 26 proteins. They have duties such as capsid transport to the nucleus and other organelles, activation of early gene transcription, and mRNA degradation. The icosahedral nucleocapsid is similar to that of tailed bacteriophage in the order Caudovirales. This capsid has 161 capsomers consisting of 150 hexons and 11 pentons, as well as a portal complex that allows entry and exit of DNA into the capsid.
Life cycle
All herpesviruses are nuclear-replicating—the viral DNA is transcribed to mRNA within the infected cells nucleus.Infection is initiated when a viral particle contacts a cell with specific types of receptor molecules on the cell surface. Following binding of viral envelope glycoproteins to cell membrane receptors, the virion is internalized and dismantled, allowing viral DNA to migrate to the cell nucleus. Within the nucleus, replication of viral DNA and transcription of viral genes occurs.During symptomatic infection, infected cells transcribe lytic viral genes. In some host cells, a small number of viral genes termed latency-associated transcript (LAT) accumulate, instead. In this fashion, the virus can persist in the cell (and thus the host) indefinitely. While primary infection is often accompanied by a self-limited period of clinical illness, long-term latency is symptom-free.Chromatin dynamics regulate the transcription competency of entire herpes virus genomes. When the virus enters a cell, the cellular immune response is to protect the cell. The cell does so by wrapping the viral DNA around histones and condensing it into chromatin, causing the virus to become dormant, or latent. If cells are unsuccessful and the chromatin is loosely bundled, the viral DNA is still accessible. The viral particles can turn on their genes and replicate using cellular machinery to reactivate, starting a lytic infection.Reactivation of latent viruses has been implicated in a number of diseases (e.g. shingles, pityriasis rosea). Following activation, transcription of viral genes transitions from LAT to multiple lytic genes; these lead to enhanced replication and virus production. Often, lytic activation leads to cell death. Clinically, lytic activation is often accompanied by emergence of nonspecific symptoms, such as low-grade fever, headache, sore throat, malaise, and rash, as well as clinical signs such as swollen or tender lymph nodes and immunological findings such as reduced levels of natural killer cells.In animal models, local trauma and system stress have been found to induce reactivation of latent herpesvirus infection. Cellular stressors like transient interruption of protein synthesis and hypoxia are also sufficient to induce viral reactivation.
Evolution
The three mammalian subfamilies – Alpha-, Beta- and Gamma-herpesviridae – arose approximately 180 to 220 mya. The major sublineages within these subfamilies were probably generated before the mammalian radiation of 80 to 60 mya. Speciations within sublineages took place in the last 80 million years probably with a major component of cospeciation with host lineages.All the currently known bird and reptile species are alphaherpesviruses. Although the branching order of the herpes viruses has not yet been resolved, because herpes viruses and their hosts tend to coevolve this is suggestive that the alphaherpesviruses may have been the earliest branch.The time of origin of the genus Iltovirus has been estimated to be 200 mya while those of the mardivirus and simplex genera have been estimated to be between 150 and 100 mya.
Immune system evasions
Herpesviruses are known for their ability to establish lifelong infections. One way this is possible is through immune evasion. Herpesviruses have many different ways of evading the immune system. One such way is by encoding a protein mimicking human interleukin 10 (hIL-10) and another is by downregulation of the major histocompatibility complex II (MHC II) in infected cells.
cmvIL-10
Research conducted on cytomegalovirus (CMV) indicates that the viral human IL-10 homolog, cmvIL-10, is important in inhibiting pro-inflammatory cytokine synthesis. The cmvIL-10 protein has 27% identity with hIL-10 and only one conserved residue out of the nine amino acids that make up the functional site for cytokine synthesis inhibition on hIL-10. There is, however, much similarity in the functions of hIL-10 and cmvIL-10. Both have been shown to down regulate IFN-γ, IL-1α, GM-CSF, IL-6 and TNF-α, which are all pro-inflammatory cytokines. They have also been shown to play a role in downregulating MHC I and MHC II and up regulating HLA-G (non-classical MHC I). These two events allow for immune evasion by suppressing the cell-mediated immune response and natural killer cell response, respectively. The similarities between hIL-10 and cmvIL-10 may be explained by the fact that hIL-10 and cmvIL-10 both use the same cell surface receptor, the hIL-10 receptor. One difference in the function of hIL-10 and cmvIL-10 is that hIL-10 causes human peripheral blood mononuclear cells (PBMC) to both increase and decrease in proliferation whereas cmvIL-10 only causes a decrease in proliferation of PBMCs. This indicates that cmvIL-10 may lack the stimulatory effects that hIL-10 has on these cells.It was found that cmvIL-10 functions through phosphorylation of the Stat3 protein. It was originally thought that this phosphorylation was a result of the JAK-STAT pathway. However, despite evidence that JAK does indeed phosphorylate Stat3, its inhibition has no significant influence on cytokine synthesis inhibition. Another protein, PI3K, was also found to phosphorylate Stat3. PI3K inhibition, unlike JAK inhibition, did have a significant impact on cytokine synthesis. The difference between PI3K and JAK in Stat3 phosphorylation is that PI3K phosphorylates Stat3 on the S727 residue whereas JAK phosphorylates Stat3 on the Y705 residue. This difference in phosphorylation positions seems to be the key factor in Stat3 activation leading to inhibition of pro-inflammatory cytokine synthesis. In fact, when a PI3K inhibitor is added to cells, the cytokine synthesis levels are significantly restored. The fact that cytokine levels are not completely restored indicates there is another pathway activated by cmvIL-10 that is inhibiting cytokine system synthesis. The proposed mechanism is that cmvIL-10 activates PI3K which in turn activates PKB (Akt). PKB may then activate mTOR, which may target Stat3 for phosphorylation on the S727 residue.
MHC downregulation
Another one of the many ways in which herpes viruses evade the immune system is by down regulation of MHC I and MHC II. This is observed in almost every human herpesvirus. Down regulation of MHC I and MHC II can come about by many different mechanisms, most causing the MHC to be absent from the cell surface. As discussed above, one way is by a viral chemokine homolog such as IL-10. Another mechanism to down regulate MHCs is to encode viral proteins that detain the newly formed MHC in the endoplasmic reticulum (ER). The MHC cannot reach the cell surface and therefore cannot activate the T cell response. The MHCs can also be targeted for destruction in the proteasome or lysosome. The ER protein TAP also plays a role in MHC down regulation. Viral proteins inhibit TAP preventing the MHC from picking up a viral antigen peptide. This prevents proper folding of the MHC and therefore the MHC does not reach the cell surface.
Human herpesvirus types
Below are the nine (9) distinct viruses in this family known to cause disease in humans.
Zoonotic herpesviruses
In addition to the herpesviruses considered endemic in humans, some viruses associated primarily with animals may infect humans. These are zoonotic infections:
Animal herpesviruses
In animal virology, the best known herpesviruses belong to the subfamily Alphaherpesvirinae. Research on pseudorabies virus (PrV), the causative agent of Aujeszkys disease in pigs, has pioneered animal disease control with genetically modified vaccines. PrV is now extensively studied as a model for basic processes during lytic herpesvirus infection, and for unraveling molecular mechanisms of herpesvirus neurotropism, whereas bovine herpesvirus 1, the causative agent of bovine infectious rhinotracheitis and pustular vulvovaginitis, is analyzed to elucidate molecular mechanisms of latency. The avian infectious laryngotracheitis virus is phylogenetically distant from these two viruses and serves to underline similarity and diversity within the Alphaherpesvirinae.
Research
Research is currently ongoing into a variety of side-effect or co-conditions related to the herpesviruses. These include:
See also
Acciptrid herpesvirus 1
Agua Preta virus, a potential herpesvirus
References
External links
ICTV International Committee on Taxonomy of Viruses (official site)
Viralzone: Herpesviridae
Animal viruses
Article on Cercopithecine herpesvirus
National B Virus Resource Center
Pityriasis Rosea overview
Herpes simplex: Host viral protein interactions.A database of Host/HSV-1 interactions
Virus Pathogen Database and Analysis Resource (ViPR): Herpesviridae |
You are a medical advisor. Your role is to break down medical terminology into clear, detailed explanations for a general audience. | I've encountered the term 'Childhood arthritis' while reading about medical topics. What does it refer to exactly? | Childhood arthritis (also known as juvenile arthritis, JRA, Juvenile Idiopathic Disease or Arthritis, or Stills Disease) is any form of chronic arthritis or chronic arthritis-related conditions which affects individuals under the age of 16. Most types are autoimmune disorders.
Signs and symptoms
Several types of childhood arthritis exist, the most common being juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis (JRA) or juvenile chronic arthritis (JCA). Other types of childhood arthritis include juvenile myositis, juvenile lupus, juvenile scleroderma, vasculitis, and fibromyalgia.JRA again can be divided into three main forms: The classification is based upon symptoms, number of joints involved and the presence of certain antibodies in the blood.
Polyarticular arthritis is the first type of arthritis, which affects about 30–40% of children with arthritis and is more common in girls than boys. Typically five or more joints are affected (usually smaller joints such as the hands and feet but many also affect the hips, neck, shoulders and jaw).
Oligoarticular (aka pauciarticular) arthritis can be early or late onset and is the second type of arthritis, affecting about 50% of children with juvenile arthritis. This type affects fewer than four joints (usually the large joints such as knees, ankles or wrists) and may cause eye inflammation in girls with positive anti-nuclear antibodies (ANA). Girls younger than eight are more likely to develop this type of arthritis.
Systemic disease is the least common form, with 10–20% of children (boys and girls equally) being affected with limited movement, swelling and pain in at least one joint. A common symptom of this type is a high, spiking fever of 103 °F (39.4 °C) or higher, lasting for weeks or months, and a rash of pale red spots on the chest, thighs or other parts of the body may be visible.
Cause
In most cases, juvenile arthritis is caused by the body attacking its own healthy cells and tissues, i.e. autoimmunity, causing the joint to become inflamed and stiff. Once the joint has become inflamed and stiff, damage is done to the joint and the growth of the joint may by changed or impaired. The underlying cause in the malfuction of the autoimmune system is unknown; dietary habits and emotional state seem to have no effect on the disease.
Diagnosis
Early diagnosis and treatment by a paediatric rheumatologist or a rheumatologist can help manage inflammation, relieve pain, and prevent joint damage. However, it is difficult for doctors to diagnose the disease. Careful examination, laboratory tests (blood and urine), and various forms of imaging like X-rays may be some of the tests conducted by a doctor. Doctors may perform some of the following tests to diagnose the condition
ANA (Antinuclear Antibody) Test
Joint Aspiration
Rheumatoid Factor (RF) Test
Treatment
The treatment of juvenile arthritis includes medications, physical therapy, splints and in severe cases surgery. Methotrexate is commonly prescribed to children with juvenile arthritis. These treatments are focused on reducing swelling, relieving pain and maintaining full movement of joints. Children are encouraged to be involved in extra-curricular activities, physical activity when possible, and to live a "normal" life.
Epidemiology
In the US it affects about 250,000-294,000 children making it one of the most common childhood diseases.
References
External links
National Institute of Arthritis and Musculoskeletal and Skin Diseases - US National Institute of Arthritis and Musculoskeletal and Skin Diseases |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | I've come across the term 'Malonyl-CoA decarboxylase deficiency' in a medical context, but I'm not sure what it means. Can you clarify? | Malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA (a fatty acid precursor and a fatty acid oxidation blocker) into acetyl-CoA and carbon dioxide.
Signs and symptoms
The signs and symptoms of this disorder typically appear in early childhood. Almost all affected children have delayed development. Additional signs and symptoms can include weak muscle tone (hypotonia), seizures, diarrhea, vomiting, and low blood sugar (hypoglycemia). A heart condition called cardiomyopathy, which weakens and enlarges the heart muscle, is another common feature of malonyl-CoA decarboxylase deficiency.
Some common symptoms in Malonyl-CoA decarboxylase deficiency, such as cardiomyopathy and metabolic acidosis, are triggered by the high concentrations of Malonyl-CoA in the cytoplasm. High levels of Malonyl-CoA will inhibit β-oxidation of fatty acids through deactivating the carrier of fatty acyl group, CPT1, and thus, blocking fatty acids from going into the mitochondrial matrix for oxidation.A research conducted in Netherlands has suggested that carnitine supplements and a low fat diet may help to reduce the level of malonic acid in our body.
Genetics
Malonyl-CoA decarboxylase deficiency is caused by mutations in the MLYCD gene, located on chromosome 16q24. The gene encodes the enzyme malonyl-CoA decarboxylase. Within cells, this enzyme helps regulate the formation and breakdown of a certain group of fats called fatty acids.
Many tissues, including heart muscle, use fatty acids as a major source of energy. Mutations in the MLYCD gene reduce or eliminate the function of malonyl-CoA decarboxylase. A lack of this enzyme disrupts the normal balance of fatty acid formation and breakdown. As a result, fatty acids cannot be converted to energy, which can lead to characteristic features of this disorder, such as low blood sugar and cardiomyopathy. By-products of fatty acid processing build up in tissues, which also contributes to the signs and symptoms of malonyl-CoA decarboxylase deficiency.
Malonyl-CoA decarboxylase deficiency is inherited in an autosomal recessive pattern. This means that the defective gene is located on an autosome (chromosome 16 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 a child with an autosomal recessive disorder both carry one copy of the defective gene, but are usually not affected by the disorder.
Malonyl-CoA decarboxylase deficiency is extremely rare, evidence suggests that it is caused by the abnormality in the protein transcription regulation. Looking at the molecular basis, two distinct homozygous mutations are found to cause Malonyl-CoA Decarboxylase deficiency in human. The first mutation is the transversion of gene from C to G causing a premature stop signal in the protein. The second mutation is a base pair insertion in the mature RNA that will eventually result in the protein truncation.A research has also confirmed that the homozygous mutation which eventually leads to MCD deficiency is caused by the isodisomy of maternal UPD. This indicates that such disease is likely to be inherited from mother’s gene profile, not from paternal source.
Pathophysiology
Without the enzymatic activity of Malonyl-CoA decarboxylase, cellular Mal-CoA increases so dramatically that at the end it is instead broken down by an unspecific short-chain acyl-CoA hydrolase, which produces malonic acid and CoA. Malonic acid is a Krebs cycle inhibitor, preventing the cells to make ATP through oxidation. In this condition, the cells, to make ATP, are forced to increase glycolysis, which produces lactic acid as a by-product. The increase of lactic and malonic acid drastically lowers blood pH, and causes both lactic and malonic aciduria (acidic urine). This condition is very rare, as fewer than 20 cases have been reported.
By 1999, only seven cases of Malonyl- CoA decarboxylase deficiency had been reported in human in Australia; however, this deficiency predominately occurs during childhood. Patients from the seven reported cases of Malonyl- CoA decarboxylase deficiency have an age range between 4 days to 13 years, and they all have the common symptom of delayed neurological development. Similar study was conducted in Netherland, and found seventeen reported cases of Malonyl- CoA decarboxylase deficiency in children age range from 8 days to 12 years.Although we have not yet gained a clear understanding of the pathogenic mechanism of this deficiency, some researchers have suggested a brain-specific interaction between Malonyl-CoA and CTP1 enzyme which may leads to unexplained symptoms of the MCD deficiency.Research has found that large amount of MCD are detached in the hypothalamus and cortex of the brain where high levels of lipogenic enzymes are found, indicating that MCD plays a role in lipid synthesis in the brain. Disturbed interaction between Malonyl-CoA and CPT1 may also contributed to abnormal brain development.Malonyl-CoA decarboxylase plays an important role in the β-oxidation processes in both mitochondria and peroxisome. Some other authors have also hypothesized that it is the MCD deficiency induced inhibition of peroxisomal β-oxidation that contributes to the development delay.
Diagnosis
Treatment
See also
Combined malonic and methylmalonic aciduria (CMAMMA)
References
External links
Malonyl-CoA decarboxylase deficiency at NLM Genetics Home Reference |
You are a medical advisor. Your role is to break down medical terminology into clear, detailed explanations for a general audience. | Please help me grasp the concept behind the medical term 'Hypervitaminosis A.' | Hypervitaminosis A refers to the toxic effects of ingesting too much preformed vitamin A (retinyl esters, retinol, and retinal). Symptoms arise as a result of altered bone metabolism and altered metabolism of other fat-soluble vitamins. Hypervitaminosis A is believed to have occurred in early humans, and the problem has persisted throughout human history. Toxicity results from ingesting too much preformed vitamin A from foods (such as fish liver or animal liver), supplements, or prescription medications and can be prevented by ingesting no more than the recommended daily amount.
Diagnosis can be difficult, as serum retinol is not sensitive to toxic levels of vitamin A, but there are effective tests available. Hypervitaminosis A is usually treated by stopping intake of the offending food(s), supplement(s), or medication. Most people make a full recovery. High intake of provitamin carotenoids (such as beta-carotene) from vegetables and fruits does not cause hypervitaminosis A.
Signs and symptoms
Symptoms may include:
Causes
Hypervitaminosis A results from excessive intake of preformed vitamin A. Genetic variations in tolerance to vitamin A intake may occur, so the toxic dose will not be the same for everyone. Children are particularly sensitive to vitamin A, with daily intakes of 1500 IU/kg body weight reportedly leading to toxicity.
Types of vitamin A
It is "largely impossible" for provitamin carotenoids, such as beta-carotene, to cause toxicity, as their conversion to retinol is highly regulated. No vitamin A toxicity has ever been reported from ingestion of excessive amounts. Overconsumption of beta-carotene can only cause carotenosis, a harmless and reversible cosmetic condition in which the skin turns orange.
Preformed vitamin A absorption and storage in the liver occur very efficiently until a pathologic condition develops. When ingested, 70–90% of preformed vitamin A is absorbed and used.
Sources of toxicity
Diet – Liver is high in vitamin A. The liver of certain animals, including the polar bear, bearded seal, fish, walrus, and moose, are particularly toxic (see Liver (food) § Poisoning). It has been estimated that consumption of 500 grams of polar bear liver would result in a toxic dose for a human.
Supplements – Dietary supplements can be toxic when taken above recommended dosages.
Types of toxicity
Acute toxicity occurs over a period of hours or a few days, and is less of a problem than chronic toxicity.
Chronic toxicity results from daily intakes greater than 25,000 IU for 6 years or longer and more than 100,000 IU for 6 months or longer.
Mechanism
Absorption and storage in the liver of retinol occur very efficiently until a pathologic condition develops.
Delivery to tissues
Absorption
When ingested, 70–90% of preformed vitamin A is absorbed and used.According to a 2003 review, water-miscible, emulsified, and solid forms of vitamin A supplements are more toxic than oil-based supplement and liver sources.
Storage
80–90% of the total body reserves of preformed vitamin A are in the liver (with 80–90% of this amount being stored in hepatic stellate cells and the remaining 10–20% being stored in hepatocytes). Fat is another significant storage site, while the lungs and kidneys may also be capable of storage.
Transport
Until recently, it was thought that the sole important retinoid delivery pathway to tissues involved retinol bound to retinol-binding protein (RBP4). More recent findings, however, indicate that retinoids can be delivered to tissues through multiple overlapping delivery pathways, involving chylomicrons, very low density lipoprotein (VLDL) and low density lipoprotein (LDL), retinoic acid bound to albumin, water-soluble β-glucuronides of retinol and retinoic acid, and provitamin A carotenoids.The range of serum retinol concentrations under normal conditions is 1–3 μmol/L. Elevated amounts of retinyl ester (i.e., >10% of total circulating vitamin A) in the fasting state have been used as markers for chronic hypervitaminosis A in humans. Candidate mechanisms for this increase include decreased hepatic uptake of vitamin A and the leaking of esters into the bloodstream from saturated hepatic stellate cells.
Effects
Effects include increased bone turnover and altered metabolism of fat-soluble vitamins. More research is needed to fully elucidate the effects.
Increased bone turnover
Retinoic acid suppresses osteoblast activity and stimulates osteoclast formation in vitro, resulting in increased bone resorption and decreased bone formation. It is likely to exert this effect by binding to specific nuclear receptors (members of the retinoic acid receptor or retinoid X receptor nuclear transcription family) which are found in every cell (including osteoblasts and osteoclasts).This change in bone turnover is likely to be the reason for numerous effects seen in hypervitaminosis A, such as hypercalcemia and numerous bone changes such as bone loss that potentially leads to osteoporosis, spontaneous bone fractures, altered skeletal development in children, skeletal pain, radiographic changes, and bone lesions.
Altered fat-soluble vitamin metabolism
Preformed vitamin A is fat-soluble and high levels have been reported to affect metabolism of the other fat-soluble vitamins D, E, and K.
The toxic effects of preformed vitamin A might be related to altered vitamin D metabolism, concurrent ingestion of substantial amounts of vitamin D, or binding of vitamin A to receptor heterodimers. Antagonistic and synergistic interactions between these two vitamins have been reported, as they relate to skeletal health.
Stimulation of bone resorption by vitamin A has been reported to be independent of its effects on vitamin D.
Mitochondrial toxicity
Preformed vitamin A and retinoids exerts several toxic effects regarding redox environment and mitochondrial function.
Diagnosis
Retinol concentrations are nonsensitive indicators
Assessing vitamin A status in persons with subtoxicity or toxicity is complicated because serum retinol concentrations are not sensitive indicators in this range of liver vitamin A reserves. The range of serum retinol concentrations under normal conditions is 1–3 μmol/L and, because of homeostatic regulation, that range varies little with widely disparate vitamin A intakes.
Retinol esters have been used as markers
Retinyl esters can be distinguished from retinol in serum and other tissues and quantified with the use of methods such as high-performance liquid chromatography.Elevated amounts of retinyl ester (i.e., >10% of total circulating vitamin A) in the fasting state have been used as markers for chronic hypervitaminosis A in humans and monkeys. This increased retinyl ester may be due to decreased hepatic uptake of vitamin A and the leaking of esters into the bloodstream from saturated hepatic stellate cells.
Prevention
Hypervitaminosis A can be prevented by not ingesting more than the US Institute of Medicine Daily Tolerable Upper Level of intake for Vitamin A. This level is for synthetic and natural retinol ester forms of vitamin A. Carotene forms from dietary sources are not toxic. Possible pregnancy, liver disease, high alcohol consumption, and smoking are indications for close monitoring and limitation of vitamin A administration.
Daily tolerable upper level
Treatment
Stopping high vitamin A intake is the standard treatment. Most people fully recover.
Phosphatidylcholine (in the form of PPC or DLPC), the substrate for Lecithin retinol acyltransferase, which converts retinol into Retinyl esters (the storage forms of vitamin A).
Vitamin E may alleviate hypervitaminosis A.
Liver transplantation may be a valid option if no improvement occurs.If liver damage has progressed into fibrosis, synthesizing capacity is compromised and supplementation can replenish PC. However, recovery is dependent on removing the causative agent: halting high Vitamin A intake.
History
Vitamin A toxicity is known to be an ancient phenomenon; fossilized skeletal remains of early humans suggest bone abnormalities may have been caused by hypervitaminosis A. There are two theories for hypervitaminosis A in the isolated case of KMN-ER 1808. One of these is the increased consumption of meat and the second is an increase in insect consumption, or Entomophagy.Vitamin A toxicity has long been known to the Inuit as they will not eat the liver of polar bears or bearded seals due to them contain dangerous amounts of Vitamin A. and has been known by Europeans since at least 1597 when Gerrit de Veer wrote in his diary that, while taking refuge in the winter in Nova Zemlya, he and his men became severely ill after eating polar bear liver.In 1913, Antarctic explorers Douglas Mawson and Xavier Mertz were both poisoned (and Mertz died) from eating the livers of their sled dogs during the Far Eastern Party. Another study suggests, however, that exhaustion and diet change are more likely to have caused the tragedy.
Other animals
Some Arctic animals demonstrate no signs of hypervitaminosis A despite having 10–20 times the level of vitamin A in their livers as other Arctic animals. These animals are top predators and include the polar bear, Arctic fox, bearded seal, and glaucous gull. This ability to efficiently store higher amounts of vitamin A may have contributed to their survival in the extreme environment of the Arctic.
Treatment
These treatments have been used to help treat or manage toxicity in animals. Although not considered part of standard treatment, they might be of some benefit to humans.
Vitamin E appears to be an effective treatment in rabbits, and prevents side effects in chicks
Taurine significantly reduces toxic effects in rats. Retinoids can be conjugated by taurine and other substances. Significant amounts of retinotaurine are excreted in the bile, and this retinol conjugate is thought to be an excretory form, as it has little biological activity.
Red yeast rice ("cholestin") – significantly reduces toxic effects in rats.
Vitamin K prevents hypoprothrombinemia in rats and can sometimes control the increase in plasma/cell ratios of vitamin A.
See also
Vitamin poisoning
Far Eastern Party
Retinoic acid syndrome
Piblokto
References
External links
Facts about Vitamin A and Carotenoids, from the National Institutes of Healths Office of Dietary Supplements. |
You serve as an encyclopedia of medical terms. Deliver clear, detailed explanations, making medical language understandable to a diverse audience. | The term 'Trimipramine' keeps coming up in medical discussions. What does it stand for? | Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.
Medical uses
Trimipramines primary use in medicine is in the treatment of major depressive disorder, especially where sedation is helpful due to its prominent sedative effects. The drug is also an effective anxiolytic, and can be used in the treatment of anxiety. In addition to depression and anxiety, trimipramine is effective in the treatment of insomnia, and unlike most other hypnotics, does not alter the normal sleep architecture. In particular, it does not suppress REM sleep, and dreams are said to "brighten" during treatment. Trimipramine also has some weak antipsychotic effects with a profile of activity described as similar to that of clozapine, and may be useful in the treatment of psychotic symptoms such as in delusional depression or schizophrenia.A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that trimipramine had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.55 (95% CI –0.11 to 1.21). The certainty of evidence was rated as very low, and no data were available for longer-term treatment (3 months). For comparison, the other sedating antihistamines assessed, doxepin and doxylamine, had effect sizes (SMD) at 4 weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.47 (95% CI 0.06 to 0.89) (moderate certainty evidence), respectively.The effective dosage of trimipramine in depression is 150 to 300 mg/day. Doses of trimipramine used for insomnia range from 25 to 200 mg/day. However, it has been advised that doses be kept as low as possible, and a low dose of 25 mg/day has been recommended.
Contraindications
Contraindications include:
Recent myocardial infarction
Any degree of heart block or other cardiac arrhythmias
Mania
Severe liver disease
During breastfeeding
Hypersensitivity to trimipramine or to any of the excipients
Side effects
The side effects of trimipramine have been said to be similar to those of other tertiary amine TCAs, with a preponderance of anticholinergic and sedative effects. However, trimipramine has also been said to be associated with a different side effect profile compared to other TCAs and in general with fewer side effects, chiefly due to its lack of norepinephrine reuptake inhibition and relatively lower anticholinergic effects (although it is still a potent anticholinergic). Somnolence is the most common side effect of the drug. Dry mouth is the most common anticholinergic side effect, but others like constipation, urinary retention, and blurred vision are also present.It is described as being associated with minimal or no orthostatic hypotension, at least in comparison to clomipramine, in spite of its potent and comparable activity as an alpha-1 blocker. However, it has also been said to have a rate of orthostatic hypotension similar to that of other TCAs. Trimipramine is said to be less epileptogenic than other TCAs, although seizures have still been reported in association with it. It is also less cardiotoxic than other TCAs and cardiotoxicity is said to be minimal, with a "very favorable profile".Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later. However, on tests done on Drosophila melanogaster, nongenotoxic TCAs (amitriptyline, maprotiline, nortriptyline, and protriptyline), and genotoxic TCAs (amoxapine, clomipramine, desipramine, doxepin, imipramine, and trimipramine) were identified.
List of side effects
Common adverse effects include:
Adverse effects with an unknown incidence includes:
Confusion
Nausea
Vomiting
Extrapyramidal side effects (e.g. parkinsonism, dystonia, etc.)
Tinnitus
Paraesthesia
ECG changes
Increased liver function testsRare adverse effects include:
Seizures
Syndrome of inappropriate secretion of antidiuretic hormone
Blood dyscrasias including:
Agranulocytosis
Thrombocytopenia
Eosinophilia
Leukopenia
Myocardial infarction
Heart block
QTc interval prolongation
Sudden cardiac death
Depression worsening
Suicidal ideation
Overdose
Compared to other TCAs, trimipramine is relatively safe in overdose, although it is more dangerous than the selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) but less dangerous than bupropion in cases of overdose.
Interactions
Trimipramine should not be given with sympathomimetic agents such as epinephrine (adrenaline), ephedrine, isoprenaline, norepinephrine (noradrenaline), phenylephrine and phenylpropanolamine.
Barbiturates may increase the rate of metabolism. Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.
Pharmacology
Pharmacodynamics
The mechanism of action of trimipramine in terms of its antidepressant effects differs from that of other TCAs and is not fully clear. The mechanism of action of its anxiolytic effects is similarly unclear. Trimipramine is a very weak reuptake inhibitor of serotonin, norepinephrine, and dopamine (see below), and unlike most other TCAs, has been claimed to be devoid of clinically significant monoamine reuptake inhibition. The effects of the drug are thought to be mainly due to receptor antagonism as follows:
Very strong: H1
Strong: 5-HT2A, α1-adrenergic
Moderate: D2, mACh
Weak: 5-HT2C, D1, α2-adrenergicIn spite of its atypical nature and different profile of activity, trimipramine has been shown in head-to-head clinical studies to possess equivalent effectiveness to other antidepressants, including but not limited to other TCAs (e.g., amitriptyline, imipramine, doxepin, amineptine), tetracyclic antidepressants (TeCAs) (e.g., maprotiline), monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, isocarboxazid), and selective serotonin reuptake inhibitors (e.g., fluoxetine). In addition, trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head-to-head comparisons. Indeed, its prominent anxiolytic effects have been said to distinguish it from most other TCAs. The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression.The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.
Monoamine reuptake inhibition
Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine, and the drug has been described by various authors as devoid of monoamine reuptake inhibition. Richelson & Pfenning (1984) found a relatively high Ki for the NET of 510 nM in rat brain synaptosomes and Tatsumi et al. (1997) found a relatively high KD of 149 nM for the SERT in human HEK293 cells, but other authors and a more recent study with an improved design have not had the same findings. In the most recent study, by Haenisch et al. (2011), the researchers suggested that the discrepant findings from the Tatsumi et al. study were due to methodological differences, in particular the use of radioligand binding in isolated membranes (KD) to study interactions as opposed to actual functional reuptake inhibition (IC50).
Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition. In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and trimipramine-N-oxide in addition to trimipramine and found that these metabolites showed IC50 values for the SERT, NET, and DAT similar to those of trimipramine (see table to the right). Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than trimipramine in its norepinephrine reuptake inhibition but less potent in its inhibition of serotonin reuptake. However, desmethyltrimipramine still showed only very weak inhibition of the NET.Therapeutic concentrations of trimipramine are between 0.5 and 1.2 μM (150–350 ng/mL) and hence significant monoamine reuptake inhibition would not be expected with it or its metabolites. However, these concentrations are nearly 2-fold higher if the active metabolites of trimipramine are also considered, and studies of other TCAs have found that they cross the blood–brain barrier and accumulate in the brain to levels of up to 10-fold those in the periphery. As such, trimipramine and its metabolites might at least partially inhibit reuptake of serotonin and/or norepinephrine, though not of dopamine, at therapeutic concentrations, and this could be hypothesized to contribute at least in part to its antidepressant effects. This is relevant as Haenisch et al. has stated that these are the only actions known at present which could explain or at least contribute to the antidepressant effects of trimipramine. That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as with mirtazapine, has also been implicated in antidepressant effects.In any case, there is also clinical and animal evidence that trimipramine does not inhibit the reuptake of monoamines. Unlike other TCAs, it does not downregulate β3-adrenergic receptors, which is likely the reason that it does not cause orthostatic hypotension. It can be safely combined with MAOIs apparently without risk of serotonin syndrome or hypertensive crisis. Indeed, in rabbits, whereas hyperpyrexia (a symptom of serotonin syndrome) occurs with imipramine and an MAOI and to a lesser extent with amitriptyline and an MAOI, it does not occur at all with trimipramine and an MAOI, likely due to trimipramines lack of serotonin reuptake inhibition.
Antihistamine activity
Trimipramine is a very potent antihistamine; it has the third highest affinity for the H1 receptor (Ki = 0.27 nM) after mirtazapine (Ki = 0.14 nM) and doxepin (Ki = 0.24 nM) among the TCAs and tetracyclic antidepressants (TeCAs). The TeCA mianserin (Ki = 0.40) and the TCA amitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists, whereas other TCAs and TeCAs are less potent. These TCAs and TeCAs, including trimipramine, are far more potent than the standard antihistamine diphenhydramine (approximately 800 times for doxepin and 250 times for trimipramine), and are among the most potent antihistamines available.Trimipramine is also an antagonist of the H2 receptor with lower potency and has been found to be effective in the treatment of duodenal ulcers.
As a hypnotic
Blockade of the H1 receptor is responsible for the sedative effects of trimipramine and other TCAs and their effectiveness in the treatment of insomnia.Most antidepressants suppress REM sleep, in parallel with their alleviation of depressive symptoms (although suppression of REM sleep is not required for antidepressant effects). This includes TCAs (e.g., amitriptyline, nortriptyline), TeCAs (e.g., mianserin, maprotiline), MAOIs (e.g., clorgiline, pargyline), and SSRIs (e.g., fluoxetine, zimelidine, indalpine). Trimipramine is unique in that it is an exception and produces antidepressant effects without compromising or otherwise affecting REM sleep. Even long-term treatment with trimipramine for up to 2 years has not been found to suppress REM sleep. In addition, trimipramine has been found to decrease nocturnal cortisol levels to normal and to normalize cortisol response in depressed patients; hence, it normalizes the hypothalamic–pituitary–adrenal axis, whereas imipramine and other antidepressants tend to increase nocturnal cortisol secretion.In clinical studies, trimipramine has been found in doses of 50 to 200 mg/day to significantly increase sleep efficiency and total sleep time and to decrease waking time for up to 3 weeks in patients with insomnia. It also improved subjectively perceived sleep quality and well-being during daytime. Monitoring of patients upon discontinuation of trimipramine found that it did not cause rebound insomnia or worsening of sleep quality in subjective evaluations of sleep, although objective measurements found total sleep time below baseline in a subset of patients during trimipramine withdrawal.
Antidopaminergic activity
Trimipramine is a weak but significant antagonist of the dopamine D1 and D2 receptors, and also binds to the D4 receptor (Ki = 275 nM). Its affinities for various monoamine receptors including the D2 and 5-HT2A receptors closely resemble those of the atypical antipsychotic clozapine. In accordance, high doses of trimipramine have been found to have antipsychotic effects in schizophrenic patients, notably without causing extrapyramidal symptoms, and trimipramine has recently been found to be effective in reducing psychotic symptoms in patients with delusional depression. The lack of extrapyramidal symptoms with trimipramine may be related to its affinity for the D4 receptor, these both being properties it shares with clozapine. Unlike other TCAs, but reminiscent of antipsychotics, trimipramine has been found to markedly increase plasma prolactin levels (a marker of D2 receptor antagonism) at a dose of 75 mg/day and to increase nocturnal prolactin secretion at doses of 75 and 200 mg/day. These findings are suggestive of important antidopaminergic actions of trimipramine.Unlike various other TCAs, trimipramine shows marked antagonism of presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission. This effect has also been observed with low-potency tricyclic antipsychotics like thioridazine and chlorprothixene. Notably, these two antipsychotics have been claimed many times to also possess antidepressant effects. As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signaling could be involved in the antidepressant effects of trimipramine. However, other authors have attributed the claimed antidepressant effects of antipsychotics like the two previously mentioned to α2-adrenergic receptor antagonism, although trimipramine specifically has only weak affinity for this receptor. Aside from antidepressant effects, low doses of antipsychotics have been found to increase REM sleep, and so dopamine autoreceptor antagonism could be involved in the unique effects of trimipramine in terms of REM sleep and sleep architecture.
Pharmacokinetics
The time to peak concentrations following a dose is 2 to 4 hours. The typical antidepressant therapeutic range of trimipramine concentrations is 150 to 300 ng/mL. The terminal half-life of trimipramine has been variously reported to be as little as 8 hours (in plasma) and as long as 24 hours. In any case, the terminal half-life of trimipramine is described as shorter than that of other TCAs, which makes it ideal for use in the treatment of insomnia.Trimipramine is a racemic compound with two enantiomers.[1] CYP2C19 is responsible for the demethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP2D6 is responsible for the 2-hydroxylation of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively. CYP2D6 also metabolizes (L)-trimipramine into (L)-2-hydroxytrimipramine.
Chemistry
Trimipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, and clomipramine. Trimipramine is a derivative of imipramine with a methyl group added to its side chain and is also known as 2-methylimipramine or β-methylimipramine. The tri- prefix in its name may allude to the fact that its side chain features three methyl groups. Trimipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desmethyltrimipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and doxepin. The chemical name of trimipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C20H26N2 with a molecular weight of 294.434 g/mol. The drug is used commercially as the maleate salt. The CAS Registry Number of the free base is 739-71-9 and of the maleate is 521-78-8.
History
Trimipramine was developed by Rhône-Poulenc. It was patented in 1959 and first appeared in the literature in 1961. The drug was first introduced for medical use in 1966, in Europe. It was not introduced in the United States until later in 1979 or 1980.
Society and culture
Generic names
Trimipramine is the generic name of the drug and its INN, USAN, BAN, and DCF, while trimipramine maleate is its USAN, USP, BANM, and JAN. Its generic name in Latin is trimipraminum, in German is trimipramin, and in Spanish is trimipramina.
Brand names
Trimipramine is marketed throughout the world mainly under the brand name Surmontil. Other notable brand names of trimipramine have included Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine.
Availability
Trimipramine is no longer marketed in Australia, though it was previously.
== References == |
You are an assistant in medical learning. Your role is to clarify medical terminology, ensuring the information is both accurate and accessible. | I'm encountering the term 'Microphthalmia' in medical literature. What's its definition? | Microphthalmia (Greek: μικρός, mikros, small, ὀφθαλμός, ophthalmos, eye, also referred as microphthalmos, is a developmental disorder of the eye in which one (unilateral microphthalmia) or both (bilateral microphthalmia) eyes are abnormally small and have anatomic malformations. Microphthalmia is a distinct condition from anophthalmia and nanophthalmia. Although sometimes referred to as simple microphthalmia, nanophthalmia is a condition in which the size of the eye is small but no anatomical alterations are present.
Presentation
Microphthalmia is a congenital disorder in which the globe of the eye is as unusually small and structurally disorganized. While the axis of an adult human eye has an average length of about 23.8 mm (0.94 in), a diagnosis of microphthalmia generally corresponds to an axial length below 21 mm (0.83 in) in adults. Additionally, the diameter of the cornea is about 9–10.5 mm (0.35–0.41 in) in affected newborns and 10.5–12 mm (0.41–0.47 in) in adults with the condition. The presence of a small eye within the orbit can be a normal incidental finding but in many cases it is atypical and results in visual impairment. The prevalence of this condition is around 1 in 10,000 births, and it affects roughly 3–11% of blind children.
Causes
It has been postulated that microphthalmia arises as a result of interference with postnatal eye growth, in contrast to anophthalmia which originates much earlier during fetal development.
Genetic causes of microphthalmia include chromosomal abnormalities (e.g. Patau syndrome, mosaic trisomy 9, 13q deletion syndrome, Wolf–Hirschhorn syndrome) or monogenetic Mendelian disorders (e.g. CHARGE syndrome, Fraser syndrome, oculofaciocardiodental syndrome, Lenz microphthalmia syndrome).
Microphthalmia in newborns is sometimes associated with fetal alcohol spectrum disorder or infections during pregnancy, particularly herpes simplex virus, rubella and cytomegalovirus (CMV), but the evidence is inconclusive.The following genes, many of which are transcription and regulatory factors, have been implicated in microphthalmia, anophthalmia, and coloboma:
SOX2 has been implicated in a substantial number (10–15%) of cases and in many other cases failure to develop the ocular lens often results in microphthalmia.Microphthalmia-associated transcription factor (MITF), located on chromosome 14q32, is associated with one form of isolated microphthalmia (MCOP1). In mammals, the failure of expression of MITF in the retinal pigment epithelium prevents this structure from fully differentiating, causing a malformation of the choroid fissure of the eye and drainage of vitreous body fluid. Without this fluid, the eye fails to enlarge, resulting in microphthalmia. Waardenburg syndrome type 2 in humans may also be caused by mutations in MITF The human MITF gene is homologous to the mouse microphthalmia gene (gene symbol mi); mouse with mutations in this gene are hypopigmented in their fur. The identification of the genetics of WS type 2 owes a lot to observations of phenotypes of MITF-mutant mice.
Diagnosis
Microphthalmia is often diagnosed soon after birth. An initial diagnosis usually occurs after the eyes are inspected through the lids. In addition to visual examinations, measurements of the cornea are used in the diagnosis of this condition. An ultrasound may also be conducted to confirm whether the axial length of the eye is clinically below average (i.e. at least 2 standard deviations below the age-adjusted mean).When a case of microphthalmia is detected, the patient should visit an eye specialist as soon as possible. It is important for an ophthalmologist to conduct a thorough examination within 2 weeks after birth. The ophthalmologist will confirm the preliminary diagnosis and look for signs of other anomalies in both eyes. These abnormalities may include coloboma, optic nerve hypoplasia, retinal dystrophy, and cataract. Ultrasound may also be used to determine the presence of any internal eye issues, which may not otherwise be visible. It is possible for individuals with microphthalmia to have some vision in the affected eye(s). For this reason, the vision of infants with microphthalmia should be evaluated early on, even in severe cases. Pediatric vision tests along with electrodiagnostics are typically used to assess visual acuity.If no related symptoms are present, microphthalmia is defined as non-syndromic or isolated microphthalmia (MCOP). When occurring in conjunction with other developmental defects, it may be diagnosed as syndromic microphthalmia (MCOPS). Approximately 60 to 80% of microphthalmia cases are syndromic. Several types of MCOPS have been recognized based on their genetic causes:
Treatment
Microphthalmia cannot be cured. However, there are treatments options to manage the condition and its associated symptoms. When the affected eye(s) display some visual function, a patients eyesight can be improved (sometimes up to good state) by plus lenses, as a small eye is usually far-sighted. When one of the eyes is unaffected, caution should be taken to guard this good eye and preserve its vision. In these unilateral cases, eye glasses may be worn to offer a measure of physical protection.A key aspect of managing this condition is accounting for the small volume of the eye. The small orbit size characteristic of microphthalmia can impact the growth and structural development of the face after birth. As a result, microphthalmia can cause hemifacial asymmetry. This possibility is a particular concern for individuals with unilateral cases of microphthalmia. With one eye of average size, the asymmetry often becomes much more severe as the child ages. An axial length of less than 16 mm (0.63 in) indicates that a microphthalmic eyes growth will not be sufficient, and intervention will be necessary to reduce the degree of facial asymmetry.Minimizing facial asymmetry is important for cosmetic and structural reasons. In order to address the size discrepancy of the affected eye(s), it is important to begin eye socket expansion early in life. The face reaches 70% of its adult size by roughly 2 years of age, and 90% of its adult size by about 5.5 years of age. Additionally, the symmetry fostered by early socket expansion allows for a better prosthetic fit later in life. Typically, an infant begins wearing a conformer, or an unpainted ocular prosthesis, in the first weeks of life. The conformer is repeatedly replaced with a prothesis of a slightly larger size. This process, which takes place during the first 5 years of life, gradually enlarges the eye socket. Socket expansion through the use of implants of increasing size is another effective strategy.After socket expansion is complete, a painted prosthetic eye can be worn for cosmetic reasons. If the microphthalmic eye has functional vision, an affected individual may opt against wearing a painted prothesis. Lenses are also sometimes used for cosmetic purposes, such as a plus lens to enlarge the microphthalmic eye.
Epidemiology
Microphthalmia and anophthalmia combined are estimated to occur in about 1 in 10,000 births, though estimates have varied from 2 and 23 in 100,000 births. Approximately 3–11% of all blind children born globally have microphthalmia.
See also
References
Further reading
GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
GeneReviews/NCBI/NIH/UW entry on Microphthalmia with Linear Skin Defects Syndrome
OMIM-Online Mendelian Inheritance in Man
== External links == |
You are an assistant in medical learning. Your role is to clarify medical terminology, ensuring the information is both accurate and accessible. | I'm encountering the term 'Suicide attempt' in medical literature. What's its definition? | A suicide attempt is an attempt to die by suicide that results in survival. It may be referred to as a "failed" or "unsuccessful" suicide attempt, though these terms are discouraged by mental health professionals for implying that a suicide resulting in death is a successful and positive outcome.
Epidemiology
In the United States, the National Institute of Mental Health reports there are 11 nonfatal suicide attempts for every suicide death. The American Association of Suicidology reports higher numbers, stating that there are 25 suicide attempts for every suicide completion. The ratio of suicide attempts to suicide death is about 25:1 in youths, compared to about 4:1 in elderly. A 2008 review found that nonfatal self-injury is more common in women, and a separate study from 2008/2009 found suicidal thoughts higher among females, as well as significant differences between genders for suicide planning and suicide attempts.Suicide attempts are more common among adolescents in developing countries than developed ones. A 12-month prevalence of suicide attempt in developing countries between 2003 and 2015 was reported as 17%.
Parasuicide and self-injury
Without commonly agreed-upon operational definitions, some suicidology researchers regard many suicide attempts as parasuicide (para=near) or self harm behavior, rather than "true" suicide attempts, as in lacking suicidal intent.
Methods
Some suicide methods have higher rates of lethality than others. The use of firearms results in death 90% of the time. Wrist-slashing has a much lower lethality rate, comparatively. 75% of all suicide attempts are by drug overdose, a method that is often thwarted because the drug is nonlethal, or is used at a nonlethal dosage. These people survive 97% of the time.
Repetition
A nonfatal suicide attempt is the strongest known clinical predictor of eventual suicide. Suicide risk among self-harm patients is hundreds of times higher than in the general population. It is often estimated that about 10–15% of people who attempt suicide eventually die by suicide. The mortality risk is highest during the first months and years after the attempt: almost 1% of individuals who attempt suicide will die by suicide if the attempt is repeated within one year. Recent meta-analytic evidence suggests that the association between suicide attempt and suicidal death may not be as strong as it was thought before.
Outcomes
Suicide attempts can result in serious and permanent injuries and/or disabilities. 700,000 (or more) Americans survive a suicide attempt each year. People who attempt either hanging or carbon monoxide poisoning and survive can face permanent brain damage due to cerebral anoxia. People who take a drug overdose and survive can face severe organ damage (e.g., liver failure). Individuals who jump from a height and survive may face irreversible damage to multiple organs, as well as the spine and brain.
While a majority sustain injuries that allow them to be released following emergency room treatment, a significant minority—about 116,000—are hospitalized, of whom 110,000 are eventually discharged alive. Their average hospital stay is 79 days. Some 89,000, 17% of these people, are permanently disabled.
Criminalization of attempted suicide
Historically in the Christian church, people who attempted suicide were excommunicated because of the religiously polarizing nature of the topic. While previously criminally punishable, attempted suicide no longer is in most Western countries. It remains a criminal offense in most Islamic countries. In the late 19th century in Great Britain, attempted suicide was deemed to be equivalent to attempted murder and could be punished by hanging. In the United States, suicide is not illegal and almost no country in Europe currently considers attempted suicide to be a crime.In India, attempted suicide was decriminalized by the Mental Healthcare Act, 2017, while Singapore removed attempted suicide from their criminal code in 2020; previously it had been punishable by up to one-year in prison.Many other countries still prosecute suicide attempts. As of 2012, attempted suicide is a criminal offense in Uganda, and as of 2013, it is criminalized in Ghana.Despite having its own laws, Maryland still reserves the right to prosecute people under the English Common laws that were in place when America declared independence in 1776. These laws were used to convict a man for attempted suicide in 2018, resulting in a three-year suspended sentence and two years of supervised probation.
See also
International Survivors of Suicide Loss Day
Suicidal ideation
World Suicide Prevention Day
== References == |
You function as a medical dictionary. Offer comprehensive and accurate descriptions of medical terms, ensuring clarity and depth in your explanations. | What is the significance of the term 'Estradiol/progesterone' in the medical field? | Estradiol/progesterone (E2/P4), sold under the brand names Bijuva and Juvenum, is a combined estrogen and progestogen medication which is used in the treatment of menopausal symptoms in postmenopausal women. It contains estradiol, an estrogen, and progesterone, a progestogen, and is available in both oral and intramuscular formulations. E2/P4 differs from other estrogen–progestogen formulations in that the sex-hormonal agents used are bioidentical.
Bijuva (formerly TX-001HR/TX-12-001HR) is an oral combination of estradiol (E2), an estrogen, and progesterone (P4), a progestogen, which was developed by TherapeuticsMD and is approved in the United States for the treatment of menopausal symptoms in women. It is also under development for the treatment of endometrial hyperplasia in women. The medication contains 2 mg solubilized E2 and 200 mg P4 in each gelatin capsule. It is the first combination of E2 and P4 in oral capsule form that has been developed for clinical use. Bijuva is currently in phase III clinical trials for endometrial hyperplasia. The medication was approved by the Food and Drug Administration for the treatment of menopausal symptoms in October 2018.E2/P4 is available as an aqueous suspension of E2 and P4 encapsulated in microspheres for use by intramuscular injection once a month under the brand name Juvenum in Mexico. It was introduced for the treatment and prevention of menopausal symptoms like hot flashes, vulvovaginal symptoms, and osteoporosis in December 2014. The combination contains relatively low doses of E2 and P4 (1 mg and 20 mg, respectively) contained within microspheres that results in a slower release of the hormones. Studies of this formulation have been published.E2/P4 with 5 mg E2 and 150 to 300 mg P4 encapsulated in microspheres in an aqueous suspension has been studied as a once-a-month combined injectable contraceptive but has not been further developed or introduced for medical use. E2/P4 with 5 mg E2 and 100 mg P4 in a macrocrystalline aqueous suspension has also been studied as a once-a-month combined injectable contraceptive, but likewise was not further developed.As of April 2022, a vaginal ring containing E2/P4 (developmental code names DARE-HRT1 and JNP-0201) is under development for use in menopausal hormone therapy.
References
External links
"Estradiol mixture with progesterone". Drug Information Portal. U.S. National Library of Medicine. |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | Can you demystify the medical term 'Malaria' for me? | Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. Symptoms usually begin ten to fifteen days after being bitten by an infected mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria.Malaria is caused by single-celled microorganisms of the Plasmodium group. It is spread exclusively through bites of infected Anopheles mosquitoes. The mosquito bite introduces the parasites from the mosquitos saliva into a persons blood. The parasites travel to the liver where they mature and reproduce. Five species of Plasmodium can infect and be spread by humans. Most deaths are caused by P. falciparum, whereas P. vivax, P. ovale, and P. malariae generally cause a milder form of malaria. The species P. knowlesi rarely causes disease in humans. Malaria is typically diagnosed by the microscopic examination of blood using blood films, or with antigen-based rapid diagnostic tests. Methods that use the polymerase chain reaction to detect the parasites DNA have been developed, but are not widely used in areas where malaria is common due to their cost and complexity.The risk of disease can be reduced by preventing mosquito bites through the use of mosquito nets and insect repellents or with mosquito-control measures such as spraying insecticides and draining standing water. Several medications are available to prevent malaria for travellers in areas where the disease is common. Occasional doses of the combination medication sulfadoxine/pyrimethamine are recommended in infants and after the first trimester of pregnancy in areas with high rates of malaria. As of 2020, there is one vaccine which has been shown to reduce the risk of malaria by about 40% in children in Africa. A pre-print study of another vaccine has shown 77% vaccine efficacy, but this study has not yet passed peer review. Efforts to develop more effective vaccines are ongoing. The recommended treatment for malaria is a combination of antimalarial medications that includes artemisinin. The second medication may be either mefloquine, lumefantrine, or sulfadoxine/pyrimethamine. Quinine, along with doxycycline, may be used if artemisinin is not available. It is recommended that in areas where the disease is common, malaria is confirmed if possible before treatment is started due to concerns of increasing drug resistance. Resistance among the parasites has developed to several antimalarial medications; for example, chloroquine-resistant P. falciparum has spread to most malarial areas, and resistance to artemisinin has become a problem in some parts of Southeast Asia.The disease is widespread in the tropical and subtropical regions that exist in a broad band around the equator. This includes much of sub-Saharan Africa, Asia, and Latin America. In 2020 there were 241 million cases of malaria worldwide resulting in an estimated 627,000 deaths. Approximately 95% of the cases and deaths occurred in sub-Saharan Africa. Rates of disease have decreased from 2010 to 2014 but increased from 2015 to 2020. Malaria is commonly associated with poverty and has a significant negative effect on economic development. In Africa, it is estimated to result in losses of US$12 billion a year due to increased healthcare costs, lost ability to work, and adverse effects on tourism.
Signs and symptoms
Adults with malaria tend to experience chills and fever – classically in periodic intense bouts lasting around six hours, followed by a period of sweating and fever relief – as well as headache, fatigue, abdominal discomfort, and muscle pain. Children tend to have more general symptoms: fever, cough, vomiting, and diarrhea.Initial manifestations of the disease—common to all malaria species—are similar to flu-like symptoms, and can resemble other conditions such as sepsis, gastroenteritis, and viral diseases. The presentation may include headache, fever, shivering, joint pain, vomiting, hemolytic anemia, jaundice, hemoglobin in the urine, retinal damage, and convulsions.The classic symptom of malaria is paroxysm—a cyclical occurrence of sudden coldness followed by shivering and then fever and sweating, occurring every two days (tertian fever) in P. vivax and P. ovale infections, and every three days (quartan fever) for P. malariae. P. falciparum infection can cause recurrent fever every 36–48 hours, or a less pronounced and almost continuous fever.Symptoms typically begin 10–15 days after the initial mosquito bite, but can occur as late as several months after infection with some P. vivax strains. Travellers taking preventative malaria medications may develop symptoms once they stop taking the drugs.Severe malaria is usually caused by P. falciparum (often referred to as falciparum malaria). Symptoms of falciparum malaria arise 9–30 days after infection. Individuals with cerebral malaria frequently exhibit neurological symptoms, including abnormal posturing, nystagmus, conjugate gaze palsy (failure of the eyes to turn together in the same direction), opisthotonus, seizures, or coma.
Complications
Malaria has several serious complications. Among these is the development of respiratory distress, which occurs in up to 25% of adults and 40% of children with severe P. falciparum malaria. Possible causes include respiratory compensation of metabolic acidosis, noncardiogenic pulmonary oedema, concomitant pneumonia, and severe anaemia. Although rare in young children with severe malaria, acute respiratory distress syndrome occurs in 5–25% of adults and up to 29% of pregnant women. Coinfection of HIV with malaria increases mortality. Kidney failure is a feature of blackwater fever, where haemoglobin from lysed red blood cells leaks into the urine.Infection with P. falciparum may result in cerebral malaria, a form of severe malaria that involves encephalopathy. It is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever. An enlarged spleen, enlarged liver or both of these, severe headache, low blood sugar, and haemoglobin in the urine with kidney failure may occur. Complications may include spontaneous bleeding, coagulopathy, and shock.Malaria in pregnant women is an important cause of stillbirths, infant mortality, miscarriage and low birth weight, particularly in P. falciparum infection, but also with P. vivax.
Cause
Malaria is caused by infection with parasites in the genus Plasmodium. In humans, malaria is caused by six Plasmodium species: P. falciparum, P. malariae, P. ovale curtisi, P. ovale wallikeri, P. vivax and P. knowlesi. Among those infected, P. falciparum is the most common species identified (~75%) followed by P. vivax (~20%). Although P. falciparum traditionally accounts for the majority of deaths, recent evidence suggests that P. vivax malaria is associated with potentially life-threatening conditions about as often as with a diagnosis of P. falciparum infection. P. vivax proportionally is more common outside Africa. There have been documented human infections with several species of Plasmodium from higher apes; however, except for P. knowlesi—a zoonotic species that causes malaria in macaques—these are mostly of limited public health importance.
Parasites are typically introduced by the bite of an infected Anopheles mosquito. What these inoculated parasites, called "sporozoites", do in the skin and lymphatics, exactly, has yet to be accurately determined. However, a percentage of sporozoites follow the bloodstream to the liver, where they invade hepatocytes. They grow and divide in the liver for 2–10 days, with each infected hepatocyte eventually harboring up to 40,000 parasites. The infected hepatocytes break down, releasing this invasive form of Plasmodium cells, called "merozoites" into the bloodstream. In the blood, the merozoites rapidly invade individual red blood cells, replicating over 24–72 hours to form 16–32 new merozoites. The infected red blood cell lyses, and the new merozoites infect new red blood cells, resulting in a cycle that continuously amplifies the number of parasites in an infected person. However, most of the P. vivax replicating merozoite biomass is now (since 2021) known to be hidden in the spleen and bone marrow (perhaps elsewhere too), thereby supporting the astute, long-standing (since 2011) but previously ignored theory that non-circulating merozoites are the source many P. vivax malarial recurrences (see “Recurrent malaria” section below). Over rounds of this red blood cell infection cycle in the bloodstream and elsewhere, a small portion of parasites do not replicate, but instead develop into early sexual stage parasites called male and female "gametocytes". These gametocytes develop in the bone marrow for 11 days, then return to the blood circulation to await uptake by the bite of another mosquito. Once inside a mosquito, the gametocytes undergo sexual reproduction, and eventually form daughter sporozoites that migrate to the mosquitos salivary glands to be injected into a new host when the mosquito bites.The liver infection causes no symptoms; all symptoms of malaria result from the infection of red blood cells. Symptoms develop once there are more than around 100,000 parasites per milliliter of blood. Many of the symptoms associated with severe malaria are caused by the tendency of P. falciparum to bind to blood vessel walls, resulting in damage to the affected vessels and surrounding tissue. Parasites sequestered in the blood vessels of the lung contribute to respiratory failure. In the brain, they contribute to coma. In the placenta they contribute to low birthweight and preterm labor, and increase the risk of abortion and stillbirth. The destruction of red blood cells during infection often results in anemia, exacerbated by reduced production of new red blood cells during infection.Only female mosquitoes feed on blood; male mosquitoes feed on plant nectar and do not transmit the disease. Females of the mosquito genus Anopheles prefer to feed at night. They usually start searching for a meal at dusk, and continue through the night until they succeed. Malaria parasites can also be transmitted by blood transfusions, although this is rare.
Recurrent malaria
Symptoms of malaria can recur after varying symptom-free periods. Depending upon the cause, recurrence can be classified as recrudescence, relapse, or reinfection. Recrudescence is when symptoms return after a symptom-free period and the origin is parasites that survived in the blood as a result of inadequate or ineffective treatment. Relapse is when symptoms reappear after the parasites have been eliminated from the blood and the recurrence source is activated parasites which had persisted as dormant hypnozoites in liver cells. Relapse commonly occurs after 8–24 weeks and is often seen in P. vivax and P. ovale infections. However, relapse-like P. vivax recurrences are probably being over-attributed to hypnozoite activation. Some of them might have an extra-vascular or sequestered merozoite origin, making those recurrences recrudescences, not relapses. Newly recognised, non-hypnozoite, possible contributing sources to recurrent peripheral P. vivax parasitemia are erythrocytic forms in the bone marrow and spleen. P. vivax malaria cases in temperate areas often involve overwintering by hypnozoites, with relapses beginning the year after the mosquito bite. Reinfection means that the parasites responsible for the past infection were eliminated from the body but a new parasite(s) was introduced. Reinfection cannot readily be distinguished from relapse and recrudescence, although recurrence of infection within two weeks of treatment for the initial malarial manifestations is typically attributed to treatment failure. But doing this is not necessarily correct. People may develop some immunity when exposed to frequent infections.
Pathophysiology
Malaria infection develops via two phases: one that involves the liver (exoerythrocytic phase), and one that involves red blood cells, or erythrocytes (erythrocytic phase). When an infected mosquito pierces a persons skin to take a blood meal, sporozoites in the mosquitos saliva enter the bloodstream and migrate to the liver where they infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.After a potential dormant period in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage of the life cycle. The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their host cells to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from simultaneous waves of merozoites escaping and infecting red blood cells.Some P. vivax sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead, produce hypnozoites that remain dormant for periods ranging from several months (7–10 months is typical) to several years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in P. vivax infections, although their existence in P. ovale is uncertain.The parasite is relatively protected from attack by the bodys immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen. The blockage of the microvasculature causes symptoms such as those in placental malaria. Sequestered red blood cells can breach the blood–brain barrier and cause cerebral malaria.
Genetic resistance
According to a 2005 review, due to the high levels of mortality and morbidity caused by malaria—especially the P. falciparum species—it has placed the greatest selective pressure on the human genome in recent history. Several genetic factors provide some resistance to it including sickle cell trait, thalassaemia traits, glucose-6-phosphate dehydrogenase deficiency, and the absence of Duffy antigens on red blood cells.The impact of sickle cell trait on malaria immunity illustrates some evolutionary trade-offs that have occurred because of endemic malaria. Sickle cell trait causes a change in the haemoglobin molecule in the blood. Normally, red blood cells have a very flexible, biconcave shape that allows them to move through narrow capillaries; however, when the modified haemoglobin S molecules are exposed to low amounts of oxygen, or crowd together due to dehydration, they can stick together forming strands that cause the cell to distort into a curved sickle shape. In these strands, the molecule is not as effective in taking or releasing oxygen, and the cell is not flexible enough to circulate freely. In the early stages of malaria, the parasite can cause infected red cells to sickle, and so they are removed from circulation sooner. This reduces the frequency with which malaria parasites complete their life cycle in the cell. Individuals who are homozygous (with two copies of the abnormal haemoglobin beta allele) have sickle-cell anaemia, while those who are heterozygous (with one abnormal allele and one normal allele) experience resistance to malaria without severe anaemia. Although the shorter life expectancy for those with the homozygous condition would tend to disfavour the traits survival, the trait is preserved in malaria-prone regions because of the benefits provided by the heterozygous form.
Liver dysfunction
Liver dysfunction as a result of malaria is uncommon and usually only occurs in those with another liver condition such as viral hepatitis or chronic liver disease. The syndrome is sometimes called malarial hepatitis. While it has been considered a rare occurrence, malarial hepatopathy has seen an increase, particularly in Southeast Asia and India. Liver compromise in people with malaria correlates with a greater likelihood of complications and death.
Diagnosis
Due to the non-specific nature of malaria symptoms, diagnosis is typically suspected based on symptoms and travel history, then confirmed with a parasitological test. In areas where malaria is common, the World Health Organization (WHO) recommends clinicians suspect malaria in any person who reports having fevers, or who has a current temperature above 37.5 °C without any other obvious cause. Malaria should similarly be suspected in children with signs of anemia: pale palms or a laboratory test showing hemoglobin levels below 8 grams per deciliter of blood. In areas with little to no malaria, the WHO recommends only testing people with possible exposure to malaria (typically travel to a malaria-endemic area) and unexplained fever.Malaria is usually confirmed by the microscopic examination of blood films or by antigen-based rapid diagnostic tests (RDT). Microscopy – i.e. examining Giemsa-stained blood with a light microscope – is the gold standard for malaria diagnosis. Microscopists typically examine both a "thick film" of blood, allowing them to scan many blood cells in a short time, and a "thin film" of blood, allowing them to clearly see individual parasites and identify the infecting Plasmodium species. Under typical field laboratory conditions, a microscopist can detect parasites when there are at least 100 parasites per microliter of blood, which is around the lower range of symptomatic infection. Microscopic diagnosis is relatively resource intensive, requiring trained personnel, specific equipment, electricity, and a consistent supply of microscopy slides and stains.In places where microscopy is unavailable, malaria is diagnosed with RDTs, rapid antigen tests that detect parasite proteins in a fingerstick blood sample. A variety of RDTs are commercially available, targeting the parasite proteins histidine rich protein 2 (HRP2, detects P. falciparum only), lactate dehydrogenase, or aldolase. The HRP2 test is widely used in Africa, where P. falciparum predominates. However, since HRP2 persists in the blood for up to five weeks after an infection is treated, an HRP2 test sometimes cannot distinguish whether someone currently has malaria or previously had it. Additionally, some P. falciparum parasites in the Amazon region lack the HRP2 gene, complicating detection. RDTs are fast and easily deployed to places without full diagnostic laboratories. However they give considerably less information than microscopy, and sometimes vary in quality from producer to producer and lot to lot.Serological tests to detect antibodies against Plasmodium from the blood have been developed, but are not used for malaria diagnosis due to their relatively poor sensitivity and specificity. Highly sensitive nucleic acid amplification tests have been developed, but are not used clinically due to their relatively high cost, and poor specificity for active infections.
Classification
Malaria is classified into either "severe" or "uncomplicated" by the World Health Organization (WHO). It is deemed severe when any of the following criteria are present, otherwise it is considered uncomplicated.
Decreased consciousness
Significant weakness such that the person is unable to walk
Inability to feed
Two or more convulsions
Low blood pressure (less than 70 mmHg in adults and 50 mmHg in children)
Breathing problems
Circulatory shock
Kidney failure or haemoglobin in the urine
Bleeding problems, or hemoglobin less than 50 g/L (5 g/dL)
Pulmonary oedema
Blood glucose less than 2.2 mmol/L (40 mg/dL)
Acidosis or lactate levels of greater than 5 mmol/L
A parasite level in the blood of greater than 100,000 per microlitre (μL) in low-intensity transmission areas, or 250,000 per μL in high-intensity transmission areasCerebral malaria is defined as a severe P. falciparum-malaria presenting with neurological symptoms, including coma (with a Glasgow coma scale less than 11, or a Blantyre coma scale less than 3), or with a coma that lasts longer than 30 minutes after a seizure.
Prevention
Methods used to prevent malaria include medications, mosquito elimination and the prevention of bites. As of 2020, there is one vaccine for malaria (known as RTS,S) which is licensed for use. The presence of malaria in an area requires a combination of high human population density, high anopheles mosquito population density and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite eventually disappears from that area, as happened in North America, Europe, and parts of the Middle East. However, unless the parasite is eliminated from the whole world, it could re-establish if conditions revert to a combination that favors the parasites reproduction. Furthermore, the cost per person of eliminating anopheles mosquitoes rises with decreasing population density, making it economically unfeasible in some areas.Prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the initial costs required are out of reach of many of the worlds poorest people. There is a wide difference in the costs of control (i.e. maintenance of low endemicity) and elimination programs between countries. For example, in China—whose government in 2010 announced a strategy to pursue malaria elimination in the Chinese provinces—the required investment is a small proportion of public expenditure on health. In contrast, a similar programme in Tanzania would cost an estimated one-fifth of the public health budget. In 2021, the World Health Organization confirms that China has eliminated malaria. In areas where malaria is common, children under five years old often have anaemia, which is sometimes due to malaria. Giving children with anaemia in these areas preventive antimalarial medication improves red blood cell levels slightly but does not affect the risk of death or need for hospitalisation.
Mosquito control
Vector control refers to methods used to decrease malaria by reducing the levels of transmission by mosquitoes. For individual protection, the most effective insect repellents are based on DEET or picaridin. However, there is insufficient evidence that mosquito repellents can prevent malaria infection. Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) are effective, have been commonly used to prevent malaria, and their use has contributed significantly to the decrease in malaria in the 21st century. ITNs and IRS may not be sufficient to eliminate the disease, as these interventions depend on how many people use nets, how many gaps in insecticide there are (low coverage areas), if people are not protected when outside of the home, and an increase in mosquitoes that are resistant to insecticides. Modifications to peoples houses to prevent mosquito exposure may be an important long term prevention measure.
Insecticide-treated nets
Mosquito nets help keep mosquitoes away from people and reduce infection rates and transmission of malaria. Nets are not a perfect barrier and are often treated with an insecticide designed to kill the mosquito before it has time to find a way past the net. Insecticide-treated nets (ITNs) are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net. Between 2000 and 2008, the use of ITNs saved the lives of an estimated 250,000 infants in Sub-Saharan Africa. About 13% of households in Sub-Saharan countries owned ITNs in 2007 and 31% of African households were estimated to own at least one ITN in 2008. In 2000, 1.7 million (1.8%) African children living in areas of the world where malaria is common were protected by an ITN. That number increased to 20.3 million (18.5%) African children using ITNs in 2007, leaving 89.6 million children unprotected and to 68% African children using mosquito nets in 2015. Most nets are impregnated with pyrethroids, a class of insecticides with low toxicity. They are most effective when used from dusk to dawn. It is recommended to hang a large "bed net" above the center of a bed and either tuck the edges under the mattress or make sure it is large enough such that it touches the ground. ITNs are beneficial towards pregnancy outcomes in malaria-endemic regions in Africa but more data is needed in Asia and Latin America.In areas of high malaria resistance, piperonyl butoxide (PBO) combined with pyrethroids in mosquito netting is effective in reducing malaria infection rates. Questions remain concerning the durability of PBO on nets as the impact on mosquito mortality was not sustained after twenty washes in experimental trials.
Indoor residual spraying
Indoor residual spraying is the spraying of insecticides on the walls inside a home. After feeding, many mosquitoes rest on a nearby surface while digesting the bloodmeal, so if the walls of houses have been coated with insecticides, the resting mosquitoes can be killed before they can bite another person and transfer the malaria parasite. As of 2006, the World Health Organization recommends 12 insecticides in IRS operations, including DDT and the pyrethroids cyfluthrin and deltamethrin. This public health use of small amounts of DDT is permitted under the Stockholm Convention, which prohibits its agricultural use. One problem with all forms of IRS is insecticide resistance. Mosquitoes affected by IRS tend to rest and live indoors, and due to the irritation caused by spraying, their descendants tend to rest and live outdoors, meaning that they are less affected by the IRS. Communities using insecticide treated nets, in addition to indoor residual spraying with non-pyrethroid-like insecticides found associated reductions in malaria. Additionally, the use of pyrethroid-like insecticides in addition to indoor residual spraying did not result in a detectable additional benefit in communities using insecticide treated nets.
Housing modifications
Housing is a risk factor for malaria and modifying the house as a prevention measure may be a sustainable strategy that does not rely on the effectiveness of insecticides such as pyrethroids. The physical environment inside and outside the home that may improve the density of mosquitoes are considerations. Examples of potential modifications include how close the home is to mosquito breeding sites, drainage and water supply near the home, availability of mosquito resting sites (vegetation around the home), the proximity to live stock and domestic animals, and physical improvements or modifications to the design of the home to prevent mosquitoes from entering.
Other mosquito control methods
People have tried a number of other methods to reduce mosquito bites and slow the spread of malaria. Efforts to decrease mosquito larvae by decreasing the availability of open water where they develop, or by adding substances to decrease their development, are effective in some locations. Electronic mosquito repellent devices, which make very high-frequency sounds that are supposed to keep female mosquitoes away, have no supporting evidence of effectiveness. There is a low certainty evidence that fogging may have an effect on malaria transmission. Larviciding by hand delivery of chemical or microbial insecticides into water bodies containing low larval distribution may reduce malarial transmission. There is insufficient evidence to determine whether larvivorous fish can decrease mosquito density and transmission in the area.
Medications
There are a number of medications that can help prevent or interrupt malaria in travellers to places where infection is common. Many of these medications are also used in treatment. In places where Plasmodium is resistant to one or more medications, three medications—mefloquine, doxycycline, or the combination of atovaquone/proguanil (Malarone)—are frequently used for prevention. Doxycycline and the atovaquone/proguanil are better tolerated while mefloquine is taken once a week. Areas of the world with chloroquine-sensitive malaria are uncommon. Antimalarial mass drug administration to an entire population at the same time may reduce the risk of contracting malaria in the population, however the effectiveness of mass drug administration may vary depending on the prevalence of malaria in the area. Other factors such as drug administration plus other protective measures such as mosiquito control, the proportion of people treated in the area, and the risk of reinfection with malaria may play a role in the effectiveness of mass drug treatment approaches.The protective effect does not begin immediately, and people visiting areas where malaria exists usually start taking the drugs one to two weeks before they arrive, and continue taking them for four weeks after leaving (except for atovaquone/proguanil, which only needs to be started two days before and continued for seven days afterward). The use of preventive drugs is often not practical for those who live in areas where malaria exists, and their use is usually given only to pregnant women and short-term visitors. This is due to the cost of the drugs, side effects from long-term use, and the difficulty in obtaining antimalarial drugs outside of wealthy nations. During pregnancy, medication to prevent malaria has been found to improve the weight of the baby at birth and decrease the risk of anaemia in the mother. The use of preventive drugs where malaria-bearing mosquitoes are present may encourage the development of partial resistance.Giving antimalarial drugs to infants through intermittent preventive therapy can reduce the risk of having malaria infection, hospital admission, and anaemia.Mefloquine is more effective than sulfadoxine-pyrimethamine in preventing malaria for HIV-negative pregnant women. Cotrimoxazole is effective in preventing malaria infection and reduce the risk of getting anaemia in HIV-positive women. Giving sulfadoxine-pyrimethamine for three or more doses as intermittent preventive therapy is superior than two doses for HIV-positive women living in malaria-endemic areas.Prompt treatment of confirmed cases with artemisinin-based combination therapies (ACTs) may also reduce transmission.
Others
Community participation and health education strategies promoting awareness of malaria and the importance of control measures have been successfully used to reduce the incidence of malaria in some areas of the developing world. Recognising the disease in the early stages can prevent it from becoming fatal. Education can also inform people to cover over areas of stagnant, still water, such as water tanks that are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. This is generally used in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas. Intermittent preventive therapy is another intervention that has been used successfully to control malaria in pregnant women and infants, and in preschool children where transmission is seasonal.
Treatment
Malaria is treated with antimalarial medications; the ones used depends on the type and severity of the disease. While medications against fever are commonly used, their effects on outcomes are not clear. Providing free antimalarial drugs to households may reduce childhood deaths when used appropriately. Programmes which presumptively treat all causes of fever with antimalarial drugs may lead to overuse of antimalarials and undertreat other causes of fever. Nevertheless, the use of malaria rapid-diagnostic kits can help to reduce over-usage of antimalarials.
Uncomplicated malaria
Simple or uncomplicated malaria may be treated with oral medications. Artemisinin drugs are effective and safe in treating uncomplicated malaria. Artemisinin in combination with other antimalarials (known as artemisinin-combination therapy, or ACT) is about 90% effective when used to treat uncomplicated malaria. The most effective treatment for P. falciparum infection is the use of ACT, which decreases resistance to any single drug component. Artemether-lumefantrine (six-dose regimen) is more effective than the artemether-lumefantrine (four-dose regimen) or other regimens not containing artemisinin derivatives in treating falciparum malaria. Another recommended combination is dihydroartemisinin and piperaquine. Artemisinin-naphthoquine combination therapy showed promising results in treating falciparum malaria. However, more research is needed to establish its efficacy as a reliable treatment. Artesunate plus mefloquine performs better than mefloquine alone in treating uncomplicated falciparum malaria in low transmission settings. Atovaquone-proguanil is effective against uncomplicated falciparum with a possible failure rate of 5% to 10%; the addition of artesunate may reduce failure rate. Azithromycin monotherapy or combination therapy has not shown effectiveness in treating plasmodium or vivax malaria. Amodiaquine plus sulfadoxine-pyrimethamine may achieve less treatment failures when compared to sulfadoxine-pyrimethamine alone in uncomplicated falciparum malaria. There is insufficient data on chlorproguanil-dapsone in treating uncomplicated falciparum malaria. The addition of primaquine with artemisinin-based combination therapy for falciparum malaria reduces its transmission at day 3-4 and day 8 of infection. Sulfadoxine-pyrimethamine plus artesunate is better than sulfadoxine-pyrimethamine plus amodiaquine in controlling treatment failure at day 28. However, the latter is better than the former in reducing gametocytes in blood at day 7.Infection with P. vivax, P. ovale or P. malariae usually does not require hospitalisation. Treatment of P. vivax requires both treatment of blood stages (with chloroquine or artemisinin-based combination therapy) and clearance of liver forms with an 8-aminoquinoline agent such as primaquine or tafenoquine.To treat malaria during pregnancy, the WHO recommends the use of quinine plus clindamycin early in the pregnancy (1st trimester), and ACT in later stages (2nd and 3rd trimesters). There is limited safety data on the antimalarial drugs in pregnancy.
Severe and complicated malaria
Cases of severe and complicated malaria are almost always caused by infection with P. falciparum. The other species usually cause only febrile disease. Severe and complicated malaria cases are medical emergencies since mortality rates are high (10% to 50%).Recommended treatment for severe malaria is the intravenous use of antimalarial drugs. For severe malaria, parenteral artesunate was superior to quinine in both children and adults. In another systematic review, artemisinin derivatives (artemether and arteether) were as efficacious as quinine in the treatment of cerebral malaria in children. Treatment of severe malaria involves supportive measures that are best done in a critical care unit. This includes the management of high fevers and the seizures that may result from it. It also includes monitoring for poor breathing effort, low blood sugar, and low blood potassium. Artemisinin derivatives have the same or better efficacy than quinolones in preventing deaths in severe or complicated malaria. Quinine loading dose helps to shorten the duration of fever and increases parasite clearance from the body. There is no difference in effectiveness when using intrarectal quinine compared to intravenous or intramuscular quinine in treating uncomplicated/complicated falciparum malaria. There is insufficient evidence for intramuscular arteether to treat severe malaria. The provision of rectal artesunate before transfer to hospital may reduce the rate of death for children with severe malaria.Cerebral malaria is the form of severe and complicated malaria with the worst neurological symptoms. There is insufficient data on whether osmotic agents such as mannitol or urea are effective in treating cerebral malaria. Routine phenobarbitone in cerebral malaria is associated with fewer convulsions but possibly more deaths. There is no evidence that steroids would bring treatment benefits for cerebral malaria.Managing Cerebral Malaria
Cerebral malaria usually makes a patient comatose, if the cause of the coma is in doubt, test for other locally prevalent causes of encephalopathy (bacterial, viral or fungal infection) should be carried out. In areas where there is a high prevalence of malaria infection (e.g. tropical region) treatment can start without testing first. To manage the cerebral malaria when confirmed the following can be done:
Patients in coma should be given meticulous nursing care ( monitor vital signs, turn patient every 2 hours, avoid lying the patient in a wet bed etc.)
A sterile urethral catheter should be inserted to help with urinating
To aspirate stomach content, a sterile nasogastric tube should be inserted.
In the occasion of convulsions, a slow intravenous injection of benzodiazepine is administered.There is insufficient evidence to show that blood transfusion is useful in either reducing deaths for children with severe anaemia or in improving their haematocrit in one month. There is insufficient evidence that iron chelating agents such as deferoxamine and deferiprone improve outcomes of those with malaria falciparum infection.
Resistance
Drug resistance poses a growing problem in 21st-century malaria treatment. In the 2000s (decade), malaria with partial resistance to artemisins emerged in Southeast Asia. Resistance is now common against all classes of antimalarial drugs apart from artemisinins. Treatment of resistant strains became increasingly dependent on this class of drugs. The cost of artemisinins limits their use in the developing world. Malaria strains found on the Cambodia–Thailand border are resistant to combination therapies that include artemisinins, and may, therefore, be untreatable. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years and the availability of substandard artemisinins likely drove the selection of the resistant phenotype. Resistance to artemisinin has been detected in Cambodia, Myanmar, Thailand, and Vietnam, and there has been emerging resistance in Laos. Resistance to the combination of artemisinin and piperaquine was first detected in 2013 in Cambodia, and by 2019 had spread across Cambodia and into Laos, Thailand and Vietnam (with up to 80 percent of malaria parasites resistant in some regions).There is insufficient evidence in unit packaged antimalarial drugs in preventing treatment failures of malaria infection. However, if supported by training of healthcare providers and patient information, there is improvement in compliance of those receiving treatment.
Prognosis
When properly treated, people with malaria can usually expect a complete recovery. However, severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases of the disease, fatality rates can reach 20%, even with intensive care and treatment. Over the longer term, developmental impairments have been documented in children who have had episodes of severe malaria. Chronic infection without severe disease can occur in an immune-deficiency syndrome associated with a decreased responsiveness to Salmonella bacteria and the Epstein–Barr virus.During childhood, malaria causes anaemia during a period of rapid brain development, and also direct brain damage resulting from cerebral malaria. Some survivors of cerebral malaria have an increased risk of neurological and cognitive deficits, behavioural disorders, and epilepsy. Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups.
Epidemiology
The WHO estimates that in 2019 there were 229 million new cases of malaria resulting in 409,000 deaths. Children under 5 years old are the most affected, accounting for 67% of malaria deaths worldwide in 2019. About 125 million pregnant women are at risk of infection each year; in Sub-Saharan Africa, maternal malaria is associated with up to 200,000 estimated infant deaths yearly. There are about 10,000 malaria cases per year in Western Europe, and 1300–1500 in the United States. The United States eradicated malaria as a major public health concern in 1951, though small outbreaks persist. About 900 people died from the disease in Europe between 1993 and 2003. Both the global incidence of disease and resulting mortality have declined in recent years. According to the WHO and UNICEF, deaths attributable to malaria in 2015 were reduced by 60% from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies. In 2012, there were 207 million cases of malaria. That year, the disease is estimated to have killed between 473,000 and 789,000 people, many of whom were children in Africa. Efforts at decreasing the disease in Africa since 2000 have been partially effective, with rates of the disease dropping by an estimated forty percent on the continent.Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; in Sub-Saharan Africa, 85–90% of malaria fatalities occur. An estimate for 2009 reported that countries with the highest death rate per 100,000 of population were Ivory Coast (86.15), Angola (56.93) and Burkina Faso (50.66). A 2010 estimate indicated the deadliest countries per population were Burkina Faso, Mozambique and Mali. The Malaria Atlas Project aims to map global levels of malaria, providing a way to determine the global spatial limits of the disease and to assess disease burden. This effort led to the publication of a map of P. falciparum endemicity in 2010 and an update in 2019. As of 2010, about 100 countries have endemic malaria. Every year, 125 million international travellers visit these countries, and more than 30,000 contract the disease.The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other. Malaria is prevalent in tropical and subtropical regions because of rainfall, consistent high temperatures and high humidity, along with stagnant waters where mosquito larvae readily mature, providing them with the environment they need for continuous breeding. In drier areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall. Malaria is more common in rural areas than in cities. For example, several cities in the Greater Mekong Subregion of Southeast Asia are essentially malaria-free, but the disease is prevalent in many rural regions, including along international borders and forest fringes. In contrast, malaria in Africa is present in both rural and urban areas, though the risk is lower in the larger cities.Since 1900 there has been substantial change in temperature and rainfall over Africa. However, factors that contribute to how rainfall results in water for mosquito breeding are complex, incorporating the extent to which it is absorbed into soil and vegetation for example, or rates of runoff and evaporation. Recent research has provided a more in-depth picture of conditions across Africa, combining a malaria climatic suitability model with a continental-scale model representing real-world hydrological processes.
History
Although the parasite responsible for P. falciparum malaria has been in existence for 50,000–100,000 years, the population size of the parasite did not increase until about 10,000 years ago, concurrently with advances in agriculture and the development of human settlements. Close relatives of the human malaria parasites remain common in chimpanzees. Some evidence suggests that the P. falciparum malaria may have originated in gorillas.References to the unique periodic fevers of malaria are found throughout history. Hippocrates described periodic fevers, labelling them tertian, quartan, subtertian and quotidian. The Roman Columella associated the disease with insects from swamps. Malaria may have contributed to the decline of the Roman Empire, and was so pervasive in Rome that it was known as the "Roman fever". Several regions in ancient Rome were considered at-risk for the disease because of the favourable conditions present for malaria vectors. This included areas such as southern Italy, the island of Sardinia, the Pontine Marshes, the lower regions of coastal Etruria and the city of Rome along the Tiber. The presence of stagnant water in these places was preferred by mosquitoes for breeding grounds. Irrigated gardens, swamp-like grounds, run-off from agriculture, and drainage problems from road construction led to the increase of standing water.
The term malaria originates from Mediaeval Italian: mala aria—"bad air"; the disease was formerly called ague or marsh fever due to its association with swamps and marshland. The term appeared in English at least as early as 1768. Malaria was once common in most of Europe and North America, where it is no longer endemic, though imported cases do occur.Malaria is not referenced in the medical books of the Mayans or Aztecs. European settlers and the West Africans they enslaved likely brought malaria to the Americas starting in the 16th century.Scientific studies on malaria made their first significant advance in 1880, when Charles Louis Alphonse Laveran—a French army doctor working in the military hospital of Constantine in Algeria—observed parasites inside the red blood cells of infected people for the first time. He, therefore, proposed that malaria is caused by this organism, the first time a protist was identified as causing disease. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. A year later, Carlos Finlay, a Cuban doctor treating people with yellow fever in Havana, provided strong evidence that mosquitoes were transmitting disease to and from humans. This work followed earlier suggestions by Josiah C. Nott, and work by Sir Patrick Manson, the "father of tropical medicine", on the transmission of filariasis.
In April 1894, a Scottish physician, Sir Ronald Ross, visited Sir Patrick Manson at his house on Queen Anne Street, London. This visit was the start of four years of collaboration and fervent research that culminated in 1897 when Ross, who was working in the Presidency General Hospital in Calcutta, proved the complete life-cycle of the malaria parasite in mosquitoes. He thus proved that the mosquito was the vector for malaria in humans by showing that certain mosquito species transmit malaria to birds. He isolated malaria parasites from the salivary glands of mosquitoes that had fed on infected birds. For this work, Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius. The findings of Finlay and Ross were later confirmed by a medical board headed by Walter Reed in 1900. Its recommendations were implemented by William C. Gorgas in the health measures undertaken during construction of the Panama Canal. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against the disease.In 1896, Amico Bignami discussed the role of mosquitoes in malaria. In 1898, Bignami, Giovanni Battista Grassi and Giuseppe Bastianelli succeeded in showing experimentally the transmission of malaria in humans, using infected mosquitoes to contract malaria themselves which they presented in November 1898 to the Accademia dei Lincei.
The first effective treatment for malaria came from the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. The indigenous peoples of Peru made a tincture of cinchona to control fever. Its effectiveness against malaria was found and the Jesuits introduced the treatment to Europe around 1640; by 1677, it was included in the London Pharmacopoeia as an antimalarial treatment. It was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou.Quinine was the predominant malarial medication until the 1920s when other medications began to appear. In the 1940s, chloroquine replaced quinine as the treatment of both uncomplicated and severe malaria until resistance supervened, first in Southeast Asia and South America in the 1950s and then globally in the 1980s.The medicinal value of Artemisia annua has been used by Chinese herbalists in traditional Chinese medicines for 2,000 years. In 1596, Li Shizhen recommended tea made from qinghao specifically to treat malaria symptoms in his "Compendium of Materia Medica". Artemisinins, discovered by Chinese scientist Tu Youyou and colleagues in the 1970s from the plant Artemisia annua, became the recommended treatment for P. falciparum malaria, administered in severe cases in combination with other antimalarials. Tu says she was influenced by a traditional Chinese herbal medicine source, The Handbook of Prescriptions for Emergency Treatments, written in 340 by Ge Hong. For her work on malaria, Tu Youyou received the 2015 Nobel Prize in Physiology or Medicine.Plasmodium vivax was used between 1917 and the 1940s for malariotherapy—deliberate injection of malaria parasites to induce a fever to combat certain diseases such as tertiary syphilis. In 1927, the inventor of this technique, Julius Wagner-Jauregg, received the Nobel Prize in Physiology or Medicine for his discoveries. The technique was dangerous, killing about 15% of patients, so it is no longer in use.
The first pesticide used for indoor residual spraying was DDT. Although it was initially used exclusively to combat malaria, its use quickly spread to agriculture. In time, pest control, rather than disease control, came to dominate DDT use, and this large-scale agricultural use led to the evolution of pesticide-resistant mosquitoes in many regions. The DDT resistance shown by Anopheles mosquitoes can be compared to antibiotic resistance shown by bacteria. During the 1960s, awareness of the negative consequences of its indiscriminate use increased, ultimately leading to bans on agricultural applications of DDT in many countries in the 1970s. Before DDT, malaria was successfully eliminated or controlled in tropical areas like Brazil and Egypt by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larval stages, for example by applying the highly toxic arsenic compound Paris Green to places with standing water.Malaria vaccines have been an elusive goal of research. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunising mice with live, radiation-attenuated sporozoites, which provided significant protection to the mice upon subsequent injection with normal, viable sporozoites. Since the 1970s, there has been a considerable effort to develop similar vaccination strategies for humans. The first vaccine, called RTS,S, was approved by European regulators in 2015.
Names
Various types of malaria have been called by the names below:
Eradication efforts
Malaria has been successfully eliminated or significantly reduced in certain areas, but not globally. Malaria was once common in the United States, but the US eliminated malaria from most parts of the country in the early 20th century using vector control programs, which combined the monitoring and treatment of infected humans, draining of wetland breeding grounds for agriculture and other changes in water management practices, and advances in sanitation, including greater use of glass windows and screens in dwellings. The use of the pesticide DDT and other means eliminated malaria from the remaining pockets in southern states of the US the 1950s, as part of the National Malaria Eradication Program. Most of Europe, North America, Australia, North Africa and the Caribbean, and parts of South America, Asia and Southern Africa have also eliminated malaria. The WHO defines "elimination" (or "malaria-free") as having no domestic transmission (indigenous cases) for the past three years. They also define "pre-elimination" and "elimination" stages when a country has fewer than 5 or 1, respectively, cases per 1000 people at risk per year.
In 1955 the WHO launched the Global Malaria Eradication Program (GMEP), which supported substantial reductions in malaria cases in some countries, including India. However, due to vector and parasite resistance and other factors, the feasibility of eradicating malaria with the strategy used at the time and resources available led to waning support for the program. WHO suspended the program in 1969.
Target 6C of the Millennium Development Goals included reversal of the global increase in malaria incidence by 2015, with specific targets for children under 5 years old. Since 2000, support for malaria eradication increased, although some actors in the global health community (including voices within the WHO) view malaria eradication as a premature goal and suggest that the establishment of strict deadlines for malaria eradication may be counterproductive as they are likely to be missed.In 2006, the organization Malaria No More set a public goal of eliminating malaria from Africa by 2015, and the organization claimed they planned to dissolve if that goal was accomplished. In 2007, World Malaria Day was established by the 60th session of the World Health Assembly. As of 2018, they are still functioning.
As of 2012, The Global Fund to Fight AIDS, Tuberculosis, and Malaria has distributed 230 million insecticide-treated nets intended to stop mosquito-borne transmission of malaria. The U.S.-based Clinton Foundation has worked to manage demand and stabilize prices in the artemisinin market. Other efforts, such as the Malaria Atlas Project, focus on analysing climate and weather information required to accurately predict malaria spread based on the availability of habitat of malaria-carrying parasites. The Malaria Policy Advisory Committee (MPAC) of the World Health Organization (WHO) was formed in 2012, "to provide strategic advice and technical input to WHO on all aspects of malaria control and elimination". In November 2013, WHO and the malaria vaccine funders group set a goal to develop vaccines designed to interrupt malaria transmission with malaria eradications long-term goal.In 2015 the WHO targeted a 90% reduction in malaria deaths by 2030, and Bill Gates said in 2016 that he thought global eradication would be possible by 2040. According to the WHOs World Malaria Report 2015, the global mortality rate for malaria fell by 60% between 2000 and 2015. The WHO targeted a further 90% reduction between 2015 and 2030, with a 40% reduction and eradication in 10 countries by 2020. However, the 2020 goal was missed with a slight increase in cases compared to 2015.Before 2016, the Global Fund against HIV/AIDS, Tuberculosis and Malaria had provided 659 million ITN (insecticide treated bed nets), organise support and education to prevents malaria. The challenges are high due to the lack of funds, the fragile health structure and the remote indigenous population that could be hard to reach and educate. Most of indigenous population rely on self-diagnosis, self-treatment, healer, and traditional medicine. The WHO applied for fund to the Gates Foundation which favour the action of malaria eradication in 2007. Six countries, the United Arab Emirates, Morocco, Armenia, Turkmenistan, Kyrgyzstan, and Sri Lanka managed to have no endemic cases of malaria for three consecutive years and certified malaria-free by the WHO despite the stagnation of the funding in 2010. The funding is essential to finance the cost of medication and hospitalisation cannot be supported by the poor countries where the disease is widely spread. The goal of eradication has not been met nevertheless the decrease rate of the disease is considerable.
While 31 out of 92 endemic countries were estimated to be on track with the WHO goals for 2020, 15 countries reported an increase of 40% or more between 2015 and 2020. Between 2000 and 30 June 2021, twelve countries were certified by the WHO as being malaria-free. Argentina and Algeria were declared free of malaria in 2019. El Salvador and China were declared malaria-free in the first half of 2021.Regional disparities were evident: Southeast Asia was on track to meet WHOs 2020 goals, while Africa, Americas, Eastern Mediterranean and West Pacific regions were off-track. The six Greater Mekong Subregion countries aim for elimination of P. falciparum transmitted malaria by 2025 and elimination of all malaria by 2030, having achieved a 97% and 90% reduction of cases respectively since 2000. Ahead of World Malaria Day, 25 April 2021, WHO named 25 countries in which it is working to eliminate malaria by 2025 as part of its E-2025 initiative.A major challenge to malaria elimination is the persistence of malaria in border regions, making international cooperation crucial.One of the targets of Goal 3 of the UNs Sustainable Development Goals is to end the malaria epidemic in all countries by 2030.
In 2018, WHO announced that Paraguay was free of malaria, after a national malaria eradication effort that began in 1950.As of 2019, the eradication process is ongoing, but it will be difficult to achieve a world free of malaria with the current approaches and tools. Only one malaria vaccine is licensed for use, and it shows relatively low effectiveness, while several other vaccine candidates in clinical trials aim to provide protection for children in endemic areas and reduce the speed of malaria transmission. Approaches may require investing more in research and greater primary health care. Continuing surveillance will also be important to prevent the return of malaria in countries where the disease has been eliminated.
Society and culture
Economic impact
Malaria is not just a disease commonly associated with poverty: some evidence suggests that it is also a cause of poverty and a major hindrance to economic development. Although tropical regions are most affected, malarias furthest influence reaches into some temperate zones that have extreme seasonal changes. The disease has been associated with major negative economic effects on regions where it is widespread. During the late 19th and early 20th centuries, it was a major factor in the slow economic development of the American southern states.A comparison of average per capita GDP in 1995, adjusted for parity of purchasing power, between countries with malaria and countries without malaria gives a fivefold difference (US$1,526 versus US$8,268). In the period 1965 to 1990, countries where malaria was common had an average per capita GDP that increased only 0.4% per year, compared to 2.4% per year in other countries.Poverty can increase the risk of malaria since those in poverty do not have the financial capacities to prevent or treat the disease. In its entirety, the economic impact of malaria has been estimated to cost Africa US$12 billion every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism. The disease has a heavy burden in some countries, where it may be responsible for 30–50% of hospital admissions, up to 50% of outpatient visits, and up to 40% of public health spending.
Cerebral malaria is one of the leading causes of neurological disabilities in African children. Studies comparing cognitive functions before and after treatment for severe malarial illness continued to show significantly impaired school performance and cognitive abilities even after recovery. Consequently, severe and cerebral malaria have far-reaching socioeconomic consequences that extend beyond the immediate effects of the disease.
Counterfeit and substandard drugs
Sophisticated counterfeits have been found in several Asian countries such as Cambodia, China, Indonesia, Laos, Thailand, and Vietnam, and are a major cause of avoidable death in those countries. The WHO said that studies indicate that up to 40% of artesunate-based malaria medications are counterfeit, especially in the Greater Mekong region. They have established a rapid alert system to rapidly report information about counterfeit drugs to relevant authorities in participating countries. There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.Another clinical and public health concern is the proliferation of substandard antimalarial medicines resulting from inappropriate concentration of ingredients, contamination with other drugs or toxic impurities, poor quality ingredients, poor stability and inadequate packaging. A 2012 study demonstrated that roughly one-third of antimalarial medications in Southeast Asia and Sub-Saharan Africa failed chemical analysis, packaging analysis, or were falsified.
War
Throughout history, the contraction of malaria has played a prominent role in the fates of government rulers, nation-states, military personnel, and military actions. In 1910, Nobel Prize in Medicine-winner Ronald Ross (himself a malaria survivor), published a book titled The Prevention of Malaria that included a chapter titled "The Prevention of Malaria in War". The chapters author, Colonel C. H. Melville, Professor of Hygiene at Royal Army Medical College in London, addressed the prominent role that malaria has historically played during wars: "The history of malaria in war might almost be taken to be the history of war itself, certainly the history of war in the Christian era. ... It is probably the case that many of the so-called camp fevers, and probably also a considerable proportion of the camp dysentery, of the wars of the sixteenth, seventeenth and eighteenth centuries were malarial in origin." In British-occupied India the cocktail gin and tonic may have come about as a way of taking quinine, known for its antimalarial properties.Malaria was the most significant health hazard encountered by U.S. troops in the South Pacific during World War II, where about 500,000 men were infected. According to Joseph Patrick Byrne, "Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns."Significant financial investments have been made to procure existing and create new antimalarial agents. During World War I and World War II, inconsistent supplies of the natural antimalaria drugs cinchona bark and quinine prompted substantial funding into research and development of other drugs and vaccines. American military organisations conducting such research initiatives include the Navy Medical Research Center, Walter Reed Army Institute of Research, and the U.S. Army Medical Research Institute of Infectious Diseases of the US Armed Forces.Additionally, initiatives have been founded such as Malaria Control in War Areas (MCWA), established in 1942, and its successor, the Communicable Disease Center (now known as the Centers for Disease Control and Prevention, or CDC) established in 1946. According to the CDC, MCWA "was established to control malaria around military training bases in the southern United States and its territories, where malaria was still problematic".
Research
The Malaria Eradication Research Agenda (malERA) initiative was a consultative process to identify which areas of research and development (R&D) must be addressed for worldwide eradication of malaria.
Vaccine
A vaccine against malaria called RTS,S/AS01 (RTS,S) was approved by European regulators in 2015. As of 2019 it is undergoing pilot trials in 3 sub-Saharan African countries – Ghana, Kenya and Malawi – as part of the WHOs Malaria Vaccine Implementation Programme (MVIP).Immunity (or, more accurately, tolerance) to P. falciparum malaria does occur naturally, but only in response to years of repeated infection. An individual can be protected from a P. falciparum infection if they receive about a thousand bites from mosquitoes that carry a version of the parasite rendered non-infective by a dose of X-ray irradiation. The highly polymorphic nature of many P. falciparum proteins results in significant challenges to vaccine design. Vaccine candidates that target antigens on gametes, zygotes, or ookinetes in the mosquito midgut aim to block the transmission of malaria. These transmission-blocking vaccines induce antibodies in the human blood; when a mosquito takes a blood meal from a protected individual, these antibodies prevent the parasite from completing its development in the mosquito. Other vaccine candidates, targeting the blood-stage of the parasites life cycle, have been inadequate on their own. For example, SPf66 was tested extensively in areas where the disease was common in the 1990s, but trials showed it to be insufficiently effective.In 2021, researchers from the University of Oxford reported findings from a Phase IIb trial of a candidate malaria vaccine, R21/Matrix-M, which demonstrated efficacy of 77% over 12-months of follow-up. This vaccine is the first to meet the World Health Organizations Malaria Vaccine Technology Roadmap goal of a vaccine with at least 75% efficacy.
Medications
Malaria parasites contain apicoplasts, organelles related to the plastids found in plants, complete with their own genomes. These apicoplasts are thought to have originated through the endosymbiosis of algae and play a crucial role in various aspects of parasite metabolism, such as fatty acid biosynthesis. Over 400 proteins have been found to be produced by apicoplasts and these are now being investigated as possible targets for novel antimalarial drugs.With the onset of drug-resistant Plasmodium parasites, new strategies are being developed to combat the widespread disease. One such approach lies in the introduction of synthetic pyridoxal-amino acid adducts, which are taken up by the parasite and ultimately interfere with its ability to create several essential B vitamins. Antimalarial drugs using synthetic metal-based complexes are attracting research interest.
(+)-SJ733: Part of a wider class of experimental drugs called spiroindolone. It inhibits the ATP4 protein of infected red blood cells that cause the cells to shrink and become rigid like the aging cells. This triggers the immune system to eliminate the infected cells from the system as demonstrated in a mouse model. As of 2014, a Phase 1 clinical trial to assess the safety profile in human is planned by the Howard Hughes Medical Institute.
NITD246 and NITD609: Also belonged to the class of spiroindolone and target the ATP4 protein.On the basis of molecular docking outcomes, compounds 3j, 4b, 4h, 4m were exhibited selectivity towards PfLDH. The post docking analysis displayed stable dynamic behavior of all the selected compounds compared to Chloroquine. The end state thermodynamics analysis stated 3j compound as a selective and potent PfLDH inhibitor.
New targets
Targeting Plasmodium liver-stage parasites selectively is emerging as an alternative strategy in the face of resistance to the latest frontline combination therapies against blood stages of the parasite.In a research conducted in 2019, using experimental analysis with knockout (KO) mutants of Plasmodium berguei the authors were able to identify genes that are potentially essential in the liver stage. Moreover, they generated a computational model to analyse pre–erytrocytic development and liver–stage metabolism. Combining both methods they identified seven metabolic subsystems that become essential compared to the blood stage. Some of these metabolic pathways are fatty acid synthesis and elongation, tricarboxylic acid, amino acid and heme metabolism among others.Specifically, they studied 3 subsystems: fatty acid synthesis and elongation, and amino sugar biosynthesis. For the first two pathways they demonstrated a clear dependence of the liver stage on its own fatty acid metabolism.They proved for the first time the critical role of amino sugar biosynthesis in the liver stage of P. berghei. The uptake of N–acetyl–glucosamine appears to be limited in the liver stage, being its synthesis needed for the parasite development.These findings and the computational model provide a basis for the design of antimalarial therapies targeting metabolic proteins.
Other
A non-chemical vector control strategy involves genetic manipulation of malaria mosquitoes. Advances in genetic engineering technologies make it possible to introduce foreign DNA into the mosquito genome and either decrease the lifespan of the mosquito, or make it more resistant to the malaria parasite. Sterile insect technique is a genetic control method whereby large numbers of sterile male mosquitoes are reared and released. Mating with wild females reduces the wild population in the subsequent generation; repeated releases eventually eliminate the target population.Genomics is central to malaria research. With the sequencing of P. falciparum, one of its vectors Anopheles gambiae, and the human genome, the genetics of all three organisms in the malaria life cycle can be studied. Another new application of genetic technology is the ability to produce genetically modified mosquitoes that do not transmit malaria, potentially allowing biological control of malaria transmission.In one study, a genetically modified strain of Anopheles stephensi was created that no longer supported malaria transmission, and this resistance was passed down to mosquito offspring.Gene drive is a technique for changing wild populations, for instance to combat or eliminate insects so they cannot transmit diseases (in particular mosquitoes in the cases of malaria, zika, dengue and yellow fever).In December 2020, a review article found that malaria-endemic regions had lower reported COVID-19 case fatality rates on average than regions where malaria was not known to be endemic.
Other animals
While there are no animal reservoirs for the strains of malaria that cause human infections, nearly 200 parasitic Plasmodium species have been identified that infect birds, reptiles, and other mammals, and about 30 species naturally infect non-human primates. Some malaria parasites that affect non-human primates (NHP) serve as model organisms for human malarial parasites, such as P. coatneyi (a model for P. falciparum) and P. cynomolgi (P. vivax). Diagnostic techniques used to detect parasites in NHP are similar to those employed for humans. Malaria parasites that infect rodents are widely used as models in research, such as P. berghei. Avian malaria primarily affects species of the order Passeriformes, and poses a substantial threat to birds of Hawaii, the Galapagos, and other archipelagoes. The parasite P. relictum is known to play a role in limiting the distribution and abundance of endemic Hawaiian birds. Global warming is expected to increase the prevalence and global distribution of avian malaria, as elevated temperatures provide optimal conditions for parasite reproduction.
References
Citations
Sources
Further reading
External links
WHO site on malaria
CDC site on malaria
PAHO site on malaria |
You serve as an encyclopedia of medical terms. Deliver clear, detailed explanations, making medical language understandable to a diverse audience. | I'm seeking clarification on the medical term 'Eosinophilic gastroenteritis.' Could you explain it? | Eosinophilic gastroenteritis (EG or EGE) is a rare and heterogeneous condition characterized by patchy or diffuse eosinophilic infiltration of gastrointestinal (GI) tissue, first described by Kaijser in 1937. Presentation may vary depending on location as well as depth and extent of bowel wall involvement and usually runs a chronic relapsing course. It can be classified into mucosal, muscular and serosal types based on the depth of involvement. Any part of the GI tract can be affected, and isolated biliary tract involvement has also been reported.
The stomach is the organ most commonly affected, followed by the small intestine and the colon.
Signs and symptoms
EG typically presents with a combination of chronic nonspecific GI symptoms which include abdominal pain, diarrhea, occasional nausea and vomiting, weight loss and abdominal distension. Approximately 80% have symptoms for several years; a high degree of clinical suspicion is often required to establish the diagnosis, as the disease is extremely rare. It doesnt come all of a sudden but takes about 3–4 years to develop depending upon the age of the patient. Occasionally, the disease may manifest itself as an acute abdomen or bowel obstruction.
Mucosal EG (25–100%) is the most common variety, which presents with features of malabsorption and protein losing enteropathy. Failure to thrive and anaemia may also be present. Lower gastrointestinal bleeding may imply colonic involvement.
Muscular EG (13–70%) present with obstruction of gastric outlet or small intestine; sometimes as an obstructing caecal mass or intussusception.
Subserosal EG (4.5% to 9% in Japan and 13% in the US) presents with ascites which is usually exudative in nature, abundant peripheral eosinophilia, and has favourable responses to corticosteroids.
Other documented features are cholangitis, pancreatitis, eosinophilic splenitis, acute appendicitis and giant refractory duodenal ulcer.
Pathophysiology
Peripheral blood eosinophilia and elevated serum IgE are usual but not universal. The damage to the gastrointestinal tract wall is caused by eosinophilic infiltration and degranulation.As a part of host defense mechanism, eosinophils are normally present in gastrointestinal mucosa, though the finding in deeper tissue is almost always pathologic. What triggers such dense infiltration in EG is not clear. It is possible that different pathogenetic mechanisms of disease is involved in several subgroups of patients. Food allergy and variable IgE response to food substances has been observed in some patients which implies role of hypersensitive response in pathogenesis. Many patients indeed have history of other atopic conditions like eczema, asthma, etc.Eosinophil recruitment into inflammatory tissue is a complex process, regulated by a number of inflammatory cytokines. In EG cytokines IL-3, IL-5 and granulocyte macrophage colony stimulating factor (GM-CSF) may be behind the recruitment and activation. They have been observed immunohistochemically in diseased intestinal wall.
In addition eotaxin has been shown to have an integral role in regulating the homing of eosinophils into the lamina propria of stomach and small intestine.
In the allergic subtype of disease, it is thought that food allergens cross the intestinal mucosa and trigger an inflammatory response that includes mast cell degranulation and recruitment of eosinophils.
Diagnosis
Talley et al. suggested 3 diagnostic criteria which are still widely used:
the presence of gastrointestinal symptoms,
histological demonstration of eosinophilic infiltration in one or more areas of the gastrointestinal tract or presence of high eosinophil count in ascitic fluid (latter usually indicates subserosal variety),
no evidence of parasitic or extraintestinal disease.Hypereosinophilia, the hallmark of allergic response, may be absent in up to 20% of patients, but hypoalbuminaemia and other abnormalities suggestive of malabsorption may be present. CT scans may show nodular and irregular thickening of the folds in the distal stomach and proximal small bowel, but these findings can also be present in other conditions like Crohns disease and lymphoma.The endoscopic appearance in eosinophilic gastroenteritis is nonspecific; it includes erythematous, friable, nodular, and occasional ulcerative changes.
Sometimes diffuse inflammation results in complete loss of villi, involvement of multiple layers, submucosal oedema and fibrosis.Definitive diagnosis involves histological evidence of eosinophilic infiltration in biopsy slides. Microscopy reveals >20 eosinophils per high power field. Infiltration is often patchy, can be missed and laparoscopic full thickness biopsy may be required.
Radio isotope scan using technetium (99mTc) exametazime-labeled leukocyte SPECT may be useful in assessing the extent of disease and response to treatment but has little value in diagnosis, as the scan does not help differentiating EG from other causes of inflammation.When eosinophilic gastroenteritis is observed in association with eosinophilic infiltration of other organ systems, the diagnosis of idiopathic hypereosinophilic syndrome should be considered.
Management
Corticosteroids are the mainstay of therapy with a 90% response rate in some studies. Appropriate duration of steroid treatment is unknown and relapse often necessitates long term treatment. Various steroid sparing agents e.g. sodium cromoglycate (a stabilizer of mast cell membranes), ketotifen (an antihistamine), and montelukast (a selective, competitive leukotriene receptor antagonist) have been proposed, centering on an allergic hypothesis, with mixed results. Oral budesonide (an oral steroid) can be useful in treatment, as well. An elimination diet may be successful if a limited number of food allergies are identified.In a randomized clinical trial, lirentelimab was found to improve eosinophil counts and symptoms in individuals with eosinophilic gastritis and duodenitis.
Epidemiology
Epidemiology may differ between studies, as number of cases are small, with approximately 300 EG cases reported in published literature.
EG can present at any age and across all races, with a slightly higher incidence in males. Earlier studies showed higher incidence in the third to fifth decades of life.
Other gastrointestinal conditions associated with allergy
Eosinophilic esophagitis
Eosinophilic ascites
Coeliac disease
Protein losing enteropathy from intolerance to cows milk protein
Infantile formula protein intolerance
See also
Aeroallergen
Allergy
Gastroenteritis
Malabsorption
References
== External links == |
You are a medical knowledge base. Your task is to elucidate medical terminology, offering insights into their meanings, origins, and applications. | I've encountered the term 'Amaurosis' while reading about medical topics. What does it refer to exactly? | Amaurosis (Greek meaning darkening, dark, or obscure) is vision loss or weakness that occurs without an apparent lesion affecting the eye. It may result from either a medical condition or excess acceleration, as in flight. The term is the same as the Latin gutta serena, which means, in Latin, drop clear (or drop bright). Gutta serena is a condition of partial or complete blindness with a transparent, clear pupil. This term contrasts with suffusio nigra which means, in Latin, suffusion dark, indicating partial or complete blindness with a dark pupil, e.g., a cataract. Milton, already totally blind for twelve years (some scholars think from retinal detachment; others have diagnosed glaucoma) by the time he published Paradise Lost, refers to these terms in Book 3, lines 25–26.
Types
Lebers congenital amaurosis is an inherited disease resulting in optic atrophy and secondary severe vision loss or blindness. It was first described by Theodore Leber in the 19th century.Amaurosis fugax (Latin: fugax meaning fleeting) is a temporary loss of vision in one eye caused by decreased blood flow (ischemia) to the retina.
It may also be caused by embolization from atherosclerotic plaques in the ipsilateral (same side) internal carotid artery. It is a type of transient ischaemic attack (TIA). Those experiencing amaurosis usually experience complete symptom resolution within a few minutes. In a small minority of those who experience amaurosis, stroke or permanent vision loss results. Diabetes, hypertension and smoking are factors known to increase the risks of suffering this condition. It also can be the result of surgical repair to the mitral valve, when very small emboli may break away from the site of the repair, while the patients tissue grows to cover the plastic annuloplasty band.Quinidine toxicity can lead to cinchonism and also to quinine amaurosis.
Management
Those experiencing amaurosis are usually advised to consult a physician immediately as any form of vision loss, even if temporary, is a symptom that may indicate the presence of a serious ocular or systemic problem.
In animals
This condition can also occur in ruminants suffering from a vitamin B1 (thiamine) deficiency due to thiamine-related cerebrocortical necrosis (CCN).
== References == |
You serve as a guide in the medical field. Explain medical terms thoroughly, ensuring the information is both insightful and comprehensible. | I'm not familiar with the medical term 'Fluocinolone acetonide.' Could you provide some insights? | Fluocinolone acetonide is a corticosteroid primarily used in dermatology to reduce skin inflammation and relieve itching. It is a synthetic hydrocortisone derivative. The fluorine substitution at position 9 in the steroid nucleus greatly enhances its activity. It was first synthesized in 1959 in the Research Department of Syntex Laboratories S.A. Mexico City. Preparations containing it were first marketed under the name Synalar. A typical dosage strength used in dermatology is 0.01–0.025%. One such cream is sold under the brand name Flucort-N and includes the antibiotic neomycin.
Fluocinolone acetonide was also found to strongly potentiate TGF-β-associated chondrogenesis of bone marrow mesenchymal stem/progenitor cells, by increasing the levels of collagen type II by more than 100 fold compared to the widely used dexamethasone.Fluocinolone acetonide intravitreal implants have been used to treat non-infectious uveitis. A systematic review could not determine whether fluocinolone acetonide implants are superior to standard of care treatment for uveitis. A fluocinolone acetonide intravitreal implant with the brand name Iluvien is sold by biopharmaceutical company Alimera Sciences to treat diabetic macular edema (DME).It was approved for medical use in 1961.
Classification
Fluocinolone is a group V (0.025%) or group VI (0.01%) corticosteroid under US classification.
See also
Topical steroid
Fluocinonide
Ciprocinonide
Glucocorticoid
References
External links
"Fluocinolone acetonide". Drug Information Portal. U.S. National Library of Medicine. |
You are a medical advisor. Your role is to break down medical terminology into clear, detailed explanations for a general audience. | The term 'Irritation' keeps coming up in medical discussions. What does it stand for? | Irritation, in biology and physiology, is a state of inflammation or painful reaction to allergy or cell-lining damage. A stimulus or agent which induces the state of irritation is an irritant. Irritants are typically thought of as chemical agents (for example phenol and capsaicin) but mechanical, thermal (heat), and radiative stimuli (for example ultraviolet light or ionising radiations) can also be irritants. Irritation also has non-clinical usages referring to bothersome physical or psychological pain or discomfort.
Irritation can also be induced by some allergic response due to exposure of some allergens for example contact dermatitis, irritation of mucosal membranes and pruritus. Mucosal membrane is the most common site of irritation because it contains secretory glands that release mucous which attracts the allergens due to its sticky nature.
Chronic irritation is a medical term signifying that afflictive health conditions have been present for a while. There are many disorders that can cause chronic irritation, the majority involve the skin, vagina, eyes and lungs.
Irritation in organisms
In higher organisms, an allergic response may be the cause of irritation. An allergen is defined distinctly from an irritant, however, as allergy requires a specific interaction with the immune system and is thus dependent on the (possibly unique) sensitivity of the organism involved while an irritant, classically, acts in a non-specific manner.
It is a form of stress, but conversely, if one is stressed by unrelated matters, mild imperfections can cause more irritation than usual: one is irritable; see also sensitivity (human).
In more basic organisms, the status of pain is the perception of the being stimulated, which is not observable although it may be shared (see gate control theory of pain).
It is not proven that oysters can feel pain, but it is known that they react to irritants. When an irritating object becomes trapped within an oysters shell, it deposits layers of calcium carbonate (CaCO3), slowly increasing in size and producing a pearl. This is purely a defense mechanism, to trap a potentially threatening irritant such as a parasite inside its shell, or an attack from outside, injuring the mantle tissue. The oyster creates a pearl sac to seal off the irritation.
It has also been observed that an amoeba avoids being prodded with a pin, but there is not enough evidence to suggest how much it feels this. Irritation is apparently the only universal sense shared by even single-celled creatures.
It is postulated that most such beings also feel pain, but this is a projection – empathy. Some philosophers, notably René Descartes, denied it entirely, even for such higher mammals as dogs or primates like monkeys; Descartes considered intelligence a pre-requisite for the feeling of pain.
Types
Eye irritation
Modern office work with use of office equipment has raised concerns about possible adverse health effects. Since the 1970s, reports have linked mucosal, skin, and general symptoms to work with self-copying paper. Emission of various particulate and volatile substances has been suggested as specific causes. These symptoms have been related to Sick Building Syndrome, which involves symptoms such as irritation to the eyes, skin, and upper airways, headache and fatigue.The eye is also a source of chronic irritation. Disorders like Sjögrens syndrome, where one does not make tears, can cause a dry eye sensation which feels very unpleasant. The condition is difficult to treat and is lifelong. Besides artificial tears, there is a drug called Restasis which may help.Blepharitis is dryness and itching on the upper eyelids. This condition is often seen in young people and can lead to reddish dry eye and scaly eyebrows. To relieve the itching sensation, one may need to apply warm compresses and use topical corticosteroid creams.
Skin
Eczema is another cause of chronic irritation and affects millions of individuals. Eczema simply means a dry skin which is itchy. The condition usually starts at an early age and continues throughout life. The major complaint of people with eczema is an itchy dry skin. Sometimes, the itching will be associated with a skin rash. The affected areas are always dry, scaly, reddish and may ooze sometimes. Eczema cannot be cured, but its symptoms can be controlled. One should use moisturizers, use cold compresses and avoid frequent hot showers. There are over the counter corticosteroids creams which can be applied. Sometimes, an anti histamine has to be used to prevent the chronic itching sensations. There are also many individuals who have allergies to a whole host of substances like nuts, hair, dander, plants and fabrics. For these individuals, even the minimal exposure can lead to a full blown skin rash, itching, wheezing and coughing. Unfortunately, other than avoidance, there is no other cure. There are allergy shots which can help desensitize against an allergen but often the results are poor and the treatments are expensive. Most of these individuals with chronic irritation from allergens usually need to take anti histamines or use a bronchodilator to relieve symptoms.Another common irritation disorder in females is intertrigo. This disorder is associated with chronic irritation under folds of skin. This is typically seen under large breasts, groins and folds of the abdomen in obese individuals. Candida quickly grows in warm moist areas of these folds and presents as a chronic itch. Over time, the skin becomes red and often oozes.
Perspiration is also a chronic type of irritation which can be very annoying. Besides being socially unacceptable, sweat stain the clothes and can present with a foul odor. In some individuals, the warm moist areas often become easily infected. The best way to treat excess sweating is good hygiene, frequent change of clothes and use of deodorants/antiperspirants.
Vaginal irritation
One of the most common areas of the body associated with irritation is the vagina. Many women complain of an itch, dryness, or discharge in the perineum at some point in their lives. There are several causes of vaginal irritation including fungal vaginitis (like candida) or trichomoniasis. Often, herpes simplex infection of the mouth or genitalia can be recurrent and prove to be extremely irritating.
Sometimes, the irritation can be of the chronic type and it can be so intense that it also causes painful intercourse. Aside from infections, chronic irritation of the vagina may be related to the use of contraceptives and condoms made from latex. The majority of contraceptives are made of synthetic chemicals which can induce allergies, rash and itching. Sometimes the lubricant used for intercourse may cause irritation.
Another cause of irritation in women is post menopausal vaginitis. The decline in the female sex hormones leads to development of dryness and itching in the vagina. This is often accompanied by painful sexual intercourse. Cracks and tears often develop on outer aspects of the labia which becomes red from chronic scratching. Post menopausal vaginitis can be treated with short term use of vaginal estrogen pessary and use of a moisturizer.
Lungs
Individuals who smoke or are exposed to smog or other airborne pollutants can develop a condition known as COPD. In this disorder, there is constant irritation of the breathing tubes (trachea) and the small airways. The constant irritation results in excess production of mucus which makes breathing difficult. Frequently, these individuals wake up in the morning with copious amounts of foul smelling mucus and a cough which lasts all day. Wheeze and heavy phlegm are common findings. COPD is a lifelong disorder and there is no cure. Eventually most people develop recurrent pneumonia, lack any type of endurance, and are unable to work productively. One of the ways to avoid chronic bronchitis is to stop or not smoke.
Stomach
Gastritis or stomach upset is a common irritating disorder affecting millions of people. Gastritis is basically inflammation of the stomach wall lining and has many causes. Smoking, excess alcohol consumption and the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, account for the majority of causes of gastritis. In some cases, gastritis may develop after surgery, a major burn, infection or emotional stress. The most common symptoms of gastritis include sharp abdominal pain which may radiate to the back. This may be associated with nausea, vomiting, abdominal bloating and a lack of appetite. When the condition is severe it may even result in loss of blood on the stools. The condition often comes and goes for years because most people continue to drink alcohol or use NSAIDs. Treatment includes the use of antacids or acid neutralizing drugs, antibiotics, and avoiding spicy food and alcohol.
See also
Allergy
Irritability (psychology)
Itch
Stimulus (physiology)
== References == |
You act as a mediator between medical professionals and the public. Provide comprehensive explanations of medical terms, ensuring they are both precise and easily understood. | I'm looking for a concise explanation of the medical term 'Dutasteride/tamsulosin.' | Dutasteride/tamsulosin, sold under the brand name Jalyn among others, is a medication produced by GlaxoSmithKline for the treatment of adult male symptomatic benign prostatic hyperplasia (BPH). It is a combination of two previously existing medications: dutasteride, brand name Avodart, and tamsulosin, brand name Flomax. It contains 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride.Jalyn was the result of the CombAT (Combination of Avodart and Tamsulosin) trial of 2008. It was approved by the U.S. Food and Drug Administration (FDA) on June 14, 2010. In June 2011, the FDA approved a label change warning of "Increased Risk of High-grade Prostate Cancer" from Jalyn.
References
External links
"Dutasteride mixture with tamsulosin". Drug Information Portal. U.S. National Library of Medicine. |
You are a medical educator. Your role is to provide detailed and clear explanations for medical terms, suitable for both professionals and laypersons. | I've encountered the term 'Water intoxication' while reading about medical topics. What does it refer to exactly? | Water intoxication, also known as water poisoning, hyperhydration, overhydration, or water toxemia, is a potentially fatal disturbance in brain functions that results when the normal balance of electrolytes in the body is pushed outside safe limits by excessive water intake.
Under normal circumstances, accidentally consuming too much water is exceptionally rare. Nearly all deaths related to water intoxication in normal individuals have resulted either from water-drinking contests, in which individuals attempt to consume large amounts of water, or from long bouts of exercise during which excessive amounts of fluid were consumed. In addition, water cure, a method of torture in which the victim is forced to consume excessive amounts of water, can cause water intoxication.Water, just like any other substance, can be considered a poison when over-consumed in a brief period of time. Water intoxication mostly occurs when water is being consumed in a high quantity without adequate electrolyte intake.Excess of body water may also be a result of a medical condition or improper treatment; see "hyponatremia" for some examples. Water is considered one of the least toxic chemical compounds, with an LD50 of over 150 ml/kg in rats.
Risk factors
Low body mass (infants)
It can be very easy for children under one year old (especially those under nine months) to absorb too much water. Because of their small body mass, it is easy for them to take in a large amount of water relative to body mass and total body sodium stores.
Endurance sports
Marathon runners are susceptible to water intoxication if they drink too much while running. This is caused when sodium levels drop below 135 mmol/L when athletes consume large amounts of fluid. This has been noted to be the result of the encouragement of excessive fluid replacement by various guidelines. This has largely been identified in marathon runners as a dilutional hyponatremia. A study conducted on runners completing the 2002 Boston Marathon found that thirteen percent finished the race with hyponatremia. The study concluded that the strongest predictor of hyponatremia was weight gain while racing (over-hydration), and hyponatremia was just as likely to occur in runners who chose sports drinks as those who chose water.
Military training
Hyponatremia and other physical conditions associated with water intoxication are more often seen in those participating in military training. One US Army study found 17 trainees were admitted to hospital over a years period for water intoxication while another found that three soldiers had died, leading to a recommendation that no more than 1-1.5L of water should be consumed per hour of heavy sweating.
Overexertion and heat stress
Any activity or situation that promotes heavy sweating can lead to water intoxication when water is consumed to replace lost fluids. Persons working in extreme heat and/or humidity for long periods must take care to drink and eat in ways that help to maintain electrolyte balance. People using drugs such as MDMA (often referred to colloquially as "Ecstasy") may overexert themselves, perspire heavily, feel increased thirst, and then drink large amounts of water to rehydrate, leading to electrolyte imbalance and water intoxication – this is compounded by MDMA use increasing the levels of antidiuretic hormone (ADH), decreasing the amount of water lost through urination. Even people who are resting quietly in extreme heat or humidity may run the risk of water intoxication if they drink large amounts of water over short periods for rehydration.
Psychiatric conditions
Psychogenic polydipsia is the psychiatric condition in which patients feel compelled to drink large quantities of water, thus putting them at risk of water intoxication. This condition can be especially dangerous if the patient also exhibits other psychiatric indications (as is often the case), as the care-takers might misinterpret the hyponatremic symptoms.
Iatrogenic
When an unconscious person is being fed intravenously (for example, total parenteral nutrition) or via a nasogastric tube, the fluids given must be carefully balanced in composition to match fluids and electrolytes lost. These fluids are typically hypertonic, and so water is often co-administered. If the electrolytes are not monitored (even in an ambulatory patient), either hypernatremia or hyponatremia may result.Some neurological/psychiatric medications (oxcarbazepine, among others) have been found to cause hyponatremia in some patients. Patients with diabetes insipidus are particularly vulnerable due to rapid fluid processing.
Pathophysiology
At the onset of this condition, fluid outside the cells has an excessively low amount of solutes, such as sodium and other electrolytes, in comparison to fluid inside the cells, causing the fluid to move into the cells to balance its osmotic concentration. This causes the cells to swell. The swelling increases intracranial pressure in the brain, which leads to the first observable symptoms of water intoxication: headache, personality changes, changes in behavior, confusion, irritability, and drowsiness. These are sometimes followed by difficulty breathing during exertion, muscle weakness & pain, twitching, or cramping, nausea, vomiting, thirst, and a dulled ability to perceive and interpret sensory information. As the condition persists, papillary and vital signs may result including bradycardia and widened pulse pressure. The cells in the brain may swell to the point where blood flow is interrupted resulting in cerebral edema. Swollen brain cells may also apply pressure to the brain stem causing central nervous system dysfunction. Both cerebral edema and interference with the central nervous system are dangerous and could result in seizures, brain damage, coma or death.
Prevention
Water intoxication can be prevented if a persons intake of water does not grossly exceed their losses. Healthy kidneys are able to excrete approximately 800 millilitres to one litre of fluid water (0.84–1.04 quarts) per hour. However, stress (from prolonged physical exertion), as well as disease states, can greatly reduce this amount.
Treatment
Mild intoxication may remain asymptomatic and require only fluid restriction. In more severe cases, treatment consists of:
Diuretics to increase urination, which are most effective for excess blood volume.
Vasopressin receptor antagonists
Notable cases
1097: During the First Crusade, according to at least one chronicle, many crusaders died after drinking too much from a river while marching to Antioch.
1991, Andy Warhol: Five years after his death, Warhols family publicly accused the hospital where he had his gallbladder removed of causing his death by water intoxication administered post-operatively. A claimed autopsy weight of 68 kg (150 lb), with his weight being 58 kg (128 lb) when admitted, was cited as evidence that too much fluid had been given.
October 24, 1995: Anna Wood, a 15-year-old Australian schoolgirl, died from the effects of water intoxication.
November 16, 1995: Leah Betts, a British schoolgirl, died as the result of drinking too much water, though in the media her death was mistakenly attributed to taking an ecstasy tablet at her 18th birthday party.
2003: British actor Anthony Andrews survived a case of water intoxication. He was performing as Henry Higgins in a revival of the musical My Fair Lady at the time, and consumed up to eight litres of water a day. He was unconscious and in intensive care for three days.
February 2, 2005: Matthew Carrington, a student at Chico State University in Chico, California, died as a direct result of a fraternity hazing ritual involving forced water intoxication.
January 12, 2007: Jennifer Strange died after drinking nearly 2 gallons (7.6 liters) of water in an attempt to win a Nintendo Wii. The KDND radio stations morning show, the Morning Rave, held an on-air contest entitled "Hold Your Wee for a Wii," in which contestants were asked to drink as much water as they could without urinating. The DJs were made aware of the dangers but did not inform the contestants. KDNDs parent company, Entercom Sacramento LLC, was subsequently ordered to pay $16,577,118 in damages to Stranges family.
March 11, 2020: Zachary Sabin, an 11-year-old child, died after being forced to drink almost three liters of water in just four hours by his parents. They thought his urine was too dark, so they made him drink water until he threw up.
See also
== References == |
You are a guide to medical language. Please provide in-depth and understandable explanations of medical terms, highlighting their significance in healthcare. | The term 'Hemifacial microsomia' keeps coming up in medical discussions. What does it stand for? | Hemifacial microsomia (HFM) is a congenital disorder that affects the development of the lower half of the face, most commonly the ears, the mouth and the mandible. It usually occurs on one side of the face, but both sides are sometimes affected. If severe, it may result in difficulties in breathing due to obstruction of the trachea—sometimes even requiring a tracheotomy. With an incidence in the range of 1:3500 to 1:4500, it is the second most common birth defect of the face, after cleft lip and cleft palate.[1] HFM shares many similarities with Treacher Collins syndrome.
Presentation
The clinical presentation of HFM is quite variable. The severity may depend on the extent of the area with an insufficient blood supply in utero, and the gestational age of the fetus at which this occurs. In some people, the only physical manifestation may be a small and underdeveloped external ear. In more severe cases, multiple parts of the face may be affected. Some people with HFM may have sensorineural hearing loss and decreased visual acuity or even blindness.It can be thought of as a particularly severe form of HFM, in which extracranial anomalies are present to some extent. Some of the internal organs (especially the heart, kidneys, and lungs) may be underdeveloped, or in some cases even absent altogether. The affected organs are typically on the same side as the affected facial features, but bilateral involvement occurs in approximately 10% of cases. Deformities of the vertebral column such as scoliosis may also be observed.While there is no universally accepted grading scale, the OMENS scale (standing for Orbital, Mandible, Ear, Nerves and Soft tissue) was developed to help describe the heterogeneous phenotype that makes up this sequence or syndrome.Intellectual disability is not typically seen in people with HFM. Hemifacial microsomia sometimes results in temporomandibular joint disorders.
Cause
The condition develops in the fetus at approximately 4 weeks gestational age, when some form of vascular problem such as blood clotting leads to insufficient blood supply to the face. This can be caused by physical trauma, though there is some evidence of it being hereditary [2]. This restricts the developmental ability of that area of the face. Currently there are no definitive reasons for the development of the condition.
Diagnosis
Classification
Figueroa and Pruzanksky classified HFM patients into three different types:
Type I : Mild hypoplasia of the ramus, and the body of the mandible is slightly affected.
Type II : The condyle and ramus are small, the head of the condyle is flattened, the glenoid fossa is absent, the condyle is hinged on a flat, often convex, infratemporal surface, the coronoid may be absent.
Type III: The ramus is reduced to a thin lamina of bone or is completely absent. There is no evidence of a TMJ.
Treatment
Depending upon the treatment required, it is sometimes most appropriate to wait until later in life for a surgical remedy – the childhood growth of the face may highlight or increase the symptoms. When surgery is required, particularly when there is a severe disfiguration of the jaw, it is common to use a rib graft to help correct the shape.According to literature, HFM patients can be treated with various treatment options such as functional therapy with an appliance, distraction osteogenesis, or costochondral graft. The treatment is based on the type of severity for these patients. According to Pruzankskys classification, if the patient has moderate to severe symptoms, then surgery is preferred. If patient has mild symptoms, then a functional appliance is generally used.According to Dr. Harry Pepe, a pediatrician from Hollywood, Fl, the goal of treatment in hemifacial microsomia is to elongate the deficient jaw bone to restore facial symmetry and correct the slanting bite (occlusion).Patients can also benefit from a Bone Anchored Hearing Aid (BAHA).
Terminology
The condition is also known by various other names:
Lateral facial dysplasia
First and second branchial arch syndrome
Oral-mandibular-auricular syndrome
Otomandibular dysostosis
Craniofacial microsomia
See also
Condylar hypoplasia
Goldenhar syndrome
Parry–Romberg syndrome
References
^ "Hemifacial Microsomia" at the Tennessee Craniofacial Center. Accessed 20 January 2008.
^ "Hemifacial Microsomia" at the Childrens Hospital and Health System of Wisconsin. Accessed 20 January 2008.
External links
GeneReviews/NCBI/NIH/UW entry on Craniofacial Microsomia Overview |
You are a medical educator. Your role is to provide detailed and clear explanations for medical terms, suitable for both professionals and laypersons. | Could you offer a clear explanation of the term 'Acne miliaris necrotica' as used in the medical field? | Acne miliaris necrotica is a rare condition consisting of follicular vesicopustules, sometimes occurring as solitary lesions that are usually very itchy. The condition affects middle aged and elderly individuals. Affected areas can include the scalp, frontal hairline, face, and chest.
Causes
It has been hypothesized that the body overreacts to an organism such as the S. aureus bacterium.
Diagnosis
Treatment
There are multiple medications that are able to treat acne varioliformis.
Topical
Clindamycin 1% lotion or Benzoyl peroxide/clindamycin gel
Erythromycin 2% gel
1% hydrocortisone cream
Systemic
Doxycycline 50 mg twice daily
Isotretinoin 0.5 mg/kg daily
See also
List of cutaneous conditions
References
== External links == |
You act as a bridge between medical jargon and everyday language. Explain medical terms in a manner that is comprehensive yet approachable for non-experts. | What does the medical term 'Tretinoin' encompass? | Tretinoin, also known as all-trans retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For leukemia, it is taken by mouth for up to three months. Topical tretinoin is also the most extensively investigated retinoid therapy for photoaging.Common side effects when used as a cream are limited to the skin and include skin redness, peeling, and sun sensitivity. When used by mouth, side effects include shortness of breath, headache, numbness, depression, skin dryness, itchiness, hair loss, vomiting, muscle pains, and vision changes. Other severe side effects include high white blood cell counts and blood clots. Use during pregnancy is contraindicated due to the risk of birth defects. It is in the retinoid family of medications.Tretinoin was patented in 1957, and approved for medical use in 1962. It is on the World Health Organizations List of Essential Medicines. Tretinoin is available as a generic medication. In 2019, it was the 244th most commonly prescribed medication in the United States, with more than 1 million prescriptions.
Medical uses
Skin use
Tretinoin is most commonly used to treat acne, both inflammatory and noninflammatory. Multiple studies support the efficacy of topical retinoids in the treatment of acne vulgaris. It is sometimes used in conjunction with other topical acne medications to enhance their penetration. In addition to treating active acne, retinoids accelerate the resolution of acne-induced postinflammatory hyperpigmentation. It is also useful as maintenance therapy for people who have responded to their initial treatment, reducing the prolonged use of antibiotics for acne.
Leukemia
Tretinoin is used to induce remission in people with acute promyelocytic leukemia who have a mutation (the t(15;17) translocation 160 and/or the presence of the PML/RARα gene) and who do not respond to anthracyclines or cannot take that class of drug. It is not used for maintenance therapy.The evidence is very uncertain about the effect of tretinoin in addition to chemotherapy for patients with an acute myeloid leukemia on diarrhoea, nausea/vomiting and heart-related toxicity grades III/IV. Furthermore, tretinoin in addition to chemotherapy probably results in little to no difference in the mortality, relapse, progress, mortality during the trial and infections grade III/IV.
Photoaging
Photoaging is premature skin aging resulting from prolonged and repeated exposure to solar radiation. Features of photoaging include fine and coarse wrinkles, change in skin pigmentation, and loss of elasticity. In human skin, topical retinoids increase collagen production, induce epidermal hyperplasia, and decrease keratinocyte and melanocyte atypia. Topical tretinoin is the most extensively investigated retinoid therapy for photoaging. Topical tretinoin can be used for mild to severe photoaging in people of all skin types. Several weeks or months of use are typically required before improvement is appreciated. The benefits of topical tretinoin are lost upon discontinuation. Although it has only been studied for a duration of two years, it may be continued indefinitely. A long-term maintenance regimen with a lower concentration or less frequent application may be an alternative to continued use.
Side effects
Skin use
Topical tretinoin is only for use on the skin and should not be applied to eyes or mucosal tissues. Common side effects include skin irritation, redness, swelling, and blistering. If irritation is a problem, a decrease in the frequency of application to every other or every third night can be considered, and the frequency of application can be increased as tolerance improves. The fine skin flaking that is often seen can be gently exfoliated with a washcloth. A non-comedogenic facial moisturizer can also be applied if needed. Delaying application of the retinoid for at least 20 minutes after washing and drying the face may also be helpful. Topical retinoids are not true photosensitizing drugs, but people using topical retinoids have described symptoms of increased sun sensitivity. This is thought to be due to thinning of the stratum corneum leading to a decreased barrier against ultraviolet light exposure, as well as an enhanced sensitivity due to the presence of cutaneous irritation.
Leukemia use
The oral form of the drug has boxed warnings concerning the risks of retinoic acid syndrome and leukocytosis.Other significant side effects include a risk of thrombosis, benign intracranial hypertension in children, high lipids (hypercholesterolemia and/or hypertriglyceridemia), and liver damage.There are many significant side effects from this drug that include malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), and myalgia (14%).Respiratory side effects usually signify retinoic acid syndrome, and include upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), and expiratory wheezing (14%), and many others at less than 10%.Around 23% of people taking the drug have reported earache or a feeling of fullness in their ears.Gastrointestinal disorders include bleeding (34%), abdominal pain (31%), diarrhea (23%), constipation (17%), dyspepsia (14%), and swollen belly (11%) and many others at less than 10%.In the cardiovascular system, side effects include arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), and cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy.In the nervous system, side effects include dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), and many others at less than 10% frequency.In the urinary system, side effects include chronic kidney disease (11%) and several others at less than 10% frequency.
Mechanism of action
For its use in cancer, its mechanism of action is unknown, but on a cellular level, laboratory tests show that tretinoin forces APL cells to differentiate and stops them from proliferating; in people there is evidence that it forces the primary cancerous promyelocytes to differentiate into their final form, allowing normal cells to take over the bone marrow. Recent study shows that ATRA inhibits and degrades active PIN1.For its use in acne, tretinoin (along with other retinoids) are vitamin A derivatives that act by binding to two nuclear receptor families within keratinocytes: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation. The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation. Retinoids also down-regulate expression of toll-like receptor (TLR)-2, which has been implicated in the inflammatory response in acne. Moreover, tretinoin and retinoids may enhance the penetration of other topical acne medications.The combination of the 10% benzoyl peroxide and light results in more than 50% degradation of tretinoin in about 2 hours and 95% in 24 hours. This lack of stability in the presence of light and oxidizing agents has led to the development of novel formulations of the drug. When microencapsulated tretinoin is exposed to benzoyl peroxide and light only 1% degradation takes place in about 4 hours and only 13% after 24 hours.
Biosynthesis
Tretinoin is synthesized from beta-carotene. The beta-carotene is firstly cleaved into beta-carotene 15-15-monooxygenase through site 1 double bond oxidized to epoxide. The epoxide is attacked by water to form diol in site 1. NADH, as a reduction agent, reduce the alcohol group to aldehydes.
History
Tretinoin was co-developed for its use in acne by James Fulton and Albert Kligman when they were at University of Pennsylvania in the 1960s. Phase I trials, the first conducted on human subjects, were performed on inmates at Holmesburg Prison during a long-running regime of non-therapeutic and unethical testing on prison inmates at Holmesburg. The University of Pennsylvania held the patent for Retin-A, which it licensed to pharmaceutical companies.Treatment of acute promyelocytic leukemia was first introduced at Ruijin Hospital in Shanghai by Wang Zhenyi in a 1988 clinical trial.
Etymology
The origin of the name tretinoin is uncertain, although several sources agree (one with probability, one with asserted certainty) that it probably comes from trans- + retinoic [acid] + -in, which is plausible given that tretinoin is the all-trans isomer of retinoic acid. The name isotretinoin is the same root tretinoin plus the prefix iso-. Regarding pronunciation, the following variants apply equally to both tretinoin and isotretinoin. Given that retinoic is pronounced , it is natural that is a commonly heard pronunciation. Dictionary transcriptions also include (tri-TIN-oh-in) and .
Research
Tretinoin has been explored as a treatment for hair loss, potentially as a way to increase the ability of minoxidil to penetrate the scalp, but the evidence is weak and contradictory.It has been used off-label to treat and reduce the appearance of stretch marks. It has also been studied in skin aging.
References
External links
"Tretinoin". Drug Information Portal. U.S. National Library of Medicine.
"Tretinoin Topical". MedlinePlus. |
You are a medical lexicon. Explain medical terminology with depth and clarity, making sure the information is both accurate and easy to grasp. | Can you demystify the medical term 'Yaz' for me? | Yaz may refer to:
People
Yazmith Bataz (born 1972), Mexican sprinter
Yaz Mubarakai (born 1975), Australian politician
Carl Yastrzemski (born 1939), American Hall-of-Fame baseball player
Mike Yastrzemski (born 1990), American professional baseball player, grandson of Carl
Other uses
Yaz culture, an early Iron Age culture of Bactria and Margiana, c. 1500-1100 BC
Yaz-class river patrol craft, Russian Coast Guard vessels
YAZ, IATA code for Tofino Airport in Tofino, British Columbia, Canada
yaz, ISO 639-3 code for the Yakö language, spoken by the Yakö people of Nigeria
Yaz (band) or Yazoo, an English synth-pop band
Yaz Pistachio, a female character from the comic strip Bloom County
Yaz (drug), a brand name for a birth control pill containing drospirenone that may also be used for other indications
YAZ, a programmer toolkit for development of Z39.50 clients and servers
See also
Yazz (born 1960), pseudonym used by English singer Yasmin Evans
Yazz The Greatest, a stage name of American actor and rapper Bryshere Y. Gray |
You act as a mediator between medical professionals and the public. Provide comprehensive explanations of medical terms, ensuring they are both precise and easily understood. | Could you please explain the term 'Bowel infarction' in simple language? | Bowel infarction or gangrenous bowel represents an irreversible injury to the intestine resulting from insufficient blood flow. It is considered a medical emergency because it can quickly result in life-threatening infection and death. Any cause of bowel ischemia, the earlier reversible form of injury, may ultimately lead to infarction if uncorrected. The causes of bowel ischemia or infarction include primary vascular causes (for example, mesenteric ischemia) and other causes of bowel obstruction.
Causes
Primary vascular causes of bowel infarction, also known as mesenteric ischemia, are due to blockages in the arteries or veins that supply the bowel. Types of mesenteric ischemia are generally separated into acute and chronic processes, because this helps determine treatment and prognosis.Bowel obstruction is most often caused by intestinal adhesions, which frequently form after abdominal surgeries, or by chronic infections such as diverticulitis, hepatitis, and inflammatory bowel disease. The condition may be difficult to diagnose, as the symptoms may resemble those of other bowel disorders. Bowel volvulus describes a specific form of bowel obstruction, where the intestine and/or mesentery are twisted, resulting in ischemia.
Management
An infarcted or dead intestinal segment is a serious medical problem because intestines contain non-sterile contents within the lumen. Although the fecal content and high bacterial loads of the intestine are normally safely contained, progressive ischemia causes tissue breakdown and inevitably leads to bacteria spreading to the bloodstream. Untreated bowel infarction quickly leads to life-threatening infection and sepsis, and may be fatal.The only treatment for bowel infarction is immediate surgical repair and eventually removal of the dead bowel segment.Patients who have undergone extensive resection of the small bowel may develop malabsorption, indicating the need for dietary supplements.
Additional images
See also
Adhesions
Ischemic colitis
Volvulus
References
== External links == |
You act as a bridge between medical jargon and everyday language. Explain medical terms in a manner that is comprehensive yet approachable for non-experts. | I'd like to learn more about the medical term 'Doxepin.' Can you provide some details? | Doxepin is a medication used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.Common side effects include sleepiness, dry mouth, constipation, nausea, and blurry vision. Serious side effects may include increased risk of suicide in those under the age of 25, mania, and urinary retention. A withdrawal syndrome may occur if the dose is rapidly decreased. Use during pregnancy and breastfeeding is not generally recommended. Doxepin is a tricyclic antidepressant (TCA). Although how it works for treating depression remains an area of active inquiry, it may involve increasing the levels of norepinephrine, along with blocking histamine, acetylcholine, and serotonin.Doxepin was approved for medical use in the United States in 1969. It is available as a generic medication. In 2017, it was the 240th most commonly prescribed medication in the United States, with more than two million prescriptions.
Medical uses
Doxepin is used as a pill to treat major depressive disorder, anxiety disorders, and chronic hives, and for short-term help with trouble remaining asleep after going to bed (a form of insomnia). As a cream it is used for short-term treatment of itchiness caused by atopic dermatitis or lichen simplex chronicus.
Insomnia
Doxepin is used in the treatment of insomnia. In 2016, the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short-term help maintaining sleep, on the basis of weak evidence. The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar. A 2015 Agency for Healthcare Research and Quality review of treatments for insomnia had similar findings.A major systematic review and network meta-analysis of medications for the treatment of insomnia published in 2022 found that doxepin had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.30 (95% CI –0.05 to 0.64). The certainty of evidence was rated as very low, and no data were available for longer-term treatment (3 months). For comparison, the other sedating antihistamines assessed, trimipramine and doxylamine, had effect sizes (SMD) at 4 weeks of 0.55 (95% CI –0.11 to 1.21) (very low certainty evidence) and 0.47 (95% CI 0.06 to 0.89) (moderate certainty evidence), respectively. Benzodiazepines and Z-drugs generally showed larger effect sizes (e.g., SMDs of 0.45 to 0.83) than doxepin, whereas the effect sizes of orexin receptor antagonists, such as suvorexant, were more similar (SMDs of 0.23 to 0.44).Doses of doxepin used for sleep normally range from 3 to 6 mg, but high doses of up to 25 to 50 mg may be used as well.
Other uses
A 2010 review found that topical doxepin is useful to treat itchiness.A 2010 review of treatments for chronic hives found that doxepin had been superseded by better drugs but was still sometimes useful as a second-line treatment.
Contraindications
Known contraindications include:
Hypersensitivities to doxepin, other TCAs, or any of the excipients inside the product used
Glaucoma
A predisposition to developing urinary retention such as in benign prostatic hyperplasia
Use of monoamine oxidase inhibitors in last 14 days
Pregnancy and lactation
Its use in pregnant and lactating women is advised against, although the available evidence suggests it is unlikely to cause negative effects on fetal development. The lack of evidence from human studies, however, means it is currently impossible to rule out any risk to the fetus and it is known to cross the placenta. Doxepin is secreted in breast milk and neonatal cases of respiratory depression in association with maternal doxepin use have been reported.
Side effects
Doxepins side effects profile may differ from the list below in some countries where it is licensed to be used in much smaller doses (viz., 3 mg and 6 mg).
Central nervous system: fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, difficulty sleeping, seizures (infrequently), temporary confusion (delirium), rarely induction of hypomania and schizophrenia (stop medication immediately), extrapyramidal side effects (rarely), abuse in patients with polytoxicomania (rarely), ringing in the ears (tinnitus)
Anticholinergic: dry mouth, constipation, even ileus (rarely), difficulties in urinating, sweating, precipitation of glaucoma
Antiadrenergic: Low blood pressure, (if patient arises too fast from the lying/sitting position to standing—known as orthostatic hypotension), abnormal heart rhythms (e.g., sinus tachycardia, bradycardia, and atrioventricular block)
Allergic/toxic: skin rash, photosensitivity, liver damage of the cholestatic type (rarely), hepatitis (extremely rare), leuko- or thrombocytopenia (rarely), agranulocytosis (very rarely), hypoplastic anemia (rarely)
Others: frequently increased appetite and weight gain, rarely nausea, rarely high blood pressure. May increase or decrease liver function in some people.The side effects of low-dose doxepin for insomnia in long-term clinical trials (28 to 85 days) in adults and elderly people were as follows:
Overdose
Like other TCAs, doxepin is highly toxic in cases of overdose. Mild symptoms include drowsiness, stupor, blurred vision, and excessive dryness of mouth. More serious adverse effects include respiratory depression, hypotension, coma, convulsions, cardiac arrhythmia, and tachycardia. Urinary retention, decreased gastrointestinal motility (paralytic ileus), hyperthermia (or hypothermia), hypertension, dilated pupils, and hyperactive reflexes are other possible symptoms of doxepin overdose. Management of overdose is mostly supportive and symptomatic, and can include the administration of a gastric lavage so as to reduce absorption of the doxepin. Supportive measures to prevent respiratory aspiration is also advisable. Antiarrhythmic agents may be an appropriate measure to treat cardiac arrhythmias resulting from doxepin overdose. Slow intravenous administration of physostigmine may reverse some of the toxic effects of overdose such as anticholinergic effects. Haemodialysis is not recommended due to the high degree of protein binding with doxepin. ECG monitoring is recommended for several days after doxepin overdose due to the potential for cardiac conduction abnormalities.
Interactions
Doxepin should not be used within 14 days of using a monoamine oxidase inhibitor (MAOI) such as phenelzine due to the potential for hypertensive crisis or serotonin syndrome to develop. Its use in those taking potent CYP2D6 inhibitors such as fluoxetine, paroxetine, sertraline, duloxetine, bupropion, and quinidine is recommended against owing to the potential for its accumulation in the absence of full CYP2D6 catalytic activity. Hepatic enzyme inducers such as carbamazepine, phenytoin, and barbiturates are advised against in patients receiving TCAs like doxepin owing to the potential for problematically rapid metabolism of doxepin to occur in these individuals. Sympathomimetic agents may have their effects potentiated by TCAs like doxepin. Doxepin also may potentiate the adverse effects of anticholinergic agents such as benztropine, atropine and hyoscine (scopolamine). Tolazamide, when used in conjunction with doxepin has been associated with a case of severe hypoglycaemia in a type II diabetic individual. Cimetidine may influence the absorption of doxepin. Alcohol may potentiate some of the CNS depressant effects of doxepin. Antihypertensive agents may have their effects mitigated by doxepin. Cotreatment with CNS depressants such as the benzodiazepines can cause additive CNS depression. Co-treatment with thyroid hormones may also increase the potential for adverse reactions.
Pharmacology
Doxepin is a tricyclic antidepressant (TCA). It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) (a reuptake inhibitor of serotonin and norepinephrine), with additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities.
Pharmacodynamics
Doxepin is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor (SNRI), and has additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities. It is specifically an antagonist of the histamine H1 and H2 receptors, the serotonin 5-HT2A and 5-HT2C receptors, the α1-adrenergic receptor, and the muscarinic acetylcholine receptors (M1–M5). Similarly to other tricyclic antidepressants, doxepin is often prescribed as an effective alternative to SSRI medications. Doxepin is also a potent blocker of voltage-gated sodium channels, and this action is thought to be involved in both its lethality in overdose and its effectiveness as an analgesic (including in the treatment of neuropathic pain, and as a local anesthetic). The potencies of doxepin in terms of its receptor antagonism specifically are as follows:
Extremely strong: Histamine H1 receptor
Strong: α1-adrenergic receptor, 5-HT2A and muscarinic acetylcholine receptors
Moderate: 5-HT2C and 5-HT1A receptors
Weak: α2-adrenergic and D2 receptorsBased on its IC50 values for monoamine reuptake inhibition, doxepin is relatively selective for the inhibition of norepinephrine reuptake, with a much weaker effect on the serotonin transporter. Although there is a significant effect that takes place at one of the specific serotonergic binding sites, the 5-HT2A serotonin receptor subtype. There is negligible influence on dopamine reuptake.The major metabolite of doxepin, nordoxepin (desmethyldoxepin), is pharmacologically active similarly, but relative to doxepin, is much more selective as a norepinephrine reuptake inhibitor. In general, the demethylated variants of tertiary amine TCAs like nordoxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities.Antidepressant doses of doxepin are defined as 25 to 300 mg/day, although are typically above 75 mg/day. Antihistamine doses, including for dermatological uses and as a sedative/hypnotic for insomnia, are considered to be 3 to 25 mg, although higher doses between 25 and 50 mg and in some cases even up to 150 mg have been used to treat insomnia. At low doses, below 25 mg, doxepin is a pure antihistamine and has more of a sedative effect. At antidepressant doses of above 75 mg, doxepin is more stimulating with antiadrenergic, antiserotonergic, and anticholinergic effects, and these activities contribute to its side effects.Doxepin is a mixture of (E) and (Z) stereoisomers with an approximate ratio of 85:15. When doxepin was developed, no effort was made to separate or balance the mixture following its synthesis, resulting in the asymmetric ratio. (Z)-Doxepin is more active as an inhibitor of serotonin and norepinephrine reuptake than (E)-doxepin. The selectivity of doxepin for inhibition of norepinephrine reuptake over that of serotonin is likely due to the 85% presence of (E)-doxepin in the mixture. Most other tertiary amine TCAs like amitriptyline and imipramine do not exhibit E-Z isomerism or such mixture asymmetry and are comparatively more balanced inhibitors of serotonin and norepinephrine reuptake.
As a hypnotic
Doxepin is a highly potent antihistamine, with this being its strongest activity. In fact, doxepin has been said to be the most or one of the most potent H1 receptor antagonists available, with one study finding an in vitro Ki of 0.17 nM. It is the most potent and selective H1 receptor antagonist of the TCAs (although the tetracyclic antidepressant (TeCA) mirtazapine is slightly more potent), and other sedating antihistamines, for instance the over-the-counter diphenhydramine (Ki = 16 nM) and doxylamine (Ki = 42 nM), show far lower affinities for this receptor in comparison. The affinity of doxepin for the H1 receptor is far greater than its affinity for other sites, and 10- to 100-fold higher doses are needed for antidepressant effects. In accordance, although it is often described as a "dirty drug" due to its highly promiscuous binding profile, doxepin acts as a highly selective antagonist of the H1 receptor at very low doses (less than 10 mg; typically 3 to 6 mg). At these doses, it notably has no clinically relevant anticholinergic effects such as dry mouth or cognitive/memory impairment, unlike most other sedating antihistamines, and similarly has no effect on other receptors such as adrenergic and serotonin receptors.The H1 receptor antagonism of doxepin is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses. The incidence of side effects with doxepin and its safety at these doses was similar to that of placebo in clinical trials; the most frequent side effects were headache and somnolence/sedation, both with an incidence of less than 5%. Other side effects sometimes associated with antihistamines, including daytime sedation, increased appetite, and weight gain, all were not observed. Clinical evidence of H1 receptor antagonists and TCAs for the treatment insomnia shows mixed effectiveness and is limited in its quality due to weaknesses like small sample sizes and poor generalizability. However, doxepin is a unique and notable exception; it has been well-studied in the treatment of insomnia and shows consistent benefits with excellent tolerability and safety. Aside from diphenhydramine and doxylamine, which have historical approval as hypnotics, doxepin is the only H1 receptor antagonist that is specifically approved for the treatment of insomnia in the United States.The effect sizes of very low-dose doxepin in the treatment of insomnia range from small to medium. These include subjective and objective measures of sleep maintenance, sleep duration, and sleep efficiency. Conversely, very low-dose doxepin shows relatively weak effects on sleep initiation and does not significantly separate from placebo on this measure. This is in contrast to benzodiazepines and nonbenzodiazepine (Z-drug) hypnotics, which are additionally effective in improving sleep onset latency. However, it is also in contrast to higher doses of doxepin (50 to 300 mg/day), which have been found to significantly reduce latency to sleep onset. A positive dose–response relationship on sleep measures was observed for doses of doxepin between 1 and 6 mg in clinical studies, whereas the incidence of adverse effects remained constant across this dose range in both young and older adults. However, the incidence of adverse effects appeared to increase with longer treatment duration. A dose of doxepin as low as 1 mg/day was found to significantly improve most of the assessed sleep measures, but unlike the 3 and 6 mg/day doses, was not able to improve wake time during sleep. This, along with greater effect sizes with the higher doses, was likely the basis for the approval of the 3 and 6 mg doses of doxepin for insomnia and not the 1 mg dose.At very low doses, doxepin has not shown discontinuation or withdrawal effects nor rebound insomnia. Sustained effectiveness without apparent tolerance was demonstrated in clinical studies of up to 12 weeks duration. This appears to be in contrast to over-the-counter antihistamines like diphenhydramine and doxylamine and all other first-generation antihistamines, which are associated with rapid development of tolerance and dependence (by day 3 or 4 of continuous dosing) and loss of hypnotic effectiveness. It is for this reason that, unlike doxepin, they are not recommended for the chronic management of insomnia and are advised for only short-term treatment (i.e., 1 week). It is not entirely clear why doxepin and first-generation antihistamines are different in this regard, but it has been suggested that it may have to do with the lack of selectivity for the H1 receptor of the latter or may have to do with the use of optimal doses. Unlike very-low-dose doxepin, most first-generation antihistamines also have marked anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention, and confusion. This is particularly true in older people, and antihistamines with concomitant anticholinergic effects are not recommended in adults over the age of 65. Anticholinergic activity notably may interfere with the sleep-promoting effects of H1 receptor blockade.Antagonism of the H1, 5-HT2A, 5-HT2C, and α1-adrenergic receptors is thought to have sleep-promoting effects and to be responsible for the sedative effects of TCAs including those of doxepin. Although doxepin is selective for the H1 receptor at doses lower than 25 mg, blockade of serotonin and adrenergic receptors may also be involved in the hypnotic effects of doxepin at higher doses. However, in contrast to very low doses of doxepin, rebound insomnia and daytime sedation are significantly more frequent than placebo with moderate doses (25 to 50 mg/day) of the drug. In addition, one study found that although such doses of doxepin improved sleep measures initially, most of the benefits were lost with chronic treatment (by 4 weeks). Due to limited data however, more research on potential tolerance and withdrawal effects of moderate doses of doxepin is needed. At these doses of doxepin, dry mouth, an anticholinergic effect, was common (71%), and other side effects such as headache (25%), increased appetite (21%), and dizziness (21%) were also frequently observed, although these adverse effects were notably not significantly more frequent than with placebo in the study in question. In any case, taken together, higher doses of doxepin than very low doses are associated with an increased rate of side effects as well as apparent loss of hypnotic effectiveness with chronic treatment.Doxepin at a dose of 25 mg/day for 3 weeks has been found to decrease cortisol levels by 16% in adults with chronic insomnia and to increase melatonin production by 26% in healthy volunteers. In individuals with neuroendocrine dysregulation in the form of nocturnal melatonin deficiency presumably due to chronic insomnia, very-low-dose doxepin was found to restore melatonin levels to near-normal values after 3 weeks of treatment. These findings suggest that normalization of the hypothalamic–pituitary–adrenal axis and the circadian sleep–wake cycle may be involved in the beneficial effects of doxepin on sleep and insomnia.
CYP2D6 inhibition
Doxepin has been identified as an inhibitor of CYP2D6 in vivo in a study of human patients being treated with 75 to 250 mg/day for depression. While it significantly altered metabolic ratios for sparteine and its metabolites, doxepin did not convert any of the patients to a different metabolizer phenotype (e.g., extensive to intermediate or poor). Nonetheless, inhibition of CYP2D6 by doxepin could be of clinical importance.
Pharmacokinetics
Absorption
Doxepin is well-absorbed from the gastrointestinal tract but between 55 and 87% undergoes first-pass metabolism in the liver, resulting in a mean oral bioavailability of approximately 29%. Following a single very low dose of 6 mg, peak plasma levels of doxepin are 0.854 ng/mL (3.06 nmol/L) at 3 hours without food and 0.951 ng/mL (3.40 nmol/L) at 6 hours with food. Plasma concentrations of doxepin with antidepressant doses are far greater, ranging between 50 and 250 ng/mL (180 to 900 nmol/L). Area-under-curve levels of the drug are increased significantly when it is taken with food.
Distribution
Doxepin is widely distributed throughout the body and is approximately 80% plasma protein-bound, specifically to albumin and α1-acid glycoprotein.
Metabolism
Doxepin is extensively metabolized by the liver via oxidation and N-demethylation. Its metabolism is highly stereoselective. Based on in vitro research, the major enzymes involved in the metabolism of doxepin are the cytochrome P450 enzymes CYP2D6 and CYP2C19, with CYP1A2, CYP2C9, and CYP3A4 also involved to a lesser extent. The major active metabolite of doxepin, nordoxepin, is formed mainly by CYP2C19 (>50% contribution), while CYP1A2 and CYP2C9 are involved to a lesser extent, and CYP2D6 and CYP3A4 are not involved. Both doxepin and nordoxepin are hydroxylated mainly by CYP2D6, and both doxepin and nordoxepin are also transformed into glucuronide conjugates. The elimination half-life of doxepin is about 15–18 hours, whereas that of nordoxepin is around 28–31 hours. Up to 10% of Caucasian individuals show substantially reduced metabolism of doxepin that can result in up to 8-fold elevated plasma concentrations of the drug compared to normal.Nordoxepin is a mixture of (E) and (Z) stereoisomers similarly to doxepin. Whereas pharmaceutical doxepin is supplied in an approximate 85:15 ratio mixture of (E)- and (Z)-stereoisomers and plasma concentrations of doxepin remain roughly the same as this ratio with treatment, plasma levels of the (E)- and (Z)-stereoisomers of nordoxepin, due to stereoselective metabolism of doxepin by cytochrome P450 enzymes, are approximately 1:1.
Elimination
Doxepin is eliminated primarily in the urine and predominantly in the form of glucuronide conjugates, with less than 3% of a dose excreted unchanged as doxepin or nordoxepin.
Pharmacogenetics
Since doxepin is mainly metabolized by CYP2D6, CYP2C9, and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of doxepin may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drugs efficacy.
Individuals can be categorized into different types of cytochrome P450 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most people are extensive metabolizers, and have "normal" metabolism of doxepin. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers break down doxepin much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.
A study assessed the metabolism of a single 75 mg oral dose of doxepin in healthy volunteers with genetic polymorphisms in CYP2D6, CYP2C9, and CYP2C19 enzymes. In CYP2D6 extensive, intermediate, and poor metabolizers, the mean clearance rates of (E)-doxepin were 406, 247, and 127 L/hour, respectively (~3-fold difference between extensive and poor). In addition, the bioavailability of (E)-doxepin was about 2-fold lower in extensive relative to poor CYP2D6 metabolizers, indicating a significant role of CYP2D6 in the first-pass metabolism of (E)-doxepin. The clearance of (E)-doxepin in CYP2C9 slow metabolizers was also significantly reduced at 238 L/hour. CYP2C19 was involved in the metabolism of (Z)-doxepin, with clearance rates of 191 L/hour in CYP2C19 extensive metabolizers and 73 L/hour in poor metabolizers (~2.5-fold difference). Area-under-the-curve (0–48 hour) levels of nordoxepin were dependent on the genotype of CYP2D6 with median values of 1.28, 1.35, and 5.28 nM•L/hour in CYP2D6 extensive, intermediate, and poor metabolizers, respectively (~4-fold difference between extensive and poor). Taken together, doxepin metabolism appears to be highly stereoselective, and CYP2D6 genotype has a major influence on the pharmacokinetics of (E)-doxepin. Moreover, CYP2D6 poor metabolizers, as well as patients taking potent CYP2D6 inhibitors (which can potentially convert a CYP2D6 extensive metabolizer into a poor metabolizer), may be at an increased risk for adverse effects of doxepin due to their slower clearance of the drug.Another study assessed doxepin and nordoxepin metabolism in CYP2D6 ultra-rapid, extensive, and poor metabolizers following a single 75 mg oral dose. They found up to more than 10-fold variation in total exposure to doxepin and nordoxepin between the different groups. The researchers suggested that in order to achieve equivalent exposure, based on an average dose of 100%, the dosage of doxepin might be adjusted to 250% in ultra-rapid metabolizers, 150% in extensive metabolizers, 50% in intermediate metabolizers, and 30% in poor metabolizers.
Chemistry
Doxepin is a tricyclic compound, specifically a dibenzoxepin, and possesses three rings fused together with a side chain attached in its chemical structure. It is the only TCA with a dibenzoxepin ring system to have been marketed. Doxepin is a tertiary amine TCA, with its side chain-demethylated metabolite nordoxepin being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and trimipramine. Doxepin is a mixture of (E) and (Z) stereoisomers (the latter being known as cidoxepin or cis-doxepin) and is used commercially in a ratio of approximately 85:15. The chemical name of doxepin is (E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H21NO with a molecular weight of 279.376 g/mol. The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely. The CAS Registry Number of the free base is 1668-19-5 and of the hydrochloride is 1229-29-4.
History
Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969. It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.
Society and culture
Generic names
Doxepin is the generic name of the drug in English and German and its INN and BAN, while doxepin hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are doxepina, in French and its DCF are doxépine, and in Latin is doxepinum.The cis or (Z) stereoisomer of doxepin is known as cidoxepin, and this is its INN while cidoxepin hydrochloride is its USAN.
Brand names
It was introduced under the brand names Quitaxon and Aponal by Boehringer and as Sinequan by Pfizer.Doxepin is marketed under many brand names worldwide, including: Adnor, Anten, Antidoxe, Colian, Deptran, Dofu, Doneurin, Dospin, Doxal, Doxepini, Doxesom, Doxiderm, Flake, Gilex, Ichderm, Li Ke Ning, Mareen, Noctaderm, Oxpin, Patoderm, Prudoxin, Qualiquan, Quitaxon, Sagalon, Silenor, Sinepin, Sinequan, Sinquan, and Zonalon. It is also marketed as a combination drug with levomenthol under the brand name Doxure.
Approvals
The oral formulations of doxepin are FDA-approved for the treatment of depression and sleep-maintenance insomnia, and its topical formulations are FDA-approved the short-term management for some itchy skin conditions. In Australia and the United Kingdom, the only licensed indications are in the treatment of major depression and pruritus in eczema.
Research
Antihistamine
Cidoxepin is under development by Elorac, Inc. for the treatment of chronic urticaria (hives). As of 2017, it is in phase II clinical trials for this indication. The drug was also under investigation for the treatment of allergic rhinitis, atopic dermatitis, and contact dermatitis, but development for these indications was discontinued.
Headache
Doxepin was under development by Winston Pharmaceuticals in an intranasal formulation for the treatment of headache. As of August 2015, it was in phase II clinical trials for this indication. Oxetorone is an antimigraine agent.
Neuropathic pain
As of 2017, there was no good evidence that topical doxepin was useful to treat localized neuropathic pain.
References
External links
Media related to Doxepin at Wikimedia Commons
"Doxepin". Drug Information Portal. U.S. National Library of Medicine.
"Doxepin hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
You function as a medical dictionary. Offer comprehensive and accurate descriptions of medical terms, ensuring clarity and depth in your explanations. | Could you offer a clear explanation of the term 'Primary biliary cholangitis' as used in the medical field? | Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.
Common symptoms are tiredness, itching, and in more advanced cases, jaundice. In early cases, the only changes may be those seen in blood tests.PBC is a relatively rare disease, affecting up to one in 3,000–4,000 people. It is much more common in women, with a sex ratio of at least 9:1 female to male.The condition has been recognised since at least 1851, and was named "primary biliary cirrhosis" in 1949. Because cirrhosis is a feature only of advanced disease, a change of its name to "primary biliary cholangitis" was proposed by patient advocacy groups in 2014.
Signs and symptoms
People with PBC experience fatigue (80%); this is a nonspecific symptom and can be debilitating, with a huge impact on quality of life. Its pathogenesis is still unknown, and is quite challenging to explore its specificity and to treat. Comorbidities that could contribute or worsen fatigue, such as depression, hypothyroidism, anaemia, obesity, or medication side effects, should be promptly identified and treated. Dry skin and dry eyes are also common. Itching (pruritus) occurs in 20–70% of cases, and can develop at any stage of the disease; it does not correlate with progression of liver disease, and may even improve or disappear as the disease advances. It is typically mild-to-moderate in intensity. Given the impact on quality of life and night sleep, pruritus is correlated with fatigue. It can rarely be severe, nonresponsive to medical therapy, and requiring liver transplant. Pruritus is characteristically intermittent, worse at night, and improves during summer.
People with more severe PBC may have jaundice (yellowing of the eyes and skin). PBC impairs bone density and the risk of fracture increases. Xanthelasma (skin lesions around the eyes) or other xanthoma may be present as a result of increased cholesterol levels.PBC can eventually progress to cirrhosis of the liver. This, in turn, may lead to a number of symptoms or complications, including:
Fluid retention in the abdomen (ascites) in more advanced disease
Enlarged spleen in more advanced disease
Oesophageal varices in more advanced disease
Hepatic encephalopathy, including coma in extreme cases in more advanced disease.People with PBC may also sometimes have the findings of an associated extrahepatic autoimmune disorder such as thyroid disease or rheumatoid arthritis or Sjögrens syndrome (in up to 80% of cases).
Causes
PBC has an immunological basis, and is classified as an autoimmune disorder. It results from a slow, progressive destruction of the small bile ducts of the liver, with the intralobular ducts and the canals of Hering (intrahepatic ductules) being affected early in the disease.
Most people with PBC (more than 90%) have antimitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex found in the mitochondria. People who are negative for AMAs are usually found to be positive when more sensitive methods of detection are used.People with PBC may also have been diagnosed with another autoimmune disease, such as a rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological condition, suggesting shared genetic and immune abnormalities.
Common associations include Sjögrens syndrome, systemic sclerosis, rheumatoid arthritis, lupus, hypothyroidism, and coeliac disease.A genetic predisposition to disease has been thought to be important for some time. Evidence for this includes cases of PBC in family members, identical twins both having the condition (concordance), and clustering of PBC with other autoimmune diseases. In 2009, a Canadian-led group of investigators reported in the New England Journal of Medicine results from the first PBC genome-wide association study. This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the aetiology of the disease in addition to the HLA region. In 2012, two independent PBC association studies increased the total number of genomic regions associated to 26, implicating many genes involved in cytokine regulation such as TYK2, SH2B3 and TNFSF11.A study of over 2,000 patients identified a gene, POGLUT1, that appeared to be associated with this condition. Earlier studies have also suggested that this gene may be involved. The implicated protein is an endoplasmic reticulum O-glucosyltransferase.
An environmental Gram-negative Alphaproteobacterium — Novosphingobium aromaticivorans has been associated with this disease, with several reports suggesting an aetiological role for this organism. The mechanism appears to be a cross-reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells. The gene encoding CD101 may also play a role in host susceptibility to this disease.A failure of immune tolerance against the mitochondrial pyruvate dehydrogenase complex (PDC-E2) is a primary cause, with shedding of the antigen into apoptotic bodies or "apotopes" leading to the anatomic localization. Such autoreactivity may also be the case with other proteins, including the gp210 and p62 nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients, and these proteins may be associated with prognosis.
Diagnosis
Most patients are currently diagnosed when asymptomatic, having been referred to the hepatologist for abnormal liver function tests (mostly raised GGT or alkaline phosphatase) performed for annual screening blood tests. Other frequent scenarios include screening of patients with nonliver autoimmune diseases, e.g. rheumatoid arthritis, or investigation of elevated cholesterol, evaluation of itch or unresolved cholestasis post partum. Diagnosing PBC is generally straightforward. The basis for a definite diagnosis are:
Abnormalities in liver enzyme tests are usually present and elevated gamma-glutamyl transferase and alkaline phosphatase are found in early disease. Elevations in bilirubin occur in advanced disease.
Antimitochondrial antibodies are the characteristic serological marker for PBC, being found in 90–95% of patients and only 1% of controls. PBC patients have AMA against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria. Those people who are AMA negative but with disease similar to PBC have been found to have AMAs when more sensitive detection methods are employed.
Other auto-antibodies may be present:Antinuclear antibody measurements are not diagnostic for PBC because they are not specific, but may have a role in prognosis.
Anti-glycoprotein-210 antibodies, and to a lesser degree anti-p62 antibodies, correlate with the diseases progression toward end-stage liver failure. Anti-gp210 antibodies are found in 47% of PBC patients.
Anti-centromere antibodies often correlate with developing portal hypertension.
Anti-np62 and anti-sp100 are also found in association with PBC.Abdominal ultrasound, magnetic resonance cholangiopancreatography or a CT scan is usually performed to rule out blockage to the bile ducts. This may be needed if a condition causing secondary biliary cirrhosis, such as other biliary duct disease or gallstones, needs to be excluded. A liver biopsy may help, and if uncertainty remains as in some patients, an endoscopic retrograde cholangiopancreatography, an endoscopic investigation of the bile duct, may be performed.Given the high specificity of serological markers, liver biopsy is not necessary for the diagnosis of PBC; however, it is still necessary when PBC-specific antibodies are absent, or when co-existent autoimmune hepatitis or nonalcoholic steatohepatitis is suspected. Liver biopsy can be useful to stage the disease for fibrosis and ductopenia. Finally, it may also be appropriate in the presence of other extrahepatic comorbidities.
Liver biopsy
On microscopic examination of liver biopsy specimens, PBC is characterized by chronic, nonsuppurative inflammation, which surrounds and destroys interlobular and septal bile ducts. These histopathologic findings in primary biliary cholangitis include:
Inflammation of the bile ducts, characterized by intraepithelial lymphocytes
Periductal epithelioid granulomas.
Proliferation of bile ductules
Fibrosis (scarring)The Ludwig and Scheuer scoring systems have historically been used to stratify four stages of PBC, with stage 4 indicating the presence of cirrhosis. In the new system of Nakanuma, the stage of disease is based on fibrosis, bile duct loss, and features of cholestasis, i.e. deposition of orcein-positive granules, whereas the grade of necroinflammatory activity is based on cholangitis and interface hepatitis. The accumulation of orcein-positive granules occurs evenly across the PBC liver, which means that staging using the Nakanuma system is more reliable regarding sampling variability.
Liver biopsy for the diagnosis and staging of PBC lost favour after the evidence of a patchy distribution of the duct lesions and fibrosis across the organ. The widespread availability of noninvasive measures of fibrosis means that liver biopsy for staging of PBC is somewhat obsolete.
Liver biopsy does, however, remain useful in certain settings. The main indications are to confirm the diagnosis of PBC when PBC-specific antibodies are absent and confirm a diagnosis of PBC with AIH features (i.e. overlap PBC-AIH). Liver biopsy is also useful to assess the relative contribution of each liver injury when a comorbid liver disease is present, such as non-alcoholic steatohepatitis. In patients with inadequate response to UDCA, liver biopsy may provide the explanation and could undoubtedly inform risk stratification. For example, it may identify a previously unsuspected variant syndrome, steatohepatitis, or interface hepatitis of moderate or greater severity. It is also useful in AMA and ANA-specific antibody negative cholestatic patients to indicate an alternative process, e.g. sarcoidosis, small duct PSC, adult idiopathic ductopenia.
Histopathology stages (by Ludwig and Scheuer systems)
Stage 1 – portal stage: Normal-sized triads, portal inflammation, subtle bile duct damage: Granulomas are often detected in this stage.
Stage 2 – periportal stage: Enlarged triads, periportal fibrosis and/or inflammation, typically characterized by the finding of a proliferation of small bile ducts
Stage 3 – septal stage: Active and/or passive fibrous septa
Stage 4 – biliary cirrhosis: Nodules present, garland or jigsaw puzzle pattern
Treatment
Cholestasis
Medical therapy of PBC targets disease progression and symptom control. The first-line treatment for PBC is ursodeoxycholic acid (UDCA). UDCA has been the only drug available for two decades and more recently obeticholic acid (OCA), a semi-synthetic hydrophobic bile acid analogue, has been licensed in patients failing UDCA response or intolerant to UDCA. Several other agents have been studied, including immunosuppressants, but robust evidence of benefit is lacking.UDCA improves liver enzyme levels, slows down histological progression, and improves liver transplant-free survival. UDCA also reduces the need for liver transplantation. UDCA should be taken at a dose of 13 to 15 mg per kg of body weight per day, usually in two divided doses each day. Liver chemistries usually improve within a few weeks of starting UDCA, and 90% of any benefit is observed after 6–9 months of therapy. Liver chemistries should be re-evaluated after 1 year of treatment. UDCA is usually continued lifelong. Up to 40% of people do not respond to treatment with UDCA. Patients with PBC who have an inadequate response to UDCA or those few (less than 3%) who are intolerant to UDCA are candidates for second-line therapies.
Obeticholic acid (OCA) is FDA-approved for the treatment of PBC in individuals intolerant or unresponsive to UDCA. OCA is a farnesoid X receptor agonist, and results in increased bile flow (choleresis). OCA is started at 5 mg daily, and liver chemistries should be rechecked after 3 months of treatment. If the liver chemistries remain elevated, then the dose of OCA may be increased to 10 mg per day. The most common side effect of OCA is pruritus.
Fibric acid derivatives, or fibrates, are agonists of the peroxisome proliferator activator receptor (PPAR), a nuclear receptor involved in several metabolic pathways. While fibrates are approved for the treatment of hypertriglyceridemia, they exert anticholestatic effects and have been studied for the treatment of PBC. Among the fibrates, bezafibrate and fenofibrate, PPAR-alpha selective agonists, have been extensively studied as therapeutic agents because of their potential ability to decrease bile acid synthesis and bile acid-related hepatic inflammation. A randomized, controlled trial in 2018 showed its efficacy in patients with inadequate response to UDCA. While fibrates can be considered as off-label treatment for PBC that does not respond to UDCA, they should not be used in decompensated cirrhosis.Several additional medications have been investigated as potential treatments for PBC, and found to be ineffective as single agents (monotherapy), including: chlorambucil, colchicine, cyclosporine, corticosteroids, azathioprine, malotilate, methotrexate, mycophenolate mofetil, penicillamine, and thalidomide. Budesonide may be used as an off-label treatment for PBC, although its efficacy is controversial.
Itching
Pruritus is a common symptom in people with PBC. First-line treatment of pruritus consists of anion-exchange resins, such as cholestyramine, colestipol, or colesevalam. These anion-exchange resins are nonabsorbed, highly positively charged substances that bind bile acids, which are negatively charged anions. Anion-exchange resins relieve itching caused by excess bile acids in circulation by binding bile acids in the gut and facilitating elimination. Bloating or constipation may occur with anion-exchange resins. Cholestyramine may affect absorption of UDCA; if cholestyramine is necessary, it should be taken at least 60 minutes before or 4 hours after UDCA is taken.Treatment options for pruritus that does not improve with anion-exchange resins include: rifampicin, naltrexone, or sertraline. Rifampicin may rarely cause drug induced liver injury and should be avoided if serum bilirubin is elevated (greater than 2.5 mg/dL). Liver enzymes should be monitored after starting rifampin. Rifampicin induces enzymes, resulting in numerous potential drug-drug interactions. Opioid antagonists may cause a self-limited opioid withdrawal like reaction, with abdominal pain, elevated blood pressure, tachycardia, goose bumps, nightmares, and depersonalization. To avoid such reactions, the dose should start low and gradually be increased.
Other therapies
Fatigue is a nonspecific but often-reported symptom in PBC, and represents an unmet need since no therapies are licensed. A structured approach to management, quantifying fatigue and its impacts (through the use of disease-specific tools such as the PBC-40 quality-of-life measures), addressing contributing and exacerbating factors, and supporting patients to cope with its impact is effective. Drugs such as coenzyme Q and rituximab have been shown to be ineffective. A graded programme of exercise helps some individuals.
People with PBC may have poor lipid-dependent absorption of oil-soluble vitamins (A, D, E, and K). Appropriate supplementation is recommended when bilirubin is elevated.
People with PBC are at elevated risk of developing osteoporosis as compared to the general population and others with liver disease. Screening and treatment of this complication is an important part of the management of PBC.
As in all liver diseases, consumption of alcohol should be restricted or eliminated.
In patients with advanced liver disease, the only curative therapy is liver transplant. Outcomes are favourable, with five-year patient survival rates better than for most other indications for LT (80–85%).
Prognosis
The introduction of UDCA has dramatically changed the pattern and the course of the disease. Numerous trials and observational studies have demonstrated its efficacy on liver biochemistry, histological progression, and transplant-free survival.Among the UDCA-treated patients, the degree of the liver biochemistry improvement, i.e. the UDCA-response, identifies patients with different long-term prognosis. In the absence of cirrhosis, people who experience an improvement of liver enzymes to the normal range on treatment with UDCA have excellent survival, which may be similar to the general population. Survival is significantly reduced though, in those with abnormal liver biochemistry on treatment.
The two most important parameters in evaluating response to UDCA are alkaline phosphatase and total bilirubin. Qualitative and quantitative definitions of UDCA-response have been developed, based on changes of bilirubin, transaminases and ALP, after a period of 6 to 24 months of treatment with UDCA at 13–15 mg/kg/day.Patients at diagnosis can be risk-stratified based on the probability of UDCA-response. This is relevant to identify patients who would be eligible for second-line therapies before waiting for the treatment failure under UDCA, with potential impact on disease course.Hepatocellular carcinoma (HCC) is infrequent in PBC. Recent large-scale cohort studies highlighted that the lack of UDCA-response after 12 months of therapy and male sex are associated with increased future risk of developing HCC in PBC.
After liver transplant, the recurrence of disease may be as high as 18% at five years, and up to 30% at 10 years. No consensus exists on risk factors for recurrence of the disease.
Epidemiology
Epidemiologic studies report heterogeneous incidence rates of 0.33 to 5.8 per 100,000 inhabitants per year, and prevalence rates of 1.9 to 40.2 per 100,000 inhabitants. Such figures, in particular the prevalence, have shown some increase in the last decades. Improvement of diagnostic tools, increasing disease awareness, and digitised patient registration with facilitation of case-findings, along with improved survival, likely contributed to the rising prevalence rates.
The disease has been described worldwide, though North America and Northern Europe have shown the highest incidence and prevalence rates. Whether a true variation in disease prevalence exists among populations of different geographical areas and of different ethnicity or if this is a consequence of a difference in study quality is unknown. PBC is more common in women, with a female:male ratio of at least 9:1. The peak incidence of PBC is in the fifth decade of life. In some areas of the US and UK, the prevalence is estimated to be as high as one in 4,000. This is much more common than in South America or Africa, which may be due to better recognition in the US and UK. First-degree relatives may have as much as a 500 times increase in prevalence, but if this risk is greater in the same-generation relatives or the one that follows is debated.
PBC is considered a prime example of the female preponderance in autoimmunity with a female to male ratio of up to 9:1, confirmed by large cohort studies, although some recent data, using administrative registries, suggest an increasing male prevalence. Major defects of sex chromosomes, i.e. enhanced monosomy X in female patients and an enhanced Y chromosome loss in male patients, have been described and might well explain the greater female predisposition to develop PBC.An association of a greater incidence of PBC at latitudes more distant from the Equator is similar to the pattern seen in multiple sclerosis.Typical disease onset is between 30 and 60 years, though cases have been reported of patients diagnosed at the ages of 15 and 93. Prevalence of PBC in women over the age of 45 years could exceed one in an estimated 800 individuals.
History
The first report of the disease dates back 1851 by Addison and Gull, who described a clinical picture of progressive jaundice in the absence of mechanical obstruction of the large bile ducts. Ahrens et al. in 1950 published the first detailed description of 17 patients with this condition, and coined the term "primary biliary cirrhosis". In 1959, Dame Sheila Sherlock reported a further series of PBC patients and recognised that the disease could be diagnosed in a precirrhotic stage and proposed the term "chronic intrahepatic cholestasis" as more appropriate description of this disease, but this nomenclature failed to gain acceptance, and the term "primary biliary cirrhosis" lasted for decades. In 2014, to correct the inaccuracy and remove the social stigmata of cirrhosis, as well as all the misunderstanding, disadvantages, and discrimination emanating from this misnomer in daily life for patients, international liver associations agreed to rename the disease "primary biliary cholangitis", as it is now known.
Society and culture
Support groups
PBC Foundation
The PBC Foundation is a UK-based international charity offering support and information to people with PBC and their families and friends. It campaigns for increasing recognition of the disorder, improved diagnosis, and treatments, and estimates over 8,000 people are undiagnosed in the UK. The Foundation has supported research into PBC including the development of the PBC-40 quality of life measure published in 2004 and helped establish the PBC Genetics Study. It was founded by Collette Thain in 1996, after she was diagnosed with the condition. Thain was awarded an MBE Order of the British Empire in 2004 for her work with the Foundation. The PBC Foundation helped initiate the name change campaign in 2014.
PBCers Organization
The PBCers Organization is a US-based nonprofit patient support group that was founded by Linie Moore in 1996; it advocates for greater awareness of the disease and new treatments. It supported the name change initiative.
References
External links
Primary Biliary Cirrhosis page from the National Digestive Diseases Information Clearinghouse
Alagille syndrome |
You are a facilitator of medical knowledge. Provide thorough and accessible explanations of medical terms, catering to both specialists and non-specialists. | I've come across the term 'Myxoma' in a medical context, but I'm not sure what it means. Can you clarify? | A myxoma (New Latin from Greek muxa for mucus) is a myxoid tumor of primitive connective tissue. It is most commonly found in the heart (and is the most common primary tumor of the heart in adults) but can also occur in other locations.
Types
Table below:
1.^ SMA, smooth muscle actin. 2.^ MSA, muscle-specific actin. 3.^ EMA, epithelial membrane antigen.
Symptoms and signs
Symptoms associated with cardiac myxomas are typically due to the effect of the mass of the tumor obstructing the normal flow of blood within the chambers of the heart. Because pedunculated myxomas are somewhat mobile, symptoms may only occur when the patient is in a particular position.
Some symptoms of myxoma may be associated with the release of interleukin 6 (IL-6) by the myxoma. High levels of IL-6 may be associated with a higher risk of embolism of the myxoma.Symptoms of a cardiac myxoma include:
Dyspnea on exertion
Paroxysmal nocturnal dyspnea
Fever
Weight loss (see cachexia)
Lightheadedness or syncope (Loss of consciousness)
Hemoptysis
Sudden death
Tachycardia or milder heartrate, i.e. 75 - 100 cycl/min
Location
Ocular myxoma
Myxoma is a rare, benign stromal tumor of mesenchymal origin often confused with other conjunctival stromal tumors. Conjunctival myxomas are thought to originate in Tenons capsule and can masquerade as conjunctival lymphoma, lymphangioma, ocular surface squamous neoplasia (OSSN), or amelanotic melanoma.
Atrial myxoma
Cutaneous myxoma
Odontogenic myxoma
Atrial myxoma
Myxomas are usually located in either the left or right atrium of the heart; about 86 percent occur in the left atrium.Myxomas are typically pedunculated, with a stalk that is attached to the interatrial septum. The most common location for attachment of the stalk is the fossa ovalis region of the interatrial septum.An atrial myxoma may create an extra heart sound, audible to auscultation just after S2. It is most seen on echocardiography, as a pedunculated mass that is heterogeneous in appearance. A left atrial myxoma will cause an increase in pulmonary capillary wedge pressure.The differential diagnosis include other cardiac tumors such as lipomas and rhabdomyomas (and rarely teratomas). These other tumors of the heart are typically not pedunculated, however, and are more likely to infiltrate the muscle of the heart. Cardiac magnetic resonance imaging (MRI) can help non-invasively diagnose cardiac tumors. However, diagnosis usually requires examination of a tissue sample by a pathologist.
Treatment
Myxomas are usually removed surgically. The surgeon removes the myxoma, along with at least 5 surrounding millimeters of atrial septum. The septum is then repaired, using material from the pericardium.
Epidemiology
Cardiac myxomas predominantly appear in females in their 30s to 40s. Myxomas are the most common primary cardiac tumor affecting adults, accounting for one quarter to half of primary cardiac tumors seen in clinical practice.
See also
Myxoid tumor
Cutaneous myxoma
Carney complex
Myxomatosis
Primary tumors of the heart
Myxomatous degeneration
References
External links
03-031b. at Merck Manual of Diagnosis and Therapy Home Edition
Myxomatous degeneration at Wikidoc |
You function as a medical dictionary. Offer comprehensive and accurate descriptions of medical terms, ensuring clarity and depth in your explanations. | I'm trying to understand 'Seborrhoeic dermatitis' within a medical context. Could you shed some light on it? | Seborrhoeic dermatitis, sometimes inaccurately referred to as seborrhoea, is a long-term skin disorder. Symptoms include red, scaly, greasy, itchy, and inflamed skin. Areas of the skin rich in oil-producing glands are often affected including the scalp, face, and chest. It can result in social or self-esteem problems. In babies, when the scalp is primarily involved, it is called cradle cap. Dandruff is a milder form of the condition without inflammation.The cause is unclear but believed to involve a number of genetic and environmental factors. Risk factors include poor immune function, Parkinsons disease, and alcoholic pancreatitis. The condition may worsen with stress or during the winter. The Malassezia yeast is believed to play a role. It is not a result of poor hygiene. Diagnosis is typically based on the symptoms. The condition is not contagious.The typical treatment is antifungal cream and anti-inflammatory agents. Specifically, ketoconazole or ciclopirox are effective. It is unclear if other antifungals, such as miconazole, are equally effective as they have been poorly studied. Other options may include salicylic acid, coal tar, benzoyl peroxide, and phototherapy.The condition is most common in infants within the first 3 months or in adults aged 30 to 70 years. In adults between 1% and 10% of people are affected. Males are more often affected than females. Up to 70% of babies may be affected at some point in time.
Signs and symptoms
Seborrhoeic dermatitis symptoms appear gradually, and usually the first signs are flaky skin and scalp. Symptoms occur most commonly anywhere on the skin of the scalp, behind the ears, on the face, and in areas where the skin folds. Flakes may be yellow, white or grayish. Redness and flaking may also occur on the skin near the eyelashes, on the forehead, around the sides of the nose, on the chest, and on the upper back.
In more severe cases, yellowish to reddish scaly pimples appear along the hairline, behind the ears, in the ear canal, on the eyebrows, on the bridge of the nose, around the nose, on the chest, and on the upper back.Commonly, patients experience mild redness, scaly skin lesions and in some cases hair loss. Other symptoms include patchy scaling or thick crusts on the scalp, red, greasy skin covered with flaky white or yellow scales, itching, soreness and yellow or white scales that may attach to the hair shaft.Seborrhoeic dermatitis can occur in infants younger than three months and it causes a thick, oily, yellowish crust around the hairline and on the scalp. Itching is not common among infants. Frequently, a stubborn diaper rash accompanies the scalp rash.
Causes
The cause of seborrhoeic dermatitis has not been fully clarified.In addition to the presence of Malassezia, genetic, environmental, hormonal, and immune-system factors are necessary for and/or modulate the expression of seborrhoeic dermatitis. The condition may be aggravated by illness, psychological stress, fatigue, sleep deprivation, change of season, and reduced general health. In children and babies, excessive vitamin A intake or issues with Δ6-desaturase enzymes have been correlated with increased risk. Seborrhoeic dermatitis-like eruptions are also associated with vitamin B6 deficiency. Those with immunodeficiency (especially infection with HIV) and with neurological disorders such as Parkinsons disease (for which the condition is an autonomic sign) and stroke are particularly prone to it.
Climate
Low humidity and low temperature are responsible for high frequency of seborrheic dermatitis.
Fungi
The condition is thought to be due to a local inflammatory response to over-colonization by Malassezia fungi species in sebum-producing skin areas including the scalp, face, chest, back, underarms, and groin. This is based on observations of high counts of Malassezia species in skin affected by seborrhoeic dermatitis and on the effectiveness of antifungals in treating the condition. Such species of Malassezia include M. furfur (formerly Pityrosporum ovale), M. globosa, M. restricta, M. sympodialis, and M. slooffiae. Although Malassezia appears to be the central predisposing factor in seborrhoeic dermatitis, it is thought that other factors are necessary for the presence of Malassezia to result in the pathology characteristic of the condition. This is based on the fact that summer growth of Malassezia in the skin alone does not result in seborrhoeic dermatitis. Besides antifungals, the effectiveness of anti-inflammatory drugs, which reduce inflammation, and antiandrogens, which reduce sebum production, provide further insights into the pathophysiology of seborrhoeic dermatitis. Eunuchs, owing to their low androgen levels and small sebaceous glands, do not develop seborrheic dermatitis.
Management
Humidity
A humidifier can be used to prevent low indoor humidity during winter (especially with indoor heating), and dry season. And a dehumidifier can be used during seasons with excessive humidity.
Medications
A variety of different types of medications are able to reduce symptoms of seborrhoeic dermatitis. These include certain antifungals, anti-inflammatory agents like corticosteroids and nonsteroidal anti-inflammatory drugs, antiandrogens, and antihistamines, among others.
Antifungals
Regular use of an over-the-counter or prescription antifungal shampoo or cream may help those with recurrent episodes. The topical antifungal medications ketoconazole and ciclopirox have the best evidence. It is unclear if other antifungals are equally effective as this has not been sufficiently studied. Antifungals that have been studied and found to be effective in the treatment of seborrhoeic dermatitis include ketoconazole, fluconazole, miconazole, bifonazole, sertaconazole, clotrimazole, flutrimazole, ciclopirox, terbinafine, butenafine, selenium sulfide, and lithium salts such as lithium gluconate and lithium succinate. Topical climbazole appears to have little effectiveness in the treatment of seborrhoeic dermatitis. Systemic therapy with oral antifungals including itraconazole, fluconazole, ketoconazole, and terbinafine is effective.
Anti-inflammatory treatments
Topical corticosteroids have been shown to be effective in short-term treatment of seborrhoeic dermatitis and are as effective or more effective than antifungal treatment with azoles. There is also evidence for the effectiveness of calcineurin inhibitors like tacrolimus and pimecrolimus as well as lithium salt therapy.Oral immunosuppressive treatment, such as with prednisone, has been used in short courses as a last resort in seborrhoeic dermatitis due to its potential side effects.
Antiandrogens
Seborrhoea, which is sometimes associated with seborrhoeic dermatitis, is recognized as an androgen-sensitive condition – that is, it is caused or aggravated by androgen sex hormones such as testosterone and dihydrotestosterone – and is a common symptom of hyperandrogenism (e.g., that seen in polycystic ovary syndrome). In addition, seborrhoea, as well as acne, are commonly associated with puberty due to the steep increase of androgen levels at that time.In accordance with the involvement of androgens in seborrhoea, antiandrogens, such as cyproterone acetate, spironolactone, flutamide, and nilutamide, are highly effective in alleviating the condition. As such, they are used in the treatment of seborrhoea, particularly severe cases. While beneficial in seborrhoea, effectiveness may vary with different antiandrogens; for instance, spironolactone (which is regarded as a relatively weak antiandrogen) has been found to produce a 50% improvement after three months of treatment, whereas flutamide has been found to result in an 80% improvement within three months. Cyproterone acetate, similarly more potent and effective than spironolactone, results in considerable improvement or disappearance of acne and seborrhoea in 90% of patients within three months.Systemic antiandrogen therapy is generally used to treat seborrhoea only in women, not in men, as these medications can result in feminization (e.g., gynecomastia), sexual dysfunction, and infertility in males. In addition, antiandrogens theoretically have the potential to feminize male fetuses in pregnant women and, for this reason, are usually combined with effective birth control in sexually active women who can or may become pregnant.
Antihistamines
Antihistamines are used primarily to reduce itching, if present. However, research studies suggest that some antihistamines have anti-inflammatory properties.
Other treatments
Coal tar can be effective. Although no significant increased risk of cancer in human treatment with coal tar shampoos has been found, caution is advised since coal tar is carcinogenic in animals, and heavy human occupational exposures do increase cancer risks.
Isotretinoin, a sebosuppressive agent, may be used to reduce sebaceous gland activity as a last resort in refractory disease. However, isotretinoin has potentially serious side effects, and few patients with seborrhoeic dermatitis are appropriate candidates for therapy.
Keratolytics like topical urea
Metronidazole
Topical 4% nicotinamide
Phototherapy
Another potential option is natural and artificial UV radiation since it can curb the growth of Malassezia yeast. Some recommend photodynamic therapy using UV-A and UV-B laser or red and blue LED light to inhibit the growth of Malassezia fungus and reduce seborrhoeic inflammation.
Epidemiology
Seborrhoeic dermatitis affects 1 to 5% of the general population. It is slightly more common in men, but affected women tend to have more severe symptoms. The condition usually recurs throughout a persons lifetime. Seborrhoeic dermatitis can occur in any age group but usually starts at puberty and peaks in incidence at around 40 years of age. It can reportedly affect as many as 31% of older people. Severity is worse in dry climates. Seborrhoeic dermatitis is common in this with alcoholism, between 7 and 11 percent, which is twice the normal expected occurrence.
See also
Seborrheic keratosis
Eczema herpeticum, condition that primarily manifests in childhood
References
External links
American Academy of Dermatology: Seborrheic dermatitis |
You are a medical interpreter. Your duty is to translate medical terms into easily digestible information, maintaining accuracy and detail. | I'm seeking clarification on the medical term 'Hashimotos encephalopathy.' Could you explain it? | Hashimotos encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a neurological condition characterized by encephalopathy, thyroid autoimmunity, and good clinical response to corticosteroids. It is associated with Hashimotos thyroiditis, and was first described in 1966. It is sometimes referred to as a neuroendocrine disorder, although the conditions relationship to the endocrine system is widely disputed. It is recognized as a rare disease by the NIH Genetic and Rare Diseases Information Center.Up to 2005, almost 200 case reports of this disease were published. Between 1990 and 2000, 43 cases were published. Since that time, research has expanded and numerous cases are being reported by scientists around the world, suggesting that this rare condition is likely to have been significantly undiagnosed in the past. Over 100 scientific articles on Hashimotos encephalopathy were published between 2000 and 2013.
Signs and symptoms
The onset of symptoms tends to be fairly gradual and to occur over 1-12 years.Symptoms of Hashimotos encephalopathy may include:
Personality changes
Aggression
Delusional behavior
Concentration and memory problems
Coma
Disorientation
Headaches
Jerks in the muscles (myoclonus – 65% of cases)
Lack of coordination (ataxia – 65% of cases)
Partial paralysis on the right side
Psychosis
Seizures (60% of cases)
Sleep abnormalities (55% of cases)
Speech problems (transient aphasia – 80% of cases)
Status epilepticus (20% of cases)
Tremors (80% of cases)
Pathogenesis
The mechanism of pathogenesis is not known, but is thought to be an autoimmune disorder, similar to Hashimotos thyroiditis, as its name suggests.Consistent with this hypothesis, autoantibodies to alpha-enolase have been found to be associated with Hashimotos encephalopathy. Since enolase is the penultimate step in glycolysis, if it were inhibited (for example by being bound by autoantibodies), one would expect decreased energy production by each cell, leading to resulting atrophy of the affected organ.This would occur most likely through each cell shrinking in size in response to the energy deficit (and/or in extreme situations from some cells dying via either apoptosis or necrosis, depending on location). This may occur as a result of enough ATP not being available to maintain cellular functions - notably, failure of the Na/K ATPase, resulting in a loss of the gradient to drive the Na/Ca antiporter, which normally keeps Ca+2 out of cells so it does not build to toxic levels that will rupture cell lysosomes leading to apoptosis. An additional feature of a low-energy state is failure to maintain axonal transport via dynein/kinesin ATPases, which in many diseases results in neuronal injury to both the brain and/or periphery.
Pathology
Very little is known about the pathology of Hashimotos encephalopathy. Post mortem studies of some individuals have shown lymphocytic vasculitis of venules and veins in the brain stem and a diffuse gliosis involving gray matter more than white matter.As mentioned above, autoantibodies to alpha-enolase associated with Hashimotos encephalopathy have thus far been the most hypothesized mechanism of injury.
Diagnosis
Laboratory and radiological findings
Increased liver enzyme levels (55% cases)
Increased thyroid-stimulating hormone (55% cases)
Increased erythrocyte sedimentation rate (25% cases)Cerebrospinal fluid findings:
Raised protein (25% cases)
Negative for 14–3–3 protein
May contain antithyroid antibodies
Magnetic resonance imaging abnormalities consistent with encephalopathy (26% f cases)
Single photon emission computed tomography shows focal and global hypoperfusion (75% of cases)
Cerebral angiography is normalThyroid hormone abnormalities are common (>80% of cases):
Subclinical hypothyroidism (35% of cases)
Overt hypothyroidism (20% of cases)
Hyperthyroidism (5% of cases)
Euthyroid on levothyroxine (10% of cases)
Euthyroid not on levothyroxine (20% of cases)Thyroid antibodies – both antithyroid peroxidase antibodies (anti-TPO, antithyroid microsomal antibodies, anti-M) and antithyroglobulin antibodies (anti-Tg) – in the disease are elevated, but their levels do not correlate with the severity.Electroencephalogram studies, while almost always abnormal (98% of cases), are usually not diagnostic. The most common findings are diffuse or generalized slowing or frontal intermittent rhythmic delta activity. Prominent triphasic waves, focal slowing, epileptiform abnormalities, and photoparoxysmal and photomyogenic responses may be seen.A study from 2006 suggested the following diagnostic criteria:
Encephalopathy with cognitive impairment and at least one of the following features:
neuropsychiatric symptoms (e.g. hallucination, delusion or paranoia)
Myoclonus, generalised tonic-clonic or partial seizures
focal-neurological deficits
Elevated titres of thyroid tissue antibodies (TPO-ab or microsomal)
Euthyroidism (potentially achieved by treatment with L-T4 or L-T3) or mild hypothyroidism with TSH concentration below 20 mIU/L
No evidence for infectious, toxic, metabolic or neoplastic processes in blood, urine or CSF analyses
No serological evidence for neuronal antibodies (e.g. voltage-gated calcium channel, voltage-gated potassium channel, or other currently recognized paraneoplastic antibodies) to support another diagnosis
In imaging studies no evidence for vascular, neoplastic or structural lesions that might explain the symptoms
Complete or nearly complete remission after initiation of glucocorticoid therapy.
Definition
A relapsing encephalopathy occurs in association with autoimmune (Hashimotos or Ords thyroiditis), with high titers of antithyroid antibodies. Clinically, the condition may present one or more symptoms. Onset is often gradual and may go unnoticed by the patient and close associates to the patients. Symptoms sometimes resolve themselves within days to weeks, leaving a patient undiagnosed. For many other patients, the condition may result in ongoing problems with a variety of manifestations, often confusing clinicians due to the diffuse nature of symptoms.
Differential diagnosis
Alzheimers disease
Cerebrovascular accidents (stroke)
Creutzfeldt–Jakob disease
Epilepsy
Migraine (including basilar, hemiplegic, and retinal types)
Other forms of autoimmune encephalitis, including forms of limbic encephalitis such as anti-NMDA receptor encephalitis
Schizophrenia
Spontaneous cerebrospinal fluid leak
Viral encephalitis
Transient ischemic attack
Treatment
Because most patients respond to corticosteroids or immunosuppressant treatment, this condition is now also referred to as steroid-responsive encephalopathy.Initial treatment is usually with oral prednisone (50–150 mg/day) or high-dose intravenous methylprednisolone (1 g/day) for 3–7 days. Thyroid hormone treatment is also included if required.Failure of some patients to respond to this first-line treatment has produced a variety of alternative treatments, including azathioprine, cyclophosphamide, chloroquine, methotrexate, periodic intravenous immunoglobulin, and plasma exchange. No controlled trials have been conducted, so the optimal treatment is not known.Seizures, if present, are controlled with typical antiepileptic agents.
Prognosis
Duration of treatment is usually between 2 and 25 years. Earlier reports suggested that 90% of cases stay in remission after discontinuation of treatment, but this is at odds with more recent studies, which suggest that relapse commonly occurs after initial high-dose steroid treatment. Left untreated, this condition can result in coma and death.
Epidemiology
The prevalence has been estimated to be 2.1/100,000 with a male-to-female ratio of 1:4. The mean age of onset is 44 with 20% of cases presenting before the age of 18 years. Most reported cases occur during the patients fifth decade of life.
History
The first case of HE was described by Brain et al. in 1966. The patient was a 48-year-old man with hypothyroidism, multiple episodes of encephalopathy, stroke-like symptoms, and Hashimotos thyroiditis confirmed by elevated antithyroid antibodies.
Alternative names
Steroid-responsive encephalopathy associated with autoimmune thyroiditis, SREAT
Nonvasculitic autoimmune meningoencephalitis, NAIM
Encephalopathy associated with autoimmune thyroid disease, EAATD
References
Further reading
Hashimotos Encephalopathy SREAT Alliance (2013). Understanding Hashimotos Encephalopathy: A Guide for Patients, Families, and Caregivers, Featuring Stories of HE Patients from Around the World. North Charleston, SC: CreateSpace Independent Publishing Platform. ISBN 9781484883099. OCLC 890816771.
Schiess N, Pardo CA (October 2008). "Hashimotos encephalopathy". Annals of the New York Academy of Sciences. 1142 (1): 254–65. Bibcode:2008NYASA1142..254S. doi:10.1196/annals.1444.018. PMID 18990131. S2CID 1312798.
Taylor SE, Garalda ME, Tudor-Williams G, Martinez-Alier N (February 2003). "An organic cause of neuropsychiatric illness in adolescence". The Lancet. 361 (9357): 572. doi:10.1016/S0140-6736(03)12517-2. PMID 12598143. S2CID 35053683. |
You act as a medical communicator. Your goal is to translate medical terms into comprehensive, yet straightforward language for all readers. | I've encountered the term 'Flunisolide' while reading about medical topics. What does it refer to exactly? | Flunisolide (marketed as AeroBid among others) is a corticosteroid often prescribed as treatment for allergic rhinitis. Intranasal corticosteroids are the most effective medication for controlling symptoms. The principal mechanism of action of flunisolide is to activate glucocorticoid receptors, meaning it has an anti-inflammatory action. The effects of topical corticosteroids is not immediate and requires regular use and at least a few days to start experiencing noticeable symptom relief. As-needed use has been shown to be not as effective as regular recommended use. Flunisolide should not be used in the presence of nasal infection. It should not be continued if there is no relief of symptoms after regular use over two to three weeks. It was patented in 1958 and approved for medical use in 1978. It is on the World Health Organizations List of Essential Medicines.
Side effects
Temporary nose and throat dryness, irritation, bleeding or unpleasant taste or smell may occur. Nasal septum perforation is rarely reported. Rare, but localized infections of the nose and pharynx with Candida albicans have been reported and long-term use may raise the chance of cataracts or glaucoma.Flunisolide nasal spray is absorbed into the circulatory system (blood). Corticosteroid nasal sprays may affect the hypothalamic-pituitary-adrenal axis function in humans. After the desired clinical effect is obtained, the maintenance dose should be reduced to the smallest amount necessary to control symptoms, which can be as low as 1 spray in each nostril a day. Utilizing the minimum effective dose will reduce possibility of side effects. Recommended amounts of intranasal corticosteroids are generally not associated with systemic side effects.
Corticosteroids inhibit wound healing. Therefore, use of corticosteroid nasal sprays in patients who have experienced recent nasal septal ulcers, recurrent epistaxis, nasal surgery or trauma, a nasal corticosteroid should be used with caution until healing has occurred. In pregnancy, recommended doses of intranasal corticosteroids are safe and effective.
== References == |
You act as a mediator between medical professionals and the public. Provide comprehensive explanations of medical terms, ensuring they are both precise and easily understood. | I'm trying to expand my medical knowledge. Can you elucidate the term 'Blood blister'? | A blood blister is a type of blister that forms when subdermal tissues and blood vessels are damaged without piercing the skin. It consists of a pool of lymph, blood and other body fluids trapped beneath the skin. If punctured, it suppurates a dark fluid. Sometimes the fluids are cut off from the rest of the body and dry up, leaving behind dead cell material inside the blister with a texture like putty. Some blood blisters can be extremely painful due to bruising where the blister occurred.
There are also blood blister-like aneurysms as these are known to be located in the supraclinoid internal carotid artery and have been recognized as having unique pathological and clinical features.
Causes
Blood blisters are commonly caused by accidents in which the skin is pinched by a tool, mechanism, or heavy weight without protective equipment. Blood blisters can also arise from forcible human contact, including grappling.
Blood blisters also may occur with friction caused by constant rubbing of skin against a surface. Ill-fitting shoes that rub on the skin can cause the blood vessels in the skin to break and form a blood clot under the skin, resulting in a blood blister. Certain sports activities that require repeated movement and rubbing of the skin against equipment may also cause this. So baseball pitchers, rowers, and drummers often contract blood blisters on the fingers and palms. They also form as a result of frostbite.
Blood blisters can also occur in the mouth for a variety of reasons including side effects to certain medications, nutritional deficiencies, and mouth injuries.
Treatment
There are several methods of healing blood blisters, including elevation of the wound combined with application of a cold pack, and application of padded dressings or splints.
See also
Bleeding – Loss of blood escaping from the circulatory system
Blister – Small pocket of fluid within the upper layers of the skin
Bruise – Type of localized bleeding in tissues outside blood vessels
Cherry angioma – Small bright red dome-shaped bump on the skin
== References == |
You are an assistant in medical learning. Your role is to clarify medical terminology, ensuring the information is both accurate and accessible. | Could you please explain the term 'Diastematomyelia' in simple language? | Diastematomyelia (occasionally diastomyelia) is a congenital disorder in which a part of the spinal cord is split, usually at the level of the upper lumbar vertebra in the longitudinal (sagittal) direction. Females are affected much more commonly than males. This condition occurs in the presence of an osseous, cartilaginous or fibrous septum in the central portion of the spinal canal which then produces a complete or incomplete sagittal division of the spinal cord into two hemicords. When the split does not reunite distally to the spur, the condition is referred to as diplomyelia, which is true duplication of the spinal cord.
Signs and symptoms
The signs and symptoms of diastematomyelia may appear at any time of life, although the diagnosis is usually made in childhood. Cutaneous lesions (or stigmata), such as a hairy patch, dimple, Hemangioma, subcutaneous mass, Lipoma or Teratoma over the affected area of the spine is found in more than half of cases. Neurological symptoms are nonspecific, indistinguishable from other causes of cord tethering. The symptoms are caused by tissue attachments that limit the movement of the spinal cord within the spinal column. These attachments cause an abnormal stretching of the spinal cord.
The course of the disorder is progressive. In children, symptoms may include the "stigmata" mentioned above and/or foot and spinal deformities; weakness in the legs; low back pain; scoliosis; and incontinence. In adulthood, the signs and symptoms often include progressive sensory and motor problems and loss of bowel and bladder control. This delayed presentation of symptoms is related to the degree of strain placed on the spinal cord over time.
Tethered spinal cord syndrome appears to be the result of improper growth of the neural tube during fetal development, and is closely linked to spina bifida.
Tethering may also develop after spinal cord injury and scar tissue can block the flow of fluids around the spinal cord. Fluid pressure may cause cysts to form in the spinal cord, a condition called syringomyelia. This can lead to additional loss of movement, feeling or the onset of pain or autonomic symptoms.
Cervical diastematomyelia can become symptomatic as a result of acute trauma, and can cause major neurological deficits, like hemiparesis, to result from otherwise mild trauma.The following definitions may help to understand some of the related entities:
Diastematomyelia (di·a·stem·a·to·my·elia) is a congenital anomaly, often associated with spina bifida, in which the spinal cord is split into halves by a bony spicule or fibrous band, each half being surrounded by a dural sac.
Myeloschisis (my·elos·chi·sis) is a developmental anomaly characterized by a cleft spinal cord, owing to failure of the neural plate to form a complete neural tube or to rupture of the neural tube after closure.
Diplomyelia (diplo.my.elia) is a true duplication of spinal cord in which these are two dural sacs with two pairs of anterior and posterior nerve roots.
Pathophysiology
Diastematomyelia is a "dysraphic state" of unknown embryonic origin, but is probably initiated by an accessory neurenteric canal (an additional embryonic spinal canal.) This condition may be an isolated phenomenon or may be associated with other segmental anomalies of the vertebral bodies such as spina bifida, kyphoscoliosis, butterfly vertebra, hemivertebra and block vertebrae which are observed in most of the cases. Scoliosis is identified in more than half of these patients. In most of the symptomatic patients, the spinal cord is split into halves by a bony spicule or fibrous band, each half being surrounded by a dural sac. Other conditions, such as intramedullary tumors, tethered cord, dermoids, lipoma, syringomyelia, hydromyelia and Arnold–Chiari malformations have been described in medical literature, but they are exceptionally rare.
Diastematomyelia usually occurs between 9th thoracic and 1st sacral levels of the spinal column with most being at the level of the upper lumbar vertebra. Cervical diastematomyelia is a very rare entity. The extent (or length of spinal cord involved) varies from one affected individual to another. In approximately 60% of patients with diastematomyelia, the two hemicords, each covered by an intact layer of pia arachnoid, travel through a single subarachnoid space surrounded by a single dural sac. Each hemicord has its own anterior spinal artery. This form of diastematomyelia is not accompanied by any bony spur or fibrous band and is rarely symptomatic unless hydromyelia or tethering is present. The other 40% of patients have a bony spur or a fibrous band that passes through the two hemicords. In these cases, the dura and arachnoid are split into two separate dural and arachnoidal sacs, each surrounding the corresponding hemicord which are not necessarily symmetric. Each hemicord contains a central canal, one dorsal horn (giving rise to a dorsal nerve root), and one ventral horn (giving rise to a ventral nerve root.) One study showed the bony spur typically situated at the most inferior aspect of the dural cleft. They advised that if the imaging appears to show otherwise, a second spur (present in about 5% of patients with diastematomyelia) is likely to be present.
The conus medullaris is situated below the L2 level in more than 75% of these diastematomyelia patients. Thickening of the filum terminale is seen in over half of the cases. While the level of the cleft is variable, it is most commonly found in the lumbar region. The two hemicords usually reunite caudally to the cleft. Occasionally, however, the cleft will extend unusually low and the cord will end with two separate coni medullarae and two fila terminale ("Diplomyelia").
Diagnosis
Adult presentation in diastematomyelia is unusual. With modern imaging techniques, various types of spinal dysraphism are being diagnosed in adults with increasing frequency. The commonest location of the lesion is at first to third lumbar vertebrae. Lumbosacral adult diastematomyelia is even rarer. Bony malformations and dysplasias are generally recognized on plain x-rays. MRI scanning is often the first choice of screening and diagnosis. MRI generally give adequate analysis of the spinal cord deformities although it has some limitations in giving detailed bone anatomy. Combined myelographic and post-myelographic CT scan is the most effective diagnostic tool in demonstrating the detailed bone, intradural and extradural pathological anatomy of the affected and adjacent spinal canal levels and of the bony spur.
Prenatal ultrasound diagnosis of this anomaly is usually possible in the early to mid third-trimester. An extra posterior echogenic focus between the fetal spinal laminae is seen with splaying of the posterior elements, thus allowing for early surgical intervention and have a favorable prognosis. Prenate ultrasound could also detect whether the diastematomyelia is isolated, with the skin intact or association with any serious neural tube defects. Progressive neurological lesions may result from the "tethering cord syndrome" (fixation of the spinal cord) by the diastematomyelia phenomenon or any of the associated disorders such as myelodysplasia, dysraphia of the spinal cord.
Treatment
Surgery
Surgical intervention is warranted in patients who present with new onset neurological signs and symptoms or have a history of progressive neurological manifestations that can be related to this abnormality. The surgical procedure required for the effective treatment of diastematomyelia includes decompression (surgery) of neural elements and removal of bony spur. This may be accomplished with or without resection and repair of the duplicated dural sacs. Resection and repair of the duplicated dural sacs is preferred since the dural abnormality may partly contribute to the "tethering" process responsible for the symptoms of this condition.
Post-myelographic CT scanning provides individualized detailed maps that enable surgical treatment of cervical diastematomyelia, first performed in 1983.Observation
Asymptomatic patients do not require surgical treatment. These patients should have regular neurological examinations since it is known that the condition can deteriorate. If any progression is identified, then a resection should be performed.
References
== External links == |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | Could you provide a brief overview of 'Trospium chloride' in a medical context? | Trospium chloride is used to treat overactive bladder.It has side effects typical of drugs like it, namely dry mouth, stomach upset, and constipation; these side effects cause problems with people taking their medicine as directed. However it doesnt cause central nervous system side effects like other drugs of its class. It is pregnancy category C and is excreted somewhat in breast milk.Chemically it is a quaternary ammonium cation which causes it to stay in periphery rather than crossing the blood-brain barrier. It works by causing the smooth muscle in the bladder to relax.It was patented in 1966 and approved for medical use in 1974. It was first approved in the US in 2004, and an extended release version with once-daily dosing was brought to market in 2007. It became generic in Europe in 2009 and in the US the first extended-release generic was approved in 2012.
Medical uses
Trospium chloride is used for the treatment of overactive bladder with symptoms of urge incontinence and frequent urination.It shouldnt be used with people who retain urine, who have severe digestive conditions, myasthenia gravis, narrow-angle glaucoma, or tachyarrhythmia.It should be used in caution with people who have problems with their autonomous nervous system (dysautonomia) or who have gastroesophageal reflux disease, or in whom fast heart rates are undesirable, such as people with hyperthyroidism, coronary artery disease and congestive heart failure.Trospium chloride is rated Pregnancy Category C, as there are no adequate and well-controlled studies of trospium chloride in pregnant women and there were signs of harm to the fetus in animal studies. The drug was excreted somewhat in the milk of nursing mothers. The drug was studied in children.
Side effects
Side effects are typical of gastrointestinal effects of anticholinergic drugs, and include dry mouth, indigestion, and constipation. These side effects lead to problems with adherence, especially for older people.
The only CNS side effect is headache, which was very rare. Tachycardia is a rare side effect.
Mechanism of action
Trospium chloride is a muscarinic antagonist. Trospium chloride blocks the effect of acetylcholine on muscarinic receptors organs that are responsive to the compounds, including the bladder. Its parasympatholytic action relaxes the smooth muscle in the bladder. Receptor assays showed that trospium chloride has negligible affinity for nicotinic receptors as compared to muscarinic receptors at concentrations obtained from therapeutic doses.
Pharmacokinetics
After oral administration, less than 10% of the dose is absorbed. Mean absolute bioavailability of a 20 mg dose is 9.6% (range: 4.0 to 16.1%). Peak plasma concentrations (Cmax) occur between 5 and 6 hours post-dose. Mean Cmax increases greater than dose-proportionally; a 3-fold and 4-fold increase in Cmax was observed for dose increases from 20 mg to 40 mg and from 20 mg to 60 mg, respectively. AUC exhibits dose linearity for single doses up to 60 mg. Trospium chloride exhibits diurnal variability in exposure with a decrease in Cmax and AUC of up to 59% and 33%, respectively, for evening relative to morning doses.Administration with a high fat meal resulted in reduced absorption, with AUC and Cmax values 70 to 80% lower than those obtained when trospium chloride was administered while fasting. Therefore, it is recommended that trospium chloride should be taken at least one hour prior to meals or on an empty stomach.Protein binding ranged from 50 to 85% when concentration levels of trospium chloride (0.5 to 50 ng/mL) were incubated with human serum in vitro. The 3H-trospium chloride ratio of plasma to whole blood was 1.6:1. This ratio indicates that the majority of 3H-trospium chloride is distributed in plasma. The apparent volume of distribution for a 20 mg oral dose is 395 (± 140) liters.The metabolic pathway of trospium in humans has not been fully defined. Of the 10% of the dose absorbed, metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. Cytochrome P450 is not expected to contribute significantly to the elimination of trospium. Data taken from in vitro human liver microsomes investigating the inhibitory effect of trospium on seven cytochrome P450 isoenzyme substrates (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) suggest a lack of inhibition at clinically relevant concentrations.The plasma half-life for trospium chloride following oral administration is approximately 20 hours. After oral administration of an immediate-release formulation of 14C-trospium chloride, the majority of the dose (85.2%) was recovered in feces and a smaller amount (5.8% of the dose) was recovered in urine; 60% of the radioactivity excreted in urine was unchanged trospium. The mean renal clearance for trospium (29 L/hour) is 4-fold higher than average glomerular filtration rate, indicating that active tubular secretion is a major route of elimination for trospium. There may be competition for elimination with other compounds that are also renally eliminated.
Chemical properties
Anticholinergic drugs used to treat overactive bladder were all amines as of 2003. Quaternary ammonium cations in general are more hydrophilic than other amines and dont cross membranes well, so they tend to be poorly absorbed from the digestive system, and to not cross the blood-brain barrier. Oxybutynin, tolterodine, darifenacin, and solifenacin are tertiary amines while trospium chloride and propantheline are quaternary amines.
History
The synthesis of trospium was described by scientists from Dr. Robert Pfleger Chemische Fabrik GmbH, Heinz Bertholdt, Robert Pfleger, and Wolfram Schulz, in US. Pat. No. 3,480,626 (the US equivalent to DE119442), and its activity was first published in the literature in 1967.The first regulatory approval was granted in Germany in August 1999 to Madaus AG for Regurin 20 mg Tablets.: 13 Madaus is considered the originator for regulatory filings worldwide. The German filing was recognized throughout Europe under the Mutual Recognition Procedure.: 13 Madaus licensed the US rights to trospium chloride to Interneuron in 1999 and Interneuron ran clinical trials in the US to win FDA approval. Interneuron changed its name to Indevus in 2002 Indevus entered into a partnership with Odyssey Pharmaceuticals, a subsidiary of Pliva, to market the drug in April 2004, and won FDA approval for the drug, which it branded as Sanctura, in May 2004. The approval earned Indevus a milestone payment of $120M from Pliva, which had already paid Indevus $30 million at signing; the market for overactive bladder therapies was estimated to be worth $1.1 billion in 2004. In 2005 Pliva exited the relationship, selling its rights to Esprit Pharma, and in September 2007 Allergan acquired Esprit, and negotiated a new agreement with Indevus under which Allergan would completely take over the US manufacturing, regulatory approvals, and marketing. A month before, Indevus had received FDA approval for an extended release formulation that allowed once a day dosing, Sanctura XR. Indevus had developed intellectual property around the extended release formulation which it licensed to Madaus for most of the world.In 2012 the FDS approved the first generic version of the extended release formulation, granting approval to the ANDA that Watson Pharmaceuticals had filed in 2009. Annual sales in the US at that time were $67M. European patents had expired in 2009.As of 2016, the drug is available worldwide under many brand names and formulations, including oral, extended release, suppositories, and injections.
Society and culture
Marketing rights to the drug became subject to parallel import litigation in Europe in the case of Speciality European Pharma Ltd v Doncaster Pharmaceuticals Group Ltd / Madaus GmbH (Case No. A3/2014/0205) which was resolved in March 2015. Madaus had exclusively licensed the right to use the Regurin trademark to Speciality European Pharma Ltd. In 2009, when European patents expired on the drug, Doncaster Pharmaceuticals Group, a well known parallel importer, which had been selling the drug in the UK under another label, Ceris, which was used in France, began to put stickers on their packaging with the Regurin name. Speciality and Madaus sued and initially won based on the argument that 90% of prescriptions were already generic, but Doncaster appealed and won the appeal based on the argument that it could not charge a premium with a generic label. The case has broad implications for trade in the EU.
Research
In 2007 Indevus partnered with Alkermes to develop and test an inhaled form of trospium chloride as a treatment for COPD; it was in Phase II trials at that time.
References
External links
Trospium chloride at the US National Library of Medicine Medical Subject Headings (MeSH) |
You are a medical advisor. Your role is to break down medical terminology into clear, detailed explanations for a general audience. | Could you please explain the term 'Finasteride/tadalafil' in simple language? | Finasteride/tadalafil, sold under the brand name Entadfi, is a fixed-dose combination medication used for the treatment of benign prostatic hyperplasia (BPH). It contains finasteride and tadalafil. It is taken by mouth.It was approved for medical use in the United States in December 2021.
Medical uses
Finasteride/tadalafil is indicated to treat benign prostatic hyperplasia (BPH) in men.
References
External links
"Finasteride". Drug Information Portal. U.S. National Library of Medicine.
"Tadalafil". Drug Information Portal. U.S. National Library of Medicine. |
You are a medical interpreter. Your duty is to translate medical terms into easily digestible information, maintaining accuracy and detail. | Could you provide a brief overview of 'Arm' in a medical context? | In human anatomy, the arm refers to the upper limb in common usage, although academically the term specifically means the upper arm between the glenohumeral joint (shoulder joint) and the elbow joint. The distal part of the upper limb between the elbow and the radiocarpal joint (wrist joint) is known as the forearm or "lower" arm, and the extremity beyond the wrist is the hand.
By anatomical definitions, the bones, ligaments and skeletal muscles of the shoulder girdle, as well as the axilla between them, is considered parts of the upper limb, and thus also components of the arm. The Latin term brachium, which serves as a root word for naming many anatomical structures, may refer to either the upper limb as a whole or to the upper arm on its own.
Anatomy
Bones
The humerus is one of the three long bones of the arm. It joins with the scapula at the shoulder joint and with the other long bones of the arm, the ulna and radius at the elbow joint. The elbow is a complex hinge joint between the end of the humerus and the ends of the radius and ulna.
Muscles
The arm is divided by a fascial layer (known as lateral and medial intermuscular septa) separating the muscles into two osteofascial compartments: the anterior and the posterior compartments of the arm. The fascia merges with the periosteum (outer bone layer) of the humerus.The anterior compartment contains three muscles: biceps brachii, brachialis and coracobrachialis muscles. They are all innervated by the musculocutaneous nerve. The posterior compartment contains only the triceps brachii muscle, supplied by the radial nerve.
Nerve supply
The musculocutaneous nerve, from C5, C6, C7, is the main supplier of muscles of the anterior compartment. It originates from the lateral cord of the brachial plexus of nerves. It pierces the coracobrachialis muscle and gives off branches to the muscle, as well as to brachialis and biceps brachii. It terminates as the anterior cutaneous nerve of the forearm.
The radial nerve, which is from the fifth cervical spinal nerve to the first thoracic spinal nerve, originates as the continuation of the posterior cord of the brachial plexus. This nerve enters the lower triangular space (an imaginary space bounded by, amongst others, the shaft of the humerus and the triceps brachii) of the arm and lies deep to the triceps brachii. Here it travels with the deep artery of the arm, which sits in the radial groove of the humerus. This fact is very important clinically as a fracture of the shaft of the bone here can cause lesions or even transections in the nerve.
Other nerves passing through give no supply to the arm. These include:
The median nerve, nerve origin C5-T1, which is a branch of the lateral and medial cords of the brachial plexus. This nerve continues in the arm, travelling in a plane between the biceps and triceps muscles. At the cubital fossa, this nerve is deep to the pronator teres muscle and is the most medial structure in the fossa. The nerve passes into the forearm.
The ulnar nerve, origin C8-T1, is a continuation of the medial cord of the brachial plexus. This nerve passes in the same plane as the median nerve, between the biceps and triceps muscles. At the elbow, this nerve travels posterior to the medial epicondyle of the humerus. This means that condylar fractures can cause lesion to this nerve.
Blood supply
The main artery in the arm is the brachial artery. This artery is a continuation of the axillary artery. The point at which the axillary becomes the brachial is distal to the lower border of teres major. The brachial artery gives off an unimportant branch, the deep artery of arm. This branching occurs just below the lower border of teres major.
The brachial artery continues to the cubital fossa in the anterior compartment of the arm. It travels in a plane between the biceps and triceps muscles, the same as the median nerve and basilic vein. It is accompanied by venae comitantes (accompanying veins). It gives branches to the muscles of the anterior compartment. The artery is in between the median nerve and the tendon of the biceps muscle in the cubital fossa. It then continues into the forearm.
The deep artery of the arm travels through the lower triangular space with the radial nerve. From here onwards it has an intimate relationship with the radial nerve. They are both found deep to the triceps muscle and are located on the spiral groove of the humerus. Therefore, fracture of the bone may not only lead to lesion of the radial nerve, but also haematoma of the internal structures of the arm. The artery then continues on to anastamose with the recurrent radial branch of the brachial artery, providing a diffuse blood supply for the elbow joint.
Veins
The veins of the arm carry blood from the extremities of the limb, as well as drain the arm itself. The two main veins are the basilic and the cephalic veins. There is a connecting vein between the two, the median cubital vein, which passes through the cubital fossa and is clinically important for venepuncture (withdrawing blood).
The basilic vein travels on the medial side of the arm and terminates at the level of the seventh rib.
The cephalic vein travels on the lateral side of the arm and terminates as the axillary vein. It passes through the deltopectoral triangle, a space between the deltoid and the pectoralis major muscles.
Society and culture
In Hindu, Buddhist and Egyptian iconography the symbol of the arm is used to illustrate the power of the sovereign. In Hindu tradition gods are depicted with several arms which carry specific symbols of their powers. It is believed that several arms depict omnipotence of gods. In popular culture Thakur did not have arms in the movie Sholay.
In West Africa, the Bambara use forearm to symbolize the spirit, which is a link between God and man.
Symbolic gestures of raising both hands signal surrender, appeals for mercy, and justice.
Clinical significance
The cubital fossa is clinically important for venepuncture and for blood pressure measurement.When the arm is fractured this may refer to a fracture of the humerus bone.
Veins on the arm may be taken when a coronary artery bypass graft is needed.
Other animals
In other animals, the term arm can also be used for homologous or analogous structures (such as one of the paired forelimbs of a four-legged animal or the arms of cephalopods, respectively). In anatomical usage, the term arm may sometimes refer specifically to the segment between the shoulder and the elbow, while the segment between the elbow and wrist is the forearm. However, in common, literary, and historical usage, arm refers to the entire upper limb from shoulder to wrist. This article uses the former definition; see upper limb for the wider definition.In primates the arm is adapted for precise positioning of the hand and thus assist in the hands manipulative tasks. The ball and socket shoulder joint allows for movement of the arms in a wide circular plane, while the structure of the two forearm bones which can rotate around each other allows for additional range of motion at that level.
Additional images
See also
Axilla – also known as armpit, underarm or oxter
Common flexor tendon
== References == |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | Can you demystify the medical term 'Liver failure' for me? | Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute-on-chronic liver failure (ACLF) is increasingly being recognized.
Acute
Acute liver failure is defined as "the rapid development of hepatocellular dysfunction, specifically coagulopathy and mental status changes (encephalopathy) in a patient without known prior liver disease".:1557The disease process is associated with the development of a coagulopathy of liver aetiology, and clinically apparent altered level of consciousness due to hepatic encephalopathy. Several important measures are immediately necessary when the patient presents for medical attention. The diagnosis of acute liver failure is based on a physical exam, laboratory findings, patient history, and past medical history to establish mental status changes, coagulopathy, rapidity of onset, and absence of known prior liver disease respectively.:1557The exact definition of "rapid" is somewhat questionable, and different sub-divisions exist, which are based on the time from onset of first hepatic symptoms to onset of encephalopathy. One scheme defines "acute hepatic failure" as the development of encephalopathy within 26 weeks of the onset of any hepatic symptoms. This is sub-divided into "fulminant hepatic failure", which requires onset of encephalopathy within 8 weeks, and "subfulminant", which describes onset of encephalopathy after 8 weeks but before 26 weeks. Another scheme defines "hyperacute" as onset within 7 days, "acute" as onset between 7 and 28 days, and "subacute" as onset between 28 days and 24 weeks.:1557
Chronic
Chronic liver failure usually occurs in the context of cirrhosis, itself potentially the result of many possible causes, such as excessive alcohol intake, hepatitis B or C, autoimmune, hereditary and metabolic causes (such as iron or copper overload, steatohepatitis or non-alcoholic fatty liver disease).
Acute on chronic
"Acute on chronic liver failure (ACLF)" is said to exist when someone with chronic liver disease develops features of liver failure. A number of underlying causes may precipitate this, such as alcohol misuse or infection. People with ACLF can be critically ill and require intensive care treatment, and occasionally a liver transplant. Mortality with treatment is 50%.
References
== External links == |
You are a facilitator of medical knowledge. Provide thorough and accessible explanations of medical terms, catering to both specialists and non-specialists. | What does the medical term 'Lymphangitis' encompass? | Lymphangitis is an inflammation or an infection of the lymphatic channels that occurs as a result of infection at a site distal to the channel. The most common cause of lymphangitis in humans is Streptococcus pyogenes (Group A strep), hemolytic streptococci, and in some cases, mononucleosis, cytomegalovirus, tuberculosis, syphilis, and the fungus Sporothrix schenckii. Lymphangitis is sometimes mistakenly called "blood poisoning". In reality, "blood poisoning" is synonymous with sepsis.
Lymphatic vessels are smaller than capillaries and tiny venules and are ubiquitous in the body. These vessels are fitted with valves to direct flow in only one direction. Fluid diffusing through the thin-walled small capillaries should be collected and the lymphatic system does just that: a fluid rich in protein, minerals, nutrients, and other substances useful for tissue growth. As well as essential nutrients, the lymphatic system can also transport or carry cancer cells, defective or damaged cells, and pathogens such as bacteria and viruses, as well as foreign bodies and organisms. The lymph nodes are found in close proximity to unique white blood cells that engulf or metabolize pathogens (bacteria and viruses) and defective or cancerous cells, preventing infections and malignant cancer cells from spreading.
Infection spreads out of the wound site to enter the lymphatic system. The wound may be small or it may be an abscess constantly feeding bacteria into the lymphatic system. After infection, lymph nodes enlarge. Ear, skin, nose, and eye infections can spread into the lymphatic system. Red streaks in the skin along the direction of regional lymph nodes indicate lymphatic involvement. Infection may spread within hours and can cause sepsis and death.
Symptoms and signs
Warm skin over site of infection. The person may also have chills and a high fever - between 38 and 40 degrees Celsius - along with moderate throbbing pain and swelling. The red streaks can be clearly outlined and demarcated or just barely visible, particularly in dark-skinned patients. Malaise, tenderness at the site of infection, skin ulcers (a rare symptom of lymphangitis), rapid pulse, and enlarged, swollen, and tender lymph nodes are also seen. Appetite loss has been documented with the presence of inflammation (inflammation-associated anorexia), but it is unclear whether appetite loss seen in patients with lymphangitis leads to weight loss; in cases that develop after lymphedema—which can be upwards of 8.14% of the time—weight gain has actually been documented.If these symptoms are absent, it is suggestive of other underlying disorders such as tuberculosis, lymphoma, or Hodgkin’s disease. A person with lymphangitis should be hospitalized and closely monitored by medical professionals. In very minor cases, regular application of antibiotic creams and cleanliness of the area can accelerate the healing process with no medical professional intervention or consultation required. When the inferior limbs are affected, the redness of the skin runs over the great saphenous vein location and can be confused for thrombophlebitis.
Chronic lymphangitis is a cutaneous condition that is the result of recurrent bouts of acute bacterial lymphangitis.: 261
Diagnosis
To detect and identify infectious agents such as streptococci and staphylococci bacterial strains blood tests and bacteria cultures can be used. Bacteria culture is suitable for identifying infectious agents in cases of severe lymphangitis that do not respond well to treatment.
Differential Diagnosis
Infectious lymphangitis should be differentiated from other conditions such as superficial thrombophlebitis (swelling is local to the affected vein), cat scratch (swellings feels hard to the touch), acute streptococcal hemolytic gangrene and necrotizing fasciitis (infected area crackles to the touch and the patient looks very ill).
Treatment
Both drug and non-drug based treatment options are available to treat with lymphanginitis. The wound should be treated properly, dead tissues should be removed from the wound site, and pus drained. Applying heat to the affected lymph node using hot, moist compresses, or heating pads. Immobilizing and elevating the affected limb whenever it is possible, and administering analgesics to control pain. If a local infection is invasive, immediate antibiotic drug therapy is required. Streptococci strains are the most common infectious agents and respond well to cephalosporins – cephalexin at a dose of 0.5 mg for between 7 and 10 days – or extended-spectrum penicillin. Methiciline-resistant staphylococcus aureus is common in communities and hence the need to use improved antibiotic drugs such as trimethoprim-sulfamethoxazole for 7 to 10 days. Naficillin, oxacillin, and dicloxacillin are also effective against infections of the lymphatic system.
See also
Chronic lymphangitis
Lymphadenopathy
Lymphangitis carcinomatosa
References
== External links == |
You function as a medical informant. Please provide in-depth yet accessible descriptions of medical terms, suitable for a broad audience. | I've come across the term 'Lisinopril/hydrochlorothiazide' in a medical context, but I'm not sure what it means. Can you clarify? | Lisinopril/hydrochlorothiazide, sold under the brand name Zestoretic among others, is a fixed-dose combination medication used for the treatment of high blood pressure. It contains lisinopril, an ACE inhibitor, and hydrochlorothiazide, a diuretic. Typically, it becomes an option once a person is doing well on the individual components. It is taken by mouth.Common side effects include dizziness, headache, cough, and feeling tired. Severe side effects may include angioedema and low blood pressure. Use during pregnancy may harm the baby.The combination was approved for medical use in the United States in 1989. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 50th most commonly prescribed medication in the United States, with more than 13 million prescriptions.
References
External links
"Hydrochlorothiazide mixture with lisinopril". Drug Information Portal. U.S. National Library of Medicine. |
You are a facilitator of medical knowledge. Provide thorough and accessible explanations of medical terms, catering to both specialists and non-specialists. | Can you demystify the medical term 'Cardiac fibrosis' for me? | Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. Fibrotic cardiac muscle is stiffer and less compliant and is seen in the progression to heart failure. The description below focuses on a specific mechanism of valvular pathology but there are other causes of valve pathology and fibrosis of the cardiac muscle.
Fibrocyte cells normally secrete collagen, and function to provide structural support for the heart. When over-activated this process causes thickening and fibrosis of the valve, with white tissue building up primarily on the tricuspid valve, but also occurring on the pulmonary valve. The thickening and loss of flexibility eventually may lead to valvular dysfunction and right-sided heart failure.
Types
Following are types of myocardial fibrosis:
Interstitial fibrosis, which is unspecific, and has been described in congestive heart failure, hypertension, and normal aging.
Subepicardial fibrosis, also unspecific, and is associated with non-infarction diagnoses such as myocarditis and non-ischemic cardiomyopathy.
Replacement fibrosis, which indicates an older infarction.
Connection with excess blood serotonin (5-HT)
Certain diseases such as neuroendocrine tumor of the small intestine (also known by the obsolete term carcinoid), which sometimes release large amounts of 5-hydroxytryptamine, commonly known as 5-HT or serotonin into the blood, may produce a characteristic pattern of mostly right-sided cardiac fibrosis which can be identified with echocardiography. Cardiac fibrosis is a significant source of morbidity and mortality in patients with functional neuroendocrine tumors. This pathology has also been seen in certain East-African tribes who eat foods (Matoke —a green banana) containing excess amounts of serotonin.
Connection with direct serotonergic agonist drugs
Elevated prevalence of cardiac fibrosis and related valvopathies was found to be associated with use of a number of unrelated drugs following long-term statistical analysis once the drugs had been on the market for some time. The cause of this was unknown at the time, but eventually it was realised that all the implicated drugs acted as agonists at 5-HT2B receptors in the heart in addition to their intended sites of action elsewhere in the body.The precise mechanisms involved remain elusive however, as while the cardiotoxicity shows some dose–response relationship, it does not always develop, and consistent daily use over an extended period tends to be most strongly predictive of development of valvopathy.The drugs most classically associated with the condition are weight loss drugs such as fenfluramine and chlorphentermine, and antiparkinson drugs such as pergolide and cabergoline, which are prescribed for chronic use.The heart valve changes seen with moderate and intermittent use can result in permanent damage and life-threatening heart problems if use of the causative drug is increased or continued, however longitudinal studies of former patients suggest that the damage will heal over time to some extent at least.
Anorectics
Some appetite suppressant drugs such as fenfluramine (which in combination with phentermine was marketed as Pondimin and commonly referred to as fen-phen), chlorphentermine, and aminorex (along with its analogue 4-Methylaminorex which has seen sporadic use as a recreational drug) induce a similar pattern of cardiac fibrosis (and pulmonary hypertension), apparently by overstimulating 5HT2B receptors on the cardiac fibroblast cells.These drugs consequently tend to cause increased risk of heart valve damage and subsequent heart failure, which eventually led to them being withdrawn from the market.
Antimigraine drugs
Certain antimigraine drugs which are targeted at serotonin receptors as vasoconstrictive agents, have long been known to be associated with pulmonary hypertension and Raynauds phenomenon (both vasoconstrictive effects), as well as retroperitoneal fibrosis (a fibrotic cell/fibrocyte proliferation effect, thought to be similar to cardiac valve fibrosis).These drugs include ergotamine and methysergide and both drugs can also cause cardiac fibrosis.
Antiparkinson drugs
Certain antiparkinson drugs, although targeted at dopaminergic receptors, cross-react with serotoninergic 5-HT2B receptors as well, and have been reported to cause cardiac fibrosis.
These drugs include pergolide and cabergoline.
Antihypertensive drugs
Guanfacine may be a 5-HT2B agonist, based on the results of theoretical modeling and high-throughput screening.
Pergolide
Pergolide was an antiparkinson medications that was in decreasing use since reported in 2003 to be associated with cardiac fibrosis. In March 2007, pergolide was withdrawn from the U.S. market due to serious valvular damage that was shown in two independent studies.
Cabergoline
Like pergolide, cabergoline has been linked to cardiac damage. Among similar antiparkinsonian drugs, cabergoline exhibits the same type of serotonin receptor binding as pergolide. Although lisuride, a related drug, also binds to the 5-HT2B receptor, it acts as an antagonist rather than as an agonist.In January 2007, cabergoline (Dostinex) was reported also to be associated with valvular proliferation heart damage.
Recreational drugs
Several serotonergic recreational drugs, including the empathogens MDA and MDMA ("ecstasy"), and some hallucinogens such as DOI and Bromo-DragonFLY, have all been shown to act as 5-HT2B agonists in vitro, but how significant this may be as a risk factor associated with their recreational use is unclear.
The piperazine derivative mCPP (a major metabolite of trazodone) is a 5-HT2B agonist in animal models, but actually behaves as a 5-HT2B antagonist in humans.
MDMA
One study of human users of MDMA ("ecstasy") found that they did have heart valve changes suggestive of early cardiac fibrosis, which were not present in non-MDMA using controls, suggesting that MDMA use certainly has the potential to cause this kind of heart damage.On the other hand, there is as yet no statistical evidence to establish or negate significant increases in rates of cardiac valvopathies in current or former MDMA users. Absent studies on point, it may be speculated that as with other 5-HT2B agonists, development of heart valve damage may be dependent on the frequency and duration of use and the total cumulative exposure over time. If that is the case, then the heaviest users are likely to face the greatest risk of heart damage.
Other serotonergic pharmacologics in question
The SSRI antidepressants raise blood serotonin levels, and thus may be capable of the same risks, though it is thought that the risk is substantially lower with such drugs. The amino acid L-tryptophan also raises blood serotonin, and may present the same risk as well; though, again, the risk is considered to be low.However, the tryptophan derivative 5-HTP (5-hydroxytryptophan), used in the treatment of depression, raises blood serotonin level considerably. It has yet to be reported to be associated with valve disease or other fibrosis, but for the previous theoretical reasons, it has been suggested as a possible danger.When 5-HTP is used in medicine, it is generally administered along with carbidopa, which prevents the peripheral decarboxylation of 5-HTP to serotonin and so ensures that only brain serotonin levels are increased without producing peripheral side effects, however 5-HTP is also sold without carbidopa as a dietary supplement, and may have increased risks when taken by itself without carbidopa.
In non-human great apes
Cardiac fibrosis is common in non-human great apes in human care. The term idiopathic myocardial fibrosis was coined to emphasize this disease is likely different from the above described forms of cardiac fibrosis in humans. The etiology is not known, though vitamin D deficiency is a potential suspected cause at least in chimpanzees.
Possible treatments
The most obvious treatment for cardiac valve fibrosis or fibrosis in other locations, consists of stopping the stimulatory drug or production of serotonin. In the case of a functional neuroendocrine tumor, somatostatin analogs such as octreotide are used to reduce the production of serotonin by tumor cells, which often highly express inhibitory somatostatin receptors.Surgical tricuspid valve replacement, sometimes combined with a pulmonary valve replacement, can be necessary in some patients.A compound found in red wine, resveratrol has been found to slow the development of cardiac fibrosis. More sophisticated approaches of countering cardiac fibrosis like microRNA inhibition (miR-21, for example) are being tested in animal models.
== References == |
You are a medical interpreter. Your duty is to translate medical terms into easily digestible information, maintaining accuracy and detail. | I'm encountering the term 'Optic disc drusen' in medical literature. What's its definition? | Optic disc drusen (ODD) are globules of mucoproteins and mucopolysaccharides that progressively calcify in the optic disc. They are thought to be the remnants of the axonal transport system of degenerated retinal ganglion cells.
ODD have also been referred to as congenitally elevated or anomalous discs, pseudopapilledema, pseudoneuritis, buried disc drusen, and disc hyaline bodies.
Anatomy
The optic nerve is a cable connection that transmits images from the retina to the brain. It consists of over one million retinal ganglion cell axons. The optic nerve head, or optic disc is the anterior end of the nerve that is in the eye and hence is visible with an ophthalmoscope. It is located nasally and slightly inferior to the macula of the eye. There is a blind spot at the optic disc because there are no rods or cones beneath it to detect light. The central retinal artery and vein can be seen in the middle of the disc as it exits the scleral canal with the optic nerve to supply the retina. The vessels send branches out in all directions to supply the retina.
Pathophysiology
In children, optic disc drusen are usually buried and undetectable by fundoscopy except for a mild or moderate elevation of the optic disc. With age, the overlying axons become atrophied and the drusen become exposed and more visible. They may become apparent with an ophthalmoscope and some visual field loss at the end of adolescence. ODD can compress and eventually compromise the vasculature and retinal nerve fibers. Rarely, choroidal neovascularization may develop as the juxtapapillary nerve fibers are disrupted, with subsequent subretinal hemorrhage and retinal scarring. Even more rarely, vitreous hemorrhage may develop.
Diagnosis
Differential diagnosis
In most patients, optic disc drusen are an incidental finding. It is important to differentiate them from other conditions that present with optic disc elevation, especially papilledema, which could imply raised intracranial pressure or tumors. True papilledema may present with exudates or cotton-wool spots, unlike ODD. The optic disc margins are characteristically irregular in ODD but not blurred as there is no swelling of the retinal nerve fibers. Spontaneous venous pulsations are present in about 80 percent of patients with ODD, but absent in cases of true disc edema. Other causes of disc elevation clinicians must exclude may be: hyaloid traction, epipapillary glial tissue, myelinated nerve fibres, scleral infiltration, vitreopapillary traction and high hyperopia. Disorders associated with disc elevation include: Alagille syndrome, Down syndrome, Kenny-Caffey syndrome, Leber Hereditary Optic Neuropathy and linear nevus sebaceous syndrome.
Management
Patients with optic disc drusen should be monitored periodically via ophthalmoscopy, Snellen acuity, contrast sensitivity, color vision, intraocular pressure and threshold visual fields. For those with visual field defects optical coherence tomography has been recommended for follow up of nerve fiber layer thickness. Associated conditions such as angioid streaks and retinitis pigmentosa should be screened for. Both the severity of optic disc drusen and the degree of intraocular pressure elevation have been associated with visual field loss. There is no widely accepted treatment for ODD, although some clinicians will prescribe eye drops designed to decrease the intra-ocular pressure and theoretically relieve mechanical stress on fibers of the optic disc. Rarely choroidal neovascular membranes may develop adjacent to the optic disc threatening bleeding and retinal scarring. Laser treatment or photodynamic therapy or other evolving therapies may prevent this complication.
Prognosis
Optic nerve damage is progressive and insidious. Some of patients will develop some peripheral field defects. These can include nasal step defects, enlarged blind spots, arcuate scotomas, sectoral field loss and altitudinal defects. Clinical symptoms correlate to visibility of the drusen. Central vision loss is a rare complication of bleeding from peripapillar choroidal neovascular membranes. Anterior ischemic optic neuropathy (AION) is a potential complication.
Epidemiology
Optic disc drusen are found clinically in about 1% of the population but this increases to 3.4% in individuals with a family history of ODD. About two thirds to three quarters of clinical cases are bilateral. A necropsy study of 737 cases showed a 2.4% incidence with 2 out of 15 (13%) bilateral, perhaps indicating the insidious nature of many cases. An autosomal dominant inheritance pattern with incomplete penetrance and associated inherited dysplasia of the optic disc and its blood supply is suspected. Males and females are affected at equal rates. Caucasians are the most susceptible ethnic group. Certain conditions have been associated with disc drusen such as retinitis pigmentosa, angioid streaks, Usher syndrome, Noonan syndrome and Alagille syndrome. Optic disc drusen are not related to Bruch membrane drusen of the retina which have been associated with age-related macular degeneration.
See also
Drusen
References
Further reading
Online Mendelian Inheritance in Man (OMIM): Pseudopapilledema - 177800
Wirtschafter JD (1983). "Optic nerve axons and acquired alterations in the appearance of the optic disc". Trans Am Ophthalmol Soc. 81: 1034–91. PMC 1312472. PMID 6203209.
== External links == |
You are a medical interpreter. Your duty is to translate medical terms into easily digestible information, maintaining accuracy and detail. | The term 'Gerodermia osteodysplastica' keeps coming up in medical discussions. What does it stand for? | Gerodermia osteodysplastica (GO) is a rare autosomal recessive connective tissue disorder included in the spectrum of cutis laxa syndromes.Usage of the name "Walt Disney dwarfism" is attributed to the first known case of the disorder, documented in a 1950 journal report, in which the authors described five affected members from a Swiss family as having the physical appearance of dwarves from a Walt Disney film.The terms "geroderma" or "gerodermia" can be used interchangeably with "osteodysplastica" or "osteodysplasticum", with the term "hereditaria" sometimes appearing at the end.
Presentation
Gerodermia osteodysplastica is characterized by symptoms and features which affect the connective tissues, skin and skeletal system.These are: wrinkly, loose skin over the face, abdomen, and extremities (hands, feet) on the dorsal sides usually worsened by chronic joint laxity and hyperextensibility; fragmented elastic fibers of the skin that are reduced in number, with disorientation of collagen fibers; osteopenia and osteoporosis, with associated fractures; malar hypoplasia (underdeveloped cheek bone), maxillary hypoplasia (underdeveloped upper jaw), mandibular prognathism (protrusion of the lower jaw and chin), bowed long bones, platyspondyly (flattened spine) related to vertebral collapse; kyphoscoliosis (scoliosis with kyphosis, or "hunch back"), metaphyseal peg (an unusual outgrowth of metaphyseal tissue which protrudes into the epiphyseal region of the bone, near the knee); and the overall physical effects and facial appearance of dwarfism with premature aging.Other features and findings include: intrauterine growth retardation, congenital hip dislocations, winged scapulae (shoulder blades), pes planus (fallen arches), pseudoepiphyses of the second metacarpals (upper bone of the fingers), hypotelorism (close-set eyes), malformed ears,developmental delay,failure to thrive and abnormal electroencephalograph (EEG) readings.Dental and orthodontal abnormalities in addition to maxillary hypoplasia and mandibular prognathism have also been observed in gerodermia osteodysplastica. Including malocclusion of the dental arches (the maxilla and mandible), radiological findings in some cases have indicated significant overgrowth of the mandibular premolar and molar roots;hypercementosis (overproduction of cementum) of the molars and maxillary incisors; enlarged, funnel-shaped mandibular lingula (spiny structures on the ramus of the mandible); and a radiolucent effect on portions of many teeth, increasing their transparency to x-rays.
Genetics
Originally believed to be inherited in an X-linked recessive fashion, gerodermia osteodysplastica is now known to display strictly autosomal recessive inheritance. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order 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.It has been associated with SCYL1BP1.
Diagnosis
Differential diagnosis
Many features of gerodermia osteodysplastica (GO) and another autosomal recessive form of cutis laxa, wrinkly skin syndrome (WSS, Online Mendelian Inheritance in Man (OMIM): 278250), are similar to such an extent that both disorders were believed to be variable phenotypes of a single disorder.Several delineating factors, however, suggest that gerodermia osteodysplastica and wrinkly skin syndrome are distinct entities, but share the same clinic spectrum.While the prevailing feature of wrinkly, loose skin is more localized with GO, it is usually systemic, yet eases in severity with age during the course of WSS. Also, as the fontanelles ("soft spots") are usually normal on the heads of infants with GO, they are often enlarged in WSS infants.While WSS is associated with mutations of genes on chromosomes 2, 5, 7, 11 and 14; GO has been linked to mutations in the protein GORAB. A serum sialotransferrin type 2 pattern, also observed with WSS, is not present in GO patients.But perhaps the most notable feature, differentiating GO from WSS and similar cutis laxa disorders, is the age-specific metaphyseal peg sometimes found in GO-affected long bone, near the knee. Not appearing until around age 4–5, then disappearing by physeal closure, this oddity of bone is thought to represent a specific genetic marker unique to GO and its effects on bone development.
Treatment
See also
Ehlers–Danlos syndromes
Progeria
Skeletal dysplasia
References
== External links == |
You are a guide to medical language. Please provide in-depth and understandable explanations of medical terms, highlighting their significance in healthcare. | The term 'Odynorgasmia' keeps coming up in medical discussions. What does it stand for? | Odynorgasmia, or painful ejaculation, is a physical syndrome described by pain or burning sensation of the urethra or perineum during or following ejaculation. Causes include infections associated with urethritis, prostatitis, epididymitis, as well as use of anti-depressants.
== References == |
You are an expert in medical terminology. Explain medical terms in a way that is both precise and easy to understand for non-medical audiences. | Can you demystify the medical term 'Sebaceoma' for me? | Sebaceoma (also known as a "sebaceous epithelioma") is a cutaneous condition that appears as a yellow or orange papule.: 662
See also
Sebaceous carcinoma
Sebaceous adenoma
Skin lesion
== References == |
You act as a bridge between medical jargon and everyday language. Explain medical terms in a manner that is comprehensive yet approachable for non-experts. | I'm seeking clarification on the medical term 'Hypersomnia.' Could you explain it? | Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes (such as seasonal affective disorder) and can cause distress and problems with functioning. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), hypersomnolence, of which there are several subtypes, appears under sleep-wake disorders.Hypersomnia is a pathological state characterized by a lack of alertness during the waking episodes of the day. It is not to be confused with fatigue, which is a normal physiological state. Daytime sleepiness appears most commonly during situations where little interaction is needed.Since the patients’ attention levels (wakefulness) are impaired, their quality of life may be impacted as well. This is especially true for people whose jobs request high levels of attention, such as in the healthcare field.
Symptoms
The main symptom of hypersomnia is excessive daytime sleepiness (EDS), or prolonged nighttime sleep, which has occurred for at least 3 months prior to diagnosis.Sleep drunkenness is also a symptom found in hypersomniac patients. It is a difficulty transitioning from sleep to wake. Individuals experiencing sleep drunkenness report waking with confusion, disorientation, slowness and repeated returns to sleep.It also appears in non-hypersomniac persons, for example after a night of insufficient sleep. Fatigue and consumption of alcohol or hypnotics can cause sleep drunkenness as well. It is also associated with irritability: people who get angry shortly before sleeping tend to experience sleep drunkenness.According to the American Academy of Sleep Medicine, hypersomniac patients often take long naps during the day that are mostly unrefreshing. Researchers found that naps are usually more frequent and longer in patients than in controls. Furthermore, 75% of the patients report that short naps are not refreshing, compared to controls.
Diagnosis
"The severity of daytime sleepiness needs to be quantified by subjective scales (at least the Epworth Sleepiness Scale) and objective tests such as the multiple sleep latency test (MSLT)." The Stanford sleepiness scale (SSS) is another frequently-used subjective measurement of sleepiness. After it is determined that excessive daytime sleepiness is present, a complete medical examination and full evaluation of potential disorders in the differential diagnosis (which can be tedious, expensive and time-consuming) should be undertaken.
Differential diagnosis
Hypersomnia can be primary (of central/brain origin), or it can be secondary to any of numerous medical conditions. More than one type of hypersomnia can coexist in a single patient. Even in the presence of a known cause of hypersomnia, the contribution of this cause to the complaint of excessive daytime sleepiness needs to be assessed. When specific treatments of the known condition do not fully suppress excessive daytime sleepiness, additional causes of hypersomnia should be sought. For example, if a patient with sleep apnea is treated with CPAP (continuous positive airway pressure), which resolves their apneas but not their excessive daytime sleepiness, it is necessary to seek other causes for the excessive daytime sleepiness. Obstructive sleep apnea "occurs frequently in narcolepsy and may delay the diagnosis of narcolepsy by several years and interfere with its proper management."
Primary hypersomnias
The true primary hypersomnias include:
Narcolepsy (with and without cataplexy)
Idiopathic hypersomnia
Recurrent hypersomnias (like Kleine-Levin syndrome)
Primary hypersomnia mimics
There are also several genetic disorders that may be associated with primary/central hypersomnia. These include the following: Prader-Willi syndrome; Norrie disease; Niemann–Pick disease, type C; and myotonic dystrophy. However, hypersomnia in these syndromes may also be associated with other secondary causes, so it is important to complete a full evaluation. Myotonic dystrophy is often associated with SOREMPs (sleep onset REM periods, such as occur in narcolepsy).There are many neurological disorders that may mimic the primary hypersomnias, narcolepsy and idiopathic hypersomnia: brain tumors; stroke-provoking lesions; and dysfunction in the thalamus, hypothalamus, or brainstem. Also, neurodegenerative conditions such as Alzheimers disease, Parkinsons disease, or multiple system atrophy are frequently associated with primary hypersomnia. However, in these cases, one must still rule out other secondary causes.Early hydrocephalus can also cause severe excessive daytime sleepiness. Additionally, head trauma can be associated with a primary/central hypersomnia, and symptoms similar to those of idiopathic hypersomnia can be seen within 6–18 months following the trauma. However, the associated symptoms of headaches, memory loss, and lack of concentration may be more frequent in head trauma than in idiopathic hypersomnia. "The possibility of secondary narcolepsy following head injury in previously asymptomatic individuals has also been reported."
Secondary hypersomnias
Secondary hypersomnias are extremely numerous.
Hypersomnia can be secondary to disorders such as clinical depression, multiple sclerosis, encephalitis, epilepsy, or obesity. Hypersomnia can also be a symptom of other sleep disorders, like sleep apnea. It may occur as an adverse effect of taking certain medications, of withdrawal from some medications, or of substance use. A genetic predisposition may also be a factor. In some cases it results from a physical problem, such as a tumor, head trauma, or dysfunction of the autonomic or central nervous system.Sleep apnea is the second most frequent cause of secondary hypersomnia, affecting up to 4% of middle-aged adults, mostly men. Upper airway resistance syndrome (UARS) is a clinical variant of sleep apnea that can also cause hypersomnia. Just as other sleep disorders (like narcolepsy) can coexist with sleep apnea, the same is true for UARS. There are many cases of UARS in which excessive daytime sleepiness persists after CPAP treatment, indicating an additional cause, or causes, of the hypersomnia and requiring further evaluation.Sleep movement disorders, such as restless legs syndrome (RLS) and periodic limb movement disorder (PLMD or PLMS) can also cause secondary hypersomnia. Although RLS does commonly cause excessive daytime sleepiness, PLMS does not. There is no evidence that PLMS plays "a role in the etiology of daytime sleepiness. In fact, two studies showed no correlation between PLMS and objective measures of excessive daytime sleepiness. In addition, EDS in these patients is best treated with psychostimulants—and not with dopaminergic agents known to suppress PLMS."Neuromuscular diseases and spinal cord diseases often lead to sleep disturbances due to respiratory dysfunction causing sleep apnea, and they may also cause insomnia related to pain. "Other sleep alterations, such as periodic limb movement disorders in patients with spinal cord disease, have also been uncovered with the widespread use of polysomnography."Primary hypersomnia in diabetes, hepatic encephalopathy, and acromegaly is rarely reported, but these medical conditions may also be associated with hypersomnia secondary to sleep apnea and periodic limb movement disorder (PLMD).Chronic fatigue syndrome and fibromyalgia can also be associated with hypersomnia. Chronic fatigue syndrome is "characterized by persistent or relapsing fatigue that does not resolve with sleep or rest. Polysomnography shows reduced sleep efficiency and may include alpha intrusion into sleep EEG. It is likely that a number of cases labeled as chronic fatigue syndrome are unrecognized cases of upper airway resistance syndrome" or other sleep disorders, such as narcolepsy, sleep apnea, PLMD, etc.As with chronic fatigue syndrome, fibromyalgia may be associated with anomalous alpha wave activity (typically associated with arousal states) during NREM sleep. Also, researchers have shown that disrupting stage IV sleep consistently in young, healthy subjects causes a significant increase in muscle tenderness—similar to that experienced in "neurasthenic musculoskeletal pain syndrome". This pain resolved when the subjects were able to resume their normal sleep patterns.Chronic kidney disease is commonly associated with sleep symptoms and excessive daytime sleepiness. 80% of those on dialysis have sleep disturbances. Sleep apnea can occur 10 times as often in uremic patients than in the general population and can affect up to 30-80% of patients on dialysis, though nighttime dialysis can improve this. About 50% of dialysis patients have hypersomnia, as severe kidney disease can cause uremic encephalopathy, increased sleep-inducing cytokines, and impaired sleep efficiency. About 70% of dialysis patients are affected by insomnia, and RLS and PLMD affect 30%, though these may improve after dialysis or kidney transplant.Most forms of cancer and their therapies can cause fatigue and disturbed sleep, affecting 25-99% of patients and often lasting for years after treatment completion. "Insomnia is common and a predictor of fatigue in cancer patients, and polysomnography demonstrates reduced sleep efficiency, prolonged initial sleep latency, and increased wake time during the night." Paraneoplastic syndromes can also cause insomnia, hypersomnia, and parasomnias.Autoimmune diseases, especially lupus and rheumatoid arthritis, are often associated with hypersomnia. Morvans syndrome is an example of a rarer autoimmune illness that can also lead to hypersomnia. Celiac disease is another autoimmune disease associated with poor sleep quality (which may lead to hypersomnia), "not only at diagnosis but also during treatment with a gluten-free diet." There are also some case reports of central hypersomnia in celiac disease. And RLS "has been shown to be frequent in celiac disease," presumably due to its associated iron deficiency.Hypothyroidism and iron deficiency with or without (iron-deficiency anemia) can also cause secondary hypersomnia. Various tests for these disorders are done so they can be treated. Hypersomnia can also develop within months after viral infections such as Whipples disease, mononucleosis, HIV, and Guillain–Barré syndrome.Behaviorally induced insufficient sleep syndrome must be considered in the differential diagnosis of secondary hypersomnia. This disorder occurs in individuals who fail to get sufficient sleep for at least three months. In this case, the patient has chronic sleep deprivation, although they may not necessarily be aware of it. This situation is becoming more prevalent in western society due to the modern demands and expectations placed upon the individual.Many medications can lead to secondary hypersomnia. Therefore, a patients complete medication list should be carefully reviewed for sleepiness or fatigue as side effects. In these cases, careful withdrawal from the possibly offending medication(s) is needed; then, medication substitution can be undertaken.Mood disorders, like depression, anxiety disorder and bipolar disorder, can also be associated with hypersomnia. The complaint of excessive daytime sleepiness in these conditions is often associated with poor sleep at night. "In that sense, insomnia and EDS are frequently associated, especially in cases of depression." Hypersomnia in mood disorders seems to be primarily related to "lack of interest and decreased energy inherent in the depressed condition rather than an increase in sleep or REM sleep propensity". In all cases with these mood disorders, the MSLT is normal (not too short and no SOREMPs).
Posttraumatic hypersomnias
In some cases, hypersomnia can be caused by a brain injury. Researchers found that the level of sleepiness is correlated with the severity of the injury. Even if patients reported an improvement, sleepiness remained present for a year in about a quarter of patients with traumatic brain injury.
Recurrent hypersomnias
Recurrent hypersomnias are defined by several episodes of hypersomnia persisting from a few days to weeks. These episodes can occur weeks or months apart from each other. There are 2 subtypes of recurrent hypersomnias: Kleine-Levin syndrome and menstrual-related hypersomnia.Kleine-Levin syndrome is characterized by the association of episodes of hypersomnias with behavioral, cognitive and mood abnormalities. The behavioral disturbances can be composed of hyperphagia, irritability, or sexual disinhibition. The cognitive disorders consist of confusion, hallucinations or delusions. Mood symptoms are characterized by anxiety or depression.Menstrual-related hypersomnia is characterized by episodes of excessive sleepiness associated with the menstrual cycle. Researchers found that the degree of premenstrual symptoms were correlated with daytime sleepiness. Unlike Kleine-Levin syndrome, hyperphagia and hypersexuality are not reported in people with menstrual-related hypersomnia, but hypophagia could be present. Ordinarily, these episodes appear 2 weeks before menstruation. A few studies have attested that some hormones as prolactin and progesterone could be responsible for Menstrual-Related Hypersomnia. Therefore, different contraceptive pills could improve the symptoms. The sleep architecture changes. There is a decrease of slow-wave sleep and an increase of slow-Theta-wave activity.
Assessment tools
Polysomnography
Polysomnography is an objective sleep assessment method. It comprises a lot of electrodes which measure physiological variables related to sleep. Polysomnography often includes electroencephalography, electromyography, electrocardiography, muscle activity and respiratory function.Polysomnography is helpful to identify the very short sleep onset latency period, the very efficient sleep (more than 90%), the increased slow wave sleep, and sometimes an elevated amount of sleep spindles in idiopathic hypersomnia patients.
Multiple sleep latency test (MSLT)
The multiple sleep latency test (MSLT) is an objective tool which indicates the degree of sleepiness by measuring the sleep latency (i.e. the speed of falling asleep). It also gives information regarding the presence of abnormal REM sleep onset episodes. During that test, patients have a series of opportunities to sleep at 2-h intervals across the day in a darkened room and with no external alerting influences.The MSLT is often administered the day after recording the polysomnography, and the mean sleep latency score is often found to be around (or less than) 8 minutes in idiopathic hypersomnia patients. Some patients might even have a sleep onset latency of 5 minutes or less. These patients are often even more aware of sleeping during naps than narcolepsy patients.
Actigraphy
Actigraphy, which operates by analyzing the patients limb movements, is used to record the sleep and wake cycles. In order to report them, the patient has to wear continuously a device on his or her wrist, which looks like a watch and does not contain any electrodes.
The advantage actigraphy shows over polysomnography is that it is possible to record for 24-hours a day for weeks. Furthermore, unlike the polysomnography, it is less expensive and non-invasive.An actigraphy over several days can show longer sleep periods, which are characteristic for idiopathic hypersomnia. Actigraphy is also helpful in ruling out other sleep disorders, especially circadian disorders, leading to an excess of sleepiness during the day, too.
The maintenance of wakefulness test (MWT)
The maintenance of wakefulness test (MWT) is a test that measures the ability to stay awake. It is used to diagnose disorders of excessive somnolence, such as hypersomnia, narcolepsy or obstructive sleep apnea. During that test, patients sit comfortably and are instructed to try to stay awake.
The Stanford sleepiness scale (SSS)
The Stanford sleepiness scale (SSS) is a self-report scale that measures the different steps of sleepiness. For each statement, patients report their level of sleepiness using a 7-point scale, going from very alert to excessively sleepy. Researchers found that the SSS was highly correlated with performances to monotonous and boring tasks, which are found to be very sensitive to sleepiness. These results suggest that the SSS is a good tool to assess sleepiness in patients.
The Epworth sleepiness scale (ESS)
The Epworth sleepiness scale (ESS) is also a self-reported questionnaire that measures the general level of sleepiness in a day The patients have to rate specific daily situations by means of a scale going from 0 (would never doze) to 3 (high chance of dozing). The results found in the ESS correlate with the sleep latency indicated by the Multiple Sleep Latency Test.
Treatment
Although there has been no cure of chronic hypersomnia, there are several treatments that may improve patients quality of life—depending on the specific cause or causes of hypersomnia that are diagnosed.Because the causes of hypersomnia are unknown, it is only possible to treat symptoms and not directly the cause of this disorder. Behavioral treatments, as well as sleep hygiene, have to be discussed with the patient and are recommended.
There are several pharmacological agents that have been prescribed to patients with hypersomnia, but few have been found to be efficient. Modafinil has been found to be the most effective drug against the excessive sleepiness, and has even been shown to be helpful in children with hypersomnia. The dosage is started at 100 mg per day, and then slowly increased to 400 mg per day.In general, patients with hypersomnia or excessive sleepiness should only go to bed to sleep or for sexual activity. All other activities, such as eating or watching television, should be done elsewhere. For those patients, it is also important to go to bed only when they feel tired, than trying to fall asleep for hours. In that case, they probably should get out of bed and read or watch television until they get sleepy.
Epidemiology
Hypersomnia affects approximately 5% to 10% of the general population, "with a higher prevalence for men due to the sleep apnea syndromes".
See also
Encephalitis lethargica
Reticular formation
Sleep medicine
Somnolence
References
External links
Help: I cant stay awake! - Public Radio Interview with Dr. David Rye
med/3129 at eMedicine - "Primary Hypersomnia" |
You act as a mediator between medical professionals and the public. Provide comprehensive explanations of medical terms, ensuring they are both precise and easily understood. | I'm looking for a concise explanation of the medical term 'Carcinoid syndrome.' | Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and less frequently, heart failure, vomiting and bronchoconstriction. It is caused by endogenous secretion of mainly serotonin and kallikrein.
Signs and symptoms
The carcinoid syndrome occurs in approximately 5% of carcinoid tumors and becomes manifest when vasoactive substances from the tumors enter the systemic circulation escaping hepatic degradation. If the primary tumor is from the gastrointestinal tract (hence releasing serotonin into the hepatic portal circulation), carcinoid syndrome generally does not occur until the disease is so advanced that it overwhelms the livers ability to metabolize the released serotonin.
Flushing: The most important clinical finding is flushing of the skin, usually of the head and the upper part of thorax.
Diarrhea: It may be associated with abdominal cramping. This symptom is due to the action of serotonin, histamine, and gastrin
Abdominal pain: It is due to hepatomegaly, small bowel obstruction or lack of oxygen to small bowel.
Bronchoconstriction, which may be histamine or serotonin-induced, affects about 15% of those having carcinoid syndrome and often accompanies flushing, sneezing, and shortness of breath.
Carcinoid heart disease: About 19% to 60% of the those affected by carcinoid syndrome develop carcinoid heart disease. Serotonin induces fibrosis in valves of the right heart especially tricuspid valve.
Pathophysiology
Carcinoid tumors produce several vasoactive substances, most prominently serotonin. It is commonly thought that serotonin is the cause of the flushing, but this is only partially correct. The flushing also results from secretion of kallikrein, the enzyme that catalyzes the conversion of kininogen to lysyl-bradykinin. The latter is further converted to bradykinin, one of the most powerful vasodilators known.
Other components of the carcinoid syndrome are diarrhea (probably caused by the increased serotonin, which greatly increases peristalsis, leaving less time for fluid absorption), a pellagra-like syndrome (probably caused by diversion of large amounts of tryptophan from synthesis of the vitamin B3 niacin, which is needed for NAD production, to the synthesis of serotonin and other 5-hydroxyindoles), fibrotic lesions of the endocardium, particularly on the right side of the heart resulting in insufficiency of the tricuspid valve and, less frequently, the pulmonary valve and, uncommonly, bronchoconstriction.The pathogenesis of the cardiac lesions and the bronchoconstriction is unknown, but the former probably involves activation of serotonin 5-HT2B receptors by serotonin. When the primary tumor is in the gastrointestinal tract, as it is in the great majority of cases, the serotonin and kallikrein are inactivated in the liver; manifestations of carcinoid syndrome do not occur until there are metastases to the liver or when the cancer is accompanied by liver failure (cirrhosis). Carcinoid tumors arising in the bronchi may be associated with manifestations of carcinoid syndrome without liver metastases because their biologically active products reach the systemic circulation before passing through the liver and being metabolized.In most patients, there is an increased urinary excretion of 5-HIAA (5-hydroxyindoleacetic acid), a degradation product of serotonin.The biology of these tumors differs from many other tumor types. Ongoing research on the biology of these tumors may reveal new mechanisms for tumor development.
Diagnosis
With a certain degree of clinical suspicion, the most useful initial test is the 24-hour urine levels of 5-HIAA (5-hydroxyindoleacetic acid), the end product of serotonin metabolism. Patients with carcinoid syndrome usually excrete more than 25 mg of 5-HIAA per day.
Imaging
For localization of both primary lesions and metastasis, the initial imaging method is Octreoscan, where indium-111 labelled somatostatin analogues (octreotide) are used in scintigraphy for detecting tumors expressing somatostatin receptors. Median detection rates with octreoscan are about 89%, in contrast to other imaging techniques such as CT scan and MRI with detection rates of about 80%. Gallium-68 labelled somatostatin analogues such as 68Ga-DOTA-Octreotate (DOTATATE), performed on a PET/CT scanner is superior to conventional Octreoscan.
Usually, on a CT scan, a spider-like/crab-like change is visible in the mesentery due to the fibrosis from the release of serotonin. 18F-FDG PET/CT, which evaluate for increased metabolism of glucose, may also aid in localizing the carcinoid lesion or evaluating for metastases. Chromogranin A and platelets serotonin are increased.Transthoracic echocardiogram shows valve thickening and reduction in mobility of the valves. Cardiac MRI is useful in showing ventricular anatomy and function.
Localization of tumour
Tumour localization may be extremely difficult. Barium swallow and follow-up examination of the intestine may occasionally show the tumor. Capsule video endoscopy has recently been used to localize the tumor. Often laparotomy is the definitive way to localize the tumour. Another form of localizing a tumor is the octreoscan. A tracer agent of Indium 111 is injected into a vein where then the tumors absorb the radionuclide Indium 111 and become visible on the scanner. Only the tumors absorb the somatostatin agent Indium 111 making the scan highly effective.
Treatment
For symptomatic relief of carcinoid syndrome:
Octreotide (a somatostatin analogue which decreases the secretion of serotonin by the tumor and, secondarily, decreases the breakdown product of serotonin (5-HIAA))
Telotristat ethyl (Xermelo) along with a somatostatin analogue in patients not responding to somatostatin analogue monotherapy. It is a tryptophan hydroxylase inhibitor and reduces the production of serotonin.
Peptide receptor radionuclide therapy (PRRT) with lutetium-177, yttrium-90 or indium-111 labeled to octreotate is highly effective
Methysergide maleate (antiserotonin agent but not used because of the serious side effect of retroperitoneal fibrosis)
Cyproheptadine (an antihistamine drug with antiserotonergic effects)Alternative treatment for qualifying patients:
Surgical resection of tumor and chemotherapy (5-FU and doxorubicin)
Endovascular, chemoembolization, targeted chemotherapy directly delivered to the liver through special catheters mixed with embolic beads (particles that block blood vessels), used for patients with liver metastases.
Uncertainties
Disease progression is difficult to ascertain because the disease can metastasize anywhere in the body and can be too small to identify with any current technology. Markers of the condition such as chromogranin-A are imperfect indicators of disease progression.
Prognosis
Prognosis varies from individual to individual. It ranges from a 95% 5-year survival for localized disease to an 80% 5-year survival for those with liver metastases. The average survival time from the start of octreotide treatment has increased to about 12 years.
See also
Carcinoid
Neuroendocrine tumor
Small intestine neuroendocrine tumor
Kulchitsky cells
Apudoma
Serotonin Syndrome
References
Further reading
== External links == |
You are a medical knowledge base. Your task is to elucidate medical terminology, offering insights into their meanings, origins, and applications. | Can you demystify the medical term 'Aschers syndrome' for me? | Aschers syndrome, is a rare disorder first described in 1920. It is characterized by repeated episodes of lip and eyelid edema and occasionally euthyroid goiter. The syndrome generally occurs within the first 20 years of life. About 100 cases had been described by 1998.
Signs and Symptoms
Blepharochalasis : Recurrent episodes of swelling cause stretching and atrophy of the upper eyelid skin. This results in the relaxation of the tarsal fold allowing tissue to slack over the palpebral fissure. In severe cases, the lower eyelid is also involved.
Double Upper Lip : Swelling causes duplication between the inner and outer parts of the upper lip. Occasionally the lower lip is involved.
Euthyroid Goiter : Occurs in 10% of cases. It is not usually associated with toxic symptoms. Goiter usually presents several years after initial eyelid and lip edema.
Diagnosis
Treatment
Cosmetic surgery is generally the treatment of choice.
References
== External links == |
You are a medical educator. Your role is to provide detailed and clear explanations for medical terms, suitable for both professionals and laypersons. | Could you provide a brief overview of 'Cutis laxa' in a medical context? | Cutis laxa or pachydermatocele is a group of rare connective tissue disorders in which the skin becomes inelastic and hangs loosely in folds.
Signs and symptoms
It is characterised by skin that is loose, hanging, wrinkled, and lacking in elasticity. The loose skin can be either generalised or localised. Biopsies have shown reduction and degeneration of dermal elastic fibres in the affected areas of skin. The loose skin is often most noticeable on the face, resulting in a prematurely aged appearance. The affected areas of skin may be thickened and dark. In addition, the joints may be loose (hypermobile) because of lax ligaments and tendons. When cutis laxa is severe, it can also affect the internal organs. The lungs, heart (supravalvular pulmonary stenosis), intestines, or arteries may be affected with a variety of severe impairments. In some cases, hernias and outpouching of the bladder can be observed. Patients can also present with whites of the eyes that are blue.
Causes
In many cases, cutis laxa is inherited. Autosomal dominant, autosomal recessive, and X-linked recessive forms have been described, but acquired forms also occur.Cutis laxa is associated with deficient or absent elastin fibers in the extracellular matrix. This can be related to decreased elastin synthesis or structural defects in the extracellular matrix.Cutis laxa may be caused by mutations in the genes: ELN, ATP6V0A2,ATP7A, FBLN4, FBLN5, and PYCR1. A related neurocutaneous syndrome may be caused by mutations in the gene ALDH18A1 (P5CS). Cutis laxa may also be seen in association with inherited connective tissue disorders such as Ehlers–Danlos syndromes. Another syndrome associated with cutis laxa is Lenz-Majewski syndrome which is due to a mutation in the phosphatidylserine synthase 1 (PTDSS1) gene.In contrast, acquired cutis laxa often has a triggering event such as urticaria, drugs (such as penicillin) or neoplasms. Acquired cutis laxa may also be immunologically mediated, as it can involve dermal deposit of immunoglobulins and it can occur with autoimmune diseases. Acquired cutis laxa has been associated with granular immunoglobulin A deposits as well as abundant neutrophils. One hypothesis for the cause is excessive elastase release from neutrophils and macrophages. It has also been considered that mutations in elastin (ELN) and fibulin-5 (FBLN5) genes can increase susceptibility of elastic fibres to inflammatory degradation in acquired cutis laxa.Acquired cutis laxa has also been seen in conjunction with a number of conditions including: rheumatoid arthritis, systemic lupus erythematosus, celiac disease, and monoclonal gammopathies. It can also occur as a postinflammatory response after urticaria. Urticarial skin fibroblasts have shown a 2- to 3- fold increase in elastase activity in a patient with acquired cutis laxa.
Diagnosis
Treatment
As of 2019, there is no treatment for cutis laxa. Procedures aimed at mitigating symptoms and identifying subsequent conditions are often advised. No pharmacological agent has been able to stop the progression of the disease. However, cosmetic surgeries are potentially an option as cutis laxa does not generally involve vascular fragility.
See also
Occipital horn syndrome
List of cutaneous conditions
References
Further reading
External links
Medscape entry on Cutis Laxa |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | I'm not familiar with the medical term 'Disruptive mood dysregulation disorder.' Could you provide some insights? | Disruptive mood dysregulation disorder (DMDD) is a mental disorder in children and adolescents characterized by a persistently irritable or angry mood and frequent temper outbursts that are disproportionate to the situation and significantly more severe than the typical reaction of same-aged peers. DMDD was added to the DSM-5 as a type of depressive disorder diagnosis for youths. The symptoms of DMDD resemble those of attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), anxiety disorders, and childhood bipolar disorder .DMDD first appeared as a disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) in 2013 and is classified as a mood disorder. Treatments include medication to manage mood symptoms as well as individual and family therapy to address emotion-regulation skills. Children with DMDD are at risk for developing depression and anxiety later in life.
Signs and symptoms
Children with DMDD show severe and recurrent temper outbursts three or more times per week. These outbursts can be verbal or behavioral. Verbal outbursts often are described by observers as "rages", "fits", or "tantrums". Children may scream, yell, and cry for excessively long periods of time, sometimes with little provocation. Physical outbursts may be directed toward people or property. Children may throw objects; hit, slap, or bite others; destroy toys or furniture; or otherwise act in a harmful or destructive manner.
Children with DMDD also display persistently irritable or angry mood that is observable by others. Parents, teachers, and classmates describe these children as habitually angry, touchy, grouchy, or easily "set off". Unlike the irritability that can be a symptom of other childhood disorders, such as ODD, anxiety disorders, and major depressive disorder, the irritability displayed by children with DMDD is not episodic or situation-dependent. In DMDD, the irritability or anger is severe and is shown most of the day, nearly every day in multiple settings, lasting for one or more years.
Note
DMDD is a newly classified disorder, first appearing in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in 2013. The DSM is used for the assessment and diagnosis of mental disorders; it does not include specific guidelines for the treatment of any disorder.
Researchers at the National Institute of Mental Health (NIMH) developed the DMDD diagnosis to diagnose more accurately youth who may have been previously diagnosed with pediatric bipolar disorder (despite not experiencing the symptoms needed for a diagnosis of bipolar disorder).The DSM-5 includes several additional diagnostic criteria which describe the duration, setting, and onset of the disorder: the outbursts must be present for at least 12 months and occur in at least two settings (e.g. home and school), and it must be severe in at least one setting. Symptoms appear before the age of 10, and diagnosis must be made between ages 6 and 18.
Comorbidity
The core features of DMDD—temper outbursts and chronic irritability—are sometimes seen in children and adolescents with other psychiatric conditions. Differentiating DMDD from these other conditions can be difficult. Three disorders that most closely resemble DMDD are attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and bipolar disorder in children.
ADHD
ADHD is a neurodevelopmental disorder characterized by problems with inattention and/or hyperactivity-impulsivity.
ODD
ODD is a disruptive behavior disorder characterized by oppositional, defiant, and sometimes hostile actions directed towards others. The DSM-5 considers DMDD a severe manifestation of symptoms associated with ODD. A diagnosis of both DMDD and ODD is not permitted or necessary; individuals who meet the diagnostic requirements for DMDD also meet the requirements for ODD.
Bipolar disorder
One of the main differences between DMDD and bipolar disorder is that the irritability and anger outbursts associated with DMDD are not episodic; symptoms of DMDD are chronic and displayed constantly on an almost daily basis. On the other hand, bipolar disorder is characterized by distinct manic or hypomanic episodes usually lasting a few days, or a few weeks at most, that parents should be able to differentiate from their childs typical mood and behavior in between episodes. The DSM precludes a dual diagnosis of DMDD and bipolar disorder. Bipolar disorder alone should be used for youths who show classic symptoms of episodic mania or hypomania.Prior to adolescence, DMDD is much more common than bipolar disorder. Most children with DMDD see a decrease in symptoms as they enter adulthood, whereas individuals with bipolar disorder typically display symptoms for the first time as teenagers and young adults. Children with DMDD are more at risk for developing major depressive disorder or generalized anxiety disorder when theyre older rather than bipolar disorder.
Conduct Disorder
Conduct disorder is a behavior disorder characterized by repeated, persistent patterns of behavior that violate the rights of others and disregard major societal norms and rules. While both DMDD and conduct disorder are associated with argumentative and defiant behavior, DMDD is distinctly differentiated from conduct disorder by the DSM. Individuals with DMDD experience severe emotional dysregulation not seen in conduct disorder. Additionally, conduct disorder is described by a distinct lack of remorse and repeated physical harm and threats of harm to people and/or animals. Evidence of conduct disorder during childhood is one of the criteria for an adult diagnosis of antisocial personality disorder, however adults with a continued diagnosis of conduct disorder do not necessarily have antisocial personality disorder.
Causes
Youth with DMDD have difficulty attending, processing, and responding to negative emotional stimuli and social experiences in their everyday lives. For example, some studies have shown youths with DMDD to have problems interpreting the social cues and emotional expressions of others. These youths may be especially bad at judging others negative emotional displays, such as feelings of sadness, fearfulness, and anger. Functional MRI studies suggest that under-activity of the amygdala, the brain area that plays a role in the interpretation and expression of emotions and novel stimuli, is associated with these deficits. Deficits in interpreting social cues may predispose children to instances of anger and aggression in social settings with little provocation. For examples, youths with DMDD may selectively attend to negative social cues (e.g., others scowling, teasing) and minimize all other information about the social events. They may also misinterpret the emotional displays of others, believing others benign actions to be hostile or threatening. Consequently, they may be more likely than their peers to act in impulsive and angry ways.Children with DMDD may also have difficulty regulating negative emotions once they are elicited. To study these problems with emotion regulation, researchers asked children with DMDD to play computer games that are rigged so that children will lose. While playing these games, children with DMDD report more agitation and negative emotional arousal than their typically developing peers. Furthermore, youths with DMDD showed markedly greater activity in the medial frontal gyrus and anterior cingulate cortex compared to other youths. These brain regions are important because they are involved in evaluating and processing negative emotions, monitoring ones own emotional state, and selecting an effective response when upset, angry, or frustrated. Altogether, these findings suggest that youths with DMDD are more strongly influenced by negative events than other youths. They may become more upset and select less effective and socially acceptable ways to deal with negative emotions when they arise.
Treatment
Medication
Evidence for treatment is weak, and treatment is determined based on the physicians response to the symptoms that people with DMDD present. Because the mood stabilizing medication, lithium, is effective in treating adults with bipolar disorder, some physicians have used it to treat DMDD although it has not been shown to be better than placebo in alleviating the signs and symptoms of DMDD. DMDD is treated with a combination of medications that target the childs symptom presentation. For youths with DMDD alone, antidepressant medication is sometimes used to treat underlying problems with irritability or sadness. For youths with unusually strong temper outbursts, an atypical antipsychotic medication, such as risperidone, may be warranted. Both medications, however, are associated with significant side effects in children. Finally, for children with both DMDD and ADHD, stimulant medication is sometimes used to reduce symptoms of impulsivity.
Psychosocial
Several cognitive-behavioral interventions have been developed to help youths with chronic irritability and temper outbursts. Because many youths with DMDD show problems with ADHD and oppositional-defiant behavior, experts initially tried to treat these children using contingency management. This type of intervention involves teaching parents to reinforce childrens appropriate behavior and extinguish (usually through systematic ignoring or time out) inappropriate behavior. Although contingency management can be helpful for ADHD and ODD symptoms, it does not seem to reduce the most salient features of DMDD, namely, irritability and anger.
Epidemiology
There are not good estimates of the prevalence of DMDD, but primary studies have found a rate of 0.8 to 3.3%. Epidemiological studies show that approximately 3.2% of children in the community have chronic problems with irritability and temper, the essential features of DMDD. These problems are probably more common among clinic-referred youths. Parents report that approximately 30% of children hospitalized for psychiatric problems meet diagnostic criteria for DMDD; 15% meet criteria based on the observations of hospital staff.
What is the difference between typical irritability and severe irritability?
All children can become irritable sometimes. It’s a normal reaction to frustration. Children experiencing severe irritability (as observed in DMDD) have difficulty tolerating frustration and have outbursts that are out of proportion for the situation at hand. These outbursts occur more often and are more severe than what you would typically expect for children of this age.
For example, a parent tells the child to stop playing a game and do their homework. Any child might be frustrated or annoyed. But a child with DMDD may become extremely upset and emotional and have an intense temper outburst with yelling or hitting. A child with DMDD experiences these intense temper outbursts a few times a week.
History
Beginning in the 1990s, some clinicians began observing children with hyperactivity, irritability, and severe temper outbursts. These symptoms greatly interfered with their lives at home, school, and with friends. Because other diagnoses, like ADHD and ODD, did not capture the severity of childrens irritability and anger, many of these children were diagnosed with bipolar disorder. Longitudinal studies showed that children with chronic irritability and temper outbursts often developed later problems with anxiety and depression, and rarely developed bipolar disorder in adolescence or adulthood. Consequently, the developers of DSM-5 created a new diagnostic label, DMDD, to describe children with persistent irritability and angry outbursts. In 2013, the American Psychiatric Association (APA) added DMDD to the DSM-5 and classified it as a depressive disorder.
== References == |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | I've encountered the term 'Constipation in children' while reading about medical topics. What does it refer to exactly? | Constipation in children refers to the medical condition of constipation in children. It is a functional gastrointestinal disorder.
Presentation
Children have different bowel movement patterns than adults. In addition, there is a wide spectrum of normalcy when considering childrens bowel habits. On average, infants have 3-4 bowel movements/day, and toddlers have 2-3 bowel movements per day. At around age 4, children develop an adult-like pattern of bowel movements (1-2 stools/day). Children benefit from scheduled toilet breaks, once early in the morning and 30 minutes after meals. The Rome III Criteria for constipation in children helps to define constipation for various age groups.
Causes
While it is difficult to assess an exact age at which constipation most commonly arises, children frequently experience constipation in conjunction with life-changes. Examples include: toilet training, starting or transferring to a new school, and changes in diet. Especially in infants, changes in formula or transitioning from breast milk to formula can cause constipation. Fortunately, the majority of constipation cases are not tied to a medical disease, and treatment can be focused on simply relieving the symptoms.
Congenital causes
A number of diseases present at birth can result in constipation. They are as a group uncommon with Hirschsprungs disease (HD) being the most common. HD is more common in males than females, affecting 1 out of 5000 babies. In people with HD, specific types of cells called neural crest cells fail to migrate to parts of the colon. This causes the affected portion of the colon to be unable to contract and relax to help push out a bowel movement. The affected portion of the colon remains contracted, making it difficult for stool to pass through. Concern for HD should be raised in a child who has not passed stool during the first 48 hours of life. Milder forms of HD, in which only a small portion of the colon is affected, can present later in childhood as constipation, abdominal pain, and bloating. Similar disorders to HD include anal achalasia and hypoganglionosis. In hypoganglionosis, there is a low number of neural crest cells, so the colon remains contracted. In anal achalasia, the internal anal sphincter remains contracted, making it difficult for stool to pass. However, there is a normal number of neural crest cells present.There are also congenital structural anomalies that can lead to constipation, including anterior displacement of the anus, imperforate anus, strictures, and small left colon syndrome. Anterior displacement of the anus can be diagnosed on physical exam. The disease causes constipation because the inappropriate positioning of the anus which make it difficult to pass a bowel movement. Imperforate anus is an anus that ends in a blind pouch and does not connect to the rest of the persons intestines. Small left colon syndrome is a rare disease in which the left side of the babies colon has a small diameter, which makes it difficult for stool to pass. A risk factor for small left colon syndrome is having a mother with diabetes.Some symptoms that may indicate an underlying disease include:
Bowel movements that contain blood.
Severe abdominal bloating.
Peri-anal fistula
Absent anal wink reflex
Sacral dimple
Failure to thrive
Diagnosis
The Rome process suggests a diagnosis of constipation in children fewer than 4 years old when the child has 2 or more of the following complaints for at least 1 month. For children older than 4 years, there must be 2 of these complaints for at least 2 months.
2 or fewer bowel movements per week
Passing large bowel movements
On physical exam, a doctor may find large amounts of feces within the childs rectum.
A child who is already toilet trained has at least 1 accident per week involving a bowel movement.
Child demonstrates withholding behavior in which he or she actively tries not to pass a bowel movement.
Hard stools
Pain with defecation.For children, the degree of constipation may be scored by the Leech or the Barr systems:
The Leech system assigns a score of 0 to 5 based on the amount of feces:0: no visible feces
1: scanty feces visible
2: mild fecal loading
3: moderate fecal loading
4: severe fecal loading
5: severe fecal loading with bowel dilatation
These score are assigned separately for the right colon, the left colon and the rectosigmoid colon, resulting in a maximum score of 15. A Leech score of 9 or greater is regarded as positive for constipation.The Barr system rates both the amount and consistency of the faeces, and assigns a score separately for the ascending colon, transverse colon, descending colon and rectum. Its maximum score is 22, and a score of 10 or greater is regarded as positive for constipation.
Treatment
Lactulose and milk of magnesia have been compared with polyethylene glycol (PEG) in children. All had similar side effects, but PEG was more effective at treating constipation. Osmotic laxatives are recommended over stimulant laxatives.
Epidemiology
There is wide variation in the rates of constipation as reported by research in various countries. The variation in research data makes it challenging to describe the true global situation.Approximately 3% of children have constipation, with girls and boys being equally affected. With constipation accounting for approximately 5% of general pediatrician visits and 25% of pediatric gastroenterologist visits, the symptom carries a significant financial impact upon our healthcare system.
Society and culture
Constipation is often emotionally stressful for children and their caregivers. It is common for parents to bring their children to doctors for this condition. The experience of going to a doctor for this can be stressful.Too often, children at doctors receive unnecessary health care when they get medical imaging for constipation. Children should only get tests when there is an indication.
== References == |
You function as a medical explainer. Your task is to convey the meanings of medical terms in a detailed, yet easy-to-understand manner. | I'm looking for a concise explanation of the medical term 'Sojourn.' | Sojourn may refer to:
Books and periodicals
Sojourn (comics), a CrossGen comic book series
Sojourn (journal), a journal of social and cultural issues in Southeast Asia
Sojourn (novel), the 1991 novel in the Dark Elf Trilogy by R. A. Salvatore
The Sojourn, a 2011 novel by Andrew Krivak
Music
Sojourn (album), a 1977 album by Mickey Tucker
"Sojourn", a song by Natasha Bedingfield from Unwritten
Sojourn Music, an American Christian music group
Other uses
"Sojourn" (American Horror Story), a television episode
Sojourn, a predecessor of TorilMUD, a text-based online role-playing game
Sevoflurane, trade name Sojourn, an inhalational anaesthetic
Sojourn Shelton (born 1994), American football player
See also
Sojourner (disambiguation) |
You are a resource for medical understanding. Offer detailed explanations of medical terms, making complex concepts clear and comprehensible. | What does the medical term 'Ranolazine' encompass? | Ranolazine, sold under the brand name Ranexa among others, is a medication used to treat heart related chest pain. Typically it is used together with other medications when those are insufficient. Benefits appear smaller in women than men. It is taken by mouth.Common side effects include constipation, headache, nausea, and dizziness. Serious side effects may include QT prolongation. Use is not recommended in those with liver cirrhosis. How it works is not clear but may involve adenosine triphosphate.Ranolazine was approved for medical use in the United States in 2006. In 2019, it was the 211th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
Medical uses
Ranolazine is used to treat chronic angina. It may be used concomitantly with β blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. It is also effective at preventing atrial fibrillation, and has been studied as monotherapy as well as in combination with other medications used to treat irregular heartbeat.Its use is not recommended in Scotland as of 2019.
Contraindications
Some contraindications for ranolazine are related to its metabolism and are described under Drug Interactions. Additionally, in clinical trials ranolazine slightly increased QT interval in some patients and the FDA label contains a warning for doctors to beware of this effect in their patients. The drugs effect on the QT interval is increased in the setting of liver dysfunction; thus it is contraindicated in persons with mild to severe liver disease.
Side effects
The most common side effects are dizziness (11.5%) and constipation (10.9%). Other side effects include headache and nausea.
Drug interactions
Ranolazine is metabolized mainly by the CYP3A enzyme. It also inhibits another metabolizing enzyme, cytochrome CYP2D6. For this reason, the doses of ranolazine and drugs that interact with those enzymes need to be adjusted when they are used by the same patient.
Ranolazine should not be used with drugs such as ketoconazole, clarithromycin, and nelfinavir that strongly inhibit CYP3A, nor with drugs that activate CYP3A, such as rifampin and phenobarbital.For drugs that are moderate CYP3A inhibitors, such as diltiazem, verapamil, and erythromycin, the dose of ranolazine should be reduced.Drugs that are metabolized by CYP2D6, such as tricyclic antidepressants, may need to be given at reduced doses when administered with ranolazine.
Mechanism of action
Ranolazine inhibits persistent or late inward sodium current (INa) in heart muscle in a variety of voltage-gated sodium channels. Inhibiting that current leads to reductions in intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle. The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential. Ranolazine also exhibits its effects on the delayed rectifier current (hERG/IKr potassium channels), it readily stimulates myogenesis, it reduces a pro-oxidant inflammation/oxidative condition, and activates the calcium signaling pathway.Ranolazine prolongs the action potential duration, with corresponding QT interval prolongation on electrocardiography, blocks the INa current, and prevents calcium overload caused by the hyperactive INa current, thus it stabilizes the membrane and reducing excitability.
History
Syntex Inc. originally began developing ranolazine in 1985 and 61 studies were completed from then until 1994. Afterwards, Phase 2 studies were done however it was found that the formulation did not result in adequate plasma concentrations of drug. It is due to this that the sustained-release (SR) formulation of ranolazine was created.Roche acquired Syntex in 1994 In 1996, CV Therapeutics licensed the North American and European rights to ranolazine from Syntex, a subsidiary of Roche, which had discovered the drug and had developed it through Phase II trials in angina. In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche. In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to Menarini.
In 2009, Gilead acquired CV Therapeutics. In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia.
Society and culture
Legal status
Ranolazine was approved by the FDA in January 2006, for the treatment of patients with chronic angina as a second-line treatment in addition to other drugs. In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs. In April 2008 ranolazine was approved by the European EMEA for use in angina.
Commercial aspects
Ranolazine is manufactured and sold as Ranexa by Gilead. According to a Gilead annual income statement, combined sales for Ranexa and another Gilead product, AmBisom, were $621 million for the fourth quarter of 2016.
References
External links
"Ranolazine". Drug Information Portal. U.S. National Library of Medicine. |
You are a medical interpreter. Your duty is to translate medical terms into easily digestible information, maintaining accuracy and detail. | The term 'Triparesis' keeps coming up in medical discussions. What does it stand for? | Triparesis is a medical condition, similar to triplegia, but the major difference between the two is primarily that triplegia is total loss of function in three limbs, and triparesis denotes weakening of three limbs.
== References == |
You are a medical knowledge base. Your task is to elucidate medical terminology, offering insights into their meanings, origins, and applications. | I'm trying to expand my medical knowledge. Can you elucidate the term 'Elexacaftor/tezacaftor/ivacaftor'? | Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta (US) and Kaftrio (EU), is a fixed-dose combination medication used to treat cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.It is approved for use in the United States for people aged six years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene. It is also approved for use in Canada, the European Union and Australia.
Medical uses
The combination is indicated for the treatment of people aged six years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene.
Side effects
The most common side effects affecting more than 5% of patients are headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis and blood bilirubin increased.
Interactions
Concomitant use with CYP3A inducers is not recommended. Dosage must be adjusted with moderate or strong CYP3A inhibitors.Other drugs with the potential for interaction include: warfarin, digoxin, statins, glyburide, nateglinide, repaglinide.
Pharmacology
Cystic fibrosis and CFTR
Cystic fibrosis is an autosomal recessive genetic disorder of the CFTR protein which reduces chloride and sodium ion transport through the cell membrane, causing thicker than normal mucus secretions. The CFTR protein is found in epithelial cells of the lung, liver, pancreas, digestive tract, and reproductive tracts. CFTR has a role in the production of mucus, sweat, and digestive fluids. The thickened mucus can lead to inflammation, respiratory infections, and clogged ducts.
Mechanism of action
Elexacaftor/tezacaftor/ivacaftor is a tridrug treatment in which the medications work together to increase the transport of chloride and sodium ions, and reducing thick mucus production.
CFTR channel potentiator
Ivacaftor is a selective small-molecule potentiator of the CFTR protein that increases the proteins ability to open chloride channels. Its effectiveness is highly dependent on the amount of CFTR protein at the cell surface and the responsiveness of the mutant CFTR protein. Ivacaftors primary target is to treat class III CFTR gating mutations like G551D as well as other less common mutations. In the crystalline figure, you can see ivacaftor, shown as a gray ball and stick model on the bottom-right, bound to CFTR docked in a cleft formed by transmembrane helices at the protein-lipid interface.
CFTR correctors
Elexacaftor and Tezacaftor act as CFTR correctors to repair F508del processing by binding to the CFTR protein to increase the availability of CFTR protein on the cell surface. They work by modulating the position of the CFTR protein into the right position on the cell surface.The combination of increased CFTR protein in the correct position on the cell surface with ivacaftors potentiation of chloride channel opening results in increased transport of chloride and thinned mucus secretions.
Pharmacokinetics
Elexacaftor/tezacaftor/ivacaftor is primarily metabolized by CYP3A4 /5. This medication should be taken with a high fat meal to improve absorption through the gut. It is excreted as metabolites or unchanged mainly through feces and to a smaller extent urine. The mean effective half-life of elexacaftor, tezacaftor, and ivacaftor is 27.4 hours, 25.1 hours, and 15 hours, respectively.
History
A phase III trial showed people treated with elexacaftor/tezacaftor/ivacaftor improved in FEV1 at four weeks with sustained improvement at 24 weeks. Rate of pulmonary exacerbation was 63% lower and sweat chloride concentration was 41.8 mmol/L lower. Its effectiveness is dependent on the type of CF mutations the patient has.
Society and culture
Legal status
United States
The combination was approved for use in the United States in 2019 for people twelve years and older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population. In December 2020, after an additional clinical trial was completed, and FDA approval was expanded for 177 other cystic fibrosis mutations. FDA approval for children aged 6–11 was added in January 2021, after a third clinical trial was completed.The U.S. Food and Drug Administration (FDA) granted the application priority review, in addition to fast track, breakthrough therapy, and orphan drug designations. The drugs manufacturer Vertex Pharmaceuticals will receive a rare pediatric disease priority review voucher for having developed this therapy.
Australia
In March 2021, health regulators in Australia approved trikafta for patients aged 12 years and older with at least one copy of the F508del mutation. At the end of April 2022, it was placed on PBS, thus reducing the cost from tens of thousands of dollars a month, to tens of dollars a month.
Canada
In June 2020, Health Canada approved Trikafta for patients ages 12 and up. In September 2021, the provinces Alberta and Saskatchewan announced they will join Ontario in funding the medication. They will determine coverage on a case-by-case basis using criteria that has not yet been announced.
European Union
In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended its approval for the treatment of cystic fibrosis. It was approved for medical use in the European Union in August 2020.
Norway
On 25 April 2022, Beslutningsforum for nye metoder approved Kaftrio for treatment of cystic fibrosis.
New Zealand
In February 2022, Pharmac recommended, with medium priority, funding for patients age 12 and above.
Spain
In November 2021, the Spanish government approved the reimbursement of Kaftrio for patients ages 12 and older with at least one copy of the F508del mutation.
Economics
United States
The list price of a years treatment in the US is US$311,000. However, a 2020 report by Institute for Clinical and Economic Review found that the price has made the treatment not cost effective and that "an appropriate health-benefit price would range from $67,900–$85,500 per year".
Australia
Following the listing of Trikafta on the Pharmaceutical Benefits Scheme in 2022, the cost for CF patients 12 years or older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator gene is $42.50 per month, or $6.80 for concession card holders.
Research
CFTR mutations that are responsive to elexacaftor/tezacaftor/ivacaftor were determined by an in-vitro study of Fischer Rat Thyroid (FRT) cells that expressed mutant CFTR. Elexacaftor/tezacaftor/ivacaftor showed effectiveness with mutations where the CFTR protein was being successfully delivered to the cell surface.
References
External links
"Elexacaftor". Drug Information Portal. U.S. National Library of Medicine.
"Ivacaftor regimen with Tezacaftor". Drug Information Portal. U.S. National Library of Medicine. |
You serve as an encyclopedia of medical terms. Deliver clear, detailed explanations, making medical language understandable to a diverse audience. | Could you provide a brief overview of 'Tenonitis' in a medical context? | Tenonitis is a rare eye disease that is represented by inflammation of Tenons capsule. Tenons capsule, also known as the fascial sheath of the eyeball, is a structure surrounding the eyeball, and when it becomes inflamed it may cause issues in regards to vision. Also known as orbital tenonitis, tenonitis is associated with the SLC26A3 gene. The inflammation of the Tenon capsule resulting from heightened blood flow may also affect the lacrimal gland and the extraocular muscles.
Signs and Symptoms
Signs and symptoms depend on the severity of the case with tenonitis. In mild cases it may just be an uncomfortable sensation in the eye socket. In extreme cases it may cause permanent blindness or eye removal is needed.
Swelling
Intraocular pressure
Blindness
Causes
There are no specific causes of this disease. With this being so rare not enough research has been allocated to pinpoint a specific cause of this disease. The main thing that we know about this disease is that the inflammation of the Tenon capsule may be related to macular retinal edema and intraocular pressure quantitative trait locus.
Mechanism
With the lack of research and understanding about this specific disease it is hard to come up with a mechanism that outlines how this arises in the body. Although we cannot pinpoint specifically how it occurs, there are some findings that may help us get to that point in the future. A gene that is associated with orbital tenonitis is the SLC26A3 gene. This gene mediates chloride and bicarbonate exchange and additionally transports sulfate and other anions at the apical membrane, part of the plasma membrane of enterocytes. It is also known that related phenotypes are Increased shRNA abundance (Z-score > 2).
Diagnosis
Tenonitis can be identified and diagnosed a few different ways. Tenons capsule may have inflammation from a disease called idiopathic orbital inflammation syndrome. There is no history of trauma or adjacent focus of infection with this disease. In order to diagnose tenonitis some type of imaging is needed, such as a CT or MRI. The imaging is used to capture the inflammation and to spot any possible chance of infection. For chronic diseases a biopsy may be needed to determine an underlying condition that may be causing the recurring inflammation.
Treatment
The main course of treatment for this specific disease would be to surgically excise the capsule. There is no info that implies the inflammation of this capsule will go down over time so the known course of action would be to have it surgically removed in order to relieve discomfort and to prevent further irritation to this area.
Prognosis
Although this may not be a lethal disease, it will progressively get worse over time. Depending on the severity of the disease, this may have months of progression. When going past 3 months of having issues, the main course of action would be to surgically relieve the pain or total excision of the affected area.
Epidemiology
This disease has no specific population it targets more. With the information that is provided by previous research, this is a typically universal disease that can affect any population.
Research Directions
Currently there havent been many studies conducted in regards to Tenons capsule. In one study the objective was to see the efficacy of excision of the capsule by way of trabeculectomy alone, and also combined with partial tenonectomy. There is further research needed to be done to determine the cause of this specific disease, what happens during the progression of it, and treatment plans that need to be put in place.
== References == |
You are a guide to medical language. Please provide in-depth and understandable explanations of medical terms, highlighting their significance in healthcare. | Please help me grasp the concept behind the medical term 'Biliary dyskinesia.' | Biliary dyskinesia is a disorder of some component of biliary part of the digestive system in which bile cannot physically move in the proper direction through the tubular biliary tract. It most commonly involves abnormal biliary tract peristalsis muscular coordination within the gallbladder in response to dietary stimulation of that organ to squirt the liquid bile through the common bile duct into the duodenum. Ineffective peristaltic contraction of that structure produces postprandial (after meals) right upper abdominal pain (cholecystodynia) and almost no other problem. When the dyskinesia is localized at the biliary outlet into the duodenum just as increased tonus of that outlet sphincter of Oddi, the backed-up bile can cause pancreatic injury with abdominal pain more toward the upper left side. In general, biliary dyskinesia is the disturbance in the coordination of peristaltic contraction of the biliary ducts, and/or reduction in the speed of emptying of the biliary tree into the duodenum.
Mechanism
Normally, the downstream gallbladder stores and concentrates the bile which originates in liver hepatocyte cells and is released into the microscopic component of the biliary system by the liver. Through aggregating tubules of increasing diameter, the bile leaves the liver and reaches the upstream (proximal) component of the common bile duct. Apparently, the common bile duct beyond (distal to) the gallbladder tends to normally have a greater tone so that the bile backs up into the gallbladder. When bile enters the duodenum (the first part of the small intestine), it aids in digesting the fat within food leaving the stomach. When the bile can not be properly propelled from the not-mechanically-obstructed gallbladder or can not flow out of the end of the common bile duct properly, there is a state of biliary dyskinesia.
So, biliary dyskinesia is a dynamically (functional...not fixed mechanical) obstructive, pain-producing disorder. Obstruction by a stone or tumor is a static, mechanical obstruction and tends to produce a more intense pain known as biliary colic.
Failure of the biliary sphincter of Oddi can be distinguished from failure of the pancreatic sphincter.
Diagnosis
Diagnosis may or may not be determined by an ultrasound, but most likely the disease and other biliary diseases of the liver, gallbladder, and bile duct are found by what is most commonly referred to as a hepatobiliary or HIDA scan. This type of imaging is known as cholescintigraphy.
Cholescintigraphy
Cholescintigraphy or hepatobiliary scintigraphy is scintigraphy of the hepatobiliary tract, including the gallbladder and bile ducts. The image produced by this type of medical imaging, called a cholescintigram, is also known by other names depending on which radiotracer is used, such as HIDA scan, PIPIDA scan, DISIDA scan, or BrIDA scan. Cholescintigraphic scanning is a nuclear medicine procedure to evaluate the health and function of the gallbladder and biliary system. A radioactive tracer is injected through any accessible vein and then allowed to circulate to the liver and starts accumulating in the gall bladder which can take up to an hour. A standard fatty meal (usually a high fat milk shake) is then given and more imaging is performed for another hour so that the response to the fatty meal by the gall bladder can be shown. The gall bladder should respond and begin emptying into the duodenum, the amount of bile ejected can then be calculated as an ejection fraction (EF). An EF < 35% is considered to be diagnostic of biliary dyskinesia and suitable for cholecystectomy to be considered.
Treatment
Laparoscopic cholecystectomy has been used to treat the condition when due to dyskinesia of the gallbladder.
Prognosis
Symptoms may persist after cholecystectomy, and have been linked to the use of proton pump inhibitors.
See also
Bile acid malabsorption, an entry of the bile acid into a large intestine due to malabsorption the bile in the ileum, which may cause chronic diarrhea.
References
== External links == |
You are a guide to medical language. Please provide in-depth and understandable explanations of medical terms, highlighting their significance in healthcare. | Please help me grasp the concept behind the medical term 'Gestational age.' | In obstetrics, gestational age is a measure of the age of a pregnancy which is taken from the beginning of the womans last menstrual period (LMP), or the corresponding age of the gestation as estimated by a more accurate method if available. Such methods include adding 14 days to a known duration since fertilization (as is possible in in vitro fertilization), or by obstetric ultrasonography. The popularity of using this definition of gestational age is that menstrual periods are essentially always noticed, while there is usually a lack of a convenient way to discern when fertilization occurred. Gestational age is contrasted with fertilization age which takes the date of fertilization as the start date of gestation.
The initiation of pregnancy for the calculation of gestational age can differ from definitions of initiation of pregnancy in context of the abortion debate or beginning of human personhood.
Methods
According to American College of Obstetricians and Gynecologists, the main methods to calculate gestational age are:
Directly calculating the days since the beginning of the last menstrual period
Early obstetric ultrasound, comparing the size of an embryo or fetus to that of a reference group of pregnancies of known gestational age (such as calculated from last menstrual periods) and using the mean gestational age of other embryos or fetuses of the same size. If the gestational age as calculated from an early ultrasound is contradictory to the one calculated directly from the last menstrual period, it is still the one from the early ultrasound that is used for the rest of the pregnancy.
In case of in vitro fertilization, calculating days since oocyte retrieval or co-incubation and adding 14 days.Gestational age can also be estimated by calculating days from ovulation if it was estimated from related signs or ovulation tests, and adding 14 days by convention.A more complete listing of methods is given in following table:
As a general rule, the official gestational age should be based on the actual beginning of the last menstrual period, unless any of the above methods gives an estimated date that differs more than the variability for the method, in which case the difference cannot probably be explained by that variability alone. For example, if there is a gestational age based on the beginning of the last menstrual period of 9.0 weeks, and a first-trimester obstetric ultrasonography gives an estimated gestational age of 10.0 weeks (with a 2 SD variability of ±8% of the estimate, thereby giving a variability of ±0.8 weeks), the difference of 1.0 weeks between the tests is larger than the 2 SD variability of the ultrasonography estimate, indicating that the gestational age estimated by ultrasonography should be used as the official gestational age.Once the estimated due date (EDD) is established, it should rarely be changed, as the determination of gestational age is most accurate earlier in the pregnancy.Following are diagrams for estimating gestational age from obstetric ultrasound, by various target parameters:
Comparison to fertilization age
The fertilization or conceptional age (also called embryonic age and later fetal age) is the time from the fertilization. It usually occurs within a day of ovulation, which, in turn, occurs on average 14.6 days after the beginning of the preceding menstruation (LMP). There is also considerable variability in this interval, with a 95% prediction interval of the ovulation of 9 to 20 days after menstruation even for an average woman who has a mean LMP-to-ovulation time of 14.6. In a reference group representing all women, the 95% prediction interval of the LMP-to-ovulation is 8.2 to 20.5 days. The actual variability between gestational age as estimated from the beginning of the last menstrual period (without the use of any additional method mentioned in previous section) is substantially larger because of uncertainty which menstrual cycle gave rise to the pregnancy. For example, the menstruation may be scarce enough to give the false appearance that an earlier menstruation gave rise to the pregnancy, potentially giving an estimated gestational age that is approximately one month too large. Also, vaginal bleeding occurs during 15-25% of first trimester pregnancies, and may be mistaken as menstruation, potentially giving an estimated gestational age that is too low.
Uses
Gestational age is used for example for:
The events of prenatal development, which usually occur at specific gestational ages. Hence, the gestational timing of a fetal toxin exposure, fetal drug exposure or vertically transmitted infection can be used to predict the potential consequences to the fetus.
Estimated date of delivery
Scheduling prenatal care
Estimation of fetal viability
Calculating the results of various prenatal tests, (for example, in the triple test).
Birth classification into for example preterm, term or postterm.
Classification of infant deaths and stillbirths
Postnatally (after birth) to estimate various risk factors
Estimation of due date
The mean pregnancy length has been estimated to be 283.4 days of gestational age as timed from the first day of the last menstrual period and 280.6 days when retrospectively estimated by obstetric ultrasound measurement of the fetal biparietal diameter (BPD) in the second trimester. Other algorithms take into account other variables, such as whether this is the first or subsequent child, the mothers race, age, length of menstrual cycle, and menstrual regularity. In order to have a standard reference point, the normal pregnancy duration is assumed by medical professionals to be 280 days (or 40 weeks) of gestational age. Furthermore, actual childbirth has only a certain probability of occurring within the limits of the estimated due date. A study of singleton live births came to the result that childbirth has a standard deviation of 14 days when gestational age is estimated by first-trimester ultrasound and 16 days when estimated directly by last menstrual period.The most common system used among healthcare professionals is Naegeles rule, which estimates the expected date of delivery (EDD) by adding a year, subtracting three months, and adding seven days to the first day of a womans last menstrual period (LMP) or corresponding date as estimated from other means.
Medical fetal viability
There is no sharp limit of development, gestational age, or weight at which a human fetus automatically becomes viable. According to studies between 2003 and 2005, 20 to 35 percent of babies born at 23 weeks of gestation survive, while 50 to 70 percent of babies born at 24 to 25 weeks, and more than 90 percent born at 26 to 27 weeks, survive. It is rare for a baby weighing less than 500 g (17.6 ounces) to survive. A babys chances for survival increases 3-4% per day between 23 and 24 weeks of gestation and about 2-3% per day between 24 and 26 weeks of gestation. After 26 weeks the rate of survival increases at a much slower rate because survival is high already. Prognosis depends also on medical protocols on whether to resuscitate and aggressively treat a very premature newborn, or whether to provide only palliative care, in view of the high risk of severe disability of very preterm babies.
Birth classification
Using gestational age, births can be classified into broad categories:
Using the LMP (last menstrual period) method, a full-term human pregnancy is considered to be 40 weeks (280 days), though pregnancy lengths between 38 and 42 weeks are considered normal. A fetus born prior to the 37th week of gestation is considered to be preterm. A preterm baby is likely to be premature and consequently faces increased risk of morbidity and mortality. An estimated due date is given by Naegeles rule.
According to the WHO, a preterm birth is defined as "babies born alive before 37 weeks of pregnancy are completed." According to this classification, there are three sub-categories of preterm birth, based on gestational age: extremely preterm (fewer than 28 weeks), very preterm (28 to 32 weeks), moderate to late preterm (32 to 37 weeks). Various jurisdictions may use different classifications.
In classifying perinatal deaths, stillbirths and infant deaths
For most of the 20th Century, official definitions of a live birth and infant death in the Soviet Union and Russia differed from common international standards, such as those established by the World Health Organization in the latter part of the century. Babies who were fewer than 28 weeks of gestational age, or weighed fewer than 1000 grams, or fewer than 35 cm in length – even if they showed some sign of life (breathing, heartbeat, voluntary muscle movement) – were classified as "live fetuses" rather than "live births." Only if such newborns survived seven days (168 hours) were they then classified as live births. If, however, they died within that interval, they were classified as stillbirths. If they survived that interval but died within the first 365 days they were classified as infant deaths.
More recently, thresholds for "fetal death" continue to vary widely internationally, sometimes incorporating weight as well as gestational age. The gestational age for statistical recording of fetal deaths ranges from 16 weeks in Norway, to 20 weeks in the US and Australia, 24 weeks in the UK, and 26 weeks in Italy and Spain.The WHO defines the perinatal period as "The perinatal period commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth." Perinatal mortality is the death of fetuses or neonates during the perinatal period. A 2013 study found that "While only a small proportion of births occur before 24 completed weeks of gestation (about 1 per 1000), survival is rare and most of them are either fetal deaths or live births followed by a neonatal death."
Postnatal use
Gestational age (as well as fertilization age) is sometimes used postnatally (after birth) to estimate various risk factors. For example, it is a better predictor than postnatal age for risk of intraventricular hemorrhage in premature babies treated with extracorporeal membrane oxygenation.
Factors affecting pregnancy length
Childs gestational age at birth (pregnancy length) is associated with various likely causal maternal non-genetic factors: stress during pregnancy, age, parity, smoking, infection and inflammation, BMI. Also, preexisting maternal medical conditions with genetic component, e.g., diabetes mellitus type 1, systemic lupus erythematosus, anaemia. Parental ancestral background (race) also plays a role in pregnancy duration. Gestational age at birth is on average shortened by various pregnancy aspects: twin pregnancy, prelabor rupture of (fetal) membranes, pre-eclampsia, eclampsia, intrauterine growth restriction. The ratio between fetal growth rate and uterine size (reflecting uterine distension) is suspected to partially determine the pregnancy length.
Heritability of pregnancy length
Family-based studies showed that gestational age at birth is partially (from 25% to 40%) determined by genetic factors.
See also
Pregnancy
Maternity
Prenatal development
Gestation periods in mammals
Abortion law
Reproductive rights
Fetal rights
== References == |
You act as a mediator between medical professionals and the public. Provide comprehensive explanations of medical terms, ensuring they are both precise and easily understood. | I'm seeking clarification on the medical term 'Argininosuccinic aciduria.' Could you explain it? | Argininosuccinic aciduria is an inherited disorder that causes the accumulation of argininosuccinic acid (also known as "ASA") in the blood and urine. Some patients may also have an elevation of ammonia, a toxic chemical, which can affect the nervous system. Argininosuccinic aciduria may become evident in the first few days of life because of high blood ammonia, or later in life presenting with "sparse" or "brittle" hair, developmental delay, and tremors.
An infant with argininosuccinic aciduria may seem lethargic or be unwilling to eat, have poorly controlled breathing rate or body temperature, experience seizures or unusual body movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen. Immediate treatment and lifelong management (following a strict diet and using appropriate supplements) may prevent many of these complications.
Occasionally, an individual may inherit a mild form of the disorder in which ammonia accumulates in the bloodstream only during periods of illness or other stress.
Genetics
Mutations in the ASL gene cause argininosuccinic aciduria. Argininosuccinic aciduria belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions in the cells of the liver. It processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys.In argininosuccinic aciduria, the enzyme argininosuccinate lyase, involved in the conversion of arginino succinate to arginine within the urea cycle, is damaged or missing. The urea cycle cannot proceed normally, and nitrogen accumulates in the bloodstream in the form of ammonia. Ammonia is especially damaging to the nervous system, so argininosuccinic aciduria causes neurological problems as well as eventual damage to the liver.This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.
Diagnosis
Diagnosis is based mainly on clinical findings and laboratory test results. Plasma concentrations of ammonia (>150 μmol/L) and citrulline (200-300 μmol/L) are elevated. Elevated levels of argininosuccinic acid (5-110 μmol/L) in the plasma or urine are diagnostic. Molecular genetic testing confirms diagnosis. Newborn screening for ASA is available in the U.S. and parts of Australia, and is considered in several European countries
Treatment
During an acute hyperammonemic episode, oral proteins must be avoided and intravenous (I.V.) lipids, glucose and insulin (if needed) should be given to promote anabolism. I.V. nitrogen scavenging therapy (with sodium benzoate and/or sodium phenylacetate) should normalize ammonia levels, but if unsuccessful, hemodialysis is recommended. Long-term management involves dietary protein restriction as well as arginine supplementation. In those with frequent episodes of metabolic decompensation or with hyperammonemia even when following a protein-restricted diet, daily oral nitrogen scavenging therapy may be successful. Orthotopic liver transplantation offers long-term relief of hyperammonemia but does not seem to sufficiently correct neurological complications. Arterial hypertension can be treated by restoring nitric oxide deficiency
Prognosis
Due to the rarity of the disease, it is hard to estimate mortality rates or life expectancy. One 2003 study which followed 88 cases receiving two different kinds of treatment found that very few persons lived beyond age 20 and none beyond age 30.
Incidence
Argininosuccinic aciduria occurs in approximately 1 in 70,000 live births. Many patients can now be detected on the newborn screen if their blood citrulline is elevated.
References
Literature
Kleijer WJ, Garritsen VH, Linnebank M, Mooyer P, Huijmans JG, Mustonen A, Simola KO, Arslan-Kirchner M, Battini R, Briones P, Cardo E, Mandel H, Tschiedel E, Wanders RJ, Koch HG (2002). "Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families". J Inherit Metab Dis. 25 (5): 399–410. doi:10.1023/A:1020108002877. PMID 12408190. S2CID 11129281.
Lee B, Goss J (2001). "Long-term correction of urea cycle disorders". J Pediatr. 138 (1 Suppl): S62–71. doi:10.1067/mpd.2001.111838. PMID 11148551.
Reid Sutton V, Pan Y, Davis EC, Craigen WJ (2003). "A mouse model of argininosuccinic aciduria: biochemical characterization". Mol Genet Metab. 78 (1): 11–6. doi:10.1016/S1096-7192(02)00206-8. PMID 12559843.
Scaglia F, Brunetti-Pierri N, Kleppe S, Marini J, Carter S, Garlick P, Jahoor F, OBrien W, Lee B (2004). "Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism". J Nutr. 134 (10 Suppl): 2775S–2782S, discussion 2796S–2797S. doi:10.1093/jn/134.10.2775S. PMID 15465784. Full text
Stadler S, Gempel K, Bieger I, Pontz BF, Gerbitz KD, Bauer MF, Hofmann S (2001). "Detection of neonatal argininosuccinate lyase deficiency by serum tandem mass spectrometry". J Inherit Metab Dis. 24 (3): 370–8. doi:10.1023/A:1010560704092. PMID 11486903. S2CID 11543156.
Wilcken B, Smith A, Brown DA (1980). "Urine screening for aminoacidopathies: is it beneficial? Results of a long-term follow-up of cases detected bny screening one million babies". J Pediatr. 97 (3): 492–7. doi:10.1016/S0022-3476(80)80216-2. PMID 7411317.
External links
ucd-overview at NIH/UW GeneTests |
You are a guide to medical language. Please provide in-depth and understandable explanations of medical terms, highlighting their significance in healthcare. | I'm trying to expand my medical knowledge. Can you elucidate the term 'Fungemia'? | Fungemia is the presence of fungi or yeasts in the blood. The most common type, also known as candidemia, candedemia, or systemic candidiasis, is caused by Candida species; candidemia is also among the most common bloodstream infections of any kind. Infections by other fungi, including Saccharomyces, Aspergillus and Cryptococcus, are also called fungemia. It is most commonly seen in immunosuppressed or immunocompromised patients with severe neutropenia, cancer patients, or in patients with intravenous catheters. It has been suggested the otherwise immunocompetent patients taking infliximab may be at a higher risk for fungemia.
Diagnosis is difficult, as routine blood cultures have poor sensitivity.
Signs and symptoms
Symptoms can range from mild to extreme—often described as extreme flu-like symptoms. Many symptoms may be associated with fungemia, including pain, acute confusion, chronic fatigue, and infections. Skin infections can include persistent or non-healing wounds and lesions, sweating, itching, and unusual discharge or drainage.
Risk factors
Pathogens
The most commonly known pathogen is Candida albicans, causing roughly 70% of fungemias, followed by Candida glabrata with 10%, Aspergillus with 1% and Saccharomyces as the fourth most common. However, the frequency of infection by C. glabrata, Saccharomyces boulardii, Candida tropicalis, C. krusei and C. parapsilosis is increasing, perhaps because significant use of fluconazole is common or due to increase in antibiotic use.Candida auris is an emerging multidrug-resistant (MDR) yeast that can cause invasive infections and is associated with high mortality. It was first described in 2009 after being isolated from external ear discharge of a patient in Japan. Since the 2009 report, C. auris infections, specifically fungemia, have been reported from South Korea, India, South Africa, and Kuwait. Although published reports are not available, C. auris has also been identified in Colombia, Venezuela, Pakistan, and the United Kingdom.In a single reported instance, Psilocybe cubensis was reported to have been cultured from a case of fungemia in which an individual self-injected an underprocessed decoction of fungal matter. The patient, who had been suffering from mild depression, attempted to self-medicate with the mushrooms but was frustrated by the lag time between eating the mushrooms and experiencing the psychedelic effects. In an attempt to bypass this, the patient boiled and filtered the mushrooms into a mushroom tea which was then administered by injection. The patient had multiple organ failure, but this was successfully reversed and the infection treated with antifungal drugs. Two other examples of fungemia as a result of injecting fungal matter in this way have been described in medical literature, both dating to 1985.
Diagnosis
The gold standard for the diagnosis of invasive candidiasis and candidemia is a positive culture. Blood cultures should be obtained in all patients with suspected candidemia.
Treatment
Neutropenic vs non-neutropenic candidemia is treated differently.An intravenous echinocandin such as anidulafungin, caspofungin or micafungin is recommended as first-line therapy for fungemia, specifically candidemia. Oral or intravenous fluconazole is an acceptable alternative. The lipid formulation amphotericin B is a reasonable alternative if there is limited antifungal availability, antifungal resistance, or antifungal intolerance.
See also
Bacteremia
Candidiasis
Fungicide
Mycosis
References
== External links == |
You function as a medical explainer. Your task is to convey the meanings of medical terms in a detailed, yet easy-to-understand manner. | I need a basic explanation for the medical term 'Zinc gluconate.' | Zinc gluconate is the zinc salt of gluconic acid. It is an ionic compound consisting of two anions of gluconate for each zinc(II) cation. Zinc gluconate is a popular form for the delivery of zinc as a dietary supplement providing 14.35% elemental zinc by weight.
Gluconic acid is found naturally, and is industrially made by the fermentation of glucose, typically by Aspergillus niger, but also by other fungi, e.g. Penicillium, or by bacteria, e.g. Acetobacter, Pseudomonas and Gluconobacter. In its pure form, it is a white to off-white powder. It can also be made by electrolytic oxidation, although this is a more expensive process. The advantages are a lower microbiological profile, and a more complete reaction, yielding a product with a longer shelf life.
Zinc gluconate and the common cold
Zinc gluconate has been used in lozenges for treating the common cold. However, controlled trials with lozenges which include zinc acetate have found it has the greatest effect on the duration of colds. Zinc has also been administered nasally for treating the common cold, but has been reported to cause anosmia in some cases.
Safety concerns
Instances of anosmia (loss of smell) have been reported with intranasal use of some products containing zinc gluconate. In September 2003, Zicam faced lawsuits from users who claimed that the product, a nasal gel containing zinc gluconate and several inactive ingredients, negatively affected their sense of smell and sometimes taste. Some plaintiffs alleged experiencing a strong and very painful burning sensation when they used the product. Matrixx Initiatives, Inc., the maker of Zicam, responded that only a small number of people had experienced problems and that anosmia can be caused by the common cold itself. In January 2006, 340 lawsuits were settled for $12 million.The U.S. Food and Drug Administration (FDA) considers zinc gluconate to be generally recognized as safe (GRAS) when used in accordance with good manufacturing practice, although this does not constitute a finding by the FDA that the substance is a useful dietary supplement. On 16 June 2009 the FDA "warned consumers to stop using and discard three zinc-containing Zicam intranasal products. The products may cause a loss of sense of smell. ... FDA is concerned that the loss of sense of smell may be permanent." Matrixx responded that the FDAs allegations were "unfounded and misleading", citing a lack of evidence from controlled tests that Zicam causes anosmia. In its warning, the FDA stated, "This warning does not involve oral zinc tablets and lozenges taken by mouth. Dietary zinc is also not subject to this warning."
Veterinary use
A zinc gluconate-based product, also containing arginine, is used as a veterinary chemical castration drug. For dogs, the product is injected directly into the testicles. It has been sold under various brand names, including Neutersol and Esterilsol.
References
External links
A12CB02 (WHO) |
You act as a mediator between medical professionals and the public. Provide comprehensive explanations of medical terms, ensuring they are both precise and easily understood. | What is the significance of the term 'Edwards syndrome' in the medical field? | Edwards syndrome, also known as trisomy 18, is a genetic disorder caused by the presence of a third copy of all or part of chromosome 18. Many parts of the body are affected. Babies are often born small and have heart defects. Other features include a small head, small jaw, clenched fists with overlapping fingers, and severe intellectual disability.Most cases of Edwards syndrome occur due to problems during the formation of the reproductive cells or during early development. The rate of disease increases with the mothers age. Rarely, cases may be inherited from a persons parents. Occasionally, not all cells have the extra chromosome, known as mosaic trisomy, and symptoms in these cases may be less severe. An ultrasound during pregnancy can increase suspicion for the condition, which can be confirmed by amniocentesis.Treatment is supportive. After having one child with the condition, the risk of having a second is typically around one percent. It is the second-most common condition due to a third chromosome at birth, after Down syndrome.Edwards syndrome occurs in around 1 in 5,000 live births. Many of those affected die before birth. Some studies suggest that more babies that survive to birth are female. Survival beyond a year of life is around 5–10%. It is named after English geneticist John Hilton Edwards, who first described the syndrome in 1960.
Signs and symptoms
Children born with Edwards syndrome may have some or all of these characteristics: kidney malformations, structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus), intestines protruding outside the body (omphalocele), esophageal atresia, intellectual disability, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, and arthrogryposis (a muscle disorder that causes multiple joint contractures at birth).Some physical malformations associated with Edwards syndrome include small head (microcephaly) accompanied by a prominent back portion of the head (occiput), low-set, malformed ears, abnormally small jaw (micrognathia), cleft lip/cleft palate, upturned nose, narrow eyelid openings (blepharophimosis), widely spaced eyes (ocular hypertelorism), drooping of the upper eyelids (ptosis), a short breast bone, clenched hands, choroid plexus cysts, underdeveloped thumbs and/or nails, absent radius, webbing of the second and third toes, clubfoot or rocker bottom feet, and in males, undescended testicles.In utero, the most common characteristic is cardiac anomalies, followed by central nervous system anomalies such as head shape abnormalities. The most common intracranial anomaly is the presence of choroid plexus cysts, which are pockets of fluid on the brain. These are not problematic in themselves, but their presence may be a marker for trisomy 18. Sometimes, excess amniotic fluid or polyhydramnios is exhibited. Although uncommon in the syndrome, Edwards syndrome causes a large portion of prenatally diagnosed cases of Dandy–Walker malformation.
Genetics
Edwards syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 18th chromosome, either in whole (trisomy 18) or in part (such as due to translocations). The additional chromosome usually occurs before conception. The effects of the extra copy vary greatly, depending on the extent of the extra copy, genetic history, and chance. Edwards syndrome occurs in all human populations, but is more prevalent in female offspring.A healthy egg and/or sperm cell contains individual chromosomes, each of which contributes to the 23 pairs of chromosomes needed to form a normal cell with a typical human karyotype of 46 chromosomes. Numerical errors can arise at either of the two meiotic divisions and cause the failure of a chromosome to segregate into the daughter cells (nondisjunction). This results in an extra chromosome, making the haploid number 24 rather than 23. Fertilization of eggs or insemination by sperm that contain an extra chromosome results in trisomy, or three copies of a chromosome rather than two.Trisomy 18 (47,XX,+18) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 18; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo has 47 chromosomes, with three copies of chromosome 18.A small percentage of cases occur when only some of the bodys cells have an extra copy of chromosome 18, resulting in a mixed population of cells with a differing number of chromosomes. Such cases are sometimes called mosaic Edwards syndrome. Very rarely, a piece of chromosome 18 becomes attached to another chromosome (translocated) before or after conception. Affected individuals have two copies of chromosome 18 plus extra material from chromosome 18 attached to another chromosome. With a translocation, a person has a partial trisomy for chromosome 18, and the abnormalities are often less severe than for the typical Edwards syndrome.
Diagnosis
Ultrasound can increase suspicion for the condition, which can be confirmed by CVS or amniocentesis.Levels of PAPP-A, AFP, uE3, free β-hCG, all of which are generally decreased during pregnancy.
Prognosis
About 95% of pregnancies that are affected do not result in a live birth. Major causes of death include apnea and heart abnormalities. It is impossible to predict an exact prognosis during pregnancy or the neonatal period. Half of the live infants do not survive beyond the first week of life. The median lifespan is five to 15 days. About 8–12% of infants survive longer than 1 year. One percent of children live to age 10. However, these estimates may be pessimistic; a retrospective Canadian study of 254 children with trisomy 18 demonstrated ten-year survival of 9.8%, and another found that 68.6% of children with surgical intervention survived infancy.
Epidemiology
Edwards syndrome occurs in about one in 5,000 live births, but more conceptions are affected by the syndrome because the majority of those diagnosed with the condition prenatally will not survive to birth. Although women in their 20s and early 30s may conceive babies with Edwards syndrome, the risk of conceiving a child with it increases with a womans age. The average maternal age for conceiving a child with this disorder is 32+1⁄2.
History
Edwards syndrome was first identified by John Hilton Edwards in 1960, although he originally believed it to be caused by a trisomy of chromosome 17. Klaus Patau and Eeva Therman reported another two cases shortly thereafter. They identified the extra chromosome as being part of what Pataus lab called "group E", containing chromosomes 16, 17, and 18, but were unable to determine which chromosome was responsible at the time. Analyzing 5 more cases, they were able to determine that the extra chromosome was in fact chromosome 18.
See also
18q deletion syndrome
References
External links
Edwards syndrome at Curlie
Perinatal Hospice Care - Preparing for birth and death"
Humpath #5389 |
You are a resource for medical understanding. Offer detailed explanations of medical terms, making complex concepts clear and comprehensible. | I'm encountering the term 'Moxetumomab pasudotox' in medical literature. What's its definition? | Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti-CD22 immunotoxin medication for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Moxetumomab pasudotox is a CD22-directed cytotoxin and is the first of this type of treatment for adults with HCL. The drug consists of the binding fragment (Fv) of an anti-CD22 antibody fused to a toxin called PE38. This toxin is a 38 kDa fragment of Pseudomonas exotoxin A.
Hairy cell leukemia (HCL) is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.
Medical uses
Moxetumomab pasudotox as monotherapy is indicated for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) after receiving at least two prior systemic therapies, including treatment with a purine nucleoside analogue (PNA).
Adverse effects
Common side effects include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.The prescribing information for moxetumomab pasudotox includes a boxed warning about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The boxed warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells.Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities.Women who are breastfeeding should not be given moxetumomab pasudotox.
Discovery and ownership background
On 1 November 2005, Cambridge Antibody Technology (CAT) announced it was acquiring two anti-CD22 immunotoxin products from Genencor, namely GCR-3888 and GCR-8015. Genencor is the biotechnology division of Danisco and the acquisition meant CAT would hire certain former Genencor key employees to be responsible for the development of the programmes.GCR-3888 and GCR-8015 were discovered and initially developed by the National Cancer Institute, which is part of the U.S. National Institutes of Health. Genencor licensed the candidates for hematological malignancies and entered into a Cooperative Research and Development Agreement (CRADA) with the NIH, which will now be continued by CAT. Under the original
license agreement with the NIH, CAT gained the rights to a portfolio of intellectual property associated with the programs and would pay future royalties to the NIH.
CAT intended to file an Investigational New Drug (IND) application for GCR-8015 in various CD22 positive B-cell malignancies, including Non-Hodgkin lymphoma and chronic lymphocytic leukemia, following a period of manufacturing development which is expected to be complete by the end of 2006 and to support the NCIs ongoing development of GCR-3888 in Hairy cell leukemia (HCL) and pediatric acute lymphoblastic leukemia (pALL).CAT-8015 exhibited a greater affinity for CD22 than its predecessor, CAT-3888 and CATs language such as "CAT will support the NCIs ongoing development of CAT-3888..." suggested at the time that their focus was on the second generation candidate.CAT was acquired by AstraZeneca, who also acquired MedImmune, combining the two into a biologics division. MedImmune renamed CAT-8015 to moxetumomab pasudotox.On 16 May 2013, AstraZeneca announced that CAT-8015 had started Phase III clinical trials.
History
On 5 December 2008, orphan designation (EU/3/08/592) was granted by the European Commission to Medimmune Limited, United Kingdom, for murine anti-CD22 antibody variable region fused to truncated Pseudomonas exotoxin 38 for the treatment of hairy cell leukaemia. It was renamed to Moxetumomab pasudotox. The sponsorship was transferred to AstraZeneca AB, Sweden, in January 2019.On 17 July 2013, orphan designation (EU/3/13/1150) was granted by the European Commission to MedImmune Ltd, United Kingdom, for moxetumomab pasudotox for the treatment of B-lymphoblastic leukaemia / lymphoma. The sponsorship was transferred to AstraZeneca AB, Sweden, in January 2019.Moxetumomab pasudotox was approved for use in the United States in September 2018.The efficacy of moxetumomab pasudotox was studied in a single-arm, open-label clinical trial of 80 subjects who had received prior treatment for hairy cell leukemia with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of subjects in the trial achieved durable CR, and the overall response rate (number of subjects with partial or complete response to therapy) was 75 percent.The US Food and Drug Administration (FDA) granted the application for moxetumomab pasudotox fast track, priority review, and orphan drug designations. The FDA granted the approval of a Biologics License Application for Lumoxiti to AstraZeneca Pharmaceuticals. This was subsequently transferred to Innate Pharma in March 2020.On 10 December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Lumoxiti, intended for the treatment of relapsed or refractory hairy cell leukemia after two prior systemic therapies including a purine nucleoside analog. The orphan designation for Lumoxiti for treatment of hairy cell leukaemia was also maintained. The applicant for this medicinal product is AstraZeneca AB. Moxetumomab pasudotox was approved for medical use in the European Union in February 2021. The EU marketing authorization was withdrawn in July 2021.
References
External links
"Moxetumomab pasudotox". Drug Information Portal. U.S. National Library of Medicine.
"Moxetumomab Pasudotox-tdfk". National Cancer Institute. 24 October 2018.
"Moxetumomab Pasudotox-tdfk". NCI Drug Dictionary. National Cancer Institute. |
You act as a bridge between medical jargon and everyday language. Explain medical terms in a manner that is comprehensive yet approachable for non-experts. | Could you please explain the term 'Diabetes' in simple language? | Diabetes mellitus, commonly known as diabetes, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased appetite. If left untreated, diabetes can cause many health complications. Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes and cognitive impairment.Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body not responding properly to the insulin produced. Insulin is a hormone which is responsible for helping glucose from food get into cells to be used for energy. There are three main types of diabetes mellitus:
Type 1 diabetes results from failure of the pancreas to produce enough insulin due to loss of beta cells. This form was previously referred to as "insulin-dependent diabetes mellitus" or "juvenile diabetes". The loss of beta cells is caused by an autoimmune response. The cause of this autoimmune response is unknown. Although Type 1 diabetes usually appears during childhood or adolescence, it can also develop in adults.
Type 2 diabetes begins with insulin resistance, a condition in which cells fail to respond to insulin properly. As the disease progresses, a lack of insulin may also develop. This form was previously referred to as "non insulin-dependent diabetes mellitus" or "adult-onset diabetes". Type 2 diabetes is more common in older adults, but a significant increase in the prevalence of obesity among children has led to more cases of type 2 diabetes in younger people. The most common cause is a combination of excessive body weight and insufficient exercise.
Gestational diabetes is the third main form, and occurs when pregnant women without a previous history of diabetes develop high blood sugar levels. In women with gestational diabetes, blood sugar usually returns to normal soon after delivery. However, women who had gestational diabetes during pregnancy have a higher risk of developing type 2 diabetes later in life.Type 1 diabetes must be managed with insulin injections. Prevention and treatment of type 2 diabetes involves maintaining a healthy diet, regular physical exercise, a normal body weight, and avoiding use of tobacco. Type 2 diabetes may be treated with oral antidiabetic medications, with or without insulin. Control of blood pressure and maintaining proper foot and eye care are important for people with the disease. Insulin and some oral medications can cause low blood sugar (hypoglycemia). Weight loss surgery in those with obesity is sometimes an effective measure in those with type 2 diabetes. Gestational diabetes usually resolves after the birth of the baby.As of 2019, an estimated 463 million people had diabetes worldwide (8.8% of the adult population), with type 2 diabetes making up about 90% of the cases. Rates are similar in women and men. Trends suggest that rates will continue to rise. Diabetes at least doubles a persons risk of early death. In 2019, diabetes resulted in approximately 4.2 million deaths. It is the 7th leading cause of death globally. The global economic cost of diabetes-related health expenditure in 2017 was estimated at US$727 billion. In the United States, diabetes cost nearly US$327 billion in 2017. Average medical expenditures among people with diabetes are about 2.3 times higher.
Signs and symptoms
The classic symptoms of untreated diabetes are unintended weight loss, polyuria (increased urination), polydipsia (increased thirst), and polyphagia (increased hunger). Symptoms may develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in type 2 diabetes.Several other signs and symptoms can mark the onset of diabetes although they are not specific to the disease. In addition to the known symptoms listed above, they include blurred vision, headache, fatigue, slow healing of cuts, and itchy skin. Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Long-term vision loss can also be caused by diabetic retinopathy. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.
Diabetic emergencies
People with diabetes (usually but not exclusively in type 1 diabetes) may also experience diabetic ketoacidosis (DKA), a metabolic disturbance characterized by nausea, vomiting and abdominal pain, the smell of acetone on the breath, deep breathing known as Kussmaul breathing, and in severe cases a decreased level of consciousness. DKA requires emergency treatment in hospital. A rarer but more dangerous condition is hyperosmolar hyperglycemic state (HHS), which is more common in type 2 diabetes and is mainly the result of dehydration caused by high blood sugars.Treatment-related low blood sugar (hypoglycemia) is common in people with type 1 and also type 2 diabetes depending on the medication being used. Most cases are mild and are not considered medical emergencies. Effects can range from feelings of unease, sweating, trembling, and increased appetite in mild cases to more serious effects such as confusion, changes in behavior such as aggressiveness, seizures, unconsciousness, and rarely permanent brain damage or death in severe cases. Rapid breathing, sweating, and cold, pale skin are characteristic of low blood sugar but not definitive. Mild to moderate cases are self-treated by eating or drinking something high in rapidly absorbed carbohydrates. Severe cases can lead to unconsciousness and must be treated with intravenous glucose or injections with glucagon.
Complications
All forms of diabetes increase the risk of long-term complications. These typically develop after many years (10–20) but may be the first symptom in those who have otherwise not received a diagnosis before that time.The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease and about 75% of deaths in people with diabetes are due to coronary artery disease. Other macrovascular diseases include stroke, and peripheral artery disease. These complications are also a strong risk factor for severe COVID-19 illness.The primary complications of diabetes due to damage in small blood vessels include damage to the eyes, kidneys, and nerves. Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood vessels in the retina of the eye, and can result in gradual vision loss and eventual blindness. Diabetes also increases the risk of having glaucoma, cataracts, and other eye problems. It is recommended that people with diabetes visit an eye doctor once a year. Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplantation. Damage to the nerves of the body, known as diabetic neuropathy, is the most common complication of diabetes. The symptoms can include numbness, tingling, sudomotor dysfunction, pain, and altered pain sensation, which can lead to damage to the skin. Diabetes-related foot problems (such as diabetic foot ulcers) may occur, and can be difficult to treat, occasionally requiring amputation. Additionally, proximal diabetic neuropathy causes painful muscle atrophy and weakness.
There is a link between cognitive deficit and diabetes. Compared to those without diabetes, those with the disease have a 1.2 to 1.5-fold greater rate of decline in cognitive function. Having diabetes, especially when on insulin, increases the risk of falls in older people.
Causes
Diabetes mellitus is classified into six categories: type 1 diabetes, type 2 diabetes, hybrid forms of diabetes, hyperglycemia first detected during pregnancy, "unclassified diabetes", and "other specific types". "Hybrid forms of diabetes" include slowly evolving, immune-mediated diabetes of adults and ketosis-prone type 2 diabetes. "Hyperglycemia first detected during pregnancy" includes gestational diabetes mellitus and diabetes mellitus in pregnancy (type 1 or type 2 diabetes first diagnosed during pregnancy). The "other specific types" are a collection of a few dozen individual causes. Diabetes is a more variable disease than once thought and people may have combinations of forms.
Type 1
Type 1 diabetes is characterized by loss of the insulin-producing beta cells of the pancreatic islets, leading to insulin deficiency. This type can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of an immune-mediated nature, in which a T cell-mediated autoimmune attack leads to the loss of beta cells and thus insulin. It causes approximately 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Although it has been called "juvenile diabetes" due to the frequent onset in children, the majority of individuals living with type 1 diabetes are now adults."Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally used to describe the dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be used. Still, type 1 diabetes can be accompanied by irregular and unpredictable high blood sugar levels, and the potential for diabetic ketoacidosis or serious low blood sugar levels. Other complications include an impaired counterregulatory response to low blood sugar, infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (e.g., Addisons disease). These phenomena are believed to occur no more frequently than in 1% to 2% of persons with type 1 diabetes.
Type 1 diabetes is partly inherited, with multiple genes, including certain HLA genotypes, known to influence the risk of diabetes. In genetically susceptible people, the onset of diabetes can be triggered by one or more environmental factors, such as a viral infection or diet. Several viruses have been implicated, but to date there is no stringent evidence to support this hypothesis in humans. Among dietary factors, data suggest that gliadin (a protein present in gluten) may play a role in the development of type 1 diabetes, but the mechanism is not fully understood.Type 1 diabetes can occur at any age, and a significant proportion is diagnosed during adulthood. Latent autoimmune diabetes of adults (LADA) is the diagnostic term applied when type 1 diabetes develops in adults; it has a slower onset than the same condition in children. Given this difference, some use the unofficial term "type 1.5 diabetes" for this condition. Adults with LADA are frequently initially misdiagnosed as having type 2 diabetes, based on age rather than a cause.
Type 2
Type 2 diabetes is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion. The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor. However, the specific defects are not known. Diabetes mellitus cases due to a known defect are classified separately. Type 2 diabetes is the most common type of diabetes mellitus. Many people with type 2 diabetes have evidence of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) before meeting the criteria for type 2 diabetes. The progression of prediabetes to overt type 2 diabetes can be slowed or reversed by lifestyle changes or medications that improve insulin sensitivity or reduce the livers glucose production.Type 2 diabetes is primarily due to lifestyle factors and genetics. A number of lifestyle factors are known to be important to the development of type 2 diabetes, including obesity (defined by a body mass index of greater than 30), lack of physical activity, poor diet, stress, and urbanization. Excess body fat is associated with 30% of cases in people of Chinese and Japanese descent, 60–80% of cases in those of European and African descent, and 100% of Pima Indians and Pacific Islanders. Even those who are not obese may have a high waist–hip ratio.Dietary factors such as sugar-sweetened drinks are associated with an increased risk. The type of fats in the diet is also important, with saturated fat and trans fats increasing the risk and polyunsaturated and monounsaturated fat decreasing the risk. Eating white rice excessively may increase the risk of diabetes, especially in Chinese and Japanese people. Lack of physical activity may increase the risk of diabetes in some people.Adverse childhood experiences, including abuse, neglect, and household difficulties, increase the likelihood of type 2 diabetes later in life by 32%, with neglect having the strongest effect.Antipsychotic medication side effects (specifically metabolic abnormalities, dyslipidemia and weight gain) and unhealthy lifestyles (including poor diet and decreased physical activity), are potential risk factors.
Gestational diabetes
Gestational diabetes resembles type 2 diabetes in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness. It occurs in about 2–10% of all pregnancies and may improve or disappear after delivery. It is recommended that all pregnant women get tested starting around 24–28 weeks gestation. It is most often diagnosed in the second or third trimester because of the increase in insulin-antagonist hormone levels that occurs at this time. However, after pregnancy approximately 5–10% of women with gestational diabetes are found to have another form of diabetes, most commonly type 2. Gestational diabetes is fully treatable, but requires careful medical supervision throughout the pregnancy. Management may include dietary changes, blood glucose monitoring, and in some cases, insulin may be required.Though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to the baby include macrosomia (high birth weight), congenital heart and central nervous system abnormalities, and skeletal muscle malformations. Increased levels of insulin in a fetuss blood may inhibit fetal surfactant production and cause infant respiratory distress syndrome. A high blood bilirubin level may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as a result of poor placental perfusion due to vascular impairment. Labor induction may be indicated with decreased placental function. A caesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.
Other types
Maturity onset diabetes of the young (MODY) is a rare autosomal dominant inherited form of diabetes, due to one of several single-gene mutations causing defects in insulin production. It is significantly less common than the three main types, constituting 1–2% of all cases. The name of this disease refers to early hypotheses as to its nature. Being due to a defective gene, this disease varies in age at presentation and in severity according to the specific gene defect; thus, there are at least 13 subtypes of MODY. People with MODY often can control it without using insulin.Some cases of diabetes are caused by the bodys tissue receptors not responding to insulin (even when insulin levels are normal, which is what separates it from type 2 diabetes); this form is very uncommon. Genetic mutations (autosomal or mitochondrial) can lead to defects in beta cell function. Abnormal insulin action may also have been genetically determined in some cases. Any disease that causes extensive damage to the pancreas may lead to diabetes (for example, chronic pancreatitis and cystic fibrosis). Diseases associated with excessive secretion of insulin-antagonistic hormones can cause diabetes (which is typically resolved once the hormone excess is removed). Many drugs impair insulin secretion and some toxins damage pancreatic beta cells, whereas others increase insulin resistance (especially glucocorticoids which can provoke "steroid diabetes"). The ICD-10 (1992) diagnostic entity, malnutrition-related diabetes mellitus (ICD-10 code E12), was deprecated by the World Health Organization (WHO) when the current taxonomy was introduced in 1999.
Yet another form of diabetes that people may develop is double diabetes. This is when a type 1 diabetic becomes insulin resistant, the hallmark for type 2 diabetes or has a family history for type 2 diabetes. It was first discovered in 1990 or 1991.
The following is a list of disorders that may increase the risk of diabetes:
Pathophysiology
Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially liver, adipose tissue and muscle, except smooth muscle, in which insulin acts via the IGF-1. Therefore, deficiency of insulin or the insensitivity of its receptors play a central role in all forms of diabetes mellitus.The body obtains glucose from three main sources: the intestinal absorption of food; the breakdown of glycogen (glycogenolysis), the storage form of glucose found in the liver; and gluconeogenesis, the generation of glucose from non-carbohydrate substrates in the body. Insulin plays a critical role in regulating glucose levels in the body. Insulin can inhibit the breakdown of glycogen or the process of gluconeogenesis, it can stimulate the transport of glucose into fat and muscle cells, and it can stimulate the storage of glucose in the form of glycogen.Insulin is released into the blood by beta cells (β-cells), found in the islets of Langerhans in the pancreas, in response to rising levels of blood glucose, typically after eating. Insulin is used by about two-thirds of the bodys cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage. Lower glucose levels result in decreased insulin release from the beta cells and in the breakdown of glycogen to glucose. This process is mainly controlled by the hormone glucagon, which acts in the opposite manner to insulin.If the amount of insulin available is insufficient, or if cells respond poorly to the effects of insulin (insulin resistance), or if the insulin itself is defective, then glucose is not absorbed properly by the body cells that require it, and is not stored appropriately in the liver and muscles. The net effect is persistently high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as metabolic acidosis in cases of complete insulin deficiency.When glucose concentration in the blood remains high over time, the kidneys reach a threshold of reabsorption, and the body excretes glucose in the urine (glycosuria). This increases the osmotic pressure of the urine and inhibits reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume is replaced osmotically from water in body cells and other body compartments, causing dehydration and increased thirst (polydipsia). In addition, intracellular glucose deficiency stimulates appetite leading to excessive food intake (polyphagia).
Diagnosis
Diabetes mellitus is diagnosed with a test for the glucose content in the blood, and is diagnosed by demonstrating any one of the following:
Fasting plasma glucose level ≥ 7.0 mmol/L (126 mg/dL). For this test, blood is taken after a period of fasting, i.e. in the morning before breakfast, after the patient had sufficient time to fast overnight.
Plasma glucose ≥ 11.1 mmol/L (200 mg/dL) two hours after a 75 gram oral glucose load as in a glucose tolerance test (OGTT)
Symptoms of high blood sugar and plasma glucose ≥ 11.1 mmol/L (200 mg/dL) either while fasting or not fasting
Glycated hemoglobin (HbA1C) ≥ 48 mmol/mol (≥ 6.5 DCCT %).A positive result, in the absence of unequivocal high blood sugar, should be confirmed by a repeat of any of the above methods on a different day. It is preferable to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete and offers no prognostic advantage over the fasting test. According to the current definition, two fasting glucose measurements above 7.0 mmol/L (126 mg/dL) is considered diagnostic for diabetes mellitus.
Per the WHO, people with fasting glucose levels from 6.1 to 6.9 mmol/L (110 to 125 mg/dL) are considered to have impaired fasting glucose. People with plasma glucose at or above 7.8 mmol/L (140 mg/dL), but not over 11.1 mmol/L (200 mg/dL), two hours after a 75 gram oral glucose load are considered to have impaired glucose tolerance. Of these two prediabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus, as well as cardiovascular disease. The American Diabetes Association (ADA) since 2003 uses a slightly different range for impaired fasting glucose of 5.6 to 6.9 mmol/L (100 to 125 mg/dL).Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.
Prevention
There is no known preventive measure for type 1 diabetes. Type 2 diabetes—which accounts for 85–90% of all cases worldwide—can often be prevented or delayed by maintaining a normal body weight, engaging in physical activity, and eating a healthy diet. Higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%. Dietary changes known to be effective in helping to prevent diabetes include maintaining a diet rich in whole grains and fiber, and choosing good fats, such as the polyunsaturated fats found in nuts, vegetable oils, and fish. Limiting sugary beverages and eating less red meat and other sources of saturated fat can also help prevent diabetes. Tobacco smoking is also associated with an increased risk of diabetes and its complications, so smoking cessation can be an important preventive measure as well.The relationship between type 2 diabetes and the main modifiable risk factors (excess weight, unhealthy diet, physical inactivity and tobacco use) is similar in all regions of the world. There is growing evidence that the underlying determinants of diabetes are a reflection of the major forces driving social, economic and cultural change: globalization, urbanization, population aging, and the general health policy environment.
Management
Diabetes management concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with dietary changes, exercise, weight loss, and use of appropriate medications (insulin, oral medications).
Learning about the disease and actively participating in the treatment is important, since complications are far less common and less severe in people who have well-managed blood sugar levels. Per the American College of Physicians, the goal of treatment is an HbA1C level of 7-8%. Attention is also paid to other health problems that may accelerate the negative effects of diabetes. These include smoking, high blood pressure, metabolic syndrome obesity, and lack of regular exercise. Specialized footwear is widely used to reduce the risk of diabetic foot ulcers by relieving the pressure on the foot.The principles of managing diabetes may be similar across the general population with diabetes, however some considerations may need to be addressed when tailoring intervention, mainly in special populations.
Considering those with severe mental illness, the efficacy of type 2 diabetes self-management interventions is still poorly explored, with insufficient scientific evidence to show whether these interventions have similar results to those observed in general population.
Lifestyle
People with diabetes can benefit from education about the disease and treatment, dietary changes, and exercise, with the goal of keeping both short-term and long-term blood glucose levels within acceptable bounds. In addition, given the associated higher risks of cardiovascular disease, lifestyle modifications are recommended to control blood pressure.Weight loss can prevent progression from prediabetes to diabetes type 2, decrease the risk of cardiovascular disease, or result in a partial remission in people with diabetes. No single dietary pattern is best for all people with diabetes. Healthy dietary patterns, such as the Mediterranean diet, low-carbohydrate diet, or DASH diet, are often recommended, although evidence does not support one over the others. According to the ADA, "reducing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia", and for individuals with type 2 diabetes who cannot meet the glycemic targets or where reducing anti-glycemic medications is a priority, low or very-low carbohydrate diets are a viable approach. For overweight people with type 2 diabetes, any diet that achieves weight loss is effective.
Medications
Glucose control
Most medications used to treat diabetes act by lowering blood sugar levels through different mechanisms. There is broad consensus that when people with diabetes maintain tight glucose control – keeping the glucose levels in their blood within normal ranges – they experience fewer complications, such as kidney problems or eye problems. There is however debate as to whether this is appropriate and cost effective for people later in life in whom the risk of hypoglycemia may be more significant.There are a number of different classes of anti-diabetic medications. Type 1 diabetes requires treatment with insulin, ideally using a "basal bolus" regimen that most closely matches normal insulin release: long-acting insulin for the basal rate and short-acting insulin with meals. Type 2 diabetes is generally treated with medication that is taken by mouth (e.g. metformin) although some eventually require injectable treatment with insulin or GLP-1 agonists.Metformin is generally recommended as a first-line treatment for type 2 diabetes, as there is good evidence that it decreases mortality. It works by decreasing the livers production of glucose. Several other groups of drugs, mostly given by mouth, may also decrease blood sugar in type 2 diabetes. These include agents that increase insulin release (sulfonylureas), agents that decrease absorption of sugar from the intestines (acarbose), agents that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4) that inactivates incretins such as GLP-1 and GIP (sitagliptin), agents that make the body more sensitive to insulin (thiazolidinedione) and agents that increase the excretion of glucose in the urine (SGLT2 inhibitors). When insulin is used in type 2 diabetes, a long-acting formulation is usually added initially, while continuing oral medications. Doses of insulin are then increased until glucose targets are reached.
Blood pressure lowering
Cardiovascular disease is a serious complication associated with diabetes, and many international guidelines recommend blood pressure treatment targets that are lower than 140/90 mmHg for people with diabetes. However, there is only limited evidence regarding what the lower targets should be. A 2016 systematic review found potential harm to treating to targets lower than 140 mmHg, and a subsequent systematic review in 2019 found no evidence of additional benefit from blood pressure lowering to between 130 – 140mmHg, although there was an increased risk of adverse events.2015 American Diabetes Association recommendations are that people with diabetes and albuminuria should receive an inhibitor of the renin-angiotensin system to reduce the risks of progression to end-stage renal disease, cardiovascular events, and death. There is some evidence that angiotensin converting enzyme inhibitors (ACEIs) are superior to other inhibitors of the renin-angiotensin system such as angiotensin receptor blockers (ARBs), or aliskiren in preventing cardiovascular disease. Although a more recent review found similar effects of ACEIs and ARBs on major cardiovascular and renal outcomes. There is no evidence that combining ACEIs and ARBs provides additional benefits.
Aspirin
The use of aspirin to prevent cardiovascular disease in diabetes is controversial. Aspirin is recommended by some in people at high risk of cardiovascular disease, however routine use of aspirin has not been found to improve outcomes in uncomplicated diabetes. 2015 American Diabetes Association recommendations for aspirin use (based on expert consensus or clinical experience) are that low-dose aspirin use is reasonable in adults with diabetes who are at intermediate risk of cardiovascular disease (10-year cardiovascular disease risk, 5–10%). National guidelines for England and Wales by the National Institute for Health and Care Excellence (NICE) recommend against the use of aspirin in people with type 1 or type 2 diabetes who do not have confirmed cardiovascular disease.
Surgery
Weight loss surgery in those with obesity and type 2 diabetes is often an effective measure. Many are able to maintain normal blood sugar levels with little or no medications following surgery and long-term mortality is decreased. There is, however, a short-term mortality risk of less than 1% from the surgery. The body mass index cutoffs for when surgery is appropriate are not yet clear. It is recommended that this option be considered in those who are unable to get both their weight and blood sugar under control.A pancreas transplant is occasionally considered for people with type 1 diabetes who have severe complications of their disease, including end stage kidney disease requiring kidney transplantation.
Self-management and support
In countries using a general practitioner system, such as the United Kingdom, care may take place mainly outside hospitals, with hospital-based specialist care used only in case of complications, difficult blood sugar control, or research projects. In other circumstances, general practitioners and specialists share care in a team approach. Home telehealth support can be an effective management technique.The use of technology to deliver educational programs for adults with type 2 diabetes includes computer-based self-management interventions to collect for tailored responses to facilitate self-management. There is no adequate evidence to support effects on cholesterol, blood pressure, behavioral change (such as physical activity levels and dietary), depression, weight and health-related quality of life, nor in other biological, cognitive or emotional outcomes.
Epidemiology
In 2017, 425 million people had diabetes worldwide, up from an estimated 382 million people in 2013 and from 108 million in 1980. Accounting for the shifting age structure of the global population, the prevalence of diabetes is 8.8% among adults, nearly double the rate of 4.7% in 1980. Type 2 makes up about 90% of the cases. Some data indicate rates are roughly equal in women and men, but male excess in diabetes has been found in many populations with higher type 2 incidence, possibly due to sex-related differences in insulin sensitivity, consequences of obesity and regional body fat deposition, and other contributing factors such as high blood pressure, tobacco smoking, and alcohol intake.The WHO estimates that diabetes resulted in 1.5 million deaths in 2012, making it the 8th leading cause of death. However another 2.2 million deaths worldwide were attributable to high blood glucose and the increased risks of cardiovascular disease and other associated complications (e.g. kidney failure), which often lead to premature death and are often listed as the underlying cause on death certificates rather than diabetes. For example, in 2017, the International Diabetes Federation (IDF) estimated that diabetes resulted in 4.0 million deaths worldwide, using modeling to estimate the total number of deaths that could be directly or indirectly attributed to diabetes.Diabetes occurs throughout the world but is more common (especially type 2) in more developed countries. The greatest increase in rates has however been seen in low- and middle-income countries, where more than 80% of diabetic deaths occur. The fastest prevalence increase is expected to occur in Asia and Africa, where most people with diabetes will probably live in 2030. The increase in rates in developing countries follows the trend of urbanization and lifestyle changes, including increasingly sedentary lifestyles, less physically demanding work and the global nutrition transition, marked by increased intake of foods that are high energy-dense but nutrient-poor (often high in sugar and saturated fats, sometimes referred to as the "Western-style" diet). The global number of diabetes cases might increase by 48% between 2017 and 2045.
History
Diabetes was one of the first diseases described, with an Egyptian manuscript from c. 1500 BCE mentioning "too great emptying of the urine." The Ebers papyrus includes a recommendation for a drink to take in such cases. The first described cases are believed to have been type 1 diabetes. Indian physicians around the same time identified the disease and classified it as madhumeha or "honey urine", noting the urine would attract ants.The term "diabetes" or "to pass through" was first used in 230 BCE by the Greek Apollonius of Memphis. The disease was considered rare during the time of the Roman empire, with Galen commenting he had only seen two cases during his career. This is possibly due to the diet and lifestyle of the ancients, or because the clinical symptoms were observed during the advanced stage of the disease. Galen named the disease "diarrhea of the urine" (diarrhea urinosa).The earliest surviving work with a detailed reference to diabetes is that of Aretaeus of Cappadocia (2nd or early 3rd century CE). He described the symptoms and the course of the disease, which he attributed to the moisture and coldness, reflecting the beliefs of the "Pneumatic School". He hypothesized a correlation between diabetes and other diseases, and he discussed differential diagnosis from the snakebite, which also provokes excessive thirst. His work remained unknown in the West until 1552, when the first Latin edition was published in Venice.Two types of diabetes were identified as separate conditions for the first time by the Indian physicians Sushruta and Charaka in 400–500 CE with one type being associated with youth and another type with being overweight. Effective treatment was not developed until the early part of the 20th century when Canadians Frederick Banting and Charles Herbert Best isolated and purified insulin in 1921 and 1922. This was followed by the development of the long-acting insulin NPH in the 1940s.
Etymology
The word diabetes ( or ) comes from Latin diabētēs, which in turn comes from Ancient Greek διαβήτης (diabētēs), which literally means "a passer through; a siphon". Ancient Greek physician Aretaeus of Cappadocia (fl. 1st century CE) used that word, with the intended meaning "excessive discharge of urine", as the name for the disease. Ultimately, the word comes from Greek διαβαίνειν (diabainein), meaning "to pass through", which is composed of δια- (dia-), meaning "through" and βαίνειν (bainein), meaning "to go". The word "diabetes" is first recorded in English, in the form diabete, in a medical text written around 1425.
The word mellitus ( or ) comes from the classical Latin word mellītus, meaning "mellite" (i.e. sweetened with honey; honey-sweet). The Latin word comes from mell-, which comes from mel, meaning "honey"; sweetness; pleasant thing, and the suffix -ītus, whose meaning is the same as that of the English suffix "-ite". It was Thomas Willis who in 1675 added "mellitus" to the word "diabetes" as a designation for the disease, when he noticed the urine of a person with diabetes had a sweet taste (glycosuria). This sweet taste had been noticed in urine by the ancient Greeks, Chinese, Egyptians, Indians, and Persians.
Society and culture
The 1989 "St. Vincent Declaration" was the result of international efforts to improve the care accorded to those with diabetes. Doing so is important not only in terms of quality of life and life expectancy but also economically – expenses due to diabetes have been shown to be a major drain on health – and productivity-related resources for healthcare systems and governments.
Several countries established more and less successful national diabetes programmes to improve treatment of the disease.People with diabetes who have neuropathic symptoms such as numbness or tingling in feet or hands are twice as likely to be unemployed as those without the symptoms.In 2010, diabetes-related emergency room (ER) visit rates in the United States were higher among people from the lowest income communities (526 per 10,000 population) than from the highest income communities (236 per 10,000 population). Approximately 9.4% of diabetes-related ER visits were for the uninsured.
Naming
The term "type 1 diabetes" has replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes mellitus. Likewise, the term "type 2 diabetes" has replaced several former terms, including adult-onset diabetes, obesity-related diabetes, and noninsulin-dependent diabetes mellitus. Beyond these two types, there is no agreed-upon standard nomenclature.Diabetes mellitus is also occasionally known as "sugar diabetes" to differentiate it from diabetes insipidus.
Other animals
In animals, diabetes is most commonly encountered in dogs and cats. Middle-aged animals are most commonly affected. Female dogs are twice as likely to be affected as males, while according to some sources, male cats are more prone than females. In both species, all breeds may be affected, but some small dog breeds are particularly likely to develop diabetes, such as Miniature Poodles.Feline diabetes is strikingly similar to human type 2 diabetes. The Burmese, Russian Blue, Abyssinian, and Norwegian Forest cat breeds are at higher risk than other breeds. Overweight cats are also at higher risk.The symptoms may relate to fluid loss and polyuria, but the course may also be insidious. Diabetic animals are more prone to infections. The long-term complications recognized in humans are much rarer in animals. The principles of treatment (weight loss, oral antidiabetics, subcutaneous insulin) and management of emergencies (e.g. ketoacidosis) are similar to those in humans.
References
External links
American Diabetes Association
IDF Diabetes Atlas
National Diabetes Education Program
ADAs Standards of Medical Care in Diabetes 2019
Polonsky KS (October 2012). "The past 200 years in diabetes". The New England Journal of Medicine. 367 (14): 1332–1340. doi:10.1056/NEJMra1110560. PMID 23034021. S2CID 9456681.
"Diabetes". MedlinePlus. U.S. National Library of Medicine. |
You are an assistant in medical learning. Your role is to clarify medical terminology, ensuring the information is both accurate and accessible. | Can you break down the meaning of the medical term 'Dexlansoprazole' for me? | Dexlansoprazole, sold under the trade names Dexilant and Biozodex among others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease. Effectiveness is similar to other proton pump inhibitors (PPIs). It is taken by mouth.Common side effects include diarrhea, abdominal pain, and nausea. Serious side effects may include osteoporosis, low blood magnesium, Clostridium difficile infection, anaphylaxis, and pneumonia. Use in pregnancy and breastfeeding is of unclear safety. It works by blocking H+/K+-ATPase in the parietal cells of the stomach.Dexlansoprazole was approved for medical use in the United States in 2009. In Canada in 2016, it was the most expensive PPI available. In 2019, it was the 218th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
Medical use
Dexlansoprazole is used to heal and maintain healing of erosive esophagitis and to treat heartburn associated with gastroesophageal reflux disease (GERD). It lasts longer than lansoprazole, to which it is chemically related, and needs to be taken less often. There is no good evidence that it works better than other PPIs.
Adverse effects
The most significant adverse reactions (≥2%) reported in clinical trials were diarrhea, abdominal pain, bloating, nausea, upper respiratory tract infection, vomiting, and flatulence.
Mechanism of action
Like lansoprazole, dexlansoprazole permanently binds to the proton pump and blocks it, preventing the formation of gastric acid.
Chemistry
Dexlansoprazole is the (R)-(+)-enantiomer of lansoprazole, which is a racemic mixture of its (R)-(+) and (S)-(−)-enantiomers. The Takeda drug has a dual release pharmaceutical formulation, with two types of granules of dexlansoprazole, each with a coating that dissolves at a different pH level.
Pharmacokinetics
Dexlansoprazole ((R)-(+)-lansoprazole) has the same binding affinity to the proton pump as the (S)-enantiomer, but is associated with a three- to five-fold greater area under the plasma drug concentration time curve (AUC) compared with (S)-lansoprazole. With its dual release pharmaceutical formulation, the first quick release produces a plasma peak concentration about one hour after application, with a second delayed release producing another peak about four hours later.
History
Dexlansoprazole was approved by the U.S. Food and Drug Administration (FDA) in 2009, and was approved in Canada in 2010 and in Mexico in 2011.Since Kapidex was approved in 2009, there have been reports of dispensing errors because of confusion with the drugs Casodex (bicalutamide) and Kadian (morphine), which have very different uses from Kapidex and from each other. In 2010, the FDA approved a name change for Kapidex to avoid confusion with the two other medications and Takeda began marketing it under the new name Dexilant. It is also available in Bangladesh for the first time as Dexlan by IBN SINA Pharmaceuticals Ltd. in April 2014 and after them DEXILEND by Ziska Pharmaceuticals Ltd., Desopra by Alco Pharma, Delanix by Incepta Pharmaceuticals, Dexogut by Popular Pharmaceuticals Ltd. also introduced it in BD market. In 2020 many other Pharmaceuticals have launched Dexlansoprazole.
References
External links
"Dexlansoprazole". Drug Information Portal. U.S. National Library of Medicine. |
You function as a medical dictionary. Offer comprehensive and accurate descriptions of medical terms, ensuring clarity and depth in your explanations. | I need a basic explanation for the medical term 'Degos disease.' | Degos disease, also known as Köhlmeier-Degos disease or malignant atrophic papulosis, is an extremely rare condition caused by blockage of arteries and veins. Individuals with this condition will develop papules. Those diagnosed with this disease may also develop complications due to impairment of internal organs. The exact underlying mechanism is still unknown, and an effective treatment is still being developed. There are fewer than 50 living patients presently known worldwide, and fewer than 200 reported in medical literature. However, many individuals may go undiagnosed due to rarity of the disease. Most individuals develop symptoms between the ages of 20–50; however, cases outside of this age range have been reported as well.
Symptoms and signs
The characteristic symptom of Degos disease is the development of papules. Initially, individuals may have skin lesions or rashes, but they will proceed to develop distinct bumps, or papules. Papules are circular in shape, have a porcelain-white center and red border. As papules age, the white centers will skin in and only the border will remain raised. Typically, papules range from 0.5 to 1 cm in width. Papules appear on the trunk and upper extremities and are not found on the individuals palms, soles, scalp, or face.Symptoms vary, depending on whether an individual has the benign variant or malignant variant of the disease. Both the benign and malignant forms have development of the characteristic papules. Individuals with the benign form will have the typical papules persisting anywhere from a few years to throughout their whole lives. In the benign form, no inner organs are affected. If an individual develops the malignant form, it means that not only are the papules present, but inner organs are involved. Most malignant cases involve problems of the gastrointestinal tract leading to small intestine lesions, abdominal pain, diarrhea, and bowel perforation. If the central nervous system is involved, symptoms can include headaches, dizziness, seizures, paralysis of cranial nerves, weakness, stroke, damage to small areas of the brain due to artery blockage (cerebral infarcts, and cerebral hemorrhage). Additional organs commonly impacted include the heart, lungs, and kidneys. Symptoms that may develop from damage to these organs include double vision (diplopia), clouding of lenses of eyes, swelling of the optic disc (papilledema), partial loss of vision, shortness of breath, chest pain, epilepsy, and thickening of pericardium.Someone with the benign form may suddenly develop symptoms of the malignant form. Symptoms can last anywhere from a few weeks to several years. Onset of symptoms typically begins to manifest between the ages of 20–50. A few cases of this condition in newborns have also been described.
Causes
The papules characteristic for this disease develop due to infarctions, or blockages in small-medium arteries and veins. The underlying cause is unknown for this disease. Though not confirmed, some cases have shown signs of inheritance between first-degree relatives. It has been suggested that the disease has a familial inheritance pattern; it is thought to be an autosomal dominant disorder. In most cases of familial inheritance, the benign variant of the disease has been present.Due to the lack of knowledge of the pathomechanism for this condition prevention strategies are not known. However, in order to prevent worsening of symptoms, consistent evaluations should be conducted by a physician.
Mechanism
Although this disease has been known for around 70 years, the pathomechanism underlying it is still unknown. Several hypotheses have been developed regarding the underlying mechanism for Degos disease. One theory suggests that inflammation of blood vessels may trigger the condition. Another theory has to do with Degos disease as a coagulopathy. Development of a thrombus and resulting reduction of blood flow is common in this condition. A reduction in blood flow throughout the body can lead to damaged endothelial cells and may perhaps lead to the formation of the characteristic papules. Another hypothesis suggests that abnormal swelling and proliferation of the vascular endothelium can lead to intestinal and central nervous system thrombosis, and ultimately lead to development of symptoms associated with Degos disease. Overall, individuals with Degos disease have abnormal blockages in their arteries and veins; however, the cause of these blockages is unknown.
Diagnosis
Clinical evaluation and identification of characteristics papules may allow a dermatologist to diagnose Degos disease. The papules have a white center and are bordered with a red ring. After lesions begin to appear, the diagnosis for Degos disease can be supported by histological findings. Most cases will show a wedge-shaped connective tissue necrosis in the deep corium. This shape is due to the blockage/occlusion of small arteries.Individuals may be diagnosed with the benign form if only the papules are present. However, an individual may be diagnosed with the malignant form if involvement of other organs like the lungs, intestine and/or central nervous system occurs. The malignant, or systematic form of this condition may suddenly develop even after having papules present for several years. In order to quickly diagnose this shift to the malignant variant of the disease, it is important for individuals to have consistent follow-up evaluations. In these evaluations, depending on which organs are suspected to be involved, the following procedures and tests may be conducted: skin inspection, brain magnetic resonance tomography, colonoscopy, chest X-ray, and/or abdominal ultrasound.
Treatment
Due to the lack of knowledge around the underlying mechanism of malignant atrophic papulosis, an effective treatment method has not been developed. Treatment for this condition is symptomatic. However, several treatment methods have been tested and are still being developed as more information regarding the condition is found. Fibrinolytic and immunosuppressive therapeutic regimens were tested and found to be mostly unsuccessful as treatment methods.After treating conditions comorbid with Degos disease, physicians have recently found improvement in symptoms with the use of eculizumab and treprostinil. Discovered by dermatopathologist, Cynthia Magro, response to eculizumab is often immediate and dramatic, but has been of limited duration and is expensive, needing to be infused every 14 days. Treprostinil use has been reported to result in clearing of gastrointestinal and central nervous system findings as well as clearing of cutaneous lesions, but reports are limited. Treprostinil may be more effective than other vasodilators because it may also increase the population of circulating endothelial cells, allowing angiogenesis.
Recent research
A 46-year-old male patient was diagnosed with the malignant, systemic form of the disease and was severely ill. The diagnosing dermatopathologist, Cynthia Magro MD, identified the presence of C5b-9 complexes in the involved vessels of the skin biopsy. For treatment of the thrombotic microangiopathy in this patient, she suggested the use of eculizumab, a humanized monoclonal antibody drug developed by Alexion Pharmaceuticals and approved by the Food and Drug Administration for treatment of Paroxysmal nocturnal hemoglobinuria. The patient experienced a dramatic improvement in his condition. Lee Shapiro MD and Aixa Toledo-Garcia MD at Albany Medical College learned of the success with the adult patient, and became the first physicians to successfully treat a pediatric Degos patient with eculizumab.Dr. Shapiro later observed the resolution of Degos skin lesions in an adult patient with an overlap syndrome involving systemic lupus, systemic sclerosis, and Degos disease who was treated with treprostinil for her pulmonary hypertension. His pediatric Degos patient was developing significant complications despite treatment with eculizumab, so Dr. Shapiros group became the first to treat a Degos patient with treprostinil. To this point, all known long-term survivors of systemic Degos disease are being treated with a combination of eculizumab and treprostinil.
History
In 1941, this disease was first described by Köhlmeier. However, it was not until 1942 that the disease was recognized as a new clinical entity by Robert Degos. Initially the condition was referred to as Degos disease or Köhlmeier-Degos disease. However, Degos himself subsequently suggested the name "papulose atrophiante maligne," translated as malignant atrophic papulosis.
References
Notes
Further reading
== External links == |
You are a facilitator of medical knowledge. Provide thorough and accessible explanations of medical terms, catering to both specialists and non-specialists. | Could you offer a clear explanation of the term 'Adrenaline' as used in the medical field? | Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). Adrenaline is normally produced by the adrenal glands and by a small number of neurons in the medulla oblongata. It plays an essential role in the fight-or-flight response by increasing blood flow to muscles, heart output by acting on the SA node, pupil dilation response, and blood sugar level. It does this by binding to alpha and beta receptors. It is found in many animals, including humans, and some single-celled organisms. In 1901, Japanese chemist Jōkichi Takamine developed a purified extract from the adrenal glands, which Parke, Davis & Co trademarked in the US. The British Approved Name and European Pharmacopoeia term for this drug is hence adrenaline.
Medical uses
As a medication, it is used to treat several conditions, including allergic reaction anaphylaxis, cardiac arrest, and superficial bleeding. Inhaled adrenaline may be used to improve the symptoms of croup. It may also be used for asthma when other treatments are not effective. It is given intravenously, by injection into a muscle, by inhalation, or by injection just under the skin. Common side effects include shakiness, anxiety, and sweating. A fast heart rate and high blood pressure may occur. Occasionally it may result in an abnormal heart rhythm. While the safety of its use during pregnancy and breastfeeding is unclear, the benefits to the mother must be taken into account.A case has been made for the use of adrenaline infusion in place of the widely accepted treatment of inotropes for preterm infants with clinical cardiovascular compromise. Although sufficient data strongly recommends adrenaline infusions as a viable treatment, more trials are needed to conclusively determine that these infusions will successfully reduce morbidity and mortality rates among preterm, cardiovascularly compromised infants.
Physiological effects
The adrenal medulla is a
Major contributor to total circulating catecholamines (L-DOPA is at a higher concentration in the plasma), though it contributes over 90% of circulating adrenaline. Little adrenaline is found in other tissues, mostly in scattered chromaffin cells and in a small number of neurons that use adrenaline as a neurotransmitter. Following adrenalectomy, adrenaline disappears below the detection limit in the bloodstream.Pharmacological doses of adrenaline stimulate α1, α2, β1, β2, and β3 adrenoceptors of the sympathetic nervous system. Sympathetic nerve receptors are classified as adrenergic, based on their responsiveness to adrenaline. The term "adrenergic" is often misinterpreted in that the main sympathetic neurotransmitter is noradrenaline, rather than adrenaline, as discovered by Ulf von Euler in 1946. Adrenaline has a β2 adrenoceptor-mediated effect on metabolism and the airway, with no direct neural connection from the sympathetic ganglia to the airway.Walter Bradford Cannon originally proposed the concept of the adrenal medulla and the sympathetic nervous system being involved in the flight, fight, and fright response. But the adrenal medulla, in contrast to the adrenal cortex, is not required for survival. In adrenalectomized patients, hemodynamic and metabolic responses to stimuli such as hypoglycemia and exercise remain normal.
Exercise
One physiological stimulus to adrenaline secretion is exercise. This was first demonstrated by measuring the dilation of a (denervated) pupil of a cat on a treadmill, later confirmed using a biological assay of urine samples. Biochemical methods for measuring catecholamines in plasma were published from 1950 onwards. Although much valuable work has been published using fluorimetric assays to measure total catecholamine concentrations, the method is too non-specific and insensitive to accurately determine the very small quantities of adrenaline in plasma. The development of extraction methods and enzyme–isotope derivate radio-enzymatic assays (REA) transformed the analysis down to a sensitivity of 1 pg for adrenaline. Early REA plasma assays indicated that adrenaline and total catecholamines rise late in exercise, mostly when anaerobic metabolism commences.During exercise, the adrenaline blood concentration rises partially from the increased secretion of the adrenal medulla and partly from the decreased metabolism of adrenaline due to reduced blood flow to the liver. Infusion of adrenaline to reproduce exercise circulating concentrations of adrenaline in subjects at rest has little hemodynamic effect other than a slight β2-mediated fall in diastolic blood pressure. Infusion of adrenaline well within the physiological range suppresses human airway hyper-reactivity sufficiently to antagonize the constrictor effects of inhaled histamine.A link between the sympathetic nervous system and the lungs was shown in 1887 when Grossman showed that stimulation of cardiac accelerator nerves reversed muscarine-induced airway constriction. In experiments in the dog, where the sympathetic chain was cut at the level of the diaphragm, Jackson showed that there was no direct sympathetic innervation to the lung, but bronchoconstriction was reversed by the release of adrenaline from the adrenal medulla. An increased incidence of asthma has not been reported for adrenalectomized patients; those with a predisposition to asthma will have some protection from airway hyper-reactivity from their corticosteroid replacement therapy. Exercise induces progressive airway dilation in normal subjects that correlates with workload and is not prevented by beta-blockade. The progressive airway dilation with increasing exercise is mediated by a progressive reduction in resting vagal tone. Beta blockade with propranolol causes a rebound in airway resistance after exercise in normal subjects over the same time course as the bronchoconstriction seen with exercise-induced asthma. The reduction in airway resistance during exercise reduces the work of breathing.
Emotional responses
Every emotional response has a behavioral component, an autonomic component, and a hormonal component. The hormonal component includes the release of adrenaline, an adrenomedullary response that occurs in response to stress and that is controlled by the sympathetic nervous system. The major emotion studied in relation to adrenaline is fear. In an experiment, subjects who were injected with adrenaline expressed more negative and fewer positive facial expressions to fear films compared to a control group. These subjects also reported a more intense fear from the films and greater mean intensity of negative memories than control subjects. The findings from this study demonstrate that there are learned associations between negative feelings and levels of adrenaline. Overall, the greater amount of adrenaline is positively correlated with an aroused state of negative emotions. These findings can be an effect in part that adrenaline elicits physiological sympathetic responses, including an increased heart rate and knee shaking, which can be attributed to the feeling of fear regardless of the actual level of fear elicited from the video. Although studies have found a definite relation between adrenaline and fear, other emotions have not had such results. In the same study, subjects did not express a greater amusement to an amusement film nor greater anger to an anger film. Similar findings were also supported in a study that involved rodent subjects that either were able or unable to produce adrenaline. Findings support the idea that adrenaline has a role in facilitating the encoding of emotionally arousing events, contributing to higher levels of arousal due to fear.
Memory
It has been found that adrenergic hormones, such as adrenaline, can produce retrograde enhancement of long-term memory in humans. The release of adrenaline due to emotionally stressful events, which is endogenous adrenaline, can modulate memory consolidation of the events, ensuring memory strength that is proportional to memory importance. Post-learning adrenaline activity also interacts with the degree of arousal associated with the initial coding. There is evidence that suggests adrenaline does have a role in long-term stress adaptation and emotional memory encoding specifically. Adrenaline may also play a role in elevating arousal and fear memory under particular pathological conditions, including post-traumatic stress disorder. Overall, "Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects."
Studies have also found that recognition memory involving adrenaline depends on a mechanism that depends on β adrenoceptors. Adrenaline does not readily cross the blood-brain barrier, so its effects on memory consolidation are at least partly initiated by β adrenoceptors in the periphery. Studies have found that sotalol, a β adrenoceptor antagonist that also does not readily enter the brain, blocks the enhancing effects of peripherally administered adrenaline on memory. These findings suggest that β adrenoceptors are necessary for adrenaline to have an impact on memory consolidation.
Pathology
Increased adrenaline secretion is observed in pheochromocytoma, hypoglycemia, myocardial infarction, and to a lesser degree, in essential tremor (also known as benign, familial, or idiopathic tremor). A general increase in sympathetic neural activity is usually accompanied by increased adrenaline secretion, but there is selectivity during hypoxia and hypoglycemia, when the ratio of adrenaline to noradrenaline is considerably increased. Therefore, there must be some autonomy of the adrenal medulla from the rest of the sympathetic system.
Myocardial infarction is associated with high levels of circulating adrenaline and noradrenaline, particularly in cardiogenic shock.Benign familial tremor (BFT) is responsive to peripheral β adrenergic blockers, and β2-stimulation is known to cause tremor. Patients with BFT were found to have increased plasma adrenaline but not noradrenaline.Low or absent concentrations of adrenaline can be seen in autonomic neuropathy or following adrenalectomy. Failure of the adrenal cortex, as with Addisons disease, can suppress adrenaline secretion as the activity of the synthesizing enzyme, phenylethanolamine-N-methyltransferase, depends on the high concentration of cortisol that drains from the cortex to the medulla.
Terminology
In 1901, Jōkichi Takamine patented a purified extract from the adrenal glands, which was trademarked by Parke, Davis & Co in the US. The British Approved Name and European Pharmacopoeia term for this drug is hence adrenaline.However, the pharmacologist John Abel had already prepared an extract from adrenal glands as early as 1897, and he coined the name epinephrine to describe it (from Ancient Greek ἐπῐ́ (epí), "upon", and νεφρός (nephrós), "kidney"). In the belief that Abels extract was the same as Takamines (a belief since disputed), epinephrine became the generic name in the US and remains the pharmaceuticals United States Adopted Name and International Nonproprietary Name (though the name adrenaline is frequently used).
The terminology is now one of the few differences between the INN and BAN systems of names. Although European health professionals and scientists preferentially use the term adrenaline, the converse is true among American health professionals and scientists. Nevertheless, even among the latter, receptors for this substance are called adrenergic receptors or adrenoceptors, and pharmaceuticals that mimic its effects are often called adrenergics. The history of adrenaline and epinephrine is reviewed by Rao.
Mechanism of Action
As a hormone, adrenaline acts on nearly all body tissues by binding to adrenergic receptors. Its effects on various tissues depend on the type of tissue and expression of specific forms of adrenergic receptors. For example, high levels of adrenaline cause smooth muscle relaxation in the airways but causes contraction of the smooth muscle that lines most arterioles.
Adrenaline is a nonselective agonist of all adrenergic receptors, including the major subtypes α1, α2, β1, β2, and β3. Adrenalines binding to these receptors triggers a number of metabolic changes. Binding to α-adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis and inhibits insulin-mediated glycogenesis in muscle. β adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects increase blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.Adrenaline causes liver cells to release glucose into the blood, acting through both alpha and beta-adrenergic receptors to stimulate glycogenolysis. Adrenaline binds to β2 receptors on liver cells, which changes conformation and helps Gs, a heterotrimeric G protein, exchange GDP to GTP. This trimeric G protein dissociates to Gs alpha and Gs beta/gamma subunits. Gs alpha stimulates adenylyl cyclase, thus converting adenosine triphosphate into cyclic adenosine monophosphate (AMP). Cyclic AMP activates protein kinase A. Protein kinase A phosphorylates and partially activates phosphorylase kinase. Adrenaline also binds to α1 adrenergic receptors, causing an increase in inositol trisphosphate, inducing calcium ions to enter the cytoplasm. Calcium ions bind to calmodulin, which leads to further activation of phosphorylase kinase. Phosphorylase kinase phosphorylates glycogen phosphorylase, which then breaks down glycogen leading to the production of glucose.Adrenaline also has significant effects on the cardiovascular system. It increases peripheral resistance via α1 receptor-dependent vasoconstriction and increases cardiac output by binding to β1 receptors. The goal of reducing peripheral circulation is to increase coronary and cerebral perfusion pressures and therefore increase oxygen exchange at the cellular level. While adrenaline does increase aortic, cerebral, and carotid circulation pressure, it lowers carotid blood flow and end-tidal CO2 or ETCO2 levels. It appears that adrenaline improve macrocirculation at the expense of the capillary beds where perfusion takes place.
Measurement in biological fluids
Adrenaline may be quantified in blood, plasma, or serum as a diagnostic aid, to monitor therapeutic administration, or to identify the causative agent in a potential poisoning victim. Endogenous plasma adrenaline concentrations in resting adults usually are less than 10 ng/L, but they may increase by 10-fold during exercise and by 50-fold or more during times of stress. Pheochromocytoma patients often have plasma adrenaline levels of 1000–10,000 ng/L. Parenteral administration of adrenaline to acute-care cardiac patients can produce plasma concentrations of 10,000 to 100,000 ng/L.
Biosynthesis
In chemical terms, adrenaline is one of a group of monoamines called the catecholamines. Adrenaline is synthesized in the chromaffin cells of the adrenal glands adrenal medulla and a small number of neurons in the medulla oblongata in the brain through a metabolic pathway that converts the amino acids phenylalanine and tyrosine into a series of metabolic intermediates and, ultimately, adrenaline. Tyrosine is first oxidized to L-DOPA by tyrosine hydroxylase; this is the rate-limiting step. Then it is subsequently decarboxylated to give dopamine by DOPA decarboxylase (aromatic L-amino acid decarboxylase). Dopamine is then converted to noradrenaline by dopamine beta-hydroxylase, which utilizes ascorbic acid (vitamin C) and copper. The final step in adrenaline biosynthesis is the methylation of the primary amine of noradrenaline. This reaction is catalyzed by the enzyme phenylethanolamine N-methyltransferase (PNMT), which utilizes S-adenosyl methionine (SAMe) as the methyl donor. While PNMT is found primarily in the cytosol of the endocrine cells of the adrenal medulla (also known as chromaffin cells), it has been detected at low levels in both the heart and brain.
Regulation
The major physiologic triggers of adrenaline release center upon stresses, such as physical threat, excitement, noise, bright lights, and high or low ambient temperature. All of these stimuli are processed in the central nervous system.Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of tyrosine hydroxylase and dopamine β-hydroxylase, two key enzymes involved in catecholamine synthesis. ACTH also stimulates the adrenal cortex to release cortisol, which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most often done in response to stress. The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of adrenaline. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and, thus, the release of adrenaline (and noradrenaline) into the bloodstream. For noradrenaline to be acted upon by PNMT in the cytosol, it must first be shipped out of granules of the chromaffin cells. This may occur via the catecholamine-H+ exchanger VMAT1. VMAT1 is also responsible for transporting newly synthesized adrenaline from the cytosol back into chromaffin granules in preparation for release.Unlike many other hormones, adrenaline (as with other catecholamines) does not exert negative feedback to down-regulate its own synthesis. Abnormally adrenaline levels can occur in various conditions, such as surreptitious adrenaline administration, pheochromocytoma, and other tumors of the sympathetic ganglia.
Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by monoamine oxidase and catechol-O-methyl transferase.
History
Extracts of the adrenal gland were first obtained by Polish physiologist Napoleon Cybulski in 1895. These extracts, which he called nadnerczyna ("adrenalin"), contained adrenaline and other catecholamines. American ophthalmologist William H. Bates discovered adrenalines usage for eye surgeries prior to 20 April 1896. In 1897, John Jacob Abel (1857–1938), the father of modern pharmacology, found a natural substance produced by the adrenal glands that he named epinephrine. The first hormone to be identified, it remains a crucial, first-line treatment for cardiac arrests, severe allergic reactions, and other conditions. Japanese chemist Jōkichi Takamine and his assistant Keizo Uenaka independently discovered adrenaline in 1900. In 1901, Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen. Adrenaline was first synthesized in the laboratory by Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904.Although secretin is mentioned as the first hormone, adrenaline is the first hormone since the discovery of the activity of adrenal extract on blood pressure was observed in 1895 before that of secretin in 1902. In 1895, George Oliver (1841–1915), a general practitioner in North Yorkshire, and Edward Albert Schäfer (1850–1935), a physiologist at University College of London published a paper about the active component of adrenal gland extract causing the increase in blood pressure and heart rate was from the medulla, but not the cortex of the adrenal gland. In 1897, John Jacob Abel (1857–1938) of Johns Hopkins University, the first chairman of the first US department of pharmacology, found a compound called epinephrine with the molecular formula of C17H15NO4. Abel claimed his principle from adrenal gland extract was active.
In 1900, Jōkichi Takamine (1854–1922), a Japanese chemist, worked with his assistant, Keizo Uenaka (1876–1960), to purify a 2000 times more active principle than epinephrine from the adrenal gland, named adrenaline with the molecular formula C10H15NO3. Additionally, in 1900 Thomas Aldrich of Parke-Davis Scientific Laboratory also purified adrenaline independently. Takamine and Parke-Davis later in 1901 both got the patent for adrenaline. The fight for terminology between adrenaline and epinephrine was not ended until the first adrenaline structural discovery by Hermann Pauly (1870-1950) in 1903 and the first adrenaline synthesis by Friedrich Stolz (1860–1936), a German chemist in 1904. They both believed that Takamines compound was the active principle while Abels compound was the inactive one.
Society and culture
Adrenaline junkie
An adrenaline junkie is someone who engages in sensation-seeking behavior through "the pursuit of novel and intense experiences without regard for physical, social, legal or financial risk". Such activities include extreme and risky sports, substance abuse, unsafe sex, and crime. The term relates to the increase in circulating levels of adrenaline during physiological stress. Such an increase in the circulating concentration of adrenaline is secondary to the activation of the sympathetic nerves innervating the adrenal medulla, as it is rapid and not present in animals where the adrenal gland has been removed. Although such stress triggers adrenaline release, it also activates many other responses within the central nervous system reward system, which drives behavioral responses; while the circulating adrenaline concentration is present, it may not drive behavior. Nevertheless, adrenaline infusion alone does increase alertness and has roles in the brain, including the augmentation of memory consolidation.
Strength
Adrenaline has been implicated in feats of great strength, often occurring in times of crisis. For example, there are stories of a parent lifting part of a car when their child is trapped underneath.
See also
Noradrenaline
Catecholamines
Adrenal gland
References
External links
"U.S. National Library of Medicine: Drug Information Portal – Epinephrine". Archived from the original on 14 December 2019. |
You are an assistant in medical learning. Your role is to clarify medical terminology, ensuring the information is both accurate and accessible. | Can you break down the meaning of the medical term 'Activity' for me? | Activity may refer to:
Action (philosophy), in general
Human activity: human behavior, in sociology behavior may refer to all basic human actions, economics may study human economic activities and along with cybernetics and psychology may study their modulation
Recreation, or activities of leisure
The Aristotelian concept of energeia, Latinized as actus
Activity (UML), a major task in Unified Modeling Language
Activity, the rate of catalytic activity, such as enzyme activity (enzyme assay), in physical chemistry and enzymology
Thermodynamic activity, the effective concentration of a solute for the purposes of mass action
Activity (project management)
Activity, the number of radioactive decays per second
Activity (software engineering)
Activity (soil mechanics)
HMS Activity (D94), an aircraft carrier of the Royal Navy
"Activity", a song by Way Out West from Intensify
Cultural activities, activities referred to culture.
See also
Activity theory, a learning theory in education
Social activity (disambiguation), several concepts in the social sciences
Activiti (software), an open source Business Process Management platform
Active (disambiguation) |
You function as a medical dictionary. Offer comprehensive and accurate descriptions of medical terms, ensuring clarity and depth in your explanations. | I've come across the term 'Lenticonus' in a medical context, but I'm not sure what it means. Can you clarify? | Lenticonus (/len·ti·co·nus/ (len″tĭ-ko´nus)) [lens + L. conus, cone] is a rare congenital anomaly of the eye characterized by a conical protrusion on the crystalline lens capsule and the underlying cortex. It can reach a diameter of 2 to 7 mm. The conus may occur anteriorly or posteriorly. If the bulging is spherical, instead of conical, the condition is referred to as lentiglobus. It produces a decrease in visual acuity and irregular refraction that cannot be corrected by either spectacle or contact lenses.Biomicroscopically lenticonus is characterized by a transparent, localized, sharply demarcated conical projection of the lens capsule and cortex, usually axial in localization. In an early stage, retro-illumination shows an oil dropletconfiguration. Using a narrow slit, the image of a conus is observed. In a more advanced stage associated subcapsular and cortical opacities appear. Retinoscopically the oil droplet produces a pathognomonic scissors movement of the light reflex. This phenomenon is due to the different refraction in the central and the peripheral area of the lens. Ultrasonography also can illustrate the existence of a lenticonus. A-scan ultrasonography may reveal an increased lens thickness and B- scanultrasonography may show herniated lenticular material, suggestive of a lenticonus. Amblyopia, cataract, strabismus and loss of central fixation may be observed in association with lenticonus posterior. Cataract, flecked retinopathy, posterior polymorphous dystrophy and corneal arcus juvenilis may be encountered in association with lenticonus anterior that occurs as a part of the Alport syndrome.There exist two distinct types of lenticonus based on the face of the lens affected.
Types
Lenticonus anterior; lenticonus anterior is part of the waardenburg syndrome
Lenticonus posterior; lenticonus posterior is more common than lenticonus anterior and is sometimes found in Lowe syndromeAlport syndrome mostly causes anterior lenticonus. It can rarely cause posterior lenticonus, but this is uncommon.
== References == |
You are a medical knowledge base. Your task is to elucidate medical terminology, offering insights into their meanings, origins, and applications. | Could you offer a clear explanation of the term 'Cerebellopontine angle syndrome' as used in the medical field? | The cerebellopontine angle syndrome is a distinct neurological syndrome of deficits that can arise due to the closeness of the cerebellopontine angle to specific cranial nerves. Indications include unilateral hearing loss (85%), speech impediments, disequilibrium, tremors or other loss of motor control. The cerebellopontine angle cistern is a subarachnoid cistern formed by the cerebellopontine angle that lies between the cerebellum and the pons. It is filled with cerebrospinal fluid and is a common site for the growth of acoustic neuromas or schwannomas.
Signs and Symptoms
Tumors within the nerve canaliculi initially present with unilateral sensorineural hearing loss, unilateral tinnitus, or disequilibrium (vertigo is rare, on account of the slow growth of neuromas). Speech discrimination out of proportion to hearing loss, difficulty talking on the telephone are frequent accompaniments. Tumors extending into the CPA will likely present with disequilibrium or ataxia depending on the amount of extension on the brainstem. With brainstem extension, midfacial and corneal hypesthesia, hydrocephalus, and other cranial neuropathies become more prevalent.
For example, involvement of CN V from a cerebellopontine mass lesion often results in loss of the ipsilateral (same side of the body) corneal reflex (involuntary blink).
Patients with larger tumours can develop Bruns nystagmus (dancing eyes) due to compression of the flocculi.
Causes
In most cases, the cause of acoustic neuromas is unknown. The only statistically significant risk factor for developing an acoustic neuroma is having a rare genetic condition called neurofibromatosis type 2 (NF2). There are no confirmed environmental risk factors for acoustic neuroma. There are conflicting studies on the association between acoustic neuromas and cellular phone use and repeated exposure to loud noise. In 2011, an arm of the World Health Organization released a statement listing cell phone use as a low grade cancer risk. The Acoustic Neuroma Association recommends that cell phone users use a hands-free device.
Meningiomas are significantly more common in women than in men; they are most common in middle-aged women. Two predisposing factors associated with meningiomas for which at least some evidence exists are exposure to ionizing radiation (cancer treatment of brain tumors) and hormone replacement therapy.
Pathophysiology
Various kinds of tumors, usually primary and benign, are represented in the pathology. Lesions in the area of cerebellopontine angle cause signs and symptoms secondary to compression of nearby cranial nerves, including cranial nerve V (trigeminal), cranial nerve VII (facial), and cranial nerve VIII (vestibulocochlear). The most common cerebellopontine angle (CPA) tumor is a vestibular schwannoma affecting cranial nerve VIII (80%), followed by meningioma (10%). The cranial nerves affected are (from most common to least common) : VIII (cochlear component), VIII (vestibular component), V
Acoustic neuroma/vestibular schwannoma
Meningioma, a tumor of the meninges or membranes that surround the nerves passing through the CPA
Cerebellar astrocytoma, a malignant tumor of star-shaped glial cells called astrocytes in the cerebellum
Intracranial epidermoid cyst
Lipoma
Glomus jugulare associated with the glossopharyngeal nerve
Idiopathic hypertrophic pachymeningitis
IgG4-related hypertrophic pachymeningitis
CPA Metastases in cancer patients with inner ear symptoms (rare)
Diagnosis
Radiography
Subsequent to diagnosis of sensorineural hearing loss, and differential diagnosis of retrocochlear or neural etiologies,
radiological assessment of the CPA is performed to assess the presence of anatomical retrocochlear lesions.
Traditional protocols
Before the advent of MRI, electronystagmography and Computed Tomography were employed for diagnosis of acoustic neuroma.
Auditory brainstem response audiometry and adjunct tests
The auditory brainstem response (ABR) test gives information about the inner ear (cochlea) and nerve pathways for hearing via ongoing electrical activity in the brain measured by electrodes placed on the scalp. Five different waves (I to V) are measured for each ear. Each waveform represents specific anatomical points along the auditory neural pathway. Delays of one side relative to the other suggest a lesion in cranial nerve VIII between the ear and brainstem or in the brainstem itself. The most reliable indicator for acoustic neuromas from the ABR is the interaural latency differences in wave V: the latency in the impaired ear is prolonged. Different studies have indicated the sensitivity of ABR for detection of acoustic neuromas 1cm or larger to be between 90 and 95%. Sensitivity for neuromas smaller than 1cm are 63-77%. A newer technology, stacked ABR, may have sensitivity as high as 95% with specificity 88% for smaller tumors. ABR is considerably more cost effective, but MRI provides more information.
Stapedius reflex (SR) and caloric vestibular response (CVR) are non-invasive otologic tests for auditory neural function. These are not primary diagnostics for CPA neuromas, and are usually used in conjunction
with ABR.
Magnetic resonance imaging
Several different types of magnetic resonance imaging (MRI) may be employed in diagnosis: MRI without contrast, Gd contrast enhanced T1-weighted MRI (GdT1W) or T2-weighted enhanced MRI (T2W or T2*W). Non-contrast enhanced MRI is considerably less expensive than any of the contrast enhanced MRI scans. The gold standard in diagnosis is GdT1W MRI.
The reliability of non-contrast enhanced MRI is highly dependent on the sequence of scans, and the experience of the operator.
Management
Acoustic neuromas are managed by either surgery, radiation therapy, or observation with regular MRI scanning. With treatment, the likelihood of hearing preservation varies inversely with the size of the tumor; for large tumors, preservation of hearing is rare. Because acoustic neuromas, meningiomas and most other CPA tumors are benign, slow growing or non-growing, and non-invasive, observation is a viable management option.
Stereotactic radiosurgery
The objective of irradiation is to halt the growth of the acoustic neuroma tumour, it does not excise it from the body, as the term radiosurgery or gammaknife implies. Radiosurgery is only suitable for small to medium size tumors.
Surgical
There are three modalities of surgical treatment (excision) depending on where the anatomical location of the incision to access the tumor is made: retrosigmoid (a variant of what was formerly called suboccipital), translabyrinthine, and middle fossa.
The goals of surgery are to control the tumor, and preserve hearing as well as facial nerves. Especially in the case of larger tumors, there may be a tradeoff between tumor removal and preservation of nerve functionality.
There are different defined degrees of surgical excision, termed subtotal resection, radical subtotal resection, near-total resection, and total resection in order or increasing proportion of tumor removed. Lesser amount of tumor removal may increase likelihood of preservation of nerve function (hence better post-operative hearing), but also likelihood of tumor regrowth, necessitating additional treatment.
Outcome and complications
The overall complication rate following surgery is around 20%; cerebrospinal fluid leak is the most common.
See also
Cerebellum
Pons
References
== External links == |
You are a resource for medical understanding. Offer detailed explanations of medical terms, making complex concepts clear and comprehensible. | I'm seeking clarification on the medical term 'Asterixis.' Could you explain it? | Asterixis, more colloquially referred to as flapping tremor, is a tremor of the hand when the wrist is extended, sometimes said to resemble a bird flapping its wings. This motor disorder is characterized by an inability to maintain a position, which is demonstrated by jerking movements of the outstretched hands when bent upward at the wrist. The tremor is caused by abnormal function of the diencephalic motor centers in the brain, which regulate the muscles involved in maintaining position. Asterixis is associated with various encephalopathies due especially to faulty metabolism. The term derives from the Greek a, "not" and stērixis, "fixed position".
Asterixis is the inability to maintain posture due to a metabolic encephalopathy. This can be elicited on physical exam by having the patient extend their arms and bend their hands back.
With a metabolic encephalopathy, the patient is unable to hold their hands back resulting in a “flapping” motion consistent with asterixis. It can be seen in any metabolic encephalopathy e.g. chronic kidney failure, severe congestive heart failure, acute respiratory failure and commonly in decompensated liver failure.
Associated conditions and presentation
Usually there are brief, arrhythmic interruptions of sustained voluntary muscle contraction causing brief lapses of posture, with a frequency of 3–5 Hz. It is bilateral, but may be asymmetric. Unilateral asterixis may occur with structural brain disease.
It can be a sign of hepatic encephalopathy, damage to brain cells presumably due to the inability of the liver to metabolize ammonia to urea. The cause is thought to be predominantly related to abnormal ammonia metabolism.
Asterixis is seen most often in drowsy or stuporous patients with metabolic encephalopathies, especially in decompensated cirrhosis or acute liver failure.
It is also seen in some patients with kidney failure and azotemia.
It can also be a feature of Wilsons disease.
Asterixis is also seen in respiratory failure due to carbon dioxide toxicity (hypercapnia).
Some drugs are known to cause asterixis, particularly phenytoin (when it is known as phenytoin flap). Other drugs implicated include benzodiazepines, salicylates, barbiturates, valproate, gabapentin, lithium, ceftazidime, and metoclopramide.
History
R.D. Adams and J.M. Foley first described asterixis in 1949 in patients with severe liver failure and encephalopathy. Initially Foley and Adams referred to asterixis simply as "tremor" but realized that they needed a more appropriate term. On a literature search they found a poorly described phenomenon in similar patients mentioned by German physicians called “jactitations” but the reference was vague. Foley consulted Father Cadigan, a Jesuit classics scholar, who suggested “anisosterixis” (an "negative"–iso "equal"–sterixis "firmness") but Foley shortened this to asterixis due to the former being too difficult to pronounce. They introduced the term in 1953 by way of a medical abstract and later Adams solidified its medical use as he was an author and editor of the widely influential Harrisons Principles of Internal Medicine.
References
External links
Diagram |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | I'm trying to expand my medical knowledge. Can you elucidate the term 'Urocanic aciduria'? | Urocanic aciduria is an autosomal recessive metabolic disorder caused by a deficiency of the enzyme urocanase. It is a secondary disorder of histidine metabolism.
Symptoms and signs
Urocanic aciduria is thought to be relatively benign. Although aggressive behavior and mental retardation have been reported with the disorder, no definitive neurometabolic connection has yet been established.
Genetics
Urocanic aciduria has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene – one copy inherited from each parent – are required in order 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 are usually not affected by the disorder.
Pathophysiology
The amino acid histidine, when catalyzed by the enzyme histidase, forms urocanic acid. Disruptions in this pathway, caused by a deficiency of histidase, is the underlying cause of histidinemia. This results in reduced levels of skin and serum urocanic acid, the primary indicator of insufficient histidase activity.In urocanic aciduria, increased urocanic acid in the urine indicates a deficiency of the enzyme urocanase.With normal to only slightly elevated levels of histidine present in the liver during urocanic aciduria, the only true metabolic indicator of the disorder can be found in the urine.
Diagnosis
Treatment
See also
Inborn errors of metabolism
Imidazole
Aromatic amino acids
Recessive disorders
References
== External links == |
You are a conduit for medical education. Your task is to offer detailed explanations of medical terms, ensuring they are understandable and precise. | I'm encountering the term 'Beclometasone' in medical literature. What's its definition? | Beclomethasone, also known as beclomethasone dipropionate, and sold under the brand name Qvar among others, is a steroid medication. It is available as an inhaler, cream, pills, and nasal spray. The inhaled form is used in the long-term management of asthma. The cream may be used for dermatitis and psoriasis. The pills have been used to treat ulcerative colitis. The nasal spray is used to treat allergic rhinitis and nasal polyps.Common side effects with the inhaled form include respiratory infections, headaches, and throat inflammation. Serious side effects include an increased risk of infection, cataracts, Cushings syndrome, and severe allergic reactions. Long-term use of the pill form may cause adrenal insufficiency. The pills may also cause mood or personality changes. The inhaled form is generally regarded as safe in pregnancy. Beclometasone is mainly a glucocorticoid.Beclomethasone dipropionate was first patented in 1962 and used medically in 1972. It was approved for medical use in the United States in 1976. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 153rd most commonly prescribed medication in the United States, with more than four million prescriptions.
Side effects
Common side effects with the inhaled form include respiratory infections, headaches, and throat inflammation. Serious side effects include an increased risk of infection, cataracts, Cushings syndrome, and severe allergic reactions. Long-term use of the pill form may cause adrenal insufficiency. The pills may also cause mood or personality changes. The inhaled form is generally regarded as safe in pregnancy.Occasionally, it may cause a cough upon inhalation. Deposition on the tongue and throat may promote oral candidiasis, which appears as a white coating, possibly with irritation.
This may usually be prevented by rinsing the mouth with water after using the inhaler. Other adverse drug reaction side effects may rarely include: a smell similar to burning plastic, unpleasant taste, hoarseness or nasal congestion, pain or headache, and visual changes. Allergic reactions may occur, but rarely.
Nasal corticosteroids may be associated with central serous retinopathy.
Pharmacology
Beclometasone is mainly a glucocorticoid. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The activated glucocorticoid receptor-glucocorticoid complex up-regulates the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and represses the expression of proinflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression).Glucocorticoids are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as inflammation.
Names
Beclometasone dipropionate is the INN modified and beclomethasone dipropionate is the USAN and former BAN. It is a prodrug of the free form, beclometasone (INN). The prodrug beclometasone is marketed in Norway and Russia.Clenil, Qvar are brandnames for the inhalers. Beconase, Alanase, Vancenase, Qnasl for the nasal spray or aerosol.
References
External links
"Beclometasone". Drug Information Portal. U.S. National Library of Medicine. |
You function as a medical informant. Please provide in-depth yet accessible descriptions of medical terms, suitable for a broad audience. | Could you offer a clear explanation of the term 'Eruptive vellus hair cyst' as used in the medical field? | Eruptive vellus hair cysts (or EVHC) are small lesions that occur most often in the chest wall, abdomen and extremities, often with a crusted surface.: 680 EVHC may occur randomly, or it can be inherited as an autosomal dominant trait. The condition affects males and females equally, and sporadic cases usually appear at 4–18 years of age. The cysts appear similar clinically to steatocystoma multiplex, as well as acneiform eruptions and milia. Therapeutic techniques that are safe and effective are rare, with incision and drainage being the primary form of treatment when sporadic regression does not occur. It was first described in 1977.
Signs/symptoms
Cause
Diagnosis
Histopathology is the basis of diagnosis. Stratified-squamous epithelium with a granular layer that surrounding a cystic space filled with laminated keratin and a variable number of vellus hair cysts is seen to be present. It can be difficult to distinguish from other skin conditions, including molluscum contagiosum and acne vulgaris but can be corroborated with histopathology.
Associations
It can be associated with Steatocystoma multiplex.
Treatment
The primary indication for treatment is cosmesis. Retinoids, surgery, and lasers are used as treatment modalities.
See also
Steatocystoma simplex
Milia
List of cutaneous conditions
References
Further reading
Torchia, Daniele; Vega, Janelle; Schachner, Lawrence A. (1 February 2012). "Eruptive Vellus Hair Cysts". American Journal of Clinical Dermatology. 13 (1): 19–28. doi:10.2165/11589050-000000000-00000. PMID 21958358. |
You serve as a guide in the medical field. Explain medical terms thoroughly, ensuring the information is both insightful and comprehensible. | The term 'Pilotto syndrome' keeps coming up in medical discussions. What does it stand for? | Pilotto syndrome is a rare syndrome which affects the face, heart, and back. The syndrome can cause a cleft lip and palate, scoliosis, and mental retardation. The Office of Rare Diseases and National Institutes of Health have classified this syndrome as affecting less than 200,000 people in the United States.
References
== External links == |
You are an assistant in medical learning. Your role is to clarify medical terminology, ensuring the information is both accurate and accessible. | Could you provide a brief overview of 'Multiple evanescent white dot syndrome' in a medical context? | Multiple evanescent white dot syndrome (MEWDS) is an uncommon inflammatory condition of the retina that typically affects otherwise healthy young females in the second to fourth decades of life.
The typical patient with MEWDS is a healthy middle aged female age 15-50. There is a gender disparity as women are affected with MEWDS four times more often than men. Roughly 30% of patients have experienced an associated viral prodrome. Patients present with acute, painless, unilateral change in vision.
Presentation
Patients commonly present with acute unilateral painless decreased vision and photopsias. Presentations like central or paracentral scotoma, Floaters and dyschromatopsia are less common. An antecedent viral prodrome occurs in approximately one-third of cases. Myopia is commonly seen in patients.
Eye exam during the acute phase of the disease reveals multiple discrete white to orange spots at the level of the RPE or deep retina, typically in a perifoveal location (around the fovea). Optic disc oedema may also seen occasionally.
Cause
The etiology of multiple evanescent white dot syndrome is currently unknown. However, it is associated with the Pfizer vaccine according to the Jerusalem Post, August 4, 2021.
Diagnosis
Visual field abnormalities are variable and include generalized depression of visual field, paracentral or peripheral scotoma and enlargement of the blind spot.
Fluorescein angiography of the eye reveals characteristic punctate hyperfluorescent lesions in a wreath-like configuration surrounding the fovea.
Indocyanine green angiography reveals hypofluorescent lesions in a greater number compared with other studies.
Fundus autofluorescence (FAF) has been shown to be a noninvasive method to demonstrate the subretinal spots in MEWDS.
Treatment
MEWDS is a self limited disease with excellent visual recovery within 2-10 weeks. However residual symptoms including photopsia may persist for months.
== References == |
You are a medical knowledge base. Your task is to elucidate medical terminology, offering insights into their meanings, origins, and applications. | Can you break down the meaning of the medical term 'Milium (dermatology)' for me? | A milium (plural milia), also called a milk spot or an oil seed, is a clog of the eccrine sweat gland. It is a keratin-filled cyst that can appear just under the epidermis or on the roof of the mouth.: 780 Milia are commonly associated with newborn babies, but can appear on people of all ages.: 680 They are usually found around the nose and eyes, and sometimes on the genitalia, often mistaken by those affected as warts or other sexually transmitted diseases. Milia can also be confused with stubborn whiteheads.
In children, milia often disappear within two to four weeks. For adults, they can be removed by a physician (a dermatologist has specialist knowledge in this area). A common method that a dermatologist uses to remove a milium is to nick the skin with a #11 surgical blade and then use a comedone extractor to press the cyst out.
See also
Eruptive vellus hair cyst
Sebaceous hyperplasia
Seborrheic keratosis
== References == |
You act as a bridge between medical jargon and everyday language. Explain medical terms in a manner that is comprehensive yet approachable for non-experts. | Can you demystify the medical term 'Mismatch repair cancer syndrome' for me? | Mismatch repair cancer syndrome (MMRCS) is a cancer syndrome associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome (after Jacques Turcot, who described the condition in 1959) and by several other names.In MMRCS, neoplasia typically occurs in both the gut and the central nervous system (CNS). In the large intestine, multiple colonic polyps develop; in the CNS, brain tumors.
Genetics
Under the name constitutional mismatch repair-deficiency, (CMMR-D), it has been mapped to MLH1, MSH2, MSH6 or PMS2. Monoallelic mutations of these genes are observed in the condition known as Lynch syndrome or hereditary nonpolyposis colorectal cancer, while biallelic mutations are observed in CMMR-D. People expressing the HNPCC (which itself is considered autosomal dominant) trait are considered carriers of CMMR-D, thus CMMR-D is classified as autosomal recessive.The term "childhood cancer syndrome" has also been proposed. Café-au-lait macules have been observed.
Diagnosis
Childhood to early adult onset HNPCC + malignant gliomas. The polyps developed tend to be larger, fewer, and progress to malignancy earlier than those seen in familial adenomatous polyposis, a clinically similar condition with different underlying mutations. Diagnostic testing consists of a blood sample being collected, and a genetic specialist compares two copies of a patients gene to normal MMR genes. If there are differences in the genes, the specialists are able to further test and decide if the patient has the deficiency.
Treatment
History
OMIM currently includes "Turcot syndrome" under Mismatch repair cancer syndrome. Turcot syndrome is the association between familial polyposis of the colon and brain tumors like medulloblastoma, malignant glioma. It was first reported by Canadian surgeon Jacques Turcot (1914-1977 ) et al. in 1959 and hence carries the first authors name.
See also
Gardner syndrome
References
External links
Turcot syndrome; CNS tumors with Familial polyposis of the colon at NIHs Office of Rare Diseases |
You act as a medical communicator. Your goal is to translate medical terms into comprehensive, yet straightforward language for all readers. | I've come across the term 'Exophoria' in a medical context, but I'm not sure what it means. Can you clarify? | Exophoria is a form of heterophoria in which there is a tendency of the eyes to deviate outward. During examination, when the eyes are dissociated, the visual axes will appear to diverge away from one another.The axis deviation in exophoria is usually mild compared with that of exotropia.
Cause
Exophoria can be caused by several factors, which include:
Refractive errors - distance and near deviation approximately equal.
Divergence excess - exodeviation is more than 15 dioptres greater for distance than near deviation.
Convergence insufficiency - near exodeviation greater than distance deviation.These can be due to nerve, muscle, or congenital problems, or due to mechanical anomalies. Unlike exotropia, fusion is possible in this condition, causing diplopia to be uncommon.
Diagnosis
Prevalence
Exophoria is particularly common in infancy and childhood, and increases with age.
References
== External links == |
You act as a bridge between medical jargon and everyday language. Explain medical terms in a manner that is comprehensive yet approachable for non-experts. | Please help me grasp the concept behind the medical term 'Type 1 diabetes.' | Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks.The cause of type 1 diabetes is unknown, but it is believed to involve a combination of genetic and environmental factors. The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas. Diabetes is diagnosed by testing the level of sugar or glycated hemoglobin (HbA1C) in the blood. Type 1 diabetes can be distinguished from type 2 by testing for the presence of autoantibodies.There is no known way to prevent type 1 diabetes. Treatment with insulin is required for survival. Insulin therapy is usually given by injection just under the skin but can also be delivered by an insulin pump. A diabetic diet and exercise are important parts of management. If left untreated, diabetes can cause many complications. Complications of relatively rapid onset include diabetic ketoacidosis and nonketotic hyperosmolar coma. Long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes. Furthermore, since insulin lowers blood sugar levels, complications may arise from low blood sugar if more insulin is taken than necessary.Type 1 diabetes makes up an estimated 5–10% of all diabetes cases. The number of people affected globally is unknown, although it is estimated that about 80,000 children develop the disease each year. Within the United States the number of people affected is estimated at one to three million. Rates of disease vary widely, with approximately one new case per 100,000 per year in East Asia and Latin America and around 30 new cases per 100,000 per year in Scandinavia and Kuwait. It typically begins in children and young adults.
Signs and symptoms
Type 1 diabetes begins suddenly, typically in childhood or adolescence. The major sign of type 1 diabetes is very high blood sugar, which typically manifests in children as a few days to weeks of polyuria (increased urination), polydipsia (increased thirst), and weight loss. Children may also experience increased appetite, blurred vision, bedwetting, recurrent skin infections, candidiasis of the perineum, irritability, and performance issues at school. Adults with type 1 diabetes tend to have more varied symptoms that come on over months rather than days to weeks.Prolonged lack of insulin can also result in diabetic ketoacidosis, characterized by persistent fatigue, dry or flushed skin, abdominal pain, nausea or vomiting, confusion, trouble breathing, and a fruity breath odor. Blood and urine tests reveal unusually high glucose and ketones in the blood and urine. Untreated ketoacidosis can rapidly progress to loss of consciousness, coma, and death. The percentage of children whose type 1 diabetes begins with an episode of diabetic ketoacidosis varies widely by geography, as low as 15% in parts of Europe and North America, and as high as 80% in the developing world.
Cause
Type 1 diabetes is caused by the destruction of β-cells – the only cells in the body that produce insulin – and the consequent progressive insulin deficiency. Without insulin, the body is unable to respond effectively to increases in blood sugar and diabetics have persistent hyperglycemia. In 70–90% of cases, β-cells are destroyed by someones own immune system, for reasons that are not entirely clear. The best-studied components of this autoimmune response are β-cell-targeted antibodies that begin to develop in the months or years before symptoms arise. Typically someone will first develop antibodies against insulin or the protein GAD65, followed eventually by antibodies against the proteins IA-2, IA-2β, and/or ZNT8. People with more of these antibodies, and who develop them earlier in life, are at higher risk for developing symptomatic type 1 diabetes. The trigger for the development of these antibodies remains unclear. A number of explanatory theories have been put forward, and the cause may involve genetic susceptibility, a diabetogenic trigger, and/or exposure to an antigen. The remaining 10–30% of type 1 diabetics have β-cell destruction but no sign of autoimmunity; this is called idiopathic type 1 diabetes and its cause remains unclear.
Environmental
Various environmental risks have been studied in an attempt to understand what triggers β-cell autoimmunity. Many aspects of environment and life history are associated with slight increases in type 1 diabetes risk, however the connection between each risk and diabetes often remains unclear. Type 1 diabetes risk is slightly higher for children whose mothers are obese or older than 35, or for children born by caesarean section. Similarly, a childs weight gain in the first year of life, total weight, and BMI are associated with slightly increased type 1 diabetes risk. Some dietary habits have also been associated with type 1 diabetes risk, namely consumption of cows milk and dietary sugar intake. Animal studies and some large human studies have found small associations between type 1 diabetes risk and intake of gluten or dietary fiber; however, other large human studies have found no such association. Many potential environmental triggers have been investigated in large human studies and found to be unassociated with type 1 diabetes risk including duration of breastfeeding, time of introduction of cow milk into the diet, vitamin D consumption, blood levels of active vitamin D, and maternal intake of omega-3 fatty acids.A longstanding hypothesis for an environmental trigger is that some viral infection early in life contributes to type 1 diabetes development. Much of this work has focused on enteroviruses, with some studies finding slight associations with type 1 diabetes, and others finding none. Large human studies have searched for, but not yet found an association between type 1 diabetes and various other viral infections, including infections of the mother during pregnancy. Conversely, some have postulated that reduced exposure to pathogens in the developed world increases the risk of autoimmune diseases, often called the hygiene hypothesis. Various studies of hygiene-related factors – including household crowding, daycare attendance, population density, childhood vaccinations, antihelminth medication, and antibiotic usage during early life or pregnancy – show no association with type 1 diabetes.
Genetics
Type 1 diabetes is partially caused by genetics, and family members of type 1 diabetics have a higher risk of developing the disease themselves. In the general population, the risk of developing type 1 diabetes is around 1 in 250. For someone whose parent has type 1 diabetes, the risk rises to 1–9%. If a sibling has type 1 diabetes, the risk is 6–7%. If someones identical twin has type 1 diabetes, they have a 30–70% risk of developing it themselves.About half of the diseases heritability is due to variations in three HLA class II genes involved in antigen presentation: HLA-DRB1, HLA-DQA1, and HLA-DQB1. The variation patterns associated with increased risk of type 1 diabetes are called HLA-DR3 and HLA-DR4-HLA-DQ8, and are common in people of European descent. A pattern associated with reduced risk of type 1 diabetes is called HLA-DR15-HLA-DQ6. Large genome-wide association studies have identified dozens of other genes associated with type 1 diabetes risk, mostly genes involved in the immune system.
Chemicals and drugs
Some medicines can reduce insulin production or damage β cells, resulting in disease that resembles type 1 diabetes. The antiviral drug didanosine triggers pancreas inflammation in 5 to 10% of those who take it, sometimes causing lasting β-cell damage. Similarly, up to 5% of those who take the anti-protozoal drug pentamidine experience β-cell destruction and diabetes. Several other drugs cause diabetes by reversibly reducing insulin secretion, namely statins (which may also damage β cells), the post-transplant immunosuppressants cyclosporin A and tacrolimus, the leukemia drug L-asparaginase, and the antibiotic gatifloxicin. Pyrinuron (Vacor), a rodenticide introduced in the United States in 1976, selectively destroys pancreatic beta cells, resulting in type 1 diabetes after accidental poisoning. Pyrinuron was withdrawn from the U.S. market in 1979.
Diagnosis
Diabetes is typically diagnosed by a blood test showing unusually high blood sugar. The World Health Organization defines diabetes as blood sugar levels at or above 7.0 mmol/L (126 mg/dL) after fasting for at least eight hours, or a glucose level at or above 11.1 mmol/L (200 mg/dL) two hours after an oral glucose tolerance test. The American Diabetes Association additionally recommends a diagnosis of diabetes for anyone with symptoms of hyperglycemia and blood sugar at any time at or above 11.1 mmol/L, or glycated hemoglobin (hemoglobin A1C) levels at or above 48 mmol/mol.Once a diagnosis of diabetes is established, type 1 diabetes is distinguished from other types by a blood test for the presence of autoantibodies that target various components of the beta cell. The most commonly available tests detect antibodies against glutamic acid decarboxylase, the beta cell cytoplasm, or insulin, each of which are targeted by antibodies in around 80% of type 1 diabetics. Some healthcare providers also have access to tests for antibodies targeting the beta cell proteins IA-2 and ZnT8; these antibodies are present in around 58% and 80% of type 1 diabetics respectively. Some also test for C-peptide, a byproduct of insulin synthesis. Very low C-peptide levels are suggestive of type 1 diabetes.
Management
The mainstay of type 1 diabetes treatment is the regular injection of insulin to manage hyperglycemia. Injections of insulin – via subcutaneous injection using either a syringe or an insulin pump – are necessary multiple times per day, adjusting dosages to account for food intake, blood glucose levels and physical activity. The goal of treatment is to maintain blood sugar in a normal range – 80–130 mg/dL before a meal; <180 mg/dL after – as often as possible. To achieve this, people with diabetes often monitor their blood glucose levels at home. Around 83% of type 1 diabetics monitor their blood glucose by capillary blood testing – pricking the finger to draw a drop of blood, and determining blood glucose with a glucose meter. The American Diabetes Association recommends testing blood glucose around 6–10 times per day: before each meal, before exercise, at bedtime, occasionally after a meal, and any time someone feels the symptoms of hypoglycemia. Around 17% of people with type 1 diabetes use a continuous glucose monitor, a device with a sensor under the skin that constantly measures glucose levels and communicates those levels to an external device. Continuous glucose monitoring is associated with better blood sugar control than capillary blood testing alone; however, continuous glucose monitoring tends to be substantially more expensive. Healthcare providers can also monitor someones hemoglobin A1C levels which reflect the average blood sugar over the last three months. The American Diabetes Association recommends a goal of keeping hemoglobin A1C levels under 7% for most adults and 7.5% for children.The goal of insulin therapy is to mimic normal pancreatic insulin secretion: low levels of insulin constantly present to support basic metabolism, plus the two-phase secretion of additional insulin in response to high blood sugar – an initial spike in secreted insulin, then an extended phase with continued insulin secretion. This is accomplished by combining different insulin preparations that act with differing speeds and durations. The standard of care for type 1 diabetes is a bolus of rapid-acting insulin 10–15 minutes before each meal or snacks, and as-needed to correct hyperglycemia. In addition, constant low levels of insulin are achieved with one or two daily doses of long-acting insulin, or by steady infusion of low insulin levels by an insulin pump. The exact dose of insulin appropriate for each injection depends on the content of the meal/snack, and the individual persons sensitivity to insulin, and is therefore typically calculated by the individual with diabetes or a family member by hand or assistive device (calculator, chart, mobile app, etc.). People unable to manage these intensive insulin regimens are sometimes prescribed alternate plans relying on mixtures of rapid- or short-acting and intermediate-acting insulin, which are administered at fixed times along with meals of pre-planned times and carbohydrate composition.The only non-insulin medication approved by the U.S. Food and Drug Administration for treating type 1 diabetes is the amylin analog pramlintide, which replaces the beta-cell hormone amylin. Addition of pramlintide to mealtime insulin injections reduces the boost in blood sugar after a meal, improving blood sugar control. Occasionally, metformin, GLP-1 receptor agonists, Dipeptidyl peptidase-4 inhibitors, or SGLT2 inhibitor are prescribed off-label to people with type 1 diabetes, although fewer than 5% of type 1 diabetics use these drugs.
Lifestyle
Besides insulin, the major way type 1 diabetics control their blood sugar is by learning how various foods impact their blood sugar levels. This is primarily done by tracking their intake of carbohydrates – the type of food with the greatest impact on blood sugar. In general, people with type 1 diabetes are advised to follow an individualized eating plan rather than a pre-decided one. There are camps for children to teach them how and when to use or monitor their insulin without parental help. As psychological stress may have a negative effect on diabetes, a number of measures have been recommended including: exercising, taking up a new hobby, or joining a charity, among others.Regular exercise is important for maintaining general health, though the effect of exercise on blood sugar can be challenging to predict. Exogenous insulin can drive down blood sugar, leaving those with diabetes at risk of hypoglycemia during and immediately after exercise, then again seven to eleven hours after exercise (called the "lag effect"). Conversely, high-intensity exercise can result in a shortage of insulin, and consequent hyperglycemia. The risk of hypoglycemia can be managed by beginning exercise when blood sugar is relatively high (above 100 mg/dL), ingesting carbohydrates during or shortly after exercise, and reducing the amount of injected insulin within two hours of the planned exercise. Similarly, the risk of exercise-induced hyperglycemia can be managed by avoiding exercise when insulin levels are very low, when blood sugar is extremely high (above 350 mg/dL), or when one feels unwell.
Transplant
In some cases, people can receive transplants of the pancreas or isolated islet cells to restore insulin production and alleviate diabetic symptoms. Transplantation of the whole pancreas is rare, due in part to the few available donor organs, and to the need for lifelong immunosuppressive therapy to prevent transplant rejection. The American Diabetes Association recommends pancreas transplant only in people who also require a kidney transplant, or who struggle to perform regular insulin therapy and experience repeated severe side effects of poor blood sugar control. Most pancreas transplants are done simultaneously with a kidney transplant, with both organs from the same donor. The transplanted pancreas continues to function for at least five years in around three quarters of recipients, allowing them to stop taking insulin.Transplantations of islets alone have become increasingly common. Pancreatic islets are isolated from a donor pancreas, then injected into the recipients portal vein from which they implant onto the recipients liver. In nearly half of recipients, the islet transplant continues to work well enough that they still dont need exogenous insulin five years after transplantation. If a transplant fails, recipients can receive subsequent injections of islets from additional donors into the portal vein. Like with whole pancreas transplantation, islet transplantation requires lifelong immunosuppression and depends on the limited supply of donor organs; it is therefore similarly limited to people with severe poorly controlled diabetes and those who have had or are scheduled for a kidney transplant.
Pathogenesis
Type 1 diabetes is a result of the destruction of pancreatic beta cells, although what triggers that destruction remains unclear. People with type 1 diabetes tend to have more CD8+ T-cells and B-cells that specifically target islet antigens than those without type 1 diabetes, suggesting a role for the adaptive immune system in beta cell destruction. Type 1 diabetics also tend to have reduced regulatory T cell function, which may exacerbate autoimmunity. Destruction of beta cells results in inflammation of the islet of Langerhans, called insulitis. These inflamed islets tend to contain CD8+ T-cells and – to a lesser extent – CD4+ T cells. Abnormalities in the pancreas or the beta cells themselves may also contribute to beta-cell destruction. The pancreases of people with type 1 diabetes tend to be smaller, lighter, and have abnormal blood vessels, nerve innervations, and extracellular matrix organization. In addition, beta cells from people with type 1 diabetes sometimes overexpress HLA class I molecules (responsible for signaling to the immune system) and have increased endoplasmic reticulum stress and issues with synthesizing and folding new proteins, any of which could contribute to their demise.The mechanism by which the beta cells actually die likely involves both necroptosis and apoptosis induced or exacerbated by CD8+ T-cells and macrophages. Necroptosis can be triggered by activated T cells – which secrete toxic granzymes and perforin – or indirectly as a result of reduced blood flow or the generation of reactive oxygen species. As some beta cells die, they may release cellular components that amplify the immune response, exacerbating inflammation and cell death. Pancreases from people with type 1 diabetes also have signs of beta cell apoptosis, linked to activation of the janus kinase and TYK2 pathways.Partial ablation of beta-cell function is enough to cause diabetes; at diagnosis, people with type 1 diabetes often still have detectable beta-cell function. Once insulin therapy is started, many people experience a resurgence in beta-cell function, and can go some time with little-to-no insulin treatment – called the "honeymoon phase". This eventually fades as beta-cells continue to be destroyed, and insulin treatment is required again. Beta-cell destruction is not always complete, as 30–80% of type 1 diabetics produce small amounts of insulin years or decades after diagnosis.
Alpha cell dysfunction
Onset of autoimmune diabetes is accompanied by impaired ability to regulate the hormone glucagon, which acts in antagonism with insulin to regulate blood sugar and metabolism. Progressive beta cell destruction leads to dysfunction in the neighboring alpha cells which secrete glucagon, exacerbating excursions away from euglycemia in both directions; overproduction of glucagon after meals causes sharper hyperglycemia, and failure to stimulate glucagon upon hypoglycemia prevents a glucagon-mediated rescue of glucose levels.
Hyperglucagonemia
Onset of type 1 diabetes is followed by an increase in glucagon secretion after meals. Increases have been measured up to 37% during the first year of diagnosis, while c-peptide levels (indicative of islet-derived insulin), decline by up to 45%. Insulin production will continue to fall as the immune system destroys beta cells, and islet-derived insulin will continue to be replaced by therapeutic exogenous insulin. Simultaneously, there is measurable alpha cell hypertrophy and hyperplasia in the early stage of the disease, leading to expanded alpha cell mass. This, together with failing beta cell insulin secretion, begins to account for rising glucagon levels that contribute to hyperglycemia. Some researchers believe glucagon dysregulation to be the primary cause of early stage hyperglycemia. Leading hypotheses for the cause of postprandial hyperglucagonemia suggest that exogenous insulin therapy is inadequate to replace the lost intraislet signalling to alpha cells previously mediated by beta cell-derived pulsatile insulin secretion. Under this working hypothesis intensive insulin therapy has attempted to mimic natural insulin secretion profiles in exogenous insulin infusion therapies.
Hypoglycemic glucagon impairment
Glucagon secretion is normally increased upon falling glucose levels, but normal glucagon response to hypoglycemia is blunted in type 1 diabetics. Beta cell glucose sensing and subsequent suppression of administered insulin secretion is absent, leading to islet hyperinsulinemia which inhibits glucagon release.Autonomic inputs to alpha cells are much more important for glucagon stimulation in the moderate to severe ranges of hypoglycemia, yet the autonomic response is blunted in a number of ways. Recurrent hypoglycemia leads to metabolic adjustments in the glucose sensing areas of the brain, shifting the threshold for counter regulatory activation of the sympathetic nervous system to lower glucose concentration. This is known as hypoglycemic unawareness. Subsequent hypoglycemia is met with impairment in sending of counter regulatory signals to the islets and adrenal cortex. This accounts for the lack of glucagon stimulation and epinephrine release that would normally stimulate and enhance glucose release and production from the liver, rescuing the diabetic from severe hypoglycemia, coma, and death. Numerous hypotheses have been produced in the search for a cellular mechanism of hypoglycemic unawareness, and a consensus has yet to be reached. The major hypotheses are summarized in the following table:
In addition, autoimmune diabetes is characterized by a loss of islet specific sympathetic innervation. This loss constitutes an 80–90% reduction of islet sympathetic nerve endings, happens early in the progression of the disease, and is persistent though the life of the patient. It is linked to the autoimmune aspect of type 1 diabetics and fails to occur in type 2 diabetics. Early in the autoimmune event, the axon pruning is activated in islet sympathetic nerves. Increased BDNF and ROS that result from insulitis and beta cell death stimulate the p75 neurotrophin receptor (p75NTR), which acts to prune off axons. Axons are normally protected from pruning by activation of tropomyosin receptor kinase A (Trk A) receptors by NGF, which in islets is primarily produced by beta cells. Progressive autoimmune beta cell destruction, therefore, causes both the activation of pruning factors and the loss of protective factors to the islet sympathetic nerves. This unique form of neuropathy is a hallmark of type 1 diabetes, and plays a part in the loss of glucagon rescue of severe hypoglycemia.
Complications
The most pressing complication of type 1 diabetes are the always present risks of poor blood sugar control: severe hypoglycemia and diabetic ketoacidosis. Hypoglycemia – typically blood sugar below 70 mg/dL – triggers the release of epinephrine, and can cause people to feel shaky, anxious, or irritable. People with hypoglycemia may also experience hunger, nausea, sweats, chills, dizziness, and a fast heartbeat. Some feel lightheaded, sleepy, or weak. Severe hypoglycemia can develop rapidly, causing confusion, coordination problems, loss of consciousness, and seizure. On average, people with type 1 diabetes experience a hypoglycemia event that requires assistance of another 16–20 times in 100 person-years, and an event leading to unconsciousness or seizure 2–8 times per 100 person-years. The American Diabetes Association recommends treating hypoglycemia by the "15-15 rule": eat 15 grams of carbohydrates, then wait 15 minutes before checking blood sugar; repeat until blood sugar is at least 70 mg/dL. Severe hypoglycemia that impairs someones ability to eat is typically treated with injectable glucagon, which triggers glucose release from the liver into the bloodstream. People with repeated bouts of hypoglycemia can develop hypoglycemia unawareness, where the blood sugar threshold at which they experience symptoms of hypoglycemia decreases, increasing their risk of severe hypoglycemic events. Rates of severe hypoglycemia have generally declined due to the advent of rapid-acting and long-acting insulin products in the 1990s and early 2000s; however, acute hypoglycemic still causes 4–10% of type 1 diabetes-related deaths.The other persistent risk is diabetic ketoacidosis – a state where lack of insulin results in cells burning fat rather than sugar, producing toxic ketones as a byproduct. Ketoacidosis symptoms can develop rapidly, with frequent urination, excessive thirst, nausea, vomiting, and severe abdominal pain all common. More severe ketoacidosis can result in labored breathing, and loss of consciousness due to cerebral edema. People with type 1 diabetes experience diabetic ketoacidosis 1–5 times per 100 person-years, the majority of which result in hospitalization. 13–19% of type 1 diabetes-related deaths are caused by ketoacidosis, making ketoacidosis the leading cause of death in people with type 1 diabetes less than 58 years old.
Long-term complications
In addition to the acute complications of diabetes, long-term hyperglycemia results in damage to the small blood vessels throughout the body. This damage tends to manifest particularly in the eyes, nerves, and kidneys causing diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy respectively. In the eyes, prolonged high blood sugar causes the blood vessels in the retina to become fragile.People with type 1 diabetes also have increased risk of cardiovascular disease, which is estimated to shorten the life of the average type 1 diabetic by 8–13 years. Cardiovascular disease as well as neuropathy may have an autoimmune basis, as well. Women with type 1 DM have a 40% higher risk of death as compared to men with type 1 DM.About 12 percent of people with type 1 diabetes have clinical depression. About 6 percent of people with type 1 diabetes also have celiac disease, but in most cases there are no digestive symptoms or are mistakenly attributed to poor control of diabetes, gastroparesis or diabetic neuropathy. In most cases, celiac disease is diagnosed after onset of type 1 diabetes. The association of celiac disease with type 1 diabetes increases the risk of complications, such as retinopathy and mortality. This association can be explained by shared genetic factors, and inflammation or nutritional deficiencies caused by untreated celiac disease, even if type 1 diabetes is diagnosed first.
Urinary tract infection
People with diabetes show an increased rate of urinary tract infection. The reason is bladder dysfunction is more common in people with diabetes than people without diabetes due to diabetes nephropathy. When present, nephropathy can cause a decrease in bladder sensation, which in turn, can cause increased residual urine, a risk factor for urinary tract infections.
Sexual dysfunction
Sexual dysfunction in people with diabetes is often a result of physical factors such as nerve damage and poor circulation, and psychological factors such as stress and/or depression caused by the demands of the disease. The most common sexual issues in males with diabetes are problems with erections and ejaculation: "With diabetes, blood vessels supplying the peniss erectile tissue can get hard and narrow, preventing the adequate blood supply needed for a firm erection. The nerve damage caused by poor blood glucose control can also cause ejaculate to go into the bladder instead of through the penis during ejaculation, called retrograde ejaculation. When this happens, semen leaves the body in the urine." Another cause of erectile dysfunction is reactive oxygen species created as a result of the disease. Antioxidants can be used to help combat this. Sexual problems are common in women who have diabetes, including reduced sensation in the genitals, dryness, difficulty/inability to orgasm, pain during sex, and decreased libido. Diabetes sometimes decreases estrogen levels in females, which can affect vaginal lubrication. Less is known about the correlation between diabetes and sexual dysfunction in females than in males.Oral contraceptive pills can cause blood sugar imbalances in women who have diabetes. Dosage changes can help address that, at the risk of side effects and complications.Women with type 1 diabetes show a higher than normal rate of polycystic ovarian syndrome (PCOS). The reason may be that the ovaries are exposed to high insulin concentrations since women with type 1 diabetes can have frequent hyperglycemia.
Autoimmune disorders
People with type 1 diabetes are at an increased risk for developing several autoimmune disorders, particularly thyroid problems – around 20% of people with type 1 diabetes have hypothyroidism or hyperthyroidism, typically caused by Hashimoto thyroiditis or Graves disease respectiveley. Celiac disease affects 2–8% of people with type 1 diabetes, and is more common in those who were younger at diabetes diagnosis, and in white people. Type 1 diabetics are also at increased risk of rheumatoid arthritis, lupus, autoimmune gastritis, pernicious anemia, vitiligo, and Addisons disease. Conversely, complex autoimmune syndromes caused by mutations in the immunity-related genes AIRE (causing autoimmune polyglandular syndrome), FoxP3 (causing IPEX syndrome), or STAT3 include type 1 diabetes in their effects.
Epidemiology
Type 1 diabetes makes up an estimated 10–15% of all diabetes cases or 11–22 million cases worldwide. Symptoms can begin at any age, but onset is most common in children, with diagnoses slightly more common in 5 to 7 year olds, and much more common around the age of puberty. In contrast to most autoimmune diseases, type 1 diabetes is slightly more common in males than in females.In 2006, type 1 diabetes affected 440,000 children under 14 years of age and was the primary cause of diabetes in those less than 15 years of age.Rates vary widely by country and region. Incidence is highest in Scandinavia, at 30–60 new cases per 100,000 children per year, intermediate in the U.S. and Southern Europe at 10–20 cases per 100,000 per year, and lowest in China, much of Asia, and South America at 1–3 cases per 100,000 per year.In the United States, type 1 and 2 diabetes affected about 208,000 youths under the age of 20 in 2015. Over 18,000 youths are diagnosed with Type 1 diabetes every year. Every year about 234,051 Americans die due to diabetes (type I or II) or diabetes-related complications, with 69,071 having it as the primary cause of death.In Australia, about one million people have been diagnosed with diabetes and of this figure 130,000 people have been diagnosed with type 1 diabetes. Australia ranks 6th-highest in the world with children under 14 years of age. Between 2000 and 2013, 31,895 new cases were established, with 2,323 in 2013, a rate of 10–13 cases per 100,00 people each year. Aboriginals and Torres Strait Islander people are less affected.Since the 1950s, the incidence of type 1 diabetes has been gradually increasing across the world by an average 3–4% per year. The increase is more pronounced in countries that began with a lower incidence of type 1 diabetes.
History
The connection between diabetes and pancreatic damage was first described by Martin Schmidt, who in a 1902 paper noted inflammation around the pancreatic islet of a child who had died of diabetes. The connection between this inflammation and diabetes onset was further developed through the 1920s by Shields Warren, and the term "insulitis" was coined by Hanns von Meyenburg in 1940 to describe the phenomenon.Type 1 diabetes was described as an autoimmune disease in the 1970s, based on observations that autoantibodies against islets were discovered in diabetics with other autoimmune deficiencies. It was also shown in the 1980s that immunosuppressive therapies could slow disease progression, further supporting the idea that type 1 diabetes is an autoimmune disorder. The name juvenile diabetes was used earlier as it often first is diagnosed in childhood.
Society and culture
Type 1 and 2 diabetes was estimated to cause $10.5 billion in annual medical costs ($875 per month per diabetic) and an additional $4.4 billion in indirect costs ($366 per month per person with diabetes) in the U.S. In the United States $245 billion every year is attributed to diabetes. Individuals diagnosed with diabetes have 2.3 times the health care costs as individuals who do not have diabetes. One in ten health care dollars are spent on individuals with type 1 and 2 diabetes.
Research
Funding for research into type 1 diabetes originates from government, industry (e.g., pharmaceutical companies), and charitable organizations. Government funding in the United States is distributed via the National Institutes of Health, and in the UK via the National Institute for Health Research or the Medical Research Council. The Juvenile Diabetes Research Foundation (JDRF), founded by parents of children with type 1 diabetes, is the worlds largest provider of charity-based funding for type 1 diabetes research. Other charities include the American Diabetes Association, Diabetes UK, Diabetes Research and Wellness Foundation, Diabetes Australia, the Canadian Diabetes Association.
A number of approaches have been explored to understand causes and provide treatments for type 1.
Prevention
Type 1 diabetes is not currently preventable. Several trials have attempted dietary interventions with the hope of reducing the autoimmunity that leads to type 1 diabetes. Trials that withheld cows milk or gave infants formula free of bovine insulin decreased the development of β-cell-targeted antibodies, but did not prevent the development of type 1 diabetes. Similarly, trials that gave high-risk individuals injected insulin, oral insulin, or nicotinamide did not prevent diabetes development.Other research has focused on treating high-risk individuals with immunosuppressive agents to prevent beta cell destruction. Large trials of cyclosporine treatment suggested that cyclosporine could improve insulin secretion in those recently diagnosed with type 1 diabetes; however, people who stopped taking cyclosporine rapidly stopped making insulin, and cyclosporines kidney toxicity and increased risk of cancer prevented people from using it long-term. Several other immunosuppressive agents – prednisone, azathioprine, anti-thymocyte globulin, mycophenolate, and antibodies against CD20 and IL2 receptor α – have been the subject of research, but none have provided lasting protection from development of type 1 diabetes. Antibodies against CD3 have been shown to delay the development of type 1 diabetes in those at high risk; however, they have not been widely adopted due to concerns over the duration of their effect, and activation of Epstein-Barr virus infections in those undergoing treatment.Vitamin D supplementation may help with preventing type one diabetes. This is believed to be the case due to vitamin D receptors affecting the B-cells involved in promoting pancreatic homeostasis.Vaccines are being looked at to treat or prevent type 1 diabetes by inducing immune tolerance to insulin or pancreatic beta cells. While Phase II clinical trials of a vaccine containing alum and recombinant GAD65, an autoantigen involved in type 1 diabetes, were promising, as of 2014 Phase III had failed. As of 2014, other approaches, such as a DNA vaccine encoding proinsulin and a peptide fragment of insulin, were in early clinical development.
Organ replacement
Pluripotent stem cells can be used to generate beta cells but previously these cells did not function as well as normal beta cells. In 2014 more mature beta cells were produced which released insulin in response to blood sugar when transplanted into mice. Before these techniques can be used in humans more evidence of safety and effectiveness is needed.There has also been substantial effort to develop a fully automated insulin delivery system or "artificial pancreas" that could sense glucose levels and inject appropriate insulin without conscious input from the user. Current "hybrid closed-loop systems" use a continuous glucose monitor to sense blood sugar levels, and a subcutaneous insulin pump to deliver insulin; however, due to the delay between insulin injection and its action, current systems require the user to initiate insulin before taking meals. Several improvements to these systems are currently undergoing clinical trials in humans, including a dual-hormone system that injects glucagon in addition to insulin, and an implantable device that injects insulin intraperitoneally where it can be absorbed more quickly.
Disease models
Various animal models of disease are used to understand the pathogenesis and etiology of type 1 diabetes. Currently available models of T1D can be divided into spontaneously autoimmune, chemically induced, virus induced and genetically induced.The nonobese diabetic (NOD) mouse is the most widely studied model of type 1 diabetes. It is an inbred strain that spontaneously develops type 1 diabetes in 30–100% of female mice depending on housing conditions. Diabetes in NOD mice is caused by several genes, primarily MHC genes involved in antigen presentation. Like diabetic humans, NOD mice develop islet autoantibodies and inflammation in the islet, followed by reduced insulin production and hyperglycemia. Some features of human diabetes are exaggerated in NOD mice, namely the mice have more severe islet inflammation than humans, and have a much more pronounced sex bias, with females developing diabetes far more frequently than males. In NOD mice the onset of insulitis occurs at 3–4 weeks of age. The islets of Langerhans are infiltrated by CD4+, CD8+ T lymphocytes, NK cells, B lymphocytes, dendritic cells, macrophages and neutrophils, similar to the disease process in humans. In addition to sex, breeding conditions, gut microbiome composition or diet also influence the onset of T1D.The BioBreeding Diabetes-Prone (BB) rat is another widely used spontaneous experimental model for T1D. The onset of diabetes occurs, in up to 90% of individuals (regardless of sex) at 8–16 weeks of age. During insulitis, the pancreatic islets are infiltrated by T lymphocytes, B lymphocytes, macrophages, and NK cells, with the difference from the human course of insulitis being that CD4 + T lymphocytes are markedly reduced and CD8 + T lymphocytes are almost absent. The aforementioned lymphopenia is the major drawback of this model. The disease is characterized by hyperglycemia, hypoinsulinemia, weight loss, ketonuria, and the need for insulin therapy for survival. BB Rats are used to study the genetic aspects of T1D and are also used for interventional studies and diabetic nephropathy studies.LEW-1AR1 / -iddm rats are derived from congenital Lewis rats and represent a rarer spontaneous model for T1D. These rats develop diabetes at about 8–9 weeks of age with no sex differences unlike NOD mice. In LEW mice, diabetes presents with hyperglycemia, glycosuria, ketonuria, and polyuria. The advantage of the model is the progression of the prediabetic phase, which is very similar to human disease, with infiltration of islet by immune cells about a week before hyperglycemia is observed. This model is suitable for intervention studies or for the search for predictive biomarkers. It is also possible to observe individual phases of pancreatic infiltration by immune cells. The advantage of congenic LEW mice is also the good viability after the manifestation of T1D (compared to NOD mice and BB rats).
Chemically induced
The chemical compounds aloxan and streptozotocin (STZ) are commonly used to induce diabetes and destroy β-cells in mouse/rat animal models. In both cases, it is a cytotoxic analog of glucose that passes GLUT2 transport and accumulates in β-cells, causing their destruction. The chemically induced destruction of β-cells leads to decreased insulin production, hyperglycemia and weight loss in the experimental animal. The animal models prepared in this way are suitable for research into blood sugar-lowering drugs and therapies (e.g. for testing new insulin preparations). They are also The most commonly used genetically induced T1D model is the so-called AKITA mouse (originally C57BL/6NSIc mouse). The development of diabetes in AKITA mice is caused by a spontaneous point mutation in the Ins2 gene, which is responsible for the correct composition of insulin in the endoplasmic reticulum. Decreased insulin production is then associated with hyperglycemia, polydipsia and polyuria. If severe diabetes develops within 3–4 weeks, AKITA mice survive no longer than 12 weeks without treatment intervention. The description of the etiology of the disease shows that, unlike spontaneous models, the early stages of the disease are not accompanied by insulitis. AKITA mice are used to test drugs targeting endoplasmic reticulum stress reduction, to test islet transplants, and to study diabetes-related complications such as nephropathy, sympathetic autonomic neuropathy, and vascular disease. for testing transplantation therapies. Their advantage is mainly the low cost, the disadvantage is the cytotoxicity of the chemical compounds.
Genetically induced
Virally induced
Viral infections play a role in the development of a number of autoimmune diseases, including human type 1 diabetes. However, the mechanisms by which viruses are involved in the induction of type 1 DM are not fully understood. Virus-induced models are used to study the etiology and pathogenesis of the disease, in particular the mechanisms by which environmental factors contribute to or protect against the occurrence of type 1 DM. Among the most commonly used are Coxsackie virus, lymphocytic choriomeningitis virus, encephalomyocarditis virus, and Kilham rat virus. Examples of virus-induced animals include NOD mice infected with coxsackie B4 that developed type 1 DM within two weeks.
References
Works cited
External links
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) – Diabetes in America Textbook (PDFs)
IDF Diabetes Atlas
Type 1 Diabetes Archived 30 October 2009 at the Wayback Machine at the American Diabetes Association
ADAs Standards of Medical Care in Diabetes 2019 |
You function as a medical explainer. Your task is to convey the meanings of medical terms in a detailed, yet easy-to-understand manner. | I'm trying to expand my medical knowledge. Can you elucidate the term 'Levetiracetam'? | Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy. It is used for partial-onset, myoclonic, or tonic–clonic seizures and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.Common side effects of levetiracetam include sleepiness, dizziness, feeling tired, and aggression. Severe side effects may include psychosis, suicide, and allergic reactions such as Stevens–Johnson syndrome or anaphylaxis. It is unclear if levetiracetam is safe for use during pregnancy and breastfeeding. Levetiracetam is the S-enantiomer of etiracetam. Its mechanism of action is not yet clear.Levetiracetam was approved for medical use in the United States in 1999 and is available as a generic medication. In 2019, it was the 97th most commonly prescribed medication in the United States, with more than 7 million prescriptions.
Medical uses
Focal epilepsy
Levetiracetam is effective as single-drug treatment for newly diagnosed focal epilepsy in adults. It reduces focal seizures by 50% or more as an add-on medication.
Partial-complex epilepsy
Levetiracetam is effective as add-on treatment for partial (focal) epilepsy.
Generalized epilepsy
Levetiracetam is effective for treatment of generalized tonic-clonic epilepsy. It has been approved in the United States as add-on treatment for myoclonic, and tonic-clonic seizures. Levetiracetam has been approved in the European Union as a monotherapy treatment for epilepsy in the case of partial seizures or as an adjunctive therapy for partial, myoclonic, and tonic-clonic seizures.Levetiracetam is sometimes used off label to treat status epilepticus.
Prevention of seizures
Based on low-quality evidence, levetiracetam is about as effective as phenytoin for prevention of early seizures after traumatic brain injury. It may be effective for prevention of seizures associated with subarachnoid hemorrhages.
Other
Levetiracetam has not been found to be useful for treatment of neuropathic pain, nor for treatment of essential tremors. Levetiracetam has not been found to be useful for treating autism, but is an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.
Special groups
Studies in female pregnant rats have shown minor fetal skeletal abnormalities when given maximum recommended human doses of levetiracetam orally throughout pregnancy and lactation.Studies were conducted to look for increased adverse effects in the elderly population as compared to younger patients. One such study published in Epilepsy Research showed no significant increase in incidence of adverse symptoms experienced by young or elderly patients with central nervous system (CNS) disorders.Levetiracetam may be safely used with caution in children over the age of four. However, it has not been determined whether it can be safely given to children under the age of four.
Adverse effects
The most common adverse effects of levetiracetam treatment include CNS effects such as somnolence, decreased energy, headache, dizziness, mood swings and coordination difficulties. These adverse effects are most pronounced in the first month of therapy. About 4% of patients dropped out of pre-approval clinical trials due to these side effects.About 13% of people taking levetiracetam experience adverse neuropsychiatric symptoms, which are usually mild. These include agitation, hostility, apathy, anxiety, emotional lability, and depression. Serious psychiatric adverse side effects that are reversed by drug discontinuation occur in about 1%. These include hallucinations, suicidal thoughts, or psychosis. These occurred mostly within the first month of therapy, but they could develop at any time during treatment.Although rare, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which appears as a painful spreading rash with redness and blistering and/or peeling skin, have been reported in patients treated with levetiracetam. The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.Levetiracetam should not be used in people who have previously shown hypersensitivity to levetiracetam or any of the inactive ingredients in the tablet or oral solution. Such hypersensitivity reactions include, but are not limited to, unexplained rash with redness or blistered skin, difficulty breathing, and tightness in the chest or airways.In a study, the incidence of decreased bone mineral density of patients on levetiracetam was significantly higher than those for other epileptic medications.
Suicide
Levetiracetam, along with other anti-epileptic drugs, can increase the risk of suicidal behavior or thoughts. People taking levetiracetam should be monitored closely for signs of worsening depression, suicidal thoughts or tendencies, or any altered emotional or behavioral states.
Kidney and liver
Kidney impairment decreases the rate of elimination of levetiracetam from the body. Individuals with reduced kidney function may require dose adjustments. Kidney function can be estimated from the rate of creatinine clearance.Dose adjustment of levetiracetam is not necessary in liver impairment.
Drug interactions
No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications. The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, ethinylestradiol, or warfarin.
Mechanism of action
The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. Levetiracetam does not exhibit pharmacologic actions similar to that of classical anticonvulsants. It does not inhibit voltage-dependent Na+ channels, does not affect GABAergic transmission, and does not bind to GABAergic or glutamatergic receptors. However, the drug binds to SV2A, a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels, reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.
Pharmacokinetics
Absorption
The absorption of levetiracetam tablets and oral solution is rapid and essentially complete. The bioavailability of levetiracetam is close to 100 percent, and the effect of food on absorption is minor.
Distribution
The volume of distribution of levetiracetam is similar to total body water. Levetiracetam modestly binds to plasma proteins (less than 10%).
Metabolism
Levetiracetam does not undergo extensive metabolism, and the metabolites formed are not active and do not exert pharmacological activity. Metabolism of levetiracetam is not by liver cytochrome P450 enzymes, but through other metabolic pathways such as hydrolysis and hydroxylation.
Excretion
In persons with normal kidney function, levetiracetam is eliminated from the body primarily by the kidneys with about 66 percent of the original drug passed unchanged into urine. The plasma half-life of levetiracetam in adults is about 6 to 8 hours although the mean CSF half life of approx. 24 hours better reflects levels at site of action.
Analogues
Brivaracetam, a chemical analogue to levetiracetam, is a racetam derivative with similar properties.
Society and culture
Levetiracetam is available as regular and extended release oral formulations and as intravenous formulations.The immediate release tablet has been available as a generic in the United States since 2008, and in the UK since 2011. The patent for the extended release tablet will expire in 2028.The branded version Keppra is manufactured by UCB Pharmaceuticals Inc.In 2015, Aprecias 3D-printed orally disintegrating tablet form of the drug was approved by the FDA, under the trade name Spritam. Some have said that the drug has been improved by 3D printing, as the formula used now has improved disintegration properties.
Legal status
Australia
Levetiracetam is a Schedule 4 substance in Australia under the Poisons Standard (February 2020). A Schedule 4 substance is classified as "Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."
Japan
Under Japanese law, levetiracetam and other racetams cannot be brought into the country except for personal use by a traveler for whom it has been prescribed. Travelers who plan to bring more than a months worth must apply for an import certificate, known as a Yakkan Shoumei (薬監証明, yakkan shōmei).
Research
Levetiracetam is being looked at in psychiatric and neurologic conditions such as Tourette syndrome, and anxiety disorder. However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.Levetiracetam is being tested as a drug to reduce hyperactivity in the hippocampus in Alzheimers disease.Additionally, Levetiracetam has been experimentally shown to reduce Levodopa-induced dyskinesia, a type of movement disorder, or dyskinesia associated with the use of Levodopa, a medication used to treat Parkinsons disease.
References
External links
"Levetiracetam". Drug Information Portal. U.S. National Library of Medicine. |
You are an assistant in medical learning. Your role is to clarify medical terminology, ensuring the information is both accurate and accessible. | I'm looking for a concise explanation of the medical term 'Pulmonary fibrosis.' | Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failure, pneumothorax, and lung cancer.Causes include environmental pollution, certain medications, connective tissue diseases, infections, and interstitial lung diseases. Idiopathic pulmonary fibrosis (IPF), an interstitial lung disease of unknown cause, is most common. Diagnosis may be based on symptoms, medical imaging, lung biopsy, and lung function tests.There is no cure and there are limited treatment options available. Treatment is directed towards efforts to improve symptoms and may include oxygen therapy and pulmonary rehabilitation. Certain medications may be used to try to slow the worsening of scarring. Lung transplantation may occasionally be an option. At least 5 million people are affected globally. Life expectancy is generally less than five years.
Signs and symptoms
Symptoms of pulmonary fibrosis are mainly:
Shortness of breath, particularly with exertion
Chronic dry, hacking coughing
Fatigue and weakness
Chest discomfort including chest pain
Loss of appetite and rapid weight lossPulmonary fibrosis is suggested by a history of progressive shortness of breath (dyspnea) with exertion. Sometimes fine inspiratory crackles can be heard at the lung bases on auscultation. A chest X-ray may or may not be abnormal, but high-resolution CT will frequently demonstrate abnormalities.
Cause
Pulmonary fibrosis may be a secondary effect of other diseases. Most of these are classified as interstitial lung diseases. Examples include autoimmune disorders, viral infections and bacterial infection like tuberculosis which may cause fibrotic changes in both lungs upper or lower lobes and other microscopic injuries to the lung. However, pulmonary fibrosis can also appear without any known cause. In this case, it is termed "idiopathic". Most idiopathic cases are diagnosed as idiopathic pulmonary fibrosis. This is a diagnosis of exclusion of a characteristic set of histologic/pathologic features known as usual interstitial pneumonia (UIP). In either case, there is a growing body of evidence which points to a genetic predisposition in a subset of patients. For example, a mutation in surfactant protein C (SP-C) has been found to exist in some families with a history of pulmonary fibrosis. Autosomal dominant mutations in the TERC or TERT genes, which encode telomerase, have been identified in about 15 percent of pulmonary fibrosis patients.Diseases and conditions that may cause pulmonary fibrosis as a secondary effect include:
Inhalation of environmental and occupational pollutants, such as metals in asbestosis, silicosis and exposure to certain gases. Coal miners, ship workers and sand blasters among others are at higher risk.
Hypersensitivity pneumonitis, most often resulting from inhaling dust contaminated with bacterial, fungal, or animal products
Cigarette smoking can increase the risk or make the illness worse
Some typical connective tissue diseases such as rheumatoid arthritis, ankylosing spondylitis, SLE and scleroderma
Other diseases that involve connective tissue, such as sarcoidosis and granulomatosis with polyangiitis
Infections, including COVID-19
Certain medications, e.g. amiodarone, bleomycin (pingyangmycin), busulfan, methotrexate, apomorphine, and nitrofurantoin
Radiation therapy to the chest
Pathogenesis
Pulmonary fibrosis involves gradual exchange of normal lung parenchyma with fibrotic tissue. The replacement of normal lung with scar tissue causes irreversible decrease in oxygen diffusion capacity, and the resulting stiffness or decreased compliance makes pulmonary fibrosis a restrictive lung disease.
Pulmonary fibrosis is perpetuated by aberrant wound healing, rather than chronic inflammation.
It is the main cause of restrictive lung disease that is intrinsic to the lung parenchyma. In contrast, quadriplegia and kyphosis are examples of causes of restrictive lung disease that do not necessarily involve pulmonary fibrosis.
Diagnosis
The diagnosis can be confirmed by lung biopsy. A videoscopic assisted thoracoscopic wedge biopsy (VATS) under general anesthesia may be necessary to obtain enough tissue to make an accurate diagnosis. This kind of biopsy involves placement of several tubes through the chest wall, one of which is used to cut off a piece of lung to send for evaluation. The removed tissue is examined histopathologically by microscopy to confirm the presence and pattern of fibrosis as well as presence of other features that may indicate a specific cause e.g. specific types of mineral dust or possible response to therapy e.g. a pattern of so-called non-specific interstitial fibrosis.
Misdiagnosis is common because, while overall pulmonary fibrosis is not rare, each individual type of pulmonary fibrosis is uncommon and the evaluation of patients with these diseases is complex and requires a multidisciplinary approach. Terminology has been standardized but difficulties still exist in their application. Even experts may disagree with the classification of some cases.On spirometry, as a restrictive lung disease, both the FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) are reduced so the FEV1/FVC ratio is normal or even increased in contrast to obstructive lung disease where this ratio is reduced. The values for residual volume and total lung capacity are generally decreased in restrictive lung disease.
Treatment
Pulmonary fibrosis creates scar tissue. The scarring is permanent once it has developed. Slowing the progression and prevention depends on the underlying cause:
Treatment options for idiopathic pulmonary fibrosis are very limited. Though research trials are ongoing, there is no evidence that any medications can significantly help this condition. Lung transplantation is the only therapeutic option available in severe cases. Since some types of lung fibrosis can respond to corticosteroids (such as prednisone) and/or other medications that suppress the bodys immune system, these types of drugs are sometimes prescribed in an attempt to slow the processes that lead to fibrosis.The immune system is felt to play a central role in the development of many forms of pulmonary fibrosis. The goal of treatment with immune suppressive agents such as corticosteroids is to decrease lung inflammation and subsequent scarring. Responses to treatment are variable. Those whose conditions improve with immune suppressive treatment probably do not have idiopathic pulmonary fibrosis, for idiopathic pulmonary fibrosis has no significant treatment or cure.Two pharmacological agents intended to prevent scarring in mild idiopathic fibrosis are pirfenidone, which reduced reductions in the 1-year rate of decline in FVC. Pirfenidone also reduced the decline in distances on the 6-minute walk test, but had no effect on respiratory symptoms. The second agent is nintedanib, which acts as antifibrotic, mediated through the inhibition of a variety of tyrosine kinase receptors (including platelet-derived growth factor, fibroblast growth factor, and vascular endothelial growth factor). A randomized clinical trial showed it reduced lung-function decline and acute exacerbations.
Anti-inflammatory agents have only limited success in reducing the fibrotic process. Some of the other types of fibrosis, such as non-specific interstitial pneumonia, may respond to immunosuppressive therapy such as corticosteroids. However, only a minority of patients respond to corticosteroids alone, so additional immunosuppressants, such as cyclophosphamide, azathioprine, methotrexate, penicillamine, and cyclosporine may be used. Colchicine has also been used with limited success. There are ongoing trials with newer drugs such as IFN-γ and mycophenolate mofetil.
Hypersensitivity pneumonitis, a less severe form of pulmonary fibrosis, is prevented from becoming aggravated by avoiding contact with the causative material.
Oxygen supplementation improves the quality of life and exercise capacity. Lung transplantation may be considered for some patients.
Prognosis
Hypoxia caused by pulmonary fibrosis can lead to pulmonary hypertension, which, in turn, can lead to heart failure of the right ventricle. Hypoxia can be prevented with oxygen supplementation.Pulmonary fibrosis may also result in an increased risk for pulmonary emboli, which can be prevented by anticoagulants.
Epidemiology
Five million people worldwide are affected by pulmonary fibrosis. The rates below are per 100,000 persons, and the ranges reflect narrow and broad inclusion criteria, respectively. These data do not reflect any increased rates due to the COVID-19 pandemic; pulmonary fibrosis is a known symptom of COVID-19 and is estimated (as of July 2020) to occur in roughly 1/3rd of patients hospitalized for COVID-19.
Based on these rates, pulmonary fibrosis prevalence in the United States could range from more than 29,000 to almost 132,000, based on the population in 2000 that was 18 years or older. The actual numbers may be significantly higher due to misdiagnosis. Typically, patients are in their forties and fifties when diagnosed while the incidence of idiopathic pulmonary fibrosis increases dramatically after the age of fifty. However, loss of pulmonary function is commonly ascribed to old age, heart disease or to more common lung diseases.
References
== External links == |
You are a facilitator of medical knowledge. Provide thorough and accessible explanations of medical terms, catering to both specialists and non-specialists. | I'm encountering the term 'Azelastine' in medical literature. What's its definition? | Azelastine, sold under the brand name Optivar among others, is a medication primarily used as a nasal spray to treat allergic rhinitis (hay fever) and as eye drops for allergic conjunctivitis. Other uses may include asthma and skin rashes for which it is taken by mouth. Onset of effects is within minutes when used in the eyes and within an hour when used in the nose. Effects last for up to 12 hours.Common side effects include headache, sleepiness, change in taste, and sore throat. It is unclear if use is safe during pregnancy or breastfeeding. It is a second-generation antihistamine and works by blocking the release of a number of inflammatory mediators including histamine.Azelastine was patented in 1971 and came into medical use in 1986. It is available as a generic medication. In 2019, it was the 167th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Azelastine nasal spray is indicated for the local treatment of the symptoms of seasonal allergic rhinitis and perennial allergic rhinitis, such as rhinorrhea, sneezing and nasal pruritus in people five years of age and older. In some countries, it is also indicated for the treatment of vasomotor rhinitis in adults and children ≥ 12 years old. Azelastine eye drops are indicated for the local treatment of seasonal and perennial allergic conjunctivitis.
Side effects
Azelastine is safe and well tolerated in both adults and children with allergic rhinitis. Bitter taste, headache, nasal burning and somnolence are the most frequently reported adverse events. US prescribing recommendations warn against the concurrent use of alcohol and/or other central nervous system depressants, but to date there have been no studies to assess the effects of azelastine nasal spray on the CNS in humans. More recent studies have shown similar degrees of somnolence (approx. 2%) compared with placebo treatment.
The most common side effect is a bitter taste (about 20% of people). Due to this, the manufacturer has produced another formulation of azelastine with sucralose. The problem of bitter taste may also be reduced by correct application of the nasal spray (i.e. slightly tipping the head forward and not inhaling the medication too deeply), or alternatively using the azelastine/sucralose formulation.In addition, anosmia (loss in the ability to smell) can occur with nasal spray antihistamines (including both formulations of azelastine).
Pharmacology
Pharmacodynamics
Azelastine has a triple mode of action:
Anti-histamine effect,
Mast-cell stabilizing effect and
Anti-inflammatory effect.
Pharmacokinetics
The systemic bioavailability of azelastine is approximately 40% when administered intranasally. Maximum plasma concentrations (Cmax) are observed within 2–3 hours. The elimination half life, steady-state volume of distribution and plasma clearance are 22 h, 14.5 L/kg and 0.5 L/h/kg respectively (based on intravenous and oral administration data). Approximately 75% of an oral dose is excreted in feces. Pharmacokinetics of orally administered azelastine are not affected by age, gender or hepatic impairment.
Metabolism
Azelastine is oxidatively metabolized by the cytochrome P450 family into its active metabolite, desmethylazelastine, and two inactive carboxylic acid metabolites.
Chemical properties
The chemical nomenclature of azelastine is (±)-1-(2H)-phthalazinone, 4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-monohydrochloride. It is white, almost odorless with a bitter taste.
References
External links
"Azelastine". Drug Information Portal. U.S. National Library of Medicine.
"Azelastine hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
You act as a medical communicator. Your goal is to translate medical terms into comprehensive, yet straightforward language for all readers. | I'm looking for a concise explanation of the medical term '9q34.3 deletion syndrome.' | 9q34 deletion syndrome is a rare genetic disorder. Terminal deletions of chromosome 9q34 have been associated with childhood hypotonia, a distinctive facial appearance and developmental disability. The facial features typically described include arched eyebrows, small head circumference, midface hypoplasia, prominent jaw and a pouting lower lip. Individuals with this disease may often have speech impediments, such as speech delays. Other characteristics of this disease include: epilepsy, congenital and urogenital defects, microcephaly, corpulence, and psychiatric disorders. From analysis of chromosomal breakpoints, as well as gene sequencing in suggestive cases, Kleefstra and colleagues identified EHMT1 as the causative gene.
This gene is responsible for producing the protein histone methyltransferase which functions to alter histones. Ultimately, histone methyltransferases are important in deactivating certain genes, needed for proper growth and development. Moreover, a frameshift, missense, or nonsense error in the coding sequence of EHMT1 can result in this condition in an individual.
Signs and symptoms
Physical symptoms
Heart defects
Characteristics of autism
Genital defects (in males)
Childhood hypotonia
Respiratory infections
Motor delay
Renal defects
Severe delay or total lack of speech
Happy disposition
Dysmorphic facial featuresBehavioural symptoms
Passiveness
Sociability
Aggression
Biting or hitting
Moodiness
Disliking routine changes
Genetics
Despite the associated effects of Kleefstra, there is insubstantial information regarding to the lethality of Kleefstras. Most of the documented cases are de novo with the exception of one case due to hereditary factors; however, some cases may be a result of chromosomal translocations. In the exception case, the mother transferred the EHMT1 point mutation on to her child as she was a carrier of this gene defect. According to Mitter, et al. (2012), the mothers phenotype of the NM_024757.4:c.2712+1G>A mutation displayed mosaicism at certain tissues. This mutation resulted in the disregard of exon 18 on the EHMT1 gene, as opposed to removing it through the spliceosomes. In another transcript, however, an intron was placed between exon 18 and 19 of the EHMT1 gene. The combination of the intron insertion and the mosaicism in the mother was transferred to the child, resulting in the pathogenesis of the disease.In the past, research showed that the austerity of the disease was directly proportional to the number of EHMT1 deletions prevalent in an individual. The greater the deletions, the greater the severity of the condition. However, in recent studies, 9q34 deletion syndrome occurs when the EHMT1 gene is non-functioning, as opposed to strictly deletion.
Diagnosis
Tests are either conducted at birth, or later in early childhood via: fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH), and EHMT1 sequencing.FISH is a screening test that uses multicolour probes or comparative genomic hybridization to find any chromosome irregularities in a genome. It can be used for gene mapping, detecting aneuploidy, locating tumours etc. The multicolour probes attach to a certain DNA fragment. MLPA is a test that finds and records DNA copy change numbers through the use of PCR. MLPA can be used to detect tumours in the glial cells of the brain, as well as chromosomal abnormalities. Array-based comparative genomic hybridization (aCGH) tracks chromosome deletions and or amplifications using fluorescent dyes on genomic sequences of DNA samples. The DNA samples (which are 25-80 base pairs in length) are then placed on slides to be observed under microscope. Lastly, EHMT1 sequencing is a process in which a single-strand of DNA from the EHMT1 gene is removed, and DNA polymerase is added in order to synthesize complementary strands. In turn, this allows scientists to map out a persons DNA sequence allowing for a diagnosis to be made.
Treatment
Individual manifestations are treated by a multidisciplinary team.
Epidemiology
Kleefstra syndrome affects males and females equally and approximately 75% of all documented cases are caused by Eu-HMTase1 disruptions while only 25% are caused by 9q34.3 deletions. There are no statistics on the effect the disease has on life expectancy due to the lack of information available.
History
Kleefstra syndrome is a new condition that has only been known about for a few years and there have been fewer than 200 cases, reported. Due to the lack of cases worldwide, the history behind the origination is unclear.
Research
A study published by the American Journal of Human Genetics performed an EHMT1 mutation analysis on 23 patients that showed symptoms of 9q34 deletion syndrome. The patients all varied in age. With respect to all the analyses, however, the clinical data focused on five patients, the majority being children. The first patient developed epilepsy early on in childhood, and had speech problems past age 8. He had hypoplasia and had prominent facial features, such as lips and mouth. The second patient had no trace of mitral regurgitation (MR) in her family history, but had slight hypotonia. Patient three was the oldest at 36 who began to walk at age 3. She later gained weight at eleven and developed epilepsy in her late twenties. The fourth patient had problems associated with eating as a young child and was diagnosed with slowed development. Patient five had behavioural issues and struggled with MR in addition to being overweight. The geneticists discovered three new mutations within the EHMT1 gene. The first was an interstitial deletion, while the second and third were a nonsense and frameshift. Their findings supported the notion that a disruption in the EHMT1 gene contributes to the pathogenesis of Kleefstra syndrome.In another study published by the Journal of Medical Genetics, DNA from forty patients were extracted and subjected to MLPA, FISH or EHMT1 sequencing. The forty patients were divided into two groups: 1 group of 16 patients with the 9q34 deletion, and 1 group of 24 with typical FISH/MPLA results. The geneticists examined how a missense mutation would affect the function of the DNA by looking at DNA models. After, they screened each persons DNA using one of three tests, the results for the first group showed six patients had the same deletion of the same size (700 kb). In the second group, after EHMT1 sequencing was performed, six intragenic mutations were discovered. The scientists investigating this experiment conclude these mutations may be infective agents for the disease. Lastly, the patients behavioural, physical, and psychiatric symptoms are included on the data chart.
References
External links
The Genetics Home Reference website |
You are a medical knowledge base. Your task is to elucidate medical terminology, offering insights into their meanings, origins, and applications. | I need a basic explanation for the medical term 'Benzyl alcohol.' | Benzyl alcohol is an aromatic alcohol with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn" (not to be confused with "Bz" which is used for benzoyl), thus benzyl alcohol is denoted as BnOH. Benzyl alcohol is a colorless liquid with a mild pleasant aromatic odor. It is a useful solvent due to its polarity, low toxicity, and low vapor pressure. Benzyl alcohol has moderate solubility in water (4 g/100 mL) and is miscible in alcohols and diethyl ether. The anion produced by deprotonation of the alcohol group is known as benzylate or benzyloxide.
Natural occurrences
Benzyl alcohol is produced naturally by many plants and is commonly found in fruits and teas. It is also found in a variety of essential oils including jasmine, hyacinth and ylang-ylang. It is also found in castoreum from the castor sacs of beavers. Benzyl esters also occur naturally.
Preparation
Benzyl alcohol is produced industrially from toluene via benzyl chloride, which is hydrolyzed:
C6H5CH2Cl + H2O → C6H5CH2OH + HClAnother route entails hydrogenation of benzaldehyde, a by-product of the oxidation of toluene to benzoic acid.For laboratory use, Grignard reaction of phenylmagnesium bromide (C6H5MgBr) with formaldehyde and the Cannizzaro reaction of benzaldehyde also give benzyl alcohol. The latter also gives benzoic acid, an example of an organic disproportionation reaction.
Reactions
Like most alcohols, it reacts with carboxylic acids to form esters. In organic synthesis, benzyl esters are popular protecting groups because they can be removed by mild hydrogenolysis.Benzyl alcohol reacts with acrylonitrile to give N-benzylacrylamide. This is an example of a Ritter reaction:
C6H5CH2OH + NCCHCH2 → C6H5CH2N(H)C(O)CHCH2
Applications
Benzyl alcohol is used as a general solvent for inks, waxes, shellacs, paints, lacquers, and epoxy resin coatings. Thus it can be used in paint strippers, especially when combined with compatible viscosity enhancers to encourage the mixture to cling to painted surfaces.It is a precursor to a variety of esters and ethers, used in the soap, perfume, and flavor industries.
E.g. benzyl benzoate, benzyl salicylate, benzyl cinnamate, dibenzyl ether, benzyl butyl phthalate.
It can be used as a local anesthetic, especially with epinephrine.As a dye solvent, it enhances the process of dying wool, nylon, and leather.
Use in health care
Benzyl alcohol is used as a bacteriostatic preservative at low concentration in intravenous medications, cosmetics, and topical drugs. Some caution is necessary if a high percent of Benzyl alcohol is used as benzaldehyde arises from benzyl alcohol when used as preservative in an injectable formulation solution.
Benzyl alcohol, sold under the brand name Ulesfia, was approved by the U.S. Food and Drug Administration (FDA) in 2009, as a 5% solution for the treatment of head lice in people 6 months of age and older. It affects the louses spiracles, preventing them from closing. These then become clogged with water or mineral oil or other matter and cause the insect to die from asphyxiation.Benzyl alcohol is used effectively for treating lice infestations as the active ingredient in lotion shampoo with 5% benzyl alcohol.
Contact dermatitis
Benzyl alcohol is an ingredient used in the manufacture of soaps, topical creams, skin lotions, shampoos, and facial cleansers and is popular due to its anti-bacterial and anti-fungal properties. It is a common ingredient in a variety of
household products and can cause severe allergic contact dermatitis in a significant percentage of the population.
Safety
Benzyl alcohol has low acute toxicity with an LD50 of 1.2 g/kg in rats. It oxidizes rapidly in healthy individuals to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid. Very high concentrations can result in toxic effects including respiratory failure, vasodilation, hypotension, convulsions, and paralysis.
Benzyl alcohol is toxic to neonates and is associated with the gasping syndrome.Benzyl alcohol is severely toxic and highly irritating to the eye. Pure benzyl alcohol produces corneal necrosis.Benzyl alcohol is not considered to be a carcinogen, and no data are available regarding teratogenic or reproductive effects.
References
External links
International Chemical Safety Card 0833
"Benzyl alcohol". Drug Information Portal. U.S. National Library of Medicine. |
Subsets and Splits