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Subacute cutaneous lupus erythematosus | Subacute cutaneous lupus erythematosus is a clinically distinct subset of cases of lupus erythematosus that is most often present in white women aged 15 to 40, consisting of skin lesions that are scaly and evolve as poly-cyclic annular lesions or plaques similar to those of plaque psoriasis.Characteristically the lesions appear in sun-exposed areas such as the vee of the neckline or the forearms, but not the face. It may be brought on by sun-sensitizing medications, but is usually associated with autoimmune disorders such as rheumatoid arthritis and Sjögrens syndrome.Therapy generally involves sun avoidance and protection and topical corticosteroids. Sometimes systemic drug treatment is necessary. Besides corticosteroids other immunosuppressants such as methotrexate are also used.Lesions of SCLE may have an annular (shaped like a ring) configuration, with raised red borders and central clearing.
See also
Lupus erythematosus
List of cutaneous conditions
List of human leukocyte antigen alleles associated with cutaneous conditions
References
== External links == |
3C syndrome | 3C syndrome is a rare condition whose symptoms include heart defects, cerebellar hypoplasia, and cranial dysmorphism. It was first described in the medical literature in 1987 by Ritscher and Schinzel, for whom the disorder is sometimes named.
Signs and symptoms
The classical triad of symptoms that defines 3C syndrome includes certain heart defects, hypoplasia (underdevelopment) of the cerebellum, and cranial dysmorphisms, which can take various forms. The heart defects and cranial dysmorphisms are heterogeneous in individuals who are all classed as having Ritscher-Schinzel syndrome.Heart defects commonly seen with Ritscher-Schinzel syndrome are associated with the endocardial cushion and are the most important factor in determining a diagnosis. The mitral valve and tricuspid valve of the heart can be malformed, the atrioventricular canal can be complete instead of developing into the interatrial septum and interventricular septum, and conotruncal heart defects, which include tetralogy of Fallot, double outlet right ventricle, transposition of the great vessels, and hypoplastic left heart syndrome. Aortic stenosis and pulmonary stenosis have also been associated with 3C syndrome.The cranial dysmorphisms associated with 3C syndrome are heterogeneous and include a degree of macrocephaly, a large anterior fontanel, a particularly prominent occiput and forehead, ocular hypertelorism (wide-set eyes), slanted palpebral fissures, cleft palate, a depressed nasal bridge, cleft palate with associated bifid uvula, low-set ears, micrognathia (an abnormally small jaw), brachycephaly (flattened head), and ocular coloboma. Low-set ears are the most common cranial dysmorphism seen in 3C syndrome, and ocular coloboma is the least common of the non-concurrent symptoms (cleft lip co-occurring with cleft palate is the least common).Cranial dysplasias associated with 3C syndrome are also reflected in the brain. Besides the cerebellar hypoplasia, cysts are commonly found in the posterior cranial fossa, the ventricles and the cisterna magna are dilated/enlarged, and Dandy–Walker malformation is present. These are reflected in the developmental delays typical of the disease. 75% of children with 3C syndrome have Dandy-Walker malformation and hydrocephalus.Signs and symptoms in other body systems are also associated with 3C syndrome. In the skeletal system, ribs may be absent, and hemivertebrae, syndactyly (fusion of fingers together), and clinodactyly (curvature of the fifth finger) may be present. In the GI and genitourinary systems, anal atresia, hypospadia (misplaced urethra), and hydronephrosis may exist. Adrenal hypoplasia and growth hormone deficiency are associated endocrine consequences of Ritscher-Schinzel syndrome. Some immunodeficiency has also been reported in connection with 3C syndrome. Many children with the disorder die as infants due to severe congenital heart disease. The proband of Ritscher and Schinzels original study was still alive at the age of 21. A fetus with 3C syndrome may have an umbilical cord with one umbilical artery instead of two.
Genetics
3C syndrome is an autosomal recessive disease, caused by a mutation on the long arm of chromosome 8 at 8q24.13, the locus for KIAA0196, the gene for the protein strumpellin. Strumpellin is highly expressed in skeletal muscle cells and mutations in it are also associated with spastic paraplegia. Strumpellin is involved in endosomal transport and cell death processes. The mutation occurs at a splice site and causes a substantial decrease in the amount of strumpellin produced by the cell. The phenotype is similar to 6pter-p24 deletion syndrome and 6p25 deletion syndrome but has a different etiology.
Screening for the condition prenatally may be done with ultrasound.
First-trimester ultrasounds can detected nuchal abnormalities
Second-trimester ultrasounds can pick up characteristic major structural abnormalities.Prenatal diagnosis is possible through genetic testing.
Chorionic villus sampling or chorionic villus biopsy (CVS) in the first-trimester.
Amniocentesis in the second-trimester.Because 3C syndrome is an autosomal recessive disorder, parents with one child with the disorder have a 25% chance of having another child with the disorder.
Diagnosis
Differential diagnosis
There is an overlap in symptoms between 3C syndrome and Joubert syndrome. Joubert syndrome often manifests with similar cerebellar hypoplasia and its sequelae, including hyperpnea, ataxia, changes in eye movement, and cleft lip and palate. Occasionally, Joubert syndrome will include heart malformations. Brachmann–de Lange syndrome must also be differentiated from 3C syndrome. It presents with similar craniofacial and heart abnormalities and can include Dandy–Walker phenotype, making it difficult to distinguish. Dandy-Walker malformation is also occasionally seen in Ellis–Van Creveld syndrome, which is characterized by heart defects and malformed alveolar ridge. Many disorders include the Dandy–Walker phenotype and thus it is not pathognomonic for 3C syndrome.CHARGE syndrome can also be misdiagnosed. This is because both CHARGE syndrome and 3C syndrome share symptoms of ocular colobomas, cardiac defects, growth retardation, and minor facial abnormalities.Coffin–Siris syndrome presents with fifth-finger deformities and congenital heart defects. It is distinguished from 3C syndrome by differences in facial dysmorphisms.
Management
The outcome of this disease is dependent on the severity of the cardiac defects. Approximately 1 in 3 children with this diagnosis require shunting for the hydrocephaly that is often a consequence. Some children require extra assistance or therapy for delayed psychomotor and speech development, including hypotonia.
Prognosis
Prognoses for 3C syndrome vary widely based on the specific constellation of symptoms seen in an individual. Typically, the gravity of the prognosis correlates with the severity of the cardiac abnormalities. For children with less severe cardiac abnormalities, the developmental prognosis depends on the cerebellar abnormalities that are present. Severe cerebellar hypoplasia is associated with growth and speech delays, as well as hypotonia and general growth deficiencies.
Epidemiology
3C syndrome is very rare, occurring in less than 1 birth per million. Because of consanguinity due to a founder effect, it is much more common in a remote First Nations village in Manitoba, where 1 in 9 people carries the recessive gene.
History
The syndrome was first reported in 1987 in two sisters who had similar craniofacial abnormalities, Dandy–Walker phenotype, and congenital heart abnormalities. Neither of the parents was affected, indicating that the disorder was transmitted in an autosomal recessive pattern. The syndromes symptoms were further refined in 1989 when the third case of the syndrome was reported, with similar craniofacial abnormalities to the first two cases, ventricular septal defect, and enlargement of the cisterna magna and fourth ventricle of the brain.
Other animals
Animal models of 3C syndrome have not been created; however, strumpellin is a highly conserved protein, with 12 known homologs and 83 known orthologs.
References
== External links == |
Leech | Leeches are segmented parasitic or predatory worms that comprise the subclass Hirudinea within the phylum Annelida. They are closely related to the oligochaetes, which include the earthworm, and like them have soft, muscular segmented bodies that can lengthen and contract. Both groups are hermaphrodites and have a clitellum, but leeches typically differ from the oligochaetes in having suckers at both ends and in having ring markings that do not correspond with their internal segmentation. The body is muscular and relatively solid, and the coelom, the spacious body cavity found in other annelids, is reduced to small channels.
The majority of leeches live in freshwater habitats, while some species can be found in terrestrial or marine environments. The best-known species, such as the medicinal leech, Hirudo medicinalis, are hematophagous, attaching themselves to a host with a sucker and feeding on blood, having first secreted the peptide hirudin to prevent the blood from clotting. The jaws used to pierce the skin are replaced in other species by a proboscis which is pushed into the skin. A minority of leech species are predatory, mostly preying on small invertebrates.
The eggs are enclosed in a cocoon, which in aquatic species is usually attached to an underwater surface; members of one family, Glossiphoniidae, exhibit parental care, the eggs being brooded by the parent. In terrestrial species, the cocoon is often concealed under a log, in a crevice or buried in damp soil. Almost seven hundred species of leech are currently recognised, of which some hundred are marine, ninety terrestrial and the remainder freshwater.
Leeches have been used in medicine from ancient times until the 19th century to draw blood from patients. In modern times, leeches find medical use in treatment of joint diseases such as epicondylitis and osteoarthritis, extremity vein diseases, and in microsurgery, while hirudin is used as an anticoagulant drug to treat blood-clotting disorders.
Diversity and phylogeny
Some 680 species of leech have been described, of which around 100 are marine, 480 freshwater and the remainder terrestrial. Among Euhirudinea, the true leeches, the smallest is about 1 cm (1⁄2 in) long, and the largest is the giant Amazonian leech, Haementeria ghilianii, which can reach 30 cm (12 in). Except for Antarctica, leeches are found throughout the world but are at their most abundant in temperate lakes and ponds in the northern hemisphere. The majority of freshwater leeches are found in the shallow, vegetated areas on the edges of ponds, lakes and slow-moving streams; very few species tolerate fast-flowing water. In their preferred habitats, they may occur in very high densities; in a favourable environment with water high in organic pollutants, over 10,000 individuals were recorded per square metre (over 930 per square foot) under rocks in Illinois. Some species aestivate during droughts, burying themselves in the sediment, and can lose up to 90% of their bodyweight and still survive. Among the freshwater leeches are the Glossiphoniidae, dorso-ventrally flattened animals mostly parasitic on vertebrates such as turtles, and unique among annelids in both brooding their eggs and carrying their young on the underside of their bodies.The terrestrial Haemadipsidae are mostly native to the tropics and subtropics, while the aquatic Hirudinidae have a wider global range; both of these feed largely on mammals, including humans. A distinctive family is the Piscicolidae, marine or freshwater ectoparasites chiefly of fish, with cylindrical bodies and usually well-marked, bell-shaped, anterior suckers. Not all leeches feed on blood; the Erpobdelliformes, freshwater or amphibious, are carnivorous and equipped with a relatively large, toothless mouth to ingest insect larvae, molluscs, and other annelid worms, which are swallowed whole. In turn, leeches are prey to fish, birds, and invertebrates.The name for the subclass, Hirudinea, comes from the Latin hirudo (genitive hirudinis), a leech; the element -bdella found in many leech group names is from the Greek βδέλλα bdella, also meaning leech. The name Les hirudinées was given by Jean-Baptiste Lamarck in 1818. Leeches were traditionally divided into two infraclasses, the Acanthobdellidea (primitive leeches) and the Euhirudinea (true leeches). The Euhirudinea are divided into the proboscis-bearing Rhynchobdellida and the rest, including some jawed species, the "Arhynchobdellida", without a proboscis.The phylogenetic tree of the leeches and their annelid relatives is based on molecular analysis (2019) of DNA sequences. Both the former classes "Polychaeta" (bristly marine worms) and "Oligochaeta" (including the earthworms) are paraphyletic: in each case the complete groups (clades) would include all the other groups shown below them in the tree. The Branchiobdellida are sister to the leech clade Hirudinida, which approximately corresponds to the traditional subclass Hirudinea. The main subdivision of leeches is into the Rhynchobdellida and the Arhynchobdellida, though the Acanthobdella are sister to the clade that contains these two groups.
Evolution
The most ancient annelid group consists of the free-living polychaetes that evolved in the Cambrian period, being plentiful in the Burgess Shale about 500 million years ago. Oligochaetes evolved from polychaetes and the leeches branched off from the oligochaetes. The oldest leech fossils are from the Jurassic period around 150 million years ago, but a fossil with external ring markings found in Wisconsin in the 1980s, with what appears to be a large sucker, seems to extend the groups evolutionary history back to the Silurian, some 437 million years ago.
Anatomy and physiology
Leeches show a remarkable similarity to each other in morphology, very different from typical annelids which are cylindrical with a fluid-filled space, the coelom (body cavity). In leeches, the coelom is reduced to four slender longitudinal channels, and the interior of the body is filled with a solid dermis in between the various organs. Typically, the body is dorso-ventrally flattened and tapers at both ends. Longitudinal and circular muscles in the body wall are supplemented by diagonal muscles, giving the leech the ability to adopt a large range of body shapes and show great flexibility. Most leeches have a sucker at both the anterior (front) and posterior (back) ends, but some primitive leeches have a single sucker at the back.
Like other annelids, the leech is a segmented animal, but unlike other annelids, the segmentation is masked by external ring markings (annulations). The number of annulations varies, both between different regions of the body and between species. In one species, the body surface is divided into 102 annuli, but the body consists of 33 segments, a number constant across all leech species. Of these segments, the first five are designated as the head and include the anterior brain, several ocelli (eyespots) dorsally and the sucker ventrally. The following 21 mid-body segments each contain a nerve ganglion, and between them contain two reproductive organs, a single female gonopore and nine pairs of testes. The last seven segments contain the posterior brain and are fused to form the animals tail sucker.The body wall consists of a cuticle, an epidermis and a thick layer of fibrous connective tissue in which are embedded the circular muscles, the diagonal muscles and the powerful longitudinal muscles. There are also dorso-ventral muscles. The coelomic channels run the full length of the body, the two main ones being on either side; these have taken over the function of the hemal system (blood vessels) in other annelids. Part of the lining epithelium consists of chloragogen cells which are used for the storage of nutrients and in excretion. There are 10 to 17 pairs of metanephridia (excretory organs) in the mid-region of the leech. From these, ducts typically lead to a urinary bladder, which empties to the outside at a nephridiopore.
Reproduction and development
Leeches are hermaphrodites, with the male reproductive organs, the testes, maturing first and the ovaries later. In hirudinids, a pair will line up with the clitellar regions in contact, with the anterior end of one leech pointing towards the posterior end of the other; this results in the male gonopore of one leech being in contact with the female gonopore of the other. The penis passes a spermatophore into the female gonopore and sperm is transferred to, and probably stored in, the vagina.Some jawless leeches (Rhynchobdellida) and proboscisless leeches (Arhynchobdellida) lack a penis, and in these, sperm is passed from one individual to another by hypodermic injection. The leeches intertwine and grasp each other with their suckers. A spermatophore is pushed by one through the integument of the other, usually into the clitellar region. The sperm is liberated and passes to the ovisacs, either through the coelomic channels or interstitially through specialist "target tissue" pathways.Some time after copulation, the small, relatively yolkless eggs are laid. In most species, an albumin-filled cocoon is secreted by the clitellum and receives one or more eggs as it passes over the female gonopore. In the case of the North American Erpobdella punctata, the clutch size is about five eggs, and some ten cocoons are produced. Each cocoon is fixed to a submerged object, or in the case of terrestrial leeches, deposited under a stone or buried in damp soil. The cocoon of Hemibdella soleae is attached to a suitable fish host. The glossiphoniids brood their eggs, either by attaching the cocoon to the substrate and covering it with their ventral surface, or by securing the cocoon to their ventral surface, and even carrying the newly hatched young to their first meal.When breeding, most marine leeches leave their hosts and become free-living in estuaries. Here they produce their cocoons, after which the adults of most species die. When the eggs hatch, the juveniles seek out potential hosts when these approach the shore. Leeches mostly have an annual or biannual life cycle.
Feeding and digestion
About three quarters of leech species are parasites that feed on the blood of a host, while the remainder are predators. Leeches either have a pharynx that they can protrude, commonly called a proboscis, or a pharynx that they cannot protrude, which in some groups is armed with jaws.In the proboscisless leeches, the jaws (if any) of Arhynchobdellids are at the front of the mouth, and have three blades set at an angle to each other. In feeding, these slice their way through the skin of the host, leaving a Y-shaped incision. Behind the blades is the mouth, located ventrally at the anterior end of the body. It leads successively into the pharynx, a short oesophagus, a crop (in some species), a stomach and a hindgut, which ends at an anus located just above the posterior sucker. The stomach may be a simple tube, but the crop, when present, is an enlarged part of the midgut with a number of pairs of ceca that store ingested blood. The leech secretes an anticoagulant, hirudin, in its saliva which prevents the blood from clotting before ingestion. A mature medicinal leech may feed only twice a year, taking months to digest a blood meal.
The bodies of predatory leeches are similar, though instead of a jaw many have a protrusible proboscis, which for most of the time they keep retracted into the mouth. Such leeches are often ambush predators that lie in wait until they can strike prey with the proboscises in a spear-like fashion. Predatory leeches feed on small invertebrates such as snails, earthworms and insect larvae. The prey is usually sucked in and swallowed whole. Some Rhynchobdellida however suck the soft tissues from their prey, making them intermediate between predators and blood-suckers.
Blood-sucking leeches use their anterior suckers to connect to hosts for feeding. Once attached, they use a combination of mucus and suction to stay in place while they inject hirudin into the hosts blood. In general, blood-feeding leeches are non host-specific, and do little harm to their host, dropping off after consuming a blood meal. Some marine species however remain attached until it is time to reproduce. If present in great numbers on a host, these can be debilitating, and in extreme cases, cause death.Leeches are unusual in that they do not produce certain digestive enzymes such as amylases, lipases or endopeptidases. A deficiency of these enzymes and of B complex vitamins is compensated for by enzymes and vitamins produced by endosymbiotic microflora. In Hirudo medicinalis, these supplementary factors are produced by an obligatory mutualistic relationship with the bacterial species, Aeromonas veronii. Non-bloodsucking leeches, such as Erpobdella octoculata, are host to morew bacterial symbionts. In addition, leeches produce intestinal exopeptidases which remove amino acids from the long protein molecules one by one, possibly aided by proteases from endosymbiotic bacteria in the hindgut. This evolutionary choice of exopeptic digestion in Hirudinea distinguishes these carnivorous clitellates from oligochaetes, and may explain why digestion in leeches is so slow.
Nervous system
A leechs nervous system is formed of a few large nerve cells; their large size makes leeches convenient as model organisms for the study of invertebrate nervous systems. The main nerve centre consists of the cerebral ganglion above the gut and another ganglion beneath it, with connecting nerves forming a ring around the pharynx a little way behind the mouth. A nerve cord runs backwards from this in the ventral coelomic channel, with 21 pairs of ganglia in segments six to 26. In segments 27 to 33, other paired ganglia fuse to form the caudal ganglion. Several sensory nerves connect directly to the cerebral ganglion; there are sensory and motor nerve cells connected to the ventral nerve cord ganglia in each segment.Leeches have between two and ten pigment spot ocelli, arranged in pairs towards the front of the body. There are also sensory papillae arranged in a lateral row in one annulation of each segment. Each papilla contains many sensory cells. Some rhynchobdellids have the ability to change colour dramatically by moving pigment in chromatophore cells; this process is under the control of the nervous system but its function is unclear as the change in hue seems unrelated to the colour of the surroundings.Leeches can detect touch, vibration, movement of nearby objects, and chemicals secreted by their hosts; freshwater leeches crawl or swim towards a potential host standing in their pond within a few seconds. Species that feed on warm-blooded hosts move towards warmer objects. Many leeches avoid light, though some blood feeders move towards light when they are ready to feed, presumably increasing the chances of finding a host.
Gas exchange
Leeches live in damp surroundings and in general respire through their body wall. The exception to this is in the Piscicolidae, where branching or leaf-like lateral outgrowths from the body wall form gills. Some rhynchobdellid leeches have an extracellular haemoglobin pigment, but this only provides for about half of the leechs oxygen transportation needs, the rest occurring by diffusion.
Movement
Leeches move using their longitudinal and circular muscles in a modification of the locomotion by peristalsis, self-propulsion by alternately contracting and lengthening parts of the body, seen in other annelids such as earthworms. They use their posterior and anterior suckers (one on each end of the body) to enable them to progress by looping or inching along, in the manner of geometer moth caterpillars. The posterior end is attached to the substrate, and the anterior end is projected forward peristaltically by the circular muscles until it touches down, as far as it can reach, and the anterior end is attached. Then the posterior end is released, pulled forward by the longitudinal muscles, and reattached; then the anterior end is released, and the cycle repeats. Leeches explore their environment with head movements and body waving. The Hirudinidae and Erpobdellidae can swim rapidly with up-and-down or sideways undulations of the body; the Glossiphoniidae in contrast are poor swimmers and curl up and fall to the sediment below when disturbed.
Interactions with humans
Bites
Leech bites are generally alarming rather than dangerous, though a small percentage of people have severe allergic or anaphylactic reactions and require urgent medical care. Symptoms of these reactions include red blotches or an itchy rash over the body, swelling around the lips or eyes, a feeling of faintness or dizziness, and difficulty in breathing. An externally attached leech will detach and fall off on its own accord when it is satiated on blood, which may take from twenty minutes to a few hours; bleeding from the wound may continue for some time. Internal attachments, such as inside the nose, are more likely to require medical intervention.Bacteria, viruses, and protozoan parasites from previous blood sources can survive within a leech for months, so leeches could potentially act as vectors of pathogens. Nevertheless, only a few cases of leeches transmitting pathogens to humans have been reported.Leech saliva is commonly believed to contain anaesthetic compounds to numb the bite area, but this has never been proven. Although morphine-like substances have been found in leeches, they have been found in the neural tissues, not the salivary tissues. They are used by the leeches in modulating their own immunocytes and not for anaesthetising bite areas on their hosts. Depending on the species and size, leech bites can be barely noticeable or they can be fairly painful.
In human culture
The leech appears in Proverbs 30:15 as an archetype of insatiable greed. More generally, a leech is a persistent social parasite or sycophant.The medicinal leech Hirudo medicinalis, and some other species, have been used for clinical bloodletting for at least 2,500 years: Ayurvedic texts describe their use for bloodletting in ancient India. In ancient Greece, bloodletting was practised according to the theory of humours found in the Hippocratic Corpus of the fifth century BC, which maintained that health depended on a balance of the four humours: blood, phlegm, black bile and yellow bile. Bloodletting using leeches enabled physicians to restore balance if they considered blood was present in excess.Pliny the Elder reported in his Natural History that the horse leech could drive elephants mad by climbing up inside their trunks to drink blood. Pliny also noted the medicinal use of leeches in ancient Rome, stating that they were often used for gout, and that patients became addicted to the treatment. In Old English, lǣce was the name for a physician as well as for the animal, though the words had different origins, and lǣcecraft, leechcraft, was the art of healing.
William Wordsworths 1802 poem "Resolution and Independence" describes one of the last of the leech-gatherers, people who travelled Britain catching leeches from the wild, and causing a sharp decline in their abundance, though they remain numerous in Romney Marsh. By 1863, British hospitals had switched to imported leeches, some seven million being imported to hospitals in London that year.
In the nineteenth century, demand for leeches was sufficient for hirudiculture, the farming of leeches, to become commercially viable. Leech usage declined with the demise of humoral theory, but made a small-scale comeback in the 1980s after years of decline, with the advent of microsurgery, where venous congestion can arise due to inefficient venous drainage. Leeches can reduce swelling in the tissues and promote healing, helping in particular to restore circulation after microsurgery to reattach body parts. Other clinical applications include varicose veins, muscle cramps, thrombophlebitis, and joint diseases such as epicondylitis and osteoarthritis.Leech secretions contain several bioactive substances with anti-inflammatory, anticoagulant and antimicrobial effects. One active component of leech saliva is a small protein, hirudin. It is widely used as an anticoagulant drug to treat blood-clotting disorders, and manufactured by recombinant DNA technology.In 2012 and 2018, Ida Schnell and colleagues trialled the use of Haemadipsa leeches to gather data on the biodiversity of their mammalian hosts in the tropical rainforest of Vietnam, where it is hard to obtain reliable data on rare and cryptic mammals. They showed that mammal mitochondrial DNA, amplified by the polymerase chain reaction, can be identified from a leechs blood meal for at least four months after feeding. They detected Annamite striped rabbit, small-toothed ferret-badger, Truong Son muntjac, and serow in this way.
Water pollution
Exposure to synthetic estrogen as used in contraceptive medicines, which may enter freshwater ecosystems from municipal wastewater, can affect leeches reproductive systems. Although not as sensitive to these compounds as fish, leeches showed physiological changes after exposure, including longer sperm sacs and vaginal bulbs, and decreased epididymis weight.
Notes
References
General bibliography
Ruppert, Edward E.; Fox, Richard S.; Barnes, Robert D. (2004). Invertebrate Zoology, 7th Edition. Cengage Learning. ISBN 978-81-315-0104-7.
External links
Media related to Hirudinea at Wikimedia Commons
Data related to Hirudinea at Wikispecies
The dictionary definition of leech at Wiktionary |
Subacute combined degeneration of spinal cord | Subacute combined degeneration of spinal cord, also known as myelosis funiculus, or funicular myelosis, also Lichtheims disease, and Putnam-Dana syndrome, refers to degeneration of the posterior and lateral columns of the spinal cord as a result of vitamin B12 deficiency (most common), vitamin E deficiency, and copper deficiency. It is usually associated with pernicious anemia.
Signs and symptoms
The onset is gradual and uniform. The pathological findings of subacute combined degeneration consist of patchy losses of myelin in the dorsal and lateral columns. Patients present with weakness of the legs, arms, and trunk, and tingling and numbness that progressively worsens. Vision changes and change of mental state may also be present. Bilateral spastic paresis may develop and pressure, vibration and touch sense are diminished. A positive Babinski sign may be seen. Prolonged deficiency of vitamin B12 leads to irreversible nervous system damage. HIV-associated vacuolar myelopathy can present with a similar pattern of dorsal column and corticospinal tract demyelination.It has been thought that if someone is deficient in vitamin B12 and folic acid, the vitamin B12 deficiency must be treated first. However, the basis for this has been challenged, although due to ethical considerations it is no longer able to be tested if "neuropathy is made more
severe as a result of giving folic acid to vitamin B12-
deficient individuals". And that if this were the case, then the mechanism remains unclear.Administration of nitrous oxide anesthesia can precipitate subacute combined degeneration in people with subclinical vitamin B12 deficiency, while chronic nitrous oxide exposure can cause it even in persons with normal B12 levels.
Posterior column dysfunction decreases vibratory sensation and proprioception (joint sense). Lateral corticospinal tract dysfunction produces spasticity and dorsal spinocerebellar tract dysfunction causes ataxia.
Cause
In general, the most common cause of this condition is a deficiency of vitamin B12.
This may be due to a dietary deficiency, malabsorption in the terminal ileum, lack of intrinsic factor secreted from gastric parietal cells, or low gastric pH inhibiting attachment of intrinsic factor to ileal receptors.Vitamin E deficiency, which is associated with malabsorption disorders such as cystic fibrosis and Bassen-Kornzweig syndrome, can cause a similar presentation due to the degeneration of the dorsal columns.
Diagnosis
Serum vitamin B12, methylmalonic acid, Schilling test, and a complete blood count, looking for megaloblastic anemia if there is also folic acid deficiency or macrocytic anemia. The Schilling test is no longer available in most areas.MRI-T2 images may reveal increased signal within the white matter of the spinal cord, predominantly in the posterior columns and possibly in the spinothalamic tracts.
Treatment
Therapy with vitamin B12 results in partial to full recovery where SACD has been caused by vitamin B12 deficiency, depending on the duration and extent of neurodegeneration.
References
== External links == |
Prognathism | Prognathism, also called Habsburg jaw or Habsburgs jaw primarily in the context of its prevalence amongst members of the House of Habsburg, is a positional relationship of the mandible or maxilla to the skeletal base where either of the jaws protrudes beyond a predetermined imaginary line in the coronal plane of the skull. In general dentistry, oral and maxillofacial surgery, and orthodontics, this is assessed clinically or radiographically (cephalometrics). The word prognathism derives from Greek πρό (pro, meaning forward) and γνάθος (gnáthos, jaw). One or more types of prognathism can result in the common condition of malocclusion, in which an individuals top teeth and lower teeth do not align properly.
Presentation
Prognathism in humans can occur due to normal variation among phenotypes. In human populations where prognathism is not the norm, it may be a malformation, the result of injury, a disease state or a hereditary condition.Prognathism is considered a disorder only if it affects chewing, speech or social function as a byproduct of severely affected aesthetics of the face.Clinical determinants include soft tissue analysis where the clinician assesses nasolabial angle, the relationship of the soft tissue portion of the chin to the nose, and the relationship between the upper and lower lips; also used is dental arch relationship assessment such as Angles classification.Cephalometric analysis is the most accurate way of determining all types of prognathism, as it includes assessments of skeletal base, occlusal plane angulation, facial height, soft tissue assessment and anterior dental angulation. Various calculations and assessments of the information in a cephalometric radiograph allow the clinician to objectively determine dental and skeletal relationships and determine a treatment plan.Prognathism should not be confused with micrognathism, although combinations of both are found. It affects the middle third of the face, causing it to jut out, thereby increasing the facial area, similar to the phenotype of archaic hominids and other apes. Mandibular prognathism is a protrusion of the mandible, affecting the lower third of the face. Alveolar prognathism is a protrusion of that portion of the maxilla where the teeth are located, in the dental lining of the upper jaw.Prognathism can also be used to describe ways that the maxillary and mandibular dental arches relate to one another, including malocclusion (where the upper and lower teeth do not align). When there is maxillary or alveolar prognathism which causes an alignment of the maxillary incisors significantly anterior to the lower teeth, the condition is called an overjet. When the reverse is the case, and the lower jaw extends forward beyond the upper, the condition is referred to as retrognathia (reverse overjet).
Classification
Alveolar prognathism
Not all alveolar prognathism is anomalous, and significant differences can be observed among different ethnicities.Harmful habits such as thumb sucking or tongue thrusting can result in or exaggerate an alveolar prognathism, causing teeth to misalign. Functional appliances can be used in growing children to help modify bad habits and neuro-muscular function, with the aim of correcting this condition.Alveolar prognathism can also easily be corrected with fixed orthodontic therapy. However, relapse is quite common, unless the cause is removed or a long-term retention is used.
Maxillary prognathism
In disease states, maxillary prognathism is associated with Cornelia de Lange syndrome; however, so-called false maxillary prognathism, or more accurately, retrognathism, where there is a lack of growth of the mandible, is by far a more common condition.Prognathism, if not extremely severe, can be treated in growing patients with orthodontic functional or orthopaedic appliances. In adult patients this condition can be corrected by means of a combined surgical/orthodontic treatment, where most of the time a mandibular advancement is performed. The same can be said for mandibular prognathism.
Mandibular prognathism (progenism)
Pathologic mandibular prognathism is a potentially disfiguring genetic disorder where the lower jaw outgrows the upper, resulting in an extended chin and a crossbite. In both humans and animals, it can be the result of inbreeding. In brachycephalic or flat-faced dogs, like shih tzus and boxers, it can lead to problems such as underbite.In humans, it results in a condition sometimes called lantern jaw, reportedly derived from 15th century horn lanterns, which had convex sides. Traits such as these were often exaggerated by inbreeding, and can be traced within specific families.Although more common than appreciated, the best known historical example is Habsburg jaw, or Habsburg or Austrian lip, due to its prevalence in members of the House of Habsburg, which can be traced in their portraits. The process of portrait-mapping has provided tools for geneticists and pedigree analysis; most instances are considered polygenic, but a number of researchers believe that this trait is transmitted through an autosomal recessive type of inheritance.
Allegedly introduced into the family by a member of the Piast dynasty, it is clearly visible on family tomb sculptures in St. Johns Cathedral, Warsaw. A high propensity for politically motivated intermarriage among Habsburgs meant the dynasty was virtually unparalleled in the degree of its inbreeding. Charles II of Spain, who lived 1661 to 1700, is said to have had the most pronounced case of the Habsburg jaw on record, due to the high number of consanguineous marriages in the dynasty preceding his birth.
Treatment
Prior to the development of modern dentistry, there was no treatment for this condition; those who had it simply endured it. Today, the most common treatment for mandibular prognathism is a combination of orthodontics and orthognathic surgery. The orthodontics can involve braces, removal of teeth, or a mouthguard.
In insects
In entomology, prognathous means that the mouthparts face forwards, being at the front of the head, rather than facing downwards as in some insects.
See also
Dental pathology
Notes
References
Sources
Beuchat, Carol (12 March 2015). "Why all the fuss about inbreeding?". Institute of Canine Biology. Retrieved 16 April 2020.
Mitchell, Sylvia Z (2013). Mariana of Austria and Imperial Spain: Court, Dynastic, and International Politics in Seventeenth-Century Europe (Thesis).
Vilas, Román; Ceballos, Francisco C.; Al-Soufi, Laila; González-García, Raúl; Moreno, Carlos; Moreno, Manuel; Villanueva, Laura; Ruiz, Luis; Mateos, Jesús; González, David; Ruiz, Jennifer; Cinza, Aitor; Monje, Florencio; Álvarez, Gonzalo (17 November 2019). "Is the Habsburg jaw related to inbreeding?". Annals of Human Biology. 46 (7–8): 553–561. doi:10.1080/03014460.2019.1687752. PMID 31786955. S2CID 208536371.
Vioarsdóttir, US; OHiggins, O; Stringer, C (2002). "A geometric morphometric study of regional differences in the ontogeny of the modern human facial skeleton". J. Anat. 201 (3): 211–229. doi:10.1046/j.1469-7580.2002.00092.x. PMC 1570912. PMID 12363273.
Wolff, G; Wienker, T F; Sander, H (1 February 1993). "On the genetics of mandibular prognathism: analysis of large European noble families". Journal of Medical Genetics. 30 (2): 112–116. doi:10.1136/jmg.30.2.112. PMC 1016265. PMID 8445614.
External links
The dictionary definition of prognathism at Wiktionary |
Kearns–Sayre syndrome | Kearns–Sayre syndrome (KSS), oculocraniosomatic disorder or oculocranionsomatic neuromuscular disorder with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chronic progressive external ophthalmoplegia (abbreviated CPEO), a syndrome that is characterized by isolated involvement of the muscles controlling movement of the eyelid (levator palpebrae, orbicularis oculi) and eye (extra-ocular muscles). This results in ptosis and ophthalmoplegia respectively. KSS involves a combination of the already described CPEO as well as pigmentary retinopathy in both eyes and cardiac conduction abnormalities. Other symptoms may include cerebellar ataxia, proximal muscle weakness, deafness, diabetes mellitus, growth hormone deficiency, hypoparathyroidism, and other endocrinopathies. In both of these diseases, muscle involvement may begin unilaterally but always develops into a bilateral deficit, and the course is progressive. This discussion is limited specifically to the more severe and systemically involved variant.
Signs and symptoms
Individuals with KSS present initially in a similar way to those with typical CPEO. Onset is in the first and second decades of life.The first symptom of this disease is a unilateral ptosis, or difficulty opening the eyelids, that gradually progresses to a bilateral ptosis. As the ptosis worsens, the individual commonly extends their neck, elevating their chin in an attempt to prevent the eyelids from occluding the visual axis. Along with the insidious development of ptosis, eye movements eventually become limited causing a person to rely more on turning the head side to side or up and down to view objects in the peripheral visual field.
Mitochondrial retinopathy
Kearns and Sayre described patients with “pigmentary degeneration” on funduscopy, night vision abnormalities, and some histologic similarities, but also clinical differences, to retinitis pigmentosa Subsequently, the retinal phenotype of KSS was described as retinitis pigmentosa, atypical retinitis pigmentosa, tapetoretinal degeneration, salt-and-pepper retinopathy, and pigmentary retinopathy. As the clinical characterization, however, was not always comprehensive the term "mitochondrial retinopathy" appears most accurate and the diagnosis of RP may have been imprecise. Patients with KSS show widespread granular pigmented alterations in the posterior fundus which correspond to granular patterns on fundus autofluorescence imaging. Associated changes on optical coherence tomography (OCT) include reflectivity changes predominantly at the level of the ellipsoid and interdigitation zone and an increased distance between the ellipsoid band and the retinal pigment epithelium. Night blindness may be seen in patients with KSS. Visual acuity loss is usually mild and only occurs in 40–50% of patients.
Cardiac conduction abnormalities
These most often occur years after the development of ptosis and ophthalmoplegia. Atrioventricular (abbreviated "AV") block is the most common cardiac conduction deficit. This often progresses to a Third-degree atrioventricular block, which is a complete blockage of the electrical conduction from the atrium to the ventricle. Symptoms of heart block include syncope, exercise intolerance, and bradycardia.
Cerebral folate deficiency
Kearns-Sayre patients are consistently found to have cerebral folate deficiency, a syndrome in which 5-MTHF levels are decreased in the cerebrospinal fluid despite being normal in serum. Treatment with folinic acid can in some cases alleviate the associated symptoms and partially correct associated brain abnormalities, especially if started early in the course of illness. The proposed cause of cerebral folate deficiency in the Kearns–Sayre syndrome is the failure of the mechanisms in the choroid plexus that are responsible for passage of folates from the serum to the cerebrospinal fluid.
Cause and prevalence
As characterized in Kearns original publication in 1965 and in later publications, inconsistent features of KSS that may occur are weakness of facial, pharyngeal, trunk, and extremity muscles, hearing loss, small stature, electroencephalographic changes, cerebellar ataxia and elevated levels of cerebrospinal fluid protein.Kearns–Sayre syndrome occurs spontaneously in the majority of cases. In some cases it has been shown to be inherited through mitochondrial, autosomal dominant, or autosomal recessive inheritance. There is no predilection for race or sex, and there are no known risk factors. As of 1992 there were only 226 cases reported in published literature. Although NIH and other studies estimate occurrence in the population to be 1–3 and some as high as 9 in 100,000 individuals but a failure to be referred to specialist centres and recognise the disease symptoms is common
Genetics
KSS is the result of deletions in mitochondrial DNA (mtDNA) that cause a particular constellation of medical signs and symptoms. mtDNA is transmitted exclusively from the mothers ovum. Mitochondrial DNA is composed of 37 genes found in the single circular chromosome measuring 16,569 base pairs in length. Among these, 13 genes encode proteins of the electron transport chain (abbreviated "ETC"), 22 encode transfer RNA (tRNA), and two encode the large and small subunits that form ribosomal RNA (rRNA). The 13 proteins involved in the ETC of the mitochondrion are necessary for oxidative phosphorylation. Mutations in these proteins results in impaired energy production by mitochondria. This cellular energy deficit manifests most readily in tissues that rely heavily upon aerobic metabolism such as the brain, skeletal and cardiac muscles, sensory organs, and kidneys. This is one factor involved in the presentation of mitochondrial diseases.There are other factors involved in the manifestation of a mitochondrial disease besides the size and location of a mutation. Mitochondria replicate during each cell division during gestation and throughout life. Because the mutation in mitochondrial disease most often occurs early in gestation in these diseases, only those mitochondria in the mutated lineage are defective. This results in an uneven distribution of dysfunctional mitochondria within each cell, and among different tissues of the body. This describes the term heteroplasmic which is characteristic of mitochondrial diseases including KSS. The distribution of mutated mtDNA in each cell, tissue, and organ, is dependent on when and where the mutation occurs. This may explain why two patients with an identical mutation in mtDNA can present with entirely different phenotypes and in turn different syndromes. A publication in 1992 by Fischel-Ghodsian et al. identified the same 4,977-bp deletion in mtDNA in two patients presenting with two entirely different diseases. One of the patients had characteristic KSS, while the other patient had a very different disease known as Pearson marrow pancreas syndrome. Complicating the matter, in some cases Pearsons syndrome has been shown to progress into KSS later in life.More recent studies have concluded that mtDNA duplications may also play a significant role in determining what phenotype is present. Duplications of mtDNA seem to be characteristic of all cases of KSS and Pearsons syndrome, while they are absent in CPEO.Deletions of mtDNA in KSS vary in size (1.3–8kb), as well as position in the mitochondrial genome. The most common deletion is 4.9kb and spans from position 8469 to position 13147 on the genome. This deletion is present in approximately ⅓ of people with KSS
Diagnosis
A neuro-ophthalmologist is usually involved in the diagnosis and management of KSS. An individual should be suspected of having KSS based upon clinical exam findings. Suspicion for myopathies should be increased in patients whose ophthalmoplegia does not match a particular set of cranial nerve palsies (oculomotor nerve palsy, fourth nerve palsy, sixth nerve palsy). Initially, imaging studies are often performed to rule out more common pathologies. Diagnosis may be confirmed with muscle biopsy, and may be supplemented with PCR determination of mtDNA mutations.
Biopsy findings
It is not necessary to biopsy an ocular muscle to demonstrate histopathologic abnormalities. Cross-section of muscle fibers stained with Gömöri trichrome stain is viewed using light microscopy. In muscle fibers containing high ratios of the mutated mitochondria, there is a higher concentration of mitochondria. This gives these fibers a darker red color, causing the overall appearance of the biopsy to be described as "ragged red fibers. Abnormalities may also be demonstrated in muscle biopsy samples using other histochemical studies such as mitochondrial enzyme stains, by electron microscopy, biochemical analyses of the muscle tissue (ie electron transport chain enzyme activities), and by analysis of muscle mitochondrial DNA."
Laboratory studies
Blood lactate and pyruvate levels usually are elevated as a result of increased anaerobic metabolism and a decreased ratio of ATP:ADP. CSF analysis shows an elevated protein level, usually >100 mg/dl, as well as an elevated lactate level.
Management
Currently there is no curative treatment for KSS. Because it is a rare condition, there are only case reports of treatments with very little data to support their effectiveness. Several promising discoveries have been reported which may support the discovery of new treatments with further research. Satellite cells are responsible for muscle fiber regeneration. It has been noted that mutant mtDNA is rare or undetectable in satellite cells cultured from patients with KSS. Shoubridge et al. (1997) asked the question whether wildtype mtDNA could be restored to muscle tissue by encouraging muscle regeneration. In the forementioned study, regenerating muscle fibers were sampled at the original biopsy site, and it was found that they were essentially homoplasmic for wildtype mtDNA. Perhaps with future techniques of promoting muscle cell regeneration and satellite cell proliferation, functional status in KSS patients could be greatly improved.One study described a patient with KSS who had reduced serum levels of coenzyme Q10. Administration of 60–120 mg of coenzyme Q10 for three months resulted in normalization of lactate and pyruvate levels, improvement of previously diagnosed first degree AV block, and improvement of ocular movements.A screening ECG is recommended in all patients presenting with CPEO. In KSS, implantation of pacemaker is advised following the development of significant conduction disease, even in asymptomatic patients.Screening for endocrinologic disorders should be performed, including measuring serum glucose levels, thyroid function tests, calcium and magnesium levels, and serum electrolyte levels. Hyperaldosteronism is seen in 3% of KSS patients.
History
The triad of CPEO, bilateral pigmentary retinopathy, and cardiac conduction abnormalities was first described in a case report of two patients in 1958 by Thomas P. Kearns (1922–2011), MD., and George Pomeroy Sayre (1911–1992), MD. A second case was published in 1960 by Jager and co-authors reporting these symptoms in a 13-year-old boy. Previous cases of patients with CPEO dying suddenly had been published, occasionally documented as from a cardiac dysrhythmia. Other cases had noted a peculiar pigmentation of the retina, but none of these publications had documented these three pathologies occurring together as a genetic syndrome. Kearns published a defining case in 1965 describing nine unrelated cases with this triad. In 1988, the first connection was made between KSS and large-scale deletions of muscle mitochondrial DNA (abbreviated mtDNA) Since this discovery, numerous deletions in mitochondrial DNA have been linked to the development of KSS.
References
External links
kearns_sayre at NINDS
Kearns Sayre syndrome at NIHs Office of Rare Diseases |
Smith–Lemli–Opitz syndrome | Smith–Lemli–Opitz syndrome is an inborn error of cholesterol synthesis. It is an autosomal recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a broad spectrum of effects, ranging from mild intellectual disability and behavioural problems to lethal malformations.
Signs and symptoms
SLOS can present itself differently in different cases, depending on the severity of the mutation and other factors. Originally, SLOS patients were classified into two categories (classic and severe) based on physical and mental characteristics, alongside other clinical features. Since the discovery of the specific biochemical defect responsible for SLOS, patients are given a severity score based on their levels of cerebral, ocular, oral, and genital defects. It is then used to classify patients as having mild, classical, or severe SLOS.
Physical characteristics
The most common facial features of SLOS include microcephaly, bitemporal narrowing (reduced distance between temples), ptosis, a short and upturned nose, micrognathia, epicanthal folds, and capillary hemangioma of the nose. Other physical characteristics include:
low-set and posteriorly rotated ears
high-arched, narrow, hard palate
cleft lip/palate
agenesis or hypoplasia of the corpus callosum
cerebellar hypoplasia
increased ventricular size
decreased frontal lobe size
polydactyly of hands or feet
short, proximally placed thumb
other finger malformations
syndactyly of second and third toes
ambiguous or female-like male genitalia
congenital heart defects
renal, pulmonary, liver and eye abnormalities
Behavioural characteristics
Certain behaviours and attributes are commonly seen among patients with SLOS. They may have low normal intelligence, and react negatively or with hypersensitivity to different sensory stimuli. This is particularly true for certain auditory and visual stimuli. Many patients show aggressiveness and self-injurious behaviours, and sleep disturbances are common. Specific behaviours resembling those of people with autism are often present as well as hyperactivity, which provides genetic and biological insights into autism spectrum disorders. The autistic behaviours most characteristic of SLOS patients are opisthokinesis (an upper body movement), stretching of the upper body, and hand flicking. Autism is typically diagnosed separately from SLOS using the DSM-V, and approximately 50–75% of SLOS patients meet the criteria for autism.Other behaviours associated with SLOS can be linked directly to physical abnormalities. For example, infants often show feeding problems or feeding intolerance, and patients may require increased caloric intake due to accelerated metabolism. Recurrent infections, including ear infections and pneumonia, are also common.
Biochemical phenotype
Given that SLOS is caused by a mutation in an enzyme involved in cholesterol synthesis, the resulting biochemical characteristics may be predictable. Most patients have lowered plasma cholesterol levels (hypocholesterolemia). However, approximately 10% may show normal cholesterol levels, and decreased concentrations of cholesterol are not solely indicative of SLOS. Increased levels of cholesterol precursors are also common in SLOS. In particular, elevated levels of 7-dehydrocholesterol are fairly specific to SLOS.
Genetics
DHCR7
The gene encoding DHCR7 (labeled as DHCR7) was cloned in 1998, and has been mapped to chromosome 11q12-13. It is 14100 base pairs of DNA in length, and contains nine exons, the corresponding mRNA is 2786 base pairs in length (the remaining DNA sequence is intronic). The structure of the DHCR7 rat gene is very similar to the structure of the human gene.The highest levels of DHCR7 expression have been detected in the adrenal gland, the testis, the liver and in brain tissue. Its expression is induced by decreased sterol concentrations via sterol regulatory binding proteins (SREBP). There is also evidence that its activity may be regulated by tissue specific transcription, and alternative splicing.As outlined above, the enzyme DHCR7 catalyzes the reduction of 7DHC to cholesterol, as well as the reduction of 7-dehydrodesmosterol to desmosterol. It requires NADPH as a cofactor for this reduction, and may involve the activity of cytochrome-P450 oxidoreductase. It is also thought to contain iron. DHCR7 is an integral membrane protein of the endoplasmic reticulum, and computer models have predicted up to nine transmembrane domains. DHCR7 is most efficient at reducing 7DHC, but it is known to reduce the carbon 7 double bond of other sterols, indicating a range of substrate specificity. The human version of this enzyme is predicted to have a molecular weight of 54,489 kDa, and an isoelectric point of 9.05.The amino acid sequence that encodes DHCR7 is predicted to contain 475 amino acids, as well as several protein motifs. It contains multiple sterol reductase motifs, as would be expected given its function. It contains a potential sterol-sensing domain (SSD), whose function is unknown but thought to be necessary for binding sterol substrates. It also includes multiple sites of phosphorylation, including potential protein kinase C and tyrosine kinase sites (regulatory enzymes responsible for phosphorylation). The exact function of phosphorylating DHCR7 is yet unknown, but it is thought to be involved in the regulation of its activity.
Mutations and incidence
SLOS is an autosomal recessive disorder. More than 130 different types of mutations have been identified. Missense mutations (single nucleotide change resulting in a code for a different amino acid) are the most common, accounting for 87.6% of the SLOS spectrum. These typically reduce the function of the enzyme but may not inhibit it completely. Much depends on the nature of the mutation (i.e. which amino acid is replaced and where). Null mutations are much less common, these mutations produce either a completely dysfunctional enzyme, or no enzyme at all. Thus, missense mutations may be more common overall because they are less lethal than nonsense mutations; nonsense mutations may simply result in spontaneous abortion.The IVS8-1G>C is the most frequently reported mutation in DHCR7. This disrupts the joining of exons eight and nine, and results in the insertion of 134 nucleotides into the DHCR7 transcript. This is a nonsense mutation, thus patients that are homozygous for this allele are severely affected. It is thought that this mutation first occurred in the British Isles, and it has a carrier (those that are heterozygous for the allele but not affected) frequency of 1.09% for Caucasians of European heritage. The frequency of mutations differs for various ethnicities, depending on the origin of the mutation. In all Caucasian populations, this particular mutation has an estimated carrier frequency of 3%.The next most common mutation is 278C>T, and results in a threonine at the amino acid position 93. It is a missense mutation and tends to be associated with less severe symptoms. This mutation is the most common one seen in patients of Italian, Cuban, and Mediterranean descent.The third most common mutation is 452G>A. This nonsense mutation causes protein termination, such that the enzyme DHCR7 would not be formed. It is thought to have arisen in Southern Poland and is most common in Northern Europe.Other mutations are less common, although appear to target certain protein domains more so than others. For example, the sterol reductase motifs are common sites of mutation. Overall, there is an estimated carrier frequency (for any DHCR7 mutation causing SLOS) of 3-4% in Caucasian populations (it is less frequent among Asian and African populations). This number indicates a hypothetical birth incidence between 1/2500 and 1/4500. However, the measured incidence is between 1/10,000 to 1/60,000 (it differs depending on heritage and descent). This is much lower than expected. This indicates that many cases of SLOS are undetected, and is likely due to either spontaneous abortion caused by severe mutations (miscarriage), or mild cases that are undiagnosed. Females lack the characteristic genital malformations that affected males have, and thus are less likely to be correctly diagnosed.
Cholesterol metabolism and function
Metabolism
Cholesterol can be obtained through the diet, but it can also be formed by metabolism in the body. Cholesterol metabolism primarily takes place in the liver, with significant amounts in the intestine as well. It should also be noted that cholesterol cannot pass the blood–brain barrier, thus within the brain, biosynthesis is the only source of cholesterol.
In humans, cholesterol synthesis begins with the mevalonate pathway (see diagram), leading to the synthesis of farnesyl pyrophosphate (FPP). This pathway uses two acetyl-CoA and two NADPH to make mevalonate, which is metabolized to isopentenyl pyrophosphate (IPP) using three ATP. From there, three IPP are needed to make one FPP. The combination of two FPP leads to the formation of squalene; this represents the first committed step towards cholesterol biosynthesis. Squalene leads to the creation of lanosterol, from which there are multiple pathways that lead to cholesterol biosynthesis. The rate limiting step of cholesterol synthesis is the conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate, this is an early step in the mevalonate pathway catalyzed by HMG-CoA reductase.
Through a complicated series of reactions, lanosterol leads to the formation of zymosterol. As shown in a diagram to the right, it is at this point that the pathway diverges. In humans, the main pathway leading to cholesterol is known as the Kandutsch–Russell pathway. Zymosterol is metabolized to 5α-cholesta-7,24-dien-3β-ol, then to lathosterol, and then to 7-dehydrocholesterol, or 7-DHC. 7-DHC is the immediate precursor to cholesterol, and the enzyme DHCR7 is responsible for converting 7-DHC to cholesterol. DHCR7 reduces the double bond on carbon 7 of 7-DHC, leading to the unesterified product. Mutations in this enzyme are responsible for the wide range of defects present in SLOS. In another pathway leading to cholesterol synthesis, DHCR7 is required for the reduction of 7-Dehydrodesmosterol to desmosterol.
Regulation
Regulation of cholesterol synthesis is complex and occurs primarily through the enzyme HMG-CoA reductase (catalyst of the rate-limiting step). It involves a feedback loop that is sensitive to cellular levels of cholesterol. The four main steps of regulation are:
The synthesis of the enzyme HMG-CoA reductase is controlled by sterol regulatory element binding protein (SREBP). This is a transcription factor that is inactive when cholesterol levels are high, and active when cholesterol levels are low. When cholesterol levels fall, SREBP is released from the nuclear membrane or endoplasmic reticulum, it then migrates to the nucleus and causes the transcription of the HMG-CoA reductase gene.
The translation (creating the enzyme from the mRNA transcript) of HMG-CoA reductase is inhibited by derivatives of mevalonate and by dietary cholesterol.
The degradation of HMG-CoA reductase is tightly controlled. The part of the enzyme that is bound to the endoplasmic reticulum senses signals, such as increased cholesterol levels, that lead to its degradation or proteolysis.
When HMG-CoA reductase is phosphorylated, its activity decreases. This means cholesterol synthesis is reduced when cell energy (ATP) levels are low.
Function
Cholesterol is an important lipid involved in metabolism, cell function, and structure. It is a structural component of the cell membrane, such that it provides structure and regulates the fluidity of the phospholipid bilayer. Furthermore, cholesterol is a constituent in lipid rafts. These are congregations of proteins and lipids (including sphingolipids and cholesterol) that float within the cell membrane, and play a role in the regulation of membrane function. Lipid rafts are more ordered or rigid than the membrane bilayer surrounding them. Their involvement in regulation stems mostly from their association with proteins; upon binding substrates, some proteins have a higher affinity for attaching to lipid rafts. This brings them in close proximity with other proteins, allowing them to affect signaling pathways. Cholesterol specifically acts as a spacer and a glue for lipid rafts; absence of cholesterol leads to the dissociation of proteins.Given its prevalence in cell membranes, cholesterol is highly involved in certain transport processes. It may influence the function of ion channels and other membrane transporters. For example, cholesterol is necessary for the ligand binding activity of the serotonin receptor. In addition, it appears to be very important in exocytosis. Cholesterol modulates the properties of the membrane (such as membrane curvature), and may regulate the fusion of vesicles with the cell membrane. It may also facilitate the recruitment of complexes necessary for exocytosis. Given that neurons rely heavily on exocytosis for the transmission of impulses, cholesterol is a very important part of the nervous system.
One particularly relevant pathway in which cholesterol takes place is the Hedgehog signaling pathway. This pathway is very important during embryonic development, and involved in deciding the fate of cells (i.e., which tissue they need to migrate to). Hedgehog proteins are also involved in the transcription of genes that regulate cell proliferation and differentiation. Cholesterol is important to this pathway because it undergoes covalent bonding to Hedgehog proteins, resulting in their activation. Without cholesterol, the signaling activity is disrupted and cell differentiation may be impaired.Cholesterol is a precursor for many important molecules. These include bile acids (important in processing dietary fats), oxysterols, neurosteroids (involved in neurotransmission and excitation), glucocorticoids (involved in immune and inflammatory processes), mineralocorticoids (osmotic balance), and sex steroids (i.e. estrogen and testosterone; wide range of function but involved in genital development prenatally). Finally, cholesterol is a major component of myelin, a protective layer around neurons. Myelination occurs most rapidly during prenatal development, meaning that the demand for cholesterol biosynthesis is very high.
Pathogenesis
Given that the function of cholesterol encompasses a very wide range, it is unlikely that the symptoms of SLOS are due to a single molecular mechanism. Some of the molecular effects are yet unknown, but could be extrapolated based on the role of cholesterol. In general, the negative effects are due to decreased levels of cholesterol and increased levels of cholesterol precursors-most notably, 7DHC. Although 7DHC is structurally similar to cholesterol, and could potentially act as a substitute, the effects of this are still being studied.Most patients with SLOS present decreased cholesterol levels, particularly in the brain (where cholesterol levels rely primarily on new synthesis). This also means that any sterol derivatives of cholesterol would also have reduced concentrations. For example, reduced levels of neurosteroids may be seen in SLOS. These are lipids which take part in signaling within the brain, and must be produced within the brain itself. They are responsible for interacting with nuclear steroid receptors, and bind to neurotransmitter-gated ion channels. Specifically, they modulate the effects of GABA and NMDA receptors, resulting in calming effects, improved memory, and more. Thus, given that some characteristics of SLOS are the opposite of these effects (hyperactivity, anxiety), a reduction in neurosteroids could influence both neurological development and behaviour.
Furthermore, as outlined above, cholesterol is an important aspect in Hedgehog signaling. With lower levels of cholesterol, hedgehog proteins would not undergo the necessary covalent modification and subsequent activation. This would result in impaired embryonic development, and may contribute to the observed physical birth defects in SLOS. One particular hedgehog signaling protein, sonic hedgehog (SHH), is important in the pattern of the central nervous system, facial features, and limbs. Other hedgehog proteins may be involved in the development of the genital tract and the skeleton.The altered sterol levels in SLOS are particularly relevant to cell membranes, which are made primarily of lipids. SLOS patients may show cell membranes with abnormal properties or composition, and reduced cholesterol levels greatly affect the stability and proteins of lipid rafts. Despite their structural similarity, 7DHC is unable to replace cholesterol in lipid rafts. In addition, a lack of cholesterol contributes to the increased fluidity of the cell membrane, and may cause abnormal granule secretions. All of these changes in the membrane likely contribute to changes in transport functions that are observed in SLOS. They may cause defects in IgE receptor-mediated mast cell degranulation and cytokine production, which are cells involved in allergic and immune responses. The NMDA receptor is affected, as well as the binding capability of the hippocampal serotonin receptor. Cell to cell interaction, which is very important in development, may be impaired. Exocytosis in synaptic vesicles has been shown to be reduced, likely due to impaired vesicle fusion to the cell membrane, or poor vesicle recycling. Finally, cholesterol is highly prevalent in myelin, therefore SLOS patients show reduced myelination of the cerebral hemispheres, peripheral nerves, and cranial nerves.In addition to lowered levels of cholesterol, many of the symptoms shown in SLOS stem from the toxic effects of 7DHC. 7DHC is known to impair intracellular cholesterol transport. It also increases the degradation of HMG-CoA reductase (the enzyme that catalyzes the rate-limiting step in cholesterol synthesis). 7DHC leads to novel oxysterol and steroid derivatives, and many of their functions or effects are yet unknown. A very important finding with respect to 7DHC is that it is the most reactive lipid for lipid peroxidation, and results in systemic oxidative stress. Lipid peroxidation is known to destroy membranes of both cells and membrane-bound organelles. The derivative of 7DHC that is used to indicate oxidative stress is 3β,5α-dihydroxy-cholest-7-en-6-one (DHCEO); it is formed from a primary product of 7DHC peroxidation, 7-DHC-5α,6α-epoxide. DHCEO is toxic to cortical neuronal and glial cells, and accelerates their differentiation and arborization. Through oxidative stress, 7DHC is thought to be responsible for the increased photosensitivity shown in SLOS patients. Normal UVA exposure may lead to oxidative stress in skin cells. Given that 7DHC is more readily oxidized, it enhances the effects of UVA, leading to increased membrane lipid oxidation and increased production of reactive oxygen species (ROS).Typically, more altered the levels of 7DHC and cholesterol lead to more severe symptoms of SLOS. The levels of these metabolites also correspond to the severity of the mutation (nonsense versus missense); some mutations of DHCR7 may still show residual cholesterol synthesis, and others may not. However, even individuals with the same mutations or genotype may still show variability in their symptoms. This may be due to maternal factors, such as the transfer of cholesterol to the fetus during pregnancy, as well as the amount of cholesterol present in the brain before the blood–brain barrier forms prenatally. The rate of accumulation and excretion of toxic metabolites may vary from person to person. Maternal apolipoprotein E has also been implicated in individual variability in SLOS, although the exact nature of this relationship is unknown. There are likely more factors contributing to the wide spectrum of effects in SLOS which have not yet been discovered.
Screening and diagnosis
Prenatally
The most characteristic biochemical indicator of SLOS is an increased concentration of 7DHC (reduced cholesterol levels are also typical, but appear in other disorders as well). Thus, prenatally, SLOS is diagnosed upon finding an elevated 7DHC:total sterol ratio in fetal tissues, or increased levels of 7DHC in amniotic fluid. The 7DHC:total sterol ratio can be measured at 11–12 weeks of gestation by chorionic villus sampling, and elevated 7DHC in amniotic fluid can be measured by 13 weeks. Furthermore, if parental mutations are known, DNA testing of amniotic fluid or chorionic villus samples may be performed.
Amniocentesis (process of sampling amniotic fluid) and chorionic villus sampling cannot be performed until approximately 3 months into the pregnancy. Given that SLOS is a very severe syndrome, parents may want to choose to terminate their pregnancy if their fetus is affected. Amniocentesis and chorionic villus sampling leave very little time to make this decision (abortions become more difficult as the pregnancy advances), and can also pose severe risks to the mother and baby. Thus, there is a very large desire for noninvasive midgestation diagnostic tests. Examining the concentrations of sterols in maternal urine is one potential way to identify SLOS prenatally. During pregnancy, the fetus is solely responsible for synthesizing the cholesterol needed to produce estriol. A fetus with SLOS cannot produce cholesterol, and may use 7DHC or 8DHC as precursors for estriol instead. This creates 7- or 8-dehydrosteroids (such as 7-dehydroestriol), which may show up in the maternal urine. These are novel metabolites due to the presence of a normally reduced double bond at carbon 7 (caused by the inactivity of DHCR7), and may be used as indicators of SLOS. Other cholesterol derivatives which possess a double bond at the 7th or 8th position and are present in maternal urine may also be indicators of SLOS. 7- and 8-dehydropregnanetriols have been shown to be present in the urine of mothers with an affected fetus but not with an unaffected fetus, and thus are used in diagnosis. These pregnadienes originated in the fetus and traveled through the placenta before reaching the mother. Their excretion indicates that neither the placenta nor the maternal organs have necessary enzymes needed to reduce the double bond of these novel metabolites.
Postnatally
If SLOS goes undetected until after birth, diagnosis may be based on the characteristic physical features as well as finding increased plasma levels of 7DHC.There are many different ways of detecting 7DHC levels in blood plasma, one way is using the Liebermann–Burchard (LB) reagent. This is a simple colorimetric assay developed with the intention of use for large scale screening. When treated with the LB reagent, SLOS samples turn pink immediately and gradually become blue; normal blood samples are initially colorless and develop a faint blue color. Although this method has limitations and is not used to give a definitive diagnosis, it has appeal in that it is a much faster method than using cell cultures.Another way of detecting 7DHC is through gas chromatography, a technique used to separate and analyze compounds. Selected ion
monitoring gas chromatography/mass-spectrometry (SIM-GC/MS) is a very sensitive version of gas chromatography, and permits detection of even mild cases of SLOS. Other methods include time-of-flight mass spectrometry, particle-beam LC/MS, electrospray tandem MS, and ultraviolet absorbance, all of which may be used on either blood samples, amniotic fluid, or chorionic villus. Measuring levels of bile acids in patients urine, or studying DCHR7 activity in tissue culture are also common postnatal diagnostic techniques.
Treatment
Management of individuals with SLOS is complex and often requires a team of specialists. Some of the congenital malformations (cleft palate) can be corrected with surgery. Other treatments have yet to be proven successful in randomized studies, however anecdotally they appear to cause improvements.
Cholesterol supplementation
Currently, the most common form of treatment for SLOS involves dietary cholesterol supplementation. Anecdotal reports indicate that this has some benefits; it may result in increased growth, lower irritability, improved sociability, less self-injurious behaviour, less tactile defensiveness, fewer infections, more muscle tone, less photosensitivity and fewer autistic behaviours. Cholesterol supplementation begins at a dose of 40–50 mg/kg/day, increasing as needed. It is administered either through consuming foods high in cholesterol (eggs, cream, liver), or as purified food grade cholesterol. Younger children and infants may require tube feeding. However, dietary cholesterol does not reduce the levels of 7DHC, cannot cross the blood–brain barrier, and does not appear to improve developmental outcomes. One empirical study found that cholesterol supplementation did not improve developmental delay, regardless of the age at which it began. This is likely because most developmental delays stem from malformations of the brain, which dietary cholesterol cannot ameliorate due to its inability to cross the blood–brain barrier.
Simvastatin therapy
HMG-CoA reductase inhibitors have been examined as treatment for SLOS. Given that this catalyzes the rate-limiting step in cholesterol synthesis, inhibiting it would reduce the buildup of toxic metabolites such as 7DHC. Simvastatin is a known inhibitor of HMG-CoA reductase, and most importantly is able to cross the blood–brain barrier. It has been reported to decrease the levels of 7DHC, as well as increase the levels of cholesterol. The increased cholesterol levels are due to simvastatins effect on the expression of different genes. Simvastatin increases the expression of DHCR7, likely leading to increased activity of DHCR7. It has also been shown to increase the expression of other genes involved in cholesterol synthesis and uptake. However, these benefits are dependent on the amount of residual cholesterol synthesis. Because some individuals possess less severe mutations and demonstrate some amount of DCHR7 activity, these people benefit the most from simvastatin therapy as they still have a partially functioning enzyme. For individuals that show no residual DCHR7 activity, such as those homozygous for null alleles or mutations, simvastatin therapy may actually be toxic. This highlights the importance of identifying the specific genotype of the SLOS patient before administering treatment. It is still unknown if simvastatin will improve the behavioural or learning deficits in SLOS.
Antioxidant supplementation
Antioxidants are those which inhibit the oxidation of molecules or reduce metabolites that were previously oxidized. Given that some symptoms of SLOS are thought to result from the peroxidation of 7DHC and its derivatives, inhibiting this peroxidation would likely have beneficial effects. Antioxidants have been shown to increase the level of lipid transcripts in SLOS cells, these transcripts play a role in lipid (cholesterol) biosynthesis and are known to be down-regulated in SLOS. Furthermore, vitamin E specifically is known to decrease DHCEO levels, which is an indicator of oxidative stress in SLOS, as well as present beneficial changes in gene expression. Vitamin E appears to be the most powerful antioxidant for treating SLOS, and in mouse models has reduced the levels of oxysterols in the brain. However, antioxidants have only been studied in animal models of SLOS or isolated SLOS cells. Thus, their clinical significance and negative side effects are still unknown, and their use has yet to be studied in humans.
Further considerations
When treating SLOS, a recurring issue is whether or not the intellectual and behavioural deficits are due to fixed developmental problems (i.e. fixed brain malformations), or due to ongoing abnormal sterol levels that interrupt the normal function of the brain and other tissues. If the latter is true, then treatments which change the sterol levels and ratios, particularly in the brain, will likely improve the developmental outcome of the patient. However, if the former is true, then treatment is likely to help only with symptoms and not with specific developmental deficits.
Research
The most common animal used to study SLOS is the mouse. According to BioCyc, cholesterol biosynthesis in mice is very similar to that of humans. Most importantly, mice possess both DHCR7 (the enzyme responsible for SLOS), and HMG-CoA reductase (the rate limiting step of cholesterol synthesis. Rats are similar to mice and have also been used. There are two popular |
Smith–Lemli–Opitz syndrome | ways in which animal models of SLOS are created. The first is using teratogens, the second is using genetic manipulations to create mutations in the DHCR7 gene.
Teratogenic models
Teratogenic models are induced by feeding pregnant rats or mice inhibitors of DCHR7. Two common inhibitors are BM15766 (4-(2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl)-benzoic acid) and AY9944 (trans-l,4-bis(2-chlorobenzylaminomethy1)cyclohexane dihydrochloride). These compounds have different chemical and physical properties, but induce similar effects. AY9944 has been shown to induce holoprosencephaly and sexual malformations similar to those seen in humans with SLOS. It is also known to cause impairments in the serotonin receptor, another defect commonly seen in SLOS patients. BM15766 has produced the lack of cholesterol and bile acid synthesis that is seen in SLOS patients with homozygous mutations. All teratogenic models can be effectively used to study SLOS; however, they present lower levels of 7-DHC and 8-DHC than are seen in humans. This can be explained by the fact that humans experience a permanent block in their DHCR7 activity, where mice and rats treated with inhibitors experience only transient blocks. Furthermore, different species of mice and rats are more resistant to teratogens, and may be less effective as models of SLOS. Teratogenic models are most commonly used to study more long-term effects of SLOS, because they survive longer than genetic models. For example, one study examined the retinal degeneration of SLOS, which in rats does not occur until at least one month after birth.
Genetic models
Genetic models of SLOS are created by knocking out the DHCR7 gene. One study used homologous recombination to disrupt DCHR7 in mouse embryonic stem cells. Similar to what is found in humans, heterozygous mice (having only one mutated allele) were phentoypically normal, and were crossed to produce pups (young mice) homozygous for the mutated allele. Although these pups died within the first day of life due to their inability to feed, they showed characteristics similar to humans with SLOS. They had decreased levels of cholesterol, increased levels of 7- and 8DHC, showed less growth and smaller birth weights, had craniofacial malformations, and less movement. Many also had a cleft palate, and decreased neuronal responses to glutamate. Overall however, the pups had fewer dysmorphic features than human patients with SLOS; they did not present limb, renal, adrenal or central nervous system malformations. This is explained by the fact that in rodents, maternal cholesterol can cross the placenta, and actually appears to be essential for the development of the fetus. In humans, very little maternal cholesterol is transferred to the fetus. In sum, the genetic mouse model is helpful to explain the neuropathophysiology of SLOS.
Discoveries
Many discoveries in SLOS research have been made using animal models. They have been used to study different treatment techniques, including the effectiveness of simvastatin therapy. Other studies have examined behavioural characteristics while attempting to explain their underlying pathogenesis. A common finding is that mouse models of SLOS show abnormal serotonergic development, which may be at least partially responsible for the autistic behaviours seen in SLOS. Mouse models have also been used to develop diagnostic techniques; multiple studies have examined biomarkers that result from the oxidation of 7DHC, such as DHCEO. It is likely that as animal models are improved, they will lead to many more discoveries in SLOS research.
Eponym
It is named after David Weyhe Smith (1926–1981), an American pediatrician; Luc Lemli (1935–), a Belgian physician; and John Marius Opitz (1935–), a German-American physician. These are the researchers who first described the symptoms of SLOS.
References
This article incorporates public domain material from Genetics Home Reference. United States National Library of Medicine.
External links
GeneReview/UW/NIH on Smith–Lemli–Opitz syndrome |
Nasal septum deviation | Nasal septum deviation is a physical disorder of the nose, involving a displacement of the nasal septum. Some displacement is common, affecting 80% of people, mostly without their knowledge.
Signs and symptoms
The nasal septum is the bone and cartilage in the nose that separates the nasal cavity into the two nostrils. The cartilage is called the quadrangular cartilage and the bones comprising the septum include the maxillary crest, vomer and the perpendicular plate of the ethmoid. Normally, the septum lies centrally, and thus the nasal passages are symmetrical. A deviated septum is an abnormal condition in which the top of the cartilaginous ridge leans to the left or the right, causing obstruction of the affected nasal passage.
It is common for nasal septa to depart from the exact centerline; the septum is only considered deviated if the shift is substantial or causes problems. By itself, a deviated septum can go undetected for years and thus be without any need for correction.Symptoms of a deviated septum include infections of the sinus and sleep apnea, snoring, repetitive sneezing, facial pain, nosebleeds, mouth breathing, difficulty with breathing and mild to severe loss of the ability to smell. Only more severe cases of a deviated septum will cause symptoms of difficulty breathing and require treatment.
Causes
It is most frequently caused by impact trauma, such as by a blow to the face. It can also be a congenital disorder, caused by compression of the nose during childbirth. Deviated septum is associated with genetic connective tissue disorders such as Marfan syndrome, Homocystinuria and Ehlers–Danlos syndrome.
Diagnosis
Nasal septum deviation is the most common cause of nasal obstruction. A history of trauma to the nose is often present including trauma from the process of birth or microfractures. A medical professional, such as an otorhinolaryngologist (ears, nose, and throat doctor), typically makes the diagnosis after taking a thorough history from the affected person and performing a physical examination. Imaging of the nose is sometimes used to aid in making the diagnosis as well.
Treatment
Medical therapy with nasal sprays including decongestants, antihistamines, or nasal corticosteroid sprays is typically tried first before considering a surgical approach to correct nasal septum deviation. Medication temporarily relieves symptoms, but does not correct the underlying condition. Non-medical relief can also be obtained using nasal strips.
A minor surgical procedure known as septoplasty can cure symptoms related to septal deviations. The surgery lasts roughly one hour and does not result in any cosmetic alteration or external scars. Nasal congestion, pain, drainage, or swelling may occur within the first few days after the surgery. Recovery from the procedure may take anywhere from 2 days to 4 weeks to heal completely. Septal bones never regrow. If symptoms reappear they are not related to deviations. Reappearance of symptoms may be due to mucosal metaplasia of the nose.Currently, the most gentle and effective treatment is laser septo-chondroplasty for the septal cartilage segment deformity and ultrasound septoplasty — effective for the septal cartilage and bone deformation.
Complications of septoplasty
Nasal septum perforation due to bilateral trauma of the mucoperichondrial flaps opposite each other.
Incomplete correction with persistent nasal symptoms
External nasal deformity
Septal hematoma and septal abscess.
Scarring inside the nose and nose bleeding
Adhesions and synechiae between septal mucosa and lateral nasal wall
Saddle nose due to over-resection of the dorsal wall of the septal cartilage
Dropped nasal tip due to resection of the caudal margin
See also
Nasal septum perforation
References
== External links == |
Postpericardiotomy syndrome | Postpericardiotomy syndrome (PPS) is a medical syndrome referring to an immune phenomenon that occurs days to months (usually 1–6 weeks) after surgical incision of the pericardium (membranes encapsulating the human heart). PPS can also be caused after a trauma, a puncture of the cardiac or pleural structures (such as a bullet or stab wound), after percutaneous coronary intervention (such as stent placement after a myocardial infarction or heart attack), or due to pacemaker or pacemaker wire placement.
Signs and symptoms
The typical signs of post-pericardiotomy syndrome include fever, pleuritis (with possible pleural effusion), pericarditis (with possible pericardial effusion), occasional but rare pulmonary infiltrates, and fatigue. Cough, pleuritic or retrosternal chest pain, joint pain and decreased oxygen saturation can also be seen in some cases.Other signs include arthritis, together with petechiae on the skin and palate.: 827
Complications
Complications include pericarditis, pericardial effusion, pleuritis, pulmonary infiltration, and very rarely pericardial tamponade. Of these cardiac tamponade is the most life-threatening complication. The pericardial fluid increases intra-pericardial pressure therefore preventing complete expansion of the atria and the ventricles upon the diastole. This causes equilibration of the pressure in all four heart chambers, and results in the common findings of the tamponade which are pulsus paradoxus, Becks triad of hypotension, muffled heart sounds, and raised jugular venous pressure, as well as EKG or Holter monitor findings such as electrical alternans. Physically the patients who progress to severe pericardial tamponade obtundate, become mentally altered, and lethargic. If left untreated, severe decrease in cardiac output, vascular collapse, and hypoperfusion of body including the brain results in death.
Pathogenesis
The cause is believed to be an autoimmune response against damaged cardiac tissue. This is supported by excellent response to immunosuppressive (steroid) therapy.This condition is a febrile illness caused by immune attack of the pleura and the pericardium. Possible cell mediated immunity led by Helper T-cells and Cytotoxic T-cells is postulated to be important in the pathogenesis of this condition. There is also possibility of anti-cardiac antibodies created idiopathically, or due to concurrent cross-reactivity of the antibodies produced against viral antigens, however the latter assumption is not fool-proof or completely reliable due to conflicting studies.
Diagnosis
A chest X-ray might depict pleural effusion, pulmonary infiltration, or pericardial effusion.During medical doctor examination, a pericardial friction rub can be auscultated indicating pericarditis. Auscultation of the lungs can show crackles indicating pulmonary infiltration, and there can be retrosternal/pleuritic chest pain worse on inspiration (breathing in). Patient can also depict sweating (diaphoresis) and agitation or anxiety.
Treatment
Colchicine
Colchicine has been used effectively to prevent pericarditis, and inflammation that follows surgery of the pericardium. Although no current drug on the market prevents post-pericardiotomy syndrome, colchicine seems to provide an effective and safe way to treat pericarditis by reducing inflammation. Colchicine is a natural product extracted from plants, and is a secondary metabolite (an organic compound not directly related to growth and development in an organism).Colchicine interferes with the inflammatory process by altering several important steps in the pathway. Microtubules are structural components of the cytoskeleton that lengthen and shrink for important cell functions. Colchicine binds to β- tubulin and forms tubulin-colchicine complexes., These complexes interfere with microtubule formation microtubules. Low doses of colchicine can inhibit the formation of microtubules, while high doses depolymerize or break down a polymer to a monomer. Therefore, any process involving cytoskeleton change, including mitosis and motility of white blood cells, are highly impacted.Microtubule disruption decrease neutrophil adhesion, an important step for inflammation. Neutrophils are recruited to the target location of inflammation via signals from the endothelium where they adhere and play a role in the inflammatory response. Colchicine diminishes neutrophil adhesion by decreasing expression of selectins, a family of cell adhesion molecules. In addition, colchicine prevents the movement and secretion of intercellular granules, substances, proinflammatory enzymes from neutrophils, thus making a significant impact on inflammatory processes within the body. The high concentration of colchicine in neutrophils, sixteen times greater compared the plasma levels, can account for the positive therapeutic effects.Many mediators are altered to assist neutrophils during inflammation, including the monokine tumor necrosis factor-alpha (TNFα). Cytokines help stimulate the acute phase reaction in response to inflammation. Colchicine inhibits macrophage production of TNFα, leading to the interference between TNFα and neutrophil interaction. There are many more effects of colchicine that are currently under research, and some aspects of this metabolite are not fully understood.There was great hope that Colchicine could be a primary preventive measure in treating Post-Pericardiotomy Syndrome due to its anti-inflammatory effects. In the COPPS-2 trial, however, perioperative use of colchicine compared with placebo reduced the incidence of postpericardiotomy syndrome but not of postoperative AF or postoperative pericardial/pleural effusion. The increased risk of gastrointestinal adverse effects reduced the potential benefits of colchicine in this setting. Thus colchicine is not likely going to be the ideal way to prevent this problem.
Epidemiology
More common in children and often common in patients receiving cardiac operations that involves opening the pericardium. CABG surgery is a common culprit.
See also
Skin lesion
Dressler syndrome
References
== External links == |
Nasal vestibulitis | Nasal vestibulitis is the diffuse dermatitis of nasal vestibule. It is often caused by Staphylococcus aureus. It may be secondary to chronic rhinorrhea, nose picking or viral infections. In acute vestibulitis, the skin is red, swollen and tender. In chronic vestibulitis, induration of vestibular skin and crusting is seen. Antibiotic steroid ointment is sometimes helpful. Chronic fissures can be cauterized with Silver Nitrate.
== References == |
Breast disease | Breast diseases make up a number of conditions. The most common symptoms are a breast mass, breast pain, and nipple discharge.A majority of breast diseases are noncancerous.
Tumor
A breast tumor is an abnormal mass of tissue in the breast as a result of neoplasia. A breast neoplasm may be benign, as in fibroadenoma, or it may be malignant, in which case it is termed breast cancer. Either case commonly presents as a breast lump. Approximately 7% of breast lumps are fibroadenomas and 10% are breast cancer, the rest being other benign conditions or no disease.Phyllodes tumor is a fibroepithelial tumor which can either benign, borderline or malignant.
Breast cancer
Breast cancer is cancer of the breast tissues, most commonly arising from the milk ducts. Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases. It is most common in women over age 50.
Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, a newly inverted nipple, or a red or scaly patch of skin. Diagnosis may also be made when the cancer is asymptomatic, through breast cancer screening programs, such as mammograms. Outcomes for breast cancer vary depending on the cancer type, extent of disease, and persons age. Survival rates in the developed world are high, with between 80% and 90% of those in England and the United States alive for at least 5 years.
Fibrocystic breast changes
Also called: fibrocystic breast disease, chronic cystic mastitis, diffuse cystic mastopathy, mammary dysplasia
Infections and inflammations
These may be caused among others by trauma, secretory stasis/milk engorgement, hormonal stimulation, infections or autoimmune reactions.
Repeated occurrence unrelated to lactation requires endocrinological examination.
bacterial mastitis
mastitis from milk engorgement or secretory stasis
mastitis
chronic subareolar abscess
tuberculosis of the breast
syphilis of the breast
retromammary abscess
actinomycosis of the breast
duct ectasia syndrome
breast engorgement
Other breast conditions
Mondors disease
Pagets disease of the breast
nipple discharge, galactorrhea
breast cyst
mastalgia
galactocoele
See also
Mammary gland
References
Further reading
Irshad, A.; Ackerman, S. J.; Pope, T. L.; Moses, C. K.; Rumboldt, T.; Panzegrau, B. (2008). "Rare Breast Lesions: Correlation of Imaging and Histologic Features with WHO Classification1". Radiographics. 28 (5): 1399–1414. doi:10.1148/rg.285075743. PMID 18794315.
== External links == |
Neonatal acne | Neonatal acne, also known as acne neonatorum, is an acneiform eruption that occurs in newborns or infants within the first 4-6 weeks of life, and presents with open and closed comedones on the cheeks, chin and forehead.The main cause is not known for certain but it may be caused by maternal androgens transferred from the mother to the newborn from the placenta and androgens produced by the fetal adrenal gland and neonatal testicles that stimulate sebaceous glands to increase production of sebum. As a self-limiting condition, neonatal acne tends to resolve on its own but treatment options can include topical benzoyl peroxide, topical retinoids, topical antibiotics and topical antifungals.
Signs and Symptoms
Neonatal acne presents from birth to within the first 4-6 weeks of life. Common symptoms are open and closed comedones such as papules and pustules that occur most commonly on the face on the areas of the cheeks, chin and forehead. Less commonly, lesions can be present on the chest and back.
Causes
It is believed that maternal androgens passed to the infant through the placenta has a role in stimulating sebaceous glands leading to increased sebum production that causes comedone formation. Dehydroepiandrosterone (DHEA) produced from the fetal adrenal gland and androgen production from neonatal testicles may also stimulate sebum production from sebaceous glands.The role of genetics is unclear but a positive family history supports association with neonatal acne.Some researchers suggest the role of Malassezia colonization causing hypersensitivity reactions in skin but this tends to be linked to neonatal cephalic pustulosis more so than neonatal acne.
Diagnosis
A work up is suggested in cases of severe acneiform eruptions or with signs of growth abnormalities to rule out potential endocrine diseases, tumor formation, or gonadal development abnormalities. A referral to a pediatric endocrinologist may be warranted.
Differential Diagnosis
Other causes of acneiform eruptions such as those induced by the use of topical products like creams, ointments and shampoos on the skin are often ruled out before diagnosis. Maternal medications like lithium and high dose corticosteroids may also induce formulation of pustules in newborns and can be assessed with a thorough family history. Likewise, newborns can be assessed for infection whether bacterial, fungal or viral in nature. Erythema toxicum neonatorum, neonatal cephalic pustulosis, transient neonatal pustular melanosis, folliculitis, miliaria and milia are often ruled out before diagnosis.Some experts consider neonatal cephalic pustulosis (NCP) a form of neonatal acne while others do not. NCP presents with facial papules and pustules but no comedones. NCP has been linked to Malassezia colonization, a normal yeast found on skin, but inconsistent patterns of positive colonization and NCP suggests that Malassezia hypersensitivity reactions in susceptible newborns are the cause of the acneiform eruptions rather than colonization itself.
Treatment
Neonatal acne will typically resolve by itself in 2-6 months. In mild cases, cleansing the face daily with gentle soap and water while avoiding use of potential comedogenic soaps, lotions and oils is often enough. Further treatment is not necessary but in severe or persistent cases topical therapy can be initiated.
Benzoyl Peroxide
Topical benzoyl peroxide (BPO) may be indicated in persistent or inflammatory cases. BPO is a lipophilic agent that penetrates into sebaceous glands and generates reactive oxygen species that kill P. acnes. It also has comedolytic and anti-inflammatory properties and can prevent development of antimicrobial resistance.
Topical Retinoids
Topical retinoids can be used alone or in combination with BPO. Retinoids are derived from vitamin A. They bind to retinoic receptors to normalize the rate of keratinocyte growth and prevent inflammation. Overactive keratinocyte production can lead to comedone formation.
Topical Antibiotics
In cases where scarring is a concern, topical antibiotics may be recommended. Topical clindamycin and erythromycin are the most commonly prescribed options for acne. Antibiotics kill P. acnes on skin that could be causing inflammation. With the emergence of resistant P. acnes, experts recommend topical antibiotics to be used in combination with BPO to reduce the risk of development of antimicrobial resistance. The most common side effects of topical antibiotics are stinging, burning and redness at the site of application.
Topical antifungals
Some experts suggest the use of topical ketoconazole in newborns with more pustular neonatal acne as there is evidence it shortens duration of lesions. This may be in cases more suggestive of neonatal cephalic pustulosis than neonatal acne.
Epidemiology
20% of newborns will develop neonatal acne however there has been debate if this is an accurate representation of actual diagnosed cases of acne as this could include other acneiform eruptions that do not present with comedones like neonatal cephalic pustulosis. Neonatal acne occurs more often in boys than in girls.
See also
Acne aestivalis
Infantile acne
List of cutaneous conditions
References
Further reading
Katsambas AD, Katoulis AC, Stavropoulos P (February 1999). "Acne neonatorum: a study of 22 cases". Int. J. Dermatol. 38 (2): 128–30. doi:10.1046/j.1365-4362.1999.00638.x. PMID 10192162.
OConnor NR, McLaughlin MR, Ham P (January 2008). "Newborn skin: Part I. Common rashes". Am Fam Physician. 77 (1): 47–52. PMID 18236822. |
Rothmund–Thomson syndrome | Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive skin condition.
There have been several reported cases associated with osteosarcoma. A hereditary basis, mutations in the DNA helicase RECQL4 gene, causing problems during initiation of DNA replication has been implicated in the syndrome.
Signs and symptoms
Sun-sensitive rash with prominent poikiloderma and telangiectasias
Juvenile cataracts
Saddle nose
Congenital bone defects, including short stature and radial ray anomalies such as absent thumbs
Hair growth problems (absent eyelashes, eyebrows and/or hair)
Hypogonadism has not been well documented
Hypodontia
Calcium problems (not documented in journals)
Ear problems (not documented in journals but identified by patients in support groups)
Produces osteosarcomaThe skin is normal at birth. Between 3 and 6 months of age, the affected carrier develops poikiloderma on the cheeks. This characteristic "rash" that all RTS carriers have can develop on the arms, legs and buttocks. "Poikiloderma consists of areas of increased and decreased pigmentation, prominent blood vessels, and thinning of the skin."
Accelerated aging
In humans, individuals with RTS, and carrying the RECQL4 germline mutation, can have several clinical features of accelerated aging. These features include atrophic skin and pigment changes, alopecia, osteopenia, cataracts and an increased incidence of cancer. Also in mice, RECQL4 mutants show features of accelerated aging.
Causes
RTS is caused by a mutation of the RECQL4 gene, located at chromosome 8q24.3. The disorder is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome (chromosome 8 is 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.
DNA repair
RECQL4 has a crucial role in DNA end resection that is the initial step required for homologous recombination (HR)-dependent double-strand break repair. When RECQL4 is depleted, HR-mediated repair and 5’ end resection are severely reduced in vivo. RECQL4 also appears to be necessary for other forms of DNA repair including non-homologous end joining, nucleotide excision repair and base excision repair. The association of deficient RECQL4-mediated DNA repair with accelerated aging is consistent with the DNA damage theory of aging.
Diagnosis
Management
History
The condition was originally described by August von Rothmund (1830–1906) in 1868. Matthew Sydney Thomson (1894–1969) published further descriptions in 1936.
See also
Poikiloderma vasculare atrophicans
List of cutaneous conditions
List of radiographic findings associated with cutaneous conditions
References
External links
GeneReviews/NCBI/NIH/UW entry on Rothmund-Thomson Syndrome
Poikiloderma of Rothmund-Thomson at NIHs Office of Rare Diseases |
Spondyloarthropathy | Spondyloarthropathy or spondyloarthrosis refers to any joint disease of the vertebral column. As such, it is a class or category of diseases rather than a single, specific entity. It differs from spondylopathy, which is a disease of the vertebra itself, but many conditions involve both spondylopathy and spondyloarthropathy.
Spondyloarthropathy with inflammation is called axial spondyloarthritis. In the broadest sense, the term spondyloarthropathy includes joint involvement of vertebral column from any type of joint disease, including rheumatoid arthritis and osteoarthritis, but the term is often used for a specific group of disorders with certain common features, which are often specifically termed seronegative spondylarthropathies. They have an increased incidence of HLA-B27, as well as negative rheumatoid factor and ANA. Enthesopathy is also sometimes present in association with seronegative spondarthritides.
Non-vertebral signs and symptoms of degenerative or other not directly infected inflammation, in the manner of spondyloarthropathies, include asymmetric peripheral arthritis (which is distinct from rheumatoid arthritis), arthritis of the toe interphalangeal joints, sausage digits, Achilles tendinitis, plantar fasciitis, costochondritis, iritis, and mucocutaneous lesions. But lower back pain is the most common clinical presentation of the causes of spondyloarthropoathies; this back pain is unique because it decreases with activity.
Seronegative spondyloarthropathy
Seronegative spondyloarthropathy (or seronegative spondyloarthritis) is a group of diseases involving the axial skeleton and having a negative serostatus.
"Seronegative" refers to the fact that these diseases are negative for rheumatoid factor, indicating a different pathophysiological mechanism of disease than is commonly seen in rheumatoid arthritis.
Conditions
The following conditions are typically included in the group of seronegative spondylarthropathies:
Some sources also include Behçets disease and Whipples disease.
Common characteristics
These diseases have the following conditions in common:
Seronegative (i.e. rheumatoid factor is not present)
They are in relation to HLA-B27
Inflammatory axial arthritis, generally sacroiliitis and spondylitis
Oligoarthritis, generally with asymmetrical presentation
Enthesitis (inflammation of the entheses, the sites where tendons or ligaments insert into the bone.), e.g. Plantar fasciitis, Achilles tendinitis, costochondritis.
Familial aggregation occurs
Extra-articular features, such as involvement of eyes (anterior uveitis), skin, genitourinary tract, and aortic regurgitation
Overlap is likely between several of the causative conditions
Classification
Assessment of Spondylarthritis International Society (ASAS criteria) is used for classification of axial spondyloarthritis (to be applied for patients with back pain greater than or equal to 3 months and age of onset less than 45 years). It is of two broad types:
Sacroiliitis on imaging plus 1 SpA feature, or
HLA-B27 plus 2 other SpA featuresSacroiliitis on imaging:
Active (acute) inflammation on MRI highly suggestive of SpA-associated sacroiliitis and/or
Definite radiographic sacroiliitisSpA features:
Inflammatory back pain
Arthritis
Enthesitis
Anterior uveitis
Dactylitis
Psoriasis
Crohns disease or ulcerative colitis
Good response to NSAIDs
Family history of SpA
HLA-B27
Elevated CRP
Treatment
Many patients have more than one of the spondyloarthritis disease manifestations. Some immunosuppressive drugs have shown efficacy in more than one of the diseases, e.g. tumor necrosis factor (TNF) inhibitors. But some of the immunosuppressive drugs are particularly effective for a specific inflamed tissue and approved in only one or two of the disease entities, so an interdisciplinary approach is required.
Epidemiology
Worldwide prevalence of spondyloarthropathy is approximately 1.9%.
References
== External links == |
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 == |
Atypical lichen myxedematosus | Atypical lichen myxedematosus is a skin condition caused by fibroblasts producing abnormally large amounts of mucopolysaccharides.: 186
See also
Lichen myxedematosus
Skin lesion
References
== External links == |
Excoriated acne | Excoriated acne is a mild acne accompanied by extensive excoriations caused by the person picking at the pimples (that is, scratching or squeezing them).
See also
List of cutaneous conditions
References
== External links == |
Central pain syndrome | Central pain syndrome is a neurological condition consisting of constant, moderate to severe pain due to damage to the central nervous system (CNS) which causes a sensitization of the pain system. The extent of pain and the areas affected are related to the cause of the injury.
Signs and symptoms
Pain can either be relegated to a specific part of the body or spread to the entire body. It is typically constant, and may be moderate to severe in intensity. Those who are afflicted describe it as being stuck in a loop of pain. It is often made worse by touch, movement, emotions, barometric pressure and temperature changes, usually cold temperatures along with many other similar triggers. Cold temperatures regularly make the burning pain worse in certain body parts. Burning pain is the most common sensation, but patients also report pins and needles, pressing, lacerating, aching, and extreme bursts or constant sharp or unremitting excruciating pain. Individuals may have reduced sensitivity to touch in the areas affected by the pain, as if the part is falling asleep. The burning and loss of sense of touch are usually, but not always, most severe on the distant parts of the body, such as the feet or hands, spreading until it is in some cases felt from head to toe. Usually the burning pain in body parts is a result of old injuries that seem like they should have healed long ago, yet the pain lingers on and even years afterwards. For some patients with intense affliction, there often can be unremitting nausea, causing vomiting. The pain can also bring on hyperventilation. Blood pressure can rise due to the pain.
Cause
Damage to the CNS can be caused by car accidents, limb amputations, trauma, spinal cord injury, tumors, stroke, immune system disorders or diseases, such as multiple sclerosis, Parkinsons, Graves or Addisons disease, rheumatoid arthritis, and epilepsy. It may develop months or years after injury or damage to the CNS.
Diagnosis
A diagnosis of central pain syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Central pain syndrome is suspected in individuals who complain of pain or other abnormal sensations following injury to the central nervous system. Other conditions that cause pain may need to be excluded before a diagnosis of central pain syndrome is made.
Treatment
Pain medications often provide some reduction of pain, but not complete relief of pain, for those affected by central pain syndrome. Tricyclic antidepressants such as nortriptyline or anticonvulsants such as neurontin (gabapentin) can be useful, but also provide incomplete relief. Lowering stress levels appears to reduce pain. For regular treatment some people prefer body length heating pads while others rely on warm baths.
Prognosis
Central pain syndrome is not a fatal disorder, but the syndrome causes disabling chronic pain and suffering among the majority of individuals who have it.
See also
Thalamic syndrome
References
Further reading
Canavero S, & Bonicalzi V (2007) Central pain syndrome. New York: Cambridge university press (1st ed) ISBN 0-521-86692-8 (2011) new edition
External links
USA National Institute of Neurological disorders and Stroke - Authoritative 4 paragraphs on central pain. |
Alveolar rhabdomyosarcoma | Alveolar rhabdomyosarcoma (ARMS) is a subtype of the rhabdomyosarcoma soft tissue cancer family whose lineage is from mesenchymal cells and are related to skeletal muscle cells. ARMS tumors resemble the alveolar tissue in the lungs. Tumor location varies from patient to patient, but is commonly found in the head and neck region, male and female urogenital tracts, the torso, and extremities. Two fusion proteins can be associated with ARMS, but are not necessary, PAX3-FKHR (now known as FOXO1). and PAX7-FKHR. In children and adolescents ARMS accounts for about 1 percent of all malignancies, has an incidence rate of 1 per million, and most cases occur sporadically with no genetic predisposition. PAX3-FOXO1 is now known to drive cancer-promoting gene expression programs through creation of distant genetic elements called super enhancers.
Genetics
There is no genetic predisposition for developing ARMS, but there are a few genetic recombination events that occurs to cause the fusion protein to be synthesized. In order to have the PAX3-FOXO1 fusion there needs to be a recombination event that translocates part of chromosome 13 to chromosome 2, and for PAX7-FOXO1 fusion there must be a translocation of part of chromosome 13 to chromosome 1. The 2;13 translocation reciprocal is often balanced and not amplified, while the 1;13 translocation reciprocal is sometimes viewed as balanced and sometimes not, so it is often amplified. The PAX7-FOXO1 fusion is often amplified in tumors (about 70 percent of all PAX7-FOXO1 fusion positive tumors) and the PAX3-FOXO1 fusion is rarely amplified (only in 5 percent of all PAX3-FOXO1 fusion positive tumors). About 60 percent of all ARMS cases are positive for PAX3-FOXO1 fusion gene, 20 percent are positive for PAX7-FOXO1 fusion gene, and the remaining 20 percent are fusion negative ARMS cases. Both fusion genes are composed of either the PAX3 or PAX7 DNA binding domains and the FOXO1 transactivation domain. This fusion causes a dysregulation of transcription and acts as an oncogene promoting cancer formation.
Pathology
ARMS cells are often small with little cytoplasm. The nuclei of the cells are round with normal, dull, chromatin structures. The ARMS cells often clump together and have fibrovascular septae that interrupts the aggregates. The fibrovascular septae that disrupts the aggregates often give the tumor the physiology of the alveoli found in the lungs. In a few cases, there may not be any fibrovascular septae and this gives the tumor a more solid phenotype and no alveoli physiology. Immunostaining for myogenin and for MyoD can be used to determine ARMS from other rhabdomyosarcoma tumors and immunostaining for AP2β and p-cadherin can distinguish fusion positive ARMS from fusion negative.
Embryonic origin and epidemiology
ARMS usually occurs in the skeletal muscles and is postulated to be derived from precursor cells within the muscle tissue. During embryonic development ARMS occurs in the mesoderm which is the precursor for the skeletal muscle tissue. ARMS accounts for roughly 20 to 30 percent of all rhabdomyosarcoma tumors and therefore accounts for roughly 1 percent of malignancies found in children and adolescents. There is an age determination on which PAX proteins fuse together with the FOXO1 transcription factor. PAX3-FOXO1 positive subset of ARMS occurs mostly in older children and young adults, while PAX7-FOXO1 positive subset of ARMS and fusion negative subsets occur most often in younger children.
Clinical
ARMS usually occurs in the skeletal muscle tissue of the extremities, but it is still very common in the torso, head, and neck regions. The primary tumor often presents itself as a soft mass of tissue that is painless, but the tumor can be detected if it starts to put pressure on other structures in the primary site. A large fraction of patients who are diagnosed with ARMS, roughly 25–30 percent, will have metastases at the time of diagnosis. The standard sites for metastases to form are the bone marrow, the bones, and distal nodes. Typical treatment options for patients who have been diagnosed with ARMS include standard surgery, radiation therapy, and intensive chemotherapy.
Prognosis
Patients who have been diagnosed with ARMS often have poor outcomes. The four year survival rate without remission for local ARMS tumors is 65 percent, while the four year survival rate with metastatic ARMS is only 15 percent. Patients who have metastatic ARMS positive with PAX3-FOXO1 fusion often have a poorer outcome than patients positive with PAX7-FOXO1 fusion, with a four-year survival rate of 8 percent and 75 percent respectively. Other variables affect the four year survival rate, such as primary tumor site, size of primary tumor, amount of local invasion, number of distal lymph nodes spread to, and whether metastasis has occurred. Prognosis for patients who have primary tumor sites within the bones often have higher survival rates and respond well to treatment options. While patients who have primary tumor sites within the nasopharynx region with metastases to the breast have very poor outcomes. Patients who are fusion protein negative with low risk clinical features should be treated with reduced therapy, while patients who are fusion protein positive with low risk clinical features should be treated as an intermediate risk and have more intensive therapy regimens.
See also
FOXO genes
Oncology
Pax genes
References
== External links == |
Corneal opacity | The human cornea is a transparent membrane which allows light to pass through it. The word corneal opacification literally means loss of normal transparency of cornea. The term corneal opacity is used particularly for the loss of transparency of cornea due to scarring. Transparency of the cornea is dependent on the uniform diameter and the regular spacing and arrangement of the collagen fibrils within the stroma. Alterations in the spacing of collagen fibrils in a variety of conditions including corneal edema, scars, and macular corneal dystrophy is clinically manifested as corneal opacity. The term corneal blindness is commonly used to describe blindness due to corneal opacity.
Types
Depending on the density, corneal opacity is graded as nebular, macular and leucomatous.
Nebular corneal opacity
Nebular corneal opacity is a faint opacity which results due to superficial scars involving Bowmans layer and superficial stroma. A nebular corneal opacity allows the details of the iris to be seen through the opacity. A thin, diffuse nebula covering the pupillary area interferes more with vision than a strictly localized dense leucoma, so long as the latter does not block the whole pupillary area. This is because the leucoma stops all the light which falls upon it, whereas the nebula refracts it irregularly, allowing many of the rays to fall upon the retina where they blur the image formed by the regularly refracted rays.
Macular corneal opacity
Macular corneal opacity is a semidense opacity produced when scarring involves about half the corneal stroma.
Leucomatous corneal opacity (leucoma simplex)
Leucomatous corneal opacity is a dense white opacity which results due to scarring of more than half of the stroma. A number of different presentations of leucomatous corneal opacity exist:
Adherent leucoma: results when healing occurs after perforation of cornea with incarceration of iris. The iris is adherent to the back of a leucomatous cornea. One of the major complication of adherent leucoma is Secondary glaucoma
Corneoiridic scar: if iris tissue is incarcerated and incorporated within the scar tissue, as occurs in healing of a large sloughed corneal ulcer, it is called a corneoiridic scar.
Corneal facet: corneal surface depressed at the site of healing (due to less fibrous tissue); such a scar is called facet.
Kerectasia: In this condition, corneal curvature is increased at the site of opacity (bulge due to weak scar).
Presentation
Signs and symptoms include the following:
Loss of vision or blindness (when dense opacity covers the pupillary area)
Blurred vision (due to astigmatic effect and light scattering)
Glare
Complications
Congenital corneal opacity that affecting vision will cause amblyopia. That type of amblyopia is known as form-deprivation amblyopia (or amblyopia ex anopsia).
Secondary changes in corneal opacity
Secondary changes may be seen in long-standing cases include: hyaline degeneration, calcareous degeneration, pigmentation and atheromatous ulceration.
Causes
Congenital opacities may occur as developmental anomalies or following birth trauma. Causes of congenital corneal opacities include sclerocornea, trauma, ulcer, mucopolysaccharidosis, Peter’s anomaly, congenital hereditary endothelial dystrophy.
Ocular trauma
Corneal ulceration
Xerophthalmia, caused by Vitamin A deficiency
Trachoma
Onchocerciasis
Mucous membrane pemphigoid: Ocular form of mucous membrane pemphigoid may cause corneal opacity and loss of vision.
Genetics
Pediatric corneal opacities may be congenital or acquired.
Congenital corneal opacities
Congenital reasons for this condition include:
Congenital hereditary endothelial dystrophy (CHED): There are 2 forms of congenital hereditary endothelial dystrophy (CHED). Commonest is an autosomal recessive form, which is present at birth, but nonprogressive. Nystagmus is seen in association with this form. Another is an autosomal dominant form that occurs within the first few years of life. This form is progressive, but nystagmus is not seen. Deafness and CHED are seen in Harboyan syndrome. The histologic findings are very similar to those seen in pseudophakic/ aphakic bullous keratopathy. The appearance of the cornea is similar to that in congenital glaucoma but without increased corneal diameter and elevated intraocular pressure.
Posterior polymorphous corneal dystrophy (PPMD, PPCD): PPCD, also known as Schlichting dystrophy, is an autosomal dominant disorder of the corneal endothelium and Descemet’s membrane. It is usually present in the second or third decade of life. It has the same entity as the first form of CHED. Most cases of PPMD are asymptomatic, and these cases generally do not require treatment. PPMD patients with bilateral, corneal opacities that can affect vision, descemet’s membrane endothelial keratoplasty or penetrating keratoplasty are the treatments of choice to improve vision and to avoid amblyopia.
Congenital hereditary stromal dystrophy (CHSD): CHSD is also known as Congenital stromal corneal dystrophy or Congenital stromal dystrophy of the cornea. It is a rare autosomal dominant disease caused by mutations in the DCN gene. In this bilateral Snowflake, whitish opacities appear throughout the cornea. The stromal lamellae are abnormal and may be separated by amorphous deposits. Moderate to severe vision loss may occur due to corneal opacity. In case of severe vision loss, treatment of choice is penetrating keratoplasty.
Peters anomaly: Peters anomaly, also known as iridocorneal adhesions or keratolenticular adhesions, is a posterior corneal defect with an overlying stromal opacity, often accompanied by adherent iris strands (Peters anomaly type 1). The size and density of the opacity can range from a mild to dense central leukoma.
Congenital anterior staphyloma: Congenital anterior staphyloma is a rare form of anterior segment dysgenesis that shares similarities with Peters anomaly. It is characterized by an ectatic protrusion of a central opacified cornea lined by uveal tissue. The protrusion extends beyond the plane of the eyelid margins and it can be unilateral or bilateral.
Lattice corneal dystrophy: Lattice corneal dystrophy is an autosomal-dominant characterized by amyloid deposition in the corneal stroma. Due to deposits, lattice-like corneal opacities may occur in stroma. Three types of dystrophies are there, type 1, type 2 and type 3. Type 1 is also known as Biber-Haab-Dimmer corneal dystrophy, TGFBI type Lattice Dystrophy, or Classic Lattice Dystrophy. LCD type II is not included in corneal dystrophies.
Granular corneal dystrophy: Two types, Type 1 and Type 2 are there. Both have autosomal dominant inheritance. In Type 1, Discrete crumb-like opacities are seen in the central anterior stroma. Visual symptoms such as glare and photophobia may occur early in life. In Type 2, deposits begin to appear in early childhood or adolescence as tiny whitish dots in the anterior stroma. Larger stellate, ring, or snowflake opacities may occur in later stages. Decrease in vision starts earlier in type2 than type1.
Sclerocornea: Sclerocornea is a congenital disorder in which the cornea is opaque and resembles the sclera, making the limbus indistinct. The central cornea is clearer than the periphery.
Cystinosis: Cystinosis is a rare autosomal recessive metabolic disease characterized by elevated levels of cystine within the cell. Early deposition of cystine crystals in the cornea cause tinsel-like corneal opacities.
Ichthyosis: X-linked ichthyosis is a genetic skin disorder caused by the hereditary deficiency of the steroid sulfatase enzyme. Ocular manifestations of XLI include superficial or deep corneal opacities.
Trisomy 8 mosaicism (T8M): It is a rare chromosome disorder caused by the presence of an extra chromosome 8 in some cells of the body. Dense corneal opacities may occur in trisomy 8 mosaicism.
Farbers disease: Nodular corneal opacity may be seen in association with this rare autosomal recessive disease.
Acquired pediatric corneal opacities
Acquired reasons for this condition include:
Traumatic: Traumatic breaks in Descemet membrane may cause corneal opacity. Injuries to Descemet membrane occur during delivery. Opacity is commonly unilateral.
Congenital or infantile glaucoma: In Congenital glaucoma, the cornea becomes edematous, cloudy, and enlarged. Treatment should be done to reduce Intraocular pressure.
Congenital corneal ulcers: Unilateral corneal opacity may occur in association with conjunctival injection and other signs of inflammation.
Mucopolysaccharidoses: The mucopolysaccharidoses are a group of inherited metabolic diseases caused by the absence or malfunctioning of certain enzymes the body needs to break down molecules called glycosaminoglycans. It is an autosomal recessive disorder. Sometimes, Corneal haze may be present in early life. Treatment options for significant opacities include penetrating keratoplasty and DALK.
Treatment
Keratoplasty
Keratoplasty also known as corneal transplantation is the main treatment option for visual improvement in corneal opacity. In this, the opaque cornea is replaced with donor tissue. Depending on type and density of corneal opacity different types of keratoplasty may be used such as:
Penetrating keratoplasty: It is the traditional full thickness corneal transplant procedure, in which trephine (a circular cutting device) is used to cut opaque cornea, a similar-sized portion of the donor cornea is removed with a second trephine. The removed part of donor cornea is known as corneal button. The donor tissue is then sutured to the patient eye. Dense corneal opacity which occupies all the corneal layers may be treated with penetrating keratoplasty.
Superficial lamellar keratoplasty: Superficial lamellar keratoplasty is used to treat superficial corneal opacities, which occupies superficial one third part of stroma. In this technique, the opaque part of the cornea is removed and replaced with donor tissue, leaving healthy part of the cornea including deeper parts of stroma and endothelium.
Deep anterior lamellar keratoplasty: DALK may be considered in deep opacities with normal endothelium and descemets membrane. In this procedure, the anterior layers of cornea are removed and replaced with donor tissue, leaving the endothelial layer and the descemets membrane in place.
Optical iridectomy
Optical iridectomy creates a clear entrance pupil, improving vision in patients with segmental corneal opacities. An area of clear peripheral cornea can produce retinal images compatible with good visual acuity.
Phototherapeutic keratectomy (PTK)
Excimer laser phototherapeutic keratectomy (PTK) is useful in superficial (nebular) corneal opacities.
Tattooing of scar
Keratopigmentation or corneal tattooing is a procedure used for centuries to improve the cosmetic appearance of corneal scars. Tattooing will not improve vision. For tattooing procedure Indian black ink, gold or platinum may be used.
Techniques
Staining method: In this technique, tattoo ink is directly applied to anterior surface of cornea. Benefits of this procedure include fast procedure with uniform dye application. Risk of fading is a main drawback.
Femtosecond laser-assisted corneal tattooing: Femtosecond laser-assisted corneal tattooing is a new corneal tattooing technique, with many benefits.
Keratoprosthesis
Keratoprosthesis is a surgical procedure where damaged or opaque cornea is replaced with an artificial cornea. Artificial corneas currently in commercial use include Boston keratoprosthesis, Osteo-Odonto-Keratoprosthesis (OOKP), AlphaCor, KeraKlear Artificial Cornea etc.
Epidemiology
Corneal opacity is the 4th main cause of blindness globally (5.1%). Using the World Health Organizations (WHO; Geneva, Switzerland) blindness definition,1 45 million people worldwide are bilaterally blind, of which 6 to 8 million are blind due to corneal disease. In some African areas, nearly 90% of the total blindness is due to corneal pathology.
Europe
The prevalence of congenital corneal opacities (CCO) is estimated to be 3 in 100,000 newborns. This number increases to 6 in 100,000 if congenital glaucoma patients are included. A study of live births in Spain reported that corneal opacities accounted for 3.11% of congenital eye malformations (Bermejo et al, 1998). About 4% of keratoplasties done in the pediatric population in Denmark are due to congenital anomalies (Hovlykke et al, 2014).
India
In NPCB survey (2001-2002) Corneal opacity was the 6th major cause of blindness in India, which accounts for 0.9% of total blind population. In the RAAB (Rapid Assessment of Avoidable Blindness) survey (2006-2007) Corneal opacity including Trachoma was mentioned as the second major cause of blindness, which accounts for 6.5% of total blindness.
See also
Corneal transplantation
Corneal ulcer
Corneal button
== References == |
Microvillous inclusion disease | Microvillus inclusion disease, previously known as Davidsons disease, congenital microvillus atrophy and, less specifically, microvillus atrophy (note: microvillus is often misspelled as microvillous), is a rare genetic disorder of the small intestine that is inherited in an autosomal recessive pattern.
Presentation
It is characterized by chronic, intractable diarrhea in new-born infants, starting in the first few days of life.
This results in metabolic acidosis and severe dehydration. Pregnancy and birth are usually normal.
Pathophysiology
It is caused by a congenital villus atrophy, atrophy of apical microvilli and intracellular accumulation of apical enzymes and transporters in the epithelial cells of the small intestine. MVID is in ost cases caused by mutations in the MYO5B gene. A minority of cases involves mutations in the STX3 gene.
Diagnosis
Prenatal screening in utero is currently offered by several medical centers since the gene(s) involved in the disease were recently discovered to be MYO5B; Diagnosis is typically made by biopsy of the small intestine.
Biopsy
The appearance of microvillous inclusion disease on light microscopy is similar to celiac sprue; however, it usually lacks the intraepithelial lymphocytic infiltration characteristic of celiac sprue and stains positive for carcinoembryonic antigen (CEA). The definitive diagnosis is dependent on electron microscopy.
Differential diagnosis
The differential diagnosis of chronic and intractable diarrhea is:
Intestinal epithelial dysplasia
Syndromatic diarrhea
Immunoinflammatory enteropathy
Prognosis
It is nearly always fatal unless, like short bowel syndrome patients, treated with parenteral nutrition or an intestinal transplant. The patient is often classified as being in "intestinal failure" and treated with the cohort of patients known as "short bowel syndrome" patients.One patient from the UK was documented as achieving nutritional independence at age 3. On 26 June 2009, a six-year-old girl with microvillus inclusion disease became the third person in the UK to die of swine flu. This was attributed to her weakened immune system.
Prevalence
Microvillus inclusion disease is extremely rare, however, no prevalence data have been published. An estimate of a few hundred children with the disease in Europe has been made but no time frame to which this count applies is given. Countries with a higher degrees of consanguinity experience higher prevalence rates due to its autosomal recessive transmission.
History
Microvillus inclusion disease was first described in 1978 by Davidson et al. It was originally described as familial enteropathy.
References
== External links == |
Diabetic embryopathy | Diabetic embryopathy refers to congenital maldevelopments that are linked to maternal diabetes. Prenatal exposure to hyperglycemia can result in spontaneous abortions, perinatal mortality, and malformations. Type 1 and Type 2 diabetic pregnancies both increase the risk of diabetes induced teratogenicity. The rate of congenital malformations is similar in Type 1 and 2 mothers because of increased adiposity and the age of women with type 2 diabetes. Genetic predisposition and different environmental factors both play a significant role in the development of diabetic embryopathy. Metabolic dysfunction in pregnant mothers also increases the risk of fetal malformations.
Risk factors
Women with pregestational diabetes are at the highest risk for fetal malformations. The risk of congenital malformations in pregestational type 1 diabetes is directly correlated with glucose and glycohemoglobin levels in the blood. It is also inversely related to the gestational age at first exposure. The comorbidities associated with pregestational type 2 diabetes include advanced maternal age, lipid preroxidation and obesity. Overweight women (BMI ≥ 25) who develop gestational diabetes have an intermediate risk for malformations. Pregnant women who have gestational diabetes but dont have prediabetic markers experience perinatal outcomes that are similar to women without diabetes.
Gestational consequences
Malformations
Type 1 diabetes in pregnant women can result in malformations that affect the musculoskeletal , urogenital, and central nervous systems. Most of these malformations occur within the first 4 weeks of gestation. Caudal dysgenesis is one of the most strongly associated diseases to diabetes. This malformation has the highest risk for diabetic embryopathy. Infants from diabetic mothers usually have several blastogenic malformations. Diabetic embryopathy is therefore an etiological subgroup of defects of blastogenesis that present different monotopic and polytopic developmental defects.
Abortion and perinatal deaths
Diabetic embryopathy may result in early or late spontaneous abortion and stillbirth. In maternal diabetes, 90% of pregnancy losses happen in the first trimester due to oxidative stress. Diabetic embryopathy abortions in the second-trimester are most likely due to severe birth defect, maternal metabolic derangement, placental insufficiency and fetal hypoxia due to membrane rupture.
Pathogenesis
The development of birth defects associated with maternal hyperglycemia is multi-factorial. Environmental factors and genetic predisposition (paternal, maternal and offspring genome) are important in diabetic embryopathy. The diets of diabetic mothers impacts the rate at which malformations form in their offspring. Furthermore, there is evidence that resistance to certain malformations caused by diabetes is genetic. Epigenetics and its relationship with various environmental factors such as metabolism and diet play a significant role in teratogenesis. Hyperglycemia and associated teratogenic mediators influence DNA methylation, non-coding RNA expression, histone modifications and other epigenetic regulation mechanisms. Research is focused on exploring the impact of diabetic embryopathy on methylation signatures, which could potentially serve as a diagnostic biomarker for the condition.
Prevention
Preconception
The probability of major birth defects in offspring of mothers with diabetes is 0.7-4.4% for glycohemoglobin levels <7%. For glycohemoglobin levels >10% the probability of major birth defects is 16.1-100% with an average of 26.6%. The National Institute of Health and Clinical Excellence in the UK indicated that glycohemoglobin levels <6.1% are correlated with the lowest risk of malformations while the reproductive risks are higher in women above this threshold and prohibitive for glycohemoglobin levels >10%.Consumption of folic acid and antioxidant substances before fertilization result in a reduced rate of malformations in the offspring of mothers with diabetes. Antioxidants such as lipoic acid, vitamin C, and vitamin E, increase the probability of favorable prenatal outcomes in offspring of diabetic mothers because oxidative stress is a teratogenic mediator of hyperglycemia in mothers with diabetes.
After fertilization
Optimal weight and glycemic management encourage good outcomes because diabetes has the potential to influence the mother and fetus during the entire pregnancy. The integrity of embryofetal development and placental function can be monitored by fetal echocardiography and ultrasound scanning.
See also
Diabetic diet
== References == |
Metachromatic leukodystrophy | Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation. Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.
Signs and symptoms
Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult.
In the late infantile form, which is the most common form of MLD (50–60%), affected children begin having difficulty walking after the first year of life, usually at 15–24 months. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner.
Children with the juvenile form of MLD (onset between 3 and 10 years of age) usually begin with impaired school performance, mental deterioration, and dementia, then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset. Some patients can live for several decades after onset. A recent trend is to try to distinguish early-juvenile (ages 3–7) and late-juvenile forms of the disease. Generally early-juveniles have motor skill declines as their first symptoms while late-juveniles show cognitive declines first.
The adult form commonly begins after age 16 often with an onset in the 4th or 5th decade of life and presents as a psychiatric disorder or progressive dementia. Adult-onset MLD usually progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.Palliative care can help with many of the symptoms and usually improves quality of life and longevity.Carriers have low enzyme levels compared to their family population ("normal" levels vary from family to family) but even low enzyme levels are adequate to process the bodys sulfatide.
Causes
MLD is directly caused by a deficiency of the enzyme arylsulfatase A (ARSA) and is characterized by enzyme activity in leukocytes that is less than 10% of normal controls. However, assay of the ARSA enzyme activity alone is not sufficient for diagnosis; ARSA pseudodeficiency, which is characterized by enzyme activity that is 5~20% of normal controls does not cause MLD. Without this enzyme, sulfatides build up in many tissues of the body, eventually destroying the myelin sheath of the nervous system. The myelin sheath is a fatty covering that protects nerve fibers. Without it, the nerves in the brain (central nervous system – CNS) and the peripheral nerves (peripheral nervous system – PNS) which control, among other things the muscles related to mobility, cease to function properly.Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor. When the arylsulfatase A enzyme level is normal but the sulfatides are still high – meaning that they are not being broken down because the enzyme is not activated – the resulting disease is saposin B deficiency, which presents similar to MLD. Saposin B Deficiency is very rare, much more rare than traditional MLD. The enzyme that is present is not "enabled" to a normal level of efficiency and cant break down the sulfatides which results in all of the same MLD symptoms and progression.A 2011 study contended sulfatide is not completely responsible for MLD because it is nontoxic. It has been suggested lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro.
Genetics
MLD has an autosomal recessive inheritance pattern. The inheritance probabilities per birth are as follows:
If both parents are carriers:
25% (1 in 4) children will have the disease
50% (2 in 4) children will be carriers, but unaffected
25% (1 in 4) children will be free of MLD – unaffected child that is not a carrier
If one parent is affected and one is free of MLD:
0% (0) children will have the disorder – only one parent is affected, other parent always gives normal gene
100% (4 in 4) children will be carriers (but unaffected)
If one parent is a carrier and the other is free of MLD:
50% (2 in 4) children will be carriers (but unaffected)
50% (2 in 4) children will be free of MLD – unaffected child that is not a carrierIn addition to these frequencies there is a pseudo-deficiency that affects 7–15% of the population. People with the pseudo deficiency do not have any MLD problems unless they also have affected status. With the current diagnostic tests, Pseudo-deficiency reports as low enzyme levels but sulfatide is processed normally so MLD symptoms do not exist. This phenomenon wreaks havoc with traditional approaches to Newborn Screening so new screening methods are being developed.
Diagnosis
Clinical examination and MRI are often the first steps in an MLD diagnosis. MRI can be indicative of MLD but is not adequate as a confirming test. An ARSA-A enzyme level blood test with a confirming urinary sulfatide test is the best biochemical test for MLD. The confirming urinary sulfatide is important to distinguish between MLD and pseudo-MLD blood results. Genomic sequencing may also confirm MLD, however, there are likely more mutations than the over 200 already known to cause MLD that are not yet ascribed to MLD that cause MLD so in those cases a biochemical test is still warranted.
Newborn screening
MLD Foundation formally launched a newborn screening initiative in late 2017. The screen development started in the early 2010s at the University of Washington Gelb Biochemistry lab. A deidentified pilot study launched in April 2016 in Washington state. Positive results led to MLD being included in the ScreenPlus identified baby research project in New York state, which is currently scheduled to launch in Q12021.
Treatment
There is currently no approved treatment for MLD in symptomatic late infantile patients or for juvenile and adult-onset with advanced symptoms. These patients typically receive clinical treatment focused on pain and symptom management.Pre-symptomatic late infantile MLD patients, as well as those with juvenile or adult MLD that are either presymptomatic or displaying mild symptoms, can consider bone marrow transplantation (including stem cell transplantation), which may slow down the progression of the disease in the central nervous system. However, results in the peripheral nervous system have been less dramatic, and the long-term results of these therapies have been mixed.In 2020 the European Medical Agency, approved the Cell Therapy Drug Libmeldy for treatment of infantile and juvenile forms of metachromatic leukodystrophy in Europe. Libmeldy is a type of advanced therapy medicine called a ‘gene therapy’. This type of medicine works by delivering genes into the body. The active substance in Libmeldy is stem cells, (CD34+ cells), derived from the patient’s own bone marrow or blood, that have been modified to contain a copy of the gene to make ARSA and can divide to produce other sorts of blood cells.
Atidarsagene autotemcel
A gene therapy called atidarsagene autotemcel was approved for medical use in the European Union in December 2020 and is sold under the trade name Libmeldy. The indication is for use in children with the late infantile or early juvenile forms of MLD who have been identified as carriers of the defective gene but have not yet developed symptoms. It is also indicated in children who have been diagnosed with the early juvenile form who have started developing symptoms but still have the ability to walk independently and before the onset of cognitive decline.In the United States, an Investigational New Drug application for atidarsagene autotemcel was accepted by the Food and Drug Administration in late 2020.
Research directions
Several therapy options are currently being investigated using clinical trials primarily in late infantile patients. These therapies include gene therapy, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and potentially enzyme enhancement therapy (EET). In addition to the clinical trials, there are several other pre-clinical gene therapy research projects underway.
Epidemiology
The incidence of metachromatic leukodystrophy is estimated to occur in 1 in 40,000 to 1 in 160,000 individuals worldwide. There is a much higher incidence in certain genetically isolated populations, such as 1 in 75 in Habbanites (a small group of Jews who immigrated to Israel from southern Arabia), 1 in 2,500 in the western portion of the Navajo Nation, and 1 in 8,000 among Arab groups in Israel.As an autosomal recessive disease, 1 in 40,000 equates to a 1 in 100 carrier frequency in the general population.There are an estimated 3,600 MLD births per year, with 1,900 alive in the US, 3,100 in Europe, and 49,000 alive worldwide with MLD.MLD is considered a rare disease in the US and other countries.
Research
Bone marrow and stem cell transplant therapies
Several trials are underway to continue to improve the effectiveness and reduce the risks of bone marrow and stem cell transplants.
Gene therapy
(current as of April 2021)
Two different approaches to gene therapy are currently being researched for MLD.
Gene therapy with an autologous stem cell transplant – Italian researchers at the San Raffaele Telethon Institute tested a novel approach combining gene therapy with an autologous stem cell transplant.Gene therapy for late infantile and early juvenile patients was approved by the European Commission in December 2020 after receiving a favorable European Medicines Agency CHMP review in October 2020. The product is being marketed in the EU as Libmeldy. Libmeldy is a gene therapy medicinal product, for which CD34+ haematopoietic stem and progenitor cells are collected either from the patients own bone marrow or mobilised peripheral blood. These cells are transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A gene to insert a functional gene to produce the ARSA enzyme. When the modified cells are transplanted back into the patient as a one-time infusion, the cells have been shown to produce the missing ARSA enzyme. The children by the age of five were all in good condition and going to kindergarten when normally by this age, children with the disease can not even speak. Additional information can be found on the MLD Foundations Gene Therapy page and at the Clinical Trials.gov site.
In November, 2020, Orchard Therapeutics acknowledged IND discussions with the FDA as the part of their effort to seek FDA approval in the USA.
A trial for late juveniles was launched in February 2020.
Orchard Therapeutics acquired the gene therapy IP from GSK in April 2018.
Recruiting for the Phase I/II Clinical Trial formally started on March 24, 2010, after approval from the Italian Authorities. Recruiting the initial cohort of 8 patients was completed in mid-March 2013. The trial was to test the efficacy and safety of autologous (using the patients own cells) hematopoietic stem cell transplantation (HSCT) after genetic modification to deliver a super-therapeutic (over-expressing) ARSA enzyme to the nervous system by the route of the blood cells. Using the patients own stem cells with genetic correction should reduce or eliminate the complications of graft vs. host disease and provide a long-term solution to proper ARSA expression in MLD patients. Bench and animal tests showed positive results. The researchers published 2-year outcomes for the first three patients in July 2013. Results were described as promising.
The Phase I/II clinical trial is complete. No additional patients are being recruited while the data is analyzed and work progresses to improve the manufacturability and repeatability of the technology while expansion to other geographies to increase access is being considered.
Recruiting was completed for the 20 patient cohort in April 2015, which includes an expansion in December 2014 to add 6 additional patients.
Inclusion criteria are pre-symptomatic late infantiles and both pre- and early-symptomatic juveniles. See details on inclusion criteria and the trial protocol here.
The trial was at a single center at the San Raffaele Institute in Milan, Italy. All costs were to be paid by the researchers. This was a 3-year study. In March 2013, the last of the 8 primary trial patients started therapy. The trial had several compassionate access patients and ultimately was expanded to 20 patients
In late 2013 GSK exercised its option for the San Rafaelle gene therapy technology and is working with the Milan Investigators to prepare for the next phase of study.
Intracerebral Gene therapy – A Phase I/II Clinical Trial started recruiting in Paris in late March, 2013 for an Intracerebral Gene Therapy clinical trial where special "vectors" carrying genetically modified material are directly injected into a dozen sites in the brain. The hope is that the corrected cells and the enzyme they produce will then diffuse into surrounding areas of the brain. Extensive work in the lab and some encouraging ALD studies provided the basis for this trial. This trial was subsequently terminated before completion.
Enzyme replacement therapy (ERT)
(current as of February 2021)
Takeda acquired the MLD ERT from Shire in early 2018 and continues to develop and studying their intrathecal SHP 611 (formerly HGT-1110) ERT [Enzyme Replacement Therapy].
Clinical Trial
A third global trial studying the late infantile form of MLD for 42 patients aged 6 – 72 months launched in April 2019 and was fully recruited in January 2021. This is the first time ERT study sites are open in the US.
Clinical trial information & inclusion criteria can be found on the MLD Foundations ERT page and at the Clinical Trials.gov site.
Substrate reduction therapy
Biomarin South (formerly Zacharon before being acquired by Biomarin in January 2013) from San Diego had initiated a drug discovery program for MLD. This program is based on using assays which measure sulfatide accumulation in cultured fibroblasts as a means to discover and develop small molecule drugs for MLD. (This approach differs from other approaches which have measured enzyme activity to discover effective drugs.) As of July 2011, Zacharon has begun adapting the assays it developed for other lysosomal storage diseases so that they can be employed to discover and develop drugs for MLD. (current March 2013)
The Cooper Health System (New Jersey) sponsored a clinical trial underway to determine the safety and efficacy of a Vitamin K antagonist (Warfarin) in treating Metachromatic Leukodystrophy (MLD) in 2009. No results are known to have been published. (current March 2013)
Natural history studies
A natural history study (NHS) launched in Washington, DC in January 2014 to study 30 patients with additional study centers opened in the US, Europe, South America, Southeast Asia, and South America. Due to challenges in recruiting this study has been cancelled.
A natural history study has been underway in Pittsburgh, PA since November 2012.
See also
The Myelin Project
Multiple sclerosis
References
Some portions of this article are courtesy of the public domain text available at the National Institute of Neurological Disorders and Stroke:
"NINDS Metachromatic Leukodystrophy Information Page". Retrieved 2009-06-07.
== External links == |
Lung infarction | Lung infarction occurs when an artery to the lung becomes blocked and part of the lung dies. It is most often caused by pulmonary embolism.
Because of the dual blood supply to the lungs from both the bronchial circulation and the pulmonary circulation, this tissue is more resistant to infarction. An occlusion of the bronchial circulation does not cause infarction, but it can still occur in pulmonary embolism when the pulmonary circulation is blocked and the bronchial circulation cannot fully compensate for it.
References
== External links == |
Encephalitis | Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations, trouble speaking, memory problems, and problems with hearing.Causes of encephalitis include viruses such as herpes simplex virus and rabies virus as well as bacteria, fungi, or parasites. Other causes include autoimmune diseases and certain medications. In many cases the cause remains unknown. Risk factors include a weak immune system. Diagnosis is typically based on symptoms and supported by blood tests, medical imaging, and analysis of cerebrospinal fluid.Certain types are preventable with vaccines. Treatment may include antiviral medications (such as acyclovir), anticonvulsants, and corticosteroids. Treatment generally takes place in hospital. Some people require artificial respiration. Once the immediate problem is under control, rehabilitation may be required. In 2015, encephalitis was estimated to have affected 4.3 million people and resulted in 150,000 deaths worldwide.
Signs and symptoms
Adults with encephalitis present with acute onset of fever, headache, confusion, and sometimes seizures. Younger children or infants may present with irritability, poor appetite and fever. Neurological examinations usually reveal a drowsy or confused person. Stiff neck, due to the irritation of the meninges covering the brain, indicates that the patient has either meningitis or meningoencephalitis.
Cause
Viral
Viral encephalitis can occur either as a direct effect of an acute infection, or as one of the sequelae of a latent infection. The majority of viral cases of encephalitis have an unknown cause, however the most common identifiable cause of viral encephalitis is from herpes simplex infection. Other causes of acute viral encephalitis are rabies virus, poliovirus, and measles virus.Additional possible viral causes are arboviral flavivirus (St. Louis encephalitis, West Nile virus), bunyavirus (La Crosse strain), arenavirus (lymphocytic choriomeningitis virus), reovirus (Colorado tick virus), and henipavirus infections. The Powassan virus is a rare cause of encephalitis.
Bacterial and other
It can be caused by a bacterial infection, such as bacterial meningitis, or may be a complication of a current infectious disease syphilis (secondary encephalitis).Certain parasitic or protozoal infestations, such as toxoplasmosis, malaria, or primary amoebic meningoencephalitis, can also cause encephalitis in people with compromised immune systems. Lyme disease or Bartonella henselae may also cause encephalitis.Other bacterial pathogens, like Mycoplasma and those causing rickettsial disease, cause inflammation of the meninges and consequently encephalitis. A non-infectious cause includes acute disseminated encephalitis which is demyelinated.
Limbic encephalitis
Limbic encephalitis refers to inflammatory disease confined to the limbic system of the brain. The clinical presentation often includes disorientation, disinhibition, memory loss, seizures, and behavioral anomalies. MRI imaging reveals T2 hyperintensity in the structures of the medial temporal lobes, and in some cases, other limbic structures. Some cases of limbic encephalitis are of autoimmune origin.
Autoimmune encephalitis
Autoimmune encephalitis signs can include catatonia, psychosis, abnormal movements, and autonomic dysregulation. Antibody-mediated anti-N-methyl-D-aspartate-receptor encephalitis and Rasmussen encephalitis are examples of autoimmune encephalitis. Anti-NMDA receptor encephalitis is the most common autoimmune form, and is accompanied by ovarian teratoma in 58 percent of affected women 18–45 years of age.
Encephalitis lethargica
Encephalitis lethargica is identified by high fever, headache, delayed physical response, and lethargy. Individuals can exhibit upper body weakness, muscular pains, and tremors, though the cause of encephalitis lethargica is not currently known. From 1917 to 1928, an epidemic of encephalitis lethargica occurred worldwide.
Diagnosis
People should only be diagnosed with encephalitis if they have a decreased or altered level of consciousness, lethargy, or personality change for at least twenty-four hours without any other explainable cause. Diagnosing encephalitis is done via a variety of tests:
Brain scan, done by MRI, can determine inflammation and differentiate from other possible causes.
EEG, in monitoring brain activity, encephalitis will produce abnormal signal.
Lumbar puncture (spinal tap), this helps determine via a test using the cerebral-spinal fluid, obtained from the lumbar region.
Blood test
Urine analysis
Polymerase chain reaction (PCR) testing of the cerebrospinal fluid, to detect the presence of viral DNA which is a sign of viral encephalitis.
Prevention
Vaccination is available against tick-borne and Japanese encephalitis and should be considered for at-risk individuals. Post-infectious encephalomyelitis complicating smallpox vaccination is avoidable, for all intents and purposes, as smallpox is nearly eradicated. Contraindication to Pertussis immunization should be observed in patients with encephalitis.
Treatment
An ideal drug to treat brain infection should be small, moderately lipophilic at pH of 7.4, low level of plasma protein binding, volume of distribution of litre per kg, does not have strong affinity towards binding with P-glycoprotein, or other efflux pumps on the surface of blood–brain barrier. Some drugs such as isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones have good penetration to blood brain barrier.Treatment (which is based on supportive care) is as follows:
Pyrimethamine-based maintenance therapy is often used to treat Toxoplasmic Encephalitis (TE), which is caused by Toxoplasma gondii and can be life-threatening for people with weak immune systems. The use of highly active antiretroviral therapy (HAART), in conjunction with the established pyrimethamine-based maintenance therapy, decreases the chance of relapse in patients with HIV and TE from approximately 18% to 11%. This is a significant difference as relapse may impact the severity and prognosis of disease and result in an increase in healthcare expenditure.The effectiveness of intravenous immunoglobulin for the management of childhood encephalitis is unclear. Systematic reviews have been unable to draw firm conclusions because of a lack of randomised double-blind studies with sufficient numbers of patients and sufficient follow-up. There is the possibility of a benefit of intravenous immunoglobulin for some forms of childhood encephalitis on some indicators such as length of hospital stay, time to stop spasms, time to regain consciousness, and time to resolution of neuropathic symptoms and fever. Intravenous immunoglobulin for Japanese Encephalitis appeared to have no benefit when compared with placebo (pretend) treatment.
Prognosis
Identification of poor prognostic factors include cerebral edema, status epilepticus, and thrombocytopenia. In contrast, a normal encephalogram at the early stages of diagnosis is associated with high rates of survival.
Epidemiology
The number of new cases a year of acute encephalitis in Western countries is 7.4 cases per 100,000 people per year. In tropical countries, the incidence is 6.34 per 100,000 people per year. The number of cases of encephalitis has not changed much over time, with about 250,000 cases a year from 2005 to 2015 in the US. Approximately seven per 100,000 people were hospitalized for encephalitis in the US during this time. In 2015, encephalitis was estimated to have affected 4.3 million people and resulted in 150,000 deaths worldwide. Herpes simplex encephalitis has an incidence of 2–4 per million of the population per year.
Terminology
Encephalitis with meningitis is known as meningoencephalitis, while encephalitis with involvement of the spinal cord is known as encephalomyelitis.The word is from Ancient Greek ἐγκέφαλος, enképhalos "brain", composed of ἐν, en, "in" and κεφαλή, kephalé, "head", and the medical suffix -itis "inflammation".
See also
References
Further reading
External links
WHO: Viral Encephalitis |
Barbiturate dependence | Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect. Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected persons age, comorbidity and the pharmacological pathways of barbiturates.Psychological addiction to barbiturates can develop quickly. The patients will then have a strong desire to take any barbiturate-like drug. The chronic use of barbiturates leads to moderate degradation of the personality with narrowing of interests, passivity and loss of volition. The somatic signs include hypomimia, problems articulating, weakening of reflexes, and ataxia.The GABAA receptor, one of barbiturates main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric "high" that results from their use. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other and poly drug administration of barbiturates and alcohol used to be common.
The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. People who use barbiturates tend to prefer rapid-acting barbiturates (amobarbital, pentobarbital, secobarbital) rather than long-acting barbiturates (barbital, phenobarbital). The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. A cold turkey withdrawal can in some cases lead to death. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required. The withdrawal symptoms after ending barbiturate consumption are quite severe and last from 4 to 7 days.
References
== External links == |
Pancreatic abscess | Pancreatic abscess is a late complication of acute necrotizing pancreatitis, occurring more than 4 weeks after the initial attack. A pancreatic abscess is a collection of pus resulting from tissue necrosis, liquefaction, and infection. It is estimated that approximately 3% of the patients with acute pancreatitis will develop an abscess.According to the Balthazar and Ransons radiographic staging criteria, patients with a normal pancreas, an enlargement that is focal or diffuse, mild peripancreatic inflammations or a single collection of fluid (pseudocyst) have less than 2% chances of developing an abscess. However, the probability of developing an abscess increases to nearly 60% in patients with more than two pseudocysts and gas within the pancreas.
Signs and symptoms
Patients with pancreatic abscesses may experience abdominal pain, chills and fever or the inability to eat. Whereas some patients present an abdominal mass, others do not. Nausea and vomiting may also occur.
Complications
An unremoved infected abscess may lead to sepsis. Also, multiple abscesses may occur. Other complications may include fistula formation and recurrent pancreatitis.
Causes
Pancreatic abscesses usually develop in patients with pancreatic pseudocysts that become infected. They may also form as a result of fibrous wall formation around fluid collections or penetrating peptic ulcers. Other causes include gall stones or alcohol consumption and, in rare cases, drugs, blunt trauma and following extension abscess from nearby structures.
Diagnosis
Most patients who develop pancreatic abscesses have had pancreatitis, so a complete medical history is required as a first step in diagnosing abscesses. On the other hand, a white blood cell count is the only laboratory test that may indicate the presence of an abscess.
Some of the imaging tests are more commonly used to diagnose this condition. Abdominal CT scans, MRIs and ultrasounds are helpful in providing clear images of the inside of the abdomen and successfully used in the diagnosing process. These tests may reveal the presence of infected necrosis which has not yet developed into an abscess and as a result, doctors usually order repeated imaging tests in patients with acute pancreatitis whose abdominal pain worsens and who develop signs of abdominal obstruction. Also, it is recommended that patients who have a prolonged clinical response are tested repeatedly as a prevention method to avoid the development of an abscess that may rupture.
Prevention
In some cases, abscesses may be prevented by draining an existing pseudocyst which is likely to become inflamed. However, in most cases the developing of abscesses cannot be prevented.
Treatment
Antibiotics are commonly used as a curing method for pancreatic abscesses although their role remains controversial. Prophylactic antibiotics are normally chosen based on the type of flora and the degree of antibiotic penetration into the abscess. Pancreatic abscesses are more likely to host enteric organisms and pathogens such as E. coli, Klebsiella pneumoniae, Enterococcus faecalis, Staphylococcus aureus, Pseudomonas aeruginosa, Proteus mirabilis, and Streptococcus species. Medical therapy is usually given to people whose general health status does not allow surgery. On the other hand, antibiotics are not recommended in patients with pancreatitis, unless the presence of an infected abscess has been proved.
Although there have been reported cases of patients who were given medical treatment and survived, primary drainage of the abscess is the main treatment used to cure this condition. Drainage usually involves a surgical procedure. It has been shown that CT-guided drainage brought inferior results than open drainage. Hence, open surgical procedure is preferred to successfully remove the abscess. However, CT-guided drainage is the option treatment for patients who may not tolerate an open procedure. Endoscopic treatment is at the same time a treatment option that increased in popularity over the last years.
Prognosis
The outlook is generally based on the severity of the infection. It is however a severe complication which may result in the death of the patient if the appropriate treatment is not administered. Patients are at risk of sepsis and multiple organ failure and in cases in which the infected abscess is not removed through surgery, the mortality rate can reach 100%.
References
== External links == |
Mongolian spot | A Mongolian spot, also known as slate grey nevus or congenital dermal melanocytosis, is a benign, flat, congenital birthmark with wavy borders and an irregular shape. In 1883, it was described and named after Mongolians by Erwin Bälz, a German anthropologist based in Japan, who erroneously believed it to be most prevalent among his Mongolian patients. It normally disappears three to five years after birth and almost always by puberty. The most common color is blue, although they can be blue-gray, blue-black or deep brown.
Cause
Mongolian spot is a congenital developmental condition—that is, one existing from birth—exclusively involving the skin. The blue colour is caused by melanocytes, melanin-containing cells, that are usually located in the surface of the skin (the epidermis), but are in the deeper region (the dermis) in the location of the spot. Usually, as multiple spots or one large patch, it covers one or more of the lumbosacral area (lower back), the buttocks, sides, and shoulders. It results from the entrapment of melanocytes in the lower half to two-thirds of the dermis during their migration from the neural crest to the epidermis during embryonic development.Male and female infants are equally predisposed to slate grey nevus. People who are not aware of the background of the slate grey nevus may mistake them for bruises, possibly resulting in mistaken concerns about abuse.
Anthropological description
The French anthropologist Robert Gessain interested himself in what he called the tache pigmentaire congenitale or coloured birthmark, publishing multiple papers in the Journal de la Société des Américanistes, an academic journal covering the cultural anthropology of the Americas. Gessain spent time with the Huehuetla Tepehua people in Hidalgo, Mexico, and wrote in 1947 about the spots "location, shape, colour, histology, chemistry, genetic transmission, and racial distribution". He had previously spent several winters in Greenland, and wrote an overview in 1953 of what was known about the spot. He hypothesised that the age at which it faded in various populations might prove to be a distinguishing characteristic of those groups. Gessain claimed that the spot was first observed amongst the Inuit.Hans Egede Saabye, a Danish priest and botanist, spent 1770–1778 in Greenland. His diaries, published in 1816 and translated into several European languages, contained much ethnographic information. He described the spot on newborns, saying he had seen it often when the infants were presented naked for baptism. A second Danish observer was doctor and zoologist Daniel Frederik Eschricht, mainly based in Copenhagen. In 1849 he wrote of the "mixed" babies he had delivered at the lying-in hospital. He also says that "the observation made for the first time by Saabye about Inuit children has been completely confirmed by Captain Holbøll", who sent him a fetus pickled in alcohol.Gessain goes on to state that it was only in 1883 that an anthropologist mentions the spot. It was Erwin Bälz, a German working in Tokyo, who described a dark blue mark on Japanese infants. He presented his findings in 1901 in Berlin, and from that point on, Bälzs name was associated with certain skin cells containing pigment. Captain Gustav Frederik Holm wrote in 1887 that his Greenlandic interpreter Johannes Hansen (known as Hanserak) attested to the existence of the birthmark over the kidney region of newborns, which grows larger as they grow older. That year, the Danish anthropologist Soren Hansen drew the connection between the observations of Bälz in Japan and Saabye in Greenland. "This cannot be a coincidence. It is not the first time that the resemblance between the Japanese and the Eskimo has been pointed out." Fridtjof Nansen, the Norwegian polar explorer, said that the spot was widespread in the mixed Danish-Inuit population of West Greenland. Soren Hansen confirmed this. A missionary in Bethel, Alaska, a traditional gathering place of Yupik people, reported that the spots were common on children. Rudolf Trebitsch, an Austrian linguist and ethnologist, spent the summer of 1906 on the West Coast of Greenland, and listed all the examples he came across. Gessain went to north Labrador in 1926, looking for children with these spots. In 1953 Dr Saxtorph, medical advisor to the Greenland department (part of the Danish government), wrote that the Greenlanders do not like outsiders to see or discuss these birthmarks; "they doubtless feel as a reminiscence of the time when they lived on a low cultural level".The presence or absence of the slate grey nevus was used by racial theorists such as Joseph Deniker (1852-1918), the French anthropologist.The Journal of Cutaneous Diseases Including Syphilis, Volume 23 contained several accounts of the slate grey nevus on children in the Americas:
Holm ("Ethnological Sketch. Communications on Greenland," X., Copenhagen, 1887) announced the presence of the spot in the east part of Greenland. Bartels ("The So-Called Mongolian Spots on Infants of Esquimaux," Ethnologic Review, 1903) received letters regarding it from East Greenland and also from Esquimaux of Alaska. In half-breed European-Esquimaux, Hansen says he has encountered it. Among Indians of North Vancouver, British Columbia, there are observations made by Baelz as well as by Tenkate (secondhand). In the Mayas of Central America, Starrs (Data on the Ethnography of Western Mexico, Part H., 1902) facts are corroborated by Herman (Aparecimiento de la Mancha Mongolica. Revista de Ethnologia, 1904). He cites A. F. Chamberlain (Pigmentary Spots, American Anthropologist, 1902,) and Starr (Sacral Spots of Mayan Indians, Science, New Series, xvii., 1903).
In Central America, according to these authorities, the spot is called Uits, "pan," and it is an insult to speak of it. It disappears in the tenth month. It is bluish-reddish (in these Native people), and is remarkable by its small size. The mulberry colored spot is very well known in Afro-Brazilians. In Brazil, among individuals of mixed Indigenous American and West African descent (pardo) it is called "genipapo", from its resemblance in color (bluish-gray) to an indigenous fruit of Brazil, named genipapo (a Native word adopted into Portuguese).
Prevalence
Infants may be born with one or more slate grey nevus ranging from small area on the buttocks to a larger area on the back. The birthmark is prevalent among East, South, Southeast, North and Central Asian peoples, Indigenous Oceanians (chiefly Micronesians and Polynesians), certain populations in Africa, Amerindians, non-European Latin Americans and Caribbeans of mixed-race descent.They occur in around 80% of Asians, and 80% to 85% of Native American infants. Approximately 90% of Polynesians and Micronesians are born with slate grey nevus, as are about 46% of children in Latin America, where they are associated with non-European descent. These spots also appear on 5–10% of babies of full Caucasian descent; Coria del Río in Spain has a high incidence due to the presence of descendants of members of the delegation led by Hasekura Tsunenaga, the first Japanese official envoy to Spain in the early 17th century. African American babies have slate grey nevus at a frequencies of 90% to 96%.According to a 2006 study examining the Mongolian spot among newborns in the Turkish city of İzmir, it was found out that 26% of the examined babies had the condition. It was noted the prevalence rate was 20% and 31% in boys and girls, respectively. The study also reported that no children born with light hair had the mark, meanwhile 47% of the children with dark hair having it.Since the last century, extensive research has been made regarding the prevalence of said spot in populations of mixed European-Amerindian ancestry. A publication from 1905, citing field research made by the anthropologist Frederick Starr, states that the spot is not present in Mestizo populations, however, if Starrs actual research is consulted it is observed the he declares that "seven Mayan children presented the spot, three mixed children didnt have it...", Starr therefore does not make an absolute judgement, as he does not say how many mixed children were analyzed in total. Nowadays it is completely accepted that the big majority of Mexicos and Latin Americas mixed-race populations have the Mongolian spot and that its presence works as an indicator of the actual degree of mestizaje present in a given population, having its lower frequency in Uruguay with 36%, followed by Argentina with an incidence 44%, Mexico with 50%-52%, 68% in Hispanic-Americans and 88% in highland Peruvians.A study performed in hospitals of Mexico City reported that, on average, 51.8% of Mexican newborns presented slate grey nevus, while it was absent on 48.2% of the analyzed babies. According to the Mexican Social Security Institute nationwide, around half of Mexican babies have the slate grey nevus.Central American indigenous children were subjected to racism due to their slate grey nevus but progressive circles began to make having the slate grey nevus popular after the late 1960s.Highland Peruvians have the slate grey nevus.
Treatment
As a congenital benign nevus, Mongolian spots do not require treatment and in most cases disappear before adolescence. No cases of malignant degeneration have been reported.
Cultural terminology
The slate grey nevus is referred to in the Japanese idiom shiri ga aoi (尻が青い), meaning "to have a blue butt", which is a reference to immaturity or inexperience.
In Mongolian language, it is known as "Хөх толбо".
Korean mythology explains the nevus as a bruise formed when Samshin halmi or Samsin Halmoni (Korean: 삼신할머니), a shaman spirit to whom people pray around childbirth, slapped the babys behind to hasten the baby to quickly get out from the mothers womb. "Mongolian Mark", the middle third of the 2004–5 novel The Vegetarian, is named after the title characters nevus, which obsesses her brother-in-law.
In Chinese, it is referred to as "青痕" (Pinyin: Qīng Hén; literally: blue mark). Among common folk it is said to be caused by the Buddhist goddess of childbirth Songzi Guanyin (Simplified Chinese: 送子观音; Pinyin: Sòng Zǐ Guān Yīn; literally: the goddess of baby sending) when she is slapping the babys backside, telling it to be born. Others say it is because the baby does not want to leave the mothers womb, so Songzi Guanyin will kick it out, leaving the bruise. A small portion of people wrongfully believe it is caused when the doctor is slapping the babys backside to make it cry. Scientifically, it is also referred to as "蒙古斑" (Pinyin: Měng Gǔ Bān; literally: mongolian spot)
In Khmer, it is known as "khnau" (ខ្នៅ) which translates to Mongolian spot as well as other skin conditions such as vitiligo and leucoderma.The mark is also common among Maya people of the Yucatan Peninsula where is referred to as Wa in Maya, which means "circle".
In Ecuador, the native Indians of Colta are insultingly referred to in Spanish by a number of terms which allude to the slate grey nevus.In Spanish it is called mancha mongólica and mancha de Baelz (see Erwin Bälz).In Iñupiaq, is it called auttaq or auktaq, which relates to the word for blood and also means mole.
See also
Nevus flammeus nuchae, also known as stork bite
List of cutaneous conditions
References
== External links == |
Hairball | A hairball is a small collection of hair or fur formed in the stomach of animals, and uncommonly in humans, that is occasionally vomited up when it becomes too big. Hairballs are primarily a tight elongated cylinder of packed fur, but may include bits of other elements such as swallowed food. Animals with hairballs are sometimes mistaken as having other conditions of the stomach such as lymphosarcoma, tuberculosis, and tumor of the spleen. Cats are especially prone to hairball formation since they groom themselves by licking their fur, and thereby ingest it. Rabbits are also prone to hairballs because they groom themselves in the same fashion as cats, but hairballs are especially dangerous for rabbits because they cannot regurgitate them. Due to the fragility of their digestive systems, hairballs in rabbits must be treated immediately or they may cause the animal to stop feeding and ultimately die due to dehydration. Cattle are also known to accumulate hairballs but, as they do not vomit, these are found usually after death and can be quite large.
Clinical significance
A trichobezoar is a bezoar (a mass found trapped in the gastrointestinal system) formed from the ingestion of hair. Trichobezoars are often associated with trichotillomania (compulsive hair pulling). Trichobezoars are rare, but can be fatal if undetected. Surgical intervention is often required.
Society and culture
Although uncommon in humans, some hairballs have been reported. These hairballs occur when hair strands collect in the stomach and are unable to be ejected as a result of the friction on the surface of the gastric mucosa. Hairballs are often seen in young girls as a result of trichophagia, trichotillomania, and pica. In 2003, a 3-year-old girl in Red Deer, Alberta, Canada, had a grapefruit-sized hairball surgically removed from her stomach; in 2006, an 18-year-old woman from Chicago, Illinois, had a 4.5 kg (9.9 lb) hairball surgically removed from her stomach; and in 2014, a 9-pound hairball was removed from the stomach of an 18-year-old in Kyrgyzstan. Hairballs can be quite hazardous in humans since hair cannot be digested or passed by the human gastrointestinal system, and (assuming it is identified) even vomiting may be ineffective at removing the hair mass. This can result in the general impairment of the digestive system.
See also
Pellet (ornithology)
Rapunzel syndrome
== References == |
Advanced sleep phase disorder | Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening (e.g. 7-9 PM) sleepiness and very early morning awakening (e.g. 2-4 AM). This sleep phase advancement can interfere with daily social and work schedules, and results in shortened sleep duration and excessive daytime sleepiness. The timing of sleep and melatonin levels are regulated by the bodys central circadian clock, which is located in the suprachiasmatic nucleus in the hypothalamus.
Symptoms
Individuals with ASPD report being unable to stay awake until conventional bedtime, falling asleep early in the evening, and being unable to stay asleep until their desired waking time, experiencing early morning insomnia. When someone has advanced sleep phase disorder their melatonin levels and core body temperature cycle hours earlier than an average person. These symptoms must be present and stable for a substantial period of time to be correctly diagnosed.
Diagnosis
Individuals expressing the above symptoms may be diagnosed with ASPD using a variety of methods and tests. Sleep specialists measure the patients sleep onset and offset, dim light melatonin onset, and evaluate Horne-Ostberg morningness-eveningness questionnaire results. Sleep specialists may also conduct a polysomnography test to rule out other sleep disorders like narcolepsy. Age and family history of the patient is also taken into consideration.
Treatment
Once diagnosed, ASPD may be treated with bright light therapy in the evenings, or behaviorally with chronotherapy, in order to delay sleep onset and offset. The use of pharmacological approaches to treatment are less successful due to the risks of administering sleep-promoting agents early in the morning. Additional methods of treatment, like timed melatonin administration or hypnotics have been proposed, but determining their safety and efficacy will require further research. Unlike other sleep disorders, ASPD does not necessarily disrupt normal functioning at work during the day and some patients may not complain of excessive daytime sleepiness. Social obligations may cause an individual to stay up later than their circadian rhythm requires, however, they will still wake up very early. If this cycle continues, it can lead to chronic sleep deprivation and other sleep disorders.
Epidemiology
ASPD is more common among middle and older adults. The estimated prevalence of ASPD is about 1% in middle-age adults, and is believed to affect men and women equally. The disorder has a strong familial tendency, with 40-50% of affected individuals having relatives with ASPD. A genetic basis has been demonstrated in one form of ASPD, familial advanced sleep phase disorder (FASPS), which implicates missense mutations in genes hPER2 and CKIdelta in producing the advanced sleep phase phenotype. The identification of two different genetic mutations suggests that there is heterogeneity of this disorder.
Familial advanced sleep phase syndrome
FASPS symptoms
While advanced sleep and wake times are relatively common, especially among older adults, the extreme phase advance characteristic of familial advanced sleep phase syndrome (also known as familial advanced sleep phase disorder) is rare. Individuals with FASPS fall asleep and wake up 4–6 hours earlier than the average population, generally sleeping from 7:30pm to 4:30am. They also have a free running circadian period of 22 hours, which is significantly shorter than the average human period of slightly over 24 hours. The shortened period associated with FASPS results in a shortened period of activity, causing earlier sleep onset and offset. This means that individuals with FASPS must delay their sleep onset and offset each day in order to entrain to the 24-hour day. On holidays and weekends, when the average persons sleep phase is delayed relative to their workday sleep phase, individuals with FASPS experience further advance in their sleep phase.Aside from the unusual timing of sleep, FASPS patients experience normal quality and quantity of sleep. Like general ASPD, this syndrome does not inherently cause negative impacts, however, sleep deprivation may be imposed by social norms causing individuals to delay sleep until a more socially acceptable time, causing them to losing sleep due to earlier-than-usual wakeup time.Another factor that distinguishes FASPS from other advanced sleep phase disorders is its strong familial tendency and life-long expression. Studies of affected lineages have found that approximately 50% of directly related family members experience the symptoms of FASPS, which is an autosomal dominant trait. Diagnosis of FASPS can be confirmed through genetic sequencing analysis by locating genetic mutations known to cause the disorder. Treatment with sleep and wake scheduling and bright light therapy can be used to try to delay sleep phase to a more conventional time frame, however treatment of FASPS has proven largely unsuccessful. Bright light exposure in the evening (between 7:00 and 9:00), during the delay zone as indicated by the phase response curve to light, has been shown to delay circadian rhythms, resulting in later sleep onset and offset in patients with FASPS or other advanced sleep phase disorders.
Discovery
In 1999, Louis Ptáček conducted a study at the University of Utah in which he coined the term familial advanced sleep phase disorder after identifying individuals with a genetic basis for an advanced sleep phase. The first patient evaluated during the study reported "disabling early evening sleepiness" and "early morning awakening"; similar symptoms were also reported in her family members. Consenting relatives of the initial patient were evaluated, as well as those from two additional families. The clinical histories, sleep logs and actigraphy patterns of subject families were used to define a hereditary circadian rhythm variant associated with a short endogenous (i.e. internally-derived) period. The subjects demonstrated a phase advance of sleep-wake rhythms that was distinct not only from control subjects, but also to sleep-wake schedules widely considered to be conventional. The subjects were also evaluated using the Horne-Östberg questionnaire, a structured self-assessment questionnaire used to determine morningness-eveningness in human circadian rhythms. The Horne-Östberg scores of first-degree relatives of affected individuals were higher than those of marry-in spouses and unrelated control subjects. While much of morning and evening preference is heritable, the allele causing FASPS was hypothesized to have a quantitatively larger effect on clock function than the more common genetic variations that influence these preferences. Additionally, the circadian phase of subjects was determined using plasma melatonin and body core temperature measurements; these rhythms were both phase-advanced by 3–4 hours in FASPS subjects compared with control subjects. The Ptáček group also constructed a pedigree of the three FASPS kindreds which indicated a clear autosomal dominant transmission of the sleep phase advance.In 2001, the research group of Phyllis C. Zee phenotypically characterized an additional family affected with ASPS. This study involved an analysis of sleep/wake patterns, diurnal preferences (using a Horne-Östberg questionnaire), and the construction of a pedigree for the affected family. Consistent with established ASPS criteria, the evaluation of subject sleep architecture indicated that the advanced sleep phase was due to an alteration of circadian timing rather than an exogenous (i.e. externally-derived) disruption of sleep homeostasis, a mechanism of sleep regulation. Furthermore, the identified family was one in which an ASPS-affected member was present in every generation; consistent with earlier work done by the Ptáček group, this pattern suggests that the phenotype segregates as a single gene with an autosomal dominant mode of inheritance.In 2001, the research groups of Ptáček and Ying-Hui Fu published a genetic analysis of subjects experiencing the advanced sleep phase, implicating a mutation in the CK1-binding region of PER2 in producing the FASPS behavioral phenotype. FASPS is the first disorder to link known core clock genes directly with human circadian sleep disorders. As the PER2 mutation is not exclusively responsible for causing FASPS, current research has continued to evaluate cases in order to identify new mutations that contribute to the disorder.
Mechanisms (Per2 and CK1)
Two years after reporting the finding of FASPS, Ptáčeks and Fus groups published results of genetic sequencing analysis on a family with FASPS. They genetically mapped the FASPS locus to chromosome 2q where very little human genome sequencing was then available. Thus, they identified and sequenced all the genes in the critical interval. One of these was Period2 (Per2) which is a mammalian gene sufficient for the maintenance of circadian rhythms. Sequencing of the hPer2 gene (h denoting a human strain, as opposed to Drosophila or mouse strains) revealed a serine-to-glycine point mutation in the Casein Kinase I (CK1) binding domain of the hPER2 protein that resulted in hypophosphorylation of hPER2 in vitro. The hypophosphorylation of hPER2 disrupts the transcription-translation (negative) feedback loop (TTFL) required for regulating the stable production of hPER2 protein. In a wildtype individual, Per2 mRNA is transcribed and translated to form a PER2 protein. Large concentrations of PER2 protein inhibits further transcription of Per2 mRNA. CK1 regulates PER2 levels by binding to a CK1 binding site on the protein, allowing for phosphorylation which marks the protein for degradation, reducing protein levels. Once proteins become phosphorylated, PER2 levels decrease again, and Per2 mRNA transcription can resume. This negative feedback regulates the levels and expression of these circadian clock components.Without proper phosphorylation of hPER2 in the instance of a mutation in the CK1 binding site, less Per2 mRNA is transcribed and the period is shortened to less than 24 hours. Individuals with a shortened period due to this phosphorylation disruption entrain to a 24h light-dark cycle, which may lead to a phase advance, causing earlier sleep and wake patterns. However, a 22h period does not necessitate a phase shift, but a shift can be predicted depending on the time the subject is exposed to the stimulus, visualized on a Phase Response Curve (PRC). This is consistent with studies of the role of CK1ɛ (a unique member of the CK1 family) in the TTFL in mammals and more studies have been conducted looking at specific regions of the Per2 transcript. In 2005, Fus and Ptáčeks labs reported discovery of a mutation in CKIδ (a functionally redundant form of CK1ɛ in the phosphorylation process of PER2) also causing FASPS. An A-to-G missense mutation resulted in a threonine-to-alanine alteration in the protein. This mutation prevented the proper phosphorylation of PER2. The evidence for both a mutation in the binding domain of PER2 and a mutation in CKIδ as causes of FASPS is strengthened by the lack of the FASPS phenotype in wild type individuals and by the observed change in the circadian phenotype of these mutant individuals in vitro and an absence of said mutations in all tested control subjects. Fruit flies and mice engineered to carry the human mutation also demonstrated abnormal circadian phenotypes, although the mutant flies had a long circadian period while the mutant mice had a shorter period. The genetic differences between flies and mammals that account for this difference circadian phenotypes are not known. Most recently, Ptáček and Fu reported additional studies of the human Per2 S662G mutation and generation of mice carrying the human mutation. These mice had a circadian period almost 2 hours shorter than wild-type animals under constant darkness. Genetic dosage studies of CKIδ on the Per2 S662G mutation revealed that depending on the binding site on Per2 that CK1δ interacts with, CK1δ may lead to hypo- or hyperphosphorylation of the Per2 gene.
See also
Delayed sleep phase disorder
Irregular sleep–wake rhythm
Non-24-hour sleep–wake disorder
References
== External links == |
Tonsillitis | Tonsillitis is inflammation of the tonsils in the upper part of the throat. Tonsillitis is a type of pharyngitis that typically comes on fast (rapid onset). Symptoms may include sore throat, fever, enlargement of the tonsils, trouble swallowing, and large lymph nodes around the neck. Complications include peritonsillar abscess.Tonsillitis is most commonly caused by a viral infection and about 5% to 40% of cases are caused by a bacterial infection. When caused by the bacterium group A streptococcus, it is referred to as strep throat. Rarely bacteria such as Neisseria gonorrhoeae, Corynebacterium diphtheriae, or Haemophilus influenzae may be the cause. Typically the infection is spread between people through the air. A scoring system, such as the Centor score, may help separate possible causes. Confirmation may be by a throat swab or rapid strep test.Treatment efforts involve improving symptoms and decreasing complications. Paracetamol (acetaminophen) and ibuprofen may be used to help with pain. If strep throat is present the antibiotic penicillin by mouth is generally recommended. In those who are allergic to penicillin, cephalosporins or macrolides may be used. In children with frequent episodes of tonsillitis, tonsillectomy modestly decreases the risk of future episodes.About 7.5% of people have a sore throat in any three-month period and 2% of people visit a doctor for tonsillitis each year. It is most common in school-aged children and typically occurs in the colder months of autumn and winter. The majority of people recover with or without medication. In 82% of people, symptoms resolve within one week, regardless if bacteria or viruses were present. Antibiotics probably reduce the number of people experiencing sore throat or headache, but the balance between modest symptom reduction and the potential hazards of antimicrobial resistance must be recognised.
Signs and symptoms
Those with tonsillitis usually experience sore throat, painful swallowing, malaise, and fever. Their tonsils – and often the back of the throat – appear red and swollen, and sometimes give off a white discharge. Some also have tender swelling of the cervical lymph nodes.Many viral infections that cause tonsillitis will also cause cough, runny nose, hoarse voice, or blistering in the mouth or throat. Infectious mononucleosis can cause the tonsils to swell with red spots or white discharge that may extend to the tongue. This can be accompanied by fever, sore throat, cervical lymph node swelling, and enlargement of the liver and spleen. Bacterial infections that cause tonsillitis can also cause a distinct "scarletiniform" rash, vomiting, and tonsillar spots or discharge.Tonsilloliths occur in up to 10% of the population frequently due to episodes of tonsillitis.
Causes
Viral infections cause 40 to 60% of cases of tonsillitis. Many viruses can cause inflammation of the tonsils (and the rest of throat) including adenovirus, rhinovirus, coronavirus, influenza virus, parainfluenza virus, coxsackievirus, measles virus, Epstein-Barr virus, cytomegalovirus, respiratory syncytial virus, and herpes simplex virus. Tonsillitis can also be part of the initial reaction to HIV infection. An estimated 1 to 10% of the cases are caused by Epstein-Barr virus.Tonsillitis can also stem from infection with bacteria, predominantly Group A β-hemolytic streptococci (GABHS), which causes strep throat. Bacterial infection of the tonsils usually follows the initial viral infection. When tonsillitis recurs after antibiotic treatment for streptococcus bacteria, it is usually due to the same bacteria as the first time, which suggests that the antibiotic treatment was not fully effective. Less common bacterial causes include: Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Bordetella pertussis, Fusobacterium sp., Corynebacterium diphtheriae, Treponema pallidum, and Neisseria gonorrhoeae.Anaerobic bacteria have been implicated in tonsillitis, and a possible role in the acute inflammatory process is supported by several clinical and scientific observations.Sometimes tonsillitis is caused by an infection of spirochaeta and treponema, which is called Vincents angina or Plaut-Vincent angina.Within the tonsils, white blood cells of the immune system destroy the viruses or bacteria by producing inflammatory cytokines like phospholipase A2, which also lead to fever. The infection may also be present in the throat and surrounding areas, causing inflammation of the pharynx.
Diagnosis
There is no firm distinction between a sore throat that is specifically tonsillitis and a sore throat caused by inflammation in both the tonsils and also nearby tissues. An acute sore throat may be diagnosed as tonsillitis, pharyngitis, or tonsillopharyngitis (also called pharyngotonsillitis), depending upon the clinical findings.
In primary care settings, the Centor criteria are used to determine the likelihood of group A beta-hemolytic streptococcus (GABHS) infection in an acute tonsillitis and the need of antibiotics for tonsillitis treatment. However, the Centor criteria have their weaknesses in making precise diagnosis for adults. The Centor criteria are also ineffective in diagnosis for tonsillitis in children and in secondary care settings (hospitals). A modified version of the Centor criteria, which modified the original Centor criteria in 1998, is often used to aid in diagnosis. The original Centor criteria had four major criteria but the modified Centor criteria have five. The five major criteria of the modified Centor score are:
Presence of tonsillar exudate
Painful neck lymph nodes
History of fever
Age between five and fifteen years
Absence of coughThe possibility of GABHS infection increases with increasing score. The probability for getting GABHS is 2 to 23% for the score of 1, and 25 to 85% for the score of 4.
The diagnosis of GABHS tonsillitis can be confirmed by culture of samples obtained by swabbing the throat and plating them on blood agar medium. This small percentage of false-negative results are part of the characteristics of the tests used but are also possible if the person has received antibiotics prior to testing. Identification requires 24 to 48 hours by culture but rapid screening tests (10–60 minutes), which have a sensitivity of 85–90%, are available. In 40% of the people without any symptoms, the throat culture can be positive. Therefore, throat culture is not routinely used in clinical practice for the detection of GABHS.Bacterial culture may need to be performed in cases of a negative rapid streptococcal test. An increase in antistreptolysin O (ASO) streptococcal antibody titer following the acute infection can provide retrospective evidence of GABHS infection and is considered definitive proof of GABHS infection, but not necessarily of the tonsils.
Epstein Barr virus serology can be tested for those who may have infectious mononucleosis with a typical lymphocyte count in full blood count result. Blood investigations are only required for those with hospital admission requiring intravenous antibiotics. Increased values of secreted phospholipase A2 and altered fatty acid metabolism observed in people with tonsillitis may have diagnostic utility.Nasoendoscopy can be used for those with severe neck pain and inability to swallow any fluids to rule out masked epiglotitis and supraglotitis. Routine nasoendscopy is not recommended for children.
Treatment
Treatments to reduce the discomfort from tonsillitis include:
pain and fever reducing medications such as paracetamol (acetaminophen) and ibuprofen
warm salt water gargle, lozenges, honey, or warm liquidsThere are no antiviral medical treatments for virally caused tonsillitis.
Antibiotics
If the tonsillitis is caused by group A streptococcus, then antibiotics are useful, with penicillin or amoxicillin being primary choices. Cephalosporins and macrolides are considered good alternatives to penicillin in the acute care setting. A macrolide, such as azithromycin or erythromycin, is used for people allergic to penicillin. If penicillin therapy fails, bacterial tonsillitis may respond to treatment effective against beta-lactamase producing bacteria such as clindamycin or amoxicillin-clavulanate. Aerobic and anaerobic beta lactamase producing bacteria that reside in the tonsillar tissues can "shield" group A streptococcus from penicillins. There is no significant difference in efficacy of various groups of antibiotics for treating tonsillitis. Intravenous antibiotics can be for those who are hospitalized with inability to swallow and presented with complications. Oral antibiotics can be resumed immediately if the person is clinically improved and able to swallow orally. Antibiotic treatment is usually taken for seven to ten days.
Pain medication
Paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to treat throat pain in children and adults. Codeine is avoided in children under 12 years of age to treat throat pain or following tonsilectomy. NSAIDs (such as ibuprofen) and opioids (such as codeine and tramadol) are equally effective at relieving pain, however, precautions should be taken with these pain medications. NSAIDs can cause peptic ulcer disease and kidney damage. Opioids can cause respiratory depression in those who are vulnerable. Anaesthetic mouthwash can also be used for symptomatic relief.
Corticosteroids
Corticosteroids reduce tonsillitis pain and improve symptoms in 24 to 48 hours. Oral corticosteroids are recommended unless the person is unable to swallow medications.
Surgery
When tonsillitis recurs frequently, often arbitrarily defined as at least five episodes of tonsillitis in a year, or when the palatine tonsils become so swollen that swallowing is difficult as well as painful, a tonsillectomy can be performed to surgically remove the tonsils.
Children have had only a modest benefit from tonsillectomy for repeated cases of tonsillitis.
Prognosis
Since the advent of penicillin in the 1940s, a major preoccupation in the treatment of streptococcal tonsillitis has been the prevention of rheumatic fever, and its major effects on the nervous system and heart.
Complications may rarely include dehydration and kidney failure due to difficulty swallowing, blocked airways due to inflammation, and pharyngitis due to the spread of infection.An abscess may develop lateral to the tonsil during an infection, typically several days after the onset of tonsillitis. This is termed a peritonsillar abscess (or quinsy).
Rarely, the infection may spread beyond the tonsil resulting in inflammation and infection of the internal jugular vein giving rise to a spreading infectious thrombophlebitis (Lemierres syndrome).In strep throat, diseases like post-streptococcal glomerulonephritis can occur. These complications are extremely rare in developed nations but remain a significant problem in poorer nations.
Epidemiology
Tonsillitis occurs throughout the world, without racial or ethnic differences. Most children have tonsillitis at least once during their childhood, although it rarely occurs before the age of two. It most typically occurs between the ages of four and five; bacterial infections most typically occur at a later age.
Society and culture
Tonsillitis is described in the ancient Greek Hippocratic Corpus.Recurrent tonsillitis can interfere with vocal function and the ability to perform among people who use their voices professionally.
References
Books cited
Dean-Jones L (2013). "The Child Patient of the Hippocratics: Early Pediatrics?". In Grubbs JE, Parkin T (eds.). The Oxford Handbook of Childhood and Education in the Classical World. Oxford University Press. doi:10.1093/oxfordhb/9780199781546.013.005. ISBN 9780199781546.
Ferri FF (2015). Ferris Clinical Advisor 2016: 5 Books in 1 (first ed.). Elsevier Health Sciences. ISBN 978-0323280471.
Jones R (2005). Oxford Textbook of Primary Medical Care. Oxford University Press. ISBN 9780198567820.
Lang F (2009). Encyclopedia of Molecular Mechanisms of Disease. Springer Science & Business Media. ISBN 9783540671367.
Nour SG, Mafee MR, Valvassori GE, Valbasson GE, Becker M (2005). Imaging of the head and neck. Stuttgart: Thieme. p. 716]. ISBN 978-1-58890-009-8.
Sataloff RT, Hawkshaw MJ (2019). "Medical Care of Voice Disorders". In Eidsheim NS, Meisel K (eds.). The Oxford Handbook of Voice Studies. New York, NY: Oxford University Press. pp. 54–75. doi:10.1093/oxfordhb/9780199982295.013.11. ISBN 978-0-19-998229-5. OCLC 1076410526.
Simon HB (2005). "Bacterial infections of the upper respiratory tract". In Dale DC, Federman DD (eds.). ACP Medicine, 2006 Edition (Two Volume Set) (Second ed.). WebMD Professional Publishing. ISBN 978-0-9748327-6-0.
Sommers M, Fannin E (2015). Diseases & Disorders: A Nursing Therapeutics Manual (5th ed.). F.A. Davis Company. ISBN 978-0803638556.
Stadelman-Cohen TK, Hillman RE (2019). "Voice Dysfunction and Recovery". In Welch GF, Howard DM, Nix J (eds.). The Oxford Handbook of Singing. Oxford University Press. pp. 30–52. doi:10.1093/oxfordhb/9780199660773.013.018. ISBN 978-0-19-966077-3.
Thuma P (2001). "Pharyngitis and tonsillitis". In Hoekelman RA, Adam HM, Nelson NM, Weitzman ML (eds.). Primary pediatric care (4th ed.). St. Louis: Mosby. ISBN 978-0-323-00831-0.
Wetmore RF (2007). "Tonsils and adenoids". In Kliegman RM, Behrman RE, Jenson HB, Stanton BF (eds.). Nelson textbook of pediatrics (18th ed.). Philadelphia: Saunders. ISBN 978-1-4160-2450-7. |
Dravet syndrome | Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before 1 year of age, with 6 months being the age that seizures, characterized by prolonged convulsions and triggered by fever, usually begin.
Signs and symptoms
Dravet syndrome has been characterized by prolonged febrile and non-febrile seizures within the first year of a childs life. This disease progresses to other seizure types like myoclonic and partial seizures, psychomotor delay, and ataxia. It is characterized by cognitive impairment, behavioural disorders, and motor deficits. Behavioural deficits often include hyperactivity and impulsiveness, and in more rare cases, autistic-like behaviours. Dravet syndrome is also associated with sleep disorders including somnolence and insomnia. The seizures experienced by people with Dravet syndrome become worse as the patient ages, as the disease is not very observable when symptoms first appear. This coupled with the range of severity differing between each individual diagnosed and the resistance of these seizures to drugs has made it challenging to develop treatments.Dravet syndrome appears during the first year of life, often beginning around six months of age with frequent febrile seizures (fever-related seizures). Children with Dravet syndrome typically experience a lagged development of language and motor skills, hyperactivity and sleep difficulties, chronic infection, growth and balance issues, and difficulty relating to others. The effects of this disorder do not diminish over time, and children diagnosed with Dravet syndrome require fully committed caretakers with tremendous patience and the ability to closely monitor them.Febrile seizures are divided into two categories known as simple and complex. A febrile seizure would be categorized as complex if it has occurred within 24 hours of another seizure or if it lasts longer than 15 minutes. A febrile seizure lasting less than 15 minutes would be considered simple. Sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals. However, any seizure uninterrupted after 5 minutes, without a resumption of postictal (more normal; recovery-type; after-seizure) consciousness can lead to potentially fatal status epilepticus.
Causes
In most cases the mutations in Dravet syndrome are not hereditary and the mutated gene is found for the first time in a single family member. In 70–90% of patients, Dravet syndrome is caused by nonsense mutations in the SCN1A gene resulting in a premature stop codon and thus a non-functional protein. This gene normally codes for neuronal voltage-gated sodium channel Nav1.1. In mouse models, these loss-of-function mutations have been observed to result in a decrease in sodium currents and impaired excitability of GABAergic interneurons of the hippocampus. The researchers found that loss of Nav1.1 channels was sufficient to cause the epilepsy and premature death seen in Dravet syndrome.The timing of the first signs and symptoms in Dravet syndrome occur about the same time as normal childhood vaccinations, leading some to believe the vaccine was the cause. However, this is likely a non-specific response to fever, as vaccination often induces fever, and fever is known to be associated with seizures in persons with Dravet syndrome. Some of the patients who put forth vaccine injury claims from encephalopathy were later found, upon testing, to actually have Dravet syndrome.
Genetics
The genotypic explanation of the disorder has been located on the specific voltage-gated sodium channel genes known as SCN1A and SCN2A. These genes are located on the long (q) arm of chromosome 2 at position 24.3 and code for the alpha subunit of the transmembrane sodium channel protein. A mutation in either of these two genes will cause an individual to develop dysfunctional sodium channels, which are crucial in the pathway for sending chemical signals in the brain, causing the phenotypic display of myoclonic epilepsy from the individual. A properly functioning channel would respond to a voltage difference across the membrane and form a pore through which only sodium ions can pass. The influx of sodium induces the generation of action potential by temporarily changing the charge of the cell. When the gene is mutated, the eventually translated protein improperly folds its pore segment within the cell membrane because it has different amino acid chemistry, which renders the channel inactive. It is also possible for a mutation to reduce the number of channels produced by an individual, which leads to the development of Dravet syndrome.Currently, the SCN1A gene is the most clinically relevant; the largest number of epilepsy related mutations characterized thus far occur in this gene. Typically, a missense mutation in either the S5 or S6 segment of the sodium channel pore results in a loss of channel function and the development of Dravet syndrome. A heterozygous inheritance of an SCN1A mutation is all that is necessary to develop a defective sodium channel; patients with Dravet syndrome will still have one normal copy of the gene.
Diagnosis
According to the Dravet Syndrome Foundation, the diagnostic criteria for DS requires the patient to present with several of the following symptoms:
Onset of seizures in the first year of life in an otherwise healthy infant
Initial seizures are typically prolonged and are generalized or unilateral
Presence of other seizure types (i.e. myoclonic seizures)
Seizures associated with fever due to illness or vaccinations
Seizures induced by prolonged exposure to warm temperatures
Seizures in response to strong lighting or certain visual patterns
Initially normal EEGs and later EEGs with slowing and severe generalized polyspikes
Normal initial development followed by slow development during the first few years of life
Some degree of hypotonia
Unstable gait and balance issues
Ankle pronation and flat feet and/or development of a crouched gait with age
Treatment
Seizures in Dravet syndrome can be difficult to manage but may be reduced by anticonvulsant medications such as clobazam, stiripentol, topiramate and valproate. Because the course of the disorder varies from individual to individual, treatment protocols may vary. A diet high in fats and low in carbohydrates may also be beneficial, known as a ketogenic diet. Although diet adjustment can help, it does not eliminate the symptoms. Until a better form of treatment or cure is discovered, those with this disease will have myoclonic epilepsy for the rest of their lives.Certain anticonvulsant medications that are classed as sodium channel blockers are now known to make seizures worse in most Dravet patients. These medications include carbamazepine, gabapentin, lamotrigine, and phenytoin.Treatments include cognitive rehabilitation through psychomotor and speech therapy. In addition, valproate is often administered to prevent recurrence of febrile seizures and a benzodiazepine is used for long lasting seizures, but these treatments are usually insufficient.Stiripentol was the only medication for which a double-blind placebo-controlled randomized controlled trial was performed and this medication showed efficacy in trials. It acts as a GABAergic agent and as a positive allosteric modulator of GABAA receptor. Stiripentol, can improve focal refractory epilepsy, as well as Dravets syndrome, supplemented with clobazam and valproate was approved in Europe in 2007 as a therapy for Dravet syndrome and has been found to reduce overall seizure rate by 70%. In cases with more drug-resistant seizures, topiramate and the ketogenic diet are used as alternative treatments.Cannabidiol (CBD) was approved in United States for treatment of Dravet syndrome in 2018. A 2017 study showed that the frequency of seizures per month decreased from 12 to 6 with the use of cannabidiol, compared with a decrease from 15 to 14 with placebo.In 2020, fenfluramine was approved for the medical treatment in the European Union and the USA.
Epidemiology
Dravet syndrome is a severe form of epilepsy, responsible for roughly 10% of cases in children. It is a rare genetic disorder that affects an estimated 1 in every 20,000–40,000 births.
COVID-19
Although it is not clear whether people with Dravet syndrome are specially vulnerable to COVID-19 infection, recent publications have shown that affected individuals and their families have suffered some indirect consequences during the COVID-19 pandemic, such as healthcare barriers, loss of therapies or economic issues.
History
Charlotte Dravet first described severe myoclonic epilepsy of infancy in Centre Saint Paul, Marseille, France in 1978 and the name was later changed to Dravet syndrome in 1989. Similar descriptions were given by Bernardo Dalla Bernardina in Verona.Charlotte Figi, who was diagnosed as having Dravet syndrome, was the focus of a cause célèbre to provide a means for use of cannabidiol for persons with intractable seizures. She died from pneumonia, possibly caused by COVID-19, in April, 2020.
References
== External links == |
Tauopathy | Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles (Neurofibrillary tangle) in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known as tau, causing the protein to dissociate from microtubules and form insoluble aggregates. (These aggregations are also called paired helical filaments.) The mechanism of tangle formation is not well understood, and whether tangles are a primary cause of Alzheimers disease or play a peripheral role is unknown.
Detection and imaging
Post-mortem
Tau tangles are seen microscopically in stained brain samples.Pre-mortem
In living patients tau tangle locations can be imaged with a PET scan using a suitable radio-emissive agent.
Alzheimers disease
Neurofibrillary tangles were first described by Alois Alzheimer in one of his patients with Alzheimers disease (AD). The tangles are considered a secondary tauopathy. AD is also classified as an amyloidosis because of the presence of senile plaques.When tau becomes hyperphosphorylated, the protein dissociates from the microtubules in axons. Then, tau becomes misfolded and the protein begins to aggregate, which eventually forms the neurofibrillary tangles seen in Alzheimers patients. Microtubules also destabilize when tau is dissociated. The combination of the neurofibrillary tangles and destabilized microtubules result in disruption of processes such as axonal transport and neural communication.The degree of NFT involvement in AD is defined by Braak stages. Braak stages I and II are used when NFT involvement is confined mainly to the transentorhinal region of the brain, stages III and IV when theres also involvement of limbic regions such as the hippocampus, and V and VI when theres extensive neocortical involvement. This should not be confused with the degree of senile plaque involvement, which progresses differently.
Other diseases
Primary age-related tauopathy (PART) dementia, with NFTs similar to AD, but without amyloid plaques.
Chronic traumatic encephalopathy (CTE)
Progressive supranuclear palsy (PSP)
Corticobasal degeneration (CBD)
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)
Vacuolar tauopathy
Lytico-bodig disease (Parkinson-dementia complex of Guam)
Ganglioglioma and gangliocytoma
Meningioangiomatosis
Postencephalitic parkinsonism
Subacute sclerosing panencephalitis (SSPE)
As well as lead encephalopathy, tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, and lipofuscinosisIn both Picks disease and corticobasal degeneration, tau proteins are deposited as inclusion bodies within swollen or "ballooned" neurons.Argyrophilic grain disease (AGD), another type of dementia, is marked by an abundance of argyrophilic grains and coiled bodies upon microscopic examination of brain tissue. Some consider it to be a type of Alzheimers disease. It may co-exist with other tauopathies such as progressive supranuclear palsy and corticobasal degeneration, and also Picks disease.Tauopathies are often overlapped with synucleinopathies, possibly due to interaction between the synuclein and tau proteins.The non-Alzheimers tauopathies are sometimes grouped together as "Picks complex" due to their association with frontotemporal dementia, or frontotemporal lobar degeneration.
See also
Proteopathy
References
== External links == |
Tailors bunion | Tailors bunion is a condition caused as a result of inflammation of the fifth metatarsal bone at the base of the little toe.It is usually characterized by inflammation, pain and redness of the little toe.
Often a tailors bunion is caused by a faulty mechanical structure of the foot. The fifth metatarsal bone starts to protrude outward, while the little toe moves inward. This change in alignment creates an enlargement on the outside of the foot.
It is mostly similar to a bunion (the same type of ailment affecting the big toe). It is called Tailors bunion because in past centuries, tailors sat cross-legged, and this was thought to cause this protrusion on the outside aspect of the foot.
Patients will present with a history of pain of the lateral bunion, plantar callous, and pain that increases with constrictive shoe wear. Studies have shown that tight shoe wear can cause both bunions as well as Tailors bunions.
Treatment
Non-surgical therapies include:
Shoe modifications: wearing shoes that have a wide toe box, and avoiding those with pointed toes or high heels.
Oral nonsteroidal anti-inflammatory drugs may help in relieving the pain and inflammation.
Injections of corticosteroid are commonly used to treat the inflammation.
Bunionette pads placed over the affected area may help reduce pain.
An ice pack may be applied to reduce pain and inflammation.Surgery is often considered when pain continues for a long period with no improvement in these non-surgical therapies.
Surgical therapies include:
Distal and proximal osteotomies of the 5th metatarsal can be used to correct the intermetatarsal and metatarsophalangeal angle causing the TB.
Diagnosis
Tailors bunion is easily diagnosed because the protrusion is visually apparent. X-rays may be ordered to help the surgeon find out the severity of the deformity.
Types of Tailors bunions
Type 1: The head of the 5th metatarsal is thickened and enlarged.
Type 2: A 5th metatarsal with an increased lateral curve and a normal fourth and fifth inter-metatarsal angle.
Type 3: Has the greatest lateral angular disposition of the 5th metatarsal compared to the 4th metatarsal, this phenomenon increases the 4th and 5th inter-metatarsal angles. This is generally the most symptomatic type of Tailors bunion.
Type 4: A combination of at least two types of bunionettes (TB).
Lesser toe deformities leading to falls
Five studies examined associations between falls and foot disorders. Significant associations were found between falls and plantar fasciitis, corns or bunions and lesser toe deformity (such as Tailors bunions). The results of these studies show that "Older people who fell were more likely to have foot pain, hallux valgus, and lesser toe deformity".
See also
Tailors muscle
Bunion, also known as hallux valgus, a similar condition of the big toe.
== References == |
Pelizaeus–Merzbacher disease | Pelizaeus–Merzbacher disease is an X-linked neurological disorder that damages oligodendrocytes in the central nervous system. It is caused by mutations in proteolipid protein 1 (PLP1), a major myelin protein. It is characterized by a decrease in the amount of insulating myelin surrounding the nerves (hypomyelination) and belongs to a group of genetic diseases referred to as leukodystrophies.
Signs and symptoms
The hallmark signs and symptoms of Pelizaeus–Merzbacher disease include little or no movement in the arms or legs, respiratory difficulties, and characteristic horizontal movements of the eyes left to right.The onset of Pelizaeus–Merzbacher disease is usually in early infancy. The most characteristic early signs are nystagmus (rapid, involuntary, rhythmic motion of the eyes) and low muscle tone. Motor abilities are delayed or never acquired, mostly depending upon the severity of the mutation. Most children with Pelizaeus–Merzbacher disease learn to understand language, and usually have some speech. Other signs may include tremor, lack of coordination, involuntary movements, weakness, unsteady gait, and over time, spasticity in legs and arms. Muscle contractures often occur over time. Mental functions may deteriorate. Some patients may have convulsions and skeletal deformation, such as scoliosis, resulting from abnormal muscular stress on bones.
Cause
Pelizaeus–Merzbacher disease is caused by X-linked recessive mutations in the major myelin protein proteolipid protein 1 (PLP1). This causes hypomyelination in the central nervous system and severe neurological disease. The majority of mutations result in duplications of the entire PLP1 gene. Deletions of PLP1 locus (which are rare) cause a milder form of Pelizaeus–Merzbacher disease than is observed with the typical duplication mutations, which demonstrates the critical importance of gene dosage at this locus for normal CNS function.
Diagnosis
The diagnosis of Pelizaeus–Merzbacher disease is often first suggested after identification by magnetic resonance imaging of abnormal white matter (high T2 signal intensity, i.e. T2 lengthening) throughout the brain, which is typically evident by about 1 year of age, but more subtle abnormalities should be evident during infancy. Unless a family history consistent with sex-linked inheritance exists, the condition is often misdiagnosed as cerebral palsy. Once a PLP1 mutation is identified, prenatal diagnosis or preimplantation genetic diagnostic testing is possible.
Classification
The disease is one in a group of genetic disorders collectively known as leukodystrophies that affect the growth of the myelin sheath, the fatty covering—which acts as an insulator—on nerve fibers in the central nervous system. The several forms of Pelizaeus–Merzbacher disease include classic, congenital, transitional, and adult variants.Milder mutations of the PLP1 gene that mainly cause leg weakness and spasticity, with little or no cerebral involvement, are classified as spastic paraplegia 2 (SPG2).
Treatment
No cure for Pelizaeus–Merzbacher disease has been developed. Outcomes are variable: people with the most severe form of the disease do not usually survive to adolescence, although with milder forms, survival into adulthood is possible.
Research
In December 2008, StemCells, Inc received clearance in the United States to conduct a phase I clinical trials of human neural stem cell transplantation. The trial did not show meaningful efficacy and the company has since gone bankrupt.In 2019 Paul Tesar, a professor at Case Western Reserve University, used CRISPR and antisense therapy in a mouse model of Pelizaeus–Merzbacher with success. In 2022 Case Western Reserve University entered a exclusive licensing agreement with Ionis Pharmaceuticals to develop a human treatment for the disorder.
See also
The Myelin Project
The Stennis Foundation
References
Further reading
Uhlenberg, Birgit; Schuelke, Markus; Rüschendorf, Franz; Ruf, Nico; Kaindl, Angela M.; Henneke, Marco; Thiele, Holger; Stoltenburg-Didinger, Gisela; Aksu, Fuat; Topaloğlu, Haluk; Nürnberg, Peter; Hübner, Christoph; Weschke, Bernhard; Gärtner, Jutta (August 2004). "Mutations in the Gene Encoding Gap Junction Protein α12 (Connexin 46.6) Cause Pelizaeus-Merzbacher–Like Disease". The American Journal of Human Genetics. 75 (2): 251–260. doi:10.1086/422763. PMC 1216059. PMID 15192806.
External links
Pelizaeus-Merzbacher Disease - PMD Foundation
Pelizaeus-Merzbacher Disease. NINDS/National Health Institutes.
pmd at NIH/UW GeneTests |
Infantile digital fibromatosis | Infantile digital fibromatosis (IDF), also termed inclusion body fibromatosis, Reye tumor, or Reyes tumor, usually occurs as a single, small, asymptomatic, nodule in the dermis on a finger or toe of infants and young children. IMF is a rare disorder with approximately 200 cases reported in the medical literature as of 2021. The World Health Organization, 2020, classified these nodules as a specific benign tumor type in the category of fibroblastic and myofibroblastic tumors. IDF was first described by the Australian pathologist, Douglas Reye, in 1965.IDF consists of an overgrowth of spindle-shaped cells in a collagen fiber-rich background located in the dermis (i.e. the layer of skin between the epidermis and subcutaneous tissue) but may extend into the subcutaneous tissue. These spindle-shaped cells contain distinctive inclusion bodies within their cytoplasm that greatly help in distinguishing IDF from other fibrous skin diseases. These inclusions are composed of densely packed vimentin and actin filamentsIDF lesions are usually painless and have a tendency to regress spontaneously. Consequently, the current recommended treatment for IDF nodules is conservative observation. If the lesions cause local deformities and/or functional impairments or continue to increase in size over long observation periods, surgical removal is recommended. However, surgically removed IDF lesions have had high rates of recurrence and this surgery may cause post-operative digital deformities.
Presentation
IDF typically presents as a solitary painless, smooth, flesh-colored to red, dome-shaped nodule located on the dorsal or lateral aspect of a finger or toe but sparing the thumb or great toe; they occur principally in the first two years of life with about 1/3 of cases having a lesion since birth. However: 1) lesions with appearances similar to, and diagnosed as, IPF have been described in extra digital sites such as the arm, breast, tongue, thigh, and chest; 2) unusual cases have presented with multiple lesions, i.e. 2–3, uncommonly 7–15, and one case with 74 lesions in a 2018 review study; 3) cases have been reported in children up to the age 10 and one case was reported in a 52-year-old adult; 4) the lesions are typically smaller than 2 cm in maximum diameter but rarely have been tumor-sized, e.g. 4.5 cm; 5) the lesions, particularly when larger-sized, may be painful and/or compromise the functions of nearby joints and digits; and 6) the lesions occasionally invade the periosteum and erode a nearby bone.
Pathology
Microscopic histopathological analyses of appropriately dye-stained IDF tissues typically show a non-encapsulated small tumor composed of bundles of uniform spindle-shaped cells that combine physical features of fibroblasts (the most common cell type in connective tissue) with those of myofibroblasts (contractile, spindle-shaped cells that are identifiable by their expression of α-smooth muscle actin) in a background of collagen fibers. In hematoxylin and eosin-stained tissues, the spindle-shaped cells have pale eosinophilic (i.e. red or pink due to uptake of eosin) cytoplasm with plump and elongated nuclei composed of granulated (i.e. having many small, distinct parts) chromatin. The most pathognomonic (i.e. indicative of a particular disease) feature of these cells is the presence of cytoplasmic perinuclear inclusion bodies which usually are small, round, pale pink bodies on hematoxylin and eosin staining that often indent their parent cells nuclei. These inclusions are composed of densely packed vimentin and actin filaments. Newer tumors show relatively abundant inclusion bodies and scarce collagen fibers while older tumors show few or no detectable inclusion bodies and abundant collagen fibers. Immunohistochemical analyses show that the spindle-shaped cells typically express α-smooth muscle actin, calponin, desmin, and CD99 proteins but not S100 protein or glial fibrillary acidic protein.
Diagnosis
The diagnosis of IDF is usually based on its presentation in newborn or young infants and biopsy or fine needle aspirate analyses of the tumors pathology. These analyses should show the presence of spindle-shaped cells bearing eosinophilic paranuclear inclusions consisting of actin and vimentin filaments, which, if necessary, can be confirmed by immunofluorescence staining of the filaments. Inclusions may not be evident in older lesions stained with hematoxylin and eosin but may be apparent when stained with other reagents such as the Massons trichrome stain, phosphotungstic acid-haematoxylin stain, elastic Van Giesons stain, or Lendrums phloxine-tartrazine stain. Demonstration of these filaments is not necessary for a diagnosis of IMF if the clinical picture and other histological findings are consistent with the disorder. Findings of one or a few usually small lesions centered in the dermis of a digit consisting of spindle-shaped cells and expressing α-smooth muscle actin, desmin, and calponin proteins would support the diagnosis of IDF.Infantile myofibromatosis (IMF) is, like IDF, a disease in which benign tumors develop primarily in the fingers and toes of newborns and infants and consists of spindle-shaped cells in a collagen fibrous background. IDF was once regarded as a sub-type of infantile myofibromatosis. However, IMF tumors can be far more aggressinve than IDF lesions and consist of cells that do not have paranuclear inclusions. The World Health Organization (2020) classification includes IPF but not IMF as a tumor in the category of benign fibroblastic and myofibroblastic tumors.
Treatment
Infantile digital fibroma lesions were once thought to be potentially malignant and therefore treated with surgical excision and even digital amputations. Currently, these tumors are known to be benign, may spontaneously regress, and often recur after surgical removal. Consequently, IDF lesions are usually treated by a watchful waiting observation approach with surgical resections limited to cases with functional impairment, significant symptoms, or progressive, long-term growth. Alternate or supplemental treatments used to treat IDF include injection of the glucocorticoid, triamcinolone, or the chemotherapy drug, 5-fluorouracil, directly into the lesions. Since these injection treatments have not been evaluated in large studies to date, surgical resection is the most accepted treatment of highly symptomatic or progressively enlarging IDF lesions. Overall, the prognosis for IDF is excellent.
See also
Infantile fibromatosis
Skin lesion
References
== External links == |
Milium (dermatology) | 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 == |
Gastric varices | Gastric varices are dilated submucosal veins in the lining of the stomach, which can be a life-threatening cause of bleeding in the upper gastrointestinal tract. They are most commonly found in patients with portal hypertension, or elevated pressure in the portal vein system, which may be a complication of cirrhosis. Gastric varices may also be found in patients with thrombosis of the splenic vein, into which the short gastric veins that drain the fundus of the stomach flow. The latter may be a complication of acute pancreatitis, pancreatic cancer, or other abdominal tumours, as well as hepatitis C. Gastric varices and associated bleeding are a potential complication of schistosomiasis resulting from portal hypertension.
Patients with bleeding gastric varices can present with bloody vomiting (hematemesis), dark, tarry stools (melena), or rectal bleeding. The bleeding may be brisk, and patients may soon develop shock. Treatment of gastric varices can include injection of the varices with cyanoacrylate glue, or a radiological procedure to decrease the pressure in the portal vein, termed transjugular intrahepatic portosystemic shunt or TIPS. Treatment with intravenous octreotide is also useful to shunt blood flow away from the stomachs circulation. More aggressive treatment, including splenectomy (surgical removal of the spleen) or liver transplantation, may be required in some cases.
Signs and symptoms
Gastric varices can present in two major ways. First, patients with cirrhosis may be enrolled in screening gastroscopy programs to detect esophageal varices. These evaluations may detect gastric varices that are asymptomatic. When gastric varices are symptomatic, however, they usually present acutely and dramatically with upper gastrointestinal bleeding. The symptoms can include vomiting blood, melena (passing black, tarry stools); or passing maroon stools or frank blood in the stools. Many people with bleeding gastric varices present in shock due to the profound loss of blood.Secondly, patients with acute pancreatitis may present with gastric varices as a complication of a blood clot in the splenic vein. The splenic vein sits over the pancreas anatomically, and inflammation or cancers of the pancreas may result in a blood clot forming in the splenic vein. As the short gastric veins of the fundus of the stomach drain into the splenic vein, thrombosis of the splenic vein will result in increased pressure and engorgement of the short veins, leading to varices in the fundus of the stomach.Laboratory testing usually shows low red blood cell count and often a low platelet count. If cirrhosis is present, there may be coagulopathy manifested by a prolonged INR; both of these may worsen the bleeding from gastric varices.In very rare cases, gastric varices are caused by splenic vein occlusion as a result of the mass effect of slow-growing pancreatic neuroendocrine tumors.
Diagnosis
Diagnosis of gastric varices is often made at the time of upper endoscopy.
Classification
The Sarin classification of gastric varices identifies four different anatomical types of gastric varices, which differ in terms of treatment modalities.
Treatment
Initial treatment of bleeding from gastric varices focuses on resuscitation, much as with esophageal varices. This includes administration of fluids, blood products, and antibiotics.Another treatment for gastric varices is injection of the varices with cyanoacrylate, first described by German surgeon Nib Soehendra and colleagues in 1986. The results from two randomized trials comparing band ligation vs cyanoacrylate suggests that endoscopic injection of cyanoacrylate, known as gastric variceal obliteration or GVO is superior to band ligation in preventing rebleeding rates. Cyanoacrylate, a common component in super glue is often mixed 1:1 with lipiodol to prevent polymerization in the endoscopy delivery optics, and to show on radiographic imaging. GVO is usually performed in specialized therapeutic endoscopy centers. Complications include sepsis, embolization of glue, and obstruction from polymerization in the lumen of the stomach.Other techniques for refractory bleeding include:
Transjugular intrahepatic portosystemic shunts (TIPS)
Balloon occluded retrograde transvenous obliteration techniques (BORTO)
Coil-Assisted Retrograde Transvenous Obliteration (CARTO)
Gastric variceal ligation, although this modality is falling out of favour
Intra-gastric balloon tamponade as a bridge to further therapy
a caveat is that a larger balloon is required to occupy the fundus of the stomach where gastric varices commonly occur
Liver transplantation
See also
Gastric antral vascular ectasia
References
== External links == |
Macrocephaly | Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to determine whether the syndrome is accompanied by particular disorders. Those with benign or familial macrocephaly are considered to have megalencephaly.
Causes
Many people with abnormally large heads or large skulls are healthy, but macrocephaly may be pathological. Pathologic macrocephaly may be due to megalencephaly (enlarged brain), hydrocephalus (abnormally increased cerebrospinal fluid), cranial hyperostosis (bone overgrowth), and other conditions. Pathologic macrocephaly is called "syndromic", when it is associated with any other noteworthy condition, and "nonsyndromic" otherwise. Pathologic macrocephaly may be caused by congenital anatomic abnormalities, genetic conditions, or by environmental events.Many genetic conditions are associated with macrocephaly, including familial macrocephaly related to the holgate gene, autism, PTEN mutations such as Cowden disease, neurofibromatosis type 1, and tuberous sclerosis; overgrowth syndromes such as Sotos syndrome (cerebral gigantism), Weaver syndrome, Simpson–Golabi–Behmel syndrome (bulldog syndrome), and macrocephaly-capillary malformation (M-CMTC) syndrome; neurocardiofacial-cutaneous syndromes such as Noonan syndrome, Costello syndrome, Gorlin syndrome, (also known as Basal Cell Nevus Syndrome) and cardiofaciocutaneous syndrome; Fragile X syndrome; leukodystrophies (brain white matter degeneration) such as Alexander disease, Canavan disease, and megalencephalic leukoencephalopathy with subcortical cysts; and glutaric aciduria type 1 and D-2-hydroxyglutaric aciduria.At one end of the genetic spectrum, duplications of chromosomes have been found to be related to autism and macrocephaly; at the other end, deletions of chromosomes have been found to be related to schizophrenia and microcephaly.Environmental events associated with macrocephaly include infection, neonatal intraventricular hemorrhage (bleeding within the infant brain), subdural hematoma (bleeding beneath the outer lining of the brain), subdural effusion (collection of fluid beneath the outer lining of the brain), and arachnoid cysts (cysts on the brain surface).In research, cranial height or brain imaging may be used to determine intracranial volume more accurately.
Below is a list of causes of macrocephaly from Swaimans Pediatric Neurology: Principles and Practice noted in The Little Black Book of Neurology:
Hydrocephalus
Noncommunicating
Arnold–Chiari malformation
Aqueductal stenosis
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) syndrome (L1CAM)
Dandy–Walker malformation
Galenic vein aneurysm or malformation
Neoplasms, supratentorial, and infratentorial
Arachnoid cyst, infratentorial
Holoprosencephaly with dorsal interhemispheric sac
Communicating
External or extraventricular obstructive hydrocephalus (dilated subarachnoid space)
Arachnoid cyst, supratentorial
Meningeal fibrosis/obstruction
Postinflammatory
Posthemorrhagic
Neoplastic infiltration
Vascular
Arteriovenous malformation
Intracranial hemorrhage
Dural sinus thrombosis
Choroid plexus papilloma
Neurocutaneous syndromes
Incontinentia pigmenti
Destructive lesions
Hydranencephaly
Porencephaly
Familial, autosomal-dominant, autosomal-recessive, X-linked
Subdural fluid
Hematoma
Hygroma
Empyema
Brain edema (toxic-metabolic)
Intoxication
Lead
Vitamin A
Tetracycline
Endocrine (hypoparathyroidism, hypoadrenocorticism)
Galactosemia
Idiopathic (pseudotumorcerebri)
Thick skull or scalp (hyperostosis)
Familial variation
Anemia
Osteoporosis, severe precocious autosomal-recessive osteoporosis (CLCN7, TCIRG1)
Pycnodysostosis (CTSK)
Craniometaphyseal dysplasia (ANKH)
Craniodiaphyseal dysplasia
Pyle dysplasia
Sclerosteosis (SOST)
Juvenile Paget disease
Idiopathic hyperphosphatasia
Familial osteoectasia
Osteogenesis imperfecta
Rickets
Cleidocranial dysostosis
Hyperostosis corticalis generalisata (van Buchem disease)
Proteus syndrome
Megalencephaly and hemimegalencephaly
Diagnosis
Macrocephaly is customarily diagnosed if head circumference is greater than two standard deviations (SDs) above the mean. Relative macrocephaly occurs if the measure is less than two SDs above the mean, but is disproportionately above that when ethnicity and stature are considered. Diagnosis can be determined in utero or can be determined within 18–24 months after birth in some cases where head circumference tends to stabilize in infants. Diagnosis in infants includes measuring the circumference of the childs head and comparing how significant it falls above the 97.5 percentile of children similar to their demographic. If falling above the 97.5th percentile then the patient will be checked to determine whether there is any intracranial pressure present and whether or not immediate surgery is needed. If immediate surgery is not needed then further testing will be done to determine whether the patient has either macrocephaly or benign macrocephaly.
Diagnosis for macrocephaly involves the comparison of the infants head circumference to that of other infants of the same age and ethnicity. If a patient is suspected of having macrocephaly molecular testing will be used to confirm diagnosis. Symptoms vary on the cause of macrocephaly on the child and if the child has any other accompanying syndromes which will be determined through molecular testing.
Benign or familial macrocephaly
Benign macrocephaly can occur without reason or be inherited by one or both parents (in which it is considered benign familial macrocephaly and is considered megalencephaly form of macrocephaly). Diagnoses for familial macrocephaly is determined by measuring the head circumference of both parents and comparing it to the childs. Benign and familial macrocephaly is not associated with neurological disorders. While benign and familial macrocephaly does not result in neurological disorders, neurodevelopment will still be assessed.
Although neurological disorders do not occur, temporary symptoms of benign and familial macrocephaly include: developmental delay, epilepsy, and mild hypotonia.Neurodevelopment is assessed for all cases and suspected cases of macrocephaly to determine whether and what treatments may be needed, and whether any other syndrome/s may be present or likely to develop.
Treatment
Treatment varies depending on whether or not it occurs with other medical conditions in the child and where cerebrospinal fluid is present.
If benign and found between the brain and skull then no surgery is needed.
If excess fluid is found between the ventricle spaces in the brain then surgery will be needed.
Associated syndromes
Below is a list of syndromes associated with macrocephaly that are noted in Signs and Symptoms of Genetic Conditions: A Handbook.
Include multiple major and or minor anomalies
Acrocallosal syndrome
Apert syndrome
Bannayan–Riley–Ruvalcaba syndrome
Cardiofaciocutaneous syndrome
Chromosome 14 - maternal disomy
Chromosome 22qter deletion
Cleidocranial dysostosis
Costello syndrome
Encephalocraniocutaneous lipomatosis
FG syndrome
Hallermann–Streiff syndrome
Hydrolethalus syndrome
Hypomelanosis syndrome
Hypomelanosis of Ito
Kelvin Peter anomaly plus syndrome
Lujan–Fryns syndrome
Macrocephaly-CM (MCAP)
Marshall–Smith syndrome
Neuhauser megalocornea/MR syndrome
Neurofibromatosis type I
Nevoid basal-cell carcinoma syndrome
Noonan syndrome
Ocular-ectodermal syndrome
Osteopathia striata - cranial sclerosis
Perlman syndrome
Robinow syndrome
Simpson–Golabi–Behmel syndrome
Sotos syndrome
Sturge–Weber syndrome
Weaver syndrome
Wiedemann–Rautenstrauch syndrome
3C syndrome
Secondary to a metabolic disorder
Glutaric aciduria type II
GM1 gangliosidosis
Hunter syndrome
Hurler syndrome
MPS VII
Sanfilippo syndrome
Zellweger syndrome
Associated with a skeletal dysplasia
Achondroplasia
Campomelic dysplasia
Craniodiaphyseal dysplasia
Craniometaphyseal dysplasia
Hypochondrogenesis
Hypochondroplasia
Kenny-Caffey syndrome
Kniest dysplasia
Lenz–Majewski syndrome
Osteogenesis imperfecta III
Osteopetrosis, autosomal recessive form
Schneckenbecken dysplasia
Sclerosteosis
Short rib syndrome, beemer-langer type
Short rib-polydactyly 2 (majewski type)
Spondyloepiphyseal dysplasia congenita
Thanatophoric dysplasia
With no obvious physical findings
Alexander disease
Canavan disease
Cobalamin deficiency (combined methylmalonic aciduria and homocystinuria)
Dandy–Walker malformation
Glutaric aciduria type 1
L-2-hydroxyglutaric aciduria
Megalencephalic leukoencephalopathy with subcortical cysts
Osteogenesis imperfecta IV
Osteopathia striata-cranial sclerosis
Periventricular heterotopia
Sandhoff disease
Tay–Sachs disease
See also
Microcephaly
Megalencephaly
Hydrocephalus
References
External links
GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS)
GeneReviews/NCBI/NIH/UW entry on 9q22.3 Microdeletion |
Visual release hallucinations | Visual release hallucinations, also known as Charles Bonnet syndrome or CBS, are a type of psychophysical visual disturbance in which a person with partial or severe blindness experiences visual hallucinations.
First described by Charles Bonnet in 1760, the term Charles Bonnet syndrome was first introduced into English-speaking psychiatry in 1982. A related type of hallucination that also occurs with lack of visual input is the closed-eye hallucination.
Signs and symptoms
People with significant vision loss may have vivid recurrent visual hallucinations (fictive visual percepts). One characteristic of these hallucinations is that they usually are "lilliputian" (hallucinations in which the characters or objects are smaller than normal). Depending on the content, visual hallucinations can be classified as either simple or complex. Simple visual hallucinations are commonly characterized by shapes, photopsias, and grid-like patterns. Complex visual hallucinations consist of highly detailed representations of people and objects. The most common hallucination is of faces or cartoons. Sufferers understand that the hallucinations are not real, and the hallucinations are only visual, that is, they do not occur in any other senses (such as hearing, smell or taste). Visual hallucinations generally appear when the eyes are open, fading once the visual gaze shifts. It is widely claimed that sensory deprivation is instrumental in the progression of CBS. During episodes of inactivity, hallucinations are more likely to occur. The majority of those suffering from CBS describe the duration of hallucinations to continue for up to a few minutes, multiple times a day or week.Even though people of all ages may be afflicted by Charles Bonnet syndrome, those within the age range of 70 to 80 are primarily affected. Among older adults (> 65 years) with significant vision loss, the prevalence of Charles Bonnet syndrome has been reported to be between 10% and 40%; a 2008 Australian study found the prevalence to be 17.5%. Two Asian studies, however, report a much lower prevalence. The high incidence of underreporting this disorder is the greatest hindrance to determining the exact prevalence. Underreporting is thought to be a result of sufferers being afraid to discuss the symptoms out of fear that they will be labeled of unsound mind.
Pathophysiology
There is no general consensus on the definition of CBS. Predominant factors correlated with CBS are a decrease of visual acuity, visual field loss, and elderly age. While characteristic features of visual hallucinations are not specifically linked to the anatomical site of the ocular injury, they usually match to the location of visual loss. The most commonly accepted theory for Charles Bonnet Syndrome proposes that extreme visual impairment promotes sensory deafferentation, leading to disinhibition, thus resulting in sudden neural firings of the visual cortical regions. A few studies record that visual hallucinations are likely to be concentrated in the blind regions. Functional magnetic resonance imaging (fMRI) of Charles Bonnet Syndrome patients displays a relationship between visual hallucinations and activity in the ventral occipital lobe. A connection between age-related macular degeneration (AMD) and colored visual hallucinations has been presented. Color vision signals travel through the parvocellular layers of the lateral geniculate nucleus (LGN), later transmitting down the color regions of the ventral visual pathway. Due to cone photoreceptor damage located in the macula, there is a significant reduction of visual input to the visual association cortex, stirring endogenous activation in the color areas and thus leading to colored hallucinations. Patients with CBS alongside macular degeneration exhibit hyperactivity in the color areas of the visual association cortex (as shown in fMRIs). Those who have significant ocular disease yet maintain visual acuity may still be susceptible to CBS.The Deep Boltzmann Machine (DBM) is a way of utilizing an undirected probabilistic process in a neural framework. Researchers argue that the DBM has the ability to model features of cortical learning, perception, and the visual cortex (the locus of visual hallucinations). Compelling evidence details the role homeostatic operations in the cortex play in regards to stabilizing neuronal activity. By using the DBM, researchers show that when sensory input is absent, neuron excitability is influenced, thus potentially triggering complex hallucinations.
A short-term change in the levels of feedforward and feedback flows of information may intensely affect the presence of hallucinations. In periods of drowsiness, CBS related hallucinations are more prone to arise. Disrupting cortical homeostatic processes after vision has been lost may prevent or setback the emergence of hallucinations. At varying stages of the cortical grading, acetylcholine (ACh) may impact the balance of thalamic and intracortical inputs as well as the balance in between bottom-up and top-down. Particularly in CBS, a shortage of acetylcholine at cortical locations should correspond to the onset of hallucinations.The syndrome can also develop after bilateral optic nerve damage due to methyl alcohol poisoning.
Diagnosis
A variety of disciplines including optometry, ophthalmology, geriatric medicine, psychiatry, and neurology play a part in securing the diagnosis of CBS. Since CBS is not commonly recognized by all clinicians, it oftentimes goes misdiagnosed and identified as psychosis, delirium, or dementia. As a result of this, it is estimated that almost 60% of CBS patients hesitate to notify their physicians. By focusing on the specific type of visual hallucination, one may find an accurate diagnosis. If a patient presents symptoms indicative of Charles Bonnet syndrome, basic laboratory examinations like metabolic panel and blood count tests, as well as neuroimaging, may aid in an accurate diagnosis.
Prognosis
There is no treatment of proven effectiveness for CBS. For those experiencing CBS, knowing that they are suffering from this syndrome and not a mental illness seems to be the most comforting treatment so far, as it improves their ability to cope with the hallucinations. As time passes from the initial onset of visual hallucinations, studies show that around 60% of those living with CBS feel that visual hallucinations have no effect on their lives, 33% of people feel that the hallucinations are disruptive to their lives, and 7% of people even find pleasure in the hallucinations.A large proportion of those suffering from CBS develop the visual hallucinations as vision begins to deteriorate and stop hallucinating once vision is entirely gone. Complex hallucinations may progress over time if the primary loss of vision is due to damage of the early cortical areas. If activation of the early cortical areas is suppressed when CBS symptoms have already been exhibited, hallucinations may temporarily terminate. Also, interrupting vision for a short time by closing the eyes or blinking may be helpful.It is possible for a stressful life event to alter the disposition of hallucinatory experiences as well as the emotional experiences (from unconcerning to concerning) in CBS. As expressed in some patients, an interplay between CBS and an acute or post-traumatic stress disorder may exist. The role that trauma plays in CBS may affect how and when a hallucinatory episode is triggered.
History
The disease was first noted by the Swiss naturalist Charles Bonnet, who described the condition in 1760. He documented it in his 90-year-old grandfather who was nearly blind from cataracts in both eyes. After Bonnet’s grandfather received bilateral cataract surgery, his vision evolved from slightly better to complete deterioration over time. It was around this period that his visual hallucinations started. His hallucinations consisted of perceptions of men, women, birds, carriages, buildings, tapestries, physically impossible circumstances and scaffolding patterns. Even though his health was in good shape and he had an absence of any psychiatric disorders, the source of the hallucinations remained unknown. At forty years old, Charles Bonnet himself suffered from an unrevealed cause of severe vision loss and experienced the hallucinations.In 1936, Jean Lhermitte and Julian de Ajuriaguerra, concluded that visual hallucinations consist of thalamic lesions as well as ocular pathology.In 1967, French-Swiss neurologist, Georges de Morsier, coined the term Charles Bonnet Syndrome in Bonnets honor. De Morsier’s description of CBS implies a concentrated neurodegeneration, usually occurring in the elderly with typical cognition. In psychiatric literature, the most commonly accepted interpretation of CBS is that of Gold and Rabins’. In 1989, they detailed that the hallucinations associated with CBS are not affecting other sensory modalities. They believed that the visual hallucinations are oftentimes stereotyped, persistent, and/or repetitive in nature.
Society and culture
The syndrome is discussed in:
Vilayanur S. Ramachandrans book Phantoms in the Brain. Ramachandran suggests that James Thurber, who was blinded in one eye as a child, may have derived his extraordinary imagination from the syndrome.
Vikram Chandras book Sacred Games (2006)
David Eaglemans book Incognito: The Secret Lives of the Brain
Oliver Sacks 2012 book Hallucinations
The Indian movie Jawan of Vellimala, released in 2012, in which Mammootty is a victim of the syndrome
The Black Canvas (2014), a chamber opera by the Greek composer Spyros Syrmos, is about a celebrated painter whose visions are caused by CBS.
Margaret Atwoods short story "Torching the Dusties"
Deborah Lawrensons novel The Lantern (2011)
Gareth Brookes graphic novel A Thousand Coloured Castles (2017)
Dealt, 2017 documentary about notable card mechanic Richard Turner
The 2019 Netflix film Velvet Buzzsaw
See also
Phantom eye syndrome
Musical ear syndrome – Auditory hallucination associated with hearing loss
Ganzfeld effect – Psychological phenomenon
Hypnagogia – State of consciousness leading into sleep
Anton–Babinski syndrome
References
External links
Information on Charles Bonnet syndrome from RNIB
National Public Radio article with an audio segment about Charles Bonnet syndrome
Oliver Sacks: What hallucination reveals about our minds Archived 2013-07-08 at the Wayback Machine Ted Talk, Feb 2009.
Fortean Times article on Charles Bonnet syndrome
Damn Interesting article on Charles Bonnet syndrome
W Burke (2002). "The neural basis of Charles Bonnet hallucinations: a hypothesis". Journal of Neurology, Neurosurgery & Psychiatry. 73 (5): 535–541. doi:10.1136/jnnp.73.5.535. PMC 1738134. PMID 12397147. |
Epiploic appendagitis | Epiploic appendagitis (EA) is an uncommon, benign, self-limiting inflammatory process of the epiploic appendices. Other, older terms for the process include appendicitis epiploica and appendagitis, but these terms are used less now in order to avoid confusion with acute appendicitis.
Epiploic appendices are small, fat-filled sacs or finger-like projections along the surface of the upper and lower colon and rectum. They may become acutely inflamed as a result of torsion (twisting) or venous thrombosis. The inflammation causes pain, often described as sharp or stabbing, located on the left, right, or central regions of the abdomen. There is sometimes nausea and vomiting. The symptoms may mimic those of acute appendicitis, diverticulitis, or cholecystitis. The pain is characteristically intense during/after defecation or micturition (espec. in the sigmoid type) due to the effect of traction on the pedicle of the lesion caused by straining and emptying of the bowel and bladder. Initial lab studies are usually normal. EA is usually diagnosed incidentally on CT scan which is performed to exclude more serious conditions.
Although it is self-limiting, epiploic appendagitis can cause severe pain and discomfort. It is usually thought to be best treated with an anti-inflammatory and a moderate to severe pain medication (depending on the case) as needed. Surgery is not recommended in nearly all cases. Sand and colleagues, however, recommend laparoscopic surgery to excise the inflamed appendage in most cases in order to prevent recurrence.
Signs and symptoms
The condition commonly occurs in patients in their 40s and 50s predominantly in men. Epiploic appendagitis is normally misdiagnosed in most patients. Epiploic appendagitis presents with an acute onset of pain, commonly in the left lower quadrant the symptoms often lead to a misdiagnosis for diverticulitis. Diverticulitis manifests with evenly distributed lower abdominal pain accompanied with nausea, fever, and leukocytosis. Patients with acute epiploic appendagitis do not normally report a change in bowel habits, while a small number may have constipation or diarrhea.
Peritoneal loose body
It is rare however possible for epiploic appendagitis to result in a peritoneal loose body. Peritoneal loose body is a free floating mass of dead fibrous tissue surrounded by several layers of calcification (deposit of calcium salts). The loose body is the result of torsed, infarcted or detached epiploic appendages that eventually become fibrotic (inflammation and scarring) masses. If the loose body becomes large enough it can cause urinary retention (inability to empty bladder) or bowel obstructions.
Background
Epiploic appendages are also called appendices epiploicae. The appendages themselves are 50–100 appendages that are oriented in two rows anterior and posterior. The appendages are parallel to the superficial section of the taenia coli. Furthermore, the appendages are between 0.5 and 5 cm long, each appendage is attached with one or two arterioles and a venule within vascular stalks attached to the colon. Torsion (twisting or wrenching motion) of the appendages can cause ischemia which can cause painful symptoms that mimic other conditions such as diverticulitis, and appendicitis; however, it is rare. The pain associated with the inflamed appendages is located in the left and sometimes in the right lower abdominal quadrant. Diagnosis of epiploic appendagitis can be challenging due to its infrequency.
Diagnosis
Epiploic appendagitis is more common in patients older than 40 years of age; however, it can occur at any age. "The reported ages range from 12 to 82 years. Men are slightly more affected than woman." Patients with epiploic appendicitis describe having a localized, strong, non-migratory sharp pain after eating. Patients generally have tender abdomens as a symptom. Symptoms do not include fever, vomiting, or leukocytosis. The pain is typically located in the right or left lower abdominal quadrant. When there is pain in the right lower quadrant, it can mimic appendicitis; however, it more commonly mimics diverticulitis, with pain present on the left side.
Differential diagnosis
There are several conditions that mimic the symptoms of epiploic appendicitis.
Omental infarction: Omental infarction is uncommon reason for acute abdomen. It is similar to acute appendicitis. The pain is of a few days duration centering in the right lower or upper quadrant. Imaging is required to obtain an accurate diagnosis due to the common misdiagnosis of omental infarction as appendicitis or cholecystitis. Omental infarction occurs commonly in pediatric patients approximately 15 percent of cases. The most frequent cause of non- torsion related omental infarction is due to trauma as well as thrombosis or the omental veins. The predisposition for omental infarction includes obesity, strenuous activity, congestive heart failure, digitalis administration, recent abdominal surgery and trauma. "The typical CT findings are a solitary large non-enhancing omental mass with heterogeneous attenuation, which is most often located in the right lower quadrant, deep to the rectus abdominis muscle and either anterior to the transverse colon or anteromedial to the ascending colon". Omental Infarction can be difficult to differentiate from diverticulitis however omental infarction is not normally attributed with bowel wall thickening. It is rare that the colonic wall will be thickened due to spread of the inflammation from the omentum (a fold of peritoneum connecting or supporting abdominal structures) to the tenia omentalis of the colon.Diverticulitis: Diverticulitis normally happens in older patients than in epiploic appendagitis. The two inflammatory conditions are quite indistinguishable based on physical manifestations. Patients with diverticulitis will present with nausea, vomiting, fever, elevated leukocyte count rebound tenderness, and will have more extensive lower abdominal pain than patients with epiploic appendagitis. Additionally inflammation from diverticulitis may spread to the epiploic appendages making it difficult to diagnose, for inflammation of the appendices epiploicae may be resultant to other inflammatory conditions in the colonic wall and surrounding mesocolon.
Radiologic evaluation
Ultrasound and CT scans are the normal means of positive diagnosis of Epiploic Appendagitis. Ultrasound scans show "an oval, non-compressible hyperechoic mass with a subtle hypoechoic rim directly under the site of maximum tenderness". Normally, epiploic appendages cannot be seen on CT scan. After cross-sectional imaging and the increased use of abdominal CT for evaluating lower abdominal pain, EA is increasingly diagnosed. Pathognomonic CT scan data represent EA as 2–4 cm, oval shaped, fat density lesions, surrounded by inflammation. Contrasting with diverticulitis findings, the colonic wall is mostly unchanged.
Management
Epiploic appendagitis is self-limiting and can be managed conservatively with NSAIDs.
Epidemiology
Acute epiploic appendigitis is usually associated with obesity, hernia and unaccustomed exercise. The inflammation of the epiploic appendages normally resolves on its own for most patients. It is possible however uncommon for acute epiploic appendigitis to result in adhesion, bowel obstruction, intussusception, intraperitoneal loose body, peritonitis, and/or abscess formation. Treatment consists of reassurance of the patient and analgesics. Under non invasive treatment, symptoms resolve in two weeks. Hospitalization is not necessary.
References
== External links == |
Psoriatic arthritis | Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. This often happens in association with changes to the nails such as small depressions in the nail (pitting), thickening of the nails, and detachment of the nail from the nailbed. Skin changes consistent with psoriasis (e.g., red, scaly, and itchy plaques) frequently occur before the onset of psoriatic arthritis but psoriatic arthritis can precede the rash in 15% of affected individuals. It is classified as a type of seronegative spondyloarthropathy.
Genetics are thought to be strongly involved in the development of psoriatic arthritis. Obesity and certain forms of psoriasis are thought to increase the risk.Psoriatic arthritis affects up to 30% of people with psoriasis and occurs in both children and adults. Approximately 40–50% of individuals with psoriatic arthritis have the HLA-B27 genotype. The condition is less common in people of Asian or African descent and affects men and women equally.
Signs and symptoms
Pain, swelling, or stiffness in one or more joints is commonly present in psoriatic arthritis. Psoriatic arthritis is inflammatory, and affected joints are generally red or warm to the touch. Asymmetrical oligoarthritis, defined as inflammation affecting two to four joints during the first six months of disease, is present in 70% of cases. However, in 15% of cases, the arthritis is symmetrical. The joints of the hand that is involved in psoriasis are the proximal interphalangeal (PIP), the distal interphalangeal (DIP), the metacarpophalangeal (MCP), and the wrist. Involvement of the distal interphalangeal joints (DIP) is a characteristic feature and is present in 15% of cases.
In addition to affecting the joints of the hands and wrists, psoriatic arthritis may affect the fingers, nails, and skin. Sausage-like swelling in the fingers or toes, known as dactylitis, may occur. Psoriasis can also cause changes to the nails, such as pitting or separation from the nail bed, onycholysis, hyperkeratosis under the nails, and horizontal ridging. Psoriasis classically presents with scaly skin lesions, which are most commonly seen over extensor surfaces such as the scalp, natal cleft and umbilicus.
In psoriatic arthritis, pain can occur in the area of the sacrum (the lower back, above the tailbone), as a result of sacroiliitis or spondylitis, which is present in 40% of cases. Pain can occur in and around the feet and ankles, especially enthesitis in the Achilles tendon (inflammation of the Achilles tendon where it inserts into the bone) or plantar fasciitis in the sole of the foot.Along with the above-noted pain and inflammation, there is extreme exhaustion that does not go away with adequate rest. The exhaustion may last for days or weeks without abatement. Psoriatic arthritis may remain mild or may progress to more destructive joint disease. Periods of active disease, or flares, will typically alternate with periods of remission. In severe forms, psoriatic arthritis may progress to arthritis mutilans which on X-ray gives a "pencil-in-cup" appearance.Because prolonged inflammation can lead to joint damage, early diagnosis and treatment to slow or prevent joint damage is recommended.
Causes
The exact causes are not yet known, however silica dust exposure has been identified in Australia and a number of genetic associations have been identified in a genome-wide association study of psoriasis and psoriatic arthritis including HLA-B27.
Diagnosis
There is no definitive test to diagnose psoriatic arthritis. Symptoms of psoriatic arthritis may closely resemble other diseases, including rheumatoid arthritis. A rheumatologist (a physician specializing in autoimmune diseases) may use physical examinations, health history, blood tests and x-rays to accurately diagnose psoriatic arthritis.
Factors that contribute to a diagnosis of psoriatic arthritis include the following:
Psoriasis in the patient, or a family history of psoriasis or psoriatic arthritis.
A negative test result for rheumatoid factor, a blood factor associated with rheumatoid arthritis.
Arthritis symptoms in the distal Interphalangeal articulations of hand (the joints closest to the tips of the fingers). This is not typical of rheumatoid arthritis.
Ridging or pitting of fingernails or toenails (onycholysis), which is associated with psoriasis and psoriatic arthritis.
Radiologic images demonstrating degenerative joint changes.Other symptoms that are more typical of psoriatic arthritis than other forms of arthritis include enthesitis (inflammation in the Achilles tendon (at the back of the heel) or the plantar fascia (bottom of the feet)), and dactylitis (sausage-like swelling of the fingers or toes).
Differential diagnosis
Several conditions can mimic the clinical presentation of psoriatic arthritis including rheumatoid arthritis, osteoarthritis, reactive arthritis, gouty arthritis, systemic lupus erythematosus, and inflammatory bowel disease-associated arthritis. In contrast to psoriatic arthritis, rheumatoid arthritis tends to affect the proximal joints (e.g., the metacarpophalangeal joints), involves a greater number of joints than psoriatic arthritis, and affect them symmetrically. Involvement of the spinal joints is more suggestive of psoriatic arthritis than rheumatoid arthritis. Osteoarthritis shares certain clinical features with psoriatic arthritis such as its tendency to affect multiple distal joints in an asymmetric pattern. Unlike psoriatic arthritis, osteoarthritis does not typically involve inflammation of the sacroiliac joint. Psoriatic arthritis sometimes affects only one joint and is sometimes confused for gout or pseudogout when this happens.
Classification
There are five main types of psoriatic arthritis:
Oligoarticular: This type affects around 70% of patients and is generally mild. This type does not occur in the same joints on both sides of the body and usually only involves fewer than 3 joints.
Polyarticular: This type accounts for around 25% of cases, and affects five or more joints on both sides of the body simultaneously. This type is most similar to rheumatoid arthritis and is disabling in around 50% of all cases.
Arthritis mutilans (M07.1): Affects less than 5% of patients and is a severe, deforming and destructive arthritis. This condition can progress over months or years causing severe joint damage. Arthritis mutilans has also been called chronic absorptive arthritis, and may be seen in rheumatoid arthritis as well.
Spondyloarthritis (M07.2): This type is characterized by stiffness of the neck or the sacroiliac joint of the spine, but can also affect the hands and feet, in a similar fashion to symmetric arthritis.
Distal interphalangeal predominant (M07.0): This type of psoriatic arthritis is found in about 5% of patients, and is characterized by inflammation and stiffness in the joints nearest to the ends of the fingers and toes. Nail changes are often marked.
Treatments
The underlying process in psoriatic arthritis is inflammation; therefore, treatments are directed at reducing and controlling inflammation. Milder cases of psoriatic arthritis may be treated with NSAIDs alone; however, there is a trend toward earlier use of disease-modifying antirheumatic drugs or biological response modifiers to prevent irreversible joint destruction.
Nonsteroidal anti-inflammatory drugs
Typically the medications first prescribed for psoriatic arthritis are NSAIDs such as ibuprofen and naproxen, followed by more potent NSAIDs like diclofenac, indomethacin, and etodolac. NSAIDs can irritate the stomach and intestine, and long-term use can lead to gastrointestinal bleeding. Coxibs (COX-2 inhibitors) e.g. Celecoxib or Etoricoxib, are associated with a statistically significant 50 to 66% relative risk reduction in gastrointestinal ulcers and bleeding complications compared to traditional NSAIDs, but carry an increased rate of cardiovascular events such as myocardial infarction (MI) or heart attack, and stroke. Both COX-2 inhibitors and other non-selective NSAIDS have potential adverse effects that include damage to the kidneys.
Disease-modifying antirheumatic drugs
These are used in persistent symptomatic cases without exacerbation. Rather than just reducing pain and inflammation, this class of drugs helps limit the amount of joint damage that occurs in psoriatic arthritis. Most DMARDs act slowly and may take weeks or even months to take full effect. Drugs such as methotrexate or leflunomide are commonly prescribed; other DMARDS used to treat psoriatic arthritis include cyclosporin, azathioprine, and sulfasalazine. According to a recent Cochrane review, low dose oral methotrexate was slightly more effective than placebos. Immunosuppressant drugs can also reduce psoriasis skin symptoms but can lead to liver and kidney problems and an increased risk of serious infection.
Biological response modifiers
A new class of therapeutics called biological response modifiers or biologics has been developed using recombinant DNA technology. Biologic medications are derived from living cells cultured in a laboratory. Unlike traditional DMARDS that affect the entire immune system, biologics target specific parts of the immune system. They are given by injection or intravenous (IV) infusion.
Biologics prescribed for psoriatic arthritis are TNF-α inhibitors, including infliximab, etanercept, golimumab, certolizumab pegol and adalimumab, as well as the IL-12/IL-23 inhibitor ustekinumab, and the IL-17a inhibitor secukinumab. Recently, the Jak inhibitor, tofacitinib (Xeljanz), was approved for the use in active psoriatic arthritis.Biologics may increase the risk of minor and serious infections. More rarely, they may be associated with nervous system disorders, blood disorders or certain types of cancer.
Phosphodiesterase-4 inhibitors
A first-in-class treatment option for the management of psoriatic arthritis is apremilast; a small molecule phosphodiesterase-4 inhibitor approved for use by the FDA in 2014. By inhibiting PDE4, an enzyme which breaks down cyclic adenosine monophosphate, cAMP levels rise, resulting in the down-regulation of various pro-inflammatory factors including TNF-α, interleukin 17 and interleukin 23, as well as the up-regulation of anti-inflammatory factor interleukin 10.
It is given in tablet form and taken by mouth. Side effects include headaches, back pain, nausea, diarrhea, fatigue, nasopharyngitis and upper respiratory tract infections, as well as depression and weight loss.
It was patented in 2014 and manufactured by Celgene. There is no current generic equivalent available on the market.
Other treatments
A review found tentative evidence of benefit of low level laser therapy and concluded that it could be considered for relief of pain and stiffness associated RA.Retinoid etretinate is effective for both arthritis and skin lesions. Photochemotherapy with methoxy psoralen and long-wave ultraviolet light (PUVA) are used for severe skin lesions. Doctors may use joint injections with corticosteroids in cases where one joint is severely affected. In psoriatic arthritis patients with severe joint damage orthopedic surgery may be implemented to correct joint destruction, usually with the use of a joint replacement. Surgery is effective for pain alleviation, correcting joint disfigurement, and reinforcing joint usefulness and strength.
Epidemiology
Seventy percent of people who develop psoriatic arthritis first show signs of psoriasis on the skin, 15 percent develop skin psoriasis and arthritis at the same time, and 15 percent develop skin psoriasis following the onset of psoriatic arthritis.Psoriatic arthritis can develop in people who have any level severity of psoriatic skin disease, ranging from mild to very severe.Psoriatic arthritis tends to appear about 10 years after the first signs of psoriasis. For the majority of people, this is between the ages of 30 and 55, but the disease can also affect children. The onset of psoriatic arthritis symptoms before symptoms of skin psoriasis is more common in children than adults.More than 80% of patients with psoriatic arthritis will have psoriatic nail lesions characterized by nail pitting, separation of the nail from the underlying nail bed, ridging and cracking, or more extremely, loss of the nail itself (onycholysis).Enthesitis is observed in 30 to 50% of patients and most commonly involves the plantar fascia and Achilles’ tendon, but it may cause pain around the patella, iliac crest, epicondyles, and supraspinatus insertionsMen and women are equally affected by this condition. Like psoriasis, psoriatic arthritis is more common among Caucasians than African or Asian people.
References
External links
Psoriatic Arthritis at Patient.info
Guidelines of care for the management of psoriasis and psoriatic arthritis—National Guideline Clearinghouse
US National Institute of Arthritis and Musculoskeletal and Skin Diseases |
Visceroptosis | Visceroptosis is a prolapse or a sinking of the abdominal viscera (internal organs) below their natural position. "Ptosis" being the defining term, any or all of the organs may be displaced downward. When only the intestines are involved, the condition is known as enteroptosis. When the stomach is found below its normal position, the term gastroptosis is used. The condition exists in all degrees of severity and may not give rise to any adverse symptoms.
Generally, when adverse symptoms are associated with the condition, however, there may be loss of appetite, heartburn, nervous indigestion, constipation, diarrhea, abdominal distention, headache, vertigo, emaciation, and loss of sleep. Any or all of these symptoms may be present.
The condition may be brought about by loss of muscular tone, particularly of the abdominal muscles, with relaxation of the ligaments that typically hold the viscera in place. Tightlacing has been held to be a cause as well. Corsets to reduce the circumference of womens waists have been used to enable fashionable styles occurring during several historical periods, such as the late 1800s and early 1900s, when these symptoms were described for treatment by physicians.
Adverse symptoms may be alleviated by supporting the organs with a properly applied bandage, or other similar device. Rest in bed, attention to diet, hygiene, exercise, and general muscular strengthening will cure the majority of cases. In some cases, surgical intervention may become necessary.Visceroptosis is a known risk factor for the development of Superior mesenteric artery syndrome.
Visceroptosis also is known as Glénards disease (after French physician Frantz Glénard [1848–1920]).
Glénards theory – the theory that abdominal ptosis is a nutritional disease with atrophy and prolapse of the intestine
Glénards test (also called girdle test) – while standing behind the patient, the examiner places his arms around the patient, so that his hands meet in front of the patients abdomen; he squeezes, raising the viscera, and then allows them to fall suddenly; Glénards theory suggests that if the patient feels relieved by the raising pressure and experiences distress on the release, the condition is probably one of splanchnoptosis
Stillers theory – the theory that gastroptosis is due to universal asthenia characterized by weakness and laxity of the viscera
References
External links
This article incorporates text from a publication now in the public domain: Gilman, D. C.; Peck, H. T.; Colby, F. M., eds. (1905). New International Encyclopedia (1st ed.). New York: Dodd, Mead. {{cite encyclopedia}}: Missing or empty |title= (help) |
Lamellar ichthyosis | Lamellar ichthyosis, also known as ichthyosis lamellaris and nonbullous congenital ichthyosis, is a rare inherited skin disorder, affecting around 1 in 600,000 people.
Presentation
Affected babies are born in a collodion membrane, a shiny, waxy-appearing outer layer to the skin. This is shed 10–14 days after birth, revealing the main symptom of the disease, extensive scaling of the skin caused by hyperkeratosis.
With increasing age, the scaling tends to be concentrated around joints in areas such as the groin, the armpits, the inside of the elbow and the neck. The scales often tile the skin and may resemble fish scales.
Collodion baby
In medicine, the term collodion baby applies to newborns who appear to have an extra layer of skin (known as a collodion membrane) that has a collodion-like quality. It is a descriptive term, not a specific diagnosis or disorder (as such, it is a syndrome).
Appearance and treatment at birth
The appearance is often described as a shiny film looking like a layer of Vaseline. The eyelids and mouth may have the appearance of being forced open due to the tightness of the skin. There can be associated eversion of the eyelids (ectropion).
Collodion babies can have severe medical consequences, mainly because the baby can lose heat and fluid through the abnormal skin. This can lead to hypothermia and dehydration. Strategies to prevent these problems are the use of emollients or nursing the baby in a humidified incubator. There is also an increased risk of skin infection and mechanical compression, leading to problems like limb ischemia. There is also a risk of intoxication by cutaneous absorption of topical products, for example salicylate intoxication (similar to aspirin overdose) due to keratolytics.The condition is not thought to be painful or in itself distressing to the child. Nursing usually takes place in a neonatal intensive care unit, and good intensive care seems to have improved the prognosis markedly. The collodion membrane should peel off or "shed" 2 to 4 weeks after birth, revealing the underlying skin disorder.
The condition can resemble but is different from harlequin type ichthyosis.
Long term course
The appearance can be caused by several skin diseases, and it is most often not associated with other birth defects. In most cases, the baby develops an ichthyosis or ichthyosis-like condition or other rare skin disorder.
Most cases (approximately 75%) of collodion baby will go on to develop a type of autosomal recessive congenital ichthyosis (either lamellar ichthyosis or congenital ichthyosiform erythrodema).In around 10% of cases the baby sheds this layer of skin and has normal skin for the rest of its life. This is known as self-healing collodion baby.
The remaining 15% of cases are caused by a variety of diseases involving keratinization disorders. Known causes of collodion baby include ichthyosis vulgaris and trichothiodystrophy. Less well documented causes include Sjögren-Larsson syndrome, Netherton syndrome, Gaucher disease type 2, congenital hypothyroidism, Conradi syndrome, Dorfman-Chanarin syndrome, ketoadipiaciduria, koraxitrachitic syndrome, ichthyosis variegata and palmoplantar keratoderma with anogenital leukokeratosis. Since many of these conditions have an autosomal recessive inheritance pattern, they are rare and can be associated with consanguinity.Tests that can be used to find the cause of collodion baby include examination of the hairs, blood tests and a skin biopsy.
Associated medical problems
Overheating: The scaling of the skin prevents normal sweating so hot weather and/or vigorous exercise can cause problems.
Eye problems: The eyelids can be pulled down by the tightness of the skin and this can make eyelids (but usually just the lower one) very red and they are prone to drying and irritation.
Constriction bands: Very rarely children with this condition can have tight bands of skin around their fingers or toes (usually at the tips) that can prevent proper blood circulation to the area.
Hair loss: Severe scaling of the skin on the scalp can lead to patchy loss of hair, but this is rarely permanent.
Genetics
This condition is an autosomal recessive genetic disorder,: 561 which means the defective gene is located on an autosome, and both parents must carry one copy of the defective gene in order to have a child born with the disorder. Carriers of a recessive gene usually do not show any signs or symptoms of the disorder.
One form of ichthyosis lamellaris (LI1) is associated with a deficiency of the enzyme keratinocyte transglutaminase.
Genes involved include:
Diagnosis
Treatments
As with all types of ichthyosis, there is no cure but the symptoms can be relieved.
Moisturizers
Prevention of overheating
Eye drops (to prevent the eyes from becoming dried out)
Systemic Retinoids (isotretinoin and acitretin are very effective, but careful monitoring for toxicity is required. Only severe cases may require intermittent therapy.)Psychological therapy or support may be required as well.
Ophthalmology Consult
ENT consult
Adequate nutrition
Monitor electrolytes < Collodion baby: An update with a focus on practical management. Renata Prado MD, Lixia Z Ellis MD, PhD, Ryan Gamble MD, Tracy Funk MD, Harvey Alan Arbuckle MD, Anna L Bruckner. Journal of the American Academy of Dermatology 2012;67:1362-1374>
See also
Ichthyosis
Congenital ichthyosiform erythrodema
Bullous congenital ichthyosiform erythroderma
References
== External links == |
Myxobolus cerebralis | Myxobolus cerebralis is a myxosporean parasite of salmonids (salmon, trout, and their allies) that causes whirling disease in farmed salmon and trout and also in wild fish populations. It was first described in rainbow trout in Germany a century ago, but its range has spread and it has appeared in most of Europe (including Russia), the United States, South Africa, Canada and other countries. In the 1980s, M. cerebralis was found to require a tubificid oligochaete (a kind of segmented worm) to complete its life cycle. The parasite infects its hosts with its cells after piercing them with polar filaments ejected from nematocyst-like capsules.
Whirling disease affects juvenile fish (fingerlings and fry) and causes skeletal deformation and neurological damage. Fish "whirl" forward in an awkward, corkscrew-like pattern instead of swimming normally, find feeding difficult, and are more vulnerable to predators. The mortality rate is high for fingerlings, up to 90% of infected populations, and those that do survive are deformed by the parasites residing in their cartilage and bone. They act as a reservoir for the parasite, which is released into water following the fishs death. M. cerebralis is one of the most economically important myxozoans in fish, as well as one of the most pathogenic. It was the first myxosporean whose pathology and symptoms were described scientifically. The parasite is not transmissible to humans.
Taxonomy
The taxonomy and naming of both M. cerebralis, and of myxozoans in general, have complicated histories. It was originally thought to infect fish brains (hence the specific epithet cerebralis) and nervous systems, though it soon was found to primarily infect cartilage and skeletal tissue. Attempts to change the name to Myxobolus chondrophagus, which would more accurately describe the organism, failed because of nomenclature rules. Later, the organisms previously called Triactinomyxon dubium and T. gyrosalmo (class Actinosporea) were found to be, in fact, triactinomyxon stages of M. cerebralis, the life cycle of which was expanded to include the triactinomyxon stage. Similarly, other actinosporeans were folded into the life cycles of various myxosporeans.Today, the myxozoans, previously thought to be multicellular protozoans, are considered animals by most scientists, though their status has not officially changed. Recent molecular studies suggest they are related to Bilateria or Cnidaria, with Cnidaria being closer morphologically because both groups have extrusive filaments. Bilateria were somewhat closer in some genetic studies, but those were found to have used samples that were contaminated by material from the host organism, and a 2015 study confirms they are cnidarians.
Morphology
M. cerebralis has many diverse stages ranging from single cells to relatively large spores, not all of which have been studied in detail.
Triactinomyxon stage
The stages that infect fish, called triactinomyxon spores, are made of a single style that is about 150 micrometers (μm) long and three processes or "tails", each about 200 micrometers long. A sporoplasm packet at the end of the style contains 64 germ cells surrounded by a cellular envelope. There are also three polar capsules, each of which contains a coiled polar filament between 170 and 180 μm long. Polar filaments in both this stage and in the myxospore stage (see picture above) rapidly shoot into the body of the host, creating an opening through which the sporoplasm can enter.
Sporoplasm stage
Upon contact with fish hosts and firing of the polar capsules, the sporoplasm contained within the central style of the triactinomyxon migrates into the epithelium or gut lining. Firstly, this sporoplasm undergoes mitosis to produce more amoeboid cells, which migrate into deeper tissue layers, to reach the cerebral cartilage.
Myxosporean stage
Myxospores, which develop from sporogonic cell stages inside fish hosts, are lenticular. They have a diameter of about 10 micrometers and are made of six cells. Two of these cells form polar capsules, two merge to form a binucleate sporoplasm, and two form protective valves. Myxospores are infective to oligochaetes, and are found among the remains of digested fish cartilage. They are often difficult to distinguish from related species because of morphological similarities across genera. Though M. cerebralis is the only myxosporean ever found in salmonid cartilage, other visually similar species may be present in the skin, nervous system, or muscle.
Life cycle
Myxobolus cerebralis has a two-host life cycle involving a salmonid fish and a tubificid oligochaete. So far, the only worm known to be susceptible to M. cerebralis infection is Tubifex tubifex, though what scientists currently call T. tubifex may in fact be more than one species. First, myxospores are ingested by tubificid worms. In the gut lumen of the worm, the spores extrude their polar capsules and attach to the gut epithelium by polar filaments. The shell valves then open along the suture line and the binucleate germ cell penetrates between the intestinal epithelial cells of the worm. This cell multiplies, producing many amoeboid cells by an asexual cell fission process called merogony. As a result of the multiplication process, the intercellular space of the epithelial cells in more than 10 neighbouring worm segments may become infected.Around 60–90 days postinfection, sexual cell stages of the parasite undergo sporogenesis, and develop into pansporocysts, each of which contains eight triactinomyxon-stage spores. These spores are released from the oligochaete anus into the water. Alternatively, a fish can become infected by eating an infected oligochaete. Infected tubificids can release triactinomyxons for at least a year. The triactinomyxon spores are carried by the water currents, where they can infect a salmonid through the skin. Penetration of the fish by these spores takes only a few seconds. Within five minutes, a sac of germ cells called a sporoplasm has entered the fish epidermis, and within a few hours, the sporoplasm splits into individual cells that will spread through the fish.Within the fish, both intracellular and extracellular stages reproduce in its cartilage by asexual endogeny, meaning new cells grow from within old cells. The final stage within the fish is the creation of the myxospore, which is formed by sporogony. They are released into the environment when the fish decomposes or is eaten. Some recent research indicates some fish may expel viable myxospores while still alive.Myxospores are extremely tough: "it was shown that Myxobolus cerebralis spores can tolerate freezing at −20°C for at least 3 months, aging in mud at 13°C for at least 5 months, and passage through the guts of northern pike Esox lucius or mallards Anas platyrhynchos without loss of infectivity" to worms. Triactinomyxons are much shorter-lived, surviving 34 days or less, depending on temperature.
Pathology
M. cerebralis infections have been reported from a wide range of salmonid species: eight species of "Atlantic" salmonids, Salmo; four species of "Pacific" salmonids, Oncorhynchus; four species of char, Salvelinus; the grayling, Thymallus thymallus; and the huchen, Hucho hucho. M. cerebralis causes damage to its fish hosts through attachment of triactinomyxon spores and the migrations of various stages through tissues and along nerves, as well as by digesting cartilage. The fishs tail may darken, but aside from lesions on cartilage, internal organs generally appear healthy. Other symptoms include skeletal deformities and "whirling" behavior (tail-chasing) in young fish, which was thought to have been caused by a loss of equilibrium, but is actually caused by damage to the spinal cord and lower brain stem. Experiments have shown that fish can kill Myxobolus in their skin (possibly using antibodies), but that the fish do not attack the parasites once they have migrated to the central nervous system. This response varies from species to species.In T. tubifex, the release of triactinomyxon spores from the intestinal wall damages the worms mucosa; this may happen thousands of times in a single worm, and is believed to impair nutrient absorption. Spores are released from the worm almost exclusively when the temperature is between 10 °C and 15 °C, so fish in warmer or cooler waters are less likely to be infected, and infection rates vary seasonally.
Susceptibility
Fish size, age, concentration of triactinomyxon spores, and water temperature all affect infection rates in fish, as does the species of the fish in question. The disease has the most impact on fish less than five months old because their skeletons have not ossified. This makes young fish more susceptible to deformities and provides M. cerebralis more cartilage on which to feed. In one study of seven species of many strains, brook trout and rainbow trout (except one strain) were far more heavily affected by M. cerebralis after two hours of exposure than other species were, while bull trout, Chinook salmon, brown trout, and Arctic grayling were least severely affected. While brown trout may harbor the parasite, they typically do not show any symptoms, and this species may have been M. cerebralis original host. This lack of symptoms in brown trout meant that the parasite was only discovered after nonnative rainbow trouts were introduced in Europe.
Diagnosis
Moderate or heavy clinical infection of fish with whirling disease can be presumptively diagnosed on the basis of changes in behavior and appearance about 35 to 80 days after initial infection, though "injury or deficiency in dietary tryptophan and ascorbic acid can evoke similar signs", so conclusive diagnosis may require finding myxospores in the fishs cartilage. In heavy infections, only examining cartilage microscopically may be necessary to find spores. In less severe infections, the most common test involves digestion of the cranial cartilage with the proteases pepsin and trypsin (pepsin-trypsin digest—PTD) before looking for spores. The head and other tissues can be further examined using histopathology to confirm whether the location and morphology of the spores matches what is known for M. cerebralis. Serological identification of spores in tissue sections using an antibody raised against the spores is also possible. Parasite identity can also be confirmed using polymerase chain reaction to amplify the 415 base pair 18S rRNA gene from M. cerebralis. Fish should be screened at the life stage most susceptible to the parasites, with particular focus on fish in aquaculture units.
Impact
Although originally a mild pathogen of Salmo trutta in central Europe and other salmonids in northeast Asia, the introduction of the rainbow trout (Oncorhynchus mykiss) has greatly increased the impact of this parasite. Having no innate immunity to M. cerebralis, rainbow trout are particularly susceptible, and can release so many spores that even more resistant species in the same area, such as S. trutta, can become overloaded with parasites and incur 80%–90% mortalities. Where M. cerebralis has become well-established, it has caused decline or even elimination of whole cohorts of fish.
Impact in Europe
The impact of M. cerebralis in Europe is somewhat lessened because the species is endemic to this region, giving native fish stocks a degree of immunity. Rainbow trout, the most susceptible species to this parasite, are not native to Europe; successfully reproducing feral populations are rare, so few wild rainbow trout are young enough to be susceptible to infection. On the other hand, they are widely reared for restocking sport-fishing waters and for aquaculture, where this parasite has its greatest impact. Hatching and rearing methods designed to prevent infection of rainbow trout fry have proved successful in Europe. These techniques include hatching eggs in spore-free water and rearing fry to the "ossification" stage in tanks or raceways. These methods give particular attention to the quality of water sources to guard against spore introduction during water exchanges. Fry are moved to earthen ponds only once they are considered to be clinically resistant to the parasite, after skeletal ossification occurs.
Impact in New Zealand
M. cerebralis was first found in New Zealand in 1971. The parasite has only been found in rivers in the South Island, away from the most important aquaculture sites. Additionally, salmonid species commercially aquacultured in New Zealand have low susceptibility to whirling disease, and the parasite has also not been shown to affect native salmonids. An important indirect effect of the parasites presence is quarantine restriction placed on exports of salmon products to Australia.
Impact in the United States
M. cerebralis was first recorded in North America in 1956 in Pennsylvania, having been introduced via infected trout imported from Europe, and has spread steadily south and westwards. Until the 1990s, whirling disease was considered a manageable problem affecting rainbow trout in hatcheries. However, it has recently become established in natural waters of the Rocky Mountain states (Colorado, Wyoming, Utah, Montana, Idaho, New Mexico), where it is causing heavy mortalities in several sportfishing rivers. Some streams in the western United States have lost 90% of their trout. In addition, whirling disease threatens recreational fishing, which is important for the tourism industry, a key component of the economies of some U.S. western states. For example, "the Montana Whirling Disease Task Force estimated trout fishing generated US $300,000,000 in recreational expenditures in Montana alone". Making matters worse, some of the fish species that M. cerebralis infects (bull trout, cutthroat trout, and steelhead) are already threatened or endangered, and the parasite could worsen their already precarious situations. For reasons that are poorly understood, but probably have to do with environmental conditions, the impact on infected fish has been greatest in Colorado and Montana, and least in California, Michigan, and New York.
Impact in Canada
Whirling disease was first detected in fish in Johnson Lake in Banff National Park in May, 2016. CFIA Labs confirmed in August and Parks Canada announced the outbreak August 23, 2016. Although it was first discovered in Banff, it is not necessarily where the disease originated and spread. The Government of Alberta is currently sampling and testing fish in 6 different watersheds (Peace River, Athabasca, North Saskatchewan, Red Deer, Bow and Oldman) to see where the disease has spread. Initial sample fish were collected in 2016, and are currently being processed by the Government of Alberta and CFIA labs. Since testing began, it has been detected in the Upper Bow River, and in May 2017 it was confirmed that whirling disease had also been detected in the Oldman River Basin. The declaration does not mean that every susceptible finfish population within the Bow and Oldman River watersheds are infected with the disease.As a result of the new declaration, a domestic movement permit will be required from the CFIA for susceptible species and end uses identified in the Domestic Movement Control Program, the vector Tubifex tubifex, the disease causing agent Myxobolus cerebralis, and/or related things out of the infected and buffer areas of Alberta. Recreational and sport fishing, including fishing led by a professional guide, will not require a CFIA permit.
Prevention and control
Some biologists have attempted to disarm triactinomyxon spores by making them fire prematurely. In the laboratory, only extreme acidity or basicity, moderate to high concentrations of salts, or electric current caused premature filament discharge; neurochemicals, cnidarian chemosensitizers, and trout mucus were ineffective, as were anesthetized or dead fish. If spores could be disarmed, they would be unable to infect fish, but further research is needed to find an effective treatment.Some strains of fish are more resistant than others, even within species; using resistant strains may help reduce the incidence and severity of whirling disease in aquaculture. There is also some circumstantial evidence that fish populations can develop resistance to the disease over time. Additionally, aquaculturists may avoid M. cerebralis infections by not using earthen ponds for raising young fish; this keeps them away from possibly infected tubificids and makes it easier to eliminate spores and oligochaetes through filtration, chlorination, and ultraviolet bombardment. To minimise tubificid populations, techniques include periodic disinfection of the hatchery or aquaculture ponds, and the rearing of small trout indoors in pathogen-free water. Smooth-faced concrete or plastic-lined raceways that are kept clean and free of contaminated water keep aquaculture facilities free of the disease.Lastly, some drugs, such as furazolidone, furoxone, benomyl, fumagillin, proguanil and clamoxyquine, have been shown to impede spore development, which reduces infection rates. For example, one study showed that feeding fumagillin to O. mykiss reduced the number of infected fish from between 73% and 100% to between 10% and 20%. Unfortunately, this treatment is considered unsuitable for wild trout populations, and no drug treatment has ever been shown to be effective in the studies required for United States Food and Drug Administration approval.Recreational and sports fishers can help to prevent the spread of the parasite by not transporting fish from one body of water to another, not disposing of fish bones or entrails in any body of water, and ensuring boots and shoes are clean before moving between different bodies of water. Federal, state, provincial, and local regulations on the use of bait should be followed.
See also
Ceratomyxa shasta – another pathogenic myxosporean parasite of salmonids
Infectious salmon anemia (ISA) – a viral infection of Atlantic salmon
Kudoa thyrsites – a myxosporean parasite of many species, which causes fish tissues to liquefy on death
Tetracapsuloides bryosalmonae – the enigmatic myxosporean which causes "proliferative kidney disease" in salmonids
Salmonid susceptibility to whirling disease
Notes
External links
Report of the World Trade Organization on Australian restrictions on salmon imports
The Whirling Disease Initiative
Whirling disease maps and data
Species Profile- Whirling Disease (Myxobolus cerebralis), National Invasive Species Information Center, United States National Agricultural Library, lists general information and resources for whirling disease
Whirling Disease - Yellowstone National Park (U.S. National Park Service)
Whirling Disease - Stop Aquatic Hitchhikers
Whirling disease - Utah Division of Wildlife Resources
Colorado Parks & Wildlife - Whirling Disease and Colorados Trout
What is Whirling Disease? - North Central Regional Aquaculture Center - Mohamed Faisal - Donald Garling
Whirling disease | Alberta.ca |
Sclerema neonatorum | Sclerema neonatorum is a rare and severe skin condition that is characterized by diffuse hardening of the subcutaneous tissue with minimal inflammation. It usually affects premature, ill newborns. Prognosis is poor.
Minimal inflammation helps distinguish sclerema neonaturum from subcutaneous fat necrosis of the newborn.
See also
Panniculitis
Skin lesion
List of cutaneous conditions
References
== External links == |
Chorea | Chorea (or choreia, occasionally) is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term chorea is derived from the Ancient Greek: χορεία ("dance"; see choreia), as the quick movements of the feet or hands are comparable to dancing.
The term hemichorea refers to chorea of one side of the body, such as chorea of one arm but not both (analogous to hemiballismus).
Presentation
Chorea is characterized by brief, semi-directed, irregular movements that are not repetitive or rhythmic, but appear to flow from one muscle to the next. These dance-like movements of chorea often occur with athetosis, which adds twisting and writhing movements. Walking may become difficult, and include odd postures and leg movements. Unlike ataxia, which affects the quality of voluntary movements, or Parkinsonism, which is a hindrance of voluntary movements, the movements of chorea and ballism occur on their own, without conscious effort. Thus, chorea is said to be a hyperkinetic movement disorder. When chorea is serious, slight movements will become thrashing motions; this form of severe chorea is referred to as ballism, or ballismus.
Causes
Huntingtons disease
Huntingtons disease is a neurodegenerative disease and most common inherited cause of chorea. The condition was formerly called Huntingtons chorea but was renamed because of the important non-choreic features including cognitive decline and behavioural change.
Other genetic causes
Other genetic causes of chorea are rare. They include the classical Huntingtons disease mimic or phenocopy syndromes, called Huntingtons disease-like syndrome types 1, 2 and 3; inherited prion disease, the spinocerebellar ataxias type 1, 3 and 17, neuroacanthocytosis, dentatorubral-pallidoluysian atrophy (DRPLA), brain iron accumulation disorders, Wilsons disease, benign hereditary chorea, Friedreichs ataxia, mitochondrial disease and Rett syndrome.
Acquired causes
The most common acquired causes of chorea are cerebrovascular disease and, in the developing world, HIV infection—usually through its association with cryptococcal disease.Sydenhams chorea occurs as a complication of streptococcal infection. Twenty percent (20%) of children and adolescents with rheumatic fever develop Sydenhams chorea as a complication. It is increasingly rare, which may be partially due to penicillin, improved social conditions, and/or a natural reduction in the bacteria (Streptococcus) it has stemmed from. Psychological symptoms may precede or accompany this acquired chorea and may be relapsing and remitting. The broader spectrum of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection can cause chorea and are collectively referred to as PANDAS.Chorea gravidarum refers to choreic symptoms that occur during pregnancy. If left untreated, the disease resolves in 30% of patients before delivery but, in the other 70%, it persists. The symptoms then progressively disappear in the next few days following the delivery.Chorea may also be caused by drugs (commonly levodopa, anti-convulsants and anti-psychotics).Other acquired causes include CSF leak, systemic lupus erythematosus, antiphospholipid syndrome, kappa light-chain monoclonal gammopathy of undetermined significance, thyrotoxicosis, polycythaemia rubra vera, transmissible spongiform encephalopathies and coeliac disease.
Treatment
There is no standard course of treatment for chorea. Treatment depends on the type of chorea and the associated disease. Although there are many drugs that can control it, no cure has yet been identified.
History
Historically, choreas like Huntington disease and Sydenhams chorea were called Saint Vitus dance, related to a series of social phenomena of the same name.
See also
Choreoathetosis
Dancing mania
Tic
Notes
External links
Chorea Gravidarum~clinical at eMedicine |
Visual impairment | Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individuals better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment– visual impairment may cause the individual difficulties with normal daily tasks including reading and walking. Low vision is a functional definition of visual impairment that is chronic, uncorrectable with treatment or correctable lenses, and impacts daily living. As such low vision can be used as a disability metric and varies based on an individuals experience, environmental demands, accommodations, and access to services. The American Academy of Ophthalmology defines visual impairment as the best-corrected visual acuity of less than 20/40 in the better eye, and the World Health Organization defines it as a presenting acuity of less than 6/12 in the better eye. The term blindness is used for complete or nearly complete vision loss. In addition to the various permanent conditions, fleeting temporary vision impairment, amaurosis fugax, may occur, and may indicate serious medical problems.
The most common causes of visual impairment globally are uncorrected refractive errors (43%), cataracts (33%), and glaucoma (2%). Refractive errors include near-sightedness, far-sightedness, presbyopia, and astigmatism. Cataracts are the most common cause of blindness. Other disorders that may cause visual problems include age-related macular degeneration, diabetic retinopathy, corneal clouding, childhood blindness, and a number of infections. Visual impairment can also be caused by problems in the brain due to stroke, premature birth, or trauma, among others. These cases are known as cortical visual impairment. Screening for vision problems in children may improve future vision and educational achievement. Screening adults without symptoms is of uncertain benefit. Diagnosis is by an eye exam.The World Health Organization (WHO) estimates that 80% of visual impairment is either preventable or curable with treatment. This includes cataracts, the infections river blindness and trachoma, glaucoma, diabetic retinopathy, uncorrected refractive errors, and some cases of childhood blindness. Many people with significant visual impairment benefit from vision rehabilitation, changes in their environment, and assistive devices.As of 2015 there were 940 million people with some degree of vision loss. 246 million had low vision and 39 million were blind. The majority of people with poor vision are in the developing world and are over the age of 50 years. Rates of visual impairment have decreased since the 1990s. Visual impairments have considerable economic costs both directly due to the cost of treatment and indirectly due to decreased ability to work.
Classification
In 2010, the WHO definition for visual impairment was changed and now follows the ICD-11. The previous definition which used "best corrected visual acuity" was changed to "presenting visual acuity". This change was made as newer studies showed that best-corrected vision overlooks a larger proportion of the population who has visual impairment due to uncorrected refractive errors, and/or lack of access to medical or surgical treatment.Distance vision impairment:
Category 0: No or mild visual impairment –presenting visual acuity better than 6/18
Category 1: Moderate visual impairment –presenting visual acuity worse than 6/18 and better than 6/60
Category 2: Severe visual impairment –presenting visual acuity worse than 6/60 and better than 3/60
Category 3: Blindness –presenting visual acuity worse than 3/60 and better than 1/60
Category 4: Blindness—presenting visual acuity worse than 1/60 with light perception
Category 5: Blindness—irreversible blindness with no light perceptionNear vision impairment:
Near visual acuity worse than N6 or M.08 at 40 cm.
United Kingdom
Severely sight impaired
Defined as having central visual acuity of less than 3/60 with normal fields of vision, or gross visual field restriction.
Unable to see at 3 metres (10 ft) what the normally sighted person sees at 60 metres (200 ft).Sight impaired
Able to see at 3 metres (10 ft), but not at 6 metres (20 ft), what the normally sighted person sees at 60 metres (200 ft)
Less severe visual impairment is not captured by registration data, and its prevalence is difficult to quantifyLow vision
A visual acuity of less than 6/18 but greater than 3/60.
Not eligible to drive and may have difficulty recognising faces across a street, watching television, or choosing clean, unstained, co-ordinated clothing.In the UK, the Certificate of Vision Impairment (CVI) is used to certify patients as severely sight impaired or sight impaired. The accompanying guidance for clinical staff states: "The National Assistance Act 1948 states that a person can be certified as severely sight impaired if they are so blind as to be unable to perform any work for which eye sight is essential". Certification is based on whether a person can do any work for which eyesight is essential, not just one particular job (such as their job before becoming blind).In practice, the definition depends on individuals visual acuity and the extent to which their field of vision is restricted. The Department of Health identifies three groups of people who may be classified as severely visually impaired.
Those below 3/60 (equivalent to 20/400 in US notation) Snellen (most people below 3/60 are severely sight impaired).
Those better than 3/60 but below 6/60 Snellen (people who have a very contracted field of vision only).
Those 6/60 Snellen or above (people in this group who have a contracted field of vision especially if the contraction is in the lower part of the field).The Department of Health also state that a person is more likely to be classified as severely visually impaired if their eyesight has failed recently or if they are an older individual, both groups being perceived as less able to adapt to their vision loss.
United States
In the United States, any person with vision that cannot be corrected to better than 20/200 in the best eye, or who has 20 degrees (diameter) or less of visual field remaining, is considered legally blind or eligible for disability classification and possible inclusion in certain government sponsored programs.
In the United States, the terms partially sighted, low vision, legally blind and totally blind are used by schools, colleges, and other educational institutions to describe students with visual impairments. They are defined as follows:
Partially sighted indicates some type of visual problem, with a need of person to receive special education in some cases.
Low vision generally refers to a severe visual impairment, not necessarily limited to distance vision. Low vision applies to all individuals with sight who are unable to read the newspaper at a normal viewing distance, even with the aid of eyeglasses or contact lenses. They use a combination of vision and other senses to learn, although they may require adaptations in lighting or the size of print, and, sometimes, braille.
Legally blind indicates that a person has less than 20/200 vision in the better eye after best correction (contact lenses or glasses), or a field of vision of less than 20 degrees in the better eye.
Totally blind students learn via braille or other non-visual media.In 1934, the American Medical Association adopted the following definition of blindness:
Central visual acuity of 20/200 or less in the better eye with corrective glasses or central visual acuity of more than 20/200 if there is a visual field defect in which the peripheral field is contracted to such an extent that the widest diameter of the visual field subtends an angular distance no greater than 20 degrees in the better eye.
The United States Congress included this definition as part of the Aid to the Blind program in the Social Security Act passed in 1935. In 1972, the Aid to the Blind program and two others combined under Title XVI of the Social Security Act to form the Supplemental Security Income program which states:
An individual shall be considered to be blind for purposes of this title if he has central visual acuity of 20/200 or less in the better eye with the use of a correcting lens. An eye which is accompanied by a limitation in the fields of vision such that the widest diameter of the visual field subtends an angle no greater than 20 degrees shall be considered for purposes of the first sentence of this subsection as having a central visual acuity of 20/200 or less. An individual shall also be considered to be blind for purposes of this title if he is blind as defined under a State plan approved under title X or XVI as in effect for October 1972 and received aid under such plan (on the basis of blindness) for December 1973, so long as he is continuously blind as so defined.
Temporary vision impairment
Vision impairment for a few seconds, or minutes, may occur due to any of a variety of causes, some serious and requiring medical attention.
Health effects
General functioning
Visual impairments may take many forms and be of varying degrees. Visual acuity alone is not always a good predictor of an individuals function. Someone with relatively good acuity (e.g., 20/40) can have difficulty with daily functioning, while someone with worse acuity (e.g., 20/200) may function reasonably well if they have low visual demands. It is also important to note that best-corrected visual acuity differs from presenting visual acuity; a person with a "normal" best corrected acuity can have "poor" presenting acuity (e.g. individual who has uncorrected refractive error). Thus, measuring an individuals general functioning depends on ones situational and contextual factors, as well as access to treatment.The American Medical Association has estimated that the loss of one eye equals 25% impairment of the visual system and 24% impairment of the whole person; total loss of vision in both eyes is considered to be 100% visual impairment and 85% impairment of the whole person.Some people who fall into this category can use their considerable residual vision – their remaining sight – to complete daily tasks without relying on alternative methods. The role of a low vision specialist (optometrist or ophthalmologist) is to maximize the functional level of a patients vision by optical or non-optical means. Primarily, this is by use of magnification in the form of telescopic systems for distance vision and optical or electronic magnification for near tasks.
People with significantly reduced acuity may benefit from training conducted by individuals trained in the provision of technical aids. Low vision rehabilitation professionals, some of whom are connected to an agency for the blind, can provide advice on lighting and contrast to maximize remaining vision. These professionals also have access to non-visual aids, and can instruct patients in their uses.
Mobility
Older adults with visual impairment are at an increased risk of physical inactivity, slower gait speeds, and fear of falls.Physical activity is a useful predictor of overall well-being, and routine physical activity reduces the risk of developing chronic diseases and disability. Older adults with visual impairment (including glaucoma, age-related macular degeneration, and diabetic retinopathy) have decreased physical activity as measured with self-reports and accelerometers. The US National Health and Nutrition Examination Survey (NHANES) showed that people with corrected visual acuity of less than 20/40 spent significantly less time in moderate to vigorous physical activity. Age-related macular degeneration is also associated with a 50% decrease in physical activity–however physical activity is protective against age-related macular degeneration progression.In terms of mobility, those with visual impairment have a slower gait speed than those without visual impairment; however, the rate of decline remains proportional with increasing age in both groups. Additionally, the visually impaired also have greater difficulty walking a quarter mile (400 m) and walking up stairs, as compared to those with normal vision.
Cognitive
Older adults with vision loss are at an increased risk of memory loss, cognitive impairment, and cognitive decline.
Social and psychological
Studies demonstrate an association between older adults with visual impairment and a poor mental health; discrimination was identified as one of the causes of this association. Older adults with visual impairment have a 1.5-fold risk of reporting perceived discrimination and of these individuals, there was a 2-fold risk of loneliness and 4-fold risk of reporting a lower quality of life. Among adults with visual impairment, the prevalence of moderate loneliness is 28.7% (18.2% in general population) and prevalence of severe loneliness is 19.7% (2.7% in general population). The risk of depression and anxiety are also increased in the visually impaired; 32.2% report depressive symptoms (12.01% in general population), and 15.61% report anxiety symptoms (10.69% in general population).The subjects making the most use of rehabilitation instruments, who lived alone, and preserved their own mobility and occupation were the least depressed, with the lowest risk of suicide and the highest level of social integration.
Those with worsening sight and the prognosis of eventual blindness are at comparatively high risk of suicide and thus may be in need of supportive services. Many studies have demonstrated how rapid acceptance of the serious visual impairment has led to a better, more productive compliance with rehabilitation programs. Moreover, psychological distress has been reported to be at its highest when sight loss is not complete, but the prognosis is unfavorable. Therefore, early intervention is imperative for enabling successful psychological adjustment.
Associated conditions
Blindness can occur in combination with such conditions as intellectual disability, autism spectrum disorders, cerebral palsy, hearing impairments, and epilepsy. Blindness in combination with hearing loss is known as deafblindness.
It has been estimated that over half of completely blind people have non-24-hour sleep–wake disorder, a condition in which a persons circadian rhythm, normally slightly longer than 24 hours, is not entrained (synchronized) to the light–dark cycle.
Cause
The most common causes of visual impairment globally in 2010 were:
Refractive error (42%)
Cataract (33%)
Glaucoma (2%)
Age-related macular degeneration (1%)
Corneal opacification (1%)
Diabetic retinopathy (1%)
Childhood blindness
Trachoma (1%)
Undetermined (18%)The most common causes of blindness worldwide in 2010 were:
Cataracts (51%)
Glaucoma (8%)
Age-related macular degeneration (5%)
Corneal opacification (4%)
Childhood blindness (4%)
Refractive errors (3%)
Trachoma (3%)
Diabetic retinopathy (1%)
Undetermined (21%)About 90% of people who are visually impaired live in the developing world. Age-related macular degeneration, glaucoma, and diabetic retinopathy are the leading causes of blindness in the developed world.Among working-age adults who are newly blind in England and Wales the most common causes in 2010 were:
Hereditary retinal disorders (20.2%)
Diabetic retinopathy (14.4%)
Optic atrophy (14.1%)
Glaucoma (5.9%)
Congenital abnormalities (5.1%)
Disorders of the visual cortex (4.1%)
Cerebrovascular disease (3.2%)
Degeneration of the macula and posterior pole (3.0%)
Myopia (2.8%)
Corneal disorders (2.6%)
Malignant neoplasms of the brain and nervous system (1.5%)
Retinal detachment (1.4%)
Cataracts
Cataracts are the greying or opacity of the crystalline lens, which can be caused in children by intrauterine infections, metabolic disorders, and genetically transmitted syndromes. Cataracts are the leading cause of child and adult blindness that doubles in prevalence with every ten years after the age of 40. Consequently, today cataracts are more common among adults than in children. That is, people face higher chances of developing cataracts as they age. Nonetheless, cataracts tend to have a greater financial and emotional toll upon children as they must undergo expensive diagnosis, long term rehabilitation, and visual assistance. Also, according to the Saudi Journal for Health Sciences, sometimes patients experience irreversible amblyopia after pediatric cataract surgery because the cataracts prevented the normal maturation of vision prior to operation. Despite the great progress in treatment, cataracts remain a global problem in both economically developed and developing countries. At present, with the variant outcomes as well as the unequal access to cataract surgery, the best way to reduce the risk of developing cataracts is to avoid smoking and extensive exposure to sun light (i.e. UV-B rays).
Glaucoma
Glaucoma is an eye disease often characterized by increased pressure within the eye or intraocular pressure (IOP). Glaucoma causes visual field loss as well as severs the optic nerve. Early diagnosis and treatment of glaucoma in patients is imperative because glaucoma is triggered by non-specific levels of IOP. Also, another challenge in accurately diagnosing glaucoma is that the disease has four causes: 1) inflammatory ocular hypertension syndrome (IOHS); 2) severe uveitic angle closure; 3) corticosteroid-induced; and 4) a heterogonous mechanism associated with structural change and chronic inflammation. In addition, often pediatric glaucoma differs greatly in cause and management from the glaucoma developed by adults. Currently, the best sign of pediatric glaucoma is an IOP of 21 mm Hg or greater present within a child. One of the most common causes of pediatric glaucoma is cataract removal surgery, which leads to an incidence rate of about 12.2% among infants and 58.7% among 10-year-olds.
Infections
Childhood blindness can be caused by conditions related to pregnancy, such as congenital rubella syndrome and retinopathy of prematurity. Leprosy and onchocerciasis each blind approximately 1 million individuals in the developing world.
The number of individuals blind from trachoma has decreased in the past 10 years from 6 million to 1.3 million, putting it in seventh place on the list of causes of blindness worldwide.
Central corneal ulceration is also a significant cause of monocular blindness worldwide, accounting for an estimated 850,000 cases of corneal blindness every year in the Indian subcontinent alone. As a result, corneal scarring from all causes is now the fourth greatest cause of global blindness.
Injuries
Eye injuries, most often occurring in people under 30, are the leading cause of monocular blindness (vision loss in one eye) throughout the United States. Injuries and cataracts affect the eye itself, while abnormalities such as optic nerve hypoplasia affect the nerve bundle that sends signals from the eye to the back of the brain, which can lead to decreased visual acuity.
Cortical blindness results from injuries to the occipital lobe of the brain that prevent the brain from correctly receiving or interpreting signals from the optic nerve. Symptoms of cortical blindness vary greatly across individuals and may be more severe in periods of exhaustion or stress. It is common for people with cortical blindness to have poorer vision later in the day.
Blinding has been used as an act of vengeance and torture in some instances, to deprive a person of a major sense by which they can navigate or interact within the world, act fully independently, and be aware of events surrounding them. An example from the classical realm is Oedipus, who gouges out his own eyes after realizing that he fulfilled the awful prophecy spoken of him. Having crushed the Bulgarians, the Byzantine Emperor Basil II blinded as many as 15,000 prisoners taken in the battle, before releasing them. Contemporary examples include the addition of methods such as acid throwing as a form of disfigurement.
Genetic defects
People with albinism often have vision loss to the extent that many are legally blind, though few of them actually cannot see. Leber congenital amaurosis can cause total blindness or severe sight loss from birth or early childhood. Retinitis pigmentosa is characterized by decreased peripheral vision and trouble seeing at night.
Advances in mapping of the human genome have identified other genetic causes of low vision or blindness. Two such examples are Bardet–Biedl syndrome.
Poisoning
Rarely, blindness is caused by the intake of certain chemicals. A well-known example is methanol, which is only mildly toxic and minimally intoxicating, and breaks down into the substances formaldehyde and formic acid which in turn can cause blindness, an array of other health complications, and death. When competing with ethanol for metabolism, ethanol is metabolized first, and the onset of toxicity is delayed. Methanol is commonly found in methylated spirits, denatured ethyl alcohol, to avoid paying taxes on selling ethanol intended for human consumption. Methylated spirits are sometimes used by alcoholics as a desperate and cheap substitute for regular ethanol alcoholic beverages.
Other
Amblyopia: is a category of vision loss or visual impairment that is caused by factors unrelated to refractive errors or coexisting ocular diseases. Amblyopia is the condition when a childs visual systems fail to mature normally because the child either has been born premature, measles, congenital rubella syndrome, vitamin A deficiency, or meningitis. If left untreated during childhood, amblyopia is currently incurable in adulthood because surgical treatment effectiveness changes as a child matures. Consequently, amblyopia is the worlds leading cause of child monocular vision loss, which is the damage or loss of vision in one eye. In the best case scenario, which is very rare, properly treated amblyopia patients can regain 20/40 acuity.
Corneal opacification
Degenerative myopia
Diabetic retinopathy: is one of the manifestation microvascular complications of diabetes, which is characterized by blindness or reduced acuity. That is, diabetic retinopathy describes the retinal and vitreous hemorrhages or retinal capillary blockage caused by the increase of A1C, which a measurement of blood glucose or sugar level. In fact, as A1C increases, people tend to be at greater risk of developing diabetic retinopathy than developing other microvascular complications associated with diabetes (e.g. chronic hyperglycemia, diabetic neuropathy, and diabetic nephropathy). Despite the fact that only 8% of adults 40 years and older experience vision-threatening diabetic retinopathy (e.g. nonproliferative diabetic retinopathy or NPDR and proliferative diabetic retinopathy or PDR), this eye disease accounted for 17% of cases of blindness in 2002.
Retinitis pigmentosa
Retinopathy of prematurity: The most common cause of blindness in infants worldwide. In its most severe form, ROP causes retinal detachment, with attendant visual loss. Treatment is aimed mainly at prevention, via laser or Avastin therapy.
Stargardts disease
Uveitis: is a group of 30 intraocular inflammatory diseases caused by infections, systemic diseases, organ-specific autoimmune processes, cancer or trauma. That is, uveitis refers to a complex category of ocular diseases that can cause blindness if either left untreated or improperly diagnosed. The current challenge of accurately diagnosing uveitis is that often the cause of a specific ocular inflammation is either unknown or multi-layered. Consequently, about 3–10% of those with uveitis in developed countries, and about 25% of those with uveitis in the developing countries, become blind from incorrect diagnosis and from ineffectual prescription of drugs, antibiotics or steroids. In addition, uveitis is a diverse category of eye diseases that are subdivided as granulomatous (or tumorous) or non-granulomatous anterior, intermediate, posterior or pan uveitis. In other words, uveitis diseases tend to be classified by their anatomic location in the eye (e.g. uveal tract, retina, or lens), as well as can create complication that can cause cataracts, glaucoma, retinal damage, age-related macular degeneration or diabetic retinopathy.
Xerophthalmia, often due to vitamin A deficiency, is estimated to affect 5 million children each year; 500,000 develop active corneal involvement, and half of these go blind.
Diagnosis
It is important that people be examined by someone specializing in low vision care prior to other rehabilitation training to rule out potential medical or surgical correction for the problem and to establish a careful baseline refraction and prescription of both normal and low vision glasses and optical aids. Only a doctor is qualified to evaluate visual functioning of a compromised visual system effectively. The American Medical Association provides an approach to evaluating visual loss as it affects an individuals ability to perform activities of daily living.Screening adults who have no symptoms is of uncertain benefit.
Prevention
The World Health Organization estimates that 80% of visual loss is either preventable or curable with treatment. This includes cataracts, onchocerciasis, trachoma, glaucoma, diabetic retinopathy, uncorrected refractive errors, and some cases of childhood blindness. The Center for Disease Control and Prevention estimates that half of blindness in the United States is preventable.
Management
Mobility
Many people with serious visual impairments can travel independently, using a wide range of tools and techniques. Orientation and mobility specialists are professionals who are specifically trained to teach people with visual impairments how to travel safely, confidently, and independently in the home and the community. These professionals can also help blind people to practice travelling on specific routes which they may use often, such as the route from ones house to a convenience store. Becoming familiar with an environment or route can make it much easier for a blind person to navigate successfully.
Tools such as the white cane with a red tip – the international symbol of blindness – may also be used to improve mobility. A long cane is used to extend the users range of touch sensation. It is usually swung in a low sweeping motion, across the intended path of travel, to detect obstacles. However, techniques for cane travel can vary depending on the user and/or the situation. Some visually impaired persons do not carry these kinds of canes, opting instead for the shorter, lighter identification (ID) cane. Still others require a support cane. The choice depends on the individuals vision, motivation, and other factors.
A small number of people employ guide dogs to assist in mobility. These dogs are trained to navigate around various obstacles, and to indicate when it becomes necessary to go up or down a step. However, the helpfulness of guide dogs is limited by the inability of dogs to understand complex directions. The human half of the guide dog team does the directing, based upon skills acquired through previous mobility training. In this sense, the handler might be likened to an aircrafts navigator, who must know how to get from one place to another, and the dog to the pilot, who gets them there safely.
GPS devices can also be used as a mobility aid. Such software can assist blind people with orientation and navigation, but it is not a replacement for traditional mobility tools such as white canes and guide dogs.
Some blind people are skilled at echolocating silent objects simply by producing mouth clicks and listening to the returning echoes. It has been shown that blind echolocation experts use what is normally the "visual" part of their brain to process the echoes.Government actions are sometimes taken to make public places more accessible to blind people. Public transportation is freely available to blind people in many cities. Tactile paving and audible traffic signals can make it easier and safer for visually impaired pedestrians to cross streets. In addition to making rules about who can and cannot use a cane, some governments mandate the right-of-way be given to users of white canes or guide dogs.
Reading and magnification
Most visually impaired people who are not totally blind read print, either of a regular size or enlarged by magnification devices. Many also read large-print, which is easier for them to read without such devices. A variety of magnifying glasses, some handheld, and some on desktops, can make reading easier for them.
Others read braille (or the infrequently used Moon type), or rely on talking books and readers or reading machines, which convert printed text to speech or braille. They use computers with special hardware such as scanners and refreshable braille displays as well as software written specifically for the blind, such as optical character recognition applications and screen readers.
Some people access these materials through agencies for the blind, such as the National Library Service for the Blind and Physically Handicapped in the United States, the National Library for the Blind or the RN |
Visual impairment | IB in the United Kingdom.
Closed-circuit televisions, equipment that enlarges and contrasts textual items, are a more high-tech alternative to traditional magnification devices.
There are also over 100 radio reading services throughout the world that provide people with vision impairments with readings from periodicals over the radio. The International Association of Audio Information Services provides links to all of these organizations.
Computers and mobile technology
Access technology such as screen readers, screen magnifiers and refreshable braille displays enable the blind to use mainstream computer applications and mobile phones. The availability of assistive technology is increasing, accompanied by concerted efforts to ensure the accessibility of information technology to all potential users, including the blind. Later versions of Microsoft Windows include an Accessibility Wizard & Magnifier for those with partial vision, and Microsoft Narrator, a simple screen reader. Linux distributions (as live CDs) for the blind include Vinux and Adriane Knoppix, the latter developed in part by Adriane Knopper who has a visual impairment. macOS and iOS also come with a built-in screen reader called VoiceOver, while Google TalkBack is built in to most Android devices.
The movement towards greater web accessibility is opening a far wider number of websites to adaptive technology, making the web a more inviting place for visually impaired surfers.
Experimental approaches in sensory substitution are beginning to provide access to arbitrary live views from a camera.
Modified visual output that includes large print and/or clear simple graphics can be of benefit to users with some residual vision.
Other aids and techniques
Blind people may use talking equipment such as thermometers, watches, clocks, scales, calculators, and compasses. They may also enlarge or mark dials on devices such as ovens and thermostats to make them usable. Other techniques used by blind people to assist them in daily activities include:
Adaptations of coins and banknotes so that the value can be determined by touch. For example:
In some currencies, such as the euro, the pound sterling and the Indian rupee, the size of a note increases with its value.
On US coins, pennies and dimes, and nickels and quarters are similar in size. The larger denominations (dimes and quarters) have ridges along the sides (historically used to prevent the "shaving" of precious metals from the coins), which can now be used for identification.
Some currencies banknotes have a tactile feature to indicate denomination. For example, the Canadian currency tactile feature is a system of raised dots in one corner, based on braille cells but not standard braille.
It is also possible to fold notes in different ways to assist recognition.
Labeling and tagging clothing and other personal items
Placing different types of food at different positions on a dinner plate
Marking controls of household appliancesMost people, once they have been visually impaired for long enough, devise their own adaptive strategies in all areas of personal and professional management.
For the blind, there are books in braille, audio-books, and text-to-speech computer programs, machines and e-book readers. Low vision people can make use of these tools as well as large-print reading materials and e-book readers that provide large font sizes.
Computers are important tools of integration for the visually impaired person. They allow, using standard or specific programs, screen magnification and conversion of text into sound or touch (braille line), and are useful for all levels of visual impairment. OCR scanners can, in conjunction with text-to-speech software, read the contents of books and documents aloud via computer. Vendors also build closed-circuit televisions that electronically magnify paper, and even change its contrast and color, for visually impaired users. For more information, consult assistive technology.
In adults with low vision there is no conclusive evidence supporting one form of reading aid over another. In several studies stand-mounted devices allowed faster reading than hand-held or portable optical aids. While electronic aids may allow faster reading for individuals with low vision, portability, ease of use, and affordability must be considered for people.Children with low vision sometimes have reading delays, but do benefit from phonics-based beginning reading instruction methods. Engaging phonics instruction is multisensory, highly motivating, and hands-on. Typically students are first taught the most frequent sounds of the alphabet letters, especially the so-called short vowel sounds, then taught to blend sounds together with three-letter consonant-vowel-consonant words such as cat, red, sit, hot, sun. Hands-on (or kinesthetically appealing) VERY enlarged print materials such as those found in "The Big Collection of Phonics Flipbooks" by Lynn Gordon (Scholastic, 2010) are helpful for teaching word families and blending skills to beginning readers with low vision. Beginning reading instructional materials should focus primarily on the lower-case letters, not the capital letters (even though they are larger) because reading text requires familiarity (mostly) with lower-case letters. Phonics-based beginning reading should also be supplemented with phonemic awareness lessons, writing opportunities, and many read-alouds (literature read to children daily) to stimulate motivation, vocabulary development, concept development, and comprehension skill development. Many children with low vision can be successfully included in regular education environments. Parents may need to be vigilant to ensure that the school provides the teacher and students with appropriate low vision resources, for example technology in the classroom, classroom aide time, modified educational materials, and consultation assistance with low vision experts.
Epidemiology
The WHO estimates that in 2012 there were 285 million visually impaired people in the world, of which 246 million had low vision and 39 million were blind.Of those who are blind 90% live in the developing world. Worldwide for each blind person, an average of 3.4 people have low vision, with country and regional variation ranging from 2.4 to 5.5.By age: Visual impairment is unequally distributed across age groups. More than 82% of all people who are blind are 50 years of age and older, although they represent only 19% of the worlds population. Due to the expected number of years lived in blindness (blind years), childhood blindness remains a significant problem, with an estimated 1.4 million blind children below age 15.
By gender: Available studies consistently indicate that in every region of the world, and at all ages, females have a significantly higher risk of being visually impaired than males.By geography: Visual impairment is not distributed uniformly throughout the world. More than 90% of the worlds visually impaired live in developing countries.Since the estimates of the 1990s, new data based on the 2002 global population show a reduction in the number of people who are blind or visually impaired, and those who are blind from the effects of infectious diseases, but an increase in the number of people who are blind from conditions related to longer life spans.In 1987, it was estimated that 598,000 people in the United States met the legal definition of blindness. Of this number, 58% were over the age of 65. In 1994–1995, 1.3 million Americans reported legal blindness.
Society and culture
Legal definition
To determine which people qualify for special assistance because of their visual disabilities, various governments have specific definitions for legal blindness. In North America and most of Europe, legal blindness is defined as visual acuity (vision) of 20/200 (6/60) or less in the better eye with best correction possible. This means that a legally blind individual would have to stand 20 feet (6.1 m) from an object to see it—with corrective lenses—with the same degree of clarity as a normally sighted person could from 200 feet (61 m). In many areas, people with average acuity who nonetheless have a visual field of less than 20 degrees (the norm being 180 degrees) are also classified as being legally blind.
Approximately fifteen percent of those deemed legally blind, by any measure, have no light or form perception. The rest have some vision, from light perception alone to relatively good acuity. Low vision is sometimes used to describe visual acuities from 20/70 to 20/200.
Literature and art
Antiquity
The Moche people of ancient Peru depicted the blind in their ceramics.In Greek myth, Tiresias was a prophet famous for his clairvoyance. According to one myth, he was blinded by the gods as punishment for revealing their secrets, while another holds that he was blinded as punishment after he saw Athena naked while she was bathing. In the Odyssey, the one-eyed Cyclops Polyphemus captures Odysseus, who blinds Polyphemus to escape. In Norse mythology, Loki tricks the blind god Höðr into killing his brother Baldr, the god of happiness.
The New Testament contains numerous instances of Jesus performing miracles to heal the blind. According to the Gospels, Jesus healed the two blind men of Galilee, the blind man of Bethsaida, the blind man of Jericho and the man who was born blind.
The parable of the blind men and an elephant has crossed between many religious traditions and is part of Jain, Buddhist, Sufi and Hindu lore. In various versions of the tale, a group of blind men (or men in the dark) touch an elephant to learn what it is like. Each one feels a different part, but only one part, such as the side or the tusk. They then compare notes and learn that they are in complete disagreement.
"Three Blind Mice" is a medieval English nursery rhyme about three blind mice whose tails are cut off after chasing the farmers wife. The work is explicitly incongruous, ending with the comment Did you ever see such a sight in your life, As three blind mice?
Modern times
Poet John Milton, who went blind in mid-life, composed "On His Blindness", a sonnet about coping with blindness. The work posits that [those] who best Bear [God]s mild yoke, they serve him best.
The Dutch painter and engraver Rembrandt often depicted scenes from the apocryphal Book of Tobit, which tells the story of a blind patriarch who is healed by his son, Tobias, with the help of the archangel Raphael.Slaver-turned-abolitionist John Newton composed the hymn "Amazing Grace" about a wretch who "once was lost, but now am found, Was blind, but now I see." Blindness, in this sense, is used both metaphorically (to refer to someone who was ignorant but later became knowledgeable) and literally, as a reference to those healed in the Bible. In the later years of his life, Newton himself would go blind.
H. G. Wells story "The Country of the Blind" explores what would happen if a sighted man found himself trapped in a country of blind people to emphasise societys attitude to blind people by turning the situation on its head.
Bob Dylans anti-war song "Blowin in the Wind" twice alludes to metaphorical blindness: How many times can a man turn his head // and pretend that he just doesnt see... How many times must a man look up // Before he can see the sky?
Contemporary fiction contains numerous well-known blind characters. Some of these characters can see by means of devices, such as the Marvel Comics superhero Daredevil, who can see via his super-human hearing acuity, or Star Treks Geordi La Forge, who can see with the aid of a VISOR, a fictional device that transmits optical signals to his brain.
Sports
Blind and partially sighted people participate in sports, such as swimming, snow skiing and athletics. Some sports have been invented or adapted for the blind, such as goalball, association football, cricket, golf, tennis, bowling, and beep baseball. The worldwide authority on sports for the blind is the International Blind Sports Federation. People with vision impairments have participated in the Paralympic Games since the 1976 Toronto summer Paralympics.
Metaphorical uses
The word "blind" (adjective and verb) is often used to signify a lack of knowledge of something. For example, a blind date is a date in which the people involved have not previously met; a blind experiment is one in which information is kept from either the experimenter or the participant to mitigate the placebo effect or observer bias. The expression "blind leading the blind" refers to incapable people leading other incapable people. Being blind to something means not understanding or being aware of it. A "blind spot" is an area where someone cannot see: for example, where a car driver cannot see because parts of his cars bodywork are in the way; metaphorically, a topic on which an individual is unaware of their own biases, and therefore of the resulting distortions of their own judgements (see Bias blind spot).
Research
A 2008 study tested the effect of using gene therapy to help restore the sight of patients with a rare form of inherited blindness, known as Lebers congenital amaurosis or LCA. Lebers Congenital Amaurosis damages the light receptors in the retina and usually begins affecting sight in early childhood, with worsening vision until complete blindness around the age of 30. The study used a common cold virus to deliver a normal version of the gene called RPE65 directly into the eyes of affected patients. All three patients, aged 19, 22 and 25, responded well to the treatment and reported improved vision following the procedure.
Two experimental treatments for retinal problems include a cybernetic replacement and transplant of fetal retinal cells.There is no high-quality evidence on the effect of assistive technologies on educational outcomes and quality of life in children with low vision as of 2015, nor is there evidence on magnifying reading aids in children. Low-vision rehabilitation does not appear to have an important impact on health-related quality of life, though some low-vision rehabilitation interventions, particularly psychological therapies and methods of enhancing vision, may improve vision-related quality of life in people with sight loss.
Other animals
Statements that certain species of mammals are "born blind" refers to them being born with their eyes closed and their eyelids fused together; the eyes open later. One example is the rabbit. In humans, the eyelids are fused for a while before birth, but open again before the normal birth time; however, very premature babies are sometimes born with their eyes fused shut, and opening later. Other animals, such as the blind mole rat, are truly blind and rely on other senses.The theme of blind animals has been a powerful one in literature. Peter Shaffers Tony Award-winning play, Equus, tells the story of a boy who blinds six horses. Theodore Taylors classic young adult novel, The Trouble With Tuck, is about a teenage girl, Helen, who trains her blind dog to follow and trust a seeing-eye dog.
See also
References
External links
Blindness at Curlie
Chisholm, Hugh, ed. (1911). "Blindness". Encyclopædia Britannica (11th ed.). Cambridge University Press. |
Meconium aspiration syndrome | Meconium aspiration syndrome (MAS) also known as neonatal aspiration of meconium is a medical condition affecting newborn infants. It describes the spectrum of disorders and pathophysiology of newborns born in meconium-stained amniotic fluid (MSAF) and have meconium within their lungs. Therefore, MAS has a wide range of severity depending on what conditions and complications develop after parturition. Furthermore, the pathophysiology of MAS is multifactorial and extremely complex which is why it is the leading cause of morbidity and mortality in term infants.The word meconium is derived from the Greek word mēkōnion meaning juice from the opium poppy as the sedative effects it had on the foetus were observed by Aristotle.Meconium is a sticky dark-green substance which contains gastrointestinal secretions, amniotic fluid, bile acids, bile, blood, mucus, cholesterol, pancreatic secretions, lanugo, vernix caseosa and cellular debris. Meconium accumulates in the foetal gastrointestinal tract throughout the third trimester of pregnancy and it is the first intestinal discharge released within the first 48 hours after birth. Notably, since meconium and the whole content of the gastrointestinal tract is located extracorporeally, its constituents are hidden and normally not recognised by the foetal immune system.For the meconium within the amniotic fluid to successfully cause MAS, it has to enter the respiratory system during the period when the fluid-filled lungs transition into an air-filled organ capable of gas exchange.
Causes
The main theories of meconium passage into amniotic fluid are caused by fetal maturity or from foetal stress as a result of hypoxia or infection. Other factors that promote the passage of meconium in utero include placental insufficiency, maternal hypertension, pre-eclampsia and maternal drug use of tobacco and cocaine. However, the exact mechanism for meconium passage into the amniotic fluid is not completely understood and it may be a combination of several factors.
Meconium passage as a result of foetal distress
There may be an important association between foetal distress and hypoxia with MSAF. It is believed that foetal distress develops into foetal hypoxia causing the foetus to defecate meconium resulting in MSAF and then perhaps MAS. Other stressors which causes foetal distress, and therefore meconium passage, includes when umbilical vein oxygen saturation is below 30%.Foetal hypoxic stress during parturition can stimulate colonic activity, by enhancing intestinal peristalsis and relaxing the anal sphincter, which results in the passage of meconium. Then, because of intrauterine gasping or from the first few breaths after delivery, MAS may develop. Furthermore, aspiration of thick meconium leads to obstruction of airways resulting in a more severe hypoxia.The association between foetal distress and meconium passage is not a definite cause-effect relationship as over 3⁄4 of infants with MSAF are vigorous at birth and do not have any distress or hypoxia. Additionally, foetal distress occurs frequently without the passage of meconium as well.
Meconium passage as a result of foetal maturity
Although meconium is present in the gastrointestinal tract early in development, MSAF rarely occurs before 34 weeks gestation.Peristalsis of the foetal intestines is present as early as 8 weeks gestation and the anal sphincter develops at about 20–22 weeks. The early control mechanisms of the anal sphincter are not well understood, however there is evidence that the foetus does defecate routinely into the amniotic cavity even in the absence of distress. The presence of fetal intestinal enzymes have been found in the amniotic fluid of women who are as early as 14–22 weeks pregnant. Thus, suggesting there is free passage of the intestinal contents into the amniotic fluid.Motilin is found in higher concentrations in post-term than pre-term foetal gastrointestinal tracts. Similarly, intestinal parasympathetic innervation and myelination also increases in later gestations. Therefore, the increased incidence of MAS in post-term pregnancies may reflect the maturation and development of the peristalsis within the gastrointestinal tract in the newborn.
Pathophysiology
As MAS describes a spectrum of disorders of newborns born through MSAF, without any congenital respiratory disorders or other underlying pathology, there are numerous hypothesised mechanisms and causes for the onset of this syndrome. Long-term consequences may arise from these disorders, for example, infants that develop MAS have higher rates of developing neurodevelopmental defects due to poor respiration.
Airway obstruction
In the first 15 minutes of meconium aspiration, there is obstruction of larger airways which causes increased lung resistance, decreased lung compliance, acute hypoxemia, hypercapnia, atelectasis and respiratory acidosis. After 60 minutes of exposure, the meconium travels further down into the smaller airways. Once within the terminal bronchioles and alveoli, the meconium triggers inflammation, pulmonary edema, vasoconstriction, bronchoconstriction, collapse of airways and inactivation of surfactant.
Foetal hypoxia
The lung areas which do not or only partially participate in ventilation, because of obstruction and/or destruction, will become hypoxic and an inflammatory response may consequently occur. Partial obstruction will lead to air trapping and hyperinflation of certain lung areas and pneumothorax may follow. Chronic hypoxia will lead to an increase in pulmonary vascular smooth muscle tone and persistent pulmonary hypertension causing respiratory and circulatory failure.
Infection
Microorganisms, most commonly Gram-negative rods, and endotoxins are found in samples of MSAF at a higher rate than in clear amniotic fluid, for example 46.9% of patients with MSAF also had endotoxins present. A microbial invasion of the amniotic cavity (MIAC) is more common in patients with MSAF and this could ultimately lead to an intra-amniotic inflammatory response. MIAC is associated with high concentrations of cytokines (such as IL-6), chemokines (such as IL-8 and monocyte chemoattractant protein-1), complement, phospholipase A2 and matrix-degrading enzymes. Therefore, these aforementioned mediators within the amniotic fluid during MIAC and intra-amniotic infection could, when aspirated in utero, induce lung inflammation within the foetus.
Pulmonary inflammation
Meconium has a complex chemical composition, so it is difficult to identify a single agent responsible for the several diseases that arise. As meconium is stored inside the intestines, and is partly unexposed to the immune system, when it becomes aspirated the innate immune system recognises as a foreign and dangerous substance. The immune system, which is present at birth, responds within minutes with a low specificity and no memory in order to try to eliminate microbes. Meconium perhaps leads to chemical pneumonitis as it is a potent activator of inflammatory mediators which include cytokines, complement, prostaglandins and reactive oxygen species.Meconium is a source of pro-inflammatory cytokines, including tumour necrosis factor (TNF) and interleukins (IL-1, IL-6, IL-8), and mediators produced by neutrophils, macrophages and epithelial cells that may injure the lung tissue directly or indirectly. For example, proteolytic enzymes are released from neutrophilic granules and these may damage the lung membrane and surfactant proteins. Additionally, activated leukocytes and cytokines generate reactive nitrogen and oxygen species which have cytotoxic effects. Oxidative stress results in vasoconstriction, bronchoconstriction, platelet aggregation and accelerated cellular apoptosis. Recently, it has been hypothesised that meconium is a potent activator of toll-like receptor (TLRs) and complement, key mediators in inflammation, and may thus contribute to the inflammatory response in MAS.Meconium contains high amounts of phospholipase A2 (PLA2), a potent proinflammatory enzyme, which may directly (or through the stimulation of arachidonic acid) lead to surfactant dysfunction, lung epithelium destruction, tissue necrosis and an increase in apoptosis. Meconium can also activate the coagulation cascade, production of platelet-activating factor (PAF) and other vasoactive substances that may lead to destruction of capillary endothelium and basement membranes. Injury to the alveolocapillary membrane results in leakage of liquid, plasma proteins, and cells into the interstitium and alveolar spaces.
Surfactant inactivation
Surfactant is synthesised by type II alveolar cells and is made of a complex of phospholipids, proteins and saccharides. It functions to lower surface tension (to allow for lung expansion during inspiration), stabilise alveoli at the end of expiration (to prevent alveolar collapse) and prevents lung oedema. Surfactant also contributes to lung protection and defence as it is also an anti-inflammatory agent. Surfactant enhances the removal of inhaled particles and senescent cells away from the alveolar structure.The extent of surfactant inhibition depends on both the concentration of surfactant and meconium. If the surfactant concentration is low, even very highly diluted meconium can inhibit surfactant function whereas, in high surfactant concentrations, the effects of meconium are limited. Meconium may impact surfactant mechanisms by preventing surfactant from spreading over the alveolar surface, decreasing the concentration of surfactant proteins (SP-A and SP-B), and by changing the viscosity and structure of surfactant. Several morphological changes occur after meconium exposure, the most notable being the detachment of airway epithelium from stroma and the shedding of epithelial cells into the airway. These indicate a direct detrimental effect on lung alveolar cells because of the introduction of meconium into the lungs.
Persistent Pulmonary Hypertension
Persistent pulmonary hypertension (PPHN) is the failure of the foetal circulation to adapt to extra-uterine conditions after birth. PPHN is associated with various respiratory diseases, including MAS (as 15-20% of infants with MAS develop PPHN), but also pneumonia and sepsis. A combination of hypoxia, pulmonary vasoconstriction and ventilation/perfusion mismatch can trigger PPHN, depending on the concentration of meconium within the respiratory tract. PPHN in newborns is the leading cause of death in MAS.
Apoptosis
Apoptosis is an important mechanism in the clearance of injured cells and in tissue repair, however too much apoptosis may cause harm, such as acute lung injury. Meconium induces apoptosis and DNA cleavage of lung airway epithelial cells, this is detected by the presence of fragmented DNA within the airways and in alveolar epithelial nuclei. Meconium induces an inflammatory reaction within the lungs as there is an increase of autophagocytic cells and levels of caspase 3 after exposure. After 8 hours of meconium exposure, in rabbit foetuses, the total amount of apoptotic cells is 54%. Therefore, the majority of meconium-induced lung damage may be due to the apoptosis of lung epithelium.
Diagnosis
Respiratory distress in an infant born through the darkly coloured MSAF as well as meconium obstructing the airways is usually sufficient enough to diagnose MAS. Additionally, newborns with MAS can have other types of respiratory distress such as tachypnea and hypercapnia. Sometimes it is hard to diagnose MAS as it can be confused with other diseases that also cause respiratory distress, such as pneumonia. Additionally, X-rays and lung ultrasounds can be quick, easy and cheap imaging techniques to diagnose lung diseases like MAS.
Prevention
In general, the incidence of MAS has been significantly reduced over the past two decades as the number of post-term deliveries has minimized.
Prevention during pregnancy
Prevention during pregnancy may include amnioinfusion and antibiotics but the effectiveness of these treatments are questionable.
Prevention during parturition
As previously mentioned, oropharyngeal and nasopharyngeal suctioning is not an ideal preventative treatment for both vigorous and depressed (not breathing) infants.
Treatment
Most infants born through MSAF do not require any treatments (other than routine postnatal care) as they show no signs of respiratory distress, as only approximately 5% of infants born through MSAF develop MAS. However, infants which do develop MAS need to be admitted to a neonatal unit where they will be closely observed and provided any treatments needed. Observations include monitoring heart rate, respiratory rate, oxygen saturation and blood glucose (to detect worsening respiratory acidosis or the development of hypoglycemia). In general, treatment of MAS is more supportive in nature.
Assisted ventilation techniques
To clear the airways of meconium, tracheal suctioning can be used however, the efficacy of this method is in question and it can cause harm.In cases of MAS, there is a need for supplemental oxygen for at least 12 hours in order to maintain oxygen saturation of haemoglobin at 92% or more. The severity of respiratory distress can vary significantly between newborns with MAS, as some require minimal or no supplemental oxygen requirement and, in severe cases, mechanical ventilation may be needed. The desired oxygen saturation is between 90 and 95% and PaO2 may be as high as 90mmHg. In cases where there is thick meconium deep within the lungs, mechanical ventilation may be required. In extreme cases, extracorporeal membrane oxygenation (ECMO) may be utilised in infants who fail to respond to ventilation therapy. While on ECMO, the body can have time to absorb the meconium and for all the associated disorders to resolve. There has been an excellent response to this treatment, as the survival rate of MAS while on ECMO is more than 94%.Ventilation of infants with MAS can be challenging and, as MAS can affect each individual differently, ventilation administration may need to be customised. Some newborns with MAS can have homogenous lung changes and others can have inconsistent and patchy changes to their lungs. It is common for sedation and muscle relaxants to be used to optimise ventilation and minimise the risk of pneumothorax associated with dyssynchronous breathing.
Inhaled nitric oxide
Inhaled nitric oxide (iNO) acts on vascular smooth muscle causing selective pulmonary vasodilation. This is ideal in the treatment of PPHN as it causes vasodilation within ventilated areas of the lung thus, decreasing the ventilation-perfusion mismatch and thereby, improves oxygenation. Treatment utilising iNO decreases the need for ECMO and mortality in newborns with hypoxic respiratory failure and PPHN as a result of MAS. However, approximately 30-50% of infants with PPHN do not respond to iNO therapy.
Antiinflammatories
As inflammation is such a huge issue in MAS, treatment has consisted of anti-inflammatories.
Glucocorticoids
Glucocorticoids have a strong anti-inflammatory activity and works to reduce the migration and activation of neutrophils, eosinophils, mononuclear cells, and other cells. They reduce the migration of neutrophils into the lungs ergo, decreasing their adherence to the endothelium. Thus, there is a reduction in the action of mediators released from these cells and therefore, a reduced inflammatory response.Glucocorticoids also possess a genomic mechanism of action in which, once bound to a glucocorticoid receptor, the activated complex moves into the nucleus and inhibits transcription of mRNA. Ultimately, effecting whether various proteins get produced or not. Inhibiting the transcription of nuclear factor (NF-κB) and protein activator (AP-1) attenuates the expression of pro-inflammatory cytokines (IL-1, IL-6, IL-8 and TNF etc.), enzymes (PLA2, COX-2, iNOs etc.) and other biologically active substances. The anti-inflammatory effect of glucocorticoids is also demonstrated by enhancing the activity of lipocortines which inhibit the activity of PLA2 and therefore, decrease the production of arachidonic acid and mediators of lipoxygenase and cyclooxygenase pathways.Anti-inflammatories need to be administered as quickly as possible as the effect of these drugs can diminish even just an hour after meconium aspiration. For example, early administration of dexamethasone significantly enhanced gas exchange, reduced ventilatory pressures, decreased the number of neutrophils in the bronchoalveolar area, reduced oedema formation and oxidative lung injury. However, glucocorticoids may increase the risk of infection and this risk increases with the dose and duration of glucocorticoid treatment. Other issues can arise, such as aggravation of diabetes mellitus, osteoporosis, skin atrophy and growth retardation in children.
Inhibitors of phosphodiesterase
Phosphodiesterases (PDE) degrades cAMP and cGMP and, within the respiratory system of a newborn with MAS, various isoforms of PDE may be involved due to their pro-inflammatory and smooth muscle contractile activity. Therefore, non-selective and selective inhibitors of PDE could potentially be used in MAS therapy. However, the use of PDE inhibitors can cause cardiovascular side effects. Non-selective PDE inhibitors, such as methylxanthines, increase concentrations of cAMP and cGMP in the cells leading to bronchodilation and vasodilation. Additionally, methylxanthines decreases the concentrations of calcium, acetylcholine and monoamines, this controls the release of various mediators of inflammation and bronchoconstriction, including prostaglandins. Selective PDE inhibitors target one subtype of phosphodiesterase and in MAS the activities of PDE-3, PDE-4, PDE-5 and PDE-7 may become enhanced. For example, Milrinone (a selective PDE3 inhibitor) improved oxygenation and survival of neonates with MAS.
Inhibitors of cyclooxygenase
Arachidonic acid is metabolised, via cyclooxygenase (COX) and lipoxygenase, to various substances including prostaglandins and leukotrienes, which exhibit potent pro-inflammatory and vasoactive effects. By inhibiting COX, and more specifically COX-2, (either through selective or non-selective drugs) inflammation and oedema can be reduced. However, COX inhibitors may induce peptic ulcers and cause hyperkalemia and hypernatremia. Additionally, COX inhibitors have not shown any great response in the treatment of MAS.
Antibiotics
Meconium is typically sterile however, it can contain various cultures of bacteria so appropriate antibiotics may need to be prescribed.
Surfactant treatment
Lung lavage with diluted surfactant is a new treatment with potentially beneficial results depending on how early it is administered in newborns with MAS. This treatment shows promise as it has a significant effect on air leaks, pneumothorax, the need for ECMO and death. Early intervention and using it on newborns with mild MAS is more effective. However, there are risks as a large volume of fluid instillation to the lung of a newborn can be dangerous (particularly in cases of severe MAS with pulmonary hypertension) as it can exacerbate hypoxia and lead to mortality.
Previous treatments
Originally, it was believed that MAS developed as a result of the meconium being a physical blockage of the airways. Thus, to prevent newborns, who were born through MSAF, from developing MAS, suctioning of the oropharyngeal and nasopharyngeal area before delivery of the shoulders followed by tracheal aspiration was utilised for 20 years. This treatment was believed to be effective as it was reported to significantly decrease the incidence of MAS compared to those newborns born through MSAF who were not treated. This claim was later disproved and future studies concluded that oropharyngeal and nasopharyngeal suctioning, before delivery of the shoulders in infants born through MSAF, does not prevent MAS or its complications. In fact, it can cause more issues and damage (e.g. mucosal damage), thus it is not a recommended preventative treatment. Suctioning may not significantly reduce the incidence of MAS as meconium passage and aspiration may occur in-utero. Thereby making the suctioning redundant and useless as the meconium may already be deep within the lungs at the time of birth.Historically, amnioinfusion has been used when MSAF was present, which involves a transcervical infusion of fluid during labour. The idea was to dilute the thick meconium to reduce its potential pathophysiology and reduce cases of MAS, since MAS is more prevalent in cases of thick meconium. However, there are associated risks, such as umbilical cord prolapse and prolongation of labour. The UK National Institute of Health and Clinical Excellence (NICE) Guidelines recommend against the use of amnioinfusion in women with MSAF.
Prevalence
1 in every 7 pregnancies have MSAF and, of these cases, approximately 5% of these infants develop MAS. MSAF is observed 23-52% in pregnancies at 42 weeks therefore, the frequency of MAS increases as the length of gestation increases, such that the prevalence is greatest in post-term pregnancies. Conversely, preterm births are not frequently associated with MSAF (only approximately 5% in total contain MSAF). The rate of MAS declines in populations where labour is induced in women that have pregnancies exceeding 41 weeks. There are many suspected pre-disposing factors that are thought to increase the risk of MAS. For example, the risk of MSAF is higher in African American, African and Pacific Islander mothers, compared to mothers from other ethnic groups.
Future research
Research is being focused on developing both a successful method for preventing MAS as well as an effective treatment. For example, investigations are being made in the efficiency of anti-inflammatory agents, surfactant replacement therapy and antibiotic therapy. More research needs to be conducted on the pharmacological properties of, for example, glucocorticoids, including dosages, administration, timing or any drug interactions. Additionally, there is still research being conducted on whether intubation and suctioning of meconium in newborns with MAS is beneficial, harmful or is simply a redundant and outdated treatment. In general, there is still no generally accepted therapeutic protocol and effective treatment plan for MAS.
See also
Aspiration pneumonia
References
External links
eMedicines article about meconium aspiration syndrome |
Imperforate hymen | An imperforate hymen is a congenital disorder where a hymen without an opening completely obstructs the vagina. It is caused by a failure of the hymen to perforate during fetal development. It is most often diagnosed in adolescent girls when menstrual blood accumulates in the vagina and sometimes also in the uterus. It is treated by surgical incision of the hymen.
Signs and symptoms
Affected newborns may present with acute urinary retention. In adolescent females, the most common symptoms of an imperforate hymen are cyclic pelvic pain and amenorrhea; other symptoms associated with hematocolpos include urinary retention, constipation, low back pain, nausea, and diarrhea. Other vaginal anomalies can have similar symptoms to an imperforate hymen. Vaginal atresia and a transverse vaginal septum require differentiation. A strong urge to defecate has been observed in a few women.
Complications
If untreated or unrecognized before puberty, an imperforate hymen can lead to peritonitis or endometriosis due to retrograde bleeding. Additionally, it can lead to mucometrocolpos (dilatation of the vaginal canal and uterus due to mucus buildup) or hematometrocolpos (dilatation due to buildup of menstrual fluid). Mucometrocolpos and hematocolpos can in turn cause urinary retention, constipation, and urinary tract infection.
Pathophysiology
An imperforate hymen is formed during fetal development when the sinovaginal bulbs fail to canalize with the rest of the vagina. Although some instances of familial occurrence have been reported, the conditions occurrence is mostly sporadic, and no genetic markers or mutations have been linked to its cause.
Diagnosis
An imperforate hymen is most often diagnosed in adolescent girls after the age of menarche with otherwise normal development. In adolescent girls of menarcheal age, the typical presentation of the condition is amennorhea and cyclic pelvic pain, indicative of hematocolpos secondary to vaginal obstruction. An imperforate hymen is usually visible on vaginal inspection as a bulging blue membrane. If hematocolpos is present, a mass is often palpable on abdominal or rectal examination. The diagnosis of an imperforate hymen is usually made based purely on the physical exam, although if necessary the diagnosis can be confirmed by transabdominal, transperineal or transrectal ultrasound.An imperforate hymen can also be diagnosed in newborn babies and it is occasionally detected on ultrasound scans of the foetus during pregnancy. In newborns the diagnosis is based on the findings of an abdominal or pelvic mass or a bulging hymen. Examination of the normal neonatal vagina usually reveals a track of mucus at the posterior commissure of the labia majora; an absence of mucus may indicate an imperforate hymen or another vaginal obstruction.A similar condition, cribriform hymen, is diagnosed when the hymen contains many minute openings.
Management
Before surgical intervention in adolescents, symptoms can be relieved by the combined oral contraceptive pill taken continuously to suppress the menstrual cycle or NSAIDs to relieve pain. Surgical treatment of the imperforate hymen by hymenotomy typically involves making cruciate incisions of the hymen, excising segments of hymen from their bases, and draining the vaginal canal and uterus. For affected girls who wish (or whose parents wish) to have their hymens preserved, surgical techniques to excise of a central flange of the hymen can be used. The timing of surgical hymen repair is controversial: some doctors believe it is best to intervene immediately after the neonatal period, while others believe that surgical repair should be delayed until puberty, when estrogenization is complete.
Epidemiology
Imperforate hymen is the most common vaginal obstruction of congenital origin. Estimates of the frequency of imperforate hymen vary from 1 in 1000 to 1 in 10,000 females.
References
Glavan, N; Haller, H; Brnčić-Fischer, A; Glavan-Gačanin, L; Miletić, D; Jonjić, N (2016). "Imperforate hymen presenting as vaginal cyst in a 16-month-old child - considerations for an early diagnosis". Scottish Medical Journal. 61 (1): 48–50. doi:10.1177/0036933015615263. PMID 26659454. S2CID 27077599.
Imperforate hymen at Medscape
== External links == |
Spondyloperipheral dysplasia | Spondyloperipheral dysplasia is an autosomal dominant disorder of bone growth. The condition is characterized by flattened bones of the spine (platyspondyly) and unusually short fingers and toes (brachydactyly). Some affected individuals also have other skeletal abnormalities, short stature, nearsightedness (myopia), hearing loss, and mental retardation. Spondyloperipheral dysplasia is a subtype of collagenopathy, types II and XI.
Genetics
Spondyloperipheral dysplasia is one of a spectrum of skeletal disorders caused by mutations in the COL2A1 gene, located on chromosome 12q13.11-q13.2. The protein made by this gene forms type II collagen, a molecule found mostly in cartilage and in the clear gel that fills the vitreous humour (the eyeball). Type II collagen is essential for the normal development of bones and other connective tissues (the tissues that form the bodys supportive framework).Mutations in the COL2A1 gene interfere with the assembly of type II collagen molecules. The protein made by the altered COL2A1 gene cannot be used to make type II collagen, resulting in a reduced amount of this type of collagen in the body. Instead of forming collagen molecules, the abnormal protein builds up in cartilage cells (chondrocytes). These changes disrupt the normal development of bones, leading to the signs and symptoms of spondyloperipheral dysplasia.The disorder is believed to be inherited in an autosomal dominant manner. This indicates that the defective gene responsible for the disorder is located on an autosome (chromosome 12 is an autosome), and only one copy of the defective gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.
Diagnosis
Management
References
This article incorporates public domain text from
Spondyloperipheral dysplasia at NLM Genetics Home Reference
External links
Spondyloperipheral dysplasia short ulna at NIHs Office of Rare Diseases |
Lipopolysaccharide | Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer membrane of Gram-negative bacteria. Today, the term endotoxin is often used synonymously with LPS, although there are a few endotoxins (in the original sense of toxins that are inside the bacterial cell that are released when the cell disintegrates) that are not related to LPS, such as the so-called delta endotoxin proteins produced by Bacillus thuringiensis.Lipopolysaccharides can have substantial impacts on human health, primarily through interactions with the immune system. LPS is a potent activator of the immune system and pyrogen (agent that causes fever). In severe cases, LPS can play a role in causing septic shock. In lower levels and over a longer time period, there is evidence LPS may play an important and harmful role in autoimmunity, obesity, depression, and cellular senescence.
Discovery
The toxic activity of LPS was first discovered and termed endotoxin by Richard Friedrich Johannes Pfeiffer. He distinguished between exotoxins, toxins that are released by bacteria into the surrounding environment, and endotoxins, which are toxins "within" the bacterial cell and released only after destruction of the bacterial outer membrane. Subsequent work showed that release of LPS from gram negative microbes does not necessarily require the destruction of the bacterial cell wall, but rather, LPS is secreted as part of the normal physiological activity of membrane vesicle trafficking in the form of bacterial outer membrane vesicles (OMVs), which may also contain other virulence factors and proteins.
Functions in bacteria
LPS is a major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria and protecting the membrane from certain kinds of chemical attack. LPS is the most abundant antigen on the cell surface of most Gram-negative bacteria, contributing up to 80% of the outer membrane of E. coli and Salmonella. LPS increases the negative charge of the cell membrane and helps stabilize the overall membrane structure. It is of crucial importance to many Gram-negative bacteria, which die if the genes coding for it are mutated or removed. However, it appears that LPS is nonessential in at least some Gram-negative bacteria, such as Neisseria meningitidis, Moraxella catarrhalis, and Acinetobacter baumannii. It has also been implicated in non-pathogenic aspects of bacterial ecology, including surface adhesion, bacteriophage sensitivity, and interactions with predators such as amoebae. LPS is also required for the functioning of omptins, a class of bacterial protease.
Composition
Lipopolysaccharides are composed of three parts: The O antigen (or O polysaccharide), the Core oligosaccharide, and Lipid A.
O-antigen
The repetitive glycan polymer contained within an LPS is referred to as the O antigen, O polysaccharide, or O side-chain of the bacteria. The O antigen is attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. The composition of the O chain varies from strain to strain; there are over 160 different O antigen structures produced by different E. coli strains. The presence or absence of O chains determines whether the LPS is considered "rough" or "smooth". Full-length O-chains would render the LPS smooth, whereas the absence or reduction of O-chains would make the LPS rough. Bacteria with rough LPS usually have more penetrable cell membranes to hydrophobic antibiotics, since a rough LPS is more hydrophobic. O antigen is exposed on the very outer surface of the bacterial cell, and, as a consequence, is a target for recognition by host antibodies.
Core
The core domain always contains an oligosaccharide component that attaches directly to lipid A and commonly contains sugars such as heptose and 3-Deoxy-D-manno-oct-2-ulosonic acid (also known as KDO, keto-deoxyoctulosonate). The LPS cores of many bacteria also contain non-carbohydrate components, such as phosphate, amino acids, and ethanolamine substituents.
Lipid A
Lipid A is, in normal circumstances, a phosphorylated glucosamine disaccharide decorated with multiple fatty acids. These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane, and the rest of the LPS projects from the cell surface. The lipid A domain is responsible for much of the toxicity of Gram-negative bacteria. When bacterial cells are lysed by the immune system, fragments of membrane containing lipid A are released into the circulation, causing fever, diarrhea, and possible fatal endotoxic shock (also called septic shock). The Lipid A moiety is a very conserved component of the LPS. However Lipid A structure varies among bacterial species. Lipid A structure largely defines the degree and nature of the overall host immune activation.
Lipooligosaccharides
The "rough form" of LPS has a lower molecular weight due to the absence of the O polysaccharide. In its place is a short oligosaccharide: this form is known as Lipooligosaccharide (LOS), and is a glycolipid found in the outer membrane of some types of Gram-negative bacteria, such as Neisseria spp. and Haemophilus spp. LOS plays a central role in maintaining the integrity and functionality of the outer membrane of the Gram negative cell envelope. LOS play an important role in the pathogenesis of certain bacterial infections because they are capable of acting as immunostimulators and immunomodulators. Furthermore, LOS molecules are responsible for the ability of some bacterial strains to display molecular mimicry and antigenic diversity, aiding in the evasion of host immune defenses and thus contributing to the virulence of these bacterial strains. In the case of Neisseria meningitidis, the lipid A portion of the molecule has a symmetrical structure and the inner core is composed of 3-deoxy-D-manno-2-octulosonic acid (KDO) and heptose (Hep) moieties. The outer core oligosaccharide chain varies depending on the bacterial strain.
LPS detoxification
A highly conserved host enzyme called acyloxyacyl hydrolase (AOAH) may detoxify LPS when it enters, or is produced in, animal tissues. It may also convert LPS in the intestine into an LPS inhibitor. Neutrophils, macrophages and dendritic cells produce this lipase, which inactivates LPS by removing the two secondary acyl chains from lipid A to produce tetraacyl LPS. If mice are given LPS parenterally, those that lack AOAH develop high titers of non-specific antibodies, develop prolonged hepatomegaly, and experience prolonged endotoxin tolerance. LPS inactivation may be required for animals to restore homeostasis after parenteral LPS exposure. Although mice have many other mechanisms for inhibiting LPS signaling, none is able to prevent these changes in animals that lack AOAH.
Dephosphorylation of LPS by intestinal alkaline phosphatase can reduce the severity of Salmonella tryphimurium and Clostridioides difficile infection restoring normal gut microbiota. Alkaline phosphatase prevents intestinal inflammation (and
"leaky gut") from bacteria by dephosphorylating the Lipid A portion of LPS.
Biosynthesis and transport
Biological effects on hosts infected with Gram-negative bacteria
Immune response
LPS acts as the prototypical endotoxin because it binds the CD14/TLR4/MD2 receptor complex in many cell types, but especially in monocytes, dendritic cells, macrophages and B cells, which promotes the secretion of pro-inflammatory cytokines, nitric oxide, and eicosanoids. Bruce Beutler was awarded a portion of the 2011 Nobel Prize in Physiology or Medicine for his work demonstrating that TLR4 is the LPS receptor.As part of the cellular stress response, superoxide is one of the major reactive oxygen species induced by LPS in various cell types that express TLR (toll-like receptor). LPS is also an exogenous pyrogen (fever-inducing substance).LPS function has been under experimental research for several years due to its role in activating many transcription factors. LPS also produces many types of mediators involved in septic shock. Humans are much more sensitive to LPS than other animals (e.g., mice). A dose of 1 µg/kg induces shock in humans, but mice will tolerate a dose up to a thousand times higher. This may relate to differences in the level of circulating natural antibodies between the two species.
Said et al. showed that LPS causes an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L1.Endotoxins are in large part responsible for the dramatic clinical manifestations of infections with pathogenic Gram-negative bacteria, such as Neisseria meningitidis, the pathogens that causes meningococcal disease, including meningococcemia, Waterhouse–Friderichsen syndrome, and meningitis.
Portions of the LPS from several bacterial strains have been shown to be chemically similar to human host cell surface molecules; the ability of some bacteria to present molecules on their surface which are chemically identical or similar to the surface molecules of some types of host cells is termed molecular mimicry. For example, in Neisseria meningitidis L2,3,5,7,9, the terminal tetrasaccharide portion of the oligosaccharide (lacto-N-neotetraose) is the same tetrasaccharide as that found in paragloboside, a precursor for ABH glycolipid antigens found on human erythrocytes. In another example, the terminal trisaccharide portion (lactotriaose) of the oligosaccharide from pathogenic Neisseria spp. LOS is also found in lactoneoseries glycosphingolipids from human cells. Most meningococci from groups B and C, as well as gonococci, have been shown to have this trisaccharide as part of their LOS structure. The presence of these human cell surface mimics may, in addition to acting as a camouflage from the immune system, play a role in the abolishment of immune tolerance when infecting hosts with certain human leukocyte antigen (HLA) genotypes, such as HLA-B35.LPS can be sensed directly by hematopoietic stem cells (HSCs) through the bonding with TLR4, causing them to proliferate in reaction to a systemic infection. This response activate the TLR4-TRIF-ROS-p38 signaling within the HSCs and through a sustained TLR4 activation can cause a proliferative stress, leading to impair their competitive repopulating ability. Infection in mice using S. typhimurium showed similar results, validating the experimental model also in vivo.
Effect of variability on immune response
O-antigens (the outer carbohydrates) are the most variable portion of the LPS molecule, imparting the antigenic specificity. In contrast, lipid A is the most conserved part. However, lipid A composition also may vary (e.g., in number and nature of acyl chains even within or between genera). Some of these variations may impart antagonistic properties to these LPS. For example, Rhodobacter sphaeroides diphosphoryl lipid A (RsDPLA) is a potent antagonist of LPS in human cells, but is an agonist in hamster and equine cells.It has been speculated that conical Lipid A (e.g., from E. coli) are more agonistic, less conical lipid A like those of Porphyromonas gingivalis may activate a different signal (TLR2 instead of TLR4), and completely cylindrical lipid A like that of Rhodobacter sphaeroides is antagonistic to TLRs. In general, LPS gene clusters are highly variable between different strains, subspecies, species of bacterial pathogens of plants and animals.Normal human blood serum contains anti-LOS antibodies that are bactericidal and patients that have infections caused by serotypically distinct strains possess anti-LOS antibodies that differ in their specificity compared with normal serum. These differences in humoral immune response to different LOS types can be attributed to the structure of the LOS molecule, primarily within the structure of the oligosaccharide portion of the LOS molecule.
In Neisseria gonorrhoeae it has been demonstrated that the antigenicity of LOS molecules can change during an infection due to the ability of these bacteria to synthesize more than one type of LOS, a characteristic known as phase variation. Additionally, Neisseria gonorrhoeae, as well as Neisseria meningitidis and Haemophilus influenzae, are capable of further modifying their LOS in vitro, for example through sialylation (modification with sialic acid residues), and as a result are able to increase their resistance to complement-mediated killing or even down-regulate complement activation or evade the effects of bactericidal antibodies. Sialylation may also contribute to hindered neutrophil attachment and phagocytosis by immune system cells as well as a reduced oxidative burst. Haemophilus somnus, a pathogen of cattle, has also been shown to display LOS phase variation, a characteristic which may help in the evasion of bovine host immune defenses.
Taken together, these observations suggest that variations in bacterial surface molecules such as LOS can help the pathogen evade both the humoral (antibody and complement-mediated) and the cell-mediated (killing by neutrophils, for example) host immune defenses.
Non-canonical pathways of LPS recognition
Recently, it was shown that in addition to TLR4 mediated pathways, certain members of the family of the transient receptor potential ion channels recognize LPS. LPS-mediated activation of TRPA1 was shown in mice and Drosophila melanogaster flies. At higher concentrations, LPS activates other members of the sensory TRP channel family as well, such as TRPV1, TRPM3 and to some extent TRPM8.
LPS is recognized by TRPV4 on epithelial cells. TRPV4 activation by LPS was necessary and sufficient to induce nitric oxide production with a bactericidal effect.
Health effects
In general the health effects of LPS are due to its abilities as a potent activator and modulator of the immune system, especially its inducement of inflammation.
Endotoxemia
The presence of endotoxins in the blood is called endotoxemia. High level of endotoxemia can lead to septic shock, while lower concentration of endotoxins in the bloodstream is called metabolic endotoxemia. Endotoxemia is associated with obesity, diet, cardiovascular diseases, and diabetes, while also host genetics might have an effect.Moreover, endotoxemia of intestinal origin, especially, at the host-pathogen interface, is considered to be an important factor in the development of alcoholic hepatitis, which is likely to develop on the basis of the small bowel bacterial overgrowth syndrome and an increased intestinal permeability.Lipid A may cause uncontrolled activation of mammalian immune systems with production of inflammatory mediators that may lead to septic shock. This inflammatory reaction is mediated by Toll-like receptor 4 which is responsible for immune system cell activation. Damage to the endothelial layer of blood vessels caused by these inflammatory mediators can lead to capillary leak syndrome, dilation of blood vessels and a decrease in cardiac function and can lead to septic shock. Pronounced complement activation can also be observed later in the course as the bacteria multiply in the blood. High bacterial proliferation triggering destructive endothelial damage can also lead to disseminated intravascular coagulation (DIC) with loss of function of certain internal organs such as the kidneys, adrenal glands and lungs due to compromised blood supply. The skin can show the effects of vascular damage often coupled with depletion of coagulation factors in the form of petechiae, purpura and ecchymoses. The limbs can also be affected, sometimes with devastating consequences such as the development of gangrene, requiring subsequent amputation. Loss of function of the adrenal glands can cause adrenal insufficiency and additional hemorrhage into the adrenals causes Waterhouse-Friderichsen syndrome, both of which can be life-threatening.
It has also been reported that gonococcal LOS can cause damage to human fallopian tubes.
Auto-immune disease
The molecular mimicry of some LOS molecules is thought to cause autoimmune-based host responses, such as flareups of multiple sclerosis. Other examples of bacterial mimicry of host structures via LOS are found with the bacteria Helicobacter pylori and Campylobacter jejuni, organisms which cause gastrointestinal disease in humans, and Haemophilus ducreyi which causes chancroid. Certain C. jejuni LPS serotypes (attributed to certain tetra- and pentasaccharide moieties of the core oligosaccharide) have also been implicated with Guillain–Barré syndrome and a variant of Guillain–Barré called Miller-Fisher syndrome.
Link to obesity
Epidemiological studies have shown that increased endotoxin load, which can be a result of increased populations of endotoxin-producing bacteria in the intestinal tract, is associated with certain obesity-related patient groups. Other studies have shown that purified endotoxin from Escherichia coli can induce obesity and insulin-resistance when injected into germ-free mouse models. A more recent study has uncovered a potentially contributing role for Enterobacter cloacae B29 toward obesity and insulin resistance in a human patient. The presumed mechanism for the association of endotoxin with obesity is that endotoxin induces an inflammation-mediated pathway accounting for the observed obesity and insulin resistance. Bacterial genera associated with endotoxin-related obesity effects include Escherichia and Enterobacter.
Depression
There is experimental and observational evidence that LPS might play a role in depression. Administration of LPS in mice can lead to depressive symptoms, and there seem to be elevated levels of LPS in some people with depression. Inflammation may sometimes play a role in the development of depression, and LPS is pro-inflammatory.
Cellular senescence
Inflammation induced by LPS can induce cellular senescence, as has been shown for the lung epithelial cells and microglial cells (the latter leading to neurodegeneration).
Role as contaminant in biotechnology and research
Lipopolysaccharides are frequent contaminants in plasmid DNA prepared from bacteria or proteins expressed from bacteria, and must be removed from the DNA or protein to avoid contaminating experiments and to avoid toxicity of products manufactured using industrial fermentation.Ovalbumin is frequently contaminated with endotoxins. Ovalbumin is one of the extensively studied proteins in animal models and also an established model allergen for airway hyper-responsiveness (AHR). Commercially available ovalbumin that is contaminated with LPS can falsify research results, as it does not accurately reflect the effect of the protein antigen on animal physiology.In pharmaceutical production, it is necessary to remove all traces of endotoxin from drug product containers, as even small amounts of endotoxin will cause illness in humans. A depyrogenation oven is used for this purpose. Temperatures in excess of 300 °C are required to fully break down LPS.The standard assay for detecting presence of endotoxin is the Limulus Amebocyte Lysate (LAL) assay, utilizing blood from the Horseshoe crab (Limulus polyphemus). Very low levels of LPS can cause coagulation of the limulus lysate due to a powerful amplification through an enzymatic cascade. However, due to the dwindling population of horseshoe crabs, and the fact that there are factors that interfere with the LAL assay, efforts have been made to develop alternative assays, with the most promising ones being ELISA tests using a recombinant version of a protein in the LAL assay, Factor C.
See also
Bioaerosol
Depyrogenation
Host-pathogen interface
Mucopolysaccharide
Nesfatin-1
Schwartzman reaction
AOAH
References
External links
Lipopolysaccharides at the US National Library of Medicine Medical Subject Headings (MeSH) |
Thrombocytopenia | Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in 20% of medical patients and a third of surgical patients.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. Values outside this range do not necessarily indicate disease. One common definition of thrombocytopenia requiring emergency treatment is a platelet count below 50,000 per microliter. Thrombocytopenia can be contrasted with the conditions associated with an abnormally high level of platelets in the blood: thrombocythemia (when the cause is unknown), and thrombocytosis (when the cause is known).
Signs and symptoms
Thrombocytopenia usually has no symptoms and is picked up on a routine complete blood count. Some individuals with thrombocytopenia may experience external bleeding such as nosebleeds, or bleeding gums. Some women may have heavier or longer periods or breakthrough bleeding. Bruising, particularly purpura in the forearms and petechiae in the feet, legs, and mucous membranes, may be caused by spontaneous bleeding under the skin.Eliciting a full medical history is vital to ensure the low platelet count is not secondary to another disorder. Ensuring that the other blood cell types, such as red blood cells and white blood cells are not also suppressed, is also important.
Painless, round, and pinpoint (1 to 3 mm in diameter) petechiae usually appear and fade, and sometimes group to form ecchymoses. Larger than petechiae, ecchymoses are purple, blue, or yellow-green areas of skin that vary in size and shape. They can occur anywhere on the body.A person with this disease may also complain of malaise, fatigue, and general weakness (with or without accompanying blood loss). Acquired thrombocytopenia may be associated with the use of certain drugs. Inspection typically reveals evidence of bleeding (petechiae or ecchymoses), along with slow, continuous bleeding from any injuries or wounds. Adults may have large, blood-filled bullae in the mouth. If the persons platelet count is between 30,000 and 50,000/mm3, bruising with minor trauma may be expected; if it is between 15,000 and 30,000/mm3, spontaneous bruising will be seen (mostly on the arms and legs).
Causes
Thrombocytopenia can be inherited or acquired.
Decreased production
Abnormally low platelet production may be caused by:
Dehydration, Vitamin B12 or folic acid deficiency
Leukemia, myelodysplastic syndrome, or aplastic anemia
Decreased production of thrombopoietin by the liver in liver failure
Sepsis, systemic viral or bacterial infection
Leptospirosis
Hereditary syndromesACTN1-related thrombocytopenia
Amegakaryocytic thrombocytopenia with radio-ulnar synostosis
ANKRD26 related thrombocytopenia
Autosomal dominant thrombocytopenia
Bernard–Soulier syndrome (associated with giant platelet disorder)
Congenital amegakaryocytic thrombocytopenia
Congenital amegakaryocytic thrombocytopenia and radioulnar synostosis
CYCS-related thrombocytopenia
Epstein syndrome (associated with giant platelet disorder)
ETV6 related thrombocytopenia
Fanconi anemia
Filaminopathies A
FYB related thrombocytopenia
Glanzmanns thrombasthenia
GNE myopathy with congenital thrombocytopenia
Gray platelet syndrome (associated with giant platelet disorder)
Harris platelet syndrome (associated with giant platelet disorder)
Macrothrombocytopenia and hearing loss
May–Hegglin anomaly (associated with giant platelet disorder)
MYH9-related disease (associated with giant platelet disorder)
PRKACG-related thrombocytopenia
Paris-Trousseau thrombocytopenia/Jacobsen syndrome
Sebastian syndrome
SLFN14-related thrombocytopenia
Stormorken syndrome
TRPM7-related thrombocytopenia
Thrombocytopenia absent radius syndrome
Tropomyosin 4-related thrombocytopenia
TUBB1-related thrombocytopenia
Upshaw–Schulman syndrome
Wiskott–Aldrich syndrome
X-linked thrombocytopenia
X-linked thrombocytopenia with thalassemia
Increased destruction
Abnormally high rates of platelet destruction may be due to immune or nonimmune conditions, including:
Immune thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Hemolytic–uremic syndrome
Disseminated intravascular coagulation
Paroxysmal nocturnal hemoglobinuria
Antiphospholipid syndrome
Systemic lupus erythematosus
Post-transfusion purpura
Neonatal alloimmune thrombocytopenia
Hypersplenism
Dengue fever
Gauchers disease
Zika virus
Medication-induced
These medications can induce thrombocytopenia through direct myelosuppression:
Valproic acid
Methotrexate
Carboplatin
Interferon
Isotretinoin
Panobinostat
H2 blockers and proton-pump inhibitors
Other causes
Lab error, possibly due to the anticoagulant EDTA in CBC specimen tubes; a citrated platelet count is a useful follow-up study
Snakebite
Niacin toxicity
Lyme disease
Thrombocytapheresis (also called plateletpheresis)
Niemann–Pick disease
Diagnosis
Laboratory tests for thrombocytopenia might include full blood count, liver enzymes, kidney function, vitamin B12 levels, folic acid levels, erythrocyte sedimentation rate, and peripheral blood smear. If the cause for the low platelet count remains unclear, a bone marrow biopsy is usually recommended to differentiate cases of decreased platelet production from cases of peripheral platelet destruction.Thrombocytopenia in hospitalized alcoholics may be caused by spleen enlargement, folate deficiency, and most frequently, the direct toxic effect of alcohol on production, survival time, and function of platelets. Platelet count begins to rise after 2 to 5 days abstinence from alcohol. The condition is generally benign, and clinically significant hemorrhage is rare.In severe thrombocytopenia, a bone marrow study can determine the number, size, and maturity of the megakaryocytes. This information may identify ineffective platelet production as the cause of thrombocytopenia and rule out a malignant disease process at the same time.
Treatment
Treatment is guided by the severity and specific cause of the disease. Treatment focuses on eliminating the underlying problem, whether that means discontinuing drugs suspected to cause it or treating underlying sepsis. Diagnosis and treatment of serious thrombocytopenia is usually directed by a hematologist. Corticosteroids may be used to increase platelet production. Lithium carbonate or folate may also be used to stimulate platelet production in the bone marrow.
Platelet transfusions
Platelet transfusions may be suggested for people who have a low platelet count due to thrombocytopenia.
Thrombotic thrombocytopenic purpura
Treatment of thrombotic thrombocytopenic purpura (TTP) is a medical emergency, since the associated hemolytic anemia and platelet activation can lead to kidney failure and changes in the level of consciousness. Treatment of TTP was revolutionized in the 1980s with the application of plasmapheresis. According to the Furlan-Tsai hypothesis, this treatment works by removing antibodies against the von Willebrand factor-cleaving protease ADAMTS-13. The plasmapheresis procedure also adds active ADAMTS-13 protease proteins to the patient, restoring a normal level of von Willebrand factor multimers. Patients with persistent antibodies against ADAMTS-13 do not always manifest TTP, and these antibodies alone are not sufficient to explain how plasmapheresis treats TTP.
Immune thrombocytopenic purpura
Many cases of immune thrombocytopenic purpura (ITP) also known as idiopathic thrombocytopenic purpura, can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts under 50,000 are usually monitored with regular blood tests, and those with counts under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such low platelet counts. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although exceptions to this observation have been documented.Thrombopoetin analogues have been tested extensively for the treatment of ITP. These agents had previously shown promise, but had been found to stimulate antibodies against endogenous thrombopoietin or lead to thrombosis. Romiplostim (trade name Nplate, formerly AMG 531) was found to be safe and effective for the treatment of ITP in refractory patients, especially those who relapsed following splenectomy.
Heparin-induced thrombocytopenia
Discontinuation of heparin is critical in a case of heparin-induced thrombocytopenia (HIT). Beyond that, however, clinicians generally treat to avoid thrombosis. Treatment may include a direct thrombin inhibitor, such as lepirudin or argatroban. Other blood thinners sometimes used in this setting include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HIT because thrombosis, not bleeding, is the primary problem. Warfarin is not recommended until platelets have normalized.
Congenital amegakaryocytic thrombocytopenia
Bone marrow/stem cell transplants are the only known cures for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death before the transplant can be performed, although this is not always the case.
Human induced pluripotent stem cell-derived platelets
Human induced pluripotent stem cell-derived platelets is a technology currently being researched by the private sector, in association with the Biomedical Advanced Research and Development Authority and the U.S. Department of Health and Human Services, that would create platelets outside the human body.
Neonatal thrombocytopenia
Thrombocytopenia affects a few newborns, and its prevalence in neonatal intensive care units is high. Normally, it is mild and resolves without consequences. Most cases affect preterm birth infants and result from placental insufficiency and/or fetal hypoxia. Other causes, such as alloimmunity, genetics, autoimmunity, and infection, are less frequent.Thrombocytopenia that starts after the first 72 hours since birth is often the result of underlying sepsis or necrotizing enterocolitis. In the case of infection, PCR tests may be useful for rapid pathogen identification and detection of antibiotic resistance genes. Possible pathogens include viruses (e.g. cytomegalovirus, rubella virus, HIV), bacteria (e.g. Staphylococcus spp., Enterococcus spp., Streptococcus agalactiae, Listeria monocytogenes, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Yersinia enterocolitica), fungi (e.g. Candida spp.), and Toxoplasma gondii. The severity of thrombocytopenia may be correlated with pathogen type; some research indicates that the most severe cases are related to fungal or Gram-negative bacterial infection. The pathogen may be transmitted during or before birth, by breast feeding, or during transfusion. Interleukin-11 is being investigated as a drug for managing thrombocytopenia, especially in cases of sepsis or necrotizing enterocolitis.
References
== External links == |
Anton syndrome | Anton syndrome, also known as Antons blindness and visual anosognosia, is a rare symptom of brain damage occurring in the occipital lobe. Those who have it are cortically blind, but affirm, often quite adamantly and in the face of clear evidence of their blindness, that they are capable of seeing. Failing to accept being blind, people with Anton syndrome dismiss evidence of their condition and employ confabulation to fill in the missing sensory input. It is named after the neurologist Gabriel Anton. Only 28 cases have been published.Although sometimes the two terms are used as synonymous, Anton syndrome must not be confused with Anton–Babinski syndrome which is characterised clinically by contralateral sensory neglect, anosognosia with associated affective indifference toward the condition (anosodiaphoria), construction and dressing apraxia. Anton–Babinski syndrome is the right-hemisphere equivalent of Gerstmann syndrome and it is due to non-dominant inferior parietal lobule damage.
Presentation
Anton syndrome is mostly seen following a stroke, but may also be seen after head injury. Neurologist Macdonald Critchley describes it thus:
The sudden development of bilateral occipital dysfunction is likely to produce transient physical and psychological effects in which mental confusion may be prominent. It may be some days before the relatives, or the nursing staff, stumble onto the fact that the patient has actually become sightless. This is not only because the patient ordinarily does not volunteer the information that they have become blind, but he furthermore misleads his entourage by behaving and talking as though they were sighted. Attention is aroused however when the patient is found to collide with pieces of furniture, to fall over objects, and to experience difficulty in finding his way around. They may try to walk through a wall or through a closed door on his way from one room to another. Suspicion is still further alerted when they begin to describe people and objects around them which, as a matter of fact, are not there at all.
Thus we have the twin symptoms of anosognosia (or lack of awareness of defect) and confabulation, the latter affecting both speech and behaviour.
Anton syndrome may be thought of ideally as the opposite of blindsight, blindsight occurring when part of the visual field is not consciously experienced, but some reliable perception does in fact occur.
Causes
Why patients with Anton syndrome deny their blindness is unknown, although there are many theories. One hypothesis is that damage to the visual cortex results in the inability to communicate with the speech-language areas of the brain. Visual imagery is received but cannot be interpreted; the speech centers of the brain confabulate a response.Patients have also reported visual anosognosia after experiencing ischemic vascular cerebral disease. A 96-year-old man, who was admitted to an emergency department complaining of a severe headache and sudden loss of vision, was discovered to have had a posterior cerebral artery thrombosis with consequent loss of vision. He adamantly claimed he was able to see despite an ophthalmologic exam proving otherwise. An MRI of his brain proved that his right occipital lobe was ischemic. Similarly, a 56-year-old woman was admitted to the emergency department in a confused state and with severely impaired psychomotor skills. Ocular movements and pupil reflexes were still intact, but the patient could not name objects and was not aware of light changes in the room, and seemed unaware of her visual deficit.
Diagnosis
History
Most cases of Anton syndrome are reported from adults. The European Journal of Neurology published an article in 2007 that examines a case study of a six-year-old child with Anton syndrome and early stages of adrenoleukodystrophy. The child reportedly had abnormal eye movements, would often fall, and would reach for things and often miss his target. When his sight was tested at 20/20 he was still unable to read the large letters on the chart. He denied having headaches, diplopia, or eye pain and seemed unconcerned and unaware of his poor eyesight. Upon examination, his pupils were equal in shape, round, and reactive to light. His mother commented that he developed unusual eye movements and that they had a "roving quality".
Culture and society
Anton syndrome was featured in a two-part episode of the television series House M.D., titled "Euphoria", although it was ascribed to primary amoebic meningoencephalitis, a disease that usually does not cause the syndrome in real life. The syndrome features prominently in the Rupert Thomson novel The Insult. It is also mentioned in the science fiction novel Blindsight, by Peter Watts.It is mentioned frequently as "Antons Blindness" as one of the primary metaphors in Raj Patels The Value of Nothing. In Lars von Triers film Dogville, the character Jack McKay acts as if he can see but gives many signs he cannot.The syndrome is also the main theme of the Malaysian movie Desolasi (Desolation), where the patients live in their own world of imagination, while unable to see the real world. It is also mentioned in Oliver Sackss An Anthropologist on Mars.
See also
Prosopagnosia – Cognitive disorder of face perception
Riddoch syndrome – Type of visual impairment
Visual release hallucinations
== References == |
Wildervanck syndrome | Wildervanck syndrome or cervico-oculo-acoustic syndrome comprises a triad of:
Duane syndrome
Klippel-Feil anomaly (fused cervical vertebrae)
congenital hearing lossWildervanck syndrome is a developmental disorder that may be characterized by accessory tragi.
References
== External links == |
Oligodendroglioma | Oligodendrogliomas are a type of glioma that are believed to originate from the oligodendrocytes of the brain or from a glial precursor cell. They occur primarily in adults (9.4% of all primary brain and central nervous system tumors) but are also found in children (4% of all primary brain tumors).
Signs and symptoms
Oligodendroglioma arise mainly in the frontal lobe and in 50–80% of cases, the first symptom is the onset of seizure activity, without having any symptoms beforehand. Headaches combined with increased intracranial pressure are also a common symptom of oligodendroglioma. Depending on the location of the tumor, many different neurological deficits can be induced, including, but not limited to, visual loss, motor weakness and cognitive decline. A computed tomography (CT) or magnetic resonance imaging (MRI) scan is necessary to characterize tumor size, location, and hetero- or homogeneity. Final diagnosis relies on biopsy and histopathologic examination of the tumor mass.
Cause
The cause of oligodendrogliomas is unknown. Some studies have linked oligodendroglioma with a viral cause. A 2009 Oxford Neurosymposium study illustrated a 69% correlation between NJDS gene mutation and the tumor initiation. A single case report has linked oligodendroglioma to irradiation of pituitary adenoma.
Diagnosis
Microscopic appearance
Oligodendrogliomas cannot currently be differentiated from other brain lesions solely by their clinical or radiographic appearance. As such, a brain biopsy is the only method of definitive diagnosis. Oligodendrogliomas recapitulate the appearance of the normal resident oligodendroglia of the brain. (Their name derives from the Greek roots oligo meaning " few" and dendro meaning "trees".) They are generally composed of cells with small to slightly enlarged round nuclei with dark, compact nuclei and a small amount of eosinophilic cytoplasm. They are often referred to as "fried egg" cells due to their histologic appearance. They appear as a monotonous population of mildly enlarged round cells infiltrating normal brain parenchyma and producing vague nodules. Although the tumor may appear to be vaguely circumscribed, it is by definition a diffusely infiltrating tumor.Classically they tend to have a vasculature of finely branching capillaries that may take on a "chicken wire" appearance. When invading grey matter structures such as cortex, the neoplastic oligodendrocytes tend to cluster around neurons exhibiting a phenomenon referred to as "perineuronal satellitosis". Oligodendrogliomas may invade preferentially around vessels or under the pial surface of the brain.Oligodendrogliomas must be differentiated from the more common astrocytoma. Non-classical variants and combined tumors of both oligodendroglioma and astrocytoma differentiation are seen, making this distinction controversial between different neuropathology groups. Molecular diagnostics may make this differentiation obsolete in the future.
Other glial and glioneuronal tumors with which they are often confused due to their monotonous round cell appearance include pilocytic astrocytoma, central neurocytoma, the so-called dysembryoplastic neuroepithelial tumor, or occasionally ependymoma.
Histopathological grading
The histopathologic grading of oligodendrogliomas is controversial. Currently, the most commonly used grading schema is based on the year 2007 World Health Organization (WHO) guidelines. An updated classification is in progress. Oligodendrogliomas are generally dichotomized into grade II (low grade) tumor.
Unfortunately, the WHO guidelines include subjective criteria in grade II. In addition, the presence of low mitotic activity, vascular proliferation and necrosis, including pseudopallisading necrosis, is insufficient by itself to elevate the grade of this tumor. This leads to inevitable interobserver variability in diagnosis by pathologists. The ultimate responsibility for making treatment decisions and interpretation of this diagnosis lies with the oncologist in consultation with the patient and their family.
It has been proposed that WHO guidelines should contain a category for grade IV oligodendrogliomas which essentially appear to be glial neoplasms with overwhelming features of glioblastoma multiforme (GBM) arising from known lower grade oligodendrogliomas or GBM with a significant proportion of oligodendroglial differentiation. The diagnostic utility of this latter category is uncertain as these tumors may behave either like glioblastoma or grade III Anaplastic oligodendrogliomas. As such,this is an exceptionally unusual diagnosis.
The updated WHO guidelines published in 2007 recommends classifying such tumors for the time being as glioblastoma with oligodendroglioma component. It remains to be established whether or not these tumors carry a better prognosis than standard glioblastomas.
Molecular genetics
By far, the most common structural deformity found is co-deletion of chromosomal arms 1p and 19q. The high frequency of co-deletion is a striking feature of this glial tumour and is considered as a "genetic signature" of oligodendroglioma. Allelic losses on 1p and 19q, either separately or combined, are more common in classic oligodendrogliomas than in either astrocytomas or oligoastrocytomas. In one study, classic oligodendrogliomas showed 1p loss in 35 of 42 (83%) cases, 19q loss in 28 of 39 (72%), and these were combined in 27 of 39 (69%) cases; there was no significant difference in 1p/19q loss of heterozygosity status between low-grade and anaplastic oligodendroglioma. 1p/19q co-deletion has been correlated with both chemosensitivity and improved prognosis in oligodendrogliomas. The gene products lost as a consequence of this codeletion may include mediators of resistance to genotoxic therapies. Alternatively, 1p/19q loss might be an early oncogenic lesion promoting the formation of glial neoplasms, which retain high sensitivity to genotoxic stress. Most larger cancer treatment centers routinely check for the deletion of 1p/19q as part of the pathology report for oligodendrogliomas. The status of the 1p/19q loci can be detected by FISH, loss of heterozygosity (LOH) analysis or virtual karyotyping. Virtual karyotyping has the advantage of assessing the entire genome in one assay, as well as the 1p/19q loci. This allows assessment of other key loci in glial tumors, such as EGFR and TP53 copy number status.
Whereas the prognostic relevance of 1p and 19q deletions is well established for mixed oligoastrocytomas, the prognostic relevance of the deletions for low-grade gliomas is more controversial. In terms of low-grade gliomas, a recent study also suggests that 1p/19q co-deletion may be associated with a (1;19)(q10;p10) translocation which, like the combined 1p/19q deletion, is associated with superior overall survival and progression-free survival in low-grade glioma patients. Oligodendrogliomas show only rarely mutations in the p53 gene, which is in contrast to other gliomas. Epidermal growth factor receptor amplification and whole 1p/19q codeletion are mutually exclusive and predictive of completely different outcomes, with EGFR amplification predicting poor prognosis. There is a strong correlation between 1p/19q codeletion and the expression of proneural genes, suggesting that gliomas with a 1p19q codeletion represent a subgroup of proneural gliomas.
Treatment
Oligodendrogliomas are generally felt to be incurable using current treatments. However compared to the more common astrocytomas, they are slowly growing with prolonged survival. In one series, median survival times for oligodendrogliomas were 11.6 years for grade II.However, such figures can be misleading since they do not factor in the types of treatment nor the genetic signature of the tumors. A recent study analyzed survival based on chromosomal deletions and the effects of radiation or chemotherapy as treatment, with the following results (both low-grade and anaplastic oligodendrogliomas): 1p/19q deletion with radiation = 121 months (mean), 1p/19q deletion with chemotherapy = over 160 months (mean not yet reached), no 1p/19q deletion with radiation = 58 months (mean), and no 1p/19q deletion with chemotherapy = 75 months (mean).Because of the indolent nature of this tumor and the potential morbidity associated with neurosurgery, chemotherapy and radiation therapy, most neurooncologists will initially pursue a course of watchful waiting and treat patients symptomatically. Symptomatic treatment often includes the use of anticonvulsants for seizures and steroids for brain swelling.
The standard dosing schedule of temozolomide is 5 consecutive days of daily dosing during 28-day cycles. However, different dosing schedules may produce better results, such as continuous daily dosing using lower amounts of drug (e.g. 21-day dosing during 28-day cycles). As an example of an altered dosing schedule, promising results have been shown using lower daily doses on each day for 7 weeks, followed by a 4-week off periods. Regarding the duration of dosing, for oligodendrogliomas the duration prescribed by oncologists varies considerably and seems to range from 6 cycles to over 32 cycles (i.e. over 3 years). In one study, researchers compared patients who received temozolomide for at least 12 months on the 5/28 day cycle, dividing such patients into two groups: "short term" patients receiving temozolomide for 12–18 cycles and those "long term" patients receiving 19 or more cycles (range was 19 to 32 cycles). Researchers found that there was a statistically significant advantage for "long term" treatment (median progression free survival for "short term" patients was 95 weeks (follow up of 73 weeks), but for "long term" patients the median progression free survival was not yet reached (follow up of 134 weeks)).Because of their diffusely infiltrating nature, oligodendrogliomas cannot be completely resected and are not curable by surgical excision. If the tumor mass compresses adjacent brain structures, a neurosurgeon will typically remove as much of the tumor as he or she can without damaging other critical, healthy brain structures. Surgery may be followed up by chemotherapy, radiation, or a mix of both, but recent studies suggest that radiation does not improve overall survival (even when age, clinical data, histological grading, and type of surgery are considered).
Prognosis
Oligodendrogliomas, like all other infiltrating gliomas, have a very high (almost uniform) rate of recurrence and gradually increase in grade over time. Recurrent tumors are generally treated with more aggressive chemotherapy and radiation therapy. Recently, stereotactic surgery has proven successful in treating small tumors that have been diagnosed early.
Long-term survival is reported in a minority of patients. With aggressive treatment and close monitoring, it is possible to outlive the typical life expectancies for low grade oligodendroglioma. Westergaards study (1997) showed that patients younger than 20 years had a median survival of 17.5 years. For patients that are over 30, the survival rate is lower but as treatment options grow, the survival rate is higher. However, a patient with bad general health is more likely to pass sooner than those that have good general health.
Another study shows a 34% survival rate after 20 years. However, as discussed above, such figures can be misleading since they do not factor in the types of treatment nor the genetic signature of the tumors. Additionally, such historic data loses significance due to the relatively long survival of patients (compared to other types of brain tumors) and the introduction of newer treatment options over time.
References
External links
Brain and Spinal Tumors: Hope Through Research (National Institute of Neurological Disorders and Stroke)
CT and MR Scans Classic Radiology Imaging of Oligodendroglioma
http://www.reseau-pola.org/app/download/24869531/La+Lettre_RENOP_5.pdf |
Choanal atresia | Choanal atresia is a congenital disorder where the back of the nasal passage (choana) is blocked, usually by abnormal bony or soft tissue (membranous) due to failed hole development of the nasal fossae during prenatal development. It causes persistent rhinorrhea, and with bilateral choanal atresia and obstructed airway that can cause cyanosis and hypoxia.
Choanal atresia is diagnosed based on the inability to place a nasal catheter, and radiology results (particularly CT scans). Treatment involves maintaining an open airway, and may involve surgery to reopen the airway, potentially with a stent. Choanal atresia is a fairly rare condition, affecting between 1 in 7,000 to 1 in 5,000 live births.
Presentation
Choanal atresia can be unilateral or bilateral.
A unilateral choanal atresia may not be detected until much later in life because the baby manages to get along with only one nostril available for breathing. Symptoms are minor, including persistent rhinorrhea (mainly normal mucus) and chronic sinusitis.
Bilateral choanal atresia is a life-threatening condition because the baby will be unable to breathe directly after birth as babies are obligate nasal breathers (they mainly use their noses to breathe). In some cases, this may present as cyanosis while the baby is feeding, because the oral air passages are blocked by the tongue, further restricting the airway. Cyanosis may improve when the baby cries, as the oral airway is used. These babies may require airway resuscitation soon after birth.
Associated conditions
Choanal atresia is associated with a higher risk of other airway problems, including:
tracheomalacia.
laryngomalacia.
subglottic stenosis.Sometimes, babies born with choanal atresia also have other abnormalities:
coloboma.
heart defects and cardiovascular disease.
intellectual disability.
growth impairment.
genital hypoplasia.
CHARGE syndrome.
others.Also any condition that causes significant depression of the nasal bridge or midface retraction can be associated with choanal atresia. Examples include the craniosynostosis syndromes such as Crouzon syndrome, Pfeiffer syndrome, Treacher Collins syndrome, Apert syndrome, and Antley-Bixler syndrome.
Cause
Choanal atresia is caused by problems with the development of the nasal cavity and the palate. Development begins with neural crest cells. Frontonasal processes fold, forming nasal placodes (nasal pits). The nasobuccal membrane must rupture in places to form the choanae. A number of theories exist as to how this developmental process causes choanal atresia.
Risk factors
Very few risk factors for choanal atresia have been identified. In general, choanal atresia is associated with a higher risk of other birth defects. Bilateral choanal atresia is more associated than unilateral choanal atresia.While causes are unknown, both genetic and environmental triggers are suspected. One study suggests that chemicals that act as endocrine disrupters may put an unborn infant at risk. A 2012 epidemiological study looked at atrazine, a commonly used herbicide in the U.S., and found that women who lived in counties in Texas with the highest levels of this chemical being used to treat agricultural crops were 80 times more likely to give birth to infants with choanal atresia or stenosis compared to women who lived in the counties with the lowest levels. Another epidemiological report in 2010 found even higher associations between increased incidents of choanal atresia and exposure to second-hand-smoke, coffee consumption, high maternal zinc and B-12 intake and exposure to anti-infective urinary tract medications. The anti-thyroid medication methimazole has been associated with the development of choanal atresia in rare cases if given during the first trimester of pregnancy.
Mechanism
Choanal atresia causes closure of the posterior choanae in the nasal cavity. Around 30% of these affect just the bone, while around 70% affect both bone and membranes. Bones affected can include the body of the sphenoid bone, the vomer, the medial pterygoid process of the sphenoid bone, and the horizontal plate of the palatine bone.
Diagnosis
Nasal catheter
Choanal atresia can be suspected if it is impossible to insert a nasal catheter. The length of catheter that can be inserted indicates where choanal atresia has occurred: shorter distances indicate a problem with the vomer, while longer distances indicate a problem with the posterior choanae. Mucus can be cleared (using suction) to visualise the abnormality.
Radiology
Diagnosis is confirmed using CT scan. This is also useful for differential diagnosis.
Treatment
Airway management
As bilateral choanal atresia is an emergency, the airway is secured. A small tube may be placed to the laryngopharynx. Tracheal intubation can also be used. If surgery cannot be performed soon after birth, tracheostomy may have better outcomes.
Surgery
Surgery may be used to reopen the airway, particularly with bilateral choanal atresia. This may be approaches through the nasal cavity or through the palate (accessed through the mouth). A stent may be inserted to keep the newly formed airway patent. Repeated dilatation may be performed. CT guidance may be used.
Epidemiology
Choanal atresia is fairly rare. It may have a frequency between 1 in 7,000 births and 1 in 5,000 births.
History
Choanal atresia was first described by Roederer in 1755.
Society and culture
In the movie City of Angels, Dr. Maggie Rice (played by Meg Ryan) correctly diagnoses the cause of a newborn babys failure to thrive as due to choanal atresia.
References
== External links == |
Germ cell tumor | Germ cell tumor (GCT) is a neoplasm derived from germ cells. Germ-cell tumors can be cancerous or benign. Germ cells normally occur inside the gonads (ovary and testis). GCTs that originate outside the gonads may be birth defects resulting from errors during development of the embryo.
Classification
GCTs are classified by their histology, regardless of location in the body. However, as more information about the genetics of these tumors become available, they may be classified based on specific gene mutations that characterize specific tumors. They are broadly divided in two classes:
The germinomatous or seminomatous germ-cell tumors (GGCT, SGCT) include only germinoma and its synonyms dysgerminoma and seminoma.
The nongerminomatous or nonseminomatous germ-cell tumors (NGGCT, NSGCT) include all other germ-cell tumors, pure and mixed.The two classes reflect an important clinical difference. Compared to germinomatous tumors, nongerminomatous tumors tend to grow faster, have an earlier mean age at time of diagnosis (around 25 years versus 35 years, in the case of testicular cancers), and have a lower five-year survival rate. The survival rate for germinomatous tumors is higher in part because these tumors are very sensitive to radiation, and they also respond well to chemotherapy. The prognosis for nongerminomatous tumours has improved dramatically, however, due to the use of platinum-based chemotherapy regimens.
Germinomatous
Nongerminomatous
Mixed
Mixed germ cell tumors occur in many forms. Among these, a common form is teratoma with endodermal sinus tumor.
Teratocarcinoma refers to a germ cell tumor that is a mixture of teratoma with embryonal carcinoma, or with choriocarcinoma, or with both. This kind of mixed germ cell tumor may be known simply as a teratoma with elements of embryonal carcinoma or choriocarcinoma, or simply by ignoring the teratoma component and referring only to its malignant component: embryonal carcinoma and/or choriocarcinoma. They can present in the anterior mediastinum.
Cause
Some investigators suggest that this distribution arises as a consequence of abnormal migration of germ cells during embryogenesis. Others hypothesize a widespread distribution of germ cells to multiple sites during normal embryogenesis, with these cells conveying genetic information or providing regulatory functions at somatic sites.Extragonadal GCTs were thought initially to be isolated metastases from an undetected primary tumor in a gonad, but many germ cell tumors are now known to be congenital and originate outside the gonads. The most notable of these is sacrococcygeal teratoma, the single most common tumor diagnosed in babies at birth.Of all anterior mediastinal tumors, 15–20% are GCTs of which about 50% are benign teratomas. Ovarian teratomas may be associated with anti-NMDA receptor encephalitis.
Location
Despite their name, GCTs occur both within and outside the ovary and testis. They are found in:}
head
inside the cranium — pineal and suprasellar locations are most commonly reported
inside the mouth — a fairly common location for teratoma
neck
mediastinum — account for 1% to 5% of all germ cell neoplasms
pelvis, particularly sacrococcygeal teratomaIn females, GCTs account for 30% of ovarian tumors, but only 1 to 3% of ovarian cancers in North America. In younger women, they are more common, thus in patients under the age of 21, 60% of ovarian tumors are of the germ-cell type, and up to one-third are malignant. In males, GCTs of the testis occur typically after puberty and are malignant (testicular cancer). In neonates, infants, and children younger than 4 years, most are sacrococcygeal teratomas.Males with Klinefelter syndrome have a 50 times greater risk of GSTs. In these persons, GSTs usually contain nonseminomatous elements, present at an earlier age, and seldom are gonadal in location.
Treatment
Women with benign GCTs such as mature teratomas (dermoid cysts) are cured by ovarian cystectomy or oophorectomy. In general, all patients with malignant GCTs have the same staging surgery that is done for epithelial ovarian cancer. If the patient is in her reproductive years, an alternative is unilateral salpingoophorectomy, while the uterus, the ovary, and the fallopian tube on the opposite side can be left behind. This is not an option when the cancer is in both ovaries. If the patient has finished having children, the surgery involves complete staging, including salpingoophorectomy on both sides, as well as hysterectomy.Patients with germ-cell cancer often need to be treated with combination chemotherapy for at least three cycles, but female patients with early-stage disease may not require this treatment. The chemotherapy regimen most commonly used in GCTs is called PEB (or BEP), and consists of bleomycin, etoposide, and a platinum-based antineoplastic (cisplatin). Targeted treatments, such as immunotherapy, hormonal therapy and kinase inhibitors, are being evaluated for tumors that do not respond to chemotherapy.
Prognosis
The 1997 International Germ Cell Consensus Classification is a tool for estimating the risk of relapse after treatment of malignant germ-cell tumor.
A small study of ovarian tumors in girls reports a correlation between cystic and benign tumors, and conversely, solid and malignant tumors. Because the cystic extent of a tumor can be estimated by ultrasound, MRI, or CT scan before surgery, this permits selection of the most appropriate surgical plan to minimize risk of spillage of a malignant tumor.Access to appropriate treatment has a large effect on outcome. A 1993 study of outcomes in Scotland found that for 454 men with nonseminomatous (nongerminomatous) GCTs diagnosed between 1975 and 1989, five-year survival increased over time and with earlier diagnosis. Adjusting for these and other factors, survival was 60% higher for men treated in a cancer unit that treated the majority of these men, though the unit treated more men with the worst prognosis.Choriocarcinoma of the testicles has the worst prognosis of all germ-cell cancers.
See also
Embryonic stem cells
Cancer research
References
External links
humpath #2658 (Pathology images)
Childhood Extracranial Germ Cell Tumors
Extragonadal Germ Cell Tumors
Ovarian Germ Cell Tumors
Packer RJ, Cohen BH, Cooney K, Coney K (2000). "Intracranial germ cell tumors". The Oncologist. 5 (4): 312–320. doi:10.1634/theoncologist.2000-0312. PMID 10964999.
Cancer.Net: Germ Cell Tumor |
Chapare mammarenavirus | Chapare mammarenavirus or Chapare virus is a virus from the family Arenaviridae which causes a hemorrhagic fever in humans known as Chapare hemorrhagic fever. It was first described after an outbreak of a novel zoonotic mammarenavirus infection occurred in the village of Samuzabeti, Chapare Province, Bolivia, in January 2003. A small number of people were infected and one person died.In 2019, nine people became infected with the virus in the La Paz regional area, four of whom died. Nosocomial and human-to-human transmission of the virus occurred in at least three of the cases which resulted in the death of a medical intern and a gastroenterologist. Like other members of the Arenavirus family, the specific zoonotic reservoir and primary transmission vector is suspected to be a rodent, probably the small-eared pygmy rice rat.
Virology
The Chapare virus is an enveloped virus with a bi-segmented single-stranded ambisense RNA genome. The two RNA segments are denoted Small (S) and Large (L). It belongs to the New World Clade B lineage of mammarenaviruses and is most closely related to the Sabia virus.
Symptoms
After an incubation period of around 9–19 days, initial symptoms include fever, malaise, headache, myalgia, back pain, dizziness, nausea, vomiting and diarrhoea. The disease often progresses to include hemorrhagic and neurological symptoms, such as gingival hemorrhage, anaemia, leukopaenia, confusion, seizures, echymoses, bleeding from mucous membranes, hemorrhagic shock and multi-organ failure.Chapare virus RNA was detected in the blood, urine, conjunctiva, semen and in broncho-alveolar and nasopharyngeal samples of the infected patients. Those who survived often had prolonged residual neurological symptoms. Viral RNA was detected in survivors up to 170 days after infection and infectious Chapare virus was obtained in a semen sample of one patient 86 days after symptom onset.
Treatment
Treatment relies mostly on supportive care and early diagnosis. Specific antiviral therapy for Chapare virus infection has yet to be properly investigated.
References
== External links == |
Smoke inhalation | Smoke inhalation is the breathing in of harmful fumes (produced as by-products of combusting substances) through the respiratory tract. This can cause smoke inhalation injury (subtype of acute inhalation injury) which is damage to the respiratory tract caused by chemical and/or heat exposure as well as possible systemic toxicity after smoke inhalation. Smoke inhalation can occur from fires of various sources such as residential, vehicle, and wildfires. Morbidity and mortality rates in fire victims with burns are increased in those with smoke inhalation injury. Victims of smoke inhalation injury can present with cough, difficulty breathing, low oxygen saturation, smoke debris and/or burns on the face. Smoke inhalation injury can affect the upper respiratory tract (above the larynx), usually due to heat exposure, or the lower respiratory tract (below the larynx), usually due to exposure to toxic fumes. Initial treatment includes taking the victim away from the fire and smoke, give 100% oxygen at high flow through face mask (non-rebreather if available), and check the victim for injuries to the body. Treatment for smoke inhalation injury is largely supportive with varying degrees of consensus on benefits of specific treatments.
Epidemiology
The U.S. Fire Administration reported almost 1.3 million fires in 2019 causing 3,704 deaths and almost 17,000 injuries. Residential fires were found to be most often cooking related and resulted in the highest amount of deaths when compared to other fire types such as vehicle and outdoor fires. It has been found that men have higher rates of fire-related death and injury than women do, and that African American and American Indian men have higher rates of fire-related death and injury than other ethnic and racial groups. The age group with the highest rate of death from smoke inhalation is people over 85, while the age group with the highest injury rate is people of ages 50–54. Some reports also show increased rates of death and injury in children, due to their lower physical and mental capabilities. In 2019, the overall U.S. national fire death rate was 10.7 people per million population and the injury rate was 50.6 people per million population. Smoke inhalation injury is the most common cause of death in fire victims. Fire victims with both burns to their body and smoke inhalation injury have increased mortality rate and length of hospital stay compared to those with burns alone.
Signs and symptoms
Some of the signs and symptoms of smoke inhalation injury include recent fire exposure followed by cough, wheezing, stridor, confusion, difficulty breathing, low oxygen saturation, smoke debris (especially on face and/or in saliva), burns (especially of the face), singed facial or nose hairs, and/or hoarse voice. A careful history can be helpful in determining where the fire occurred and therefore, what chemical fumes could have been inhaled with accompanying systemic toxicities.Smoke inhalation injury can lead to respiratory complications ranging from minor to major. Acute Respiratory Distress Syndrome (ARDS) is a relatively delayed complication of smoke inhalation injury caused by chemical fumes inducing an inflammatory response in the lung tissue especially the small air sacs known as alveoli where critical gas exchange occurs. Another potential complication is swelling of the upper airway from both heat and chemical damage and can become profound enough to obstruct breathing. The onset of airway swelling can be relatively delayed making it difficult to intubate later on thus endotracheal intubation should be considered early in certain patients. Other possible complications include pneumonia, vocal cord damage and/or dysfunction, and tracheal stenosis (usually delayed).
Mechanism
Inhalation of chemical toxins produced by combusting materials can cause damage to tissues of both the upper (above larynx) and lower respiratory tract (below larynx). Damage to lower airways, air sacs, and lung tissue is due to an inflammatory cascade in response to the noxious chemicals which causes a variety of downstream effects such as increased secretions and exudative material thus clogging the airways and/or air sacs, collapse of air sacs (atelectasis), vascular permeability leading to pulmonary edema (fluid in the lungs), bronchoconstriction, activation of the coagulation cascade, and impaired function of the mucociliary escalator.Inhalation of hot fumes can cause thermal damage to tissues usually limited to the upper respiratory tract (above larynx). Damage in this location can result in sloughing of the damaged tissue and swelling both of which can cause obstruction of the respiratory tract, ulceration, increased secretions, and redness (erythema).Systemic toxicity can occur from inhalation of chemical compounds produced as byproducts of combustion in a fire. Carbon monoxide poisoning is the most common systemic toxicity after smoke inhalation and can cause organ failure from lack of oxygen (often heart attack). Carbon monoxide is a common byproduct of combusting substances in fires and is colorless and odorless. It has a much higher binding affinity for hemoglobin compared to oxygen and thus can block oxygen from binding to hemoglobin causing hypoxia. Additionally, carbon monoxide decreases the ability of oxygen to dissociate from hemoglobin to diffuse into tissues thus causing hypoxia.
Treatment
First responders often take the victim away from the fire and smoke, give 100% oxygen at high flow through a face mask (non-rebreather if available), assess level of consciousness, and check the victim for burns and/or injuries to the body for initial care. Upper respiratory tract injury due to heat exposure often results in swelling. Intubation should be considered early given that the swelling can have a slow, delayed onset but once present, will make intubation very difficult.Lower respiratory tract injury due to exposure to noxious fumes often consists of supportive measures such as intubation and ventilator support if indicated, suctioning of the airways (pulmonary hygiene), and other supportive measures. Intravenous fluids are a mainstay in treatment of fire victims with extensive burns to the body, however, there are differing perspectives on the risks/benefits of IV fluids in fire victims with both burns and smoke inhalation injury due to the potential worsening of pulmonary edema with large amounts of IV fluids typically given in burn victims.Other treatments with differing perspectives and study findings on utility in smoke inhalation injury include nebulized bronchodilators (such as beta-2-agonists), IV corticosteroids, nebulized corticosteroids, nebulized epinephrine, nebulized heparin, and nebulized N-acetylcysteine.Carbon monoxide poisoning is initially treated with high flow 100% oxygen. Hyperbaric oxygen therapy can be considered but there are differing views on its clinical benefit in terms of outcomes.
See also
Acute inhalation injury
References
== External links == |
Li–Fraumeni syndrome | Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni, Jr., who first recognized the syndrome after reviewing the medical records and death certificates of 648 childhood rhabdomyosarcoma patients. This syndrome is also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.
The syndrome is linked to germline mutations of the p53 tumor suppressor gene, which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The mutations can be inherited, or can arise from mutations early in embryogenesis, or in one of the parents germ cells.
Presentation
Li–Fraumeni syndrome is characterized by early onset of cancer, a wide variety of types of cancers, and development of multiple cancers throughout ones life.
Pathology
LFS1: Mutations in TP53
Normal conditions: TP53 is a tumor suppressor gene on chromosome 17 that normally assists in the control of cell division and growth through action on the normal cell cycle. TP53 typically become expressed due to cellular stressors, such as DNA damage, and can halt the cell cycle to assist with either the repair of repairable DNA damage, or can induce apoptosis of a cell with irreparable damage. The repair of "bad" DNA, or the apoptosis of a cell, prevents the proliferation of damaged cells.
Mutant conditions: Mutations of TP53 can inhibit its normal function, and allow cells with damaged DNA to continue to divide. If these DNA mutations are left unchecked, some cells can divide uncontrollably, forming tumors (cancers). Further mutations in the DNA could lead to malignant cells that can travel to, and develop cancer in, different areas of the body. Many individuals with Li–Fraumeni syndrome have been shown to be heterozygous for a TP53 mutation. Recent studies have shown that 60% to 80% of classic LFS families harbor detectable germ-line TP53 mutations, the majority of which are missense mutations in the DNA-binding domain. These missense mutations cause a decrease in the ability of p53 to bind to DNA, thus inhibiting the normal TP53 mechanism.
Unique Brazilian mutation: Although other mutations leading to Li–Fraumeni syndrome have been found outside the DNA-binding domain, a mutation at codon 337 of the tetramerization domain of TP53 has shown a particularly high frequency. The tetramerization domain plays a major role in the oligomerization of the p53 protein, which exists as a tetramer. This mutation has only been found in Brazilian families, and is located in exon 10 of the TP53 gene. The mutation causes an amino acid change from arginine to histidine at codon 337. With pH in the low to normal physiological range (up to 7.5), the mutant protein forms normal oligomers and retains its suppressor function. However, at a high physiological pH, p53 is unable to assemble into a tetramer. This unique feature may contribute to why families with this particular mutation often show incomplete penetrance.
Dominant negative mutations: Most individuals with Li–Fraumeni syndrome are heterozygous for a mutant TP53 gene, and some p53 mutants can inhibit the function of the wild-type p53 in a dominant negative manner. Mutated p53 proteins are typically more stable than wild-type, and can inhibit the activity of the wild-type protein in suppressing cell proliferation and in inducing cell cycle arrest. Due to the mutant p53 being able to inhibit some wild-type p53, damaged cells are at an even greater susceptibility to proliferate and become transformed, resulting in cancer.LFS2: mutations in CHEK2
Another variant of Li–Fraumeni that remains somewhat controversial, is a mutation of the CHEK2 (or CHK2) gene. CHK2 is also a tumor suppressor gene; it regulates the action of p53 and is activated by ATM, which detects DNA damage, and in this way, DNA damage information can be conveyed to p53 to indirectly arrest the cell cycle at that point for DNA repair to be able to take place or to cause apoptosis (programmed cell death).
LFS-L:
Families who do not conform to the criteria of classical Li–Fraumeni syndrome have been termed "LFS-like". LFS-like individuals generally do not have any detectable p53 mutations, and tend to be diagnosed on either the Birch or Eeles criteria.
A third locus has been mapped to the long arm of chromosome 1 (1q23), but no gene has yet been identified.Another locus that has been linked to this syndrome is CDKN2A-CDKN2B.
Clinical
The classical LFS malignancies - sarcoma, cancers of the breast, brain, and adrenal glands - comprise about 80% of all cancers that occur in this syndrome.
The risk of developing any invasive cancer (excluding skin cancer) is about 50% by age 30 (1% in the general population) and is 90% by age 70. Early-onset breast cancer accounts for 25% of all the cancers in this syndrome. This is followed by soft-tissue sarcomas (20%), bone sarcoma (15%), and brain tumors - especially glioblastomas - (13%). Other tumours seen in this syndrome include leukemia, lymphoma, and adrenocortical carcinoma.
About 90% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years. Females with this syndrome have almost a 100% lifetime risk of developing cancer. This compares with 73% for affected males. The difference may be due to much smaller breast tissue in males and increased estrogen levels in females.
The risks of sarcoma, female breast cancer, and haematopoietic malignancies in mutation carriers are more than 100 times greater than those seen in the general population.
Other tumours reported in this syndrome, but not yet proved to be linked with it, include melanoma, Wilms and other kidney tumors, hepatocellular carcinoma, gonadal germ cell, pancreatic, gastric, choroid plexus, colorectal, and prostate cancers.
Around 80% of children with adrenocortical carcinoma and 2–10% of childhood brain tumors have p53 mutations. About 2-3% of osteosarcomas, 9% of rhabdomyosarcomas, and 7-20% of patients with multiple primary tumours have p53 mutations.Although most cases of this syndrome have early onset of cancer, cases have also been reported later in life.
Diagnosis
Li–Fraumeni syndrome is diagnosed if these three criteria are met:
The patient has been diagnosed with a sarcoma at a young age (below 45).
A first-degree relative has been diagnosed with any cancer at a young age (below 45).
Another first- or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age.Other criteria have also been proposed:
A proband with any childhood cancer or sarcoma, brain tumor or adrenal cortical carcinoma diagnosed before age 45
A first- or second-degree relative with a typical LFS malignancy (sarcoma, leukaemia, or cancers of the breast, brain or adrenal cortex) regardless of age at diagnosis
A first- or second-degree relative with any cancer diagnosed before age 60A third criterion has been proposed:
Two first- or second-degree relatives with LFS-related malignancies at any age.
Management
Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for them as people with Li–Fraumeni are likely to develop another primary malignancy at a future time (57% within 30 years of diagnosis).
Chompret criteria
A 2015 revision of the traditional Chompret criteria for screening has been proposed - a proband who has:
A tumor belonging to LFS tumor spectrum (e.g., premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, CNS tumor, adrenocortical carcinoma) before age 46 years, and at least one first- or second-degree relative with LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors at any age
Multiple tumors (except multiple breast tumors), two of which belong to LFS spectrum with the initial cancer occurring before the age of 46 years
An adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, at any age of onset, irrespective of family history
Breast cancer before age 31
Recommendations
Recommendations for individuals from families affected by the syndrome include:
Avoidance of radiation therapy to reduce risk of secondary radiation-induced malignancies
Children and adults undergo comprehensive annual physical examination
Women undergo age-specific breast cancer monitoring beginning at age 25 years
All patients consult a physician promptly for evaluation of lingering symptoms and illnesses
Suggestions
Adults should undergo routine screening for colorectal cancer beginning no later than age 25 years.
Individuals should undergo organ-targeted surveillance based on the pattern of cancer observed in their families.
Prophylactic mastectomy to reduce the risk of breast cancer is an option.
Epidemiology
Li–Fraumeni syndrome (LFS) is rare; as of 2011, cases had been reported in more than 500 families. The syndrome was discovered using an epidemiological approach. Li and Fraumeni identified four families in which siblings or cousins of rhabdomyosarcoma patients had a childhood sarcoma, which suggested a familial cancer syndrome. Identification of TP53s the gene affected by mutation was suggested by the same approach. Over half of the cancers in LFS families had been previously associated with inactivating mutations of the p53 gene and in one primary research study, DNA sequencing in samples taken from five Li–Fraumeni syndrome families showed autosomal dominant inheritance of a mutated TP53 gene.
See also
OSLAM syndrome
References
Further reading
Li–Fraumeni Syndrome by Katherine Schneider, MPH, Kristin Zelley, MS, Kim E Nichols, MD and Judy Garber, MD, MPH, in GeneReviews, a section of GeneTests, published online by the University of Washington with funds from the National Institutes of Health
Li–Fraumeni syndrome, in the National Library of Medicine
Li–Fraumeni syndrome; LFS1, entry in Online Mendelian Inheritance in Man (OMIM), published by Johns Hopkins University and the National Institutes of Health |
Single transverse palmar crease | In humans, a single transverse palmar crease is a single crease that extends across the palm of the hand, formed by the fusion of the two palmar creases (known in palmistry as the "heart line" and the "head line"). Although it is found more frequently in persons with several abnormal medical conditions, it is not predictive of any of these conditions since it is also found in perfectly healthy persons. It is found in 1.5% of the world population in at least one hand.
Former name
Because it resembles the usual condition of non-human simians, it was, in the past, called the simian crease or simian line. These terms have widely fallen out of favor due to their pejorative connotation.
Medical significance
The presence of a single transverse palmar crease has no medical significance. It is found in 1.5% of all people, and though it is found at a higher frequency in people with abnormal medical conditions, in every one of these conditions many people do not have a single transverse palmer crease, thus it has low predictive value.
Males are twice as likely as females to have this characteristic, and it tends to run in families. In its non-symptomatic form, it is more common among Asians and Native Americans than among other populations, and in some families there is a tendency to inherit the condition unilaterally; that is, on one hand only.While it is often found in people with Down Syndrome, many who have this syndrome do not have this crease, and thus is not a diagnostic indicator of the Down Syndrome.
The presence of a single transverse palmar has been associated with a number of abnormal medical conditions — that is, it is found at a higher than 1.5% frequency, but in all of these conditions many do not have this crease. Examples of conditions with such an association are fetal alcohol syndrome, and with the genetic chromosomal abnormalities Down syndrome (chromosome 21), cri du chat syndrome (chromosome 5), Klinefelter syndrome, Wolf-Hirschhorn Syndrome, Noonan syndrome (chromosome 12), Patau syndrome (chromosome 13), IDIC 15/Dup15q (chromosome 15), Edwards syndrome (chromosome 18), and Aarskog-Scott syndrome (X-linked recessive), or autosomal recessive disorder, such as Leukocyte adhesion deficiency-2 (LAD2). A unilateral single palmar crease was also reported in a case of chromosome 9 mutation causing Nevoid basal cell carcinoma syndrome and Robinow syndrome. It is also sometimes found on the hand of the affected side of patients with Poland syndrome, and craniosynostosis.
A 1971 study refutes the hypothesis that the phenomenon is caused by fetal hand movement: the appearance of the crease occurs around the second month of gestation, before the digital movement phase in the womb begins.
See also
Dermatoglyphics
References
== External links == |
Papular eruption of blacks | Papular eruption of blacks is a cutaneous condition characterized clinically by small, pruritic papules and histologically by a mononuclear cell-eosinophil perivascular infiltrate.
See also
Pachydermatous eosinophilic dermatitis
List of cutaneous conditions
== References == |
Infestation | Infestation is the state of being invaded or overrun by pests or parasites. It can also refer to the actual organisms living on or within a host.
Terminology
In general, the term "infestation" refers to parasitic diseases caused by animals such as arthropods (i.e. mites, ticks, and lice) and worms, but excluding (except) conditions caused by protozoa, fungi, bacteria, and viruses, which are called infections.
External and internal
Infestations can be classified as either external or internal with regards to the parasites location in relation to the host.
External or ectoparasitic infestation is a condition in which organisms live primarily on the surface of the host (though porocephaliasis can penetrate viscerally) and includes those involving mites, ticks, head lice and bed bugs.An internal (or endoparasitic) infestation is a condition in which organisms live within the host and includes those involving worms (though swimmers itch stays near the surface).
Medically, the term "infestation" is often reserved only for external ectoparasitic infestations while the term infection refers to internal endoparasitic conditions.
References
External links
Introduction to Anaerobic Soil Disinfestation as a Fumigant Alternative
New technique predicts risk of plant disease and infestation |
Factitious disorder imposed on self | Factitious disorder imposed on self, also known as Munchausen syndrome, is a factitious disorder in which those affected feign or induce disease, illness, injury, abuse, or psychological trauma to draw attention, sympathy, or reassurance to themselves. Munchausen syndrome fits within the subclass of factitious disorder with predominantly physical signs and symptoms, but patients also have a history of recurrent hospitalization, travelling, and dramatic, extremely improbable tales of their past experiences. The condition derives its name from the fictional character Baron Munchausen.
Factitious disorder imposed on self is related to factitious disorder imposed on another, which refers to the abuse of another person, typically a child, in order to seek attention or sympathy for the abuser. This drive to create symptoms for the victim can result in unnecessary and costly diagnostic or corrective procedures.
Signs and symptoms
In factitious disorder imposed on self, the affected person exaggerates or creates symptoms of illnesses in themselves to gain examination, treatment, attention, sympathy or comfort from medical personnel. It often involves elements of victim playing and attention seeking. In some extreme cases, people with Munchausen syndrome are highly knowledgeable about the practice of medicine and are able to produce symptoms that result in lengthy and costly medical analysis, prolonged hospital stays, and unnecessary operations. The role of patient is a familiar and comforting one, and it fills a psychological need in people with this syndrome. This disorder is distinct from hypochondriasis and other somatoform disorders in that those with the latter do not intentionally produce their somatic symptoms. Factitious disorder is distinct from malingering in that people with factitious disorder imposed on self do not fabricate symptoms for material gain such as financial compensation, absence from work, or access to drugs.
The exact cause of factitious disorder is not known, but researchers believe both biological and psychological factors play a role in the development of this disorder. Risk factors for developing factitious disorder may include childhood traumas, growing up with parents/caretakers who were emotionally unavailable due to illness or emotional problems, a serious illness as a child, failed aspirations to work in the medical field, personality disorders, and low self-esteem. While there are no reliable statistics regarding the number of people in the United States who have factitious disorder, FD is believed to be most common in mothers having the above risk factors. Those with a history of working in healthcare are also at greater risk of developing it.Arrhythmogenic Munchausen syndrome describes individuals who simulate or stimulate cardiac arrhythmias to gain medical attention.A related behavior called factitious disorder imposed on another has been documented in the parent or guardian of a child or the owner of a pet animal. The adult ensures that their child will experience some medical condition, therefore compelling the child to suffer through treatments and spend a significant portion during youth in hospitals. Furthermore, a disease may actually be initiated in the child by the parent or guardian. This condition is considered distinct from Munchausen syndrome. There is growing consensus in the pediatric community that this disorder should be renamed "medical abuse" to highlight the harm caused by the deception and to make it less likely that the sufferer can use a psychiatric defense when harm is done.
Diagnosis
Due to the behaviors involved, diagnosing factitious disorder is very difficult. If the healthcare provider finds no physical reason for the symptoms, they may refer the person to a psychiatrist or psychologist (mental health professionals who are specially trained to diagnose and treat mental illnesses). Psychiatrists and psychologists use thorough history, physical examinations, laboratory tests, imagery, and psychological testing to evaluate a person for physical and mental conditions. Once the persons history has been thoroughly evaluated, diagnosing factitious disorder imposed on self requires a clinical assessment. Clinicians should be aware that those presenting with symptoms (or persons reporting for that person) may exaggerate, and caution should be taken to ensure there is evidence for a diagnosis. Lab tests may be required, including complete blood count (CBC), urine toxicology, drug levels from blood, cultures, coagulation tests, assays for thyroid function, or DNA typing. In some cases CT scan, magnetic resonance imaging, psychological testing, electroencephalography, or electrocardiography may also be employed. A summary of more common and reported cases of factitious disorder (Munchausen syndrome), and the laboratory tests used to differentiate these from physical disease is provided below:
There are several criteria that together may point to factitious disorder, including frequent hospitalizations, knowledge of several illnesses, frequently requesting medication such as pain killers, openness to extensive surgery, few or no visitors during hospitalizations, and exaggerated or fabricated stories about several medical problems. Factitious disorder should not be confused with hypochondria, as people with factitious disorder syndrome do not really believe they are sick; they only want to be sick, and thus fabricate the symptoms of an illness. It is also not the same as pretending to be sick for personal benefit such as being excused from work or school.People may fake their symptoms in multiple ways. Other than making up past medical histories and faking illnesses, people might inflict harm on themselves by consuming laxatives or other substances, self-inflicting injury to induce bleeding, and altering laboratory samples". Many of these conditions do not have clearly observable or diagnostic symptoms and sometimes the syndrome will go undetected because patients will fabricate identities when visiting the hospital several times. Factitious disorder has several complications, as these people will go to great lengths to fake their illness. Severe health problems, serious injuries, loss of limbs or organs, and even death are possible complications.
Treatment
Because there is uncertainty in treating suspected factitious disorder imposed on self, some advocate that health care providers first explicitly rule out the possibility that the person has another early-stage disease. Then they may take a careful history and seek medical records to look for early deprivation, childhood abuse, or mental illness. If a person is at risk to themself, psychiatric hospitalization may be initiated.Healthcare providers may consider working with mental health specialists to help treat the underlying mood or other disorder as well as to avoid countertransference. Therapeutic and medical treatment may center on the underlying psychiatric disorder: a mood disorder, an anxiety disorder, or borderline personality disorder. The patients prognosis depends upon the category under which the underlying disorder falls; depression and anxiety, for example, generally respond well to medication or cognitive behavioral therapy, whereas borderline personality disorder, like all personality disorders, is presumed to be pervasive and more stable over time, and thus offers a worse prognosis.
People affected may have multiple scars on their abdomen due to repeated "emergency" operations.
History
The name "Munchausen syndrome" derives from Baron Munchausen, a literary character loosely based on the German nobleman Hieronymus Karl Friedrich, Freiherr von Münchhausen (1720–1797). The historical baron became a well-known storyteller in the late 18th century for entertaining dinner guests with tales about his adventures during the Russo-Turkish War. In 1785, German-born writer and con artist Rudolf Erich Raspe anonymously published a book in which a heavily fictionalized version of "Baron Munchausen" tells many fantastic and impossible stories about himself. Raspes Munchausen became a sensation, establishing a literary exemplar of a bombastic liar or exaggerator.In 1951, Richard Asher was the first to describe a pattern of self-harm, wherein individuals fabricated histories, signs, and symptoms of illness. Remembering Baron Munchausen, Asher named this condition Munchausens Syndrome in his article in The Lancet in February 1951, quoted in his obituary in the British Medical Journal:
Here is described a common syndrome which most doctors have seen, but about which little has been written. Like the famous Baron von Munchausen, the persons affected have always travelled widely; and their stories, like those attributed to him, are both dramatic and untruthful. Accordingly the syndrome is respectfully dedicated to the Baron, and named after him.
Ashers nomenclature sparked some controversy, with medical authorities debating the appropriateness of the name for about fifty years. While Asher was praised for bringing cases of factitious disorder to light, participants in the debate objected variously that a literary allusion was inappropriate given the seriousness of the disease; that its use of the anglicized spelling "Munchausen" showed poor form; that the name linked the disease with the real-life Münchhausen, who did not have it; and that the names connection to works of humor and fantasy, and to the essentially ridiculous character of the fictional Baron Munchausen, was disrespectful to patients with the disorder.Originally, this term was used for all factitious disorders. Now, however, in the DSM-5, "Munchausen syndrome" and "Munchausen by proxy" have been replaced with "factitious disorder imposed on self" and "factitious disorder imposed on another" respectively.
Munchausen by Internet
Munchausen by Internet is a term describing the pattern of behavior in factitious disorder imposed on self, wherein those affected feign illnesses in online venues. It has been described in medical literature as a manifestation of factitious disorder imposed on self. Reports of users who deceive Internet forum participants by portraying themselves as gravely ill or as victims of violence first appeared in the 1990s due to the relative newness of Internet communications. The specific internet pattern was named "Münchausen by Internet" in 1998 by psychiatrist Marc Feldman. New Zealand PC World Magazine called Munchausen by Internet "cybermunch", and those who posed online "cybermunchers".People may attempt to gain sympathy from a group whose sole reason for existence is to support others. Some have speculated that health care professionals, with their limited time, greater medical knowledge, and tendency to be more skeptical in their diagnoses, may be less likely to provide that support.In an article published in The Guardian, Steve Jones, speculated that the anonymity of the Internet impedes peoples abilities to realize when someone is lying. Online interaction has only been possible since the 1980s, steadily growing over the years.When discovered, forum members are frequently banned from some online forums. Because no money is exchanged and laws are rarely broken, there is little legal recourse to take upon discovery of someone faking illness.Such dramatic situations can polarize online communities. Members may feel ashamed for believing elaborate lies, while others remain staunch supporters. Feldman admits that an element of sadism may be evident in some of the more egregious abuses of trust.Other perpetrators react by issuing general accusations of dishonesty to everyone, following the exposure of such fabrications. The support groups themselves often bar discussion about the fraudulent perpetrator, in order to avoid further argument and negativity. Many forums do not recover, often splintering or shutting down.In 2004, members of the blog hosting service LiveJournal established a forum dedicated to investigating cases of members of online communities dying—sometimes while online. In 2007 The LiveJournal forum reported that, of the deaths reported to them, about 10% were real.
See also
Hypochondriasis
Psychosomatic illness
Sickened, an autobiography by Julie Gregory
References
Bibliography
Feldman, Marc (2004). Playing sick?: untangling the web of Munchausen syndrome, Munchausen by proxy, malingering & factitious disorder. Philadelphia: Brunner-Routledge. ISBN 978-0-415-94934-7.
Fisher JA (2006). "Playing patient, playing doctor: Munchausen syndrome, clinical S/M, and ruptures of medical power". The Journal of Medical Humanities. 27 (3): 135–49. doi:10.1007/s10912-006-9014-9. PMID 16817003. S2CID 40739963.
Fisher JA (2006). "Investigating the Barons: narrative and nomenclature in Munchausen syndrome". Perspect. Biol. Med. 49 (2): 250–62. doi:10.1353/pbm.2006.0024. PMID 16702708. S2CID 12418075.
Friedel, Robert O., MD (4 August 2004). Borderline Personality Disorder Demystified. pp. 9–10. ISBN 978-1-56924-456-2.{{cite book}}: CS1 maint: multiple names: authors list (link)
Davidson, G.; et al. (2008). Abnormal Psychology - 3rd Canadian Edition. Mississauga: John Wiley & Sons Canada, Ltd. p. 412. ISBN 978-0-470-84072-6.
Prasad, A.; Oswald, A. G. (1985). "Munchausens syndrome: an annotation". Acta Psychiatrica Scandinavica. 72 (4): 319–22. doi:10.1111/j.1600-0447.1985.tb02615.x. PMID 4072733. S2CID 40707.
Leila Schneps and Coralie Colmez (2013). "[Chapter 1:] Math error number 1: multiplying non-independent probabilities. The case of Sally Clark: motherhood under attack". Math on trial. How numbers get used and abused in the courtroom. Basic Books. ISBN 978-0-465-03292-1.
Staff, Mayo Clinic (13 May 2011). "Munchausen syndrome". Mayo Foundation for Medical Education and Research. Retrieved 11 April 2013.
External links
Article in Discover magazine, July 1993, by Abigail Zuger |
Johnson–McMillin syndrome | Johnson–McMillin syndrome, also known as Johnson neuroectodermal syndrome, is a neuroectodermal syndrome characterized by conductive hearing loss and alopecia, microtia, conductive hearing loss, anosmia/hyposmia, and hypogonadotropic hypogonadism.
See also
List of cutaneous conditions
References
== External links == |
Macular degeneration | Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur but these do not represent a mental illness.Macular degeneration typically occurs in older people. Genetic factors and smoking also play a role. It is due to damage to the macula of the retina. Diagnosis is by a complete eye exam. The severity is divided into early, intermediate, and late types. The late type is additionally divided into "dry" and "wet" forms with the dry form making up 90% of cases.The difference between the two forms is the change of macula. Those with dry form AMD have drusen, cellular debris in their macula that gradually damages light-sensitive cells and leads to vision loss. In wet form AMD, blood vessels grow under the macula, causing blood and fluid to leak into the retina.Preventive efforts include exercising, eating well, and not smoking. There is no cure or treatment that returns vision already lost. In the wet form, anti-VEGF medication injected into the eye or less commonly laser coagulation or photodynamic therapy may slow worsening. Antioxidant vitamins and minerals do not appear to be useful for prevention. However, dietary supplements may slow the progression in those who already have the disease.Age-related macular degeneration is a main cause of central blindness among the working-aged population worldwide. As of 2020, it affects more than 190 million people globally with the prevalence expected to increase to 288 million people by 2040 as the proportion of elderly persons in the population increases. It is equally seen in males and females and it is more common in those of European or North American ancestry. In 2013, it was the fourth most common cause of blindness after cataracts, preterm birth, and glaucoma. It most commonly occurs in people over the age of fifty and in the United States is the most common cause of vision loss in this age group. About 0.4% of people between 50 and 60 have the disease, while it occurs in 0.7% of people 60 to 70, 2.3% of those 70 to 80, and nearly 12% of people over 80 years old.
Signs and symptoms
Early or intermediate AMD may be asymptomatic, or it may present with blurred or decreased vision in one or both eyes. This may manifest initially as difficulty with reading or driving (especially in poorly lit areas). Other symptoms of AMD include distortion of vision and blind spots (especially in and around the central visual field).Other signs and symptoms of macular degeneration include:
Distorted vision in the form of metamorphopsia, in which a grid of straight lines appears wavy and parts of the grid may appear blank: Patients often first notice this when looking at things like miniblinds in their home or telephone poles while driving. There may also be central scotomas, shadows or missing areas of vision
Slow recovery of visual function after exposure to bright light (photostress test)
Visual acuity drastically decreasing (two levels or more), e.g.: 20/20 to 20/80
Blurred vision: Those with nonexudative (wet) macular degeneration may be asymptomatic or notice a gradual loss of central vision, whereas those with exudative (dry) macular degeneration often notice a rapid onset of vision loss (often caused by leakage and bleeding of abnormal blood vessels).
Trouble discerning colors, specifically dark ones from dark ones and light ones from light ones
A loss in contrast sensitivity
Formed visual hallucinations and flashing lights have also been associated with severe visual loss secondary to wet AMD Macular degeneration by itself will not lead to total blindness. For that matter, only a small number of people with visual impairment are totally blind. In almost all cases, some vision remains, mainly peripheral. Other complicating conditions may lead to such an acute condition (severe stroke or trauma, untreated glaucoma, etc.), but few macular degeneration patients experience total visual loss.The area of the macula constitutes only about 2.1% of the retina, and the remaining 97.9% (the peripheral field) remains unaffected by the disease. Even though the macula provides such a small fraction of the visual field, almost half of the visual cortex is devoted to processing macular information.In addition, people with dry macular degeneration often do not experience any symptoms but can experience gradual onset of blurry vision in one or both eyes. People with wet macular degeneration may experience acute onset of visual symptoms.
Risk factors
Key risk factors are age, race/ethnicity, smoking, and family history. Advanced age is the strongest predictor of AMD, particularly over 50.
Race/Ethnicity
As illustrated by the Figure in this section, derived from data presented by the National Eye Institute of the United States (https://www.nei.nih.gov/learn-about-eye-health/eye-health-data-and-statistics/age-related-macular-degeneration-amd-data-and-statistics/age-related-macular-degeneration-amd-tables), among those over 80 years of age, White individuals are more than 6-fold more likely to develop AMD than Black or Hispanic individuals. Thus, white background is a major risk factor for AMD.
In Caucasian (White) skin, there is a specific group of polymorphic genes (with single nucleotide alterations) that encode for enzymes and transcription factors responsible for the early steps (including the first step, formation of L-DOPA from the amino acid tyrosine) of the melanin synthesis pathway. Many of these enzymes and transcription factors are reviewed by Markiewicz and Idowu. Also, as reviewed by Sturm et al. “increasing intracellular concentrations of either tyrosine or L-DOPA both result in an increase in melanogenesis” or formation of the black pigment melanin. Thus there appears to be an association between reduced L-DOPA production and white skin. As suggested by the Figure and information in this section, reduced L-DOPA, resulting in white skin, appears to be associated with an increased risk of macular degeneration for white individuals over the age of 80.
Environment and lifestyle
Smoking: Smoking tobacco increases the risk of AMD by two to three times that of someone who has never smoked, and may be the most important modifiable factor in its prevention. A review of previous studies found "a strong association between current smoking and AMD.... Cigarette smoking is likely to have toxic effects on the retina."
Hypertension (high blood pressure): In the ALIENOR study 2013, early and late AMD were not significantly associated with systolic or diastolic blood pressure (BP), hypertension, or use of antihypertensive medications, but elevated pulse pressure [(PP) systolic BP minus diastolic BP] was significantly associated with an increased risk of late AMD.
Atherosclerosis
High cholesterol: Elevated cholesterol may increase the risk of AMD
Obesity: Abdominal obesity is a risk factor, especially among men
Fat intake: Consuming high amounts of certain fats, including saturated fats, trans fats, and omega-6 fatty acids, likely contributes to AMD, while monounsaturated fats are potentially protective. In particular, omega-3 fatty acids may decrease the risk of AMD.
Exposure to UV light from sunlight is maybe associated with an increased risk of developing AMD, although evidence is weaker than other causes.
A digital screen does not radiate harmful energy against human eyes, but staring at the screen for a long time without pauses does increase eye strain. There is no evidence to support the claim that exposure to digital screens contributes to the risk of macular degeneration.
Genetics
AMD is a highly heritable condition. Recurrence ratios for siblings of an affected individual are three- to six-fold higher than in the general population. Genetic linkage analysis has identified 5 sets of gene variants at three locations on different chromosomes (1, 6 and 10) as explaining at least 50% of the risk. These genes have roles regulating the immune response, inflammatory processes and homeostasis of the retina. Variants of these genes give rise to different kinds of dysfunction in these processes. Over time, this results in accumulation of intracellular and extracellular metabolic debris. This can cause scarring of the retina or breakdown of its vascularization.
The list of genetic variations association with AMD include complement factors, apolipoprotein E, fibroblast growth factor 2, DNA excision repair protein, and age-related maculopathy susceptibility protein 2.Although genetic testing can lead to the identification of genetic variation which can predispose to AMD, the complex pathogenesis of the condition prevents the use of these tests in routine practice. Nevertheless, they can be useful in selecting patients for clinical trials and analysing their response to treatment. The three loci where identified gene variants are found are designated:
Complement Factor H (CFH) on chromosome 1 at location 1q31.3
HTRA serine peptidase 1/Age Related Maculopathy Susceptibility 2 (HTRA1/ARMS2) on chromosome 10 at location 10q26
Complement Factor B/Complement Component 2 (CFB/CC2) on chromosome 6 at 6p21.3
Specific genes
Polymorphisms in genes for complement system proteins: Variation in the genes for the complement system proteins factor H (CFH), factor B (CFB) and factor 3 (C3), among others, are strongly associated with a persons risk for developing AMD. CFH is involved in inhibiting the inflammatory response. The mutation in CFH (Y402H) results in reduced ability of the protein to localise to and protect tissues such as the retina from complement overactivation. Absence of the complement factor H-related genes R3 and R1 protects against AMD. Two independent studies in 2007 showed a certain common mutation Arg80Gly in the C3 gene, which is a central protein of the complement system, is strongly associated with the occurrence of AMD. The authors of both papers consider their study to underscore the influence of the complement pathway in the pathogenesis of this disease.
In two 2006 studies, another gene that has implications for the disease, called HTRA1 (encoding a secreted serine protease), was identified.
Six mutations of the gene SERPING1 (Serpin Peptidase Inhibitor, Clade G (C1 Inhibitor), Member 1) are associated with AMD. Mutations in this gene can also cause hereditary angioedema.
Fibulin-5 mutation: Rare forms of the disease are caused by genetic defects in fibulin-5, in an autosomal dominant manner. In 2004, Stone et al. performed a screen on 402 AMD patients and revealed a statistically significant correlation between mutations in fibulin-5 and incidence of the disease.
Mitochondrial-related gene polymorphisms such as that in the MT-ND2 molecule, predicts wet AMD.
Pathophysiology
The pathogenesis of age-related macular degeneration is not well known, although some theories have been put forward, including oxidative stress, mitochondrial dysfunction, and inflammatory processes.
The imbalance between the production of damaged cellular components and degradation leads to the accumulation of harmful products, for example, intracellular lipofuscin and extracellular drusen. Incipient atrophy is demarcated by areas of retinal pigment epithelium (RPE) thinning or depigmentation that precede geographic atrophy in the early stages of AMD. In advanced stages of AMD, atrophy of the RPE (geographic atrophy) and/or development of new blood vessels (neovascularization) result in the death of photoreceptors and central vision loss.
In the dry (nonexudative) form, drusen accumulates between the retina and the choroid, causing atrophy and scarring to the retina. In the wet (exudative) form, which is more severe, blood vessels grow up from the choroid (neovascularization) behind the retina which can leak exudate and fluid and also cause hemorrhaging.
Early work demonstrated a family of immune mediators was plentiful in drusen. Complement factor H (CFH) is an important inhibitor of this inflammatory cascade, and a disease-associated polymorphism in the CFH gene strongly associates with AMD. Thus an AMD pathophysiological model of chronic low grade complement activation and inflammation in the macula has been advanced. Lending credibility to this has been the discovery of disease-associated genetic polymorphisms in other elements of the complement cascade including complement component 3 (C3).A powerful predictor of AMD is found on chromosome 10q26 at LOC 387715. An insertion/deletion polymorphism at this site reduces expression of the ARMS2 gene though destabilization of its mRNA through deletion of the polyadenylation signal. ARMS2 protein may localize to the mitochondria and participate in energy metabolism, though much remains to be discovered about its function.
Other gene markers of progression risk includes tissue inhibitor of metalloproteinase 3 (TIMP3), suggesting a role for extracellular matrix metabolism in AMD progression. Variations in cholesterol metabolising genes such as the hepatic lipase, cholesterol ester transferase, lipoprotein lipase and the ATP-binding cassette A1 correlate with disease progression. The early stigmata of disease, drusen, are rich in cholesterol, offering face validity to the results of genome-wide association studies.
Stages
In AMD there is a progressive accumulation of characteristic yellow deposits, called drusen (buildup of extracellular proteins and lipids), in the macula (a part of the retina), between the retinal pigment epithelium and the underlying choroid. This accumulation is believed to damage the retina over time. Amyloid beta, which builds up in Alzheimers disease brains, is one of the proteins that accumulate in AMD, which is a reason why AMD is sometimes called "Alzheimers of the eye" or "Alzheimers of the retina".
AMD can be divided into 3 stages: early, intermediate, and late, based partially on the extent (size and number) of drusen.AMD-like pathology begins with small yellow deposits (drusen) in the macula, between the retinal pigment epithelium and the underlying choroid. Most people with these early changes (referred to as age-related maculopathy) still have good vision. People with drusen may or may not develop AMD. In fact, the majority of people over age 60 have drusen with no adverse effects. The risk of developing symptoms is higher when the drusen are large and numerous, and associated with the disturbance in the pigmented cell layer under the macula. Large and soft drusen are thought to be related to elevated cholesterol deposits.
Early AMD
Early AMD is diagnosed based on the presence of medium-sized drusen, about the width of an average human hair. Early AMD is usually asymptomatic.
Intermediate AMD
Intermediate AMD is diagnosed by large drusen and/or any retinal pigment abnormalities. Intermediate AMD may cause some vision loss, but, like early AMD, it is usually asymptomatic.Recently, subgroups of intermediate AMD have been identified, which have a very high risk of progression toward late AMD. This subgroup (depending on the precise definitions) is termed nascent GA and/or iRORA (incomplete retinal pigment epithelium and outer retinal atrophy). These high-risk subgroups of intermediate AMD can be used to inform patients of theirs prognosis. In addition, these can be applied in clinical trials as endpoints.
Late AMD
In late AMD, enough retinal damage occurs that, in addition to drusen, people will also begin to experience symptomatic central vision loss. The damage can either be the development of atrophy or the onset of neovascular disease. Late AMD is further divided into two subtypes based on the types of damage: Geographic atrophy and Wet AMD (also called Neovascular AMD).
Dry AMD
Dry AMD (also called nonexudative AMD) is a broad designation, encompassing all forms of AMD that are not neovascular (wet AMD). This includes early and intermediate forms of AMD, as well as the advanced form of dry AMD known as geographic atrophy. Dry AMD patients tend to have minimal symptoms in the earlier stages; visual function loss occurs more often if the condition advances to geographic atrophy. Dry AMD accounts for 80–90% of cases and tends to progress slowly. In 10–20% of people, dry AMD progresses to the wet type.
Geographic atrophy
Geographic atrophy (also called atrophic AMD) is an advanced form of AMD in which progressive and irreversible loss of retinal cells leads to a loss of visual function. There are multiple layers that make up the retina, and in geographic atrophy, there are three specific layers that undergo atrophy: the choriocapillaris, retinal pigment epithelium, and the overlying photoreceptors.
The three layers that undergo atrophy in geographic atrophy are all adjacent to each other. The photoreceptors are the most superficial and they are the cells that are responsible for converting energy from the light from the outside world, into an electrical signal to be sent to the brain. There are several functions of the retinal pigment epithelium. One of the main functions of the retinal pigment epithelium is to minimize oxidative stress. It does so by absorbing light, and thus preventing it from getting to the underlying layers. The layers underlying the retinal pigment epithelium are very vascularlized so they have very high oxygen tension. Thus, if light was to get to those layers, many free radicals would form and cause damage to nearby tissues. The deepest layer that undergoes atrophy in geographic atrophy is called the choriocappilaris. It is a capillary network that provides nutrients to the retinal pigment epithelium.
The pathophysiology of geographic atrophy is still uncertain. Some studies questioned whether it was due to a deficient retinal pigment epithelium, leading to increased oxidative stress. Other studies have looked for inflammatory causes of damage. Thus far, the medical community is still not certain. Recent studies have begun to look at each layer individually. They found that decrease blood flow in the choriocapillaris precedes atrophy of the retinal pigment epithelium and the overlying photoreceptors. Since the choriocapillaris is a vascular layer, this may be used as an argument for why geographic atrophy could be a disease due to decreased blood flow.
Wet AMD
Neovascular or exudative AMD, the "wet" form of advanced AMD, causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) in the choriocapillaris, through Bruchs membrane. It is usually, but not always, preceded by the dry form of AMD. The proliferation of abnormal blood vessels in the retina is stimulated by vascular endothelial growth factor (VEGF). Because these blood vessels are abnormal, these are also more fragile than typical blood vessels, which ultimately leads to blood and protein leakage below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated.
Oxidative stress
Age-related accumulation of low-molecular-weight, phototoxic, pro-oxidant melanin oligomers within lysosomes in the retinal pigment epithelium (RPE) may be partly responsible for decreasing the digestive rate of photoreceptor outer rod segments (POS) by the RPE – autophagy. A decrease in the digestive rate of POS has been shown to be associated with lipofuscin formation – a classic sign associated with AMD.The role of retinal oxidative stress in the cause of AMD by resulting in further inflammation of the macula is suggested by the enhanced rate of disease in smokers and those exposed to UV irradiation.Mitochondrial dysfunction may play a role. Evidence was recently reviewed that damage to mitochondrial DNA may be an essential element of AMD pathogenesis and that overproduction of reactive oxygen species may play a role in this process.
Diagnosis
Diagnosis of age-related macular degeneration depends on signs in the macula, not necessarily vision. Early diagnosis of AMD can prevent further visual deterioration and potentially improve vision.Diagnosis of dry (or early stage) AMD may include the following clinical examinations as well as procedures and tests:
The transition from dry to wet AMD can happen rapidly, and if it is left untreated can lead to legal blindness in as little as six months. To prevent this from occurring and to initiate preventive strategies earlier in the disease process, dark adaptation testing may be performed. A dark adaptometer can detect subclinical AMD at least three years earlier than it is clinically evident.
There is a loss of contrast sensitivity, so that contours, shadows, and color vision are less vivid. The loss in contrast sensitivity can be quickly and easily measured by a contrast sensitivity test like Pelli Robson performed either at home or by an eye specialist.
When viewing an Amsler grid, some straight lines appear wavy and some patches appear blank
When viewing a Snellen chart, at least 2 lines decline
In dry macular degeneration, which occurs in 85–90 percent of AMD cases, drusen spots can be seen in Fundus photography
Using an electroretinogram, points in the macula with a weak or absent response compared to a normal eye may be found
Farnsworth-Munsell 100 hue test and Maximum Color Contrast Sensitivity test (MCCS) for assessing color acuity and color contrast sensitivity
Optical coherence tomography is now used by most ophthalmologists in the diagnosis and the follow-up evaluation of the response to treatment with antiangiogenic drugs.Diagnosis of wet (or late stage) AMD may include the following in addition to the above tests:
Preferential hyperacuity perimetry changes (for wet AMD). Preferential hyperacuity perimetry is a test that detects drastic changes in vision and involves the macula being stimulated with distorted patterns of dots and the patient identification of where in the visual field this occurs.
In wet macular degeneration, angiography can visualize the leakage of bloodstream behind the macula. Fluorescein angiography allows for the identification and localization of abnormal vascular processes.
Histology
Pigmentary changes in the retina – In addition to the pigmented cells in the iris (the colored part of the eye), there are pigmented cells beneath the retina. As these cells break down and release their pigment, dark clumps of released pigment and later, areas that are less pigmented may appear
Exudative changes: hemorrhages in the eye, hard exudates, subretinal/sub-RPE/intraretinal fluid
Drusen, tiny accumulations of extracellular material that build up on the retina. While there is a tendency for drusen to be blamed for the progressive loss of vision, drusen deposits can be present in the retina without vision loss. Some patients with large deposits of drusen have normal visual acuity. If normal retinal reception and image transmission are sometimes possible in a retina when high concentrations of drusen are present, then, even if drusen can be implicated in the loss of visual function, there must be at least one other factor that accounts for the loss of vision.
Prevention
A 2017 Cochrane review found the use of vitamin and mineral supplements, alone or in combination, by the general population did not affect whether or not AMD started.Refraining from smoking, including fish in the diet and maintaining a healthy weight can prevent AMDThere appears to be a preventive effect of oral L-DOPA against AMD. Several reviews refer to a 2016 retrospective medical records study of 87,000,000 unique individuals by Brilliant et al. In this study those who were on, or had been on, L-DOPA oral medicine for movement disorders (Parkinson’s Disease, etc.) were significantly less likely to develop AMD compared to those not on L-DOPA. If the individuals on L-DOPA did develop AMD, the age of occurrence of the disease was about eight years later than for those without L-DOPA treatment, and for wet AMD, it was about five years later.
At least two further reviews summarize a small “proof of concept” clinical research study by Figueroa et al. in 2021 that evaluated whether individuals who already had wet AMD could receive improvement if they took oral L-DOPA. The summary given by both reviews indicates that oral L-DOPA could cause retinal fluid to decrease by almost 30% even without standard anti-VEGF treatment, and this was accompanied by improvement in visual acuity. In addition, there was about a 50% reduction in the need for anti-VEGF injections.
RPE and L-DOPA in amelioration of wet AMD
The retinal pigment epithelium (RPE) (see diagram) has an essential role in the eye. It secretes a large variety of factors including at least 22 proteins important in maintaining the structure, function and micro-environments on the two sides of the RPE. (The two sides of the RPE include the choroid side, where blood vessels form and bring nourishment to the eye, and the photoreceptor side, with rods and cones that receive light signals.) In particular, the RPE secretes vascular endothelial growth factor (VEGF) at its basement membrane, with the VEGF reaching the choriocapillaris to maintain proper blood vessel formation in the choroid region.
Many factors, including genetic factors, hypoxia, oxidative stress and inflammatory stressors, may cause pathologic over-production of VEGF by the RPE. This over-production causes excess blood vessel formation in the choroid region (the choriocapillaris), which is a major cause of wet AMD. However, the RPE has a G-protein coupled receptor, GPR143, that is activated by its ligand, extracellular L-DOPA. Activation of GPR143 reduces RPE secretion of VEGF. Activation of GPR143, with the reduction in VEGF, may be the main protective role of L-DOPA against wet AMD.
Management
Treatment of AMD varies depending on the category of the disease at the time of diagnosis. In general, treatment is aimed at slowing down the progression of AMD. As of 2018, there are no treatments to reverse the effects of AMD. Early-stage and intermediate-stage AMD is managed by modifying known risk factors such as smoking cessation, management of hypertension and atherosclerosis and making dietary modifications. For intermediate-stage AMD, management also includes antioxidant and mineral supplementation. Advanced-stage AMD is managed based on the presence of choroidal neovascularization (CNV): dry AMD (no CNV present) or wet AMD (CNV present). No effective treatments exist for dry AMD. The CNV present in wet AMD is managed with vascular endothelial growth factor (VEGF) inhibitors. Daily use of an Amsler grid or other home visual monitoring tools can be used to monitor for development of distorted vision, which may be a sign of disease progression.
Vitamin and mineral supplementation
The age related eye disease studies 1 and 2 (AREDS) showed that those with bilateral early or intermediate AMD, or intermediate AMD in one eye and advanced AMD in the other eye may benefit from specific vitamin and mineral supplementation. The specific vitamins and minerals in AREDS-1 are vitamin C (500 mg), zinc (80 mg), vitamin E (400 IU), copper (2 mg) and beta-carotene (15 mg). In the AREDS-2 formulation, lutein (10 mg) and zeaxanthin (2 mg) replaced beta-carotene due to the risk of lung cancer in smokers taking beta-carotene. These specific micronutrient supplementations were associated with a lower risk of progression to more severe forms of AMD and greater visual acuity at 5 years. There is no evidence that micronutrient supplementation prevents AMD progression in those with severe disease or prevents disease onset in those without AMD.
Dry AMD
There is no cure for dry AMD. While there is increasing academic and pharmaceutical interest in developing complement inhibitors to treat ophthalm |
Macular degeneration | ic inflammation, with several clinical trials underway for dry AMD, the first such agent to complete Phase 3 trials in AMD (the anti-factor D agent, lampalizumab) did not significantly improve the rate of disease progression. Nevertheless, strategies targeting different aspects of the complement system are ongoing.
Wet AMD
Ranibizumab, aflibercept, brolucizumab and faricimab are approved VEGF inhibitors for the treatment of CNV in wet AMD. All three drugs are administered via intravitreal injection, meaning they are injected directly into the eye. Bevacizumab is another VEGF inhibitor that has been shown to have similar efficacy and safety as the previous two drugs, however, is not currently indicated for AMD. AMD can also be treated with laser coagulation therapy.A randomized control trial found that bevacizumab and ranibizumab had similar efficacy, and reported no significant increase in adverse events with bevacizumab. A 2014 Cochrane review found that the systemic safety of bevacizumab and ranibizumab are similar when used to treat neovascular AMD, except for gastrointestinal disorders. Bevacizumab however is not FDA approved for treatment of macular degeneration. A controversy in the UK involved the off-label use of cheaper bevacizumab over the approved, but expensive, ranibizumab. Ranibizumab is a smaller fragment, Fab fragment, of the parent bevacizumab molecule specifically designed for eye injections. Other approved antiangiogenic drugs for the treatment of neo-vascular AMD include pegaptanib and aflibercept.These anti-VEGF agents may be administered monthly or adaptively. For adaptive anti-VEGF treatment, two approaches are conventionally applied. In the case of pro re nata, the patient comes at fixed intervals, but treatment is only administered if an activity is detected (i.e., presence of fluid). In the case of treat-and-extend, the patients always receive treatment, but the interval to the next visit is extended if the lesion was inactive.
Recently, researchers have started to apply AI algorithms to predict the future need for treatment. But these approaches have not been validated for clinical use as of today.
The American Academy of Ophthalmology practice guidelines do not recommend laser coagulation therapy for macular degeneration, but state that it may be useful in people with new blood vessels in the choroid outside of the fovea who dont respond to drug treatment. There is strong evidence that laser coagulation will result in the disappearance of drusen but does not affect choroidal neovascularisation. A 2007 Cochrane review on found that laser photocoagulation of new blood vessels in the choroid outside of the fovea is effective and economical method, but that the benefits are limited for vessels next to or below the fovea.Photodynamic therapy has also been used to treat wet AMD. The drug verteporfin is administered intravenously; light of a certain wavelength is then applied to the abnormal blood vessels. This activates the verteporfin destroying the vessels.
Cataract surgery could improve visual outcomes for people with AMD, though there have been concerns about surgery increasing the progression of AMD. A randomized controlled trial found that people who underwent immediate cataract surgery (within two weeks) had improved visual acuity and better quality of life outcomes than those who underwent delayed cataract surgery (6 months).Radiotherapy has been proposed as a treatment for wet AMD but the evidence to support the use of modern stereotactic radiotherapy combined with anti-VEGF is currently uncertain and is awaiting the results of ongoing studies.Nucleoside reverse transcription inhibitors like they are used in anti-HIV therapy was associated with a reduced risk of developing atrophic macular degeneration. This is because Alu elements undergo L1 (protein)-mediated reverse transcription in the cytoplasm resulting in DNA synthesis. First clinical trials are being prepared as of January 2021.
Adaptive devices
Because peripheral vision is not affected, people with macular degeneration can learn to use their remaining vision to partially compensate. Assistance and resources are available in many countries and every state in the U.S. Classes for "independent living" are given and some technology can be obtained from a state department of rehabilitation.
Adaptive devices can help people read. These include magnifying glasses, special eyeglass lenses, computer screen readers, electronic glasses, and TV systems that enlarge the reading material.
Computer screen readers such as JAWS or Thunder work with standard Windows computers.
Also, Apple devices provide a wide range of features (voice-over, screen readers, Braille etc.).
Video cameras can be fed into standard or special-purpose computer monitors, and the image can be zoomed in and magnified. These systems often include a movable table to move the written material.
Accessible publishing provides larger fonts for printed books, patterns to make tracking easier, audiobooks and DAISY books with both text and audio.
Epidemiology
The prevalence of any age-related macular degeneration is higher in Europeans than in Asians and Africans. There is no difference in prevalence between Asians and Africans. The incidence of age-related macular degeneration and its associated features increases with age and is low in people <55 years of age. Smoking is the strongest modifiable risk factor. As of 2008, age-related macular degeneration accounts for more than 54% of all vision loss in the white population in the US. An estimated 8 million Americans are affected with early age-related macular degeneration, of whom over 1 million will develop advanced age-related macular degeneration within the next 5 years. In the UK, age-related macular degeneration is the cause of blindness in almost 42% of those who go blind aged 65–74 years, almost two-thirds of those aged 75–84 years, and almost three-quarters of those aged 85 years or older.
Research directions
Association with other age-related diseases
Studies indicate drusen associated with AMD are similar in molecular composition to amyloid beta (Aβ) plaques and deposits in other age-related diseases such as Alzheimers disease and atherosclerosis. This suggests that similar pathways may be involved in the etiologies of AMD and other age-related diseases. AMD also shares several genetic and environmental risk factors with the kidneys, which have a similar structure to the eye.
Genetic testing
Genetic testing can help identify whether a patient with AMD is at a greater risk of developing the condition and can inform disease progression. Genetic testing can also allow researchers to identify whether patients are more or less likely to respond to treatments, such anti-VEGF medication or complement inhibitors. However, there remain several challenges to using predictive tools which incorporate genetic variation in clinical practice. As well as our limited understanding of the way that different genetic variants and environmental factors interact to influence AMD risk, the single nucleotide polymorphisms which are common in the population have small effects on individual patients with AMD. Therefore, there is increasing interest in understanding the functional consequences of rare mutations, which often have more pronounced effects. Genetic testing to guide clinical management is not currently recommended.
Stem cell transplant
Cell based therapies using bone marrow stem cells as well as retinal pigment epithelial transplantation are being studied. A number of trials have occurred in humans with encouraging results.
Genome editing
CRISPR-Cas9 genome editing may be used to treat wet age-related macular degeneration caused by VEGFA. Scientists described an approach in which engineered lentiviruses are injected into the affected anatomical regions for transient editing that could reduce the area of choroidal neovascularization by 63% without inducing undesired off-target edits or anti-Cas9 immune responses.
Artificial intelligence for prediction
Research is exploring if artificial intelligence can help in predicting wet AMD early enough to make prevention possible. A study tested an AI model for predicting whether people with wet AMD in one eye would develop it in the other within six months. Compared to doctors and optometrists the AI model predicted the development more accurately.
Other types
There are a few other (rare) kinds of macular degeneration with similar symptoms but unrelated in etiology to Wet or Dry age-related macular degeneration. They are all genetic disorders that may occur in childhood or middle age.
Vitelliform macular dystrophy
Sorsbys fundus dystrophy is an autosomal dominant, retinal disease characterized by sudden acuity loss resulting from untreatable submacular neovascularisation
Stargardts disease (juvenile macular degeneration, STGD) is an autosomal recessive retinal disorder characterized by juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material.Similar symptoms with a very different etiology and different treatment can be caused by epiretinal membrane or macular pucker or any other condition affecting the macula, such as central serous retinopathy.
Notable cases
Judi Dench
Joan Plowright
Peter Sallis
June Brown
S. Robert Morgan
See also
Ophthalmology
Macula of retina
Visual impairment
Gene therapy for color blindness
Gene therapy of the human retina
Stem cell therapy for macular degeneration
References
External links
Macular degeneration at Curlie |
Myeloperoxidase deficiency | Myeloperoxidase deficiency is a disorder featuring lack in either the quantity or the function of myeloperoxidase–an iron-containing protein expressed primarily in neutrophil granules. There are two types of myeloperoxidase deficiency: primary/inherited and secondary/acquired. Lack of functional myeloperoxidase leads to less efficient killing of intracellular pathogens, particularly Candida albicans, as well as less efficient production and release of neutrophil extracellular traps (NETs) from the neutrophils to trap and kill extracellular pathogens. Despite these characteristics, more than 95% of individuals with myeloperoxidase deficiency experience no symptoms in their lifetime. For those who do experience symptoms, the most common symptom is frequent infections by Candida albicans. Individuals with myeloperoxidase deficiency also experience higher rates of chronic inflammatory conditions. Myeloperoxidase deficiency is diagnosed using flow cytometry or cytochemical stains. There is no treatment for myeloperoxidase deficiency itself. Rather, in the rare cases that individuals experience symptoms, these infections should be treated.
Pathophysiology
The innate immune system responds quickly to infection, with neutrophils (a type of white blood cells) being the first responders. Neutrophils enter the site of infection and begin to phagocytose (take up) pathogens. Once engulfed, the neutrophils must then degrade the captured pathogens–a process known as intracellular killing.One method of intracellular killing which takes place in the phagolysosomes of neutrophils involves the reaction of myeloperoxidase with hydrogen peroxide (H2O2) acquired in the cells from NADPH oxidase through the respiratory bursts. This reaction generates several acidic products including hypochlorous acid (HClO), which can break down pathogens. Bacteria such as Pseudomonas aeruginosa and fungi such as Candida albicans are killed in this manner.Neutrophils are also involved in killing extracellular pathogens (pathogens outside of the cell) through the release of NETs. These NETs contain myeloperoxidase, among other antimicrobial proteins. Once released outside of the cell, NETs trap pathogens and may in some cases kill them. Although myeloperoxidase is not required for all NET formation/release, NETs are only formed and released in response to Candida albicans when myeloperoxidase is present. Myeloperoxidase proteins in NETs can still react with H2O2 to form HClO and break down some extracellular pathogens. In myeloperoxidase deficient individuals, this extracellular pathogen killing doesn’t typically occur.Finally, during infection, neutrophils can migrate to the lymph nodes, where they deposit myeloperoxidase. Although the mechanisms of this process aren’t well understood, there is evidence that this extracellular myeloperoxidase interacts with dendritic cells (cells of the adaptive immune system) in the lymph nodes, leading to a decrease in adaptive immune system activity in response to infection.
Presentation
About 1:1,000 to 1:4,000 individuals in the United States and Europe and 1:55,000 individuals in Japan experience myeloperoxidase deficiency. The most common symptom of myeloperoxidase deficiency is frequent infections, particularly by the fungus Candida albicans. This symptom is especially frequent in individuals who also experience diabetes mellitus.The majority of myeloperoxidase-deficient individuals, however, do not display any significant tendencies towards chronic infections from most bacteria. This is likely due to the fact that the absence of myeloperoxidase leads to increased neutrophil phagocytosis and degranulation as well as increased development of the adaptive immune system. That is, other aspects of the immune system typically compensate for the lack of myeloperoxidase, leading to relatively mild symptoms.
Nonetheless, myeloperoxidase-deficient individuals have been found to experience more chronic inflammatory conditions (such as rheumatoid arthritis, pulmonary/skin inflammation, kidney/heart disease, etc.) than individuals with sufficient myeloperoxidase. Researchers hypothesize this may be a result of heightened adaptive immune system activity in individuals with myeloperoxidase deficiency. There is also some evidence that congenital myeloperoxidase deficiency is correlated with higher rates of malignant tumors.
Types
MPO deficiency is broken down into two categories: primary/congenital and secondary/acquired. Primary MPO deficiency is an autosomal recessive genetic disorder, which is caused by mutations in the myeloperoxidase gene on chromosome 17q23. There are several different known mutations of this gene which all lead to myeloperoxidase deficiency.Secondary MPO deficiency, on the other hand, occurs in various clinical situations as a result of hematological neoplasm, disseminated cancers, some drugs, iron deficiency, lead intoxication, thrombotic disease, renal transplantation, severe infectious disease, diabetes mellitus, neuronal lipofuscinosis, or pregnancy. Secondary MPO deficiency is typically partial, meaning only a portion of the affected individual’s neutrophils lack functional myeloperoxidase.
Diagnosis
Myeloperoxidase deficiency can be diagnosed via flow cytometry and cytochemical stains. Various devices can divide up leukocyte (white blood cell) populations based on their size and peroxidase activity. Specific stains bind to myeloperoxidase, and individuals who display large, granulated cells without this stain through flow cytometry typically have myeloperoxidase deficiency. In this way, it’s apparent when neutrophils are present in an individual but peroxidase activity is absent.Note, myeloperoxidase deficiency can cause false positives in the diagnosis of chronic granulomatous disease, a condition which includes dysfunctional NADPH oxidase. Both disorders interfere with neutrophils’ abilities to kill pathogens through reaction with oxidative species. However, chronic granulomatous disease leads to inadequate H2O2 production, while myeloperoxidase deficiency is characterized by a lack of myeloperoxidase to interact with present H2O2. Testing with NADPH oxidase-specific assays can lead to positive results for chronic granulomatous disease and negative results for myeloperoxidase deficiency.
Treatment
Most individuals with myeloperoxidase deficiency do not need regular treatment, as they experience only mild symptoms, if any at all. Continued antibiotic use is not recommended in myeloperoxidase-deficient patients who don’t experience recurrent infections.Acquired myeloperoxidase deficiency typically goes away when the underlying condition is treated. In particular, when myeloperoxidase deficiency is caused by severe iron deficiency, treatment with iron returns myeloperoxidase function to normal.
References
== External links == |
Nutritional muscular dystrophy | Nutritional Muscular Dystrophy (Nutritional Myopathy or White Muscle Disease) is a disease caused by a deficiency of selenium and vitamin E in dietary intake. Soils that contains low levels of selenium produce forages and grains that are deficient in selenium. Similarly, if the forage is of low quality or is not stored properly it may be deficient in vitamin E. If an animal consumes this type of diet without additional supplementation they become susceptible to this disease. This condition often affects young ruminants, such as calves and lambs.Selenium and vitamin E are antioxidants. Therefore, deficiencies of these nutrients lead to oxidative damage to cells within the body. The muscle cells are the most vulnerable to damage in livestock species.
Clinical symptoms
The oxidative damage causes degeneration of muscles, in particular those within the skeletal and cardiac systems. If the cardiac muscles are impaired the animal may exhibit signs of respiratory distress. While deterioration of skeletal muscles results in stiffness, weakness, and recumbency.
Treatment & Prevention
If the diet is deficient supplement with selenium and/or vitamin E. Injections can be given to treat the condition or as a preventative measure.
Horses
In equids, it is most common in the first twelve months of life. Neonatal foals born to dams that are selenium-deficient often develop the condition. There are two forms: peracute, and subacute. The peracute form is characterized by recumbency, tachypnea, dyspnea, myalgia, cardiac arrhythmias, and rapid death. The subacute form causes weakness, fasciculations, cramping, and stiffness of muscles, which can lead to recumbency, as well as a stilted gait, dysphagia, ptyalism, and a weak suckle. It may be treated with selenium supplementation, but there is a 30–45% mortality rate. Other sequelae include aspiration pneumonia, failure of passive transfer, and stunting of growth.
Clinical laboratory changes include evidence of rhabdomyolysis (elevated CK and AST, myoglobinuria) and low blood selenium levels. On necropsy, muscles are pale with areas of necrosis and edema evidenced as white streaks.Horses may also develop a more chronic delayed form of the disease called Neuroaxonal Dystrophy (NAD) or Equine Degenerative Myeloencephalopathy (EDM). EDM is a more severe form of NAD. The diseases are characterized by the damage and degeneration of the central nervous system. This disease process is heritable in certain breed bloodlines, such as Quarter Horse, Appaloosa, Morgan, Lusitano, and Arabian. It is hypothesized that horses develop this disease continuum because they have a defect in the uptake or utilization of Vitamin E and therefore have a higher baseline requirement.
Sheep (Stiff Lamb Disease)
In lambs, the disease typically occurs between 3 and 8 weeks of age, but may occur in older lambs as well. Progressive paralysis occurs, which is evident through the following symptoms: arched back, difficulty moving and an open shouldered stance. Cardiac failure may occur in two forms: sudden heart failure or gradual cardiac failure characterized by lung anemia that causes death due to suffocation.Ewes may be given an injection of vitamin E/selenium prior to lambing to prevent deficiencies in lambs. In areas, such as Ontario, where lambs are highly susceptible to the condition, management practices should include vitamin E/selenium injections.
Cattle
In dairy breeds, the disease may occur in calves between birth and 4 months of age. In rustic breeds or beef cattle, heifers and young steers up to 12 months of age can be affected. In calves, muscles in upper portion of the front legs and the hind legs are degraded, causing the animal to have a stiff gait and it may have difficulty standing. The disease may also present in the form of respiratory distress.
Gallery
External links
Description of the disease in Merck Veterinary Manual
== References == |
Poland syndrome | Poland syndrome is a birth defect characterized by an underdeveloped chest muscle and short webbed fingers on one side of the body. There may also be short ribs, less fat, and breast and nipple abnormalities on the same side of the body. Typically, the right side is involved. Those affected generally have normal movement and health.The cause of Poland syndrome is unknown. One theory is that it is due to disruption of blood flow during embryonic development. It is generally not inherited from a persons parents, and no genes that contribute to the disorder have been identified. Diagnosis of Poland syndrome is based on its symptoms. Often, those with the syndrome remain undiagnosed, and some may not realize they have it until puberty.Treatment of Poland syndrome depends on its severity and may include surgical correction. The syndrome affects about 1 in 20,000 newborns, and males are affected twice as often as females. It is named after English surgeon Sir Alfred Poland, who described the condition when he was a student in 1841.
Signs and symptoms
A list of the common side effects broken down by frequency.Very frequent
Abnormal gastrointestinal tract
Absent pectoral muscles
Brachydactyly (Short fingers)
Dextrocardia
Diaphragmatic hernia/defect
Humerus absent/abnormal
Liver/biliary tract anomalies
Maternal diabetes
Oligodactyly/missing fingers
Radius absent/abnormal
Rhizomelic micromelia (relatively shorter proximal segment of the limbs compared to the middle and the distal segments)
Sparsity or abnormality of axillary hair on affected side
Syndactyly of fingers (webbing)
Ulna absent/abnormal
Upper limb asymmetry
Abnormal rib
Simian crease on affected sideFrequent
Hypoplastic/absent nipples
Scapula anomalyOccasional
Agenesis/hypoplasia of kidneys
Encephalocele/exencephaly
Abnormal morphology of hypothalamic-hypophyseal axis
Abnormal function of hypothalamic-hypophyseal axis
Microcephaly
Preaxial polydactyly
Ureteric anomalies (reflux/duplex system)
Vertebral segmentation anomalyIt is usually considered a unilateral condition. Some have claimed that the term can be applied in bilateral presentation, but others recommend using alternate terminology in those cases.
Causes
The cause of Poland syndrome is unknown. However, an interruption of the embryonic blood supply to the arteries that lie under the collarbone (subclavian arteries) at about the 46th day of embryonic development is the prevailing theory.The subclavian arteries normally supply blood to embryonic tissues that give rise to the chest wall and hand. Variations in the site and extent of the disruption may explain the range of signs and symptoms that occur in Poland syndrome. Abnormality of an embryonic structure called the apical ectodermal ridge, which helps direct early limb development, may also be involved in this disorder.
Diagnosis
Poland syndrome is usually diagnosed at birth, based upon the physical characteristics. Imaging techniques such as a CT scan may reveal the extent to which the muscles are affected. The syndrome varies in severity and as such is often not reported until puberty, when lopsided growth becomes apparent.
Treatment
Technique
The complete or partial absence of the pectoralis muscle is the malformation that defines Poland syndrome. It can be treated by inserting a custom implant designed by CAD (computer aided design). A 3D reconstruction of the patients chest is done using an implant shaped from a medical scan and designed to be perfectly adapted to the anatomy. The implant is made of medical grade silicone rubber. The treatment is purely cosmetic and does not restore the patients imbalanced upper body strength.The Poland syndrome malformations are morphological, so correction by custom implant is the first-line treatment. This technique allows a wide variety of patients to be treated with good outcomes. Poland Syndrome can be associated with bones, subcutaneous and mammary atrophy: the first, as for pectus excavatum, is successfully corrected by a custom implant, while the others can require surgical intervention such as lipofilling or silicone breast implant, in a second operation.
Surgery
The surgery takes place under general anaesthesia and lasts less than 1 hour. The surgeon prepares the locus to the size of the implant after performing an 8-centimetre (3.1 in) axillary incision, then inserts the implant beneath the skin. The closure is made in two planes.The implant replaces the pectoralis major muscle, thus enabling the thorax to be symmetrical and, in women, the breast as well. If necessary, especially in the case of women, a second operation will complement the result by the implantation of a breast implant and / or lipofilling.Lipomodelling is progressively used in the correction of breast and chest wall deformities. In Poland syndrome, this technique appears to be a major advance that will probably revolutionize the treatment of severe cases. This is mainly due to its ability to achieve previously unachievable quality of reconstruction with minimal scarring.
Epidemiology
Poland syndrome affects males three times as often as females and affects the right side of the body twice as often as the left. The incidence is estimated to range from one in 7,000 to one in 100,000 live births.
History
It was named in 1962 by Patrick Clarkson, a New Zealand-born British plastic surgeon working at Guys Hospital and Queen Marys Hospital, London. He noticed that three of his patients had both a hand deformity and an underdeveloped breast on the same side. He discussed this with his colleague at Guys Hospital, Dr Philip Evans, who agreed that the syndrome was "not widely appreciated". Clarkson found a reference to a similar deformity published by Alfred Poland, an English surgeon, over a hundred years earlier in Guys Hospital reports, in 1841. Clarkson was able to find the hand specimen dissected by Poland, which was still held in the hospital pathology museum.Poland had dissected a convict known as George Elt, who was said to be unable to draw his hand across his chest. Poland noted the chest wall deformity, and this was illustrated in his article; the hand was also dissected and preserved for posterity in Guys Hospital museum where it remains today. It cannot be truly said that Poland described this syndrome because he only described one isolated case. Clarkson published his series of three cases and named the syndrome after Poland in his article.
Notable cases
TV presenter Jeremy Beadle (1948–2008) was known for having this condition. His Poland syndrome manifested itself in the form of his disproportionately small right hand.
Olympic boxer Jérôme Thomas is also affected by Poland syndrome, as his left arm and hand are significantly shorter and smaller than his right. Thomas also lacks a left pectoral muscle.
PGA Tour golfer Bryce Molder has Poland syndrome, with an absent left pectoral muscle and a small left hand. Several surgeries in his childhood repaired syndactyly on the left hand.
Actor Ted Danson, famous for starring in the TV show Cheers, admitted he had the condition in 2000 to Orange Coast magazine and said that he was bullied as a child because of it.
Formula One World Champion Fernando Alonso is affected by Poland syndrome; he is missing the right pectoral muscle.
Cricketer Lewis Hatchett was born with Poland syndrome.
Australian Paralympian Mathew Silcocks is affected by Poland syndrome.
Hailey Dawson of Nevada (born 2010) has a missing right pectoral muscle and is missing three fingers on her right hand due to the condition. She has thrown out the ceremonial first pitch at all 30 Major League Baseball parks, using a 3D-printed robotic right hand fitted for her by engineers at the University of Nevada, Las Vegas.
Actor Gary Burghoff, best known for the television series M*A*S*H, has Poland syndrome manifesting in brachydactyly on his left hand. It was seldom noticeable throughout the shows run, Burghoff usually putting his hand in his pocket or concealing it under props such as the clipboards carried by his character Radar OReilly.
English singer-songwriter Matt Goss has Poland syndrome, manifesting as a missing lower pectoral on his right side.
References
== External links == |
Fucosidosis | Fucosidosis is a rare lysosomal storage disorder in which the FUCA1 gene experiences mutations that severely reduce or stop the activity of the alpha-L-fucosidase enzyme. The result is a buildup of complex sugars in parts of the body, which leads to death.
Fucosidosis is one of nine identified glycoprotein storage diseases. The gene encoding the alpha-fucosidase, FUCA 1, was found to be located to the short arm of chromosome 1p36 - p34, by Carrit and co-workers, in 1982.
Cause
Fucosidosis is an autosomal recessive disorder that affects many areas of the body. Mutations in the FUCA1 gene causes fucosidosis. The FUCA1 gene provides instructions for making an enzyme called alpha-L-fucosidase. The enzyme plays a role in the breakdown of complex sugars in the body. The disorder is characterized by lysosomal accumulation of a variety of glycoproteins, glycolipids, and oligosaccharides that contain fucose moieties. The deficiency of the enzyme alpha-L-fucosidase, which is used to metabolize complex compounds in the body (fucose-containing glycolipids and fucose-containing glycoproteins). With the lack of this enzyme activity, the result is incomplete breakdown of glycolipids and glycoproteins. These partially broken down compounds accumulate in various parts of the body and begin to cause malfunction in cells, and can eventually cause cell death. Brain cells are especially sensitive to this buildup. Other results are progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease, and coarsening of facial features. Fucosidosis is the consequence of faulty degradation of both sphingolipids and polysaccharides. Major accumulation of the H-antigen (a member of the ABO blood group antigens), a glycolipid, is seen primarily in the liver of fucosidosis patients.
Diagnosis
Diagnosis: A special urine test is available to check for any partially broken-down-sugars. If they are present, a skin or blood sample will be taken to test for below-normal amounts of alpha-fucosidase.- Fucosidosis is an autosomal recessive disorder, which means that both parents have to have the mutation and pass it on to the child. When both parents have the mutation, there is a 25% chance of each child having fucosidosis.
Type 1
Type 1 usually begins somewhere in the first three to 18 months of age and in considered the most severe of the three types. Symptoms include:
Coarse facial features
Enlarged liver, spleen, and/or heart
Intellectual disability
Seizures
Abnormal bone formation of many bones
Progressive deterioration of brain and spinal cord
Increased or decreased perspirationPatients have no vascular lesions, but have rapid psychomotor regression, severe and rapidly progressing neurologic signs, elevated sodium and chloride excretion in the sweat, and fatal outcome before the sixth year.
Type 2
Type 2 appears when a child is around 18 months of age and in considered milder than Type 1 but still severe. Symptoms include:
Symptoms similar to Type 1 but milder and progress more slowly.
Type 3
Type 3 appears around 1–2 years of age and is considered mild.
Treatment
Treatment: There is no treatment or way to reverse the disease. Treatment will focus on the symptoms an individual has, such as seizure medication.
It is possible that if an individual receives a bone marrow transplant, they could receive healthy bone marrow cells which would produce normal amounts of fucosidase. But there not is enough research to prove this is an effective treatment.
History
Fucosidosis is an extremely rare disorder first described in 1962 in two Italian siblings who showed progressive intellectual disability and neurological deterioration. The disease itself is extremely rare (less than 100 documented cases) only affecting 1:2,000,000, with most cases being occurring in Italy, Cuba, and the southwest U.S. The disease has three different types. Type 1 and 2 are considered severe, and Type 3 being a mild disease. Symptoms are highly variable with mild cases being able to live to within the third or fourth decade. Type 1 and 2 are both linked with mental retardation. Severe cases can develop life-threatening complications early in childhood.
Because the major accumulating glycoconjugate in fucosidosis patients is the blood group H-antigen, it is intriguing to speculate, but the evidence is not clear at this time, that blood type may affect the course of the disease.
Other forms
Canine fucosidosis is found in the English Springer Spaniel.Typically affecting dogs between 18 months and four years, symptoms include:
Loss of learned behavior
Change in temperament
Blindness
Loss of balance
Deafness
Weight loss
From the onset, disease progress is quick and fatal.Just like the human version, canine fucosidosis is a recessive disorder and two copies of the gene must be present, one from each parent, in order to show symptoms of the disease.
See also
Sialidosis
References
External links
http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1095/viewAbstract - Rare diseases.org |
Minamata disease | Minamata disease is a neurological disease caused by severe mercury poisoning. Signs and symptoms include ataxia, numbness in the hands and feet, general muscle weakness, loss of peripheral vision, and damage to hearing and speech. In extreme cases, insanity, paralysis, coma, and death follow within weeks of the onset of symptoms. A congenital form of the disease can also affect fetuses in the womb and may cause cerebral palsy.
Minamata disease was first discovered in the city of Minamata, Kumamoto Prefecture, Japan, in 1956, hence its name. It was caused by the release of methylmercury in the industrial wastewater from a chemical factory owned by the Chisso Corporation, which continued from 1932 to 1968. It has also been suggested that some of the mercury sulfate in the wastewater was also metabolized to methylmercury by bacteria in the sediment. This highly toxic chemical bioaccumulated and biomagnified in shellfish and fish in Minamata Bay and the Shiranui Sea, which, when eaten by the local population, resulted in mercury poisoning. While cat, dog, pig, and human deaths continued for 36 years, Chisso and the Kumamoto prefectural government did little to prevent the epidemic. The animal effects were severe enough in cats that they came to be named as having "dancing cat fever".As of March 2001, 2,265 victims had been officially recognized as having Minamata disease and over 10,000 had received financial compensation from Chisso. By 2004, Chisso had paid US$86 million in compensation, and in the same year was ordered to clean up its contamination. On March 29, 2010, a settlement was reached to compensate as-yet uncertified victims.A second outbreak of Minamata disease occurred in Niigata Prefecture in 1965. The original Minamata disease and Niigata Minamata disease are considered two of the Four Big Pollution Diseases of Japan.
1908–1955
In 1908, the Chisso Corporation first opened a chemical factory in Minamata, Kumamoto Prefecture, located on the west coast of the southern island of Kyūshū. Initially producing fertilisers, the factory followed the nationwide expansion of Japans chemical industry, branching out into production of acetylene, acetaldehyde, acetic acid, vinyl chloride, and octanol, among others. The Minamata factory became the most advanced in all of Japan, both before and after World War II. The waste products resulting from the manufacture of these chemicals were released into Minamata Bay through the factory wastewater. These pollutants had an environmental impact. Fisheries were damaged in terms of reduced catches, and in response Chisso reached two separate compensation agreements with the fishery cooperative in 1926 and 1943.The rapid expansion of the Chisso factory spurred on the local economy, and as the company prospered so did Minamata. This fact, combined with the lack of other industry, meant that Chisso had great influence in the city. At one point, over half of the tax revenue of Minamata City authority came from Chisso and its employees, and the company and its subsidiaries were responsible for creating a quarter of all jobs in Minamata. The city was even dubbed Chissos "castle town," in reference to the capital cities of feudal lords who ruled Japan during the Edo period.The Chisso factory first started acetaldehyde production in 1932, with 210 tons that year. In 1951, production had jumped to 6,000 tons and eventually peaked at 45,245 tons in 1960. The factorys output historically amounted to between a quarter and a third of Japans total acetaldehyde production. The chemical reaction used to produce the acetaldehyde employed mercury sulfate as a catalyst. Starting in August 1951, the co-catalyst was changed from manganese dioxide to ferric sulfide. A side reaction of this catalytic cycle led to the production of a small amount (about 5% of the outflow) of the organic mercury compound methylmercury. As a result of the catalyst change, this highly toxic compound was released into Minamata Bay regularly between 1951 and 1968, when this production method was finally discontinued.
1956–1959
On 21 April 1956, a five-year-old girl was examined at Chissos factory hospital in Minamata. The physicians were puzzled by her symptoms: difficulty walking, difficulty speaking, and convulsions. Two days later, her younger sister also began to exhibit the same symptoms and she, too, was hospitalised. The girls mother informed doctors that her neighbours daughter was also experiencing similar problems. After a house-to-house investigation, eight further patients were discovered and hospitalised. On 1 May, the hospital director reported to the local public health office the discovery of an "epidemic of an unknown disease of the central nervous system", marking the official discovery of Minamata disease.To investigate the epidemic, the city government and various medical practitioners formed the Strange Disease Countermeasures Committee at the end of May 1956. Owing to the localised nature of the disease, it was suspected to be contagious and as a precaution patients were isolated and their homes disinfected. Although contagion was later disproved, this initial response contributed to the stigmatisation and discrimination experienced by Minamata survivors from the local community. During its investigations, the committee uncovered surprising anecdotal evidence of the strange behaviour of cats and other wildlife in the areas surrounding patients homes. From around 1950 onward, cats had been seen to have convulsions, go mad, and die. Locals called it the "cat dancing disease", owing to their erratic movement. Crows had fallen from the sky, seaweed no longer grew on the sea bed, and fish floated dead on the surface of the sea. As the extent of the outbreak was understood, the committee invited researchers from Kumamoto University (or Kumadai) to help in the research effort.The Kumamoto University Research Group was formed on 24 August 1956. Researchers from the School of Medicine began visiting Minamata regularly and admitted patients to the university hospital for detailed examinations. A more complete picture of the symptoms exhibited by patients was gradually uncovered. The disease developed without any prior warning, with patients complaining of a loss of sensation and numbness in their hands and feet. They became unable to grasp small objects or fasten buttons. They could not run or walk without stumbling, their voices changed in pitch, and many patients complained of difficulties seeing, hearing, and swallowing. In general, these symptoms worsened and were followed by severe convulsions, coma, and eventually death. By October 1956, forty patients had been discovered, fourteen of whom had died: an alarming case fatality rate of 35%.
Finding the cause
Researchers from Kumadai also began to focus on the cause of the strange disease. They found that the victims, often members of the same family, were clustered in fishing hamlets along the shore of Minamata Bay. The staple food of victims was invariably fish and shellfish from Minamata Bay. The cats in the local area, which tended to eat scraps from the family table, had died with symptoms similar to those now discovered in humans. This led the researchers to believe that the outbreak was caused by some kind of food poisoning, with contaminated fish and shellfish being the prime suspects.
On 4 November, the research group announced its initial findings: "Minamata disease is rather considered to be poisoning by a heavy metal, presumably it enters the human body mainly through fish and shellfish."
Identification of mercury
As soon as the investigation identified a heavy metal as the causal substance, the wastewater from the Chisso factory was immediately suspected as the origin. The companys own tests revealed that its wastewater contained many heavy metals in concentrations sufficiently high to bring about serious environmental degradation, including lead, mercury, manganese, arsenic, thallium, and copper, plus the chalcogen selenium. Identifying which particular poison was responsible for the disease proved to be extremely difficult and time-consuming. During 1957 and 1958, many different theories were proposed by different researchers. At first, manganese was thought to be the causal substance due to the high concentrations found in fish and the organs of the deceased. Thallium, selenium, and a multiple contaminant theory were also proposed, but in March 1958, visiting British neurologist Douglas McAlpine suggested that Minamata symptoms resembled those of organic mercury poisoning, so the focus of the investigation centered on mercury.
In February 1959, the mercury distribution in Minamata Bay was investigated. The results shocked the researchers involved. Large quantities of mercury were detected in fish, shellfish, and sludge from the bay. The highest concentrations centred around the Chisso factory wastewater canal in Hyakken Harbour and decreased going out to sea, clearly identifying the plant as the source of contamination. Pollution was so heavy at the mouth of the wastewater canal, a figure of 2 kg of mercury per ton of sediment was measured: a level that would be economically viable to mine. Indeed, Chisso did later set up a subsidiary to reclaim and sell the mercury recovered from the sludge.Hair samples were taken from the individuals with the disease and also from the Minamata population in general. In patients, the maximum mercury level recorded was 705 parts per million (ppm), indicating very heavy exposure and in nonsymptomatic Minamata residents, the level was 191 ppm. This compared to an average level of 4 ppm for people living outside the Minamata area.On 12 November 1959, the Ministry of Health and Welfares Minamata Food Poisoning Subcommittee published its results:
Minamata disease is a poisoning disease that affects mainly the central nervous system and is caused by the consumption of large quantities of fish and shellfish living in Minamata Bay and its surroundings, the major causative agent being some sort of organic mercury compound.
1959
During the Kumadai investigation, the causal substance had been identified as a heavy metal and it was widely presumed that the Chisso factory was the source of the contamination. Chisso was coming under closer scrutiny and to deflect criticism, the wastewater output route was changed. Chisso knew of the environmental damage caused by its wastewater and was well aware that it was the prime suspect in the Minamata disease investigation. Despite this, from September 1958, instead of discharging its waste into Hyakken Harbour (the focus of investigation and source of original contamination), it discharged wastewater directly into Minamata River. The immediate effect was the death of fish at the mouth of the river, and from that point on, new Minamata disease victims began to appear in other fishing villages up and down the coast of the Shiranui Sea, as the pollution spread over an even greater area.Chisso failed to co-operate with the Kumadai research team. It withheld information on its industrial processes, leaving researchers to speculate what products the factory was producing and by what methods. The Chisso factorys hospital director, Hajime Hosokawa, established a laboratory in the research division of the facility to carry out his own experiments into Minamata disease in July 1959. Food to which factory wastewater had been added was fed to healthy cats. Seventy-eight days into the experiment, cat 400 exhibited symptoms of Minamata disease and pathological examinations confirmed a diagnosis of organic mercury poisoning. Chisso did not reveal these significant results to the investigators and ordered Hosokawa to stop his research.In an attempt to undermine Kumadai researchers organic mercury theory, Chisso and other parties with a vested interest that the factory remain open (including the Ministry of International Trade and Industry and the Japan Chemical Industry Association) funded research into alternative causes of the disease, other than its own waste.
Compensation of fishermen and patients, 1959
Polluting wastewater had damaged the fisheries around Minamata ever since the opening of the Chisso factory in 1908. The Minamata Fishing Cooperative had managed to win small payments of "sympathy money" from the company in 1926 and again in 1943, but after the outbreak of Minamata disease, the fishing situation was becoming critical. Fishing catches had declined by 91% between 1953 and 1957. The Kumamoto prefectural government issued a partial ban on the sale of fish caught in the heavily polluted Minamata Bay – but not an all-out ban, which would have legally obliged it to compensate the fishermen. The fishing cooperative protested against Chisso and angrily forced their way into the factory on 6 August and 12 August, demanding compensation. A committee was set up by Minamata Mayor Todomu Nakamura to mediate between the two sides, but this committee was stacked heavily in the companys favour. On 29 August, the fishing cooperative agreed to the mediation committees proposal, stating: "In order to end the anxiety of the citizens, we swallow our tears and accept". Chisso paid the cooperative ¥20 million (US$183,477 — about US$1.7 million in 2021 value) and set up a ¥15 million ($137,608 — about 1.25 million today) fund to promote the recovery of fishing.
Since the change of route of wastewater output in 1958, pollution had spread up and down the Shiranui Sea, damaging fisheries there as well. Emboldened by the success of the small Minamata cooperative, the Kumamoto Prefectural Alliance of Fishing Cooperatives also decided to seek compensation from Chisso. On 17 October, 1,500 fishermen from the alliance descended on the factory to demand negotiations. When this produced no results, the alliance members took their campaign to Tokyo, securing an official visit to Minamata by members of the Japanese Diet. During the visit on 2 November, alliance members forced their way into the factory and rioted, causing many injuries and ¥10 million ($100,000) worth of damage. The violence was covered widely in the media, bringing the nations attention to the Minamata issue for the first time since the outbreak began. Another mediation committee was set up, and an agreement was hammered out and signed on 17 December. Some ¥25 million of "sympathy money" was paid to the alliance and a ¥65 million fishing recovery fund was established.
In 1959, the people with Minamata disease were in a much weaker position than the fishermen. The recently formed Minamata Disease Patients Families Mutual Aid Society was much more divided than the fishing cooperatives. Patients families were the victims of discrimination and ostracism from the local community. Local people felt that the company (and their city that depended upon it) was facing economic ruin. To some patients, this ostracism by the community represented a greater fear than the disease itself. After beginning a sit-in at the Chisso factory gates in November 1959, the patients asked Kumamoto Prefecture Governor Hirosaku Teramoto to include the patients request for compensation with the mediation that was ongoing with the prefectural fishing alliance. Chisso agreed and after a few weeks further negotiation, another "sympathy money" agreement was signed. Patients who were certified by a Ministry of Health and Welfare committee would be compensated: adult patients received ¥100,000 ($917) per year; children ¥30,000 ($275) per year, and families of dead patients would receive a one-off ¥320,000 ($2935) payment.
Wastewater treatment
On 21 October 1959, Chisso was ordered by the Ministry of International Trade and Industry to switch back its wastewater drainage from the Minamata River to Hyakken Harbour and to speed up the installation of wastewater treatment systems at the factory. Chisso installed a Cyclator purification system on 19 December 1959, and opened it with a special ceremony. Chissos president Kiichi Yoshioka drank a glass of water supposedly treated through the Cyclator to demonstrate that it was safe. In fact, the wastewater from the factory, which the company knew still contained mercury and led to Minamata disease when fed to cats, was not being treated through the Cyclator at the time. Testimony at a later Niigata Minamata disease trial proved that Chisso knew the Cyclator to be completely ineffective: "The purification tank was installed as a social solution and did nothing to remove organic mercury."The deception was successful and almost all parties involved in Minamata disease were duped into believing that the factorys wastewater had been made safe from December 1959 onward. This widespread assumption meant that doctors were not expecting new patients to appear, resulting in numerous problems in the years to follow as the pollution continued. In most peoples minds, the issue of Minamata disease had been resolved.
1959–1969
The years between the first set of "sympathy money" agreements in 1959 and the start of the first legal action to be taken against Chisso in 1969 are often called the "ten years of silence". In fact, much activity on the part of the patients and fishermen took place during this period, but nothing had a significant impact on the actions of the company or the coverage of Minamata in the Japanese media.
Continued pollution
Despite the almost universal assumption to the contrary, the wastewater treatment facilities installed in December 1959 had no effect on the level of organic mercury being released into the Shiranui Sea. The pollution and the disease it caused continued to spread. The Kumamoto and Kagoshima prefectural governments conducted a joint survey in late 1960 and early 1961 into the level of mercury in the hair of people living around the Shiranui Sea. The results confirmed that organic mercury had spread all around the inland sea and that people were still being poisoned by contaminated fish. Hundreds of people were discovered to have levels greater than 50 ppm of mercury in their hair, the level at which people are likely to experience nerve damage. The highest result recorded was that of a woman from Goshonoura island who had 920 ppm in her sample.
The prefectural governments did not publish the results and did nothing in response to these surveys. The participants who had donated hair samples were not informed of their result, even when they requested it. A follow-up study ten years later discovered that many had died from "unknown causes".
Congenital Minamata disease
Local doctors and medical officials had noticed for a long time an abnormally high frequency of cerebral palsy and other infantile disorders in the Minamata area. In 1961, a number of medical professionals, including Masazumi Harada (later to be honored by the United Nations for his body of work on Minamata disease), set about re-examining children diagnosed with cerebral palsy. The symptoms of the children closely mirrored those of adult Minamata disease patients, but many of their mothers did not exhibit symptoms. The fact that these children had been born after the initial outbreak and had never been fed contaminated fish also led their mothers to believe they were not victims. At the time the medical establishment believed the placenta would protect the foetus from toxins in the bloodstream, which is indeed the case with most chemicals. What was not known at the time was that exactly the opposite is the case with methylmercury: the placenta removes it from the mothers bloodstream and concentrates the chemical in the foetus.
After several years of study and the autopsies of two children, the doctors announced that these children had an as-yet unrecognised congenital form of Minamata disease. The certification committee convened on 29 November 1962 and agreed that the two dead children and the sixteen children still alive should be certified as patients, and therefore liable for "sympathy" payments from Chisso, in line with the 1959 agreement.
Outbreak of Niigata Minamata disease
Minamata disease broke out again in 1965, this time along the banks of the Agano River in Niigata Prefecture. The polluting factory (owned by Showa Denko) employed a chemical process using a mercury catalyst very similar to that used by Chisso in Minamata. As in Minamata, from the autumn of 1964 to the spring of 1965, cats living along the banks of the Agano River had been seen to go mad and die. Before long, patients appeared with identical symptoms to patients living on the Shiranui Sea, and the outbreak was made public on 12 June 1965. Researchers from the Kumamoto University Research Group and Hajime Hosokawa (who had retired from Chisso in 1962) used their experience from Minamata and applied it to the Niigata outbreak. In September 1966, a report was issued proving Showa Denkos pollution to be the cause of this second Minamata disease outbreak.
Unlike the patients in Minamata, the victims of Showa Denkos pollution lived a considerable distance from the factory and had no particular link to the company. As a result, the local community was much more supportive of patients groups and a lawsuit was filed against Showa Denko in March 1968, only three years after discovery.
The events in Niigata catalysed a change in response to the original Minamata incident. The scientific research carried out in Niigata forced a re-examination of that done in Minamata and the decision of Niigata patients to sue the polluting company allowed the same response to be considered in Minamata. Masazumi Harada has said that, "It may sound strange, but if this second Minamata disease had not broken out, the medical and social progress achieved by now in Kumamoto... would have been impossible."Around this time, two other pollution-related diseases were also grabbing headlines in Japan. People with Yokkaichi asthma and itai-itai disease were forming citizens groups and filed lawsuits against the polluting companies in September 1967 and March 1968, respectively. As a group, these diseases came to be known as the four big pollution diseases of Japan.Slowly but surely, the mood in Minamata and Japan as a whole was shifting. Minamata patients found the public gradually becoming more receptive and sympathetic as the decade wore on. This culminated in 1968 with the establishment in Minamata of the Citizens Council for Minamata Disease Countermeasures, which was to become the chief citizens support group to the Minamata patients. A founding member of the citizens council was Michiko Ishimure, a local housewife and poet who later that year published Pure Land, Poisoned Sea: Our Minamata disease, a book of poetic essays that received national acclaim.
1969–1973
Official government recognition
Finally on 26 September 1968 – twelve years after the discovery of the disease (and four months after Chisso had stopped production of acetaldehyde using its mercury catalyst) – the Japanese government issued an official conclusion as to the cause of Minamata disease:
Minamata disease is a disease of the central nervous system, a poisoning caused by long-term consumption, in large amounts, of fish and shellfish from Minamata Bay. The causative agent is methylmercury. Methylmercury produced in the acetaldehyde acetic acid facility of Shin Nihon Chissos Minamata factory was discharged in factory wastewater... Minamata disease patients last appeared in 1960, and the outbreak has ended. This is presumed to be because consumption of fish and shellfish from Minamata Bay was banned in the fall of 1957, and the fact that the factory had waste-treatment facilities in place from January 1960.
The conclusion contained many factual errors: eating fish and shellfish from other areas of the Shiranui Sea, not just Minamata Bay, could cause the disease; eating small amounts, as well as large amounts of contaminated fish over a long time also produced symptoms; the outbreak had not, in fact, ended in 1960 nor had mercury-removing wastewater facilities been installed in January 1960. Nevertheless, the government announcement brought a feeling of relief to a great many victims and their families. Many felt vindicated in their long struggle to force Chisso to accept responsibility for causing the disease and expressed thanks that their plight had been recognised by their social superiors. The struggle now focused on to what extent the victims should be compensated.
Struggle for a new agreement
In light of the government announcement, the patients of the Mutual Aid Society decided to ask for a new compensation agreement with Chisso and submitted the demand on 6 October. Chisso replied that it was unable to judge what would be fair compensation and asked the Japanese government to set up a binding arbitration committee to decide. This proposal split the members of the patients society, many of whom were extremely wary of entrusting their fate to a third party, as they had done in 1959 with unfortunate results. At a meeting on the 5 April 1969, the opposing views within the society could not be reconciled and the organisation split into the pro-arbitration group and the litigation group (who decided to sue the company). That summer, Chisso sent gifts to the families who opted for arbitration rather than litigation.
An arbitration committee was duly set up by the Ministry of Health and Welfare on 25 April, but it took almost a year to draw up a draft compensation plan. A newspaper leak in March 1970 revealed that the committee would ask Chisso to pay only ¥2 million ($5,600) for dead patients and ¥140,000 to ¥200,000 ($390 to $560) per year to surviving patients. The arbitration group were dismayed by the sums on offer. They petitioned the committee, together with patients and supporters of the litigation group, for a fairer deal. The arbitration committee announced their compensation plan on 25 May in a disorderly session at the Ministry of Health and Welfare in Tokyo. Thirteen protesters were arrested.
Instead of accepting the agreement as they had promised, the arbitration group asked for increases. The committee was forced to revise its plan and the patients waited inside the ministry building for two days while they did so. The final agreement was signed on 27 May. Payments for deaths ranged from ¥1.7 million to ¥4 million ($4,700 to $11,100), one-time payments from ¥1 million to ¥4.2 million ($2,760 to $11,660) and annual payments between ¥170,000 and ¥380,000 ($470 to $1,100) for surviving patients. On the day of the signing, the Minamata Citizens Council held a protest outside the Chisso factory gates. One of the Chisso trade unions held an eight-hour strike in protest at the poor treatment of the arbitration group by their own company.The litigation group, representing 41 certified patients (17 already deceased) in 28 families, submitted their suit against Chisso in the Kumamoto District Court on 14 June 1969. The leader of the group, Eizō Watanabe (a former leader of the Mutual Aid Society), declared, "Today, and from this day forth, we are fighting against the power of the state." Those who decided to sue the company came under fierce pressure to drop their lawsuits. One woman was visited personally by a Chisso executive and harassed by her neighbours. She was blackballed by the community, her familys fishing boat used without permission, their fishing nets were cut, and human faeces were thrown at her in the street.The litigation group and their lawyers were helped substantially by an informal national network of citizens groups that had sprung up around the country in 1969. The Associations to Indict those Responsible for Minamata Disease were instrumental in raising awareness and funds for the lawsuit. The Kumamoto branch, in particular, was especially helpful to the case. In September 1969, they set up a Trial Research Group, which included law professors, medical researchers (including Harada), sociologists and even Michiko Ishimure to provide useful material to the lawyers to improve their legal arguments. Their report, Corporate Responsibility for Minamata Disease: Chissos Illegal Acts, published in August 1970, formed the basis of the ultimately successful lawsuit.The trial lasted almost four years. The litigation groups lawyers sought to prove Chissos corporate negligence. Three main legal points had to be overcome to win the case. First, the lawyers had to show that methylmercury caused Minamata disease and that the companys factory was the source of pollution. The extensive research by Kumadai and the governments conclusion meant that this point was proved quite easily. Second, they needed to show that Chisso could and should have anticipated the |
Minamata disease | effect of its wastewater and taken steps to prevent the tragedy (i.e., was the company negligent in its duty of care). Third, it had to disprove that the "sympathy money" agreement of 1959, which forbade the patients from claiming any further compensation, was a legally binding contract.
The trial heard from patients and their families, but the most important testimony came from Chisso executives and employees. The most dramatic testimony came from Hosokawa, who spoke on 4 July 1970 from his hospital bed where he was dying of cancer. Hosokawa explained his experiments with cats, including the infamous "cat 400", which developed Minamata disease after being fed factory wastewater. He also spoke of his opposition to the 1958 change in wastewater output route to Minamata River. Hosokawas testimony was backed up by a colleague who also told how Chisso officials had ordered them to halt their cat experiments in the autumn of 1959. Hosokawa died three months after giving his testimony. Former factory manager Eiichi Nishida admitted that the company put profits ahead of safety, resulting in dangerous working conditions and a lack of care with mercury. Former Chisso President Kiichi Yoshioka admitted that the company promoted a theory of dumped World War II explosives, though it knew it to be unfounded.
The verdict handed down on 20 March 1973 represented a complete victory for the patients of the litigation group:
The defendants factory was a leading chemical plant with the most advanced technology and... should have assured the safety of its wastewater. The defendant could have prevented the occurrence of Minamata disease or at least have kept it at a minimum. We cannot find that the defendant took any of the precautionary measures called for in this situation whatsoever. The presumption that the defendant had been negligent from beginning to end in discharging wastewater from its acetaldehyde plant is amply supported. The defendant cannot escape liability for negligence.
The "sympathy money" agreement was found to be invalid and Chisso was ordered to make one-time payments of ¥18 million ($66,000) for each deceased patient and from ¥16 million to ¥18 million ($59,000 to $66,000) for each surviving patient. The total compensation of ¥937 million ($3.4 million) was the largest sum ever awarded by a Japanese court.
Uncertified patients fight to be recognised
While the struggles of the arbitration and litigation groups against Chisso were continuing, a new group of individuals with Minamata disease emerged. To qualify for compensation under the 1959 agreement, patients had to be officially recognised by various ad hoc certification committees according to their symptoms. However, in an effort to limit the liability and financial burden on the company, these committees were sticking to a rigid interpretation of Minamata disease. They required that patients must exhibit all symptoms of Hunter-Russell syndrome – the standard diagnosis of organic mercury poisoning at the time, which originated from an industrial accident in the United Kingdom in 1940. The committee certified only patients exhibiting explicit symptoms of the British syndrome, rather than basing their diagnosis on the disease in Japan. This resulted in many applicants being rejected by the committee, leaving them confused and frustrated.
Legacies
Epidemiology
As of March 2001, 2,265 victims had been officially certified and over 10,000 people had received financial compensation from Chisso, although they were not recognised as official victims. The issue of quantifying the impact of Minamata disease is complicated, as a full epidemiological study has never been conducted and patients were recognised only if they voluntarily applied to a certification council to seek financial compensation. Many individuals with Minamata disease faced discrimination and ostracism from the local community if they came out into the open about their symptoms. Some people feared the disease to be contagious, and many local people were fiercely loyal to Chisso, depending on the company for their livelihoods. In this atmosphere, those affected were reluctant to come forward and seek certification. Despite these factors, over 17,000 people have applied to the council for certification. Also, in recognising an applicant as having Minamata disease, the certification council qualified that patient to receive financial compensation from Chisso. For that reason, the council has always been under immense pressure to reject claimants and minimise the financial burden placed on Chisso. Rather than being a council of medical recognition, the decisions of the council were always affected by the economic and political factors surrounding Minamata and the Chisso corporation. Furthermore, compensation of the victims led to continued strife in the community, including unfounded accusations that some of the people who sought compensation did not actually have the disease. More properly, the impact should be called a criminal poisoning, not a clinical disease. These forms of obfuscation are commonly experienced by environmental victims in many countries.In 1978, the National Institute for Minamata Disease was established in Minamata. It consists of four departments: The Department of Basic Medical Science, The Department of Clinical Medicine, The Department of Epidemiology and The Department of International Affairs and Environmental Sciences. In 1986, The Institute became a WHO Collaborating Centre for Studies on the Health Effects of Mercury Compounds. The Institute seeks to improve medical treatment of Minamata disease patients and conducts research on mercury compounds and their impact on organisms as well as potential detoxification mechanisms. In April, 2008 the Institute invented a method for absorbing gaseous mercury in order to prevent air pollution and enable recycling of the metal.
Environmental protection
The movement for redress by Minamata victims and activists and the national outrage their movement elicited played a central role in the rise of environmental protection in Japan. The 1970 session of the Japanese Diet became remembered as the "Pollution Diet", as the Japanese government took action under rising pressure from the Minamata disease movement as well as other major environmental catastrophes such as Yokkaichi asthma and itai-itai disease. Fourteen new environmental laws were passed in a single session, giving Japan what at the time were the most stringent environmental protection laws in the world. These new laws included a Water Pollution Act and nationwide regulations of toxic discharges. The "polluter pays" principle was introduced. A national Environmental Agency, which later developed into the Ministry of Environment, was founded in 1971. National governmental expenditures on environmental issues almost doubled between 1970 and 1975 and tripled at the local government level.
Democratizing effects
According to historian Timothy S. George, the environmental protests that surrounded the disease appeared to aid in the democratization of Japan. When the first cases were reported and subsequently suppressed, the rights of the victims were not recognised, and they were given no compensation. Instead, the affected were ostracised from their community due to ignorance about the disease, as people were afraid that it was contagious.
The people directly impacted by the pollution of Minamata Bay were not originally allowed to participate in actions that would affect their future. Disease victims, fishing families, and company employees were excluded from the debate. Progress occurred when Minamata victims were finally allowed to come to a meeting to discuss the issue. As a result, postwar Japan took a small step toward democracy.
Through the evolution of public sentiments, the victims and environmental protesters were able to acquire standing and proceed more effectively in their cause. The involvement of the press also aided the process of democratization because it caused more people to become aware of the facts of Minamata disease and the pollution that caused it. However, although the environmental protests did result in Japan becoming more democratized, it did not completely rid Japan of the system that first suppressed the fishermen and individuals with Minamata disease.
Popular culture
Toshiko Akiyoshi, touched by the plight of the fishing village, wrote a jazz suite, "Minamata", that was to be the central piece of the Toshiko Akiyoshi-Lew Tabackin Big Bands 1976 album on RCA, Insights. The piece was constructed in three parts, to musically reflect the tragedy – "Peaceful Village", "Prosperity & Consequence", and "Epilogue". Akiyoshi used Japanese vocalists to sing the Japanese lyrics of a tone poem that were part of the composition. The album won many awards in jazz circles, including Downbeats best album award, largely on the strength of this piece, which brought some further attention to the tragedy. Insights (Toshiko Akiyoshi – Lew Tabackin Big Band)
The song "Kepone Factory" on Dead Kennedys In God We Trust, Inc. makes reference to the disaster in its chorus.
The song "The Disease of the Dancing Cats" by the band Bush on the album The Science of Things is in reference to the disaster.
Visual documentation
Photographic documentation of Minamata started in the early 1960s. One photographer who arrived in 1960 was Shisei Kuwabara, straight from university and photo school, who had his photographs published in Weekly Asahi as early as May 1960. The first exhibition of his photographs of Minamata was held in the Fuji Photo Salon in Tokyo in 1962, and the first of his book-length anthologies, Minamata Disease, was published in Japan in 1965. He has returned to Minamata many times since.A dramatic photographic essay by W. Eugene Smith brought world attention to Minamata disease. He and his Japanese wife lived in Minamata from 1971 to 1973. The most famous and striking photo of the essay, Tomoko and Mother in the Bath (1972), shows Ryoko Kamimura holding her severely deformed daughter, Tomoko, in a Japanese bath chamber. Tomoko was poisoned by methylmercury while still in the womb. The photo was very widely published. It was posed by Smith with the co-operation of Ryoko and Tomoko to dramatically illustrate the consequences of the disease. It has subsequently been withdrawn from circulation at the request of Tomokos family, so does not appear in recent anthologies of Smiths works. Smith and his wife were extremely dedicated to the cause of the people with Minamata disease, closely documenting their struggle for recognition and right to compensation. Smith was himself attacked and seriously injured by Chisso employees in an incident in Goi, Ichihara city, near Tokyo on January 7, 1972, in an attempt to stop the photographer from further revealing the issue to the world. The 54-year-old Smith survived the attack, but his sight in one eye deteriorated and his health never fully recovered before his death in 1978. Johnny Depp plays W. Eugene Smith in Minamata (2020) a drama based on the book written by Smiths wife.
Japanese photographer Takeshi Ishikawa, who assisted Smith in Minamata, has since exhibited his own photographs documenting the disease. His photographs cover the years 1971 to the present, with Minamata victims as his subjects.The prominent Japanese documentary filmmaker Noriaki Tsuchimoto made a series of films, starting with Minamata: The Victims and Their World (1971) and including The Shiranui Sea (1975), documenting the incident and siding with the victims in their struggle against Chisso and the government.
Kikujiro Fukushima, a well-known Japanese photographer and journalist, published a series of photographs in 1980 concerning pollution in Japan, including Minamata disease. Some negatives of these photos are available on the website, and Kyodo News Images holds the rights to them.
Today
Minamata disease remains an important issue in contemporary Japanese society. Lawsuits against Chisso and the prefectural and national governments are still continuing and many regard the government responses to date as inadequate. The companys "historical overview" in its current website makes no mention of their role in the mass contamination of Minamata and the dreadful aftermath. Their 2004 Annual Report, however, reports an equivalent of about US$50 million (5,820 million yen) in "Minamata Disease Compensation Liabilities". From 2000 to 2003, the company also reported total compensation liabilities of over US$170 million. Their 2000 accounts also show that the Japanese and Kumamoto prefectural governments waived an enormous US$560 million in related liabilities. Their FY2004 and FY2005 reports refer to Minamata disease as "mad hatters disease", a term coined from the mercury poisoning experienced by hat-makers of the last few centuries (cf. Erethism).A memorial service was held at the Minamata Disease Municipal Museum on 1 May 2006 to mark 50 years since the official discovery of the disease. Despite bad weather, the service was attended by over 600 people, including Chisso chairman Shunkichi Goto and Environment Minister Yuriko Koike.On Monday, March 29, 2010, a group of 2,123 uncertified victims reached a settlement with the government of Japan, the Kumamoto Prefectural government, and Chisso Corporation to receive individual lump-sum payments of 2.1 million yen and monthly medical allowances.Most congenital patients are now in their forties and fifties and their health is deteriorating. Their parents, who are often their only source of care, are into their seventies or eighties or already deceased. Often, these patients find themselves tied to their own homes and the care of their family, effectively isolated from the local community. Some welfare facilities for patients do exist. One notable example is Hot House, a vocational training centre for congenital patients as well as other disabled people in the Minamata area. Hot House members are also involved in raising awareness of Minamata disease, often attending conferences and seminars as well as making regular visits to elementary schools throughout Kumamoto Prefecture.
See also
Heavy metal poisoning
Minamata Convention on Mercury
Ontario Minamata disease
Mercury in fish
References
Further reading
"Minamata Disease: The History and Measures", The Ministry of the Environment, (2002), retrieved 17 January 2007
"Minamata Disease Archives" by the National Institute for Minamata Disease, retrieved 29 October 2006
Harada, Masazumi. (1972). Minamata Disease. Kumamoto Nichinichi Shinbun Centre & Information Center/Iwanami Shoten Publishers. ISBN 4-87755-171-9 C3036
George, S. Timothy. (2001). Minamata: Pollution and the Struggle for Democracy in Postwar Japan. Harvard University Press. ISBN 0-674-00785-9
Ui, Jun. (1992). Industrial Pollution in Japan. United Nations University Press. ISBN 92-808-0548-7. Chapter 4, section IV
Smith, W. E. and Smith, A. M. (1975). Minamata. Chatto & Windus, Ltd. (London), ISBN 0-7011-2131-9
Eto, K., Marumoto, M. and Takeya, M. (2010) "The pathology of methylmercury poisoning (Minamata disease)", retrieved 7 December 2013
Oiwa, Keibo. (2001). Rowing the Eternal Sea: The Story of a Minamata Fisherman. Rowman & Littlefield Publishers. ISBN 0-7425-0021-7
Steingraber, Sandra. (2001). Having Faith: An Ecologist Journey to Motherhood. Perseus Publishing. ISBN 0-425-18999-6
Approaches to Water Pollution Control, Minamata City, Kumamoto Prefecture
Allchin, Douglas. The Poisoning of Minamata
Saito, Hisashi. (2009). Niigata Minamata Disease: Methyl Mercury Poisoning in Niigata, Japan. Niigata Nippo.
Walker, Brett. (2010) "Toxic Archipelago: A History of Industrial Disease in Japan." University of Washington Press. ISBN 0-295-98954-8
External links
ATSDR – ToxFAQs: Mercury – Frequently asked questions about Mercury
National Institute for Minamata Disease
Minamata Disease: The History and Measures – The Ministry of the Environments summary of Minamata disease
Soshisha – The Supporting Center for Minamata Disease and the Minamata Disease Museum
Aileen Archive – Copyright holder of W. Eugene Smiths Minamata photos
Photograph by W. Eugene Smith – Tomoko Uemura in Her Bath, 1972
Minamata disease – Chapter from Industrial Pollution in Japan by Dr Jun Ui
Toxic Archipelago: Industrial Pollution in Japan – A talk by Brett Walker, September 16, 2010
Minamata Timeline by Minamata City Council.
Minamata disease museum |
Post-dural-puncture headache | Post-dural-puncture headache (PDPH) is a complication of puncture of the dura mater (one of the membranes around the brain and spinal cord). The headache is severe and described as "searing and spreading like hot metal", involving the back and front of the head and spreading to the neck and shoulders, sometimes involving neck stiffness. It is exacerbated by movement and sitting or standing and is relieved to some degree by lying down. Nausea, vomiting, pain in arms and legs, hearing loss, tinnitus, vertigo, dizziness and paraesthesia of the scalp are also common.PDPH is a common side effect of lumbar puncture and spinal anesthesia. Leakage of cerebrospinal fluid causes reduced fluid levels in the brain and spinal cord. Onset occurs within two days in 66% of cases and three days in 90%. It occurs so rarely immediately after puncture that other possible causes should be investigated when it does.Using a pencil point needle rather than a cutting spinal needle decreases the risk. The size of the pencil point needle does not appear to make a difference. PDPH is estimated to occur in between 0.1% and 36% people following dural puncture.
Signs and symptoms
PDPH typically occurs hours to days after puncture and presents with symptoms such as headache (which is mostly bi-frontal or occipital) and nausea that typically worsen when the patient assumes an upright posture. The headache usually occurs 24–48 hours after puncture but may occur as many as 12 days after. It usually resolves within a few days but has been rarely documented to take much longer.
Pathophysiology
PDPH is thought to result from a loss of cerebrospinal fluid into the epidural space. A decreased hydrostatic pressure in the subarachnoid space then leads to traction to the meninges with associated symptoms.
Diagnosis
Differential diagnosis
Although in very rare cases the headache may present immediately after a puncture, this is almost always due to another cause such as increased intracranial pressure and requires immediate attention.
Prevention
Using a pencil point rather than a cutting spinal needle decreases the risk. The size of the pencil point needle does not appear to make a difference, while smaller cutting needles have a low risk compared to larger ones. Modern, atraumatic needles such as the Sprotte or Whitacre spinal needle leave a smaller perforation and reduce the risk for PDPH. However, the evidence that atraumatic needles reduce the risk of post-dural puncture headache (PDPH) without increasing adverse events such as paraesthesia or backache is moderate-quality and further research should be done.Morphine, cosyntropin, and aminophylline appear effective in reducing post dural puncture headaches. Evidence does not support the use of bed rest or intravenous fluids to prevent PDPH.
Treatment
Some people require no other treatment than pain medications and bed rest. A 2015 review found tentative evidence to support the use of caffeine. Vigorous hydration is routinely encouraged in postpartum patients as a noninvasive, low-risk therapy.Pharmacological treatments as; gabapentin, pregabalin, neostigmine/atropine, methylxanthines, and triptans. Minimally invasive procedures as; bilateral greater occipital nerve block or sphenopalatine ganglion block. Persistent and severe PDPH may require an epidural blood patch. A small amount of the persons blood is injected into the epidural space near the site of the original puncture; the resulting blood clot then "patches" the meningeal leak.
EBP is effective, and further intervention is rarely necessary. 25-35% of patients suffer from transient back pain after EBP. More rare complications of EBP include misplacement of blood leading to spinal subdural hematoma or intrathecal injection and arachnoiditis, infection with subdural abscess, facial nerve paralysis, spastic paraparesis and cauda equina syndrome.
Epidemiology
Estimates for the overall incidence of PDPH vary between 0.1% and 36%. It is more common in younger patients (especially in the 18–30 age group), females (especially those who are pregnant), and those with a low body mass index (BMI). The low prevalence in elderly patients may be due to a less stretchable dura mater. It is also more common with the use of larger diameter needles. A 2006 review reported an incidence of:
12% if a needle between 0.4128 mm (0.01625 in) and 0.5652 mm (0.02225 in) is used;
40% if a needle between 0.7176 mm (0.02825 in) and 0.9081 mm (0.03575 in) is used; and
70% if a needle between 1.067 mm (0.0420 in) and 1.651 mm (0.0650 in) is used.On the Birmingham gauge, these correspond to the values 27–24G, 22–20G and 19–16G.PDPH is roughly twice as common in lumbar puncture than spinal anaesthesia, almost certainly due to the atraumatic needles used in spinal anaesthesia.
References
== External links == |
Sea-blue histiocytosis | Sea-blue histiocytosis is a cutaneous condition that may occur as a familial inherited syndrome or as an acquired secondary or systemic infiltrative process.: 720
Causes
It can be associated with the gene APOE.It can also be acquired. Sea-blue histiocyte syndrome is seen in patients receiving fat emulsion as a part of long-term parenteral nutrition (TPN) for intestinal failure.
Pathophysiology
The high lipid content in the blood leads to excessive cytoplasm loading of lipids within histiocytes.
The subsequent incomplete degradation of these lipids leads to the formation of cytoplasmic lipid pigments.
High lipid content may also cause membrane abnormality of the hemopoietic cells which is recognized by macrophages and therefore, increased accumulation within the bone marrow.
These lipid laden histiocytes appear blue with May-Giemsa/PAS stain hence the name of Sea-Blue Histocyte Syndrome.
Sea-blue histiocytosis is also seen in lipid disorders.
Diagnosis
See also
Non-X histiocytosis
References
== External links == |
Hyperoxaluria | Hyperoxaluria is an excessive urinary excretion of oxalate. Individuals with hyperoxaluria often have calcium oxalate kidney stones. It is sometimes called Birds disease, after Golding Bird, who first described the condition.
Causes
Hyperoxaluria can be primary (as a result of a genetic defect) or secondary to another disease process.
Type I primary hyperoxaluria (PH1) is associated mutations in the gene encoding AGXT, a key enzyme involved in oxalate metabolism. PH1 is an example of a protein mistargeting disease, wherein AGXT shows a trafficking defect. Instead of being trafficked to peroxisomes, it is targeted to mitochondria, where it is metabolically deficient despite being catalytically active. Type II is associated with GRHPR.Secondary hyperoxaluria can occur as a complication of jejunoileal bypass, or in a patient who has lost much of the ileum with an intact colon. In these cases, hyperoxaluria is caused by excessive gastrointestinal oxalate absorption.Excessive intake of oxalate-containing food, such as rhubarb, may also be a cause in rare cases.
Diagnosis
Types
Primary hyperoxaluria
Enteric hyperoxaluria
Idiopathic hyperoxaluria
Oxalate poisoning
Treatment
The main therapeutic approach to primary hyperoxaluria is still restricted to symptomatic treatment, i.e. kidney transplantation once the disease has already reached mature or terminal stages. However, through genomics and proteomics approaches, efforts are currently being made to elucidate the kinetics of AGXT folding which has a direct bearing on its targeting to appropriate subcellular localization. Secondary hyperoxaluria is much more common than primary hyperoxaluria, and should be treated by limiting dietary oxalate and providing calcium supplementation. A child with primary hyperoxaluria was treated with a liver and kidney transplant. A favorable outcome is more likely if a kidney transplant is complemented by a liver transplant, given the disease originates in the liver.
Controversy
Perhaps the key difficulty in understanding pathogenesis of primary hyperoxaluria, or more specifically, why AGXT ends up in mitochondria instead of peroxisomes, stems from AGXTs somewhat peculiar evolution. Namely, prior to its current peroxysomal destiny, AGXT indeed used to be bound to mitochondria. AGXTs peroxisomal targeting sequence is uniquely specific for mammalian species, suggesting the presence of additional peroxisomal targeting information elsewhere in the AGT molecule. As AGXT was redirected to peroxisomes over the course of evolution, it is plausible that its current aberrant localization to mitochondria owes to some hidden molecular signature in AGXTs spatial configuration unmasked by PH1 mutations affecting the AGXT gene.
References
External links
GeneReviews/NIH/NCBI/UW entry on Primary Hyperoxaluria Type 1 |
Aspartylglucosaminuria | Aspartylglucosaminuria (AGU) is an inherited disease that is characterized by a decline in mental functioning, accompanied by an increase in skin, bone and joint issues.
The disease is caused by a defect in an enzyme known as aspartylglucosaminidase. This enzyme plays a significant role in our bodies because it aids in breaking down certain sugars (for example, oligosaccharides) that are attached to specific proteins (for example, glycoproteins). Aspartylglucosaminuria itself is characterized as a lysosomal disease because it does deal with inadequate activity in an enzymes function. Aspartylglucosaminidase functions to break down glycoproteins. These proteins are most abundant in the tissues of the body and in the surfaces of major organs, such as the liver, spleen, thyroid and nerves. When glycoproteins are not broken down, aspartylglucosaminidase backs up in the lysosomes along with other substances. This backup causes progressive damage to the tissues and organs.
Signs and symptoms
At birth, there is no sign that a child will develop symptoms of aspartylglucosaminuria. Typically, signs and symptoms become apparent between two and four years of age and become progressively worse as the individual ages. The following signs and symptoms may appear:
Individuals are more prone to respiratory infections
Development of scoliosis
Seizures or difficulty with movement
Skin and joints may become loose
Facial features change progressively; this may include:thickening of the skin
features becoming more prominent
large head
broad lower jaw
short, broad nose
rounded cheeksProgression of developmental and mental disabilities, including:progressive loss of speech
decrease in mental functioning
before school age, concentration lowers
development continues, but becomes slower than usualAn intellectual peak occurs in the mid-teens and allows a plateau for the disease. Once an individual hits the age of 25-30 the decrease begins again, including:learned skills become lost which result in severe learning disabilities
motor skills deteriorate
individuals become less mobile and more dependent(Children are physically uncoordinated, but remain able to play sports and do everyday activities until they reach adulthood.)
During the first year of life inguinal and umbilical hernias are common.
Less severe symptoms include:enlargement of the spleen and liver
diarrheaPeople with aspartylglucosaminuria may have lower than average height, because they tend to go through puberty earlier.
Epilepsy may develop in adulthood.
Finnish studies have shown that life expectancy is shorter than average.
Genetics
Aspartylglucosaminuria is an autosomal recessive genetic condition that is inherited from both parents. The AGU patient is born with two copies of the mutated AGA gene. One copy comes from the mother’s egg and the other copy comes from the father’s sperm. In order to develop aspartylglucosaminuria, the individual must inherit changes in both of his AGU genes (autonomic recessive inheritance). When a person receives one changed form of the gene AGU from one of the parents, the individual is then classified as a carrier.
Diagnosis
In order to be diagnosed with AGU an individual takes a urine test, which will show indication of an increased amount of aspartylglucosamin being secreted. The confirmation of the diagnosis of aspartylglucosaminuria requires a blood test. This helps show if the enzyme aspartylglucosaminidase is present or partially absent. A skin simple will also show the amount of aspartylglucosaminidase present.
Pre-natal diagnosis
When families have a child who has already been diagnosed with AGU, they have the option to observe the enzymes activity that codes for AGU in future pregnancy, to help determine if the next child will also have a positive diagnosis for aspartylglucosaminuria.
Treatment
No treatment is available to cure or slow down the progression of aspartylglucosaminuria. Bone marrow transplants have been conducted in hope that the bone marrow will produce the missing enzyme. The results of the tests thus far have shown to be inconclusive.
Preventions/interventions to signs and symptoms
Since ear infections and respiratory infections are common for children diagnosed with aspartylglucosaminuria, it is best to have regular checkups for both the ears and the respiratory tract.Extreme sensitivity to the sun’s rays may develop; the best way to protect an individual diagnosed with aspartylglucosaminuria is to have them wear sunglasses, hats or caps to protect their eyes.Epilepsy and insomnia can both be treated with medication.It will be beneficial to children who are diagnosed with AGU to receive an education from a school with special teaching.
Habilitation
The process of habilitation for individuals diagnosed with AGU needs to be established in their early stages of life. The team for habilitation should include professionals who are experienced in disabilities and the effects that having a disability can have on everyday life. Habilitation will include assessments, assistance with the choice of aids, and information concerning disabilities and counseling.
Prognosis
Individuals with AGU typically have normal development in infancy. Around the age of 2–4 years, they begin showing signs of developmental delay, but development is still progressing. Initial symptoms may present as clumsiness and/or speech delay. Individuals with AGU also show increased upper respiratory infections. Development continues until about puberty; however, an individual at 13–16 years of age typically shows mental and motor development similar to a 5-6 year old. Around puberty, a gradual decline in mental abilities and motor skills occurs. This progressive decline continues until about age 25–28, when rapid impairment of abilities occurs, resulting in severe intellectual disability.
Epidemiology
Aspartylglucosaminuria is estimated to affect 1 in 18,500 people in Finland. This condition is less common in other countries, but the incidence is unknown. Even though this disease can occur in various races and ethnicities, another study backed this finding up by stating that 1 in 26,000 people in Finland had the disease and that 1 in 18,000 were carriers.After trisomy 21 and fragile X syndrome, this is the most frequent multiple congenital anomaly/intellectual disability syndrome in Finland.
See also
Inborn error of metabolism
References
External links
Aspartylglycosaminuria at NIHs Office of Rare Diseases |
Persistent left superior vena cava | In anatomy, a persistent left superior vena cava is the most common variation of the thoracic venous system. It is present in between 0.3% and 0.5% of the population, and is an embryologic remnant that results from a failure to involute.
Presentation
In persistent left superior vena cava, the left brachiocephalic vein does not develop fully and the left upper limb and head and neck drain into the right atrium via the coronary sinus.In isolation, the variation is considered benign, but is very frequently associated with cardiac abnormalities (e.g. ventricular septal defect, atrioventricular septal defect) that have a significant mortality and morbidity. It is more frequent in patients with congenital heart defects.The (right) superior vena cava is almost always unaffected by the presence of persistent left superior vena cava.
Diagnosis
If an anomaly is detected during a routine ultrasound, a fetal echocardiogram is performed to determine whether a fetus has the condition. Otherwise, it is often unnoticed unless an extenuating circumstance warrants further examination of the heart, usually much later in life.CT and MRI scans in a parasagittal section may show a "pipe" sign where the left superior vena cava occurs.
Treatment
If no other cardiac abnormalities are present, persistent left superior vena cava will not be treated, as it is usually asymptomatic and unharmful. If it drains into the left atrium, then deoxygenated blood enters the circulation to the body, and cyanosis may occur.
References
== External links == |
Cogan syndrome | Cogan syndrome (also Cogans syndrome) is a rare disorder characterized by recurrent inflammation of the front of the eye (the cornea) and often fever, fatigue, and weight loss, episodes of vertigo (dizziness), tinnitus (ringing in the ears) and hearing loss. It can lead to deafness or blindness if untreated. The classic form of the disease was first described by D. G. Cogan in 1945.
Signs and symptoms
Cogan syndrome is a rare, rheumatic disease characterized by inflammation of the ears and eyes. Cogan syndrome can lead to vision difficulty, hearing loss and dizziness. The condition may also be associated with blood-vessel inflammation (called vasculitis) in other areas of the body that can cause major organ damage in 15% of those affected or, in a small number of cases, even death. It most commonly occurs in a persons 20s or 30s. The cause is not known. However, one theory is that it is an autoimmune disorder in which the bodys immune system mistakenly attacks tissue in the eye and ear.
Causes
It is currently thought that Cogan syndrome is an autoimmune disease. The inflammation in the eye and ear are due to the patients own immune system producing antibodies that attack the inner ear and eye tissue. Autoantibodies can be demonstrated in the blood of some patients, and these antibodies have been shown to attack inner ear tissue in laboratory studies. Infection with the bacteria Chlamydia pneumoniae has been demonstrated in some patients prior to the development of Cogan syndrome, leading some researchers to hypothesize that the autoimmune disease may be initiated by the infection. C. pneumoniae is a common cause of mild pneumonia, and the vast majority of patients who are infected with the bacteria do not develop Cogan syndrome.
Diagnosis
While the white blood cell count, erythrocyte sedimentation rate, and C-reactive protein tests may be abnormal and there may be abnormally high levels of platelets in the blood or too few red blood cells in the blood, none of these findings is a reliable indicator of the disease. A slit-lamp examination is essential. Recent work has suggested that high-resolution MRI and antibodies to inner ear antigens may be helpful. Cogan syndrome can occur in children, and is particularly difficult
to recognize in that situation.
Treatment
For more severe disease, oral corticosteroids may be necessary to reduce the inflammatory response. When large amounts of steroids are required or if the disease is severe and is not responding to steroid therapy, other immunosuppressive medications often are recommended. These immunosuppressive drugs include methotrexate, cyclophosphamide, cyclosporine or azathioprine. In some cases, combinations of these medicines are prescribed. Occasionally, if the disease has damaged blood vessels in the ear, cochlear implantation may be used to restore some sense of hearing.Cinnarizine is mainly used to treat nausea and vomiting associated with motion sickness, vertigo, Ménières disease, or Cogan syndrome. Studies have shown it to produce significant improvement in hearing loss in some patients.
History
In 1945, the ophthalmologist David Glendenning Cogan (1908–1993) first described the "nonsyphilitic interstitial keratitis and vestibuloauditory symptoms" that would later bear his name. In 1963, the atypical form of Cogan syndrome, also known as "Logan Syndrome" was first described.
References
Further reading
Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS (November 1980). "Cogan syndrome: studies in thirteen patients, long-term follow-up, and a review of the literature". Medicine. 59 (6): 426–41. doi:10.1097/00005792-198011000-00003. PMID 6969345.
Gluth MB, Baratz KH, Matteson EL, Driscoll CL (April 2006). "Cogan syndrome: a retrospective review of 60 patients throughout a half century". Mayo Clinic Proceedings. 81 (4): 483–8. doi:10.4065/81.4.483. PMID 16610568.
Norton EW, Cogan DG (May 1959). "Syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms; a long-term follow-up". Archives of Ophthalmology. 61 (5): 695–7. doi:10.1001/archopht.1959.00940090697004. PMID 13636563.
Bicknell JM, Holland JV (March 1978). "Neurologic manifestations of Cogan syndrome". Neurology. 28 (3): 278–81. doi:10.1212/wnl.28.3.278. PMID 305011. S2CID 22367876.
Casselman JW, Majoor MH, Albers FW (January 1994). "MR of the inner ear in patients with Cogan syndrome". American Journal of Neuroradiology. 15 (1): 131–8. PMC 8332073. PMID 8141044.
Allen NB, Cox CC, Cobo M, et al. (March 1990). "Use of immunosuppressive agents in the treatment of severe ocular and vascular manifestations of Cogans syndrome". The American Journal of Medicine. 88 (3): 296–301. doi:10.1016/0002-9343(90)90157-9. PMID 2309745.
Kundell SP, Ochs HD (July 1980). "Cogan syndrome in childhood". The Journal of Pediatrics. 97 (1): 96–8. doi:10.1016/s0022-3476(80)80142-9. PMID 7381656.
== External links == |
Fracture blister | Fracture blisters occur on skin overlying a fractured bone, and fractures complicated by the development of overlying blisters remain a clinical dilemma in orthopedics.: 43 Fracture blisters are tense vesicles or bullae that arise on markedly swollen skin directly overlying a fracture. Fracture blisters pop up in trauma patients occasionally. A fracture blister typically occurs near fractures where the skin has little subcutaneous tissue between it and bone. These include elbows, knees, ankles, and wrists. They tend to complicate fracture management because they interfere with splinting, casting, and incision planning for open reduction procedures. They can appear anytime within a few hours of injury to 2–3 weeks later.
These blisters are thought to be caused by shearing forces applied at the time of injury. There are two types described, based on their color: clear fluid and hemorrhagic. The difference lies in the level of the shear. Clear fluid blisters have separated within the epidermis, and hemorrhagic blisters separate at the dermal-epidermal junction. The clinical difference is healing time; clear blisters take about 12 days and hemorrhagic blisters heal in about 16 days.
The decision to pop the blisters in order to treat the fracture, or wait for them to heal first usually hinges on the preferences of the orthopaedic surgeon as there is a lack of data on what treatment is ideal. Waiting delays care an average of 7 days, and longer for tibial plateau and calcaneal fractures. Operating immediately anecdotally increases wound infection rates.
Additional images
== References == |
Reactive attachment disorder | Reactive attachment disorder (RAD) is described in clinical literature as a severe and relatively uncommon disorder that can affect children, although these issues do occasionally persist into adulthood. RAD is characterized by markedly disturbed and developmentally inappropriate ways of relating socially in most contexts. It can take the form of a persistent failure to initiate or respond to most social interactions in a developmentally appropriate way—known as the "inhibited form". In the DSM-5, the "disinhibited form" is considered a separate diagnosis named "disinhibited attachment disorder".
RAD arises from a failure to form normal attachments to primary caregivers in early childhood. Such a failure could result from severe early experiences of neglect, abuse, abrupt separation from caregivers between the ages of six months and three years, frequent changes of caregivers, or a lack of caregiver responsiveness to a childs communicative efforts. Not all, or even a majority of such experiences, result in the disorder. It is differentiated from pervasive developmental disorder or developmental delay and from possibly comorbid conditions such as intellectual disability, all of which can affect attachment behavior. The criteria for a diagnosis of a reactive attachment disorder are very different from the criteria used in assessment or categorization of attachment styles such as insecure or disorganized attachment.
Children with RAD are presumed to have grossly disturbed internal working models of relationships that may lead to interpersonal and behavioral difficulties in later life. There are few studies of long-term effects, and there is a lack of clarity about the presentation of the disorder beyond the age of five years. However, the opening of orphanages in Eastern Europe following the end of the Cold War in the early 1990s provided opportunities for research on infants and toddlers brought up in very deprived conditions. Such research broadened the understanding of the prevalence, causes, mechanism and assessment of disorders of attachment and led to efforts from the late 1990s onwards to develop treatment and prevention programs and better methods of assessment. Mainstream theorists in the field have proposed that a broader range of conditions arising from problems with attachment should be defined beyond current classifications.Mainstream treatment and prevention programs that target RAD and other problematic early attachment behaviors are based on attachment theory and concentrate on increasing the responsiveness and sensitivity of the caregiver, or if that is not possible, placing the child with a different caregiver. Most such strategies are in the process of being evaluated. Mainstream practitioners and theorists have presented significant criticism of the diagnosis and treatment of alleged reactive attachment disorder or the theoretically baseless "attachment disorder" within the controversial form of psychotherapy commonly known as attachment therapy. Attachment therapy has a scientifically unsupported theoretical base and uses diagnostic criteria or symptom lists markedly different from criteria under ICD-10 or DSM-IV-TR, or to attachment behaviors. A range of treatment approaches are used in attachment therapy, some of which are physically and psychologically coercive, and considered to be antithetical to attachment theory.
Signs and symptoms
Pediatricians are often the first health professionals to assess and raise suspicions of RAD in children with the disorder. The initial presentation varies according to the childs developmental and chronological age, although it always involves a disturbance in social interaction. Infants up to about 18–24 months may present with non-organic failure to thrive and display abnormal responsiveness to stimuli. Laboratory investigations will be unremarkable barring possible findings consistent with malnutrition or dehydration, while serum growth hormone levels will be normal or elevated.The core feature is severely inappropriate social relating by affected children. This can manifest itself in three ways:
Indiscriminate and excessive attempts to receive comfort and affection from any available adult, even relative strangers (older children and adolescents may also aim attempts at peers). This may oftentimes appear as denial of comfort from anyone as well.
Extreme reluctance to initiate or accept comfort and affection, even from familiar adults, especially when distressed.
Actions that otherwise would be classified as conduct disorder, such as mutilating animals, harming siblings or other family, or harming themselves intentionally.While RAD occurs in relation to neglectful and abusive treatment, automatic diagnoses on this basis alone cannot be made, as children can form stable attachments and social relationships despite marked abuse and neglect. However, the instances of that ability are rare.The name of the disorder emphasizes problems with attachment but the criteria include symptoms such as failure to thrive, a lack of developmentally appropriate social responsiveness, apathy, and onset before 8 months.
Assessment tools
There is as yet no universally accepted diagnostic protocol for reactive attachment disorder. Often a range of measures is used in research and diagnosis. Recognized assessment methods of attachment styles, difficulties or disorders include the Strange Situation Procedure (devised by developmental psychologist Mary Ainsworth), the separation and reunion procedure and the Preschool Assessment of Attachment, the Observational Record of the Caregiving Environment, the Attachment Q-sort and a variety of narrative techniques using stem stories, puppets or pictures. For older children, actual interviews such as the Child Attachment Interview and the Autobiographical Emotional Events Dialogue can be used. Caregivers may also be assessed using procedures such as the Working Model of the Child Interview.More recent research also uses the Disturbances of Attachment Interview (DAI) developed by Smyke and Zeanah (1999). The DAI is a semi-structured interview designed to be administered by clinicians to caregivers. It covers 12 items, namely "having a discriminated, preferred adult", "seeking comfort when distressed", "responding to comfort when offered", "social and emotional reciprocity", "emotional regulation", "checking back after venturing away from the care giver", "reticence with unfamiliar adults", "willingness to go off with relative strangers", "self-endangering behavior", "excessive clinging", "vigilance/hypercompliance" and "role reversal". This method is designed to pick up not only RAD but also the proposed new alternative categories of disorders of attachment.
Causes
Although increasing numbers of childhood mental health problems are being attributed to genetic defects, reactive attachment disorder is by definition based on a problematic history of care and social relationships. Abuse can occur alongside the required factors, but on its own does not explain attachment disorder. It has been suggested that types of temperament, or constitutional response to the environment, may make some individuals susceptible to the stress of unpredictable or hostile relationships with caregivers in the early years. In the absence of available and responsive caregivers it appears that most children are particularly vulnerable to developing attachment disorders.While similar abnormal parenting may produce the two distinct forms of the disorder, inhibited and disinhibited, studies show that abuse and neglect were far more prominent and severe in the cases of RAD, disinhibited type. The issue of temperament and its influence on the development of attachment disorders has yet to be resolved. RAD has never been reported in the absence of serious environmental adversity yet outcomes for children raised in the same environment are the same.In discussing the neurobiological basis for attachment and trauma symptoms in a seven-year twin study, it has been suggested that the roots of various forms of psychopathology, including RAD, borderline personality disorder (BPD), and post-traumatic stress disorder (PTSD), can be found in disturbances in affect regulation. The subsequent development of higher-order self-regulation is jeopardized and the formation of internal models is affected. Consequently, the "templates" in the mind that drive organized behavior in relationships may be impacted. The potential for "re-regulation" (modulation of emotional responses to within the normal range) in the presence of "corrective" experiences (normative caregiving) seems possible.
Diagnosis
RAD is one of the least researched and most poorly understood disorders in the DSM. There is little systematic epidemiologic information on RAD, its course is not well established and it appears difficult to diagnose accurately. There is a lack of clarity about the presentation of attachment disorders over the age of five years and difficulty in distinguishing between aspects of attachment disorders, disorganized attachment or the consequences of maltreatment.According to the American Academy of Child and Adolescent Psychiatry (AACAP), children who exhibit signs of reactive attachment disorder need a comprehensive psychiatric assessment and individualized treatment plan. The signs or symptoms of RAD may also be found in other psychiatric disorders and AACAP advises against giving a child this label or diagnosis without a comprehensive evaluation. Their practice parameter states that the assessment of reactive attachment disorder requires evidence directly obtained from serial observations of the child interacting with his or her primary caregivers and history (as available) of the childs patterns of attachment behavior with these caregivers. It also requires observations of the childs behavior with unfamiliar adults and a comprehensive history of the childs early caregiving environment including, for example, pediatricians, teachers, or caseworkers. In the US, initial evaluations may be conducted by psychologists, psychiatrists, Licensed Marriage and Family Therapists, Licensed Professional Counselors, specialist Licensed Clinical Social Workers or psychiatric nurses.In the UK, the British Association for Adoption and Fostering (BAAF) advise that only a psychiatrist can diagnose an attachment disorder and that any assessment must include a comprehensive evaluation of the childs individual and family history.According to the AACAP Practice Parameter (2005) the question of whether attachment disorders can reliably be diagnosed in older children and adults has not been resolved. Attachment behaviors used for the diagnosis of RAD change markedly with development and defining analogous behaviors in older children is difficult. There are no substantially validated measures of attachment in middle childhood or early adolescence. Assessments of RAD past school age may not be possible at all as by this time children have developed along individual lines to such an extent that early attachment experiences are only one factor among many that determine emotion and behavior.
Criteria
ICD-10 describes reactive attachment disorder of childhood, known as RAD, and disinhibited attachment disorder, less well known as DAD. DSM-IV-TR also describes reactive attachment disorder of infancy or early childhood divided into two subtypes, inhibited type and disinhibited type, both known as RAD. The two classifications are similar and both include:
markedly disturbed and developmentally inappropriate social relatedness in most contexts (e.g., the child is avoidant or unresponsive to care when offered by caregivers or is indiscriminately affectionate with strangers);
the disturbance is not accounted for solely by developmental delay and does not meet the criteria for pervasive developmental disorder;
onset before five years of age (there is no age specified before five years of age at which RAD cannot be diagnosed);
a history of significant neglect;
an implicit lack of identifiable, preferred attachment figure.ICD-10 states in relation to the inhibited form only that the syndrome probably occurs as a direct result of severe parental neglect, abuse, or serious mishandling. DSM states in relation to both forms there must be a history of "pathogenic care" defined as persistent disregard of the childs basic emotional or physical needs or repeated changes in primary caregiver that prevents the formation of a discriminatory or selective attachment that is presumed to account for the disorder. For this reason, part of the diagnosis is the childs history of care rather than observation of symptoms.
In DSM-IV-TR the inhibited form is described as persistent failure to initiate or respond in a developmentally appropriate fashion to most social interactions, as manifest by excessively inhibited, hypervigilant, or highly ambivalent and contradictory responses (e.g., the child may respond to caregivers with a mixture of approach, avoidance, and resistance to comforting or may exhibit "frozen watchfulness", hypervigilance while keeping an impassive and still demeanour). Such infants do not seek or accept comfort at times of threat, alarm or distress, thus failing to maintain "proximity", an essential element of attachment behavior. The disinhibited form shows diffuse attachments as manifest by indiscriminate sociability with marked inability to exhibit appropriate selective attachments (e.g., excessive familiarity with relative strangers or lack of selectivity in choice of attachment figures). There is therefore a lack of "specificity" of attachment figure, the second basic element of attachment behavior.
The ICD-10 descriptions are comparable save that ICD-10 includes in its description several elements not included in DSM-IV-TR as follows:
abuse, (psychological or physical), in addition to neglect;
associated emotional disturbance;
poor social interaction with peers, aggression towards self and others, misery, and growth failure in some cases (inhibited form only);
evidence of capacity for social reciprocity and responsiveness as shown by elements of normal social relatedness in interactions with appropriately responsive, non-deviant adults (disinhibited form only).The first of these is somewhat controversial, being a commission rather than omission and because abuse in and of itself does not lead to attachment disorder.
The inhibited form has a greater tendency to ameliorate with an appropriate caregiver, while the disinhibited form is more enduring. ICD-10 states the disinhibited form "tends to persist despite marked changes in environmental circumstances". Disinhibited and inhibited are not opposites in terms of attachment disorder and can coexist in the same child. The question of whether there are two subtypes has been raised. The World Health Organization acknowledges that there is uncertainty regarding the diagnostic criteria and the appropriate subdivision. One reviewer has commented on the difficulty of clarifying the core characteristics of and differences between atypical attachment styles and ways of categorizing more severe disorders of attachment.As of 2010, the American Psychiatric Association has proposed to redefine RAD into two distinct disorders in the DSM-V. Corresponding with the inhibited type, one disorder will be reclassified as Reactive Attachment Disorder of Infancy and Early Childhood.In regards to pathogenic care, or the type of care in which these behaviors are present, a new criterion for Disinhibited Social Engagement Disorder now includes chronically harsh punishment or other types of severely inept caregiving. Relating to pathogenic care for both proposed disorders, a new criterion is rearing in atypical environments such as institutions with high child/caregiver ratios that cut down on opportunities to form attachments with a caregiver.
Differential diagnosis
The diagnostic complexities of RAD mean that careful diagnostic evaluation by a trained mental health expert with particular expertise in differential diagnosis is considered essential. Several other disorders, such as conduct disorders, oppositional defiant disorder, anxiety disorders, post traumatic stress disorder and social phobia share many symptoms and are often comorbid with or confused with RAD, leading to over and under diagnosis. RAD can also be confused with neuropsychiatric disorders such as autism, pervasive developmental disorder, childhood schizophrenia and some genetic syndromes. Infants with this disorder can be distinguished from those with organic illness by their rapid physical improvement after hospitalization. Autistic children are likely to be of normal size and weight and often exhibit a degree of intellectual disability. They are unlikely to improve upon being removed from the home.
Alternative diagnosis
In the absence of a standardized diagnosis system, many popular, informal classification systems or checklists, outside the DSM and ICD, were created out of clinical and parental experience within the field known as attachment therapy. These lists are unvalidated and critics state they are inaccurate, too broadly defined or applied by unqualified persons. Many are found on the websites of attachment therapists. Common elements of these lists such as lying, lack of remorse or conscience and cruelty do not form part of the diagnostic criteria under either DSM-IV-TR or ICD-10. Many children are being diagnosed with RAD because of behavioral problems that are outside the criteria. There is an emphasis within attachment therapy on aggressive behavior as a symptom of what they describe as attachment disorder whereas mainstream theorists view these behaviors as comorbid, externalizing behaviors requiring appropriate assessment and treatment rather than attachment disorders. However, knowledge of attachment relationships can contribute to the cause, maintenance and treatment of externalizing disorders.The Randolph Attachment Disorder Questionnaire or RADQ is one of the better known of these checklists and is used by attachment therapists and others. The checklist includes 93 discrete behaviours, many of which either overlap with other disorders, like conduct disorder and oppositional defiant disorder, or are not related to attachment difficulties. Critics assert that it is unvalidated and lacks specificity.
Treatment
Assessing the childs safety is an essential first step that determines whether future intervention can take place in the family unit or whether the child should be removed to a safe situation. Interventions may include psychosocial support services for the family unit (including financial or domestic aid, housing and social work support), psychotherapeutic interventions (including treating parents for mental illness, family therapy, individual therapy), education (including training in basic parenting skills and child development), and monitoring of the childs safety within the family environmentIn 2005 the American Academy of Child and Adolescent Psychiatry laid down guidelines (devised by N.W. Boris and C.H. Zeanah) based on its published parameters for the diagnosis and treatment of RAD. Recommendations in the guidelines include the following:
"The most important intervention for young children diagnosed with reactive attachment disorder and who lack an attachment to a discriminated caregiver is for the clinician to advocate for providing the child with an emotionally available attachment figure."
"Although the diagnosis of reactive attachment disorder is based on symptoms displayed by the child, assessing the caregivers attitudes toward and perceptions about the child is important for treatment selection."
"Children with reactive attachment disorder are presumed to have grossly disturbed internal models for relating to others. After ensuring that the child is in a safe and stable placement, effective attachment treatment must focus on creating positive interactions with caregivers."
"Children who meet criteria for reactive attachment disorder and who display aggressive and oppositional behavior require adjunctive (additional) treatments."Mainstream prevention programs and treatment approaches for attachment difficulties or disorders for infants and younger children are based on attachment theory and concentrate on increasing the responsiveness and sensitivity of the caregiver, or if that is not possible, placing the child with a different caregiver. These approaches are mostly in the process of being evaluated. The programs invariably include a detailed assessment of the attachment status or caregiving responses of the adult caregiver as attachment is a two-way process involving attachment behavior and caregiver response. Some of these treatment or prevention programs are specifically aimed at foster carers rather than parents, as the attachment behaviors of infants or children with attachment difficulties often do not elicit appropriate caregiver responses. Approaches include "Watch, wait and wonder," manipulation of sensitive responsiveness, modified "Interaction Guidance", "Clinician-Assisted Videofeedback Exposure Sessions (CAVES)", "Preschool Parent Psychotherapy", "Circle of Security", "Attachment and Biobehavioral Catch-up" (ABC), the New Orleans Intervention, and parent–child psychotherapy. Other treatment methods include Developmental, Individual-difference, and Relationship-based therapy (DIR, also referred to as Floor Time) by Stanley Greenspan, although DIR is primarily directed to treatment of pervasive developmental disorders.The relevance of these approaches to intervention with fostered and adopted children with RAD or older children with significant histories of maltreatment is unclear.
Attachment therapy
The terms attachment disorder, attachment problems, and attachment therapy, although increasingly used, have no clear, specific, or consensus definitions. However, the terms and therapies often are applied to children who are maltreated, particularly those in the foster care, kinship care, or adoption systems, and related populations such as children adopted internationally from orphanages.Outside the mainstream programs is a form of treatment generally known as attachment therapy, a subset of techniques (and accompanying novel diagnosis) for supposed attachment disorders including RAD. These "attachment disorders" use diagnostic criteria or symptom lists different from criteria under ICD-10 or DSM-IV-TR, or to attachment behaviors. Those with "attachment disorder" are said to lack empathy and remorse.
Treatments of this pseudoscientific disorder are called "Attachment therapy". In general, these therapies are aimed at adopted or fostered children with a view to creating attachment in these children to their new caregivers. The theoretical base is broadly a combination of regression and catharsis, accompanied by parenting methods which emphasize obedience and parental control. There is considerable criticism of this form of treatment and diagnosis as it is largely unvalidated and has developed outside the scientific mainstream. There is little or no evidence base and techniques vary from non-coercive therapeutic work to more extreme forms of physical, confrontational and coercive techniques, of which the best known are holding therapy, rebirthing, rage-reduction and the Evergreen model. These forms of the therapy may well involve physical restraint, the deliberate provocation of rage and anger in the child by physical and verbal means including deep tissue massage, aversive tickling, enforced eye contact and verbal confrontation, and being pushed to revisit earlier trauma. Critics maintain that these therapies are not within the attachment paradigm, are potentially abusive, and are antithetical to attachment theory. The APSAC Taskforce Report of 2006 notes that many of these therapies concentrate on changing the child rather than the caregiver. Children may be described as "RADs", "Radkids" or "Radishes" and dire predictions may be made as to their supposedly violent futures if they are not treated with attachment therapy. The Mayo Clinic, a well known U.S. non-profit medical practice and medical research group, cautions against consulting with mental health providers who promote these types of methods and offer evidence to support their techniques; to date, this evidence base is not published within reputable medical or mental health journals.
Prognosis
The AACAP guidelines state that children with reactive attachment disorder are presumed to have grossly disturbed internal models for relating to others. However, the course of RAD is not well studied and there have been few efforts to examine symptom patterns over time. The few existing longitudinal studies (dealing with developmental change with age over a period of time) involve only children from poorly run Eastern European institutions.Findings from the studies of children from Eastern European orphanages indicate that persistence of the inhibited pattern of RAD is rare in children adopted out of institutions into normative care-giving environments. However, there is a close association between duration of deprivation and severity of attachment disorder behaviors. The quality of attachments that these children form with subsequent care-givers may be compromised, but they probably no longer meet criteria for inhibited RAD. The same group of studies suggests that a minority of adopted, institutionalized children exhibit persistent indiscriminate sociability even after more normative caregiving environments are provided. Indiscriminate sociability may persist for years, even among children who subsequently exhibit preferred attachment to their new caregivers. Some exhibit hyperactivity and attention problems as well as difficulties in peer relationships. In the only longitudinal study that has followed children with indiscriminate behavior into adolescence, these children were significantly more likely to exhibit poor peer relationships.Studies of children who were reared in institutions have suggested that they are inattentive and overactive, no matter what quality of care they received. In one investigation, some institution-reared boys were reported to be inattentive, overactive, and markedly unselective in their social relationships, while girls, foster-reared children, and some institution-reared children were not. It is not yet clear whether these behaviors should be considered as part of disordered attachment.There is one case study on maltreated twins published in 1999 with a follow-up in 2006. This study assessed the twins between the ages of 19 and 36 months, during which time they had multiple moves and placements. The paper explores the similarities, differences and comorbidity of RAD, disorganized attachment and post traumatic stress disorder. The girl showed signs of the inhibited form of RAD while the boy showed signs of the indiscriminate form. It was noted that the diagnosis of RAD ameliorated with better care but symptoms of post traumatic stress disorder and signs of disorganized attachment came and went as the infants progressed through multiple placement changes. At age three, some lasting relationship disturbance was evident.
In the follow-up case study when the twins were aged three and eight years, the lack of longitudinal research on maltreated as opposed to institutionalized children was again highlighted. The girls symptoms of disorganized attachment had developed into controlling behaviors—a well-documented outcome. The boy still exhibited self-endangering behaviors, not within RAD criteria but possibly within "secure base distortion", (where the child has a preferred familiar caregiver, but the relationship is such that the child cannot use the adult for safety while gradually exploring the environment). At age eight the children were assessed with a variety of measures including those designed to access representational systems, or the childs "internal working models". The twins symptoms were indicative of different trajectories. The girl showed externalizing symptoms (particularly deceit), contradictory reports of current functioning, chaotic personal narratives, struggles with friendships, and emotional disengagement with her caregiver, resulting in a clinical picture described as "quite concerning". The boy still evidenced self-endangering behaviors as well as avoidance in relationships and emotional expression, separation anxiety and impulsivity and attention difficulties. It was apparent that life stressors had impacted each child differently. The narrative measures used were considered helpful in tracking how early attachment disruption is associated with later expectations about relationships.One paper using questionnaires found that children aged three to six, diagnosed with RAD, scored lower on empathy but higher on self-monitoring (regulating your behavior to "look good"). These differences were especially pronounced based on ratings by parents, and suggested that children with RAD may systematically report their personality traits in overly positive ways. Their scores also indicated considerably more behavioral problems than scores of the control children.
Epidemiology
Epidemiological data are limited, but reactive attachment disorder appears to be very uncommon. The prevalence of RAD is unclear but it is probably quite rare, other than in populations of children being reared in the most extreme, deprived settings such as some orphanages. There is little systematically gathered epidemiologic information on RAD. A cohort study of 211 Copenhagen children to the age of 18 months found a prevalence of 0.9%.Attachment disorders tend to occur in a definable set of contexts such as within some types of institutions, in the presence of repeated changes of primary caregiver or of extremely neglectful identifiable primary caregivers who show persistent disregard for the childs basic attachment needs, but not all children raised in these conditions develop an attachment disorder. Studies undertaken on children from Eastern European orphanages from the mid-1990s showed significantly higher levels of both forms of RAD and of insecure patterns of attachment in the institutionalized children, regardless of how long they had been there. It would appear that children in institutions like these are unable to form selective attachments to their caregivers. The difference between the institutionalized children and the control group had lessened in the follow-up study three years later, although the institutionalized children continued to show significantly higher levels of indiscriminate friendliness. However, even among children raised in the most deprived institutional conditions the majority did not show symptoms of this disorder.A 2002 study of children in residential nurseries in Bucharest, in which the DAI was used, challenged the current DSM and ICD conceptualizations of disordered attachment and showed that inhibited and disinhibited disorders could coexist in the same child.There are two studies on the incidence of RAD relating to high risk and maltreated children in the U.S. Both used ICD, DSM and the DAI. The first, in 2004, reported that children from the maltreatment sample were significantly more likely to meet criteria for one or more attachment disorders than children from the other groups, however this was mainly the proposed new classification of disrupted attachment disorder rather than the DSM or ICD classified RAD or DAD. The second study, also in 2004, attempted to ascertain the prevalence of RAD and whether it could be reliably identified in maltreated rather than neglected toddlers. Of the 94 maltreated toddlers in foster care, 35% were identified as having ICD RAD and 22% as having ICD DAD, and 38% fulfilled the DSM criteria for RAD. This study found that RAD could be reliably identified and also that the inhibited and disinhibited forms were not independent. However, there are some methodological concerns with this study. A number of the children identified as fulfilling the criteria for RAD did in fact have a preferred attachment figure.It has been suggested by some within the field of attachment therapy that RAD may be quite prevalent because severe child maltreatment, which is known to increase risk for RAD, is prevalent and because children who are severely abused may exhibit behaviors similar to RAD behaviors. The APSAC Taskforce consider this inference to be flawed and questionable. Severely abused children may exhibit similar behaviors to RAD behaviors but there are several far more common and demonstrably treatable diagnoses which may better account for these difficulties. Further, many children experience severe maltreatment and do not develop clinical disorders. Resilience is a common and normal human characteristic. RAD does not underlie all or even most of the behavioral and emotional problems seen in foster children, adoptive children, or children who are maltreated and rates of child abuse and/or neglect or problem behaviors are not a benchmark for estimates of RAD.There are few data on comorbid conditions, but there are some conditions that arise in the same circumstances in which RAD arises, such as institutionalization or maltreatment. These are principally developmental delays and language disorders associated with neglect. Conduct disorders, oppositional defiant disorder, anxiety disorders, post-traumatic stress disorder and social phobia share many symptoms and are often comorbid with or confused with RAD. Attachment disorder behaviors amongst institutionalized children are correlated with attentional and conduct problems and cognitive levels but nonetheless appear to index a distinct set of symptoms and behaviors.
History
Reactive attachment disorder first made its appearance in standard nosologies of psychological disorders in DSM-III |
Reactive attachment disorder | , 1980, following an accumulation of evidence on institutionalized children. The criteria included a requirement of onset before the age of 8 months and was equated with failure to thrive. Both these features were dropped in DSM-III-R, 1987. Instead, onset was changed to being within the first 5 years of life and the disorder itself was divided into two subcategories, inhibited and disinhibited. These changes resulted from further research on maltreated and institutionalized children and remain in the current version, DSM-IV, 1994, and its 2000 text revision, DSM-IV-TR, as well as in ICD-10, 1992. Both nosologies focus on young children who are not merely at increased risk for subsequent disorders but are already exhibiting clinical disturbance.The broad theoretical framework for current versions of RAD is attachment theory, based on work conducted from the 1940s to the 1980s by John Bowlby, Mary Ainsworth and René Spitz. Attachment theory is a framework that employs psychological, ethological and evolutionary concepts to explain social behaviors typical of young children. Attachment theory focuses on the tendency of infants or children to seek proximity to a particular attachment figure (familiar caregiver), in situations of alarm or distress, behavior which appears to have survival value. This is known as a discriminatory or selective attachment. Subsequently, the child begins to use the caregiver as a base of security from which to explore the environment, returning periodically to the familiar person. Attachment is not the same as love and/or affection although they are often associated. Attachment and attachment behaviors tend to develop between the ages of six months and three years. Infants become attached to adults who are sensitive and responsive in social interactions with the infant, and who remain as consistent caregivers for some time. Caregiver responses lead to the development of patterns of attachment, that in turn lead to internal working models which will guide the individuals feelings, thoughts, and expectations in later relationships. For a diagnosis of reactive attachment disorder, the childs history and atypical social behavior must suggest the absence of formation of a discriminatory or selective attachment.
The pathological absence of a discriminatory or selective attachment needs to be differentiated from the existence of attachments with either typical or somewhat atypical behavior patterns, known as styles or patterns. There are four attachment styles ascertained and used within developmental attachment research. These are known as secure, anxious-ambivalent, anxious-avoidant, (all organized) and disorganized. The latter three are characterised as insecure. These are assessed using the Strange Situation Procedure, designed to assess the quality of attachments rather than whether an attachment exists at all.A securely attached toddler will explore freely while the caregiver is present, engage with strangers, be visibly upset when the caregiver departs, and happy to see the caregiver return. The anxious-ambivalent toddler is anxious of exploration, extremely distressed when the caregiver departs but ambivalent when the caregiver returns. The anxious-avoidant toddler will not explore much, avoid or ignore the parent—showing little emotion when the parent departs or returns—and treat strangers much the same as caregivers with little emotional range shown. The disorganized/disoriented toddler shows a lack of a coherent style or pattern for coping. Evidence suggests this occurs when the caregiving figure is also an object of fear, thus putting the child in an irresolvable situation regarding approach and avoidance. On reunion with the caregiver, these children can look dazed or frightened, freezing in place, backing toward the caregiver or approaching with head sharply averted, or showing other behaviors implying fear of the person who is being sought. It is thought to represent a breakdown of an inchoate attachment strategy and it appears to affect the capacity to regulate emotions.Although there are a wide range of attachment difficulties within the styles which may result in emotional disturbance and increase the risk of later psychopathologies, particularly the disorganized style, none of the styles constitute a disorder in themselves and none equate to criteria for RAD as such. A disorder in the clinical sense is a condition requiring treatment, as opposed to risk factors for subsequent disorders. Reactive attachment disorder denotes a lack of typical attachment behaviors rather than an attachment style, however problematic that style may be, in that there is an unusual lack of discrimination between familiar and unfamiliar people in both forms of the disorder. Such discrimination does exist as a feature of the social behavior of children with atypical attachment styles. Both DSM-IV and ICD-10 depict the disorder in terms of socially aberrant behavior in general rather than focusing more specifically on attachment behaviors as such. DSM-IV emphasizes a failure to initiate or respond to social interactions across a range of relationships and ICD-10 similarly focuses on contradictory or ambivalent social responses that extend across social situations. The relationship between patterns of attachment in the Strange Situation and RAD is not yet clear.There is a lack of consensus about the precise meaning of the term "attachment disorder". The term is frequently used both as an alternative to reactive attachment disorder and in discussions about different proposed classifications for disorders of attachment beyond the limitations of the ICD and DSM classifications. It is also used within the field of attachment therapy, as is the term reactive attachment disorder, to describe a range of problematic behaviors not within the ICD or DSM criteria or not related directly to attachment styles or difficulties at all.
Research
Research from the late 1990s indicated there were disorders of attachment not captured by DSM or ICD and showed that RAD could be diagnosed reliably without evidence of pathogenic care, thus illustrating some of the conceptual difficulties with the rigid structure of the current definition of RAD. Research published in 2004 showed that the disinhibited form can endure alongside structured attachment behavior (of any style) towards the childs permanent caregivers.Some authors have proposed a broader continuum of definitions of attachment disorders ranging from RAD through various attachment difficulties to the more problematic attachment styles. There is as yet no consensus, on this issue but a new set of practice parameters containing three categories of attachment disorder has been proposed by C.H. Zeanah and N. Boris. The first of these is disorder of attachment, in which a young child has no preferred adult caregiver. The proposed category of disordered attachment is parallel to RAD in its inhibited and disinhibited forms, as defined in DSM and ICD. The second category is secure base distortion, where the child has a preferred familiar caregiver, but the relationship is such that the child cannot use the adult for safety while gradually exploring the environment. Such children may endanger themselves, cling to the adult, be excessively compliant, or show role reversals in which they care for or punish the adult. The third type is disrupted attachment. Disrupted attachment is not covered under ICD-10 and DSM criteria, and results from an abrupt separation or loss of a familiar caregiver to whom attachment has developed. This form of categorisation may demonstrate more clinical accuracy overall than the current DSM-IV-TR classification, but further research is required. The practice parameters would also provide the framework for a diagnostic protocol. Most recently, Daniel Schechter and Erica Willheim have shown a relationship between some maternal violence-related posttraumatic stress disorder and secure base distortion (see above) which is characterized by child recklessness, separation anxiety, hypervigilance, and role-reversal.Some research indicates there may be a significant overlap between behaviors of the inhibited form of RAD or DAD and aspects of disorganized attachment where there is an identified attachment figure.An ongoing question is whether RAD should be thought of as a disorder of the childs personality or a distortion of the relationship between the child and a specific other person. It has been noted that as attachment disorders are by their very nature relational disorders, they do not fit comfortably into nosologies that characterize the disorder as centered on the person. Work by C.H. Zeanah indicates that atypical attachment-related behaviors may occur with one caregiver but not with another. This is similar to the situation reported for attachment styles, in which a particular parents frightened expression has been considered as possibly responsible for disorganized/disoriented reunion behavior during the Strange Situation Procedure.The draft of the proposed DSM-V suggests dividing RAD into two disorders, Reactive Attachment Disorder for the current inhibited form of RAD, and Disinhibited Social Engagement Disorder for what is currently the disinhibited form of RAD, with some alterations in the proposed DSM definition.
See also
Attachment parenting
Borderline personality disorder
Child development
Emotional dysregulation
Notes
References
Further reading
Zeanah, Charles H.; Chesher, Tessa; Boris, Neil W.; AACAP Committee on Quality Issues (November 2016). "Practice Parameter for the Assessment and Treatment of Children and Adolescents With Reactive Attachment Disorder and Disinhibited Social Engagement Disorder". Journal of the American Academy of Child and Adolescent Psychiatry. 55 (11): 990–1003. doi:10.1016/j.jaac.2016.08.004. PMID 27806867. |
Complex partial status epilepticus | Complex partial status epilepticus (CPSE) is one of the non-convulsive forms of status epilepticus, a rare form of epilepsy defined by its recurrent nature. CPSE is characterized by seizures involving long-lasting stupor, staring and unresponsiveness. Sometimes this is accompanied by motor automatisms, such as eye twitching.
Diagnosis
As is the case with other non-convulsive status epilepticus forms, CPSE is dangerously underdiagnosed. This is due to the potentially fatal yet veiled nature of the symptoms. Usually, an electroencephalogram, or EEG, is needed to confirm a neurologists suspicions. The EEG is also needed to differentiate between absence status epilepticus (which affects the entire brain), and CPSE, which only affects one region.
Treatment
Treatment is in the form of anti-epileptic drugs, such as barbiturates, benzodiazepines and topiramate.
References
== External links == |
Ectopic beat | Ectopic beat is a disturbance of the cardiac rhythm frequently related to the electrical conduction system of the heart, in which beats arise from fibers or group of fibers outside the region in the heart muscle ordinarily responsible for impulse formation (i.e., the sinoatrial node). An ectopic beat can be further classified as either a premature ventricular contraction, or a premature atrial contraction.Some patients describe this experience as a "flip" or a "jolt" in the chest, or a "heart hiccup", while others report dropped or missed beats. Ectopic beats are more common during periods of stress, exercise or debility; they may also be triggered by consumption of some food like carbohydrates, strong cheese, or chocolate.It is a form of cardiac arrhythmia in which ectopic foci within either ventricular or atrial myocardium, or from finer branches of the electric transduction system, cause additional beats of the heart. Some medications may worsen the phenomenon.Ectopic beats are considered normal and are not indicative of cardiac pathology. Ectopic beats often remain undetected and occur as part of minor errors in the heart conduction system. They are rarely indicative of cardiac pathology, although may occur more frequently or be more noticeable in those with existing cardiac abnormalities. Ectopic beats are a type of cardiac arrhythmias, which is a variety of cardiac abnormalities relating to rate or rhythm of the cardiac cycle.Ectopic beats may become more frequent during anxiety, panic attack, and the fight-or-flight response due to the increase in sympathetic nervous activity or due to parasympathetic failure, stimulating either more frequent or more vigorous contractions and increasing stroke volume. The consumption of nicotine, alcohol, epinephrine and caffeine may also increase the incidence of ectopic beats, due to their influence on the action of cardiomyocytes.
See also
Heart arrhythmia § Origin of impulse
Ectopia (disambiguation)
Junctional escape beat
Palpitation
Premature junctional contraction
Ventricular escape beat
References
== External links == |
Cutaneous meningioma | Cutaneous meningioma (also known as "Heterotopic meningeal tissue," and "Rudimentary meningocele") is a developmental defect, and results from the presence of meningocytes outside the calvarium.: 622
See also
List of cutaneous conditions
== References == |
Desmin-related myofibrillar myopathy | Desmin-related myofibrillar myopathy, is a subgroup of the myofibrillar myopathy diseases and is the result of a mutation in the gene that codes for desmin which prevents it from forming protein filaments, instead forming aggregates of desmin and other proteins throughout the cell.
Presentation
Common symptoms of the disease are weakness and atrophy in the distal muscles of the lower limbs which progresses to the hands and arms, then to the trunk, neck and face. Respiratory impairment often follows.
Genetics
There are three major types of inheritance for this disease: Autosomal dominant, autosomal recessive and de novo.
The most severe form is autosomal recessive and it also has the earliest onset. It usually involves all three muscle tissues and leads to cardiac and respiratory failure as well as intestinal obstruction.
Autosomal Dominant inheritance shows a later onset and slower progression. It usually involves only one or two of the muscle tissues.
De novo diseases occur when a new mutation arises in the person that was not inherited through either parent. This form has a wide range of symptoms and varies depending on the mutation made.
Pathophysiology
The sarcomeres become misaligned and result in the disorganization of muscle fibers. This mutation also results in muscle cell death by apoptosis and necrosis. The muscle cell may also be disorganized because the aggregates may interrupt other filament structures and/or normal cellular function.Desminopathies are very rare diseases and As of 2004 only 60 patients have been diagnosed, however this number probably does not accurately represent the population due to frequent mis or under diagnosis.
Diagnosis
Desminopathies are diagnosed by genetic analysis. Because mutations in several further genes might be pathogenic for skeletal and cardiac myopathies, gene panels or whole exome sequence analysis are mostly used. Sanger sequencing is consequently used to verify NGS-data.
Treatment
There is currently no cure for the disease but treatments to help the symptoms are available.
Prognosis
Prognosis strongly depends on which subtype of disease it is. Some are deadly in infancy but most are late onset and mostly manageable.
References
== External links == |
Retained antrum syndrome | Retained antrum syndrome or retained gastric antrum syndrome is one of the rare postgastrectomy syndromes. It happens after Billroth II surgery and the mechanism involved is the inadequate removal of the distal antrum and pylorus during resection of the antrum and gastrojejunostomy.Lack of the usual acid-secreting gastric glands makes the antral segment continually exposed to the alkaline environment of the duodenum, which causes it to secrete excessive acid and be prone to form ulcers.
== References == |
Wendigo | Wendigo () is a mythological creature or evil spirit originating from the folklore of Plains and Great Lakes Natives as well as some First Nations. It is based in and around the East Coast forests of Canada, the Great Plains region of the United States, and the Great Lakes region of the United States and Canada, grouped in modern ethnology as speakers of Algonquian-family languages. The wendigo is often said to be a malevolent spirit, sometimes depicted as a creature with human-like characteristics, which possesses human beings. The wendigo is said to invoke feelings of insatiable greed/hunger, the desire to cannibalize other humans, and the propensity to commit murder in those that fall under its influence.In some representations the wendigo is described as a giant humanoid with a heart of ice; a foul stench or sudden, unseasonable chill might precede its approach. Possibly because of longtime identification by Europeans with their own superstitions about werewolves, for example as mentioned in The Jesuit Relations below, Hollywood film representations often label human/beast hybrids featuring antlers or horns with the "wendigo" name, but such animal features do not appear in the original indigenous stories.In modern psychiatry the wendigo lends its name to a form of psychosis known as "Wendigo psychosis", which is characterized by symptoms such as an intense craving for human flesh and an intense fear of becoming a cannibal. Wendigo psychosis is described as a culture-bound syndrome. In some First Nations communities other symptoms such as insatiable greed and destruction of the environment are also thought to be symptoms of Wendigo psychosis.
Etymology
The word appears in many Native American languages, and has many alternative translations. The source of the English word is the Ojibwe word wiindigoo. In the Cree language it is wīhtikow, also transliterated wetiko. Other transliterations include Wiindigoo, Weendigo, Windego, Wiindgoo, Windgo, Windago, Windiga, Wendego, Windagoo, Widjigo, Wiijigoo, Wijigo, Weejigo, Wìdjigò, Wintigo, Wentigo, Wehndigo, Wentiko, Windgoe, Wītikō, and Wintsigo.
A plural form windigoag is also spelled windegoag, wiindigooag, or windikouk.The Proto-Algonquian term has been reconstructed as *wi·nteko·wa, which may have meant "owl".
Parallels
The Wechuge is a similar being that appears in the legends of the Athabaskan people of the Northwest Pacific Coast. It too is cannibalistic; however, it is characterized as enlightened with ancestral insights.
Folklore
Description
The wendigo is part of the traditional belief system of a number of Algonquin-speaking peoples, including the Ojibwe, the Saulteaux, the Cree, the Naskapi, and the Innu. Although descriptions can vary somewhat, common to all these cultures is the view that the wendigo is a malevolent, cannibalistic, supernatural being. They were strongly associated with winter, the north, coldness, famine, and starvation.Basil H. Johnston, an Ojibwe teacher and scholar from Ontario, gives a description of a wendigo:
The Wendigo was gaunt to the point of emaciation, its desiccated skin pulled tightly over its bones. With its bones pushing out against its skin, its complexion the ash-gray of death, and its eyes pushed back deep into their sockets, the Wendigo looked like a gaunt skeleton recently disinterred from the grave. What lips it had were tattered and bloody ... Unclean and suffering from suppuration of the flesh, the Wendigo gave off a strange and eerie odor of decay and decomposition, of death and corruption.
In Ojibwe, Eastern Cree, Westmain Swampy Cree, Naskapi, and Innu lore, wendigos are often described as giants that are many times larger than human beings, a characteristic absent from myths in other Algonquian cultures. Whenever a wendigo ate another person, it would grow in proportion to the meal it had just eaten, so it could never be full. Therefore, wendigos are portrayed as simultaneously gluttonous and extremely thin due to starvation.
The wendigo is seen as the embodiment of gluttony, greed, and excess: never satisfied after killing and consuming one person, they are constantly searching for new victims.
A wendigo need not lose the humans powers of cognition or speech and in some depictions may clearly communicate with its prospective victims or even threaten or taunt them. A specimen of folk story collected in the early 20th century by Lottie Chicogquaw Marsden, an ethnographer of the Chippewas of Rama First Nation, in which a wendigo also exhibits tool use, an ability to survive partial dismemberment, and autocannibalism, reads:One time long ago a big Windigo stole an Indian boy, but the boy was too thin, so the Windigo didnt eat him up right away, but he travelled with the Indian boy waiting for him till hed get fat. The Windigo had a knife and hed cut the boy on the hand to see if he was fat enough to eat, but the boy didnt get fat. They travelled too much. One day they came to an Indian village and the Windigo sent the boy to the Indian village to get some things for him to eat. He just gave the boy so much time to go there and back. The boy told the Indians that the Windigo was near them, and showed them his hand where the Windigo cut him to see if he was fat enough to eat. They heard the Windigo calling the boy. He said to the boy "Hurry up. Dont tell lies to those Indians." All of these Indians went to where the Windigo was and cut off his legs. They went back again to see if he was dead. He wasnt dead. He was eating the juice (marrow) from the inside of the bones of his legs that were cut off. The Indians asked the Windigo if there was any fat on them. He said, "You bet there is, I have eaten lots of Indians, no wonder they are fat." The Indians then killed him and cut him to pieces. The end of this Giant Windigo.
Human cannibalism
In some traditions, humans overpowered by greed could turn into wendigos; the myth thus served as a method of encouraging cooperation and moderation. Other sources say wendigos were created when a human resorted to cannibalism to survive. Humans could also turn into wendigos by being in contact with them for too long.
Taboo reinforcement ceremony
Among the Assiniboine, the Cree, and the Ojibwe, a satirical ceremonial dance is sometimes performed during times of famine to reinforce the seriousness of the wendigo taboo. The ceremony, known as wiindigookaanzhimowin, was performed during times of famine, and involved wearing masks and dancing backward around a drum. The last known wendigo ceremony conducted in the United States was at Lake Windigo of Star Island of Cass Lake, within the Leech Lake Indian Reservation in northern Minnesota.
Psychosis
In historical accounts of retroactively diagnosed Wendigo psychosis, it has been reported that humans became possessed by the wendigo spirit, after being in a situation of needing food and having no other choice besides cannibalism. In 1661, The Jesuit Relations reported:
Although in many recorded cases of Wendigo psychosis the individual has been killed to prevent cannibalism from resulting, some Cree folklore recommends treatment by ingestion of fatty animal meats or drinking animal grease; those treated may sometimes vomit ice as part of the curing process.One of the more famous cases of Wendigo psychosis reported involved a Plains Cree trapper from Alberta, named Swift Runner. During the winter of 1878, Swift Runner and his family were starving, and his eldest son died. Twenty-five miles away from emergency food supplies at a Hudsons Bay Company post, Swift Runner butchered and ate his wife and five remaining children. Given that he resorted to cannibalism so near to food supplies, and that he killed and consumed the remains of all those present, it was revealed that Swift Runners was not a case of pure cannibalism as a last resort to avoid starvation, but rather of a man with Wendigo psychosis. He eventually confessed and was executed by authorities at Fort Saskatchewan.Another well-known case involving Wendigo psychosis was that of Jack Fiddler, an Oji-Cree chief and medicine man known for his powers at defeating wendigos. In some cases, this entailed killing people with Wendigo psychosis. As a result, in 1907, Fiddler and his brother Joseph were arrested by the Canadian authorities for homicide. Jack committed suicide, but Joseph was tried and sentenced to life in prison. He ultimately was granted a pardon but died three days later in jail before receiving the news of this pardon.Fascination with Wendigo psychosis among Western ethnographers, psychologists, and anthropologists led to a hotly debated controversy in the 1980s over the historicity of this phenomenon. Some researchers argued that, essentially, Wendigo psychosis was a fabrication, the result of naïve anthropologists taking stories related to them at face value without observation. Others have pointed to a number of credible eyewitness accounts, both by Algonquians and others, as evidence that Wendigo psychosis was a factual historical phenomenon.The frequency of Wendigo psychosis cases decreased sharply in the 20th century as Boreal Algonquian people came into greater and greater contact with European ideologies and more sedentary, less rural, lifestyles.In his 2004 treatise Revenge of the Windigo on disorders and treatments of the behavioral health industry in the United States and Canada that are peculiar to indigenous people, James B. Waldram wrote,
...no actual cases of windigo psychosis have ever been studied, and Lou Maranos scathing critique in 1985 should have killed off the cannibal monster within the psychiatric annals. The windigo, however, continues to seek revenge for this attempted scholarly execution by periodically duping unsuspecting passers-by, like psychiatrists, into believing that windigo psychosis not only exists but that a psychiatrist could conceivably encounter a patient suffering from this disorder in his or her practice today! Windigo psychosis may well be the most perfect example of the construction of an Aboriginal mental disorder by the scholarly professions, and its persistence dramatically underscores how constructions of the Aboriginal by these professions have, like Frankensteins monster, taken on a life of their own.
The 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) classifies "Windigo" as a culture-specific disorder, describing it as "Rare, historic accounts of cannibalistic obsession... Symptoms included depression, homicidal or suicidal thoughts, and a delusional, compulsive wish to eat human flesh... Some controversial new studies question the syndromes legitimacy, claiming cases were actually a product of hostile accusations invented to justify the victims ostracism or execution."
As a concept or metaphor
In addition to denoting a cannibalistic monster from certain traditional folklore, some Native Americans also understand the wendigo conceptually. As a concept, the wendigo can apply to any person, idea, or movement infected by a corrosive drive toward self-aggrandizing greed and excessive consumption, traits that sow disharmony and destruction if left unchecked. Ojibwe scholar Brady DeSanti asserts that the wendigo "can be understood as a marker indicating... a person... imbalanced both internally and toward the larger community of human and spiritual beings around them." Out of equilibrium and estranged by their communities, individuals thought to be afflicted by the wendigo spirit unravel and destroy the ecological balance around them. Chippewa author Louise Erdrichs novel The Round House, winner of the National Book Award, depicts a situation where an individual person becomes a wendigo. The novel describes its primary antagonist, a rapist whose violent crimes desecrate a sacred site, as a wendigo who must be killed because he threatens the reservations safety.
In addition to characterizing individual people who exhibit destructive tendencies, the wendigo can also describe movements and events with similarly negative effects. According to Professor Chris Schedler, the figure of the wendigo represents "consuming forms of exclusion and assimilation" through which groups dominate other groups." This application allows Native Americans to describe colonialism and its agents as wendigos since the process of colonialism ejected natives from their land and threw the natural world out of balance. DeSanti points to the 1999 horror film Ravenous as an illustration of this argument equating "the cannibal monster" to "American colonialism and manifest destiny". This movie features a character who articulates that expansion brings displacement and destruction as side effects, explaining that "manifest destiny" and "western expansion" will bring "thousands of gold-hungry Americans... over the mountains in search of new lives... This country is seeking to be whole... Stretching out its arms... and consuming all it can. And we merely follow".As a concept, wendigo can apply to situations other than some Native American-European relations. It can serve as a metaphor explaining any pattern of domination by which groups subjugate and dominate or violently destroy and displace. Joe Lockhard, English professor at Arizona State University, argues that wendigos are agents of "social cannibalism" who know "no provincial or national borders; all human cultures have been visited by shape-shifting wendigos. Their visitations speak to the inseparability of human experience... National identity is irrelevant to this borderless horror." Lockhards ideas explain that wendigos are an expression of a dark aspect of human nature: the drive toward greed, consumption, and disregard for other life in the pursuit of self-aggrandizement.
Romantic scholar and documentarian Emily Zarka, also a professor at Arizona State University, observes that two commonalities among the indigenous cultures of Algonquian language family speakers are that they are situated in climes where harsh winters are frequent and may be accompanied by starvation. She states that the wendigo symbolically represents three major concepts: it is the incarnation of winter, the embodiment of hunger, and the personification of selfishness.
In popular culture
Although distinct from how it appears in the traditional lore, one of the first appearances of a character inspired by, or named after, a wendigo in non-Indigenous literature is Algernon Blackwoods 1910 novella The Wendigo. Joe Nazare wrote that Blackwoods "subtly-demonizing rhetoric transforms the Wendigo from a native myth into a descriptive template for the Indian savage."Blackwoods work has influenced many of the subsequent portrayals in mainstream horror fiction, such as August Derleths "The Thing that Walked on the Wind" and "Ithaqua" (1933 and 1941), which in turn inspired the character in Stephen Kings novel Pet Sematary, where it is a personification of evil, an ugly grinning creature with yellow-grey eyes, ears replaced by rams horns, white vapor coming from its nostrils, and a pointed, decaying yellow tongue. These works set the template for later portrayals in popular culture, at times even replacing the Native American lore. In an early short story by Thomas Pynchon, "Mortality and Mercy in Vienna" (first published in 1959), the plot centers around a character developing Wendigo syndrome and going on a killing spree.
A character inspired by the wendigo appears in American comic books published by Marvel Comics. Created by the writer Steve Englehart and artist Herb Trimpe, the monster is the result of a curse that afflicts those who commit acts of cannibalism. It first appeared in The Incredible Hulk #162 (April 1973), and again in the October 1974 issue.Without explicitly using the term, the 1995 novel Solar Storms by Chickasaw author and poet Linda K. Hogan both explored the mythology of the wendigo and used the creatures as a device to interrogate issues of independence, spirituality, and politics, an individuals relationship to the family, and as a metaphor for corporate voracity, exploitation, and power viewed as a form of cannibalism.
Other creatures based on the legend, or named for it, appear in various films and television shows, including Dark Was the Night and Ravenous. Television series include Teen Wolf, Supernatural, Blood Ties, Charmed, Grimm, and Hannibal, where an FBI profiler has recurring dreams or visions of a wendigo that symbolizes the titular cannibalistic serial killer. A wendigo appears in My Little Pony: Friendship Is Magic "Hearths Warming Eve" under the pun title of "Windigo", and in the DuckTales Christmas special, "Last Christmas!", in which the creatures are described as "poor souls turned into monsters by obsession and desperation." A wendigo also appears in the 2020 horror film The Retreat.The 2015 horror survival video game Until Dawn by Supermassive Games features wendigos as the main antagonists. Wrist, the 2016 debut novel by Canadian horror fiction writer Nathan Niigan Noodin Adler, was based on the story of the wendigo.The 2015 series Summoner by Taran Matharu featured a type of demon known as a Wendigo.In the 2018 role-playing game Fallout 76 by Bethesda Game Studios, wendigos are featured as one of the cryptid enemies found in the area of Appalachia; mutated from people who consumed human flesh in isolation.In the 2018 first-person shooter video game Dusk, wendigos are featured as strong enemies that remain invisible to the player until they receive damage. Several of these creatures also appear in the games cover art.In the 2021 film Antlers by Scott Cooper, Frank, Lucas father, transforms into a wendigo, which is portrayed as a deer-like creature with a glowing heart that moves from person to person with a never ending hunger. Guillermo del Toro, producer of the film, developed the wendigo on the basis that the more the creature eats, the more it gets hungry and the more it gets hungry, the weaker it becomes.
References
Citations
General and cited sources
Brightman, Robert A. (1988). "The Windigo in the Material World" (PDF). Ethnohistory. 35 (4): 337–379. doi:10.2307/482140. JSTOR 482140. Archived from the original (PDF) on April 8, 2019.
Colombo, J.R. ed. Wendigo. Western Producer Prairie Books, Saskatoon: 1982.
Goddard, Ives (1969). "Owls and Cannibals: Two Algonquian Etymologies". Paper Presented at the Second Algonquian Conference, St. Johns, Newfoundland.
Johnston, Basil (1990) [1976]. Ojibway Heritage. Lincoln: University of Nebraska Press.
Johnston, Basil (2001) [1995]. The Manitous. St. Paul: Minnesota Historical Society Press.
Marano, Lou (1982). "Windigo Psychosis: The Anatomy of an Emic-Etic Confusion". Current Anthropology. 23: 385–412. doi:10.1086/202868. S2CID 147398948.
Parker, Seymour (1960). "The Wiitiko Psychosis in the Context of Ojibwa Personality and Culture". American Anthropologist. 62 (4): 603–623. doi:10.1525/aa.1960.62.4.02a00050.
Smallman, Shawn (2014). Dangerous Spirits: The Windigo in Myth and History. Victoria, BC: Heritage House Publishing Company. ISBN 9781772030334.
Teicher, Morton I. (1961). "Windigo Psychosis: A Study of Relationship between Belief and Behaviour among the Indians of Northeastern Canada." In Proceedings of the 1960 Annual Spring Meeting of the American Ethnological Society, ed. Verne P. Ray. Seattle: University of Washington Press.
External links
Seeing Wetiko: on Capitalism, Mind Viruses, and Antidotes for a World in Transition
"Windigo: The Flesh-Eating Monster of Native American Legend", Monstrum documentary short series from PBS Digital Studios |
Spasmodic torticollis | Spasmodic torticollis is an extremely painful chronic neurological movement disorder causing the neck to involuntarily turn to the left, right, upwards, and/or downwards. The condition is also referred to as "cervical dystonia". Both agonist and antagonist muscles contract simultaneously during dystonic movement.
Causes of the disorder are predominantly idiopathic. A small number of patients develop the disorder as a result of another disorder or disease. Most patients first experience symptoms midlife. The most common treatment for spasmodic torticollis is the use of botulinum toxin type A.
Signs and symptoms
Initial symptoms of spasmodic torticollis are usually mild. Some feel an invisible tremor of their head for a few months at onset. Then the head may turn, pull or tilt in jerky movements, or sustain a prolonged position involuntarily. Over time, the involuntary spasm of the neck muscles will increase in frequency and strength until it reaches a plateau. Symptoms can also worsen while the patient is walking or during periods of increased stress. Other symptoms include muscle hypertrophy, neck pain, dysarthria and tremor. Studies have shown that over 75% of patients report neck pain, and 33% to 40% experience tremor of the head.
Pathophysiology
The pathophysiology of spasmodic torticollis is still relatively unknown. Spasmodic torticollis is considered neurochemical in nature, and does not result in structural neurodegenerative changes. Although no lesions are present in the basal ganglia in primary spasmodic torticollis, fMRI and PET studies have shown abnormalities of the basal ganglia and hyper activation of the cortical areas. Studies have suggested that there is a functional imbalance in the striatal control of the globus pallidus, specifically the substantia nigra pars reticulata. The studies hypothesize the hyper activation of the cortical areas is due to reduced pallidal inhibition of the thalamus, leading to over activity of the medial and prefrontal cortical areas and under activity of the primary motor cortex during movement. It has also been suggested that the functional imbalance is due to an imbalance of neurotransmitters such as dopamine, acetylcholine, and gamma-aminobutyric acid. These neurotransmitters are secreted from the basal ganglia, traveling to muscle groups in the neck. An increase in neurotransmitters causes spasms to occur in the neck, resulting in spasmodic torticollis.
Studies of local field potentials have also shown an increase of 4–10 Hz oscillatory activity in the globus pallidus internus during myoclonic episodes and an increase of 5–7 Hz activity in dystonic muscles when compared to other primary dystonias. This indicates that oscillatory activity in these frequency bands may be involved in the pathophysiology of spasmodic torticollis.
Diagnosis
The most commonly used scale to rate the severity of spasmodic torticollis is the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). It has been shown that this rating system has widespread acceptance for use in clinical trials, and has been shown to have “good interobserver reliability.” There are three scales in the TWSTRS: torticollis severity scale, disability scale, and pain scale. These scales are used to represent the severity, the pain, and the general lifestyle of spasmodic torticollis.
Classification
Spasmodic torticollis is a form of focal dystonia, a neuromuscular disorder that consists of sustained muscle contractions causing repetitive and twisting movements and abnormal postures in a single body region. There are two main ways to categorize spasmodic torticollis: age of onset, and cause. The disorder is categorized as early onset if the patient is diagnosed before the age of 27, and late onset thereafter. The causes are categorized as either primary (idiopathic) or secondary (symptomatic). Spasmodic torticollis can be further categorized by the direction and rotation of head movement.
Primary
Primary spasmodic torticollis is defined as having no other abnormality other than dystonic movement and occasional tremor in the neck. This type of spasmodic torticollis is usually inherited. Studies have shown that the DYT7 locus on chromosome 18p in a German family and the DYT13 locus on chromosome 1p36 in an Italian family is associated with spasmodic torticollis. The inheritance for both loci is autosomal dominant. These loci are all autosomal dominantly inherited with reduced penetrance. Although these loci have been found, it is still not clear the extent of influence the loci have on spasmodic torticollis.
Secondary
When other conditions lead to spasmodic torticollis, it is said that the spasmodic torticollis is secondary. A variety of conditions can cause brain injury, from external factors to diseases. These conditions are listed below:
Central nervous system tumor
Central pontine myelinolysis
Cerebrovascular diseases
Drug induced
Infectious or post infectious encephalopathies
Kernicterus
Metabolic
Paraneoplastic syndromes
Perinatal (during birth) cerebral injury
Peripheral or central trauma
ToxinsSecondary spasmodic torticollis is diagnosed when any of the following are present: history of exogenous insult or exposure, neurological abnormalities other than dystonia, abnormalities on brain imaging, particularly in the basal ganglia.
Head positions
To further classify spasmodic torticollis, one can note the position of the head.
Torticollis is the horizontal turning (rotational collis) of the head, and uses the ipsilateral splenius, and contralateral sternocleidomastoid muscles. This is the "chin-to-shoulder" version.
Laterocollis is the tilting of the head from side to side. This is the "ear-to-shoulder" version. This involves many more muscles: ipsilateral sternocleidomastoid, ipsilateral splenius, ipsilateral scalene complex, ipsilateral levator scapulae, and ipsilateral posterior paravertebrals.
The flexion of the neck (head tilts forwards) is anterocollis. This is the "chin-to-chest" version and is the most difficult version to address. This movement utilizes the bilateral sternocleidomastoid, bilateral scalene complex, bilateral submental complex.
Retrocollis is the extension of the neck (head tilts back) and uses the following muscles for movement: bilateral splenius, bilateral upper trapezius, bilateral deep posterior paravertebrals. This is the "chin-in-the-air" version.A combination of these head positions is common; many patients experience turning and tilting actions of the head.
Treatment
There are several treatments for spasmodic torticollis, the most commonly used being botulinum toxin injections in the dystonic muscle of the neck. Other treatments include sensory trick for a mild occasional twinge, oral medications, and deep brain stimulation. Combinations of these treatments have been used to control spasmodic torticollis. In addition, selective surgical denervation of nerves triggering muscle contractions may offer relief from spasms and pain, and limit damage to the spine as a result of torqued posture. Spinal fibrosis (i.e., locking of spinal facets due to muscular contortion resulting in fused vertebrae) may occur rapidly.
This suggests that the desynchronization of the frequency range is movement related.
Obtaining relief via a "sensory trick", also known as a geste antagoniste, is a common characteristic present in focal dystonias, most prevalently in cervical dystonia; however, it has also been seen in patients with blepharospasm. Sensory tricks offer only temporary and often partial relief of spasmodic torticollis. 74% of patients report only partial relief of spasmodic torticollis compared to 26% reporting complete relief. The sensory trick must also be applied by the patient themselves. When the sensory trick is applied by an examiner, only 32% of patients report relief comparable to relief during self-application. Since the root of the problem is neurological, doctors have explored sensorimotor retraining activities to enable the brain to "rewire" itself and eliminate dystonic movements.
Oral medications
In the past, dopamine blocking agents have been used in the treatment of spasmodic torticollis. Treatment was based on the theory that there is an imbalance of the neurotransmitter dopamine in the basal ganglia. These drugs have fallen out of fashion due to various serious side effects: sedation, parkinsonism, and tardive dyskinesia.
Other oral medications can be used in low doses to treat early stages of spasmodic torticollis. Relief from spasmodic torticollis is higher in those patients who take anticholinergic agents when compared to other oral medications. Many have reported complete management with gabapentin alone or in combination with another drug such as clonazepam. 50% of patients who use anticholinergic agents report relief, 21% of patients report relief from clonazepam, 11% of patients report relief from baclofen, and 13% from other benzodiazepines.Higher doses of these medications can be used for later stages of spasmodic torticollis; however, the frequency and severity of side effects associated with the medications are usually not tolerated. Side effects include dry mouth, cognitive disturbance, drowsiness, diplopia, glaucoma and urinary retention.
Botulinum toxin
The most commonly used treatment for spasmodic torticollis is the use of botulinum toxin injection in the dystonic musculature. Botulinum toxin type A is most often used; it prevents the release of acetylcholine from the presynaptic axon of the motor end plate, paralyzing the dystonic muscle. By disabling the movement of the antagonist muscle, the agonist muscle is allowed to move freely. With botulinum toxin injections, patients experience relief from spasmodic torticollis for approximately 12 to 16 weeks. There are several type A preparations available worldwide and in the United States.Some patients experience or develop immunoresistance to botulinum toxin type A and must use botulinum toxin type B. Approximately 4% to 17% of patients develop botulinum toxin type A antibodies. The only botulinum toxin type B accessible in the United States is Myobloc. Treatment using botulinum toxin type B is comparable to type A, with an increased frequency of the side effect dry mouth.Common side effects include pain at the injection site (up to 28%), dysphagia due to the spread to adjacent muscles (11% to 40%), dry mouth (up to 33%), fatigue (up to 17%), and weakness of the injected or adjacent muscle (up to 56%). A Cochrane review published in 2016 reported moderate-quality evidence that a single Botulinum toxin-B treatment session could improve cervical dystonia symptoms by 10% to 20%, although with an increased risk of dry mouth and swallowing difficulties. Another Cochrane review published in 2020 for Botulinum toxin-A found similar results.
Deep brain stimulation
Deep brain stimulation to the basal ganglia and thalamus has recently been used as a successful treatment for tremors of patients with Parkinsons disease. This technique is currently, as of 2007, being trialed in patients with spasmodic torticollis. Patients are subjected to stimulation of the globus pallidus internus, or the subthalamic nucleus. The device is analogous to a pacemaker: an external battery is placed subcutaneously, with wires under the skin which enter the skull and a region of the brain. To stimulate the globus pallidus internus, microelectrodes are placed into the globus pallidus internus bilaterally. After the surgery is performed, multiple visits are required to program the settings for the stimulator. The stimulation of the globus pallidus internus disrupts the abnormal discharge pattern in the globus pallidus internus, resulting in inhibition of hyperactive cortical activity. Globus pallidus internus deep brain stimulation is the preferred surgical procedure, due to the lower frequency of side effects. Advantages of deep brain stimulation include the reversibility of the procedure, and the ability to adjust the settings of the stimulation.In one study, patients who had developed immunoresistance to botulinum toxin underwent globus pallidus internus deep brain stimulation, showing improvement by 54.4% after three to six months.There is a low rate of side effects for those who undergo deep brain stimulation. The most common side effect is headache, occurring in 15% of patients, followed by infection (4.4%) and cognitive dysfunction (4%). Serious side effects are seizure (1.2%), intracerebral hemorrhage (0.6%), intraventricular hemorrhage (0.6%), and large subdural hematoma (0.3%).
Physical Interventions
Physical treatment options for cervical dystonia include biofeedback, mechanical braces as well as patients self-performing a geste antagoniste. Physical therapy also has an important role in managing spasmodic torticollis by providing stretching and strengthening exercises to aid the patient in keeping their head in proper alignment with their body. Patients with cervical dystonia ranked physical therapy intervention second to botulinum toxin injections in overall effectiveness in reducing symptoms and patients receiving physiotherapy in conjunction with botulinum toxin injections reported enhanced effects of treatment compared to the injections alone. One study examined patients with cervical dystonia who were treated with a physiotherapy program that included muscle stretching and relaxation, balance and coordination training, and exercises for muscle strengthening and endurance. A significant reduction in pain and severity of dystonia as well as increased postural awareness and quality of life was found.
Epidemiology
Spasmodic torticollis is one of the most common forms of dystonia seen in neurology clinics, occurring in approximately 0.390% of the United States population in 2007 (390 per 100,000). Worldwide, it has been reported that the incidence rate of spasmodic torticollis is at least 1.2 per 100,000 person years, and a prevalence rate of 57 per 1 million.
The exact prevalence of the disorder is not known; several family and population studies show that as many as 25% of cervical dystonia patients have relatives that are undiagnosed. Studies have shown that spasmodic torticollis is not diagnosed immediately; many patients are diagnosed well after a year of seeking medical attention. A survey of 59 patients diagnosed with spasmodic torticollis show that 43% of the patients visited at least four physicians before the diagnosis was made.There is a higher prevalence of spasmodic torticollis in females; females are 1.5 times more likely to develop spasmodic torticollis than males. The prevalence rate of spasmodic torticollis also increases with age, most patients show symptoms from ages 50–69. The average onset age of spasmodic torticollis is 41.
References
Dystonia Medical Research Foundation: Cervical Dystonia
== External links == |
Spinal muscular atrophy | Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death. It may also appear later in life and then have a milder course of the disease. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.The age of onset and the severity of symptoms form the basis of the traditional classification of spinal muscular atrophy into a number of types.Spinal muscular atrophy is due to an abnormality (mutation) in the SMN1 gene which encodes SMN, a protein necessary for survival of motor neurons. Loss of these neurons in the spinal cord prevents signalling between the brain and skeletal muscles. Another gene, SMN2, is considered a disease modifying gene, since usually the more the SMN2 copies, the milder is the disease course. The diagnosis of SMA is based on symptoms and confirmed by genetic testing.Usually, the mutation in the SMN1 gene is inherited from both parents in an autosomal recessive manner, although in around 2% of cases it occurs during early development (de novo). The incidence of spinal muscular atrophy worldwide varies from about 1 in 4,000 births to around 1 in 16,000 births, with 1 in 7,000 and 1 in 10,000 commonly quoted for Europe and the US respectively.Outcomes in the natural course of the disease vary from death within a few weeks after birth in the most acute cases to normal life expectancy in the protracted SMA forms. The introduction of causative treatments in 2016 has significantly improved the outcomes. Medications that target the genetic cause of the disease include nusinersen, risdiplam, and the gene therapy medication onasemnogene abeparvovec. Supportive care includes physical therapy, occupational therapy, respiratory support, nutritional support, orthopaedic interventions, and mobility support.
Classification
5q SMA is a single disease that manifests over a wide range of severity, affecting infants through adults. Before its genetics was understood, its varying manifestations were thought to be different diseases – Werdnig–Hoffmann disease when young children were affected and Kugelberg–Welander disease for late-onset cases.In 1990, it was realised that these separate diseases formed a spectrum of the same disorder. Spinal muscular atrophy was then classified into 3–5 clinical types based either on the age of symptom onset or on the maximum motor function achieved. Currently, the consensus is that the phenotype of spinal muscular atrophy spans a continuum of symptoms without clear delineation of subtypes. However, the traditional classification, outlined in the table below, is still used today both in clinical research and sometimes, controversially, as a criterion of access to therapies.
For convenience, care-focused publications classify patients into "non-sitters", "sitters" and "walkers" based on their actual functional status.
Motor development and disease progression in people with SMA is usually assessed using validated functional scales – CHOP-INTEND (The Childrens Hospital of Philadelphia Infant Test of Neuromuscular Disorders) or HINE (Hammersmith Infant Neurological Examination) in infants; and either the MFM (Motor Function Measure) or one of several variants of the HFMS (Hammersmith Functional Motor Scale) in older patients.
The eponymous label Werdnig–Hoffmann disease (sometimes misspelled with a single n) refers to the earliest clinical descriptions of childhood SMA by Johann Hoffmann and Guido Werdnig. The eponymous term Kugelberg–Welander disease named after Erik Klas Hendrik Kugelberg (1913–1983) and Lisa Welander (1909–2001), who first documented the late-onset form and distinguished it from muscular dystrophy. Very rarely used Dubowitz disease (not to be confused with Dubowitz syndrome) is named after Victor Dubowitz, an English neurologist who authored several studies on the intermediate SMA phenotype.
Signs and symptoms
The symptoms vary depending on the SMA type, the stage of the disease as well as individual factors. Signs and symptoms below are most common in the severe SMA type 0/I:
Areflexia, particularly in extremities
Overall muscle weakness, poor muscle tone, limpness or a tendency to flop
Difficulty achieving developmental milestones, difficulty sitting/standing/walking
In small children: adopting of a frog-leg position when sitting (hips abducted and knees flexed)
Loss of strength of the respiratory muscles: weak cough, weak cry (infants), accumulation of secretions in the lungs or throat, respiratory distress
Bell-shaped torso (caused by using only abdominal muscles for respiration) in severe SMA type
Fasciculations (twitching) of the tongue
Difficulty sucking or swallowing, poor feeding
Causes
Spinal muscular atrophy is caused by a genetic mutation in the SMN1 gene.Human chromosome 5 contains two nearly identical genes at location 5q13: a telomeric copy SMN1 and a centromeric copy SMN2. In healthy individuals, the SMN1 gene codes the survival of motor neuron protein (SMN) which, as its name says, plays a crucial role in survival of motor neurons. The SMN2 gene, on the other hand – due to a variation in a single nucleotide (840.C→T) – undergoes alternative splicing at the junction of intron 6 to exon 8, with only 10–20% of SMN2 transcripts coding a fully functional survival of motor neuron protein (SMN-fl) and 80–90% of transcripts resulting in a truncated protein compound (SMNΔ7) which is rapidly degraded in the cell.In individuals affected by SMA, the SMN1 gene is mutated in such a way that it is unable to correctly code the SMN protein – due to either a deletion occurring at exon 7 or to other point mutations (frequently resulting in the functional conversion of the SMN1 sequence into SMN2). Almost all people, however, have at least one functional copy of the SMN2 gene (with most having 2–4 of them) which still codes 10–20% of the usual level of the SMN protein, allowing some neurons to survive. In the long run, however, the reduced availability of the SMN protein results in gradual death of motor neuron cells in the anterior horn of spinal cord and the brain. Skeletal muscles, which all depend on these motor neurons for neural input, now have decreased innervation (also called denervation), and therefore have decreased input from the central nervous system (CNS). Decreased impulse transmission through the motor neurons leads to decreased contractile activity of the denervated muscle. Consequently, denervated muscles undergo progressive atrophy (waste away).Muscles of lower extremities are usually affected first, followed by muscles of upper extremities, spine and neck and, in more severe cases, pulmonary and mastication muscles. Proximal muscles are always affected earlier and to a greater degree than distal muscles.The severity of SMA symptoms is broadly related to how well the remaining SMN2 genes can make up for the loss of function of SMN1. This partly depends on the number of copies of the SMN2 gene present on the chromosome. Whilst healthy individuals usually carry two SMN2 gene copies, people with SMA can have anything between 1 and 5 (or more) of them; the greater the number of SMN2 copies, the milder the disease severity. Thus, most SMA type I babies have one or two SMN2 copies; people with SMA II and III usually have at least three SMN2 copies; and people with SMA IV normally have at least four of them. However, the correlation between symptom severity and SMN2 copy number is not absolute and there seem to exist other factors affecting the disease phenotype.Spinal muscular atrophy is inherited in an autosomal recessive pattern, which means that the defective gene is located on an autosome. Two copies of the defective gene – one from each parent – are required to inherit the disorder: the parents may be carriers and not personally affected. SMA seems to appear de novo (i.e., without any hereditary causes) in around 2–4% of cases.Spinal muscular atrophy affects individuals of all ethnic groups, unlike other well known autosomal recessive disorders, such as sickle cell disease and cystic fibrosis, which have significant differences in occurrence rate among ethnic groups. The overall prevalence of SMA, of all types and across all ethnic groups, is in the range of 1 per 10,000 individuals; the gene frequency is around 1:100, therefore, approximately one in 50 persons are carriers. There are no known health consequences of being a carrier. A person may learn carrier status only if ones child is affected by SMA or by having the SMN1 gene sequenced.Affected siblings usually have a very similar form of SMA. However, occurrences of different SMA types among siblings do exist – while rare, these cases might be due to additional de novo deletions of the SMN gene, not involving the NAIP gene, or the differences in SMN2 copy numbers.
Diagnosis
SMA is diagnosed using genetic testing that detects homozygous deletion of the SMN1 gene in over 95% of cases, and a compound SMN1 mutation in the remaining patients. Genetic testing is usually carried out using a blood sample, and MLPA is one of more frequently used genetic testing techniques, as it also allows establishing the number of SMN2 gene copies, which has clinical importance.Symptomatically, SMA can be diagnosed with a degree of certainty only in children with the acute form who manifest a progressive illness with paradoxical breathing, bilateral low muscle tone and absent tendon reflexes.
Early diagnosis
Early diagnosis of SMA, at the asymptomatic stage of the disease, allows for
Preimplantation testing
Preimplantation genetic diagnosis can be used to screen for SMA-affected embryos during in-vitro fertilisation.
Prenatal testing
Prenatal testing for SMA is possible through chorionic villus sampling, cell-free fetal DNA analysis and other methods.
Newborn screening
Routine newborn screening for SMA is becoming increasingly commonplace in developed countries, given the availability of causative treatments that are most effective at the asymptomatic stage of the disease. In 2018, newborn screening for SMA was added to the US list of recommended newborn screening tests and as of April 2020 it has been adopted in 39 US states. As of May 2021, SMA newborn screening has been implemented in Taiwan and is in the course of implementation in Australia, Belgium, Canada, France, Germany, Netherlands, Poland, Serbia and Slovenia. Additionally, pilot projects are being conducted in Australia, China, Italy, and Japan.
Carrier testing
Those at risk of being carriers of SMN1 deletion, and thus at risk of having offspring affected by SMA, can undergo carrier analysis using a blood or saliva sample. The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant be tested to see if they are a carrier. The carrier frequency of SMA is comparable to other disorders like thalassemia and in a north Indian cohort has been found to be 1 in 38. However, genetic testing will not be able to identify all individuals at risk since about 2% of cases are caused by de novo mutations and 5% of the normal population have two copies of SMN1 on the same chromosome, which makes it possible to be a carrier by having one chromosome with two copies and a second chromosome with zero copies. This situation will lead to a false negative result, as the carrier status will not be correctly detected by a traditional genetic test.
Management
The management of SMA varies based upon the severity and type. In the most severe forms (types 0/1), individuals have the greatest muscle weakness requiring prompt intervention. Whereas the least severe form (type 4/adult onset), individuals may not seek the certain aspects of care until later (decades) in life. While types of SMA and individuals among each type may differ, therefore specific aspects of an individuals care can differ.
Medication
Nusinersen (marketed as Spinraza) is used to treat spinal muscular atrophy. It is an antisense nucleotide that modifies the alternative splicing of the SMN2 gene. It is given directly to the central nervous system using an intrathecal injection. Nusinersen prolongs survival and improves motor function in infants with SMA. It was approved for use in the US in 2016, and for use in the EU in 2017.Onasemnogene abeparvovec (marketed as Zolgensma) is a gene therapy treatment which uses self-complementary adeno-associated virus type 9 (scAAV-9) as a vector to deliver the SMN1 transgene. The therapy was first approved in the US in May 2019 as an intravenous formulation for children below 24 months of age. Approval in the European Union, Japan and other countries followed, albeit often with different approval scopes.Risdiplam (marketed as Evrysdi) is a medication taken by mouth in liquid form. It is a pyridazine derivative that works by increasing the amount of functional survivor motor neuron protein produced by the SMN2 gene through modifying its splicing pattern. Risdiplam was first approved for medical use in the United States in August 2020 and has since been approved in over 30 countries.
Breathing
The respiratory system is the most common system to be affected and the complications are the leading cause of death in SMA types 0/1 and 2. SMA type 3 can have similar respiratory problems, but it is more rare. The complications that arise due to weakened intercostal muscles because of the lack of stimulation from the nerve. The diaphragm is less affected than the intercostal muscles. Once weakened, the muscles never fully recover the same functional capacity to help in breathing and coughing as well as other functions. Therefore, breathing is more difficult and pose a risk of not getting enough oxygen/shallow breathing and insufficient clearance of airway secretions. These issues more commonly occurs while asleep, when muscles are more relaxed. Swallowing muscles in the pharynx can be affected, leading to aspiration coupled with a poor coughing mechanism increases the likelihood of infection/pneumonia. Mobilizing and clearing secretions involve manual or mechanical chest physiotherapy with postural drainage, and manual or mechanical cough assistance device. To assist in breathing, Non-invasive ventilation (BiPAP) is frequently used and tracheostomy may be sometimes performed in more severe cases; both methods of ventilation prolong survival to a comparable degree, although tracheostomy prevents speech development.
Nutrition
The more severe the type of SMA, the more likely to have nutrition related health issues. Health issues can include difficulty in feeding, jaw opening, chewing and swallowing. Individuals with such difficulties can be at increase risk of over or undernutrition, failure to thrive and aspiration. Other nutritional issues, especially in individuals that are non-ambulatory (more severe types of SMA), include food not passing through the stomach quickly enough, gastric reflux, constipation, vomiting and bloating. Therein, it could be necessary in SMA type I and people with more severe type II to have a feeding tube or gastrostomy. Additionally, metabolic abnormalities resulting from SMA impair β-oxidation of fatty acids in muscles and can lead to organic acidemia and consequent muscle damage, especially when fasting. It is suggested that people with SMA, especially those with more severe forms of the disease, reduce intake of fat and avoid prolonged fasting (i.e., eat more frequently than healthy people) as well as choosing softer foods to avoid aspiration. During an acute illness, especially in children, nutritional problems may first present or can exacerbate an existing problem (example: aspiration) as well as cause other health issues such as electrolyte and blood sugar disturbances.
Orthopaedics
Skeletal problems associated with weak muscles in SMA include tight joints with limited range of movement, hip dislocations, spinal deformity, osteopenia, an increase risk of fractures and pain. Weak muscles that normally stabilize joints such as the vertebral column lead to development of kyphosis and/or scoliosis and joint contracture. Spine fusion is sometimes performed in people with SMA I/II once they reach the age of 8–10 to relieve the pressure of a deformed spine on the lungs. Furthermore, immobile individuals, posture and position on mobility devices as well as range of motion exercises, and bone strengthening can be important to prevent complications. People with SMA might also benefit greatly from various forms of physiotherapy, occupational therapy and physical therapy.Orthotic devices can be used to support the body and to aid walking. For example, orthotics such as AFOs (ankle foot orthoses) are used to stabilise the foot and to aid gait, TLSOs (thoracic lumbar sacral orthoses) are used to stabilise the torso. Assistive technologies may help in managing movement and daily activity and greatly increase the quality of life.
Other
Although the heart is not a matter of routine concern, a link between SMA and certain heart conditions has been suggested.Children with SMA do not differ from the general population in their behaviour; their cognitive development can be slightly faster, and certain aspects of their intelligence are above the average. Despite their disability, SMA-affected people report high degree of satisfaction from life.Palliative care in SMA has been standardised in the Consensus Statement for Standard of Care in Spinal Muscular Atrophy which has been recommended for standard adoption worldwide.
Prognosis
In the absence of pharmacological treatment, people with SMA tend to deteriorate over time. Recently, survival has increased in severe SMA patients with aggressive and proactive supportive respiratory and nutritional support.If left untreated, the majority of children diagnosed with SMA type 0 and 1 do not reach the age of 4, recurrent respiratory problems being the primary cause of death. With proper care, milder SMA type I cases (which account for approx. 10% of all SMA1 cases) live into adulthood. Long-term survival in SMA type I is not sufficiently evidenced; however, as of 2007 advances in respiratory support seem to have brought down mortality.In untreated SMA type II, the course of the disease is slower to progress and life expectancy is less than the healthy population. Death before the age of 20 is frequent, although many people with SMA live to become parents and grandparents. SMA type III has normal or near-normal life expectancy if standards of care are followed. Type IV, adult-onset SMA usually means only mobility impairment and does not affect life expectancy.
Research directions
Since the underlying genetic cause of SMA was identified in 1995, several therapeutic approaches have been proposed and investigated that primarily focus on increasing the availability of SMN protein in motor neurons. The main research directions have been as follows:
SMN1 gene replacement
Gene therapy in SMA aims at restoring the SMN1 gene function through inserting specially crafted nucleotide sequence (a SMN1 transgene) into the cell nucleus using a viral vector. This approach has been exploited by the first approved gene therapy for SMA, scAAV-9 based treatment onasemnogene abeparvovec.
SMN2 alternative splicing modulation
This approach aims at modifying the alternative splicing of the SMN2 gene to force it to code for higher percentage of full-length SMN protein. Sometimes it is also called gene conversion, because it attempts to convert the SMN2 gene functionally into SMN1 gene. It is the therapeutic mechanism of the approved medications nusinersen and risdiplam.
Branaplam is another SMN2 splicing modulator that has reached the clinical stage of development.Historically, this research direction investigated also other molecules. RG3039, also known as Quinazoline495, was a proprietary quinazoline derivative developed by Repligen and licensed to Pfizer in March 2014 which was discontinued shortly after, having only completed phase I trials. PTK-SMA1 was a proprietary small-molecule splicing modulator of the tetracyclines group developed by Paratek Pharmaceuticals and about to enter clinical development in 2013 which however never happened due to Paratek downsizing at that time. RG7800, developed by Hoffmann-La Roche, was a molecule akin to risdiplam that has undergone phase I testing but was discontinued due to animal toxicity. Early leads also included sodium orthovanadate and aclarubicin.Morpholino-type antisense oligonucleotides, with the same cellular target as nusinersen, remain a subject of research in treating SMA and other single-gene diseases, including at the University College London and at the University of Oxford.
SMN2 gene activation
This approach aims at increasing expression (activity) of the SMN2 gene, thus increasing the amount of full-length SMN protein available.
Oral salbutamol (albuterol), a popular asthma medicine, showed therapeutic potential in SMA both in vitro and in three small-scale clinical trials involving patients with SMA types 2 and 3, besides offering respiratory benefits.A few compounds initially showed promise but failed to demonstrate efficacy in clinical trials. Butyrates (sodium butyrate and sodium phenylbutyrate) held some promise in in vitro studies but a clinical trial in symptomatic people did not confirm their efficacy. Another clinical trial in pre-symptomatic types 1–2 infants was completed in 2015 but no results have been published.
Valproic acid (VPA) was used in SMA on an experimental basis in the 1990s and 2000s because in vitro research suggested its moderate effectiveness. However, it demonstrated no efficacy in achievable concentrations when subjected to a large clinical trial. It has also been proposed that it may be effective in a subset of people with SMA but its action may be suppressed by fatty acid translocase in others. Others argue it may actually aggravate SMA symptoms. It is currently not used due to the risk of severe side effects related to long-term use. A 2019 meta-analysis suggested that VPA may offer benefits, even without improving functional score.
Hydroxycarbamide (hydroxyurea) was shown effective in mouse models and subsequently commercially researched by Novo Nordisk, Denmark, but demonstrated no effect on people with SMA in subsequent clinical trials.Compounds which increased SMN2 activity in vitro but did not make it to the clinical stage include growth hormone, various histone deacetylase inhibitors, benzamide M344, hydroxamic acids (CBHA, SBHA, entinostat, panobinostat, trichostatin A, vorinostat), prolactin as well as natural polyphenol compounds like resveratrol and curcumin. Celecoxib, a p38 pathway activator, is sometimes used off-label by people with SMA based on a single animal study but such use is not backed by clinical-stage research.
SMN stabilisation
SMN stabilisation aims at stabilising the SMNΔ7 protein, the short-lived defective protein coded by the SMN2 gene, so that it is able to sustain neuronal cells.No compounds have been taken forward to the clinical stage. Aminoglycosides showed capability to increase SMN protein availability in two studies. Indoprofen offered some promise in vitro.
Neuroprotection
Neuroprotective drugs aim at enabling the survival of motor neurons even with low levels of SMN protein.
Olesoxime was a proprietary neuroprotective compound developed by the French company Trophos, later acquired by Hoffmann-La Roche, which showed stabilising effect in a phase-II clinical trial involving people with SMA types 2 and 3. Its development was discontinued in 2018 in view of competition from nusinersen and underwhelming data from an open-label extension trial.Of clinically studied compounds which did not show efficacy, thyrotropin-releasing hormone (TRH) held some promise in an open-label uncontrolled clinical trial but did not prove effective in a subsequent double-blind placebo-controlled trial. Riluzole, a drug that offers limited clinical benefit in amyotrophic lateral sclerosis, was proposed to be similarly tested in SMA; however, a 2008–2010 trial in SMA types 2 and 3 was stopped early due to the lack of satisfactory results. Other compounds that displayed some neuroprotective effect in in vitro research but never moved on to in vivo studies include β-lactam antibiotics (e.g., ceftriaxone) and follistatin.
Muscle restoration
This approach aims to counter the effect of SMA by targeting the muscle tissue instead of neurons.
Reldesemtiv (CK-2127107, CK-107) is a skeletal troponin activator developed by Cytokinetics in cooperation with Astellas. The drug aims at increasing muscle reactivity despite lowered neural signalling. The molecule showed some success in phase II clinical trial in adolescent and adults with SMA types 2, 3, and 4.
Apitegromab (SRK-015) is monoclonal antibody that blocks the activation of the skeletal muscle protein myostatin, thereby promoting muscle tissue growth. As of 2021, the molecule showed success as an experimental add-on treatment in paediatric and adult patients treated with nusinersen.
GYM329 (RO7204239), developed by Hoffman-La Roche, works similarly to apitegromab by blocking myostatin activation. As of 2022, it is undergoing clinical development in non-ambulant children with SMA aged 2–10, combined with risdiplam.
Stem cells
Whilst stem cells never form a part of any recognised therapy for SMA, a number of private companies, usually located in countries with lax regulatory oversight, take advantage of media hype and market stem cell injections as a "cure" for a vast range of disorders, including SMA. The medical consensus is that such procedures offer no clinical benefit whilst carrying significant risk, therefore people with SMA are advised against them. In 2013–2014, a small number of SMA1 children in Italy received court-mandated stem cell injections following the Stamina scam, but the treatment was reported having no effect
Registries
People with SMA in the European Union can participate in clinical research by entering their details into registries managed by TREAT-NMD.
See also
Accomable
Motor neuron disease
References
Further reading
External links
Spinal muscular atrophy at Curlie
SMA at NINDS
SMArt Moves. Cure SMA. Retrieved 3 December 2021. |
Vasculitic neuropathy | Vasculitic neuropathy is a peripheral neuropathic disease. In a vasculitic neuropathy there is damage to the vessels that supply blood to the nerves. It can be as part of a systemic problem or can exist as a single-organ issue only affecting the peripheral nervous system (PNS). It is diagnosed with the use of electrophysiological testing, blood tests, nerve biopsy and clinical examination. It is a serious medical condition that can cause prolonged morbidity and disability and generally requires treatment. Treatment depends on the type but it is mostly with corticosteroids or immunomodulating therapies.
Types
There are three main categories of vasculitic neuropathies: primary, secondary and non-systemic.
Primary systemic vasculitic neuropathy
Some patients with systemic vasculitis will have their multi-organ disease spread to the peripheral nervous system; this is primary vasculitic neuropathy. Some examples of systemic vasculitic disease are: IgA vasculitis, Hypocomplementemic urticarial vasculitis, polyarteritis nodosa (PAN) and anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides such as granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis (MPA).
Vasculitic neuropathy secondary to other disease
Some patients with a non-vasculitic systemic disease or another illness such as infection or malignancy can subsequently develop vasculitic neuropathy as a direct consequence of the former illness; this is secondary vasculitic neuropathy. Some examples of such illness which can cause vasculitic neuropathy are:
Connective tissue diseases: rheumatoid arthritis, systemic lupus erythematosus, primary sjögrens, dermatomyositis.
Infectious diseases: hepatitis B, hepatitis C, human immunodeficiency virus (HIV), cytomegalovirus, lyme disease, human T-cell-lymphotrophic virus-I, parvovirus B19.
Malignancy.
Drugs (amphetamines, sympathomimetics, cocaine, etc.)
Vaccinations.
Non-systemic vasculitic neuropathy
Non-systemic vasculitic neuropathy (NSVN) is a diagnosis of elimination. When no systemic illness can be found, yet evidence of a vasculitic neuropathy exists, a diagnosis of non-systemic vasculitic neuropathy is made. It is a single-organ problem. A nerve biopsy is required in order to make the diagnosis of non-systemic vasculitic neuropathy.
There are distinct subtypes of NSVN with evolving categorisation in the literature. Currently accepted subtypes are:
Classical distal-predominant NSVN
Wartenberg migratory sensory neuropathy
Post-surgical inflammatory neuropathy
Diabetic radiculoplexus neuropathy (lumbosacral, thoracic or cervical predominant)
Neuralgic amyotrophy
Non-systemic skin/nerve vasculitis (for example, cutaneous PAN)
Classical distal-predominant NSVN
There is an ongoing debate over this categorisation, particularly its overlap with the condition non-diabetic radiculoplexus neuropathy. This neuropathy involves a clinical picture where the nerve damage is distally predominant as demonstrated in a nerve biopsy.
Warternberg migratory sensory neuropathy
Warternberg migratory sensory neuropathy is typically a multi-focal neuropathy where there is pure sensory deficits. It is characterised by sudden-onset and chronicity as well as having a propensity for relapse. It generally resolves slowly with time.
Postsurgical inflammatory neuropathy
Postsurgical inflammatory neuropathy is typically a multi-focal neuropathy which manifests thirty days after a surgical procedure. It mostly presents with motor and sensory symptoms. It is generally a self-limiting condition that has resolved with and without treatment.
Diagnosis
Diagnosis of a vasculitic neuropathy depends on whether the patient first presents with multiple symptoms pointing at a systemic disorder or else primary neuropathic complaints. In the former case the patient is more likely to be assessed first by a rheumatologist and in the latter a neurologist or neurosurgeon.
Treatments
Treatment of vasculitic neuropathy depends on the type.
== References == |
Lenz microphthalmia syndrome | Lenz microphthalmia syndrome is a very rare inherited disorder characterized by abnormal smallness of one or both eyes (microphthalmos) sometimes with droopy eyelids (blepharoptosis), resulting in visual impairment or blindness. Eye problems may include coloboma, microcornea, and glaucoma. Some affected infants may have complete absence of the eyes (anophthalmia). Most affected infants have developmental delay and intellectual disability, ranging from mild to severe. Other physical abnormalities associated with this disorder can include an unusually small head (microcephaly), and malformations of the teeth, ears, fingers or toes, skeleton, and genitourinary system. The range and severity of findings vary from case to case. Formal diagnosis criteria do not exist.
Lenz microphthalmia syndrome is also known as LMS, Lenz syndrome, Lenz dysplasia, Lenz dysmorphogenetic syndrome, or microphthalmia with multiple associated anomalies (MAA: OMIM 309800). It is named after Widukind Lenz, a German geneticist and dysmorphologist.
Genetics
Lenz microphthalmia syndrome is inherited as an X-linked recessive genetic trait and is fully expressed in males only. Females who carry one copy of the disease gene (heterozygotes) may exhibit some of the symptoms associated with the disorder, such as an abnormally small head (microcephaly), short stature, or malformations of the fingers or toes. Molecular genetic testing of BCOR (MCOPS2 locus), the only gene known to be associated with Lenz microphthalmia syndrome, is available on a clinical basis. One additional locus on the X chromosome (MCOPS1) is known to be associated with LMS.
Diagnosis
Differential diagnosis
A somewhat similar X-linked syndrome of microphthalmia, called oculofaciocardiodental syndrome (OFCD) is associated with mutations in BCOR. OFCD syndrome is inherited in an X-linked dominant pattern with male lethality.
Management
References
Lenz Microphthalmia Syndrome |
Oophoritis | Oophoritis is an inflammation of the ovaries.
It is often seen in combination with salpingitis (inflammation of the fallopian tubes). It may develop in response to infection.
See also
Pelvic inflammatory disease
References
== External links == |
Odontogenic cyst | Odontogenic cyst are a group of jaw cysts that are formed from tissues involved in odontogenesis (tooth development). Odontogenic cysts are closed sacs, and have a distinct membrane derived from rests of odontogenic epithelium. It may contain air, fluids, or semi-solid material. Intra-bony cysts are most common in the jaws, because the mandible and maxilla are the only bones with epithelial components. That odontogenic epithelium is critical in normal tooth development. However, epithelial rests may be the origin for the cyst lining later.
Not all oral cysts are odontogenic cyst. For example, mucous cyst of the oral mucosa and nasolabial duct cyst are not of odontogenic origin.
In addition, there are several conditions with so-called (radiographic) pseudocystic appearance in jaws; ranging from anatomic variants such as Stafne static bone cyst, to the aggressive aneurysmal bone cyst.
Classification
I. Cysts of the jaws
A. Epithelial-lined cysts
1. Developmental origin
(a) Odontogenic
i. Gingival cyst of infants
ii. Odontogenic keratocyst
iii. Dentigerous cyst
iv. Eruption cyst
v. Gingival cyst of adults
vi. Developmental lateral periodontal cyst
vii. Botryoid odontogenic cyst
viii. Glandular odontogenic cyst
ix. Calcifying odontogenic cyst
(b) Non-odontogenic
i. Midpalatal raphé cyst of infants
ii. Nasopalatine duct cyst
iii. Nasolabial cyst
2. Inflammatory origin
i. Radicular cyst, apical and lateral
ii. Residual cyst
iii. Paradental cyst and juvenile paradental cyst
iv. Inflammatory collateral cyst
B. Non-epithelial-lined cysts
1. Solitary bone cyst
2. Aneurysmal bone cyst
II. Cysts associated with the maxillary antrum
1. Mucocele
2. Retention cyst
3. Pseudocyst
4. Postoperative maxillary cyst
III. Cysts of the soft tissues of the mouth, face and neck
1. Dermoid and epidermoid cysts
2. Lymphoepithelial (branchial) cyst
3. Thyroglossal duct cyst
4. Anterior median lingual cyst (intralingual cyst of foregut origin)
5. Oral cysts with gastric or intestinal epithelium (oral alimentary tract cyst)
6. Cystic hygroma
7. Nasopharyngeal cyst
8. Thymic cyst
9. Cysts of the salivary glands: mucous extravasation cyst; mucous retention cyst; ranula; polycystic (dysgenetic) disease of the parotid
10. Parasitic cysts: hydatid cyst; Cysticercus cellulosae; trichinosis
Buccal bifurcation cyst
Calcifying odontogenic cyst
Dentigerous cyst (associated with the crowns of non-erupted teeth)
Glandular odontogenic cyst
Keratocyst (in the jaws, these can appear solitary or associated with the Gorlin-Goltz or Nevoid basal cell carcinoma syndrome.
Paradental cyst
Periapical cyst (The periapical cyst, otherwise known as radicular cyst, is the most common odontogenic cyst.)
Radicular cyst (associated with the roots of non-vital teeth, also known as Periapical cyst)
Residual cyst
Cystic neoplasm
Most cysts in the body are benign (dysfunctional) tumors, the result of plugged ducts or other natural body outlets for secretions. However, sometimes these masses are considered neoplasm:
Keratocyst
Calcifying odontogenic cyst
According to the current (2005) classification of the World Health Organization, both (parakeratizied) odontogenic keratocyst and calcifying odontogenic cyst have neoplastic characteristics, thus renamed as Keratocystic odontogenic tumor and Calcifying odontogenic tumor, respectively.
Cystic ameloblastoma
Long standing dentigerous cyst, odontogenic keratocyst, and residual cyst may have neoplastic potential converting into the locally aggressive ameloblastoma, or the malignant squamous cell carcinoma and mucoepidermoid carcinoma.
Diagnosis
On histopathology, cholesterol clefts indicate mainly a periapical (radicular) cyst or an inflamed dentigerous cyst.
Treatment
Treatment ranges from simple enucleation of the cyst to curettage to resection. For example, small radicular cyst may resolved after successful endodontic ("root-canal") treatment. Because of high recurrence potential and aggressive behaviour, curettage is recommended for keratocyst. However, the conservative enucleation is the treatment of choice for most odontogenic cysts. The removed cyst must be evaluated by pathologist to confirm the diagnosis, and to rule out other neoplastic lesions with similar clinical or radiographic features (e.g., cystic or solid ameloblastoma, central mucoepidermoid carcinoma). There are cysts, e.g. buccal bifurcation cyst with self-resolation nature, in which close observation can be employed unless the cyst is infected and symptomatic.
See also
Cyst
Mucous cyst of the oral mucosa
== References == |
Late congenital syphilitic oculopathy | Late congenital syphilitic oculopathy is a disease of the eye, a manifestation of late congenital syphilis. It can appear as:
Interstitial keratitis – this commonly appears between ages 6 and 12. Symptoms include lacrimation and photophobia. Pathological vascularization of the cornea cause it to turn pink or salmon colored. 90% of cases affect both eyes.
Episcleritis or scleritis – nodules appear in or overlying the sclera (white of eye)
Iritis or iris papules – vascular infiltration of the iris causes rosy color change and yellow/red nodules.
Chorioretinitis, papillitis, retinal vasculitis – retinal changes can resemble retinitis pigmentosa.
Exudative retinal detachmentCongenital syphilis is categorized by the age of the child. Early congenital syphilis occurs in children under 2 years old, and late congenital syphilis in children at or greater than 2 years old. Manifestations of late congenital syphilis are similar to those of secondary syphilis and tertiary syphilis in adults.
References
eMedicine: Ocular Manifestations of Syphilis
== External links == |
Parathyroid hormone | Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.PTH influences bone remodeling, which is an ongoing process in which bone tissue is alternately resorbed and rebuilt over time. PTH is secreted in response to low blood serum calcium (Ca2+) levels. PTH indirectly stimulates osteoclast activity within the bone matrix (osteon), in an effort to release more ionic calcium (Ca2+) into the blood to elevate a low serum calcium level. The bones act as a (metaphorical) "bank of calcium" from which the body can make "withdrawals" as needed to keep the amount of calcium in the blood at appropriate levels despite the ever-present challenges of metabolism, stress, and nutritional variations. PTH is "a key that unlocks the bank vault" to remove the calcium.
PTH is secreted primarily by the chief cells of the parathyroid glands. The gene for PTH is located on chromosome 11. It is a polypeptide containing 84 amino acids, which is a prohormone. It has a molecular mass around 9500 Da. Its action is opposed by the hormone calcitonin.
There are two types of PTH receptors. Parathyroid hormone 1 receptors, activated by the 34 N-terminal amino acids of PTH, are present at high levels on the cells of bone and kidney. Parathyroid hormone 2 receptors are present at high levels on the cells of central nervous system, pancreas, testes, and placenta. The half-life of PTH is about 4 minutes.Disorders that yield too little or too much PTH, such as hypoparathyroidism, hyperparathyroidism, and paraneoplastic syndromes can cause bone disease, hypocalcemia, and hypercalcemia.
Structure
hPTH-(1-84) crystallizes as a slightly bent, long, helical dimer. The extended helical conformation of hPTH-(1-84) is the likely bioactive conformation. The N-terminal fragment 1-34 of parathyroid hormone (PTH) has been crystallized and the structure has been refined to 0.9 Å resolution.
Function
Regulation of serum calcium
Parathyroid hormone regulates serum calcium through its effects on bone, kidney, and the intestine:In bone, PTH enhances the release of calcium from the large reservoir contained in the bones. Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their secretion of osteoprotegerin (OPG). Free OPG competitively binds to RANKL as a decoy receptor, preventing RANKL from interacting with RANK, a receptor for RANKL. The binding of RANKL to RANK (facilitated by the decreased amount of OPG available for binding the excess RANKL) stimulates osteoclast precursors, which are of a monocyte lineage, to fuse. The resulting multinucleated cells are osteoclasts, which ultimately mediate bone resorption. Estrogen also regulates this pathway through its effects on PTH. Estrogen suppresses T cell TNF production by regulating T cell differentiation and activity in the bone marrow, thymus, and peripheral lymphoid organs. In the bone marrow, estrogen downregulates the proliferation of hematopoietic stem cells through an IL-7 dependent mechanism.In the kidney, around 250 mmol of calcium ions are filtered into the glomerular filtrate per day. Most of this (245 mmol/d) is reabsorbed from the tubular fluid, leaving about 5 mmol/d to be excreted in the urine. This reabsorption occurs throughout the tubule (most, 60-70%, of it in the proximal tubule), except in the thin segment of the loop of Henle. Circulating parathyroid hormone only influences the reabsorption that occurs in the distal tubules and the renal collecting ducts (but see Footnote). A more important effect of PTH on the kidney is, however, its inhibition of the reabsorption of phosphate (HPO42−) from the tubular fluid, resulting in a decrease in the plasma phosphate concentration. Phosphate ions form water-insoluble salts with calcium. Thus, a decrease in the phosphate concentration of the blood plasma (for a given total calcium concentration) increases the amount of calcium that is ionized. A third important effect of PTH on the kidney is its stimulation of the conversion of 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D (calcitriol), which is released into the circulation. This latter form of vitamin D is the active hormone which stimulates calcium uptake from the intestine.Via the kidney, PTH enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D. Vitamin D activation occurs in the kidney. PTH up-regulates 25-hydroxyvitamin D3 1-alpha-hydroxylase, the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to its active form (1,25-dihydroxy vitamin D). This activated form of vitamin D increases the absorption of calcium (as Ca2+ ions) by the intestine via calbindin.
PTH was one of the first hormones to be shown to use the G-protein adenylyl cyclase second messenger system.
Regulation of serum phosphate
PTH reduces the reabsorption of phosphate from the proximal tubule of the kidney, which means more phosphate is excreted through the urine.
However, PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, absorption of both calcium and phosphate is mediated by an increase in activated vitamin D. The absorption of phosphate is not as dependent on vitamin D as is that of calcium. The end result of PTH release is a small net drop in the serum concentration of phosphate.
Vitamin D synthesis
PTH upregulates the activity of 1-α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol, the major circulating form of inactive vitamin D, into 1,25-dihydroxycholecalciferol, the active form of vitamin D, in the kidney.
Interactive pathway map
Regulation of PTH secretion
Secretion of parathyroid hormone is determined chiefly by serum ionized calcium concentration through negative feedback. Parathyroid cells express calcium-sensing receptors on the cell surface. PTH is secreted when [Ca2+] is decreased (calcitonin is secreted when serum calcium levels are elevated). The G-protein-coupled calcium receptors bind extracellular calcium and may be found on the surface on a wide variety of cells distributed in the brain, heart, skin, stomach, C cells, and other tissues. In the parathyroid gland, high concentrations of extracellular calcium result in activation of the Gq G-protein coupled cascade through the action of phospholipase C. This hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to liberate intracellular messengers IP3 and diacylglycerol (DAG). Ultimately, these two messengers result in a release of calcium from intracellular stores into the cytoplasmic space. Hence a high extracellular calcium concentration leads to an increase in the cytoplasmic calcium concentration. In contrast to the mechanism that most secretory cells use, this high cytoplasmic calcium concentration inhibits the fusion of vesicles containing granules of preformed PTH with the membrane of the parathyroid cell, and thus inhibits release of PTH.
In the parathyroids, magnesium serves this role in stimulus-secretion coupling. A mild decrease in serum magnesium levels stimulates the reabsorptive activity PTH has on the kidneys. Severe hypomagnesemia inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible.
Stimulators
Decreased serum [Ca2+].
Mild decreases in serum [Mg2+].
An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH).
Adrenaline
Histamine
Inhibitors
Increased serum [Ca2+].
Severe decreases in serum [Mg2+], which also produces symptoms of hypoparathyroidism (such as hypocalcemia).
Calcitriol
Increase in serum phosphate. Fibroblast growth factor-23 (FGF23) is produced in osteoblasts (from bone) in response to increases in serum phosphate (Pi). It binds to the fibroblast growth factor receptor of the parathyroid and suppresses PTH release. This may seem contradictory because PTH actually helps rid the blood of phosphates but it is also causes release of phosphate into the blood from bone resorption. FGF23 inhibits PTH and then takes its place helping inhibit re-absorption of phosphate in the kidney without the phosphate releasing effect on bones.
Disorders
Hyperparathyroidism, the presence of excessive amounts of parathyroid hormone in the blood, occurs in two very distinct sets of circumstances. Primary hyperparathyroidism is due to autonomous, abnormal hypersecretion of PTH from the parathyroid gland, while secondary hyperparathyroidism is an appropriately high PTH level seen as a physiological response to hypocalcemia. A low level of PTH in the blood is known as hypoparathyroidism and is most commonly due to damage to or removal of parathyroid glands during thyroid surgery.
There are a number of rare but well-described genetic conditions affecting parathyroid hormone metabolism, including pseudohypoparathyroidism, familial hypocalciuric hypercalcemia, and autosomal dominant hypercalciuric hypocalcemia. Of note, PTH is unchanged in pseudopseudohypoparathyroidism. In osteoporotic women, administration of an exogenous parathyroid hormone analogue (teriparatide, by daily injection) superimposed on estrogen therapy produced increases in bone mass and reduced vertebral and nonvertebral fractures by 45 to 65%.
Measurement
PTH can be measured in the blood in several different forms: intact PTH; N-terminal PTH; mid-molecule PTH, and C-terminal PTH, and different tests are used in different clinical situations. The level may be stated in pg/dL or pmol/L (sometimes abbreviated mmol/L); multiply by 0.1060 to convert from pg/dL to pmol/L.A US source states the average PTH level to be 8–51 pg/mL. In the UK the biological reference range is considered to be 1.6-6.9 pmol/L. Normal total plasma calcium level ranges from 8.5 to 10.2 mg/dL (2.12 mmol/L to 2.55 mmol/L).
Interpretive guide
The intact PTH and calcium normal ranges are different for age; calcium is also different for sex.
Model organisms
Model organisms have been used in the study of PTH function. A conditional knockout mouse line called Pthtm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping
See also
Disorders of calcium metabolism
Parathyroid hormone family
Parathyroid hormone-related protein
Preotact
Footnote
References
Further reading
External links
Media related to Parathyroid hormone at Wikimedia Commons
Parathyroid hormone: analyte monograph - the Association for Clinical Biochemistry and Laboratory Medicine
Overview of all the structural information available in the PDB for UniProt: P01270 (Parathyroid hormone) at the PDBe-KB. |
Perinephritis | Perinephritis is an infection of the surroundings of the kidney either right or left. It can be the result of extravasated infiltration of the bacteria out of the renal pelvis (pyelonephritis) or a result of another kidney infection. The consequences include the infection of the neighbouring organs (for example transverse colon) or retroperitoneum, and/or hypertension. Perirenal abscess also may occur.
== References == |
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