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Keratoderma climactericum | Keratoderma climactericum is a skin condition characterized by hyperkeratosis of the palms and soles beginning at about the time of menopause.: 213
Causes
Keratoderma climactericum is either inherited through an abnormal gene, or it is acquired through a change in the health or environment of the individual.
See also
Keratoderma
List of cutaneous conditions
== References == |
Fusarium | Fusarium /fjuˈzɛəriəm/ is a large genus of filamentous fungi, part of a group often referred to as hyphomycetes, widely distributed in soil and associated with plants. Most species are harmless saprobes, and are relatively abundant members of the soil microbial community. Some species produce mycotoxins in cereal crops that can affect human and animal health if they enter the food chain. The main toxins produced by these Fusarium species are fumonisins and trichothecenes. Despite most species apparently being harmless (some existing on the skin as commensal members of the skin flora), some Fusarium species and subspecific groups are among the most important fungal pathogens of plants and animals.
The name of Fusarium comes from Latin fusus, meaning a spindle.
Taxonomy
The taxonomy of the genus is complex. A number of different schemes have been used, and up to 1,000 species have been identified at times, with approaches varying between wide and narrow concepts of speciation (lumpers and splitters).Phylogenetic studies indicate seven major clades within the genus.There is a proposed concept – widely subscribed by specialists – that would include essentially the genus as it now stands, including especially all agriculturally significant Fusaria. There is a counterproposal (unrelated to Watanabe 2011) that goes far in the other direction, with seven entirely new genera.
Subdivision
Various schemes have subdivided the genus into subgenera and sections. There is a poor correlation between sections and phylogenetic clades.Sections previously described include:
Species
Selected species include:
Etymology
The name of Fusarium comes from Latin fusus, meaning a spindle.
Pathogen
The genus includes a number of economically important plant pathogenic species.
Fusarium graminearum commonly infects barley if there is rain late in the season. It is of economic impact to the malting and brewing industries, as well as feed barley. Fusarium contamination in barley can result in head blight, and in extreme contaminations, the barley can appear pink. The genome of this wheat and maize pathogen has been sequenced. F. graminearum can also cause root rot and seedling blight. The total losses in the US of barley and wheat crops between 1991 and 1996 have been estimated at $3 billion.Fusarium oxysporum f.sp. cubense is a fungal plant pathogen that causes Panama disease of banana (Musa spp.), also known as fusarium wilt of banana. Panama disease affects a wide range of banana cultivars, which are propagated asexually from offshoots and therefore have very little genetic diversity. Panama disease is one of the most destructive plant diseases of modern times, and caused the commercial disappearance of the once dominant Gros Michel cultivar. A more recent strain also affects the Cavendish cultivars which commercially replaced Gros Michel. It is considered inevitable that this susceptibility will spread globally and commercially wipe out the Cavendish cultivar, for which there are currently no acceptable replacements.
Fusarium oxysporum f. sp. narcissi causes rotting of the bulbs (basal rot) and yellowing of the leaves of daffodils (Narcissi).
In 2021 it was discovered that Fusarium xyrophilum was able to hijack a South American species of yellow-eyed Xyris grass, creating fake flowers, fooling bees and other pollinating insects into visiting them, taking fungal spores to other plants.
In humans
Some species may cause a range of opportunistic infections in humans. In humans with normal immune systems, fusarial infections may occur in the nails (onychomycosis) and in the cornea (keratomycosis or mycotic keratitis). In humans whose immune systems are weakened in a particular way, (neutropenia, i.e., very low neutrophils count), aggressive fusarial infections penetrating the entire body and bloodstream (disseminated infections) may be caused by members of the Fusarium solani complex, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum and, rarely, other fusarial species.
Research
The isolation medium for Fusaria is usually peptone PCNB agar (peptone pentachloronitrobenzene agar, PPA).: 7 For F. oxysporum specifically, Komadas medium is most common.: 7 Differential identification is difficult in some strains. Vegetative compatibility group analysis is best for some, is one usable method for others, and requires such a large number of assays that it is too complicated for yet others.
Use as human food
Fusarium venenatum is produced industrially for use as a human food by Marlow Foods, Ltd., and is marketed under the name Quorn in Europe and North America.
Also, Fusarium str. yellowstonensis is under investigation for similar foods.Some consumers of fusarium products have shown food allergies similar in nature to peanut and other food allergies. People with known sensitivities to molds should exercise caution when consuming such products.
Biological warfare
Mass casualties occurred in the Soviet Union in the 1930s and 1940s when Fusarium-contaminated wheat flour was baked into bread, causing alimentary toxic aleukia with a 60% mortality rate. Symptoms began with abdominal pain, diarrhea, vomiting, and prostration, and within days, fever, chills, myalgias and bone marrow depression with granulocytopenia and secondary sepsis occurred. Further symptoms included pharyngeal or laryngeal ulceration and diffuse bleeding into the skin (petechiae and ecchymoses), melena, bloody diarrhea, hematuria, hematemesis, epistaxis, vaginal bleeding, pancytopenia and gastrointestinal ulceration. Fusarium sporotrichoides contamination was found in affected grain in 1932, spurring research for medical purposes and for use in biological warfare. The active ingredient was found to be trichothecene T-2 mycotoxin, and it was produced in quantity and weaponized prior to the passage of the Biological Weapons Convention in 1972. The Soviets were accused of using the agent, dubbed "yellow rain", to cause 6,300 deaths in Laos, Kampuchea, and Afghanistan between 1975 and 1981. The "biological warfare agent" was later purported to be merely bee feces, but the issue remains disputed.
Pest
Fusarium has posed a threat to the ancient cave paintings in Lascaux since 1955, when the caves were first opened to visitors. The caves subsequently closed and the threat subsided, but the installation of an air conditioning system in 2000 caused another outbreak of the fungus which is yet to be resolved.
Microbiota
Fusarium may be part of microbiota including digestive as well as oral/dental, there have been rare cases of Fusariosis presenting as a necrotic ulceration of the gingiva, extending to the alveolar bone has been reported in a granulocytopenic patient.
References
Bibliography
Nelson PE, Dignani MC, Anaissie EJ (October 1994). "Taxonomy, biology, and clinical aspects of Fusarium species". Clinical Microbiology Reviews. 7 (4): 479–504. doi:10.1128/cmr.7.4.479. PMC 358338. PMID 7834602.
Moretti A (2009). "Taxonomy of Fusarium genus: A continuous fight between lumpers and splitters". Zbornik Matice Srpske Za Prirodne Nauke (117): 7–13. doi:10.2298/ZMSPN0917007M.
Watanabe M, Yonezawa T, Lee K, Kumagai S, Sugita-Konishi Y, Goto K, Hara-Kudo Y (November 2011). "Molecular phylogeny of the higher and lower taxonomy of the Fusarium genus and differences in the evolutionary histories of multiple genes". BMC Evolutionary Biology. 11 (1): 322. doi:10.1186/1471-2148-11-322. PMC 3270093. PMID 22047111.
Summerell BA, Laurence MH, Liew EC, Leslie JF (14 September 2010). "Biogeography and phylogeography of Fusarium: a review". Fungal Diversity. 44 (1): 3–13. doi:10.1007/s13225-010-0060-2. S2CID 37051295.
External links
Fusarium and Verticillium Wilts of Tomato, Potato, Pepper, and Eggplant
Fusarium Root Rot in Container Tree Nurseries
Fusarium Blight on Turfgrass
Fusarium Keratitis
Evolution of Fusarium taxonomy. FAO 2014
Fusarium Comparative Database
Asan A (2011). "Checklist of Fusarium Species Reported from Turkey" (PDF). Mycotaxon. 116: 479.
Simple explanation of Fusarium. FAO 2014 |
Median palatal cyst | The median palatal cyst is a rare cyst that may occur anywhere along the median palatal raphe. It may produce swelling because of infection and is treated by excision or surgical removal.
Some investigators now believe that this cyst represents a more posterior presentation of a nasopalatine duct cyst, rather than a separate cystic degeneration of epithelial rests at the line of fusion of the palatine shelves.
References
Sanjay Saraf (1 December 2008). Textbook of Oral Pathology. Jaypee Brothers Publishers. p. 66. ISBN 978-81-8061-655-6. |
Immature personality disorder | Immature Personality Disorder (IPD) is an ICD-10 diagnosis characterized by lack of emotional development, low tolerance of stress and anxiety, inability to accept personal responsibility, and reliance on age-inappropriate defense mechanisms. The disorder has been "gaining prominence" in the 21st century. It is listed under "F60.8 Other specific personality disorders". A study in Denmark found that together, these 6 "Other" types constituted 2.4% of all personality disorder diagnoses.While borderline personality disorder is the most common personality disorder among those who commit non-suicidal self-harm, the overall rate of deliberate self-harm is highest among those with immature personality disorder.It has been noted for displaying "an absence of mental disability", and demonstrating "ineffectual responses to social, psychological and physical demands."
Mechanics
IPD involves a weakness of the ego, which limits the ability to restrain impulses or properly model anxiety. They fail to integrate the aggressive and libidinal factors at play in other people, and thus are not able to parse their own experiences.It can be caused by a neurobiological immaturity of brain functioning, or through a childhood trauma, or other means.
In law and custom
In the 1980s, it was noted that immature personality disorder was one of the most common illnesses invoked by the Roman Catholic Church in order to facilitate annulment of undesired marriages.In 1978, David Augustine Walton was tried in Barbados for killing two passers by who had offered his mother and girlfriend a ride following an argument, and pleaded diminished capacity resulting from his immature personality disorder; he was nevertheless convicted of murder.In 1989, a former employee of the Wisconsin Department of Transportation had his claim of discrimination dismissed, after alleging that his employment had been terminated due to his Immature Personality Disorder alongside a sexual fetish in which he placed chocolate bars under the posteriors of women whose driving capabilities he was testing.A 1994 Australian case regarding unemployment benefits noted that while "mere personal distaste for certain work is not relevant, but a condition (such as immature personality disorder) may foreclose otherwise suitable prospects".In 2017, an individual whose sole diagnosis was Immature Personality Disorder was allowed to die through Belgian euthanasia laws that require a medical diagnosis of a life-long condition that could impair well-being.
== References == |
Dens evaginatus | Dens evaginatus is a rare odontogenic developmental anomaly that is found in teeth where the outer surface appears to form an extra bump or cusp.
Premolars are more likely to be affected than any other tooth. It could occur unilaterally or bilaterally. Dens evaginatus (DE) typically occurs bilaterally and symmetrically. This may be seen more frequently in Asians (including Chinese, Malay, Thai, Japanese, Filipino and Indian populations).The prevalence of DE ranges from 0.06% to 7.7% depending on the race. It is more common in men than in women, more frequent in the mandibular teeth than the maxillary teeth. Patients with Ellis-van Creveld syndrome, incontinentia pigmenti achromians, Mohr syndrome, Rubinstein-Taybi syndrome and Sturge Weber syndrome are at a higher risk of having DE.
Signs and symptoms
It is important to diagnose DE early and provide appropriate treatment to help prevent periodontal disease, caries, pulpal complications and malocclusion. It occurs on the cingulum/occlusal surface of the teeth. The extra cusp can cause occlusal interference, displace of the affected tooth and/or opposing teeth, irritates the tongue when speaking and eating and decay the developmental grooves. Temporomandibular joint pain could be experienced secondarily due to occlusal trauma caused by the tubercle.This cusp could be worn away or fractured easily. In 70% of the cases, the fine pulpal extension were exposed which can lead to infection, pulpal necrosis and periapical pathosis.
Associated anomalies
Additional tubercules
Aesthetic and/or occlusion problems
Agenesis
Bifid cingula
Exaggerated cusp of Carabelli
Gemination
Impaction
Labial drifting
Labial groove
Mesiodens
Megadont
Odontoma
Peg-shaped lateral incisor
Prominent marginal ridge
Shallow groove in the lateral incisor
Shovel-shaped incisor
Supernumerary
Cause
The cause of DE is still unclear. There is literature indicating that DE is an isolated anomaly. During the bell stage of tooth formation, DE may occur as a result of an unusual growth and folding of the inner enamel epithelium and ectomesenchymal cells of dental papilla into the stellate reticulum of the enamel organ.
Diagnosis
Diagnosis of DE can be difficult when there is no signs and symptoms of necrotic or infected pulp. It is a challenging task to differentiate between a true periapical lesion and a normal periapical radiolucency of a dental follicle of an immature apex.
Pulp tests (test results of immature teeth can be misleading, as they are known to give unreliable results)
Check and see if there is an elevated, flat wear facet on the occlusal surface of the tooth
Test cavity which has an absence of pain sensation and has an empty pulp chamber/ canal.
Radiographs (usually periapical) - a V-shaped radiopaque structure could be seen superimposing on top of the affected crown. It could detect DE before tooth eruption. However, DE presentation on the radiograph can be quite similar to a mesiodens or a compound odontoma.
Classification
The anterior DE tubercles have an average width of 3.5mm and length of 6.0mm, while posterior tubercles have an average 2.0mm in width and length of up to 3.5mm. If the cusp of Carabelli is present, the tooth associated are often larger mesiodistally and it is not uncommon that a DE involved tooth has an abnormal root pattern.There are 4 different ways to classify/ categorize DE involved teeth.
Schulge (1987) classification, teeth falls into 5 categories according to the location of the tubercles
Tubercle on the inclined plane of the lingual cusp
Cone-like enlargement of the buccal cusp
Tubercle on the inclined plane of the buccal cusp
Tubercle arising from the occlusal surface obliterating the central groove
Laus classification, divide teeth into groups according to their anatomical shapeSmooth
Grooved
Terraced
Ridged
Oehlers classification, teeth categorized depending on the pulp contents within the tubercle (histological appearance of the pulps were examined)Wide pulp horns (34%)
Narrow pulp horns (22%)
Constricted pulp horns (14%)
Isolated pulp horn remnants (20%)
No pulp horn (10%)
Hattab et al. classificationAnterior teeth
Type 1 - Talon, a well defined additional cusp that projects palatally and extends at least half the distance from the cementoenamel junction (CEJ) to the incisal edge
Type 2 - Semitalon, an additional cusp that extends less than half the distance from the CEJ to the incisal edge
Type 3 - Trace talon, prominent cingula
Posterior teeth
Occlusal DE
Buccal DE
Palatal DE/ Lingual DE
Management
If the tooth involved is asymptomatic or small, no treatment is needed and a preventative approach should be taken.
Preventative measures include:
Oral hygiene instruction
Scaling and polishing
Application of topical fluoride on reduced cusp
Application of fissure sealant
Frequent dental check-up, pay extra attention to fissures
Perform direct or indirect pulp capping in cases with pulpal extension, to try increase the rate of reparative dentin formation (but may result in obliteration of the canal)
Seal exposed dentin with microhybrid acid-etched flowable light-cured resin
Perform pulpotomy with MTA using a modified Cvek techniqueFor teeth with normal pulp and mature apex, reduce the opposing occluding tooth. Reinforce the tubercle by applying flowable composite. Occlusion, restoration, pulp and periapex assessment should be done yearly. When there is adequate pulp recession, tubercle can be removed and tooth can be restored.For teeth with normal pulp and immature apex, reduce the opposing occluding tooth. Apply flowable composite to the tubercle. Occlusion, restoration, pulp and periapex assessment should be done every 3–4 months until the apex matures. When there are signs of adequate pulp recession, tubercle can be removed and tooth can be restored.For teeth with inflamed pulp and mature apex, conventional root canal treatment could be carried out and restored accordingly.For teeth with inflamed pulp and immature apex, shallow MTA pulpotomy could be performed and then restore with glass ionomer and composite.For teeth with necrotic pulp and mature apex, conventional root canal therapy could be done and restored.For teeth with necrotic pulp and immature apex, MTA root-end barrier could be carried out. Glass ionomer layer and composite could be used to restore the tooth.If there is occlusal interference, the opposing projection should be reduced. Make sure that the tubercle does not contact other teeth in all excursive movement. This is usually done over a few appointments, 6 to 8 weeks apart to allow the formation of reparative dentin to protect the pulp. Fluoride varnish should be applied onto the ground surface. Recall the patient for follow-up after 3, 6 and 12 months.In some cases, extraction could be considered (e.g. for orthodontic purposes, failed apexification)
References
== External links == |
Intersection syndrome | Intersection syndrome is a painful condition that affects the lateral side of the forearm when inflammation occurs at the intersection of the muscle bellies of the abductor pollicis longus and extensor pollicis brevis cross over the extensor carpi radialis longus and the extensor carpi radialis brevis. These 1st and 2nd dorsal muscle compartments intersect at this location, hence the name. The mechanism of injury is usually repetitive resisted extension, as with rowing, weight lifting, or pulling.Intersection syndrome is often confused with another condition called DeQuervains syndrome, which is an irritation of the thumb-sided set of tendons at the wrist, called the first dorsal compartment.
References
== External links == |
Globozoospermia | Globozoospermia is a rare and severe form of monomorphic teratozoospermia. This means that the spermatozoa show the same abnormality, and over 85% of spermatozoa in sperm have this abnormality. Globozoospermia is responsible for less than 0.1% of male infertility. It is characterised by round-headed spermatozoa without acrosomes, an abnormal nuclear membrane and midpiece defects. Affected males therefore suffer from either reduced fertility or infertility. Studies suggest that globozoospermia can be either total (100% round-headed spermatozoa without acrosomes) or partial (20-60% round acrosomeless spermatozoa with normal sperm also identified in the sperm count), however it is unclear whether these two forms are variations on the same syndrome, or actually different syndromes.Infertility in this condition results from the sperm heads missing their acrosome. These sperm, therefore, have a characteristic round or spherically shaped head. Given the absence of the acrosome, these sperm are unable to penetrate the oocyte and are unable to achieve fertilization through conventional means; however, these sperm are able to fertilize the egg through in vitro fertilization with intracytoplasmic sperm injection, which is the treatment of choice for these patients.Studies have suggested mutations or deletions in three genes are responsible for this condition: SPATA16, PICK1 and DPY19L2. ICSI (intracytoplasmic sperm injection) has previously been used to assist reproduction in globozoospermic patients, however it has not been particularly effective in all patients, due to low fertilisation rates.
Types of globozoospermia
There are two types of globozoospermia:
Type 1 globozoospermia exhibits a complete lack of acrosome and acrosomal enzymes and spherical arrangement of the chromatin. This makes the sperm completely unable to penetrate the zona pellucida.
The sperm in Type 2 globozoospermia has some acrosomal covering surrounded by large droplets of cytoplasmic material, suggesting secondary degenerative changes. There is also a conical nucleus. It is thought that infertility in this type of globozoospermia is due to incorrect chromatin packaging which prevents proper fertilization.
Symptoms
Aside from the effect on fertility globozoospermia is symptomless. People with globozoospermia have normal physical and mental development, normal clinical features and normal hormonal profile.
Genetics
Table 1: Gene mutations that have been identified in globozoospermia and the impact these mutations have on sperm function and successful fertilization.
Diagnosis
The presence of round headed sperm in a semen analysis sample confirms the diagnosis of globozoospermia. The lack of acrosome can be ascertained by either morphology staining or immunofluorescence.
Treatment
Until 1995, the only options for people with globozoospermia who wished to conceive were adoption or sperm donation. With the advancement of assisted reproductive techniques (ART) it is now possible for those with globozoospermia to conceive using their own sperm. The main technique used is intracytoplasmic sperm injection (ICSI) where fertilisation is achieved by a single sperm being injected into the egg. Some studies have shown it is possible for a viable embryo to be created with this technique alone, however others have found it necessary to also use calcium ionophore treatment for fertilisation to be successful. Calcium ionophore treatment is used to artificially activate the oocyte. This treatment may be necessary as globozoospermic sperm can be less likely to activate the oocyte, an important stage in fertilisation.The treatment options currently available focus on overcoming the prognosis of infertility which is associated with globozoospermia. So far there are no treatment options to prevent or cure globozoospermia.
Research
Research into globozoospermia is aimed at improving understanding of its cause and developing treatment options.
Genetics
The observation has been made many times that globozoospermia arises in siblings which points towards an underlying genetic cause. Recent progress has been made into determining what genes could be implicated in this pathology, with the previously mentioned genes being found to play a role. There are more genes which have been shown to be mutated in globozoospermia in mice, but these are yet to be connected to the human disease process. Examples of these include Gopc, Hrb and Csnka2. There are thousands of genes which guide the process of spermatogenesis, and knowing how they’re involved in globozoospermia is an important current area of research.
ICSI
The development of intracytoplasmic sperm injection made conception a possibility for patients with a variety of male infertility conditions, including globozoospermia. However, fertility rates with this approach are still low, and research is ongoing into how this can be improved.It has been found that treating globozoospermia with ICSI along with oocyte activation by calcium ionophore (an ion carrier used to increase intracellular calcium is more likely to result in conception than ICSI alone. Another promising treatment area also looks at causing oocyte activation in conjunction with ICSI, this time using spermatic binding-proteins, phospholipase C zeta (PLCζ) and postacrosomal sheath WW domain binding protein (PAWP).
== References == |
Alkalosis | Alkalosis is the result of a process reducing hydrogen ion concentration of arterial blood plasma (alkalemia). In contrast to acidemia (serum pH 7.35 or lower), alkalemia occurs when the serum pH is higher than normal (7.45 or higher). Alkalosis is usually divided into the categories of respiratory alkalosis and metabolic alkalosis or a combined respiratory/metabolic alkalosis.
Signs and symptoms
Metabolic alkalosis is usually accompanied by low blood potassium concentration, causing, e.g., muscular weakness, muscle pain, and muscle cramps (from disturbed function of the skeletal muscles), and muscle spasms (from disturbed function of smooth muscles).
It may also cause low blood calcium concentration. As the blood pH increases, blood transport proteins, such as albumin, become more ionized into anions. This causes the free calcium present in blood to bind more strongly with albumin. If severe, it may cause tetany.
Causes
Respiratory alkalosis is caused by hyperventilation, resulting in a loss of carbon dioxide. Compensatory mechanisms for this include release of hydrogen ion from tissue buffers and excretion of bicarbonate in the kidneys, both of which lower blood pH. Hyperventilation-induced alkalosis can be seen in several deadly central nervous system diseases such as strokes or Rett syndrome.Metabolic alkalosis can be caused by repeated vomiting, resulting in a loss of hydrochloric acid in the stomach contents. Severe dehydration, and the consumption of alkali, are other causes. It can also be caused by administration of diuretics and endocrine disorders such as Cushings syndrome. Compensatory mechanism for metabolic alkalosis involve slowed breathing by the lungs to increase serum carbon dioxide, a condition leaning toward respiratory acidosis. As respiratory acidosis often accompanies the compensation for metabolic alkalosis, and vice versa, a delicate balance is created between these two conditions.
See also
References
External links
IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "alkalosis". doi:10.1351/goldbook.A00221 |
Phakomatosis | Phakomatoses, also known neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes. The majority of phakomatoses are single-gene disorders that may be inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Presentations may vary dramatically between patients with the same particular syndrome due to mosaicism, variable expressivity, and penetrance.Many phakomatoses are caused by mutations which alter functioning of the RAS–mitogen-activated protein kinase (MAPK) pathway that regulates cellular growth, differentiation, proliferation and death. This results in a tendency for individuals with these mutations to develop various types of benign or malignant tumors depending on the particular mutation. The presence of these tumors may result in functional and/or cosmetic problems depending on their type and location.
History
The term phakomatosis originated in 1923, when the Dutch ophthalmologist van der Hoeve used the term phakoma to refer to a "mother spot" or birthmark, a physical characteristic common to patients with tuberous sclerosis and neurofibromatosis that he examined. The term phakomatoses was derived from phakos, the Greek term for birthmark. He originally used the phrase to describe two diseases: neurofibromatosis and tuberous sclerosis. This term later became imprecise when van der Hoeve also used it to include those with Sturge-Weber syndrome as they do not have similar lesions on the skin. In addition, the term phakomatosis makes no reference to the central nervous system involvement. The term neurocutaneous syndrome was subsequently defined by the Russian-American neurologist Paul Ivan Yakovlev and psychiatrist Riley H. Guthrie and it is currently more commonly used.The first clinical description was made in “Monstrorum Historia” by an Italian physician and naturalist named Ulisse Aldrovandi who described a patient with probable neurofibromatosis type I in 1592. He described a short man with a large tumor which was likely a plexiform neurofibroma. However, there are artistic or descriptive representations which have been speculated to depict individuals with phakomatoses as far back as the Hellenistic period and ancient Egypt.Over time, the number of neurocutaneous syndromes have increased and there are several dozen that have been characterized.
Types
There are a large number of neurocutaneous syndromes that exceed the scope of this article. Therefore, characteristics of a few of the more common types are summarized.
Neurofibromatosis Type I (von Recklinghausen disease)
Neurofibromatosis type 1 is the most common phakomatosis and it affects approximately 1 in 2500-3000 live births. It is a genetic disorder due to a germline mutation in the NF1 gene. This gene encodes a protein called neurofibromin that is involved in controlling cellular growth. Malfunction of the gene results in multisystem manifestations involving the skin, central nervous system, peripheral nervous system, eyes and musculoskeletal system. The condition is inherited in an autosomal dominant manner. However, approximately one-half of patients with this condition have no family history and the mutation occurs spontaneously. In most instances, neurofibromatosis type 1 can be diagnosed clinically according to consensus criteria and genetic testing is only used in atypical presentations or for family planning decisions.Café au lait spots are one of the most characteristic features of neurofibromatosis type 1. They are hyperpigmented lesions of the skin that increase in number and size during the first years of life. They are present in almost all patients but do not have malignant potential. Freckling in the axillary and inguinal regions are another common presenting feature seen in as many as 90% of patients during childhood. Lisch nodules (benign hamartomas of the iris) are seen in almost all patients but they do not cause any visual or ocular impairment.
Neurofibromas are benign nerve sheath tumors that occur in peripheral nerves. These typically develop during the teenage years. Neurofibromas do not become malignant but can cause cosmetic concerns as well as local pruritus. When present in the spine they can affect nerve roots and result in both motor and sensory defects. Surgery may be required in some cases. On the contrary, plexiform neurofibromas arise from multiple nerve fascicles and malignant transformation occurs in approximately 10% of cases. They may result in significant morbidity as they may cause organ compression, vascular occlusions, bone destruction, pain and cosmetic issues. Plexiform neurofibromas are seen in 30-50% of patients.Optic pathway gliomas are seen in 15-20% of patients with neurofibromatosis type 1. They most often arise during childhood. They often do not cause additional morbidity but may in up to one-half of patients. Neurocognitive impairment, attention-deficit hyperactivity disorder, autism spectrum disorder and behavioral disorders are also commonly seen in patients with neurofibromatosis type 1. Epilepsy is seen in 4-7% of patients.Musculoskeletal system manifestations can develop in patients with neurofibromatosis type 1. Common findings include sphenoid wing dysplasia, osteopenia, osteoporosis, anterior chest wall deformities as well as scoliosis. Patients are at a much greater risk for fractures than the general population.Vascular abnormalities are also frequently encountered in patients with neurofibromatosis type 1. These may include renal artery stenosis, pulmonary artery stenosis, cerebral artery stenosis and aneurysms. Complications may include myocardial infarction and stroke.
Relative to the general population the risk for certain types of cancer is increased significantly. For instance, the risk for brain tumors and breast cancer is increased by 5 times.
Neurofibromatosis Type II
Neurofibromatosis type 2 is an autosomal dominant condition that affects approximately 1 in 35,000-40,000 people. It is caused by mutations in the NF2 gene on chromosome 22 which has a high penetrance though most patients do not present with symptoms until adulthood. Approximately half of patients have de novo mutations and as many as 59.7% are mosaic. Patients who present in childhood tend to have a more severe phenotype.Bilateral vestibular schwannomas are the most characteristic finding and in the vast majority of cases are benign. However, they are responsible for significant morbidity and are responsible for the most common presenting symptom of hearing loss in adults. They can also less commonly present with dizziness or balance impairment. It is estimated that schwannomas occur in over 90% of patients.Meningiomas are the second most common tumor in NF2. Approximately half of patients have an intracranial meningioma and extramedullary spinal meningiomas occur in one-fifth of patients. Relative to the general population, meningiomas in NF2 tend to occur at a younger age, are more likely to be multiple and are associated with increased mortality.Spinal cord ependymomas occur in 20-50% of patients but they are asymptomatic in the majority of cases. In cases that they are symptomatic the specific presentation will depend upon where they are located. Potential symptoms include back pain, weakness and sensory changes.
Peripheral neuropathy eventually occurs in most patients with NF2. In some cases, a mononeuropathy affecting the facial nerve can occur as the first presenting symptom of NF2. Other potential manifestations include focal amyotrophy, mononeuropathy multiplex or a severe generalized polyneuropathy in 3-5% of patients.Ophthalmologic manifestations are also common with 60-80% of patients developing cataracts. Optic nerve meningiomas and retinal hamartomas can result in vision loss.
Approximately, 70% of patients will have cutaneous manifestations but only 10% have more than 10 lesions. The majority of skin lesions are schwannomas but neurofibromas can also occur.
Tuberous sclerosis (Bourneville syndrome)
Tuberous sclerosis complex (TSC) is a multisystemic disorder due to autosomal dominant mutations in either TSC1 or TSC2 which results in the impaired inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway. This leads to impaired regulation of cellular proliferation, survival, homeostasis, migration and other critical functions. The most typically affected organs include the brain, skin, kidney, heart and lung. The incidence of TSC is approximately 1 in 6,000 live births. Similar to other neurocutaneous disorders there is variable penetrance and expressivity. TSC1 mutations tend to have a less severe phenotype and are more likely to be familial. A major development in the treatment of this condition occurred in 2010s when the FDA approved mTOR inhibitors for the treatment of several manifestations of TSC.
Epilepsy is among the most common manifestations of TSC and it occurs 80-90% of patients. It usually presents during the first few years of life and is medically refractory in two-thirds of patients. Approximately, one-third of patients have infantile spasms. There are several types of brain lesions that can be found in TSC including subependymal nodules (SENs), cortical tubers and subependymal giant cell astrocytomas (SEGAs). SENs and cortical tubers occur in approximately 80% and 90% of patients, respectively. SEGAs occur in 10-15% of patients and are a major potential cause of morbidity and potentially mortality. They tend to present during the first 20 years of life. TSC-Associated Neuropsychiatric Disorder (TAND) refers to the behavioral, intellectual and psychiatric manifestations of TSC including autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, depression and anxiety. Approximately 90% of patients will have at least 1 symptom of TAND.Lymphangioleiomyomatosis (LAM) occurs in the lung and may result in pneumothorax, cystic lung destruction and pleural effusions. Symptoms which occur as a result may include fatigue, chest pain and shortness of breath. It occurs in approximately 30-40% of women with TSC, up to 80% by the age of 40, and it is much less common in men.Renal angiomyolipomas and cysts are the most common manifestations of TSC involving the kidney. Renal disease is among the most common causes of early death in TSC. One study found that renal lesions were present in 80% of patients by a mean age of 10.5 years. Renal cell carcinoma occurs in 2-5% of patients with TSC at a mean age of 28–30 years.Cardiac rhabdomyomas are benign hamartomas and are the most common cardiac manifestations of TSC. It is found in approximately two-third of newborns with TSC. Most of the time they do not cause symptoms and spontaneously regress. In a minority of cases, they may result in heart failure, arrhythmias, and murmurs.Dermatological manifestations occur in almost all patients and may include facial angiofibromas, confetti skin lesions, ungual fibromas, shagreen patches, hypomelanotic macules and fibrous cephalic plaques.[13] None of these tend to result in significant complications however facial angiofibromas may cause significant cosmetic concerns.
Sturge–Weber Syndrome
Sturge-Weber syndrome occurs in approximately 1 in 20,000-50,000 live births and is caused by a somatic activating mutation in GNAQ. Normally, GNAQ is involved in cell growth signal transmission. It is classically characterized by a facial port-wine stain in the ophthalmic division of the trigeminal nerve, glaucoma and leptomeningeal angioma. However, the clinical presentation can vary significantly depending on the timing of the somatic mutation ranging from an isolated port-wine stain to complete Sturge-Weber syndrome.The characteristic port-wine stain, also called nevus flammeus, is caused by a capillary or venular malformation. It is present from birth while the extent and size of it is associated with the risk of leptomeningeal and ophthalmologic involvement. The greatest risk is associated with port-wine stains that appear to involve the entire V1 distribution followed by partial V1 involvement. There is ontroversy as to whether or not the distribution of port-wine stains truly follows trigeminal nerve branches per se. Port-wine stains are most often unilateral but can be bilateral. Typically, brain and eye involvement occur on the same side as the port-wine stain. Over time, port-wine stains can develop soft tissue or bone hypertrophy, proliferative nodules, and progressive ectasia which can lead to significant disfigurement.The two most common ocular manifestations include glaucoma and choroidal hemagioma. Glaucoma is estimated to occur in 30-70% with a bimodal peak occurring at the time of birth in 60% and between childhood and adolescence in 40%. The most frequent form of glaucoma is open-angle however closed-angle glaucoma may also occur. Congenital onset glaucoma is associated with other changes of the eye including megalocornea and buphthalmos. The choroidal hemangioma occurs in 40-50% of patients. They are usually asymptomatic but they may become thickened overtime and may be associated with an increased risk for glaucoma.Seizures typically develop within the first two years of life and occur in 75-100% of patients. Onset of seizures occur in 95% by the age of 5 years. Status epilepticus occurs in approximately 50% of patients. Approximately 25% of patients develop drug-resistant epilepsy. In these cases, surgery may be pursued with the two main approaches being lesionectomy and hemispherectomy.Neurological impairment can accrue gradually over time and may occur in the context of stroke-like episodes which may be triggered by seizures or head injuries. Intellectual disability occurs in approximately one-half of patients. In addition, patients with Sturge-Weber syndrome have an increased prevalence of depression, endocrinological abnormalities, headaches with migraine-like features, ADHD and behavioral problems. Cortically mediated visual field defects and hemiparesis occur in approximately one-third and one-half of patients, respectively.
Von Hippel–Lindau syndrome (hemangiomatosis)
Von Hippel-Lindau (VHL) disease is an autosomal dominant condition caused by mutations of the VHL gene. Approximately one-in-five cases are de novo rather than familial and it has nearly complete penetrance. VHL occurs in an estimated 1 in 36,000-45,000 live births. VHL normally functions as a tumor suppressor gene and thus when not functioning normally results in the development of benign and malignant tumors as well as cysts. Some of the most common manifestations include hemangioblastomas in the retina and central nervous system, clear cell renal cell carcinomas, pheochromocytomas, endolymphatic sac tumors and pancreatic neuroendocrine tumors. Life expectancy is reduced for individuals with this condition and one study found a median age of death at 52 years.CNS hemangioblastomas are the cardinal feature of VHL and occur in as many as 80% of cases. The most common locations include the cerebellum, spinal cord and brainstem. These tumors are benign however they may cause significant morbidity as well as mortality due to mass effect. Tumor growth rates can be highly variable. Treatment options include resection and radiation.Retinal hemangioblastomas occur in approximately half of patients and are often the first presenting manifestation of VHL. One longitudinal study that followed patients for a mean period of 7.3 years found that in individuals with unilateral disease 100% had bilateral involvement by the age of 56 years. Blindness or severe visual impairment occurs in less than 10% of patients. Laser photocoagulation and cryotherapy are the most common surgical treatments.Renal cell carcinoma is a major cause of death in patients with VHL and it occurs in 70% of patients. Lesions larger than 3 cm are associated with a risk of metastasis and thus present a recommended threshold for resection. Nephron sparing surgery allows for preservation of kidney function and 10-year survival rates up to 81%.Additional manifestations of VHL may include pheochromocytomas in as many as 16% of patients with VHL. They are most often unilateral but can be bilateral or multifocal. Approximately 5% are malignant.Pancreatic involvement occurs in 77% of patients with VHL. Asymptomatic cysts consist of the majority of cases. Neuroendocrine tumors occur in approximately 15% of cases. Less than 10% with neuroendocrine tumors will develop metastases.
Genetics
The majority of neurocutaneous syndromes are single-gene disorders however they are caused by different genes and have different inheritance patterns. For instance, neurofibromatosis 1 and 2, Tuberous sclerosis complex, Von Hippel-Lindau syndrome and Legius syndrome are inherited in an autosomal dominant manner. Incontinentia pigmenti is X-linked dominant and Sturge-Weber syndrome is sporadic. Some neurocutaneous disorders are found exclusively as mosaics such as Sturge-Weber syndrome and Proteus syndrome. Others such as neurofibromatosis type 1 and 2 as well as tuberous sclerosis complex can potentially be mosaics but may not be. Mosaicism may be suspected in cases with either a mild or incomplete presentation of a neurocutaneous disorder. A definitive diagnosis is most likely to be obtained if testing of affected tissues is possible.Patients and families of those affected by neurocutaneous disorders often benefit from genetic counseling. It may provide an opportunity to provide a better understanding of the potential risk to future offspring as well as to improve coping with the various implications of the condition. If desired, a prenatal diagnosis can be obtained by either amniocentesis or chorionic villus sampling. Another potential option is preimplantation genetic diagnosis where an embryo that does not have the mutation can be selectively implanted into the mother.
Diagnosis
Many neurocutaneous syndromes have established diagnostic criteria which may facilitate a diagnosis without necessarily requiring genetic testing. For instance, neurofibromatosis types 1 and 2, tuberous sclerosis complex and incontinentia pigmenti have formal diagnostic criteria. Whereas other syndromes such as Noonan syndrome with multiple lentigines, for instance, do not. In cases where conditions that do not have diagnostic criteria are suspected, genetic testing is more likely to be necessary. Diagnostic criteria are not perfect as sensitivity and specificity is not 100%. Similarly, genetic testing can produce false negatives. For example, genetic testing is positive in only 75-90% of cases of tuberous sclerosis complex. Thus, clinicians must apply clinical judgement when evaluating an individual suspected to have a neurocutaneous syndrome.
Treatment
The treatment of each neurocutaneous syndrome is unique. For some neurocutaneous syndromes such as neurofibromatosis 1 and tuberous sclerosis complex there are guidelines with recommendations for surveillance and management. For less common syndromes such guidelines are not yet available. Surveillance is a necessity for many neurocutaneous syndromes because new manifestations may develop over time which may only be detected with specific and focused testing. Thus, patients may be advised to obtain particular evaluations (e.g., MRI, ophthalmologic or dermatological examinations) within recommended intervals over time with the aim of detecting new manifestations of the syndrome early on.
Most of the currently available treatments for neurocutaneous syndromes do not address the underlying genetic cause. For example, epilepsy surgery in tuberous sclerosis complex or vestibular schwannoma surgery in neurofibromatosis type 2. However, there are some treatments that do address the underlying cause such as the use of mTOR inhibitors in tuberous sclerosis complex. There are currently significant efforts underway to develop additional treatments that address the underlying causes of neurocutaneous syndromes.Neurocutaneous syndromes are complex, lifelong conditions that have the potential to affect many different organ systems over time. Thus, patients may benefit from a multidisciplinary approach for care. Integrated, multidisciplinary clinics have developed in an effort to optimize the long-term care for patients with neurocutaneous syndromes. Specialties represented at these clinics may include genetics, neurology, ophthalmology, hematology-oncology, neurosurgery, psychiatry, dermatology and more.
References
External links
OMIM is an Online Catalog of Human Genes and Genetic Disorders |
Autosomal dominant nocturnal frontal lobe epilepsy | Autosomal dominant nocturnal frontal lobe epilepsy is an epileptic disorder that causes frequent violent seizures during sleep. These seizures often involve complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or crying are also common. ADNFLE is often misdiagnosed as nightmares. Attacks often occur in clusters and typically first manifest in childhood. There are four known loci for ADNFLE, three with known causative genes. These genes, CHRNA4, CHRNB2, and CHRNA2, encode various nicotinic acetylcholine receptor α and β subunits.
Signs and symptoms
ADNFLE is a partial epilepsy disorder characterized by brief violent seizures during sleep. Seizures are complex, consisting of arm and leg movements, fist clenching, and vocalizations such as yelling and moaning. These seizures often occur in clusters and can first manifest in childhood. Diagnosis is often initially incorrectly made as nightmares, night terrors, parasomnias and various psychiatric disorders.
Causes
While not well understood, it is believed that malfunction in thalamocortical loops plays a vital role in ADNFLE. The reasons for this belief are threefold. Firstly, thalamocortical loops are important in sleep and the frontal cortex is the origin of ADNFLE seizures. Secondly, both the thalamus and cortex receive cholinergic inputs and acetylcholine receptor subunits comprise the three known causative genes for ADNFLE. Thirdly, K-complex are almost invariably present at the start of seizures.
It is thought that epilepsy is caused because these receptor subunits are expressed presynaptically by neurons that release the inhibitory transmitter GABA. Therefore, the mutation in the α4 subunit could lead to reduced GABA release, causing hyperexcitability.
Pathophysiology
CHRNA4
The first mutation associated with ADNFLE is a serine to phenylalanine transition at position 248 (S248F), located in the second transmembrane spanning region of the gene encoding a nicotinic acetylcholine receptor α4 subunit. Using the numbering based on the human CHRNA4 protein, this mutation is called S280F. Receptors containing this mutant subunit are functional, but desensitize at a much faster pace compared to wild-type only receptors. These mutant containing receptors also recover from desensitization at a much slower rate than wild-type only receptors. These mutant receptors also have a decreased single channel conductance than wild-type and have a lower affinity for acetylcholine. Also importantly, this mutation along with the others in CHRNA4 produce receptors less sensitive to calcium.The second discovered ADNFLE mutation was also in CHRNA4. This mutation, L259_I260insL, is caused by the insertion of three nucleotides (GCT) between a stretch of leucine amino acids and an isoleucine. As with the S248F mutation, the L259_I260insL mutation is located in the second transmembrane spanning region. Electrophysiological experiments have shown that this mutant is tenfold more sensitive to acetylcholine than wild-type. Calcium permeability, however is notably decreased in mutant compared to wild-type containing receptors. Furthermore, this mutant shows slowed desensitization compared to both wild-type and S248F mutant receptors.Also located in the second transmembrane spanning region, the S252L mutation has also been associated with ADNFLE. This mutant displays increased affinity for acetylcholine faster desensitization compared to wild-type receptors.The most recently discovered mutation in CHRNA4 associated with ADNFLE is T265M, again located in the second transmembrane spanning segment. This mutation has been little studied and all that is known is that it produces receptors with increased sensitivity to acetylcholine and has a low penetrance.
15q24
Some families have been shown to not have mutations in CHRNA4 and, furthermore, to show no linkage around it. Instead some of these families show strong linkage on chromosome 15 (15q24) near CHRNA3, CHRNA5, and CHRNB4. Causative genes in this area are still unknown.
CHRNB2
Three mutations have been found in the gene CHRNB2, which encodes an acetylcholine receptor β2 subunit. Two of these mutations, V287L and V287M, occur at the same amino acid, again in the second transmembrane spanning region. The V287L mutation results in receptors that desensitize at a much slower rate compared to wild-type. The V287M mutant displays a higher affinity for acetylcholine when compared to wild-type receptors. As with the mutations in CHRNA4, these mutants lead to receptors less sensitive to calcium.The other known mutation in CHRNB2 is I312M, located in the third membrane-spanning region. Receptors containing these mutant subunits display much larger currents and a higher sensitivity to acetylcholine than wild-type receptors.
CHRNA2
Recently, the I279N mutation has been discovered in the first transmembrane spanning segment of CHRNA2, which encodes a nicotinic acetylcholine receptor α2 subunit similar to the nAChR α4 encoded by CHRNA4. This mutant shows a higher sensitivity to acetylcholine and unchanged desensitization compared to wild-type.
Diagnosis
Diagnosis is typically made upon patient history, although EEG recordings can be confirmatory if they occur during attacks.
Management
Anti-epileptic drugs are normally used to combat ADNFLE. These drugs are discussed in the main epilepsy article.
Footnotes
Further reading
GeneReviews/NCBI/NIH/UW entry on Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
== External links == |
Cephalic presentation | A cephalic presentation or head presentation or head-first presentation is a situation at childbirth where the fetus is in a longitudinal lie and the head enters the pelvis first; the most common form of cephalic presentation is the vertex presentation, where the occiput is the leading part (the part that first enters the birth canal). All other presentations are abnormal (malpresentations) and are either more difficult to deliver or not deliverable by natural means.
Engagement
The movement of the fetus to cephalic presentation is called head engagement. It occurs in the third trimester. In head engagement, the fetal head descends into the pelvic cavity so that only a small part (or none) of it can be felt abdominally. The perineum and cervix are further flattened and the head may be felt vaginally. Head engagement is known colloquially as the baby drop, and in natural medicine as the lightening because of the release of pressure on the upper abdomen and renewed ease in breathing. However, it severely reduces bladder capacity resulting in a need to void more frequently.
Classification
In the vertex presentation the head is flexed and the occiput leads the way. This is the most common configuration and seen at term in 95% of singletons. If the head is extended, the face becomes the leading part. Face presentations account for less than 1% of presentations at term. In the sinicipital presentation the large fontanelle is the presenting part; with further labor the head will either flex or extend more so that in the end this presentation leads to a vertex or face presentation. In the brow presentation the head is slightly extended, but less than in the face presentation. The chin presentation is a variant of the face presentation with maximum extension of the head.
Non-cephalic presentations are the breech presentation (3.5%) and the shoulder presentation (0.5%).
Vertex presentation
The vertex is the area of the vault bounded anteriorly by the anterior fontanelle and the coronal suture, posteriorly by the posterior fontanelle and the lambdoid suture and laterally by 2 lines passing through the parietal eminences.
In the vertex presentation the occiput typically is anterior and thus in an optimal position to negotiate the pelvic curve by extending the head. In an occiput posterior position, labor becomes prolonged, and more operative interventions are deemed necessary. The prevalence of the persistent occiput posterior is given as 4.7%.The vertex presentations are further classified according to the position of the occiput, both right, left, or transverse and anterior or posterior:
Left Occipito-Anterior (LOA), Left Occipito-Posterior (LOP), Left Occipito-Transverse (LOT)
Right Occipito-Anterior (ROA), Right Occipito-Posterior (ROP), Right Occipito-Transverse (ROT)The Occipito-Anterior position is ideal for birth; it means that the baby is lined up so as to fit through the pelvis as easily as possible. The baby is head down, facing the spine, with its back anterior. In this position, the babys chin is tucked onto its chest, so that the smallest part of its head will be applied to the cervix first. The position is usually "Left Occiput Anterior", or LOA. Occasionally, the baby may be "Right Occiput Anterior", or ROA.
Face presentation
Factors that predispose to face presentation are prematurity, macrosomia, anencephaly and other malformations, cephalopelvic disproportion, and polyhydramnios. In an uncomplicated face presentation duration of labor is not altered. Perinatal losses with face presentation occur with traumatic version and extraction and midforceps procedures Duff indicates that the prevalence of face presentations is about 1/500–600., while Benedetti et al. found it to be 1/1,250 term deliveries.Face presentations are classified according to the position of the chin (mentum):
Left Mento-Anterior (LMA), Left Mento-Posterior (LMP), Left Mento-Transverse (LMT)
Right Mento-Anterior (RMA), Right Mento-Posterior (RMP), Right Mento-Transverse (RMT)
Brow presentation
While some consider the brow presentation as an intermediate stage towards the face presentation, others disagree. Thus Bhal et al. indicated that both conditions are about equally common (1/994 face and 1/755 brow positions), and that prematurity was more common with face while postmaturity was more common with brow positions.
Oskie presentation
The Oskie presentation is similar to the Occipito-Anterior position, where the baby is head down, facing the spine, with back on the ventral side of the uterus; however, in this position, while the torso is aligned with the mothers longitudinal axis, the legs of the fetus are extended straight along the frontal axis of the mother, as if the baby is creating a right angle with its body. For the Oskie position to occur the babys head must be far down the pelvis in order to allow room for leg extension, typically the arms are bent, tucked against the babys body. There are no known complications for labor and delivery. This presentation is rare and is not well researched.
Reasons for predominance
The piriform (pear-shaped) morphology of the uterus has been given as the major cause for the finding that most singletons favor the cephalic presentation at term. The fundus is larger and thus a fetus will adapt its position so that the bulkier and more movable podalic pole makes use of it, while the head moves to the opposite site. Factors that influence this positioning include the gestational age (earlier in gestation breech presentations are more common as the head is relatively bigger), size of the head, malformations, amount of amniotic fluid, presence of multiple gestations, presence of tumors, and others.
Two-thirds of all vertex presentations are LOA, possibly because of the asymmetry created by the descending colon that is on the left side of the pelvis.
Diagnosis
Usually performing the Leopold maneuvers will demonstrate the presentation and possibly the position of the fetus. Ultrasound examination delivers the precise diagnosis and may indicate possible causes of a malpresentation. On vaginal examination, the leading part of the fetus becomes identifiable after the amniotic sac has been broken and the head is descending in the pelvis.
Management
Many factors determine the optimal way to deliver a baby. A vertex presentation is the ideal situation for a vaginal birth, although occiput posterior positions tend to proceed more slowly, often requiring intervention in the form of forceps, vacuum extraction, or Cesarean section. In a large study, a majority of brow presentations were delivered by Cesarean section, however, because of postmaturity, factors other than labour dynamics may have played a role. Most face presentations can be delivered vaginally as long as the chin is anterior; there is no increase in fetal or maternal mortality. Mento-posterior positions cannot be delivered vaginally in most cases (unless rotated) and are candidates for Cesarean section in contemporary management.
References
== External links == |
Purtschers retinopathy | Purtschers retinopathy is a disease where part of the eye (retina) is damaged. Usually associated with severe head injuries, it may also occur with other types of trauma, such as long bone fractures, or with several non-traumatic systemic diseases. However, the exact cause of the disease is not well understood. There are no treatments specific for Purtschers retinopathy, and the prognosis varies. The disease can threaten vision, sometimes causing temporary or permanent blindness.
It is named for the Austrian ophthalmologist, Othmar Purtscher (1852–1927), who detected it in 1910 and described it fully in 1912.
Presentation
Associated diseases
Severe head, chest, or long bone trauma
Acute pancreatitis
Amniotic fluid embolism
Chronic kidney failure
Dermatomyositis
Fat embolism syndrome
Scleroderma
Systemic lupus erythematosus (SLE)
Thrombotic thrombocytopenic purpura (TTP)
Pathophysiology
Purtschers retinopathy likely involves complex pathophysiology, with several contributing factors, including complement-mediated aggregates, fat, air, fibrin clots and platelet clumps. The diseases leads to the formation of cotton wool spots in the retina, a finding observed in several other diseases, and atrophy of the optic nerve.
Diagnosis
Where trauma is involved, only a funduscopic examination of the back of the eye (retina) is necessary to make the diagnosis. Fluoroscein angiography may show a decrease in blood flow to the areas of whiteness in the retina.
Treatment
It may be treated with triamcinolone in some cases. However, in general, there are no treatments for Purtschers retinopathy. If it is caused by a systemic disease or emboli, then those conditions should be treated.
Prognosis
Purtschers retinopathy can lead to loss of vision, and recovery of vision may occur very little. However, vision recovery does occur in some cases, and reports have varied on the long-term prognosis.
History
Purtschers retinopathy was first characterized in 1910 and 1912 as a syndrome of sudden blindness after head trauma, with patches of hemorrhage and whitening of the retina in both eyes. Later, it was discovered to occur after other types of trauma, such as chest trauma, and is associated with several non-traumatic systemic diseases. Purtschers retinopathy may also be associated with acute pancreatitis, vasculitis, embolization of such materials as fat and amniotic fluid, systemic lupus erythematosus, thrombotic thrombocytopenic purpura, and chronic kidney failure. Purtschers retinopathy may be caused by extensive fractures of the long bones.
References
== External links == |
Megalopapilla | Megalopapilla is a non-progressive human eye condition in which the optic nerve head (optic disc) has an enlarged diameter, exceeding 2.1 mm with no other morphological abnormalities.
Clinical features
In megalopapilla the optic disc diameter exceeds 2.1 mm (or surface area more than 2.5 mm2) with an increased cup-to-disc ratio. Although the optic disc is looks abnormal, the disc colour, sharpness of disc margin, rim volume, configuration of blood vessels and intraocular pressure will be normal. Visual field is normal except for an enlarged blind spot. Visual acuity may be normal, or occasionally reduced.
Types
There are two types of megalopapilla. Type 1, which is the most common, is bilateral with a normal configuration of the optic cup. Type 2 is unilateral with a superiorly displaced cup that eliminates the adjacent neuro-retinal rim.
Diagnosis and differential diagnosis
Large disc size can be seen in fundus examination by ophthalmoscopy. Since OCT is not influenced by disc size, it can be used in differentiating normal and glaucomatous eyes with large discs.Since the clinical appearance of megalopapilla resembles that of glaucomatous optic disc, it should be differentiated from Normal tension glaucoma and other pseudo-glaucomatous diseases. Other conditions that resembles megalopapilla includes coloboma of optic disc and orbital optic disc glioma.
History
Bock and Franceschetti were the first to use the term megalopapilla to describe larger-than-normal optic disks.
== References == |
Atrophic vaginitis | Atrophic vaginitis is inflammation of the vagina as a result of tissue thinning due to not enough estrogen. Symptoms may include pain with sex, vaginal itchiness or dryness, and an urge to urinate or burning with urination. It generally does not resolve without ongoing treatment. Complications may include urinary tract infections.The lack of estrogen typically occurs following menopause. Other causes may include when breastfeeding or as a result of specific medications. Risk factors include smoking. Diagnosis is typically based on symptoms.Treatment is generally with estrogen cream applied to the vagina. Other measures that may help include vaginal lubricants. It is recommended that soaps and other irritants are avoided. About half of postmenopausal women are affected. Many however are not being treated. Women often report reduced enjoyment in sex as well as life generally.
Signs and symptoms
After menopause the vaginal epithelium changes and becomes a few layers thick. Many of the signs and symptoms that accompany menopause occur in atrophic vaginitis. Genitourinary symptoms include
dryness
pain
itching
burning
soreness
pressure
white discharge
malodorous discharge due to infection
painful sexual intercourse
bleeding after intercourse
painful urination
blood in the urine
increased urinary frequency
incontinence
increased susceptibility to infections
decreased vaginal lubrication
urinary tract infections
painful urination
difficulty sitting
difficulty wiping
Diagnosis
Since women can have signs and symptoms that could be attributed to other causes, diagnosis is based upon the symptoms that cannot be better accounted for by another diagnosis. Lab tests usually do not provide information that will aid in diagnosing. A visual exam is useful. The observations of the following may indicate lower estrogen levels: little pubic hair, loss of the labial fat pad, thinning and resorption of the labia minora, and the narrowing of the vaginal opening. An internal exam will reveal the presence of low vaginal muscle tone, the lining of the vagina appears smooth, shiny, pale with loss of folds. The cervical fornices may have disappeared and the cervix can appear flush with the top of the vagina. Inflammation is apparent when the vaginal lining bleeds easily and appears swollen. The vaginal pH will be measured at 4.5 and higher.
Treatment
Symptoms of genitourinary syndrome of menopause (GSM) will unlikely be resolved without treatment. Women may have many or a few symptoms so treatment is provided that best suits each woman. If other health problems are also present, these can be taken into account when determining the best course of treatment. For those who have symptoms related to sexual activities, a lubricant may be sufficient. If both urinary and genital symptoms exist, local, low-dose estrogen therapy can be effective. Those women who are survivors of hormone-sensitive cancer may need to be treated more cautiously. Some women can have symptoms that are widespread and may be at risk for osteoporosis. Estrogen and adjuvants may be best.Topical treatment with estrogen is effective when the symptoms are severe and relieves the disruption in pH to restore the microbiome of the vagina. When symptoms include those related to the urinary system, systematic treatment can be used. Recommendations for the use of the lowest effective dose for the shortest duration help to prevent adverse endometrial effects.Some treatments have been developed more recently. These include selective estrogen receptor modulators, vaginal dehydroepiandrosterone, and laser therapy. Other treatments are available without a prescription such as vaginal lubricants and moisturizers. Vaginal dilators may be helpful. Since GSM may also cause urinary problems related to pelvic floor dysfunction, a woman may benefit from pelvic floor strengthening exercises. Women and their partners have reported that estrogen therapy resulted in less painful sex, more satisfaction with sex, and an improvement in their sex life.
Epidemiology
Up to 50% of postmenopausal women have at least some degree of vaginal atrophy. It is likely to be underdiagnosed and undertreated.
Terminology
Vulvovaginal atrophy, and atrophic vaginitis have been the preferred terms for this condition and cluster of symptoms until recently. These terms are now regarded as inaccurate in describing changes to the entire genitourinary system occurring after menopause. The term atrophic vaginitis suggests that the vagina is inflamed or infected. Though this may be true, inflammation and infection are not the major components of postmenopausal changes to the vagina. The former terms do not describe the negative effects on the lower urinary tract which can be the most troubling symptoms of menopause for women. Genitourinary syndrome of menopause (GSM) was determined to be more accurate than vulvovaginal atrophy by two professional societies. The term atrophic vaginitis does not reflect the related changes of the labia, clitoris, vestibule, urethra and bladder.
Research
The FDA has approved the use of lasers in the treatment of many disorders. The treatment of GSM is not specifically mentioned in the list of disorders by the United States Food and Drug Administration (FDA) but laser treatments have had success. Larger studies are still needed. The laser treatment works by resurfacing the vaginal epithelium and activating growth factors that increases blood flow, deposition of collage and the thickness of the vaginal lining. Women treated with laser therapy reported diminished symptoms of dryness, burning, itching, pain during sexual intercourse, and painful urination. Few adverse effects were noted.In 2018, the FDA issued a warning that lasers and other high energy devices were not approved for this application and it had received multiple reports of injuries.
References
== External links == |
Cystitis glandularis | Cystitis glandularis is the transformation of mucosal cells lining the urinary bladder. They undergo glandular metaplasia, a process in which irritated tissues take on a different form, in this case that of a gland. The main importance is in the findings of test results, in this case histopathology. They must distinguish a benign metaplastic change from the cancerous condition urothelial cell carcinoma. It is a very common finding in bladder biopsies and cystectomies, and most often found in the trigone area. Cystitis glandularis lesions are usually present as small microscopic foci; however, occasionally it can form raised intramucosal or polypoid lesions. The cystitis glandularis lesions are within the submucosa.
Types
There are two main types of cystitis glandularis, non-mucinous and mucinous (intestinal). The difference is in the cellular production of mucin, a normal feature of colonic and intestinal epithelial cells but not of urothelial cells. Another distinction is made between focal areas and diffuse involvement of the bladder. Whereas focal areas are more common, diffuse involvement is seen in chronically irritated bladders, such as in paraplegics or those with bladder stones or indwelling catheters. Individuals with diffuse intestinal-type cystitis glandularis are at increased risk for developing bladder cancer.
Related lesions
Cystitis glandularis arises from and merges with Von Brunns nests, which are groups of urothelial cells (cells of urinary tract) within the lamina propria and submucosa, formed from budding from the surface mucosa. They are considered normal. Cystitis cystica is a similar lesion to cystitis glandularis, where the central area of the Von Brunns nests have degenerated, leaving cystic lesions. Other metaplastic entities in the urinary bladder include squamous metaplasia and nephrogenic adenoma.
References
== Further reading == |
Leukocoria | Leukocoria (also white pupillary reflex) is an abnormal white reflection from the retina of the eye. Leukocoria resembles eyeshine, but leukocoria can also occur in animals that lack eyeshine because their retina lacks a tapetum lucidum.
Leukocoria is a medical sign for a number of conditions, including Coats disease, congenital cataract, corneal scarring, melanoma of the ciliary body, Norrie disease, ocular toxocariasis, persistence of the tunica vasculosa lentis (PFV/PHPV), retinoblastoma, and retrolental fibroplasia.
Because of the potentially life-threatening nature of retinoblastoma, a cancer, that condition is usually considered in the evaluation of leukocoria. In some rare cases (1%) the leukocoria is caused by Coats disease (leaking retinal vessels).
Diagnosis
On photographs taken using a flash, instead of the familiar red-eye effect, leukocoria can cause a bright white reflection in an affected eye. Leukocoria may appear also in low indirect light, similar to eyeshine.
Leukocoria can be detected by a routine eye exam (see Ophthalmoscopy). For screening purposes, the red reflex test is used. In this test, when a light is shone briefly through the pupil, an orange red reflection is normal. A white reflection is leukocoria.
Society
The fictional serial killer known as "The Collector", the main antagonist of the films The Collector (2009) and The Collection (2012), had the condition in both eyes. (confirmed by first movie actor Juan Fernández de Alarcon)
References
== External links == |
Annular pancreas | Annular pancreas is a rare condition in which the second part of the duodenum is surrounded by a ring of pancreatic tissue continuous with the head of the pancreas. This portion of the pancreas can constrict the duodenum and block or impair the flow of food to the rest of the intestines. It is estimated to occur in 1 out of 12,000 to 15,000 newborns. The ambiguity arises from the fact that not all cases are symptomatic.
Signs and symptoms
Early signs of abnormality include polyhydramnios (an excess of amniotic fluid), low birth weight, and feeding intolerance immediately after birth, in particular a tendency to develop epigastric distention associated with non-biliary vomiting (the obstruction is generally above the papilla of Vater, therefore superior to the junction with the bile ducts).
Different chromosomal diseases (for example trisomy 21 and, with a minor frequency, trisomy 18 and trisomy 13) are present in about 33% of subjects affected by annular pancreas.
In adults, the clinical picture is often dominated by the sensation of postprandial distension, abdominal pain in the epigastric region, nausea and vomiting that may be present for a long time (sometimes for years) before reaching a precise diagnosis.
Causes
It is typically associated with abnormal embryological development, however adult cases can develop. It can result from growth of a bifid ventral pancreatic bud around the duodenum, where the parts of the bifid ventral bud fuse with the dorsal bud, forming a pancreatic ring. It can also result if the ventral pancreatic bud fails to fully rotate, so it remains on the right or if the dorsal bud rotates in the wrong direction, such that the duodenum is surrounded by pancreatic tissue. Blockage of the duodenum develops if inflammation (pancreatitis) develops in the annular pancreas.
Diagnosis
Postnatal diagnostic procedures include abdominal x-ray and ultrasound, CT scan, and upper GI and small bowel series.
Abdominal radiography can show the classic sign of the "double bubble": the presence of air in the stomach and duodenum. Unfortunately, this double-bubble sign is not pathognomonic for annular pancreas, as it can also be observed in other conditions, such as duodenal atresia and intestinal malrotation.
Upper GI series may be suggestive of annular pancreas, especially if they show a duodenal narrowing of the second portion of the duodenum and the concomitant dilatation of the proximal duodenum. In some cases it is possible to have signs of inverse peristalsis of the duodenal tract which is proximal to the narrowing caused by the annular pancreas, and the dilatation of the duodenal portion distal to the anomaly.
An abdominal CT scan or an MRI allows to highlight the narrowing of the descending duodenal tract and the ring of pancreatic tissue surrounding the duodenum: this ring can be complete or, in patients with an incomplete annular pancreas, extended in a postero-lateral or anterolateral direction with respect to the second part of the duodenum.
ERCP or MRCP with secretin allow precise delineation of the anatomical structure and in particular a good visualization of pancreatic ducts, as well as a careful analysis of pancreatic secretion into the duodenum lumen.
Treatment
In neonates, treatment for relief of obstruction usually is bypassing the obstructed segment of duodenum by duodeno-jejunostomy. In adults, due to the minor duodenal mobility, the approach is laparoscopic gastrojejunostomy or duodenojejunostomy.
References
== External links == |
IgG4-related disease | IgG4-related disease (IgG4-RD), formerly known as IgG4-related systemic disease, is a chronic inflammatory condition characterized by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, various degrees of fibrosis (scarring) and a usually prompt response to oral steroids. In approximately 51–70% of people with this disease, serum IgG4 concentrations are elevated during an acute phase.It is a relapsing-remitting disease associated with a tendency to mass forming, tissue-destructive lesions in multiple sites, with a characteristic histopathological appearance in whichever site is involved. Inflammation and the deposition of connective tissue in affected anatomical sites can lead to organ dysfunction, organ failure, or even death if not treated.Early detection is important to avoid organ damage and potentially serious complications. Treatment is recommended in all symptomatic cases of IgG4-RD and also in asymptomatic IgG4-RD involving certain anatomical sites.
Signs and symptoms
IgG4-related disease has been described as an indolent condition. Although possibly based on opinion rather than on objective assessments, symptoms, if any, are commonly described as mild in the medical literature.
This can be in spite of considerable underlying organ destruction. People are often described as being generally well at the time of diagnosis, although some may give a history of weight loss.
Pain is generally not a feature of inflammation. However, it may occur as a secondary effect, for example, due to either obstruction or compression.
Often diagnosis is made due to the presence of painless swellings or mass lesions, or due to complications of masses, e.g. jaundice due to involvement of the pancreas, biliary tree or liver. Symptoms are commonly attributed to other conditions and other diagnoses may have been made years before diagnosis, e.g. urinary symptoms in men attributed to common prostate conditions. Lesions may also be detected incidentally on radiological images, but can be easily misdiagnosed as malignancies.Reported cases do include some significant symptoms or findings however:
Individual organ manifestations
IgG4-RD can involve one or multiple sites in the body. With multiorgan involvement, the sites involved can be affected at the same time (synchronously) or at different unrelated periods (metachronously).
Several different diseases that have been known for many years are now considered to be manifestations of IgG4-RD. These include: type 1 autoimmune pancreatitis, interstitial nephritis, Riedels thyroiditis, Mikuliczs disease, Küttners tumor, inflammatory pseudotumors (in various sites of the body), mediastinal fibrosis and some cases of retroperitoneal fibrosis.
This is not a complete list, as IgG4-RD can involve any site in the body.
Other affected sites, confirmed on histology to be manifestations of IgG4-RD, include:
heart; hard palate, esophagus, stomach, small intestine, rectum, adrenal gland, ovary, uterus, ureter, bladder, urachus, and synovium. Approximately 1/3 of cases exhibit increases in blood eosinophil counts, either eosinophilia or hypereosinophilia.Radiologic evidence suggestive of involvement of the superior vena cava and seminal vesicle has been reported in confirmed cases of IgG4-RD.
Histology
Whatever area of the body is involved, the hallmark histopathological features of IgG4-RD are:
A dense lymphoplasmacytic (lymphocytes and plasma cells) infiltrate rich in IgG4-positive plasma cells.
IgG4 immunostaining needs to be specifically requested and performed in order to detect IgG4-positive plasma cells.
Fibrosis, arranged at least focally in a "storiform" pattern.
"Storiform" is commonly referred to as meaning having a cartwheel pattern, but its literal meaning is the appearance of a woven mat [Latin: storea] (of rush or straw).
Obliterative phlebitis.
The venous channels are obliterated by a dense lymphoplasmacytic infiltrate, within both the venous walls and the lumen.Other histopathological features associated with IgG4-RD are:
Phlebitis without obliteration of the lumen.
Tissue has increased numbers of eosinophils.
Submandibular gland research
In an article from 1977, histological research into 349 cases of Küttners tumor (now known as IgG4-related sialadenitis) identified four distinct stages of the fibroinflammatory process:
Stage 1: Focal periductal (around the salivary ducts) infiltration of lymphocytes
Stage 2: Diffuse infiltration of lymphocytes and severe periductal fibrosis (scarring around the salivary ducts)
Stage 3: Prominent infiltration of lymphocytes, atrophy of parenchyma (i.e. loss of functional areas due to shrinkage), and periductal sclerosis (scarring resulting in hardening around the salivary ducts)
Stage 4: Marked loss of and sclerosis (hardening) of the parenchyma (functional area) - similar to the process involved in cirrhosis where there is shrinkage and loss of functional areas of the liverThis may reflect the inflammatory process and development of fibrosis that occurs in other organs involved in IgG4-RD.
Diagnosis
Diagnosis requires tissue biopsy of an affected organ with characteristic histological findings. Serum immunoglobulin G4 is often elevated but this is not always the case.
Treatment
The goal of treatment is the induction and maintenance of remission so as to prevent progression of fibrosis and organ destruction in affected organ(s).
An international panel of experts have developed recommendations for the management of IgG4-RD. They concluded that in all cases of symptomatic, active IgG4-RD that treatment is required. Some cases with asymptomatic IgG4-RD also require treatment, as some organs tend to not cause symptoms until the late stages of disease. Urgent treatment is advised with certain organ manifestations, such as aortitis, retroperitoneal fibrosis, proximal biliary strictures, tubulointerstitial nephritis, pachymeningitis, pancreatic enlargement and pericarditis.
Induction of remission
In untreated patients with active disease, the recommended first-line agent for induction of remission is glucocorticoids unless contraindications exist. Glucocorticoids characteristically result in a rapid and often dramatic improvement in clinical features and often a resolution of radiographic features. However, where advanced fibrotic lesions have resulted in irreversible damage, the response to glucocorticoids and other current treatment options may be poor or even absent.
Although not validated yet in clinical trials, the common induction regime is prednisolone 30–40 mg per day for 2–4 weeks, then gradually tapered over 3 to 6 months. Recurrences during or after tapering of glucocorticoids are frequent, however. Steroid-sparing immunosuppressive agents might be considered, depending on local availability of these drugs, for use in combination with glucocorticoids from the start of treatment in order to reduce the side-effects of prolonged glucocorticoid usage. Steroid-sparing agents that have been used include rituximab, azathioprine, methotrexate, and cyclophosphamide, although trials are needed to ascertain the effectiveness of each drug in IgG4-RD.
Maintenance
Following a successful induction of remission, maintenance therapy might be given in some cases, for example when there is a high risk of relapse or in patients with organ-threatening manifestations. Common maintenance therapy is prednisolone 2.5–5 mg per day, or use of a steroid-sparing agent instead.
Relapse
Relapses are common, and a previous history of relapse appears to be a strong predictor of future relapse. When relapse occurs while off therapy and there has been a prolonged disease remission following initial glucocorticoid induction, then the relapse can usually be managed successfully with a re-induction strategy using glucocorticoids. Introducing a steroid-sparing agent might also need to be considered for relapses; however, none has been tested in prospective, controlled studies, and evidence for their efficacy beyond that offered by concomitant glucocorticoid therapy is scarce.In one retrospective cohort study, baseline concentrations of serum IgG4, IgE and blood eosinophils were found to be independently predictive of relapse risk following treatment with rituximab with or without glucocorticoids; the higher the baseline values, the greater the relapse risk and the shorter the time to relapse.
Other interventions
When organ involvement causes local mechanical problems, further organ-specific interventions may be necessary. For example, when a tumefactive lesion causes obstruction of the bile duct, it may be necessary to insert a biliary stent to allow the bile to drain freely.
Similarly, ureteral or vascular stents, surgical resection or radiotherapy may be considered for various different presenting problems.
Trials
Research is also underway to evaluate the effect and safety of plasmablast-directed therapy with a monoclonal antibody (XmAb5871) which inhibits B-cell function without depleting these immune cells. XmAb5871 targets CD19 with its variable domain and has an Fc domain that has increased affinity to FcγRIIb.
Epidemiology
As recognition of IgG4-RD is relatively recent, there are limited studies on its epidemiology. It is therefore difficult to make an accurate estimation of prevalence. Furthermore, age of onset is almost impossible to estimate; age at diagnosis is frequently misused as the age of onset.
A 2011 study estimated the incidence of IgG4-RD in Japan at 2.8–10.8/million population, with a median age of onset of 58 years.
Nomenclature
Prior to 2011, IgG4-RD used to get mentioned in the medical literature under various different names.At the 2011 International Symposium on IgG4-Related Diseases, the consensus name of IgG4-related disease was endorsed for the condition. This name had already been agreed upon as a consensus name among Japanese investigators, notably choosing not to use the term systemic as that might lead to malignant tumours in other organs getting incorrectly diagnosed as being just another manifestation of the IgG4-related condition.However, some experts at the international symposium did express reservations about naming the disease after IgG4, as its role in pathogenesis is questionable and the use of serum IgG4 concentrations as a biomarker is unreliable.An expanded term, Immunoglobulin G4-related disease, has sometimes been used also. However, this term was never referenced in the 2012 recommendations for nomenclature, and its use would appear to be erroneous.
See also
IgG4-related ophthalmic disease
IgG4-related prostatitis
IgG4-related skin disease
References
External links
Overview of IgG4-related disease - UpToDates article on IgG4-related disease.
DermNet NZ entry |
Metabolic bone disease | Metabolic bone disease is an abnormality of bones caused by a broad spectrum of disorders. Most commonly these disorders are caused by deficiencies of minerals such as calcium, phosphorus, magnesium or vitamin D leading to dramatic clinical disorders that are commonly reversible once the underlying defect has been treated. These disorders are to be differentiated from a larger group of genetic bone disorders where there is a defect in a specific signaling system or cell type that causes the bone disorder. There may be overlap. For example, genetic or hereditary hypophosphatemia may cause the metabolic bone disorder osteomalacia. Although there is currently no treatment for the genetic condition, replacement of phosphate often corrects or improves the metabolic bone disorder. Metabolic bone disease in captive reptiles is also common, and is typically caused by calcium deficiency in a reptiles diet.
Conditions considered to be metabolic bone disorders
osteoporosis
osteomalacia (adults) & rickets (children)
osteitis fibrosa cystica
Pagets disease of bone
pyramiding (turtles)Osteoporosis is due to causal factors like atrophy of disuse and gonadal deficiency. Hence osteoporosis is common in postmenopausal women and in men above 50 yrs. Hypercorticism may also be a causal factor, as osteoporosis may be seen as a feature of Cushings syndrome.
References
== External links == |
Chloroquine retinopathy | Chloroquine retinopathy is a form of toxic retinopathy (damage of the retina) caused by the drugs chloroquine or hydroxychloroquine, which are sometimes used in the treatment of autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus. This eye toxicity limits long-term use of the drugs.
Presentation
The risk of toxicity is low for individuals without complicating conditions during the first five years of treatment using less than 6.5 mg/kg/day of hydroxychloroquine or 3 mg/kg/day of chloroquine, and/or cumulative doses of less than 1000 gram and 460 gram (total dose), respectively. Some physicians suggest that lean body weight is more accurate when calculating daily dosage.Most patients are routinely given 400 mg of hydroxychloroquine daily (or 250 mg chloroquine). This dose is considered acceptable.
Early stage
The earliest signs of toxicity include bilateral paracentral visual field changes (best detected with a red test object) and a subtle granular depigmentation of the paracentral RPE.
Advanced stage
With continued drug exposure, there is progressive development of a bilateral atrophic bulls-eye maculopathy and paracentral scotomata, which may in severe cases ultimately spread over the entire fundus, causing widespread retinal atrophy and visual loss.
Pathophysiology
Both agents bind to melanin pigment in the RPE, and this may serve to concentrate the drugs or to prolong their adverse effects.
Diagnosis
Patients and their primary care physicians must be made fully aware of the ophthalmic risks and the need for regular screening examinations to detect retinal toxicity at an early stage.
Baseline evaluation for patients beginning treatment with a chloroquine derivative should include a complete eye examination by an eye care professional, retinal photography for follow-up comparisons, and Visual field testing with a white pattern. Central visual field assessment should test the central 10° of vision with a white test target (such as Humphrey 10-2 program).
In patients at risk or those with unclear presentation, optical coherence tomography (loss of IS/OS junctions), fundus autofluorescence (focal hyper or hypoautofluorescence), and multifocal electroretinography (paracentral depressions) may be obtained.
Profound abnormalities detected with visual field and multifocal electroretinography testing can be observed in the presence of a normal retinal appearance. Retinal examinations are advised for documentation, but visible bulls-eye maculopathy is a late change, and the goal of screening is to recognize toxicity at an earlier stage. Annual screening should begin after 5 years (or sooner if there are unusual risk factors).
Treatment
Cessation of the drug at the first sign of toxicity is recommended. No treatment exists as yet for this disorder, so it is imperative that patients and their ophthalmologists be aware of the best practices for minimizing toxic damage.
Prognosis
Associated visual loss rarely recovers and may even progress after the drug is discontinued.
== References == |
Placentitis | Placentitis is an inflammation of the placenta. The main forms of placentitis are:
Villitis, inflammation of chorionic villi.
Intervillositis, inflammation of the intervillous space.It may be caused by vertically transmitted infections.
Because of the close proximity, placentitis often occurs simultaneously as funisitis (inflammation of the umbilical cord) and chorioamnionitis (inflammation of the fetal membranes).
Chronic lymphocytic placental inflammation occurs in 5% to 15% of pregnancies, and are generally not associated with documented infection.
Villitis of unknown etiology
Villitis of unknown etiology (VUE), also known as chronic villitis, is a placental injury. VUE is an inflammatory condition involving the chorionic villi (placental villi). VUE is a recurrent condition and can be associated with intrauterine growth restriction (IUGR). IUGR involves the poor growth of the foetus, stillbirth, miscarriage, and premature delivery. VUE recurs in about 1/3 of subsequent pregnancies.VUE is a common lesion characterised by inflammation in the placental chorionic villi. VUE is also characterised by the transfer of maternal lymphocytes across the placenta.VUE is diagnosed in 7–10% placentas in pregnancies. Roughly 80% of the VUE cases are in term placentas (greater than 37 weeks of pregnancy). A case of VUE in a placenta less than 32 weeks old should be screened for infectious villitis.
Chronic histiocytic intervillositis
Chronic Histiocytic Intervillositis (CHI or CHIV) also known as Chronic Intervillositis of Unknown (A)etiology (CIUE) and Massive Chronic Intervillositis (MCI) is defined as a diffuse infiltration of mononuclear cells (histiocytes, lymphocytes, monocytes) of maternal origin into the intervillous space within the placenta. It often results in severe intrauterine growth restriction which can lead to miscarriage or stillbirth. Overall perinatal mortality rate is high: 41% to 77%. Recurrence rate is also high: 67% to 100%.
See also
Chorioamnionitis
References
External links
CHI Support
CHI Facebook Support Group |
Scrub typhus | Scrub typhus or bush typhus is a form of typhus caused by the intracellular parasite Orientia tsutsugamushi, a Gram-negative α-proteobacterium of family Rickettsiaceae first isolated and identified in 1930 in Japan.Although the disease is similar in presentation to other forms of typhus, its pathogen is no longer included in genus Rickettsia with the typhus bacteria proper, but in Orientia. The disease is thus frequently classified separately from the other typhi.
Signs and symptoms
Signs and symptoms include fever, headache, muscle pain, cough, and gastrointestinal symptoms. More virulent strains of O. tsutsugamushi can cause hemorrhaging and intravascular coagulation. Morbilliform rash, eschar, splenomegaly, and lymphadenopathies are typical signs. Leukopenia and abnormal liver function tests are commonly seen in the early phase of the illness. Pneumonitis, encephalitis, and myocarditis occur in the late phase of illness. It has particularly been shown to be the most common cause of acute encephalitis syndrome in Bihar, India.
Causes
Scrub typhus is transmitted by some species of trombiculid mites ("chiggers", particularly Leptotrombidium deliense), which are found in areas of heavy scrub vegetation. The mites feed on infected rodent hosts and subsequently transmit the parasite to other rodents and humans. The bite of this mite leaves a characteristic black eschar that is useful to the doctor for making the diagnosis.Scrub typhus is endemic to a part of the world known as the tsutsugamushi triangle (after O. tsutsugamushi). This extends from northern Japan and far-eastern Russia in the north, to the territories around the Solomon Sea into northern Australia in the south, and to Pakistan and Afghanistan in the west. It may also be endemic in parts of South America.The precise incidence of the disease is unknown, as diagnostic facilities are not available in much of its large native range, which spans vast regions of equatorial jungle to the subtropics. In rural Thailand and Laos, murine and scrub typhus account for around a quarter of all adults presenting to hospital with fever and negative blood cultures. The incidence in Japan has fallen over the past few decades, probably due to land development driving decreasing exposure, and many prefectures report fewer than 50 cases per year.It affects females more than males in Korea, but not in Japan, which may be because sex-differentiated cultural roles have women tending garden plots more often, thus being exposed to vegetation inhabited by chiggers.
The incidence is increasing in the southern part of the Indian subcontinent and in northern areas around Darjeeling.
Diagnosis
In endemic areas, diagnosis is generally made on clinical grounds alone. However, overshadowing of the diagnosis is quite often as the clinical symptoms overlap with other infectious diseases such as dengue fever, paratyphoid, and pyrexia of unknown origin (PUO). If the eschar can be identified, it is quite diagnostic of scrub typhus, but this can be unreliable on dark skin, and moreover, the site of eschar which is usually where the mite bites is often located in covered areas. Unless it is actively searched for, the eschar can easily be missed. History of mite bite is often absent since the bite does not inflict pain and the mites are almost too small to be seen by the naked eye. Usually, scrub typhus is often labelled as PUO in remote endemic areas, since blood culture is often negative, yet it can be treated effectively with chloramphenicol. Where doubt exists, the diagnosis may be confirmed by a laboratory test such as serology. Again, this is often unavailable in most endemic areas, since the serological test involved is not included in the routine screening tests for PUO, especially in Burma (Myanmar).The choice of laboratory test is not straightforward, and all currently available tests have their limitations. The cheapest and most easily available serological test is the Weil-Felix test, but this is notoriously unreliable. The gold standard is indirect immunofluorescence, but the main limitation of this method is the availability of fluorescent microscopes, which are not often available in resource-poor settings where scrub typhus is endemic. Indirect immunoperoxidase, a modification of the standard IFA method, can be used with a light microscope, and the results of these tests are comparable to those from IFA. Rapid bedside kits have been described that produce a result within one hour, but the availability of these tests is severely limited by their cost. Serological methods are most reliable when a four-fold rise in antibody titre is found. If the patient is from a nonendemic area, then diagnosis can be made from a single acute serum sample. In patients from endemic areas, this is not possible because antibodies may be found in up to 18% of healthy individuals.Other methods include culture and polymerase chain reaction, but these are not routinely available and the results do not always correlate with serological testing, and are affected by prior antibiotic treatment. The currently available diagnostic methods have been summarised.
Treatment
Without treatment, the disease is often fatal. Since the use of antibiotics, case fatalities have decreased from 4–40% to less than 2%.The drug most commonly used is doxycycline or tetracycline, but chloramphenicol is an alternative. Strains that are resistant to doxycycline and chloramphenicol have been reported in northern Thailand. Rifampicin and azithromycin are alternatives. Azithromycin is an alternative in children and pregnant women with scrub typhus, and when doxycycline resistance is suspected. Ciprofloxacin cannot be used safely in pregnancy and is associated with stillbirths and miscarriage.
Combination therapy with doxycycline and rifampicin is not recommended due to possible antagonism.
Vaccine
No licensed vaccines are available.An early attempt to create a scrub typhus vaccine occurred in the United Kingdom in 1937 (with the Wellcome Foundation infecting around 300,000 cotton rats in a classified project called "Operation Tyburn"), but the vaccine was not used. The first known batch of scrub typhus vaccine actually used to inoculate human subjects was dispatched to India for use by Allied Land Forces, South-East Asia Command in June 1945. By December 1945, 268,000 cc had been dispatched. The vaccine was produced at Wellcomes laboratory at Ely Grange, Frant, Sussex. An attempt to verify the efficacy of the vaccine by using a placebo group for comparison was vetoed by the military commanders, who objected to the experiment.Enormous antigenic variation in Orientia tsutsugamushi strains is now recognized, and immunity to one strain does not confer immunity to another. Any scrub typhus vaccine should give protection to all the strains present locally, to give an acceptable level of protection. A vaccine developed for one locality may not be protective in another, because of antigenic variation. This complexity continues to hamper efforts to produce a viable vaccine.Dora Lush, an Australian bacterioloigist, died after accidentally pricking her finger with a needle containing scrub typhus while inoculating a mouse in an attempt to develop a vaccine.
History
Severe epidemics of the disease occurred among troops in Burma and Ceylon during World War II. Several members of the U.S. Armys 5307th Composite Unit (Merrills Marauders) died of the disease, as well as many soldiers in the Burma theatre; and before 1944, no effective antibiotics or vaccines were available.World War II provides some indicators that the disease is endemic to undeveloped areas in all of Oceania in the Pacific theater, although war records frequently lack definitive diagnoses, and many records of "high fever" evacuations were also likely to be other tropical illnesses. In the chapter entitled "The Green War", General MacArthurs biographer William Manchester identifies that the disease was one of a number of debilitating afflictions affecting both sides on New Guinea in the running bloody Kokoda battles over extremely harsh terrains under intense hardships— fought during a six-month span all along the Kokoda Track in 1942–43, and mentions that to be hospital-evacuated, Allied soldiers (who cycled forces) had to run a fever of 102 °F (39 °C), and that sickness casualties outnumbered weapons-inflicted casualties 5:1. Similarly, the illness was a casualty producer in all the jungle fighting of the land battles of the New Guinea campaign and the Guadalcanal campaign. Where the Allies had bases, they could remove and cut back vegetation, or use DDT as a prophylaxis area barrier treatment, so mite- and tick-induced sickness rates in forces off the front lines were diminished.The disease was also a problem for US troops stationed in Japan after WWII, and was variously known as "Shichitō fever" (by troops stationed in the Izu Seven Islands) or "Hatsuka fever" (Chiba prefecture).Scrub typhus was first reported in Chile in 2006. This is likely the result of underdiagnosis and underreporting and not of a recent spread to Chile. In January 2020 the disease was for the first time reported in Chiles southernmost region.
See also
List of mites associated with cutaneous reactions
References
== External links == |
Ganglioglioma | Ganglioglioma is a rare, slow-growing primary central nervous system (CNS) tumor which most frequently occurs in the temporal lobes of children and young adults
Classification
Gangliogliomas are generally benign WHO grade I tumors; the presence of anaplastic changes in the glial component is considered to represent WHO grade III (anaplastic ganglioglioma). Criteria for WHO grade II have been suggested, but are not established. Malignant transformation of spinal ganglioglioma has been seen in only a select few cases. Poor prognostic factors for adults with gangliogliomas include older age at diagnosis, male sex, and malignant histologic features.
Histopathology
Histologically, ganglioglioma is composed of both neoplastic glial and ganglion cells which are disorganized, variably cellular, and non-infiltrative. Occasionally, it may be challenging to differentiate ganglion cell tumors from an infiltrating glioma with entrapped neurons. The presence of neoplastic ganglion cells forming abnormal clusters, the presence of binucleation and dysmorphic neurons are helpful clues favoring ganglioglioma over glioma. The glial component of ganglioglioma includes fibrillary astrocytes with varying degrees of cellular atypia. The neoplastic neuronal components are often clustered or irregularly oriented. Fibrovascular stroma confined to the neuronal component, perivascular lymphocytic infiltrates, and small foci of calcification are common, as is immunopositivity for synaptophysin, neuron-specific enolase, and chromogranin A. Elevated Ki-67 and p53 labeling index is associated with more aggressive tumor behavior in both children and adults with gangliogliomas. The rare occurrence of malignant transformation is confined to the glial cell population, and is characterized by increased cellularity and mitotic activity, endothelial proliferation, and necrosis.
Diagnosis
Computed Tomography (CT) is generally not a recommended modality for diagnosis and evaluation of spinal cord tumors. Evaluation with Magnetic Resonance (MR) most commonly demonstrates a circumscribed solid or mixed solid and cystic mass spanning a long segment of the cord with hypointense T1 signal and hyperintense T2 signal in the solid component. Enhancement patterns are highly variable, ranging from minimal to marked, and may be solid, rim, or nodular. Adjacent cord edema and syringomyelia and peritumoral cysts may be present in addition to reactive scoliosis.
It is nearly impossible to differentiate ganglioglioma from other more common intramedullary neoplasms based on imaging alone. Astrocytoma and ependymoma are more familiar intramedullary tumors which share many similar features to ganglioglioma, including T2 hyperintensity, enhancement, tumoral cysts, and cord edema. Poorly defined margins may be more suggestive of astrocytoma, while a central location in the spinal cord, hemorrhage, and hemosiderin staining are often seen with ependymoma. Hemangioblastoma and paraganglioma are less usual intramedullary tumors, but since they are more frequently encountered than ganglioglioma, they should also be included in the differential diagnosis.
Treatment
Definitive treatment for ganglioglioma requires gross total surgical resection, and a good prognosis is generally expected when this is achieved. However, indistinct tumor margins and the desire to preserve normal spinal cord tissue, motor and sensory function may preclude complete resection of tumor. According to a series by Lang et al., reviewing several patients with resected spinal cord ganglioglioma, the 5- and 10-year survival rates after total resection were 89% and 83%, respectively. In that study, patients with spinal cord ganglioglioma had a 3.5-fold higher relative risk of tumor recurrence compared to patients with supratentorial ganglioglioma. It has been recognized that postoperative results correlate closely with preoperative neurological status as well as the ability to achieve complete resection.
With the exception of WHO grade III anaplastic ganglioglioma, radiation therapy is generally regarded to have no role in the treatment of ganglioglioma. In fact, radiation therapy may induce malignant transformation of a recurrent ganglioglioma several years later. Adjuvant chemotherapy is also typically reserved for anaplastic ganglioglioma, but has been used anecdotally in partially resected low grade spinal cord gangliogliomas which show evidence of disease progression.
See also
Lhermitte-Duclos disease
References
== External links == |
Situs ambiguus | Situs ambiguus is a rare congenital defect in which the major visceral organs are distributed abnormally within the chest and abdomen. Clinically heterotaxy spectrum generally refers to any defect of Left-right asymmetry and arrangement of the visceral organs; however, classical heterotaxy requires multiple organs to be affected. This does not include the congenital defect situs inversus, which results when arrangement of all the organs in the abdomen and chest are mirrored, so the positions are opposite the normal placement. Situs inversus is the mirror image of situs solitus, which is normal asymmetric distribution of the abdominothoracic visceral organs. Situs ambiguus can also be subdivided into left-isomerism and right isomerism based on the defects observed in the spleen, lungs and atria of the heart.
Individuals with situs inversus or situs solitus do not experience fatal dysfunction of their organ systems, as general anatomy and morphology of the abdominothoracic organ-vessel systems are conserved. Due to abnormal arrangement of organs in situs ambiguus, orientation across the left-right axis of the body is disrupted early in fetal development, resulting in severely flawed cardiac development and function in 50–80% of cases. They also experience complications with systemic and pulmonary blood vessels, significant morbidity, and sometimes death. All patients with situs ambiguus lack lateralization and symmetry of organs in the abdominal and thoracic cavities and are clinically considered to have a form of heterotaxy syndrome.
Heterotaxy syndrome with atrial isomerism occurs in 1 out of every 10,000 live births and is associated with approximately 3% of congenital heart disease cases. Additional estimation of incidence and prevalence of isomerism proves difficult due to failure to diagnose and underestimation of the disease by clinicians. Furthermore, right isomerism is much more easily recognized than left isomerism, contributing to the failure to diagnose.Situs ambiguus is a growing field of research with findings dating back to 1973.
Signs and symptoms
There are a variety of clinical manifestations of situs ambiguus. Acute symptoms can be due to both cardiac and non-cardiac defects. Cyanosis or blue skin coloration, primarily affecting the lips and fingernails, can indicate a systemic or circulatory issue. Poor feeding, failure to thrive, and rapid shallow breathing may also be observed due to poor circulation. Upon examination, arrhythmia and heart murmur may raise further suspicion of a cardiac abnormality. Non-cardiac symptoms include impairments of the liver and gastrointestinal tract. Biliary atresia, or inflammation and destruction of the bile ducts, may lead to jaundice. Vomiting and swelling of the abdominal region are features that suggest improper positioning of the intestines. Poor positioning of the intestine also makes it more prone to blockage, which can result in numerous chronic health issues. Asplenia and polysplenia are also possible features of heterotaxy syndrome.Due to abnormal cardiac development, patients with situs ambiguus usually develop right atrial isomerism consisting of two bilaterally paired right atria, or left atrial isomerism consisting of two bilaterally paired left atria. Clinical features and symptoms can vary dependent upon assignment of left versus right atrial isomerism. In either instance, the apex of the heart will be poorly positioned, which should alert a clinician of the likelihood of atrial isomerism. It is estimated that 5–10% of isomeric patients have mesocardia, in which the heart is positioned at the center of the thorax, 25–50% have dextrocardia, in which the apex of the heart is pointed toward the right side of the thorax, and 50–70% have levocardia, in which the apex of the heart is pointed toward the left side of the thorax.
Right atrial appendage isomerism
Right atrial appendage isomerism, also called right atrial isomerism, is a cardiac development defect in which the heart has bilateral right atria and atrial attachments in the muscle wall, as opposed to the normal right atrium and left atrium. In right atrial isomerism, the pulmonary blood oxygen tract is damaged due to right-left shunting of blood. In addition, the atrial septum which distinguishes the 2 atria is absent. These impairments, in addition to congestion in the pulmonary tract, allows deoxygenated blood to mix with oxygenated blood, contributing to cyanosis and possible respiratory distress. Poor systemic circulation also results due to improper positioning of the aorta.
Left atrial appendage isomerism
Left atrial appendage isomerism, also called left atrial isomerism, is a cardiac development defect in which the heart has two bilateral left atria and atrial appendages in the muscle wall. Left atrial isomerism can have varied clinical manifestations, including a later onset of symptoms. Heart failure is often a concern because the inferior vena cava is disrupted due to the inappropriate morphology of the left ventricle to support the vena cava.
Conductive nodes and tissues
Abnormal development of the heart results in impaired doubles of conductive nodes, as well as faulty electrical fibers throughout the ventricles. Individuals with right atrial isomerism develop two sinoatrial nodes, as they have 2 mirrored right atria, whereas those with left atrial isomerism fail to develop a sinus node at all. Thus, patients with left atrial isomerism are more likely to experience atrial fibrillation, or irregular rapid heart beat, and abnormal heart rhythm, known as atrial flutter. Development of the atrioventricular node and bundle of His largely depends on physiological looping of the ventricles. Abnormal looping of the ventricles contributes to arrhythmia and heart block in fetuses.
Bronchial tree and lungs
Isomerism of the bronchial tree is not typically damaging and presents no significant clinical complications. Pulmonary valve stenosis results in issues of blood flow to the lungs.
Abdominal organs
Abdominal organs, including the liver, stomach, intestinal tract, and spleen may be randomly arranged throughout the left-right axis of the body. Distribution of these organs largely dictates treatment, clinical outcomes, and further evaluation.
The liver is typically symmetrical across the left-right axis in patients with situs ambiguus, which is abnormal. A majority of left atrial isomeric patients have defects throughout the biliary tree, which is responsible for bile production, even when the gall bladder is functional and morphologically normal. This biliary atresia can lead to acute problems such as nutrient malabsorption, pale stools, dark urine, and abdominal swelling. If this condition continues without proper treatment, cirrhosis and liver failure become a major concern. Biliary atresia is not usually observed in patients with right atrial isomerism.Random positioning of the stomach is often one of the first signals of situs ambiguus upon examination. Malrotation of the entire intestinal tract, or improper folding and bulging of the stomach and intestines, results in bowel obstruction. This impairment leads to vomiting, abdominal distension, mucus and blood in the stool. Patients may also experience abdominal pain. Intestinal malrotation is more commonly identified in patients with right atrial isomerism than in those with left atrial isomerism.Isomeric patients often experience disruptions to splenic development during embryogenesis, resulting in an overall lack a spleen (asplenia) or development of many spleens (polysplenia). Asplenia is most often observed in patients with right atrial isomerism. Polysplenia results in 90% of patients with left atrial isomerism. Although they have many spleens, each is usually ineffective resulting in functional asplenia. Rarely, left atrial isomeric patients have a single, normal, functional spleen. Patients lacking a functional spleen are in danger of sepsis and must be monitored.
Causes
Situs ambiguus has been linked to family history of malformations and maternal cocaine use, suggesting both genetic and environmental factors play a role. Several genes in the TGF-beta pathway, which controls left-right patterning of visceral organs across the body axis, have been indicated in sporadic and familial cases of atrial isomerism. There is also overlap between genes associated with situs ambiguus and primary ciliary dyskinesia, likely due to the important role of cilia is establishing left-right asymmetry. The planar cell polarity has an important role in positioning these cilia, and thus genes within this pathway are increasingly associated with situs ambiguus.Disrupted mitochondria function has also been recently linked to heterotaxy.
Pathophysiology
Molecular and cellular mechanism
Several genes have been identified in normal development of the right-left axis. These genes have been extensively researched. Gene mutations that lead to atrial isomerism is a growing area of research. Mutations in genes that encode proteins in the TGF-beta pathway, including NODAL, NKX2-5, and ZIC3, have been linked to tetralogy of Fallot and hypoplastic left heart syndrome. Mutations in the ZIC3 gene, which encodes a zinc finger family transcription factor, is linked to a 50% risk of atrial isomerism in families. It is also an X-linked disorder, so testing for ZIC3 mutations is highly encouraged in male births.The most prevalent and best characterized genetic associations of heterotaxy include:
Classical pathology
Cardiac looping malformations:
Fallots tetralogy
transposition of the great vessels
Ventricular and atrial septal defects.
Deranged abdominal organ asymmetry:
The stomach and spleen are prone to isolated reversal
The stomach, liver, and a single adrenal gland are occasionally found in the midline.
Organ malformations:
asplenia and polysplenia often lead to sepsis
More rarely, the head of the pancreas fails to form
Horseshoe kidneys develop, which can lead to cancer, kidney stones, and/or infection.
Malrotation errors cause volvulus and/or faulty peritoneal attachments, which completely obstruct the bowel.
Vascular abnormalities:
Interrupted inferior vena cava,
Bilateral superior or inferior venae cavae
Intrahepatic interruption of the inferior vena cava with connection to the azygos or hemiazygos veins
Aberrant portal veins.
Bronchial tree and lungs
Pathophysiology in the bronchial tree can be observed by radiography. Under normal development, the bronchial tree consists of two main bronchi that are anatomically different:
Hyparterial bronchus (below the pulmonary artery): supplies blood to the bi-lobed left lung
Eparterial bronchus (adjacent to the artery): supplies blood to the tri-lobed right lungIn situs ambiguus, there is a duplication of either the hyparterial or eparterial bronchus. These features are not associated with any significant clinical complications. Mechanisms leading to bronchial duplication are not thoroughly understood.
In pulmonary valve stenosis, there is a reduction in blood flow to the lungs due to an obstruction of the heart at the pulmonic valve. This contributes to cyanosis and pulmonary hypertension.
Diagnosis
For proper diagnosis of situs ambiguus, cardiac and non-cardiac features must be evaluated. Diagnostic criteria for atrial isomerism includes observation of symmetry of thoracic visceral organs upon echocardiogram, arrhythmia upon electrocardiogram, and chest x-ray for confirmation of the hearts location across the left-right axis. Additional radiographic and cross-sectional imaging may be obtained to evaluate both cardiac and non-cardiac manifestations of situs ambiguus. In addition, a series of gastrointestinal tests can be conducted for observation of intestinal malrotation, as well as a scan of the liver and spleen for biliary function.
Diagnostic techniques for cardiac causes
Echocardiography
Electrocardiography
Computed tomography
Magnetic resonance imaging
Cardiac catheterization and angiography
Chest x-ray
Diagnostic techniques for non-cardiac causes
Computed tomography
Magnetic resonance imaging
Splenic function analysis
Evaluation of biliary anatomy and cholangiogram
Evaluation of intestinal malrotation
Pulse oximeter
Other diagnostic features
Assessment of family history
Genetic testing
Management
Each of the symptoms of situs ambiguus must be managed with appropriate treatment dependent upon the organ system involved. Intestinal malrotation is treated surgically using the Ladd procedure. This procedure widens a fold in the peritoneum so that the intestines can be placed in non-rotated formation. It is not possible to return the bowel to a normal morphology However, 89% of patients that undergo the Ladd surgery experience a complete resolution of symptoms.
Following cholangiogram, a Kasai procedure is usually performed in cases of biliary atresia. In this surgery, a Y-shaped shunt is used to passage bile from the liver directly to the intestine. If this is unsuccessful, liver transplantation can be considered based on the overall health of the patient. The Kasai procedure is successful in approximately 80% of patients. Following the operation, patients are advised to take fat-soluble vitamins, choleretics, and anti-inflammatory medications.
Functionally asplenic patients have an elevated lifetime risk of sepsis, as they have no functional spleen for fighting infection. For this reason, asplenic patients are under constant observation for any signs of fever or infection. In the case of infection, patients are placed on controlled empiric antibiotic therapy to avoid development of antibiotic resistance. This therapy battles infection by both gram-positive and gram-negative bacteria.
Right-atrial and left-atrial isomerism and associated pulmonary issues are treated in a series of steps based on the severity of symptoms. Isomeric patients are first treated by inserting a shunt that will move incoming blood through the pulmonary circuit. The Fontan procedure routes blood through the patients single ventricle, to the lungs, and into systemic circulation. This process is favorable in patients aged 2 to 5 years old. About 20–30% of patients will require a heart transplant. Left-atrial isomeric patients have less severe complications, as they typically have 2 functional ventricles. In this case, they can undergo biventricular repair to form 2 separate ventricles and functional associated valves.
Prognosis
Prognosis for patients with situs ambiguus is quite varied, owed to the spectrum of clinical manifestations. Infants who experience severe cyanosis at birth may die within hours of delivery if medical intervention is not immediate. Alternatively, longevity of neonates with mild cardiac lesions is unaffected. Ten percent of patients born with right atrial isomerism die by the age of 5 without intervention. Improvements in therapies has increased the 5-year survival to 30–74% for right atrial isomeric patients and 65–84% for left atrial isomeric patients based on the cause of their disease.
Research
There have been vast amounts of research on the clinical features, racial disparities, and physiological mechanisms of heterotaxy syndrome dating back to 1973.
Mishra et al. published a review in November 2015 describing current knowledge of cardiac and non-cardiac abnormalities associated with situs ambiguus. The author stresses the importance of genetic testing prior to deciding a prognosis for affected patients. She also proposes prenatal screening and evaluation in cases at risk for development of situs ambiguus.
Recent studies have shown higher rates of heterotaxy syndrome among Hispanic infants of Mexican descent, as well as female infants of non-Hispanic black and white mothers. Additional studies must be done to clarify the mechanisms behind racial disparities in heterotaxy syndrome. Individuals of Asian descent show a higher prevalence of heterotaxy syndrome in general than members of the Western world.The National Birth Defects Prevention study (October 2014) attempted to link clinical presentations of situs ambiguus to demographics in an epidemiological study. This proved a difficult task due to the vast differences in presentation of this disorder. However, the authors are hopeful that finding a link can help inform clinical decision-making, predictive analyses, and future outcomes.
See also
References
External links
radio/639 at eMedicine |
Opsismodysplasia | Opsismodysplasia is a type of skeletal dysplasia (a bone disease that interferes with bone development) first described by Zonana and associates in 1977, and designated under its current name by Maroteaux (1984). Derived from the Greek opsismos ("late"), the name "opsismodysplasia" describes a delay in bone maturation. In addition to this delay, the disorder is characterized by micromelia (short or undersized bones), particularly of the hands and feet, delay of ossification (bone cell formation), platyspondyly (flattened vertebrae), irregular metaphyses, an array of facial aberrations and respiratory distress related to chronic infection. Opsismodysplasia is congenital, being apparent at birth. It has a variable mortality, with some affected individuals living to adulthood. The disorder is rare, with an incidence of less than 1 per 1,000,000 worldwide. It is inherited in an autosomal recessive pattern, which means the defective (mutated) gene that causes the disorder is located on an autosome, and the disorder occurs when two copies of this defective gene are inherited. No specific gene has been found to be associated with the disorder. It is similar to spondylometaphyseal dysplasia, Sedaghatian type.
Presentation
Opsismodysplasia can be characterized by a delay in bone maturation, which refers to "bone aging", an expected sequence of developmental changes in the skeleton corresponding to the chronological age of a person. Factors such as gender and ethnicity also play a role in bone age assessment. The only indicator of physical development that can be applied from birth through mature adulthood is bone age. Specifically, the age and maturity of bone can be determined by its state of ossification, the age-related process whereby certain cartilaginous and soft tissue structures are transformed into bone. The condition of epiphyseal plates (growth plates) at the ends of the long bones (which includes those of the arms, hands, legs and feet) is another measurement of bone age. The evaluation of both ossification and the state of growth plates in children is often reached through radiography (X-rays) of the carpals (bones of the hand and wrist). In opsismodysplasia, the process of ossification in long bones can be disrupted by a failure of ossification centers (a center of organization in long bones, where cartilage cells designated to await and undergo ossification gather and align in rows) to form. This was observed in a 16-month-old boy with the disorder, who had no apparent ossification centers in the carpals (bones of the hand and wrist) or tarsals (bones of the foot). This was associated with an absence of ossification in these bones, as well as disfigurement of the hands and feet at age two. The boy also had no ossification occurring in the lower femur (thigh bone) and upper tibia (the shin bone).
Genetics
Opsismodysplasia is inherited in an autosomal recessive manner. This means the defective gene(s) responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Currently, no specific mutation in any gene has been found to cause the disorder.It appears that the gene inositol polyphosphate phosphatase-like 1 is the cause of this condition in at least some cases.
Diagnosis
Epidemiology
Opsismodysplasia is a very rare disorder, and is estimated to occur in less than 1 in 1,000,000 people.
History
The disorder was first described by Jonathan Zonana and associates in 1977. Further observation of four cases of it was reported by Pierre Maroteaux and colleagues in 1982, and Maroteaux was the first to call the disorder "opsismodysplasia", in a 1984 journal report of three affected individuals. The name derives from the Greek opsismos, meaning "late", while the term dysplasia refers to development.
References
== External links == |
Vulvar intraepithelial neoplasia | Vulvar intraepithelial neoplasia (VIN) refers to particular changes that can occur in the skin that covers the vulva. VIN is an intraepithelial neoplasia, and can disappear without treatment. VINs are benign but if the changes become more severe, there is a chance of cancer developing after many years, and so it is referred to as a precancerous condition.
Classification
Medically speaking, the term denotes a squamous intraepithelial lesion of the vulva that shows dysplasia with varying degrees of atypia. The epithelial basement membrane is intact and the lesion is thus not invasive but has invasive potential.
The terminology of VIN evolved over several decades. In 1989 the Committee on Terminology, International Society for the Study of Vulvar Disease (ISSVD) replaced older terminology such as vulvar dystrophy, Bowens disease, and Kraurosis vulvae by a new classification system for Epithelial Vulvar Disease:
Nonneoplastic epithelial disorders of vulva and mucosa:
Lichen sclerosus
Squamous hyperplasia
Other dermatoses
Mixed neoplastic and nonneoplastic disorders
Intraepithelial neoplasia
Squamous vulvar intraepithelial neoplasia (VIN), previously classified as VIN 1-3:Non-squamous intraepithelial neoplasia
Extramammary Pagets disease
Tumors of melanocytes, noninvasive
Invasive disease (vulvar carcinoma)The ISSVD further revised this classification in 2004, replacing the three-grade system with a single-grade system in which only the high-grade disease is classified as VIN.
VIN is subdivided into: (Robbins Pathological Basis of Disease, 9th Ed)
Classic vulvular intraepithelial neoplasia: associated with developing into the warty and basaloid type carcinoma. This is associated with carcinogenic genotypes of HPV and/or HPV persistence factors such as cigarette smoking or immunocompromised states.
Differentiated vulvar intraepithelial neoplasia also known as VIN Simplex: is associated with vulvar dermatoses such as lichen sclerosus. It is associated with atypia of the squamous epithelium.
Risk factors
The exact cause of VIN is unknown. Studies are being done to determine the cause of VIN. The following factors have been associated with VIN:
HPV (Human Papilloma Virus)
HSV-2 (Herpes simplex Virus - Type 2)
Smoking
Immunosuppression
Chronic vulvar irritation
Conditions such as Lichen Sclerosus
Diagnosis
The person may have no symptoms, or local symptomatology including itching, burning, and pain.
The diagnosis is always based on a careful inspection and a targeted biopsy of a visible vulvar lesion.
The type and distribution of lesions varies among the two different types of VIN. In the Usual type VIN, seen more frequently in young patients, lesions tend to be multifocal over an otherwise normal vulvar skin. In the differentiated type VIN, usually seen in postmenopausal women, lesions tend to be isolated and are located over a skin with a vulvar dermatosis such as Lichen slerosus.
Prevention
Vaccinating girls with HPV vaccine before their initial sexual contact has been claimed to reduce incidence of VIN.
References
External links
VIN at DermNet.NZ |
Crouzon syndrome | Crouzon syndrome is an autosomal dominant genetic disorder known as a branchial arch syndrome. Specifically, this syndrome affects the first branchial (or pharyngeal) arch, which is the precursor of the maxilla and mandible. Since the branchial arches are important developmental features in a growing embryo, disturbances in their development create lasting and widespread effects.
This syndrome is named after Octave Crouzon, a French physician who first described this disorder. First called "craniofacial dysostosis" ("craniofacial" refers to the skull and face, and "dysostosis" refers to malformation of bone), the disorder was characterized by a number of clinical features which can be described by the rudimentary meanings of its former name. This syndrome is caused by a mutation in the fibroblast growth factor receptor 2 (FGFR2), located on chromosome 10. The developing fetuss skull and facial bones fuse early or are unable to expand. Thus, normal bone growth cannot occur. Fusion of different sutures leads to abnormal patterns of growth of the skull.
Signs and symptoms
A defining characteristic of Crouzon syndrome is craniosynostosis, which results in an abnormal head shape. This is present in combinations of: frontal bossing, trigonocephaly (fusion of the metopic suture), brachycephaly (fusion of the coronal suture), dolichocephaly (fusion of the sagittal suture), plagiocephaly (unilateral premature closure of lambdoid and coronal sutures), oxycephaly (fusion of coronal and lambdoidal sutures), and complex craniosynostosis (premature closure of some or all sutures).Exophthalmos (bulging eyes due to shallow eye sockets after early fusion of surrounding bones), hypertelorism (greater than normal distance between the eyes), and psittichorhina (beak-like nose) are also very common features. Other facial characteristics that are present in many cases include external strabismus and hypoplastic maxilla (insufficient growth of the midface), which results in relative mandibular prognathism (protruding chin) and gives the effect of the patient having a concave face.Most symptoms are secondary to the abnormal skull structure. Approximately 30% of people with Crouzon syndrome develop hydrocephalus. Sensorineural hearing loss is present in some cases. The abnormalities in the manner in which the eyes fit in the eye sockets can cause vision problems, the most common of which is corneal exposure that can lead to visual impairment. Some people with the condition have a restricted airway and can experience severe problems breathing.Common features are a narrow/high-arched palate, posterior bilateral crossbite, hypodontia (missing some teeth), and crowding of teeth. Due to maxillary hypoplasia, people with Crouzon syndrome generally have a considerable permanent underbite.
Causes
The current research indicates fibroblast growth factor receptors (FGFR) FGFR2 and FGFR3 as the leading factors in causing the autosomal dominant Crouzon syndrome. These two transmembrane proteins are two of four fibroblast growth factor receptors involved in osteoblast differentiation during embryonic development; mutations amongst these receptors are involved in several genetic disorders.There are 40 known mutations, most of which are caused by a missense mutation. FGFR2 is the most commonly mutated gene, a missense at cysteine 342 in exon 9, which creates a gain-of-function. The FGFR2lllc isoform, created via alternative splicing of exon 3 of the FGFR2 gene, uses exon 9 and is used in mesenchymal stem cells to control ossification. However, the mutation constitutively activates the transmembrane protein via a disulfide bond formed incorrectly due to the loss of cysteine 342. FGFR3 is expressed more in the frontal bones during embryonic development, guiding cranial bone development. A point mutation causes constitutive activation of tyrosine in the activation loop, located in the cytosolic region of the protein, leading to accelerated differentiation of frontal osteoblasts, resulting in premature fusion of frontal cranial bones.
Diagnosis
Diagnosis of Crouzon syndrome usually can occur at birth by assessing the physical appearance of the infant. Further analysis, including radiographs, magnetic resonance imaging (MRI) scans, genetic testing and CT scans can be used to confirm the diagnosis of Crouzon syndrome.
Treatment
Surgery is typically used to prevent the closure of sutures of the skull from damaging the brains development. Without surgery, blindness and intellectual disability are typical outcomes. To move the orbits forward, surgeons expose the skull and orbits and reshape the bone. To treat the midface deficiency, surgeons can move the lower orbit and midface bones forward.People with Crouzon syndrome tend to have multiple sutures involved, most specifically bilateral coronal craniosynostoses, and either open vault surgery or strip craniectomy (if the child is under 6 months) can be performed. In the latter scenario, a helmet is worn for several months following surgery.Once treated for the cranial vault abnormalities, Crouzon patients generally go on to live a normal lifespan.
Epidemiology
Incidence of Crouzon syndrome is currently estimated at 1.6 out of every 100,000 people. It is the most common craniostenosis syndrome.
History
Crouzon syndrome was first described by Octave Crouzon in 1912. He noted the affected patients were a mother and her daughter, implying a genetic basis.
See also
Apert syndrome
Treacher Collins syndrome
Hearing loss with craniofacial syndromes
References
External links
Crouzon syndrome on Genetics Home Reference from U.S. National Library of Medicine & National Institutes of Health
GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes |
Pelvic organ prolapse | Pelvic organ prolapse (POP) is characterized by descent of pelvic organs from their normal positions. In women, the condition usually occurs when the pelvic floor collapses after gynecological cancer treatment, childbirth or heavy lifting.In men, it may occur after the prostate gland is removed. The injury occurs to fascia membranes and other connective structures that can result in cystocele, rectocele or both. Treatment can involve dietary and lifestyle changes, physical therapy, or surgery.
Types
Anterior vaginal wall prolapse
Cystocele (bladder into vagina)
Urethrocele (urethra into vagina)
Cystourethrocele (both bladder and urethra)
Posterior vaginal wall prolapse
Enterocele (small intestine into vagina)
Rectocele (rectum into vagina)
Sigmoidocele
Apical vaginal prolapse
Uterine prolapse (uterus into vagina)
Vaginal vault prolapse (roof of vagina) – after hysterectomy
Grading
Pelvic organ prolapses are graded either via the Baden–Walker System, Shaws System, or the Pelvic Organ Prolapse Quantification (POP-Q) System.
Shaws System
Anterior wall
Upper 2/3 cystocele
Lower 1/3 urethrocelePosterior wall
Upper 1/3 enterocele
Middle 1/3 rectocele
Lower 1/3 deficient perineumUterine prolapse
Grade 0 Normal position
Grade 1 descent into vagina not reaching introitus
Grade 2 descent up to the introitus
Grade 3 descent outside the introitus
Grade 4 Procidentia
Baden–Walker
POP-Q
Management
Vaginal prolapses are treated according to the severity of symptoms.
Non-surgical
With conservative measures, such as changes in diet and fitness, Kegel exercises, and pelvic floor physical therapy.With a pessary, a rubber or silicone rubber device fitted to the patient which is inserted into the vagina and may be retained for up to several months. Pessaries are a good choice of treatment for women who wish to maintain fertility, are poor surgical candidates, or who may not be able to attend physical therapy. Pessaries require a provider to fit the device, but most can be removed, cleaned, and replaced by the woman herself. Pessaries should be offered to women considering surgery as a non-surgical alternative.
Surgery
With surgery (for example native tissue repair, biological graft repair, absorbable and non-absorbable mesh repair, colpopexy, colpocleisis). Surgery is used to treat symptoms such as bowel or urinary problems, pain, or a prolapse sensation. Evidence does not support the use of transvaginal surgical mesh compared with native tissue repair for anterior compartment prolapse owing to increased morbidity. For posterior vaginal repair, the use of mesh or graft material does not seem to provide any benefits. Safety and efficacy of many newer meshes is unknown. The use of a transvaginal mesh in treating vaginal prolapses is associated with side effects including pain, infection, and organ perforation. Transvaginal repair seems to be more effective than transanal repair in posterior wall prolapse, but adverse effects cannot be excluded. According to the FDA, serious complications are "not rare." A number of class action lawsuits have been filed and settled against several manufacturers of TVM devices.Compared to native tissue repair, transvaginal permanent mesh probably reduces womens perception of vaginal prolapse sensation and probably reduces the risk of recurrent prolapse and of having repeat surgery for prolapse. On the other hand, transvaginal mesh probably has a greater risk of bladder injury and of needing repeat surgery for stress urinary incontinence or mesh exposure. When operating a pelvic organ prolapse, introducing a mid-urethral sling during or after surgery seems to reduce stress urinary incontinence.
Epidemiology
Genital prolapse occurs in about 316 million women worldwide as of 2010 (9.3% of all females).
Research
To study POP, various animal models are employed: non-human primates, sheep, pigs, rats, and others.
See also
Perineometer
Pessary
References
== External links == |
Delirium | Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances in attention, consciousness, and cognition. It may also involve other neurological deficits, such as psychomotor disturbances (e.g. hyperactive, hypoactive, or mixed), impaired sleep-wake cycle, emotional disturbances, and perceptual disturbances (e.g. hallucinations and delusions), although these features are not required for diagnosis.
Delirium is caused by an acute organic process, which is a physically identifiable structural, functional, or chemical problem in the brain that may arise from a disease process outside the brain that nonetheless affects the brain. It may result from an underlying disease process (e.g. infection, hypoxia), side effect of a medication, withdrawal from drugs, over-consumption of alcohol, usage of hallucinogenic deliriants, or from any number of factors affecting ones overall health (e.g. malnutrition, pain, etc.). In contrast, fluctuations in mental status/function due to changes in primarily psychiatric processes or diseases (e.g. schizophrenia, bipolar disorder) do not, by definition, meet the criteria for delirium.Delirium may be difficult to diagnose without the proper establishment of a persons usual mental function. Without careful assessment and history, delirium can easily be confused with a number of psychiatric disorders or chronic organic brain syndromes because of many overlapping signs and symptoms in common with dementia, depression, psychosis, etc. Delirium may manifest from a baseline of existing mental illness, baseline intellectual disability, or dementia, without being due to any of these problems.
Treatment of delirium requires identifying and managing the underlying causes, managing delirium symptoms, and reducing the risk of complications. In some cases, temporary or symptomatic treatments are used to comfort the person or to facilitate other care (e.g. preventing people from pulling out a breathing tube). Antipsychotics are not supported for the treatment or prevention of delirium among those who are in hospital; however they will be used in cases where a patient has a history of anxiety, hallucinations or if they are a danger to themselves or others. When delirium is caused by alcohol or sedative hypnotic withdrawal, benzodiazepines are typically used as a treatment. There is evidence that the risk of delirium in hospitalized people can be reduced by systematic good general care. In a DSM assessment, delirium was found to affect 14–24% of all hospitalized individuals, with an overall prevalence for the general population as 1–2%, increasing with age, reaching 14% of adults over age 85. Among older adults, delirium was found to occur in 15–53% of those post-surgery, 70–87% of those in the ICU, and in up to 60% of those in nursing homes or post-acute care settings. Among those requiring critical care, delirium is a risk for death within the next year.
Definition
In common usage, delirium is often used to refer to drowsiness, disorientation, and hallucination. In medical terminology, however, acute disturbance in consciousness/attention and a number of different cognitive symptoms are the core features of delirium.
Several medical definitions of delirium exist (including those in the DSM and ICD-10), but the core features remain the same. In 2013, the American Psychiatric Association released the fifth edition of the DSM (DSM-5) with the following criteria for diagnosis:
A. Disturbance in attention and awareness. This is a required symptom and involves easy distraction, inability to maintain attentional focus, and varying levels of alertness.
B. Onset is acute (from hours to days), representing a change from baseline mentation with fluctuations throughout the day
C. At least one additional cognitive disturbance (in memory, orientation, language, visuospatial ability, or perception)
D. The disturbances (criteria A and C) are not better explained by another neurocognitive disorder
E. There is evidence that the disturbances above are a "direct physiological consequence" of another medical condition, substance intoxication or withdrawal, toxin, or various combinations of causes
Signs and symptoms
Delirium exists as a stage of consciousness somewhere in the spectrum between normal awakeness/alertness and coma. While requiring an acute disturbance in consciousness/attention and cognition, delirium is a syndrome encompassing an array of neuropsychiatric symptoms.The range of clinical features include: poor attention/vigilance (100%), memory impairment (64–100%), clouding of consciousness (45–100%), disorientation (43–100%), acute onset (93%), disorganized thinking/thought disorder (59–95%), diffuse cognitive impairment (77%), language disorder (41–93%), sleep disturbance (25–96%), mood lability (43–63%), psychomotor changes (e.g. hyperactive, hypoactive, mixed) (38–55%), delusions (18–68%), and perceptual change/hallucinations (17–55%). These various features of delirium are further described below:
Inattention: As a required symptom to diagnose delirium, this is characterized by distractibility and an inability to shift and/or sustain attention.
Memory impairment: Memory impairment is linked to inattention, especially reduced formation of new long-term memory where higher degrees of attention is more necessary than for short-term memory. Since older memories are retained without need of concentration, previously formed long-term memories (i.e. those formed before the onset of delirium) are usually preserved in all but the most severe cases of delirium.
Disorientation: As another symptom of confusion, and usually a more severe one, this describes the loss of awareness of the surroundings, environment and context in which the person exists. One may be disoriented to time, place, or self.
Disorganized thinking: Disorganized thinking is usually noticed with speech that makes limited sense with apparent irrelevancies, and can involve poverty of speech, loose associations, perseveration, tangentiality, and other signs of a formal thought disorder.
Language disturbances: Anomic aphasia, paraphasia, impaired comprehension, agraphia, and word-finding difficulties all involve impairment of linguistic information processing.
Sleep changes: Sleep disturbances in delirium reflect disturbed circadian rhythm regulation, typically involving fragmented sleep or even sleep-wake cycle reversal (i.e. active at night, sleeping during the day) and often preceding the onset of a delirium episode
Psychotic symptoms: Symptoms of psychosis include suspiciousness, overvalued ideation and frank delusions. Delusions are typically poorly formed and less stereotyped than in schizophrenia or Alzheimers disease. They usually relate to persecutory themes of impending danger or threat in the immediate environment (e.g. being poisoned by nurses).
Mood lability: Distortions to perceived or communicated emotional states as well as fluctuating emotional states can manifest in a delirious person (e.g. rapid changes between terror, sadness and joking).
Motor activity changes: Delirium has been commonly classified into psychomotor subtypes of hypoactive, hyperactive, and mixed, though studies are inconsistent as to the prevalence of these subtypes. Hypoactive cases are prone to non-detection or misdiagnosis as depression. A range of studies suggest that motor subtypes differ regarding underlying pathophysiology, treatment needs, and prognosis for function and mortality though inconsistent subtype definitions and poorer detection of hypoactive subtypes impacts interpretation of these findings. Liptzin and Levkoff first described these subtypes in 1992 as following:
Hyperactive symptoms include hyper-vigilance, restlessness, fast or loud speech, irritability, combativeness, impatience, swearing, singing, laughing, uncooperativeness, euphoria, anger, wandering, easy startling, fast motor responses, distractibility, tangentiality, nightmares, and persistent thoughts (hyperactive sub-typing is defined with at least three of the above).
Hypoactive symptoms include unawareness, decreased alertness, sparse or slow speech, lethargy, slowed movements, staring, and apathy (hypoactive sub-typing is defined with at least four of the above).
Causes
Delirium arises through the interaction of a number of predisposing and precipitating factors.Individuals with multiple and/or significant predisposing factors are at high risk for an episode of delirium with a single and/or mild precipitating factor. Conversely, delirium may only result in low risk individuals if they experience a serious or multiple precipitating factors. It is important to note that the factors affecting those of an individual can change over time, thus an individuals risk of delirium is dynamic.
Predisposing factors
The most important predisposing factors are:
65 or more years of age
Male sex
Cognitive impairment/dementia
Physical comorbidity (biventricular failure, cancer, cerebrovascular disease)
Psychiatric comorbidity (e.g., depression)
Sensory impairment (vision, hearing)
Functional dependence (e.g., requiring assistance for self-care or mobility)
Dehydration/malnutrition
Drugs and drug-dependence
Alcohol dependence
Precipitating factors
Any acute factors that affect neurotransmitter, neuroendocrine, or neuroinflammatory pathways can precipitate an episode of delirium in a vulnerable brain. Clinical environments can also precipitate delirium. Some of the most common precipitating factors are listed below:
Prolonged sleep deprivation
Environmental, physical/psychological stress
Inadequately controlled pain
Admission to an intensive care unit
Immobilization, use of physical restraints
Urinary retention, use of bladder catheter,
Emotional stress
Severe constipation/fecal impaction
MedicationsSedatives (benzodiazepines, opioids), anticholinergics, dopaminergics, corticosteroids, polypharmacy
General anesthetic
Substance intoxication or withdrawal
Primary neurologic diseases
Severe drop in blood pressure, relative to the patients normal blood pressure (orthostatic hypotension) resulting in inadequate blood flow to the brain (cerebral hypoperfusion)
Stroke/Transient ischemic attack(TIA)
Intracranial bleeding
Meningitis, encephalitis
Concurrent illness
Infections – especially respiratory (e.g. pneumonia, COVID-19) and urinary tract infections
Iatrogenic complications
Hypoxia, hypercapnea, anemia
Poor nutritional status, dehydration, electrolyte imbalances, hypoglycemia
Shock, heart attacks, heart failure
Metabolic derangements (e.g. SIADH, Addisons disease, hyperthyroidism, )
Chronic/terminal illness (e.g. cancer)
Post-traumatic event (e.g. fall, fracture)
Mercury poisoning (e.g. Erethism)
Surgery
Cardiac, orthopedic, prolonged cardiopulmonary bypass, thoracic surgeries
Pathophysiology
The pathophysiology of delirium is still not well understood, despite extensive research.
Animal models
The lack of animal models that are relevant to delirium has left many key questions in delirium pathophysiology unanswered. Earliest rodent models of delirium used atropine (a muscarinic acetylcholine receptor blocker) to induce cognitive and electroencephalography (EEG) changes similar to delirium, and other anticholinergic drugs, such as biperiden and hyoscine, have produced similar effects. Along with clinical studies using various drugs with anticholinergic activity, these models have contributed to a "cholinergic deficiency hypothesis" of delirium.Profound systemic inflammation occurring during sepsis is also known to cause delirium (often termed sepsis-associated encephalopathy). Animal models used to study the interactions between prior degenerative disease and overlying systemic inflammation have shown that even mild systemic inflammation causes acute and transient deficits in working memory among diseased animals. Prior dementia or age-associated cognitive impairment is the primary predisposing factor for clinical delirium and "prior pathology" as defined by these new animal models may consist of synaptic loss, abnormal network connectivity, and "primed microglia" brain macrophages stimulated by prior neurodegenerative disease and aging to amplify subsequent inflammatory responses in the central nervous system (CNS).
Cerebrospinal fluid
Studies of cerebrospinal fluid (CSF) in delirium are difficult to perform. Apart from the general difficulty of recruiting participants who are often unable to give consent, the inherently invasive nature of CSF sampling makes such research particularly challenging. However, a few studies have exploited the opportunity to sample CSF from persons undergoing spinal anesthesia for elective or emergency surgery.A 2018 systematic review showed that, broadly, delirium may be associated with neurotransmitter imbalance (namely serotonin and dopamine signaling), reversible fall in somatostatin, and increased cortisol. The leading "neuroinflammatory hypothesis" (where neurodegenerative disease and aging leads the brain to respond to peripheral inflammation with an exaggerated CNS inflammatory response) has been described, but current evidence is still conflicting and fails to concretely support this hypothesis.
Neuroimaging
Neuroimaging provides an important avenue to explore the mechanisms that are responsible for delirium. Despite progress in the development of magnetic resonance imaging (MRI), the large variety in imaging-based findings has limited our understanding of the changes in the brain that may be linked to delirium. Some challenges associated with imaging people diagnosed with delirium include participant recruitment and inadequate consideration of important confounding factors such as history of dementia and/or depression, which are known to be associated with overlapping changes in the brain also observed on MRI.Evidence for changes in structural and functional markers include: changes in white-matter integrity (white matter lesions), decreases in brain volume (likely as a result of tissue atrophy), abnormal functional connectivity of brain regions responsible for normal processing of executive function, sensory processing, attention, emotional regulation, memory, and orientation, differences in autoregulation of the vascular vessels in the brain, reduction in cerebral blood flow and possible changes in brain metabolism (including cerebral tissue oxygenation and glucose hypometabolism). Altogether, these changes in MRI-based measurements invite further investigation of the mechanisms that may underlie delirium, as a potential avenue to improve clinical management of people with this condition.
Neurophysiology
Electroencephalography (EEG) allows for continuous capture of global brain function and brain connectivity, and is useful in understanding real-time physiologic changes during delirium. Since the 1950s, delirium has been known to be associated with slowing of resting-state EEG rhythms, with abnormally decreased background alpha power and increased theta and delta frequency activity.From such evidence, a 2018 systematic review proposed a conceptual model that delirium results when insults/stressors trigger a breakdown of brain network dynamics in individuals with low brain resilience (i.e. people who already have underlying problems of low neural connectivity and/or low neuroplasticity like those with Alzheimers disease).
Neuropathology
Only a handful of studies exist where there has been an attempt to correlate delirium with pathological findings at autopsy. One research study has been reported on 7 patients who died during ICU admission. Each case was admitted with a range of primary pathologies, but all had acute respiratory distress syndrome and/or septic shock contributing to the delirium, 6 showed evidence of low brain perfusion and diffuse vascular injury, and 5 showed hippocampal involvement. A case-control study showed that 9 delirium cases showed higher expression of HLA-DR and CD68 (markers of microglial activation), IL-6 (cytokines pro-inflammatory and anti-inflammatory activities) and GFAP (marker of astrocyte activity) than age-matched controls; this supports a neuroinflammatory cause to delirium, but the conclusions are limited by methodological issues.A 2017 retrospective study correlating autopsy data with MMSE scores from 987 brain donors found that delirium combined with a pathological process of dementia accelerated MMSE score decline more than either individual process.
Diagnosis
Using the DSM-5 criteria for delirium as framework, the early recognition of signs/symptoms and a careful history, along with any of multiple clinical instruments, can help in making a diagnosis of delirium. A diagnosis of delirium cannot be made without a previous assessment of the patients baseline level of cognitive function. In other words, a mentally-disabled or impaired person might appear to be delirious, but may actually just be operating at their baseline mental ability.
General setting
Multiple guidelines recommend that delirium should be diagnosed when it presents to healthcare services. Much evidence reveal, however, that delirium is greatly under-diagnosed. Higher rates of detection of delirium in general settings can be assisted by the use of validated delirium screening tools. Many such tools have been published. They differ in duration, complexity, need for training, etc.
Examples of tools in use in clinical practice are:
Richmond Agitation and Sedation Scale (RASS) – highly sensitive and specific for diagnosing delirium in older patients
Observational Scale of Level of Arousal (OSLA) – highly sensitive and specific for diagnosing delirium in older patients
Confusion Assessment Method (CAM)
Delirium Observation Screening Scale (DOS)
Nursing Delirium Screening Scale (Nu-DESC)
Recognizing Acute Delirium As part of your Routine (RADAR)
4AT (4 As Test)
Delirium Diagnostic Tool-Provisional (DDT-Pro), also for subsyndromal delirium
Intensive care unit
People who are in the ICU are at greater risk of delirium and ICU delirium may lead to prolonged ventilation, longer stays in the hospital, increased stress on family and caregivers, and an increased chance of death. In the ICU, international guidelines recommend that every patient gets checked for delirium every day (usually twice or more a day) using a validated clinical tool. The definition of delirium that healthcare professionals use at the bedside is whether or not a patient can pay attention and follow simple commands. The two most widely used are the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC). Translations of these tools exist in over 20 languages and are used ICUs globally with instructional videos and implementation tips available.More emphasis is placed on regular screening over the choice of tool used. This, coupled with proper documentation and informed awareness by the healthcare team, can affect clinical outcomes. Without using one of these tools, 75% of ICU delirium can be missed by the healthcare team, leaving the patient without any likely interventions to help reduce the duration of delirium.
Differential diagnosis
There are conditions that might have similar clinical presentations to those seen in delirium. These include dementia, depression, psychosis, and other conditions that affect cognitive function.
Dementia: This group of disorders is acquired (non-congenital) with usually irreversible cognitive and psychosocial functional decline. Dementia usually results from an identifiable degenerative brain disease (e.g. Alzheimer disease or Huntingtons disease), requires chronic impairment (versus acute onset in delirium), and is typically not associated with changes in level of consciousness. Dementia is different from delirium in that dementia lasts long-term while delirium lasts short-term.
Depression: Similar symptoms exist between depression and delirium (especially the hypoactive subtype). Gathering a history from other caregivers can clarify baseline mentation.
Other mental illnesses: Some mental illnesses, such as a manic episode of bipolar disorder, depersonalization disorder, or some types of acute psychosis may cause a rapidly fluctuating impairment of cognitive function and ability to focus. These, however, are not technically causes of delirium per DSM-5 criteria D (i.e. fluctuating cognitive symptoms occurring as part of a primary mental disorder are results of the said mental disorder itself), while physical disorders (e.g. infections, hypoxia, etc.) can precipitate delirium as a mental side-effect/symptom.
Psychosis: Consciousness and cognition may not be impaired (however, there may be overlap, as some acute psychosis, especially with mania, is capable of producing delirium-like states).
Prevention
Using a tailored multi-faceted approach as outlined above can decrease rates of delirium by 27% among the elderly. At least 30–40% of all cases of delirium could be prevented, and high rates of delirium reflect negatively on the quality of care. Episodes of delirium can be prevented by identifying hospitalized people at risk of the condition. This includes individuals over age 65, with a cognitive impairment, with hip fracture, or with severe illness. Close observation for the early signs is recommended in such populations.
Delirium may be prevented and treated by using non-pharmacologic approaches focused on risk factors, such as constipation, dehydration, low oxygen levels, immobility, visual or hearing impairment, sleep deprivation, functional decline and removing or minimizing problematic medications. Ensuring a therapeutic environment (e.g. individualized care; clear communication; adequate reorientation and lighting during daytime; promoting uninterrupted sleep hygiene with minimal noise and light at night; minimizing bed relocation; having familiar objects like family pictures; providing earplugs; and providing adequate nutrition, pain control, and assistance toward early mobilization) can also yield benefit toward preventing delirium. Research into pharmacologic prevention and treatment is weak and insufficient to make proper recommendations.Melatonin and other pharmacological agents have been studied for prevention of postoperative delirium, but evidence is not clear. Avoidance or cautious use of benzodiazepines has been recommended for reducing the risk of delirium in critically ill individuals. It is unclear if the medication donepezil, a cholinesterase inhibitor, reduces delirium following surgery. There is also no clear evidence to suggest that citicoline, methylprednisolone, or antipsychotic medications prevent delirium.
A review of intravenous versus inhalational maintenance of anaesthesia for postoperative cognitive outcomes in elderly people undergoing non-cardiac surgery showed little or no difference in postoperative delirium according to the type of anaesthetic maintenance agents in five studies (321 participants). The authors of this review were uncertain whether maintenance of anaesthesia with propofol-based total intravenous anaesthesia (TIVA) or with inhalational agents can affect the incidence rate of postoperative delirium.
Interventions for preventing delirium in older people in institutional long-term care
The current evidence suggests that software-based interventions to identify medications that could contribute to delirium risk and recommend a pharmacists medication review probably reduces incidence of delirium in older adults in long-term care. The benefits of hydration reminders and education on risk factors and care homes solutions for reducing delirium is still uncertain.
Treatment
Delirium is a reversible impairment, however, people that are ill with delirium may need to be treated in order to prevent injury and poor outcomes.Treatment of delirium requires attention to multiple domains including: identify and treat the underlying medical disorder or cause(s), optimize physiology, optimize conditions for brain recovery, detect and manage distress and behavioral disturbances, maintaining mobility, provide rehabilitation through cognitive engagement and mobilization, communicate effectively with the patient and their carers, and provide adequate follow-up including consideration of possible dementia and post-traumatic stress. This involves optimizing oxygenation, hydration, nutrition, electrolytes/metabolites, comfort, mobilization, pain control, mental stress, therapeutic medication levels, and addressing any other possible predisposing and precipitating factors that might be disrupting brain function.
Multidomain interventions
These interventions are the first steps in managing acute delirium and there are many overlaps with delirium preventative strategies. In addition to treating immediate life-threatening causes of delirium (e.g. low O2, low blood pressure, low glucose, dehydration), interventions include optimizing the hospital environment by reducing ambient noise, providing proper lighting, offering pain relief, promoting healthy sleep-wake cycles, and minimizing room changes. Although multicomponent care and comprehensive geriatric care are more specialized for a person experiencing delirium, several studies have been unable to find evidence showing they reduce the duration of delirium.Family, friends, and other caregivers can offer frequent reassurance, tactile and verbal orientation, cognitive stimulation (e.g. regular visits, familiar objects, clocks, calendars, etc.), and means to stay engaged (e.g. making hearing aids and eyeglasses readily available). Sometimes verbal and non-verbal deescalation techniques may be required to offer reassurances and calm the person experiencing delirium. Restraints should rarely be used as an intervention for delirium. The use of restraints has been recognized as a risk factor for injury and aggravating symptoms, especially in older hospitalized people with delirium. The only cases where restraints should sparingly be used during delirium is in the protection of life-sustaining interventions, such as endotracheal tubes.Another approached called the "T-A-DA (tolerate, anticipate, dont agitate) method" can be an effective management technique for older people with delirium, where abnormal patient behaviors (including hallucinations and delusions) are tolerated and unchallenged, as long as caregiver and patient safety is not threatened. Implementation of this model may require a designated area in the hospital. All unnecessary attachments are removed to anticipate for greater mobility, and agitation is prevented by avoiding excessive reorientation/questioning.
Medications
Low-dose haloperidol when used short term (one week or less) is the most studied and standard drug for delirium. Evidence for efficacy of atypical antipsychotics (i.e. risperidone, olanzapine, ziprasidone, and quetiapine) is emerging, with the benefit for fewer side effects Use antipsychotic drugs with caution or not at all for people with conditions such as Parkinsons disease or dementia with Lewy bodies. Evidence for the effectiveness of medications (including antipsychotics and benzodiazepines) in treating delirium is weak.Benzodiazepines themselves can trigger or worsen delirium, and there is no reliable evidence for use in non-alcohol-related delirium. If the delirium involves alcohol withdrawal, benzodiazepine withdrawal, or contraindications to antipsychotics (e.g. in Parkinsons disease or neuroleptic malignant syndrome), then benzodiazepines are recommended. Similarly, people with dementia with Lewy bodies may have significant side effects to antipsychotics, and should either be treated with a none or small doses of benzodiazepines.The antidepressant trazodone is occasionally used in the treatment of delirium, but it carries a risk of over-sedation, and its use has not been well studied.For adults with delirium that are in the ICU, medications are used commonly to improve the symptoms. Dexmedetomidine may shorten the length of the delirium in adults who are critically ill and rivastigmine is not suggested. For adults with delirium who are near the end of their life (on palliative care) high quality evidence to support or refute the use of most medications to treat delirium is not available. Low quality evidence indicates that the antipsychotic medications risperidone or haloperidol may make the delirium slightly worse in people who are terminially ill, when compared to a placebo treatment. There is also moderate to low quality evidence to suggest that haloperidol and risperidone may be associated with a slight increase in side effects, specifically extrapyramidol symptoms, if the person near the end of their life has delirium that is mild to moderate in severity.
Prognosis
There is substantial evidence that delirium results in long-term poor outcomes in older persons admitted to hospital. This systematic review only included studies that looked for an independent effect of delirium (i.e., after accounting for other associations with poor outcomes, for example co-morbidity or illness severity).
In older persons admitted to hospital, individuals experiencing delirium are twice as likely to die than those who do not (meta-analysis of 12 studies). In the only prospective study conducted in the general population, older persons reporting delirium also showed higher mortality (60% increase). A large (N=82,770) two-centre study in unselected older emergency population found that delirium detected as part of normal care using the |
Delirium | 4AT tool was strongly linked to 30-day mortality, hospital length of stay, and days at home in the year following the 4AT test date.Institutionalization was also twice as likely after an admission with delirium (meta-analysis of 7 studies). In a community-based population examining individuals after an episode of severe infection (though not specifically delirium), these persons acquired more functional limitations (i.e. required more assistance with their care needs) than those not experiencing infection. After an episode of delirium in the general population, functional dependence increased threefold.The association between delirium and dementia is complex. The systematic review estimated a 13-fold increase in dementia after delirium (meta-analysis of 2 studies). However, it is difficult to be certain that this is accurate because the population admitted to hospital includes persons with undiagnosed dementia (i.e. the dementia was present before the delirium, rather than caused by it). In prospective studies, people hospitalised from any cause appear to be at greater risk of dementia and faster trajectories of cognitive decline, but these studies did not specifically look at delirium. In the only population-based prospective study of delirium, older persons had an eight-fold increase in dementia and faster cognitive decline. The same association is also evident in persons already diagnosed with Alzheimers dementia.Recent long-term studies showed that many patients still meet criteria for delirium for a prolonged period after hospital discharge, with up to 21% of patients showing persistent delirium at 6 months post-discharge.
Dementia in ICU survivors
Dementia is supposed to be an entity that continues to decline, such as Alzheimers disease. Another way of looking at dementia, however, is not strictly based on the decline component, but on the degree of memory and executive function problems. It is now known, for example, that between 50% and 70% of ICU patients have tremendous problems with ongoing brain dysfunction similar to those experienced by Alzheimers or TBI (traumatic brain injury) patients, leaving many ICU survivors permanently disabled. This is a distressing personal and public health problem and is getting an increasing amount of scrutiny in ongoing investigations.The implications of such an "acquired dementia-like illness" can profoundly debilitate a persons livelihood level, often dismantling his/her life in practical ways like impairing ones ability to find a car in a parking lot, complete shopping lists, or perform job-related tasks done previously for years. The societal implications can be enormous when considering work-force issues related to the inability of wage-earners to work due to their own ICU stay or that of someone else they must care for.
Epidemiology
The highest rates of delirium (often 50% to 75% of people) is seen among those who are critically ill in the intensive care unit (ICU) As a result, this was referred to as "ICU psychosis" or "ICU syndrome", terms largely abandoned for the more widely accepted term ICU delirium. Since the advent of validated and easy-to-implement delirium instruments for ICU patients such as the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checkllist (IC-DSC)., of the hundreds of thousands of ICU patients who develop delirium in ICUs every year, it has been recognized that most of them belong to the hypoactive variety, which is easily missed and invisible to the managing teams unless actively monitored using such instruments. The causes of delirium in such patients depend on the underlying illnesses, new problems like sepsis and low oxygen levels, and the sedative and pain medicines that are nearly universally given to all ICU patients. Outside the ICU, on hospital wards and in nursing homes, the problem of delirium is also a very important medical problem, especially for older patients.The most recent area of the hospital in which delirium is just beginning to be monitored routinely in many centers is the Emergency Department, where the prevalence of delirium among older adults is about 10%. A systematic review of delirium in general medical inpatients showed that estimates of delirium prevalence on admission ranged from 10 to 31%. About 5% to 10% of older adults who are admitted to hospital develop a new episode of delirium while in hospital. Rates of delirium vary widely across general hospital wards. Estimates of the prevalence of delirium in nursing homes are between 10% to 45%.
Society and culture
Delirium is one of the oldest forms of mental disorder known in medical history. The Roman author Aulus Cornelius Celsus used the term to describe mental disturbance from head trauma or fever in his work De Medicina.English medical writer Philip Barrow noted in 1583 that if delirium (or "frenisy") resolves, it may be followed by a loss of memory and reasoning power.Sims (1995, p. 31) points out a "superb detailed and lengthy description" of delirium in "The Strollers Tale" from Charles Dickens The Pickwick Papers.The American Delirium Society is a community of professionals dedicated to improving delirium care." The Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center is an academic center dedicated to studying and treating delirium in critically ill patient populations.
Costs
In the US, the cost of a patient admission with delirium is estimated at between $16k and $64k, suggesting the national burden of delirium may range from $38 bn to $150 bn per year (2008 estimate). In the UK, the cost is estimated as £13k per admission.
References
Further reading
== External links == |
Metachondromatosis | Metachondromatosis is an autosomal dominant, incompletely penetrant genetic disease affecting the growth of bones, leading to exostoses primarily in the hands and feet as well as enchondromas of long bone metaphyses and iliac crests. This syndrome affects mainly tubular bones, though it can also involve the vertebrae, small joints, and flat bones. The disease is thought to affect exon 4 of the PTPN11 gene. Metachondromatosis is believed to be caused by an 11 base pair deletion resulting in a frameshift and nonsense mutation. The disease was discovered and named in 1971 by Pierre Maroteaux, a French physician, when he observed two families with skeletal radiologic features with exostoses and Ollier disease. The observation of one family with five affected people led to the identification of the disease as autosomal dominant. There have been less than 40 cases of the disease reported to date.
Signs and Symptoms
Metachondromatosis is identified by the presence of both multiple enchondromas and osteochondromas in the patient, although other less characteristic symptoms are often associated with the disease. The symptoms usually become apparent in the first 10 years of life and disappear later in life. The symptoms of Metachondromatosis are seen as follows:
Enchondromas
Enchondromas are benign tumors present on the inside of bones. In Metachondromatosis, enchondromas involves the iliac crests and metaphyses of long bones, often the proximal femur. Usually, these tumors are painless; however, when present in the hands or feet, or in multiple lesions, as typically seen, bone deformity can occur.
Osteochondromas
Osteochondromas are benign tumors located on the surface of bone near growth plates. These tumors also often in the hands and feet, primarily affecting the digits of fingers and toes. These tumors tend to subside after 10-20 years of life. These tumors can become painful if they pressure sensitive tissue or nerves. Metachondromatosis is differentiated from hereditary multiple osteochondromas by the location of the location of Osteochondromas tumors as well as the lack of bone-shortening.
Abnormality of epiphysis morphology
The epiphysis is the rounded end part of bone. The structure of the epiphysis can be abnormal in metachondromatosis.
Abnormality of the metaphysis
The metaphysis is wide portion of a long bone, and also has abnormal structure in the disease.
Avascular necrosis
Avascular necrosis is the death of bone due to a decreased blood supply.
Bone pain
People with metachondromatosis often experience bone pain due to abnormal bone shapes.
Cranial nerve paralysis
Cranial nerve paralysis can affect the functions associated with the cranial nerve.
Genetics
Metachondromatosis is inherited in an autosomal dominant manner, needing only one copy of the defective gene to cause the disorder. The cause of the disorder has been linked to an 11 base pair deletion in exon four of the PTPN11 gene (12q24.13). This deletion causes a frameshift, resulting in a nonsense mutation with a premature stop codon. This causes severe truncation and loss of function in the gene’s protein product, tyrosine phosphatase SHP-2. SHP-2 plays an important role in regulating expression of the Indian Hedgehog gene (IHH), which is associated with differentiation in chondrocytes (specialized cells in cartilage tissue). Individuals affected by metachondromatosis generally demonstrate high levels of IHH expression, which is believed to be responsible for the tumor growth. Given that the mutation causes a loss of protein function and displays a dominant inheritance pattern, it is hypothesized that individuals homozygous for the disorder would display greater symptoms than heterozygous individuals, though insufficient data is available to evaluate these claims due to the rarity of the disease. Conversely, some heterozygous individuals have shown minimal effects, leading to the disorder’s designation as incompletely penetrant. The cause of this is not fully understood, but may be due to other factors influencing IHH expression.
Diagnosis
Because of its rarity, metachondromatosis is often a difficult disease to recognize and diagnose. Diagnosis can be made based on clinical observations and radiographic findings as well as family history. Using radiographic methods, osteochondromas can be seen at the metaphyses of the short tubular bones, such as those in the hands and feet, pointing towards the joints. Enchondromas would also be visible along with the osteochondromas. The differential diagnosis includes hereditary multiple osteochondromas. This is a condition in which the long bones are primarily affected, and the lesions point away from the joint or growth plate. This may also result in the shortening or deformity of the affected bones. Since metachondromatosis is hereditary, genetic counseling can be offered to patients and their families. Some available genetic tests for metachondromatosis are sequence analysis of the entire coding region, targeted variant analysis, deletion/duplication analysis, and a sequence analysis of select exons associated with the disorder.
Treatment
Osteochondromas are usually painless, and in many cases, they spontaneously regress after the first or second decade of life. Most patients are asymptomatic, making medical intervention unnecessary. However, in extreme cases such as severe malalignment of the fingers and toes, surgery can be used to remove the osteochondromas.
Epidemiology
Metachondromatosis is very rare, occurring in less than 1 in 1,000,000 people. Fewer than 40 cases have been reported around the world to date.
References
== External links == |
Subcortical dementia | Subcortical dementias includes those diseases which predominantly affects the basal ganglia along with features of cognitive decline.
Diseases such as progressive supranuclear palsy, Huntingtons chorea and Parkinsons disease are different in many features from the other cortical dementias like Alzheimers disease. Yet these patients present clinically with mild forgetfulness and slowed thought process along with abnormal movements and problems with motility.
Clinical features
Clinically subcortical dementia usually is seen with features like slowness of mental processing, forgetfulness, impaired cognition, lack of initiative-apathy, depressive symptoms (such as anhedonia, negative thoughts, loss of self-esteem and dysphoria), loss of social skills along with extrapyramidal features like tremors and abnormal movements.In most of the patients with Huntingtons diseases the first clinical feature to appear is the change in personality. The dementia is more severe in patients with early onset of Huntingtons disease.
Parkinsons disease is characterised by features of dementia in older age. The adult type "leukodystrophy" also causes subcortical dementia with prominent frontal lobe features.
As a general rule the earliest symptoms in "cortical" dementia include difficulty with high-level behaviors such as memory, language, problem-solving and reasoning, mathematics and abstract thoughts – functions associated with the cerebral cortex. Such patients have prominent apraxia and agnosia.
However, in "subcortical" dementia these high-level behaviours are less affected.
Pathophysiology
In most common types of dementias there is widespread degeneration in the cerebral cortex – such as the plaques and neuro fibrillary tangles which are the hallmark of Alzheimers disease. In subcortical dementia, there is targeted damage to regions lying under the cortex.
The pathological process that result in subcortical dementia shows neuronal changes that involve primarily the thalamus, basal ganglia, and rostral brain-stem nuclei and mostly, some projections in the white matter from these regions to the cortex, with relative sparing of the cerebral cortex.
It affects arousal, attention, mood, motivation, language, memory, abstraction, social skills (especially empathy), extrapyramidal functions, and visuospatial skills. Additionally, damage to the basal forebrain can cause amnesia and psychotic disorders.
Controversy
One of the problems with the concept of subcortical dementia is the fact that name implies that it is due to lesions confined to subcortical structures. Anatomically none of the neurodegenerative dementias are strictly cortical or subcortical. In fact, there is invariably an overlap of both cortical and subcortical neuronal changes in both types.
History
Charcot described dementia as a feature in Parkinsons disease. McHugh introduced the concept of subcortical dementia.Mayeux and Stern and their colleagues and Tierney and coworkers have been critical of the concept of subcortical dementia.
Examples
Progressive supranuclear palsy (chronic acetogenin poisoning)
Atypical Parkinsonism
Binswanger disease (and other forms of vascular dementia)
Corticobasal degeneration
Huntington disease
Multiple system atrophy
HIV-associated neurocognitive disorder (HAND)
HIV-associated dementia
== References == |
Subcutaneous fat necrosis of the newborn | Subcutaneous fat necrosis of the newborn is a rare form of lobular panniculitis occurring in newborns that is usually self-remitting and non-recurring. Proposed causes include perinatal stress, local trauma, hypoxia and hypothermia, though the exact cause is unknown. It has been suggested that the brown fat seen in newborns is more sensitive to hypoxic injury than fat seen in adults, and that such hypoxia, usually in the context of a complicated birth, leads to the fat necrosis. Complications can include hypercalcemia, hyperlipidemia, dehydration, hypoglycemia, seizures, vomiting, constipation, and thrombocytopenia, and can present months after the onset of SCFN symptoms.: 490
See also
Pancreatic panniculitis
Panniculitis
References
External links
eMedicine entry for Subcutaneous fat necrosis of the newborn |
Papular mucinosis of infancy | Papular mucinosis of infancy is a skin condition caused by fibroblasts producing abnormally large amounts of mucopolysaccharides, characterized by skin-colored or translucent papules.: 186
See also
Papular mucinosis
List of cutaneous conditions
== References == |
Ovotestis | An ovotestis is a gonad with both testicular and ovarian aspects. In humans, ovotestes are an infrequent anatomical variation associated with gonadal dysgenesis. The only mammals where ovotestes are not symptomatic of an intersex variation are moles, wherein females possess ovotestes along with a masculinized clitoris. These ovotestes in nonpregnant female moles secrete eight times as much testosterone as the ovotestes of pregnant moles. In invertebrates that are normally hermaphroditic, such as most gastropods (snails and slugs) in the clade Eupulmonata, an ovotestis is a common feature of the reproductive anatomy.
In mice, ovotestes are structured such that the central region is testicular tissue while the poles both contain ovarian tissue. Experiments involving the SOX9 gene, which is initiated by the SRY region of the Y chromosome, have shown the gene’s requirement for testicular differentiation from the presence of ovotestis formation within XX Sox9 trangenic mice. (6) Ovotestis within B6-XYPOS mice allow for gonadal development research within the same tissue to take place in ways previously unavailable.
In gastropods
An ovotestis or hermaphroditic gland (Latin: glandula hermaphroditica), is found as normal anatomical feature in the reproductive system of some gastropods including such species as the land snail Cornu aspersum.
People with Ovotestis
Anton Krzyzanowski
See also
Intersex
True hermaphroditism
== References == |
Supernumerary phantom limb | Supernumerary phantom limb is a condition where the affected individual believes and receives sensory information from limbs of the body that do not actually exist, and never have existed, in contradistinction to phantom limbs, which appear after an individual has had a limb removed from the body and still receives input from it.
An fMRI study of a subject with a supernumerary phantom left arm was done by Khateb et al. at the Laboratory of Experimental Neuropsychology at the University of Geneva. When the subject was told to touch her right cheek with the phantom limb, there was increased activity in the motor cortex of her brain in the area roughly corresponding to the left arm. When she announced that she had touched the phantom limb to her cheek, activity was monitored in the area of the somatosensory cortex that corresponded to the right cheek. At times during the experiment, the subject was asked to move the phantom limb to a location that was obstructed or otherwise unfeasible. In these instances, there was similar activation of the motor cortex but no such activity in the somatosensory cortex.
Affected areas of the brain
Motor cortex
Somatosensory cortex
Tactile (touch) controlling areas
See also
Body integrity identity disorder (BIID)
Supernumerary body part – having an extra limb
References
McGeoch, P.D. et al. (2009). Apotemnophilia – the neurological basis of a ‘psychological’ disorder. Nature Precedings DOI: 10101/npre.2009.2954.1. |
Graves disease | Graves disease (German: Morbus Basedow), also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.The exact cause of the disease is unclear; however, it is believed to involve a combination of genetic and environmental factors. A person is more likely to be affected if they have a family member with the disease. If one twin is affected, a 30% chance exists that the other twin will also have the disease. The onset of disease may be triggered by physical or emotional stress, infection or giving birth. Those with other autoimmune diseases such as type 1 diabetes and rheumatoid arthritis are more likely to be affected. Smoking increases the risk of disease and may worsen eye problems. The disorder results from an antibody, called thyroid-stimulating immunoglobulin (TSI), that has a similar effect to thyroid stimulating hormone (TSH). These TSI antibodies cause the thyroid gland to produce excess thyroid hormones. The diagnosis may be suspected based on symptoms and confirmed with blood tests and radioiodine uptake. Typically, blood tests show a raised T3 and T4, low TSH, increased radioiodine uptake in all areas of the thyroid and TSI antibodies.The three treatment options are radioiodine therapy, medications, and thyroid surgery. Radioiodine therapy involves taking iodine-131 by mouth, which is then concentrated in the thyroid and destroys it over weeks to months. The resulting hypothyroidism is treated with synthetic thyroid hormones. Medications such as beta blockers may control some of the symptoms, and antithyroid medications such as methimazole may temporarily help people while other treatments are having effect. Surgery to remove the thyroid is another option. Eye problems may require additional treatments.Graves disease will develop in about 0.5% of males and 3% of females. It occurs about 7.5 times more often in women than in men. Often, it starts between the ages of 40 and 60 but can begin at any age. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases). The condition is named after Irish surgeon Robert Graves, who described it in 1835. A number of prior descriptions also exist.
Signs and symptoms
The signs and symptoms of Graves disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions being Graves ophthalmopathy, goiter, and pretibial myxedema (which are caused by the autoimmune processes of the disease). Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, oligomenorrhea, itching, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, periodic partial muscle weakness or paralysis in those especially of Asian descent, and skin warmth and moistness. Further signs that may be seen on physical examination are most commonly a diffusely enlarged (usually symmetric), nontender thyroid, lid lag, excessive lacrimation due to Graves ophthalmopathy, arrhythmias of the heart, such as sinus tachycardia, atrial fibrillation, and premature ventricular contractions, and hypertension.
Cause
The exact cause is unclear; however, it is believed to involve a combination of genetic and environmental factors. While a theoretical mechanism occurs by which exposure to severe stressors and high levels of subsequent distress such as PTSD (Post traumatic stress disorder) could increase the risk of immune disease and cause an aggravation of the autoimmune response that leads to Graves disease, more robust clinical data are needed for a firm conclusion.
Genetics
A genetic predisposition for Graves disease is seen, with some people more prone to develop TSH receptor activating antibodies due to a genetic cause. Human leukocyte antigen DR (especially DR3) appears to play a role. To date, no clear genetic defect has been found to point to a single-gene cause.Genes believed to be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), and cytotoxic T-lymphocyte–associated antigen 4, among others.
Infectious trigger
Since Graves disease is an autoimmune disease which appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry.The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.
In the 1990s, it was suggested that Y. enterocolitica may be associated with Graves disease.
More recently, the role for Y. enterocolitica has been disputed.Epstein–Barr virus (EBV) is another potential trigger.
Mechanism
Thyroid-stimulating immunoglobulins recognize and bind to the thyrotropin receptor (TSH receptor) which stimulates the secretion of thyroxine (T4) and triiodothyronine (T3). Thyroxine receptors in the pituitary gland are activated by the surplus hormone, suppressing additional release of TSH in a negative feedback loop. The result is very high levels of circulating thyroid hormones and a low TSH level.
Pathophysiology
Graves disease is an autoimmune disorder, in which the body produces antibodies that are specific to a self-protein: the receptor for thyroid-stimulating hormone. (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.)
These antibodies cause hyperthyroidism because they bind to the TSHr and chronically stimulate it. The TSHr is expressed on the thyroid follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This, in turn, causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.
The infiltrative exophthalmos frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.
The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.
The three types of autoantibodies to the TSH receptor currently recognized are:
Thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as long-acting thyroid stimulants, activating the cells through a slower and more drawn out process compared to TSH, leading to an elevated production of thyroid hormone.
Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
Thyrotrophin binding-inhibiting immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor.
Some actually act as if TSH itself is binding to its receptor, thus inducing thyroid function.
Other types may not stimulate the thyroid gland, but prevent TSI and TSH from binding to and stimulating the receptor.Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early. Thyrotoxicosis can also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function.
Diagnosis
Graves disease may present clinically with one or more of these characteristic signs:
Rapid heartbeat (80%)
Diffuse palpable goiter with audible bruit (70%)
Tremor (40%)
Exophthalmos (protuberance of one or both eyes), periorbital edema (25%)
Fatigue (70%), weight loss (60%) with increased appetite in young people and poor appetite in the elderly, and other symptoms of hyperthyroidism/thyrotoxicosis
Heat intolerance (55%)
Tremulousness (55%)
Palpitations (50%)Two signs are truly diagnostic of Graves disease (i.e., not seen in other hyperthyroid conditions): exophthalmos and nonpitting edema (pretibial myxedema). Goiter is an enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). Diffuse goiter may be seen with other causes of hyperthyroidism, although Graves disease is the most common cause of diffuse goiter. A large goiter will be visible to the naked eye, but a small one (mild enlargement of the gland) may be detectable only by physical examination. Occasionally, goiter is not clinically detectable, but may be seen only with computed tomography or ultrasound examination of the thyroid.
Another sign of Graves disease is hyperthyroidism; that is, overproduction of the thyroid hormones T3 and T4. Normal thyroid levels are also seen, and occasionally also hypothyroidism, which may assist in causing goiter (though it is not the cause of the Graves disease). Hyperthyroidism in Graves disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free (unbound) T3 and T4.Other useful laboratory measurements in Graves disease include thyroid-stimulating hormone (TSH, usually undetectable in Graves disease due to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated). Serologically detected thyroid-stimulating antibodies, radioactive iodine (RAI) uptake, or thyroid ultrasound with Doppler all can independently confirm a diagnosis of Graves disease.
Biopsy to obtain histiological testing is not normally required, but may be obtained if thyroidectomy is performed.
The goiter in Graves disease is often not nodular, but thyroid nodules are also common. Differentiating common forms of hyperthyroidism such as Graves disease, single thyroid adenoma, and toxic multinodular goiter is important to determine proper treatment. The differentiation among these entities has advanced, as imaging and biochemical tests have improved. Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.
Eye disease
Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease (TED), is the most common extrathyroidal manifestation of Graves disease. It is a form of idiopathic lymphocytic orbital inflammation, and although its pathogenesis is not completely understood, autoimmune activation of orbital fibroblasts, which in TAO express the TSH receptor, is thought to play a central role.Hypertrophy of the extraocular muscles, adipogenesis, and deposition of nonsulfated glycosaminoglycans and hyaluronate, causes expansion of the orbital fat and muscle compartments, which within the confines of the bony orbit may lead to dysthyroid optic neuropathy, increased intraocular pressures, proptosis, venous congestion leading to chemosis and periorbital edema, and progressive remodeling of the orbital walls. Other distinctive features of TAO include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, and exposure keratopathy.Severity of eye disease may be classified by the mnemonic: "NO SPECS":
Class 0: No signs or symptoms
Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag)
Class 2: Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc.)
Class 3: Proptosis
Class 4: Extraocular muscle involvement (usually with diplopia)
Class 5: Corneal involvement (primarily due to lagophthalmos)
Class 6: Sight loss (due to optic nerve involvement)Typically the natural history of TAO follows Rundles curve, which describes a rapid worsening during an initial phase, up to a peak of maximum severity, and then improvement to a static plateau without, however, resolving back to a normal condition.
Management
Treatment of Graves disease includes antithyroid drugs that reduce the production of thyroid hormone, radioiodine (radioactive iodine I-131) and thyroidectomy (surgical excision of the gland). As operating on a hyperthyroid patient is dangerous, prior to thyroidectomy, preoperative treatment with antithyroid drugs is given to render the patient euthyroid. Each of these treatments has advantages and disadvantages, and no single treatment approach is considered the best for everyone.Treatment with antithyroid medications must be administered for six months to two years to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. The risk of recurrence is about 40–50%, and lifelong treatment with antithyroid drugs carries some side effects such as agranulocytosis and liver disease. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells. Therapy with radioiodine is the most common treatment in the United States, while antithyroid drugs and/or thyroidectomy are used more often in Europe, Japan, and most of the rest of the world.
β-Blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia and nausea until antithyroid treatments start to take effect. Pure β-blockers do not inhibit lid retraction in the eyes, which is mediated by alpha adrenergic receptors.
Antithyroid drugs
The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil/PTU. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side effect is agranulocytosis (1/250, more in PTU). Others include granulocytopenia (dose-dependent, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk. Lugols iodine may be used to block hormone synthesis before surgery.A randomized control trial testing single-dose treatment for Graves found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).No difference in outcome was shown for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However, two markers were found that can help predict the risk of recurrence. These two markers are a positive TSHr antibody (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), and a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab.
Radioiodine
Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are failed medical therapy or surgery and where medical or surgical therapy are contraindicated. Hypothyroidism may be a complication of this therapy, but may be treated with thyroid hormones if it appears. The rationale for radioactive iodine is that it accumulates in the thyroid and irradiates the gland with its beta and gamma radiations, about 90% of the total radiation being emitted by the beta (electron) particles. The most common method of iodine-131 treatment is to administer a specified amount in microcuries per gram of thyroid gland based on palpation or radiodiagnostic imaging of the gland over 24 hours. Patients who receive the therapy must be monitored regularly with thyroid blood tests to ensure they are treated with thyroid hormone before they become symptomatically hypothyroid.Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitary nodules.Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring eventual thyroid hormone supplementation in the form of a daily pill(s). The radioiodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves disease–associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered. In rare cases, radiation induced thyroiditis has been linked to this treatment.
Surgery
This modality is suitable for young and pregnant people. Indications for thyroidectomy can be separated into absolute indications or relative indications. These indications aid in deciding which people would benefit most from surgery. The absolute indications are a large goiter (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid), and people with ophthalmopathy and additionally if it is the persons preferred method of treatment or if refusing to undergo radioactive iodine treatment. Pregnancy is advised to be delayed for 6 months after radioactive iodine treatment.Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on one side and partial lobectomy on other side) are possible.
Advantages are immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea), relapse following medical treatment, infections (less common), and scarring. The increase in the risk of nerve injury can be due to the increased vascularity of the thyroid parenchyma and the development of links between the thyroid capsule and the surrounding tissues. Reportedly, a 1% incidence exists of permanent recurrent laryngeal nerve paralysis after complete thyroidectomy. Risks related to anesthesia are many, thus coordination with the anesthesiologist and patient optimization for surgery preoperatively are essential. Removal of the gland enables complete biopsy to be performed to have definite evidence of cancer anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of the thyroid). No further treatment of the thyroid is required, unless cancer is detected. Radioiodine uptake study may be done after surgery, to ensure all remaining (potentially cancerous) thyroid cells (i.e., near the nerves to the vocal cords) are destroyed. Besides this, the only remaining treatment will be levothyroxine, or thyroid replacement pills to be taken for the rest of the patients life.
A 2013 review article concludes that surgery appears to be the most successful in the management of Graves disease, with total thyroidectomy being the preferred surgical option.
Eyes
Mild cases are treated with lubricant eye drops or nonsteroidal anti-inflammatory drops. Severe cases threatening vision (corneal exposure or optic nerve compression) are treated with steroids or orbital decompression. In all cases, cessation of smoking is essential. Double vision can be corrected with prism glasses and surgery (the latter only when the process has been stable for a while).
Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full, deep sleep.
Orbital decompression can be performed to enable bulging eyes to retreat back into the head. Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty tissue to fall back into the skull.
Eyelid surgery can be performed on upper and/or lower eyelids to reverse the effects of Graves disease on the eyelids. Eyelid muscles can become tight with Graves disease, making it impossible to close the eyes all the way. Eyelid surgery involves an incision along the natural crease of the eyelid, and a scraping away of the muscle that holds the eyelid open. This makes the muscle weaker, which allows the eyelid to extend over the eyeball more effectively. Eyelid surgery helps reduce or eliminate dry eye symptoms.
For management of clinically active Graves disease, orbitopathy (clinical activity score >2) with at least mild to moderate severity, intravenous glucocorticoids are the treatment of choice, usually administered in the form of pulse intravenous methylprednisolone. Studies have consistently shown that pulse intravenous methylprednisolone is superior to oral glucocorticoids both in terms of efficacy and decreased side effects for managing Graves orbitopathy.
Prognosis
If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, bone mineral loss and, in extreme cases, death. Graves disease is often accompanied by an increase in heart rate, which may lead to further heart complications, including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. If the eyes are proptotic (bulging) enough that the lids do not close completely at night, dryness will occur – with the risk of a secondary corneal infection, which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss, as well. Prolonged untreated hyperthyroidism can lead to bone loss, which may resolve when treated.
Epidemiology
Graves disease occurs in about 0.5% of people. Graves disease data has shown that the lifetime risk for women is around 3% and 0.5% for men. It occurs about 7.5 times more often in women than in men and often starts between the ages of 40 and 60. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases).
History
Graves disease owes its name to the Irish doctor Robert James Graves, who described a case of goiter with exophthalmos in 1835. Medical eponyms are often styled nonpossessively; thus Graves disease and Graves disease are variant stylings of the same term.
The German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, on the European Continent, the terms Basedow syndrome, Basedow disease, or Morbus Basedow are more common than Graves disease.Graves disease has also been called exophthalmic goiter.Less commonly, it has been known as Parry disease, Begbie disease, Flajan disease, Flajani–Basedow syndrome, and Marsh disease. These names for the disease were derived from Caleb Hillier Parry, James Begbie, Giuseppe Flajani, and Henry Marsh. Early reports, not widely circulated, of cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810, respectively. Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th century (and a friend of Edward Miller-Gallus), described a case in 1786. This case was not published until 1825, which was still ten years ahead of Graves.However, fair credit for the first description of Graves disease goes to the 12th century Persian physician Sayyid Ismail al-Jurjani, who noted the association of goiter and exophthalmos in his Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time.
Society and culture
Notable cases
Ayaka, Japanese singer, was diagnosed with Graves disease in 2007. After going public with her diagnosis in 2009, she took a two-year hiatus from music to focus on treatment.
Susan Elizabeth Blow, American educator and founder of the first publicly funded kindergarten in the United States, was forced to retire and seek treatment for Graves disease in 1884.
George H. W. Bush, former U.S. president, developed new atrial fibrillation and was diagnosed in 1991 with hyperthyroidism due to the disease and treated with radioactive iodine. The presidents wife, Barbara Bush, also developed the disease around the same time, which, in her case, produced severe infiltrative exophthalmos.
Rodney Dangerfield, American comedian and actor
Gail Devers, American sprinter: A doctor considered amputating her feet after she developed blistering and swelling following radiation treatment for Graves disease, but she went on to recover and win Olympic medals.
Missy Elliott, American hip-hop artist
Marty Feldman, British comedy writer, comedian and actor
Sia, Australian singer and songwriter
Sammy Gravano, Italian-American former underboss of the Gambino crime family.
Jim Hamilton, Scottish rugby player, discovered he had Graves disease shortly after retiring from the sport in 2017.
Heino, German folk singer, whose dark sunglasses (worn to hide his symptoms) became part of his trademark look
Herbert Howells, British composer; the first person to be treated with radium injections
Yayoi Kusama, Japanese artist.
Nadezhda Krupskaya, Russian Communist and wife of Vladimir Lenin
Umm Kulthum was an Egyptian singer, songwriter, and film actress active from the 1920s to the 1970s.
Barbara Leigh, an American former actress and fashion model, now spokeswoman for the National Graves Disease Foundation
Keiko Masuda, Japanese singer and one-half of the duo Pink Lady.
Yūko Miyamura, Japanese voice actress
Lord Monckton, former UKIP and Conservative politician and noted climate change skeptic.
Sophia Parnok, Russian poet
Sir Cecil Spring Rice, British ambassador to the United States during World War I, died suddenly of the disease in 1918.
Christina Rossetti, English Victorian-era poet
Dame Maggie Smith, British actress
Mary Webb, British novelist and poet
Wendy Williams, American TV show host
Act Yasukawa, Japanese Professional wrestler.
Literature
In Italo Svevos novel Zenos Conscience, character Ada develops the disease.
Ern Malley was an acclaimed Australian poet whose work was not published until after his death from Graves disease in 1943. However, Malleys existence and entire biography was actually later revealed to be a literary hoax.
Research
Agents that act as antagonists at thyroid stimulating hormone receptors are currently under investigation as a possible treatment for Graves disease.
References
External links
"Graves disease". Genetics Home Reference. U.S. National Library of Medicine.
https://www.ncbi.nlm.nih.gov/gene/?term=graves about graves on ncbi |
Waardenburg Syndrome Type 1 | Waardenburg Syndrome Type 1 is a congenital disorder that caused by a mutation in the PAX3 gene that results in abnormal development in the neural crest during early development. Type 1 results in early graying and white forelock and a notable distance between the eyes, noted as dystopia canthorum. Common symptoms of the disease also includes non-progressive hearing loss in majority of patients with Type 1. Patients can display complete or partial heterochromia and hypoplastic blue irides and congenital leukemia.
Presentation
Type 1 of the Waardenburg Syndrome’s notable feature is dystopia canthorum. Along with this feature, some patients eyelids are fused medially, resulting in medial sclerae. Inferior lachrymal is moved laterally, along with punctae opposite of the cornea. Other features include high and broad nasal root and also nasi hypoplasia. A squared jaw is reported in some patients. Others present with spina bifida due to the mutation in the neural crest during early development. Other features include the white forelock and graying that occurs in most patients prior to reaching age thirty. In extremely rare cases, the forelock may even be colored red rather than white. The coloring of the forelock may differ from patient to patient. It can appear at birth, or later in the life of those affected and size may vary. It is usually observed in the midline of the hair, but it can appear in other locations as well. Associated with the hair forelock, skin pigmentation can also appear in different parts of the body and limbs (suspected to be caused by the mutation in KIT). In parts of the body of some patients, congenital leukoderma is observed.Similar to other types of the syndrome, Type 1 displays heterochromia in some patients, sometimes complete or partial. If it happens to be partial, the differently colored iris is separated from the radial segment of the eye. Deficient iris stroma along with hypoplastic blue arises have also been found in some patients with Type 1. Another one of the symptoms is hearing loss, presenting in about 69% of cases. The types of hearing loss reported in patients differ over a great spectrum. Some of which could be bilateral or unilateral, sensorineural sometimes a combination of different ones in each ear. The most common loss types reported for Type 1 are profound and bilateral. Waardenburg Type 1 is estimated to cause 3% of overall congenital deaf children.
Genetics
Type 1 Waardenburg Syndrome is a dominant autosomal disease, with extremely high penetrance of nearly 85% Type 1, as well as type 3, are linked to a mutation in the PAX3 gene located in chromosome 2q35. This gene is responsible for encoding a transaction factor named Drosophila paired (noted as prd) resulting in essential proteins. These proteins are responsible for multiple functions in early human development such as stem cell pluripotency, as well as inhibition of differentiation when needed and cell-lineage specification, migration, and proliferation in the cells . These functions are essential in properly developing the central nervous system, somites, skeletal muscles, and neural crest-derived cells that are present throughout various cell types in the body. PAX3 controls the neural crest development through regulation of c-RET, TGF-b2, and WNT1 which are essential controllers of migration and differentiation.PAX3 in combination with other transcription factors such as MITF and TRP1 can control melanocyte development. This gene also plays a major role in muscle development as it regulated myoD and myf-5, essential transcription factors in muscle development.The structure of the gene and protein are well understood in research, PAX3 consists of 10 exons and results in major proteins that has 479 amino acids. It has also been found that a majority of the mutations that occur on the PAX3 gene is located on the 2-6 exons. Heterozygous mutation is the basis of the majority of Type 1 Waardenburg Syndrome mutations.
Diagnosis
Type 1 Waardenburg Syndrome is sometimes misdiagnosed as Type 2, therefore when measuring dystopia canthorum if present in a certain patient has been set in strict guidelines. There is a biometric index used as well formula to create a discriminant analysis. These measurements are based on three indices, based on the distances of the inner canthal, interpupillary, and outer canthal. This testing of the dystopia canthorum is referred to as the W index. Other features and dysfunctions are used for diagnoses such as hearing loss or pigmentation of the skin and the notable forelock that appears in the hair. A diagnosis can also be provided through genetic testing and identification of the PAX3 mutation in the patient’s genes. Gene analysis can take on a variety of tests such as single-gene testing (focus on PAX3), a multigene panel (PAX3 along with other genes), and a more comprehensive genomic testing when available.A list of major criteria was created to assess patients for Type 1 Waardenburg Syndrome. The list includes similar features as listed above such as congenital sensorineural hearing loss, white forelock, and hair pigmentation, pigmentation abnormality of the iris, dystopia canthorum, and related family members who exhibit the disease.
Management
There is no direct treatment for the patients with Waardenburg Syndrome Type 1, however, there are multiple ways in which the symptoms are managed. There are some options for hearing loss aid depending on the type faced by the patient. In previous cases, cochlea implants were successful to aid the hearing loss. There is also some genetic screening available that can assess whether children can inherit the mutation in the PAX3 gene, but not an overall prediction on the manifestation of the disease in the future generations. Pregnant women who are at risk for children suffering from this disease are recommended Folic acid supplementation to assist with the neural crest development. Further counseling is available with life decisions such as pregnancies and starting families. Since Type 1 is a dominant autosomal disease, any offsprings of those affected are likely to also have the disease.
Medical history
Waardenburg syndrome was first described by Petrus J Waardenburg in 1951 in the American Journal of Human Genetics. It is now commonly thought that the description refers to Waardenburg syndrome Type 1. The description focused on the distinguishing feature of dystopia canthorum, the wide distance between the eyes observed in over 80% of patients with Type 1. Variations in Type 1 and the difference from Type 2 were later described by Arias in 1971. In 1991, Da-Silva in focused on Brazilian children who exhibited the physical characteristics of Type 1 followed by Winship and Beighton in 1992 with 68 children to describe the onset and manifestation of Type 1. Research in 2016 resulted in connecting the hearing loss and other physical features to the syndrome and provided more accurate diagnosis.
== References == |
Middle-of-the-night insomnia | Middle-of-the-night insomnia (MOTN) is characterized by having difficulty returning to sleep after waking up during the night or very early in the morning. This kind of insomnia (sleeplessness) is different from initial or sleep-onset insomnia, which consists of having difficulty falling asleep at the beginning of sleep.
The disrupted sleep patterns caused by middle-of-the-night insomnia make many sufferers of the condition complain of fatigue the following day. Excessive daytime sleepiness is reported nearly two times higher by individuals with nocturnal awakenings than by people who sleep through the night.Sleep research conducted in the 1990s showed that such waking up during the night may be a natural sleep pattern, rather than a form of insomnia. If interrupted sleep (called "biphasic sleeping" or "bimodal sleep") is perceived as normal and not referred to as "insomnia", less distress is caused and a return to sleep usually occurs after about one hour.
Causes
Pain
Pregnancy
Anxiety
Difficulty breathing / sleep apnea
Urge to urinate or defecate
Hunger or thirst
Illness
Shift work
Erratic sleep scheduleNocturnal awakenings are more common in older patients and have been associated with depressive disorders, chronic pain, obstructive sleep apnea, obesity, alcohol consumption, hypertension, gastroesophageal reflux disease, heart disease, menopause, prostate problems, and bipolar disorders.
Gastro-intestinal discomfort arising from food that has not been fully cooked, is also a contributor to middle of the night insomnia.
Nocturnal awakenings can be mistaken as shift work disorder.
Treatment
Middle-of-the-night insomnia is often treated with medication, although currently Intermezzo (zolpidem tartrate sublingual tablets) is the only Food and Drug Administration-approved medication specifically for treating MOTN awakening. Because most medications usually require 6–8 hours of sleep to avoid lingering effects the next day, these are often used every night at bedtime to prevent awakenings. Medication may not be prescribed in some cases, especially if the cause turns out to be the patient ingesting too much fluid during the day or just before they go to sleep.
Sleep restriction therapy and stimulus control therapy as described in insomnia have shown significance in treating middle of night insomnia.
Some studies have shown that zaleplon, which has a short elimination half-life, may be suitable for middle-of-the-night administration because it does not impair next day performance.
Prevalence
Waking up in the middle of the night, or nocturnal awakening, is the most frequently reported insomnia symptom, with approximately 35% of Americans over 18 reporting waking up three or more times per week. Of those who experience nocturnal awakenings, 43% report difficulty in resuming sleep after waking, while over 90% report the condition persisting for more than six months. Greater than 50% contend with MOTN conditions for more than five years.
A 2008 "Sleep in America" poll conducted by the National Sleep Foundation found that 42% of respondents awakened during the night at least a few nights a week, and 29% said they woke up too early and couldn’t get back to sleep. Other clinical studies have reported between 25% and 35% of people experience nocturnal awakenings at least three nights a week.
See also
Biphasic and polyphasic sleep
== References == |
Taijin kyofusho | Taijin kyofusho (Japanese: 対人恐怖症, TKS, for taijin kyofusho symptoms) is a Japanese culture-specific syndrome. The term taijin kyofusho translates into the disorder (sho) of fear (kyofu) of interpersonal relations (taijin). Those who have taijin kyofusho are likely to be extremely embarrassed about themselves or fearful of displeasing others when it comes to the functions of their bodies or their appearances. These bodily functions and appearances include their faces, odor, actions, or even looks. They do not want to embarrass other people with their presence. This culture-bound syndrome is a social phobia based on fear and anxiety.The symptoms of this disorder include avoiding social outings and activities, rapid heartbeat, shortness of breath, panic attacks, trembling, and feelings of dread and panic when around people. The causes of this disorder are mainly from emotional trauma or psychological defense mechanism. It is more common in men than women. Lifetime prevalence is estimated at 3–13%.
Subcategories
Taijin kyofusho is commonly described as a form of social anxiety (social phobia), with the person dreading and avoiding social contact, and as a subtype of shinkeishitsu (anxiety disorder). However, instead of a fear of embarrassing themselves or being harshly judged by others because of their social ineptness, sufferers of taijin kyofusho report a fear of offending or harming other people. The focus is thus on avoiding harm to others rather than to oneself.
In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) it is instead considered a sub-category of the "Other Specified Obsessive-Compulsive and Related Disorder" category [300.3 (F42)], where variants of taijin kyofusho are "Shubo-kyofu [...] that is similar to body dysmorphic disorder and is characterized by excessive fear of having a bodily deformity" and "Jikoshu-kyofu [...] characterized by fear of having an offensive body odor".One source even breaks taijin kyofusho into two different subtypes: neurotic and offensive. The first subtype can be broken into two parts that are classical type and avoidant type. The classical type being afraid of being judged negatively because of physical signs of anxiety and feeling shame due to anxiety. The physical signs that can cause fear of being judged include sweating and tremors. The second subtype deals with people thinking something about them is offensive. Some of their fears include body odor, gas, excessive or insufficient eye contact, blushing, etc.
In the official Japanese diagnostic system, taijin kyofusho is subdivided into the following categories:
Sekimen-kyofu (Japanese: 赤面恐怖), the phobia of blushing (ereuthophobia)
Shubo-kyofu (Japanese: 醜貌恐怖), the phobia of a deformed body, similar to body dysmorphic disorder
Jikoshisen-kyofu (Japanese: 自己視線恐怖), the phobia of eye contact
Jikoshu-kyofu (Japanese: 自己臭恐怖), the phobia of having foul body odor (also termed olfactory reference syndrome, osmophobia or bromidrosiphobia)Japan psychology also recognizes additional types of taijin kyofusho based on severity:
Transient: This type of taijin kyofusho is short-lived and moderately severe. It most commonly appears in teens, but may occur at any time.
Delusional: This is the most common type of taijin kyofusho and is the most similar to social phobia. It is chronic, often begins before the age of 30, and varies in severity from moderate to severe.
Phobic with schizophrenia: This is a more complicated disorder. In such cases, rather than a phobia, taijin kyofusho is a manifestation of schizophrenic symptoms.
Diagnosis
A person may be diagnosed with taijin kyofusho if they feel as if their attitudes, behavior, and physical characteristics are inadequate in social situations. As a result of these feelings, they also experience persistent suffering in the form of emotional distress through shame, embarrassment, anxiety, fear, and other tense feelings that occur when confronted with social circumstances. In addition, individuals also worry about being unable to maintain healthy relationships with others. When it comes to socializing, taijin kyofusho sufferers avoid painful social and interpersonal situations, while simultaneously being averse to doing so. Those likely to develop taijin kyofusho have more of a temperamental characteristic of being hypochondriacal. The balance between introversion and extroversion in hypochondriacal temperament is geared more towards introversion. The introversion causes sufferers to focus on themself and problems they have, and by fixating on their weaknesses they become more anxious and depressed.
Treatment
The standard Japanese treatment for taijin kyofusho is Morita therapy, developed by Shoma Morita in the 1910s as a treatment for the Japanese mental disorders taijin kyofusho and shinkeishitsu (nervousness). The original regimen involved patient isolation, enforced bed rest, diary writing, manual labor, and lectures on the importance of self-acceptance and positive endeavor. Since the 1930s, the treatment has been modified to include out-patient and group treatments. This modified version is known as neo-Morita therapy. Medications have also gained acceptance as a treatment option for taijin kyofusho. Other treatments include systematic desensitization, which includes slowly exposing one self to the fear, and learning relaxation skills, to extinguish fear and anxiety.
Milnacipran, a serotonin–norepinephrine reuptake inhibitor (SNRI), is currently used in the treatment of taijin kyofusho and has been shown to be efficacious for the related social anxiety disorder. The primary aspect of treating this disorder is getting patients to focus their attention on their body parts and sensations.
Prevalence
Typically, this disease is presaged by a childhood history of social inhibition and shyness. It is possible that it could result from a humiliating traumatic experience, or it could emerge from a lifelong onset of the illness that only comes to the surface after time.Clinical data indicates that more males have the condition than females, despite the fact that females scored higher on a social phobia scale than men, and report higher scores on proclivity towards feelings of embarrassment. This differs from Western society where the prevalence of females with social phobias is to some extent greater than that of males. The lifetime prevalence of the disorder falls anywhere between 3% and 13% with changes in severity occurring throughout ones lifetime. It is estimated that about 17% of individuals with taijin kyofusho have fears of releasing foul body odor.
See also
Anthropophobia
Avoidant personality disorder
Hikikomori
NEET
Obsessive–compulsive disorder
References
Further reading
Suzuki, K. (2003). "Is Taijin Kyofusho a Culture-Bound Syndrome?". American Journal of Psychiatry. 160 (7): 1358. doi:10.1176/appi.ajp.160.7.1358. PMID 12832264.
Maeda, F; Nathan, JH (1999). "Understanding taijin kyofusho through its treatment, Morita therapy". Journal of Psychosomatic Research. 46 (6): 525–30. doi:10.1016/S0022-3999(98)00113-5. PMID 10454167.
Matsunaga, Hisato; Kiriike, Nobuo; Matsui, Tokuzo; Iwasaki, Yoko; Stein, Dan J. (2001). "Taijin kyofusho: A form of social anxiety disorder that responds to serotonin reuptake inhibitors?". The International Journal of Neuropsychopharmacology. 4 (3): 231–7. doi:10.1017/S1461145701002474. PMID 11602029.
Nagata T.; Oshima J.; Wada A.; Yamada H.; Iketani T.; Kiriike N. (2003). "Open trial of milnacipran for Taijin-Kyofusho in Japanese patients with social anxiety disorder". International Journal of Psychiatry in Clinical Practice. 7 (2): 107–112. doi:10.1080/13651500310000690.
External links
Support Group Providers for Social Phobia Taijin kyofusho at Curlie
http://www.japanpowered.com/japan-culture/taijin-kyofusho-the-disorder-of-fear
http://anthropology.msu.edu/anp204-us12/2012/07/20/taijin-kyofusho-in-japan-and-south-korea/
McNally, Richard J.; Cassiday, Karen L.; Calamari, John E. (January 1990). "Taijin-kyofu-sho in a black American woman: Behavioral treatment of a "culture-bound" anxiety disorder". Journal of Anxiety Disorders. 4 (1): 83–87. doi:10.1016/0887-6185(90)90025-5.
http://www.stolaf.edu/depts/ciswp/khughes/papers/psychopathology.pdf
http://jcc.sagepub.com/content/43/2/219.abstract |
Serpiginous choroiditis | Serpiginous choroiditis, also known as geographic or helicoid choroidopathy, is an uncommon chronic progressive inflammatory disease affecting adult men and women equally in the second to seventh decades of life.
Presentation
In this condition the posterior uveitis shows a geographic pattern. The inflammation begins in the juxtapapillary choroid and intermittently spreads centrifugally. The overlying retinal pigment epithelium and the outer retina are involved in the inflammatory process.
A closely related condition is multifocal serpiginoid choroiditis. This is caused by tuberculosis.The distinction between these two conditions is important as the latter responds to anti tuberculosis treatment while the former does not.
Diagnosis
Treatment
References
== External links == |
Ecthyma | Ecthyma( ec·thy·ma | \ ek-ˈthī-mə )is a variation of impetigo, presenting at a deeper level of tissue.It is usually associated with Group A (beta-hemolytic) Streptococcus (abbreviated GAS).
See also
Ecthyma gangrenosum
References
== External links == |
Chorea-acanthocytosis | Chorea-acanthocytosis (ChAc, also called choreoacanthocytosis) is a rare hereditary disease caused by a mutation in a gene that directs structural proteins in red blood cells. It belongs to a group of four diseases characterized under the name neuroacanthocytosis. When a patients blood is viewed under a microscope, some of the red blood cells appear thorny. These thorny cells are called acanthocytes.
Other effects of the disease may include epilepsy, behaviour changes, muscle degeneration, and neuronal degradation similar to Huntingtons disease. The average age of onset of symptoms is 35 years. The disease is incurable and inevitably leads to premature death.
Chorea-acanthocytosis is a very complex autosomal recessive adult-onset neurodegenerative disorder. It often shows itself as a mixed movement disorder, in which chorea, tics, dystonia and even parkinsonism may appear as a symptom.This disease is also characterized by the presence of a few different movement disorders including chorea, dystonia etc.Chorea-acanthocytosis is considered an autosomal recessive disorder, although a few cases with autosomal dominant inheritance have been noted.
Signs and symptoms
There are multiple symptoms that can help this disease to be diagnosed, this disease is marked by the presence of acanthocytes in blood (these acanthocytes can sometimes be absent or even make a late appearance in the course of the disease.) and neurodegeneration causing a choreiform movement disorder.Another one of them would be that this disease should be considered in patients who have elevated levels of acanthocytes in a peripheral blood film.The serum creatine kinase is often elevated in the body of the people who are affected by this disease.People afflicted by this disease also experience a loss of neurons. Loss of neurons is a hallmark of neurodegenerative diseases. Due to the generally non-regenerative nature of neuronal cells in the adult central nervous system, this results in an irreversible and fatal process of neurodegeneration. There is also the presence of several movement related disorders including chorea, dystonia and bradykinesia, one of the more incapacitating ones includes Truncal spasms.
Cause
Choreo-acanthocytosis is caused by a mutation in both copies of the gene VPS13A, which codes for vacuolar protein sorting-associated protein 13A.
Diagnosis
Protein function tests that demonstrate a reduce in chorein levels and also genetic analysis can confirm the diagnosis given to a patient. For a disease like this it is often necessary to sample the blood of the patient on multiple occasions with a specific request given to the haematologist to examine the film for acanthocytes. Another point is that the diagnosis of the disease can be confirmed by the absence of chorein in the western blot of the erythrocyte membranes.
Treatment
The treatment to battle the disease chorea-acanthocytosis is completely symptomatic. For example, botulinum toxin injections can help to control orolingual dystonia.Deep brain stimulation is a treatment that has varied effects on the people suffering from the symptoms of this disease, for some it has helped in a large way and for other people it did not help whatsoever, it is more effective on specific symptoms of the disease. Patients with chorea-acanthocytosis should undergo a cardiac evaluation every five years to look for cardiomyopathy.
References
External links
GeneReviews/NCBI/NIH/UW entry on chorea-acanthocytosis |
Trichophyton | Trichophyton is a genus of fungi, which includes the parasitic varieties that cause tinea, including athletes foot, ringworm, jock itch, and similar infections of the nail, beard, skin and scalp. Trichophyton fungi are molds characterized by the development of both smooth-walled macro- and microconidia. Macroconidia are mostly borne laterally directly on the hyphae or on short pedicels, and are thin- or thick-walled, clavate to fusiform, and range from 4 to 8 by 8 to 50 μm in size. Macroconidia are few or absent in many species. Microconidia are spherical, pyriform to clavate or of irregular shape, and range from 2 to 3 by 2 to 4 μm in size.
Species and their habitat preference
According to current classification, the genus includes anthropophilic and zoophilic species. Anthropophilic fungi prefer to infect humans. Zoophilic fungi prefer to infect animals other than humans. Humans and animals are natural reservoirs for parasitic or dermatophytic fungi.
Other accepted species;
Mating and meiosis
Trichophyton mentagrophytes (Family Arthrodermataceae, Genus Trichophyton) is capable of both mating and meiosis.
Effect on humans
The anthropophilic varieties cause forms of dermatophytosis, that is, fungal infection of the skin. They are keratinophilic: they feed on the keratin in nails, hair, and dead skin.
Trichophyton concentricum causes "Malabar itch", a skin infection consisting of an eruption of a number of concentric rings of overlapping scales forming papulosquamous patches.Trichophyton rubrum and Trichophyton interdigitale cause athletes foot (tinea pedis), toenail fungal infections (a.k.a. tinea unguium, a.k.a. onychomycosis), crotch itch (a.k.a. tinea cruris), and ringworm (a misnomer, as there is no worm involved; it is also known as tinea corporis). Trichophyton schoenleinii cause favus (tinea capitis),Trichophyton mentagrophytes var. mentagrophytes and Trichophyton verrucosum cause Kerion (violent reaction results from infection with an animal dermatophytes). Fungal folliculitis is a rare hair follicle infection induced overwhelmingly by Trichophyton, which can be spread zoonotically. The fungi can easily spread to other areas of the body as well and to the hosts home environs (socks, shoes, clothes, showers, bathtubs, counters, floors, carpets, etc.).
They can be transmitted by direct contact, by contact with infested particles (of dead skin, nails, hair) shed by the host, and by contact with the fungis spores. These fungi thrive in warm moist dark environments, such as in the dead upper layers of skin between the toes of a sweaty foot inside a tightly enclosed shoe, or in dead skin particles on the wet floor of a communal (shared) shower. Their spores are extremely difficult to eliminate, and spread everywhere.
When the hyphae of the fungi burrow into the skin and release enzymes to digest keratin, they may irritate nerve endings and cause the host to itch, which may elicit the scratch reflex, which directs the host to scratch. Scratching directly transfers fungi and dead skin particles that are infested with the fungi to the fingers and under the finger nails. From there they can be transmitted to other parts of the hosts body when the host touches or scratches those. Scratching also damages skin layers, making it easier for the fungi to spread at the site of the infection. If the fungi and infested debris are not washed from the fingers and fingernails soon enough, the fungi can also infect the skin of the fingers (tinea manuum), and burrow underneath and into the material of the fingernails (tinea unguium). If left untreated, the fungi continue to grow and spread.
Treatments
A variety of zoophilic and anthropophilic dermatophyte treatments have varying levels of success based on species type. Treatments may take up to six months.
References
External links
Doctor Fungus
Mycology Unit at the Adelaide Womens and Childrens Hospital |
Dariers disease | Dariers disease (DAR) is an inherited skin disorder that presents with multiple greasy, crusting, thick brown bumps that merge into patches.It is an autosomal dominant disorder discovered by French dermatologist Ferdinand-Jean Darier. Dariers is characterized by dark crusty patches on the skin that are mildly greasy and that emit a strong odor. These patches, also known as keratotic papules, keratosis follicularis, or dyskeratosis follicularis, most often appear on the scalp, forehead, upper arms, chest, back, knees, elbows, and behind the ear.Mild forms of the disease are the most common, consisting solely of skin rashes that flare up under certain conditions such as high humidity, high stress, or tight-fitting clothes. Short stature, when combined with poorly-formed fingernails that contain vertical striations, is diagnostic even for mild forms of DAR. Symptoms will usually appear in late childhood or early adulthood between the ages of 15 to 30 years and will vary over the course of ones life.
Signs and symptoms
Clinical symptoms of the disease:Seborrhoeic areas
This is defined as areas where excess oil and sebum is released.
Overall greasy or scaly skin either in the central chest and back or in the folds of the skin.
Fragile or poorly formed fingernails
Nail disease leading to V-shaped nicks at the edge of the nail.
Rash that covers many areas of the body
The rash is often associated with a strong unpleasant odor
The rash can be aggravated by heat, humidity, and exposure to sunlight.
Mucosal manifestation
White cobblestone pattern of small papules
Overgrowth of gums
Usually affects the mouth, esophagus, rectum, vulva, vagina
Oral symptoms can be diagnosed by a routine dental examination
Other symptoms and their overall prevalence in the affected population:In 80 to 90% of patients
Acrokeratosis verruciformisAcrokeratosis is characterized by several small wart-like and flat-topped bumps that line the skin on typically the hand and feet.
Hypermelanotic macule
Patches on the skin that contain excess pigment, they often appear as dark patches in the skin.
Pruritus
Itching
Subungual hyperkeratotic fragments
Thickened skin that is often discolored, under nails, on either hands or feet.
Palmar pits
Usually red in color, they are pits or depressions in the palms or soles of the hands and feet.
In 30 to 79% of patients
Abnormal hair morphology
Acne conglobata
Typically described as cystic acne
Genetics
Mutations in a single gene, ATP2A2, are responsible for the development of Dariers disease. ATP2A2 encodes the SERCA2 protein, which is a calcium pump localized to the membranes of the endoplasmic reticulum (ER) in nearly all cells and the sarcoplasmic reticulum (SR) in muscle cells. The ER is where protein processing and transport begins for proteins targeted for secretion. The SR is a specialized form of ER found in muscle cells that sequesters calcium, the regulated efflux of which into the cytosol stimulates muscle fiber contraction. Calcium acts as a second messenger in many cellular signal transduction pathways. SERCA2 is required for Ca2+ signaling in cells by removing nearly all Ca2+ ions from the cytoplasm and storing them in the ER/SR compartments.
A large number of mutant alleles of ATP2A2 have been identified in association with Dariers Disease. One study of 19 families and 6 sporadic cases found 24 specific, novel mutations associated with DAR symptoms. This study reported a loose, imperfect correlation between the severity of ATP2A2 mutations with the severity of the condition. Significant variability in disease severity between members of the same family carrying the same mutation was also reported by this study, suggesting that genetic modifiers contribute to the phenotypic penetrance of certain mutations.The mutation is inherited in an autosomal dominant pattern. This means that only one allele needs to be mutated in order to express the trait. This also means that someone who is born to one parent with DAR has a 50% chance of inheriting the mutant allele and having the disease. Loss-of-function mutations typically display recessive inheritance while the gain-of-function or hyperactive function of proteins is characteristic of dominant mutations. The observation that only one mutated allele of the SERCA2 is sufficient to produce clinical symptoms suggests that proper “gene dosage” is necessary for maintaining Ca2+ homeostasis in cells. This means that two wild type copies of ATP2A2 are needed for proper cell function, which provides a logical basis for dominant phenotypes arising from loss-of-function alleles. Most ATP2A2 mutations are haploinsufficiency mutations, which means that only having only one functional copy of the functional gene results in a reduced level of protein expression that is not sufficient for wild type function for making enough of the coded protein for the cell to function properly. However, there is significant variability in disease severity in how the mutations are expressed even within families that have the same mutation. It is currently unclear in the current research why a reduction in SERCA2 expression/activity causes clinical symptoms restricted to the epidermis. One hypothesis that some researchers have given is that other cell types express additional “back-up” Ca2+ pumps that can compensate for the reduced function or expression of the SERCA2 protein, while skin cells rely exclusively on the SERCA2 gene for calcium sequestration, meaning only they are affected by its reduction in expression.As mentioned above, some cases of DAR result from somatic mutations to ATP2A2 in epidermal stem cells. These cases are referred to as instances of "linear" Dariers disease. Such individuals display phenotypic mosaicism, where the Dariers phenotype only affects the subset of epidermal tissue arising from the mutated progenitor cell. Somatic mutations are not inherited by the offspring of such individuals.
Diagnosis
Diagnosis of Darier disease is often made by the appearance of the skin, family history, or genetic testing for the mutation in the ATP2A2 gene. However, many individuals affected by this disorder are never diagnosed, due to the mildness of symptoms in most cases. Mild cases present clinically are minor rashes (without odor) that can become exacerbated by heat, humidity, stress, and sunlight. The symptoms of the disease are thought to be caused by an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion.
Dariers disease is an incommunicable disorder that is seen in males and females equally. Symptoms typically arise between the ages of 15 and 30. One study of 100 British individuals diagnosed with Dariers disease reported that affected individuals display elevated frequencies of neuropsychiatric conditions. There were high lifetime rates for mood disorders (50%), including depression (30%), bipolar disorder (4%), suicidal thoughts (31%), and suicide attempts (13%), suggesting a possible common genetic link. Several case studies have suggested affected populations display elevated frequencies of learning disorders, but this has yet to be confirmed.
Treatment
Treatment of Darier disease depends on the severity of the presented clinical symptoms. In most minor cases, the disorder can be managed using sunscreen, moisturizing lotions, avoidance of non-breathable clothing, and excessive perspiration. In more severe cases of Dariers disease, hospitalisation may be required to heal affected individuals who display frequent relapse and remit patterns. In less severe cases, signs and symptoms may clear up completely through hygienic interventions. Most patients with Dariers disease live normal, healthy lives. Rapid resolution of rash symptoms can be complicated due to the increased vulnerability of affected skin surfaces by secondary bacterial or viral infections. Epidermal Staphylococcus aureus, human papillomavirus (HPV) and herpes simplex virus (HSV) infections have been reported. In these cases, topical and/or oral antibiotic/antiviral medications may need to be prescribed.Typical recommendations are:
Application of antiseptics
Soak in astringents
Antibiotics
Benzoyl peroxide
Topical diclofenac sodiumIf Dariers is more localized, common treatments include:
Topical retinoids: used to help in the reduction of hyperkeratosis, retinoids work by causing the skin cells in the top layers to die and be shed off. The common retinoids used for this disorder are:
Adapalene
Tazarotene gel
Tretinoin
Dermabrasion
Removal of the top layer of skin to help smooth and stimulate new growth of the skin.
Electrosurgery
Used to help stop bleeding and remove abnormal skin growths.
Topical corticosteroidsIf symptoms are severe, oral retinoids be prescribed and have been proven to be 90% effective. However, there can be many adverse side-effects associated with prolonged use. Common oral retinoids are:
Acitretin
Isotretinoin
CyclosporineSome patients are able to prevent flares with use of topical sunscreens and oral vitamin C.Further information on and advocacy work for Dariers disease are provided by the FIRST Skin Foundation.
Epidemiology
Worldwide prevalence is estimated as between 1:30,000 and 1:100,000. Case studies have shown estimated prevalence by country to be 3.8:100,000 in Slovenia, 1:36,000 in north-east England, 1:30,000 in Scotland, and 1:100,000 in Denmark.
History
Dariers disease was first described in a paper from 1917 by the dermatologist Ferdinand-Jean Darier in the French dermatological journal Annales de dermatologie et de syphilographie. Darier was a well-regarded dermatologist of the time who was the head of the medical department at the Hôpital Saint-Louis. Darier was an early proponent of histopathology, or the examination of samples of diseased flesh under a microscope to determine the cause of illnesses. Using this technique, he was able to uncover the origins of Dariers disease and a host of others that also bear his name.James Clark White, a dermatologist at Harvard Medical School, independently characterized and published his observations on this dermatological disorder in the same year as Darier (1889), which is why Dariers disease is also referred to as Darier-White disease.
See also
Linear Darier disease
List of cutaneous conditions
Dariers sign
References
Cardoso CL, Freitas P, Taveira LAA, Consolaro A. Darier disease:
case report with oral manifestations. Med Oral Patol Oral
Cir Bucal 2006;11:E404-6 |
Xanthopsia | Xanthopsia is a color vision deficiency in which there is a predominance of blue in vision due to a yellowing of the optical media of the eye. The most common causes are digoxins inhibitory action on the sodium pump, and the development of cataracts which can cause a yellow filtering effect.
It has been suggested that Van Gogh contracted Xanthopsia as a result of digoxin consumption. Digoxin is a medication derived from digitalis and used to treat various heart conditions. This theory claims Xanthopsia as the cause of the yellow tinting exhibited by many of his works.Xanthopsia is also a rare side-effect of jaundice, in which bilirubin may be deposited into the eye in sufficient quantity to produce a yellow tint to the vision.
See also
Cyanopsia
References
External links
Acquired Colour Vision Deficiencies —University of Calgary, Vision & Aging Lab |
Kleptomania | Kleptomania is the inability to resist the urge to steal items, usually for reasons other than personal use or financial gain. First described in 1816, kleptomania is classified in psychiatry as an impulse control disorder. Some of the main characteristics of the disorder suggest that kleptomania could be an obsessive-compulsive spectrum disorder, but also share similarities with addictive and mood disorders.The disorder is frequently under-diagnosed and is regularly associated with other psychiatric disorders, particularly anxiety, eating disorders, alcohol and substance use. Patients with kleptomania are typically treated with therapies in other areas due to the comorbid grievances rather than issues directly related to kleptomania.Over the last 100 years, a shift from psychotherapeutic to psychopharmacological interventions for kleptomania has occurred. Pharmacological treatments using selective serotonin reuptake inhibitors (SSRIs), mood stabilizers and opioid receptor antagonists, and other antidepressants along with cognitive behavioral therapy, have yielded positive results. However, there have also been reports of kleptomania induced by selective serotonin reuptake inhibitors (SSRIs).
Signs and symptoms
Some of the fundamental components of kleptomania include recurring intrusive thoughts, impotence to resist the compulsion to engage in stealing, and the release of internal pressure following the act. These symptoms suggest that kleptomania could be regarded as an obsessive-compulsive type of disorder.People diagnosed with kleptomania often have other types of disorders involving mood, anxiety, eating, impulse control, and drug use. They also have great levels of stress, guilt, and remorse, and privacy issues accompanying the act of stealing. These signs are considered to either cause or intensify general comorbid disorders. The characteristics of the behaviors associated with stealing could result in other problems as well, which include social segregation and substance use. The many types of other disorders frequently occurring along with kleptomania usually make clinical diagnosis uncertain.There is a difference between ordinary theft and kleptomania: "ordinary theft (whether planned or impulsive) is deliberate and motivated by the usefulness of the object or its monetary worth," whereas with kleptomania, there "is the recurrent failure to resist impulses to steal items even though the items are not needed for personal use or for their monetary value."
Cause
Psychoanalytic models
Many psychoanalytic theorists suggested that kleptomania is a persons attempt "to obtain symbolic compensation for an actual or anticipated loss", and feel that the key to understanding its etiology lies in the symbolic meaning of the stolen items. Drive theory was used to propose that the act of stealing is a defense mechanism which serves as to modulate or keep undesirable feelings or emotions from being expressed. Some French psychiatrists suggest that kleptomaniacs may just want the item that they steal and the feeling they get from theft itself.
Cognitive-behavioral models
Cognitive-behavioral models have been replacing psychoanalytic models in describing the development of kleptomania. Cognitive-behavioral practitioners often conceptualize the disorders as being the result of operant conditioning, behavioral chaining, distorted cognitions, and poor coping mechanisms. Cognitive-behavioral models suggest that the behavior is positively reinforced after the person steals some items. If this individual experiences minimal or no negative consequences (punishment), then the likelihood that the behavior will reoccur is increased. As the behavior continues to occur, stronger antecedents or cues become contingently linked with it, in what ultimately becomes a powerful behavioral chain. According to cognitive-behavioral theory (CBT), both antecedents and consequences may either be in the environment or cognitions. For example, Kohn and Antonuccio (2002) describe a clients antecedent cognitions, which include thoughts such as "I’m smarter than others and can get away with it"; "they deserve it"; "I want to prove to myself that I can do it"; and "my family deserves to have better things". These thoughts were strong cues to stealing behaviors. All of these thoughts were precipitated by additional antecedents which were thoughts about family, financial, and work stressors or feelings of depression. "Maintaining" cognitions provided additional reinforcement for stealing behaviors and included feelings of vindication and pride, for example: "score one for the little guy against the big corporations". Although those thoughts were often afterward accompanied by feelings of remorse, this came too late in the operant sequence to serve as a viable punisher. Eventually, individuals with kleptomania come to rely upon stealing as a way of coping with stressful situations and distressing feelings, which serve to further maintain the behavior and decrease the number of available alternative coping strategies.
Biological models
Biological models explaining the origins of kleptomania have been based mostly on pharmacotherapy treatment studies that used selective serotonin reuptake inhibitors (SSRIs), mood stabilizers, and opioid receptor antagonists.Some studies using SSRIs have observed that opioid antagonists appear to reduce the urge to steal and mute the "rush" typically experienced immediately after stealing by some subjects with kleptomania. This would suggest that poor regulation of serotonin, dopamine, and/or natural opioids within the brain are to blame for kleptomania, linking it with impulse control and affective disorders.An alternative explanation too based on opioid antagonist studies states that kleptomania is similar to the "self-medication" model, in which stealing stimulates the persons natural opioid system. "The opioid release soothes the patients, treats their sadness, or reduces their anxiety. Thus, stealing is a mechanism to relieve oneself from a chronic state of hyperarousal, perhaps produced by prior stressful or traumatic events, and thereby modulate affective states.": 354
Diagnosis
Disagreement surrounds the method by which kleptomania is considered and diagnosed. On one hand, some researchers believe that kleptomania is merely theft and dispute the suggestion that there are psychological mechanisms involved, while others observe kleptomania as part of a substance-related addiction. Yet others categorize kleptomania as a variation of an impulse control disorder, such as obsessive-compulsive disorder or eating disorders.: 378–84 According to the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM IV-TR), a frequent and widely used guide for the diagnosis of mental disorders, the following symptoms and characteristics are the diagnostic criteria for kleptomania:
repeated inability to defend against urges to steal things that are not essential for private use or for their economic value;
escalating sense of pressure immediately prior to performing the theft;
satisfaction, fulfillment or relief at the point of performing the theft;
the theft is not executed to convey antagonism or revenge, and is not in reaction to a delusion or a fantasy; and
the thieving is not better accounted for by behavior disorder, a manic episode, or antisocial personality disorder.Skeptics have decried kleptomania as an invalid psychiatric concept exploited in legal defenses of wealthy female shoplifters. During the twentieth century, kleptomania was strongly linked with the increased prevalence of department stores, and "department store kleptomaniacs" were a widely held social stereotype that had political implications.
Comorbidity
Kleptomania seems to be linked with other psychiatric disorders, especially mood swings, anxiety, eating disorders, and alcohol and substance use. The occurrence of stealing as a behavior in conjunction with eating disorders, particularly bulimia nervosa, is frequently taken as a sign of the harshness of the eating disorder.A likely connection between depression and kleptomania was reported as early as 1911. It has since been extensively established in clinical observations and available case reports. The mood disorder could come first or co-occur with the beginning of kleptomania. In advanced cases, depression may result in self-inflicted injury and could even lead to suicide. Some people have reported relief from depression or manic symptoms after theft.It has been suggested that because kleptomania is linked to strong compulsive and impulsive qualities, it can be viewed as a variation of obsessive-compulsive spectrum disorders, together with pathological gambling, compulsive buying, pyromania, nailbiting and trichotillomania. This point achieves support from the unusually higher cases of obsessive-compulsive disorder (OCD; see below) in close relatives of patients with kleptomania.
Substance use disorder
Kleptomania and drug addictions seem to have central qualities in common, including:
recurring or compulsive participation in a behavior in spite of undesirable penalties;
weakened control over the disturbing behavior;
a need or desire condition before taking part in the problematic behavior; and
a positive pleasure-seeking condition throughout the act of the disturbing behavior.Data from epidemiological studies additionally propose that there is an affiliation between kleptomania and substance use disorders along with high rates in a unidirectional manner. Phenomenological data maintain that there is a relationship between kleptomania and drug addictions. A higher percentage of cases of kleptomania has been noted in adolescents and young adults, and a lesser number of cases among older adults, which imply an analogous natural history to that seen in substance use disorders. Family history data also propose a probable common genetic input to alcohol use and kleptomania. Substance use disorders are more common in kin of persons with kleptomania than in the general population. Furthermore, pharmacological data (e.g., the probable efficacy of the opioid antagonist, naltrexone, in the treatment of both kleptomania and substance use disorders) could present additional support for a joint relationship between kleptomania and substance use disorders. Based on the idea that kleptomania and substance use disorders may share some etiological features, it could be concluded that kleptomania would react optimistically to the same treatments. As a matter of fact, certain non-medical treatment methods that are successful in treating substance use are also accommodating in treating kleptomania.
Obsessive-compulsive disorder
Kleptomania is frequently thought of as being a part of obsessive-compulsive disorder (OCD), since the irresistible and uncontrollable actions are similar to the frequently excessive, unnecessary, and unwanted rituals of OCD. Some individuals with kleptomania demonstrate hoarding symptoms that resemble those with OCD.
Prevalence rates between the two disorders do not demonstrate a strong relationship. Studies examining the comorbidity of OCD in subjects with kleptomania have inconsistent results, with some showing a relatively high co-occurrence (45%-60%) while others demonstrate low rates (0%-6.5%). Similarly, when rates of kleptomania have been examined in subjects with OCD, a relatively low co-occurrence was found (2.2%-5.9%).
Pyromania
Pyromania, another impulse disorder, has many ties to kleptomania. Many pyromaniacs begin fires alongside petty stealing which often appears similar to kleptomania.
Treatment
Although the disorder has been known to psychologists for a long time, the cause of kleptomania is still ambiguous. Therefore, a diverse range of therapeutic approaches have been introduced for its treatment. These treatments include: psychoanalytic oriented psychotherapy, behavioral therapy, and pharmacotherapy.
Psychoanalytic and psychodynamic approach
Several explanations of the mechanics of kleptomania have been presented. A contemporary social approach proposes that kleptomania is an outcome of consumerism and the large quantity of commodities in society. Psychodynamic theories depend on a variety of points of view in defining the disorder. Psychoanalysts define the condition as an indication of a defense mechanism deriving in the unconscious ego against anxiety, prohibited intuition or desires, unsettled struggle or forbidden sexual drives, dread of castration, sexual excitement, and sexual fulfillment and orgasm throughout the act of stealing. The psychoanalytic and psycho-dynamic approach to kleptomania granted the basis for prolonged psychoanalytic or psycho-dynamic psychotherapy as the core treatment method for a number of years. Like most psychiatric conditions, kleptomania was observed within the psycho-dynamic lens instead of being viewed as a bio-medical disorder. However, the prevalence of psychoanalytic approach contributed to the growth of other approaches, particularly in the biological domain.
Behavioral and cognitive intervention
Cognitive-behavioural therapy (CBT) has primarily substituted the psychoanalytic and dynamic approach in the treatment of kleptomania. Numerous behavioural approaches have been recommended as helpful according to several cases stated in the literature. They include: hidden sensitisation by unpleasant images of nausea and vomiting, aversion therapy (for example, aversive holding of breath to achieve a slightly painful feeling every time a desire to steal or the act is imagined), and systematic desensitisation. In certain instances, the use of combining several methods such as hidden sensitisation along with exposure and response prevention were applied. Even though the approaches used in CBT need more research and investigation in kleptomania, success in combining these methods with medication was illustrated over the use of drug treatment as the single method of treatment.
Drug treatment
The phenomenological similarity and the suggested common basic biological dynamics of kleptomania and OCD, pathological gambling and trichotillomania gave rise to the theory that the similar groups of medications could be used in all these conditions. Consequently, the primary use of selective serotonin reuptake inhibitor (SSRI) group, which is a form of antidepressant, has been used in kleptomania and other impulse control disorders such as binge eating and OCD. Electroconvulsive therapy (ECT), lithium and valproic acid (sodium valproate) have been used as well.The SSRIs usage is due to the assumption that the biological dynamics of these conditions derives from low levels of serotonin in brain synapses, and that the efficacy of this type of therapy will be relevant to kleptomania and to other comorbid conditions.Opioid receptor antagonists are regarded as practical in lessening urge-related symptoms, which is a central part of impulse control disorders; for this reason, they are used in treatment of substance use. This quality makes them helpful in treating kleptomania and impulse control disorders in general. The most frequently used drug is naltrexone, a long-acting competitive antagonist. Naltrexone acts mainly at μ-receptors, but also antagonises κ- and λ-receptors.There have been no controlled studies of the psycho-pharmacological treatment of kleptomania. This could be as a consequence of kleptomania being a rare phenomenon and the difficulty in achieving a large enough sample. Facts about this issue come largely from case reports or from bits and pieces gathered from a comparatively small number of cases enclosed in a group series.
History
In the nineteenth century, French psychiatrists began to observe kleptomaniacal behavior, but were constrained by their approach. By 1890, a large body of case material on kleptomania had been developed. Hysteria, imbecility, cerebral defect, and menopause were advanced as theories to explain these seemingly nonsensical behaviors, and many linked kleptomania to immaturity, given the inclination of young children to take whatever they want. These French and German observations later became central to psychoanalytic explanations of kleptomania.
Etymology
The term kleptomania was derived from the Greek words κλέπτω (klepto) "to steal" and μανία (mania) "mad desire, compulsion". Its meaning roughly corresponds to "compulsion to steal" or "compulsive stealing".
First generation of psychoanalysis
In the early twentieth century, kleptomania was viewed more as a legal excuse for self-indulgent haut bourgeois ladies than a valid psychiatric ailment by French psychiatrists.Sigmund Freud, the creator of controversial psychoanalytic theory, believed that the underlying dynamics of human behaviours associated with uncivilized savages—impulses were curbed by inhibitions for social life. He did not believe human behaviour to be rational. He created a large theoretical corpus which his disciples applied to such psychological problems as kleptomania. In 1924, one of his followers, Wilhelm Stekel, read the case of a female kleptomaniac who was driven by suppressed sexual urges to take hold of "something forbidden, secretly". Stekel concluded that kleptomania was "suppressed and superseded sexual desire carried out through medium of a symbol or symbolic action. Every compulsion in psychic life is brought about by suppression".
Second generation of psychoanalysis
Fritz Wittels argued that kleptomaniacs were sexually underdeveloped people who felt deprived of love and had little experience with human sexual relationships; stealing was their sex life, giving them thrills so powerful that they did not want to be cured. Male kleptomaniacs, in his view, were homosexual or invariably effeminate.A famous large-scale analysis of shoplifters in the United Kingdom ridiculed Stekels notion of sexual symbolism and claimed that one out of five apprehended shoplifters was a "psychiatric".
New perspectives
Empirically based conceptual articles have argued that kleptomania is becoming more common than previously thought, and occurs more frequently among women than men. These ideas are new in recent history but echo those current in the mid to late nineteenth century.: 986–996
See also
Portrait of a Kleptomaniac
Kleptolagnia
References
External links
Media related to Kleptomania at Wikimedia Commons |
Diffuse lamellar keratitis | Diffuse lamellar keratitis (DLK) is a sterile inflammation of the cornea which may occur after refractive surgery, such as LASIK. Its incidence has been estimated to be 1 in 500 patients, though this may be as high as 32% in some cases.
Signs and symptoms
Patients typically present within one week of surgery with eye pain, photophobia, conjunctivitis, or excessive tear production.
Risk factors
DLK is predominantly associated with Lasik, as the creation of a flap creates a potential space for cells to accumulate. Individuals with atopic conditions with pre-existing allergic conjunctivitis, or ocular rosacea, are more prone to developing the condition after surgery. Some authors have reported that moderate to severe eye allergies and chronic allergic conjunctivitis are an absolute contraindication to the LASIK procedure. This is in distinction to findings of earlier studies. Keratitis can also occur after photorefractive keratectomy (PRK), although because it occurs in the setting of infection, it is distinct from the sterile infiltrates of DLK. DLK can also occur following myopic keratomileusis, in which a disc of corneal tissue is removed, shaped and sutured back into place, although this technique is more historical, having been replaced by Lasik and PRK.
Pathology
DLK is usually seen after refractive surgery. Neutrophils infiltrate the corneal stroma in a diffuse, multifocal pattern. Infiltration is confined to the surgical flap interface with no posterior or anterior extension, and overlying epithelium most often remains intact. As it is a sterile process, cultures based on swab tests are negative.
Diagnosis
Stages
There are 4 stages of disease, with stage 4 being the rarest and most severe.
Stage 1 Cells infiltrate the periphery of the flap, without involving central cornea.
Stage 2 Peripheral cells migrate to the center of the cornea, and impair vision; presentation is usually 2 to 3 days after surgery.
Stage 3 Cells at the central cornea form clumps of dense cell aggregates.
Stage 4 Otherwise known as central toxic keratopathy, stage 4 characteristically has no inflammatory cells at the anterior chamber or cornea, but there is central stromal necrosis, and the cornea becomes opacified; onset is usually 3 to 9 days after refractive surgery.
Treatment
Depending on severity, therapies may range from topical or oral anti-inflammatories to irrigation and surgical repair.
References
== External links == |
Tongue tied (disambiguation) | Tongue-tie, tongue tied or tongue-tied can refer to:
ankyloglossia, a medical condition in which the lingual frenulum (a membrane that connects the tongue to the floor of the mouth) is unusually short, causing restricted movement of the tongue.Other uses include:
Literature
Tongue-Tied, a 1997 novel by Liselotte Marshall
Tongue-Tied (short story collection), a 2002 collection of short stories by Paul Jennings
"Tongue-Tied" a short story included in the collection
Tongue-Tied: How a Tiny String Under the Tongue Impacts Nursing, Speech, Feeding, and More, a 2018 non-fiction book by Dr. Richard Baxter
Music
Tongue Tied (Red Dwarf song), a song by Danny John-Jules in character as the Cat which was featured in the Red Dwarf episode "Parallel Universe" in 1988
"Tongue Tied" (Boom Crash Opera song), 1995
"Tongue-Tied", a song by Earshot from their 2004 album Two
"Tongue Tied" (Eve 6 song), a single from their 1998 album, Eve 6
"Tongue Tied" (Faber Drive song), 2007
"Tongue Tied" (Grouplove song), 2011
"Tongue Tied" (Marshmello, Yungblud and Blackbear song), 2019
"Tongue Tied", a song by Status Quo from their 2007 album In Search of the Fourth Chord
Other uses
Tongue-tie (tack), a piece of equipment sometimes used on racehorses
"Tongue-Tied" (Orange Is the New Black), a 2015 television episode
Miley Cyrus: Tongue Tied, a 2014 short film starring Miley Cyrus |
Tangier disease | Tangier disease or hypoalphalipoproteinemia is an extremely rare inherited disorder characterized by a severe reduction in the amount of high density lipoprotein (HDL), often referred to as "good cholesterol", in the bloodstream. Worldwide, approximately 100 cases have even been identified.The disorder was originally discovered on Tangier Island off the coast of Virginia, but has now been identified in people from many different countries.
Signs and symptoms
Individuals that are homozygotes for Tangiers disease develop various cholesterol ester depositions. These are especially visible in the tonsils, as they may appear yellow/orange. The cholesterol esters may also be found in lymph nodes, bone marrow, the liver and spleen.Due to the cholesterol ester depositions the tonsils may be enlarged. Hepatosplenomegaly (enlarged liver and spleen) is common.Neuropathy and cardiovascular disease are the most devastating developments caused by Tangiers disease.
Genetics
Mutations to chromosome 9q31 lead to a defective ABCA1 transporter. These mutations prevent the ABCA1 protein from effectively transporting cholesterol and phospholipids out of cells for pickup by ApoA1 in the bloodstream. This inability to transport cholesterol out of cells leads to a deficiency of high-density lipoproteins in the circulation, which is a risk factor for coronary artery disease. Additionally, the buildup of cholesterol in cells can be toxic, causing cell death or impaired function. These combined factors lead to the signs and symptoms of Tangier disease.This condition is inherited in an autosomal recessive pattern, meaning that for the phenotype to appear, two copies of the gene must be present in the genotype. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.
Diagnosis
Tangier disease results in familial high-density lipoprotein deficiency. High-density lipoproteins are created when a protein in the bloodstream, Apolipoprotein A1 (apoA1), combines with cholesterol and phospholipids. The cholesterol and phospholipids used to form HDL originate from inside cells but are transported out of the cell into the blood via the ABCA1 transporter. People with Tangier disease have defective ABCA1 transporters resulting in a greatly reduced ability to transport cholesterol out of their cells, which leads to an accumulation of cholesterol and phospholipids in many body tissues, which can cause them to increase in size. Reduced blood levels of high-density lipoproteins is sometimes described as hypoalphalipoproteinemia.People affected by this condition also have slightly elevated amounts of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function (neuropathy). The tonsils are visibly affected by this disorder; they frequently appear orange or yellow and are extremely enlarged. Affected people often develop premature atherosclerosis, which is characterized by fatty deposits and scar-like tissue lining the arteries. Other signs of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the cornea, and early-onset cardiovascular disease.
Treatment
There are drugs that can increase serum HDL such as niacin or gemfibrozil. While these drugs are useful for patients with hyperlipidemia, Tangiers disease patients do not benefit from these pharmaceutical interventions.Therefore, the only current treatment modality for Tangiers disease is diet modification. A low-fat diet can reduce some of the symptoms, especially those involving neuropathies.
History
In 1959, a five-year-old patient named Teddy Laird from Tangier Island, Virginia, presented with strikingly large and yellow-orange tonsils which were removed by armed forces physicians. After initial diagnosis with Niemann-Pick he was transferred to Dr. Louis Avioli at the National Cancer Institute. Donald Fredrickson, then head of the Molecular Disease Branch, became aware of the case and had a hunch that the original diagnosis was incorrect. In 1960, he traveled with Dr. Avioli to Tangier Island for further investigation. After finding the same symptom in Teddys sister, an investigation revealed an extremely high number of foam cells (cholesterol ester-laden macrophages) in not only the tonsils, but also in a wide-range of tissues, including the bone marrow and spleen. During a second trip to the island, they found that the family had very low levels of HDL cholesterol, suggesting a genetic basis of the disease.
References
External links
Tangier disease at NLM Genetics Home Reference |
Liver spot | Liver spots (also known as age spot, solar lentigo, "lentigo senilis",: 686 "old age spot", "senile freckle") are blemishes on the skin associated with aging and exposure to ultraviolet radiation from the sun. They range in color from light brown to red or black and are located in areas most often exposed to the sun, particularly the hands, face, shoulders, arms and forehead, and the scalp if bald.
The spots derive their name from the fact that they were once incorrectly believed to be caused by liver problems, but they are physiologically unrelated to the liver, save for a similar color. From the age of 40, the skin is less able to regenerate from sun exposure, and liver spots are very common in this age group, particularly in those who spend time in the sun.In the overwhelming majority of cases, liver spots pose no threat and require no treatment, though they occasionally have been known to obscure the detection of skin cancer. However, despite being a benign condition, liver spots are sometimes considered unsightly and some people choose to have them removed. This can be done by electrosurgery, laser treatment, cryotherapy, or the use of depigmentation agents, such as hydroquinone, tretinoin, topical cysteamine, azelaic acid, or alpha hydroxy acids.
Causes
Differently from the melanotic nevi and the verrucous nevi on the skin, age spots change in color and in shape with time. Michelitsch and Michelitsch propose a hypothesis inspired by their misrepair-accumulation aging theory for the development of age spots. They propose that aged basal cells contain lipofuscin bodies that cannot be removed and might promote the aging of neighboring cells, generating a feedback loop that causes more and more neighbor cells to become aged and contain lipofuscins. Such cells might then aggregate into a spot with an irregular shape. They propose that the protrusion of a flat spot is a result of the death of aged cells in the spot and release of lipofuscin bodies. The aggregating cells would form a capsule, and the dense lipofuscin bodies make the protruding spot soft and dark in color. However, this proposal appeared as a preprint in 2015, has little direct empirical support, and has never been published in a peer reviewed journal.
Another group has reported that "age spots" taken from human skin biopsies of patients facial senile lentigo of Fitzpatrick skin type III or IV aged 55–62 are enriched with senescent fibroblasts compared to surrounding skin. The dark coloration appeared to be due to higher melanin levels and activity of tyrosinase in the senescent fibroblasts than in the controls, potentially related to lower SDF1 expression. Patients were then administered six weekly treatments of microneedle fractional radiofrequency aimed at eliminating dermal senescent fibroblasts; this led to a marked decrease in epidermal pigmentation compared to baseline, accompanied by a decrease in the synthesis of collagen and the normalization of suppressed SDF1 expression.
Treatment
Treatment for liver spots is almost never done for health-related reasons, though it is sometimes done for aesthetic ones. Skin-bleaching products that inhibit pigmentation or cosmetic creams containing the ingredients alpha hydroxy acids or retinoids are known to be effective. Liver spots can also be frozen off with liquid nitrogen; that is, via cryosurgery.
See also
Freckle
Lentigo
List of cutaneous conditions
References
External links
Media related to Solar lentigo at Wikimedia Commons |
Nightmare disorder | Nightmare disorder, also known as dream anxiety disorder, is a sleep disorder characterized by frequent nightmares. The nightmares, which often portray the individual in a situation that jeopardizes their life or personal safety, usually occur during the REM stages of sleep. Though most people have experienced at least one nightmare during their life, subjects with nightmare disorder experience them with a greater frequency. The disorders DSM-IV number is 307.47.
Nightmare disorders are included in the group of parasomnias, which cover all unusual behaviours during sleep. Nightmare disorders can be confused with sleep terror disorders. The difference is that after a sleep terror episode, the patient wakes up with more dramatic symptoms than with a nightmare disorder, such as screaming and crying. Furthermore, they dont remember the reason of the fear, while a patient with a nightmare disorder remembers every detail of the dream. Finally, the sleep terrors usually occur during NREM Sleep.Nightmares also have to be distinguished from bad dreams, which are less emotionally intense. Furthermore, nightmares contain more scenes of aggression than bad dreams and more unhappy endings. Finally, people experiencing nightmares feel more fear than with bad dreams.The treatment depends on whether or not there is a comorbid PTSD diagnosis. About 4% of American adults are affected.
Signs and symptoms
During the nightmare, the sleeper may scream and yell out things. The nightmare sufferer is often awakened by these threatening, frightening dreams and can often vividly remember their experience. Upon awakening, the sleeper is usually alert and oriented within their surroundings, but may have an increased heart rate and symptoms of anxiety, like sweating. They may have trouble falling back to sleep for fear they will experience another nightmare.
A person experiencing nightmare disorder may have trouble going through everyday tasks; anxiety and lack of sleep caused by the fearful dreams may hinder the individual from completing everyday tasks efficiently and correctly. Upon experiencing this, these nightmare sufferers may consult with a psychiatrist.
The sleeper may have recurring episodes of awakening while recalling the intensely disturbing dream manifestations which usually result from fear or anxiety, but can also be triggered by anger, sadness, disgust, and other dysphoric emotions. Additionally, the sleeper may experience at least one of the following two features: delayed return of going back to sleep after episodes, and having episodes in the latter half of the sleep period.
Consequences
Nightmare disorder is common: it affects about 4% of the adult population. Even if children have more nightmares than adults, only 1% of children meet the criteria of the disorder. Nightmare disorder can impair the quality of life for people who are affected by the condition. It can make the patient avoid sleep, which leads to sleep deprivation, which in turn may lead to even more intense nightmares. Some other consequences of the nightmare disorder are fatigue and insomnia.Nightmare disorders have negative consequences on several aspects of the patients life, such as sleep, cognitive and emotional functioning and well-being. Nightmares can also have negative impact on the bed partners life.
Content of idiopathic nightmares
Physical aggression is the main theme of nightmares. Other fields, such as interpersonal conflict, failure, helplessness, apprehension, being chased, accidents, evil forces, disasters, insects and environmental abnormalities may also feature in nightmares. Fear is the most frequent emotion associated with nightmares, even if other emotions such as sadness, anger, and confusion can also be present.
Criteria
According to the International Classification of Sleep Disorders, the criteria needed to diagnose a nightmare disorder are the following. First, the presence of frequent nightmares that imply danger for the person and impact mood in a negative way is needed. Second, when waking up from nightmares, the person behaves in an alert way. Finally, the disorder has to have a significant impact on the patients personal, social or professional functioning, in areas like mood, sleep, cognition, behaviour, fatigue, family and occupation.
Causes
Nightmares can be caused by extreme pressure or irritation if no other mental disorder is discovered. The death of a loved one or a stressful life event can be enough to cause a nightmare but conditions such as post-traumatic stress disorder and other psychiatric disorders have been known to cause nightmares as well. If the individual is on medication, the nightmares may be attributed to some side effects of the drug. Amphetamines, antidepressants, and stimulants like cocaine and caffeine can cause nightmares. Blood pressure medication, levodopa and medications for Parkinsons disease have also been known to cause nightmares.The nightmares may be idiopathic or could be associated with psychiatric disorders like post-traumatic stress disorder, schizophrenia, and borderline personality disorder. Nightmares can also be triggered by stress and anxiety and substance abuse, such as drugs that affect the neurotransmitters norepinephrine and dopamine and serotonin. Nevertheless, causality between drugs such as beta-blockers or alpha-agonists and nightmares is still unclear and further research needs to be done to investigate the biochemical mechanisms of nightmares.Eighty percent of patients who have PTSD report nightmares. Patients with PTSD have symptoms that are classified into three clusters: intrusive/re-experiencing, numbing, and hyperarousal. Nightmares are usually considered to be part of the intrusive/re-experiencing symptom.Some differences are existing between idiopathic and PTSD related nightmares. A PTSD person having nightmares would wake up during the night more frequently and for a longer time than with idiopathic nightmares. Consequently, people with PTSD would have a poorer sleep quality. Furthermore, nightmares related to PTSD would be more stressful than idiopathic ones. However, further studies have to be conducted in this area to obtain more reliable results.
Assessment
Polysomnography records physiological parameters, such as electroencephalography (EEG), electromyography (EMG) and electrooculography (EOG) in a sleep laboratory. However, the frequency of posttraumatic nightmares tends to decrease in an artificial lab setting, which would impact the content of nightmares. Consequently, assessment of nightmare disorders using polysomnography has to last for a longer period, in order to let the patient getting used to the artificial environment.Self-report by a questionnaire or by a diary is another way to investigate nightmare disorders. However, these methods are questionable. Indeed, when filling out questionnaires with questions about a long period, people often tend to underestimate the frequency of their nightmares because of forgetting. On the contrary, filling out a diary every day may lead to an overestimation of the numbers of nightmares, because of the focusing on this phenomenon.
Comorbidity
Studies have reported that nightmare disorders were present in 50- 70% of the cases for PTSD, in 17.5% for depression, in 18.3% for insomnia, in 16.7% for schizophrenia and in 49% for borderline personality disorder. For all psychiatric disorders taken together, nightmare disorders are present in 29.9% of the cases, a much bigger rate than for the general population, which is 2-5%. Nightmare disorders can also be associated with sleep disorders such as night terrors, chronic insomnia and sleep-disordered breathing. The presence of nightmares before a trauma would influence severity of PTSD symptoms. Furthermore, having nightmares is linked to a significantly higher risk of attempting suicide and of death by suicide.
Treatment
Stress reduction techniques such as yoga, meditation and exercise may help to eliminate stress and create a more peaceful sleeping atmosphere.Diagnosis and medication can only be given to patients that report the recurring nightmares to a psychiatrist or other physician. Medications like prazosin are sometimes used to treat nightmares in people with PTSD. Therapy usually helps to deal with the frightening themes of the nightmares and alleviate the recurrence of the dreams. The persistent nightmares will usually improve as the patient gets older. Therapy is usually efficient to treat chronic nightmares in PTSD disorder or in other population. Medication has shown efficacy to treat chronic nightmares among a PTSD population but the impact of pharmacological treatments on other populations, such as drug-related nightmares, are unknown. Furthermore, patients usually take more than one medication at a time, whatever the cause related to nightmares, leading to possible interactive effects.Eye Movement Desensitization and Reprocessing (EMDR) has demonstrated a significant nightmares reduction, especially for the treatment of PTSD. Silver, Brooks and Obenchain have found a decrease of the nightmares with Vietnam War veterans after 90 days of EMDR. Jayatunge has found significant results with people who have survived to a tsunami. Greenwald has successfully used the EMDR with children. There wasnt any negative consequence due to the EMDR sessions.
Imagery rehearsal therapy has been shown as efficient to treat nightmare disorder in PTSD as well as in non PTSD populations. In this treatment, the person has to write a new scenario of the nightmare with positive images that will be rehearsed during 10 to 20 minutes per day, in order to change the negative content of the nightmare. Cognitive behavioral therapy for insomnia (CBT-I) is also efficient to treat nightmares in the PTSD population. This method aims to change sleep habits with a clinicians help and the use of tools such as a sleep diary.Exposure, relaxation and rescripting therapy is used to treat PTSD-related nightmares. This intervention combines Imagery Rehearsal Therapy with exposure and relaxation techniques. The main objective is to work on the trauma-related themes of nightmares.Research has been undertaken to investigate if sufferers of nightmares could benefit from the ability to be aware that they are indeed dreaming, a process known as lucid dreaming. The Lucid Dreaming Therapy is a specific method of the Imagery Rehearsal Therapy. The dreamer is conscious during his dream and can modulate it. Consequently, anxiety decreases, controllability increases, expectations change, which will impact the frequency of nightmares. Several studies have shown significant results with the lucid dreaming therapy. Two studies indicate a decrease of the nightmare frequency after only 12 weeks and one study shows, in 80% of the cases, a total disappearance of the nightmares after one year. Although these studies showed the efficacy of this therapy in the reduction of nightmare frequency on patients from the general population, so far evidence for this treatment is still weak.Systematic Desensitization, using graduated exposure, has been shown to be efficient to treat chronic nightmares. The person has to face the frightening elements of nightmares in a gradually way, from the less to the most stressful. When the person starts to feel unsecure, she has to manage the stress by applying a relaxation technique.
Pharmacological treatments
Pharmacological treatments could be also efficient to treat nightmare disorder. Most of the treatments were assessed to patients with PTSD. The most efficient is an alpha-blocker, Prazosin, which reduces tone during sleep by blocking noradrenergic receptors. Prazosin would significantly decrease the number of PTSD related nightmares and would therefore improve sleep quality. However, only few studies considered the effect of Prazosin in idiopathic nightmares. Benzodiazepines are also often used to treat nightmare disorder, despite the lack of efficacy demonstrated in empirical studies. Some patients were also treated with atypical antipsychotic medications. Olanzapine has quickly decreased the nightmares. Two studies have shown the positive effects of Risperidone. Aripiprazole is more tolerated than olanzapine and has demonstrated substantial improvement in the nightmare frequency. Some other drugs as clonidine, cyproheptadine, fluvoxamine, gabapentin, nabilone, phenelzine, topiramate or trazodone have presented an amelioration of the nightmares. But some further researches are needed.
Epidemiology
About 4% of American adults are affected by nightmare disorders. Women seem to be more affected than men, the ratio being 2-4 : 1. This inequality decreases with aging because of a less high prevalence in elderly women. However, it is still unclear if the difference of prevalence between men and women is real or if it reflects a higher dream recall capacity of women.According to studies, children at the age of 6–10 years are 41% more likely to experience nightmares and 22% at the age of 11. Children with persistent nightmares range from 10% to 50%. However, only 1% of children meet the criteria of a nightmare disorder. Some factors tend to predict the development of a disorder from the presence of nightmares during childhood, such as a fear of going to sleep or going back to bed after a nightmare, an irregular sleep life and an avoidance of thinking about the nightmare.
Research
Dissociative disorders are usually paired with Nightmare Disorder 57% of the time. Nightmare disorder is believed to be associated with Dissociative Disorders as a defense mechanism that is used to escape from the traumatic event that caused the Dissociative Disorder. People with Dissociative Disorder and Nightmare disorder are more likely to self-mutilate, attempt suicide, and have Borderline Personality Disorder.
Borderline personality disorder with Nightmare Disorder is very common, since the stages of sleep vary from that of a normal person (i.e. increased stage one sleep, and less stage four sleep). People with Borderline Personality disorder and Nightmare Disorder are usually the severest of those who have Borderline Personality Disorder; therefore, treating those with Nightmare Disorder may also help some with Borderline Personality Disorder.
Hypnosis seems to be a new and effective treatment for those with Nightmare Disorder, since it increases relaxation.
Nightmare disorder is also associated with those who have lower cholesterol. This connection is unclear; however, cholesterol may affect other hormones in the body (such as serotonin) which may affect ones sleep.
References
== External links == |
Aquagenic pruritus | Aquagenic pruritus is a skin condition characterized by the development of severe, intense, prickling-like epidermal itching without observable skin lesions and evoked by contact with water.
Presentation
Presentation varies from person to person. Some people have discrete attacks, which can last between 10 and 120 minutes while others are symptomatic almost constantly due to atmospheric humidity levels and/or sweating. Itching most frequently occurs on the legs, arms, chest, back, and abdomen, though it can also occur elsewhere.Itching on contact with water that also includes hives is known as aquagenic urticaria.
Pathogenesis
The exact mechanism of the condition is unknown. Some studies have suggested the itching occurs in response to increased fibrinolytic activity in the skin, inappropriate activation of the sympathetic nervous system, increased activity of acetylcholinesterase, or an increase in mast cell degranulation that releases histamine and other chemicals into the body.
Diagnosis
No definitive medical test is known for aquagenic pruritus. Rather, diagnosis is made by excluding all other possible causes of the patients itching, including polycythemia vera. Since pruritus is a symptom of many serious diseases, it is important to rule out other causes before making a final diagnosis.
Treatment
Beta-Alanine, a nonessential amino acid and freely available as a nutritional supplement in many countries, has been found to suppress or significantly reduce the symptoms in many cases. Anecdotal evidence indicates that it is commonly consumed in doses of 750 mg to 2 grams before water contact. A study found that a dose of 2 grams twice per day led to a "dramatic and sustained improvement" of symptoms in a 13-year-old male patient, allowing him to comfortably shower, exercise, and swim.Other treatment is usually focused on topical itch management. This can be effected by the application of hot water at the end of a bath or shower, antipruritic lotions or creams such as lotion containing capsaicin, using phototherapy, or the application of hot or cold packs to the skin after water contact. Paradoxically, hot baths or showers help many patients, possibly because heat causes mast cells in the skin to release their supply of histamine and to remain depleted for up to 24 hours afterward.H1 and H2 blockers, such as loratadine, doxepin, or cimetidine, have historically been the first line of pharmacological treatment, but not all sufferers find relief with these medications. When antihistamines do work, loratadine seems to be the most effective for mild cases and doxepin most effective for more severe cases.
Naltrexone, hydrocortisone, or propranolol may relieve itching for some people.Sertraline or other Selective serotonin reuptake inhibitors (SSRIs) is also a line of treatment.
Gabapentin is very helpful.
Etymology
The name is derived from Latin: aquagenic, meaning water-induced, and pruritus, meaning itch.
See also
Aquadynia
Aquagenic urticaria
List of cutaneous conditions
List of allergies
References
Further reading
== External links == |
Cardiofaciocutaneous syndrome | Cardiofaciocutaneous (CFC) syndrome is an extremely rare genetic disorder, and is one of the RASopathies. It was first described in 1986.It is characterized by the following:
Distinctive facial appearance
Unusually sparse, brittle, curly scalp hair
A range of skin abnormalities from dermatitis to thick, scaly skin over the entire body (generalized ichthyosis)
Heart malformations in over 75% of patients (congenital or appearing later), especially an obstruction of the normal flow of blood from the lower right ventricle of the heart to the lungs (valvar pulmonary stenosis)
Growth delays
Feeding problems associated with severe gastroesophageal reflux disease (GERD)
Foot abnormalities (extra toe or fusion of two or more toes)
Intellectual disability
Failure to thrive
Presentation
Head
Individuals with the disorder usually have distinctive malformations of the craniofacial area including an unusually large head (macrocephaly), prominent forehead, and abnormal narrowing of both sides of the forehead (bitemporal constriction); The nose can be upturned and short with a low nasal bridge; and large ears that are abnormally rotated toward the back of the head. In many cases, affected individuals also have downward slanting eyelid folds, widely spaced eyes, drooping of the upper eyelids, inward deviation of the eyes, and other eye abnormalities including absent eyebrows and eyelashes.
Gastrointestinal system
Genetic
Costello and Noonan syndrome are similar to CFC and their phenotypic overlap may be due to the biochemical relationship of the genes mutated in each syndrome. Genes that are mutated in all three of these syndromes encode proteins that function in the MAP kinase pathway.
Mutations that cause CFC are found in the KRAS, BRAF, MEK1, and MEK2 genes.
Costello syndrome is caused by mutations in HRAS.
Mutations that cause Noonan syndrome have been found in PTPN11 and SOS1.The relative severity of CFC when compared to Noonan syndrome may reflect the position in the biochemical pathway occupied by the affected genes.
Shp2, the protein product of the PTPN11 gene, appears to regulate the MAP kinase pathway at or above the level of SOS1.
SOS1 in turn regulates the activities of RAS, RAF, MEK, ERK, and p90RSK.
SOS1 has been demonstrated to be a target of negative feedback by ERK and p90RSK.Thus, any activating mutation downstream of SOS1 may be subject to less regulation that might mitigate the consequence of such mutations, giving rise to the phenotypic differences seen between these syndromes.
Diagnosis
Management
References
External links
CFC Syndrome at Genetics Home Reference
GeneReview/UW/NIH entry on CFC |
Severe congenital neutropenia | Severe congenital neutropenia (SCN), also often known as Kostmann syndrome or disease, is a group of rare disorders that affect myelopoiesis, causing a congenital form of neutropenia, usually without other physical malformations. SCN manifests in infancy with life-threatening bacterial infections.Most cases of SCN respond to treatment with granulocyte colony-stimulating factor (filgrastim), which increases the neutrophil count and decreases the severity and frequency of infections. Although this treatment has significantly improved survival, people with SCN are at risk of long-term complications such as hematopoietic clonal disorders (myelodysplastic syndrome, acute myeloid leukemia).
Kostmann disease (SCN3), the initial subtype recognized, was clinically described in 1956. This type has an autosomal recessive inheritance pattern, whereas the most common subtype, SCN1, shows autosomal dominant inheritance.
Presentation
Infants with SCN have frequent infections: 50% have a significant infection within 1 month, most others by 6 months. Their etiology is usually bacterial, especially staphylococcal, and they commonly involve abscesses, both cutaneous and of internal organs, pneumonia, mastoiditis (inflammation of the mastoid process), and sepsis. All of these are life-threatening for infants.
Genetics
Kostmann disease, SCN3, is inherited in an autosomal recessive manner, but the commonest subtype of Kostmann syndrome, SCN1, is autosomal dominant.A significant proportion of SCN lacks a known mutation. The recognized subtypes of Kostmann syndrome are:
SCN1 is the commonest form of SCN, which accounts for 60-80% of SCN, and the first to be genetically typified. This autosomal dominant form that arises from mutations of the ELANE (formerly ELA2) gene on chromosome 19p13.3, which encodes neutrophil elastase. Over a hundred ELANE mutations have been found in SCN1. This same gene is mutated in cyclic neutropenia.
SCN2 is caused by heterozygous (autosomal dominant) mutation of the GFI1 gene on chromosome 1p22. GFI1 is a repressor of several transcriptional processes, including ELANE, as well as miR-21 and miR-196b micro-RNAs which influence myelopoiesis.
SCN3 is the "classical", autosomal recessive form of Kostmann disease which arises from homozygous mutations in the HAX1 gene on chromosome 1p22.1. About one third of SCN3 individuals also have neurological changes including seizures, learning disabilities, or developmental delay.
SCN4 is caused by autosomal recessive mutation of the G6PC3 gene on 17q21. SCN4 is associated with structural cardiac abnormalities, enlarged liver, intermittent thrombocytopenia and a prominent superficial venous pattern. A subset of SCN4 has severe primary pulmonary hypertension and respiratory failure.
SCN5 arises from autosomal recessive Thr224Asn mutation in the VPS45 gene on chromosome 1q21.2. Unlike classical Kostmann disease, SCN5 also has defective platelet aggregation (thrombasthenia) and myelofibrosis. This type is refractory to granulocyte colony-stimulating factor. There is an absence of lysosomes in fibroblasts and depletion of alpha granules in platelets. Accelerated apoptosis occurs in the neutrophils and bone marrow.
X-linked SCN (SCNX) is caused by mutation in the WASP gene on Xp11.SCN occasionally may arise from SBDS mutations.
Usage
Severe congenital neutropenia (SCN) is used as the overarching term for all diseases that affect myelopoiesis most prominently. Kostmann syndrome can restrictively refer to Kostmann disease specifically, or can be used synonymously with SCN as an umbrella term. These syndrome subtypes are phenotypically similar despite arising from different gene abnormalities.Kostmann disease is a form of severe congenital neutropenia (SCN), specifically type 3 (SCN3), which is a rare autosomal recessive condition in which severe chronic neutropenia is detected soon after birth. The disorder was discovered in 1956 in an extended family in northern Sweden by Rolf Kostmann, a Swedish doctor.Although mutations of more than 15 genes cause severe congenital neutropenia (in a general sense) not all of these are usually considered as SCN. Clinical usage excludes two broad categories of congenital neutropenia. Diseases are excluded that overtly affect multiple systems rather than impacting myelopoiesis most prominently. Thus SCN excludes the severe neutropenia which can occur in congenital diseases such as Shwachman–Diamond syndrome, Barth syndrome, Chédiak–Higashi syndrome, WHIM syndrome, and glycogen storage disease type Ib. A further group of other miscellaneous inherited disorders, such as hyper IgM syndrome, Hermansky–Pudlak syndrome (HPS), Griscelli syndrome (GS), PN, P14 deficiency, Cohen syndrome, Charcot–Marie–Tooth disease (CMT) can show congenital neutropenia, but lack bone marrow findings typical of SCN.This group of diseases may also have additional features such as partial albinism, retinopathy, or neuropathy, and are not inclined to degenerate into acute myelogenous leukemia.
GATA2 deficiency
GATA2 deficiency is a grouping of several disorders caused by common defect, viz., familial or sporadic inactivating mutations in one of the two parental GATA2 genes. These autosomal dominant mutations cause a reduction, i.e. a haploinsufficiency, in the cellular levels of the genes product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, or other presentations that may begin as apparently benign abnormalities but commonly progress to a more serious disorder. A small but significant percentage of individuals with GATA2 deficiencys present with congenital neutropenia. This neutropenia is typically mild, often persists for years, and therefore is not a Kostmann syndrome disorder. Over time, however, the deficiency commonly progresses to include thrombocytopenia, increases susceptibility to infections due to, e.g. atypical mycobacteria or human papillomavirus, dysfunction of non-hematological organs, the myelodysplastic syndrome, and/or a leukemia, particularly acute myelogenous leukemia.
Pathophysiology
The various mutations are responsible for the untimely initiation of apoptosis in myelocytes, usually at the promyelocyte stage, leading to their premature destruction or maturation arrest in the bone marrow. The ineffective production of neutrophils leads to a decrease in the absolute neutrophil count and a subsequent increased susceptibility to infections. There may be, in addition, other underlying molecular/genetic changes producing DNA mutations and genome instability, which contribute to initiation and progression of this disease.
Diagnosis
An absolute neutrophil count (ANC) chronically less than 500/mm3, usually less than 200/mm3, is the main sign of Kostmanns. Other elements include the severity of neutropenia, the chronology (from birth; not emerging later), and other normal findings (hemoglobin, platelets, general body health). Isolated neutropenia in infants can occur in viral infections, autoimmune neutropenia of infancy, bone marrow suppression from a drug or toxin, hypersplenism, and passive placental transfer of maternal IgG.A bone marrow test can assist in diagnosis. The bone marrow usually shows early granulocyte precursors, but myelopoietic development stops ("arrests") at the promyelocyte and/or myelocyte stage, so that few maturing forms are seen. Neutrophil survival is normal.
Treatment
Regular administration of exogenous granulocyte colony-stimulating factor (filgrastim) clinically improves neutrophil counts and immune function and is the mainstay of therapy, although this may increase risk for myelofibrosis and acute myeloid leukemia in the long term.Over 90% of SCN responds to treatment with granulocyte colony-stimulating factor (filgrastim), which has significantly improved survival.
See also
Neutropenia
Cyclic neutropenia
GATA2 deficiency
References
Klein, Christoph (2011). "Genetic Defects in Severe Congenital Neutropenia: Emerging Insights into Life and Death of Human Neutrophil Granulocytes". Annual Review of Immunology. 29: 399–413. doi:10.1146/annurev-immunol-030409-101259. PMID 21219176.
Further reading
Deotare UR, Patel PD, Parikh RP, Bhagat EA (January 2012). "Uncommon cause of recurrent infections". Indian J Med Paediatr Oncol. 33 (1): 51–3. doi:10.4103/0971-5851.96971. PMC 3385280. PMID 22754210.
External links
Search for Neutropenia to see on-going projects at Orphanet
Severe Congenital Neutropenia (SCN) of Inherited Bone Marrow Failure Syndromes (IBMFS)
Severe congenital neutropenia at NIHs Office of Rare Diseases |
Chemotherapy-induced acral erythema | Chemotherapy-induced acral erythema, also known as palmar-plantar erythrodysesthesia or hand-foot syndrome is reddening, swelling, numbness and desquamation (skin sloughing or peeling) on palms of the hands and soles of the feet (and, occasionally, on the knees, elbows, and elsewhere) that can occur after chemotherapy in patients with cancer. Hand-foot syndrome is also rarely seen in sickle-cell disease. These skin changes usually are well demarcated. Acral erythema typically disappears within a few weeks after discontinuation of the offending drug.
Signs and symptoms
The symptoms can occur anywhere between days to months after administration of the offending medication, depending on the dose and speed of administration. The patient first experiences tingling and/or numbness of the palms and soles. This is followed 2-4 days later by bright redness, which is symmetrical and sharply defined.In severe cases this may be followed by burning pain and swelling, blistering and ulceration, peeling of the skin. Healing occurs without scarring unless there has been skin ulceration or necrosis (skin loss/death). With each subsequent cycle of chemotherapy, the reaction will appear more quickly, be more severe and will take longer to heal.
Causes
Acral erythema is a common adverse reaction to cytotoxic chemotherapy drugs, particularly cabozantinib, cytarabine, doxorubicin, and fluorouracil and its prodrug capecitabine.Targeted cancer therapies, especially the tyrosine kinase inhibitors sorafenib and sunitinib, have also been associated with a high incidence of acral erythema. However, acral erythema due to tyrosine kinase inhibitors seems to differ somewhat from acral erythema due to classic chemotherapy drugs.
Pathogenesis
The cause of Palmar-plantar erythrodysesthesia (PPE) is unknown. Existing hypotheses are based on the fact that only the hands and feet are involved and posit the role of temperature differences, vascular anatomy, differences in the types of cells (rapidly dividing epidermal cells and eccrine glands).In the case of PPE caused by PLD, the following mechanism has been demonstrated: sweat deposits and spreads the drug on the skin surface; then the drug penetrates into the stratum corneum like an external agent; palms and soles have high density of sweat glands, and their stratum corneum is approximately 10 times thicker than the rest of the body, and becomes an efficient long-term reservoir for the penetrating PLD, which was deposited on the skin before.
Diagnosis
Painful red swelling of the hands and feet in a patient receiving chemotherapy is usually enough to make the diagnosis. The problem can also arise in patients after bone marrow transplants, as the clinical and histologic features of PPE can be similar to cutaneous manifestations of acute (first three weeks) graft-versus-host disease. It is important to differentiate PPE, which is benign, from the more dangerous graft-versus-host disease. As time progresses, patients with graft-versus-host disease progress to have other body parts affected, while PPE is limited to hands and feet. Serial biopsies every 3 to 5 days can also be helpful in differentiating the two disorders.
Prevention
The cooling of hands and feet during chemotherapy may help prevent PPE. Support for this and a variety of other approaches to treat or prevent acral erythema comes from small clinical studies, although none has been proven in a randomised controlled clinical trial of sufficient size.Modifying some daily activities to reduce friction and heat exposure to your hands and feet for a period of time following treatment (approximately one week after IV medication, much as possible during the time you are taking oral (by mouth) medication such as capecitabine).
Avoid long exposure of hands and feet to hot water such as washing dishes, long showers, or tub baths.
Short showers in tepid water will reduce exposure of the soles of your feet to the drug.
Dishwashing gloves should not be worn, as the rubber will hold heat against your palms.
Avoid increased pressure on the soles of the feet or palms of hands.
No jogging, aerobics, power walking, jumping - avoid long days of walking.
You should also avoid using garden tools, household tools such as screwdrivers, and other tasks where you are squeezing your hand on a hard surface.
Using knives to chop food may also cause excessive pressure and friction on your palms.
Treatment
The main treatment for acral erythema is discontinuation of the offending drug, and symptomatic treatment to provide analgesia, lessen edema, and prevent superinfection. However, the treatment for the underlying cancer of the patient must not be neglected. Often, the discontinued drug can be substituted with another cancer drug or cancer treatment.Symptomatic treatment can include wound care, elevation, and pain medication. Various emollients (creams) are recommended to keep skin moist. Corticosteroids and pyridoxine have also been used to relieve symptoms. Other studies do not support the conclusion. A number of additional remedies are listed in recent medical literature. Among them henna and 10% uridine ointment which went through clinical trial.
Prognosis
Hand-foot invariably recurs with the resumption of chemotherapy. Long-term chemotherapy may also result in reversible palmoplantar keratoderma. Symptoms resolve 1–2 weeks after cessation of chemotherapy (Apisarnthanarax and Duvic 2003). The range is 1-5 wks, so it has recovered by the time the next cycle is due. Healing occurs without scarring unless there has been skin ulceration or necrosis (skin loss/death). With each subsequent cycle of chemotherapy, the reaction will appear more quickly, be more severe and will take longer to heal.
History
Hand-foot syndrome was first reported in association with chemotherapy by Zuehlke in 1974.
Synonyms for acral erythema (AE) include: hand-foot syndrome, palmar-plantar erythrodysesthesia, peculiar AE, chemotherapy-induced AE, toxic erythema of the palms and soles, palmar-plantar erythema, and Burgdorfs reaction. Common abbreviations are HFS and PPE.
References
Further reading
Farr, Katherina Podlekareva; Safwat, Akmal (2011). "Palmar-Plantar Erythrodysesthesia Associated with Chemotherapy and Its Treatment". Case Reports in Oncology. 4 (1): 229–235. doi:10.1159/000327767. PMC 3085037. PMID 21537373.
Hand-Foot Syndrome or Palmar-Plantar Erythrodysesthesia (1 & 2) |
Long face syndrome | Long face syndrome, also referred to as skeletal open bite, is a relatively common condition characterised by excessive vertical facial development. Its causes may be either genetic or environmental. Long face syndrome is "a common dentofacial abnormality.": 369 Its diagnosis, symptomology and treatments are complex and controversial. Indeed, even its existence as a "syndrome" is disputed.
Definition and treatment
One dental textbook defines it as: "Dolicofacial, there is excess of lower facial height usually associated with lower occlusal and mandibular plane angles." This is often associated "with vertical maxillary excess and mandibular hypoplasia." Luc P. M. Tourne, a Fellow in the Department of TMJ and Craniofacial Pain at the University of Minnesota School of Dentistry, noted: "There is a clinically recognizable facial morphology, the long face syndrome, which has been incompletely described in the literature," However, her study of 31 adults with this syndrome, which included "analysis of esthetics, skeletal morphology, and occlusion" confirmed "this basic dentofacial deformity" has associations " with excessive vertical growth of the maxilla." She reported that "closed bite" and "dental open" are two of the syndromes variants.The treatment for young patients troubled by long face syndrome is to halt and control descent of the lower jaw and to prevent the eruption of posterior teeth. In severe cases of deformity, a mixture of orthodontics and orthognathic surgery may be the only effective solution. The long-term (more than 6 years) effectiveness of surgical treatments for long face syndrome has been subject to study."In the American literature, the terms long-face syndrome and short-face syndrome are often used." To be sure, there are reported "long and short face anomalies" and open bite cases. However, in the opinion of Hugo Obwegeser, there is no medical justification for naming them as a "syndrome"—the signs and symptoms do not meet the definitional threshold.: 22 There is controversy concerning the use of the descriptor "long-face syndrome." While increased anterior "total and lower face height" in many ages, combined with vertical maxillary excess in adults has been observed, the causes are controversial. Specifically, there is disagreement about possible potential environmental influences on genetic components.Anecdotally, it was said to be a genetic condition, which could only be corrected with "massive amounts" of debilitating, frequent and long dental and facial reconstructive surgery.In children, there is a concern that mouth breathing can contribute to the development of long face syndrome. A recent study finds that it is a growing problem which should be treated as "it wont just go away." In addition to mouth breathing, it may be associated with sleep apnea.Because of long face syndromes sometime association with pediatric obstructive sleep apnea (OSA) and allergic reactions, it is essential that treating physicians differentiate the conditions and the treatments; treating one may not cure the other.
Notable people
Actor and screenwriter Craig Chester says he has had the condition.
See also
Adenoid facies
Facies (medical)
Dolichocephaly
Notes
== References == |
Id reaction | Id reactions (also known as "disseminated eczema," and "generalized eczema") are types of acute dermatitis developing after days or weeks at skin locations distant from the initial inflammatory or infectious site. They can be localised or generalised. This is also known as an autoeczematous response and there must be an identifiable initial inflammatory or infectious skin problem which leads to the generalised eczema. Often intensely itchy, the red papules and pustules can also be associated with blisters and scales and are always remote from the primary lesion. It is most commonly a blistering rash with itchy vesicles on the sides of fingers and feet as a reaction to fungal infection on the feet, athletes foot. Stasis dermatitis, allergic contact dermatitis, acute irritant contact eczema and infective dermatitis have been documented as possible triggers, but the exact cause and mechanism is not fully understood. Several other types of id reactions exist including erythema nodosum, erythema multiforme, Sweets syndrome and urticaria.
Presentation
Complications
Id reactions left untreated may become infected with bacteria.
Causes
Causes include infection with dermatophytosis, Mycobacterium, viruses, bacteria and parasites. Eczematous conditions including contact allergic dermatitis and stasis dermatitis as well as stitches and trauma have also been associated with id reactions. Radiation treatment of tinea capitis has been reported as triggering an id reaction.
Pathogenesis
Potential explanations include
Atypical immune recognition of autologous skin antigens
Stimulation of normal T cells by changing skin constituents
Lower threshold for skin irritation
Spreading of infectious antigens causing a secondary response
Hematogenous dissemination of cytokines from the primary site of inflammation
Diagnosis
Although there are a multitude of varying appearances, the id reaction often presents with symmetrical red patches of eczema with papules and vesicles, particularly on the outer sides of the arms, face and trunk which occur suddenly and are intensely itchy occur a few days to a week after the initial allergic or irritant dermatitis. Most commonly, athletes foot can lead to localised vesicles on hands, bacterial infections to erythema nodosum and herpes simplex virus to erythema multiforme.The diagnosis is frequently made by treating the initial triggering skin problem and observing the improvement in the eczematous rash. Both the initial skin problem and the id reaction must be observed to make the diagnosis.Not all dyshidrotic rashes are
id reactions, but id reactions are often dyshidrotic-like.Initial tests may include isolating a fungus by taking a swab and sending it for culture. Patch testing may be considered if there is suspicion of allergic contact dermatitis.A skin biopsy is rarely necessary, but if done mostly shows an interstitial granulomatous dermatitis, some lesions being spongiotic. Id reactions cannot be distinguished from other skin diseases by histopathology. However, they can be distinguished from other id reactions by histopathology.
Differential diagnosis
Other rashes that occur in a widespread distribution can look like an id reaction. These include atopic dermatitis, contact dermatitis, dyshidrosis, photodermatitis, scabies and drug eruptions.
Treatment
Id reactions are frequently unresponsive to corticosteroid therapy, but clear when the focus of infection or infestation is treated.
: 81 Therefore, the best treatment is to treat the provoking trigger. Sometimes medications are used to relieve symptoms. These include topical corticosteroids, and antihistamines. If opportunistic bacterial infection occurs, antibiotics may be required.
Prognosis
A full recovery is expected with treatment. Recurrent id reactions are frequently due to inadequate treatment of the primary infection or dermatitis and often the cause of recurrence is unknown.
Epidemiology
With no particular affinity to any particular ethnic group, seen in all age groups and equally amongst males and females, the precise prevalence is not known.
History
The suffix -id has its origins in Greek, referring to a father–son relationship. Josef Jadassohn (1863–1936), the German dermatologist that coined the term id, had observed a dermatophytosis causing a secondary allergic skin dermatitis. In 1928, Bloch recorded that the peak of the dermatophyte infection corresponded with the id reaction.
See also
Candidid
Dermatophytid
Leukemid
List of cutaneous conditions
References
== External links == |
Fungal sinusitis | Fungal sinusitis is the inflammation of the lining mucosa of the paranasal sinuses due to fungal infection. It occurs in people with reduced immunity. The maxillary sinus is the most commonly involved. Fungi responsible for fungal sinusitis are Aspergillus fumigatus (90%), Aspergillus flavus, and Aspergillus niger. Fungal sinusitis occurs most commonly in middle-aged populations. Diabetes mellitus is the most common risk factor involved.
Types
The types of fungal sinusitis are based on invasive and non-invasive as follows:
InvasiveAcute fulminant
Chronic invasive
GranulomatousNon InvasiveSaprophytic infection
Sinus fungal ball
Eosinophil related FRS including AFRSFulminant
Difference between non-invasive, invasive and fulminant fungal sinusitis
The type of fungal disease highly depends on the immunity of the patient. When a person has low immunity, they can get non-invasive fungal sinusitis, where the fungus will infect only the skin lining of the nasal and sinus cavity. When the immunity gets lowered, it will turn into invasive fungal sinusitis, and the infection can seep into the tissues making the infection dangerous. A person can have both non-invasive and invasive fungal sinusitis at the same time at different locations.Fulminant is the rarest and the most dangerous infection that can occur when immunity is too low. In this type of disease, the infection will not only seep into the tissues but also into blood vessels. Although it comes under invasive technically, when we say invasive fungal sinusitis we often refer to non-fulminant invasive fungal sinusitis as we can clearly distinguish both irrespective of the fact that symptoms are the same. The differentiating factor between invasive and fulminant infections is that the progress of the disease is very rapid in fulminant. The progress of the disease is so quick that it can kill a person in a month if not treated. One of the most common type of fulminant fungal infection is mucormycosis.
Signs and symptoms
Individuals with the condition of fungal sinusitis mostly present with features that include facial pain and pain around the eyes, nasal congestion, rhinorrhea(running nose), headache, later there may be ophthalmoplegia (paralysis of ocular muscles).
Pathophysiology
The mechanism of fungal sinusitis depends on which form, such as:
Acute fulminant form – the fungus invades into vessels causing thrombosis, necrosis with minimum inflammation
Chronic invasive – fungal hyphae invades tissue leaving necrosis with minimal inflammation
Granulomatous form – invasive hyphae invades tissue with inflammation and non-caseating granuloma (with foreign bodies).
Saprophytic infection – growth of fungus seen on mucous crusts within sinus cavity.
Sinus fungal ball – sequestration of fungal hyphae as densely tangled, and has gritty matted appearance.
Eosinophil related Allergic fungal sinusitis – though not completely understood, a possible mechanism sees the protein component of fungus elicits IgE mediated allergic mucosal inflammation.
Diagnosis
In terms of diagnosis, the clinical examination gives an idea about fungal sinusitis, as well as:
Suggestive clinical features include - multiple recurrent episodes, persistent pathology, and absent ability to smell (the Eustachian tube may also be affected).
X-Ray - can be done if the diagnosis is not certain.
CT – can document the presence of sinusitis, in the coronal views
MRI – used to find the CNS spread (extent of the disease), to evaluate individuals who demonstrate signs of invasive fungal sinusitis
Histology studies
Treatment
Treatment for fungal sinusitis can include surgical debridement; helps by slowing progression of disease thus allowing time for recovery additionally we see the options below:
In cases where the fungus has invaded the sinus tissue, echinocandins, oral voriconazole, and I.V amphotericin may be used
For allergic fungal sinusitis, systemic corticosteroids like prednisolone, methylprednisolone are added for their anti-inflammatory effect, bronchodilators and expectorants help to clear secretions in the sinuses.
Epidemiology
Though it is widely held that fungal infections of the nose and paranasal sinuses are not common, most agree that their frequency has been increasing over past decades.
See also
Granuloma
References
Further reading
Thaler, Erica; Kennedy, David W. (2008). Rhinosinusitis: A Guide for Diagnosis and Management. Springer Science & Business Media. ISBN 9780387730622. Retrieved 22 February 2017.
Aribandi, Manohar; McCoy, Victor A.; Bazan, Carlos (2007). "Imaging Features of Invasive and Noninvasive Fungal Sinusitis: A Review". RadioGraphics. 27 (5): 1283–1296. doi:10.1148/rg.275065189. PMID 17848691.
== External links == |
Telecanthus | Telecanthus, or dystopia canthorum, refers to increased distance between the inner corners of the eyelids (medial canthi), while the inter-pupillary distance is normal. This is in contrast to hypertelorism, in which the distance between the whole eyes is increased. Telecanthus and hypertelorism are each associated with multiple congenital disorders.
The distance between the inner corners of the eyelids is called the intercanthal distance. In most people, the intercanthal distance is equal to the width of each eye (the distance between the inner and outer corners of each eye). The average interpupillary distance is 60–62 millimeters (mm), which corresponds to an intercanthal distance of approximately 30–31 mm.Traumatic telecanthus refers to telecanthus resulting from traumatic injury to the nasal-orbital-ethmoid (NOE) complex. The diagnosis of traumatic telecanthus requires a measurement in excess of those normative values. The pathology can be either unilateral or bilateral, with the former more difficult to measure.
Systemic associations
Telecanthus is often associated with many congenital disorders. Congenital disorders such as Down syndrome, fetal alcohol syndrome, cri du chat syndrome, Klinefelter syndrome, Turner syndrome, Ehlers–Danlos syndrome, Waardenburg syndrome often present with prominent epicanthal folds, and if these folds are nasal (as they most commonly are) they will cause telecanthus.
Etymology
Telecanthus comes from the Greek word τῆλε (tele, "far") and the Latin word canthus, meaning corner of the eyelid. Dystopia canthorum comes from the Greek δυσ- (dus-, “bad”) and τόπος (tópos, “place”) and the Latin word canthorum ("of the canthi").
See also
Blepharophimosis, reduced size of the eyelid openings, which can result in telecanthus
== References == |
Calf (leg) | The calf (PL: calves; Latin: sura) is the back portion of the lower leg in human anatomy. The muscles within the calf correspond to the posterior compartment of the leg. The two largest muscles within this compartment are known together as the calf muscle and attach to the heel via the Achilles tendon. Several other, smaller muscles attach to the knee, the ankle, and via long tendons to the toes.
Etymology
From Middle English calf, kalf, from Old Norse kalfi, possibly derived from the same Germanic root as English calf ("young cow"). Cognate with Icelandic kálfi ("calf of the leg"). Calf and calf of the leg are documented in use in Middle English circa AD 1350 and AD 1425 respectively.Historically, the absence of calf, meaning a lower leg without a prominent calf muscle, was regarded by some authors as a sign of inferiority: it is well known that monkeys have no calves, and still less do they exist among the lower orders of mammals.
Structure
The calf is composed of the muscles of the posterior compartment of the leg: The gastrocnemius and soleus (composing the triceps surae muscle) and the tibialis posterior. The sural nerve provides innervation.
Clinical significance
Medical conditions that result in calf swelling among other symptoms include deep vein thrombosis compartment syndrome, Achilles tendon rupture, and varicose veins.
Idiopathic leg cramps are common and typically affect the calf muscles at night. Edema also is common and in many cases idiopathic. In a small study of factory workers in good health, wearing compression garments helped to reduce edema and the pain associated with edema. A small study of runners found that wearing knee-high compression stockings while running significantly improved performance.The circumference of the calf has been used to estimate selected health risks. In Spain, a study of 22,000 persons 65 or older found that a smaller calf circumference was associated with a higher risk of undernutrition. In France, a study of 6265 persons 65 or older found an inverse correlation between calf circumference and carotid plaques.Calf augmentation and restoration is available, using a range of prosthesis devices and surgical techniques
Training and Exercise
The calves can be isolated by performing movements involving plantarflexion (pointing the toes down). The two major categories of calf exercises are those that maintain an extended knee, and those that maintain a flexed knee.
The first category includes movements such as standing calf raises, donkey calf raises and stair calves. The second category includes movements that maintain a bent knee, such as seated calf raises. Movements with a straight knee will target the gastrocnemius muscle more, and movements with a bent-knee will target the soleus muscle more. However, both variations will target both muscles to a large degree.
As the calf muscles are predominantly slow-twitch, they should be trained in a moderate to high repetition range. All repetition ranges offer their own benefits, and as such, calf training should be done in the 5-10 repetition range, the 10-20 repetition range, and the 20-30 repetition range.
It is important to train the calves relatively close to failure, which is 0-4 repetitions away from technical failure. They recover quickly, often requiring rest times of as little as 10 seconds and often no more than 60 seconds. Ensuring a 1-2 second pause at the top and bottom of the movement will put more emphasis on the muscle, and less emphasis on the achilles tendon.
See also
Gastrocnemius muscle
Calf (disambiguation)
Calf raises
Shin
Sciatica
== References == |
Neurosarcoidosis | Neurosarcoidosis (sometimes shortened to neurosarcoid) refers to a type of sarcoidosis, a condition of unknown cause featuring granulomas in various tissues, in this type involving the central nervous system (brain and spinal cord). Neurosarcoidosis can have many manifestations, but abnormalities of the cranial nerves (a group of twelve nerves supplying the head and neck area) are the most common. It may develop acutely, subacutely, and chronically. Approximately 5–10 percent of people with sarcoidosis of other organs (e.g. lung) develop central nervous system involvement. Only 1 percent of people with sarcoidosis will have neurosarcoidosis alone without involvement of any other organs. Diagnosis can be difficult, with no test apart from biopsy achieving a high accuracy rate. Treatment is with immunosuppression. The first case of sarcoidosis involving the nervous system was reported in 1905.
Signs and symptoms
Neurological
Abnormalities of the cranial nerves are present in 50–70 percent of cases. The most common abnormality is involvement of the facial nerve, which may lead to reduced power on one or both sides of the face (65 percent resp 35 percent of all cranial nerve cases), followed by reduction in visual perception due to optic nerve involvement. Rarer symptoms are double vision (oculomotor nerve, trochlear nerve or abducens nerve), decreased sensation of the face (trigeminal nerve), hearing loss or vertigo (vestibulocochlear nerve), swallowing problems (glossopharyngeal nerve) and weakness of the shoulder muscles (accessory nerve) or the tongue (hypoglossal nerve). Visual problems may also be the result of papilledema (swelling of the optic disc) due to obstruction by granulomas of the normal cerebrospinal fluid (CSF) circulation.Seizures (mostly of the tonic-clonic/"grand mal" type) are present in about 15 percent and may be the presenting phenomenon in 10 percent.Meningitis (inflammation of the lining of the brain) occurs in 3–26 percent of cases. Symptoms may include headache and nuchal rigidity (being unable to bend the head forward). It may be acute or chronic.Accumulation of granulomas in particular areas of the brain can lead to abnormalities in the function of that area. For instance, involvement of the internal capsule would lead to weakness in one or two limbs on one side of the body. If the granulomas are large, they can exert a mass effect and cause headache and increase the risk of seizures. Obstruction of the flow of cerebrospinal fluid, too, can cause headaches, visual symptoms (as mentioned above) and other features of raised intracranial pressure and hydrocephalus.Involvement of the spinal cord is rare, but can lead to abnormal sensation or weakness in one or more limbs, or cauda equina symptoms (incontinence to urine or stool, decreased sensation in the buttocks).
Endocrine
Granulomas in the pituitary gland, which produces numerous hormones, is rare but leads to any of the symptoms of hypopituitarism: amenorrhoea (cessation of the menstrual cycle), diabetes insipidus (dehydration due to inability to concentrate the urine), hypothyroidism (decreased activity of the thyroid) or hypocortisolism (deficiency of cortisol).
Mental and other
Psychiatric problems occur in 20 percent of cases; many different disorders have been reported, e.g. depression and psychosis. Peripheral neuropathy has been reported in up to 15 percent of cases of neurosarcoidosis.Other symptoms due to sarcoidosis of other organs may be uveitis (inflammation of the uveal layer in the eye), dyspnoea (shortness of breath), arthralgia (joint pains), lupus pernio (a red skin rash, usually of the face), erythema nodosum (red skin lumps, usually on the shins), and symptoms of liver involvement (jaundice) or heart involvement (heart failure).
Pathophysiology
Sarcoidosis is a disease of unknown cause that leads to the development of granulomas in various organs. While the lungs are typically involved, other organs may equally be affected. Some subforms of sarcoidosis, such as Löfgren syndrome, may have a particular precipitant and have a specific course. It is unknown which characteristics predispose sarcoidosis patients to brain or spinal cord involvement.
Diagnosis
The diagnosis of neurosarcoidosis often is difficult. Definitive diagnosis can only be made by biopsy (surgically removing a tissue sample). Because of the risks associated with brain biopsies, they are avoided as much as possible. Other investigations that may be performed in any of the symptoms mentioned above are computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, lumbar puncture, electroencephalography (EEG) and evoked potential (EP) studies. If the diagnosis of sarcoidosis is suspected, typical X-ray or CT appearances of the chest may make the diagnosis more likely; elevations in angiotensin-converting enzyme and calcium in the blood, too, make sarcoidosis more likely. In the past, the Kveim test was used to diagnose sarcoidosis. This now obsolete test had a high (85 percent) sensitivity, but required spleen tissue of a known sarcoidosis patient, an extract of which was injected into the skin of a suspected case.Only biopsy of suspicious lesions in the brain or elsewhere is considered useful for a definitive diagnosis of neurosarcoid. This would demonstrate granulomas (collections of inflammatory cells) rich in epithelioid cells and surrounded by other immune system cells (e.g. plasma cells, mast cells). Biopsy may be performed to distinguish mass lesions from tumours (e.g. gliomas).MRI with gadolinium enhancement is the most useful neuroimaging test. This may show enhancement of the pia mater or white matter lesions that may resemble the lesions seen in multiple sclerosis.Lumbar puncture may demonstrate raised protein level, pleiocytosis (i.e. increased presence of both lymphocytes and neutrophil granulocytes) and oligoclonal bands. Various other tests (e.g. ACE level in CSF) have little added value.
Criteria
Some recent papers propose to classify neurosarcoidosis by likelihood:
Definite neurosarcoidosis can only be diagnosed by plausible symptoms, a positive biopsy and no other possible causes for the symptoms
Probable neurosarcoidosis can be diagnosed if the symptoms are suggestive, there is evidence of central nervous system inflammation (e.g. CSF and MRI), and other diagnoses have been excluded. A diagnosis of systemic sarcoidosis is not essential.
Possible neurosarcoidosis may be diagnosed if there are symptoms not due to other conditions but other criteria are not fulfilled.
Treatment
Neurosarcoidosis, once confirmed, is generally treated with glucocorticoids such as prednisolone. If this is effective, the dose may gradually be reduced (although many patients need to remain on steroids long-term, frequently leading to side-effects such as diabetes or osteoporosis). Methotrexate, hydroxychloroquine, cyclophosphamide, pentoxifylline, thalidomide and infliximab have been reported to be effective in small studies. In patients unresponsive to medical treatment, radiotherapy may be required. If the granulomatous tissue causes obstruction or mass effect, neurosurgical intervention is sometimes necessary. Seizures can be prevented with anticonvulsants, and psychiatric phenomena may be treated with medication usually employed in these situations.
Prognosis
Of the phenomena occurring in neurosarcoid, only facial nerve involvement is known to have a good prognosis and good response to treatment. Long-term treatment is usually necessary for all other phenomena. The mortality rate is estimated at 10 percent
Epidemiology
Sarcoidosis has a prevalence of 40 per 100,000 in the general population. However, though those with the GG genotype at rs1049550 in the ANXA11 gene were found to have 1.5–2.5 times higher odds of sarcoidosis compared to those with the AG genotype, while those with the AA genotype had about 1.6 times lower odds. Furthermore, those with Common Variable Immunodeficiency (CVID) may be at even higher risk. One study of 80 CVID patients found eight of these had sarcoidosis, suggesting as high a prevalence in CVID populations as one in 10. Given that less than 10 percent of those with sarcoidosis will have neurological involvement, and possibly later on in their disease course, neurosarcoidosis has a prevalence of less than four per 100,000.Sarcoidosis most commonly affects young adults of both sexes, although studies have reported more cases in females. Incidence is highest for individuals younger than 40 and peaks in the age-group from 20 to 29 years; a second peak is observed for women over 50.Sarcoidosis occurs throughout the world in all races with an average incidence of 16.5/100,000 in men and 19/100,000 in women. The disease is most prevalent in Northern European countries and the highest annual incidence of 60/100,000 is found in Sweden and Iceland. In the United States sarcoidosis is more common in people of African descent than Caucasians, with annual incidence reported as 35.5 and 10.9/100,000, respectively. Sarcoidosis is less commonly reported in South America, Spain, India, Canada, and the Philippines. There may be a higher susceptibility to sarcoidosis in those with coeliac disease. An association between the two disorders has been suggested.The differing incidence across the world may be at least partially attributable to the lack of screening programs in certain regions of the world and the overshadowing presence of other granulomatous diseases, such as tuberculosis, that may interfere with the diagnosis of sarcoidosis where they are prevalent.
There may also be differences in the severity of the disease between people of different ethnicities. Several studies suggest that the presentation in people of African origin may be more severe and disseminated than for Caucasians, who are more likely to have asymptomatic disease.Manifestation appears to be slightly different according to race and sex. Erythema nodosum is far more common in men than in women and in Caucasians than in other races. In Japanese patients, ophthalmologic and cardiac involvement are more common than in other races.Sarcoidosis is one of the few pulmonary diseases with a higher prevalence in non-smokers.
Notable cases
The American television personality and actress Karen Duffy wrote "Model Patient: My Life As an Incurable Wise-Ass" on her experiences with neurosarcoidosis.
References
== External links == |
Periventricular leukomalacia | Periventricular leukomalacia (PVL) is a form of white-matter brain injury, characterized by the necrosis (more often coagulation) of white matter near the lateral ventricles. It can affect newborns and (less commonly) fetuses; premature infants are at the greatest risk of neonatal encephalopathy which may lead to this condition. Affected individuals generally exhibit motor control problems or other developmental delays, and they often develop cerebral palsy or epilepsy later in life. The white matter in preterm born children is particularly vulnerable during the third trimester of pregnancy when white matter developing takes place and the myelination process starts around 30 weeks of gestational age.This pathology of the brain was described under various names ("encephalodystrophy", "ischemic necrosis", "periventricular infarction", "coagulation necrosis", "leukomalacia," "softening of the brain", "infarct periventricular white matter", "necrosis of white matter", "diffuse symmetrical periventricular leukoencephalopathy"), and more often by German scientists, but the worldwide dissemination was the term periventricular leukomalacia, introduced in 1962 B. A. Banker and J. C. Larroche. The term can be misleading, as there is no softening of the tissue in PVL. V. V. Vlasyuk and V. P. Tumanov in 1985 published the worlds first monograph devoted to PVL. Vlasyuk (1981) first revealed the high incidence of optic radiation lesions and demonstrated that PVL - a persistent process that the old necrosis can join a new, foci of PVL may be at different stages of development.
In the process of morphogenesis focuses PVL pass through three stages: 1) necrosis, 2) resorption, and 3) the formation gliosis scars or cysts. Cysts occur when large and confluent focuses of PVL, with mixed necrosis (kollikvacia in the center and coagulation rim at the periphery). Around the foci is generally defined area of other lesions of the brain white matter - the death of prooligodendrocytes, proliferation mikrogliocytes and astrocytes, swelling, bleeding, loss of capillaries, and others (the so-called "diffuse component PVL"). However, diffuse lesions without necrosis are not PVL.
Presentation
It is often impossible to identify PVL based on the patients physical or behavioral characteristics. The white matter in the periventricular regions is involved heavily in motor control, and so individuals with PVL often exhibit motor problems. However, since healthy newborns (especially premature infants) can perform very few specific motor tasks, early deficits are very difficult to identify. As the individual develops, the areas and extent of problems caused by PVL can begin to be identified; however, these problems are usually found after an initial diagnosis has been made.
The extent of signs is strongly dependent on the extent of white matter damage: minor damage leads to only minor deficits or delays, while significant white matter damage can cause severe problems with motor coordination or organ function. Some of the most frequent signs include delayed motor development, vision deficits, apneas, low heart rates, and seizures.
Delayed motor development
Delayed motor development of infants affected by PVL has been demonstrated in multiple studies. One of the earliest markers of developmental delays can be seen in the leg movements of affected infants, as early as one month of age. Those with white matter injury often exhibit "tight coupling" of leg joints (all extending or all flexing) much longer than other infants (premature and full-term). Additionally, infants with PVL may not be able to assume the same positions for sleeping, playing, and feeding as premature or full-term children of the same age. These developmental delays can continue throughout infancy, childhood, and adulthood.
Vision deficits
Premature infants often exhibit visual impairment and motor deficits in eye control immediately after birth. However, the correction of these deficits occurs "in a predictable pattern" in healthy premature infants, and infants have vision comparable to full-term infants by 36 to 40 weeks after conception. Infants with PVL often exhibit decreased abilities to maintain a steady gaze on a fixed object and create coordinated eye movements. Additionally, children with PVL often exhibit nystagmus, strabismus, and refractive error.
Seizures
Occurrence of seizures is often reported in children with PVL. In an Israel-based study of infants born between 1995 and 2002, seizures occurred in 102 of 541, or 18.7%, of PVL patients. Seizures are typically seen in more severe cases of PVL, affecting patients with greater amounts of lesions and those born at lower gestational ages and birth weights.
Causes
Predisposing factors
Those generally considered to be at greatest risk for PVL are premature, very low birth-weight infants. It is estimated that approximately 3-4% of infants who weigh less than 1,500 g (3.3 lb) have PVL, and 4-10% of those born prior to 33 weeks of gestation (but who survive more than three days postpartum) have the disorder. Gestational CMV infection also produces PVL in neonates.
Injury pathway
Two major factors appear to be involved in the development of PVL: (1) decreased blood or oxygen flow to the periventricular region (the white matter near the cerebral ventricles) and (2) damage to glial cells, the cells that support neurons throughout the nervous system. These factors are especially likely to interact in premature infants, resulting in a sequence of events that leads to the development of white matter lesions.
The initial hypoxia (decreased oxygen flow) or ischemia (decreased blood flow) can occur for a number of reasons. Fetal blood vessels are thin-walled structures, and it is likely that the vessels providing nutrients to the periventricular region cannot maintain a sufficient blood flow during episodes of decreased oxygenation during development. Additionally, hypotension resulting from fetal distress or cesarean section births can lead to decreased blood and oxygen flow to the developing brain. These hypoxic-ischemic incidents can cause damage to the blood brain barrier (BBB), a system of endothelial cells and glial cells that regulates the flow of nutrients to the brain. A damaged BBB can contribute to even greater levels of hypoxia. Alternatively, damage to the BBB can occur due to maternal infection during fetal development, fetal infections, or infection of the newly delivered infant. Because their cardiovascular and immune systems are not fully developed, premature infants are especially at risk for these initial insults.
Damage caused to the BBB by hypoxic-ischemic injury or infection sets off a sequence of responses called the inflammatory response. Immediately after an injury, the nervous system generates "pro-inflammatory" cytokines, which are molecules used to coordinate a response to the insult. These cytokines are toxic to the developing brain, and their activity in an effort to respond to specific areas of damaged tissue is believed to cause "bystander damage" to nearby areas that were not affected by the original insult. Further damage is believed to be caused by free radicals, compounds produced during ischemic episodes. The processes affecting neurons also cause damage to glial cells, leaving nearby neurons with little or no support system.
It is thought that other factors might lead to PVL, and researchers are studying other potential pathways. A 2007 article by Miller, et al., provides evidence that white-matter injury is not a condition limited to premature infants: full-term infants with congenital heart diseases also exhibit a "strikingly high incidence of white-matter injury." In a study described by Miller, of 41 full-term newborns with congenital heart disease, 13 infants (32%) exhibited white matter injury.
Diagnosis
As previously noted, there are often few signs of white matter injury in newborns. Occasionally, physicians can make the initial observations of extreme stiffness or poor ability to suckle. The preliminary diagnosis of PVL is often made using imaging technologies. In most hospitals, premature infants are examined with ultrasound soon after birth to check for brain damage. Severe white matter injury can be seen with a head ultrasound; however, the low sensitivity of this technology allows for some white matter damage to be missed. Magnetic resonance imaging (MRI) is much more effective at identifying PVL, but it is unusual for preterm infants to receive an MRI unless they have had a particularly difficult course of development (including repeated or severe infection, or known hypoxic events during or immediately after birth). No agencies or regulatory bodies have established protocols or guidelines for screening of at-risk populations, so each hospital or doctor generally makes decisions regarding which patients should be screened with a more sensitive MRI instead of the basic head ultrasound.
PVL is overdiagnosed by neuroimaging studies and the other white matter lesions of the brain are underestimated. It is important to differentiate PVL from the following major white matter lesions in the cerebral hemispheres: edematous hemorrhagic leukoencephalopathy (OGL), telentsefalny gliosis (TG), diffuse leukomalacia (DFL), subcortical leukomalacia (SL), periventricular hemorrhagic infarction (PHI), intracerebral hemorrhage ( ICH), multicystic encephalomalacia (ME), subendymal pseudocyst. Diffuse white matter lesions of the cerebral hemispheres of the brain, accompanied by softening and spreading to the central and subcortical areas are more likely DFL, PHI and ME.
Prevention
Preventing or delaying premature birth is considered the most important step in decreasing the risk of PVL. Common methods for preventing a premature birth include self-care techniques (dietary and lifestyle decisions), bed rest, and prescribed anti-contraction medications. Avoiding premature birth allows the fetus to develop further, strengthening the systems affected during the development of PVL.
An emphasis on prenatal health and regular medical examinations of the mother can also notably decrease the risk of PVL. Prompt diagnosis and treatment of maternal infection during gestation reduces the likelihood of large inflammatory responses. Additionally, treatment of infection with steroids (especially in the 24–34 weeks of gestation) have been indicated in decreasing the risk of PVL.It has also been suggested that avoiding maternal cocaine usage and any maternal-fetal blood flow alterations can decrease the risk of PVL. Episodes of hypotension or decreased blood flow to the infant can cause white matter damage.
Treatment
Current treatments
Currently, there are no treatments prescribed for PVL. All treatments administered are in response to secondary pathologies that develop as a consequence of the PVL. Because white matter injury in the periventricular region can result in a variety of deficits, neurologists must closely monitor infants diagnosed with PVL in order to determine the severity and extent of their conditions.
Patients are typically treated with an individualized treatment. It is crucial for doctors to observe and maintain organ function: visceral organ failure can potentially occur in untreated patients. Additionally, motor deficits and increased muscle tone are often treated with individualized physical and occupational therapy treatments.
Treatment challenges
The fetal and neonatal brain is a rapidly changing, developing structure. Because neural structures are still developing and connections are still being formed at birth, many medications that are successful for treatment and protection in the adult central nervous system (CNS) are ineffective in infants. Moreover, some adult treatments have actually been shown to be toxic to developing brains.
Future treatments
Although no treatments have been approved for use in human PVL patients, a significant amount of research is occurring in developing treatments for protection of the nervous system. Researchers have begun to examine the potential of synthetic neuroprotection to minimize the amount of lesioning in patients exposed to ischemic conditions.
Prognosis
The prognosis of patients with PVL is dependent on the severity and extent of white matter damage. Some children exhibit relatively minor deficits, while others have significant deficits and disabilities.
Minor tissue damage
Minor white matter damage usually is exhibited through slight developmental delays and deficits in posture, vision systems, and motor skills. Many patients exhibit spastic diplegia, a condition characterized by increased muscle tone and spasticity in the lower body. The gait of PVL patients with spastic diplegia exhibits an unusual pattern of flexing during walking.
Progression
Those patients with severe white matter injury typically exhibit more extensive signs of brain damage. Infants with severe PVL suffer from extremely high levels of muscle tone and frequent seizures. Children and adults may be quadriplegic, exhibiting a loss of function or paralysis of all four limbs.
Cerebral palsy
Many infants with PVL eventually develop cerebral palsy. The percentage of individuals with PVL who develop cerebral palsy is generally reported with significant variability from study to study, with estimates ranging from 20% to more than 60%. One of the reasons for this discrepancy is the large variability in severity of cerebral palsy. This range corresponds to the severity of PVL, which can also be quite variable. More white matter damage leads to more severe cerebral palsy; different subtypes are identified and diagnosed by a neurologist.
Despite the varying grades of PVL and cerebral palsy, affected infants typically begin to exhibit signs of cerebral palsy in a predictable manner. Typically, some abnormal neurological signs (such as those previously mentioned) are visible by the third trimester of pregnancy (28 to 40 weeks after conception), and definitive signs of cerebral palsy are visible by six to nine months of age.
Epilepsy
Another common but severe outcome of PVL patients is the development of epilepsy. The link between the two is not entirely clear; however, it appears that both genetic and early environmental factors are involved. One study estimated that 47% of children with PVL also have epilepsy, with 78% of those patients having a form of epilepsy not easily managed by medication. Many of these affected patients exhibit some seizures, as well as spastic diplegia or more severe forms of cerebral palsy, before a diagnosis of epilepsy is made.
Frequency
Unfortunately, there are very few population-based studies on the frequency of PVL. As previously described, the highest frequency of PVL is seen in premature, very low birth weight infants. These infants are typically seen in the NICU in a hospital, with approximately 4-20% of patients in the NICU being affected by PVL. On a large autopsy material without selecting the most frequently detected PVL in male children with birth weight was 1500-2500 g., dying at 6–8 days of life. Diffuse brain damage with softening (diffus leucomalacia, DFL) are found more frequently in children weighing less than 1500 g. However, PVL is not a DFL.
Research
Animal research
Animal models are frequently used to develop improved treatments for and a more complete understanding of PVL. A rat model that has white matter lesions and experiences seizures has been developed, as well as other rodents used in the study of PVL. These animal models can be used to examine the potential efficacy of new medications in the prevention and treatment of PVL.
Clinical research
Current clinical research ranges from studies aimed at understanding the progression and pathology of PVL to developing protocols for the prevention of PVL development. Many studies examine the trends in outcomes of individuals with PVL: a recent study by Hamrick, et al., considered the role of cystic periventricular leukomalacia (a particularly severe form of PVL, involving development of cysts) in the developmental outcome of the infant.Other ongoing clinical studies are aimed at the prevention and treatment of PVL: clinical trials testing neuroprotectants, prevention of premature births, and examining potential medications for the attenuation of white matter damage are all currently supported by NIH funding.
References
== External links == |
Berylliosis | Berylliosis, or chronic beryllium disease (CBD), is a chronic allergic-type lung response and chronic lung disease caused by exposure to beryllium and its compounds, a form of beryllium poisoning. It is distinct from acute beryllium poisoning, which became rare following occupational exposure limits established around 1950. Berylliosis is an occupational lung disease.
While there is no cure, symptoms can be treated.
Signs and symptoms
With single or prolonged exposure by inhalation the lungs may become sensitized to beryllium. Berylliosis has a slow onset and progression. Some people who are sensitized to beryllium may not have symptoms. Continued exposure causes the development of small inflammatory nodules, called granulomas. Of note, the authors of a 2006 study suggested that beryllium inhalation was not the only form of exposure and perhaps skin exposure was also a cause, as they found that a reduction in beryllium inhalation did not result in a reduction in CBD or beryllium sensitization.Granulomas are seen in other chronic diseases, such as tuberculosis and sarcoidosis, and it can occasionally be hard to distinguish berylliosis from these disorders. However, granulomas of CBD will typically be non-caseating, i.e. not characterized by necrosis and therefore not exhibiting a cheese-like appearance grossly.Ultimately, this process leads to restrictive lung disease (a decrease in diffusion capacity).
The earliest symptoms are typically cough and shortness of breath. Other symptoms include chest pain, joint aches, weight loss, and fever.
Rarely, one can get granulomas in other organs including the liver.
The onset of symptoms can range from weeks up to tens of years from the initial exposure. In some individuals, a single exposure to beryllium can cause berylliosis.
Pathogenesis
In susceptible persons, beryllium exposure can lead to a cell-mediated immune response. The T-cells become sensitized to beryllium. Each subsequent exposure leads to an immune response involving CD4+ helper T-lymphocytes and macrophages accumulating in the lungs. As this response continues macrophages, CD+4 T-lymphocytes and plasma cells aggregate together to form the noncaseating granulomas. When beryllium is phagocytized by macrophages, the beryllium triggers macrophage apoptosis, thereby reducing beryllium clearance from the lungs and eventually resulting in secondary necrosis and lysis. Eventually, the outcome is fibrosis of the lung.Several studies have shown that there is a genetic component to beryllium sensitivity. Specifically, those beryllium exposed workers with a mutation at the HLA-DPB1 Glu69 position have increased prevalence of beryllium sensitization and CBD. The HLA-DPB1 gene is important for MHC class II molecule function on antigen presenting cells.According to the International Agency for Research on Cancer (IARC), beryllium and beryllium compounds are Category 1 carcinogens; they are carcinogenic to both animals and humans.
Diagnosis
The differential diagnosis for berylliosis includes:
Sarcoidosis
Granulomatous lung diseases
Tuberculosis
Fungal infections (e.g., histoplasmosis)
Granulomatosis with polyangiitis
Idiopathic pulmonary fibrosis
Hypersensitivity pneumonitis
AsthmaOf these possibilities, berylliosis presents most similarly to sarcoidosis. Some studies suggest that up to 6% of all cases of sarcoidosis are actually berylliosis.Definitive diagnosis of berylliosis is based on history of beryllium exposures, documented beryllium sensitivity and granulomatous inflammation on lung biopsy. Given the invasive nature of a lung biopsy, diagnosis can also be based on clinical history consistent with berylliosis, abnormal chest x-ray or CT scan findings, and abnormalities in pulmonary function tests.Establishing beryllium sensitivity is the first step in diagnosis. The beryllium lymphocyte proliferation test (BeLPT) is the standard way of determining sensitivity to beryllium. The test is performed by acquiring either peripheral blood or fluid from a bronchial alveolar lavage, and lymphocytes are cultured with beryllium sulfate. Cells are then counted and those with elevated number of cells are considered abnormal. Those exposed persons with two abnormal BeLPT tested with peripheral blood, or one abnormal and one borderline result, are considered beryllium sensitized. Also, those with one abnormal BeLPT tested with fluid from a bronchial alveolar lavage are considered sensitized.Chest radiography findings of berylliosis are non-specific. Early in the disease radiography findings are usually normal. In later stages interstitial fibrosis, pleural irregularities, hilar lymphadenopathy and ground-glass opacities have been reported. Findings on CT are also not specific to berylliosis. Findings that are common in CT scans of people with berylliosis include parenchymal nodules in early stages. One study found that ground-glass opacities were more commonly seen on CT scan in berylliosis than in sarcoidosis. In later stages hilar lymphadenopathy, interstitial pulmonary fibrosis and pleural thickening.
Classification
Berylliosis is an occupational disease. Relevant occupations are those where beryllium is mined, processed or converted into metal alloys, or where machining of metals containing beryllium and recycling of scrap alloys occurs. It is associated with aerospace manufacturing, microwave semiconductor electronics, beryllium mining or manufacturing of fluorescent light bulbs (which once contained beryllium compounds in their internal phosphor coating). Beryllia was used in lamp manufacture because of ceramics obvious virtues for insulation and heat resistance, and also because beryllia could be made transparent. Certain welding anodes along with other electrical contacts and even non-sparking tools are made of beryllium copper alloy and the subsequent machining of such materials would cause the disease as well.
Prevention
Typical levels of beryllium that industries may release into the air are of the order of 0.01 µg/m3, averaged over a 30-day period, or 2 µg/m3 of workroom air for an 8-hour work shift. Compliance with the current U.S. Occupational Safety and Health Administration (OSHA) permissible exposure limit for beryllium of 2 µg/m3 has been determined to be inadequate to protect workers from developing beryllium sensitization and CBD. The American Conference of Governmental Industrial Hygienists (ACGIH), which is an independent organization of experts in the field of occupational health, has proposed a threshold limit value (TLV) of 0.05 µg/m3 in a 2006 Notice of Intended Change (NIC). This TLV is 40 times lower than the current OSHA permissible exposure limit, reflecting the ACGIH analysis of best available peer-reviewed research data concerning how little airborne beryllium is required to cause sensitization and CBD.Because it can be difficult to control industrial exposures to beryllium, it is advisable to use any methods possible to reduce airborne and surface contamination by beryllium, to minimize the use of beryllium and beryllium-containing alloys whenever possible, and to educate people about the potential hazards if they are likely to encounter beryllium dust or fumes. It is important to damp wipe metallographic preparation equipment to prevent accumulation of dry particles. Sectioning, grinding, and polishing must be performed under sufficiently vented hoods equipped with special filters.On 29 January 2009, the Los Alamos National Laboratory announced it was notifying nearly 2,000 current and former employees and visitors that they may have been exposed to beryllium in the lab and may be at risk of disease. Concern over possible exposure to the material was first raised in November 2008, when a box containing beryllium was received at the laboratorys short-term storage facility.
Treatment
There is no cure for berylliosis; the goals of treatment are to reduce symptoms and slow the progression of disease.Although the evidence that stopping exposure to beryllium decreases progression of the disease is limited, it is still considered to be an accepted approach to treatment in any stage of disease.People with early stages of disease, without lung function abnormalities or clinical symptoms, are periodically monitored with physical exams, pulmonary function testing and radiography.Once clinical symptoms or significant abnormalities in pulmonary function testing appear, treatments include oxygen and oral corticosteroids and whatever supportive therapy is required.
Outcomes
Overall mortality rates are 5–38%.
Epidemiology
The number of workers in the United States exposed to beryllium vary but has been estimated to be as high as 800,000 during the 1960s and 1970s. A more recent study from 2004 estimated the number of exposed workers in the United States to be around 134,000.The rate of workers becoming sensitized to beryllium varies based on genetics and exposure levels. In one study researchers found the prevalence of beryllium sensitization to range from 9 - 19% depending on the industry. Many workers who are found to be sensitive to beryllium also meet the diagnostic criteria for CBD. In one study of nuclear workers, among those who were sensitized to beryllium, 66% were found to have CBD as well. The rate of progression from beryllium sensitization to CBD has been estimated to be approximately 6-8% per year. Stopping exposure to beryllium in those sensitized has not been definitively shown to stop the progression to CBD.The overall prevalence of CBD among workers exposed to beryllium has ranged from 1 – 5% depending on industry and time period of study.The general population is unlikely to develop acute or chronic beryllium disease because ambient air levels of beryllium are normally very low (<0.03 ng/m3). However, a study found 1% of people living within 3/4 of a mile of a beryllium plant in Lorain, Ohio, had berylliosis after exposure to concentrations estimated to be less than 1 milligram per cubic metre of air. In the United States the Beryllium Case Registry contained 900 records, early cases relating to extraction and fluorescent lamp manufacture, later ones coming from the aerospace, ceramics and metallurgical industries.
History
Since the 1920s, beryllium has been used in electronics, ceramics, research and development labs, aircraft, and the atomic energy and defense industry. Cases of bronchitis and pneumonia-like symptoms were reported in Germany and Russia in the 1930s among workers mining and refining beryllium. By 1946, a cluster of cases associated with fluorescent lamp manufacturers were apparent in the United States, and the lamp industry stopped using beryllium in 1949. At that time, most construction trades and industries were unaware of the potential risks associated with beryllium exposure.It occasionally killed early workers in nuclear weapons design, such as Herbert L. Anderson.Beryllium sensitivity testing was first performed as a cutaneous beryllium patch test in the early 1950s, but was discontinued due to the test stimulating sensitization or aggravating existing chronic beryllium disease.: 115 In the 1990s, the DOE began screening employees using the BeLPT test in facilities where beryllium was used, in order to take preventive measures against beryllium exposure; somewhat alarmingly, clerical staff who were never involved in handling the material had developed asymptomatic sensitivities.The 1954 Isaac Asimov short story "Sucker Bait" is largely concerned with a space colony dying of Beryllium poisoning.
References
External links
ATSDR Case Studies in Environmental Medicine: Beryllium Toxicity U.S. Department of Health and Human Services
CDC – Research on Beryllium Sensitization and Chronic Beryllium Disease – NIOSH Workplace Safety and Health Topic
Beryllium Network
Health-cares.net
Instant insight from the Royal Society of Chemistry examining the molecular basis of chronic beryllium disease
Rosner, David; Markowitz, Gerald E. (February 1987). "Ch. 7: Salem Sarcoid:The Origins of Beryllium Disease". Dying for work: workers safety and health in twentieth-century America. Indiana University Press. pp. 103–. ISBN 978-0-253-31825-1. |
Pre-eclampsia | Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease there may be red blood cell breakdown, a low blood platelet count, impaired liver function, kidney dysfunction, swelling, shortness of breath due to fluid in the lungs, or visual disturbances. Pre-eclampsia increases the risk of undesirable outcomes for both the mother and the fetus. If left untreated, it may result in seizures at which point it is known as eclampsia.Risk factors for pre-eclampsia include obesity, prior hypertension, older age, and diabetes mellitus. It is also more frequent in a womans first pregnancy and if she is carrying twins. The underlying mechanism involves abnormal formation of blood vessels in the placenta amongst other factors. Most cases are diagnosed before delivery. Commonly, pre-eclampsia continues into the period after delivery, then known as postpartum pre-eclampsia. Rarely, pre-eclampsia may begin in the period after delivery. While historically both high blood pressure and protein in the urine were required to make the diagnosis, some definitions also include those with hypertension and any associated organ dysfunction. Blood pressure is defined as high when it is greater than 140 mmHg systolic or 90 mmHg diastolic at two separate times, more than four hours apart in a woman after twenty weeks of pregnancy. Pre-eclampsia is routinely screened during prenatal care.Recommendations for prevention include: aspirin in those at high risk, calcium supplementation in areas with low intake, and treatment of prior hypertension with medications. In those with pre-eclampsia, delivery of the baby and placenta is an effective treatment but full recovery can take days or weeks. When delivery becomes recommended depends on how severe the pre-eclampsia and how far along in pregnancy a woman is. Blood pressure medication, such as labetalol and methyldopa, may be used to improve the mothers condition before delivery. Magnesium sulfate may be used to prevent eclampsia in those with severe disease. Bed rest and salt intake have not been found to be useful for either treatment or prevention.Pre-eclampsia affects 2–8% of pregnancies worldwide. Hypertensive disorders of pregnancy (which include pre-eclampsia) are one of the most common causes of death due to pregnancy. They resulted in 46,900 deaths in 2015. Pre-eclampsia usually occurs after 32 weeks; however, if it occurs earlier it is associated with worse outcomes. Women who have had pre-eclampsia are at increased risk of heart disease and stroke later in life.The word "eclampsia" is from the Greek term for lightning. The first known description of the condition was by Hippocrates in the 5th century BC.
Signs and symptoms
Oedema (especially in the hands and face) was originally considered an important sign for a diagnosis of pre-eclampsia. However, because oedema is a common occurrence in pregnancy, its utility as a distinguishing factor in pre-eclampsia is not high. Pitting edema (unusual swelling, particularly of the hands, feet, or face, notable by leaving an indentation when pressed on) can be significant, and should be reported to a health care provider.
In general, none of the signs of pre-eclampsia are specific, and even convulsions in pregnancy are more likely to have causes other than eclampsia in modern practice. Further, a symptom such as epigastric pain may be misinterpreted as heartburn. Common features of pre-eclampsia which are screened for during pre-natal visits include elevated blood pressure and excess protein in the urine. Diagnosis depends on finding a coincidence of several pre-eclamptic features, the final proof being their regression within the days and weeks after delivery.
Causes
There is no definitive known cause of pre-eclampsia, though it is likely related to a number of factors. Some of these factors include:
Abnormal placentation (formation and development of the placenta)
Immunologic factors
Prior or existing maternal pathology—pre-eclampsia is seen more at a higher incidence in individuals with pre-existing hypertension, obesity, or antiphospholipid antibody syndrome or those with a history of pre-eclampsia
Dietary factors, e.g. calcium supplementation in areas where dietary calcium intake is low has been shown to reduce the risk of pre-eclampsia
Environmental factors, e.g. air pollutionThose with long term high blood pressure have a risk 7 to 8 times higher than those without.Physiologically, research has linked pre-eclampsia to the following physiologic changes: alterations in the interaction between the maternal immune response and the placenta, placental injury, endothelial cell injury, altered vascular reactivity, oxidative stress, imbalance among vasoactive substances, decreased intravascular volume, and disseminated intravascular coagulation.While the exact cause of pre-eclampsia remains unclear, there is strong evidence that a major cause predisposing a susceptible woman to pre-eclampsia is an abnormally implanted placenta. This abnormally implanted placenta may result in poor uterine and placental perfusion, yielding a state of hypoxia and increased oxidative stress and the release of anti-angiogenic proteins along with inflammatory mediators into the maternal plasma. A major consequence of this sequence of events is generalized endothelial dysfunction. The abnormal implantation may stem from the maternal immune systems response to the placenta, specifically a lack of established immunological tolerance in pregnancy. Endothelial dysfunction results in hypertension and many of the other symptoms and complications associated with pre-eclampsia. Those with pre-eclampsia may have a lower risk of breast cancer.Abnormal chromosome 19 microRNA cluster (C19MC) impairs extravillus trophoblast cell invasion to the spiral arteries, causing high resistance, low blood flow, and low nutrient supply to the fetus.
Genetic factors
Despite a lack of knowledge on specific causal mechanisms of pre-eclampsia, there is strong evidence to suggest it results from both environmental and heritable factors. A 2005 study showed that women with a first-degree relative who had a pre-eclamptic birth are twice as likely to develop it themselves. Furthermore, men related to someone with affected birth have an increased risk of fathering a pre-eclamptic pregnancy. Fetuses affected by pre-eclampsia have a higher chance of later pregnancy complications including growth restriction, prematurity, and stillbirth.The onset of pre-eclampsia is thought to be caused by several complex interactions between genetics and environmental factors. Our current understanding of the specifically heritable cause involves an imbalance of angiogenic factors in the placenta. Angiogenesis involves the growth of new blood vessels from existing vessels, and an imbalance during pregnancy can affect the vascularization, growth, and biological function of the fetus. The irregular expression of these factors is thought to be controlled by multiple loci on different chromosomes. Research on the topic has been limited because of the heterogeneous nature of the disease. Maternal, paternal, and fetal genotypes all play a role as well as complex epigenetic factors such as whether the parents smoke, maternal age, sexual cohabitation, and obesity. Currently, there is very little understanding behind the mechanisms of these interactions. Due to the polygenic nature of pre-eclampsia, a majority of the studies that have been conducted thus far on the topic have utilized genome-wide association studies.One known effector of pre-eclampsia is the fetal loci FLT1. Located on chromosome 13 in the q12 region, FLT1 codes for Fms-like tyrosine kinase 1, an angiogenic factor expressed in fetal trophoblasts. Angiogenic factors are crucial for vascular growth in the placenta. An FLT1 soluble isoform caused by a splice variant is sFLT1, which works as an antiangiogenic factor, reducing vascular growth in the placenta. A healthy, normotensive pregnancy is characterized by a balance between these factors. However, upregulation of this variant and overexpression of sFL1 can contribute to endothelial dysfunction. Reduced vascular growth and endothelial dysfunction manifest primarily in maternal symptoms such as renal failure, edema, and seizures. However, these factors can also lead to inadequate oxygen, nutrient, or blood supply to the fetus. Furthermore, in this loci region, several single-nucleotide polymorphisms (SNPs) have been observed to impact the overexpression of sFL1. Specifically, SNPs rs12050029 and rs4769613s risk alleles are linked with low red blood cell counts and carry an increased risk of late-onset pre-eclampsia.
Patau syndrome, or Trisomy 13, is also associated with the upregulation of sFLT1 due to the extra copy of the 13th chromosome. Because of this upregulation of an antiangiogenic factor, women with trisomy 13 pregnancies often experience reduced placental vascularization and are at higher risk for developing pre-eclampsia.Beyond fetal loci, there have been some maternal loci identified as effectors of pre-eclampsia. Alpha-ketoglutarate-dependent hydroxylase expression on chromosome 16 in the q12 region is also associated with pre-eclampsia. Specifically, allele rs1421085 heightens the risk of not just pre-eclampsia but also an increase in BMI and hypertension. This pleiotropy is one of the reasons why these traits are considered to be a risk factor. Furthermore, ZNF831 (zinc finger protein 831) and its loci on chromosome 20q13 were identified as another significant factor in pre-eclampsia. The risk allele rs259983 is also associated with both pre-eclampsia and hypertension, further evidence that the two traits are possibly linked.
While the current understanding suggests that maternal alleles are the main hereditary cause of pre-eclampsia, paternal loci have also been implicated. In one study, paternal DLX5 (Distal-Less Homeobox 5) was identified as an imprinted gene. Located on chromosome 7 in the q21 region, DLX5 serves as a transcription factor often linked with the developmental growth of organs. When paternally inherited, DLX5 and its SNP rs73708843 are shown to play a role in trophoblast proliferation, affecting vascular growth and nutrient delivery.Besides specific loci, several important genetic regulatory factors contribute to the development of pre-eclampsia. Micro RNAs, or miRNAs, are noncoding mRNAs that down-regulate posttranscriptional gene expression through RNA-induced silencing complexes. In the placenta, miRNAs are crucial for regulating cell growth, angiogenesis, cell proliferation, and metabolism. These placental-specific miRNAs are clustered in large groups, mainly on chromosomes 14 and 19, and irregular expression of either is associated with an increased risk of an affected pregnancy. For instance, miR-16 and miR-29 are vascular endothelial growth factors (VEGFs) and play a role in upregulating sFLT-1. In particular, the overexpression of miRNA miR-210 has been shown to induce hypoxia, which affects spiral artery remodeling, an important part of the pathogenesis of pre-eclampsia.
Risk factors
Known risk factors for pre-eclampsia include:
Having never previously given birth
Diabetes mellitus
Kidney disease
Chronic hypertension
Prior history of pre-eclampsia
Family history of pre-eclampsia
Advanced maternal age (>35 years)
Obesity
Antiphospholipid antibody syndrome
Multiple gestation
Having donated a kidney
Having sub-clinical hypothyroidism or thyroid antibodies
Placental abnormalities such as placental ischemia
Pathogenesis
Although much research into mechanism of pre-eclampsia has taken place, its exact pathogenesis remains uncertain. Pre-eclampsia is thought to result from an abnormal placenta, the removal of which ends the disease in most cases. During normal pregnancy, the placenta vascularizes to allow for the exchange of water, gases, and solutes, including nutrients and wastes, between maternal and fetal circulations. Abnormal development of the placenta leads to poor placental perfusion. The placenta of women with pre-eclampsia is abnormal and characterized by poor trophoblastic invasion. It is thought that this results in oxidative stress, hypoxia, and the release of factors that promote endothelial dysfunction, inflammation, and other possible reactions.The clinical manifestations of pre-eclampsia are associated with general endothelial dysfunction, including vasoconstriction and end-organ ischemia. Implicit in this generalized endothelial dysfunction may be an imbalance of angiogenic and anti-angiogenic factors. Both circulating and placental levels of soluble fms-like tyrosine kinase-1 (sFlt-1) are higher in women with pre-eclampsia than in women with normal pregnancy. sFlt-1 is an anti-angiogenic protein that antagonizes vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), both of which are proangiogenic factors. Soluble endoglin (sEng) has also been shown to be elevated in women with pre-eclampsia and has anti-angiogenic properties, much like sFlt-1 does.Both sFlt-1 and sEng are upregulated in all pregnant women to some extent, supporting the idea that hypertensive disease in pregnancy is a normal pregnancy adaptation gone awry. As natural killer cells are intimately involved in placentation and placentation involves a degree of maternal immune tolerance for a foreign placenta, it is not surprising that the maternal immune system might respond more negatively to the arrival of some placentae under certain circumstances, such as a placenta which is more invasive than normal. Initial maternal rejection of the placental cytotrophoblasts may be the cause of the inadequately remodeled spiral arteries in those cases of pre-eclampsia associated with shallow implantation, leading to downstream hypoxia and the appearance of maternal symptoms in response to upregulated sFlt-1 and sEng.
Oxidative stress may also play an important part in the pathogenesis of pre-eclampsia. The main source of reactive oxygen species (ROS) is the enzyme xanthine oxidase (XO) and this enzyme mainly occurs in the liver. One hypothesis is that the increased purine catabolism from placental hypoxia results in increased ROS production in the maternal liver and release into the maternal circulation that causes endothelial cell damage.Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. One of the main differences found in pre-eclampsia is a shift toward Th1 responses and the production of IFN-γ. The origin of IFN-γ is not clearly identified and could be the natural killer cells of the uterus, the placental dendritic cells modulating responses of T helper cells, alterations in synthesis of or response to regulatory molecules, or changes in the function of regulatory T cells in pregnancy. Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers. It has been documented that fetal cells such as fetal erythroblasts as well as cell-free fetal DNA are increased in the maternal circulation in women who develop pre-eclampsia. These findings have given rise to the hypothesis that pre-eclampsia is a disease process by which a placental lesion such as hypoxia allows increased fetal material into the maternal circulation, that in turn leads to an immune response and endothelial damage, and that ultimately results in pre-eclampsia and eclampsia.
One hypothesis for vulnerability to pre-eclampsia is the maternal-fetal conflict between the maternal organism and fetus. After the first trimester trophoblasts enter the spiral arteries of the mother to alter the spiral arteries and thereby gain more access to maternal nutrients. Occasionally there is impaired trophoblast invasion that results in inadequate alterations to the uterine spiral arteries. It is hypothesized that the developing embryo releases biochemical signals that result in the woman developing hypertension and pre-eclampsia so that the fetus can benefit from a greater amount of maternal circulation of nutrients due to increased blood flow to the impaired placenta. This results in a conflict between maternal and fetal fitness and survival because the fetus is invested in only its survival and fitness while the mother is invested in this and subsequent pregnancies.Another evolutionary hypothesis for vulnerability to pre-eclampsia is the idea of ensuring pair-bonding between the mother and father and paternal investment in the fetus. Researchers posit that pre-eclampsia is an adaptation for the mother to terminate investment in a fetus that might have an unavailable father, as determined by repeated semen exposure of the father to the mother. Various studies have shown that women who frequently had exposure to partners semen before conception had a reduced risk of pre-eclampsia. Also, subsequent pregnancies by the same father had a reduced risk of pre-eclampsia while subsequent pregnancies by a different father had a higher risk of developing pre-eclampsia.In normal early embryonic development, the outer epithelial layer contains cytotrophoblast cells, a stem cell type found in the trophoblast that later differentiates into the fetal placenta. These cells differentiate into many placental cells types, including extravillous trophoblast cells. Extravillous trophoblast cells are an invasive cell type which remodel the maternal spiral arteries by replacing the maternal epithelium and smooth muscle lining the spiral arteries causing artery dilation. This prevents maternal vasoconstriction in the spiral arteries and allows for continued blood and nutrient supply to the growing fetus with low resistance and high blood flow.In pre-eclampsia, abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration. Specific microRNAs in this cluster which might cause abnormal spiral artery invasion include miR-520h, miR-520b, and 520c-3p. This impairs extravillus trophoblast cells invasion to the maternal spiral arteries, causing high resistance and low blood flow and low nutrient supply to the fetus. There is tentative evidence that vitamin supplementation can decrease the risk.Immune factors may also play a role.
Diagnosis
Testing for pre-eclampsia is recommended throughout pregnancy via measuring a womans blood pressure.
Diagnostic criteria
Pre-eclampsia is diagnosed when a pregnant woman develops:
Blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic on two separate readings taken at least four to six hours apart after 20 weeks gestation in an individual with previously normal blood pressure.
In a woman with essential hypertension beginning before 20 weeks gestational age, the diagnostic criteria are an increase in systolic blood pressure (SBP) of ≥30 mmHg or an increase in diastolic blood pressure (DBP) of ≥15 mmHg.
Proteinuria ≥ 0.3 grams (300 mg) or more of protein in a 24-hour urine sample or a SPOT urinary protein to creatinine ratio ≥0.3 or a urine dipstick reading of 1+ or greater (dipstick reading should only be used if other quantitative methods are not available).Suspicion for pre-eclampsia should be maintained in any pregnancy complicated by elevated blood pressure, even in the absence of proteinuria. Ten percent of individuals with other signs and symptoms of pre-eclampsia and 20% of individuals diagnosed with eclampsia show no evidence of proteinuria. In the absence of proteinuria, the presence of new-onset hypertension (elevated blood pressure) and the new onset of one or more of the following is suggestive of the diagnosis of pre-eclampsia:
Evidence of kidney dysfunction (oliguria, elevated creatinine levels)
Impaired liver function (noted by liver function tests)
Thrombocytopenia (platelet count <100,000/microliter)
Pulmonary edema
Ankle edema (pitting type)
Cerebral or visual disturbancesPre-eclampsia is a progressive disorder and these signs of organ dysfunction are indicative of severe pre-eclampsia. A systolic blood pressure ≥160 or diastolic blood pressure ≥110 and/or proteinuria >5g in a 24-hour period is also indicative of severe pre-eclampsia. Clinically, individuals with severe pre-eclampsia may also present epigastric/right upper quadrant abdominal pain, headaches, and vomiting. Severe pre-eclampsia is a significant risk factor for intrauterine fetal death.
A rise in baseline blood pressure (BP) of 30 mmHg systolic or 15 mmHg diastolic, while not meeting the absolute criteria of 140/90, is important to note but is not considered diagnostic.
Predictive tests
There have been many assessments of tests aimed at predicting pre-eclampsia, though no single biomarker is likely to be sufficiently predictive of the disorder. Predictive tests that have been assessed include those related to placental perfusion, vascular resistance, kidney dysfunction, endothelial dysfunction, and oxidative stress. Examples of notable tests include:
Doppler ultrasonography of the uterine arteries to investigate for signs of inadequate placental perfusion. This test has a high negative predictive value among those individuals with a history of prior pre-eclampsia.
Elevations in serum uric acid (hyperuricemia) is used by some to "define" pre-eclampsia, though it has been found to be a poor predictor of the disorder. Elevated levels in the blood (hyperuricemia) are likely due to reduced uric acid clearance secondary to impaired kidney function.
Angiogenic proteins such as vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) and anti-angiogenic proteins such as soluble fms-like tyrosine kinase-1 (sFlt-1) have shown promise for potential clinical use in diagnosing pre-eclampsia, though evidence is insufficient to recommend a clinical use for these markers.A recent study, ASPRE, known to be the largest multi-country prospective trial, has reported a significant performance in identifying pregnant women at high risk of pre-eclampsia yet during the first trimester of pregnancy. Utilizing a combination of maternal history, mean arterial blood pressure, intrauterine Doppler and PlGF measurement, the study has shown a capacity to identify more than 75% of the women that will develop pre-eclampsia, allowing early intervention to prevent development of later symptoms. This approach is now officially recommended by the International Federation of Gynecologists & Obstetricians (FIGO)
Recent studies have shown that looking for podocytes (specialized cells of the kidney) in the urine has the potential to aid in the prediction of pre-eclampsia. Studies have demonstrated that finding podocytes in the urine may serve as an early marker of and diagnostic test for pre-eclampsia.
Differential diagnosis
Pre-eclampsia can mimic and be confused with many other diseases, including chronic hypertension, chronic renal disease, primary seizure disorders, gallbladder and pancreatic disease, immune or thrombotic thrombocytopenic purpura, antiphospholipid syndrome and hemolytic-uremic syndrome. It must be considered a possibility in any pregnant woman beyond 20 weeks of gestation. It is particularly difficult to diagnose when pre-existing conditions such as hypertension are present. Women with acute fatty liver of pregnancy may also present with elevated blood pressure and protein in the urine, but differ by the extent of liver damage. Other disorders that can cause high blood pressure include thyrotoxicosis, pheochromocytoma, and drug misuse.
Prevention
Preventive measures against pre-eclampsia have been heavily studied. Because the pathogenesis of pre-eclampsia is not completely understood, prevention remains a complex issue. Some currently accepted recommendations are:
Diet
Supplementation with a balanced protein and energy diet does not appear to reduce the risk of pre-eclampsia. Further, there is no evidence that changing salt intake has an effect.Supplementation with antioxidants such as vitamin C, D and E has no effect on pre-eclampsia incidence; therefore, supplementation with vitamins C, E, and D is not recommended for reducing the risk of pre-eclampsia.Calcium supplementation of at least 1 gram per day is recommended during pregnancy as it prevents pre-eclampsia where dietary calcium intake is low, especially for those at high risk. Higher selenium level is associated with lower incidence of pre-eclampsia. Higher cadmium level is associated with higher incidence of pre-eclampsia.
Aspirin
Taking aspirin is associated with a 1 to 5% reduction in pre-eclampsia and a 1 to 5% reduction in premature births in women at high risk. The World Health Organization recommends low-dose aspirin for the prevention of pre-eclampsia in women at high risk and recommends it be started before 20 weeks of pregnancy. The United States Preventive Services Task Force recommends a low-dose regimen for women at high risk beginning in the 12th week. Benefits are less if started after 16 weeks.The more recent study ASPRE, besides its efficacy in identifying women suspected to develop pre-eclampsia, has also been able to demonstrate a strong drop in the rate of early pre-eclampsia (-82%) and preterm pre-eclampsia (-62%). The efficacy of aspirin is due to screening to identify high risk women, adjusted prophylaxis dosage (150 mg/day), timing of the intake (bedtime) and must start before week 16 of pregnancy.
Physical activity
There is insufficient evidence to recommend either exercise or strict bedrest as preventive measures of pre-eclampsia.
Smoking cessation
In low-risk pregnancies, the association between cigarette smoking and a reduced risk of pre-eclampsia has been consistent and reproducible across epidemiologic studies. High-risk pregnancies (those with pregestational diabetes, chronic hypertension, history of pre-eclampsia in a previous pregnancy, or multifetal gestation) showed no significant protective effect. The reason for this discrepancy is not definitively known; research supports speculation that the underlying pathology increases the risk of pre-eclampsia to such a degree that any measurable reduction of risk due to smoking is masked. However, the damaging effects of smoking on overall health and pregnancy outcomes outweighs the benefits in decreasing the incidence of pre-eclampsia. It is recommended that smoking be stopped prior to, during and after pregnancy.
Immune modulation
Some studies have suggested the importance of a womans gestational immunological tolerance to her babys father, as the baby and father share genetics. There is tentative evidence that ongoing exposure either by vaginal or oral sex to the same semen that resulted in the pregnancy decreases the risk of pre-eclampsia. As one early study described, "although pre-eclampsia is a disease of first pregnancies, the protective effect of multiparity is lost with change of partner". The study also concluded that although women with changing partners are strongly advised to use condoms to prevent sexually transmitted diseases, "a certain period of sperm exposure within a stable relation, when pregnancy is aimed for, is associated with protection against pre-eclampsia".Several other studies have since investigated the decreased incidence of pre-eclampsia in women who had received blood transfusions from their partner, those with long preceding histories of sex without barrier contraceptives, and in women who had been regularly performing oral sex.Having already noted the importance of a womans immunological tolerance to her babys paternal genes, several Dutch reproductive biologists decided to take their research a step further. Consistent with the fact that human immune systems tolerate things better when they enter the body via the mouth, the Dutch researchers conducted a series of studies that confirmed a surprisingly strong correlation between a diminished incidence of pre-eclampsia and a womans practice of oral sex, and noted that the protective effects were strongest if she swallowed her partners semen. A team from the University of Adelaide has also investigated to see if men who have fathered pregnancies which have ended in miscarriage or pre-eclampsia had low seminal levels of critical immune modulating factors such as TGF-beta. The team has found that certain men, dubbed "dangerous males", are several times more likely to father pregnancies that would end in either pre-e |
Pre-eclampsia | clampsia or miscarriage. Among other things, most of the "dangerous males" seemed to lack sufficient levels of the seminal immune factors necessary to induce immunological tolerance in their partners.As the theory of immune intolerance as a cause of pre-eclampsia has become accepted, women who with repeated pre-eclampsia, miscarriages, or in vitro fertilization failures could potentially be administered key immune factors such as TGF-beta along with the fathers foreign proteins, possibly either orally, as a sublingual spray, or as a vaginal gel to be applied onto the vaginal wall before intercourse.
Treatment
The definitive treatment for pre-eclampsia is the delivery of the baby and placenta, but danger to the mother persists after delivery, and full recovery can take days or weeks. The timing of delivery should balance the desire for optimal outcomes for the baby while reducing risks for the mother. The severity of disease and the maturity of the baby are primary considerations. These considerations are situation-specific and management will vary with situation, location, and institution. Treatment can range from expectant management to expedited delivery by induction of labor or Caesarean section, in addition to medications. Important in management is the assessment of the mothers organ systems, management of severe hypertension, and prevention and treatment of eclamptic seizures. Separate interventions directed at the baby may also be necessary. Bed rest has not been found to be useful and is thus not routinely recommended.
Blood pressure
The World Health Organization recommends that women with severe hypertension during pregnancy should receive treatment with anti-hypertensive agents. Severe hypertension is generally considered systolic BP of at least 160 or diastolic BP of at least 110. Evidence does not support the use of one anti-hypertensive over another. The choice of which agent to use should be based on the prescribing clinicians experience with a particular agent, its cost, and its availability. Diuretics are not recommended for prevention of pre-eclampsia and its complications. Labetalol, hydralazine and nifedipine are commonly used antihypertensive agents for hypertension in pregnancy. ACE inhibitors and angiotensin receptor blockers are contraindicated as they affect fetal development.The goal of treatment of severe hypertension in pregnancy is to prevent cardiovascular, kidney, and cerebrovascular complications. The target blood pressure has been proposed to be 140–160 mmHg systolic and 90–105 mmHg diastolic, although values are variable.
Prevention of eclampsia
The intrapartum and postpartum administration of magnesium sulfate is recommended in severe pre-eclampsia for the prevention of eclampsia. Further, magnesium sulfate is recommended for the treatment of eclampsia over other anticonvulsants. Magnesium sulfate acts by interacting with NMDA receptors.
Epidemiology
Pre-eclampsia affects approximately 2–8% of all pregnancies worldwide. The incidence of pre-eclampsia has risen in the U.S. since the 1990s, possibly as a result of increased prevalence of predisposing disorders, such as chronic hypertension, diabetes, and obesity.Pre-eclampsia is one of the leading causes of maternal and perinatal morbidity and mortality worldwide. Nearly one-tenth of all maternal deaths in Africa and Asia and one-quarter in Latin America are associated with hypertensive diseases in pregnancy, a category that encompasses pre-eclampsia.Pre-eclampsia is much more common in women who are pregnant for the first time. Women who have previously been diagnosed with pre-eclampsia are also more likely to experience pre-eclampsia in subsequent pregnancies. Pre-eclampsia is also more common in women who have pre-existing hypertension, obesity, diabetes, autoimmune diseases such as lupus, various inherited thrombophilias such as Factor V Leiden, renal disease, multiple gestation (twins or multiple birth), and advanced maternal age. Women who live at high altitude are also more likely to experience pre-eclampsia. Pre-eclampsia is also more common in some ethnic groups (e.g. African-Americans, Sub-Saharan Africans, Latin Americans, African Caribbeans, and Filipinos). Change of paternity in a subsequent pregnancy has been implicated as affecting risk, except in those with a family history of hypertensive pregnancy.Eclampsia is a major complication of pre-eclampsia. Eclampsia affects 0.56 per 1,000 pregnant women in developed countries and almost 10 to 30 times as many women in low-income countries as in developed countries.
Complications
Complications of pre-eclampsia can affect both the mother and the fetus. Acutely, pre-eclampsia can be complicated by eclampsia, the development of HELLP syndrome, hemorrhagic or ischemic stroke, liver damage and dysfunction, acute kidney injury, and acute respiratory distress syndrome (ARDS).Pre-eclampsia is also associated with increased frequency of Caesarean section, preterm delivery, and placental abruption. Furthermore, an elevation in blood pressure can occur in some individuals in the first week postpartum attributable to volume expansion and fluid mobilization. Fetal complications include fetal growth restriction and potential fetal or perinatal death.Long-term, an individual with pre-eclampsia is at increased risk for recurrence of pre-eclampsia in subsequent pregnancies.
Eclampsia
Eclampsia is the development of new convulsions in a pre-eclamptic patient that may not be attributed to other causes. It is a sign that the underlying pre-eclamptic condition is severe and is associated with high rates of perinatal and maternal morbidity and mortality. Warning symptoms for eclampsia in an individual with current pre-eclampsia may include headaches, visual disturbances, and right upper quadrant or epigastric abdominal pain, with a headache being the most consistent symptom. During pregnancy brisk or hyperactive reflexes are common, however ankle clonus is a sign of neuromuscular irritability that usually reflects severe pre-eclampsia and also can precede eclampsia. Magnesium sulfate is used to prevent convulsions in cases of severe pre-eclampsia.
HELLP Syndrome
HELLP syndrome is defined as hemolysis (microangiopathic), elevated liver enzymes (liver dysfunction), and low platelets (thrombocytopenia). This condition may occur in 10–20% of patients with severe pre-eclampsia and eclampsia and is associated with increased maternal and fetal morbidity and mortality. In 50% of instances, HELLP syndrome develops preterm, while 20% of cases develop in late gestation and 30% during the post-partum period.
Long term
Preeclampsia predisposes for future cardiovascular disease and a history of preeclampsia/eclampsia doubles the risk for cardiovascular mortality later in life.
Other risks include stroke, chronic hypertension, kidney disease and venous thromboembolism. Preeclampsia and cardiovascular disease share many risk factors such as age, elevated BMI, family history and certain chronic diseases.seems pre-eclampsia does not increase the risk of cancer.Lowered blood supply to the fetus in pre-eclampsia causes lowered nutrient supply, which could result in intrauterine growth restriction (IUGR) and low birth weight. The fetal origins hypothesis states that fetal undernutrition is linked with coronary heart disease later in adult life due to disproportionate growth.Because pre-eclampsia leads to a mismatch between the maternal energy supply and fetal energy demands, pre-eclampsia can lead to IUGR in the developing fetus. Infants with IUGR are prone to have poor neuronal development and in increased risk for adult disease according to the Barker hypothesis. Associated adult diseases of the fetus due to IUGR include, but are not limited to, coronary artery disease (CAD), type 2 diabetes mellitus (T2DM), cancer, osteoporosis, and various psychiatric illnesses.The risk of pre-eclampsia and development of placental dysfunction has also been shown to be recurrent cross-generationally on the maternal side and most likely on the paternal side. Fetuses born to mothers who were born small for gestational age (SGA) were 50% more likely to develop pre-eclampsia while fetuses born to both SGA parents were three-fold more likely to develop pre-eclampsia in future pregnancies.
History
The word "eclampsia" is from the Greek term for lightning. The first known description of the condition was by Hippocrates in the 5th century BC.An outdated medical term for pre-eclampsia is toxemia of pregnancy, a term that originated in the mistaken belief that the condition was caused by toxins.
References
External links
Pre-eclampsia at Curlie
MedlinePlus entry on high blood pressure in pregnancy
Mayo Clinic fact sheet on pre-eclampsia |
Genital leiomyoma | Genital leiomyomas (also known as "Dartoic leiomyomas") are leiomyomas that originate in the dartos muscles, or smooth muscles, of the genitalia, areola, and nipple. They are a subtype of cutaneous leiomyomas that affect smooth muscle found in the scrotum, labia, or nipple. They are benign tumors, but may cause pain and discomfort to patients. Signs and symptoms of Genital leiomyoma can be symptomatic or asymptomatic and is dependent on the type of leiomyoma. In most cases, pain in the affected area or region is most common. For vaginal leiomyoma, vaginal bleeding and pain may occur. Uterine leiomyoma may exhibit pain in the area as well as painful bowel movement and/or sexual intercourse. Nipple pain, enlargement, and tenderness can be a symptom of nipple-areolar leiomyomas. Genital leiomyomas can be caused by multiple factors, one can be genetic mutations that affect hormones such as estrogen and progesterone. Moreover, risk factors to the development of genital leiomyomas include age, race, and gender. Ultrasound and imaging procedures are used to diagnose genital leiomyomas, while surgically removing the tumor is the most common treatment of these diseases. Case studies for nipple areolar, scrotal, and uterine leiomyoma were used, since there were not enough secondary resources to provide more evidence.
Types of genital leiomyomas
Uterine
Uterine Leiomyomas are benign tumors that affect 70% of European people with uteri and more than 80% African descent people with uteri by the time they turn 50 years of age. Although, only 30% of people with uteri experience symptoms. Of those with uterine leiomyomas, 29% result in hospitalizations. One-third of patients with these fibroids experience life-threatening anemia, a condition where the body does not have enough oxygen due to lack of red blood cells to carry oxygen throughout the body. These tumors are mainly treated by performing hysterectomies, a procedure in which the uterus is removed, and account for approximately 40-60% of all performed hysterectomies. Symptoms are dependent on the location of the tumor, which may occur in the submucosal (under the mucous membranes and lines the inner part of some organs), intramural (within the walls of the organs), or subserosal areas (under the serosa and lines the outer part of some organs).
Nipple-areolar
Nipple-Areolar leiomyoma is a rare type of genital leiomyoma. It presents as either unilateral or bilateral growth of benign tumor of the smooth muscle that can be painful, tender, and inflamed. They are typically less than 2 cm in length. Since this is an extremely rare tumor, with only 50 cases reported in literature, it often only reported to physicians due to chronic nipple pain.
Vaginal
Vaginal paraurethral leiomyoma is another type of genital leiomyoma that is also less common compared to other types of leiomyoma. It presents as a benign tumor of the smooth muscle in the genitourinary tract, which includes urinary and genital organs, that can grow rapidly during pregnancy. On the other hand, the tumor tend to decrease in size upon menopause. This may be due to the growth of tumor that is dependent on hormones. There is not a definite cause for the development of the disease, but one that was hypothesized is that it originates from a blood vessel tissue and smooth muscle fiber residue in an embryo. Imaging and histopathological examination is used for diagnosis of the disease. Furthermore, treatment of the disease is to surgically remove the tumor.Vulvar Leiomyomas are one the most prominent types of genital leiomyomas. Lesions to the vulva may be up to 15 cm in length and they are reported to be acutely painful. Enlargement of these leiomyomas may occur during pregnancy.
Scrotal
Scrotal leiomyoma is considered to be an extremely rare type of genital leiomyoma. Because leiomyomas in the scrotum are usually painless and slowly grows over time, there is a delay in physician referral, with an average of 6–7 years. Physician referral usually occurs when people notice their testicles growing and getting heavier. A review of 11,000 cases of benign and malignant tumors of the scrotum found 11 cases of scrotal leiomyoma. Scrotal leiomyomas can affect males of any age and race, but are more common in Caucasians from the ages of 40-60. The tumor in the scrotum has an average diameter of 6.4 cm.
Signs and symptoms
People with leiomyoma can be presented as asymptomatic, or having no symptoms. However, some people may experience severe symptoms that can interfere with daily activities. Common symptoms are recurrent pain and pressure in the affected region. People with uterine leiomyoma can experience pain during urination, bowel movements, and sexual intercourse. Other symptoms are abnormal vaginal bleeding and severe menstrual cramps.Nipple-Areolar leiomyomas can affect one or both nipples, presenting with symptoms of nipple tenderness. People with leiomyomas in the scrotum generally notice a growing testicle over a span of multiple years, where it can grow and become heavy to the point of discomfort. Due to the painless and slow, progressive growth of the tumor, the time frame between recognizing the tumor and surgical removal can be anywhere from 2 to 20 years.
Causes
Uterine
Genetics
Development and progression of uterine leiomyomas may be contributed by changes in gene regulation or mutation of genes found to be associated with uterine fibroids. Abnormalities of these genes may initiate the formation or growth of these tumors. Modification of signaling pathways and genes (e.g. CYP1A1, CYP1b1, and MED12) exhibits a correlation with the development and growth of tumors in the uterus.
Hormones
The occurrence of uterine leiomyomas is mostly common during reproductive years. This suggests that the role of ovarian hormones, estrogen and progesterone, is important in the development of this disease. Studies have shown that the development of tumors rely on these hormones and that tumors have shown to affect estrogen metabolism as it can increase the amount both its estrogen and progesterone receptors.
Diet and nutrition
Long-term results suggests that diets that are mostly plant-based, composed of fruits and vegetables, and rich in Vitamin D have a positive effect on the development of diseases, including uterine leiomyomas. On the other hand, alcohol, coffee, and red meat may have an effect on the progression or growth of these diseases based on observational and epidemiological studies.
Risk Factors
Uterine
Race
At the age of 35, incidence is reported to be 60% in African-American with-uterus persons and 40% in Caucasian with-uterus persons. By the age of 50, the incidence of uterine fibroids was >80% in African-American with uterus persons and >70% of Caucasian with uterus persons.Recurrence of uterine leiomyomas 4–5 years after removal occurs up to 59% of the time for with-uterus persons of African origin.
Age
People with uteri who delay their first pregnancy past the age of 30 are at a higher risk for uterine fibroids.
Genetic factors
Specific genetic alterations may play a role in the development of uterine leiomyomas. A mutation of a single mesenchymal cell, a stem cell that plays an important role in making and repairing bone, and fat - found in the bone marrow and adipose tissues, with the involvement of progesterone and 17 b-estrodiol can lead to these fibroids.
Early menarche
Some early studies report early age onset of menstruation increases the risk of developing fibroids. However, the biological mechanism of how this occurs is not well understood and further investigation is needed.
Nipple-Areolar
Age
The occurrence of benign tumors of the nipple commonly starts at the age of 20 and peaks around the age of 40 to 50. Growth of nipple-areolar leiomyomas may increase even after menopause.
Diagnosis
There are many ways genital leiomyomas can be diagnosed. Those who have genital leiomyomas can be asymptomatic or symptomatic. Symptoms including but not limited to pelvic pain or abnormal menstrual bleeding are used to assess fibroids. Imaging are often used to detect the presence of fibroids, particularly uterine fibroids. This includes ultrasonography, a procedure that uses high-frequency sound waves to capture tissue and organ images; Sonohysterography, a painless procedure similar to ultrasonography to capture images inside the uterus; Hysteroscopy, which examines the inside of the uterus and cervix using a flexible tube called hysteroscope.
Treatment
Treatment for genital leiomyomas primarily consist of removal by surgeries. However, genital leiomyomas typically re-occur and may reappear from 6 weeks to over 15 years post-removal. When managing leiomyomas, radiation treatment should be avoided due to the inducing effect of malignant transformation in the smooth muscle of the tumor.For uterine leiomyomas, complete removal of the uterus is required. There is minimal evidence to support the use of myomectomy to preserve fertility. Evidence shows that preoperative use of gonadotropin-releasing hormone agonists, which prevents or lessen the production of hormones like progesterone, estrogen, and testosterone, can reduce surgical complications.Subareolar leiomyomas require surgical removals. Precise surgical margins are needed to prevent re-occurrences.Leiomyomas in the scrotum require an orchidectomy, or surgical removal of one or two testicles.
To manage pain that arises from the fibroids, drugs that affect smooth muscle contraction such as nitroglycerin, nifedipine, phenoxybenzamine and doxazosin can be employed to ease the pain. For nerve pain or tenderness, gabapentin and topical analgesics may be employed.
Clinical cases
Nipple-areolar leiomyomas
41-year-old-male
A 41-year-old-male presented with a yellow nodule in the upper left areola. He reported mild pain and itching, but denied other symptoms. Sebaceous glands, epidermal hyperplasia, and tumor nests were among the numerous findings that lead to preceded a diagnosis of diagnosis of areolar leiomyoma with sebaceous hyperplasia. Characteristics of the leiomyoma included positive for estrogen and progesterone receptors and high expression of epidermal growth factor, insulin-like growth factor 1, and fibroblast growth factor-2. It is suspected that these growth factors led to the growth of the leiomyoma through an autocrine process.. The patient declined resection and the region has remained stable since.
67-year-old-female
A 67-year-old-female presented with a growing mass on the left breast areolar region. The patient had been taking methotrexate to treat her rheumatoid arthritis. Magnetic resonance imaging revealed led to a conclusion that the tumor arose from the areola. A biopsy led to a diagnosis of diffuse large, non GC B-cell lymphoma that was suspected to be associated with methotrexate. The tumor reduced in size following the withdrawal of methotrexate. Three months later, another tumor developed in the areolar region of the opposite breast.
35-year-old-female
A 35-year-old-female presented with a painful lump in the right nipple. The patient reported the lump occurred after a breastfeeding injury 3 years prior to coming into the outpatient center. The tumor has been growing ever since. A biopsy was performed to confirm the leiomyoma in the nipple.
Uterine Leiomyomas
48-year-old-female
A 48-year-old-female presented with several uterine fibroids that were asymptomatic. The tumor was removed vaginally which revealed to be a vaginal leiomyoma. Vaginal leiomyomas are rare and removal by vaginal route is the preferred treatment option.
Scrotal leiomyomas
39-year-old-male
A 39-year-old-male presented with a dull aching pain in the right scrotum. The patient had a history of his right scrotum slowly growing for the past year. There were no other symptoms of urinary tract infections (UTIs), cough, fever, weight loss, or night sweats. Further examination and an ultrasound scan found a firm mass in the right scrotum with a size of 6 cm x 4 cm that was inseparable from the testis. The patient underwent a right radical orchiectomy, or a surgical operation to remove the one or more testicles, since malignancy of the tumor could not be determined. The patient recovered and was discharged home after the operation.
71-year-old-male
A 71-year-old-male presented with a large and heavy left scrotum that has been growing for 10 years. Further examination confirmed a firm tumor in the left scrotum that was attached to the testis. The tumor was measured to be 11 cm in diameter. The patient underwent orchidectomy, or surgical removal of the testicle.
See also
List of cutaneous conditions
== References == |
Platelet storage pool deficiency | Platelet storage pool deficiency is a type of coagulopathy characterized by defects in the granules in platelets, particularly a lack of granular non-metabolic adenosine diphosphate. Individuals with adenosine diphosphate deficient storage pool disease present a prolonged bleeding time due to impaired aggregation response to fibrillar collagen.
Symptoms and signs
The presentation (signs/symptoms) of an individual with platelet storage pool deficiency is as follows:
Unusual bleeding(after surgical procedure)
Anemia
Decrease mean platelet volume
Myelodysplasia
Cause
The condition of platelet storage pool deficiency can be acquired or inherited (genetically passed on from the individuals parents). Some of the causes of platelet storage pool deficiency when acquired are:
Hairy-cell leukemia
Cardiovascular bypass
Mechanism
In terms of the pathophysiology of platelet storage pool deficiency one must consider several factors including the human bodys normal function prior to such a deficiency, such as platelet alpha-granules one of three types of platelet secretory granulePlatelet α–granules are important in platelet activity, α–granules connect with plasma membrane. This in turn increases the size of the platelet. Platelet α–granules have an important role in hemostasis as well as thrombosis. SNARE accessory proteins control the secretion of α–granule.
Diagnosis
The diagnosis of this condition can be done via the following:
Flow cytometry
Bleeding time analysis
Platelet aggregation function study:
Types
This condition may involve the alpha granules or the dense granules.
Therefore, the following examples include:
Platelet alpha-granules
Gray platelet syndrome
Quebec platelet disorder
Dense granules
δ-Storage pool deficiency
Hermansky–Pudlak syndrome
Chédiak–Higashi syndrome
Treatment
Platelet storage pool deficiency has no treatment however management consists of antifibrinolytic medications if the individual has unusual bleeding event, additionally caution should be taken with usage of NSAIDS
See also
Hypocoagulability
Hypercoagulability
References
Further reading
Sandrock, Kirstin; Zieger, Barbara (2010). "Current Strategies in Diagnosis of Inherited Storage Pool Defects". Transfusion Medicine and Hemotherapy. 37 (5): 248–258. doi:10.1159/000320279. ISSN 1660-3796. PMC 2980509. PMID 21113247.
Gresele, Paolo; Fuster, Valentin; Lopez, Jose A.; Page, Clive P.; Vermylen, Jos (2007). Platelets in Hematologic and Cardiovascular Disorders: A Clinical Handbook. Cambridge University Press. ISBN 9781139468763. Retrieved 26 November 2017.
External links
PubMed |
Hemoglobinopathy | Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.There are two main groups: abnormal structural hemoglobin variants caused by mutations in the hemoglobin genes, and the thalassemias, which are caused by an underproduction of otherwise normal hemoglobin molecules. The main structural hemoglobin variants are HbS, HbE and HbC. The main types of thalassemia are alpha-thalassemia and beta thalassemia.The two conditions may overlap because some conditions which cause abnormalities in hemoglobin proteins also affect their production. Some hemoglobin variants do not cause pathology or anemia, and thus are often not classed as hemoglobinopathies.
Hemoglobin structural biology
Normal human hemoglobins are tetrameric proteins composed of two pairs of globin chains, each of which contains one alpha-like (α-like) chain and one beta-like (β-like) chain. Each globin chain is associated with an iron-containing heme moiety. Throughout life, the synthesis of the alpha-like and the beta-like (also called non-alpha-like) chains is balanced so that their ratio is relatively constant and there is no excess of either type.The specific alpha and beta-like chains that are incorporated into Hb are highly regulated during development:
Embryonic Hbs are expressed as early as four to six weeks of embryogenesis and disappear around the eighth week of gestation as they are replaced by fetal Hb. Embryonic Hbs include:
Hb Gower-1, composed of two ζ globins (zeta globins) and two ε globins (epsilon globins) (ζ2ε2)
Hb Gower-2, composed of two alpha globins and two epsilon globins (α2ε2)
Hb Portland, composed of two zeta globins and two gamma globins (ζ2γ2)
Fetal Hb (Hb F) is produced from approximately eight weeks of gestation through birth and constitutes approximately 80 percent of Hb in the full-term neonate. It declines during the first few months of life and, in the normal state, constitutes <1 percent of total Hb by early childhood. Hb F is composed of two alpha globins and two gamma globins (α2γ2).
Adult Hb (Hb A) is the predominant Hb in children by six months of age and onward; it constitutes 96-97% of total Hb in individuals without a hemoglobinopathy. It is composed of two alpha globins and two beta globins (α2β2).
Hb A2 is a minor adult Hb that normally accounts for approximately 2.5-3.5% of total Hb from six months of age onward. It is composed of two alpha globins and two delta globins (α2δ2).
Classification of hemoglobinopathies
A) Qualitative
Structural abnormalities
Hb variants: Hb structural variants are qualitative defects that cause a change in the structure (primary, secondary, tertiary, and/or quaternary) of the Hb molecule. The majority of Hb variants do not cause disease and are most commonly discovered either incidentally or through newborn screening. A subset of Hb variants can cause severe disease when inherited in the homozygous or compound heterozygous state in combination with another structural variant or a thalassemia mutation. When clinical consequences occur, they may include anemia due to hemolysis or polycythemia due to alterations in the oxygen affinity of the abnormal Hb. Common examples of hemoglobin variants associated with hemolysis include sickle Hb (Hb S) and Hb C. Hb variants can usually be detected by protein-based assay methods; however, DNA-based methods may be required for variants with ambiguous or unusual results from protein analysis.The major functional consequences of Hb structural variants can be classified as follows:
Change in physical properties (solubility): Common beta globin mutations can alter the solubility of the Hb molecule: Hb S polymerizes when deoxygenated and Hb C crystallizes.
Reduced protein stability (instability): Unstable Hb variants are mutations that cause the Hb molecule to precipitate, spontaneously or upon oxidative stress, resulting in hemolytic anemia. Precipitated, denatured Hb can attach to the inner layer of the plasma membrane of the red blood cell (RBC) and form Heinz bodies.
Change in oxygen affinity: High or low oxygen affinity Hb molecules are more likely than normal to adopt the relaxed (R, oxy) state or the tense (T, deoxy) state, respectively. High oxygen affinity variants (R state) cause polycythemia (e.g., Hb Chesapeake, Hb Montefiore). Low oxygen affinity variants can cause cyanosis (e.g., Hb Kansas, Hb Beth Israel).
Oxidation of heme iron: Mutations of the heme binding site, particularly those affecting the conserved proximal or distal histidine residues, can produce M-hemoglobin, in which the iron atom in heme is oxidized from the ferrous (Fe2+) state to the ferric (Fe3+) state, with resultant methemoglobinemia.
Chemical abnormalities
Methemoglobinemia:
a condition caused by elevated levels of methemoglobin in the blood. Methaemoglobin is a form of Hb that contains the ferric [Fe3+] form of iron. The affinity for oxygen of ferric iron is impaired. The binding of oxygen to methaemoglobin results in an increased affinity for oxygen in the remaining heme sites that are in ferrous state within the same tetrameric haemoglobin unit.
B) Quantitative
Production abnormalities
Copy number variation (e.g., deletion, duplication, insertion) is also a common genetic cause of Hb disorders, and complex rearrangements and globin gene fusions can also occur.
Thalassemias: Thalassemias are quantitative defects that lead to reduced levels of one type of globin chain, creating an imbalance in the ratio of alpha-like chains to beta-like chains. As noted above, this ratio is normally tightly regulated to prevent excess globin chains of one type from accumulating. The excess chains that fail to incorporate into Hb form non-functional aggregates that precipitate within the RBC. This can lead to premature RBC destruction in the bone marrow (beta thalassemia) and/or in the peripheral blood (alpha thalassemia). Types:
Alpha
Beta (Major)
Beta (Minor)
Hemoglobin variants
Haemoglobin variant are not necessarily pathological. For example, haemoglobin Valletta and haemoglobin Marseille are two haemoglobin variants which are non-pathological
HbS
HbC
HbE
Hb Barts
Hb D-Punjab
HbO (Hb O-Arab)
Hb G-Philadelphia
Hb H
Hb Constant Spring
Hb Hasharon
Hemoglobin Kenya
Hb Korle-Bu
Hb Lepore
Hb M
Hb Kansas
Hb J
Hb N-Baltimore
Hb Hope
Hb Pisa
Electrophoretic migration patterns
Hemoglobin variants can be detected by gel electrophoresis.
Alkaline electrophoresis
In general on alkaline electrophoresis in order of increasing mobility are hemoglobins A2, E=O=C, G=D=S=Lepore, F, A, K, J, Barts, N, I, and H.In general a sickling test is performed on abnormal hemoglobins migrating in the S location to see if the hemoglobin precipitates in solution of sodium bisulfite.
Acid electrophoresis
In general on acid electrophoresis in order of increasing mobility are hemoglobins F, A=D=G=E=O=Lepore, S, and C.This is how abnormal hemoglobin variants are isolated and identified using these two methods. For example, a Hgb G-Philadelphia would migrate with S on alkaline electrophoresis and would migrate with A on acid electrophoresis, respectively
Evolution
Some hemoglobinopathies (and also related diseases like glucose-6-phosphate dehydrogenase deficiency) seem to have given an evolutionary benefit, especially to heterozygotes, in areas where malaria is endemic. Malaria parasites live inside red blood cells, but subtly disturb normal cellular function. In patients predisposed for rapid clearance of red blood cells, this may lead to early destruction of cells infected with the parasite and increased chance of survival for the carrier of the trait.Hemoglobin functions:
Transport of oxygen from the lungs to the tissues: This is due to the peculiar cooperation of the globin chains that allows the molecule to take in more oxygen where there is increased oxygen and to release oxygen in low concentration of oxygen.
Transport of carbon dioxide from the tissues to the lungs: The end product of tissue metabolism is acidic which increases hydrogen ions in solution. The hydrogen ions combine with bicarbonates to produce water and carbon dioxide. The carbon dioxide is mop up by hemoglobin to favor this reversible reaction.
Transport of nitric oxide: Nitric oxide is a vasodilator. This assists in the regulation of vascular reaction in times of stress as experienced during inflammation.Pathology and organic structural abnormalities may lead to any of the following disease processes:
Anemia due to reduced life span of the red cells of reduced production of the cells e. g. hemoglobin S, C and E.
Increased oxygen affinity: The red blood cells do not release their oxygen content readily in hypoxic conditions. The bone marrow therefore needs to produce more red blood cells and there is polycythemia.
Unstable hemoglobins: Red blood cells are easily destroyed under stress and hemolysis occurs with possible jaundice.
Methemoglobinemia: The iron in the heme portion of hemoglobin is easily oxidised and this reduces the ability of hemoglobin to bind oxygen. More deoxygenated hemoglobin are formed and the blood becomes cyanotic.
References
== External links == |
Progressive pseudorheumatoid dysplasia | Progressive pseudorheumatoid disyplasia (PPD or PPAC) is a disorder of bone and cartilage that affects many joints. The disorder leads to stiff joints, short stature and widening of the ends of the finger and toe bones as well as other tubular bones.
Cause
PPD is due to a mutation in the Wnt1-inducible signalling protein 3 (WISP3) gene, which encodes a signalling factor involved in cartilage homeostasis.
Symptoms
Symptoms are present typically between ages three and six years.
Abnormal walking pattern
Weakness/fatigue
Stiffness in the joints of the fingers and knees
Diagnosis
Treatment
Prognosis
PPD has no severe effect on life span.
Epidemiology
PPD is an extremely rare disease. In the United States the disease is estimated to affect less than 5,000 people and approximately 1 per million people in the United Kingdom however it is believed to be more common in Turkey and the Middle East.
== References == |
Duodenal lymphocytosis | Duodenal lymphocytosis, sometimes called lymphocytic duodenitis, lymphocytic duodenosis, or duodenal intraepithelial lymphocytosis, is a condition where an increased number of intra-epithelial lymphocytes is seen in biopsies of the duodenal mucosa when these are examined microscopically. This form of lymphocytosis is often a feature of coeliac disease but may be found in other disorders.
Presentation
The condition is characterised by an increased proportion of lymphocytes in the epithelium of the duodenum, usually when this is greater than 20-25 per 100 enterocytes. Intra-epithelial lymphocyte (IEL) are normally present in intestine and numbers are normally greater in the crypts and in the jejunum; these are distinct from those found in the lamina propria of the intestinal mucosa. IELs are mostly T cells. Increased numbers of IELs are reported in around 3% of in duodenal biopsies, depending on case mix, but may be increasingly being found, in up to 7%.
Causes
The list of possible causes is wide, including coeliac disease, environmental enteropathy (tropical sprue), autoimmune enteropathy, small intestinal bacterial overgrowth, NSAID damage, Helicobacter pylori, other infections and Crohns disease.
Diagnosis
Diagnosis is made by accurate counting of intraepithelial lymphocytes during histological examination of the duodenum. The definition of the condition includes the requirement that the duodenal histological appearances are otherwise unremarkable, specifically with normal villous architecture.In coeliac disease (also known as gluten-sensitive enteropathy), duodenal lymphocytosis is found in untreated or partially treated cases. This is the least severe type of change, known as the Marsh I stage, in the classification of histological changes in coeliac disease. Additional features including villous atrophy and crypt hyperplasia are the other findings in other Marsh stages of coeliac disease.Antibodies associated with coeliac disease were reported in around 11% of cases. These IgA endomysial antibodies and anti-transglutaminase antibodies are very sensitive and specific for coeliac disease implying that this proportion of duodenal lymphocytosis cases has definite coeliac disease. Around 33% of cases have the HLA-DQ2 allele, which is found in over 90% of people with coeliac disease. Absence of HLA-DQ2 (and the rarer HLA-DQ8) makes coeliac disease most unlikely. As antibody-negative coeliac disease is recognised, HLA status, persistence or progression of the duodenal IEL numbers following a gluten challenge, followed by symptomatic improvement on a gluten-free diet, has been used to be more certain about the diagnosis, which was made in 22% of one series of over 200 adult cases. Helicobacter infection is a common finding at endoscopy and although duodenal IEL counts were found to be slightly higher with this infection, this was not considered to be a meaningful cause in children. Other infections, including Cryptosporidiosis and Giardiasis can also be associated with an increase in IELs.
Management
The management is that of any identified associated disorder such as a gluten free diet for cases with coeliac disease or treatment of associated infections.
Prognosis
When duodenal lymphocytosis is associated with other features of coeliac disease, in particular positive antibodies, or HLA-DQ2/8 and a family history, treatment with a gluten-free diet produces an improvement in IEL numbers. Diarrhoea, thyroiditis, weakness and folate deficiency were other predictors of the development of gluten sensitivity and coeliac disease, which developed in 23 of 85 patients over 2 years in one series.
== References == |
Dents disease | Dents disease (or Dent disease) is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.
"Dents disease" is often used to describe an entire group of familial disorders, including X-linked recessive nephrolithiasis with kidney failure, X-linked recessive hypophosphatemic rickets, and both Japanese and idiopathic low-molecular-weight proteinuria. About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the OCRL1 gene (Dent 2).
Signs and symptoms
Dents disease often produces the following signs and symptoms:
Extreme thirst combined with dehydration, which leads to frequent urination
Nephrolithiasis (kidney stones)
Hypercalciuria (high urine calcium - >300 mg/d or >4 mg/kg per d with normal levels blood/serum calcium)
Aminoaciduria (amino acids in urine)
Phosphaturia (phosphate in urine)
Glycosuria (glucose in urine)
Kaliuresis (potassium in urine)
Hyperuricosuria (excessive amounts of uric acid in the urine)
Impaired urinary acidification
RicketsIn a study of 25 patients with Dents disease, 9 of 15 men, and one of 10 women had end-stage kidney disease by the age of 47.
Genetics
Dent disease 1
Dents disease is a X-linked recessive disorder. The males are prone to manifesting symptoms in early adulthood with symptoms of calculi, rickets or even with kidney failure in more severe cases.In humans, gene CLCN5 is located on chromosome Xp11.22, and has a 2238-bp coding sequence that consists of 11 exons that span 25 to 30 kb of genomic DNA and encode a 746-amino-acid protein. CLCN5 belongs to the family of voltage-gated chloride channel genes (CLCN1-CLCN7, CLCKa and CLCKb) that have about 12 transmembrane domains. These chloride channels have an important role in the control of membrane excitability, transepithelial transport, and possibly cell volume.The mechanisms by which CLC-5 dysfunction results in hypercalciuria and the other features of Dents disease remain to be elucidated. The identification of additional CLCN5 mutations may help in these studies.
Dent disease 2
Dent disease 2 (nephrolithiasis type 2) is associated with the OCRL gene. Both Lowe syndrome (oculocerebrorenal syndrome) and Dent disease can be caused by truncating or missense mutations in OCRL.
Diagnosis
Diagnosis is based on genetic study of CNCL5 gene.
Treatment
As of today, no agreed-upon treatment of Dents disease is known and no therapy has been formally accepted. Most treatment measures are supportive in nature:
Thiazide diuretics (i.e. hydrochlorothiazide) have been used with success in reducing the calcium output in urine, but they are also known to cause hypokalemia.
In rats with diabetes insipidus, thiazide diuretics inhibit the NaCl cotransporter in the renal distal convoluted tubule, leading indirectly to less water and solutes being delivered to the distal tubule. The impairment of Na transport in the distal convoluted tubule induces natriuresis and water loss, while increasing the reabsorption of calcium in this segment in a manner unrelated to sodium transport.
Amiloride also increases distal tubular calcium reabsorption and has been used as a therapy for idiopathic hypercalciuria.
A combination of 25 mg of chlorthalidone plus 5 mg of amiloride daily led to a substantial reduction in urine calcium in Dents patients, but urine pH was "significantly higher in patients with Dent’s disease than in those with idiopathic hypercalciuria (P < 0.03), and supersaturation for uric acid was consequently lower (P < 0.03)."
For patients with osteomalacia, vitamin D or derivatives have been employed, apparently with success.
Some lab tests on mice with CLC-5-related tubular damage showed a high-citrate diet preserved kidney function and delayed progress of kidney disease.
History
Dents disease was first described by Charles Enrique Dent and M. Friedman in 1964, when they reported two unrelated British boys with rickets associated with renal tubular damage characterized by hypercalciuria, hyperphosphaturia, proteinuria, and aminoaciduria. This set of symptoms was not given a name until 30 years later, when the nephrologist Oliver Wrong more fully described the disease.
Wrong had studied with Dent and chose to name the disease after his mentor. Dents disease is a genetic disorder caused by mutations in the gene CLCN5, which encodes a kidney-specific voltage-gated chloride channel, a 746-amino-acid protein (CLC-5) with 12 to 13 transmembrane domains. It manifests itself through low-molecular-weight proteinuria, hypercalciuria, aminoaciduria and hypophosphataemia. Because of its rather rare occurrence, Dents disease is often diagnosed as idiopathic hypercalciuria, i.e., excess calcium in urine with undetermined causes.
References
External links
Genetic Hypercalciuria
Dent disease on Orphanet |
Clear cell acanthoma | Clear cell acanthoma (also known as Acanthome cellules claires of Degos and Civatte, Degos acanthoma, and Pale cell acanthoma) is a benign clinical and histological lesion initially described as neoplastic, which some authors now regard as a reactive dermatosis. It usually presents as a moist solitary firm, brown-red, well-circumscribed, 5 mm to 2 cm nodule or plaque on the lower extremities of middle-aged to elderly individuals. The lesion has a crusted, scaly peripheral collarette and vascular puncta on the surface. It is characterized by slow growth, and may persist for years. The clinical differential diagnosis includes: dermatofibroma, inflamed seborrheic keratosis, pyogenic granuloma, basal-cell carcinoma, squamous cell carcinoma, verruca vulgaris, psoriatic plaque, and melanoma.
Histology
Clear cell acanthoma is characterized by a sharply demarcated psoriasiform epidermal hyperplasia composed of a proliferation of slightly enlarged keratinocytes, and basal cells with pale-staining glycogen-rich cytoplasm, mild spongiosis and scattered neutrophils, which may form small intraepidermal microabscesses. Oedematous dermal papillae are typically seen with increased vascularity and a mixed inflammatory infiltrate including lymphocytes, plasma cells and neutrophils.
Treatment
Simple surgical excision is curative.
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See also
Epidermis
List of cutaneous conditions
List of cutaneous neoplasms associated with systemic syndromes
== References == |
Neurapraxia | Neurapraxia is a disorder of the peripheral nervous system in which there is a temporary loss of motor and sensory function due to blockage of nerve conduction, usually lasting an average of six to eight weeks before full recovery. Neurapraxia is derived from the word apraxia, meaning “loss or impairment of the ability to execute complex coordinated movements without muscular or sensory impairment”.
This condition is typically caused by a blunt neural injury due to external blows or shock-like injuries to muscle fibers and skeletal nerve fibers, which leads to repeated or prolonged pressure buildup on the nerve. As a result of this pressure, ischemia occurs, a neural lesion results, and the human body naturally responds with edema extending in all directions from the source of the pressure. This lesion causes a complete or partial action potential conduction block over a segment of a nerve fiber and thus a reduction or loss of function in parts of the neural connection downstream from the lesion, leading to muscle weakness.
Neurapraxia results in temporary damage to the myelin sheath but leaves the nerve intact and is an impermanent condition; thus, Wallerian degeneration does not occur in neurapraxia. In order for the condition to be considered neurapraxia, according to the Seddon classification system of peripheral nerve injury, there must be a complete and relatively rapid recovery of motor and sensory function once nerve conduction has been restored; otherwise, the injury would be classified as axonotmesis or neurotmesis. Thus, neurapraxia is the mildest classification of peripheral nerve injury.
Neurapraxia is very common in professional athletes, especially American football players, and is a condition that can and should be treated by a physician.
Signs and symptoms
A variety of nerve types can be subjected to neurapraxia and therefore symptoms of the injury range in degree and intensity. Common symptoms of neurapraxia are disturbances in sensation, weakness of muscle, vasomotor and sudomotor paralysis in the region of the affected nerve or nerves, and abnormal sensitivity of the nerve at the point of injury. It has been observed that subjective sensory symptoms include numbness, tingling, and burning sensations at the site of the injury. Objective sensory symptoms are generally minimal in regards to touch, pain, heat, and cold. In cases of motor neuron neurapraxia, symptoms consist of flaccid paralysis of the muscles innervated by the injured nerve or nerves.
Symptoms are often transient and only last for a short period of time immediately following the injury. However, in severe cases of neurapraxia, symptoms can persist for weeks or months at a time.
Causes
The cause of neurapraxia is a neural lesion which causes a temporary block of nerve conduction without transection of the axon. A conduction block is classified as a 40% reduction in action potential amplitude over a short distance on the nerve, or a 50% reduction for a longer distance on the nerve. In neurapraxia, stimulation to the injured nerve results in a greater reduction in the action potential amplitude on the proximal site of the injury as opposed to the distal site.
Anatomy
Neurapraxia occurs in the peripheral nervous system typically in the ulnar, median, and radial nerves of the upper body and in the sciatic and peroneal nerves of the lower body. Peripheral nerves are myelinated, relatively large, spatially complex cells whose size and connectivity typically make them more susceptible to damage and compromise their capacity to self-repair, although this is not the case in neurapraxia. Microscopic evidence has shown that there is damage to the myelin sheath, but not to the axon. Therefore, distal nerve fibers do not degenerate and the myelin damage can be repaired.
Order of pathology
The order of pathology within the first 24 hours after injury follows a general pattern of nerve injury. The first physical manifestation of the injury is focal swelling adjacent to the site of the injury. In the cellular dimension, a fragmentation of neurotubules and neurofilaments occurs as a result of pressure exerted on the nerve. Axons swell at some sites and are compressed at others, leading to a beaded appearance.
Mechanisms of injury
There are several mechanisms of nerve injury including mechanical lesions, ischemia, immunologic attack, metabolic disorder, toxic agents, and exposure to radiation. The most common mechanism of injury is nerve compression in which external pressure causes decreased blood flow to the nerve and deformation of the nerve fibers. Repeated or prolonged compression of the nerve results in ischemia and ultimately edema above and below the source of the pressure (I). The thinning of myelin sheaths or focal demyelination are the main consequences of the injury that lead to conduction blockage.
Diagnosis
Seddon classification
There are three distinct classifications and degrees of nerve injury:
Neurotmesis is the most serious degree of nerve injury. It involves the disruption of the nerve and the nerve sheath.
Axonotmesis occurs when the majority of the supporting structures of the nerve are preserved, but disruption of the nerve fibers is still observed. Wallerian degeneration often occurs in the near the proximity of the injury site.
Neurapraxia is least serious form of nerve injury.There are two different forms of mechanical nerve injury involving neurapraxia. The underlying causes of transient nerve injury typically include a brief ischemic episode or any form of compression. More persistent forms of nerve injury involve demyelination and axonal constriction. In certain circumstances, diagnosing neurapraxia can be uncomfortable because of the presence of severe neuropathic pain. Neuropathic pain is an indication that the lesion of the nerve is still in progress. Diagnosis of neurapraxia is almost always followed by a quick and complete recovery period.
Treatment and recovery
The entire nerve is involved in the response to traumatic injuries. The outcome of nerve repair is dependent on the degree of the nerve injury and the circumstances at the site of injury. Since neurapraxia is the least serious form of peripheral nerve injury, recovery and treatment are not extensive. Once the cause of neurapraxia is eliminated, recovery of the lesions in the nerve occurs within a short time span.
Non-operative treatment
Neurapraxia is often treated and cured by non-operative means. The primary goals of treatment are to maintain the proper nutrition of the paralyzed muscles, prevent contraction by the antagonists of the paralyzed muscles, and to consistently keep the joints mobile. A splint is often used in cases of neurapraxia because it is able to maintain a relaxed position of the paralyzed muscle. The splint prevents the paralyzed muscle from being overstretched either by the force of gravity or by other non-paralyzed antagonists. During the recovery period of neurapraxia, it is essential that the joints constantly undergo passive movement in order to preserve proper mobility. If joints are kept mobile, the limb has the best possible chance of benefit from the return of nervous function. Non-steroidal anti-inflammatory medications can also help to reduce swelling at the injury site. In addition to these non-operative remedies, it is suggested that muscles affected by neurapraxia be kept warm at all times. Circulation in the limb is stimulated with the use of heat.
Once voluntary movement has returned to the muscle, recovery and treatment continues by the participation in active exercises. Physical Therapy and Occupational Therapy are common sources of treatment during these early stages of restoration of active movement. Almost all cases of neurapraxia can be completely treated by non-operative means.
Treating cervical cord neurapraxia on the field
According to medical professionals with the Cleveland Clinic, once an athlete suffers from an episode of cervical spinal cord neurapraxia, team physician or athletic trainer first stabilize the head and neck followed by a thorough neurologic inspection. If the injury is deemed severe, injured parties should be taken to a hospital for evaluation. Athletes that suffer from severe episodes of neurapraxia are urged to consult orthopaedic or spinal medical specialists. In mild cases of neurapraxia, the athlete is able to remove themselves from the field of play. However, the athlete is still advised to seek medical consultation.
Prognosis
In cases of neurapraxia, the function of the nerves are temporarily impaired. However, the prognosis for recovery from neurapraxia is efficient and quick. Recovery begins within two to three weeks after the injury occurs, and it is complete within six to eight weeks. There are instances when function is not completely restored until four months after the instance of injury. The recovery period of neurapraxia is not an entirely ordered process, but the recovery is always complete and fast.
Epidemiology
Neurapraxia is most commonly observed in athletes involved in collision sports, such as American football. Athletes participating in collision sports most often suffer from cervical cord neurapraxia, also known as transient neurapraxia. Cervical cord neurapraxia is the result of a severe collision in which a blow to the crown of the athletes head forcefully extends or compresses the neck. Numbness, stinging, and/or weakness in the arms, legs or both, distinguish cervical cord neurapraxia. Typical episodes of transient neurapraxia only last a few seconds and symptoms dissipate entirely. Though the severity of the injury can range, transient neurapraxia does not lead to permanent paralysis of the affected muscles. Subsequent spinal cord injury after an episode of cervical cord neurapraxia has not been observed. However, athletes who experience an episode of transient cervical neurapraxia face an approximately 50% chance of a repeat episode if they continue to participate in collision sports.
American football
Cervical cord neurapraxia among American football players is commonly observed in athletes playing positions involving high-speed collisions and open-field tackling. Cases of neurapraxia in the National Football League were first described in 1986 by Joseph S. Torg, M.D., founder of the National Football Head and Neck Injury Registry (established in 1975). As a result of Dr. Torgs findings the NFL as well as other levels of American football have outlawed the act of spearing, or the lowering of the head and hitting an opponent with the crown of the helmet. The cervical spine cannot properly absorb the force of a collision when the head is even slightly lowered as is the case in spearing. In addition to outlawing acts such as spearing, prevention of neurapraxia on the football field relies on instruction and reinforcement of proper tackling technique by coaches and trainers.
In popular culture
In M*A*S*H Season 4 Episode one, Benjamin "Hawkeye" Pierce claims that Walter "Radar" OReilly has neurapraxia as an excuse for driving past a military checkpoint. Hawkeye lies about the causes and treatments to keep them from getting into trouble. When questioned by Radar if it was a real disease, he answered "Yes, but only people that bite their nails can get it" (which Radar was currently doing).
See also
Nerve injury
Neuroregeneration
Seddons classification
References
== External links == |
Volvulus | A volvulus is when a loop of intestine twists around itself and the mesentery that supports it, resulting in a bowel obstruction. Symptoms include abdominal pain, abdominal bloating, vomiting, constipation, and bloody stool. Onset of symptoms may be rapid or more gradual. The mesentery may become so tightly twisted that blood flow to part of the intestine is cut off, resulting in ischemic bowel. In this situation there may be fever or significant pain when the abdomen is touched.Risk factors include a birth defect known as intestinal malrotation, an enlarged colon, Hirschsprung disease, pregnancy, and abdominal adhesions. Long term constipation and a high fiber diet may also increase the risk. The most commonly affected part of the intestines in adults is the sigmoid colon with the cecum being second most affected. In children the small intestine is more often involved. The stomach can also be affected. Diagnosis is typically with medical imaging such as plain X-rays, a GI series, or CT scan.Initial treatment for sigmoid volvulus may occasionally occur via sigmoidoscopy or with a barium enema. Due to the high risk of recurrence, a bowel resection within the next two days is generally recommended. If the bowel is severely twisted or the blood supply is cut off, immediate surgery is required. In a cecal volvulus, often part of the bowel needs to be surgically removed. If the cecum is still healthy, it may occasionally be returned to a normal position and sutured in place.Cases of volvulus were described in ancient Egypt as early as 1550 BC. It occurs most frequently in Africa, the Middle East, and India. Rates of volvulus in the United States are about 2–3 per 100,000 people per year. Sigmoid and cecal volvulus typically occurs between the ages of 30 and 70. Outcomes are related to whether or not the bowel tissue has died. The term volvulus is from the Latin "volvere"; which means "to roll".
Signs and symptoms
Regardless of cause, volvulus causes symptoms by two mechanisms:
Bowel obstruction manifested as abdominal distension and bilious vomiting.
Ischemia (loss of blood flow) to the affected portion of intestine.Depending on the location of the volvulus, symptoms may vary. For example, in patients with cecal volvulus, the predominant symptoms may be those of small bowel obstruction (nausea, vomiting and lack of stool or flatus), because the obstructing point is close to the ileocecal valve and small intestine. In patients with sigmoid volvulus, although abdominal pain may be present, symptoms of constipation may be more prominent.
Volvulus causes severe pain and progressive injury to the intestinal wall, with accumulation of gas and fluid in the portion of the bowel obstructed. Ultimately, this can result in necrosis of the affected intestinal wall, acidosis, and death. This is known as a closed-loop obstruction because there exists an isolated ("closed") loop of bowel. Acute volvulus often requires immediate surgical intervention to untwist the affected segment of bowel and possibly resect any unsalvageable portion.Volvulus occurs most frequently in middle-aged and elderly men. Volvulus can also arise as a rare complication in persons with redundant colon, a normal anatomic variation resulting in extra colonic loops.Sigmoid volvulus is the most-common form of volvulus of the gastrointestinal tract. and is responsible for 8% of all intestinal obstructions. Sigmoid volvulus is particularly common in elderly persons and constipated patients. Patients experience abdominal pain, distension, and absolute constipation.
Cecal volvulus is slightly less common than sigmoid volvulus and is associated with symptoms of abdominal pain and small bowel obstruction.
Volvulus can also occur in patients with Duchenne muscular dystrophy due to smooth muscle dysfunction.Gastric volvulus causes nausea, vomiting, and pain in the upper abdomen. The Borchardt triad is a group of symptoms that help doctors to identify gastric volvulus. The symptoms are intractable retching, pain in the upper abdomen and inability to pass nasogastric tube into the stomach.
Complications
Strangulation
Gangrene
Perforation
Faecal peritonitis
Recurrent volvulus
Causes
Midgut volvulus occurs in people (usually babies) that are predisposed because of congenital intestinal malrotation. Segmental volvulus occurs in people of any age, usually with a predisposition because of abnormal intestinal contents (e.g. meconium ileus) or adhesions. Volvulus of the cecum, transverse colon, or sigmoid colon occurs, usually in adults, with only minor predisposing factors such as redundant (excess, inadequately supported) intestinal tissue and constipation.
Types
volvulus neonatorum
volvulus of the small intestine
midgut volvulus (due to intestinal malrotation)
volvulus of the caecum (cecum), also cecal volvulus
sigmoid colon volvulus (sigmoid volvulus)
volvulus of the transverse colon
volvulus of the splenic flexure, the rarest
gastric volvulus
ileosigmoid knot
Diagnosis
After taking a thorough history, the diagnosis of colonic volvulus is usually easily included in the differential diagnosis. Abdominal plain x-rays are commonly confirmatory for a volvulus, especially if a "bent inner tube" sign or a "coffee bean" sign are seen. These refer to the shape of the air-filled closed loop of colon which forms the volvulus. Should the diagnosis be in doubt, a barium enema may be used to demonstrate a "birds beak" at the point where the segment of proximal bowel and distal bowel rotate to form the volvulus.This area shows an acute and sharp tapering and looks like a birds beak. If a perforation is suspected, barium should not be used due to its potentially lethal effects when distributed throughout the free intraperitoneal cavity. Gastrografin, which is safer, can be substituted for barium.The differential diagnosis includes the much more common constricting or obstructing carcinoma. In approximately 80 percent of colonic obstructions, invasive carcinoma is found to be the cause of the obstruction. This is usually easily diagnosed with endoscopic biopsies.
Diverticulitis is a common condition with different presentations. Although diverticulitis may be the source of a colonic obstruction, it more commonly causes an ileus, which appears to be a colonic obstruction.
Endoscopic means can be used to secure a diagnosis although this may cause a perforation of the inflamed diverticular area. CT scanning is the more common method to diagnose diverticulitis. The scan will show mesenteric stranding in the involved segment of edematous colon which is usually in the sigmoid region. Micro perforations with free air may be seen.Ulcerative colitis or Crohns disease may cause colonic obstruction. The obstruction may be acute or chronic after years of uncontrolled disease leads to the formation of strictures and fistulas. The medical history is helpful in that most cases of inflammatory bowel disease are well known to both patient and doctor.
Other rare syndromes, including Ogilvies syndrome, chronic constipation and impaction may cause a pseudo obstruction.
Abdominal x-ray – tire-like shadow arising from right iliac fossa and passing to left
Upper GI series
Treatment
Sigmoid
Treatment for sigmoid volvulus may include sigmoidoscopy. If the mucosa of the sigmoid looks normal and pink, a rectal tube for decompression may be placed, and any fluid, electrolyte, cardiac, kidney or pulmonary abnormalities should be corrected. The affected person should then be taken to the operating room for surgical repair. If surgery is not performed, there is a high rate of recurrence.For people with signs of sepsis or an abdominal catastrophe, immediate surgery and resection are advised.
Cecal
In a cecal volvulus, the cecum may be returned to a normal position and sutured in place, a procedure known as cecopexy. If identified early, before presumed intestinal wall ischemia has resulted in tissue breakdown and necrosis, the cecal volvulus can be detorsed laparoscopically. It has been associated to several diseases, including Huntingtons disease.
Other
Laparotomy for other forms of volvulus, especially anal volvulus.
References
External links
CT of an abdomen with sigmoid volvulus |
Apudoma | In pathology, an apudoma is an endocrine tumour that arises from an APUD cell from structures such as the ampulla of Vater. They were historically thought to be derived from neural crest cells, but this has since been shown to be untrue (see neuroendocrine tumor).The term dates back to at least 1975. Because the label "apudoma" is very general, it is preferred to use a more specific term when possible.
See also
VIPoma
Carcinoid tumor
References
== External links == |
Pathologic fracture | A pathologic fracture is a bone fracture caused by weakness of the bone structure that leads to decrease mechanical resistance to normal mechanical loads. This process is most commonly due to osteoporosis, but may also be due to other pathologies such as cancer, infection (such as osteomyelitis), inherited bone disorders, or a bone cyst. Only a small number of conditions are commonly responsible for pathological fractures, including osteoporosis, osteomalacia, Pagets disease, Osteitis, osteogenesis imperfecta, benign bone tumours and cysts, secondary malignant bone tumours and primary malignant bone tumours.
Fragility fracture is a type of pathologic fracture that occurs as a result of an injury that would be insufficient to cause fracture in a normal bone. There are three fracture sites said to be typical of fragility fractures: vertebral fractures, fractures of the neck of the femur, and Colles fracture of the wrist. This definition arises because a normal human being ought to be able to fall from standing height without breaking any bones, and a fracture, therefore, suggests weakness of the skeleton.
Pathological fractures present as a chalkstick fracture in long bones, and appear as a transverse fractures nearly 90 degrees to the long axis of the bone. In a pathological compression fracture of a spinal vertebra fractures will commonly appear to collapse the entire body of vertebra.
Cause
Pathologic fractures in children and adolescents can result from a diverse array of disorders namely; metabolic, endocrine, neoplastic, infectious, immunologic, and genetic skeletal dysplasias.
Primary hyperparathyroidism
Simple bone cyst
Aneurismal bone cyst
Osteoporosis
Chronic osteomyelitis
Osteogenesis imperfecta
Osteomalacia
Rickets
Renal osteodystrophy
Malignant infantile osteopetrosis
juvenile osteoporosis
juvenile rheumatoid arthritis
Miscellaneous causes
Monostotic fibrous dysplasia
Eosinophilic granuloma
Bone atrophy secondary to diseases like polio
Diagnosis
In circumstances where other pathologies are excluded (for example, cancer), a pathologic fracture is diagnostic of osteoporosis irrespective of bone mineral density.
Management
Based on Mirels score (if the score is more than 8), bone fixation should be done prophylactically. Fixation is done by internal fixation rather than conservatively, along with treatment of the underlying cause.
References
== External links == |
Brainstem stroke syndrome | A brainstem stroke syndrome falls under the broader category of stroke syndromes, or specific symptoms caused by vascular injury to an area of brain (for example, the lacunar syndromes). As the brainstem contains numerous cranial nuclei and white matter tracts, a stroke in this area can have a number of unique symptoms depending on the particular blood vessel that was injured and the group of cranial nerves and tracts that are no longer perfused. Symptoms of a brainstem stroke frequently include sudden vertigo and ataxia, with or without weakness. Brainstem stroke can also cause diplopia, slurred speech and decreased level of consciousness. A more serious outcome is locked-in syndrome.
Syndromes
The midbrain syndromes (Significant overlap between these three syndromes)
Superior alternating hemiplegia or Webers syndrome
Paramedian midbrain syndrome or Benedikts syndrome
Claudes syndrome
Medial pontine syndrome or Middle alternating hemiplegia or Fovilles syndrome
Lateral pontine syndrome or Marie-Foix syndrome
Medial medullary syndrome or Inferior alternating hemiplegia
Lateral medullary syndrome or Wallenberg syndrome
History
A history of locked in syndromes.
Jean-Dominique Bauby
Parisian journalist Jean-Dominique Bauby had a stroke in December 1995, and, when he awoke 20 days later, he found his body was almost completely paralyzed; he could control only his left eyelid. By blinking this eye, he slowly dictated one alphabetic character at a time and, in so doing, was able over a great deal of time to write his memoir, The Diving Bell and the Butterfly. Three days after it was published in March 1997, Bauby died of pneumonia. The 2007 film The Diving Bell and the Butterfly is a screen adaptation of Baubys memoir. Jean-Dominique was instrumental in forming the Association du Locked-In Syndrome (ALIS) in France.
See also
Alternating hemiplegia
Posterior cerebral artery syndrome
Middle cerebral artery syndrome
Anterior cerebral artery syndrome
References
== External links == |
Relative afferent pupillary defect | A relative afferent pupillary defect (RAPD), also known as a Marcus Gunn pupil, is a medical sign observed during the swinging-flashlight test whereupon the patients pupils dilate when a bright light is swung from the unaffected eye to the affected eye. The affected eye still senses the light and produces pupillary sphincter constriction to some degree, albeit reduced.
Depending on severity, different symptoms may appear during the swinging flash light test:
Mild RAPD will presents as a weak pupil constriction initially, after which dilation continues to happen.
When RAPD is moderate, pupil size will remain, after which it dilates
When RAPD is severe, the pupil will dilate quickly
Cause
The most common cause of Marcus Gunn pupil is a lesion of the optic nerve (between the retina and the optic chiasm) due to glaucoma, or severe retinal disease, or due to multiple sclerosis. It is named after Scottish ophthalmologist Robert Marcus Gunn.
A second common cause of Marcus Gunn pupil is a contralateral optic tract lesion, due to the different contributions of the intact nasal and temporal hemifields.
Diagnosis
The Marcus Gunn pupil is a relative afferent pupillary defect indicating a decreased pupillary response to light in the affected eye.In the swinging flashlight test, a light is alternately shone into the left and right eyes. A normal response would be equal constriction of both pupils, regardless of which eye the light is directed at. This indicates an intact direct and consensual pupillary light reflex. When the test is performed in an eye with an afferent pupillary defect, light directed in the affected eye will cause only mild constriction of both pupils (due to decreased response to light from the afferent defect), while light in the unaffected eye will cause a normal constriction of both pupils (due to an intact efferent path, and an intact consensual pupillary reflex). Thus, light shone in the affected eye will produce less pupillary constriction than light shone in the unaffected eye.Anisocoria is absent. A Marcus Gunn pupil is seen, among other conditions, in optic neuritis. It is also common in retrobulbar optic neuritis due to multiple sclerosis but only for 3–4 weeks, until the visual acuity begins to improve in 1–2 weeks and may return to normal.A total CN II lesion, in which the affected eye perceives no light, is very similar to a Marcus Gunn pupil; to distinguish them, in a CNII total lesion shining the light in the affected eye produces zero dilation nor constriction.
See also
References
== External links == |
Coccidiosis | Coccidiosis is a parasitic disease of the intestinal tract of animals caused by coccidian protozoa. The disease spreads from one animal to another by contact with infected feces or ingestion of infected tissue. Diarrhea, which may become bloody in severe cases, is the primary symptom. Most animals infected with coccidia are asymptomatic, but young or immunocompromised animals may suffer severe symptoms and death.
While coccidia can infect a wide variety of animals, including humans, birds, and livestock, they are usually species-specific. One well-known exception is toxoplasmosis caused by Toxoplasma gondii.Humans may first encounter coccidia when they acquire a dog, cat or bird that is infected. Other than T. gondii, the infectious organisms are canine and feline-specific and are not contagious to humans, unlike the zoonotic diseases.
Coccidia in dogs
Puppies are frequently infected with coccidia from the feces of their mother, and are more likely to develop coccidiosis due to their undeveloped immune systems. Stress can trigger symptoms in susceptible animals.Symptoms in young dogs include diarrhoea with mucus and blood, poor appetite, vomiting, and dehydration. Untreated, the disease can be fatal.
Treatment is routine and effective. Diagnosis is made by low-powered microscopic examination of the feces, which is generally replete with oocysts. Readily available drugs eliminate the protozoa or reduce them enough that the animals immune system can clear the infection. Permanent damage to the gastrointestinal system is rare, and a dog will usually suffer no long-lasting negative effects.
SYMPTOM A VOMITING OF DOGS IS YELLOW AND BLACKISH.
Coccidia in chickens
Coccidiosis is a significant disease for chickens, especially affecting the young chicks. It can be fatal or leave the bird with compromised digestion. There are chick feed mixes that contain a coccidiostat to manage exposure levels and control disease. In an outbreak, coccidiocidal medications are given. Examples are toltrazuril (Baycox) or amprolium. After multiple infections, surviving chickens become resistant to the coccidia.
Coccidia in cattle
Coccidiosis (in cattle also known as Eimeriosis) is one of the most important diseases in calves and youngstock both under housing conditions and when grazing. Symptoms are generally caused by the species Eimeria zuernii and Eimeria bovis and include loss of appetite, fatigue, dehydration, and watery, sometimes bloody, diarrhoea. Outbreaks are known to occur in cattle herds. The parasite can infect all animals on the farm and in some countries the parasite is present on all farms. Coccidiosis affects the growth and sometimes survival of the calves and consequently affect the production and the profitability of cattle livestock production.
Coccidia in goats
Coccidiosis is also present in goats, and is the largest cause of diarrhea in young goats. It can also cause high temperature and loss of appetite.
Genera and species that cause coccidiosis
Genus Isospora is the most common cause of intestinal coccidiosis in dogs and cats. Species of Isospora are host-specific, infecting only one species. Species that infect dogs include I. canis, I. ohioensis, I. burrowsi, and I. neorivolta. Species that infect cats include I. felis and I. rivolta. The most common symptom is diarrhea. Sulfonamides are the most common treatment.
Genus Eimeria affects birds such as poultry and mammals such as cattle and rabbits. Species include E. tenella, E. brunetti, E. necatrix, and E. acervulina. Sulfonamides are effective.
Genus Cryptosporidium contains two species known to cause cryptosporidiosis, C. parvum and C. muris. Cattle are most commonly affected, and their feces may be a source of infection for other mammals, including humans. Recent genetic analyses of Cryptosporidium in humans have identified C. hominis as a human-specific pathogen. Infection occurs most commonly in immunocompromised individuals, such as dogs with canine distemper, cats with feline leukemia, and humans with AIDS.
Genus Hammondia is transmitted by ingestion of cysts found in the tissue of grazing animals and rodents. Dogs and cats are the definitive hosts, with H. heydorni infecting dogs and the H. hammondi and H. pardalis infecting cats. Symptoms do not usually occur.
Genus Besnoitia infects cats that ingest cysts in the tissue of rodents and opossums, but usually do not cause disease.
Genus Sarcocystis infects carnivores that ingest cysts from various intermediate hosts. Sarcocystis may cause disease in dogs and cats.
Genus Toxoplasma has one important species, T. gondii. Cats are the definitive host, but all mammals and some fish, reptiles, and amphibians can be intermediate hosts. Only cat feces will hold infective oocysts, but infection through ingestion of cysts can occur with the tissue of any intermediate host. Toxoplasmosis occurs in humans usually as low-grade fever or muscle pain for a few days. A normal immune system will suppress the infection but the tissue cysts will persist in that animal or human for years or for life. In immunocompromised individuals, dormant cysts can be reactivated and cause lesions in the brain, heart, lungs, eyes, and other tissues. A fetus may be at risk if a pregnant woman without immunity becomes infected. Symptoms in cats include fever, weight loss, diarrhea, vomiting, uveitis, and central nervous system signs. Disease in dogs includes paralysis, tremors, and seizures. Dogs and cats are usually treated with clindamycin.
Genus Neospora has one important species, N. caninum, which affects dogs in a manner similar to toxoplasmosis. Neosporosis is difficult to treat.
Genus Hepatozoon contains one species that causes hepatozoonosis in dogs and cats, H. canis. Animals become infected by ingesting an infected brown dog tick (Rhipicephalus sanguineus). Symptoms include fever, weight loss, and pain in the spine and limbs.The most common medications used to treat coccidian infections are in the sulfonamide antibiotic family.Depending on the pathogen and the condition of the animal, untreated coccidiosis may clear of its own accord, or become severe and damaging, and sometimes cause death.
== References == |
Acquired progressive lymphangioma | Acquired progressive lymphangioma is a group of lymphangiomas that occur anywhere in young individuals, grow slowly, and present as bruise-like lesions or erythematous macules.: 597
See also
List of cutaneous conditions
References
== External links == |
Synucleinopathy | Synucleinopathies (also called α-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells. There are three main types of synucleinopathy: Parkinsons disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Other rare disorders, such as various neuroaxonal dystrophies, also have α-synuclein pathologies. Additionally, autopsy studies have shown that around 6% of sporadic Alzheimers Disease exhibit α-synuclein positive Lewy pathology, and are sub-classed as Alzheimers Disease with Amygdalar Restricted Lewy Bodies (AD/ALB).
Presentation
The synucleinopathies have shared features of parkinsonism, impaired cognition, sleep disorders, and visual hallucinations.Synucleinopathies can sometimes overlap with tauopathies, possibly because of interaction between the synuclein and tau proteins.REM sleep behavior disorder (RBD) is a parasomnia in which individuals with RBD lose the paralysis of muscles (atonia) that is normal during rapid eye movement (REM) sleep, and act out their dreams or have other abnormal movements or vocalizations. Abnormal sleep behaviors may appear decades before any other symptoms, often as an early sign of a synucleinopathy. On autopsy, 94 to 98% of individuals with polysomnography-confirmed RBD are found to have a synucleinopathy—most commonly DLB or PD. Other symptoms of the specific synucleinopathy usually manifest within 15 years of the diagnosis of RBD, but may emerge up to 50 years after RBD diagnosis.Alpha-synuclein deposits can affect the cardiac muscle and blood vessels. Almost all people with synucleinopathies have cardiovascular dysfunction, although most are asymptomatic.From chewing to defecation, alpha-synuclein deposits affect every level of gastrointestinal function. Symptoms include upper gastrointestinal tract dysfunction such as delayed gastric emptying or lower gastrointestinal dysfunction, such as constipation and prolonged stool transit time.Urinary retention, waking at night to urinate, increased urinary frequency and urgency, and over- or underactive bladder are common in people with synucleinopathies. Sexual dysfunction usually appears early in synucleinopathies, and may include erectile dysfunction, and difficulties achieving orgasm or ejaculating.
Diagnosis
Differential diagnosis
Persons with PD are typically less caught up in their visual hallucinations than those with DLB. There is a lower incidence of tremor at rest in DLB than in PD, and signs of parkinsonism in DLB are more symmetrical. In MSA, autonomic dysfunction appears earlier and is more severe, and is accompanied by uncoordinated movements, while visual hallucinations and fluctuating cognition are less common than in DLB. Urinary difficulties are one of the earliest symptoms with MSA, and are often severe.
DNA damage
Alpha-synuclein modulates DNA repair processes, including the repair of DNA double-strand breaks by the non-homologous end joining pathway. The DNA repair function of alpha-synuclein appears to be compromised in Lewy body inclusion bearing neurons, and this may trigger cell death. Study of synucleinopathy mouse models of Parkinson’s disease indicates that alpha-synuclein pathogenesis is associated with increased DNA damage and activation of the DNA damage response.
See also
Proteopathy
Lewy body
== References == |
Dreadlocks | Dreadlocks, also known as locs or dreads, are rope-like strands of hair formed by locking or braiding hair.
Origins
Some of the earliest depictions of dreadlocks date back as far as 1600–1500 BCE in the Minoan Civilization, one of Europes earliest civilizations, centred in Crete (now part of Greece). Frescoes discovered on the Aegean island of Thera (modern Santorini, Greece) depict individuals with long braided hair or long dreadlocks.In ancient Egypt, examples of Egyptians wearing locked hairstyles and wigs have appeared on bas-reliefs, statuary and other artifacts. Mummified remains of Egyptians with locked wigs have also been recovered from archaeological sites.During the Bronze and Iron Ages, many peoples in the Near East, Anatolia, Caucasus, East Mediterranean and North Africa such as the Sumerians, Elamites and Ancient Egyptians were depicted in art with braided or plaited hair and beards. However, braids are not dreadlocks, and it is not always possible to tell from these images which are being depicted.
Etymology
The history of the name "dreadlocks" is unclear. Some authors have speculated that the "dread" component could refer to the reaction of British soldiers upon encountering Mau Mau fighters who had this hairstyle.
History
In Ancient Greece, kouros sculptures from the archaic period depict men wearing dreadlocks.The style was worn by Ancient Christian Ascetics in the Middle East and Mediterranean, and the Dervishes of Islam, among others. Some of the very earliest adherents of Christianity in the Middle East may have worn this hairstyle; there are descriptions of James the Just, first Bishop of Jerusalem, who is said to have worn them to his ankles.
Pre-Columbian Aztec priests were described in Aztec codices (including the Durán Codex, the Codex Tudela and the Codex Mendoza) as wearing their hair untouched, allowing it to grow long and curl around itself. Bernal Diaz del Castillo records:here were priests with long robes of black cloth ... The hair of these priests was very long and so knotted that it could not be separated or disentangled, and most of them had their ears scarified, and their hair was clotted with blood.
In Senegal, the Baye Fall, followers of the Mouride movement, a Sufi movement of Islam founded in 1887 AD by Shaykh Aamadu Bàmba Mbàkke, are famous for growing dreadlocks and wearing multi-colored gowns. Cheikh Ibra Fall, founder of the Baye Fall school of the Mouride Brotherhood, popularized the style by adding a mystic touch to it. Warriors among the Fulani, Wolof and Serer in Mauritania, and Mandinka in Mali were known for centuries to have worn cornrows when young and dreadlocks when old.
Larry Wolff in his book Inventing Eastern Europe: The Map of Civilization on the Mind of Enlightenment mentions that in Poland, for about a thousand years, some people wore a knotted hairstyle similar to that of some Scythians. Zygmunt Gloger in his Encyklopedia staropolska mentions that the Polish plait (plica polonica) hairstyle was worn by some people in the Pinsk region and the Masovia region at the beginning of the 19th century. The Polish plait can vary between one large plait and multiple plaits that resemble dreadlocks.
Dreadlocks are also worn by some Rastafarians, who believe they represent a biblical hair style worn as a symbol of devotion by the Nazirites, as described in Numbers 6:1–21.
By culture
Locks have been worn for various reasons in each culture. Their use has also been raised in debates about cultural appropriation.
Africa
Maasai warriors are known for their long, thin, red dreadlocks, dyed with red root extracts or red ochre.In Nigeria, dreadlocks are viewed in a negative light due to their stereotypical association with gangs and criminal activity; men with dreadlocks face profiling from Nigerian police.
Australia
Some Indigenous Australians of North West and North Central Australia, as well as the Gold Coast region of North East Australia, have historically worn their hair in a locked style, sometimes also having long beards that are fully or partially locked. Traditionally, some wear the dreadlocks loose, while others wrap the dreadlocks around their heads, or bind them at the back of the head. In North Central Australia, the tradition is for the dreadlocks to be greased with fat and coated with red ochre, which assists in their formation.
Buddhism
Within Tibetan Buddhism and other more esoteric forms of Buddhism, locks have occasionally been substituted for the more traditional shaved head. The most recognizable of these groups are known as the Ngagpas of Tibet. For Buddhists of these particular sects and degrees of initiation, their locked hair is not only a symbol of their vows but an embodiment of the particular powers they are sworn to carry. 1.4.15 of the Hevajra Tantra states that the practitioner of particular ceremonies "should arrange his piled up hair" as part of the ceremonial protocol.
Hinduism
The practice of Jaṭā (dreadlocks) is practiced in modern day Hinduism, most notably by Sadhus who follow Śiva. The Kapalikas, first commonly referenced in the 6th century CE, were known to wear Jaṭā as a form of deity imitation of the deva Bhairava-Śiva. Shiva is often depicted with dreadlocks.
Rastafari
Rastafari movement dreadlocks are symbolic of the Lion of Judah which is sometimes centered on the Ethiopian flag. Rastafari hold that Haile Selassie is a direct descendant of King Solomon and the Queen of Sheba, through their son Menelik I. Their dreadlocks were inspired by the Nazarites of the Bible. Haile Selassie was crowned Emperor of Ethiopia in 1930. Many Jamaican Rastafarians claimed that Selassies coronation was evidence that he was the black messiah that they believed was prophesied in the Book of Revelation. Some street preachers such as Leonard Howell, Archibald Dunkley, Robert Hinds, and Joseph Hibbert began to claim that "Haile Selassie was the returned Jesus". During the Great Depression in the 1930s, the Rastafari message spread from Kingston to the rest of Jamaica, especially among poor communities.
The cultivation of dreadlocks in the later Rastafari movement established a closer connection between like-minded people.When reggae music, which espoused Rastafarian ideals, gained popularity and mainstream acceptance in the 1970s, thanks to Bob Marleys music and cultural influence, dreadlocks (often called "dreads") became a notable fashion statement worldwide, and have been worn by prominent authors, actors, athletes and rappers.
In sports
Dreadlocks have become a popular hairstyle among professional athletes.
In professional American football, the number of players with dreadlocks has increased ever since Al Harris and Ricky Williams first wore the style during the 1990s. In 2012, about 180 National Football League players wore dreadlocks. A significant number of these players are defensive backs, who are less likely to be tackled than offensive players.In the NBA there has been controversy over the Brooklyn Nets guard Jeremy Lin, an Asian-American who garnered mild controversy over his choice of dreadlocks. Former NBA player Kenyon Martin accused Lin of appropriating African-American culture in a since-deleted social media post, after which Lin pointed out that Martin has multiple Chinese characters tattooed on his body.
In the US
On 3 July 2019, California became the first US state to prohibit discrimination over natural hair. Governor Gavin Newsom signed the CROWN Act into law, banning employers and schools from discriminating against hairstyles such as dreadlocks, braids, afros, and twists. Likewise, later in 2019, Assembly Bill 07797 became law in New York state; it "prohibits race discrimination based on natural hair or hairstyles".
Guinness Book of World Records
On 10 December 2010, the Guinness Book of World Records rested its "longest dreadlocks" category after investigation of its first and only female title holder, Asha Mandela, with this official statement:
Following a review of our guidelines for the longest dreadlock, we have taken expert advice and made the decision to rest this category. The reason for this is that it is difficult, and in many cases impossible, to measure the authenticity of the locks due to expert methods employed in the attachment of hair extensions/re-attachment of broken off dreadlocks. Effectively the dreadlock can become an extension and therefore impossible to adjudicate accurately. It is for this reason Guinness World Records has decided to rest the category and will no longer be monitoring the category for longest dreadlock.
See also
Box braids
Bob Marley
Elflock
Cornrows
French braid
Polish plait
Notes
References
Kroemer, K. (2001). Ergonomics: How to Design for Ease and Efficiency (2nd ed.). Englewood Cliffs: Prentice Hall. ISBN 0137524781.
Tacitus, Publius (or Gaius) Cornelius. De vita et moribus Iulii Agricolae.
External links
Media related to Dreadlocks at Wikimedia Commons
Dreadlocks Story – Documentary by Linda Aïnouche
Guardian article
The dictionary definition of dreadlocks at Wiktionary |
Toxoplasmic chorioretinitis | Toxoplasma chorioretinitis, more simply known as ocular toxoplasmosis, is possibly the most common cause of infections in the back of the eye (posterior segment) worldwide. The causitive agent is Toxoplasma gondii, and in the United States, most cases are acquired congenitally. The most common symptom is decreased visual acuity in one eye. The diagnosis is made by examination of the eye, using ophthalmoscopy. Sometimes serologic testing is used to rule out the disease, but due to high rates of false positives, serologies are not diagnostic of toxoplasmic retinitis.
If vision is not compromised, treatment may not be necessary. When vision is affected or threatened, treatment consists of pyrimethamine, sulfadiazine, and folinic acid for 4–6 weeks. Prednisone is sometimes used to decrease inflammation.
Signs and symptoms
A unilateral decrease in visual acuity is the most common symptom of toxoplasmic retinitis.
Under ophthalmic examination, toxoplasmic chorioretinitis classically appears as a focal, white retinitis with overlying moderate inflammation of the vitreous humour. A unifocal area of acute-onset inflammation adjacent to an old chorioretinal scar is virtually pathognomonic for toxoplasmic chorioretinitis. Focal condensation of vitreous and inflammatory cells may be seen overlying the pale yellow or gray-white raised lesion in the posterior pole.
Pathophysiology
Toxoplasma gondii is an intracellular parasite that causes a necrotizing chorioretinitis.
Congenital disease
Congenital disease occurs due to the acquisition of the organism by a pregnant woman exposed to tissue cysts or oocytes in uncooked meat or substances contaminated with cat feces. Spontaneous abortion may result if the disease is acquired during the first trimester.
Congenital toxoplasmosis may lead to hydrocephalus, seizures, lymphadenopathy, hepatosplenomegaly, rash, and fever. However, retinochoroiditis is the most common manifestation, occurring in 3/4 of cases.
In congenital toxoplasmosis, the disease is bilateral in 65–85% of cases and involves the macula in 58%.
Chronic or recurrent maternal infection during pregnancy is not thought to confer a risk of congenital toxoplasmosis because maternal immunity protects against fetal transmission. In contrast, pregnant women without serologic evidence of prior exposure to Toxoplasma should take sanitary precautions such as having someone else clean and maintain litter boxes and avoiding undercooked meats.
Diagnosis
In most instances, the diagnosis of toxoplasmic retinochoroiditis is made clinically on the basis of the appearance of the characteristic lesion on eye examination.
Seropositivity (positive blood test result) for Toxoplasma is very common and therefore not useful in diagnosis; however, a negative result i.e. absence of antibodies is often used to rule out disease. Others believe that serology is useful to confirm active toxoplasmic retinochoroiditis, not only by showing positivity but by also showing a significant elevation of titers: The mean IgG values were 147.7 ± 25.9 IU/ml for patients with active disease versus 18.3 ± 20.8 IU/ml for normal individuals.Antibodies against Toxoplasma:
IgG : appear within the first 2 weeks after infection, typically remain detectable for life, albeit at low levels;and may cross the placenta.
IgM : rise early during the acute phase of the infection, typically remain detectable for less than 1 year, and do not cross the placenta.
IgA : Measurement of IgA antibody titers may also be useful in a diagnosis of congenital toxoplasmosis in a fetus or newborn because IgM production is often weak during this period and the presence of IgG antibodies may indicate passive transfer of maternal antibodies in utero. IgA antibodies however usually disappear by 7 months.In atypical cases, ocular fluid testing to detect parasite DNA by polymerase chain reaction or to determine intraocular production of specific antibody may be helpful for establishing etiology.
Neuroimaging is warranted in AIDS patients presenting with these findings because intracranial toxoplasmic lesions have been reported in up to 29% of these patients who have toxoplasmic chorioretinitis.
Prevention
Toxoplasma infection can be prevented in large part by:
cooking meat to a safe temperature (i.e., one sufficient to kill Toxoplasma)
peeling or thoroughly washing fruits and vegetables before eating
cleaning cooking surfaces and utensils after they have contacted raw meat, poultry, seafood, or unwashed fruits or vegetables
pregnant women avoiding changing cat litter or, if no one else is available to change the cat litter, using gloves, then washing hands thoroughly
not feeding raw or undercooked meat to cats to prevent acquisition of ToxoplasmaProlonged and intense rainfall periods are significantly associated with the reactivation of toxoplasmic retinochoroiditis. Changes promoted by this climatic condition concern both the parasite survival in the soil as well as a putative effect on the host immune response due to other comorbidities.
Treatment
Small extramacular lesions (lesions not threatening vision) may be observed without treatment. Sight-threatening lesions are treated for 4–6 weeks with triple therapy consisting of pyrimethamine, sulfadiazine, and folinic acid. During treatment with pyrimethamine, leukocyte and platelet counts should be monitored weekly. Folinic acid protects against the decrease in platelets and white blood cells induced by pyrimethamine.
Prednisone may be used for 3–6 weeks to reduce macular or optic nerve inflammation and can be started on day 3 of antibiotic therapy. Corticosteroids should not be used without concurrent antibiotic treatment or in immunocompromised patients due to the risk of exacerbation of the disease. Currently, there is no published evidence from randomized controlled trials demonstrating that corticosteroids would be an effective adjunct for treating ocular toxoplasmosis.Trimethoprim-Sulfamethoxazole has been shown to be equivalent to triple therapy in the treatment of ocular toxoplasmosis and may be better tolerated. Clindamycin and azithromycin can also be considered as alternative therapies. Spiramycin may be used safely without undue risk of teratogenicity and may reduce the rate of transmission to the fetus.
AIDS patients require chronic maintenance treatment.
See also
Toxoplasmosis
References
External links
Acquired Ocular Toxoplasmosis (Univ of Iowa
Hafidi, Zouheir; Daoudi, Rajae (January 2014). "Chorioretinal Toxoplasmosis". New England Journal of Medicine. 370 (4): 361. doi:10.1056/NEJMicm1306819. |
Otosclerosis | Otosclerosis is a condition of the middle ear where portions of the dense enchondral layer of the bony labyrinth remodel into one or more lesions of irregularly-laid spongy bone. As the lesions reach the stapes the bone is resorbed, then hardened (sclerotized), which limits its movement and results in hearing loss, tinnitus, vertigo or a combination of symptoms. The term otosclerosis is something of a misnomer: much of the clinical course is characterized by lucent rather than sclerotic bony changes, so the disease is also known as otospongiosis.
Etymology
The word otosclerosis derives from Greek ὠτός (ōtos), genitive of οὖς (oûs) "ear" + σκλήρωσις (sklērōsis), "hardening".
Presentation
The primary form of hearing loss in otosclerosis is conductive hearing loss (CHL) whereby sounds reach the ear drum but are incompletely transferred via the ossicular chain in the middle ear, and thus partly fail to reach the inner ear (cochlea). This can affect one ear or both ears. On audiometry, the hearing loss is characteristically low-frequency, with higher frequencies being affected later.Sensorineural hearing loss (SNHL) has also been noted in patients with otosclerosis; this is usually a high-frequency loss, and usually manifests late in the disease. The causal link between otosclerosis and SNHL remains controversial. Over the past century, leading otologists and neurotologic researchers have argued whether the finding of SNHL late in the course of otosclerosis is due to otosclerosis or simply to typical presbycusis.Most patients with otosclerosis notice tinnitus (head noise) to some degree. The amount of tinnitus is not necessarily related to the degree or type of hearing impairment. Tinnitus develops due to irritation of the delicate nerve endings in the inner ear. Since the nerve carries sound, this irritation is manifested as ringing, roaring or buzzing. It is usually worse when the patient is fatigued, nervous or in a quiet environment.
Causes
Otosclerosis can be caused by both genetic and environmental factors, such as a viral infection (like measles). Ribonucleic acid of the measles virus has been found in stapes footplate in most patients with otosclerosis. Populations that have been vaccinated against measles had a significant reduction in otosclerosis. While the disease is considered to be hereditary, its penetrance and the degree of expression is so highly variable that it may be difficult to detect an inheritance pattern. Most of the implicated genes are transmitted in an autosomal dominant fashion. One genome-wide analysis associates otosclerosis with variation in RELN gene.Loci include:
Pathophysiology
The pathophysiology of otosclerosis is complex. The key lesions of otosclerosis are multifocal areas of sclerosis within the endochondral temporal bone. These lesions share some characteristics with Pagets Disease, but they are not thought to be otherwise related. Histopathological studies have all been done on cadaveric temporal bones, so only inferences can be made about progression of the disease histologically. It seems that the lesions go through an active "spongiotic" or hypervascular phase before developing into "sclerotic" phase lesions. There have been many genes and proteins identified that, when mutated, may lead to these lesions. Also there is mounting evidence that measles virus is present within the otosclerotic foci, implicating an infectious etiology (this has also been noted in Pagets Disease).
Conductive hearing loss (CHL) in otosclerosis is caused by two main sites of involvement of the sclerotic (or scar-like) lesions. The best understood mechanism is fixation of the stapes footplate to the oval window of the cochlea. This greatly impairs movement of the stapes and therefore transmission of sound into the inner ear ("ossicular coupling"). Additionally the cochleas round window can also become sclerotic, and in a similar way impair movement of sound pressure waves through the inner ear ("acoustic coupling").
CHL is usually concomitant with impingement of abnormal bone on the stapes footplate. This involvement of the oval window forms the basis of the name fenestral otosclerosis. The most common location of involvement of otosclerosis is the bone just anterior to the oval window at a small cleft known as the fissula ante fenestram. The fissula is a thin fold of connective tissue extending through the endochondral layer, approximately between the oval window and the cochleariform process, where the tensor tympani tendon turns laterally toward the malleus.
The mechanism of sensorineural hearing loss in otosclerosis is less well understood. It may result
from direct injury to the cochlea and spiral ligament from the lytic process or from release of proteolytic enzymes into the cochlea. There are certainly a few well documented instances of sclerotic lesions directly obliterating sensory structures within the cochlea and spiral ligament, which have been photographed and reported post-mortem. Other supporting data includes a consistent loss of cochlear hair cells in patients with otosclerosis; these cells being the chief sensory organs of sound reception. A suggested mechanism for this is the release of hydrolytic enzymes into the inner ear structures by the spongiotic lesions.
Diagnosis
Otosclerosis is traditionally diagnosed by characteristic clinical findings, which include progressive conductive
hearing loss, a normal tympanic membrane, and no evidence of middle ear inflammation. The cochlear promontory may have a faint pink tinge reflecting the vascularity of the lesion, referred to as the Schwartz sign.Approximately 0.5% of the population will eventually be diagnosed with otosclerosis. Post-mortem studies show that as many as 10% of people may have otosclerotic lesions of their temporal bone, but apparently never had symptoms warranting a diagnosis. Caucasians are the most affected race, with the prevalence in the Black and Asian populations being much lower. In clinical practice otosclerosis is encountered about twice as frequently in females as in males, but this does not reflect the true sex ratio. When families are investigated it is found that the condition is only slightly more common in women. Usually noticeable hearing loss begins at middle-age, but can start much sooner. The hearing loss was long believed to grow worse during pregnancy, but recent research does not support this belief.
Differential testing
Audiometry
Fixation of the stapes within the oval window causes a conductive hearing loss. In pure-tone audiometry, this manifests as air-bone gaps on the audiogram (i.e. a difference of more than 10 dB between the air-conduction and bone-conduction thresholds at a given test frequency). However, medial fixation of the ossicular chain impairs both the inertial and osseotympanic modes of bone conduction, increasing the bone-conduction thresholds between 500 Hz and 4 kHz, and reducing the size of air-bone gaps. As 2 kHz is the resonant frequency of the ossicular chain, the largest increase in bone-conduction threshold (around 15 dB) occurs at this frequency – the resultant notch is called Carharts notch and is a useful clinical marker for medial ossicular-chain fixation.Tympanometry measures the peak pressure (TPP) and peak-compensated static admittance (Ytm) of the middle ear at the eardrum. As the stapes is ankylosed in otosclerosis, the lateral end of the ossicular chain may still be quite mobile. Therefore, otosclerosis may only slightly reduce the admittance, resulting in either a shallow tympanogram (type AS), or a normal tympanogram (type A). Otosclerosis increases the stiffness of the middle-ear system, raising its resonant frequency. This can be quantified using multi-frequency tympanometry. Thus, a high resonant-frequency pathology such as otosclerosis can be differentiated from low resonant-frequency pathologies such as ossicular discontinuity.In the absence of a pathology, a loud sound (generally greater than 70 dB above threshold) causes the stapedius muscle to contract, reducing the admittance of the middle ear and softening the perceived loudness of the sound. If the mobility of the stapes is reduced due to otosclerosis, then stapedius muscle contraction does not significantly decrease the admittance. When acoustic reflex testing is conducted, the acoustic reflex thresholds (ART) cannot be determined when attempting to measure on the affected side. Also, a conductive pathology will attenuate the test stimuli, resulting in either elevated reflex thresholds or absent reflexes when the stimulus is presented in the affected ear and measured in the other ear.
CT imaging
Imaging is usually not pursued in those with uncomplicated conductive hearing loss and characteristic clinical findings. Those with only conductive hearing loss are often treated medically or with surgery without imaging. The diagnosis may be unclear clinically in cases of sensorineural or mixed hearing loss and may become apparent only on imaging. Therefore, imaging is often performed when the hearing loss is sensorineural or mixed.A high-resolution CT shows very subtle bone findings. However, CT is usually not needed prior to surgery.Otosclerosis on CT can be graded using the grading system suggested by Symons and Fanning.
Grade 1, solely fenestral;
Grade 2, patchy localized cochlear disease (with or without fenestral involvement) to either the basal cochlear turn (grade 2A), or the middle/apical turns (grade 2B), or both the basal turn and the middle/apical turns (grade 2C); and
Grade 3, diffuse confluent cochlear involvement (with or without fenestral involvement).
Treatment
Medical
Earlier workers suggested the use of calcium fluoride; now sodium fluoride is the preferred compound. Fluoride ions inhibit the rapid progression of disease. In the otosclerotic ear, there occurs formation of hydroxylapatite crystals which lead to stapes (or other) fixation. The administration of fluoride replaces the hydroxyl radical with fluoride leading to the formation of fluorapatite crystals. Hence, the progression of disease is considerably slowed down and active disease process is arrested.
This treatment cannot reverse conductive hearing loss, but may slow the progression of both the conductive and sensorineural components of the disease process. Otofluor, containing sodium fluoride, is one treatment. Recently, some success has been claimed with a second such treatment, bisphosphonate medications that inhibit bone destruction. However, these early reports are based on non-randomized case studies that do not meet standards of clinical trials. There are numerous side-effects to both pharmaceutical treatments, including occasional stomach upset, allergic itching, and increased joint pains which can lead to arthritis. In the worst case, bisphosphonates may lead to osteonecrosis of the auditory canal itself. Finally, neither approach has been proven to be beneficial after the commonly preferred method of surgery has been undertaken.
Surgery
There are various methods to treat otosclerosis. However the method of choice is a procedure known as stapedectomy. Early attempts at hearing restoration via the simple freeing of the stapes from its sclerotic attachments to the oval window were met with temporary improvement in hearing, but the conductive hearing loss would almost always recur. A stapedectomy consists of removing a portion of the sclerotic stapes footplate and replacing it with a middle ear implant that is secured to the incus. This procedure restores continuity of ossicular movement and allows transmission of sound waves from the eardrum to the inner ear. A modern variant of this surgery called a stapedotomy, is performed by drilling a small hole in the stapes footplate with a micro-drill or a laser, and the insertion of a piston-like prothesis. The success rate of either surgery depends greatly on the skill and the familiarity with the procedure of the surgeon. However, comparisons have shown stapedotomy to yield results at least as good as stapedectomy, with fewer complications, and thus stapedotomy is preferred in normal circumstances. Recently, Endoscopic stapedotomy has been gaining popularity since its first description by Professor Tarabichi in 1999. The endsocope provides much better view of the stapes footplate without removal of bone to access that structure.
Amplification
Although hearing aids cannot prevent, cure or inhibit the progression of otosclerosis, they can help treat the largest symptom, hearing loss. Hearing aids can be tuned to specific frequency losses. However, due to the progressive nature of this condition, use of a hearing aid is palliative at best. Without eventual surgery, deafness is likely to result.
Society and culture
Notable cases
German composer Ludwig van Beethoven was theorized to suffer from otosclerosis, although this is controversial.
Victorian journalist Harriet Martineau gradually lost her hearing during her young life, and later medical historians have diagnosed her with probably suffering from otosclerosis as well.
Margaret Sullavan, American stage and film actress, suffered from the congenital hearing defect otosclerosis that worsened as she aged, making her more and more hard of hearing.
Howard Hughes the pioneering American aviator, engineer, industrialist, and film producer also suffered from otosclerosis.
Frankie Valli, lead singer of The Four Seasons, suffered from it in the late 1960s and early 1970s, forcing him to "sing from memory" in the latter part of the 70s (surgery restored most of his hearing by 1980).
Pittsburgh Penguins forward Steve Downie suffers from otosclerosis.
The British queen Alexandra of Denmark suffered from it, leading to her social isolation; Queen Alexandras biographer, Georgina Battiscombe, was able to have "some understanding of Alexandras predicament" because she too had otosclerosis.
Adam Savage, co-host of MythBusters, uses a hearing aid due to otosclerosis.
Sir John Cornforth, Australian-British Nobel Prize in Chemistry laureate
References
External links
NIH/Medline |
Malignant infantile osteopetrosis | Malignant infantile osteopetrosis is a rare osteosclerosing type of skeletal dysplasia that typically presents in infancy and is characterized by a unique radiographic appearance of generalized hyperostosis (excessive growth of bone).
The generalized increase in bone density has a special predilection to involve the medullary portion with relative sparing of the cortices. Obliteration of bone marrow spaces and subsequent depression of the cellular function can result in serious hematologic complications. Optic atrophy and cranial nerve damage secondary to bony expansion can result in marked morbidity. The prognosis is extremely poor in untreated cases. Plain radiography provides the key information to the diagnosis. Clinical and radiologic correlations are also fundamental to the diagnostic process, with additional gene testing being confirmatory.
Presentation
Hematologic manifestations related to bone marrow suppression and subsequent pancytopenia are a major source of morbidity and mortality. Additionally, extramedullary hematopoiesis can result in liver and spleen dysfunction. Cranial nerve dysfunction and neurologic complications are usually associated with infantile osteopetrosis. Expansion of the skull bone leads to macrocephaly. Additionally, linear growth retardation that is not apparent at birth, delayed motor milestones and poor dentition can occur.
Diagnosis
Skeletal radiography
The generalized increase in bone density of the medullary portion predominates with relative sparing of the cortices. The axial and appendicular skeleton are uniformly involved. Malignant infantile osteopetrosis is known for exhibiting specific plain radiographic abnormalities:
Loss of differentiation between the medullary and cortical portions of bone is a radiographic hallmark of infantile osteopetrosis
Characteristic endobone or "bone-within-bone" appearance in the spine, or "sandwich vertebra" appearance, characterized by dense endplate sclerosis with sharp margins
Characteristic endobone or "bone-within-bone" appearance in the pelvis and long bones of extremities where areas of osteosclerosis intermingle with areas of relatively hypodense bone.
Failure of remodeling of the distal femoral and proximal humeral metaphyses giving the affected bones a funnel shaped appearance known as an Erlenmeyer flask deformity
Alternating radiolucent femoral metaphyseal bands
Pathologic fractures
Differential diagnosis
The differential diagnosis of malignant infantile osteopetrosis includes other genetic skeletal dysplasias that cause osteosclerosis. They are collectively known as osteosclerosing dysplasias. The differential diagnosis of genetic osteosclerosing dysplasias including infantile osteopetrosis has been tabulated and illustrated in literature citations.
Neuropathic infantile osteopetrosis
Infantile osteopetrosis with renal tubular acidosis
Infantile osteopetrosis with immunodeficiency
IO with leukocyte adhesion deficiency syndrome (LAD-III)
Intermediate osteopetrosis
Autosomal dominant osteopetrosis (Albers-Schonberg)
Pyknodysostosis (osteopetrosis acro-osteolytica)
Osteopoikilosis (Buschke–Ollendorff syndrome)
Osteopathia striata with cranial sclerosis
Mixed sclerosing bone dysplasia
Progressive diaphyseal dysplasia (Camurati–Engelmann disease)
SOST-related sclerosing bone dysplasias
Treatment
The only effective line of treatment for malignant infantile osteopetrosis is hematopoietic stem cell transplantation. It has been shown to provide long-term disease-free periods for a significant percentage of those treated. It can impact both hematologic and skeletal abnormalities; and has been used successfully to reverse the associated skeletal abnormalities.Radiographs of at least one case with malignant infantile osteopetrosis have demonstrated bone remodeling and recanalization of medullar canals following hematopoietic stem cell transplantation. This favorable radiographic response could be expected within one year following the procedure – nevertheless, primary graft failure can prove fatal.
References
== External links == |
Prurigo simplex | Prurigo simplex is a chronic, itchy, idiopathic skin condition characterized by extremely itchy skin nodules and lesions.: 57 Typically, there is no known direct cause of prurigo simplex, but some factors are known to trigger or aggravate it. This condition falls between chronic and acute, sometimes transitioning into a chronic condition. Many people experience a recurrence of the condition after periods of remission. Middle-aged patients are the most prone age group to this condition.
Presentation
The most common prurigo simplex symptoms are skin nodules resembling insect bites that are intensely itchy. These nodules are frequently scratched open, becoming lesions that continue to itch. Sometimes the skin thickens and becomes discolored around the nodules. The scalp, arms, legs and trunk of the body are the most frequent sites of the bumps and lesions. Itching can become severe and habitual, worsening the condition and possibly causing infections in the open sores.
Treatment
Treatment is challenging, with narrow band UVB or pimozide sometimes helpful.
Prognosis
Sometimes the nodules become less itchy and eventually disappear leaving a discolored area or scar tissue. The same nodules can persist for months or even years, though, without healing. Patients may experience a remission but then relapse with new nodules forming. The condition might also become chronic, with no periods of improvement and relief.
== References == |
Argentine hemorrhagic fever | Argentine hemorrhagic fever (AHF) or OHiggins disease, also known in Argentina as mal de los rastrojos (stubble disease) is a hemorrhagic fever and zoonotic infectious disease occurring in Argentina. It is caused by the Junín virus (an arenavirus, closely related to the Machupo virus, causative agent of Bolivian hemorrhagic fever). Its vector is the drylands vesper mouse, a rodent found in Argentina and Paraguay.
Epidemiology
The disease was first reported in the town of OHiggins in Buenos Aires province, Argentina in 1958, giving it one of the names by which it is known. Various theories about its nature were proposed: it was Weils disease, leptospirosis, caused by chemical pollution. It was associated with fields containing stubble after the harvest, giving it another of its names.
The endemic area of AHF covers approximately 150,000 km2, compromising the provinces of Buenos Aires, Córdoba, Santa Fe and La Pampa, with an estimated risk population of 5 million.
The vector, a small rodent known locally as ratón maicero ("maize mouse"; Calomys musculinus), has chronic asymptomatic infection, and spreads the virus through its saliva and urine. Infection is produced through contact of skin or mucous membranes, or through inhalation of infected particles. It is found mostly in people who reside or work in rural areas; 80% of those infected are males between 15 and 60 years of age.
Clinical aspects
AHF is a grave acute disease which may progress to recovery or death in 1 to 2 weeks. The incubation time of the disease is between 10 and 12 days, after which the first symptoms appear: fever, headaches, weakness, loss of appetite and will. These intensify less than a week later, forcing the infected to lie down, and producing stronger symptoms such as vascular, renal, hematological and neurological alterations. This stage lasts about 3 weeks.
If untreated, the mortality of AHF reaches 15–30%. The specific treatment includes plasma of recovered patients, which, if started early, is extremely effective and reduces mortality to 1%.Ribavirin also has shown some promise in treating arenaviral diseases.
The disease was first detected in the 1950s in the Junín Partido in Buenos Aires, after which its agent, the Junín virus, was named upon its identification in 1958. In the early years, about 1,000 cases per year were recorded, with a high mortality rate (more than 30%). The initial introduction of treatment serums in the 1970s reduced this lethality.
Vaccine
The Candid #1 vaccine for AHF was created in 1985 by Argentine virologist Dr. Julio Barrera Oro. The vaccine was manufactured by the Salk Institute in the United States, and became available in Argentina in 1990. The Junín vaccine has also shown cross-reactivity with Machupo virus and, as such, has been considered as a potential treatment for Bolivian hemorrhagic fever.
Candid #1 has been applied to adult high-risk population and is 95.5% effective. Between 1991 and 2005 more than 240,000 people were vaccinated, achieving a great decrease in the numbers of reported cases (94 suspect and 19 confirmed in 2005).
On 29 August 2006 the Maiztegui Institute obtained certification for the production of the vaccine in Argentina. The vaccine produced in Argentina was found to be of similar effectiveness to the US vaccine. Details of the vaccine were published in 2011, and a protocol for production of the vaccine was published in 2018.
Demand for the vaccine is insufficient to be commercially appealing due to the small target population, and it is considered an orphan drug; the Argentine government committed itself to manufacture and sponsor C#1 vaccine.
Weaponization
Argentine hemorrhagic fever was one of three hemorrhagic fevers and one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program. The Soviet Union also conducted research and developing programs on the potential of the hemorragic fever as a biological weapon.
References
Notes
Bibliography
== External links == |
Polyploidy | Polyploidy is a condition in which the cells of an organism have more than one pair of (homologous) chromosomes. Most species whose cells have nuclei (eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contains one or more chromosomes and comes from each of two parents, resulting in pairs of homologous chromosomes between sets. However, some organisms are polyploid. Polyploidy is especially common in plants. Most eukaryotes have diploid somatic cells, but produce haploid gametes (eggs and sperm) by meiosis. A monoploid has only one set of chromosomes, and the term is usually only applied to cells or organisms that are normally diploid. Males of bees and other Hymenoptera, for example, are monoploid. Unlike animals, plants and multicellular algae have life cycles with two alternating multicellular generations. The gametophyte generation is haploid, and produces gametes by mitosis, the sporophyte generation is diploid and produces spores by meiosis.
Polyploidy may occur due to abnormal cell division, either during mitosis, or more commonly from the failure of chromosomes to separate during meiosis or from the fertilization of an egg by more than one sperm. In addition, it can be induced in plants and cell cultures by some chemicals: the best known is colchicine, which can result in chromosome doubling, though its use may have other less obvious consequences as well. Oryzalin will also double the existing chromosome content.
Polyploidy occurs in highly differentiated human tissues in the liver, heart muscle, bone marrow and the placenta. It occurs in the somatic cells of some animals, such as goldfish, salmon, and salamanders, but is especially common among ferns and flowering plants (see Hibiscus rosa-sinensis), including both wild and cultivated species. Wheat, for example, after millennia of hybridization and modification by humans, has strains that are diploid (two sets of chromosomes), tetraploid (four sets of chromosomes) with the common name of durum or macaroni wheat, and hexaploid (six sets of chromosomes) with the common name of bread wheat. Many agriculturally important plants of the genus Brassica are also tetraploids. Sugarcane can have ploidy levels higher than octaploid.Polyploidization can be a mechanism of sympatric speciation because polyploids are usually unable to interbreed with their diploid ancestors. An example is the plant Erythranthe peregrina. Sequencing confirmed that this species originated from E. × robertsii, a sterile triploid hybrid between E. guttata and E. lutea, both of which have been introduced and naturalised in the United Kingdom. New populations of E. peregrina arose on the Scottish mainland and the Orkney Islands via genome duplication from local populations of E. × robertsii. Because of a rare genetic mutation, E. peregrina is not sterile.
Terminology
Types
Polyploid types are labeled according to the number of chromosome sets in the nucleus. The letter x is used to represent the number of chromosomes in a single set:
haploid (one set; 1x)
diploid (two sets; 2x)
triploid (three sets; 3x), for example sterile saffron crocus, or seedless watermelons, also common in the phylum Tardigrada
tetraploid (four sets; 4x), for example Salmonidae fish, the cotton Gossypium hirsutum
pentaploid (five sets; 5x), for example Kenai Birch (Betula kenaica)
hexaploid (six sets; 6x), for example some species of wheat, kiwifruit
heptaploid or septaploid (seven sets; 7x)
octaploid or octoploid, (eight sets; 8x), for example Acipenser (genus of sturgeon fish), dahlias
decaploid (ten sets; 10x), for example certain strawberries
dodecaploid or duodecaploid (twelve sets; 12x), for example the plants Celosia argentea and Spartina anglica or the amphibian Xenopus ruwenzoriensis.
Classification
Autopolyploidy
Autopolyploids are polyploids with multiple chromosome sets derived from a single taxon.
Two examples of natural autopolyploids are the piggyback plant, Tolmiea menzisii and the white sturgeon, Acipenser transmontanum. Most instances of autopolyploidy result from the fusion of unreduced (2n) gametes, which results in either triploid (n + 2n = 3n) or tetraploid (2n + 2n = 4n) offspring. Triploid offspring are typically sterile (as in the phenomenon of triploid block), but in some cases they may produce high proportions of unreduced gametes and thus aid the formation of tetraploids. This pathway to tetraploidy is referred to as the triploid bridge. Triploids may also persist through asexual reproduction. In fact, stable autotriploidy in plants is often associated with apomictic mating systems. In agricultural systems, autotriploidy can result in seedlessness, as in watermelons and bananas. Triploidy is also utilized in salmon and trout farming to induce sterility.Rarely, autopolyploids arise from spontaneous, somatic genome doubling, which has been observed in apple (Malus domesticus) bud sports. This is also the most common pathway of artificially induced polyploidy, where methods such as protoplast fusion or treatment with colchicine, oryzalin or mitotic inhibitors are used to disrupt normal mitotic division, which results in the production of polyploid cells. This process can be useful in plant breeding, especially when attempting to introgress germplasm across ploidal levels.Autopolyploids possess at least three homologous chromosome sets, which can lead to high rates of multivalent pairing during meiosis (particularly in recently formed autopolyploids, also known as neopolyploids) and an associated decrease in fertility due to the production of aneuploid gametes. Natural or artificial selection for fertility can quickly stabilize meiosis in autopolyploids by restoring bivalent pairing during meiosis, but the high degree of homology among duplicated chromosomes causes autopolyploids to display polysomic inheritance. This trait is often used as a diagnostic criterion to distinguish autopolyploids from allopolyploids, which commonly display disomic inheritance after they progress past the neopolyploid stage. While most polyploid species are unambiguously characterized as either autopolyploid or allopolyploid, these categories represent the ends of a spectrum of divergence between parental subgenomes. Polyploids that fall between these two extremes, which are often referred to as segmental allopolyploids, may display intermediate levels of polysomic inheritance that vary by locus.About half of all polyploids are thought to be the result of autopolyploidy, although many factors make this proportion hard to estimate.
Allopolyploidy
Allopolyploids or amphipolyploids or heteropolyploids are polyploids with chromosomes derived from two or more diverged taxa.
As in autopolyploidy, this primarily occurs through the fusion of unreduced (2n) gametes, which can take place before or after hybridization. In the former case, unreduced gametes from each diploid taxon – or reduced gametes from two autotetraploid taxa – combine to form allopolyploid offspring. In the latter case, one or more diploid F1 hybrids produce unreduced gametes that fuse to form allopolyploid progeny. Hybridization followed by genome duplication may be a more common path to allopolyploidy because F1 hybrids between taxa often have relatively high rates of unreduced gamete formation – divergence between the genomes of the two taxa result in abnormal pairing between homoeologous chromosomes or nondisjunction during meiosis. In this case, allopolyploidy can actually restore normal, bivalent meiotic pairing by providing each homoeologous chromosome with its own homologue. If divergence between homoeologous chromosomes is even across the two subgenomes, this can theoretically result in rapid restoration of bivalent pairing and disomic inheritance following allopolyploidization. However multivalent pairing is common in many recently formed allopolyploids, so it is likely that the majority of meiotic stabilization occurs gradually through selection.Because pairing between homoeologous chromosomes is rare in established allopolyploids, they may benefit from fixed heterozygosity of homoeologous alleles. In certain cases, such heterozygosity can have beneficial heterotic effects, either in terms of fitness in natural contexts or desirable traits in agricultural contexts. This could partially explain the prevalence of allopolyploidy among crop species. Both bread wheat and Triticale are examples of an allopolyploids with six chromosome sets. Cotton, peanut, or quinoa are allotetraploids with multiple origins. In Brassicaceous crops, the Triangle of U describes the relationships between the three common diploid Brassicas (B. oleracea, B. rapa, and B. nigra) and three allotetraploids (B. napus, B. juncea, and B. carinata) derived from hybridization among the diploid species. A similar relationship exists between three diploid species of Tragopogon (T. dubius, T. pratensis, and T. porrifolius) and two allotetraploid species (T. mirus and T. miscellus). Complex patterns of allopolyploid evolution have also been observed in animals, as in the frog genus Xenopus.
Aneuploid
Organisms in which a particular chromosome, or chromosome segment, is under- or over-represented are said to be aneuploid (from the Greek words meaning "not", "good", and "fold"). Aneuploidy refers to a numerical change in part of the chromosome set, whereas polyploidy refers to a numerical change in the whole set of chromosomes.
Endopolyploidy
Polyploidy occurs in some tissues of animals that are otherwise diploid, such as human muscle tissues. This is known as endopolyploidy. Species whose cells do not have nuclei, that is, prokaryotes, may be polyploid, as seen in the large bacterium Epulopiscium fishelsoni. Hence ploidy is defined with respect to a cell.
Monoploid
A monoploid has only one set of chromosomes and the term is usually only applied to cells or organisms that are normally diploid. The more general term for such organisms is haploid.
Temporal terms
Neopolyploidy
A polyploid that is newly formed.
Mesopolyploidy
That has become polyploid in more recent history; it is not as new as a neopolyploid and not as old as a paleopolyploid. It is a middle aged polyploid. Often this refers to whole genome duplication followed by intermediate levels of diploidization.
Paleopolyploidy
Ancient genome duplications probably occurred in the evolutionary history of all life. Duplication events that occurred long ago in the history of various evolutionary lineages can be difficult to detect because of subsequent diploidization (such that a polyploid starts to behave cytogenetically as a diploid over time) as mutations and gene translations gradually make one copy of each chromosome unlike the other copy. Over time, it is also common for duplicated copies of genes to accumulate mutations and become inactive pseudogenes.In many cases, these events can be inferred only through comparing sequenced genomes. Examples of unexpected but recently confirmed ancient genome duplications include bakers yeast (Saccharomyces cerevisiae), mustard weed/thale cress (Arabidopsis thaliana), rice (Oryza sativa), and an early evolutionary ancestor of the vertebrates (which includes the human lineage) and another near the origin of the teleost fishes. Angiosperms (flowering plants) have paleopolyploidy in their ancestry. All eukaryotes probably have experienced a polyploidy event at some point in their evolutionary history.
Other similar terms
Karyotype
A karyotype is the characteristic chromosome complement of a eukaryote species. The preparation and study of karyotypes is part of cytology and, more specifically, cytogenetics.
Although the replication and transcription of DNA is highly standardized in eukaryotes, the same cannot be said for their karyotypes, which are highly variable between species in chromosome number and in detailed organization despite being constructed out of the same macromolecules. In some cases, there is even significant variation within species. This variation provides the basis for a range of studies in what might be called evolutionary cytology.
Homoeologous chromosomes
Homoeologous chromosomes are those brought together following inter-species hybridization and allopolyploidization, and whose relationship was completely homologous in an ancestral species. For example, durum wheat is the result of the inter-species hybridization of two diploid grass species Triticum urartu and Aegilops speltoides. Both diploid ancestors had two sets of 7 chromosomes, which were similar in terms of size and genes contained on them. Durum wheat contains a hybrid genome with two sets of chromosomes derived from Triticum urartu and two sets of chromosomes derived from Aegilops speltoides. Each chromosome pair derived from the Triticum urartu parent is homoeologous to the opposite chromosome pair derived from the Aegilops speltoides parent, though each chromosome pair unto itself is homologous.
Examples
Animals
Examples in animals are more common in non-vertebrates such as flatworms, leeches, and brine shrimp. Within vertebrates, examples of stable polyploidy include the salmonids and many cyprinids (i.e. carp). Some fish have as many as 400 chromosomes. Polyploidy also occurs commonly in amphibians; for example the biomedically important genus Xenopus contains many different species with as many as 12 sets of chromosomes (dodecaploid). Polyploid lizards are also quite common. Most are sterile and reproduce by parthenogenesis; others, like Liolaemus chiliensis, maintain sexual reproduction. Polyploid mole salamanders (mostly triploids) are all female and reproduce by kleptogenesis, "stealing" spermatophores from diploid males of related species to trigger egg development but not incorporating the males DNA into the offspring.
While mammalian liver cells are polyploid, rare instances of polyploid mammals are known, but most often result in prenatal death. An octodontid rodent of Argentinas harsh desert regions, known as the plains viscacha rat (Tympanoctomys barrerae) has been reported as an exception to this rule. However, careful analysis using chromosome paints shows that there are only two copies of each chromosome in T. barrerae, not the four expected if it were truly a tetraploid. This rodent is not a rat, but kin to guinea pigs and chinchillas. Its "new" diploid (2n) number is 102 and so its cells are roughly twice normal size. Its closest living relation is Octomys mimax, the Andean Viscacha-Rat of the same family, whose 2n = 56. It was therefore surmised that an Octomys-like ancestor produced tetraploid (i.e., 2n = 4x = 112) offspring that were, by virtue of their doubled chromosomes, reproductively isolated from their parents.
Polyploidy was induced in fish by Har Swarup (1956) using a cold-shock treatment of the eggs close to the time of fertilization, which produced triploid embryos that successfully matured. Cold or heat shock has also been shown to result in unreduced amphibian gametes, though this occurs more commonly in eggs than in sperm. John Gurdon (1958) transplanted intact nuclei from somatic cells to produce diploid eggs in the frog, Xenopus (an extension of the work of Briggs and King in 1952) that were able to develop to the tadpole stage. The British scientist J. B. S. Haldane hailed the work for its potential medical applications and, in describing the results, became one of the first to use the word "clone" in reference to animals. Later work by Shinya Yamanaka showed how mature cells can be reprogrammed to become pluripotent, extending the possibilities to non-stem cells. Gurdon and Yamanaka were jointly awarded the Nobel Prize in 2012 for this work.
Humans
True polyploidy rarely occurs in humans, although polyploid cells occur in highly differentiated tissue, such as liver parenchyma, heart muscle, placenta and in bone marrow. Aneuploidy is more common.
Polyploidy occurs in humans in the form of triploidy, with 69 chromosomes (sometimes called 69, XXX), and tetraploidy with 92 chromosomes (sometimes called 92, XXXX). Triploidy, usually due to polyspermy, occurs in about 2–3% of all human pregnancies and ~15% of miscarriages. The vast majority of triploid conceptions end as a miscarriage; those that do survive to term typically die shortly after birth. In some cases, survival past birth may be extended if there is mixoploidy with both a diploid and a triploid cell population present. There has been one report of a child surviving to the age of seven months with complete triploidy syndrome. He failed to exhibit normal mental or physical neonatal development, and died from a Pneumocystis carinii infection, which indicates a weak immune system.Triploidy may be the result of either digyny (the extra haploid set is from the mother) or diandry (the extra haploid set is from the father). Diandry is mostly caused by reduplication of the paternal haploid set from a single sperm, but may also be the consequence of dispermic (two sperm) fertilization of the egg. Digyny is most commonly caused by either failure of one meiotic division during oogenesis leading to a diploid oocyte or failure to extrude one polar body from the oocyte. Diandry appears to predominate among early miscarriages, while digyny predominates among triploid zygotes that survive into the fetal period. However, among early miscarriages, digyny is also more common in those cases less than 8+1⁄2 weeks gestational age or those in which an embryo is present. There are also two distinct phenotypes in triploid placentas and fetuses that are dependent on the origin of the extra haploid set. In digyny, there is typically an asymmetric poorly grown fetus, with marked adrenal hypoplasia and a very small placenta. In diandry, a partial hydatidiform mole develops. These parent-of-origin effects reflect the effects of genomic imprinting.Complete tetraploidy is more rarely diagnosed than triploidy, but is observed in 1–2% of early miscarriages. However, some tetraploid cells are commonly found in chromosome analysis at prenatal diagnosis and these are generally considered harmless. It is not clear whether these tetraploid cells simply tend to arise during in vitro cell culture or whether they are also present in placental cells in vivo. There are, at any rate, very few clinical reports of fetuses/infants diagnosed with tetraploidy mosaicism.
Mixoploidy is quite commonly observed in human preimplantation embryos and includes haploid/diploid as well as diploid/tetraploid mixed cell populations. It is unknown whether these embryos fail to implant and are therefore rarely detected in ongoing pregnancies or if there is simply a selective process favoring the diploid cells.
Fish
A polyploidy event occurred within the stem lineage of the teleost fish.
Plants
Polyploidy is frequent in plants, some estimates suggesting that 30–80% of living plant species are polyploid, and many lineages show evidence of ancient polyploidy (paleopolyploidy) in their genomes. Huge explosions in angiosperm species diversity appear to have coincided with the timing of ancient genome duplications shared by many species. It has been established that 15% of angiosperm and 31% of fern speciation events are accompanied by ploidy increase.Polyploid plants can arise spontaneously in nature by several mechanisms, including meiotic or mitotic failures, and fusion of unreduced (2n) gametes. Both autopolyploids (e.g. potato) and allopolyploids (such as canola, wheat and cotton) can be found among both wild and domesticated plant species.
Most polyploids display novel variation or morphologies relative to their parental species, that may contribute to the processes of speciation and eco-niche exploitation. The mechanisms leading to novel variation in newly formed allopolyploids may include gene dosage effects (resulting from more numerous copies of genome content), the reunion of divergent gene regulatory hierarchies, chromosomal rearrangements, and epigenetic remodeling, all of which affect gene content and/or expression levels. Many of these rapid changes may contribute to reproductive isolation and speciation. However seed generated from interploidy crosses, such as between polyploids and their parent species, usually have aberrant endosperm development which impairs their viability, thus contributing to polyploid speciation.
Some plants are triploid. As meiosis is disturbed, these plants are sterile, with all plants having the same genetic constitution: Among them, the exclusively vegetatively propagated saffron crocus (Crocus sativus). Also, the extremely rare Tasmanian shrub Lomatia tasmanica is a triploid sterile species.
There are few naturally occurring polyploid conifers. One example is the Coast Redwood Sequoia sempervirens, which is a hexaploid (6x) with 66 chromosomes (2n = 6x = 66), although the origin is unclear.Aquatic plants, especially the Monocotyledons, include a large number of polyploids.
Crops
The induction of polyploidy is a common technique to overcome the sterility of a hybrid species during plant breeding. For example, triticale is the hybrid of wheat (Triticum turgidum) and rye (Secale cereale). It combines sought-after characteristics of the parents, but the initial hybrids are sterile. After polyploidization, the hybrid becomes fertile and can thus be further propagated to become triticale.
In some situations, polyploid crops are preferred because they are sterile. For example, many seedless fruit varieties are seedless as a result of polyploidy. Such crops are propagated using asexual techniques, such as grafting.
Polyploidy in crop plants is most commonly induced by treating seeds with the chemical colchicine.
Examples
Triploid crops: some apple varieties (such as Belle de Boskoop, Jonagold, Mutsu, Ribston Pippin), banana, citrus, ginger, watermelon, saffron crocus, white pulp of coconut
Tetraploid crops: very few apple varieties, durum or macaroni wheat, cotton, potato, canola/rapeseed, leek, tobacco, peanut, kinnow, Pelargonium
Hexaploid crops: chrysanthemum, bread wheat, triticale, oat, kiwifruit
Octaploid crops: strawberry, dahlia, pansies, sugar cane, oca (Oxalis tuberosa)
Dodecaploid crops: some sugar cane hybridsSome crops are found in a variety of ploidies: tulips and lilies are commonly found as both diploid and triploid; daylilies (Hemerocallis cultivars) are available as either diploid or tetraploid; apples and kinnow mandarins can be diploid, triploid, or tetraploid.
Fungi
Besides plants and animals, the evolutionary history of various fungal species is dotted by past and recent whole-genome duplication events (see Albertin and Marullo 2012 for review). Several examples of polyploids are known:
autopolyploid: the aquatic fungi of genus Allomyces, some Saccharomyces cerevisiae strains used in bakery, etc.
allopolyploid: the widespread Cyathus stercoreus, the allotetraploid lager yeast Saccharomyces pastorianus, the allotriploid wine spoilage yeast Dekkera bruxellensis, etc.
paleopolyploid: the human pathogen Rhizopus oryzae, the genus Saccharomyces, etc.In addition, polyploidy is frequently associated with hybridization and reticulate evolution that appear to be highly prevalent in several fungal taxa. Indeed, homoploid speciation (hybrid speciation without a change in chromosome number) has been evidenced for some fungal species (such as the basidiomycota Microbotryum violaceum).
As for plants and animals, fungal hybrids and polyploids display structural and functional modifications compared to their progenitors and diploid counterparts. In particular, the structural and functional outcomes of polyploid Saccharomyces genomes strikingly reflect the evolutionary fate of plant polyploid ones. Large chromosomal rearrangements leading to chimeric chromosomes have been described, as well as more punctual genetic modifications such as gene loss. The homoealleles of the allotetraploid yeast S. pastorianus show unequal contribution to the transcriptome. Phenotypic diversification is also observed following polyploidization and/or hybridization in fungi, producing the fuel for natural selection and subsequent adaptation and speciation.
Chromalveolata
Other eukaryotic taxa have experienced one or more polyploidization events during their evolutionary history (see Albertin and Marullo, 2012 for review). The oomycetes, which are non-true fungi members, contain several examples of paleopolyploid and polyploid species, such as within the genus Phytophthora. Some species of brown algae (Fucales, Laminariales and diatoms) contain apparent polyploid genomes. In the Alveolata group, the remarkable species Paramecium tetraurelia underwent three successive rounds of whole-genome duplication and established itself as a major model for paleopolyploid studies.
Bacteria
Each Deinococcus radiodurans bacterium contains 4-8 copies of its chromosome. Exposure of D. radiodurans to X-ray irradiation or desiccation can shatter its genomes into hundred of short random fragments. Nevertheless, D. radiodurans is highly resistant to such exposures. The mechanism by which the genome is accurately restored involves RecA-mediated homologous recombination and a process referred to as extended synthesis-dependent strand annealing (SDSA).Azotobacter vinelandii can contain up to 80 chromosome copies per cell. However this is only observed in fast growing cultures, whereas cultures grown in synthetic minimal media are not polyploid.
Archaea
The archaeon Halobacterium salinarium is polyploid and, like Deinococcus radiodurans, is highly resistant to X-ray irradiation and desiccation, conditions that induce DNA double-strand breaks. Although chromosomes are shattered into many fragments, complete chromosomes can be regenerated by making use of overlapping fragments. The mechanism employs single-stranded DNA binding protein and is likely homologous recombinational repair.
See also
Diploidization
Eukaryote hybrid genome
Ploidy
Polyploid complex
Polysomy
Reciprocal silencing
Sympatry
References
Further reading
External links
Polyploidy on Kim |
Polyploidy | balls Biology Pages
The polyploidy portal a community-editable project with information, research, education, and a bibliography about polyploidy. |
Crush injury | A crush injury is injury by an object that causes compression of the body. This form of injury is rare in normal civilian practice, but common following a natural disaster. Other causes include industrial accidents, road traffic collisions, building collapse, accidents involving heavy plant, disaster relief or terrorist incidents.
Presentation
Complications
Hypovolaemic Shock. Loss of plasma volume across damaged cell membranes and capillary walls can lead directly to severe hypovolaemia. Furthermore, shock can develop from myocardial depression following release of intracellular electrolytes. In addition, as a result of the mechanism of injury, blood loss from pelvic or long bone fractures may also co-exist.
Hyperkalaemia and electrolyte imbalance. Disruption of cell membranes can result in a significant release of potassium, which is a largely intracellular cation that can precipitate cardiac arrest. Sequestration of plasma calcium into injured tissue can lead to a relative hypocalcaemia, which may worsen disruption of clotting abilities and shock. Metabolic acidosis may result from reperfusion injury and hypoperfusion related to shock.
Compartment syndrome. Compartment syndrome is a common complication of crush injury as a consequence of oedematous tissue injury, redistribution of fluid into the intracellular compartment and bleeding. Established compartment syndrome may result in worsened systemic crush syndrome and irreversible muscle cell death.
Acute Kidney Injury. Release of myoglobin by injured muscle leads to rhabdomyolysis coupled with shock leads to a significant rate of acute kidney injury, estimated as up to 15%. Acute kidney injury leads to a significantly higher mortality.
Pathophysiology
Crush injury is damage to the body as a result of being crushed by an object. Crush syndrome is a systemic result of skeletal muscle injury and breakdown and subsequent release of cell contents. The severity of crush syndrome is dependent on the duration and magnitude of the crush injury as well as the bulk of muscle affected. It can result from both short duration, high-magnitude injuries (such as being crushed by a building) or from low magnitude, long-duration injuries such as coma or drug induced immobility.
Treatment
Early fluid resuscitation reduces the risk of kidney failure, reduces the severity of hyperkalaemia and may improve outcomes in isolated crush injury.For casualties with isolated crush injury who are haemodynamically stable, large volume crystalloid fluid resuscitation reduces the severity of and reduces the risk of acute kidney injury.
See also
Crush syndrome
References
Further reading
Rajasekaran S. (2005). "Ganga hospital open injury severity score - A score to prognosticate limb salvage and outcome measures in Type IIIb open tibial fractures". Indian J Orthop. 39 (1): 4–13. Archived from the original on 2016-09-16. Retrieved 2016-09-06.
== External links == |
Functional constipation | Functional constipation, known as chronic idiopathic constipation (CIC), is constipation that does not have a physical (anatomical) or physiological (hormonal or other body chemistry) cause. It may have a neurological, psychological or psychosomatic cause. A person with functional constipation may be healthy, yet has difficulty defecating.
Symptoms and diagnosis
Chronic idiopathic constipation is similar to constipation-predominant irritable bowel syndrome (IBS-C); however, people with CIC do not have other symptoms of IBS, such as abdominal pain. Diagnosing CIC can be difficult as other syndromes must be ruled out as there is no physiological cause for CIC. Doctors will typically look for other symptoms, such as blood in stool, weight loss, low blood count, or other symptoms.
To be considered functional constipation, symptoms must be present at least a fourth of the time.
Possible causes are:
Anismus
Descending perineum syndrome
Other inability or unwillingness to control the external anal sphincter, which normally is under voluntary control
A poor diet
An unwillingness to defecate
Nervous reactions, including prolonged and/or chronic stress and anxiety, that close the internal anal sphincter, a muscle that is not under voluntary control
Deeper psychosomatic disorders which sometimes affect digestion and the absorption of water in the colonThere is also possibility of presentation with other comorbid symptoms such as headache, especially in children.
Treatment
Treatment options appear similar and include prucalopride, lubiprostone, linaclotide, tegaserod, velusetrag, elobixibat, bisacodyl, sodium picosulphate, and most recently, plecanatide.
Research
A 2014 meta-analysis of three small trials evaluating probiotics showed a slight improvement in management of chronic idiopathic constipation, but well-designed studies are necessary to know the true efficacy of probiotics in treating this condition.Children with functional constipation often claim to lack the sensation of the urge to defecate, and may be conditioned to avoid doing so due to a previous painful experience. One retrospective study showed that these children did indeed have the urge to defecate using colonic manometry, and suggested behavioral modification as a treatment for functional constipation.
See also
Functional symptom
Sacral nerve stimulation
== References == |
Reynolds syndrome | Reynolds syndrome is a rare secondary laminopathy, consisting of the combination of primary biliary cirrhosis and progressive systemic sclerosis. In some patients this syndrome has also been associated with Sjögrens syndrome and hemolytic anemia. Typical clinical features include jaundice, elevated blood levels of alkaline phosphatase, calcinosis cutis, telangiectasias, and pruritus. This disease may cause white or yellow-ish spots on the arms or legs. The syndrome, a special case of scleroderma, is named after the American physician, Telfer B. Reynolds, MD (1921–2004), who first described it. He is also known for creating one of the worlds first hepatology programs at the University of Southern California.
It should not be confused with the more common Raynauds phenomenon.
References
T. B. Reynolds, E. K. Denison, H. D. Frank, F. L. Lieberman, R. L. Peters: Primary biliary cirrhosis with scleroderma, Raynauds phenomenon and telangiectasia. New syndrome. American Journal of Medicine, New York, 1971, 50 (3): 302–312.
Volker Stadie, Johannes Wohlrab, Wolfgang Christian Marsch: The Reynolds Syndrome - a Rare Combination of Two Autoimmune Diseases. Medizinische Klinik, München, 2002, 97 (1): 40–43.
== External links == |
Lysinuric protein intolerance | Lysinuric protein intolerance (LPI) is an autosomal recessive metabolic disorder affecting amino acid transport.
About 140 patients have been reported, almost half of them of Finnish origin. Individuals from Japan, Italy, Morocco and North Africa have also been reported plus one in Bixby, Oklahoma.
Signs and symptoms
Infants with LPI are usually symptom-free when breastfed because of the low protein concentration in human milk, but develop vomiting and diarrhea after weaning. The patients show failure to thrive, poor appetite, growth retardation, enlarged liver and spleen, prominent osteoporosis and osteopenia, delayed bone age and spontaneous protein aversion. Forced feeding of protein may lead to convulsions and coma. Mental development is normal if prolonged episode of hyperammonemia can be avoided. Some patients develop severe pulmonary and kidney complications. High levels of plasma glutamine and glycine are observed.
Causes
It has been associated with SLC7A7.
Mechanism
In LPI, urinary excretion of cationic amino acids (ornithine, arginine and lysine) is increased and these amino acids are poorly absorbed from the intestine. Therefore, their plasma concentrations are low and their body pools become depleted. Deficiency of arginine and ornithine restricts the function of the urea cycle and leads to hyperammonemia after protein-rich meals. Deficiency of lysine may play a major role in the skeletal and immunological abnormalities observed in LPI patients.
Diagnosis
The diagnosis is based on the biochemical findings (increased concentrations of lysine, arginine and ornithine in urine and low concentrations of these amino acids in plasma, elevation of urinary orotic acid excretion after protein-rich meals, and inappropriately high concentrations of serum ferritin and lactate dehydrogenase isoenzymes) and the screening of known mutations of the causative gene from a DNA sample.
Treatment
Treatment of LPI consists of protein-restricted diet and supplementation with oral *GeneReview/NIH/UW entry on Lysinuric Protein Intolerance citrulline. Citrulline is a neutral amino acid that improves the function of the urea cycle and allows sufficient protein intake without hyperammonemia.
Prognosis
Under proper dietary control and supplementation, the majority of the LPI patients are able to have a nearly normal life. However, severe complications including pulmonary alveolar proteinosis and chronic kidney disease may develop even with proper treatment.Fertility appears to be normal in women, but mothers with LPI have an increased risk for complications during pregnancy and delivery.
References
External links
GeneReview/NIH/UW entry on Lysinuric Protein Intolerance |
Delta-aminolevulinic acid dehydratase | Aminolevulinic acid dehydratase (porphobilinogen synthase, or ALA dehydratase, or aminolevulinate dehydratase) is an enzyme (EC 4.2.1.24) that in humans is encoded by the ALAD gene. Porphobilinogen synthase (or ALA dehydratase, or aminolevulinate dehydratase) synthesizes porphobilinogen through the asymmetric condensation of two molecules of aminolevulinic acid. All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen as a common precursor. Porphobilinogen synthase is the prototype morpheein.
Function
It catalyzes the following reaction, the second step of the biosynthesis of porphyrin:
2 5-Aminolevulinic acid
⇌
{\displaystyle \rightleftharpoons }
porphobilinogen + 2 H2OIt therefore catalyzes the condensation of 2 molecules of 5-aminolevulinate to form porphobilinogen (a precursor of heme, cytochromes and other hemoproteins). This reaction is the first common step in the biosynthesis of all biological tetrapyrroles. Zinc is essential for enzymatic activity.
Structure
The structural basis for allosteric regulation of Porphobilinogen synthase (PBGS) is modulation of a quaternary structure equilibrium between octamer and hexamer (via dimers), which is represented schematically as 6mer* ↔ 2mer* ↔ 2mer ↔ 8mer. The * represents a reorientation between two domains of each subunit that occurs in the dissociated state because it is sterically forbidden in the larger multimers.
PBGS is encoded by a single gene and each PBGS multimer is composed of multiple copies of the same protein. Each PBGS subunit consists of a ~300 residue αβ-barrel domain, which houses the enzymes active site in its center, and a >25 residue N-terminal arm domain. Allosteric regulation of PBGS can be described in terms of the orientation of the αβ-barrel domain with respect to the N-terminal arm domain.
Each N-terminal arm has up to two interactions with other subunits in a PBGS multimer. One of these interactions helps to stabilize a "closed" conformation of the active site lid. The other interaction restricts solvent access from the other end of the αβ-barrel.
In the inactive multimeric state, the N-terminal arm domain is not involved in the lid-stabilizing interaction, and in the crystal structure of the inactive assembly, the active site lid is disordered.
Allosteric regulators
As a nearly universal enzyme with a highly conserved active site, PBGS would not be a prime target for the development of antimicrobials and/or herbicides. To the contrary, allosteric sites can be much more phylogenetically variable than active sites, thus presenting more drug development opportunities.Phylogenetic variation in PBGS allostery leads to the framing of discussion of PBGS allosteric regulation in terms of intrinsic and extrinsic factors.
Intrinsic allosteric regulators
Magnesium
The allosteric magnesium ion lies at the highly hydrated interface of two pro-octamer dimers. It appears to be easily dissociable, and it has been shown that hexamers accumulate when magnesium is removed in vitro.
pH
Though it is not common to consider hydronium ions as allosteric regulators, in the case of PBGS, side chain protonation at locations other than the active site has been shown to affect the quaternary structure equilibrium, and thus to affect the rate of its catalyzed reaction as well.
Extrinsic allosteric regulators
Small molecule hexamer stabilization
Inspection of the PBGS 6mer* reveals a surface cavity that is not present in the 8mer. Small molecule binding to this phylogenetically variable cavity has been proposed to stabilize 6mer* of the targeted PBGS and consequently inhibit activity.
Such allosteric regulators are known as morphlocks because they lock PBGS in a specific morpheein form (6mer*).
Lead poisoning
ALAD enzymatic activity is inhibited by lead, beginning at blood lead levels that were once considered to be safe (<10 μg/dL) and continuing to correlate negatively across the range from 5 to 95 μg/dL. Inhibition of ALAD by lead leads to anemia primarily because it both inhibits heme synthesis and shortens the lifespan of circulating red blood cells, but also by stimulating the excessive production of the hormone erythropoietin, leading to inadequate maturation of red cells from their progenitors. A defect in the ALAD structural gene can cause increased sensitivity to lead poisoning and acute hepatic porphyria. Alternatively spliced transcript variants encoding different isoforms have been identified.
Deficiency
A deficiency of porphobilinogen synthase is usually acquired (rather than hereditary) and can be caused by heavy metal poisoning, especially lead poisoning, as the enzyme is very susceptible to inhibition by heavy metals.Hereditary insufficiency of porphobilinogen synthase is called porphobilinogen synthase (or ALA dehydratase) deficiency poprhyria. It is an extremely rare cause of porphyria, with less than 10 cases ever reported. All disease associated protein variants favor hexamer formation relative to the wild type human enzyme.
PBGS as the prototype morpheein
The morpheein model of allostery exemplified by PBGS adds an additional layer of understanding to potential mechanisms for regulation of protein function and complements the increased focus that the protein science community is placing on protein structure dynamics.This model illustrates how the dynamics of phenomena such as alternate protein conformations, alternate oligomeric states, and transient protein-protein interactions can be harnessed for allosteric regulation of catalytic activity.
References
External links
Human ALAD genome location and ALAD gene details page in the UCSC Genome Browser.
delta-Aminolevulinic+Acid+Dehydratase at the US National Library of Medicine Medical Subject Headings (MeSH)
http://www.omim.org/entry/125270?search=pbgs&highlight=pbgs
== Further reading == |
Dental fluorosis | Dental fluorosis is a common disorder, characterized by hypomineralization of tooth enamel caused by ingestion of excessive fluoride during enamel formation.It appears as a range of visual changes in enamel causing degrees of intrinsic tooth discoloration, and, in some cases, physical damage to the teeth. The severity of the condition is dependent on the dose, duration, and age of the individual during the exposure. The "very mild" (and most common) form of fluorosis, is characterized by small, opaque, "paper white" areas scattered irregularly over the tooth, covering less than 25% of the tooth surface. In the "mild" form of the disease, these mottled patches can involve up to half of the surface area of the teeth. When fluorosis is moderate, all of the surfaces of the teeth are mottled and teeth may be ground down and brown stains frequently "disfigure" the teeth. Severe fluorosis is characterized by brown discoloration and discrete or confluent pitting; brown stains are widespread and teeth often present a corroded-looking appearance.People with fluorosis are relatively resistant to dental caries (tooth decay caused by bacteria), although there may be cosmetic concern. In moderate to severe fluorosis, teeth are weakened and suffer permanent physical damage.
Diagnosis
The adequate diagnosis of fluorosis can be diagnosed by visual clinical examination. This requires inspection of dry and clean tooth surfaces under a good lighting. There are individual variations in clinical fluorosis manifestation which are highly dependent on the duration, timing, and dosage of fluoride exposure.There are different classifications to diagnose the severity based on the appearances. The clinical manifestation of mild dental fluorosis is mostly characterised a snow flaking appearance that lack a clear border, opaque, white spots, narrow white lines following the perikymata or patches as the opacities may coalesce with an intact, hard and smooth enamel surface on most of the teeth. With increasing severity, the subsurface enamel, all along the tooth becomes more porous. Enamel may appear yellow/ brown discolouration and/ or many and pitted white-brown lesions that look like cavities. They are often described as "mottled teeth". Fluorosis does not cause discolouration to the enamel directly, as upon eruption into the mouth, affected permanent teeth are not discoloured yet. In dental enamel, fluorosis causes subsurface porosity or hypomineralizations, which extend toward the dentinal-enamel junction as the condition progresses and the affected teeth become more susceptible to staining. Due to diffusion of exogenous ions (e.g., iron and copper), stains develop into the increasingly and abnormally porous enamel.
The differential diagnosis for this condition includes:
Turners hypoplasia (although this is usually more localized)
Enamel defects caused by an undiagnosed and untreated celiac disease.
Some mild forms of amelogenesis imperfecta and enamel hypoplasia
Enamel defects caused by infection of a primary tooth predecessor
Dental caries: Fluorosis-resembling enamel defects are often misdiagnosed as dental caries.
Dental trauma: Mechanical trauma to the primary tooth may cause disturbance to the maturation phase of enamel formation, which may result in enamel opacities on the permanent successors.
Classification
The two main classification systems are described below. Others include the tooth surface fluorosis index (Horowitz et al. 1984), which combines Deans index and the TF index; and the fluorosis risk index (Pendrys 1990), which is intended to define the time at which fluoride exposure occurs, and relates fluorosis risk with tooth development stage.
Deans index
Deans fluorosis index was first published in 1934 by H. Trendley Dean. The index underwent two changes, appearing in its final form in 1942. An individuals fluorosis score is based on the most severe form of fluorosis found on two or more teeth.
TF index
Proposed by Thylstrup and Fejerskov in 1978, the TF index represents a logical extension of Deans index, incorporating modern understanding of the underlying pathology of fluorosis. It scores the spectrum of fluorotic changes in enamel from 0 to 9, allowing more precise definition of mild and severe cases.
Causes
Dental fluorosis is caused by a higher than normal amount of fluoride ingestion whilst teeth are forming. Primary dentine fluorosis and enamel fluorosis can only happen during tooth formation, so fluoride exposure occurs in childhood. Enamel fluorosis has a white opaque appearance which is due to the surface of the enamel being hypomineralised.The most superficial concern in dental fluorosis is aesthetic changes in the permanent dentition (the adult teeth). The period when these teeth are at highest risk of developing fluorosis is between when the child is born up to 6 years old, though there has been some research which proposes that the most crucial course is during the first 2 years of the childs life. From roughly 7 years old thereafter, most childrens permanent teeth would have undergone complete development (except their wisdom teeth), and therefore their susceptibility to fluorosis is greatly reduced, or even insignificant, despite the amount of intake of fluoride. The severity of dental fluorosis depends on the amount of fluoride exposure, the age of the child, individual response, weight, degree of physical activity, nutrition, and bone growth. Individual susceptibility to fluorosis is also influenced by genetic factors.Many well-known sources of fluoride may contribute to overexposure including dentifrice/fluoridated mouthrinse (which young children may swallow), excessive ingestion of fluoride toothpaste, bottled waters which are not tested for their fluoride content, inappropriate use of fluoride supplements, ingestion of foods especially imported from other countries, and public water fluoridation. The last of these sources is directly or indirectly responsible for 40% of all fluorosis, but the resulting effect due to water fluoridation is largely and typically aesthetic. Severe cases can be caused by exposure to water that is naturally fluoridated to levels above the recommended levels, or by exposure to other fluoride sources such as brick tea or pollution from high fluoride coal.Dental fluorosis has been growing in the United States concurrent with fluoridation of municipal water supplies, although disproportionately by race. A 2010 CDC report acknowledges an overall incidence of dental fluorosis of 22% from 1986-87 increased to 41% in the early 21st century, with an increase in moderate to severe dental fluorosis from 1% to 4%. The 2011-12 NHANES figures documented another 31% overall increase among American teens since the previous decade, with a total adolescent population impact of 61% afflicted. More than one in five American teens (23%) have moderate to severe dental fluorosis on at least two teeth.
Mechanism
Teeth are the most studied body tissues to examine the impact of fluoride to human health. There are a few possible mechanisms that have been proposed. It is generally believed that the hypomineralization of affected enamel is mainly due to in-situ toxic effects of the fluoride on the ameloblasts in the enamel formation, and not caused by the general effects of fluoride on the calcium metabolism, or by the poisoning effects that suppress the fluoride metabolism. However, despite decades of research and studies, there have yet to be any studies that substantiates the believed mechanism whereby dental fluorosis is a result of alteration in the mineralisation that takes place when fluoride interacts with mineralising tissues.In the extra-cellular environment of maturing enamel, an excess of fluoride ions alters the rate at which enamel matrix proteins (amelogenin) are enzymatically broken down and the rate at which the subsequent breakdown products are removed. Fluoride may also indirectly alter the action of protease via a decrease in the availability of free calcium ions in the mineralization environment. This results in the formation of enamel with less mineralization. This hypomineralized enamel has altered optical properties and appears opaque and lusterless relative to normal enamel.Traditionally severe fluorosis has been described as enamel hypoplasia, however, hypoplasia does not occur as a result of fluorosis. The pits, bands, and loss of areas of enamel seen in severe fluorosis are the result of damage to the severely hypomineralized, brittle and fragile enamel which occurs after they erupt into the mouth.Hydroxyapatite is converted to fluoroapatite in a three step process. Dental fluorosis can be prevented at a population level through defluoridation. It is the downward adjustment of the level of fluoride in drinking water.
Management
Dental fluorosis may or may not be of cosmetic concern. In some cases, there may be varying degrees of negative psychosocial effects. The treatment options are:
Mild cases: Tooth bleaching
Moderate cases: Enamel microabrasion (outer affected layer of enamel is abraded in an acidic environment)
Severe cases: Composite fillings, Micro-abrasion, Veneers, Crowns
Epidemiology
Fluorosis is extremely common, with 41% of adolescents having definite fluorosis, and another 20% "questionably" having fluorosis according to the Centers for Disease Control.
As of 2005 surveys conducted by the National Institute of Dental and Craniofacial Research in the USA between 1986 and 1987 and by the Center of Disease Control between 1999 and 2004 are the only national sources of data concerning the prevalence of dental fluorosis. Before the 1999-2004 study was published, CDC published an interim report covering data from 1999 to 2002.
The U.S. Centers for Disease Control found a 9 percentage point increase in the prevalence of confirmed dental fluorosis in a 1999-2002 study of American children and adolescents than was found in a similar survey from 1986-1987 (from 22.8% in 1986-1987 to 32% in 1999-2002). In addition, the survey provides further evidence that African Americans suffer from higher rates of fluorosis than Caucasian Americans.
The condition is more prevalent in rural areas where drinking water is derived from shallow wells or hand pumps. It is also more likely to occur in areas where the drinking water has a fluoride content greater than 1 ppm (part per million).
If the water supply is fluoridated at the level of 1 ppm, one must consume one litre of water in order to take in 1 mg of fluoride. It is thus improbable a person will receive more than the tolerable upper limit from consuming optimally fluoridated water alone.
Fluoride consumption can exceed the tolerable upper limit when someone drinks a lot of fluoride-containing water in combination with other fluoride sources, such as swallowing fluoridated toothpaste, consuming food with a high fluoride content, or consuming fluoride supplements. The use of fluoride supplements as a prevention for tooth decay is rare in areas with water fluoridation, but was recommended by many dentists in the UK until the early 1990s.
In November 2006 the American Dental Association published information stating that water fluoridation is safe, effective and healthy; that enamel fluorosis, usually mild and difficult for anyone except a dental health care professional to see, can result from ingesting more than optimal amounts of fluoride in early childhood; that it is safe to use fluoridated water to mix infant formula; and that the probability of babies developing fluorosis can be reduced by using ready-to-feed infant formula or using water that is either free of fluoride or low in fluoride to prepare powdered or liquid concentrate formula. They go on to say that the way to get the benefits of fluoride but minimize the risk of fluorosis for a child is to get the right amount of fluoride, not too much and not too little. "Your dentist, pediatrician or family physician can help you determine how to optimize your childs fluoride intake."
Prevention
Dental fluorosis can be prevented by lowering the amount of fluoride intake to below the tolerable upper limit. This can be achieved by consuming de-fluorinated water and improving the general nutritional status of the people.
History
In ancient times, Galen describes what is thought to be dental fluorosis. However, it was not until the early 20th century that dental fluorosis became increasingly recognized and scientifically studied.
In 1901 Eager published the first description of the "mottled enamel" of immigrants from a small village near Naples, Italy. He writes that the condition is called "Denti di Chiaie" (Chiaie teeth), named after Stefano Chiaie, an Italian professor. In the United States of America, a dentist, Frederick McKay, set up practice in Colorado Springs in 1901 and discovered a high proportion of the residents had stained teeth, locally termed the "Colorado brown stain". He took this information to Greene Vardiman Black, a prominent American dentist of the time. After examining specimens of affected enamel, in 1916 Black described the condition as "[a]n endemic imperfection of the enamel of the teeth, heretofore unknown in the literature of dentistry." They made the interesting observation that although the mottled enamel was hypomineralized, and therefore should be more susceptible to decay, this was not the case. Gradually, they became aware of existing and further reports of a similar condition worldwide.In 1931, 3 different groups of scientists around the world published their discoveries that this condition was caused by fluoride in drinking water during childhood. The condition then started to become termed "dental fluorosis". Through epidemiological studies in the US, Henry Trendley Dean helped to identify a causal link between high concentrations of fluoride in the drinking water and mottled enamel. He also produced a classification system for dental fluorosis that is still used in modern times, Deans Index. As research continued, the protective effect of fluoride against dental decay was demonstrated.
References
== External links == |
Dermatopathia pigmentosa reticularis | Dermatopathia pigmentosa reticularis (DPR) is a rare, autosomal dominant congenital disorder that is a form of ectodermal dysplasia. Dermatopathia pigmentosa reticularis is composed of the triad of generalized reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy.: 856 DPR is a non life-threatening disease that largely affects the skin, hair, and nails. It has also been identified as a keratin disorder. Historically, as of 1992, only 10 cases had been described in world literature; however, due to recent advances in genetic analysis, five additional families studied in 2006 have been added to the short list of confirmed cases.
Signs and Symptoms (Presentation)
Symptoms include lack of sweat glands, thin hair, brittle nails, mottled skin, and lack of fingerprints. It is also characterized by a widespread, early-onset reticulate hyperpigmentation. Those affected may also have adermatoglyphia, abnormal epithelial differentiation, palmoplantar hyperkeratosis of the palms and soles, acral dorsal blistering, as well as hypohidrosis or hyperhidrosis.DPR is very similar to the related Naegeli-Franceschetti-Jadassohn syndrome (NFJS). Both cause an affected person to lack fingerprints, as well as present a lace-like pattern of hyperpigmentation and hyperkeratosis of the palms of the hands and soles of the feet. DPR is distinguished from NFJS by the duration of hyperpigmentation and lack of dental abnormalities. Since these differences are very slight and relatively minimal, researchers recommend that NFJS and DPR be considered a single disorder.
Molecular Genetics
The disease interval for DPR was found to harbor 230 genes associated with the condition. DPR and NFJS syndromes were specifically found to be differentiated from other syndromes by a mutation of the keratin 14 gene, located on chromosome 17q21.2. This was found when keratin genes KRT14, KRT16, and KRT17 were reassessed in 2006, revealing pathogenic mutations of KRT14 in all patients with NFJS/DPR, displaying a strong correlation and suggesting a potential causation. The type of mutations observed were heterozygous nonsense or frameshift mutations, meaning the function of the gene was completely disrupted (missense is correlated with EBS). The different phenotypic presentations of recessive (EBS-causing) versus dominant (NFJS/DPR-causing) premature truncation mutations in KRT14 are still unclear. The NFJS/DPR mutations were verified using two screening approaches, in which it was found that 17delG was absent from a panel of 100 control individuals, and C18X and Q7X were found to create a novel recognition site for the endonucleases DdeI and BfaI. Because the mutations were found to be heterozygous, the condition was concluded to be autosomal dominant in its inheritance pattern.Interestingly, a study conducted on five families using a two-point linkage analysis of the combined genotyping data for three families across the NFJS/DPR candidate region generated an LOD score of 6.2 at marker D17S800, with a recombination score of 0. Further analysis revealed that NFJS may be caused by an identical founder mutation located within a 6-Mb interval between D17S946 and D17S2180. This could potentially be of importance in genetically differentiating between NFJS and DPR.The disruption of the KRT14 gene in DPR suggests this gene is important during the early development of dermatoglyphics and sweat glands. Because of the aforementioned genetic similarity between NFJS and DPR, some researchers have suggested treating the disorders as a single condition.
Diagnosis
Diagnosis of DPR begins with review of a patients medical history, laboratory results, and clinical examination of symptoms. Biopsy and histopathological examination can be used to test for the presence of hyperkeratosis, parakeratosis, follicular plugging, and basal cell melanization, all indicators of DPR. Furthermore, abnormalities in skin pigmentation patterns as well as the presence of palmoplantar keratoderma with yellow tinting of the skin can indicate a possible case of DPR. Despite the presence of outward indicators, routine blood testing will not yield abnormal results.
While the aforementioned symptoms of DPR are outwardly identifiable, DPR is a rare genetic disease that requires genetic analysis to yield a confirmed diagnosis.The Genetic Testing Registry lists 15 clinical genetic tests used in obtaining a diagnosis of this disorder. Two of these tests utilize Targeted Variant Analysis, thirteen utilize sequence analysis of the entire coding region, and seven utilize deletion and duplication analysis. The type of test ordered may depend on the clinicians judgement or access to specific testing methods.
Management
To date, there is no medical treatment specific to DPR, however symptom management of palmoplantar hyperkeratosis as well as other, secondary symptoms is possible through the use of topical steroids, keratolytics, and emollients. Furthermore, cold compresses can be used to treat blistering.
Epidemiology
Since first being reported, only 12 cases of DPR have been described and diagnosed. Many studies and diagnoses have come from the same family, but a single case report was found in India. In a study conducted by Lugassy et al., the five families being studied were from geographically different places: one family, for example was Swiss, another was from the United States, and a third was from the United Kingdom.
See also
List of cutaneous conditions caused by mutations in keratins
References
== External links == |
Endolymphatic hydrops | Endolymphatic hydrops is a disorder of the inner ear. It consists of an excessive build-up of the endolymph fluid, which fills the hearing and balance structures of the inner ear. Endolymph fluid, which is partly regulated by the endolymph sac, flows through the inner ear and is critical to the function of all sensory cells in the inner ear. In addition to water, endolymph fluid contains salts such as sodium, potassium, chloride and other electrolytes. If the inner ear is damaged by disease or injury, the volume and composition of the endolymph fluid can change, causing the symptoms of endolymphatic hydrops.
Symptoms
The symptoms of endolymphatic hydrops include the feeling of pressure or fullness in the ears, hearing loss, tinnitus (ringing in the ears) and balance problems. Individuals who have Ménières disease have a degree of endolymphatic hydrops that is strong enough to trigger the symptoms of this disease, but individuals with endolymphatic hydrops do not always progress to Ménière’s disease.
Causes
Endolymphatic hydrops may occur as a result of trauma such as a blow to the head, infection, degeneration of the inner ear, allergies, dehydration and loss of electrolytes or in extremely rare circumstances a benign tumor such as an endolymphatic sac tumor. In many cases, it is not clear what causes the disorder. Ménière’s attacks occur when there is an increase in endolymphatic volume in the inner ear, causing a temporary leak in the membrane separating the perilymph (potassium poor fluid) and the endolymph (potassium rich fluid). The mix of these two fluids surrounding the vestibular sensory cells can lead to a temporary electrical blockade and loss of sensory function. The sudden change in the rate of the vestibular nerve firing results in a disturbance of signal processing in the corresponding brain regions, and thus to acute sensations of imbalance, otherwise known as vertigo.
Diagnosis
Treatment
Low salt, low sugar diet and keeping hydrated. Medications may include corticosteroids and/or diuretics.Caffeine should be avoided.
== References == |
Wrist osteoarthritis | Wrist osteoarthritis is a group of mechanical abnormalities resulting in joint destruction, which can occur in the wrist. These abnormalities include degeneration of cartilage and hypertrophic bone changes, which can lead to pain, swelling and loss of function. Osteoarthritis of the wrist is one of the most common conditions seen by hand surgeons.Osteoarthritis of the wrist can be idiopathic, but it is mostly seen as a post-traumatic condition. There are different types of post-traumatic osteoarthritis. Scapholunate advanced collapse (SLAC) is the most common form, followed by scaphoid non-union advanced collapse (SNAC). Other post-traumatic causes such as intra-articular fractures of the distal radius or ulna can also lead to wrist osteoarthritis, but are less common.
Types
SLAC and SNAC are two patterns of wrist osteoarthritis, following predictable patterns depending on the type of underlying injury. SLAC is caused by scapholunate ligament rupture, and SNAC is caused by a scaphoid fracture which does not heal and because of that will develop in a non-union fracture. SLAC is more common than SNAC; 55% of the patients with wrist osteoarthritis has a SLAC wrist.
SLAC
Scapholunate advanced collapse (SLAC) is a predictable pattern of wrist osteoarthritis that results from untreated long-standing scapholunate instability, which in turn is secondary to a rupture of the scapholunate ligament. The main type of such misalignment is dorsal intercalated segment instability (DISI) which is where the lunate angulates to the posterior side of the hand.
SNAC
Scaphoid non-union fractures changes scaphoid bone shape, which leads to abnormal joint kinematics. Due to lack of stability from the distorted scaphoid, a DISI can be developed.
Scaphoid Non-union Advanced collapse (SNAC) is the pattern of osteoarthritis that eventually develops by this process.
Stages
Post-traumatic osteoarthritis can be classified into four stages. These stages are similar between SLAC and SNAC wrists. Each stage has a different treatment.
Stage I: the osteoarthritis is only localized in the distal scaphoid and radial styloid.
Stage II: the osteoarthritis is localized in the entire radioscaphoid joint.
Stage III: the osteoarthritis is localized in the entire radioscaphoid joint with involvement of the capitolunate joint.
Stage IV: the osteoarthritis is located in the entire radiocarpal joint and in the intercarpal joints. It also may involve the distal radio-ulnar joint (DRUJ).
Signs and symptoms
The most common initial symptom of wrist osteoarthritis is joint pain. The pain is brought on by activity and increases when there is activity after resting. Other signs and symptoms, as with any joint affected by osteoarthritis, include:
Morning stiffness, which usually lasts less than 30 minutes. This is also present in patients with rheumatoid arthritis, but in those patients this typically lasts for more than 45 minutes.
Swelling of the wrist.
Crepitus (crackling), which is felt when the hand is moved passively.
Joint locking, where the joint is fixed in an extended position.
Joint instability.These symptoms can lead to loss of function and less daily activity.
Mechanism
In order to understand the cause of post-traumatic wrist osteoarthritis it is important to know and understand the anatomy of the wrist. The hand is subdivided into three parts:
Wrist
Metacarpus
DigitsThe wrist consists of eight small carpal bones. Each of these carpal bones has a different size and shape. They contribute towards the stability of the wrist and are ranked in two rows, each consisting of four bones.
Proximal row
From lateral to medial and when viewed from anterior, the proximal row is formed by the:
Scaphoid
Lunate
Triquetral
Pisiform
Distal row
From lateral to medial and when viewed from anterior, the distal row is formed by the:
Trapezium
Trapezoid
Capitate
Hamate
Diagnosis
Osteoarthritis of the wrist is predominantly a clinical diagnosis, and thus is primarily based on the patients medical history, physical examination and wrist X-rays.
Medical history
Medical history of the patient should include age, hand dominance, occupation and most important an evaluation of recent hand traumas.
Physical examination
Examination will often show tenderness at the radioscaphoid joint (when palpated or while moving the radioscaphoid joint), dorsal radial swelling and instability of the wrist joint. Notice that people may say they have trouble with rising from a chair when pressure is exerted on the hands by pushing against the handrail. Younger people may complain about not being able to do push-ups anymore because of a painful hand.
There are a number of tests and actions that can be performed when a patient is suspected of having osteoarthritis caused by SLAC or SNAC.SLAC:
Tenderness 1 cm above Lister’s tubercleTests:
Watsons test
Finger extension testSNAC:
Tenderness at the anatomical snuff box
Painful pronation and supination when performed against resistance
Pain during axial pressure
X-rays
Osteoarthritis between the radius bone and the carpals is indicated by a radiocarpal joint space of less than 2mm.SLAC
Because SLAC results from scapholunate ligament rupture, there is a larger space between the two bones, also known as the Terry Thomas sign. Osteoarthritis and a space larger than 3 mm is suspicious and a space larger than 5 mm is a proven SLAC pathology. Scaphoid instability due to the ligament rupture can be stactic or dynamic. When the X-ray is diagnostic and there is a convincing Terry Thomas sign it is a static scaphoid instability. When the scaphoid is made unstable by either the patient or by manipulation by the examining physician it is a dynamic instability.SNAC
In order to diagnose a SNAC wrist you need a PA view X-ray and a lateral view X-ray. As in SLAC, the lateral view X-ray is performed to see if there is a DISI.Computed tomography (CT) or Magnetic Resonance Imaging (MRI) are rarely used to diagnose SNAC or SLAC wrist osteoarthritis because there is no additional value. Also, these techniques are much more expensive than a standard X-ray. CT or MRI may be used if there is a strong suspicion for another underlying pathology or disease.
Treatment
Post-traumatic wrist osteoarthritis can be treated conservatively or with a surgical intervention. In many patients, a conservative (non-surgical) approach is sufficient. Because osteoarthritis is progressive and symptoms may get worse, surgical treatment is advised in any stage.
Stage I
For stage I, normally, nonsurgical treatment is sufficient. This type of therapy includes the use of splint or cast immobilization, injections of corticosteroid in the pain causing joints and the use of a systemic non-steroidal anti-inflammatory drug to reduce pain and improve the functional use of the affected joint. However, the amount of pain that can be suppressed by nonsurgical therapy is limited and with the progression of the wrist osteoarthritis surgical treatment is inevitable.In stage I surgical treatment often consists of neurectomy of the posterior interosseous nerve and is often combined with other procedures. In the case of a SLAC, the scapholunate ligament can be reconstructed in combination with a radial styloidectomy, in which the radial styloid is surgically removed from the distal radius. In the case of a SNAC, the scaphoid can be reconstructed by fixating the scaphoid with a screw or by placing a bone graft (Matti-Russe procedure) to increase the stability of the scaphoid.
Stage II
In the treatment of stage II wrist osteoarthritis, there are two treatment options that have proved to be most successful.
The first treatment option is proximal row carpectomy. During this surgical intervention the proximal row of the carpal bones is removed (scaphoid, lunate, triquetrum, pisiform). It is important that the radioscaphocapitate ligament is left intact, because if the ligament is not preserved the capitate bone will translate to the ulnar side of the wrist and move away from the distal radius. The new formed joint between the capitate and the lunate fossa of the distal radius is not as congruent as the former scaphoid-lunate-radius joint, however the results of proximal row carpectomy are generally excellent. In patients older than 40 years proximal row carpectomy is preferred because these patients have a small chance of developing osteoarthritis in the new formed capitate-radial joint during their remaining life.Patients younger than 40 years have a big chance to develop osteoarthritis in the radiocapitate joint. These patients have longer to live, therefore the incongruence of the joint will exist for a longer time. Thus, in this patient population four-corner arthrodesis is the treatment of first choice. The capitate, lunate, hamate and triquetrum are bounded together in this procedure and the scaphoid is excised. Before the arthrodesis is executed, the lunate must be reduced out of DISI position. Because the radiolunate joint is typically preserved in stage II SLAC and SNAC wrists, this joint can be the only remaining joint of the proximal wrist.
Both procedures are often combined with wrist denervation, as described in the text of treatment stage I.
Stage III
The only treatment option for stage III wrist osteoarthritis is four-corner arthrodesis, as described above in stage II. Proximal row carpectomy is not an option, because in stage III patients the capitate is already affected by the osteoarthritis. So, this procedure would merely lead to a new painful joint.
Stage IV
In this stage there are two surgical treatment options; total wrist arthroplasty and total wrist arthrodesis.
Total wrist arthrodesis has become the standard surgical treatment for patients with stage IV wrist osteoarthritis. During this procedure the carpal bones are all fused together and are then fastened to the distal radius. Patients who still want to undertake heavy labor benefit the most of this surgical approach, because after surgery and recovery this is still possible. However, the arc of motion is extremely diminished by this type of surgery.
The best option for those who wish for a motion-sparing procedure is total wrist arthroplasty. However, impact loading should be avoided, an object heavier than 4.5 kg should not be lifted. So, this surgical approach has postoperative activity restrictions. Nevertheless, patients with a total wrist arthrodesis on one side and a total wrist arthroplasty on the other, prefer the total wrist arthroplasty. The procedure exists of a couple of elements. First, the proximal row is removed and the distal row is fastened to the metacarpals. Then, one side of the arthroplasty is placed upon the distal row and the other side on the distal radius. Additionally, the head of the ulna is removed.
== References == |
Fabry disease | Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. The genetic mutation that causes Fabry disease interferes with the function of an enzyme that processes biomolecules known as sphingolipids, leading to these substances building up in the walls of blood vessels and other organs. It is inherited in an X-linked manner.
Fabry disease is sometimes diagnosed using a blood test that measures the activity of the affected enzyme called alpha-galactosidase, but genetic testing is also sometimes used, particularly in females.
The treatment for Fabry disease varies depending on the organs affected by the condition, and the underlying cause can be addressed by replacing the enzyme that is lacking.
The first descriptions of the condition were made simultaneously by dermatologist Johannes Fabry and the surgeon William Anderson in 1898.
Signs and symptoms
Symptoms are typically first experienced in early childhood and can be very difficult to diagnose; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses. Manifestations of the disease usually increase in number and severity as an individual ages.
Pain
Full-body or localized pain to the extremities (known as acroparesthesia) or gastrointestinal (GI) tract is common in patients with Fabry disease. This pain can increase over time. This acroparesthesia is believed to be related to the damage of peripheral nerve fibers that transmit pain. GI-tract pain is likely caused by accumulation of lipids in the small vasculature of the GI tract, which obstructs blood flow and causes pain.
Kidney
Kidney complications are common and serious effects of the disease; chronic kidney disease and kidney failure may worsen throughout life. The presence of protein in the urine (which causes foamy urine) is often the first sign of kidney involvement. End-stage kidney failure in those with Fabry disease typically occurs in the third decade of life, and is a common cause of death due to the disease.
Heart
Fabry disease can affect the heart in several ways. The accumulation of sphingolipids within heart muscle cells causes abnormal thickening of the heart muscle or hypertrophy. This hypertrophy can cause the heart muscle to become abnormally stiff and unable to relax, leading to a restrictive cardiomyopathy causing shortness of breath.Fabry disease can also affect the way in which the heart conducts electrical impulses, leading to both abnormally slow heart rhythms such as complete heart block, and abnormally rapid heart rhythms such as ventricular tachycardia. These abnormal heart rhythms can cause blackouts, palpitations, or even sudden cardiac death.Sphingolipids can also build up within the heart valves, thickening the valves and affecting the way they open and close. If severe, this can cause the valves to leak (regurgitation) or to restrict the forward flow of blood (stenosis). The aortic and mitral valves are more commonly affected than the valves on the right side of the heart.
Skin
Angiokeratomas (tiny, painless papules that can appear on any region of the body, but are predominant on the thighs, around the navel, buttocks, lower abdomen, and groin) are common.Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating).Additionally, patients can exhibit Raynauds disease-like symptoms with neuropathy (in particular, burning extremity pain).Ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy), i.e. clouding of the corneas. Keratopathy may be the presenting feature in asymptomatic patients, and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea). This clouding does not affect vision.Other ocular findings can include conjunctival and retinal vascular abnormalities and anterior/posterior spoke-like cataract. Visual reduction from these manifestations is uncommon.
Other manifestations
Fatigue, neuropathy (in particular, burning extremity pain, red hands and feet on and off), cerebrovascular effects leading to an increased risk of stroke - early strokes, mostly vertebrobasilar system tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical imbalances, and diarrhea are other common symptoms.
Causes
Fabry disease is caused by a DNA sequence (gene) that is not functioning as it should. A person who inherits this gene does not have enough of a functioning enzyme known as alpha-galactosidase A. The lack of alpha-galactosidase leads to Fabry disease. A deficiency of alpha galactosidase A (a-GAL A, encoded by GLA) due to mutation causes a glycolipid known as globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, other tissues, and organs. This accumulation leads to an impairment of their proper functions.At least 443 disease-causing mutations in the GLA gene have been discovered. The DNA mutations that cause the disease are X-linked recessive with incomplete penetrance in heterozygous females. The condition affects hemizygous males (i.e. all non-intersex males), as well as homozygous, and in many cases heterozygous females. While males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms. Research suggests many women experience severe symptoms ranging from early cataracts or strokes to hypertrophic left ventricular heart problems and kidney failure. This variability is thought to be due to X-inactivation patterns during embryonic development of the female.
Mechanism
Fabry disease is an inherited lysosomal storage disorder that is caused by a deficiency of alpha-galactosidase A. This enzyme deficiency is a result of an accumulation of glycosphingolipids found in the lysosomes and most cell types and tissues, which leads it to be considered a multisystem disease. Indications include painful crisis, angiokeratomas, corneal dystrophy, and hypohydrosis. In severe cases there is renal, cerebrovascular, and cardiac involvement and it is predominately responsible for premature mortality in Fabry patients. Fabry disease is X-linked and manifests mostly in homozygous males but also in heterozygous females. Cardiac involvement is recurrent in Fabry patients. Patients have developed hypertrophic cardiomyopathy, arrhythmias, conduction abnormalities, and valvular abnormalities. Deficient activity of lysosomal alpha-galactosidase results in progressive accumulation of globotriaosylceramide (GL-3) within lysosomes, that is believed to trigger a cascade of cellular events. The demonstration of marked alpha-galactosidase deficiency is the conclusive method for the diagnosis in homozygous males. It may be detected in heterozygotous females, but it is often inconclusive due to random X-chromosomal inactivation, so molecular testing (genotyping) of females is mandatory.
Diagnosis
Fabry disease is suspected based on the individuals clinical presentation, and can be diagnosed by an enzyme assay (usually done on leukocytes) to measure the level of alpha-galactosidase activity. An enzyme assay is not reliable for the diagnosis of disease in females due to the random nature of X-inactivation. Molecular genetic analysis of the GLA gene is the most accurate method of diagnosis in females, particularly if the mutations have already been identified in male family members. Many disease-causing mutations have been noted. Kidney biopsy may also be suggestive of Fabry disease if excessive lipid buildup is noted. Pediatricians, as well as internists, commonly misdiagnose Fabry disease. All immediate and extended family members in the same family have the same family mutation, so if one member of a family has a DNA sequence analysis performed, other members of the family can be diagnosed by performing a targeted sequence analysis instead of testing the entire gene. Targeted sequencing is quicker and less expensive to perform. One study reported that for every first diagnosis in a family, on average five more family members (immediate and extended) are also diagnosed.MRI is accurate in accessing left ventricular mass and thickness and hypertrophy. Late gadolinium enhancement shows increased signal of the midwall at the inferolateral wall of the base of the left ventricle, usually in the non-hypertrophic ventricle. T1-weighted imaging can show low T1 signal due to sphingolipid storage in the heart even without ventricular hypertrophy in 40% of the those affected by the disease. Thus, MRI is a useful way of diagnosing the disease early. T2 signal is increased in inflammation and oedema.
Treatment
The treatments available for Fabry disease can be divided into therapies that aim to correct the underlying problem of decreased activity of the alpha galactosidase A enzyme and thereby reduce the risk of organ damage, and therapies to improve symptoms and life expectancy once organ damage has already occurred.
Therapies targeting enzyme activity
Enzyme replacement therapy is designed to provide the enzyme the patient is missing as a result of a genetic malfunction. This treatment is not a cure, but can partially prevent disease progression, and potentially reverse some symptoms. As of March 2022, two medical drugs based on enzyme replacement therapy are available for Fabry disease:
Agalsidase alfa, sold under the brand name Replagal by the company Takeda (since its acquisition of the company Shire), is a recombinant form of alpha-galactosidase A It received approval in the EU in 2001. FDA approval was applied for the United States. However, Shire withdrew their application for approval in the United States in 2012, citing that the agency will require additional clinical trials before approval. As of March 2022, Replagal has not received FDA approval.
Agalsidase beta, sold under the brand name Fabrazyme by the company Sanofi Genzyme, is another recombinant form of alpha-galactosidase. Like replagal, it received approval in the EU in 2001. In 2003, it was the first treatment for Fabry disease to be approved by the FDA.Clinically, the two treatments are generally similar in effectiveness and safety, however they have never been compared directly in a randomized trial. Both are given by intravenous infusion every two weeks. They are available in Europe and in many other parts of the world, but treatment costs remain very high.Pharmacological chaperone therapy is another strategy to maintain enzyme activity. It does so by assisting correct folding of alpha-galactosidase despite the mutations that cause Fabry disease. As of March 2022, one medical drug based on pharmacological chaperone therapy is available for Fabry disease:
Migalastat, sold under the brand name Galafold by the company Amicus Therapeutics, is a pharmacological chaperone that can stabilize many mutant forms of alpha-galactosidase. It is taken by mouth. In a randomized trial comparing Migalastat with enzyme replacement therapy, the efficacy and safety of both treatments were similar. The US Food and Drug Administration (FDA) granted Galafold orphan drug status in 2004, and the European Commission followed in 2006. The European Medicines Agencys Committee for Medicinal Products for Human Use (CHMP) granted the drug a marketing approval under the name Galafold in May 2016. FDA approval followed in 2018.
Experimental therapies that are currently not approved for treatment as of March 2022 include the following:
A gene therapy treatment that is in early-phase clinical trials, with the technology licensed to AvroBio.
Plant-based ERT (pegunigalsidase alfa) under development by the company Protalix
The substrate reduction therapy Venglustat (Ibiglustat) under development by Sanofi-Genzyme
Bio-better ERT (CDX-6311) under pre-clinical development by the company Codexis
A gene therapy (ST-920) under development by the company Sangamo.
Organ-specific treatment
Pain associated with Fabry disease may be partially alleviated by enzyme replacement therapy in some patients, but pain management regimens may also include analgesics, anticonvulsants, and nonsteroidal anti-inflammatory drugs, though the latter are usually best avoided in kidney disease. The kidney failure seen in some of those with Fabry disease sometimes requires haemodialysis. The cardiac complications of Fabry disease include abnormal heart rhythms, which may require a pacemaker or implantable cardioverter-defibrillator, while the restrictive cardiomyopathy often seen may require diuretics.
Prognosis
Life expectancy with Fabry disease for males was 58.2 years, compared with 74.7 years in the general population, and for females 75.4 years compared with 80.0 years in the general population, according to registry data from 2001 to 2008. The most common cause of death was cardiovascular disease, and most of those had received kidney replacements.
Epidemiology
Fabry disease is panethnic, but due to its rarity, determining an accurate disease frequency is difficult. Reported incidences, ranging from one in 476,000 to one in 117,000 in the general population, may largely underestimate the true prevalence. Newborn screening initiatives have found an unexpectedly high prevalence of the disease, as high as one in about 3,100 newborns in Italy and have identified a surprisingly high frequency of newborn males around one in 1,500 in Taiwan.
Research
Enzyme replacement therapy: Replacement of the missing enzyme to clear the lipids (GL-3) from the cells
Substrate synthesis inhibition, also called substrate reduction therapy: Inhibits the production of the lipid (GL-3) that accumulates in the cells
Chaperone therapy: Uses small-molecule drugs that bind to the defective enzyme and stabilize it to increase enzyme activity and increase cellular function
Gene editing: Technology that can potentially cut and fix a broken gene in a cell
Gene therapy: Genetically modifies the affected cells to produce the missing enzyme.
History
Fabry disease was first described by dermatologist Johannes Fabry and surgeon William Anderson independently in 1898. It was recognised to be due to abnormal storage of lipids in 1952. In the 1960s, the inheritance pattern was established as being X-linked, as well as the molecular defect responsible for causing the accumulation of glycolipids.Ken Hashimoto published his classic paper on his electron microscopic findings in Fabry disease in 1965.The first specific treatment for Fabry disease was approved in 2001.
Society and culture
House ("Epic Fail", season six, episode three) centers on a patient with Fabry disease.
Scrubs ("My Catalyst", season three, episode 12) features a Fabry disease diagnosis.
Crossing Jordan ("Theres No Place Like Home", season two, episode one) features a patient who died from Fabry disease.
The Village (Korean drama): "Achiaras Secret" features daughters of a serial rapist who find each other because they share Fabry disease.
Doctor John (Korean drama): In episode two, a prisoner is diagnosed with Fabry disease.
In Lincoln Rhyme: Hunt for the Bone Collector, a copycat of the titular Bone Collector has Fabry disease and takes Galafold, which allows the detectives to learn his identity.
Partners for Justice 2 (Korean drama), features Doctor K, who had Fabry disease.
Doc (Italian drama): Series two features an episode with a tennis player who is diagnosed with Fabry disease
See also
Migalastat
References
Further reading
James, William D.; Berger, Timothy G.; Elston, Dirk (2006). Andrews Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6.
Schiffmann, Raphael; Kopp, Jeffrey B.; Austin, Howard A.; Sabnis, Sharda; Moore, David F.; Weibel, Thais; Balow, James E.; Brady, Roscoe O. (June 2001). "Enzyme replacement therapy in Fabry disease: a randomized controlled trial". JAMA. 285 (21): 2743–2749. doi:10.1001/jama.285.21.2743. PMID 11386930.
Wilcox, William R.; Banikazemi, Maryam; Guffon, Nathalie; Waldek, Stephen; Lee, Philip; Linthorst, Gabor E.; Desnick, Robert J.; Germain, Dominique P. (July 2004). "Long-term safety and efficacy of enzyme replacement therapy for Fabry disease". American Journal of Human Genetics. 75 (1): 65–74. doi:10.1086/422366. PMC 1182009. PMID 15154115.
External links
Fabry Disease Information Page at NINDS
Fabry disease at NLM Genetics Home Reference |
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