page_title
stringlengths 1
91
| page_text
stringlengths 0
34.2k
|
|---|---|
Hammer toe | A hammer toe or contracted toe is a deformity of the muscles and ligaments of the proximal interphalangeal joint of the second, third, fourth, or fifth toe causing it to be bent, resembling a hammer. In the early stage a flexible hammertoe is movable at the joints; a rigid hammertoe joint cannot be moved and usually requires surgery.Mallet toe is a similar condition affecting the distal interphalangeal joint.Claw toe is another similar condition, with dorsiflexion of the proximal phalanx on the lesser metatarsophalangeal joint, combined with flexion of both the proximal and distal interphalangeal joints. Claw toe can affect the second, third, fourth, or fifth toes.
Risk factors
Older people are more likely to develop hammer toes. Women are at higher risk, due to the construction of womens shoes. Injuries to the toes, and being born with a big toe that is short in comparison to the second toe, increase risk. Arthritis and diabetes may also increase the risk of foot deformities.
Causes
Hammertoes and clawtoes have multiple causes. Hammer toe most frequently results from wearing poorly fitting shoes that can force the toe into a bent position, such as high heels or shoes that are too short or narrow for the foot. Having the toes bent for long periods of time can cause the muscles in them to shorten, resulting in the hammer toe deformity. This is often found in conjunction with bunions or other foot problems (e.g., a bunion can force the big toe to turn inward and push the other toes).The toe muscles work in pairs; if the muscles pulling in one direction are much weaker than those pulling in the other direction, the imbalance can bend the toe. If the bend persists, then as the tendons and ligaments tighten (as they do if not stretched), the bend may become permanent. Ill-fitting shoes are especially likely to push the toes out of balance.Toe deformities can also be caused by muscle, nerve, or joint damage, resulting from conditions such as osteoarthritis, rheumatoid arthritis, stroke, Charcot–Marie–Tooth disease, complex regional pain syndrome or diabetes. Hammer toe can also be found in Friedreichs ataxia (GAA trinucleotide repeat).
Treatment
In many cases, conservative treatment consisting of physical therapy and new shoes with soft, spacious toe boxes is enough to resolve the condition, while in more severe or longstanding cases hammertoe surgery may be necessary to correct the deformity. The patients doctor may also prescribe some toe exercises that can be done at home to stretch and strengthen the muscles. For example, the individual can gently stretch the toes manually, or use the toes to pick things up off the floor.
References
External links
Hammer Toe – American Academy of Orthopedic Surgeons
Hammer Toes – American Podiatric Medical Association
Aetna Clinical Policy Bulletin: Hammertoe Repair Guidelines for surgical repair |
Hemeralopia | Hemeralopia (from Greek ημέρα hemera, "day", and αλαός alaos, "blindness") is the inability to see clearly in bright light and is the exact opposite of nyctalopia (night blindness), the inability to see clearly in low light. Hemera was the Greek goddess of day, and Nyx was the goddess of night. However, it has been used in an opposite sense by many non-English-speaking doctors. It can be described as insufficient adaptation to bright light. It is also called "heliophobia" and "day blindness".In hemeralopia, daytime vision gets worse, characterised by photoaversion (dislike/avoidance of light) rather than photophobia (eye discomfort/pain in light), which is typical of inflammations of eye. Nighttime vision largely remains unchanged due to the use of rods as opposed to cones (during the day), which are affected by hemeralopia and in turn degrade the daytime optical response. Hence, many patients feel they see better at dusk than in daytime.
Causes
Hemeralopia is known to occur in several ocular conditions. Cone dystrophy and achromatopsia, affecting the cones in the retina, and the anti-epileptic drug trimethadione are typical causes. Adies pupil, which fails to constrict in response to light; aniridia, which is absence of the iris; and albinism, where the iris is defectively pigmented, may also cause this. Central cataracts, due to the lens clouding, disperses the light before it can reach the retina and is a common cause of hemeralopia and photoaversion in the elderly. Cancer-associated retinopathy (CAR), seen when certain cancers incite the production of deleterious antibodies against retinal components, may cause hemeralopia.
Another known cause is a rare genetic condition called Cohen syndrome (aka Pepper syndrome). Cohen syndrome is mostly characterized by obesity, mental retardation and craniofacial dysmorphism due to genetic mutation at locus 8q22–23. Rarely, it may have ocular complications such as hemeralopia, pigmentary chorioretinitis, optic atrophy or retinal/iris coloboma, having a serious effect on the persons vision.
Yet another cause of hemeralopia is uni- or bilateral postchiasmatic brain injury. This may also cause concomitant nyctalopia.
Management
People with hemeralopia may benefit from sunglasses. Wherever possible, environmental illumination should be adjusted to comfortable level. Light-filtering lenses appear to help in people reporting photophobia.Otherwise, treatment relies on identifying and treating any underlying disorder.
See also
Adaptation (eye)
== References == |
Halogen acne | Halogen acne is caused by iodides, bromides and fluorides (halogens) that induce an acneiform eruption similar to that observed with steroids.
See also
Halogenoderma
List of cutaneous conditions
== References == |
Neurofibromatosis type I | Neurofibromatosis type I (NF-1) is a complex multi-system human disorder caused by the mutation of neurofibromin, a gene on chromosome 17 that is responsible for production of a protein which is needed for normal function in many human cell types. NF-1 causes tumors along the nervous system which can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any persons race or sex. NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy (or allele) of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1.As of 2015, there are at least 100,000 people in the U.S. and about 10,000 people in the UK who have been diagnosed with NF. Common symptoms of NF-1 include brownish-red spots in the colored part of the eye called Lisch nodules, benign skin tumors called neurofibromas, and larger benign tumors of nerves called plexiform neurofibromas, scoliosis (curvature of the spine), learning disabilities, vision disorders, mental disabilities, multiple café au lait spots and epilepsy. NF-1 affected individuals also have a much higher rate of cancer and cardiovascular disease than the population in general.NF-1 is a developmental syndrome caused by germline mutations in neurofibromin, a gene that is involved in the RAS pathway (RASopathy). Due to its rarity and to the fact that genetic diagnosis has been used only in recent years, in the past NF-1 was in some cases confused with Legius syndrome, another syndrome with vaguely similar symptoms, including cafe-au-lait spots.NF-1 is an age specific disease; most signs of NF-1 are visible after birth (during infancy), but many symptoms of NF-1 occur as the person ages and has hormonal changes. NF-1 was formerly known as von Recklinghausen disease, after the researcher (Friedrich Daniel von Recklinghausen) who first documented the disorder.The severity of NF-1 varies widely, and little is known about what causes a person to have a more severe or less severe case. Even within the same family (as there is a 50% chance that a parent will pass their condition to their offspring), levels of severity can vary enormously. However, 60% of people with NF-1 have mild cases, with few symptoms that have very little effect in their day-to-day lives. 20% of NF-1 patients have moderate cases, with several symptoms that have little more than cosmetic effects. The other 20% have severe cases with several symptoms that affect the persons quality of life. Even in this last group, symptoms are rarely life-threatening.
Signs and symptoms
The following is a list of conditions and complications associated with NF-1, and, where available, age range of onset and progressive development, occurrence percentage of NF-1 population, method of earliest diagnosis, and treatments and related medical specialties. The progression of the condition is roughly as follows:
Congenital musculoskeletal disorders may or may not be present
Cutaneous conditions may be observed in early infancy
Small tumors may arise in the retina which can eventually lead to blindness. Also, Lisch Nodules may grow on the iris, but these are harmless.
Learning disabilities may arise in preschool children
Neurofibromas may occur and can sometimes cause many dependent neurological conditions and cutaneous and skeletal disfigurement.
Depression and social anxiety may occur as a result of disabilities caused by the condition
Neurofibromas may, in 8-13% of cases, transition into cancer, which can be fatal The NF Clinical Program at St. Louis Childrens Hospital maintains a comprehensive list of current NF research studies Archived 2015-11-26 at the Wayback Machine.
Musculoskeletal disorder
Musculoskeletal abnormalities affecting the skull include sphenoid bone dysplasia, congenital hydrocephalus and associated neurologic impairment. These abnormalities are non-progressive and may be diagnosed in the fetus or at birth.Disorders affecting the spine include:
In NF-1, there can be a generalized abnormality of the soft tissues in the fetus, which is referred to as mesodermal dysplasia, resulting in maldevelopment of skeletal structures.
Meningoceles and formation of cystic diverticula of the dura of the spine, unrelated to Spina bifida
Radiographically, dural ectasia can lead to scalloping of the posterior vertebral bodies and to the formation of cystic diverticula of the dura of the spine. This may result in temporary or permanent loss of lower extremity sensorimotor function.
Focal scoliosis and/or kyphosis are the most common skeletal manifestation of NF-1, occurring in 20% of affected patients. Approximately 25% of patients will require corrective surgery.Skeletal muscle weakness and motor control deficits
Deficits in motor function in NF-1 have been long recognised and have been historically attributed to nerve dysfunction. In recent years however, studies suggest NF-1 is associated with a primary problem in muscle function (myopathy).Clinical findings in people with NF-1 include:
Reduced skeletal muscle size
Reduced exercise capacity
Muscle weakness (The most recent study reports between 30–50% reduced upper and lower limb muscle strength in NF-1 children compare with matched controls).Studies in genetically modified mice have thus far confirmed that the NF1 gene is vital for normal muscle development and metabolism. Knockout of the NF1 gene in muscle results in deregulated lipid metabolism and muscle weakness.NF-1 is a disease in the RASopathy family of diseases, which include Costello Syndrome, Noonan Syndrome, and Cardiofaciocutaneous syndrome. The RASopathies also present with skeletal muscle weakness. It is likely that impaired muscle function in these disorders is linked to altered Ras/MAPK signalling, however, the precise molecular mechanisms remain unknown.
Facial bones and limbs
Bowing of a long bone with a tendency to fracture and not heal, yielding a pseudarthrosis. The most common bone to be affected is the tibia, causing congenital pseudarthrosis of the tibia or CPT. CPT occurs in 2–4% of individuals with NF-1. Treatment includes limb amputation or correction by Ilizarov method as a limb-sparing technique.
Malformation of the facial bones or of the eye sockets (lambdoid suture defects, sphenoid dysplasia)
Unilateral overgrowth of a limb. When a plexiform neurofibroma manifests on a leg or arm, it will cause extra blood circulation, and may thus accelerate the growth of the limb. This may cause considerable difference in length between left and right limbs. To equalize the difference during childhood, there is an orthopedic surgery called epiphysiodesis, where growth at the epiphyseal (growth) plate is halted. It can be performed on one side of the bone to help correct an angular deformity, or on both sides to stop growth of that bone completely. The surgery must also be carefully planned with regard to timing, as it is non-reversible. The goal is that the limbs are at near-equal length at end of growth...
Skin
Flat pigmented lesions of the skin called café au lait spots, are hyper pigmented lesions that may vary in color from light brown to dark brown; this is reflected by the name of the condition, which means "coffee with milk". The borders may be smooth or irregular. These spots can grow from birth and can continue to grow throughout the persons lifetime. They can increase in size and numbers during puberty and during pregnancies. They are present in about 99% patient of European origin and in about 93% patient of Indian origin.
Freckling of the axillae or inguinal regions.
Dermal neurofibroma, manifested as single or multiple firm, rubbery bumps of varying sizes on a persons skin. Age of onset is puberty. Progressive in number and size. Not malignant. Can be treated with CO2 lasers or by removal by a plastic surgeon specialized in NF1.
Eye disease
Lisch nodules in the iris.
Optic nerve gliomas along one or both optic nerves or the optic chiasm can cause bulging of the eyes, involuntary eye movement, squinting, and / or vision loss. Treatment may include surgery, radiation +/- steroids, or chemotherapy (in children).
Neurobehavioral developmental disorder
The most common complication in patients with NF-1 is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 90% of children and adults with NF-1 and have significant effects on their schooling and everyday life. These cognitive problems have been shown to be stable into adulthood mainly in the mid 20s to early 30s and do not get worse unlike some of the other physical symptoms of NF-1. The most common cognitive problems are with perception, executive functioning and attention. Disorders include:
Approximately 42% of children with NF-1 have symptoms of autism, with 36.78% of them being severe cases, 33.33% being mild to moderate cases, and 29.89% of them having both symptoms of autism and ADHD.
Attention deficit hyperactivity disorder has been shown to be present in approximately 40% of children with NF-1.
Speech and language delays have also been identified in approximately 68% of preschool children with NF-1.
Motor deficits are common. Motor deficits due to NF-1 are probably not cerebellar.
Spatial deficit. Lovastatin, normally used to treat hypercholesterolemia, is currently in phase one of clinical trial (NCT00352599). This drug has been shown to reverse spatial deficits in mice. Simvastatin, a drug similar to lovastatin, did not show benefit on cognitive function or behaviour in two randomized controlled trials in children with NF-1.
Nervous system disease
The primary neurologic involvement in NF-1 is of the peripheral nervous system, and secondarily of the central nervous system. Schwannomatosis is a rare condition defined by the presence of multiple benign tumors of nerves that are frequently very painful. In addition to pain, weakness is a common problem. Symptoms usually begin in young or mid-adult years.
Peripheral neuropathy
Neurofibroma
A neurofibroma is a lesion of the peripheral nervous system. Its cellular lineage is uncertain, and may derive from Schwann cells, other perineural cell lines, or fibroblasts. Neurofibromas may arise sporadically, or in association with NF-1. A neurofibroma may arise at any point along a peripheral nerve. A number of drugs have been studied to treat this condition.Neurofibroma conditions are progressive and include:
Plexiform neurofibroma: Often congenital. Lesions are composed of sheets of neurofibromatous tissue that may infiltrate and encase major nerves, blood vessels, and other vital structures. These lesions are difficult and sometimes impossible to routinely resect without causing any significant damage to surrounding nerves and tissue. However, early intervention may be beneficial: a 2004 study in Germany concluded "Early surgical intervention of small superficial PNFs is uncomplicated, without burden for even the youngsters and enables total resection of the tumors. It may be considered as a preventive strategy for later disfigurement and functional deficits."
Solitary neurofibroma, affecting 8–12% of patients with NF-1. This occurs in a deep nerve trunk. Diagnosis by cross-sectional imaging (e.g., computed tomography or magnetic resonance) as a fusiform enlargement of a nerve.
Schwannomas, peripheral nerve-sheath tumors which are seen with increased frequency in NF-1. The major distinction between a schwannoma and a solitary neurofibroma is that a schwannoma can be resected while sparing the underlying nerve, whereas resection of a neurofibroma requires the sacrifice of the underlying nerve.
Nerve root neurofibroma.
Bones, especially the ribs, can develop chronic erosions (pits) from the constant pressure of adjacent neurofibroma or Schwannoma. Similarly, the neural foramen of the spine can be widened due to the presence of a nerve root neurofibroma or schwannoma. Surgery may be needed when NF-1 related tumors compress organs or other structures.
Nerve sheath tumor
Chronic pain, numbness, and/or paralysis due to peripheral nerve sheath tumor.
Other complications
Renal artery anomalies or pheochromocytoma and associated chronic hypertension
Schwannoma
Plexiform fibromas
Optic nerve glioma
Epilepsy
Central nervous system disease
Epilepsy
Occurrence. Epileptic seizures have been reported in up to 7% of NF-1 patients.
Diagnosis. Electroencephalograph, magnetic resonance imaging, computed tomographic scan, single-photon emission CT and positron emission tomographic scan.
Etiology. Due to cerebral tumors, cortical malformation, mesial temporal sclerosis.
Therapy. Drug therapy (57% amenable) where not resistant (29%).
Glial tumors
Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily:
Optic nerve gliomas and associated blindness.
Astrocytoma
Focally degenerative myelin
Another CNS manifestation of NF-1 is the so-called "unidentified bright object" or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a magnetic resonance imaging examination of the brain. These UBOs are typically found in the Cerebral peduncle, pons, midbrain, globus pallidus, thalamus, and optic radiations. Their exact identity remains a bit of a mystery since they disappear over time (usually, by age 16), and they are not typically biopsied or resected. They may represent a focally degenerative bit of myelin.
Dural ectasia
Within the CNS, NF-1 manifests as a weakness of the dura, which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement due to chronic exposure to the pressures of CSF pulsation, and typically presents as paraesthesia or loss of motor or sensory function. It has been shown that dural ectasia occur near plexiform neurofibromas which may be infiltrative leading to weakening of the dura.Acetazolamide has shown promise as a treatment for this condition, and in very few cases do dural ectasia require surgery.
Mental disorder
Children and adults with NF-1 can experience social problems, attention problems, social anxiety, depression, withdrawal, thought problems, somatic complaints, learning disabilities and aggressive behavior. Treatments include psychotherapy, antidepressants and cognitive behavioral therapy.
Puberty and height
Children diagnosed with NF-1 may experience delayed or precocious puberty. Recent studies have correlated precocious puberty in individuals with NF-1 with the presence of optic pathway tumors. Furthermore, the heights of children affected by NF-1 have been shown to increase normally until puberty, after which increases in height lessen when compared to healthy counterparts. This eventually causes a shorter stature than expected in individuals with NF-1.
Cancer
Cancer can arise in the form of malignant peripheral nerve sheath tumor resulting from malignant degeneration of a plexiform neurofibroma.
Frequency. A plexiform neurofibroma has a lifetime risk of 8–12% of transformation into a malignant tumor.
Diagnosis. MRI.
Treatment. Surgery (primary), radiation therapy.
Mortality. Malignant nerve sheath tumor was the main cause of death (60%) in a study of 1895 patients with NF-1 from France in the time period 1980–2006 indicated excess mortality in NF-1 patients compared to the general population. The cause of death was available for 58 (86.6%) patients. The study found excess mortality occurred among patients aged 10 to 40 years. Significant excess mortality was found in both males and females.
Cause
Neurofibromin 1 gene
NF-1 is a microdeletion syndrome caused by a mutation of a gene located on chromosomal segment 17q11.2 on the long arm of chromosome 17 which encodes a protein known as neurofibromin (not to be confused with the disorder itself) which plays a role in cell signaling. The Neurofibromin 1 gene is a negative regulator of the Ras oncogene signal transduction pathway. It stimulates the GTPase activity of Ras. It shows greater affinity for RAS p21 protein activator 1, but lower specific activity. The mRNA for this gene is subject to RNA editing (CGA->UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene.In 1989, through linkage and cross over analyses, neurofibromin was localized to chromosome 17. It was localized to the long arm of chromosome 17 by chance when researchers discovered chromosome exchanges between chromosome 17 with chromosome 1 and 22. This exchange of genetic material presumably caused a mutation in the neurofibromin gene, leading to the NF1 phenotype. Two recurrent microdeletion types with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion), are found in most cases.
Structure
The neurofibromin gene was soon sequenced and found to be 350,000 base pairs in length. However, the protein is 2818 amino acids long leading to the concept of splice variants. For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively.Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase activating protein (GAP) family. This homologous sequence is in the central portion of neurofibromin and being similar to the GAP family is recognized as a negative regulator of the Ras kinase.Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase, and a second with collapsin response mediator protein. Together, likely with domains yet to be discovered, neurofibromin regulates many of the pathways responsible for overactive cell proliferation, learning impairments, skeletal defects and plays a role in neuronal development.
Inheritance and spontaneous mutation
The mutant gene is transmitted with an autosomal dominant pattern of inheritance, but up to 50% of NF-1 cases arise due to spontaneous mutation. The incidence of NF-1 is about 1 in 3500 live births.
Related medical conditions
Mutations in the NF1 gene have been linked to NF-1, juvenile myelomonocytic leukemia and Watson syndrome. A condition with a separate gene mutation but similar Café au lait spots is Legius syndrome, which has a mutation on the SPRED1 gene.
Diagnosis
Prenatal testing and prenatal expectations
Prenatal testing may be used to identify the existence of NF-1 in the fetus. For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis to screen for NF-1.Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus.While the presence of NF-1 can be identified through prenatal testing the severity with which the condition will be expressed is impossible to determine.People with NF-1 have a 50% percent chance of passing the disorder on to their kids, but people can have a child born with NF-1 when they themselves do not have it. This is caused in a spontaneous change in the genes during pregnancy.
Post-natal testing
The National Institutes of Health (NIH) has created specific criteria for the diagnosis of NF-1. Two of these seven "Cardinal Clinical Features" are required for positive diagnosis. There is practical flowchart to distinguish between NF1, NF2 and schwannomatosis.
Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals. Note that multiple café-au-lait spots alone are not a definitive diagnosis of NF-1 as these spots can be caused by a number of other conditions.
Two or more neurofibromas of any type or 1 plexiform neurofibroma
Freckling in the axillary (Crowe sign) or inguinal regions
Optic nerve glioma
Two or more Lisch nodules (pigmented iris hamartomas)
A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
A first degree relative (parent, sibling, or offspring) with NF-1 by the above criteria.
Treatment
Selumetinib, sold under the brand name Koselugo, is a drug approved by FDA in April 2020 for the treatment of NF-1 in pediatric population who are two or more years of age. It is a kinase inhibitor and is indicated for use pediatric patients who are symptomatic and have plexiform neurofibromas which cannot be operated.There is no cure for the disorder itself. Instead, people with neurofibromatosis are followed by a team of specialists to manage symptoms or complications. In progress and recently concluded medical studies on NF-1 can be found by searching the official website of the National Institutes of Health.
Prognosis
NF-1 is a progressive and diverse condition, making the prognosis difficult to predict. The NF-1 gene mutations manifest the disorder differently even amongst people of the same family. This phenomenon is called variable expressivity. For example, some individuals have no symptoms, while others may have a manifestation that is rapidly more progressive and severe.
For many NF-1 patients, a primary concern is the disfigurement caused by cutaneous/dermal neurofibromas, pigmented lesions, and the occasional limb abnormalities. However, there are many more severe complications caused by NF-1 like increased cancer risk, a plexiform neurofibroma has a 10-15% chance of developing into a MPNST (Malignant Peripheral Nerve Sheath Tumour) . Many NF patients live perfectly normal and uninterrupted lives.
Epidemiology
NF-1 is estimated to affect around 25,000 people in the UK.
See also
Neurofibromatosis type II
References
External links
Friedman, J. M. (1993). "Neurofibromatosis 1". GeneReviews®. University of Washington, Seattle. PMID 20301288.
Legius, Eric; Stevenson, David (1993). "Legius Syndrome". GeneReviews®. University of Washington, Seattle. PMID 20945555. |
Nitrogen narcosis | Narcosis while diving (also known as nitrogen narcosis, inert gas narcosis, raptures of the deep, Martini effect) is a reversible alteration in consciousness that occurs while diving at depth. It is caused by the anesthetic effect of certain gases at high pressure. The Greek word νάρκωσις (narkōsis), "the act of making numb", is derived from νάρκη (narkē), "numbness, torpor", a term used by Homer and Hippocrates. Narcosis produces a state similar to drunkenness (alcohol intoxication), or nitrous oxide inhalation. It can occur during shallow dives, but does not usually become noticeable at depths less than 30 meters (100 ft).
Except for helium and probably neon, all gases that can be breathed have a narcotic effect, although widely varying in degree. The effect is consistently greater for gases with a higher lipid solubility, and although the mechanism of this phenomenon is still not fully clear, there is good evidence that the two properties are mechanistically related. As depth increases, the mental impairment may become hazardous. Divers can learn to cope with some of the effects of narcosis, but it is impossible to develop a tolerance. Narcosis can affect all divers, although susceptibility varies widely among individuals and from dive to dive. The main class of diving that deals with its prevention and treatment is scuba diving at substantial depth.
Narcosis may be completely reversed in a few minutes by ascending to a shallower depth, with no long-term effects. Thus narcosis while diving in open water rarely develops into a serious problem as long as the divers are aware of its symptoms, and are able to ascend to manage it. Diving much beyond 40 m (130 ft) is generally considered outside the scope of recreational diving. In order to dive at greater depths, as narcosis and oxygen toxicity become critical risk factors, specialist training is required in the use of various helium-containing gas mixtures such as trimix or heliox. These mixtures prevent narcosis by replacing some or all of the inert fraction of the breathing gas with non-narcotic helium.
Classification
Narcosis results from breathing gases under elevated pressure, and may be classified by the principal gas involved. The noble gases, except helium and probably neon, as well as nitrogen, oxygen and hydrogen cause a decrement in mental function, but their effect on psychomotor function (processes affecting the coordination of sensory or cognitive processes and motor activity) varies widely. The effect of carbon dioxide is a consistent diminution of mental and psychomotor function. The noble gases argon, krypton, and xenon are more narcotic than nitrogen at a given pressure, and xenon has so much anesthetic activity that it is a usable anesthetic at 80% concentration and normal atmospheric pressure. Xenon has historically been too expensive to be used very much in practice, but it has been successfully used for surgical operations, and xenon anesthesia systems are still being proposed and designed.
Signs and symptoms
Due to its perception-altering effects, the onset of narcosis may be hard to recognize. At its most benign, narcosis results in relief of anxiety – a feeling of tranquillity and mastery of the environment. These effects are essentially identical to various concentrations of nitrous oxide. They also resemble (though not as closely) the effects of alcohol and the familiar benzodiazepine drugs such as diazepam and alprazolam. Such effects are not harmful unless they cause some immediate danger to go unrecognized and unaddressed. Once stabilized, the effects generally remain the same at a given depth, only worsening if the diver ventures deeper.The most dangerous aspects of narcosis are the impairment of judgement, multi-tasking and coordination, and the loss of decision-making ability and focus. Other effects include vertigo and visual or auditory disturbances. The syndrome may cause exhilaration, giddiness, extreme anxiety, depression, or paranoia, depending on the individual diver and the divers medical or personal history. When more serious, the diver may feel overconfident, disregarding normal safe diving practices. Slowed mental activity, as indicated by increased reaction time and increased errors in cognitive function, are effects which increase the risk of a diver mismanaging an incident. Narcosis reduces both the perception of cold discomfort and shivering and thereby affects the production of body heat and consequently allows a faster drop in the core temperature in cold water, with reduced awareness of the developing problem.The relation of depth to narcosis is sometimes informally known as "Martinis law", the idea that narcosis results in the feeling of one martini for every 10 m (33 ft) below 20 m (66 ft) depth. Professional divers use such a calculation only as a rough guide to give new divers a metaphor, comparing a situation they may be more familiar with.Reported signs and symptoms are summarized against typical depths in meters and feet of sea water in the following table, closely adapted from Deeper into Diving by Lippman and Mitchell:
Causes
The cause of narcosis is related to the increased solubility of gases in body tissues, as a result of the elevated pressures at depth (Henrys law). Modern theories have suggested that inert gases dissolving in the lipid bilayer of cell membranes cause narcosis. More recently, researchers have been looking at neurotransmitter receptor protein mechanisms as a possible cause of narcosis. The breathing gas mix entering the divers lungs will have the same pressure as the surrounding water, known as the ambient pressure. After any change of depth, the pressure of gases in the blood passing through the brain catches up with ambient pressure within a minute or two, which results in a delayed narcotic effect after descending to a new depth. Rapid compression potentiates narcosis owing to carbon dioxide retention.A divers cognition may be affected on dives as shallow as 10 m (33 ft), but the changes are not usually noticeable. There is no reliable method to predict the depth at which narcosis becomes noticeable, or the severity of the effect on an individual diver, as it may vary from dive to dive even on the same day.Significant impairment due to narcosis is an increasing risk below depths of about 30 m (100 ft), corresponding to an ambient pressure of about 4 bar (400 kPa). Most sport scuba training organizations recommend depths of no more than 40 m (130 ft) because of the risk of narcosis. When breathing air at depths of 90 m (300 ft) – an ambient pressure of about 10 bar (1,000 kPa) – narcosis in most divers leads to hallucinations, loss of memory, and unconsciousness. A number of divers have died in attempts to set air depth records below 120 m (400 ft). Because of these incidents, Guinness World Records no longer reports on this figure.Narcosis has been compared with altitude sickness regarding its variability of onset (though not its symptoms); its effects depend on many factors, with variations between individuals. Thermal cold, stress, heavy work, fatigue, and carbon dioxide retention all increase the risk and severity of narcosis. Carbon dioxide has a high narcotic potential and also causes increased blood flow to the brain, increasing the effects of other gases. Increased risk of narcosis results from increasing the amount of carbon dioxide retained through heavy exercise, shallow or skip breathing, or because of poor gas exchange in the lungs.Narcosis is known to be additive to even minimal alcohol intoxication. Other sedative and analgesic drugs, such as opiate narcotics and benzodiazepines, add to narcosis.
Mechanism
The precise mechanism is not well understood, but it appears to be the direct effect of gas dissolving into nerve membranes and causing temporary disruption in nerve transmissions. While the effect was first observed with air, other gases including argon, krypton and hydrogen cause very similar effects at higher than atmospheric pressure. Some of these effects may be due to antagonism at NMDA receptors and potentiation of GABAA receptors, similar to the mechanism of nonpolar anesthetics such diethyl ether or ethylene. However, their reproduction by the very chemically inactive gas argon makes them unlikely to be a strictly chemical bonding to receptors in the usual sense of a chemical bond. An indirect physical effect – such as a change in membrane volume – would therefore be needed to affect the ligand-gated ion channels of nerve cells. Trudell et al. have suggested non-chemical binding due to the attractive van der Waals force between proteins and inert gases.Similar to the mechanism of ethanols effect, the increase of gas dissolved in nerve cell membranes may cause altered ion permeability properties of the neural cells lipid bilayers. The partial pressure of a gas required to cause a measured degree of impairment correlates well with the lipid solubility of the gas: the greater the solubility, the less partial pressure is needed.An early theory, the Meyer-Overton hypothesis, suggested that narcosis happens when the gas penetrates the lipids of the brains nerve cells, causing direct mechanical interference with the transmission of signals from one nerve cell to another. More recently, specific types of chemically gated receptors in nerve cells have been identified as being involved with anesthesia and narcosis. However, the basic and most general underlying idea, that nerve transmission is altered in many diffuse areas of the brain as a result of gas molecules dissolved in the nerve cells fatty membranes, remains largely unchallenged.
Management and diagnosis
The management of narcosis is simply to ascend to shallower depths; the effects then disappear within minutes. In the event of complications or other conditions being present, ascending is always the correct initial response. Should problems remain, then it is necessary to abort the dive. The decompression schedule can still be followed unless other conditions require emergency assistance.The symptoms of narcosis may be caused by other factors during a dive: ear problems causing disorientation or nausea; early signs of oxygen toxicity causing visual disturbances; or hypothermia causing rapid breathing and shivering. Nevertheless, the presence of any of these symptoms should imply narcosis. Alleviation of the effects upon ascending to a shallower depth will confirm the diagnosis. Given the setting, other likely conditions do not produce reversible effects. In the rare event of misdiagnosis when another condition is causing the symptoms, the initial management – ascending closer to the surface – is still essential.
Prevention
The most straightforward way to avoid nitrogen narcosis is for a diver to limit the depth of dives. The other main preventive measure is properly informed selection/choice of which gas to use for the particular dive under consideration.
Since narcosis becomes more severe as depth increases, a diver keeping to shallower depths can avoid serious narcosis. Most recreational dive schools will only certify entry level divers to depths of 18 to 20 m (60 to 70 ft), and at these depths narcosis does not present a significant risk. Further training is normally required for certification up to 30 m (100 ft) on air, and this training should include a discussion of narcosis, its effects, and management. Some diver training agencies offer specialized training to prepare recreational divers to go to depths of 40 m (130 ft), often consisting of further theory and some practice in deep dives under close supervision. Scuba organizations that train for diving beyond recreational depths, may forbid diving with gases that cause too much narcosis at depth in the average diver (such as the typical widely used nitrox mixtures suitable for most recreational diving), and strongly encourage the use of other breathing gas mixes containing helium in place of some or all of the nitrogen in air – such as trimix and heliox – because helium has no narcotic effect. The use of these gases forms part of technical diving and requires further training and certification.While the individual diver cannot predict exactly at what depth the onset of narcosis will occur on a given day, the first symptoms of narcosis for any given diver are often more predictable and personal. For example, one diver may have trouble with eye focus (close accommodation for middle-aged divers), another may experience feelings of euphoria, and another feelings of claustrophobia. Some divers report that they have hearing changes, and that the sound their exhaled bubbles make becomes different. Specialist training may help divers to identify these personal onset signs, which may then be used as a signal to ascend to avoid the narcosis, although severe narcosis may interfere with the judgement necessary to take preventive action.Deep dives should be made only after a gradual training to test the individual divers sensitivity to increasing depths, with careful supervision and logging of reactions. Scientific evidence does not show that a diver can train to overcome any measure of narcosis at a given depth or become tolerant of it.Equivalent narcotic depth (END) is a commonly used way of expressing the narcotic effect of different breathing gases. The National Oceanic and Atmospheric Administration (NOAA) Diving Manual now states that oxygen and nitrogen should be considered equally narcotic. Standard tables, based on relative lipid solubilities, list conversion factors for narcotic effect of other gases. For example, hydrogen at a given pressure has a narcotic effect equivalent to nitrogen at 0.55 times that pressure, so in principle it should be usable at more than twice the depth. Argon, however, has 2.33 times the narcotic effect of nitrogen, and is a poor choice as a breathing gas for diving (it is used as a drysuit inflation gas, owing to its low thermal conductivity). Some gases have other dangerous effects when breathed at pressure; for example, high-pressure oxygen can lead to oxygen toxicity. Although helium is the least intoxicating of the breathing gases, at greater depths it can cause high pressure nervous syndrome, a still mysterious but apparently unrelated phenomenon. Inert gas narcosis is only one factor influencing the choice of gas mixture; the risks of decompression sickness and oxygen toxicity, cost, and other factors are also important.Because of similar and additive effects, divers should avoid sedating medications and drugs, such as cannabis and alcohol before any dive. A hangover, combined with the reduced physical capacity that goes with it, makes nitrogen narcosis more likely. Experts recommend total abstinence from alcohol for at least 12 hours before diving, and longer for other drugs.
Prognosis and epidemiology
Narcosis is potentially one of the most dangerous conditions to affect the scuba diver below about 30 m (100 ft). Except for occasional amnesia of events at depth, the effects of narcosis are entirely removed on ascent and therefore pose no problem in themselves, even for repeated, chronic or acute exposure. Nevertheless, the severity of narcosis is unpredictable and it can be fatal while diving, as the result of illogical behavior in a dangerous environment.Tests have shown that all divers are affected by nitrogen narcosis, though some experience lesser effects than others. Even though it is possible that some divers can manage better than others because of learning to cope with the subjective impairment, the underlying behavioral effects remain. These effects are particularly dangerous because a diver may feel they are not experiencing narcosis, yet still be affected by it.
History
French researcher Victor T. Junod was the first to describe symptoms of narcosis in 1834, noting "the functions of the brain are activated, imagination is lively, thoughts have a peculiar charm and, in some persons, symptoms of intoxication are present." Junod suggested that narcosis resulted from pressure causing increased blood flow and hence stimulating nerve centers. Walter Moxon (1836–1886), a prominent Victorian physician, hypothesized in 1881 that pressure forced blood to inaccessible parts of the body and the stagnant blood then resulted in emotional changes. The first report of anesthetic potency being related to lipid solubility was published by Hans H. Meyer in 1899, entitled Zur Theorie der Alkoholnarkose. Two years later a similar theory was published independently by Charles Ernest Overton. What became known as the Meyer-Overton hypothesis may be illustrated by a graph comparing narcotic potency with solubility in oil.
In 1939, Albert R. Behnke and O. D. Yarborough demonstrated that gases other than nitrogen also could cause narcosis. For an inert gas the narcotic potency was found to be proportional to its lipid solubility. As hydrogen has only 0.55 the solubility of nitrogen, deep diving experiments using hydrox were conducted by Arne Zetterström between 1943 and 1945. Jacques-Yves Cousteau in 1953 famously described it as "livresse des grandes profondeurs" or the "rapture of the deep".Further research into the possible mechanisms of narcosis by anesthetic action led to the "minimum alveolar concentration" concept in 1965. This measures the relative concentration of different gases required to prevent motor response in 50% of subjects in response to stimulus, and shows similar results for anesthetic potency as the measurements of lipid solubility. The (NOAA) Diving Manual was revised to recommend treating oxygen as if it were as narcotic as nitrogen, following research by Christian J. Lambertsen et al. in 1977 and 1978.
See also
Hydrogen narcosis – Psychotropic state induced by breathing hydrogen at high partial pressures
Oxygen toxicity – Toxic effects of breathing oxygen at high concentrations
Footnotes
References
Notes
Sources
Bennett, Peter; Rostain, Jean Claude (2003). "Inert Gas Narcosis". In Brubakk, Alf O; Neuman, Tom S (eds.). Bennett and Elliotts physiology and medicine of diving (5th ed.). United States: Saunders. ISBN 0-7020-2571-2. OCLC 51607923.
Lippmann, John; Mitchell, Simon J. (2005). "Nitrogen narcosis". Deeper into Diving (2nd ed.). Victoria, Australia: J. L. Publications. pp. 103–8. ISBN 0-9752290-1-X. OCLC 66524750.
U.S. Navy Supervisor of Diving (2008). U.S. Navy Diving Manual (PDF). SS521-AG-PRO-010, revision 6. U.S. Naval Sea Systems Command. Archived from the original (PDF) on 2014-12-10. Retrieved 2014-01-21.
External links
Undersea and Hyperbaric Medical Society Scientific body, publications about nitrogen narcosis.
Rubicon Research Repository Searchable repository of Diving and Environmental Physiology Research.
Diving Diseases Research Centre (DDRC) UK charity dedicated to treatment of diving diseases.
Campbell, Ernest S. (2009-06-25). "Diving While Using Marijuana". Retrieved 2009-08-25. ScubaDocs overview of marijuana and diving.
Campbell, Ernest S. (2009-05-03). "Alcohol and Diving". Archived from the original on 2007-04-30. Retrieved 2009-08-25. ScubaDocs overview of alcohol and diving.
Campbell, George D. (2009-02-01). "Nitrogen Narcosis". Diving with Deep-Six. Retrieved 2009-08-25. |
B-cell prolymphocytic leukemia | B-cell prolymphocytic leukemia, referred to as B-PLL, is a rare blood cancer. It is a more aggressive, but still treatable, form of leukemia.
Specifically, B-PLL is a prolymphocytic leukemia (PLL) that affects prolymphocytes – immature forms of B-lymphocytes and T-lymphocytes – in the peripheral blood, bone marrow, and spleen. It is an aggressive cancer that presents poor response to treatment.Mature lymphocytes are infection-fighting immune system cells. B-lymphocytes have two responsibilities:
Production of antibodies – In response to antigens, B-lymphocytes produce and release antibodies specific to foreign substances in order to aid in their identification and elimination phagocytes
Generation of memory cells – Interactions between antibodies and antigens allow B-lymphocytes to establish cellular memories, otherwise known as immunities that allow the body to respond more rapidly and efficiently to previously encountered species
Classification
It is categorized as a lymphoproliferative disorder due to the excessive production of lymphocytes, in B-PLL there is excess production of B-prolymphocytes by the bone marrow. These immature lymphocytes are not normally found in the blood; part of their maturation process is being programmed to produce antibodies against foreign material prior to their departure from the bone marrow. In B-PLL, malignant B-prolymphocytes disrupt the adaptive capabilities of the immune system due to the lack of mature B-lymphocytes.It has been suggested that some cases may represent a variant of mantle cell lymphoma.
Signs and symptoms
This type of leukemia is characterized by:
More than 55% of circulating cells in peripheral blood (red blood cells, white blood cells and platelets collectively) are prolymphocytes. Generally, prolymphocyte proportion exceeds 90%
Minimal or absence of lymphadenopathy – abnormalities in size, number or consistency of lymph nodes
Splenomegaly - Abnormal enlargement of the spleen
High white blood cell count
B-symptoms – Fever, night sweats and/or weight lossSimilar to other leukemias, B-cell prolymphocytic leukemia is often asymptomatic. The most common signs and symptoms are the result of the inability of the bone marrow to produce normal levels of blood cells:
Anaemia – due to lack of red blood cells
More frequent, severe and prolonged infections – due to lack of normal white blood cells
Bleeding and bruising – due to lack of platelets
Diagnosis
Diagnosis of B-PLL is difficult due to its considerable overlap with other mature B-cell leukemias and lymphomas. It requires integration of morphology with diagnostic tests including immunophenotyping and chromosome analysis (cytogenetics).
Morphology
The malignant B cells are larger than average.
In order to diagnose a patient with B-PLL, b-prolymphocyte composition of a patients blood cells must exceed 55%. High white blood cell counts – greater than 100 x 109/L – are also indicative of B-PLL. B-prolymphocytes are characterized by:
Large size – approximately twice the size of a normal small lymphocyte
Round or oval-shaped nuclei
Single prominent nucleolus
Moderately condensed nuclear chromatin
High nuclear-cytoplasmic ratio – indicates more abundant cytoplasm
Immunophenotype
This technique is used to study proteins expressed in cells using immunologic markers. In B-PLL patients there is strong expression of surface immunoglobulin – a membrane-bound form of an antibody, b-lymphocyte surface antigens CD19, CD20, CD22, CD79a and FMC7, and weak expression of CD5 and CD23. Due to the similarities among lymphoproliferative disorders, it is often difficult to diagnose patients. Immunophenotyping helps distinguish B-PLL from similar diseases, one of its key identifiers is the absence in expression of the surface antigens CD10, CD11c, CD25, CD103 and cyclin D1 – an important regulator of cell-cycle progression.A case has been described as CD20+, CD22+, and CD5-.It can also be CD5+.Another case was described as CD45+, CD19+, CD20+, CD5+, HLA-DR+, CD10-, CD23+/-, CD38+ and FMC7-.
Cytogenetics
B-PLL is rare, consequently few genetic studies have focused on this disease. As a result, the associated genetic lesions underlying B-PLL are largely unknown.
Chromosomal Mutations
The most commonly reported abnormalities have occurred at chromosome 14, specifically in a region of the chromosome called band q23 (14q23). Translocations to this location lead to overexpression of the cyclin D1 gene which has been linked to both the development and progression of a number of cancers. Other chromosomal abnormalities have been reported on 6q21, 11q23, 12p12, 13q14 and 17p.It can involve deletions from chromosome 11 and chromosome 13.
TP53 Gene
Among the documented studies, mutations to the TP53 gene have occurred in 75% of all cases of B-PLL. This is the highest incidence among all sub-types of B-cell malignancies. Mutations to this gene have also been documented in other hematologic malignancies.TP53 is an important transcriptional activator of genes involved in the regulation of the G1 checkpoint of the cell cycle as well as certain genes responsible for programmed-cell death (apoptosis). It is believed that mutations to TP53 are responsible for the frequent therapy resistance and aggressive course of this disease.
c-MYC Gene
In a small number of B-PLL cases, abnormalities in the c-MYC gene have been observed. It is considered a global amplifier and influences nearly all aspects of cellular activity. Among the number of genes it regulates, most are involved in cell growth, cell cycle progression, protein biosynthesis and apoptosis. Amplification of c-MYC has been reported in B-PLL patients and while the consequences are unclear, it is generally associated with poor clinical outcome.
Biopsy
After physicians have identified an abnormality in the composition of the peripheral blood, biopsies (tissue samples) from a patients bone marrow and/or spleen are often recommended for confirmation. A bone marrow biopsy involves the removal of a small amount of tissue that is further analyzed for abnormalities, for B-PLL pathologists look for prolymphocytic infiltration where the hematopoietic stem cells of the bone marrow are replaced with prolymphocytes due to excess production. In 50% of reported cases, it was common for patients to be both anemic (lack healthy red blood cells in blood) and thrombocytopenic (deficiency of platelets in blood).
Treatment
The rarity of B-PLL paired with its considerably fast progression compared to other leukemias has resulted in difficult production of effective treatments. This disease is currently incurable, treatments and therapy are guided to reduce prolymphocyte abundance in the blood and production by the bone marrow, treating symptoms and controlling progression.
Watchful Waiting
Some patients do not require immediate treatment after diagnosis; these patients include those that do not show overt symptoms or whose cancer has not been observed to be progressing. Regular check-ups with physicians are required to actively monitor the patients condition; once there is evidence of disease progression or patient distress from symptoms, treatment will be implemented.
Chemotherapy
B-PLL has a very aggressive clinical course and refractoriness to chemotherapy; it is believed this resistance is the result of mutations to the TP53 gene. Its resistant nature has led to the use of combinations of chemotherapy drugs. Drug regimens recommended and employed by physicians are unique to each patient and are based on previous chemotherapy experience along with potential side effects. In addition to the utilization of combinations of chemotherapeutic drugs, it is most often paired with immunotherapy treatments.
Targeted Therapy
Monoclonal Antibodies
A type of targeted therapy that recognizes specific proteins in leukemia cells preventing collateral damage to normal, healthy cells. The following are compounds currently showing promising results in clinical trials and studies:
Rituximab is a widely used monoclonal antibody in treating B-cell malignancies, it is directed against the surface protein CD20. Case studies have documented successful treatment of B-PLL solely with rituximab; additional studies have reported positive activity when rituximab is paired with the chemotherapeutic drugs fludarabine or bendamustine together with the anthracyclines mitoxantrone or epirubicin
Alemtuzumab is a humanized antibody that targets the CD52 antigen which is highly expressed in malignant B-lymphocytes. In vitro tests have demonstrated that it induces cell death. Furthermore, it is most active in the blood, bone marrow and spleen, all of which are main sites involved with B-PLL and thus could serve as a potential agent in treating this disease with more research
Splenectomy or Radiation Therapy to Spleen
Patients with splenomegaly (enlarged spleen), unfit for systemic treatment or refractive to chemotherapy may have their spleens removed via splenectomy or undergo splenic irradiation in order to relieve pain, control their symptoms, and allow removal of a major proliferative focus and tumour bulk in this disease.Splenic irradiation has been used in the treatment.
Stem Cell Transplantation
A stem cell transplant is a procedure that uses highly specialized cells called hematopoietic stem cells to replace bone marrow that contains the leukemia. This procedure should be considered in younger patients that have responded well to initial treatments because the progression and spread of this disease is inevitable. However, stem cell transplantation is a high-risk procedure, with significant morbidity and mortality rates. Furthermore, it is often not a feasible option due to the presence of other systemic diseases/conditions.
Prognosis
Despite advancements in treatments and deeper understanding of pathogenesis, the prognosis for B-PLL patients is poor
, with early relapse and median survival time between 3–5 years.
Epidemiology
B-PLL represents less than 1% of all leukemia cases worldwide, mainly affecting the elderly population with a mean age of presentation between 65 and 70 years. Most cases have shown slight male predominance, with a male-to-female ratio of 1.6 to 1, and the vast majority of patients being Caucasians.
References
== External links == |
Ochronosis | Ochronosis is a syndrome caused by the accumulation of homogentisic acid in connective tissues. The condition was named after the yellowish (ocher-like) discoloration of the tissue seen on microscopic examination. Macroscopically, though, the affected tissues appear bluish-grey because of a light-scattering phenomenon known as the Tyndall effect. The condition is most often associated with alkaptonuria, but can occur from exogenous administration of phenol complexes such as hydroquinone. It was first described by Rudolf Virchow in 1865.
Types
The two types of ochronosis are endogenous and exogenous. The endogenous variety is an autosomal-recessive disease, known as alkaptonuria, that is caused by a lack of homogentisate oxidase enzyme.
Exogenous ochronosis is an avoidable dermatitis that can be caused by the topical application of compounds such as hydroquinone or phenols.
It was first seen in 1912, when a patient who used phenol on a leg ulcer was found by Beddard and Plumtre to have this condition.
Hydroquinone-induced exogenous ochronosis was found in 1975 by Findlay, who observed the condition in patients who used skin lightening creams containing the compound.The three clinical stages of exogenous ochronosis are:
Erythema and mild hyperpigmentation
Hyperpigmentation and "caviar-like" lesions
Papulonodular lesions
Signs and symptoms
Skin: The pigment is deposited throughout the skin, but only becomes apparent in certain locations, where the concentration is great enough to be seen clinically. This usually occurs in areas where connective tissue is thick (joints, tympanic membrane) or close to the surface of the skin (thenar and hypothenar eminences and the sides of the fingers). In exogenous ochronosis, the hyperpigmentation is localized to the area where the inciting agent is applied. Intradermal nevi can appear like blue nevi.
Eye: Ocular manifestations are frequent in patients with ochronosis; most commonly hyperpigmentation of the sclera, primarily observed symmetrically to both sides of the cornea within the palpebral fissure. Furthermore, brown pigment spots in the limbus are generally considered pathognomonic. These ocular signs generally occur early in the development of the disease and can serve as a valuable diagnostic feature of the disease.
Cartilage: Darkening and hardening of ear cartilage is a prominent feature of ochronosis. Nasal cartilage is also frequently involved. The voice can be affected by hardening of the laryngeal cartilage. Stiffening of the ribs with decreased lung function has also been reported. The intervertebral cartilage is also more prone to herniation.
Connective tissue: Hardening of tendons and ligaments can predispose them to rupture. Color changes in the joints can be observed clinically. Arthropathy is common due to chronic inflammation and microruptures.
Heart valves: Stenosis can results from the increased rigidity of the connective tissue as well as chronic inflammation.Symptoms of exogenous ochronosis include:
Yellow-brown, banana-shaped fibers
Caviar-like papules
Brown-grey or blue-black hyperpigmentationMost of the lesions are seen on areas of the body that get the most sun.
Causes
Exogenous ochronosis can be caused from long-term use of certain "skin-lightening" products, even if the hydroquinone is in amounts as small as 2%.
Skin-lightening products are still prevalent in many parts of the world. This may be due to aesthetic or social-standing reasons, in areas where a lighter skin tone is considered to be a sign of wealth or beauty.
Also, skin-lightening creams containing compounds such as hydroquinone are commonly used to help with hyperpigmentation disorders such as melasma.Hydroquinone is the compound most frequently used in skin-whitening products. Due to concerns about its side effects, it was almost banned by the FDA in 2006, as medical issues of carcinogenicity and reports of disfiguring ochronosis existed. In the European Union hydroquinone has been banned in cosmetic creams since 2000.Long-term use of creams containing this compound may lead to exogenous ochronotic lesions. The duration of use is directly proportional to the risk of developing the condition, with most cases occurring after years of use.
Around 10–15 million skin lightening products are sold annually, with Japan being the major buyer.
Pathophysiology
Ochronosis occurs because of deposition of phenols (such as homogentisic acid and hydroquinone) as plaques in the matrix of cartilage. The pigments can also be incorporated into collagen and elastin fibers. In the skin, the pigment alters the structure of the fibers, causing enlargement and curling.
The embedded pigments also form crosslinks with pigment depositions in adjacent fibers, stabilizing and reducing the elastic recoil of the fibers. This results in hardening of elastic structures, increasing their rigidity and brittleness. Once ruptured, the exposed pigments cause a foreign body reaction and inflammation. This pigment deposition also invokes deposition of hydroxyapatite, the mineral responsible for bone calcification, further hardening the connective tissue.
The pigment can also be excreted by glandular cells in apocrine and ceruminous sweat glands, as well as breast and prostate tissue. This results in darkly pigmented sweat and breast milk. Excretion of the pigment is only found in endogenous ochronosis and should not occur from topical phenols.
Diagnosis
The diagnosis is often made as an incidental finding intraoperatively. Cartilage exposed to the air turns dark gray or black within minutes.
Treatment
Treatment is predominantly preventive. Avoidance of topical phenols and diets low in tyrosine may help. Replacement and repair of damaged tissue is also possible.
Hydroquinone-induced exogenous ochronosis is an avoidable dermatosis that is exceedingly difficult to treat.
However, some studies show that treatment may be possible with a Q-switched alexandrite (755 nm) laser.Individuals with this disorder are recommended to stop using hydroquinone-containing compounds. Awareness of this is important, as dermatologists may think the symptoms a patient is exhibiting are a melasma, and prescribe a hydroquinone-containing cream.
See also
Alkaptonuria
Tyrosinemia
Phenylketonuria
List of cutaneous conditions
References
== External links == |
Phlebitis | Phlebitis (or Venitis) is inflammation of a vein, usually in the legs. It most commonly occurs in superficial veins. Phlebitis often occurs in conjunction with thrombosis and is then called thrombophlebitis or superficial thrombophlebitis. Unlike deep vein thrombosis, the probability that superficial thrombophlebitis will cause a clot to break up and be transported in pieces to the lung is very low.
Signs and symptoms
Localized redness and swelling
Pain or burning along the length of the vein
Vein being hard and cord-likeThere is usually a slow onset of a tender red area along the superficial veins on the skin. A long, thin red area may be seen as the inflammation follows a superficial vein. This area may feel hard, warm, and tender. The skin around the vein may be itchy and swollen. The area may begin to throb or burn. Symptoms may be worse when the leg is lowered, especially when first getting out of bed in the morning. A low-grade fever may occur. Sometimes phlebitis may occur where a peripheral intravenous line was started. The surrounding area may be sore and tender along the vein.
Cause
Phlebitis is typically caused by local trauma to a vein, usually from the insertion of an intravenous catheter. However, it can also occur due to a complication of connective tissue disorders such as lupus, or of pancreatic, breast, or ovarian cancers. Phlebitis can also result from certain medications and drugs that irritate the veins, such as desomorphine.Superficial phlebitis often presents as an early sign in thromboangiitis obliterans (Buergers disease), a vasculitis that affects small and medium-sized arteries and veins in distal extremities often associated with cigarette smoking.
Management
Treatment usually consists of NSAIDs, such as ibuprofen and local compression (e.g., by compression stockings or a compress). If the phlebitis is associated with local bacterial infection, antibiotics may be used.For acute infusion superficial thrombophlebitis, not enough evidence exists as of 2015 to determine treatment.
See also
Collapsed vein
References
Further reading
Intravenous Infusion Therapy for Nurses (Second Edition) by Dianne L. Josephson (ISBN 1-4018-0935-9)
John Hunter, "Observations on the Inflammation of the Internal Coats of Veins," Transactions of a Society for the Improvement of Medical and Chirurgical Knowledge, vol. 1 (London: 1793) pp. 18–29
External links
eMedicine Health: Phlebitis |
Paramyotonia congenita | Paramyotonia congenita (PC) is a rare congenital autosomal dominant neuromuscular disorder characterized by "paradoxical" myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders, patients with PC may also have potassium-provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis and there is debate as to whether the two disorders are actually distinct.
Symptoms and signs
Patients typically complain of muscle stiffness that can continue to focal weakness. This muscle stiffness cannot be walked off, in contrast to myotonia congenita. These symptoms are increased (and sometimes induced) in cold environments. For example, some patients have reported that eating ice cream leads to a stiffening of the throat. For other patients, exercise consistently induces symptoms of myotonia or weakness. Typical presentations of this are during squatting or repetitive fist clenching. Some patients also indicate that specific foods are able to induce symptoms of paramyotonia congenita. Isolated cases have reported that carrots and watermelon are able to induce these symptoms. The canonical definition of this disorder precludes permanent weakness in the definition of this disorder. In practice, however, this has not been strictly adhered to in the literature.
Pathophysiology
Paramyotonia congenita (as well as hyperkalemic periodic paralysis and the potassium-aggravated myotonias) is caused by mutations in a sodium channel, SCN4A. The phenotype of patients with these mutations is indicated in Table 1. These mutations affect fast inactivation of the encoded sodium channel. There are also indications that some mutations lead to altered activation and deactivation. The result of these alterations in channel kinetics is that there is prolonged inward (depolarizing) current following muscle excitation. There is also the introduction of a "window current" due to changes in the voltage sensitivity of the channel’s kinetics. These lead to a general increase in cellular excitability, as shown in figure 1.
There has been one study of a large number of patients with paramyotonia congenita. Of 26 kindreds, it found that 17 (71%) had a mutation in SCN4A while 6 (29%) had no known mutation. There is no large difference between these two groups except that patients with no known mutation have attacks precipitated less by cold but more by hunger, are much more likely to have normal muscle biopsies, and show less decreased compound muscle action potentials when compared to patients with known mutations.
Diagnosis
Diagnosis of paramyotonia congenita is made upon evaluation of patient symptoms and case history. Myotonia must increase with exercise or movement and usually must worsen in cold temperatures. Patients that present with permanent weakness are normally not characterized as having PC. Electromyography may be used to distinguish between paramyotonia congenita and myotonia congenita., Clinicians may also attempt to provoke episodes or myotonia and weakness/paralysis in patients in order to determine whether the patient has PC, hyperkalemic periodic paralysis, or one of the potassium-aggravated myotonias. Genomic sequencing of the SCN4A gene is the definitive diagnostic determinant.
Treatment
Some patients do not require treatment to manage the symptoms of paramyotonia congenita. Others require treatment for their muscle stiffness and often find mexiletine to be helpful. Others have found acetazolamide to be helpful as well. Avoidance of myotonia triggering events is also an effective method of myotonia prevention.
Epidemiology
Paramyotonia congenita is considered an extremely rare disorder, though little epidemiological work has been done. Prevalence is generally higher in European-derived populations and lower among Asians. Epidemiological estimates have been provided for the German population. There, it was estimated that the prevalence of PC is between 1:350,000 (0.00028%) and 1:180,000 (0.00056%). However, the German population of patients with PC is not uniformly distributed across the country. Many individuals with PC herald from the Ravensberg area in North-West Germany, where a founder effect seems to be responsible for most cases. The prevalence here is estimated at 1:6000 or 0.017%.
History
Originally thought to be separate from hyperkalemic periodic paralysis and the sodium channel myotonias, there is now considerable disagreement as to whether these disorders represent separate entities or overlapping phenotypes of a complex disorder spectrum. It was once thought that paramyotonia congenita was more common in males. Observation of the most recent generation has shown this to be untrue. On average, half of children in a family inherit the disorder regardless of gender.
References
Notes
Lehmann-Horn F, Rüdel R, Ricker K (1993). "Non-dystrophic myotonias and periodic paralyses. A European Neuromuscular Center Workshop held 4–6 October 1992, Ulm, Germany". Neuromuscul Disord. 3 (2): 161–8. doi:10.1016/0960-8966(93)90009-9. PMID 7689382. S2CID 20892960.
Cannon S (2006). "Pathomechanisms in channelopathies of skeletal muscle and brain". Annu Rev Neurosci. 29: 387–415. doi:10.1146/annurev.neuro.29.051605.112815. PMID 16776591.
Further reading
Paramyotonia congenita FAQ at the Periodic Paralysis News Desk. The site also hosts a mailing list for patients with the disorder and medical professionals interested in it.
Fact page from the Muscular Dystrophy Association
== External links == |
Crenated tongue | Crenated tongue is a descriptive term for the appearance of the tongue when there are indentations along the lateral borders (the sides), as the result of compression of the tongue against the adjacent teeth.The oral mucosa in the area of crenation is usually of normal color, but there may be erythema (redness) if exposed to a high degree of friction or pressure. Crenated tongue is usually asymptomatic and harmless.It is not a disease as such, but usually results from habits where the tongue is pressed against the lingual surfaces (the side facing the tongue) of the dental arches, or from any cause of macroglossia (enlarged tongue), which in itself has many causes such as Down syndrome.
Where crenation is caused by parafunctional habits, there may also be associated bruxism, linea alba, or morsicatio buccarum.
Society and culture
In traditional Chinese medicine, scalloping of the tongue is said to indicate qi vacuity. In some homeopathic sources, scalloping of the tongue is said to be indicative of high blood pressure. Both claims are unsupported by evidence.
See also
Tongue disease
References
== External links == |
Chorea gravidarum | Chorea gravidarum is a rare type of chorea which presents with involuntary abnormal movement, characterized by abrupt, brief, nonrhythmic, nonrepetitive movement of any limb, often associated with nonpatterned facial grimaces. It is a complication of pregnancy which can be associated with eclampsia and its effects upon the basal ganglia. It is not a causal or pathologically distinct entity but a generic term for chorea of any cause starting during pregnancy. It is associated with history of Sydenhams chorea. It mostly occurs in young patients; the average age is 22 years.Recently there has been a decline in incidence which is probably the result of a decline in rheumatic fever (RF), which was a major cause of chorea gravidarum before the use of antibiotics for streptococcal pharyngitis.
Pathophysiology
Several pathogenetic mechanisms for chorea gravidarum have been offered, but none have been proven.
History of either rheumatic fever or chorea is suspected: the suggestion is that estrogens and progesterone may sensitize dopamine receptors (presumably at a striatal level) and induce chorea in individuals who are vulnerable to this complication by virtue of preexisting pathology in the basal ganglia.
The relation to rheumatic fever was strengthened by many studies that showed that women with normal pregnancies before rheumatic fever developed chorea in subsequent pregnancies. At least 35% of patients have a definite history of acute rheumatic fever and Sydenham chorea; 4% of those with chorea gravidarum had acute rheumatic fever.It has been suggested that use of oral contraceptives is an infrequent cause of chorea. A patient developed this chorea with no definite evidence of previous Sydenhams chorea or recent streptococcal infections, but had anti-basal ganglia antibodies, suggesting immunological basis for the pathophysiology of this chorea.
Diagnosis
Differential diagnoses
Chorea can also be a manifestation of drug toxicity (for example, anticonvulsants, antiparkinson agents, neuroleptics, steroids, and estrogen), or a result of an infectious disease such as meningovascular syphilis, Lyme disease, viral encephalitis, and many others.
Treatment
Drug treatment is indicated for patients with severe disabling chorea. It is treated with haloperidol, chlorpromazine alone or in combination with diazepam, and also pimozide, which is another neuroleptic drug which may have fewer adverse effects than haloperidol. Valproic acid, chloral hydrate, risperidone, or phenobarbital can also be used.
See also
Chorea
References
Further reading
Palanivelu, L. M. (2007). "Chorea gravidarum". Journal of Obstetrics & Gynaecology. 27 (3): 310. doi:10.1080/01443610701241134. PMID 17464821. S2CID 119999.
== External links == |
Spondyloepimetaphyseal dysplasia | Spondyloepimetaphyseal dysplasia is a genetic condition affecting the bones.Types include:
Spondyloepimetaphyseal dysplasia, Strudwick type
Spondyloepiphyseal dysplasia congenita
Spondyloepimetaphyseal dysplasia, Pakistani type
References
== External links == |
Epiphora | Epiphora may refer to:
Epiphora (medicine), an excessive tear production usually a result from an irritation of the eye
Epistrophe, also known as epiphora, the repetition of the same word or words at the end of successive phrases, clauses or sentences
Epiphora (fungus), a fungus genus in the order Dothideomycetes
Epiphora (moth), a moth genus in the family Saturniidae
Epiphora, an orchid genus nowadays considered a synonym of Polystachya |
Geographic tongue | Geographic tongue, also known by several other terms, is a condition of the mucous membrane of the tongue, usually on the dorsal surface. It is a common condition, affecting approximately 2–3% of the general population. It is characterized by areas of smooth, red depapillation (loss of lingual papillae) which migrate over time. The name comes from the map-like appearance of the tongue, with the patches resembling the islands of an archipelago. The cause is unknown, but the condition is entirely benign (importantly, it does not represent oral cancer), and there is no curative treatment. Uncommonly, geographic tongue may cause a burning sensation on the tongue, for which various treatments have been described with little formal evidence of efficacy.
Signs and symptoms
In health, the dorsal surface of the tongue is covered in tuft-like projections called lingual papillae (some of which are associated with taste buds), which give the tongue an irregular surface texture and a white-pink color. Geographic tongue is characterized by areas of atrophy and depapillation (loss of papillae), leaving an erythematous (darker red) and smoother surface than the unaffected areas. The depapillated areas are usually well-demarcated, and bordered by a slightly raised, white, yellow or grey, serpiginous (snaking) peripheral zone. A lesion of geographic tongue may start as a white patch before the depapillation occurs. In certain cases there may be only one lesion, but this is uncommon; the lesions will typically occur in multiple locations on the tongue and coalesce over time to form the typical map-like appearance. The lesions usually change in shape and size, and migrate to other areas, sometimes within hours. The condition may affect only part of the tongue, with a predilection for the tip and the sides of the tongue, or the entire dorsal surface at any one time. The condition goes through periods of remission and relapse. Loss of the white peripheral zone is thought to signify periods of mucosal healing.There are usually no symptoms other than the unusual appearance of the tongue, but in some cases persons may experience pain or burning, e.g. when eating hot, acidic, spicy or other kinds of foods (e.g. cheese, tomatoes, fruit). Where there is a burning symptom, other causes of a burning sensation on the tongue are considered, such as oral candidiasis.
Causes
The cause is unknown. Geographic tongue does not usually cause any symptoms, and in those cases where there are symptoms, an oral parafunctional habit may be a contributory factor. Persons with parafunctional habits related to the tongue may show scalloping on the sides of the tongue (crenated tongue). Some suggest that hormonal factors may be involved, because one reported case in a female appeared to vary in severity in correlation with oral contraceptive use. People with geographic tongue frequently claim that their condition worsens during periods of psychologic stress. Geographic tongue is inversely associated with smoking and tobacco use. Sometimes geographic tongue is said to run in families, and it is reported to be associated with several different genes, though studies show family association may also be caused by similar diets. Some have reported links with various human leukocyte antigens, such as increased incidence of HLA-DR5, HLA-DRW6 and HLA-Cw6 and decreased incidence in HLA-B51. Vitamin B2 deficiency (ariboflavinosis) can cause several signs in the mouth, possibly including geographic tongue, although other sources state that geographic tongue is not related to nutritional deficiency. Fissured tongue often occurs simultaneously with geographic tongue, and some consider fissured tongue to be an end stage of geographic tongue.In the past, some research suggested that geographic tongue was associated with diabetes, seborrheic dermatitis and atopy, however newer research does not corroborate these findings. Others suggest allergy as a major factor, e.g. to nickel sulphate. Some studies have reported a link between geographic tongue and psoriasis, although 90% of children who are diagnosed with geographic tongue do not develop psoriasis. Again however, modern research studies do not support any link between psoriasis and geographic tongue. Lesions that are histologically indistinguishable from geographic tongue may also be diagnosed in reactive arthritis (arthritis, uveitis/conjunctivitis and urethritis).
Predisposing Factors
Geographic tongue (GT) is a lesion with an unknown origin. However, it has been reported more frequently in people with psoriasis, history of allergies, asthma and rhinitis. Studies have also suggested that psychological/psychiatric factors, diabetes, gastrointestinal diseases and haematological disorders may predispose to GT however, more studies with a larger cohort are needed to determine if GT could be an oral manifestation of a systemic disease.
There is strong evidence to support a high prevalence of celiac disease and iron-deficiency anaemia in patients with GT. Oral candidiasis and caries are commonly reported in patients with GT, however this can be explained by saliva of a lower pH which will promote the cariogenic process.
Most common areas in which GT can be found include; the lateral border of the tongue, followed by the anterior dorsum of the tongue and ventral surface.
Diagnosis
Diagnosis of Geographic Tongue (GT) mainly relies on clinical, intraoral findings. As GT is usually asymptomatic in the mouth it does not require treatment. A differential diagnosis between oral candidiasis and GT, two similar looking conditions, can be established through a careful and thorough examination. GT is a keratotic lesion which can be described as a round or irregular shaped white plaque, cannot be scraped off and is normally self-resolving. These lesions are known to reoccur within variable periods. Although rare, cytological techniques and biopsies can be done to aid in a clinical diagnosis. The cytological description can define the disease due to its inflammatory characteristics, with its main characteristic being nuclear demarcation. Furthermore, it is important to be aware that GT may be related to other extraoral and intraoral conditions.
The differential diagnosis includes oral lichen planus, erythematous candidiasis, leukoplakia, lupus erythematosus, glossitis, and chemical burns. Atrophic glossitis is usually distinguished from benign migratory glossitis on the basis of the migrating pattern of the lesions and the presence of a whitish border, features which are not present in atrophic glossitis, which instead shows lesions which enlarge rather than migrate. Rarely, blood tests may be required to distinguish from glossitis associated with anemia or other nutritional deficiencies. Since the appearance and the history of the condition (i.e. migrating areas of depapillation) are so striking, there is rarely any need for biopsy. When biopsy is taken, the histopathologic appearance is quite similar to psoriasis:
Hyperparakeratosis.
Acanthosis.
Subepithelial T lymphocyte inflammatory infiltrate.
Migration of neutrophilic granulocytes into the epithelial layer, which may create superficial microabscesses, similar to the Munros microabscesses described in pustular psoriasis.
Classification
Geographic tongue could be considered to be a type of glossitis. It usually presents only on the dorsal 2/3 and lateral surfaces of the tongue, but less commonly an identical condition can occur on other mucosal sites in the mouth, such as the ventral surface (undersurface) of the tongue, mucosa of the cheeks or lips, soft palate or floor of mouth; usually in addition to tongue involvement. In such cases, terms such as stomatitis erythema migrans, ectopic geographic tongue, areata migrans, geographic stomatitis, or migratory stomatitis are used instead of geographic tongue. Beside the differences in locations of presentation inside the oral cavity and prevalence among the general population, in all other aspects of clinical significance, symptoms, treatment, and histopathologic appearance, these two forms are identical.
This condition is sometimes termed (oral) erythema migrans, but this has no relation to the more common use of the term erythema migrans (erythema chronicum migrans), to describe the appearance of skin lesions in Lyme disease and southern tick-associated rash illness.
Treatment
Geographic tongue (GT) also termed benign migratory glossitis usually presents without symptoms and due to a lack of reliable evidence, researchers can not identify a specific treatment for the condition. It is currently suggested that patients are given reassurance that the condition is entirely benign and self-resolving.
Although there is no established gold standard treatment confirmed by current evidence, patients with symptomatic GT can be advised on several treatment options prescribed by the clinician on a case-by-case basis. This includes possible prescriptions of antihistamines, anxiolytics, corticosteroids and topical anaesthetics. It is recommended that patients avoid spicy and acidic foods. Research has not shown high levels of evidence for the treatment of symptomatic GT and larger study sizes are needed to come to a reliable recommendation.
Prognosis
The condition may disappear over time, but it is impossible to predict if or when this may happen.
Epidemiology
Geographic tongue is a common condition, affecting 2-3% of the adult general population, although other sources report a prevalence of up to 14%. It is one of the most common tongue disorders that occurs in children. The condition often starts in childhood, sometimes at an early age, but others report that the highest incidence occurs in the over 40 age group. Females are sometimes reported to be more commonly affected than males, in a 2:1 ratio, although others report that the gender distribution is equal.
Clinical Implications
Psoriasis
A recent study has proven the link between geographic tongue (GT) and psoriasis - the presence of geographic tongue can be a predictor of psoriasis. Clinical manifestation of GT and psoriasis can be histologically similar, however a genetic link between the two has been pathogenically identified. Patients with generalised pustular psoriasis and GT both exhibit the c.115 +6T >C mutation in the IL36RN gene. Patients who have GT have been shown to experience a greater severity of psoriasis and have a less positive response to treatment.
Oral Manifestations in Patients with COVID-19
Many articles including case reports, case-series and cross-sectional studies have been done since the recent outbreak of COVID-19, causing a global pandemic. These studies have shown that approximately 20% of patients with COVID-19 can present with mucosal manifestations in their oral cavities, including geographic tongue. Geographic tongue is also thought to appear alongside the onset of the regular symptoms of COVID-19.
Interleukin-6 (IL-6) is known to be an important biomarker in patients with COVID-19 in relation to a cytokine storm where too many inflammatory cells which have a detrimental effect on organ systems throughout the body. Geographic tongue is associated with elevated levels of IL-6, which possibly helps explain its presentation on confirmed COVID-19 patients. This evidence is minimal and requires more studies and research to confirm these claims.
Notes
References
== External links == |
Superior limbic keratoconjunctivitis | Superior limbic keratoconjunctivitis (SLK, Théodores syndrome) is a disease of the eye characterized by episodes of recurrent inflammation of the superior cornea and limbus, as well as of the superior tarsal and bulbar conjunctiva. It was first described by F. H. Théodore in 1963.
Symptoms and signs
Patients present with red eye, burning, tearing, foreign body sensation and mild photophobia. Upon examination, the conjunctiva appears inflamed and thickened, especially at the limbus.
Pathophysiology
The development and pathophysiology of SLK is not well understood, but appears to involve microtrauma of keratoconjunctival surfaces. This mechanical hypothesis is supported by the increased lid apposition of exophthalmic thyroid patients, who are known to have an increased incidence of superior limbic keratoconjunctivitis.
Diagnosis
Treatment
First-line treatments include topical corticosteroids and artificial tears. For non-responsive cases, potential treatments include topical ciclosporin A, vitamin A, autologous serum and injections of triamcinolone. Surgical treatment options include thermocauterization of the bulbar conjunctiva and conjunctival resection, typically under rose bengal (RB) staining to visualize affected areas.
Epidemiology
Superior limbic keratoconjunctivitis tends to occur more often with dry eye syndrome (keratoconjunctivitis sicca), hyperthyroidism and hyperparathyroidism. It is also a rare complication associated with rheumatoid arthritis. Rarely, it may occur as a consequence of upper eyelid blepharoplasty surgery.
References
== External links == |
Familial dysautonomia | Familial dysautonomia (FD), also known as Riley-Day Syndrome, is a rare, progressive, recessive genetic disorder of the autonomic nervous system that affects the development and survival of sensory, sympathetic and some parasympathetic neurons in the autonomic and sensory nervous system.
FD results in variable symptoms, including insensitivity to pain, inability to produce tears, poor growth and labile blood pressure (episodic hypertension and postural hypotension). People with FD have frequent vomiting crises, pneumonia, problems with speech and movement, difficulty swallowing, inappropriate perception of heat, pain and taste as well as unstable blood pressure and gastrointestinal dysmotility.
Originally reported by Drs. Conrad Milton Riley and Richard Lawrence Day in 1949, FD is one example of a group of disorders known as hereditary sensory and autonomic neuropathies (HSAN). All HSAN are characterized by widespread sensory dysfunction and variable autonomic dysfunction caused by incomplete development of sensory and autonomic neurons. The disorders are believed to be genetically distinct from each other.
Signs and symptoms
Signs and symptoms of familial dysautonomia usually commence during infancy and worsen with age, and may include: gastrointestinal dysmotility (including erratic gastric emptying, gastroesophageal reflux, abnormal esophageal peristalsis, oropharyngeal incoordination), dysphagia (as poor suckling in infancy) and frequent choking/gagging, recurrent vomiting, poor weight gain/growth, delayed development (especially walking) and puberty (especially in girls), recurrent aspiration pneumonia (due to inhalation of food or vomitus) with possible secondary chronic lung disease, absence of overflow tears during crying, corneal ulcers, red skin blotches and excessive sweating (often during eating or excitement), breath-holding spells, slurred speech/nasal voice, tongue ulcers (from accidental self-injuries), hyporeflexia (variable absence of deep tendon reflexes), hypotonia, enuresis, arrhythmias, hypertension (including episodic hypertension in response to emotional stress or visceral pain), hypotension (including orthostatic hypertension with compensatory tachycardia (invariably present)), impaired (but not absent) temperature and pain perception (leading to frequent accidental injury), impaired proprioception, a smooth glossy tongue, scoliosis (with possibly secondary restrictive lung disease), abnormal gait, short stature, chronic renal failure (common), visual impairment, variable cognitive ability, characteristic facial features that develop with time, impaired vibration perception, lack of fungiform papilla of the tongue, and impaired taste perception (especially for sweetness).
Autonomic crises - In children with FD, recurrent episodes of vomiting may occur. Such episodes may be triggered by physical (e.g. infection) or emotional stress, may occur every 15–20 minutes for over 24 hours, and may be accompanied with: significant hypertension, drenching sweat, breathing issues, fever, tachycardia, aspiration pneumonia, skin blotches, drooling, and negative personality change.
Pain insensitivity - Insensitivity or indifference to painful stimuli may lead to frequent/progressive self-mutilation, burns, and ulcers. There may be self-mutilation of the tongue (especially in toddlers during teething), lips, and cheeks, or loss of teeth. Compulsive oral biting may result in ulcers, or tumour-like masses (Riga-Fede disease).
Progression
Familial dysautonomia presents with progressive age-specific symptoms.
Though usually not diagnosed until several years of age, generalised signs of FD are present in during the newborn period >80% of those affected.Dysmorpnic facial features are not directly inherent to the disorder, however, facial asymmetry and a straightened mouth eventually develop due to abnormal tone and molding of facial bones.
Perinatal
A very high incidence of breech presentation has been noted among infants with FD. A lower birth weight as compared to siblings, premature birth, and intrauterine growth restriction have also been noted.
Neonatal
During the neonatal period, there may be hypotonia, respiratory insufficiency, poor feeding with difficulty swallowing and aspiration, developmental delay, short stature, scoliosis, and corneal disease.
Infancy
Issues related to the disorder first appear during infancy. Early manifestations include hypotonia, feeding difficulty (impaired swallowing and suckling), poor growth, absence of tears, frequent lung infections, and poor body temperature control (infants may display cold hands and feet). Developmental milestones (e.g. walking, speech) may or may not be delayed.In infants with FD, a lack of overflow tears during emotional crying may be noted after the age of 7 months (until this age, overflow emotional tearing may also not occur in unaffected infants; overflow tearing is absent in neonates and begins to appear only after 2–3 months of age).Affected infants hands may alternatively appear cool and mottled (from vasoconstriction), or red and swollen (from vasodilation). Red skin blotching is often precipitated by emotional excitement.In older infants and young children, breath-holding spells may occur, possibly leading to cyanosis or fainting. Breath-holding behaviour usually ceases by age 6.
Children
Breath-holding behaviour usually resolves by age 6. In school-age children, there may be bed wetting, vomiting episodes, impaired pain and temperature perception, impaired blood pressure control (including orthostatic hypotension, an hypertension during periods of psychological excitement or vomiting), learning disabilities (e.g. short attention span; learning disabilities are present in about a third of those with FD, and may require special education), scoliosis, poor bone quality and bone fractures, and kidney and heart issues.
Adolescence and adulthood
Issues that tend to commence during adolescence or early adulthood include lung damage due to multiple respiratory infections, impaired kidney function, and impaired vision (due to atrophy of the optic nerve). By adulthood, there are often mounting difficulties with balance and unaided walking.
Cause
Familial dysautonomia is the result of mutations in IKBKAP gene on chromosome 9, which encodes for the IKAP protein (IkB kinase complex-associated protein). There have been three mutations in IKBKAP identified in individuals with FD. The most common FD-causing mutation occurs in intron 20 of the donor gene. Conversion of T→C in intron 20 of the donor gene resulted in shift splicing that generates an IKAP transcript lacking exon 20. Translation of this mRNA results in a truncated protein lacking all of the amino acids encoded by exons 20–37. Another less common mutation is a G→C conversion resulting in one amino acid mutation in 696, where Proline substitutes normal Arginine. The decreased amount of functional IKAP protein in cells causes familial dysautonomia.
Diagnosis
Clinical diagnosis
A clinical diagnosis of FD is supported by a constellation of criteria:
No fungiform papillae on the tongue
Decreased deep tendon reflexes
Lack of an axon flare following intradermal histamine
No overflow tears with emotional crying
Genetic testing
Genetic testing is performed on a small sample of blood from the tested individual. The DNA is examined with a designed probe specific to the known mutations. The accuracy of the test is above 99%. Dr. Anat Blumenfeld of the Hadassah Medical center in Jerusalem identified chromosome number 9 as the responsible chromosome.
Prenatal testing
Familial dysautonomia is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. If both parents are shown to be carriers by genetic testing, there is a 25% chance that the child will have FD. For pregnancies at increased risk for FD, preimplantation genetic diagnosis or prenatal diagnosis by amniocentesis (at 15–17 weeks) or chorionic villus sampling (at 10–14 weeks) is possible.
Management
There is currently no cure for FD. There are only two treatment centers, one at New York University Hospital and one at the Sheba Medical Center in Israel. One is being planned for the San Francisco area. Although the FD-causing gene has been identified and it seems to have tissue specific expression, there is no definitive treatment at present.A major issue has been aspiration pneumonia. Fundoplications (by preventing regurgitation) and gastrostomy tubes (to provide non-oral nutrition) have reduced the frequency of hospitalization. Other issues which can be treated include FD crises, scoliosis, and various eye conditions due to limited or no tears.Treatment of FD remains preventative, symptomatic and supportive. FD does not express itself in a consistent manner. The type and severity of symptoms displayed vary among patients and even at different ages on the same patients so patients should have specialized individual treatment plans. Medications are used to control vomiting, eye dryness, and abnormal blood pressure. Common management strategies include: artificial tears, appropriate feeding strategy (maintenance of adequate nutrition, avoidance of aspiration (thickened formula and different shaped nipples for infants)), daily chest physiotherapy (nebulization, bronchodilators, and postural drainage) for chronic pulmonary disease, pharmaceutical management of autonomic features (e.g. intravenous or rectal diazepam, or rectal chloral hydrate), preventing accidental injury, prevention of orthostatic hypotension (hydration, leg exercise, frequent small meals, a high-salt diet, and medication (e.g. with fludrocortisone)), treatment of orthopedic problems, compensating labile blood pressure.Parents and patients should be informed regarding daily eye care and early signs of corneal problems, as well as punctal cautery. Informing patients and caretakers has resulted in decreased corneal scarring and need for more aggressive surgical measures such as tarsorrhaphy, conjunctival flaps, and corneal transplants.
Prognosis
Average age of death is in the 3rd decade of life, however, affected persons may live into the 7th decade of life. Death occurs in 50% of the affected individuals by age 30. The outlook for patients with FD depends on the particular diagnostic category. Patients with chronic, progressive, generalized dysautonomia in the setting of central nervous system degeneration have a generally poor long-term prognosis. Death can occur from pneumonia, acute respiratory failure, or sudden cardiopulmonary arrest in such patients.The survival rate and quality of life have increased since the mid-1980s mostly due to a greater understanding of the most dangerous symptoms. At present, FD patients can be expected to function independently if treatment is begun early and if major disabilities are avoided.
Epidemiology
Familial dysautonomia is seen almost exclusively in Ashkenazi Jews and is inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. The carrier frequency in Jews of Eastern and Central European (Ashkenazi) ancestry is about 1/30, while the carrier frequency in non-Jews is unknown. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of familial dysautonomia.Worldwide, there have been approximately 600 diagnoses recorded since discovery of the disease, with approximately 350 of them still living.
Research
In January 2001, researchers at Fordham University and Massachusetts General Hospital simultaneously reported finding the genetic mutation that causes FD, a discovery that opens the door to many diagnostic and treatment possibilities. Genetic screening subsequently became available in 2001, enabling Ashkenazi Jews to find out if they are carriers.Stem-cell therapy has been proposed as a potential future treatment. Eventually, treatment could be given in utero.
Research into treatments is being funded by foundations organized and run by parents of those with FD. There is no governmental support beyond recognizing those diagnosed with FD as eligible for certain programs.
See also
Dysautonomia
Medical genetics of Ashkenazi Jews
References
Further reading
Axelrod FB, Hilz MJ (2003). "Inherited autonomic neuropathies". Semin Neurol. 23 (4): 381–90. doi:10.1055/s-2004-817722. PMID 15088259.
Axelrod FB (2004). "Familial dysautonomia". Muscle Nerve. 29 (3): 352–63. doi:10.1002/mus.10499. PMID 14981733. S2CID 222032372.
Slaugenhaupt SA, Gusella JF (2002). "Familial dysautonomia". Curr Opin Genet Dev. 12 (3): 307–11. doi:10.1016/S0959-437X(02)00303-9. PMID 12076674.
Felicia B Axelrod; Gabrielle Gold-von Simson (October 3, 2007). "Hereditary sensory and autonomic neuropathies: types II, III, and IV". Orphanet Journal of Rare Diseases. 2 (39): 39. doi:10.1186/1750-1172-2-39. PMC 2098750. PMID 17915006. |
Bennetts fracture | Bennett fracture is a type of partial broken finger involving the base of the thumb, and extends into the carpometacarpal (CMC) joint.Treatment typically requires surgery.This intra-articular fracture is the most common type of fracture of the thumb, and is nearly always accompanied by some degree of subluxation or frank dislocation of the carpometacarpal joint.
Symptoms and signs
Symptoms of Bennett fracture are instability of the CMC joint of the thumb, accompanied by pain and weakness of the pinch grasp. Characteristic signs include pain, swelling, and ecchymosis around the base of the thumb and thenar eminence, and especially over the CMC joint of the thumb. Physical examination demonstrates instability of the CMC joint of the thumb. The patient will often manifest a weakened ability to grasp objects or perform such tasks as tying shoes and tearing a piece of paper. Other complaints include intense pain experienced upon catching the thumb on an object, such as when reaching into a pants pocket.
Complications
Many important activities of daily life are dependent on the ability to grasp, pinch, and oppose the thumb. In fact, thumb function constitutes about 50% of overall hand function. These abilities are in turn dependent on an intact and functional thumb CMC joint. The CMC joint of the thumb allows a wide range of motion while maintaining stability for grasp and pinch.With this in mind, failure to properly recognize and treat the Bennett fracture will not only result in an unstable, painful, arthritic CMC joint with diminished range of motion: it will also result in a hand with greatly diminished overall function.In the case of the Bennett fracture, the proximal metacarpal fragment remains attached to the anterior oblique ligament, which in turn is attached to the tubercle of the trapezium bone of the CMC joint. This ligamentous attachment ensures that the proximal fragment remains in its correct anatomical position.The distal fragment of the first metacarpal bone possesses the majority of the articular surface of the first CMC joint. Unlike the proximal fracture fragment, strong ligaments and muscle tendons of the hand tend to pull this fragment out of its correct anatomical position.Specifically:
tension from the abductor pollicis longus muscle (APL) subluxates the fragment in a dorsal, radial, and proximal direction
tension from the APL rotates the fragment into supination
tension from the adductor pollicis muscle (ADP) displaces the metacarpal head into the palmTension from the APL and ADP muscles frequently leads to displacement of the fracture fragments, even in cases where the fracture fragments are initially in their proper anatomic position. Because of the aforementioned biomechanical features, Bennett fractures nearly always require some form of intervention to ensure healing in the correct anatomical position and restoration of proper function of the thumb CMC joint.
Mechanism
The Bennett fracture is an oblique intraarticular metacarpal fracture dislocation, caused by an axial force directed against the partially flexed metacarpal. This type of compression along the metacarpal bone is often sustained when a person punches a hard object, such as the skull or tibia of an opponent, or a wall. It can also occur as a result of a fall onto the thumb. This is a common injury sustained from bike falls, as the thumb is generally extended while around the handle bars. It is also a common injury in car crashes, especially into fixed objects, from the driver holding the steering wheel during impact. The hand moves forward, while the steering wheel rim hyperextends the thumb.
Some authors have recently made an assertion against popular belief that the APL tendon is not a deforming force on the Bennett fracture.
Treatment
Though these fractures commonly appear quite subtle or even inconsequential on radiographs, they can result in severe long-term dysfunction of the hand if left untreated. In his original description of this type of fracture in 1882, Bennett stressed the need for early diagnosis and treatment in order to prevent loss of function of the thumb CMC joint, which is critical to the overall function of the hand.
In the most minor cases of Bennett fracture, there may be only small avulsion fractures, relatively little joint instability, and minimal subluxation of the CMC joint (less than 1 mm). In such cases, closed reduction followed by immobilization in a thumb spica cast and serial radiography may be all that is required for effective treatment.
For Bennett fractures where there is between 1 mm and 3 mm of displacement at the trapeziometacarpal joint, closed reduction and percutaneous pin fixation (CRPP) with Kirschner wires is often sufficient to ensure a satisfactory functional outcome. The wires are not employed to connect the two fracture fragments together, but rather to secure the first or second metacarpal to the trapezium.
For Bennett fractures where there is more than 3 mm of displacement at the trapeziometacarpal joint, open reduction and internal fixation (ORIF) is typically recommended.Regardless of which approach is employed (nonsurgical, CRPP, or ORIF), immobilization in a cast or thumb spica splint is required for four to six weeks.
Prognosis
If intraarticular trapeziometacarpal fractures (such as the Bennett or Rolando fractures) are allowed to heal in a displaced position, significant post-traumatic osteoarthritis of the base of the thumb is virtually assured. Some form of surgical treatment (typically either a CRPP or an ORIF) is nearly always recommended to ensure a satisfactory outcome for these fractures, if there is significant displacement.The long-term outcome after surgical treatment appears to be similar, whether the CRPP or the ORIF approach is used. Specifically, the overall strength of the affected hand is typically diminished, and post-traumatic osteoarthritis tends to develop in almost all cases. The degree of weakness and the severity of osteoarthritis does however appear to correlate with the quality of reduction of the fracture. Therefore, the goal of treatment of Bennett fracture should be to achieve the most precise reduction possible, whether by the CRPP or the ORIF approach.
Nomenclature
The Bennett fracture is named after Edward Hallaran Bennett, Professor of Surgery (1837–1907) at Trinity College of the University of Dublin, who described it in 1882. Bennett said his fracture "passed obliquely across the base of the bone, detaching the greater part of the articular surface, and the separated fragment was very large and the deformity that resulted there-from seemed more a dorsal subluxation of the first metacarpal".
See also
Rolando fracture
Boxers fracture
Gamekeepers thumb
References
External links
Bennett fracture at Who Named It? |
Hypervalinemia | Hypervalinemia is a rare autosomal recessive metabolic disorder in which urinary and serum levels of the branched-chain amino acid valine are elevated, without related elevation of the branched-chain amino acids leucine and isoleucine. It is caused by a deficiency of the enzyme valine transaminase.
Presentation
Presenting in infancy, symptoms include lack of appetite, vomiting, dehydration, hypotonia and failure to thrive.
Genetics
Hypervalinemia is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
Diagnosis
See also
Isovaleric acidemia
Maple syrup urine disease
Propionic acidemia
References
== External links == |
Dihydropteridine reductase deficiency | Dihydropteridine reductase deficiency (DHPRD) is a genetic disorder affecting the tetrahydrobiopterin (BH4) synthesis pathway, inherited in the autosomal recessive pattern. It is one of the six known disorders causing tetrahydrobiopterin deficiency, and occurs in patients with mutations of the QDPR gene.
The disease presents with such symptoms as elevated levels of phenylalanine (hyperphenylalaninemia), microcephaly, hypotonus, mental retardation and epileptic seizures.
Diagnostics
Besides the traditional analysis of symptoms and investigation of phenylalanine concentrations, patients suspected for DHPRD undergo the assessment of enzymatic activity using the dried blood spot method - this permits to distinguish DHPR deficiency from the other forms of BH4 deficiency.
Treatment
Patients are prescribed a phenylalanine-reduced diet, with regular monitoring of phenylalanine levels in the blood. Besides the diet, a patient may be prescribed sapropterin, a synthetic analogue of tetrahydrobiopterin.
In order to restore dopamine levels in the central nervous system, patients are given L-dopa in conjunction with an inhibitor of aromatic amino acid decarboxylase that acts outside the nervous system, so as to promote the transformation of L-dopa into dopamine inside the central nervous system, and thus to improve the efficiency of the treatment.
Since the insufficient levels of BH4 inhibit the transformation of tryptophan into 5-hydroxytryptophan in a reaction in which BH4 serves as a cofactor of the enzyme tryptophane hydroxylase 2, patients suffer from a lack of serotonin in their CNS. In order to correct this deficiency, they are given 5-hydroxytryptophan.
In patients with DHPR deficiency, a pronounced lack of 5-methyltetrahydrofolate (5-MTHF) is observed in the central nervous system. This condition, termed cerebral folate deficiency, (CFD) is more severe in DHPRD patients than in patients with other forms of BH4 deficiency. CFD is corrected by treating patients with folinic acid, a form of folate that efficiently passes the hematoencephalic barrier. The use of folic acid, the synthetic form of folate employed in food fortification, should be avoided because folic acid tightly binds to the folate receptor alpha and may inhibit the transport of folate into the central nervous system.
== References == |
Ectopia cordis | Ectopia cordis (Greek: "away / out of place" + Latin: "heart") or ectopic heart is a congenital malformation in which the heart is abnormally located either partially or totally outside of the thorax. The ectopic heart can be found along a spectrum of anatomical locations, including the neck, chest, or abdomen. In most cases, the heart protrudes outside the chest through a split sternum.
Pathology
Ectopia cordis results from a failure of proper maturation of midline mesoderm and ventral body wall (chest) formation during embryonic development. The exact etiology remains unknown, but abnormalities in the lateral body wall folds are believed to be involved. Normally, the lateral body walls are responsible for fusion at the midline to form the ventral wall. Corruption of this process may underlie ectopia cordis.Defective ventral body wall formation yields a heart unprotected by the pericardium, sternum, or skin. Other organs may also have formed outside the skin, as well. Many cases of ectopia cordis have associated congenital heart defects, in which the heart has failed to properly form.Defects more commonly associated with ectopia cordis include:
Intracardiac defects
Atrial septal defect
Ventricular septal defect
Tetralogy of Fallot
Tricuspid atresia
Double outlet right ventricle
Non-cardiac malformations
Pentalogy of Cantrell
Omphalocele
Anterior diaphragmatic hernia
Cleft palate
Diagnosis
The Diagnosis of ectopia cordis is found with a routine ultrasound as early as the first trimester or the beginning of the second trimester.
Treatment
Due to the rarity and rapid postpartum mortality of ectopia cordis, limited treatment options have been developed. Only some successful surgeries have been performed as of now, and the mortality rate remains high.
Prognosis
The prognosis of ectopia cordis depends on classification according to three factors:
Location of the defect
Cervical
Thoracic
Thoracoabdominal
Abdominal
Extent of the cardiac displacement
Presence or absence of intracardiac defectsSome studies have suggested a better prognosis with surgery in cases of thoracoabdominal ectopia cordis or less severe pentalogy of Cantrell. In general, the prognosis for ectopia cordis is poor—most cases result in death shortly after birth due to infection, hypoxemia, or cardiac failure.
Epidemiology
The occurrence of ectopia cordis is 8 per million births. It is typically classified according to location of the ectopic heart, which includes:
Cervical
Thoracic
Thoracoabdominal
AbdominalThoracic and thoraco-abdominal ectopia cordis constitute the vast majority of known cases.
References
== External links == |
Plasmacytosis | Plasmacytosis is a condition in which there is an unusually large proportion of plasma cells in tissues, exudates, or blood.: 743 Plasmacytosis may be divided into two types—cutaneous and systemic—both of which have identical skin findings.: 743
Patients with plasmacytosis have been predominantly found to have lung infections (pneumonia, tuberculosis, abscess) whereas multiple myeloma is rarely found.
See also
Cutaneous B-cell lymphoma
Multiple myeloma
Plasmacytoma
Skin lesion
References
== External links == |
Postorgasmic illness syndrome | Postorgasmic illness syndrome (POIS) is a syndrome in which people have chronic physical and cognitive symptoms following ejaculation. The symptoms usually onset within seconds, minutes, or hours, and last for up to a week. The cause and prevalence are unknown; it is considered a rare disease.
Signs and symptoms
The distinguishing characteristics of POIS are:
the rapid onset of symptoms after ejaculation;
the presence of an overwhelming systemic reaction.POIS symptoms, which are called a "POIS attack", can include some combination of the following: cognitive dysfunction, aphasia, severe muscle pain throughout the body, severe fatigue, weakness, and flu-like or allergy-like symptoms, such as sneezing, itchy eyes, and nasal irritation. Additional symptoms include headache, dizziness, lightheadedness, extreme hunger, sensory and motor problems, intense discomfort, irritability, anxiety, gastrointestinal disturbances, craving for relief, susceptibility to nervous system stresses (e.g. common cold), depressed mood, and difficulty communicating, remembering words, reading and retaining information, concentrating, and socializing. Affected individuals may also experience intense warmth or cold. An online anonymous self-report study found that 80% of respondents always experienced the symptom cluster involving fatigue, insomnia, irritation, and concentration difficulties.The symptoms usually begin within 30 minutes of ejaculation, and can last for several days, sometimes up to a week. In some cases, symptoms may be delayed by 2 to 3 days or may last up to 2 weeks.In some men, the onset of POIS is in puberty, while in others, the onset is later in life. POIS that is manifest from the first ejaculations in adolescence is called primary type; POIS that starts later in life is called secondary type.Many individuals with POIS report lifelong premature ejaculation, with intravaginal ejaculation latency time (IELT) of less than one minute.
The 7 clusters of symptoms of criterion 1:
Synonyms and related conditions
POIS has been called by a number of other names, including "postejaculatory syndrome", "postorgasm illness syndrome", "post ejaculation sickness", and "post orgasmic sick syndrome".Dhat syndrome is a condition, first described in 1960 in India, with symptoms similar to POIS. Dhat syndrome is thought to be a culture-bound psychiatric condition and is treated with cognitive behavioral therapy along with anti-anxiety and antidepressant drugs.Post-coital tristesse (PCT) is a feeling of melancholy and anxiety after sexual intercourse that lasts anywhere from five minutes to two hours. PCT, which affects both men and women, occurs only after sexual intercourse and does not require an orgasm to occur, and in that its effects are primarily emotional rather than physiological. By contrast, POIS affects only men, consists primarily of physiological symptoms that are triggered by ejaculation and that can last, in some people, for up to a week. While PCT and POIS are distinct conditions, some doctors speculate that they could be related.An array of more subtle and lingering symptoms after orgasm, which do not constitute POIS, may contribute to habituation between mates. They may show up as restlessness, irritability, increased sexual frustration, apathy, sluggishness, neediness, dissatisfaction with a mate, or weepiness over the days or weeks after intense sexual stimulation. Such phenomena may be part of human mating physiology itself.
Sexual headache is a distinct condition characterized by headaches that usually begin before or during orgasm.
Mechanism
The cause of POIS is unknown. Some doctors hypothesize that POIS is caused by an auto-immune reaction. Other doctors suspect a hormone imbalance as the cause. Different causes have also been proposed. None of the proposed causes fully explain the disease.
Allergy hypothesis
According to one hypothesis, "POIS is caused by Type-I and Type-IV allergy to the males own semen". This was conditioned by another study stating "IgE-mediated semen allergy in men may not be the potential mechanism of POIS".Alternatively, POIS could be caused by an auto-immune reaction not to semen, but to a different substance released during ejaculation, such as cytokines.
Hormone hypothesis
According to another hypothesis, POIS is caused by a hormone imbalance, such as low progesterone, low cortisol, low testosterone, elevated prolactin, hypothyroidism, or low DHEA.POIS could be caused by a defect in neurosteroid precursor synthesis. If so, the same treatment may not be effective for all individuals. Different individuals could have different missing precursors leading to a deficiency of the same neurosteroid, causing similar symptoms.
Withdrawal hypothesis
The majority of POIS symptoms like fatigue, muscle pains, sweating, mood disturbances, irritability, and poor concentration are also caused by withdrawal from different drug classes and natural reinforcers. It is unknown whether there is a relationship between hypersexuality, pornography addiction, compulsive sexual behavior and POIS. Some evidence indicates that POIS patients have a history of excessive masturbation, suggesting that POIS could be a consequence of sex addiction. There is anecdotal evidence on porn addiction internet forums, that many men experience POIS like symptoms after ejaculation.
Other possibilities
POIS could be caused by hyperglycemia or by chemical imbalances in the brain.Sexual activity for the first time may set the stage for an associated asthma attack or may aggravate pre-existing asthma. Intense emotional stimuli during sexual intercourse can lead to autonomic imbalance with parasympathetic over-reactivity, releasing mast cell mediators that can provoke postcoital asthma and / or rhinitis in these patients.It is also possible that the causes of POIS are different in different individuals. POIS could represent "a spectrum of syndromes of differing" causes.None of the proposed causes for POIS fully explain the connection between POIS and lifelong premature ejaculation.
Diagnosis
There is no generally agreed upon diagnostic criteria for POIS. One group has developed five preliminary criteria for diagnosing POIS. These are:
POIS is prone to being erroneously ascribed to psychological factors such as hypochondriasis or somatic symptom disorder.An online survey study suggested that only a small number of self-reported POIS fulfill entirely the five criteria. This study proposed to change the Criterion 3 with “In at least one ejaculatory setting (sex, masturbation, or nocturnal emission), symptoms occur after all or almost all ejaculations.”
Management
There is no standard method of treating or managing POIS. Patients need to be thoroughly examined in an attempt to find the causes of their POIS symptoms, which are often difficult to determine, and which vary across patients. Once a cause is hypothesized, an appropriate treatment can be attempted. At times, more than one treatment is attempted, until one that works is found.Affected individuals typically avoid sexual activity, especially ejaculation, or schedule it for times when they can rest and recover for several days afterwards. In case post-coital tristesse (PCT) is suspected, patients could be treated with selective serotonin reuptake inhibitors.In one patient, the POIS symptoms were so severe, that he decided to undergo removal of the testicles, prostate, and seminal vesicles in order to relieve them. The POIS symptoms were cured by this.Another patient, in whom POIS was suspected to be caused by cytokine release, was successfully treated with nonsteroidal anti-inflammatory drugs (NSAIDs) just prior to and for a day or two after ejaculation. The patient took diclofenac 75 mg 1 to 2 hours prior to sexual activity with orgasm, and continued twice daily for 24 to 48 hours.One POIS patient with erectile dysfunction and premature ejaculation had much lower severity of symptoms on those occasions when he was able to maintain penile erection long enough to achieve vaginal penetration and ejaculate inside his partner. The patient took tadalafil to treat his erectile dysfunction and premature ejaculation. This increased the number of occasions on which he was able to ejaculate inside his partner, and decreased the number of occasions on which he experienced POIS symptoms. This patient is thought to have Dhat syndrome rather than true POIS.Two patients, in whom POIS was suspected to be caused by auto-immune reaction to their own semen, were successfully treated by allergen immunotherapy with their own autologous semen. They were given multiple subcutaneous injections of their own semen for three years. Treatment with autologous semen "might take 3 to 5 years before any clinically relevant symptom reduction would become manifest".Treatments are not always successful, especially when the cause of POIS in a particular patient has not been determined. In one patient, all of whose routine laboratory tests were normal, the following were attempted, all without success: ibuprofen, 400 mg on demand; tramadol 50 mg one hour pre-coitally; and escitalopram 10 mg daily at bedtime for 3 months.
Epidemiology
The prevalence of POIS is unknown. POIS is listed as a rare disease by the American National Institutes of Health and the European Orphanet. It is thought to be underdiagnosed and underreported. POIS seems to affect mostly men from around the world, of various ages and relationship statuses.
Women
It is possible that a similar disease exists in women, though, as of 2016, there is only one documented female patient.
References
== External links == |
Nasal congestion | Nasal congestion is the blockage of nasal breathing usually due to membranes lining the nose becoming swollen from inflamed blood vessels.
Background
In about 85% of cases, nasal congestion leads to mouth breathing rather than nasal breathing. According to Jason Turowski, MD of the Cleveland Clinic, "we are designed to breathe through our noses from birth—its the way humans have evolved." This is referred to as "obligate nasal breathing."Nasal congestion can interfere with hearing and speech. Significant congestion may interfere with sleep, cause snoring, and can be associated with sleep apnea or upper airway resistance syndrome. In children, nasal congestion from enlarged adenoids has caused chronic sleep apnea with insufficient oxygen levels and hypoxia, as well as right-sided heart failure. The problem usually resolves after surgery to remove the adenoids and tonsils, however the problem often relapses later in life due to craniofacial alterations from chronic nasal congestion.
Causes
Allergies, like hay fever, allergic reaction to pollen or grass
Common cold or influenza
Rhinitis medicamentosa, a condition of rebound nasal congestion brought on by extended use of topical decongestants (e.g., oxymetazoline, phenylephrine, xylometazoline, and naphazoline nasal sprays)
Sinusitis or sinus infection
Narrow or collapsing nasal valve
Pregnancy may cause women to suffer from nasal congestion due to the increased amount of blood flowing through the body.
Nasal polyps
Gastroesophageal reflux disease (theorized to cause chronic rhinosinusitis- the "airway reflux paradigm")
COVID-19
Nasal obstruction
Nasal obstruction characterized by insufficient airflow through the nose can be a subjective sensation or the result of objective pathology. It is difficult to quantify by subjective complaints or clinical examinations alone, hence both clinicians and researchers depend both on concurrent subjective assessment and on objective measurement of the nasal airway.Prevalence of kyphosis has been linked to nasal obstruction in a study.
Treatment
According to WebMD, congestion can be addressed through the use of a humidifier, warm showers, drinking fluids, using a neti pot, using a nasal saline spray, and sleeping with ones head elevated. It also recommends a number of over the counter decongestants and antihistamines. A 2012 study concluded that combining nasal sprays with "nasal breathing exercises" (NBE) led to improvement of symptoms. Though it may seem weird, crying can also be helpful.The Cleveland Clinic also states that congestion may be a sign of a deviated septum, a condition that needs to be addressed by a doctor.
See also
Decongestant
Honeymoon rhinitis
Inhaler
References
Further reading
Nestor, James (2020). Breath: The New Science of a Lost Art. Riverhead Books. ISBN 978-0735213616.
== External links == |
Bronchomalacia | Bronchomalacia is a term for weak cartilage in the walls of the bronchial tubes, often occurring in children under a day. Bronchomalacia means floppiness of some part of the bronchi. Patients present with noisy breathing and/or wheezing. There is collapse of a main stem bronchus on exhalation. If the trachea is also involved the term tracheobronchomalacia (TBM) is used. If only the upper airway the trachea is involved it is called tracheomalacia (TM). There are two types of bronchomalacia. Primary bronchomalacia is due to a deficiency in the cartilaginous rings. Secondary bronchomalacia may occur by extrinsic compression from an enlarged vessel, a vascular ring or a bronchogenic cyst. Though uncommon, idiopathic (of unknown cause) tracheobronchomalacia has been described in older adults.
Cause
Bronchomalacia can best be described as a birth defect of the bronchus in the respiratory tract. Congenital malacia of the large airways is one of the few causes of irreversible airways obstruction in children, with symptoms varying from recurrent wheeze and recurrent lower airways infections to severe dyspnea and respiratory insufficiency. It may also be acquired later in life due to chronic or recurring inflammation resulting from infection or other airway disease.
Diagnosis
Classification
Primary Bronchomalacia
Secondary Bronchomalacia
Primary bronchomalacia
Primary Bronchomalacia is classified as congenital.
Primary Bronchomalacia is caused by a deficiency in the cartilaginous rings.
Primary airway malacia was defined as airway malacia in otherwise normal infants.
Secondary bronchomalacia
Secondary Bronchomalacia is acquired.
Secondary Bronchomalacia may occur by extrinsic compression from an enlarged vessel, a vascular ring or a bronchogenic cyst.
Secondary airway malacia was defined as airway malacia secondary to esophageal atresia, VATER/VACTERL association (condition with vertebral anomalies, anal atresia, congenital heart disease, tracheoesophageal fistula or esophageal atresia, renourinary anomalies, or radial limb defects), vascular or other external compression of the airways, or specific syndromes.
Treatment
Time
Minimally Invasive, usually in conjunction with Continuous Positive Airflow Pressure.
Continuous Positive Airflow Pressure
A method of respiratory ventilation.
Tracheotomy
Surgical procedures on the neck to open a direct airway through an incision in the trachea (the windpipe).
Prosthesis
Insertion of a prosthesis to keep the bronchial tube open.
Notes
References
Carden, KA, Boiselle, PM, Waltz, DA, et al. (2005) Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review. Chest 127,984-1005.
Clements, B Congenital malformations of the lungs and airways. Taussig, LM Landau, LI eds. Pediatric respiratory medicine 1999,1106-1136 Mosby. St. Louis, MO
Austin, J, Ali, T Tracheomalacia and Bronchomalacia in children: pathophysiology, assessment, treatment and anaesthesia management. Paediatr Anaesth 2003;13,3-11
McNamara, VM, Crabbe, DC Tracheomalacia. Paediatr Respir Rev 2004;5,147-154
Benjamin, B Tracheomalacia in infants and children. Ann Otol Rhinol Laryngol 1984;93,438-442
== External links == |
Global developmental delay | Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech, cognitive skills, and social and emotional development. There is usually a specific condition which causes this delay, such as Fragile X syndrome or other chromosomal abnormalities. However, it is sometimes difficult to identify this underlying condition.Other terms associated with this condition are failure to thrive (which focuses on lack of weight gain and physical development), intellectual disability (which focuses on intellectual deficits and the changes they cause to development) and developmental disability (which can refer to both intellectual and physical disability altering development).
Causes
Developmental delay can be caused by learning disabilities, in which case the delay can usually be overcome with time and support - such as with physiotherapists, occupational therapists,vision therapist and speech and language therapists. Other causes which may cause a permanent delay in development include genetic disorders such as Down syndrome and Fragile X, childhood infections such as meningitis or encephalitis, and metabolic disorders such as hypothyroidism. Metabolic disorders are more likely to cause delayed development in older children, as many congenital metabolic problems which are easily managed are screened for in the neonatal period. Child born prematurely (born before 37 weeks). The use of toxic substances in pregnancy, particularly alcohol, can lead to developmental delay if they affect the neurological development of the fetus, such as in fetal alcohol syndrome. Even though there are many known causes of delay, some children will never receive a diagnosis.
Investigation
Developmental monitoring is performed during wellness visits to check a childs development. Health authorities encourage parents to monitor their childs development, the CDCs program "Learn the Signs. Act Early" provides materials for a childs development is assessed based on expected milestones for actions like how they play, learn, speak, act and move. Missed milestones may be cause for concern, so the doctor or another specialist may call for a more thorough test or exam to take a closer look, this is usually done by going through Developmental Screening.
Developmental Screening is a more involved process. The evaluating professional will ask a parent to complete a research-based questionnaire that asks about a childs development, including language, movement, thinking, behavior, and emotions. Developmental Screening is recommended by the American Academy of Pediatrics (AAP) to all children at 9, 18, and 30 months. The AAP also recommends that all children be screened specifically for autism spectrum disorder (ASD) during regular well-child visits at 18 and 24 months. If a Developmental Screening indicates a delay, the child should then be assessed with a Developmental Evaluation.
Developmental Evaluations are performed by a Developmental pediatrician, child psychologist, or other trained provider with the purpose of Identifying and diagnosing developmental delays and conditions.
Chromosome microarray and karyotyping to look for trisomy, microdeletions, and duplications. It is the most sensitive diagnostic test available and is used first line in all cases, but can miss balanced translocations and low-level mosaicism.
Specific gene testing is available for certain disorders such as Rett syndrome, although these are expensive tests which arent widely available
Selective metabolic investigations may be useful in the absence of other identifiable causes, and the specific tests done will depend on the presentation. Inborn errors of metabolism causing metabolic disorders are rare and there are limited treatment options even if they are successfully diagnosed.
Targeted MRI brain can be considered second line in selected patients, and is more likely to contribute to a diagnosis if the child has abnormal physical signs such as microcephaly, macrocephaly, a change in head circumference, focal neurological signs, or epilepsy.Neonatal screening is used in the UK (Guthrie test) and can diagnose certain inborn errors of metabolism before they cause significant developmental problems, with the aim to manage them so that no permanent damage occurs.
Medium-chain acyl-CoA dehydrogenase deficiency
Homocysteinuria
Congenital hypothyroidism
Isovaleric acidaemia
Glutaricaciduria type 1
Maple syrup urine diseaseCanada, the US, and the Netherlands offer more extensive newborn screening, encompassing some other amino acid, organic, and urea cycle disorders
Management
The specific management of children with global developmental delay will depend on their individual needs and underlying diagnosis. Early intervention is essential to support the child to reach their full potential. Specialists involved in the management of GDD in children include
Speech therapists
Physical therapists
Vision therapist
Occupational therapists
Music therapists
Hearing specialists (Audiologist)
Developmental paediatricians
Neurologists
Providers of Early Intervention Services (depending on location)As well as involving professionals, parents can support the development of their child by playing with them, reading with them, showing them how to do tasks, and supporting them to participate in activities of daily living such as washing, dressing, and eating.
== References == |
Baritosis | Baritosis is a benign type of pneumoconiosis, which is caused by long-term exposure to barium dust.
Barium has a high radio-opacity and the disease may develop after few months of exposure. Extremely dense, discrete small opacities of 2–4 mm diameter, sometimes of a star-like configuration, are seen on the radiograph. Their distribution is uniform. When they are very numerous, superimposition may give the impression of confluency, but this does not seem to occur in reality. The hilar lymph nodes can be very opaque but not enlarged. After cessation of exposure, there is a gradual clearing of the opacities.
Symptoms and signs
Cough
Wheezing
Nasal irritationIn some cases, it is asymptomatic.
Diagnosis
The barium particles can be seen as opaque shadows on the chest X-rays of people with baritosis. However, being a benign condition, it neither interferes with lung function nor causes symptoms other than a mild cough.After exposure to barium dust ceases, the X-ray abnormalities gradually resolve.
Treatment
Reference
http://www.wrongdiagnosis.com/b/baritosis/intro.htm
== External links == |
Superficial thrombophlebitis | Superficial thrombophlebitis is a thrombosis and inflammation of superficial veins which presents as a painful induration with erythema, often in a linear or branching configuration forming cords.: 826–7 Superficial thrombophlebitis is due to inflammation and/or thrombosis, and less commonly infection of the vein. It is generally a benign, self-limited disorder, however, it can be complicated by deep vein thrombosis (DVT) and even pulmonary embolism (PE) Migratory superficial thrombophlebitis is known as Trousseaus syndrome.
Signs and symptoms
Findings of tenderness, induration, pain and/or erythema along the course of a superficial vein usually establish a clinical diagnosis, especially in patients with known risk factors. In addition, there is often a palpable, sometimes nodular cord, due to thrombus within the affected vein. Persistence of this cord when the extremity is raised suggests the presence of thrombus.
Complications
Superficial vein thrombosis extension to the deep vein system and/or recurrence of SVT.
Suppurative thrombophlebitis is suspected when erythema extends significantly beyond the margin of the vein and is likely to be associated with significant fever. If suspected, antibiotic treatment, surgical drainage and potentially vein excision are indicated.Venous thromboembolism can occur with superficial vein thrombosis. Estimates of the percentage of patients with SVT who also have DVT vary between 6% and 53%, and symptomatic pulmonary embolism has been reported in 0% to 10% of patients with SVT.
Risk factors
Patient characteristics and predisposing factors for thrombophlebitis nearly mirror those for DVT; thrombophlebitis is a risk factor for the development of DVT, and vice versa.
Lower extremity superficial phlebitis is associated with conditions that increase the risk of thrombosis, including abnormalities of coagulation or fibrinolysis, endothelial dysfunction, infection, venous stasis, intravenous therapy and intravenous drug abuse.
Diagnosis
Clinical evaluation is the primary diagnostic tool for thrombophlebitis. Patients with thrombophlebitis complain of pain along the affected area. Some report constitutional symptoms such as low grade fever and aches. On physical examination, the skin over the affected vein exhibits erythema, warmth, swelling, and tenderness. Later in the disease, as induration subsides, erythema gives way to a ruddy or bruised color.Duplex ultrasound identifies the presence, location and extent of venous thrombosis, and can help identify other pathology that may be a source of the patients complaints. Ultrasound is indicated if superficial phlebitis involves or extends into the proximal one-third of the medial thigh, there is evidence for clinical extension of phlebitis, lower extremity swelling is greater than would be expected from a superficial phlebitis alone or diagnosis of superficial thrombophlebitis in question.
Treatment
Treatment with compression stockings should be offered to patients with lower extremity superficial phlebitis, if not contraindicated (e.g., peripheral artery disease). Patients may find them helpful for reducing swelling and pain once the acute inflammation subsides.
Nonsteroidal anti-inflammatory drugs (NSAID) are effective in relieving the pain associated with venous inflammation and were found in a randomized trial to significantly decrease extension and/or recurrence of superficial vein thrombosis.Anticoagulation for patients with lower extremity superficial thrombophlebitis at increased risk for thromboembolism (affected venous segment of ≥5 cm, in proximity to deep venous system, positive medical risk factors).Treatment with fondaparinux reduces the risk of subsequent venous thromboembolism.Surgery reserved for extension of the clot to within 1 cm of the saphenofemoral junction in patients deemed unreliable for anticoagulation, failure of anticoagulation and patients with intense pain. Surgical therapy with ligation of saphenofemoral junction or stripping of thrombosed superficial veins appears to be associated higher rates of venous thromboembolism compared with treatment with anticoagulants.
Epidemiology
Some 125,000 cases a year have been reported in the United States, but actual incidence of spontaneous thrombophlebitis is unknown.
A fourfold increased incidence from the third to the eight decade in men and a preponderance among women of approximately 55-70%.
The average mean age of affected patients is 60 years.Thrombophlebitis can develop along the arm, back, or neck veins, the leg is by far the most common site. When it occurs in the leg, the great saphenous vein is usually involved, although other locations are possible.
See also
Septic thrombophlebitis
Superficial vein thrombosis
== References == |
Silent sinus syndrome | Silent sinus syndrome is a spontaneous, asymptomatic collapse of an air sinus (usually the maxillary sinus and orbital floor) associated with negative sinus pressures. It can cause painless facial asymmetry, diplopia and enophthalmos. Diagnosis is suspected based on symptoms, and can be confirmed using a CT scan. Treatment is surgical involving making an outlet for mucous drainage from the obstructed sinus, and, in some cases, paired with reconstruction of the orbital floor. It is slightly more common in middle age.
Signs and symptoms
Silent sinus syndrome can cause facial asymmetry (usually without pain), and vision problems (such as diplopia and enophthalmos). It may also cause headaches, and a feeling of fullness in the nose.
Mechanism
Silent sinus syndrome most often affects the maxillary sinus, usually with a collapse of the orbital floor. It may also affect the frontal sinus or the ethmoid sinus. When the maxillary sinus is involved, the inferior oblique muscle may be damaged.The cause of silent sinus syndrome is not well understood. Bacteria in the maxillary sinus may be involved. The connection to the nose may be blocked. This can create negative pressure in the sinus, as secretions are reabsorbed.
Diagnosis
Silent sinus syndrome is first suspected based on symptoms. A CT scan can be used to confirm a diagnosis. This can have characteristic features, including maxillary sinus outlet obstruction, sinus opacification, and sinus volume loss caused by inward retraction of the sinus walls.
Differential diagnosis
Silent sinus syndrome is a subtype of stage three chronic maxillary atelectasis. The distinguishing factor is that in silent sinus syndrome, there is an absence of sinusitis symptoms. To be clear, chronic maxillary sinusitis may be a primary causitive factor in a significant number of silent sinus syndrome cases, it just may be asymptomatic. Silent sinus syndrome also must be distinguished from maxillary sinus hypoplasia, which is congenital.
Treatment
Silent sinus syndrome is usually treated with surgery. The first stage involves restoring sinus function, most often by performing an endoscopic uncinectomy (removal of uncinate process) and maxillary antrostomy. The second stage, if needed, involves reconstruction of the orbital floor. While some clinics perform the two stages simultaneously, most authorities recommend waiting a minimum of 6 or as many as 18 months, as spontaneous remodeling of the orbital floor after the sinus repair will occur in many if not most cases. Any prolapsed contents (such as those from the orbit) must be put back in place, though this is an rare occurrence in an already rare syndrome. If the inferior oblique muscle is damaged, it may be partially removed (known as myectomy). Mucus and secretions must be drained from the sinus. Earlier treatment has better outcomes.
Epidemiology
Silent sinus syndrome is fairly rare. It can occur at any age, but is slightly more common in middle-aged people. It occurs equally in sinuses on each side of the face.
History
Silent sinus syndrome was first described in 1964.
References
Bibliography
Illner A, Davidson HC, Harnsberger HR, Hoffman J (2002). "The silent sinus syndrome: clinical and radiographic findings". AJR Am J Roentgenol. 178 (2): 503–6. doi:10.2214/ajr.178.2.1780503. PMID 11804926. Full text
Numa WA, Desai U, Gold DR, Heher KL, Annino DJ (2005). "Silent sinus syndrome: a case presentation and comprehensive review of all 84 reported cases". Ann Otol Rhinol Laryngol. 114 (9): 688–94. doi:10.1177/000348940511400906. PMID 16240931. S2CID 19348879.
Habicht ME, Eppenberger PE, Galassi FM, Rühli FJ, Henneberg M (2018). "Queen Meresankh III – the oldest case of bilateral Silent Sinus Syndrome (c. 2620/10 - 2570 BC)?". Anthropologie. 56 (2): 103–113. doi:10.26720/anthro.17.09.25.2.
== External links == |
Graves ophthalmopathy | Graves’ ophthalmopathy, also known as thyroid eye disease (TED), is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, lid lag, swelling, redness (erythema), conjunctivitis, and bulging eyes (exophthalmos). It occurs most commonly in individuals with Graves disease, and less commonly in individuals with Hashimotos thyroiditis, or in those who are euthyroid.It is part of a systemic process with variable expression in the eyes, thyroid, and skin, caused by autoantibodies that bind to tissues in those organs. The autoantibodies target the fibroblasts in the eye muscles, and those fibroblasts can differentiate into fat cells (adipocytes). Fat cells and muscles expand and become inflamed. Veins become compressed and are unable to drain fluid, causing edema.Annual incidence is 16/100,000 in women, 3/100,000 in men. About 3–5% have severe disease with intense pain, and sight-threatening corneal ulceration or compression of the optic nerve. Cigarette smoking, which is associated with many autoimmune diseases, raises the incidence 7.7-fold.Mild disease will often resolve and merely requires measures to reduce discomfort and dryness, such as artificial tears and smoking cessation if possible. Severe cases are a medical emergency, and are treated with glucocorticoids (steroids), and sometimes ciclosporin. Many anti-inflammatory biological mediators, such as infliximab, etanercept, and anakinra are being tried. In January 2020, the US Food and Drug Administration approved teprotumumab-trbw for the treatment of Graves’ ophthalmopathy.
Signs and symptoms
In mild disease, patients present with eyelid retraction. In fact, upper eyelid retraction is the most common ocular sign of Graves orbitopathy. This finding is associated with lid lag on infraduction (Von Graefes sign), eye globe lag on supraduction (Kochers sign), a widened palpebral fissure during fixation (Dalrymples sign) and an incapacity of closing the eyelids completely (lagophthalmos, Stellwags sign). Due to the proptosis, eyelid retraction and lagophthalmos, the cornea is more prone to dryness and may present with chemosis, punctate epithelial erosions and superior limbic keratoconjunctivitis. The patients also have a dysfunction of the lacrimal gland with a decrease of the quantity and composition of tears produced. Non-specific symptoms with these pathologies include irritation, grittiness, photophobia, tearing, and blurred vision. Pain is not typical, but patients often complain of pressure in the orbit. Periorbital swelling due to inflammation can also be observed.
Eye signsIn moderate active disease, the signs and symptoms are persistent and increasing and include myopathy. The inflammation and edema of the extraocular muscles lead to gaze abnormalities. The inferior rectus muscle is the most commonly affected muscle and patient may experience vertical diplopia on upgaze and limitation of elevation of the eyes due to fibrosis of the muscle. This may also increase the intraocular pressure of the eyes. The double vision is initially intermittent but can gradually become chronic. The medial rectus is the second-most-commonly-affected muscle, but multiple muscles may be affected, in an asymmetric fashion.In more severe and active disease, mass effects and cicatricial changes occur within the orbit. This is manifested by a progressive exophthalmos, a restrictive myopathy that restricts eye movements and an optic neuropathy. With enlargement of the extraocular muscle at the orbital apex, the optic nerve is at risk of compression. The orbital fat or the stretching of the nerve due to increased orbital volume may also lead to optic nerve damage. The patient experiences a loss of visual acuity, visual field defect, afferent pupillary defect, and loss of color vision. This is an emergency and requires immediate surgery to prevent permanent blindness.
Pathophysiology
TAO is an orbital autoimmune disease. The thyroid-stimulating hormone receptor (TSH-R) is an antigen found in orbital fat and connective tissue, and is a target for autoimmune assault.On histological examination, there is an infiltration of the orbital connective tissue by lymphocytes, plasmocytes, and mastocytes. The inflammation results in a deposition of collagen and glycosaminoglycans in the muscles, which leads to subsequent enlargement and fibrosis. There is also an induction of the lipogenesis by fibroblasts and preadipocytes, which causes enlargement of the orbital fat and extra-ocular muscle compartments. This increase in volume of the intraorbital contents within the confines of the bony orbit may lead to dysthyroid optic neuropathy (DON), increased intraocular pressures, proptosis, and venous congestion leading to chemosis and periorbital oedema. In addition, the expansion of the intraorbital soft tissue volume may also remodel the bony orbit and enlarge it, which may be a form of auto-decompression.
Diagnostic
Graves ophthalmopathy is diagnosed clinically by the presenting ocular signs and symptoms, but positive tests for antibodies (anti-thyroglobulin, anti-microsomal and anti-thyrotropin receptor) and abnormalities in thyroid hormones level (T3, T4, and TSH) help in supporting the diagnosis.Orbital imaging is an interesting tool for the diagnosis of Graves ophthalmopathy and is useful in monitoring patients for progression of the disease. It is, however, not warranted when the diagnosis can be established clinically. Ultrasonography may detect early Graves orbitopathy in patients without clinical orbital findings. It is less reliable than the CT scan and magnetic resonance imaging (MRI), however, to assess the extraocular muscle involvement at the orbital apex, which may lead to blindness. Thus, CT scan or MRI is necessary when optic nerve involvement is suspected. On neuroimaging, the most characteristic findings are thick extraocular muscles with tendon sparing, usually bilateral, and proptosis.
Classification
Mnemonic: "NO SPECS":
Prevention
Not smoking is a common suggestion in the literature. Apart from smoking cessation, there is little definitive research in this area. In addition to the selenium studies above, some recent research also is suggestive that statin use may assist.
Treatment
Even though some people undergo spontaneous remission of symptoms within a year, many need treatment. The first step is the regulation of thyroid hormone levels. Topical lubrication of the eye is used to avoid corneal damage caused by exposure. Corticosteroids are efficient in reducing orbital inflammation, but the benefits cease after discontinuation. Corticosteroids treatment is also limited because of their many side effects. Radiotherapy is an alternative option to reduce acute orbital inflammation. However, there is still controversy surrounding its efficacy. A simple way of reducing inflammation is to stop smoking, as pro-inflammatory substances are found in cigarettes. The medication teprotumumab-trbw may also be used. There is tentative evidence for selenium in mild disease. Tocilizumab, a drug used to suppress the immune system has also been studied as a treatment for TED. However, a Cochrane Review published in 2018 found no evidence (no relevant clinical studies were published) to show that tocilizumab works in people with TED.In January 2020, the US Food and Drug Administration approved teprotumumab-trbw for the treatment of Graves ophthalmopathy.
Surgery
There is some evidence that a total or sub-total thyroidectomy may assist in reducing levels of TSH receptor antibodies (TRAbs) and as a consequence reduce the eye symptoms, perhaps after a 12-month lag. However, a 2015 meta review found no such benefits, and there is some evidence that suggests that surgery is no better than medication.Surgery may be done to decompress the orbit, to improve the proptosis, and to address the strabismus causing diplopia. Surgery is performed once the persons disease has been stable for at least six months. In severe cases, however, the surgery becomes urgent to prevent blindness from optic nerve compression. Because the eye socket is bone, there is nowhere for eye muscle swelling to be accommodated, and, as a result, the eye is pushed forward into a protruded position. Orbital decompression involves removing some bone from the eye socket to open up one or more sinuses and so make space for the swollen tissue and allowing the eye to move back into normal position and also relieving compression of the optic nerve that can threaten sight.Eyelid surgery is the most common surgery performed on Graves ophthalmopathy patients. Lid-lengthening surgeries can be done on upper and lower eyelid to correct the patients appearance and the ocular surface exposure symptoms. Marginal myotomy of levator palpebrae muscle can reduce the palpebral fissure height by 2–3 mm. When there is a more severe upper lid retraction or exposure keratitis, marginal myotomy of levator palpebrae associated with lateral tarsal canthoplasty is recommended. This procedure can lower the upper eyelid by as much as 8 mm. Other approaches include müllerectomy (resection of the Müller muscle), eyelid spacer grafts, and recession of the lower eyelid retractors. Blepharoplasty can also be done to debulk the excess fat in the lower eyelid.A summary of treatment recommendations was published in 2015 by an Italian taskforce, which largely supports the other studies.
Prognosis
Risk factors of progressive and severe thyroid-associated orbitopathy are:
Age greater than 50 years
Rapid onset of symptoms under 3 months
Cigarette smoking
Diabetes
Severe or uncontrolled hyperthyroidism
Presence of pretibial myxedema
High cholesterol levels (hyperlipidemia)
Peripheral vascular disease
Epidemiology
The pathology mostly affects persons of 30 to 50 years of age. Females are four times more likely to develop TAO than males. When males are affected, they tend to have a later onset and a poor prognosis. A study demonstrated that at the time of diagnosis, 90% of the patients with clinical orbitopathy were hyperthyroid according to thyroid function tests, while 3% had Hashimotos thyroiditis, 1% were hypothyroid and 6% did not have any thyroid function tests abnormality. Of patients with Graves hyperthyroidism, 20 to 25 percent have clinically obvious Graves ophthalmopathy, while only 3–5% will develop severe ophthalmopathy.
History
In medical literature, Robert James Graves, in 1835, was the first to describe the association of a thyroid goitre with exophthalmos (proptosis) of the eye. Graves ophthalmopathy may occur before, with, or after the onset of overt thyroid disease and usually has a slow onset over many months.
See also
Infiltrative ophthalmopathy
Exophthalmos
References
Further reading
== External links == |
Lymphocytic meningoradiculitis | Lymphocytic meningoradiculitis, also known as Bannwarth syndrome, is a neurological disease characterized as intense nerve pain radiating from the spine. The disease is caused by an infection of Borrelia burgdorferi, a tick-borne spirochete bacterium also responsible for causing Lyme disease.
Signs and symptoms
Lymphocytic meningoradiculitis is characterized by an intense spinal pain in the lumbar and cervical regions, radiating to the extremities. Symptoms may include facial paralysis, abducens palsy, anorexia, tiredness, headache, double vision, paraesthesia, and erythema migrans.
Treatment
Lymphocytic meningoradiculitis is treated with antibiotics. Oral doxycycline or IV ceftriaxone are typically recommended for 14-21 days.
History
The disease was first reported in 1941 by German neurologist, Alfred Bannwarth, who described the main symptoms as intense radicular pain, facial palsy, severe headaches, and vomiting. A common feature he observed in his infected patients was an abnormal increase of lymphocytes in their cerebrospinal fluid (CSF).
See also
Tick-borne disease
References
== External links == |
Central retinal artery occlusion | Central retinal artery occlusion (CRAO) is a disease of the eye where the flow of blood through the central retinal artery is blocked (occluded). There are several different causes of this occlusion; the most common is carotid artery atherosclerosis.
Signs and symptoms
Central retinal artery occlusion is characterized by painless, acute vision loss in one eye. Upon fundoscopic exam, one would expect to find: cherry-red spot (90%) (a morphologic description in which the normally red background of the choroid is sharply outlined by the swollen opaque retina in the central retina), retinal opacity in the posterior pole (58%), pallor (39%), retinal arterial attenuation (32%), and optic disk edema (22%). During later stages of onset, one may also find plaques, emboli, and optic atrophy.
Diagnosis
One diagnostic method for the confirmation of CRAO is Fluorescein angiography, it is used to examine the retinal artery filling time after the fluorescein dye is injected into the peripheral venous system. In an eye with CRAO some branches of the retinal artery may not fill or the time it takes for the branches of the retinal artery to fill will be increased, which is visualized by the leading edge of the fluorescein moving slower than normal through the retinal artery branches to the edges of the retina. Fluorescein angiography can also be used to determine the extent of the occlusion as well as classify it into one of four types non-arteritic CRAO, non-arteritic CRAO with cilioretinal artery sparing, transient non-arteritic CRAO and arteritic CRAO. Optical coherence tomography (OCT) may also be used to confirm the diagnosis of CRAO.
Causes
CRAO can be classified based on it pathogenesis, as arteritic versus non-arteritic. Non-arteritic CRAO is most commonly caused by an embolus and occlusion at the narrowest part of the carotid retinal artery due to plaques in the carotid artery resulting in carotid retinal artery atherosclerosis. Further causes of non-arteritic CRAO may include vasculitis and chronic systemic autoimmune diseases. Arteritic CRAO is most commonly caused by giant cell arteritis. Other causes can include dissecting aneurysms and arterial spasms, and as a complication of patient positioning causing external compression of the eye compressing flow to the central retinal artery (e.g. in spine surgeries in the prone position).
Mechanism
The ophthalmic artery branches off into the central retinal artery which travels with the optic nerve until it enters the eye. This central retinal artery provides nutrients to the retina of the eye, more specifically the inner retina and the surface of the optic nerve. Variations, such as branch retinal artery occlusion, can also occur. Central retinal artery occlusion is most often due to emboli blocking the artery and therefore prevents the artery from delivering nutrients to most of the retina. These emboli originate from the carotid arteries most of the time but in 25% of cases, this is due to plaque build-up in the ophthalmic artery. The most frequent site of blockage is at the most narrow part of the artery which is where the artery pierces the dura covering the optic nerve. Some people have cilioretinal arterial branches, which may or may not be included in the blocked portion.
Treatment
While no treatment has been clearly demonstrated to be benefit for CRAO in large systematic reviews of randomized clinical trials, many of the following are frequently used:
Lowering intraocular pressure;
Dilating the CRA;
Increasing oxygenation;
Isovolemic hemodilution;
Anticoagulation;
Dislodging or fragmenting thrombus or embolus;
Thrombolysis; and
Hyperbaric oxygen.To achieve the best outcome for a person with CRAO, it is important to identify the condition in a timely manner and to refer to the appropriate specialist.
Prognosis
The artery can re-canalize over time and the edema can clear. However, optic atrophy leads to permanent loss of vision. Irreversible damage to neural tissue can occur after approximately 15 minutes of complete blockage to the central retinal artery, but this time may vary between people. Two thirds of people experience 20/400 vision while only one in six will experience 20/40 vision or better.
Epidemiology
The incidence of CRAO is approximately 1 in 100,000 people in the general population. Risk factors for CRAO include the following: being over 50 years of age, male gender, smoking, hypertension, tranexamic acid, diabetes mellitus, dyslipidemia, angina, valvular disease, transient hemiparesis, cancer, hypercoagulable blood conditions, lupus, or a family history of cerebrovascular or cardiovascular issues. Additional risk factors include endocarditis, atrial myxoma, inflammatory diseases of the blood vessels, and predisposition to forming blood clots.
See also
Central retinal vein occlusion
Branch retinal artery occlusion
Branch retinal vein occlusion
Amaurosis fugax
Ocular ischemic syndrome
References
== External links == |
Diplopodia | Diplopodia is a congenital anomaly in tetrapods that involves duplication of elements of the foot on the hind limb. It comes from the Greek roots diplo = "double" and pod = "foot". Diplopodia is often found in conjunction with other structural abnormalities and can be lethal. It is more extreme than polydactyly, the presence of extra digits.
Description
The affected leg usually has one foot that is in an approximately normal position. The extra foot is composed of at least some metatarsal or tarsal bones and extra digits, though it is usually not complete. The feet can be joined together, so that the limb appears to have one large foot, or the extra foot can be joined to the limb separately, usually above the level of the other foot. Diplopodia affects one or both of the hind limbs.
Causes
Recessive alleles of some genes involved in embryonic limb patterning produce bilateral diplopodia, and diplopodia can be experimentally induced in early embryos. Many instances of diplopodia in humans have no apparent cause.People have been able to produce diplopod limbs by increasing sonic hedgehog (shh) signaling in the limb buds of embryos. The zone of polarizing activity (ZPA) in the proximal posterior mesoderm of a tetrapod limb bud is responsible for maintaining the anterior-posterior axis of the growing limb. The ZPA secretes shh protein, which induces formation of the distal segment of the limb, or autopod, with its posterior side facing the ZPA. When ZPA cells, non-ZPA cells made to express shh, or simply shh protein-soaked beads are implanted in the anterior side of a limb bud, the end of the resulting limb is duplicated, as in diplopodia. The posterior autopod on that limb has the normal orientation, and the extra, anterior autopod has a reversed anterior-posterior axis. This is because the original ZPA and the added source of shh signaling each induce the formation of an autopod.
Diplopodia in humans
Diplopodia is often found in combination with aplasia or hypoplasia of the tibia. Sometimes, the tibia is replaced by another fibula The extra foot is almost always joined to the normal foot, though a case was described where a nearly complete extra foot joined to the back of the ankle.
Diplopodia in chickens
People have identified five recessive lethal mutations in chickens that cause bilateral diplopodia. The genes are numbered in the order of their discoveries, with the symbols dp-1, dp-2, dp-3, dp-4, and dp-5.
Chickens normally have an anisodactyl toe arrangement, with one short toe pointing backwards and three long toes pointing forwards. In diplopodia, the feet usually lack the normal hind toe and instead develop two to four extra toes at various positions between the hock joint and the front toes. The toes are almost always connected to extra tarso-metatarsal bones, though sometimes the toes do not contain any bone. Embryos with diplopodia have been found with numbers of digits on one wing ranging from one to seven, while normal embryos have three digits per wing. Diplopod limb buds first differ visibly from normal limb buds by their abnormally thick and long apical ectodermal ridges. Diplopodia usually delays the embryonic growth of cartilage, bone, and tendon by two days, particularly in the limbs. Other characteristics frequently seen in diplopodia mutants are shortened wings and legs, short upper beak, and smaller embryo size. Many embryos reach the final embryonic stage but then are unable to hatch, though, diplopod embryos can occasionally hatch and mature.Single diplopodia mutations produce wide ranges of phenotypes sharing these general characteristics and can even affect individual chickens left and right legs differently. The ranges of phenotypes produced by the different mutations also overlap broadly, so diplopodia mutations sometimes need to be distinguished by their phenotype distributions. Dr. Ursula Abbott has extensively studied the phenotypes and descriptions of the first four diplopodia mutations and has ranked them from least severe to most severe: dp-3, dp-1, dp-4, dp-2.Diplopodia-1
This autosomal mutation gives homozygotes duplicated wing tips and feet in front of the usual structures, as in the experimentally induced diplopodia described above. However, unlike the experimentally manipulated embryos, these embryos show no change in shh expression. The embryos express hoxd-11, hoxd-12, hoxd-13, Bmp-2, and Fgf-4 along the whole edge of each limb bud, even though these genes are normally only expressed at the posterior edge.Diplopodia-2
This is an autosomal trait that gives a very extreme diplopod phenotype, with up to eight toes on a foot. In some embryos, the two outer front toes on each foot are joined together. The trait is now extinct and was never fully characterized.Diplopodia-3
This is an autosomal trait that may be the least severe of the five.
Diplopodia-4
This sex-linked mutation is similar to the previous mutations, but causes the embryo to grow thicker wing bones.Diplopodia-5
This is an autosomal mutation that gives embryos webbing between the inner two front toes on each foot, in addition to the usual characteristics of diplopodia. Almost all of the embryos survive to the end of incubation, but they are unable to clear the fluid from their lungs or absorb the blood from their extraembryonic vessels. These problems always prevent them from hatching. Almost all diplopodia-5 embryos have only one or two extra toes on each foot, so this mutation causes the least extreme foot malformation.
See also
Limb development
Congenital abnormality
Dysmelia
Sonic hedgehog
Polydactyly
== References == |
Acropectoral syndrome | Acropectoral syndrome is an autosomal dominant skeletal dysplasia syndrome affecting the hands, feet, sternum, and lumbosacral spine. A recently proposed candidate gene for preaxial polydactyly is LMBR1, encoding a novel transmembrane receptor, which may be an upstream regulator of SHH. The LMBR1 gene is on human chromosome 7q36.
Presentation
Some individuals have preaxial polydactyly in the feet (unilateral in one, bilateral in 13), consisting of a small extra biphalangeal toe, in most cases with an associated rudimentary extra metatarsal, lying in a soft tissue web between the hallux and second toe. In some cases, this was accompanied by hypoplasia of the head of the first metatarsal and absence of both phalanges of the hallux.
Genetics
The cytogenetic location is 7q36 and genomic coordinates are GRCh37:147,900,000 - 159,138,663 (NCBI). Mapping of this syndrome was done by Dundar and coworkers in 2001. They showed that this phenotype was linked to a 6.4-cM region of 7q36 flanked by the EN2 gene and the marker D7S2423. Dundar and coworkers characterized and mapped acropectoral syndrome and also showed it was unrelated to acropectorovertebral syndrome. The mapping showed that the acropectoral locus was in a region where preaxial polydactyly and triphalangeal thumb-polysyndactyly had previously been mapped. This study was important because it expanded the range of phenotypes that are connected to this locus. Previously, preaxial polydactyly and sternal defects have been linked to ectopic expression of the gene Sonic hedgehog Shh in limbbud and lateral plate mesoderm during development in mice. Dundar and coworkers found that the LMBR1 gene links to pre axial polydactyly. This gene encodes for a new transmembrane receptor and it is proposed that this receptor is an upstream regulator of SHH.
Diagnosis
Management
Society
Three main support groups of this syndrome are the ASGA in Australia, The Association for Children with Genetic Disorders in Poland, and the Association of People of Genetic Disorders in Greece.
References
== External links == |
Papillary renal cell carcinoma | Papillary renal cell carcinoma (PRCC) is a malignant, heterogeneous tumor originating from renal tubular epithelial cells of the kidney, which comprises approximately 10-15% of all kidney neoplasms. Based on its morphological features, PRCC can be classified into two main subtypes, which are type 1 (basophilic) and type 2 (eosinophilic).As with other types of renal cell cancer, most cases of PRCC are discovered incidentally without showing specific signs or symptoms of cancer. In advanced stages, hematuria, flank pain, and abdominal mass are the three classic manifestation. While a complete list of the causes of PRCC remains unclear, several risk factors were identified to affect PRCC development, such as genetic mutations, kidney-related disease, environmental and lifestyle risk factors. For pathogenesis, type 1 PRCC is mainly caused by MET gene mutation while type 2 PRCC is associated with several different genetic pathways. For diagnosis, PRCC is detectable through computed tomography (CT) scans or magnetic resonance imaging (MRI), which commonly present a small homogeneous hyposvascular tumor. Nephrectomy or partial nephrectomy is usually recommended for PRCC treatment, often accompanied with several targeted molecular therapies to inhibit metastatic spread. PRCC patients are predominantly male with a mean age of 52–66 years. When compared to conventional clear cell renal cell carcinoma (RCC), the prognosis of non-metastatic PRCC is more favorable, whereas a relatively worse outcome was reported in patients with metastatic disease. Globally, the incidence of PRCC ranges between 3,500 to 5,000 cases, while it greatly varies depending on gender, age, and race/ethnicity.
Classification
In 2014, PRCC was first acknowledged as a renal tumor subtype by the World Health Organization (WHO) considering its distinct genetic, molecular and histologic characteristics. It is further divided into type 1 and type 2 based on morphological features.
Type 1 Papillary Renal Cell Carcinoma
Type 1 PRCC, also known as a renal tumor caused by a genetic predisposition of hereditary papillary renal cancer syndrome, compromises approximately 25% of all PRCCs. In the perspective of immunochemistry, it has a profile of strong CK7 and alpha-methyl acyl-CoA racemase (AMACR) expression at most focal CA-IX expression. Histologically, its epithelium is composed of relatively small-sized simple cuboidal cells lined in a single layer. These cells are well-characterized by basophilic cytoplasm. Due to its solid growth, an extremely compact papillary architecture is often observed. Other morphological characteristics include intracellular hemosiderin and foamy macrophages placed inside of papillary fibrovascular cores or psammoma bodies. In general, the nuclei of type 1 PRCC belong to grade 1-2 of the Fuhrman system.
Type 2 Papillary renal cell carcinoma
Accounting for 25% of PRCCs, type 2 PRCC is the pathological subtype that is most commonly associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. When compared to type 1, it shows more variation in protein expression mostly by loss of CK7. In a gross examination, it shows papillae covered by large cells abundant in eosinophilic cytoplasm. Its large spherical nuclei on papillary cores are arranged in a pseudo-stratified manner. Unlike type 1 PRCC, foamy macrophages and psammoma bodies are less common in case of type 2. The majority of type 2 PRCC has high Fuhrman grade nuclei with prominent nucleoli.
Signs and Symptoms
Due to its asymptomatic nature, PRCC is often undetectable, and the majority of cases are incidentally diagnosed during the radiological workup of unrelated diseases. Its clinical manifestations are similar to those of clear cell RCC, which are the classical triad of renal cell carcinoma (hematuria, flank pain and palpable abdominal mass; only 6-10% of patients) or even nonspecific symptoms including fatigue, weight loss, fever, and anorexia. Since early diagnosis is relatively uncommon, PRCC patients may experience symptoms caused by the metastatic spread to secondary sites. Specifically, metastasis occurs most frequently in the lungs followed by bone and the brain, exhibiting a wide range of symptoms including bone pain to a persistent cough.
Causes
Currently, the exact cause of PRCC remains unclear. Possible risk factors have been identified that contribute to PRCC development, which include genetic mutations, hereditary syndrome, renal injuries, and lifestyle factors. Germline mutation of c-MET oncogene and fumarate hydratase gene elevates the risk of type 1 and type 2 PRCC respectively through distinct signaling pathways. Regarding hereditary conditions, patients with hereditary papillary renal cancer syndrome showed a greater risk of type 1 PRCC, whereas those with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome have an increased risk of type 2 PRCC. Moreover, patients who experienced chronic kidney diseases or acute kidney injury exhibited a higher incidence of PRCC. Additionally, other risk factors such as smoking, obesity, and high blood pressure can influence the pathogenesis of PRCC.
Pathogenesis
Different molecular mechanisms are involved in PRCC development, which further result in distinct histologic features and clinical outcomes.Type 1 PRCC is caused by a genetic mutation or a gain in chromosome 7 where the MET gene is positioned, resulting in the promotion of oncogenic pathways in renal epithelial cells. Typically, the MET gene is upregulated for renal tissue repair and regeneration by encoding the receptor tyrosine kinase c-MET of hepatocyte growth factor. However, activation of the oncogenic pathway in the MET gene will manifest invasion, anti-apoptosis, angiogenesis, and metastasis.Type 2 PRCC is associated with irregularity of several signaling pathways, which includes CDKN2A silencing, mutation in chromatin-modifying genes, and a GpG island methylator phenotype (CIMP). CDKN2A is a tumor suppressor gene, while loss of its expression results in enhanced tumorigenesis and metastasis. Moreover, mutation of gene involved in chromatin remodeling (SETD2, BAP1, or PBRM) may lead to higher rate of TFE3/TFEB fusion. Additionally, CIMP papillary renal cell carcinoma tumors exhibited somatic FH gene mutation, which is closely associated with HLRCC syndrome.
Diagnosis
Currently, cross-sectional imaging with computed tomography (CT) and magnetic resonance imaging (MRI) is known as the best option for diagnosing papillary renal tumors.
Computed tomography (CT)
Contrast-enhanced computed tomography (CT) is most commonly used to identify the subtypes of RCC. PRCC can be differentiated from other types of RCC due to its distinguishing features, displaying a small hypovascular renal tumor on T2 weighted images. Typically, PRCC tends to appear homogeneous while clear cell RCC is likely to be in a heterogeneous form when the tumor is less than 3 cm in diameter. Comparatively, in cases of tumors larger than 3 cm in diameter, PRCC is generally heterogeneous with areas of necrosis and hemorrhage compared to chromophobe RCC. Solid, small PRCC tumors (<3 cm in diameter) are more easily viewed on nephrographic, excretory phase images rather than on unenhanced, corticomedullary phase images.
Magnetic resonance imaging (MRI)
Magnetic resonance imaging (MRI) is recommended instead of CT for patients with an allergy to iodinated contrast materials. As some renal tumors do not enhance significantly on CT, MRI examination is required to be performed with more sensitive contrast enhancement. On MRI, the distinct features of PRCC are fibrous capsules and homogeneously low single intensity on both T1- and T2-weighted images. Specifically, PRCC exhibits hypointensity due to its dense collagenous matrix or deposition of calcium and hemosiderin within the tumor. Such visual features help PRCC to be differentiated from clear cell RCC, which has heterogeneously higher single intensity shown on T2-weighted images. PRCC displays the smallest tumor-to-cortex enhancement at corticomedullary and nephrographic phases when juxtaposed with clear cell and chromophobe RCCs.
Grading System
The WHO/ISUP system is histological tumor grading system for renal cell carcinoma, suggested by the International Society of Urologic Pathologists (ISUP) in 2012 to diagnose tumor grades based on nucleolar prominence. Currently recommended by the WHO, this four-tiered WHO/ISUP grading system has also been validated for PRCC.
Earlier, the Fuhrman system was largely used, and was similarly based on nuclear features.
Treatment
First-line treatment for metastatic PRCC has not been standardized. Thus, similar treatment approaches for clear cell RCC have been used for PRCC, even though it has a distinct tumor histology.
Surgery
Nephrectomy or nephron-sharing partial nephrectomy is widely recommended to reduce the risk of metastasis by eliminating all or part of the kidney. Surgery procedures for PRCC depend on the patients status and are very similar to procedures performed on RCC patients.
Targeted Therapy
Several medications that target molecular pathways in RCC have been possible options for advanced and metastatic PRCC. Among different medications, tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors are effective in inhibiting angiogenesis, blocking growth and suppressing spread of the tumor. Sunitinib, sorafenib, and axitinib are TKIs with anti-vascular endothelial growth factor (VEGF), which inhibit cellular signaling by targeting multiple receptor tyrosine kinase. Everolimus and temsirolimus are used in deregulating the mTOR pathway. Specifically, mTOR inhibitors have crucial roles in regulating cell growth, cell proliferation and metabolism of highly active tumor cells. Other targeted agents such as MET inhibitors, epidermal growth factor receptor (EGFR) inhibitors, and monoclonal antibodies, are also promising treatment approaches for PRCC. Foretinib is one example of a multikinase inhibitor targeting c-MET. Considering that MET gene mutation is one oncogenic pathway of PRCC, MET inhibitors like tivantinib and volitinib are currently being investigated as a new targeted therapy option.
Prognosis
The five-year survival rate of PRCC has been reported as 82-90%, which is slightly higher than that of other kidney cancers. The reduced survival rate has been positively correlated to several factors, which are high nuclear grade and stage, vascular invasion, DNA aneuploidy, and more. Patients with type 1 PRCC have significantly improved survival rates than those with type 2, which is a reflection of its lower TNM stage with a well-encapsulated tumor. Compared to other common types of RCC, PRCC exhibits a relatively lower risk of tumor recurrence and cancer-related death after nephrectomy. Specifically, the cancer-specific survival rate at five years following surgery with PRCC has reached up to 91%, while clear cell RCC and chromophobe RCC were 72% and 88%, respectively.
Epidemiology
Among different histologic subtypes of RCC, PRCC is the second most predominant type and accounts for 10-15% of all renal tumors. In the case of the United States, it is estimated that the incidence of PRCC will rise to 3,500 to 5,000 cases annually. Generally, PRCC is more prevalent among men than women, while the reported sex ratio (M: F) varies from 1.8:1 to 3.8:1. The mean age at presentation is identified as 52–66 years old; however, no statistically significant difference was found in the incidence of PRCC between the younger (< 40 years) and older adult groups (>40 years). In terms of racial variation, several studies have proven that people with African or Afro-Caribbean ancestry tend to have higher chances of being diagnosed with PRCC. According to the National Cancer Database, PRCC was more common in the Non-Hispanic Black population (38.9%) when compared to other races – Asian American (18.0%), Non-Hispanic White (13.2%), and Hispanic White populations (6.1%).
References
== External links == |
Tuberculous dactylitis | Tuberculous dactylitis is a skeletal manifestation of tuberculosis, one of the commonest bacterial osteitis. It affects children more often than adults. The first radiological description of the condition is credited to Feilchenfeld in 1896; however, the first histological description was given by Rankin in 1886. The Swedish botanist and physician Carl von Linne was the first to mention the condition by the name "spina ventosa" 1746 in his "Västgöta resa".Multiple bones are involved in children and usually only a single bone is involved in adults suffering from tuberculous dactylitis. Tuberculous dactylitis affects the short tubular bones of the hands and feet in children. It often follows a mild course without fever and acute inflammatory signs as opposed to acute osteomyelitis. There may be a gap of a few months to 2 to 3 years from the time of initial infection to the point of diagnosis.Spina ventosa is the term given for tuberculous dactylitis. Nearly 85% of the patients of spina ventosa are below 6 years of age. The bones of hands are more commonly involved than those of the feet. Proximal phalanx of the index and middle fingers are the commonest sites of involvement. Up to nearly 7% of children with pulmonary tuberculosis may develop this condition. Spread to the skeletal system is believed to occur via blood and lymphatics.
Pathogenesis
In the pediatric age group, the marrow in the phalangeal bones are still active, a conducive place for the tuberculous bacilli to multiply. Slowly, the whole marrow space gets involved and this underlying granulomatous disease leads to expansion of the overlying soft cortex. Finally there is a fusiform dilation of the bone, with thinned out cortex and destruction of the marrow space leading to a balloon like shape; this cystic type of expansion of the bone is termed as spina ventosa.
Diagnosis
The diagnosis of the condition is made on the basis of histological and bacteriological studies. Tuberculosis dactylitis may be confused with conditions like osteomyelitis, gout, sarcoidosis and tumors.
Treatment
References
== External links == |
Acne fulminans | Acne fulminans (also known as "acute febrile ulcerative acne": 686 ) is a severe form of the skin disease, acne, which can occur after unsuccessful treatment for another form of acne, acne conglobata. The condition is thought to be an immunologically induced disease in which elevated level of testosterone causes a rise in sebum and population of Cutibacterium acnes bacteria. The increase in the amount of C acnes or related antigens may trigger the immunologic reaction in some individuals and lead to an occurrence of acne fulminans. In addition to testosterone, isotretinoin may also precipitate acne fulminans, possibly related to highly increased levels of C acnes antigens in the patients immune system. Acne fulminans is a rare disease. Over the past several years, fewer cases of this disease have occurred, possibly because of earlier and better treatment of acne. Approximately 100 patients with acne fulminans have been described.
Signs and symptoms
Acne fulminans begins as pain and inflammation in the joints. It eventually progresses into a swelling of the lymph nodes located at the base of the neck, causing inflexibility in the neck within weeks after the nodes swell. This swelling will eventually decrease, but this decrease will be accompanied by an increased inflammation and swelling of the joints, as well as a complete loss of appetite, though these symptoms are often ignored. After some time, the disease will cause an extreme loss of weight and atrophy of the muscles, leading to the decline of physical abilities.
Outcome and treatment
There is limited evidenced-based data concerning the treatment of AF. Treatment should be sought immediately in order to avoid hospitalization. If not treated, hospitalization for an extended period of time (usually two weeks) is likely. During hospitalization, the patient is tested for signs of system degradation, especially of the skeletal structure and the digestive tract. By this time open sores will develop on the upper torso. Some will be the size of dimes, others will be large enough to stick a couple fingers into. They will crust up, causing cohesion to any fabric the sores touch, which is extremely painful to remove. It is recommended to sleep on ones sides until the cystic condition subsides, in order to avoid any uncomfortable situations. Debridement and steroid therapy is preferred over antibiotics. Recurrent AF is extremely rare. Bone lesions typically resolve with treatment, but residual radiographic changes, such as sclerosis and hyperostosis, may remain. Scarring and fibrosis may result from this acute inflammatory process. The disease activates at the height of puberty, usually at around 13 years of age. Acne fulminans predominantly affects young males aged 13 to 22 years with a history of acne. Studies have found successful treatment with Antimicrobial Agents and Oral Prednisolone.
History
In 1958, at a meeting of the Detroit Dermatological Society, Burns and Colville presented a 16-year-old white boy with acute febrile disease and acne conglobata. Many similar cases have been reported since then. Genetic factors may play an important role in some patients; 4 sets of identical twins who developed an identical pattern of acne fulminans have been documented.
See also
List of cutaneous conditions
References
== External links == |
Pleomorphic fibroma | Pleomorphic fibromas of the skin usually present in adults, with a slight preponderance in women.
See also
Pleomorphic lipoma
List of cutaneous conditions
== References == |
Acute stress disorder | Acute stress disorder (ASD, also known as acute stress reaction, psychological shock, mental shock, or simply shock) is a psychological response to a terrifying, traumatic or surprising experience. It may bring about delayed stress reactions (better known as post-traumatic stress disorder, or PTSD) if not correctly addressed.
Types
Sympathetic
Sympathetic acute stress disorder is caused by the release of excessive adrenaline and norepinephrine into the nervous system. These hormones may speed up a persons pulse and respiratory rate, dilate pupils, or temporarily mask pain. This type of ASD developed as an evolutionary advantage to help humans survive dangerous situations. The "fight or flight" response may allow for temporarily-enhanced physical output, even in the face of severe injury. However, other physical illnesses become more difficult to diagnose, as ASD masks the pain and other vital signs that would otherwise be symptomatic.
Parasympathetic
Parasympathetic acute stress disorder is characterised by feeling faint and nauseated. This response is fairly often triggered by the sight of blood. In this stress response, the body releases acetylcholine. In many ways, this reaction is the opposite of the sympathetic response, in that it slows the heart rate and can cause the patient to either regurgitate or temporarily lose consciousness. The evolutionary value of this is unclear, although it may have allowed for prey to appear dead to avoid being eaten.
Signs and symptoms
The DSM-IV specifies that acute stress disorder must be accompanied by the presence of dissociative symptoms, which largely differentiates it from post-traumatic stress disorder.
Dissociative symptoms include a sense of numbing or detachment from emotional reactions, a sense of physical detachment – such as seeing oneself from another perspective – decreased awareness of ones surroundings, the perception that ones environment is unreal or dreamlike, and the inability to recall critical aspects of the traumatic event (dissociative amnesia).In addition to these characteristics, ASD can be present in the following symptom clusters: intrusion, negative mood, disassociation, avoidance of distressing memories and emotional arousal. Intrusion symptoms include recurring and distressing dreams, flashbacks, or memories related to the traumatic event and related somatic symptoms. Emotional arousal symptoms include sleep disturbances, hypervigilance, difficulties with concentration, more common startle response, and irritability.
Complications
There are a number of issues that can arise from acute stress. Depression, anxiety, mood disorders, and substance abuse problems can develop from acute stress. Untreated ASD can also lead to the development of post-traumatic stress disorder.
Causes
There are several theoretical perspectives on trauma response, including cognitive, biological, and psycho-biological. While PTSD-specific, these theories are still useful in understanding acute stress disorder, as the two disorders share many symptoms. A recent study found that even a single stressful event may have long-term consequences on cognitive function. This result calls the traditional distinction between the effects of acute and chronic stress into question.
Pathophysiology
Stress is characterised by specific physiological responses to adverse or noxious stimuli.
Hans Selye was the first to coin the term "general adaptation syndrome" to suggest that stress-induced physiological responses proceed through the stages of alarm, resistance, and exhaustion.The sympathetic branch of the autonomic nervous system gives rise to a specific set of physiological responses to physical or psychological stress. The bodys response to stress is also termed a "fight or flight" response, and it is characterised by an increase in blood flow to the skeletal muscles, heart, and brain, a rise in heart rate and blood pressure, dilation of pupils, and an increase in the amount of glucose released by the liver.The onset of an acute stress response is associated with specific physiological actions in the sympathetic nervous system, both directly and indirectly through the release of adrenaline and, to a lesser extent, noradrenaline from the medulla of the adrenal glands. These catecholamine hormones facilitate immediate physical reactions by triggering increases in heart rate and breathing, constricting blood vessels. An abundance of catecholamines at neuroreceptor sites facilitates reliance on spontaneous or intuitive behaviours often related to combat or escape.Normally, when a person is in a serene, non-stimulated state, the firing of neurons in the locus ceruleus is minimal. A novel stimulus, once perceived, is relayed from the sensory cortex of the brain through the thalamus to the brain stem. That route of signalling increases the rate of noradrenergic activity in the locus ceruleus, and the person becomes more alert and attentive to their environment.If a stimulus is perceived as a threat, a more intense and prolonged discharge of the locus ceruleus activates the sympathetic division of the autonomic nervous system. The activation of the sympathetic nervous system leads to the release of norepinephrine from nerve endings acting on the heart, blood vessels, respiratory centres, and other sites. The ensuing physiological changes constitute a major part of the acute stress response. The other major player in the acute stress response is the hypothalamic-pituitary-adrenal axis. Stress activates this axis and produces neuro-biological changes. These chemical changes increase the chances of survival by bringing the physiological system back to homeostasis.The autonomic nervous system controls all automatic functions in the body and contains two subsections within it that aid the response to an acute stress reaction. These two subunits are the sympathetic nervous system and the parasympathetic nervous system. The sympathetic response is colloquially known as the "fight or flight" response, indicated by accelerated pulse and respiration rates, pupil dilation, and a general feeling of anxiety and hyper-awareness. This is caused by the release of epinephrine and norepinephrine from the adrenal glands. The epinephrine and norepinephrine strike the beta receptors of the heart, which feeds the hearts sympathetic nerve fibres to increase the strength of heart muscle contraction; as a result, more blood gets circulated, increasing the heart rate and respiratory rate. The sympathetic nervous system also stimulates the skeletal system and muscular system to pump more blood to those areas to handle the acute stress. Simultaneously, the sympathetic nervous system inhibits the digestive system and the urinary system to optimise blood flow to the heart, lungs, and skeletal muscles. This plays a role in the alarm reaction stage. The parasympathetic response is colloquially known as the "rest and digest" response, indicated by reduced heart and respiration rates, and, more obviously, by a temporary loss of consciousness if the system is fired at a rapid rate. The parasympathetic nervous system stimulates the digestive system and urinary system to send more blood to those systems to increase the process of digestion. To do this, it must inhibit the cardiovascular system and respiratory system to optimise blood flow to the digestive tract, causing low heart and respiratory rates. The parasympathetic nervous system plays no role in acute stress response.Studies have shown that patients with acute stress disorder have overactive right amygdalae and prefrontal cortices; both structures are involved in the fear-processing pathway.
Diagnosis
According to the DSM-V, symptom presentation must last for three consecutive days to be classified as acute stress disorder. If symptoms persist past one month, the diagnosis of PTSD is explored.
There must be a clear temporal connection between the impact of an exceptional stressor and the onset of symptoms; onset is usually within a few minutes or days but may occur up to one month after the stressor. Also, the symptoms show a mixed and rapidly changing picture; although "daze" depression, anxiety, anger, despair, hyper-activity, and withdrawal may all be seen, no one symptom dominates for long. The symptoms usually resolve rapidly where removal from the stressful environment is possible. In cases where the stress continues, the symptoms usually begin to diminish after 24–48 hours and are usually minimal after about three days.
Evaluation of patients is done through close examination of emotional response. Using self-report from patients is a large part of diagnosing ASD, as acute stress is the result of reactions to stressful situations.The DSM-V specifies that there is a higher prevalence rate of ASD among females compared to males due to higher risk of experiencing traumatic events and neurobiological gender differences in stress response.
Treatment
This disorder may resolve itself with time or may develop into a more severe disorder, such as PTSD. However, results of Creamer, ODonnell, and Pattisons (2004) study of 363 patients suggests that a diagnosis of acute stress disorder had only limited predictive validity for PTSD. Creamer et al. found that re-experiences of the traumatic event and arousal were better predictors of PTSD. Early pharmacotherapy may prevent the development of post-traumatic symptoms. Additionally, early trauma-focused cognitive behavioural therapy (TF-CBT) for those with a diagnosis of ASD can protect an individual from developing chronic PTSD.Studies have been conducted to assess the efficacy of counselling and psychotherapy for people with acute stress disorder. Cognitive behavioural therapy, which includes exposure and cognitive restructuring, was found to be effective in preventing PTSD in patients diagnosed with acute stress disorder with clinically significant results at six-month follow-up appointments. A combination of relaxation, cognitive restructuring, imaginal exposure, and in-vivo exposure was superior to supportive counselling. Mindfulness-based stress reduction programmes also appear to be effective for stress management.The pharmacological approach has made some progress in lessening the effects of ASD. To relax patients and allow for better sleep, Prazosin can be given to patients, which regulates their sympathetic response. Hydrocortisone has shown some success as an early preventative measure following a traumatic event, typically in the treatment of PTSD.In a wilderness context where counselling, psychotherapy, and cognitive behavioural therapy is unlikely to be available, the treatment for acute stress reaction is very similar to the treatment of cardiogenic shock, vascular shock, and hypovolemic shock; that is, allowing the patient to lie down, providing reassurance, and removing the stimulus that prompted the reaction. In traditional shock cases, this generally means relieving injury pain or stopping blood loss. In an acute stress reaction, this may mean pulling a rescuer away from the emergency to calm down or blocking the sight of an injured friend from a patient.
History
The term "acute stress disorder" was first used to describe the symptoms of soldiers during World War I and II, and it was therefore also termed "combat stress reaction" (CSR). Approximately 20% of U.S. troops displayed symptoms of CSR during WWII. It was assumed to be a temporary response of healthy individuals to witnessing or experiencing traumatic events. Symptoms include depression, anxiety, withdrawal, confusion, paranoia, and sympathetic hyperactivity.The APA officially included the term ASD in the DSM-IV in 1994. Before that, symptomatic individuals within the first month of trauma were diagnosed with adjustment disorder. According to the DSM-IV, acute stress reaction refers to the symptoms experienced immediately to 48 hours after exposure to a traumatic event. In contrast, acute stress disorder is defined by symptoms experienced 48 hours to one month following the event. Symptoms experienced for longer than one month are consistent with a diagnosis of PTSD.Initially, being able to describe different ASRs was one of the goals of introducing ASD. Some criticisms surrounding ASDs focal point include issues with ASD recognising other distressing emotional reactions, like depression and shame. Emotional reactions similar to these may then be diagnosed as adjustment disorder under the current system of trying to diagnose ASD.Since its addition to the DSM-IV, questions about the efficacy and purpose of the ASD diagnosis have been raised. The diagnosis of ASD was criticized as an unnecessary addition to the progress of diagnosing PTSD, as some considered it more akin to a sign of PTSD than an independent issue requiring diagnosis. Also, the terms ASD and ASR have been criticized for not fully covering the range of stress reactions.
== References == |
Neonatal diabetes | Neonatal diabetes mellitus (NDM) is a disease that affects an infant and their bodys ability to produce or use insulin. NDM is a monogenic (controlled by a single gene) form of diabetes that occurs in the first 6 months of life. Infants do not produce enough insulin, leading to an increase in glucose accumulation. It is a rare disease, occurring in only one in 100,000 to 500,000 live births. NDM can be mistaken for the much more common type 1 diabetes, but type 1 diabetes usually occurs later than the first 6 months of life. There are two types of NDM: permanent neonatal diabetes mellitus (PNDM) is a lifelong condition. Transient neonatal diabetes mellitus (TNDM) is diabetes that disappears during the infant stage but may reappear later in life.Specific genes that can cause NDM have been identified. The onset of NDM can be caused by abnormal pancreatic development, beta cell dysfunction or accelerated beta cell dysfunction. Individuals with monogenic diabetes can pass it on to their children or future generations. Each gene associated with NDM has a different inheritance pattern.
Symptoms and signs
The first sign of neonatal diabetes is often slowed fetal growth, followed by unusually low birthweight. At some point within the first six months of life, infants with neonatal diabetes tend to experience the classic symptoms of type 1 diabetes: thirst, frequent urination, and signs of dehydration. The timing of symptom onset varies with the type of neonatal diabetes. Those with transient neonatal diabetes tend to have symptoms in the first few days or weeks of life, with affected children showing weight loss and signs of dehydration, along with high levels of sugar in the blood and urine. Some children also have high levels of ketones in the bood and urine, or signs of metabolic acidosis. Permanent neonatal diabetes starts slightly later, typicalaly around six weeks of age. Regardless of type, preterm infants tend to experience symptoms earlier, typically around one week of age.Neonatal diabetes is classified into three subtypes: permanent, transient, and syndromic; each with distinct genetic causes and symptoms.Syndromic neonatal diabetes is the term for diabetes as just one component of any of several complex syndromes that affect neonates, including IPEX syndrome, Wolcott-Rallison syndrome, and Wolfram syndrome. Symptoms vary widely based on the syndrome.
Cause
Neonatal diabetes is a genetic disease, caused by genetic variations that were either spontaneously acquired or inherited from ones parents. At least 30 distinct genetic variants can result in neonatal diabetes. The development and treatment of neonatal diabetes will vary based on the particular genetic cause. Known genetic variants cause neonatal diabetes by five major mechanisms: Preventing the development of the pancreas or β cells, promoting β-cell death by autoimmunity or endoplasmic reticulum stress, preventing β cells from recognizing glucose or secreting insulin, or abnormal expression of the 6q24 region on chromosome 6.
Mechanism
Most permanent neonatal diabetes cases are caused by variations in the ATP-sensitive potassium channel, KATP. Disease-associated variants of either subunit of KATP, KCNJ11 and ABCC8, can result in a channel that is "stuck open", rendering the β cell unable to secrete insulin in response to high blood glucose. Children born with disease-associated KATP variants often have intrauterine growth restriction and resulting low birthweight. Similarly, the second most common cause of permanent neonatal diabetes is alterations to the gene that encodes insulin. Mutations associated with neonatal diabetes tend to cause misfolding of the insulin protein; misfolded insulin accumulates in the endoplasmic reticulum (ER), leading to ER stress and β-cell death.Most transient neonatal diabetes is caused by the over-expression of a cluster of genes on chromosome 6, a region called 6q24. Over-expression of 6q24 is often caused by anomylous epigenetic regulation of the locus. The copy of 6q24 inherited from ones father normally has much higher gene expression than the copy inherited from ones mother. Therefore, inheriting two copies of the gene region from ones father (either through uniparental disomy, or receiving two copies from ones father in addition to the copy from ones mother) commonly results in over-expression of the locus. Alternatively, inheriting a maternal copy of 6q24 with defective DNA methylation can result in similar over-expression of the locus.Variants in several other genes can cause neonatal diabetes, though these cases are much rarer. Genetic changes that disable the transcription factors CNOT1, GATA4, GATA6, PDX1, PTF1A, or RFX6 – all involved in the development of the pancreas – result in a shrunken or missing pancreas. Similarly, variations in the transcription factors GLIS3, NEUROD1, NEUROG3, NKX2-2, or MNX1 can result in malformed or absent β cells that do not secrete insulin. EIF2AK3 variants can exacerbate ER stress causing β-cell death, skeletal issues, and liver dysfunction. Some variations in immune gene FOXP3 can cause IPEX syndrome, a severe and multifaceted disease that includes neonatal diabetes among its symptoms.Two genes in this region that can be associated with TNDM:
ZAC and HYMAI Genes
ZAC is a zinc-finger protein that controls apoptosis (programmed cell death) and cell cycle arrest (cell division and duplication of DNA stops when the cell detects cell damage or defects) in PLAG1
(pleomorphic adenoma gene-like 1). PLAG1 is a transcription regulator of the type 1 receptor for pituitary adenylated cyclase-activating polypeptide (is a polypeptide that activates adenylate cyclase and increases the cyclic adenosine monophosphate or cAMP. cAMP is a second messenger that is used for neighboring cells to perform signal transduction in targeted cells), which is important for insulin secretion regulation. The function of the HYMAI (hydatiform mole-associated and imprinted transcript) is unknown.Second, chromosome 6q24-TNDM is caused by over-expression of imprinted genes at 6q24 (PLAGL1 [ZAC] and HYMAI). It was discovered that a differentially methylated region (DMR) is present within the shared promoter of these genes. Generally the expression of the mothers alleles of PLAGL1 and HYMAI are blocked or not expressed by DMR methylation and only the fathers alleles of PLAG1 and HYMA1 are expressed. The previously listed genetic mechanisms result in twice the normal amount of these two genes and cause chromosome 6q24 TNDM.
ZFP57 Gene
Third, mothers hypomethylation defects (a genetic defect that stops the allele from getting a methyl group, which would inhibit transcription) can occur from an isolated genomic imprinting or occur as a defect called, "hypomethylation imprinted loci" (HIL). HIL is defined as the loss of a methyl group in the 5-methylcytosine nucleotide at a fixed position on a chromosome. Homozygous ( having two of the same alleles) or heterozygous (defined as having one each of two different alleles) ZFP57 pathogenic variant make up almost half of TNDM-HIL, but the other causes of HIL are unknown.Moreover, half of TNDM patients that contain chromosome 6q24-related TNDM experiencing re-occurrence of diabetes during their childhood or young adulthood. The onset of insulin resistance and increased insulin requirements are associated with puberty and pregnancy initiating the relapse of diabetes. In the event of remission, individuals do not show symptoms or impairment Beta-cell function in the fasting state. Insulin secretory response to intravenous glucose loading might be abnormal in those destined to have a relapse of diabetes. TNDM caused by 6q24 genomic defects are always associated with IGUR. Other contributing factors are umbilical hernia and enlarged tongue, which are present in 9 and 30% of patients with chromosome 6q24 related TNDM.
Diagnosis
Diagnosis of neonatal diabetes is complicated by the fact that hyperglycemia is common in neonates – particularly in preterm infants, 25–75% of whom have hyperglycemia. Neonatal hyperglycemia typically begins in the first ten days of life, and lasts just two to three days.
Diagnosis of TNDM and PNDM
The diagnostic evaluations are based upon the following evaluation factors: patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. TNDM patients are younger at the age of diagnosis of diabetes and have lower insulin requirements, an overlap occurs between the two groups, therefore TNDM cannot be distinguished from PNDM based clinical feature. An early onset of diabetes mellitus is unrelated to autoimmunity in most cases, relapse of diabetes is common with TNDM, and extensive follow ups are important. In addition, molecular analysis of chromosomes 6 defects, KCNJ11 and ABCC8 genes (encoding Kir6.2 and SUR1) provide a way to identify PNDM in the infant stages. Approximately 50% of PNDM are associated with the potassium channel defects which are essential consequences when changing patients from insulin therapy to sulfonylureas.
TNDM Diagnosis associated with Chromosome 6q24 Mutations
The uniparental disomy of the chromosome can be used as diagnostic method provide proof by the analysis of polymorphic markers is present on Chromosome 6. Meiotic segregation of the chromosome can be distinguished by comparing allele profiles of polymorphic makers in the child to the childs parents genome. Normally, a total uniparental disomy of the chromosome 6 is evidenced, but partial one can be identified. Therefore, genetic markers that are close to the region of interest in chromosome 6q24 can be selected. Chromosome duplication can found by that technique also.
Diagnostic Test of NDM
Fasting plasma glucose test: measures a diabetics blood glucose after he or she has gone 8 hours without eat. This test is used to detect diabetes or pre-diabetes
Oral glucose tolerance test- measures an individuals blood glucose after he or she have gone at least 8 hours without eating and two hours after the diabetic individual have drunk a glucose-containing beverage. This test can be used to diagnose diabetes or pre-diabetes
Random plasma glucose test-the doctor checks ones blood glucose without regard to when an individual may have eaten his or her last meal. This test, along with an evaluation of symptoms, are used to diagnose diabetes but not pre-diabetes.
Genetic Testing of NDM
Uniparental Disomy Test:Samples from fetus or child and both parents are needed for analysis. Chromosome of interest must be specified on request form. For prenatal samples (only): if the amniotic fluid (non-confluent culture cells) are provided. Amniotic fluid is added and charged separately. Also, if chorionic villus sample is provided, a genetic test will be added and charged separately. Microsatellites markers and polymerase chain reaction are used on the chromosomes of interest to test the DNA of the parent and child to identify the presence of uniparental disomy.
Treatment
Neonates with diabetes are initially treated by intravenous infusion of insulin, with a dose of 0.05 units/kilogram/hour commonly used.Treatment options depend on the underlying genetic variations of each person with neonatal diabetes. The most common mutations underlying neonatal diabetes – KCNJ11 and ABCC8 variants – can be treated with sulfonylureas alone, eventually transitioning off of insulin completely.In many cases, neonatal diabetes may be treated with oral sulfonylureas such as glyburide. Physicians may order genetic tests to determine whether or not transitioning from insulin to sulfonylurea drugs is appropriate for a patient.
People whose disease is caused by KATP variants can often be treated with high-dose sulfonylureas, which directly promote the closure of the KATP channel.
Prognosis
The outcome for infants or adults with NDM have different outcomes among carriers of the disease. Among affected babies, some have PNDM while others have relapse of their diabetes and other patients may experience permanent remission. Diabetes may reoccur in the patients childhood or adulthood. It was estimated that neonatal diabetes mellitus will be TNDM in about 50% are half of the cases.During the Neonatal stage, the prognosis is determined by the severity of the disease (dehydration and acidosis), also based on how rapidly the disease is diagnosed and treated. Associated abnormalities (e.g. irregular growth in the womb or enlarged tongue) can effect a persons prognosis. The long-term prognosis depends on the persons metabolic control, which effects the presence and complications of diabetes complications. The prognosis can be confirmed with genetic analysis to find the genetic cause of the disease. With proper management, the prognosis for overall health and normal brain development is normally good. It is highly advised people living with NDM seek prognosis from their health care provider.
Outcomes
People with KATP channel variations are at increased risk of developing attention deficit hyperactivity disorder, sleep disruptions, seizures, and experiencing developmental delay – all due to the presence of KATP channels in the brain. These can range from unnoticably mild to severe, and can sometimes improve with sulfonylurea treatment.Those with 6q24 overexpression tend to have transient diabetes, with hyperglycemia tending to disappear within the first year of life. Despite the return of euglycemia, people with 6q24 overexpression are at high risk of developing diabetes later in life, as teenagers or adults.Many of the genetic variations that cause neonatal diabetes are inherited in an autosomal dominant manner, i.e. receiving a single copy of the disease-associated variant results in disease. This is the case for the KATP genes KCNJ11 and ABCC8, and paternally inherited 6q24 amplifications, any of which have a 50% chance of being transmitted to each offspring of an affected individual.
Epidemiology
About 1 in 90,000 to 160,000 children born develops neonatal diabetes, with approximately half developing permanent and half transient neonatal diabetes.
Recent research
Clinical Trials of NDM
The research article is entitled, "A Successful Transition to sulfonamides treatment in male infant with novel neonatal diabetes mellitus (NDM) caused by the ABBC8 gene mutation and 3 years follow up". It is a case study on the transitioning of treatments from insulin therapy to sulfonamides therapy. NDM is not initiated by an autoimmune mechanism but mutations in KATP-sensitive channel, KCNJ11, ABCC8 and INS genes are successful targets for changing treatments from insulin to sulfonamides therapy.
Introduction: Within this study a two month old male was admitted into the intensive care unit, because he was showing signs of diabetic ketoacidosis. Other symptoms include, respiratory tract infection, sporous, dehydration, reduced subcutaneous fat, Candida mucous infection. The infants family history was negative for diseases of importance to hereditary and the eldest sibling was healthy.
Experiment: The current treatment plan consist of therapy for ketoacidosis was started upon admissions into the hospital. Also, subcutaneous insulin was given (0.025-0.05 units/kg/h) and adjusted to the glycaemic profiles and the patient was converted to euglycaemic state. After 24 hours, oral intake of insulin started and treatment continued with subcutaneous short acting insulin then intermediate acting insulin plus 2 dosage of short acting insulin. A genetic analysis was conducted for NDM and mutation of KCNJ11, ABCC8 and INS genes have been given. Sequence analysis showed a rare heterogeneous missense mutation, PF577L, in the patients exon 12 of ABCC8 gene. This confirms diagnosis of NDM caused by heterozygous mutation in the SUR1 subunit of the pancreatic ATP-sensitive potassium channel, because his parents white blood cells did not show signs of this mutation.
Results: Switching from the insulin therapy to the sulfonamides was a successful treatment. It is the current regimen used to treat NDM.
Discussion/Conclusion: ABCC8 gene produces SUR1 protein subunit that interacts with pancreatic ATP-sensitive potassium channel. When the channel opens a large amount of insulin is released. Mutations that occur in ABCC8 are associated with congential hyperinsulinism and PNDM or TNDM. Patients that have mutations in their potassium channel, improved their glucose levels with sulfonylurea regimen and glibenclamide showed successful results in managing glucose levels as well.
A 2006 study showed that 90% of patients with a KCNJ11 mutation were able to successfully transition to sulfonylurea therapy.
See also
Type 1 Diabetes
Type 2 Diabetes
References
Yorifuji, T; Kurokawa, K; Mamada, M; Imai, T; Kawai, M; Nishi, Y; Shishido, S; Hasegawa, Y; Nakahata, T (Jun 2004). "Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism". The Journal of Clinical Endocrinology and Metabolism. 89 (6): 2905–8. doi:10.1210/jc.2003-031828. PMID 15181075.
Edghill, EL; Bingham, C; Slingerland, AS; Minton, JA; Noordam, C; Ellard, S; Hattersley, AT (Dec 2006). "Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development". Diabetic Medicine. 23 (12): 1301–6. doi:10.1111/j.1464-5491.2006.01999.x. PMID 17116179.
Works cited
Atkinson MA, Mcgill DE, Dassau E, Laffel L (2020). "Type 1 Diabetes Mellitus". In Melmed S, Auchus RJ, Goldfine AB, Koeng RJ, Rosen CJ (eds.). Williams Textbook of Endocrinology (14 ed.). Elsevier. pp. 1403–1437.
De Franco E (December 2021). "Neonatal diabetes caused by disrupted pancreatic and β-cell development". Diabet Med. 38 (12): e14728. doi:10.1111/dme.14728. PMID 34665882.
Garg M, Devaskar SU (2020). "Disorders of Carbohydrate Metabolism in the Neonate". In Martin RJ, Fanaroff AA, Walsh MC (eds.). Fanaroff and Martins Neonatal-Perinatal Medicine (11 ed.). Elsevier. pp. 1584–1610. ISBN 9780323567114.
Katugampola H, Gevers EF, Dattani MT (2020). "Endocrinology of Fetal Development". In Melmed S, Auchus RJ, Goldfine AB, Koeng RJ, Rosen CJ (eds.). Williams Textbook of Endocrinology (14 ed.). Elsevier.
Lemelman MB, Letourneau L, Greeley SA (March 2018). "Neonatal Diabetes Mellitus: An Update on Diagnosis and Management". Clin Perinatol. 45 (1): 41–59. doi:10.1016/j.clp.2017.10.006. PMC 5928785. PMID 29406006.
== External links == |
Reversible cerebral vasoconstriction syndrome | Reversible cerebral vasoconstriction syndrome (RCVS, sometimes called Call-Fleming syndrome) is a disease characterized by a weeks-long course of thunderclap headaches, sometimes focal neurologic signs, and occasionally seizures. Symptoms are thought to arise from transient abnormalities in the blood vessels of the brain. In some cases, it may be associated with childbirth, vasoactive or illicit drug use, or complications of pregnancy. If it occurs after delivery it may be referred to as postpartum cerebral angiopathy.
For the vast majority of patients, all symptoms disappear on their own within three weeks. Deficits persist in a small minority of patients, with severe complications or death being very rare. Because symptoms resemble a variety of life-threatening conditions, differential diagnosis is necessary.
Signs and symptoms
The key symptom of RCVS is recurrent thunderclap headaches, which over 95% of patients experience. In two-thirds of cases, it is the only symptom. These headaches are typically bilateral, very severe and peak in intensity within a minute. They may last from minutes to days, and may be accompanied by nausea, photophobia, phonophobia or vomiting. Some patients experience only one headache, but on average there are four attacks over a period of one to four weeks. A milder, residual headache persists between severe attacks for half of patients.1–17% of patients experience seizures. 8–43% of patients show neurologic problems, especially visual disturbances, but also hemiplegia, ataxia, dysarthria, aphasia, and numbness. These neurologic issues typically disappear within minutes or a few hours; more persistent symptoms may indicate a stroke. Posterior reversible encephalopathy syndrome is present in a small minority of patients.This condition features the unique property that the patients cerebral arteries can spontaneously constrict and relax back and forth over a period of time without intervention and without clinical findings. Vasospasm is common post subarachnoid hemorrhage and cerebral aneurysm, but in RCVS only 25% of patients have symptoms post subarachnoid hemorrhage.
Causes
The direct cause of the symptoms is believed to be either constriction or dilation of blood vessels in the brain. The pathogenesis is not known definitively, and the condition is likely to result from multiple different disease processes.Up to two-thirds of RCVS cases are associated with an underlying condition or exposure, particularly vasoactive or recreational drug use, complications of pregnancy (eclampsia and pre-eclampsia), and the adjustment period following childbirth called puerperium. Vasoactive drug use is found in about 50% of cases. Implicated drugs include selective serotonin reuptake inhibitors, weight-loss pills such as Hydroxycut, alpha-sympathomimetic decongestants, acute migraine medications, pseudoephedrine, epinephrine, cocaine, and cannabis, among many others. It sometimes follows blood transfusions, certain surgical procedures, swimming, bathing, high altitude experiences, sexual activity, exercise, or coughing. Symptoms can take days or a few months to manifest after a trigger.Following a study and publication in 2007, it is also thought SSRIs, uncontrolled hypertension, endocrine abnormality, and neurosurgical trauma are indicated to potentially cause vasospasm.
Diagnosis
The clinician should first rule out conditions with similar symptoms, such as subarachnoid hemorrhage, ischemic stroke, pituitary apoplexy, cerebral artery dissection, meningitis, and spontaneous cerebrospinal fluid leak. This may involve a CT scan, lumbar puncture, MRI, and other tests. Posterior reversible encephalopathy syndrome has a similar presentation, and is found in 10–38% of RCVS patients.RCVS is diagnosed by detecting diffuse reversible cerebral vasoconstriction. Catheter angiography is ideal, but computed tomography angiography and magnetic resonance angiography can identify about 70% of cases. Multiple angiographies may be necessary. Because other diseases (such as atherosclerosis) have similar angiographic presentations, it can only be conclusively diagnosed if vasoconstriction resolves within 12 weeks.
Treatment
As of 2014, no treatment strategy has yet been investigated in a randomized clinical trial. Verapamil, nimodipine, and other calcium channel blockers may help reduce the intensity and frequency of the headaches. A clinician may recommend rest and the avoidance of activities or vasoactive drugs which trigger symptoms (see § Causes). Analgesics and anticonvulsants can help manage pain and seizures, respectively.
Prognosis
All symptoms normally resolve within three weeks, and may only last days. Permanent deficits are seen in a minority of patients, ranging from under 10% to 20% in various studies. Less than 5% of patients experience progressive vasoconstriction, which can lead to stroke, progressive cerebral edema, or even death. Severe complications appear to be more common in postpartum mothers.
Epidemiology
The incidence of RCVS is unknown, but it is believed to be "not uncommon", and likely under-diagnosed. One small, possibly biased study found that the condition was eventually diagnosed in 45% of outpatients with sudden headache, and 46% of outpatients with thunderclap headache.The average age of onset is 42, but RCVS has been observed in patients aged from 19 months to 70 years. Children are rarely affected. It is more common in females, with a female-to-male ratio of 2.4:1.
History
Case studies of the condition first appeared in the 1960s, but it was not then recognized as a distinct entity. In 1983, French researchers published a case series of 11 patients, terming the condition acute benign cerebral angiopathy. Gregory Call and Marie Fleming were the first two authors of a report in which doctors from Massachusetts General Hospital, led by C. Miller Fisher, described 4 patients, alongside 12 previous case studies, with the characteristic symptoms and abnormal cerebral angiogram findings. The name Call-Fleming syndrome refers to these researchers.A 2007 review by Leonard Calabrese and colleagues proposed the name reversible cerebral vasoconstriction syndrome, which has since gained widespread acceptance. This name merges various conditions that were previously treated as distinct entities, including Call-Fleming syndrome, postpartum angiopathy, and drug-induced angiopathy. Other names may still be used for particular forms of the condition.
References
== External links == |
Insulin autoimmune syndrome | Insulin autoimmune syndrome (IAS), a rare cause of reversible autoimmune hypoglycemia also known as Hiratas disease, was first described by Hirata in Japan in 1970.
Signs and symptoms
Affected patients are usually adults, experiencing multiple episodes of spontaneous hypoglycemia with neuroglycopenic symptoms.
Causes
The cause of IAS is not clearly understood. However, interaction of disulfide bond in the insulin molecule with sulfhydryl group drugs such as methimazole, carbimazole, captopril, isoniazid, hydralazine, imipenem, and also with lipoic acid has been suggested. Drug-induced autoimmunization is evidenced by insulin autoantibodies appearing a few weeks after the intake of drug containing the sulfhydryl group.
Additionally, IAS has a significant genetic predisposition as its association with specific HLA class has been observed.
Pathophysiology
Following a meal, glucose concentration in the bloodstream rises, providing a stimulus for insulin secretion. Autoantibodies bind to these insulin molecules, rendering them unable to exert their effects. The resultant hyperglycemia promotes further insulin release. As glucose concentration eventually falls, insulin secretion also subsides, and the total insulin level decreases. Now insulin molecules spontaneously dissociate from the autoantibodies, giving rise to a raised free insulin level inappropriate for the glucose concentration, causing hypoglycemia.
Diagnosis
Usual presenting features are multiple episodes of spontaneous hypoglycemia and appearance of insulin autoantibodies without prior history of administration of exogenous insulin. The insulin level is significantly high, usually up to 100 mIU/L, C-peptide level is markedly elevated, and insulin antibodies are positive.
Treatment
The best known treatment is recommending frequent, small meals and to avoid simple sugars. Sulfhydryl group-containing drugs should be avoided and steroids can be used in resistant cases.
== References == |
Pilomatricoma | Pilomatricoma, is a benign skin tumor derived from the hair matrix. These neoplasms are relatively uncommon and typically occur on the scalp, face, and upper extremities. Clinically, pilomatricomas present as a subcutaneous nodule or cyst with unremarkable overlying epidermis that can range in size from 0.5 to 3.0 cm, but the largest reported case was 24 cm.
Presentation
Associations
Pilomatricomas have been observed in a variety of genetic disorders including Turner syndrome, myotonic dystrophy, Rubinstein-Taybi syndrome, Trisomy 9, and Gardner syndrome. It has been reported that the prevalence of pilomatricomas in Turner syndrome is 2.6%.Hybrid cysts that are composed of epidermal inclusion cysts and pilomatricoma-like changes have been repeatedly observed in Gardner syndrome. This association has prognostic import, since cutaneous findings in children with Gardner Syndrome generally precede colonic polyposis.
Histologic features
The characteristic components of a pilomatricoma include a stroma of fibrovascular connective tissue
surrounding irregularly shaped, lobulated islands containing basaloid cells (being darkly stained, round or elongated, with indistinct cell borders and minimal cytoplasm, with nuclei being round to ovoid, deeply basophilic and generally prominent nucleoli), which abruptly or gradually transitions into ghost cells (having abundant, pale, eosinophilic cytoplasm, well defined cell borders and a central clear area, but only faint traces of nuclear material), which in turn may transition into keratinaceous to amorphous necrosis.The presence of calcifications with foreign body giant cells is common within the tumors.
Pathogenesis
Pilomatricoma is associated with high levels of beta-catenin caused by either a mutation in the APC gene or a stabilizing mutation in the beta-catenin gene, CTNNB1. High levels of beta-catenin increases cell proliferation, inhibit cell death, and ultimately leads to neoplastic growth.
See also
Malignant pilomatricoma
List of cutaneous conditions
List of cutaneous neoplasms associated with systemic syndromes
References
== External links == |
Supernumerary root | Supernumerary roots is a condition found in teeth when there may be a larger number of roots than expected. The most common teeth affected are mandibular (lower) canines, premolars, and molars, especially third molars. Canines and most premolars, except for maxillary (upper) first premolars, usually have one root. Maxillary first premolars and mandibular molars usually have two roots. Maxillary molars usually have three roots. When an extra root is found on any of these teeth, the root is described as a supernumerary root.
The clinical significance of this condition is associated with dentistry when accurate information regarding root canal anatomy is required when root canal treatment is required.
References
== External links == |
Cracked tooth syndrome | Cracked tooth syndrome (CTS) is where a tooth has incompletely cracked but no part of the tooth has yet broken off. Sometimes it is described as a greenstick fracture. The symptoms are very variable, making it a notoriously difficult condition to diagnose.
Classification and definition
Cracked tooth syndrome could be considered a type of dental trauma and also one of the possible causes of dental pain. One definition of cracked tooth syndrome is "a fracture plane of unknown depth and direction passing through tooth structure that, if not already involving, may progress to communicate with the pulp and/or periodontal ligament."
Signs and symptoms
The reported symptoms are very variable, and frequently have been present for many months before the condition is diagnosed. Reported symptoms may include some of the following:
Sharp pain when biting on a certain tooth, which may get worse if the applied biting force is increased. Sometimes the pain on biting occurs when the food being chewed is soft with harder elements, e.g. seeded bread.
"Rebound pain" i.e. sharp, fleeting pain occurring when the biting force is released from the tooth, which may occur when eating fibrous foods.
Pain on biting
Pain when grinding the teeth backward and forward and side to side.
Sharp pain when drinking cold beverages or eating cold foods, lack of pain with heat stimuli.
Pain when eating or drinking sugary substances.
Sometimes the pain is well localized, and the individual is able to determine the exact tooth from which the symptoms are originating, but not always.If the crack propagates into the pulp, irreversible pulpitis, pulpal necrosis and periapical periodontitis may develop, with the respective associated symptoms.
Pathophysiology
CTS is typically characterized by pain when releasing biting pressure on an object. This is because when biting down the segments are usually moving apart and thereby reducing the pressure in the nerves in the dentin of the tooth. When the bite is released the "segments" snap back together sharply increasing the pressure in the intradentin nerves causing pain. The pain is often inconsistent, and frequently hard to reproduce. Pain associated with CTS has been reported to occur more commonly on biting, rather than on release of pressure after biting. If untreated, CTS can lead to severe pain, possible pulpal death, abscess, and even the loss of the tooth.
If the fracture propagates into the pulp, this is termed a complete fracture, and pulpitis and pulp death may occur.
If the crack propagates further into the root, a periodontal defect may develop, or even a vertical root fracture.According to one theory, the pain on biting is caused by the 2 fractured sections of the tooth moving independently of each other, triggering sudden movement of fluid within the dentinal tubules. This activates A-type nociceptors in the dentin-pulp complex, reported by the pulp-dentin complex as pain. Another theory is that the pain upon cold stimuli results from leak of noxious substances via the crack, irritating the pulp.
Diagnosis
Cracked tooth syndrome (CTS) was defined as an incomplete fracture of a vital posterior tooth that involves the dentine and occasionally extends to the pulp by Cameron in 1964 and more recently has included a fracture plane of unknown depth and direction passing through tooth structure that, if not already involving, may progress to communicate with the pulp and/or periodontal ligament. The diagnosis of cracked tooth syndrome is notoriously difficult even for experienced clinicians. The features are highly variable and may mimic sinusitis, temporomandibular disorders, headaches, ear pain, or atypical facial pain/atypical odontalgia (persistent idiopathic facial pain). When diagnosing cracked tooth syndrome, a dentist takes many factors into consideration. Effective management and good prognosis of cracked teeth is linked to prompt diagnosis. A detailed history may reveal pain on release of pressure when eating or sharp pain when consuming cold food and drink. There are a variety of habits which predispose patients to CTS including chewing ice, pens and hard sweets etc. Recurrent occlusal adjustment of restorations due to discomfort may also be indicative of CTS, alongside a history of extensive dental treatment. Below different techniques used for diagnosing CTS are discussed.
Clinical examination
Cracks are difficult to see during a clinical exam which may limit diagnosis. However other clinical signs which may lead to the diagnosis of CTS includes wear faceting indicating excessive forces perhaps from clenching or grinding or the presence of an isolated deep periodontal pocket which may symbolise a split tooth. Removing restorations may help to visualise fracture lines but should only be carried out after gaining informed consent from the patient, as removing a restoration may prove to be of little diagnostic benefit. Tactile examination with a sharp probe may also aid diagnosis.
Gentian Violet or Methylene Blue Stains
Dyes may be used to aid visualisation of fractures. The technique requires 2–5 days to be effective and a temporary restoration may be required. The structural integrity can be weakened by this method, leading to crack propagation.
Transillumination
Transillumination is best performed by placing a fibre optic light source directly onto the tooth and optimal results can be achieved with the aid of magnification. Cracks involving dentine interrupt the light transmission. However, transillumination may cause cracks to appear enlarged as well as causing colour changes to become invisible.
Radiographs
Radiographs offer little benefit in visualising cracks. This is due to the fact that cracks propagate in a direction which is parallel to the plane of the film (Mesiodistal) however radiographs can be useful when examining the periodontal and pulpal status.
Bite Test
Different tools can be used when carrying out a bite test which produce symptoms associated with cracked tooth syndrome. Patients bite down followed by sudden release of pressure. CTS diagnosis is confirmed by pain on release of pressure. The involved cusp can be determined by biting on individual cusps separately. Tooth Slooth II (Professional Results Inc., Laguna Niguel, CA, USA) and Fractfinder (Denbur, Oak Brook, IL, USA) are commercially available tools.
Epidemiology
Aetiology of CTS is multifactorial, the causative factors include:
previous restorative procedures.
occlusal factors; patients who suffer from bruxism, or clenching are prone to have cracked teeth.
developmental conditions/anatomical considerations.
trauma
others, e.g., aging dentition or presence of lingual tongue studs.Most commonly involved teeth are mandibular molars followed by maxillary premolars, maxillary molars and maxillary premolars. in a recent audit, mandibular first molar thought to be most affected by CTS possibly due to the wedging effect of opposing pointy, protruding maxillary mesio-palatal cusp onto the mandibular molar central fissure. Studies have also found signs of cracked teeth following the cementation of porcelain inlays; it is suggested that the debonding of intracoronal restorations may be caused by unrecognized cracks in the tooth.
Treatments
There is no universally accepted treatment strategy, but, generally, treatments aim to prevent movement of the segments of the involved tooth so they do not move or flex independently during biting and grinding (stabilisation of the crack) to prevent propagation of the crack. Provisionally, a band may be placed around the tooth or a direct composite splint can be placed in supra-occlusion to minimize flexing. Definitive options include:
Bonded intra-coronal restoration
Onlay restoration, either direct or indirectly placed (currently the recommended technique)
Crown restoration (though this is associated with a high incidence of loss of vitality in teeth with CTS)Teeth originally presenting with CTS may subsequently require Root Canal therapy (if pain persists after above) or Extraction
History
The term "cuspal fracture odontalgia" was suggested in 1954 by Gibbs. Subsequently, the term "cracked tooth syndrome" was coined in 1964 by Cameron, who defined the condition as "an incomplete fracture of a vital posterior tooth that involves the dentin and occasionally extends into the pulp."
References
== External links == |
Paroxysmal hypertension | Paroxysmal hypertension is episodic and volatile high blood pressure, which may be due to stress of any sort, or from a pheochromocytoma, a type of tumor involving the adrenal medulla.Patients with paroxysmal hypertension who test negative for pheochromocytoma are said to be suffering from a clinical entity called "pseudopheochromocytoma." This disorder is due to episodic dopamine discharge and has been observed predominantly in hypertensive women whose presentation mimicked pheochromocytoma, but with subsequent testing being negative for malignancy. In patients with pseudopheochromocytoma, dopamine was found to be significantly increased post-paroxysm. The paroxysm is said to be similar to the hypertensive episodes described by Page in 1935, and has been colloquially referred to as "Pages Syndrome". These episodes can occur after diencephalic stimulation.The exact cause of pseudopheochromocytoma is unknown, though it is thought to be related to episodic dopamine discharge. External stressors that may contribute include pain, anxiety, or emotional trauma. Therefore, treatment of pseudopheochromocytoma is aimed at psychological support and intervention with antidepressants, but also treatment with alpha and then beta blockers in resistant cases.
References
Further reading
Kuchel O, Buu NT, Larochelle P, Hamet P, Genest J (1986). "Episodic dopamine discharge in paroxysmal hypertension. Pages syndrome revisited". Archives of Internal Medicine. 146 (7): 1315–20. doi:10.1001/archinte.1986.00360190079011. PMID 3718127.
Seck SM, Ka EF, Niang A, Diouf B (2009). "Pseudopheochromocytoma: An uncommon cause of malignant hypertension". Indian Journal of Nephrology. 19 (3): 122–4. doi:10.4103/0971-4065.57111. PMC 2859479. PMID 20436734.
Mann SJ (2008). "Severe paroxysmal hypertension (pseudopheochromocytoma)". Current Hypertension Reports. 10 (1): 12–8. doi:10.1007/s11906-008-0005-2. PMID 18367021. S2CID 36584198.
Páll A, Becs G, Erdei A, Sira L, Czifra A, Barna S, Kovács P, Páll D, Pfliegler G, Paragh G, Szabó Z (2014). "Pseudopheochromocytoma induced by anxiolytic withdrawal". European Journal of Medical Research. 19: 53. doi:10.1186/s40001-014-0053-9. PMC 4196012. PMID 25288254.
External links
GPnotebook entry |
Multiple sulfatase deficiency | Multiple sulfatase deficiency (MSD), also known as Austin disease, or mucosulfatidosis, is a very rare autosomal recessive: 561 lysosomal storage disease caused by a deficiency in multiple sulfatase enzymes, or in formylglycine-generating enzyme, which activates sulfatases.: 502 It is similar to mucopolysaccharidosis.
Signs and symptoms
Symptoms of this disorder commonly appear between one and two years of age. Symptoms include mildly coarsened facial features, deafness, ichthyosis and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton, such as a curving of the spine and breast bone may occur. The skin of individuals afflicted with this disorder, is typically dry. Children affected by this disorder develop more slowly than normal and may display delayed speech and walking skills.The disease is fatal, with symptoms that include neurological damage and severe mental retardation. These sulfatase enzymes are responsible for breaking down and recycling complex sulfate-containing sugars from lipids and mucopolysaccharides within the lysosome. The accumulation of lipids and mucopolysaccharides inside the lysosome results in symptoms associated with this disorder. As of 2018, 75–100 cases of MSD had been reported worldwide.
Causes
Multiple sulfatase deficiency is caused by any mutation of the SUMF1 gene which renders its protein product, the formylglycine-generating enzyme (FGE), defective. These mutations result in inactive forms of FGE. This enzyme is required for posttranslational modification of a cysteine residue in the sulfatase enzyme active site into formylglycine, which is required for its proper function.
Genetics
MSD has an autosomal recessive inheritance pattern.: 561
The inheritance probabilities per birth are as follows:
If both parents are carriers:
25% (1 in 4) children will have the disorder
50% (2 in 4) children will be carriers (but unaffected)
25% (1 in 4) children will be free of MSD - unaffected child that is not a carrier
If one parent is affected and one is free of MSD:
0% (0) children will have the disorder - only one parent is affected, other parent always gives normal gene
100% (4 in 4) children will be carriers (but unaffected)
If one parent is a carrier and the other is free of MSD:
50% (2 in 4) children will be carriers (but unaffected)
50% (2 in 4) children will be free of MSD - unaffected child that is not a carrier
Diagnosis
MSD may be diagnosed when deficiency of more than one sulfatase enzyme is identified in leukocytes or fibroblasts, or by molecular genetic testing which shows pathogenic variation in both alleles of the SUMF1 gene.
Treatment
As there is no cure for MSD, treatment is restricted to management of symptoms.
There is much research on MSD that is currently underway. MSD Action Foundation have initiated more than 15 research projects on MSD in the last 6 years. Many of these have a translational focus. It is hoped that clinical trials for MSD will happen in the not too distant future- Alan Finglas. [Ref 17. Finglas 2020]
See also
Linear porokeratosis
List of cutaneous conditions
References
[17] View from inside: When multiple sulfatase deficiency changes everything about how you live and becomes your life
Alan Finglas,
https://doi.org/10.1002/jimd.12305
== External links ==SavingDylan.com |
Chronic myelogenous leukemia | Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors is found. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.
CML is largely treated with targeted drugs called tyrosine-kinase inhibitors (TKIs) which have led to dramatically improved long-term survival rates since 2001. These drugs have revolutionized treatment of this disease and allow most patients to have a good quality of life when compared to the former chemotherapy drugs. In Western countries, CML accounts for 15–25% of all adult leukemias and 14% of leukemias overall (including the pediatric population, where CML is less common).
Signs and symptoms
The way CML presents depends on the stage of the disease at diagnosis as it has been known to skip stages in some cases.Most patients (~90%) are diagnosed during the chronic stage which is most often asymptomatic. In these cases, it may be diagnosed incidentally with an elevated white blood cell count on a routine laboratory test. It can also present with symptoms indicative of hepatosplenomegaly and the resulting left upper quadrant pain this causes. The enlarged spleen may put pressure on the stomach causing a loss of appetite and resulting weight loss. It may also present with mild fever and night sweats due to an elevated basal level of metabolism.Some (<10%) are diagnosed during the accelerated stage which most often presents bleeding, petechiae and ecchymosis. In these patients fevers are most commonly the result of opportunistic infections.Some patients are initially diagnosed in the blast phase in which the symptoms are most likely fever, bone pain and an increase in bone marrow fibrosis.
Cause
In most cases, no obvious cause for CML can be isolated.
Risk factors
CML is more common in males than in females (male to female ratio of 1.4:1) and appears more commonly in the elderly with a median age at diagnosis of 65 years. Exposure to ionising radiation appears to be a risk factor, based on a 50 fold higher incidence of CML in Hiroshima and Nagasaki nuclear bombing survivors. The rate of CML in these individuals seems to peak about 10 years after the exposure.
Pathophysiology
CML was the first cancer to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. This chromosomal abnormality is so named because it was first discovered and described in 1960 by two scientists from Philadelphia, Pennsylvania, USA: Peter Nowell of the University of Pennsylvania and David Hungerford of Fox Chase Cancer Center.In this translocation, parts of two chromosomes (the 9th and 22nd) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p210 is short for 210 kDa protein, a shorthand used for characterizing proteins based solely on size). Because abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the bcr-abl fusion gene product is also a tyrosine kinase.
The fused BCR-ABL protein interacts with the interleukin 3beta(c) receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR-ABL activates a cascade of proteins that control the cell cycle, speeding up cell division. Moreover, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia. With improved understanding of the nature of the BCR-ABL protein and its action as a tyrosine kinase, targeted therapies (the first of which was imatinib) that specifically inhibit the activity of the BCR-ABL protein have been developed. These tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of bcr-abl as the cause of CML.
Diagnosis
CML is often suspected on the basis of a complete blood count, which shows increased granulocytes of all types, typically including mature myeloid cells. Basophils and eosinophils are almost universally increased; this feature may help differentiate CML from a leukemoid reaction. A bone marrow biopsy is often performed as part of the evaluation for CML, and CML is diagnosed by cytogenetics that detects the translocation t(9;22)(q34;q11.2) which involves the ABL1 gene in chromosome 9 and the BCR gene in chromosome 22. As a result of this translocation, the chromosome looks smaller than its homologue chromosome, and this appearance is known as the Philadelphia chromosome chromosomal abnormality. Thus, this abnormality can be detected by routine cytogenetics, and the involved genes BCR-ABL1 can be detected by fluorescent in situ hybridization, as well as by PCR.Controversy exists over so-called Ph-negative CML, or cases of suspected CML in which the Philadelphia chromosome cannot be detected. Many such patients in fact have complex chromosomal abnormalities that mask the (9;22) translocation, or have evidence of the translocation by FISH or RT-PCR in spite of normal routine karyotyping. The small subset of patients without detectable molecular evidence of BCR-ABL1 fusion may be better classified as having an undifferentiated myelodysplastic/myeloproliferative disorder, as their clinical course tends to be different from patients with CML.CML must be distinguished from a leukemoid reaction, which can have a similar appearance on a blood smear.
Classification
CML is often divided into three phases based on clinical characteristics and laboratory findings. In the absence of intervention, CML typically begins in the chronic phase, and over the course of several years progresses to an accelerated phase and ultimately to a blast crisis. Blast crisis is the terminal phase of CML and clinically behaves like an acute leukemia. Drug treatment will usually stop this progression if started early. One of the drivers of the progression from chronic phase through acceleration and blast crisis is the acquisition of new chromosomal abnormalities (in addition to the Philadelphia chromosome). Some patients may already be in the accelerated phase or blast crisis by the time they are diagnosed.
Chronic phase
Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis. During this phase, patients are usually asymptomatic or have only mild symptoms of fatigue, left side pain, joint and/or hip pain, or abdominal fullness. The duration of chronic phase is variable and depends on how early the disease was diagnosed as well as the therapies used. In the absence of treatment, the disease progresses to an accelerated phase. Precise patient staging based on clinical markers and personal genomic profile will likely prove beneficial in the assessment of disease history with respect to progression risk.
Accelerated phase
Criteria for diagnosing transition into the accelerated phase are somewhat variable; the most widely used criteria are those put forward by investigators at M.D. Anderson Cancer Center, by Sokal et al., and the World Health Organization. The WHO criteria are perhaps most widely used, and define the accelerated phase by the presence of ≥1 of the following haematological/cytogenetic criteria or provisional criteria concerning response to tyrosine kinase inhibitor (TKI) therapy
Haematological/cytogenetic criteria
Persistent or increasing high white blood cell count (> 10 × 109/L), unresponsive to therapy
Persistent or increasing splenomegaly, unresponsive to therapy
Persistent thrombocytosis (> 1000 × 109/L), unresponsive to therapy
Persistent thrombocytopenia (< 100 × 109/L), unrelated to therapy
≥ 20% basophils in the peripheral blood
10―19% blasts in the peripheral blood and/or bone marrow
Additional clonal chromosomal abnormalities in Philadelphia (Ph) chromosome-positive (Ph+) cells at diagnosis, including so-called major route abnormalities (a second Ph chromosome, trisomy 8, isochromosome 17q, trisomy 19), complex karyotype, and abnormalities of 3q26.2
Any new clonal chromosomal abnormality in Ph+ cells that occurs during therapy
Provisional response-to-TKI criteria
Haematological resistance (or failure to achieve a complete haematological response d) to the first TKI
Any haematological, cytogenetic, or molecular indications of resistance to two sequential TKIs
Occurrence of two or more mutations in the BCR-ABL1 fusion gene during TKI therapyThe patient is considered to be in the accelerated phase if any of the above are present. The accelerated phase is significant because it signals that the disease is progressing and transformation to blast crisis is imminent. Drug treatment often becomes less effective in the advanced stages.
Blast crisis
Blast crisis is the final phase in the evolution of CML, and behaves like an acute leukemia, with rapid progression and short survival. Blast crisis is diagnosed if any of the following are present in a patient with CML:
>20% blasts in the blood or bone marrow
The presence of an extramedullary proliferation of blasts
Treatment
The only curative treatment for CML is a bone marrow transplant or an allogeneic stem cell transplant. Other than this there are four major mainstays of treatment in CML: treatment with tyrosine kinase inhibitors, myelosuppressive or leukopheresis therapy (to counteract the leukocytosis during early treatment), splenectomy and interferon alfa-2b treatment. Due to the high median age of patients with CML it is relatively rare for CML to be seen in pregnant women, despite this, however, chronic myelogenous leukemia can be treated with relative safety at any time during pregnancy with the cytokine Interferon-alpha.
Chronic phase
In the past, antimetabolites (e.g., cytarabine, hydroxyurea), alkylating agents, interferon alfa 2b, and steroids were used as treatments of CML in the chronic phase, but since the 2000s have been replaced by Bcr-Abl tyrosine-kinase inhibitors drugs that specifically target BCR-ABL, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation. Despite the move to replacing cytotoxic antineoplastics (standard anticancer drugs) with tyrosine kinase inhibitors sometimes hydroxyurea is still used to counteract the high leukocyte counts encountered during treatment with tyrosine kinase inhibitors like imatinib; in these situations it may be the preferred myelosuppressive agent due to its relative lack of leukemogenic effects and hence the relative lack of potential for secondary haematologic malignancies to result from treatment. IRIS, an international study that compared interferon/cytarabine combination and the first of these new drugs imatinib, with long-term follow up, demonstrated the clear superiority of tyrosine-kinase-targeted inhibition over existing treatments.
Imatinib
The first of this new class of drugs was imatinib mesylate (marketed as Gleevec or Glivec), approved by the US Food and Drug Administration (FDA) in 2001. Imatinib was found to inhibit the progression of CML in the majority of patients (65–75%) sufficiently to achieve regrowth of their normal bone marrow stem cell population (a cytogenetic response) with stable proportions of maturing white blood cells. Because some leukemic cells (as evaluated by RT-PCR) persist in nearly all patients, the treatment has to be continued indefinitely. Since the advent of imatinib, CML has become the first cancer in which a standard medical treatment may give to the patient a normal life expectancy.
Dasatinib, nilotinib, radotinib, bosutinib, and asciminib
To overcome imatinib resistance and to increase responsiveness to TK inhibitors, four novel agents were later developed. The first, dasatinib, blocks several further oncogenic proteins, in addition to more potent inhibition of the BCR-ABL protein, and was approved in 2007, by the U.S. Food and Drug Administration (FDA) to treat CML in people who were either resistant to or intolerant of imatinib. A second TK inhibitor, nilotinib, was approved by the FDA for the same indication. In 2010, nilotinib and dasatinib were also approved for first-line therapy, making three drugs in this class available for treatment of newly diagnosed CML. In 2012, radotinib joined the class of novel agents in the inhibition of the BCR-ABL protein and was approved in South Korea for people resistant to or intolerant of imatinib. Bosutinib received US FDA and EU European Medicines Agency approval on 4 September 2012, and 27 March 2013, respectively for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.Asciminib (Scemblix) was approved for medical use in the United States in October 2021.
Treatment-resistant CML
While capable of producing significantly improved responses compared with the action of imatinib, neither dasatinib nor nilotinib could overcome drug resistance caused by one particular mutation found to occur in the structure of BCR-ABL1 known as the T315I mutation (in other words, where the 315th amino acid is mutated from a threonine residue to an isoleucine residue). Two approaches were developed to the treatment of CML as a result:
In 2007, Chemgenex released results of an open-label Phase 2/3 study (CGX-635-CML-202) that investigated the use of a non BCR-ABL targeted agent omacetaxine, administered subcutaneously (under the skin) in patients who had failed with imatinib and exhibited T315I kinase domain mutation. This is a study which is ongoing through 2014. In September 2012, the FDA approved omacetaxine for the treatment of CML in the case of resistance to other chemotherapeutic agents.Independently, ARIAD pharmaceuticals, adapting the chemical structures from first and second-generation TK inhibitors, arrived at a new pan-BCR-ABL1 inhibitor which showed (for the first time) efficacy against T315I, as well as all other known mutations of the oncoprotein. The drug, ponatinib, gained FDA approval in December 2012 for treatment of patients with resistant or intolerant CML. Just as with second-generation TK inhibitors, early approval is being sought to extend the use of ponatinib to newly diagnosed CML also.
Vaccination
In 2005, encouraging but mixed results of vaccination were reported with the BCR/ABL1 p210 fusion protein in patients with stable disease, with GM-CSF as an adjuvant.
Prognosis
Before the advent of tyrosine kinase inhibitors, the median survival time for CML patients had been about 3–5 years from time of diagnosis.With the use of tyrosine kinase inhibitors, survival rates have improved dramatically. A 2006 follow-up of 553 patients using imatinib (Gleevec) found an overall survival rate of 89% after five years.A 2011 followup of 832 patients using imatinib who achieved a stable cytogenetic response found an overall survival rate of 95.2% after 8 years, which is similar to the rate in the general population. Fewer than 1% of patients died because of leukemia progression.
Epidemiology
United Kingdom
CML accounts for 8% of all leukaemias in the UK, and around 680 people were diagnosed with the disease in 2011.
United States
The American Cancer Society estimates that in 2014, about 5,980 new cases of chronic myeloid leukemia were diagnosed, and about 810 people died of the disease. This means that a little over 10% of all newly diagnosed leukemia cases will be chronic myeloid leukemia. The average risk of a person getting this disease is 1 in 588. The disease is more common in men than women, and more common in whites than African-Americans. The average age at diagnosis is 64 years, and this disease is rarely seen in children.
References
External links
Chronic Myeloid Leukemia at American Cancer Society
CML information from The Leukemia & Lymphoma Society
Chronic Myelocytic Leukemia (CML) at Merck Manual of Diagnosis and Therapy Home Edition |
Mucopolysaccharidosis | Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within the cells that help build bone, cartilage, tendons, corneas, skin and connective tissue. GAGs (formerly called mucopolysaccharides) are also found in the fluids that lubricate joints.
Individuals with mucopolysaccharidosis either do not produce enough of one of the eleven enzymes required to break down these sugar chains into simpler molecules, or they produce enzymes that do not work properly. Over time, these GAGs collect in the cells, blood and connective tissues. The result is permanent, progressive cellular damage which affects appearance, physical abilities, organ and system functioning.
The mucopolysaccharidoses are part of the lysosomal storage disease family, a group of more than 40 genetic disorders that result when the lysosome organelle in animal cells malfunctions. The lysosome can be thought of as the cells recycling center because it processes unwanted material into other substances that the cell can utilize. Lysosomes break down this unwanted matter via enzymes, highly specialized proteins essential for survival. Lysosomal disorders like mucopolysaccharidosis are triggered when a particular enzyme exists in too small an amount or is missing altogether.
Signs and symptoms
The mucopolysaccharidoses share many clinical features but have varying degrees of severity. These features may not be apparent at birth but progress as storage of GAGs affects bone, skeletal structure, connective tissues, and organs. Neurological complications may include damage to neurons (which send and receive signals throughout the body) as well as pain and impaired motor function. This results from compression of nerves or nerve roots in the spinal cord or in the peripheral nervous system, the part of the nervous system that connects the brain and spinal cord to sensory organs such as the eyes and to other organs, muscles, and tissues throughout the body.
Depending on the mucopolysaccharidosis subtype, affected individuals may have normal intellect or have cognitive impairments, may experience developmental delay, or may have severe behavioral problems. Many individuals have hearing loss, either conductive (in which pressure behind the eardrum causes fluid from the lining of the middle ear to build up and eventually congeal), neurosensory (in which tiny hair cells in the inner ear are damaged), or both. Communicating hydrocephalus—in which the normal reabsorption of cerebrospinal fluid is blocked and causes increased pressure inside the head—is common in some of the mucopolysaccharidoses. Surgically inserting a shunt into the brain can drain fluid. The eyes cornea often becomes cloudy from intracellular storage, and glaucoma and degeneration of the retina also may affect the patients vision.
Physical symptoms generally include coarse or rough facial features (including a flat nasal bridge, thick lips, and enlarged mouth and tongue), short stature with disproportionately short trunk (dwarfism), dysplasia (abnormal bone size and/or shape) and other skeletal irregularities, thickened skin, enlarged organs such as liver (hepatomegaly) or spleen (splenomegaly), hernias, and excessive body hair growth. Short and often claw-like hands, progressive joint stiffness, and carpal tunnel syndrome can restrict hand mobility and function. Recurring respiratory infections are common, as are obstructive airway disease and obstructive sleep apnea. Many affected individuals also have heart disease, often involving enlarged or diseased heart valves.
Another lysosomal storage disease often confused with the mucopolysaccharidoses is mucolipidosis. In this disorder, excessive amounts of fatty materials known as lipids (another principal component of living cells) are stored, in addition to sugars. Persons with mucolipidosis may share some of the clinical features associated with the mucopolysaccharidoses (certain facial features, bony structure abnormalities, and damage to the brain), and increased amounts of the enzymes needed to break down the lipids are found in the blood.
Genetics
It is estimated that 1 in 25,000 babies born in the United States will have some form of the mucopolysaccharidoses. Most mucopolysaccharidoses are autosomal recessive disorders, meaning that only individuals inheriting the defective gene from both parents are affected. (The exception is MPS II, or Hunter syndrome, in which the mother alone passes along the defective gene to a son.) When both people in a couple have the defective gene, each pregnancy carries with it a one in four chance that the child will be affected. The parents and siblings of an affected child may have no sign of the disorder. Unaffected siblings and select relatives of a child with one of the mucopolysaccharidoses may carry the recessive gene and could pass it to their own children.
Diagnosis
Diagnosis often can be made through clinical examination and urine tests (excess mucopolysaccharides are excreted in the urine). Enzyme assays (testing a variety of cells or body fluids in culture for enzyme deficiency) are also used to provide definitive diagnosis of one of the mucopolysaccharidoses. Prenatal diagnosis using amniocentesis and chorionic villus sampling can verify if a fetus either carries a copy of the defective gene or is affected with the disorder. Genetic counseling can help parents who have a family history of the mucopolysaccharidoses determine if they are carrying the mutated gene that causes the disorders.
Types
Seven distinct clinical types and numerous subtypes of the mucopolysaccharidoses have been identified. Although each mucopolysaccharidosis (MPS) differs clinically, most patients generally experience a period of normal development followed by a decline in physical and/or mental function. (Note: MPS-V and MPS-VIII are no longer in use as designations for any disease.)
Overview table
MPS I
MPS I is divided into three subtypes based on severity of symptoms. All three types result from an absence of, or insufficient levels of, the enzyme alpha-L-iduronidase. Children born to an MPS I parent carry the defective gene.
MPS I H (also called Hurler syndrome or α-L-iduronidase deficiency), is the most severe of the MPS I subtypes. Developmental delay is evident by the end of the first year, and patients usually stop developing between ages 2 and 4. This is followed by progressive mental decline and loss of physical skills. Language may be limited due to hearing loss and an enlarged tongue. In time, the clear layers of the cornea become clouded and retinas may begin to degenerate. Carpal tunnel syndrome (or similar compression of nerves elsewhere in the body) and restricted joint movement are common.Affected children may be quite large at birth and appear normal but may have inguinal (in the groin) or umbilical (where the umbilical cord passes through the abdomen) hernias. Growth in height may be faster than normal but begins to slow before the end of the first year and often ends around age 3. Many children develop a short body trunk and a maximum stature of less than 4 feet. Distinct facial features (including flat face, depressed nasal bridge, and bulging forehead) become more evident in the second year. By age 2, the ribs have widened and are oar-shaped. The liver, spleen, and heart are often enlarged. Children may experience noisy breathing and recurring upper respiratory tract and ear infections. Feeding may be difficult for some children, and many experience periodic bowel problems. Children with Hurler syndrome often die before age 10 from obstructive airway disease, respiratory infections, and cardiac complications.MPS I S, Scheie syndrome, is the mildest form of MPS I. Symptoms generally begin to appear after age 5, with diagnosis most commonly made after age 10. Children with Scheie syndrome have normal intelligence or may have mild learning disabilities; some may have psychiatric problems. Glaucoma, retinal degeneration, and clouded corneas may significantly impair vision. Other problems include carpal tunnel syndrome or other nerve compression, stiff joints, claw hands and deformed feet, a short neck, and aortic valve disease. Some affected individuals also have obstructive airway disease and sleep apnea. Persons with Scheie syndrome can live into adulthood.
MPS I H-S, Hurler–Scheie syndrome, is less severe than Hurler syndrome alone. Symptoms generally begin between ages 3 and 8. Children may have moderate intellectual disability and learning difficulties. Skeletal and systemic irregularities include short stature, marked smallness in the jaws, progressive joint stiffness, compressed spinal cord, clouded corneas, hearing loss, heart disease, coarse facial features, and umbilical hernia. Respiratory problems, sleep apnea, and heart disease may develop in adolescence. Some persons with MPS I H-S need continuous positive airway pressure during sleep to ease breathing. Life expectancy is generally into the late teens or early twenties.Although no studies have been done to determine the frequency of MPS I in the United States, studies in British Columbia estimate that 1 in 100,000 babies born has Hurler syndrome. The estimate for Scheie syndrome is one in 500,000 births and for Hurler-Scheie syndrome it is one in 115,000 births.
MPS II
MPS II, Hunter syndrome or iduronate sulfatase deficiency, is caused by lack of the enzyme iduronate sulfatase. Hunter syndrome has two clinical subtypes and (since it shows X-linked recessive inheritance) is the only one of the mucopolysaccharidoses in which the mother alone can pass the defective gene to a son. The incidence of Hunter syndrome is estimated to be 1 in 100,000 to 150,000 male births.
MPS III
MPS III, Sanfilippo syndrome, is marked by severe neurological symptoms. These include progressive dementia, aggressive behavior, hyperactivity, seizures, some deafness and loss of vision, and an inability to sleep for more than a few hours at a time. This disorder tends to have three main stages. During the first stage, early mental and motor skill development may be somewhat delayed. Affected children show a marked decline in learning between ages 2 and 6, followed by eventual loss of language skills and loss of some or all hearing. Some children may never learn to speak. In the syndromes second stage, aggressive behavior, hyperactivity, profound dementia, and irregular sleep may make children difficult to manage, particularly those who retain normal physical strength. In the syndromes last stage, children become increasingly unsteady on their feet and most are unable to walk by age 10.
Thickened skin and mild changes in facial features, bone, and skeletal structures become noticeable with age. Growth in height usually stops by age 10. Other problems may include narrowing of the airway passage in the throat and enlargement of the tonsils and adenoids, making it difficult to eat or swallow. Recurring respiratory infections are common.
There are four distinct types of Sanfilippo syndrome, each caused by alteration of a different enzyme needed to completely break down the heparan sulfate sugar chain. Little clinical difference exists between these four types but symptoms appear most severe and seem to progress more quickly in children with type A. The average duration of Sanfilippo syndrome is 8 to 10 years following onset of symptoms. Most persons with MPS III live into their teenage years, and some live longer.
Sanfilippo A is the most severe of the MPS III disorders and is caused by the missing or altered enzyme heparan N-sulfatase. Children with Sanfilippo A have the shortest survival rate among those with the MPS III disorders.
Sanfilippo B is caused by the missing or deficient enzyme alpha-N-acetylglucosaminidase.
Sanfilippo C results from the missing or altered enzyme acetyl-CoAlpha-glucosaminide acetyltransferase.
Sanfilippo D is caused by the missing or deficient enzyme N-acetylglucosamine 6-sulfatase.The incidence of Sanfilippo syndrome (for all four types combined) is about one in 70,000 births.
MPS IV
MPS IV, Morquio syndrome, is estimated to occur in 1 in 700,000 births. Its two subtypes result from the missing or deficient enzymes N-acetylgalactosamine-6-sulfatase (GALNS) (Type A) or beta-galactosidase (Type B) needed to break down the keratan sulfate sugar chain. Clinical features are similar in both types but appear milder in Morquio Type B. Onset is between ages 1 and 3. Neurological complications include spinal nerve and nerve root compression resulting from extreme, progressive skeletal changes, particularly in the ribs and chest; conductive and/or neurosensitive loss of hearing and clouded corneas. Intelligence is normal unless hydrocephalus develops and is not treated.
Physical growth slows generally around the age of 18 months, and stops completely by the age of 8. Skeletal abnormalities include a bell-shaped chest, a flattening or curvature of the spine, shortened long bones, and dysplasia of the hips, knees, ankles, and wrists. The bones that stabilize the connection between the head and neck can be malformed (odontoid hypoplasia); in these cases, a surgical procedure called spinal cervical bone fusion can be lifesaving. Restricted breathing, joint stiffness, and heart disease are also common. Children with the more, severe form of Morquio syndrome may not live beyond their twenties or thirties.
MPS VI
Children with MPS VI, Maroteaux–Lamy syndrome, usually have normal intellectual development but share many of the physical symptoms found in Hurler syndrome. Caused by the deficient enzyme N-acetylgalactosamine 4-sulfatase, Maroteaux-Lamy syndrome has a variable spectrum of severe symptoms. Neurological complications include clouded corneas, deafness, thickening of the dura (the membrane that surrounds and protects the brain and spinal cord), and pain caused by compressed or traumatized nerves and nerve roots.
Growth is normal at first but stops suddenly around age 8. By age 10 children have developed a shortened trunk, crouched stance, and restricted joint movement. In more severe cases, children also develop a protruding abdomen and forward-curving spine. Skeletal changes (particularly in the pelvic region) are progressive and limit movement. Many children also have umbilical or inguinal hernias. Nearly all children have some form of heart disease.
An enzyme replacement therapy was tested on patients with MPS VI and was successful in that it improved growth and joint movement. An experiment was then carried out to see whether an injection of the missing enzyme into the hips would help the range of motion and pain.
MPS VII
MPS VII, Sly syndrome, one of the least common forms of the mucopolysaccharidoses, is estimated to occur in fewer than one in 250,000 births. The disorder is caused by deficiency of the enzyme beta-glucuronidase. In its rarest form, Sly syndrome causes children to be born with hydrops fetalis, in which extreme amounts of fluid are retained in the body. Survival is usually a few months or less. Most children with Sly syndrome are less severely affected. Neurological symptoms may include mild to moderate intellectual disability by age 3, communicating hydrocephalus, nerve entrapment, corneal clouding, and some loss of peripheral and night vision. Other symptoms include short stature, some skeletal irregularities, joint stiffness and restricted movement, and umbilical and/or inguinal hernias. Some patients may have repeated bouts of pneumonia during their first years of life. Most children with Sly syndrome live into the teenage or young adult years.
MPS IX
As of 2001, only one case of MPS IX (Online Mendelian Inheritance in Man (OMIM): 601492) had been reported. The disorder results from hyaluronidase deficiency. Symptoms included nodular soft-tissue masses located around joints, with episodes of painful swelling of the masses and pain that ended spontaneously within 3 days. Pelvic radiography showed multiple soft-tissue masses and some bone erosion. Other traits included mild facial changes, acquired short stature as seen in other MPS disorders, and normal joint movement and intelligence.
Treatment
Currently there is no cure for these disorders. Medical care is directed at treating systemic conditions and improving the persons quality of life. Physical therapy and daily exercise may delay joint problems and improve the ability to move.
Changes to the diet will not prevent disease progression, but limiting milk, sugar, and dairy products has helped some individuals experiencing excessive mucus.
Surgery to remove tonsils and adenoids may improve breathing among affected individuals with obstructive airway disorders and sleep apnea. Sleep studies can assess airway status and the possible need for nighttime oxygen. Some patients may require surgical insertion of an endotrachial tube to aid breathing. Surgery can also correct hernias, help drain excessive cerebrospinal fluid from the brain, and free nerves and nerve roots compressed by skeletal and other abnormalities. Corneal transplants may improve vision among patients with significant corneal clouding.
Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain. Currently BioMarin Pharmaceutical produces enzyme replacement therapies for MPS type I and VI. Aldurazyme is an enzymatic replacement therapy for alpha-L-iduronidase produced by BioMarin for use in Type I MPS. In May 2005, galsulfase[Naglazyme®], a recombinant enzyme replacement therapy also produced by Biomarin was approved for MPS VI (Marateaux-Lamy syndrome). In July 2006, the United States Food and Drug Administration approved a synthetic version of I2S produced by Shire Pharmaceuticals Group, called Elaprase, as a treatment for MPS type II (Hunter syndrome). Vestronidase alfa (Mepsevii) is a recombinant human lysosomal beta glucuronidase for MPS VII (Sly syndrome) approved in the United States in November 2017 (Ultragenyx).Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) have had limited success in treating the mucopolysaccharidoses. Abnormal physical characteristics, except for those affecting the skeleton and eyes, may be improved, but neurologic outcomes have varied. BMT and UCBT are high-risk procedures and are usually performed only after family members receive extensive evaluation and counseling.
See also
Alder-Reilly anomaly — a morphologic abnormality of white blood cells associated with mucopolysaccharidosis
Lysosomal storage disease
References
== External links == |
Angiomatosis | Angiomatosis is a non-neoplastic condition characterised by nests of proliferating capillaries arranged in a lobular pattern, displacing adjacent muscle and fat. It consists of many angiomas.These tend to be cavernous hemangiomas, which are sharply defined, sponge-like tumors composed of large, dilated, cavernous vascular spaces.
Presentation
Associated
They often appear in:
Von Hippel–Lindau disease: It can be associated with Von Hippel–Lindau disease and is a rare genetic multi-system disorder characterized by the abnormal growth of tumours in the body. Symptoms may include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems and high blood pressure.
Bacillary angiomatosis
Klippel–Trénaunay syndrome
Sturge–Weber syndrome
Histology
It is a vascular malformation wherein blood vessels proliferate along with accompanying mature fat and fibrous tissue, lymphatics and sometimes nerves. They may involve skin, subcutaneous tissue, skeletal muscle and occasionally bone.
Prognosis
Prognosis depends on the size and location of the tumour, untreated angiomatosis may lead to blindness and/ or permanent brain damage. Death may occur, with complications in the kidney or brain.
See also
Angioma
Hemangioma
List of skin conditions
References
== External links == |
Metallosis | Metallosis is the putative medical condition involving deposition and build-up of metal debris in the soft tissues of the body.Metallosis has been known to occur when metallic components in medical implants, specifically joint replacements, abrade against one another. Metallosis has also been observed in some patients either sensitive to the implant or for unknown reasons even in the absence of malpositioned prosthesis. Though rare, metallosis has been observed at an estimated incidence of 5% of metal joint implant patients over the last 40 years. Women may be at slightly higher risk than men. If metallosis occurs, it may involve the hip and knee joints, the shoulder, wrist, elbow joints, or spine. In the spine, the wear debris and resulting inflammatory reaction may result in a mass often referred to as a "metalloma" in medical literature, which may lead to neurological impairment over time. A similar condition has been also described when titanium dental implant degradation occurs leading to inflammatory titanium particle-mediated Peri-implantitis. Titanium particles in the peri-implant tissues do not occur via functional abrasion but are thought to result from damaging hygiene procedures or due to complex electrochemical interactions caused by oral bacteria.The abrasion of metal components may cause metal ions to be solubilized. The hypothesis that the immune system identifies the metal ions as foreign bodies and inflames the area around the debris may be incorrect because of the small size of metal ions may prevent them from becoming haptens. Poisoning from metallosis is rare, but cobaltism is an established health concern. The involvement of the immune system in this putative condition has also been theorized but has never been proven.Purported symptoms of metallosis generally include pain around the site of the implant, pseudotumors (a mass of inflamed cells that resembles a tumor but is actually collected fluids), and a noticeable rash that indicates necrosis. The damaged and inflamed tissue can also contribute to loosening the implant or medical device. Metallosis can cause dislocation of non-cemented implants as the healthy tissue that would normally hold the implant in place is weakened or destroyed. Metallosis has been demonstrated to cause osteolysis.Women, those who are small in stature, and the obese are at greater risk for metallosis because their body structure causes more tension on the implant, quickening the abrasion of the metal components and the subsequent build-up of metallic debris.
Physical effects and symptoms
Persons suffering from metallosis can experience any of the following symptoms:
Extreme pain (even when not moving);
Swelling and inflammation;
Loosening of the implant;
Joint dislocation;
Bone deterioration;
Aseptic fibrosis, local necrosis;
Hip replacement failure;
Metal toxicity from grinding metal components; and
Necessary subsequent hip replacement revision or surgeries.
Complications
As the grinding components cause metal flakes to shed from the system, the implant wears down. Metallosis results in numerous additional side effects:
Confusion;
Feelings of malaise;
Gastrointestinal problems;
Dizziness;
Headaches;
Problems in the nervous system (feelings of burning, tingling, or numbness of the extremities); and
Cobalt poisoning (skin rashes, cardiomyopathy, problems with hearing, sight or cognition, tremors, and hypothyroidism).
DePuy hip replacement recall
In August 2010, DePuy recalled its hip replacement systems ASR XL Acetabular Hip Replacement System and ASR Hip Resurfacing System due to failure rates and side effects including metallosis. The recalls triggered a large number of lawsuits against DePuy and its parent company Johnson & Johnson upon claims that the companies knew about the dangers of the implants before they went on the market in the United States.
== References == |
James Hill (surgeon) | James Hill (30 October 1703 – 18 October 1776) was a Scottish surgeon working in Dumfries who advocated curative excision for cancer rather than the palliative approach adopted by many leading surgeons of the day. By follow-up of his patients over years he demonstrated that his radical approach resulted in better outcomes than those published by contemporaries. His experience in diagnosing and treating intracranial bleeding after head injury by directed trephine resulted in the best results published in the 18th century and represent an important landmark in the management of post-traumatic intracranial haemorrhage.
Early life
James Hill was the son of Rev James Hill (1676-1743), minister of the parish church of Kirkpatrick Durham in Kirkcudbrightshire, and his wife Agnes Muirhead (1678-1742), daughter of a Dumfries merchant. James Hill was born in the village of Kirkliston, West Lothian on 30 October 1703. On 17 May 1723 he was apprenticed to the Edinburgh surgeon, physician and philosopher George Young (1692-1757), from whom he learned the value of careful observation and scepticism in medicine. It is known from Hills later writing that Young was a powerfully influential figure to his young apprentice during the latters formative professional years.
Hill, like many Edinburgh surgical apprentices attended lectures at Surgeons’ Hall but like the majority of apprentices of the period did not proceed to a surgical diploma or a medical degree in the newly established University of Edinburgh Medical School. During Hills apprenticeship there was no teaching hospital in Edinburgh. He later wrote "There was no infirmary in Edinburgh when I served my apprenticeship there, so that I never had an opportunity of seeing a cancerous breast extirpated or any other capital operation performed till I performed them myself." The first teaching hospital (the "Little House") opened opposite the head of Robertsons Close on 6 July 1729.
Hill joined the Royal Navy as a surgeon in 1730. At this time naval surgeons were certified for the purpose after an examination by the Court of Examiners of the London Company of Barbers and Surgeons and many naval surgeons of the day had no other formal qualifications.
Surgical practice in Dumfries
In 1732 Hill returned to Dumfries where he set up in surgical practice. On 28 January 1733 he married Anne McCartney, whose father John owned the Blacket (or Blaiket) estate, in the Parish of Urr and it was there that they established the family home. His practice was conducted from his town house in Amisfields Lodging in the Fleshmarket, in Dumfries. There is no known portrait of James Hill but Murray provides this description: "... his height being about five feet eleven inches. He continued till his death to prefer that fashion of dress that had prevailed in his youth. He wore a full wig ; and used a large staff. He was a man of dignity both of appearance and manners."
Between 1742 and 1775, Hill trained sixteen surgical apprentices. Of these one, Benjamin Bell (1749-1806) was to achieve international fame largely through the success of his best selling textbook A System of Surgery first published in 1783.
Hill’s early writing
Hill a number of articles for the medical journal Medical Essays and Observations which had been launched in 1733 by the Society for the Improvement of Medical Knowledge, which would eventually become the Royal Society of Edinburgh. This was one of the earliest regular medical journals and it provided a vehicle for case reports and other types of article.
Hills articles give an insight into the range of conditions with which he dealt as a surgeon-apothecary, and his understanding of their causes and treatment. He contributed a case report about a patient who was temporarily ‘cured’ of syphilis by a ‘mercurial suffumigation’. After various therapies including laudanum, tonics, claret and Dr Plummers pills were unsuccessful, he resorted to mercury, a recognised treatment for syphilis and fumes were thought to be the fastest mode of delivery. The symptoms eventually and she survived for more than a year. This report demonstrates that surgeons in Scotland at this time truly acted as surgeon-apothecaries.
His report on two cases of hydatid disease describes one patient discharging hydatid cysts via a chronic cutaneous fistula from the liver and the other discharging cysts in the sputum. Both recovered without active treatment. Although able to diagnose hydatid disease he thought the condition arose because ‘some people have hydatic constitutions.’
Cases in Surgery
In 1772 Hill published Cases in Surgery a summary of his lifes work as a surgeon. Cases deals with the infectious disease sibbens, with cancers and with ‘disorders of the head from external violence’.
Sibbens
Sibbens is now known to be endemic syphilis, a Treponemal infection spread by non-sexual social contact and seen in association with deprivation, especially overcrowded living conditions, poor sanitation and malnutrition. Hills account is written ‘to rectify the mistakes’ in the MD thesis on the topic submitted to the University of Edinburgh on the topic by Adam Freer in 1767. Hill concluded that syphilis and sibbens were the same disease and that sibbens, having been introduced into a family by sexual means, could then be transmitted around the family by close non-sexual contacts, giving his own family as an example of this mode of transmission. His apprentice Benjamin Bell, who was the first to show that syphilis and gonorrhoea were different diseases, also subscribed to this mode of transmission. Hill, like Freer before him and Bell after him, believed that the most successful treatment was mercury, supplemented on occasion by Peruvian bark. Hill was clear that sibbens and what he termed West Indian yaws were distinct diseases.
Subsequent writers credited Hill and his physician colleague and friend Dr Ebenezer Gilchrist (bap1708-1774) with providing the most precise description of the clinical features and natural history of the disease in Scotland. Hill and Gilchrist also appreciated that the condition could be prevented by improving personal hygiene and avoiding contact with sufferers, and both men advocated these and similar preventive measures.
Cancers
Hills views on cancer treatment were that cancers should be radically excised aiming for cure, an approach in contrast to the mainstream view of leading European surgeons such as Alexander Monro primus, Samuel Sharp (c1709– 1778) and Henri François Le Dran (1685–1770) that cancers should only be minimally excised to relieve symptoms. He was able to review the outcome of surgery in 88 patients, 86 of whom recovered from the procedure and 77 of these enjoyed a normal expectation of life ‘according to the bills of mortality.’ These outcomes were much superior to the documented results of, for example, Alexander Monro primus. The cancers concerned were mainly skin cancers and a few breast cancers and Hill acknowledges the difficulty in dierentiating some cancers from benign lesions in the era before histological examination. He concludes that his results justify his recommendation that tumours, including ‘the most trifling,’ should be ‘cut entirely out.’
Head injuries
It is Hills chapter entitled ‘Disorders of the head from external violence’ that marks him out as a careful clinician and an innovative surgeon able to achieve remarkable outcomes by the standards of the day.
Hill recorded 18 cases of head injury which he had treated over 40 years. The cause of the injury, the clinical features, his treatment and the outcome in each case are all recorded in detail. Head injuries, he asserts, have been treated in ‘a much more rational manner’ in the previous 15 years as a result of discoveries and ‘valuable publications’ over that period. He describes the rationale for his treatment and how this changed over time as his knowledge and understanding of the problems progressively increased. He gives ‘a historical view of the gradual progress of the improvements made by others as well as by myself.’
His first patient, a five-year-old boy, sustained a depressed frontal fracture associated with an epidural haematoma (EDH). When the fracture was elevated and the haematoma drained by trepanning the skull, the boy ‘immediately recovered his senses’ but after some days the ‘stupor’ returned, indicating that some matter was lodged under the meninges’. Hill made a cruciate incision in the meninges to drain the haematoma with beneficial effect. Ganz regarded this as the first ever description of a lucid interval associated with a subdural haematoma.
This case also demonstrates Hills understanding of the clinical features of cerebral compression: ‘The smallest compression brought on a stupor, a low intermittent pulse, nausea, vomiting and sometimes convulsive twitches.’ From case 3 onwards he avoided dressings which compressed the trepanned area.
In case 3 he again relieved the features of cerebral compression by a trepan with drainage of an EDH. In case 5 drainage of a large EDH resulted in restoration of consciousness and resolution of a right sided weakness. His account of this case also shows that he appreciated the concept that paralysis on one side of the body indicated compression on the opposite side of the brain. This patient, who crucially did not have a fracture, demonstrates Hills appreciation that it was injury to the brain that caused symptoms rather than the fracture itself. Percival Pott (1714–1788) by contrast would only operate if a fracture were present.
Hills understanding of concepts of cerebral compression is demonstrated further by his use of the word ‘compression’ and by his recording of cerebral pulsation or tension in all but one of the operations described. Both of his patients who exhibited poor or absent cerebral pulsation had sustained primary cerebral damage and both died. Hill more than any other eighteenth century writer appreciated the importance of cerebral pulsation as an indicator of cerebral health.
Further evidence of his understanding of the need to decompress where possible is shown by his use of the technique of relieving pressure by shaving off cerebral hernias caused by raised intracranial pressure, a technique he learned from the writing of Henri Francois Le Dran (1685–1770).
Hills outcomes in treating patients with head injury compares favourably with those of his contemporaries with a mortality rate of 25%, much lower than that of le Dran (57%) or Percival Pott (51%). This was the result of Hills appreciation of the concept of cerebral compression and his better understanding of the indication for and location of the trephine. Hills work was recognised and was cited by the influential Edinburgh physician John Abercrombie(1780–1844), the Edinburgh surgeon John Bell (1763–1820)) and the London surgeon John Abernethy (1764–1831)
Hill’s legacy
James Hill died on 18 October 1776 and is buried in St Michaels churchyard in Dumfries. He advanced the understanding of the treatment of head injury by showing that epidural and subdural haematoma could be recognised from clinical features and successfully treated by trepan and surgical drainage to relieve compression. He appreciated the importance of cerebral compression and the significance of unilateral limb weakness in lateralising intracranial bleeding and determining on which side to operate. This work represented a significant advance in our understanding of the nature of brain injury following trauma and how it should be treated.
Further reading
Macintyre, I (12 November 2014). "The life and work of the Dumfries surgeon James Hill (1703–1776): his contributions to the management of cancer and of head injury". J Med Biogr. 24 (4): 459–468. doi:10.1177/0967772014532898. PMID 25392427. S2CID 27830324.
== References == |
Median mandibular cyst | A median mandibular cyst is a type of cyst that occurs in the midline of the mandible, thought to be created by proliferation and cystic degeneration of resting epithelial tissue that is left trapped within the substance of the bone during embryologic fusion of the two halves of the mandible, along the plane of fusion later termed the symphysis menti. A true median mandibular cyst would therefore be classified as a non-odontogenic, fissural cyst. The existence of this lesion as a unique clinical entity is controversial, and some reported cases may have represented misdiagnosed odontogenic cysts, which are by far the most common type of intrabony cyst occurring in the jaws. It has also been suggested that the mandible develops as a bilobed proliferation of mesenchyme connected with a central isthmus. Therefore, it is unlikely that epithelial tissue would become trapped as there is no ectoderm separating the lobes in the first instance.
== References == |
Satoyoshi syndrome | Satoyoshi syndrome, also known as Komura-Guerri syndrome, is a rare progressive disorder of presumed autoimmune cause, characterized by painful muscle spasms, alopecia, diarrhea, endocrinopathy with amenorrhoea and secondary skeletal abnormalities. The syndrome was first reported in 1967 by Eijiro Satoyoshi and Kaneo Yamada in Tokyo, Japan. To this date, fewer than 50 cases worldwide have been reported for the Satoyoshi syndrome.People with the syndrome typically develop symptoms of the illness at a young age, usually between the age of six and fifteen years old. The initial symptoms are muscle spasms in the legs and alopecia, also known as baldness. The spasms are painful and progressive and their frequency varies from 1 or 2 to 100 per day, each lasting a few minutes. It can be sufficiently severe to produce abnormal posturing of the affected limbs, particularly the thumbs. With progression the illness involves the pectoral girdle and trunk muscles and finally the masseters and temporal muscles. The spasms usually spare the facial muscles. Severe spasms can interfere with respiration and speech. During an attack-free period, non-stimulus-sensitive myoclonus can occur in the arms, legs and neck. Diarrhea occurs in the first 2–3 years with intolerance to carbohydrate and high glucose diets. Endocrinopathy manifests as amenorrhea and hypoplasia of the uterus. Affected children fail to attain height after 10–12 years of age.The syndrome is not known to be a primary cause of mortality, but some patients have died as a result of secondary complications, such as respiratory failure and malnourishment.
In one 6-year-old patient antibodies to GABA-producing enzyme glutamate decarboxylase were detected.
See also
Stiff person syndrome
References
== External links == |
Paralysis | Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 people have been diagnosed with some form of permanent or transient paralysis. The word "paralysis" derives from the Greek παράλυσις, meaning "disabling of the nerves" from παρά (para) meaning "beside, by" and λύσις (lysis) meaning "making loose". A paralysis accompanied by involuntary tremors is usually called "palsy".
Causes
Paralysis is most often caused by damage in the nervous system, especially the spinal cord. Other major causes are stroke, trauma with nerve injury, poliomyelitis, cerebral palsy, peripheral neuropathy, Parkinsons disease, ALS, botulism, spina bifida, multiple sclerosis, and Guillain–Barré syndrome. Temporary paralysis occurs during REM sleep, and dysregulation of this system can lead to episodes of waking paralysis. Drugs that interfere with nerve function, such as curare, can also cause paralysis.
Pseudoparalysis (pseudo- meaning "false, not genuine", from Greek ψεῦδος) is voluntary restriction or inhibition of motion because of pain, incoordination, orgasm, or other cause, and is not due to actual muscular paralysis. In an infant, it may be a symptom of congenital syphilis. Pseudoparalysis can be caused by extreme mental stresses, and is a common feature of mental disorders such as panic anxiety disorder.
Variations
Paralysis can occur in localised or generalised forms, or it may follow a certain pattern. Most paralyses caused by nervous-system damage (e.g., spinal cord injuries) are constant in nature; however, some forms of periodic paralysis, including sleep paralysis, are caused by other factors.Paralysis can occur in newborns due to a congenital defect known as spina bifida. Spina bifida causes one or more of the vertebrae to fail to form vertebral arches within the infant, which allows the spinal cord to protrude from the rest of the spine. In extreme cases, this can cause spinal cord function inferior to the missing vertebral arches to cease. This cessation of spinal cord function can result in paralysis of lower extremities. Documented cases of paralysis of the anal sphincter in newborns have been observed when spina bifida has gone untreated. While life-threatening, many cases of spina bifida can be corrected surgically if operated on within 72 hours of birth.
Ascending paralysis presents in the lower limbs before the upper limbs. It can be associated with:
Guillain–Barré syndrome (another name for this condition is Landrys ascending paralysis)
Tick paralysisAscending paralysis contrasts with descending paralysis, which occurs in conditions such as botulism.
Other animals
Many animal species use paralyzing toxins to capture prey, evade predation, or both. In stimulated muscles, the decrease in frequency of the miniature potentials runs parallel to the decrease in postsynaptic potential, and to the decrease in muscle contraction. In invertebrates, this clearly indicates that, e.g., Microbracon (wasp genus) venom causes paralysis of the neuromuscular system by acting at a presynaptic site. Philanthus venom inhibits both the fast and slow neuromuscular system at identical concentrations. It causes a decrease in the frequency of the miniature potentials without affecting their amplitude significantly.
Invertebrates
In some species of wasp, to complete the reproductive cycle, the female wasp paralyses a prey item such as a grasshopper and places it in her nest. In the species Philanthus gibbosus, the paralysed insect (most often a bee species) is coated in a thick layer of pollen. The adult P. gibbosus then lays eggs in the paralysed insect, which is devoured by the larvae when they hatch.
Vertebrates
A well-known example of a vertebrate-produced paralyzing toxin is the tetrodotoxin of fish species such as Takifugu rubripes, the famously lethal pufferfish of Japanese fugu. This toxin works by binding to sodium channels in nerve cells, inhibiting the cells proper function. A non-lethal dose of this toxin results in temporary paralysis. This toxin is also present in many other species ranging from toads to nemerteans.
Paralysis can be seen in breeds of dogs that are chondrodysplastic. These dogs have short legs, and may also have short muzzles. Their intervertebral disc material can calcify and become more brittle. In such cases, the disc may rupture, with disc material ending up in the spinal canal, or rupturing more laterally to press on spinal nerves. A minor rupture may only result in paresis, but a major rupture can cause enough damage to cut off circulation. If no signs of pain can be elicited, surgery should be performed within 24 hours of the incident, to remove the disc material and relieve pressure on the spinal cord. After 24 hours, the chance of recovery declines rapidly, since with continued pressure, the spinal cord tissue deteriorates and dies.
Another type of paralysis is caused by a fibrocartilaginous embolism. This is a microscopic piece of disc material that breaks off and becomes lodged in a spinal artery. Nerves served by the artery will die when deprived of blood.
The German Shepherd Dog is especially prone to developing degenerative myelopathy. This is a deterioration of nerves in the spinal cord, starting in the posterior part of the cord. Affected dogs will become gradually weaker in the hind legs as nerves die off. Eventually, their hind legs become useless. They often also exhibit faecal and urinary incontinence. As the disease progresses, the paresis and paralysis gradually move forward. This disease also affects other large breeds of dogs. It is suspected to be an autoimmune problem.
Cats with a heart murmur may develop blood clots that travel through arteries. If a clot is large enough to block one or both femoral arteries, there may be hind leg paralysis because the major source of blood flow to the hind leg is blocked.
Many snakes exhibit powerful neurotoxins that can cause non-permanent paralysis or death.
Also, many trees contain neurotoxins.
See also
References
== External links == |
Infantile cortical hyperostosis | Infantile cortical hyperostosis is a self-limited inflammatory disorder of infants that causes bone changes, soft tissue swelling and irritability. The disease may be present at birth or occur shortly thereafter. The cause is unknown. Both familial and sporadic forms occur. It is also known as Caffey disease or Caffeys disease.
Presentation
An affected infant typically has the following triad of signs and symptoms: soft-tissue swelling, bone lesions, and irritability. The swelling occurs suddenly, is deep, firm, and may be tender. Lesions are often asymmetric and may affect several parts of the body. Affected bones have included the mandible, tibia, ulna, clavicle, scapula, ribs, humerus, femur, fibula, skull, ilium, and metatarsals. When the mandible (lower jaw bone) is affected, infants may refuse to eat, leading to failure to thrive.
Genetics
It has been associated with COL1A1.
Pathophysiology
In the early stages of infantile cortical hyperostosis, biopsy shows inflammation of the periosteum and adjacent soft tissues. After this resolves, the periosteum remains thickened, and subperiosteal immature lamellar bone can be seen on biopsy, while the bone marrow spaces contain vascular fibrous tissue. Eventually, the inflammation and subperiosteal changes resolve, and hyperplasia of lamellar cortical bone can be seen.Radiographs initially show layers of periosteal new bone formation with cortical thickening. Periosteal new bone may cover the diaphysis of the bone, causing an increase in diameter of the bone. Over time, the periosteal new bone density increases, becoming homogeneous with the underlying cortex. Eventually, the bone remodels and resumes a normal appearance.
Diagnosis
Most infants with infantile cortical hyperostosis are diagnosed by physical examination. X-rays can confirm the presence of bone changes and soft tissue swelling. Biopsy of the affected areas can confirm the presence of typical histopathological changes. No specific blood tests exist, but tests such as erythrocyte sedimentation rate (ESR) and alkaline phosphatase levels are often elevated. A complete blood count may show anemia (low red blood cell count) and leukocytosis (high white blood cell count). Other tests may be done to help exclude other diagnoses. Ultrasound imaging can help diagnose prenatal cases.
Differential diagnosis
Osteomyelitis (bone infection), which is much more common than infantile cortical hyperostosis, must be excluded, since it requires urgent treatment. Other diagnoses that can mimic this disorder and need to be excluded include physical trauma, child abuse, Vitamin A excess, hyperphosphatemia, prostaglandin E1 and E2 administration, scurvy, infections (including syphilis), Ewing sarcoma, and metastatic neuroblastoma.
Prognosis
Infantile cortical hyperostosis is a self-limited condition, meaning that the disease resolves on its own without treatment, usually within 6–9 months. Long-term deformities of the involved bones, including bony fusions and limb-length inequalities, are possible but rare.
Epidemiology
The disease has been reported to affect 3 per 1000 infants younger than 6 months in the United States. No predilection by race or sex has been established. Almost all cases occur by the age of 5 months. The familial form is inherited in an autosomal dominant fashion with variable penetrance. The familial form tends to have an earlier onset and is present at birth in 24% of cases, with an average age at onset of 6.8 weeks. The average age at onset for the sporadic form is 9–11 weeks.
Cortical hyperostosis is a potential side effect of long-term use of prostaglandins in neonates.
History
Dr. John Caffey (1895–1978) first described infantile cortical hyperostosis in 1945. He described a group of infants with tender swelling in the soft tissues and cortical thickenings in the skeleton, with onset of these findings during the first 3 months of life. Dr. Caffey was regarded throughout the world as the father of pediatric radiology. His classic textbook, Pediatric X-Ray Diagnosis, which was first published in 1945, has become the recognized bible and authority in its field.
References
External links
Radiographs of Infantile Cortical Hyperostosis |
Cyst | A cyst is a closed sac, having a distinct envelope and division compared with the nearby tissue. Hence, it is a cluster of cells that have grouped together to form a sac (like the manner in which water molecules group together to form a bubble); however, the distinguishing aspect of a cyst is that the cells forming the "shell" of such a sac are distinctly abnormal (in both appearance and behaviour) when compared with all surrounding cells for that given location. A cyst may contain air, fluids, or semi-solid material. A collection of pus is called an abscess, not a cyst. Once formed, a cyst may resolve on its own. When a cyst fails to resolve, it may need to be removed surgically, but that would depend upon its type and location.
Cancer-related cysts are formed as a defense mechanism for the body following the development of mutations that lead to an uncontrolled cellular division. Once that mutation has occurred, the affected cells divide incessantly and become cancerous, forming a tumor. The body encapsulates those cells to try to prevent them from continuing their division and contain the tumor, which becomes known as a cyst. That said, the cancerous cells still may mutate further and gain the ability to form their own blood vessels, from which they receive nourishment before being contained. Once that happens, the capsule becomes useless, and the tumor may advance from benign to cancerous.
Some cysts are neoplastic, and thus are called cystic tumors. Many types of cysts are not neoplastic, they are dysplastic or metaplastic. Pseudocysts are similar to cysts in that they have a sac filled with fluid, but lack an epithelial lining.
Terminology
microcyst – a small cyst that requires magnification to be seen
macrocyst – a cyst that is larger than usual or compared to others
Related structures
A pseudocyst is very similar to a cyst, but is a collection of cells without a distinct membrane (epithelial or endothelial cells).
A syrinx in the spinal cord or brainstem is sometimes inaccurately referred to as a "cyst".
Cysts by location
Female reproductive system
Nabothian cyst (on the surface of the cervix)
Ovarian cyst (ovary)
Paratubal cyst (in front of fallopian tube behind the ovary)
Vaginal cystsGartners duct cyst (lateral to vaginal wall)
Bartholins cyst (at vaginal introitus)
Skenes duct cyst (Beside the urinary meatus)
Ectopic ureterocoele (around the urinary meatus)
Urethral diverticulum (In front of vaginal wall)
Male reproductive system
Rete tubular ectasia (within the rete testis)
Epididymal cyst (in the epididymis)
Hydrocele testis (testicle): clear fluid within the cavum vaginale
Spermatocele (testicle): fluid within the head of epididymis
Cutaneous and subcutaneous
Acne cyst – Pseudocysts associated with cystic acne - an inflammatory nodule with or without an associated epidermoid inclusion cyst
Arachnoid cyst (between the surface of the brain and the cranial base or on the arachnoid membrane)
Epidermoid cyst
Myxoid cyst (cutaneous condition often characterized by nail plate depression and grooves)
Pilar cyst (cyst of the scalp)
Pilonidal cyst (skin infection near tailbone)
Sebaceous cyst – sac below skin
Trichilemmal cyst – same as a pilar cyst, a familial cyst of the scalp
Head and neck
Odontogenic cyst
Ceruminous cyst (ear)
Chalazion cyst (eyelid)
Mucous cyst of the oral mucosa
Nasolabial cyst
Thyroglossal cyst
Vocal fold cyst
Chest
Fibrous cyst (breast cyst)
Pulmonary cyst (air pocket in the lung)
Pericardial cyst (abnormal dilatation of pericardium)
Abdomen
Liver cysts
Simple cysts
Hydatid cysts
Biliary cystadenoma
Biliary cystadenocarcinoma
Polycystic liver disease
Adrenal cyst (glands located above the kidneys) - It is a rare disease, affecting 0.06 to 0.18% of autopsy studies. It constitutes 5.4 to 6.0% of adrenal gland diseases. There are five major types of adrenal cysts: simple or endothelial cysts, true or epithelial cysts, pseudocysts, parasitic cysts, and cysts not classified elsewhere. 7% of the cysts can be malignant.
Renal cyst (kidneys)
Pancreatic cyst
Peritoneal inclusion cyst (lining of the abdominal cavity) - It is a cluster of fluid-filled cysts lining the abdominal cavity of reproductive age women with a history of pelvic, abdominal surgeries, or abdominal inflammation. Those affected maybe presented with an abdominal, pelvic, lower back that lasted for months.
Enteric duplication cyst
Central nervous system
Choroid plexus cyst
Colloid cyst
Pineal gland cyst (in the pineal gland in the brain)
Glial cyst
Tarlov cyst (spinal canal)
Musculoskeletal system
Aneurysmal bone cyst, a benign bone tumor with a radiographic cystic appearance.
Bakers cyst or popliteal cyst (behind the knee joint)
Mucoid cyst (ganglion cysts of the digits)
Stafne static bone cyst (an anatomic variant with radiographic cystic appearance in the posterior mandible)
Subchondral cyst (cysts near the bony joints)
Seen in various locations
Dermoid cyst (seen in ovaries, testes, and many other locations, from head to tailbone)
Ganglion cyst (hand and foot joints and tendons)
Mucoid cyst (ganglion cysts of the digits)
Infectious cysts
Cysticercal cyst – an infection due to the larval stage of Taenia sp. (Crains backs)
Hydatid cyst – an infection in the liver or other parts of the body due to the larval stage of Echinococcus granulosus (tapeworm)
Neoplastic cysts
Dermoid cyst
Keratocystic odontogenic tumor
Calcifying odontogenic cyst
Treatment
Treatment ranges from simple enucleation of the cyst to curettage to resection. There are cysts—e.g., buccal bifurcation cyst—that resolve on their own, in which just close observation may be employed, unless it is infected and symptomatic.
Cystic fibrosis
Despite being described in 1938 as "the microscopic appearance of cysts in the pancreas", cystic fibrosis is an example of a genetic disorder whose name is related to fibrosis of the cystic duct (which serves the gallbladder) and does not involve cysts.This is just one example of how the Greek root cyst-, which simply means a fluid-filled sac, also is found in medical terms that relate to the urinary bladder and the gallbladder, neither of which involve cysts.
See also
List of cutaneous conditions
References
External links
"Cyst Symptoms and Causes" by Melissa Conrad Stöppler, MD and William C. Shiel Jr., MD, FACP, FACR. |
Vitelliform macular dystrophy | Vitelliform macular dystrophy is an irregular autosomal dominant eye disorder which can cause progressive vision loss. This disorder affects the retina, specifically cells in a small area near the center of the retina called the macula. The macula is responsible for sharp central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. The condition is characterized by yellow (or orange), slightly elevated, round structures similar to the yolk (Latin vitellus) of an egg.
Genetics
Best disease is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.
The inheritance pattern of adult-onset vitelliform macular dystrophy is definitively autosomal dominant. Many affected people, however, have no history of the disorder in their family and only a small number of affected families have been reported. This is because the penetrance of the condition is incomplete; therefore, it is possible for an individual to have a copy of the mutant allele and not display the VMD phenotype. The ratio of males to females is approximately 1:1.
Pathophysiology
Mutations in the RDS and VMD2 genes cause vitelliform macular dystrophy. Mutations in the VMD2 gene are responsible for Best disease. Changes in either the VMD2 or RDS gene can cause the adult-onset form of vitelliform macular dystrophy; however, fewer than a quarter of cases result from mutations in these two genes. In most cases, the cause of the adult-onset form is unknown.
The VMD2 gene provides instructions for making a protein called bestrophin. Although its exact function is uncertain, this protein likely acts as a channel that controls the movement of negatively charged chlorine atoms (chloride ions) into or out of cells in the retina. Mutations in the VMD2 gene probably lead to the production of an abnormally shaped channel that cannot regulate the flow of chloride. Researchers have not determined how these malfunctioning channels are related to the buildup of lipofuscin in the macula and progressive vision loss.
The RDS gene provides instructions for making a protein called peripherin. This protein is essential for the normal function of light-sensing (photoreceptor) cells in the retina. Mutations in the RDS gene disrupt the structures in these cells that contain light-sensing pigments, leading to vision loss. It is unclear why RDS mutations affect only central vision in people with adult-onset vitelliform macular dystrophy.
Diagnosis
Vitelliform macular dystrophy causes a fatty yellow pigment (lipofuscin) to build up in cells underlying the macula. The retinal pigment epithelium also degenerates. Over time, the abnormal accumulation of this substance can damage the cells that are critical for clear central vision. As a result, people with this disorder often lose their central vision and may experience blurry or distorted vision, and loss is rarely symmetric. Scotomata appear, first with red light and then for green; finally, relative (or in more serious cases, absolute) scotomata occur with white light. Vitelliform macular dystrophy does not affect side (peripheral) vision or the ability to see at night.
Researchers have described two forms of vitelliform macular dystrophy with similar features. The early-onset form (known as Best disease) usually appears in childhood. The disease received its name from a German ophthalmologist Friedrich Best who defined a pedigree living with various stages of the disease in 1905. The onset of symptoms and the severity of vision loss vary widely. The adult-onset form begins later, usually in middle age, and tends to cause relatively mild vision loss. The two forms of vitelliform macular dystrophy each have characteristic changes in the macula that can be detected during an eye examination.
In the Best disease, the paraclinic evaluations such as fundus fluorescein angiography or indocyanine green angiography, along with baseline and final electrooculography (EOG) results, may shed the light on the progression of disease.
References
Further reading
External links
Vitelliform macular dystrophy at NLM Genetics Home Reference
Bests disease - eMedicine.com
GeneReviews/NCBI/NIH/UW entry on Best Vitelliform Macular Dystrophy
NCBI Genetic Testing Registry |
Plasmablastic lymphoma | Plasmablastic lymphoma (PBL) is a type of large B-cell lymphoma recognized by the World Health Organization (WHO) in 2017 as belonging to a subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation. The other lymphoid neoplasms within this subgroup are: plasmablastic plasma cell lymphoma (or the plasmacytoma variant of this disease); primary effusion lymphoma that is Kaposis sarcoma-associated herpesvirus positive or Karposis sarcoma-associated Herpesvirus negative; anaplastic lymphoma kinase-positive large B-cell lymphoma; and human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified. All of these lymphomas are malignancies of plasmablasts, i.e. B-cells that have differentiated into plasmablasts but because of their malignant nature: fail to differentiate further into mature plasma cells; proliferate excessively; and accumulate in and injure various tissues and organs.The lymphomas in the lymphoid neoplasms with plasmablastic differentiation sub-group that are not PBL have sometimes been incorrectly considered to be variants of PBL. Each of the lymphomas in this subgroup of malignancies have distinctive clinical, morphological, and abnormal gene features. However, key features of these lymphomas sometime overlap with other lymphomas including those that are in this sub-group. In consequence, correctly diagnosing these lymphomas has been challenging. Nonetheless, it is particularly important to diagnose them correctly because they can have very different prognoses and treatments than the lymphomas which they resemble.Plasmablastic lymphomas are aggressive and rare malignancies that usually respond poorly to chemotherapy and carry a very poor prognosis. They occur predominantly in males who have HIV/AIDS, had a solid organ transplant, or are immunosuppressed in other ways; ~5% of all individuals with PBL appear to be immunocompetent, i.e. to have no apparent defect in their immune system. The malignant plasmablasts in more than half the cases of PBL are infected with a potentially cancer-causing virus, Epstein–Barr virus (EBV), and rare cases of PBL appear due to the plasmablastic transformation of a preexisting low-grade B-cell lymphoma. One variant of PBL, sometimes termed plasmablastic lymphoma of the elderly, has a significantly better prognosis than most other cases of PBL. The development of this variant appears due, at least in part, to immunosenescence, i.e. the immunodeficiency occurring in old age.
Presentation
Plasmablastic lymphoma lesions are most commonly rapidly growing, soft tissue masses that may be ulcerating, bleeding, and/or painful. In a recent (2020) review of published cases, individuals presenting with PBD were typically middle-aged or elderly (range 1–88 years; median age 58 tears) males (~73% of cases). Only a few cases have been reported in pediatric cases. The PDL lesions occurred most commonly in lymph nodes (~23% of cases), the gastrointestinal tract (~18%), bone marrow (16%), and oral cavity (12%). Less frequently involved tissues include the skin, genitourinary tract, paranasal sinuses, lung, and bones. While cases of PBL may present as a primary oral, or, very rarely a skin or lymph node disease, most individuals present with a widespread stage III or IV disease which in ~40% of cases, is accompanied by systemic B-symptoms such as fever, night sweats, and recent weight loss. Some 48%-63% of PBL cases occur in individuals with HIV/AIDS; ~80% of these HIV/AIDS-afflicted individuals have EBV+ disease whereas only ~50% of PBL individuals that do not have HIV/AIDS are EBV-positive. Individuals who develop PBL following organ transplantation are EBV-positive in >85% of cases. Most post-transplant and HIV/AIDS patients have an extremely aggressive disease. However, patients whose major contributing factor to PBL-development is EBV-positivity often present with, and continue to have, a significantly less aggressive disease than other patients with PBL. It is similarly clear that, on average, elderly patients (>68 years) likewise present with, and continue to have, a significantly less aggressive cancer.
Pathophysiology
In addition to the immunodeficiency-causing viral disease, HIV/AIDS (which is an AIDS-defining clinical condition), recent studies have diagnosed PBL in individuals who have one or more other causes for immunodeficiency. These causes include prior organ transplantation; immunosuppressive drugs; autoimmune and chronic inflammatory diseases (e.g. hepatitis C, rheumatoid arthritis, Graves disease, Giant-cell arteritis, sarcoidosis, and severe psoriasis); and immunosenescence due to age (e.g. >60 years). Rare cases of PDL have also occurred as a transformation of a low grade B-cell malignancy such as chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Studies also find that 60-75% of individuals diagnosed with PBL have Epstein–Barr virus-infected plasmablasts. EBV infects ~95% of the worlds population to cause no symptoms, minor non-specific symptoms, or infectious mononucleosis. The virus then enters a latency phase in which infected individuals become lifetime asymptomatic carriers of the virus in a set of their B-cells. Some weeks, months, years, or decades thereafter, a very small fraction of these carriers, particularly those with an immunodeficiency, develop any one of various EBV-associated benign or malignant diseases, including, in extremely rare cases, Epstein–Barr virus-positive plasmablastic lymphoma. The virus in infected plasmablastic cells appears to be in its latency I phase; consequently, these infected cells express EBV products such as EBER nuclear RNAs and BART microRNAs. These RNAs promote infected cells to proliferate, avoid attack by the hosts immune systems cytotoxic T-cells, and, possibly, block the infected cells apoptosis (i.e. programmed cell death) response to injuryThe predisposing conditions described in the previous paragraph can serve to enhance the ability of the plasmablasts in PBL to: avoid the hosts immune surveillance; survive for prolonged periods, grow excessively, and acquire pro-malignant gene abnormalities. Some of the gene abnormalities found in PBL include: 1) increased expression of the MYC proto-oncogene due to its rearrangement with an antibody gene by genetic recombination or, less commonly, other causes (Myc protein, the product of this gene, enhances cell proliferation, inhibits apoptosis, and promotes malignancy); 2) loss in the expression of the PRDM1 gene whose product, PRDM1/BLMP1 protein, represses the expression of Myc protein;) 3) frequent duplications in certain areas of chromosomes 1, 7, 11, and 22 (these duplications are similar to those often seen in diffuse large cell lymphoma); 4) reduced expression of at least 13 genes that are involved in B-cell responses to signaling agents. 5) increased expression of genes which promote the maturation of B-cells toward plasma cells (e.g. CD38, CD138, IR4/MUM1, XBP1, IL21R, and, as just indicated, PRDM1); and 6) reduced expression of genes characteristic of B-cells (e.g. CD20 and PAX5).
Diagnosis
Microscopic examination of involved PBD masses and infiltrates generally reveals diffuse proliferations of immunoblast-like cells with prominent features of plasma cells, i.e. plasmablastic cells. Immunostaining of these cells indicate that they lack B-cell marker proteins (e.g. CD20 and PAX5 [in ~10% of cases CD20 may be expressed at very low levels]) but rather express plasma cell marker proteins (e.g. CD38, CD138, IR4/MUM1, XBP1, IL21R, and/or PRDM1). The abnormalities in gene structures and expressions reported in the Pathophysiology section, particularly rearrangement and/or over expression of the MYC proto-oncogene, may also be apparent in these cells. The presence of HIV/AIDS or other causes of immuno-incompetence (see previous section), a history of having a low-grade lymphoma, and/or the presence of EVB+ plasmablasts in the diseases lesions would support the diagnosis of PBL.
Differential diagnosis
Various lymphomas can exhibit the microscopic appearance, including plasmablastic cells, and presentation of PBL. These lymphomas can usually be differentiated from PBL by further examinations of the plasmablasts for various marker proteins and determining other factors that favor the diagnosis of these lymphomas rather than PBL, as indicated in the following descriptions.
Anaplastic lymphoma kinase-positive large B-cell lymphoma
Unlike PBL, the plasmablastic cells in anaplastic lymphoma kinase-positive large B-cell lymphoma strongly express the product of the ACVRL1 gene, i.e. activin receptor-like kinase 1 (ALK1) and are not infected with EBV and therefore do not express this viruss EBER or BART RNAs.
Human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified
Unlike PBL, the plasmablastic cells in human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified express products of herpesvirus 8 (also termed Karposi sarcoma virus) such as LANA-1 protein. Also unlike PBL, these plasmablastic cells do not express CD30, CD138, CD79a, or a clonal IgM antibody and usually are not EBV-infected and therefore usually do not express this viruss EBER or BART RNAs.
Primary effusion lymphoma
In contrast to PBL, the plasmablastic cells in primary effusion lymphomas, whether HHV8-positive or HHV8-negative, usually strongly express CD45 and in HHV8 cases express HHV8 proteins such as the LANA-1 protein. Primary effusion lymphoma, HH8-negative also differs from PBL in that its plasmablastic cells frequently express certain B-cell marker proteins such as CD20 and CD79a.
Plasmablastic plasma cell lymphoma
Various factors distinguish plasmablastic plasma cell lymphoma from PBL. Prior diagnosis of plasma cell lymphoma (i.e. multiple myeloma or plasmacytoma), the presence of lytic bone lesions, increased levels of serum calcium, renal insufficiency, and anemia, and the presence of a myeloma protein in the serum and/or urine favor the diagnosis of plasmablastic plasma cell lymphoma rather than plasmablastic lymphoma. Ultimately, however, the marker proteins expressed by the plasmablastic cells in the two diseases are almost identical and a diagnosis of "plasmablastic neoplasm, consistent with PBL or multiple myeloma" may be acceptable in some cases according to the current World Health Organization classification.
Other B-cell lymphomas
The plasmablastic cells in B-cell lymphomas, including diffuse B-cell lymphomas, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma generally express CD20 and often express CD45 marker proteins. While PBL plasmablastic cells weakly express CD20 in 10% of cases, the strong expression of CD20 and the expression of CD45 virtually rules out PBL.
Treatment
The treatments for PBL have ranged from radiotherapy for localized disease to various chemotherapy regimens for extensive disease. The chemotherapy regimens have included CHOP (i.e. cyclophosphamide, hydroxydoxorubicin (or doxorubicin), vincristine, and either prednisone or prednisolone; CHOP-like regimens (e.g. CHOP plus etoposide); hyper-CVAD-MA (i.e. cyclophosphamide, vincristine, doxorubicin, dexamethasone and high dose methotrexate and cytarabine); CODOX-M/IVAC (i.e. cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate and ifosfamide, etoposide, and high-dose cytarabine); COMB (i.e. cyclophosphamide, oncovin, methyl-CCNU, and bleomycin); and infusional EPOCH (i.e. etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). While the experience treating PBL with radiation alone has been limited, patients with localized disease have been treated with doxorubicin-based chemotherapy regimens plus radiotherapy.
Experimental treatments
Given the unsatisfactory results of standard chemotherapy regimens, new treatments are being explored for use in PBL. Bortezomib, a drug that inhibits proteasomes, has been used alone or in combination with radiation and/or CHOP, EPOCH, or THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisone) chemotherapy regimens to treat some scores of patients with newly diagnosed or relapsed PBL. The results of these exploratory studies have been at least modestly encouraging and provide strong support for further studies using more controlled conditions. A study sponsored by the AIDS Malignancy Consortium in collaboration with the National Cancer Institute is in its recruiting phase to study the dosages, safety, and efficacy of adding daratumumab to the EPOCH regimen in treating patients with PBL. Daratumumab is a prepared monoclonal antibody that binds to CD38 and thereby directly or indirectly kills cells, including the plasmablasts in PBL, that express this marker protein on their surfaces. An ongoing study sponsored by the City of Hope Medical Center is examining the feasibility and safety of gene therapy that uses recombinant RNA to target a key element in the HIV genome in patients who have HIV/AIDs and a non-Hodgkins lymphoma, including patients with plasmablastic lymphoma.
Prognosis
Overall, patients receiving one of the cited chemotherapy regimens have achieved disease-free survival and overall survival rates of 22 and 32 months, respectively. The National Comprehensive Cancer Network recommends the more intensive regimens (e.g. hyper-CVAD-MA or infusional EPOCH) to treat the disease. These regimens have attained 5 year overall and disease-free survivals of 38% and 40%, respectively. Too few patients have been treated with autologous hematopoietic stem cell transplant in addition to chemotherapy for conclusions to be made. A few patients with HIV/AIDS-related PBL disease who were treated with highly active antiretroviral therapy (HAART) directed against the human immunodeficiency virus (i.e. HIV) have had remissions in their PDL lesions.
History
A study by Green and Eversole published in 1989 reported on 9 individuals afflicted with HIV/AIDS who
presented with lymphomatous masses in the oral cavity; these lymphomas were populated by apparently malignant Epstein–Barr virus-infected plasmablasts that did not express T-cell lymphocyte marker proteins. Eight years later, Delecluse and colleagues described a lymphoma, which they termed plasmablastic lymphoma, that had some features of a diffuse large B-cell lymphoma but unlike this lymphoma developed exclusively in the oral cavity, consisted of plasmablasts that lacked B-cell as well as T cell marker proteins and, in 15 of 16 cases, were infected with EBV. In 2008, the World Health Organization recognized this lymphoma as a variant of the diffuse large cell lymphomas. Subsequent to this recognition, numerous studies found this lymphoma to occur in a wide range of tissues besides the oral cavity and in individuals with various other predisposing immunodeficiency conditions. In 2017, this Organization classified PBL as the most common member of a rare subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation.
See also
Lymphoma
Epstein–Barr virus–associated lymphoproliferative diseases
References
Category:Lymphoid-related cutaneous conditions |
Impetigo herpetiformis | Impetigo herpetiformis is a form of severe pustular psoriasis occurring in pregnancy which may occur during any trimester.It is the only well known pustular psoriasis which is treated with steroids.
See also
Dermatoses of pregnancy
List of cutaneous conditions
Notes
References
Yap FBB (4 June 2008). "Impetigo herpetiformis: A case report and review of literature". Egyptian Dermatology Online Journal. 1 (4). ISSN 1687-3831. Retrieved 2009-07-09.
== External links == |
Acquired hemolytic anemia | Acquired hemolytic anemia can be divided into immune and non-immune mediated forms of hemolytic anemia.
Immune
Immune mediated hemolytic anaemia (direct Coombs test is positive)
Autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia
Idiopathic
Systemic lupus erythematosus (SLE)
Evans syndrome (antiplatelet antibodies and hemolytic antibodies)
Cold antibody autoimmune hemolytic anemia
Idiopathic cold hemagglutinin syndrome
Infectious mononucleosis and mycoplasma (atypical) pneumonia
Paroxysmal cold hemoglobinuria (rare)
Alloimmune hemolytic anemia
Hemolytic disease of the newborn (HDN)
Rh disease (Rh D)
ABO hemolytic disease of the newborn
Anti-Kell hemolytic disease of the newborn
Rhesus c hemolytic disease of the newborn
Rhesus E hemolytic disease of the newborn
Other blood group incompatibility (RhC, Rhe, Kidd, Duffy, MN, P and others)
Alloimmune hemolytic blood transfusion reactions (i.e., from a non-compatible blood type)
Drug induced immune mediated hemolytic anemia
Penicillin (high dose)
Methyldopa
Non-immune
Non-immune mediated hemolytic anemia (direct Coombs test is negative)
Drugs (i.e., some drugs and other ingested substances lead to hemolysis by direct action on RBCs, e.g., ribavirin )
Toxins (e.g., snake venom; plant poisons such as aesculin)
Trauma
Mechanical (from heart valves, extensive vascular surgery, microvascular disease, repeated mechanical vascular trauma)
Microangiopathic hemolytic anemia (a specific subtype with causes such as TTP, HUS, DIC and HELLP syndrome)
Infections (Note: Direct Coombs test is sometimes positive in hemolytic anemia due to infection)
Malaria
Babesiosis
Sepsis
Membrane disorders
Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface proteins)
Liver disease
Drug induced hemolysis
Drug induced hemolysis has large clinical relevance. It occurs when drugs actively provoke red blood cell destruction. It can be divided in the following manner:
Drug-induced autoimmune hemolytic anemia
Drug-induced nonautoimmune hemolytic anemiaA total of four mechanisms are usually described, but there is some evidence that these mechanisms may overlap.
References
== External links == |
Osteoradionecrosis | Osteoradionecrosis (ORN) is a serious complication of radiation therapy in cancer treatment where radiated bone becomes necrotic and exposed. ORN occurs most commonly in the mouth during the treatment of head and neck cancer, and can arise over 5 years after radiation. Common signs and symptoms include pain, difficulty chewing, trismus, mouth-to-skin fistulas and non-healing ulcers.
The pathophysiology of ORN is fairly complex and involves drastic changes to bone tissue as a result of DNA damage and cell death caused by radiation treatment. Radiation therapy targeting tumor cells can affect normal cells as well, which can result in the death of bone tissue. Advances in radiation therapy have decreased the incidence of ORN, estimated at around 2%. Certain risk factors including the size and location of tumor, history of smoking or diabetes, and presence of dental disease can affect the chances of developing ORN.
Osteoradionecrosis is difficult to prevent and treat. Current prevention strategies are aimed at avoiding excess doses of radiation as well as maintaining excellent dental hygiene. Treatments are variable depending on the provider and disease severity, and can range from medical treatment with antibiotics to hyperbaric oxygen therapy (HBO) to surgical debridement or reconstruction.
Clinical findings
There are not many specific clinical signs of ORN. It may be first seen as an area of exposed bone which is not healing, or the non-specific signs may become evident prior to this. Symptoms vary depending on the degree of ORN that has occurred. Early indicators may be numbness or paresthesias within the mouth or jaw. Other signs and symptoms include:
Pain
Swelling
Non-healing sore or ulcer in the mouth
Trismus
An extra-oral fistula (from jaw to skin)
Infection in gums/teeth
Extra-oral draining sinuses
Lymphadenopathy
Malocclusion
Jaw fracture
Sequestrum (most commonly found below the mandible)If symptoms are evident, these should be reported to the patients doctor or healthcare team as soon as possible.
Epidemiology and etiology
Epidemiology
The epidemiology of osteoradionecrosis has proven difficult to estimate, with previous studies reporting incidence of disease between 4.74-37.5%. More recent reports have estimated the incidence to 2%, which is likely attributable to improvements in radiation therapy.
Pathophysiology
Radiation therapy destroys cancer primarily by causing DNA damage that promotes cell death. Tumor cells within a cancer are especially susceptible to damage by radiation as they frequently develop mutations in the DNA repair mechanisms that allow normal, healthy cells to recover from radiation damage. However, excessive radiation doses can cause even normal cells to be overwhelmed by DNA damage and lead to local tissue changes and necrosis. Scientists have been conducting investigations into the exact mechanisms of these changes to help create treatments since osteoradionecrosis (ORN) was first described by Regaud in 1922. Several competing theories have emerged over the years with resultant changes to accepted treatments. Initially, it was believed that ORN arose from a combination of radiation, trauma and infection. According to this belief, radiation damage to the bone caused the bone to weaken, making it susceptible to microfractures caused by trauma and allowing bacteria to invade. This theory placed ORN on a spectrum of disease with osteomyelitis, so it was primarily treated with antibiotics. In 1983, Robert E. Marx, a prominent oral and maxillofacial surgeon, refuted the notion that trauma and infection were requirements in the development of ORN. Marx proposed that ORN was the result of cumulative tissue damage caused by radiation, creating disturbances in cell metabolism and homeostasis that resulted in cell death and hypocellular tissues. In addition, radiation causes injury to the endothelial cells of local vasculature, creating a hypovascular environment which leads to decreased oxygen delivery resulting in hypoxic tissues. The decrease of vasculature helps explain why the mandible is more commonly affected than maxilla, as the mandible is served primarily by the inferior alveolar artery, whereas the maxilla is served by various arteries and has a more robust blood supply. In sum, Marx believed that ORN was essentially hypocellular-hypovascular-hypoxic tissues behaved much like chronic non-healing wounds. Initial reports by Marx and others showing that treatment with hyperbaric oxygen (HBO) prevented ORN helped support this theory. However, later studies began to raise doubts about the effectiveness of HBO therapy and question whether Marxs theory was comprehensive enough to guide treatment.Current understanding is guided primarily by the work of Delanian and Lefaix, who proposed the radiation-induced fibroatrophic (RIF) process. Advances in lab techniques allowed scientists to perform more detailed studies of ORN specimens. Analysis of samples showed that tissues undergoing ORN underwent three phases of disease: 1) prefibrotic, 2) constitutive organized and 3) late fibroatrophic phases. During the prefibrotic phase, injury to endothelial cells secondary to radiation causes destruction of local vasculature, and recruitment of inflammatory cells and fibroblasts via pro-inflammatory cytokines like TNF-α, FGF-β and TGF-β1. In addition, osteoblasts within the bone are damaged and destroyed, leading to decreased production of normal bone tissue. In the constitutive organized phase, fibroblasts persist and are converted to myofibroblasts by these same cytokines, that begin to fibrous extracellular matrix (ECM) within the affected bone. Consequently, the increased production of ECM by myofibroblasts coupled with decreased production of osteoid by osteoblasts results in weakened bony tissue. Finally, during the late fibroatrophic phase, the affected bone becomes hypocellular as myofibroblasts begin to die and leave behind weak, fibrotic tissue. Ultimately, these tissues are fragile and susceptible to damage by trauma or infection with little ability to repair or defend themselves due to the lack of vasculature caused during the pre-fibrotic phase. Given this understanding of the pathophysiology of ORN, current treatments are targeted at decreasing inflammatory cytokines and reducing free radical damage to DNA.
Risk factors
Risk factors for osteoradionecrosis include:
Size and location of tumor; the risk of developing ORN increases with larger tumors, since they require higher doses of radiation to achieve cure, subsequently exposing nearby tissues to higher doses. While radiation therapy has become more targeted and precise, patients with tumors located closer to the mandible (e.g. oral cavity) or maxilla (e.g. nasopharynx) will more commonly develop ORN since the bone is more likely fall within the radiation field.
Dose and delivery of radiation; generally speaking, higher doses of radiation are more likely to result in ORN, especially when doses exceed 65 Gy. While minimizing radiation doses and avoiding excess radiation to bone can reduce ORN, there does not appear to much evidence that different radiation strategies (i.e. conventional radiotherapy, IMRT, brachytherapy) reduce risk.
Smoking; tobacco use is associated with significant increases in risk of developing ORN. This increased risk is attributed to the vasoconstrictive properties of nicotine, which coupled with damage to endothelium by radiation, exacerbate the decreased perfusion of affected tissues.
Diabetes mellitus; diabetes is a known cause of microvascular disease, which similar to smoking, can worsen the blood supply and perfusion to tissues affected by radiation.
Dental disease and extractions; patients with poor oral hygiene and dental disease prior to radiation, including edentulous patients and those with dentures, are more susceptible to developing ORN. Diseased teeth near the radiation field may need to be extracted, and should be evaluated prior to radiation treatment.
Staging
The staging system can be useful as a baseline reference for management after a definitive diagnosis of ORN has been established.
Prevention and management
There is currently no universally accepted prevention and management of ORN and in many cases depends on how severe the condition presents. Currently, there are many preventive approaches for ORN proposed, but yet to be justified by high quality evidence. Studies have been conducted to measure effectiveness of current interventions. However, there lacks evidence to conclude that one approach is more effective than others. This leads to uncertainty for clinicians and patients on deciding the best treatment that can be provided.There are a number of classifications of ORN stages present with different basis of staging and most updated one being the Notani classification. The Notani classification of stages is based on the radiographic and clinical findings, with studies describing low grade ORN being treated conservatively and advanced ORN including pathological fractures, and oro-cutaneous fistula treated surgically.
Prevention
Prior to radiotherapy
Dental assessment
It is recommended to have a multi-disciplinary approach to care and dental assessment before the patient undergoes radiotherapy. It has been reported, that analysis of patients who have a strict preventive regime paired with IMRT resulted in no cases of ORN.
Dental extractions
As dental extractions are a major risk factor in ORN development, it was recommended to extract all teeth prior to radiotherapy. However, this is now discouraged as a treatment of choice and has many disadvantages. According to one study, the frequency of ORN pre-radiotherapy extractions and post-radiotherapy extractions are almost the same. Extractions of teeth of poor prognosis, usually less than five years is recommended and planning should take into account the likely future problems with oral care, for example if severe trismus develops and if dentures were to be prescribed, denture trauma may cause ORN. The patient’s wishes must also be taken into account.If teeth are required to be extracted, they should ideally be completed as soon as possible to maximise healing prior to radiotherapy. One study recommended a minimum of 14–21 days prior to radiotherapy. However, commencement of radiotherapy should not be delayed as there is little difference in frequency of ORN in pre- and post-radiotherapy extractions and it is recommended that trauma should be kept to a minimum during extractions.
Preventive regime
It is important to ensure that tooth brushing technique and habit is kept to a high standard. Patients undergoing head and neck radiotherapy may experience a sore mouth, therefore a soft bristle toothbrush may be preferred. Chlorhexidine mouthwash can also be used in conjunction with tooth brushing, and if too sore on the mucosa, can be diluted with equal amounts of water.A fluoride regime is also encouraged with either high fluoride toothpaste (Duraphat 5000), wearing splints with fluoride gel applied for 10 minutes/day or alcohol free fluoride mouthwashes. The patient’s oral condition needs to be taken into consideration and tailored accordingly as trismus may be present which would not allow the back of the mouth to be accessed by fluoride splints or trays. Some may also experience difficulty tolerating toothpastes and mouthwashes for a while due to altered taste and mucosal ulceration.
It is also very important that the patient maintains a high level of motivation in taking care of their oral hygiene, and attending dental appointments where a dental practitioner will be able to monitor them during and after radiotherapy. Oral preparations prescribed to aid sore or dry mouth should be fully understood by patients to avoid any preparations which can cause damage to the teeth. Any saliva substitutes given should be pH neutral.
Post-radiotherapy
Patients will still be susceptible to radiation caries and periodontal disease, more so if they present with dry mouth or access difficulty when tooth brushing. Any restorative or periodontal procedures should be commenced if indicated and endodontic treatments should take priority over extractions, although if there is a difficulty in mouth opening, endodontic treatments can be difficult or impossible. Where a tooth is deemed unrestorable, decoronation can be done. Although dentures should be avoided if a shortened dental arch is manageable, if a denture is required or being used, they should be checked routinely and any adjustment to pressure areas should be made to avoid ORN secondary to denture trauma.
Extractions post-radiotherapy
A practical recommendation is provided in some case where it is necessary to extract teeth from the jaw after radiotherapy. An assessment of the risk of ORN should be done based on the dose of radiation, the site and how easy is the extraction. Any information on risk and early signs of ORN should be given to the patient. The recommendations are listed below, however, there are some controversies on the ideal antibiotic regime and the use of hyperbaric oxygen therapy (HBO).Summary of recommendations:
0.2% chlorhexidine mouthrinse given before extraction
Oral antibiotics(3g) given 1 hour prior to extraction ( if allergic 600 mg clindamycin)
Amoxicillin 250 mg 3 times/day or metronidazole 200 mg 3 times/day for 3–5 days post-operatively.
Extractions should be completed with as little trauma as possible, and on simple extractions of mobile teeth
Primary closure for firm teeth, by a minimal periosteal flap and alveolectomy
An experienced operator
Possibly pre-operative hyperbaric oxygen for mandibular molars in areas of high radiation
Review 5 days post-extraction and weekly review after until healing is complete.
Antibiotics
Majority of studies on ORN have recommended the use of prophylactic antibiotic where extractions are needed post-radiotherapy, although there is no universally agreed choice, timing and course duration of antibiotic regime.In one study, it was discovered that cases after 1986, the incidence of ORN after extractions post-radiotherapy was 3.6% in antibiotic prescribed cases and 2.6-3.4% in cases where there is no report on the prescription of antibiotics, showing no difference in reducing the risk of ORN and possibly reconsidering antibiotic regime in preventing ORN.
Hyperbaric oxygen therapy
Results since 1986 have shown of far lower rates of ORN incidence, even without HBO (3.1-3.5%) and even a slightly higher rate for HBO patients (4.0%). Prophylactic use of HBO has been recommended in some studies with a Cochrane review suggesting evidence for some reduction in ORN. However, the use of HBO prophylaxis is not agreed by others due to the insufficient evidence. Majority of British maxillofacial surgeons who participated in a survey recommended prophylactic HBO but protocols are varied.
Management
Conservative
Antiseptic mouthwashes: Mouthrinses such as 0.02% aqueous chlorhexidine and saline can be used in acute ORN together with analgesics and anti-inflammatory drugs.
Antibiotics: In order to eliminate infection in the region, tetracyclines can be prescribed due to their selective uptake by bone. Penicillin antibiotics can also be used because of their superficial contamination with oral bacteria.
Ultrasound therapy: First introduced as a treatment modality in 1992, it involves the application of high-frequency sound waves to induce angiogenesis and improve blood circulation to muscles. Harris demonstrated that 48% of cases showed healing when 15 minutes of ultrasound therapy was applied daily on the skin affected by ORN, while combined with debridement.
Hyperbaric oxygen therapy (HBO): First described in 1973, HBO was intended to be an adjunctive treatment method in ORN. The theoretical basis behind this treatment was the fact that it causes an increase in tissue oxygen tension and an improvement in collagen synthesis, angiogenesis and epithelialization. However, its use as the only method in the management of ORN is controversial. There is little evidence to show any clinical benefit, and that it may not have therapeutical significance over a placebo.
Surgical
Multidisciplinary approach (HBO + Surgery): Studies have shown support of combining HBO therapy and a surgical approach to treat ORN. This is in order to improve local blood circulation, with resection of necrotic bone and reconstruction with a free flap. However, some studies still state lack of benefit HBO therapy brings. It does not revive dead bone, therefore microvascular reconstruction without the use of HBO therapy is still a successful method of treating ORN.
Surgery: The procedures involved in the surgical management of ORN are as listed: Removal of small sequestra, sequestrectomy, alveolectomy with primary closure, closure of orocutaneous fistula and large resections. Surgical management is usually required in cases of advanced disease, or if conservative measures fail to work. Methods used to reconstruct anatomical structures involve plates, autogenous bone grafts, regional flaps and free tissue transfer. Vascularised bone flaps are known to be the most effective mode of reconstruction.
Therapeutic approach
Research to treat ORN at a molecular level has increased with progress in the field of medicine. The pharmacological methods to treat ORN listed below were developed to treat the etiologic factors.
Pentoxifylline is methylxanthine derivative that drives vascular dilation and increased erythrocyte flexibility, resulting in enhanced blood flow. It also contains anti-tumour necrosis factor α activity, and reduces the cytokine cascade that facilitates the process of ORN. However, pentoxifylline is not meant for the long-term treatment of ORN.
Tocopherols can occur in various forms. Its alpha form, also known as vitamin E, has antioxidant properties which results in the inhibition of platelet aggregation. Alpha-tocopherol is also able to scavenge reactive oxygen species involved in the ORN disease process, by inducing cell membrane peroxidation.
Clodronate is a non-nitrogenous bisphosphonate used in the treatment of numerous diseases, such as hyperparathyroidism, osteoporosis, and multiple myeloma. Clodronate functions by inhibiting bone resorption, due to the reduction in the activity and quantity of osteoclasts. Clodronate also acts directly on osteoblasts, which increases bone formation and reduces the growth of fibroblasts.
== References == |
Cauliflower ear | Cauliflower ear is an irreversible condition that occurs when the external portion of the ear is hit and develops a blood clot or other collection of fluid under the perichondrium. This separates the cartilage from the overlying perichondrium that supplies its nutrients, causing it to die and resulting in the formation of fibrous tissue in the overlying skin. As a result, the outer ear becomes permanently swollen and deformed, resembling a cauliflower.
The condition is common in martial arts such as Brazilian jiu-jitsu, wrestling, boxing, kickboxing, judo or mixed martial arts and in full-contact sports such as rugby union.
Presentation
People presenting with possible auricular hematoma often have additional injuries (for example, head/neck lacerations) due to the frequently traumatic causes of auricular hematoma. The ear itself is often tense, fluctuant, and tender with throbbing pain. However, because of potentially more remarkable injuries often associated with auricular hematoma, auricular hematoma can easily be overlooked without directed attention.
Causes
The most common cause of cauliflower ear is blunt trauma to the ear leading to a hematoma which, if left untreated, eventually heals to give the distinct appearance of cauliflower ear. The structure of the ear is supported by a cartilaginous scaffold consisting of the following distinct components: the helix, antihelix, concha, tragus, and antitragus. The skin that covers this cartilage is extremely thin with virtually no subcutaneous fat while also strongly attached to the perichondrium, which is richly vascularized to supply the avascular cartilage.Cauliflower ear can also present in the setting of nontraumatic inflammatory injury of auricular connective tissue such as in relapsing polychondritis (RP), a rare rheumatologic disorder in which recurrent episodes of inflammation result in destruction of cartilage of the ears and nose. Joints, eyes, audiovestibular system, cardiovascular system, and respiratory tract can also be involved.
Mechanism
The components of the ear involved in cauliflower ear are the outer skin, the perichondrium, and the cartilage. The outer ear skin is tightly adherent to the perichondrium because there is almost no subcutaneous fat on the anterior of the ear. This leaves the perichondrium relatively exposed to damage from direct trauma and shear forces, created by a force pushing across the ear like a punch, and increasing the risk of hematoma formation. In an auricular hematoma, blood accumulates between the perichondrium and cartilage. The hematoma mechanically obstructs blood flow from the perichondrium to the avascular cartilage. This lack of perfusion puts the cartilage at risk for becoming necrotic and/or infected. If left untreated, disorganized fibrosis and cartilage formation will occur around the aforementioned cartilaginous components.Consequently, the concave pinna fills with disorganized connective tissue. The cartilage then deforms and kinks, resulting in the distinctive appearance somewhat resembling a cauliflower. Rapid evacuation of the hematoma restores close contact between the cartilage and perichondrium, thereby reducing the likelihood of deformity by minimizing the ischemia that would otherwise result from a remaining hematoma.Auricular hematoma most often occurs in the potential space between the helix and the antihelix (scapha) and extends anteriorly into the fossa triangularis. Less frequently, the hematoma may form in the concha or the area in and around the external auditory meatus. Importantly, an auricular hematoma can also occur on the posterior ear surface, or even both surfaces. Risk of necrotic tissue is greatest when both posterior and anterior surfaces are involved, although posterior surface involvement is less likely given its increased quantity of impact-dampening subcutaneous tissue.
Diagnosis
Perichondral hematoma and consequently cauliflower ear are diagnosed clinically. This means that the medical provider will make the diagnosis by using elements of the history of the injury (examples: participation in contact sports, trauma to the ear, previous similar episodes) and combine this with findings on physical exam (examples: tenderness to the area, bruising, deformation of the ear contours) to confirm the diagnosis and decide on the appropriate treatment for the patient.
To assist with settling on the best form of treatment for cauliflower ear Yotsuyanagi et al. created a classification system for deciding when surgery is needed and to guide the best approach.
Preventions
Headgear called a "scrum cap" in rugby, or simply "headgear" or ear guard in wrestling and other martial arts, that protects the ears is worn to help prevent this condition. A specialty ear splint can also be made to keep the ear compressed, so that the damaged ear is unable to fill thus preventing cauliflower ear. For some athletes, however, a cauliflower ear is considered a badge of courage or experience.
Treatment
There are many types of treatment for the perichondral hematoma that can lead to cauliflower ear, but the current body of research is unable to identify a single best treatment or protocol. There is definitive evidence that the drainage of this hematoma is better for the prevention of cauliflower deformity when compared to conservative treatment, but the use of bandages and/or splinting after drainage requires more research.Because an acute hematoma can lead to cauliflower ear, prompt evacuation of the blood can prevent permanent deformity. There are many described techniques for the drainage of blood in the acute stage to prevent hematoma, including simple needle drainage, continuous suction devices, placing a wick, and incision and drainage. After the blood has been drained, the prevention of re-accumulation becomes the most pressing issue. This has been achieved with many techniques including: direct pressure dressings, in and out mattress sutures, buttons placed on sutures, thermoplastic splints, sutured cotton balls, and absorbable mattress sutures. The use of simple drainage becomes less useful after six hours from the injury and when there is recurrent trauma. In these cases it has been suggested that open surgical treatment is more effective in returning the cosmetic appearance and prevention of recurrence. The outer ear is prone to infections, so antibiotics are usually prescribed. Pressure can be applied by bandaging which helps the skin and the cartilage to reconnect. Clothes pegs, magnets, and custom molded ear splints can also be used to ensure adequate pressure is applied to the damaged area Without medical intervention the ear can sustain serious damage. Disruption of the ear canal is possible. The outer ear may wrinkle and can become slightly pale due to reduced blood flow; hence the common term "cauliflower ear". Cosmetic procedures are available that can possibly improve the appearance of the ear.
History
The presentation of cauliflower ear was recorded in ancient Greece.In 19th-century Hong Kong opium dens, opium users would develop cauliflower ear from long periods sleeping on hard wooden pillows.
References
External links
Medicinenet.com |
Spitz nevus | A Spitz nevus is a benign skin lesion. A type of melanocytic nevus, it affects the epidermis and dermis.It is also known as an epithelioid and spindle-cell nevus, and misleadingly as a benign juvenile melanoma,: 691 and Spitzs juvenile melanoma).
The name juvenile melanoma is generally no longer used as it is neither a melanoma, nor does it occur only in children.
Pathophysiology
The cause of Spitz nevi is not yet known. There is an association with sunburn, but causation is not established. Genetic studies of Spitz nevi have shown that most cells have the normal number of chromosomes, however a minority (25%) of cells have been shown to contain extra copies of parts of some chromosomes, such as the short arm of chromosome 11 (11p).
Diagnosis
On histopathology, Spitz nevi characteristically have vertically arranged nests of nevus cells that have both a spindled and an epithelioid morphology. Apoptotic cells may be seen at the dermoepidermal junction. The main histologic differential diagnoses are pigmented spindle cell nevus and malignant melanoma.
Treatment
Surgical removal is usually performed, even though it is benign.
Epidemiology
Spitz nevi are uncommon. Their annual incidence was estimated in a coastal population of sub-tropical Queensland to be 1.4 cases per 100,000 people. For comparison, the annual incidence of melanoma in the same population, which is high by world standards is 25.4 cases per 100,000 people.Although they are most commonly found on people in their first two decades of life, the age range for people with Spitz nevi is from 6 months to 71 years, with a mean age of 22 years and a median age of 19 years.
Eponym
The lesion is named after Sophie Spitz, the pathologist who originally described it in 1948.
See also
List of cutaneous conditions
List of genes mutated in pigmented cutaneous lesions
Melanoma with features of a Spitz nevus
References
== External links == |
Lordosis | Lordosis is historically defined as an abnormal inward curvature of the lumbar spine. However, the terms lordosis and lordotic are also used to refer to the normal inward curvature of the lumbar and cervical regions of the human spine. Similarly, kyphosis historically refers to abnormal convex curvature of the spine. The normal outward (convex) curvature in the thoracic and sacral regions is also termed kyphosis or kyphotic. The term comes from the Greek lordōsis, from lordos ("bent backward").Lordosis in the human spine makes it easier for humans to bring the bulk of their mass over the pelvis. This allows for a much more efficient walking gait than that of other primates, whose inflexible spines cause them to resort to an inefficient forward leaning "bent-knee, bent-waist" gait. As such, lordosis in the human spine is considered one of the primary physiological adaptations of the human skeleton that allows for human gait to be as energetically efficient as it is.Lumbar hyperlordosis is excessive extension of the lumbar region, and is commonly called hollow back, sway back, or saddle back (after a similar condition that affects some horses). Lumbar kyphosis is an abnormally straight (or in severe cases flexed) lumbar region.
Types
Lumbar lordosis
Normal lordotic curvatures, also known as secondary curvatures, result in a difference in the thickness between the front and back parts of the intervertebral disc. Lordosis may also increase at puberty, sometimes not becoming evident until the early or mid-20s.In radiology, a lordotic view is an X-ray taken of a patient leaning backward.
Lumbar hyperlordosis
Lumbar hyperlordosis is a condition that occurs when the lumbar region (lower back) experiences stress or extra weight and is arched to point of muscle pain or spasms. Lumbar hyperlordosis is a common postural position where the natural curve of the lumbar region of the back is slightly or dramatically accentuated. Commonly known as swayback, it is common in dancers. Imbalances in muscle strength and length are also a cause, such as weak hamstrings, or tight hip flexors (psoas). A major feature of lumbar hyperlordosis is a forward pelvic tilt, resulting in the pelvis resting on top of the thighs.
Other health conditions and disorders can cause hyperlordosis. Achondroplasia (a disorder where bones grow abnormally which can result in short stature as in dwarfism), Spondylolisthesis (a condition in which vertebrae slip forward) and osteoporosis (the most common bone disease in which bone density is lost resulting in bone weakness and increased likelihood of fracture) are some of the most common causes of hyperlordosis. Other causes include obesity, hyperkyphosis (spine curvature disorder in which the thoracic curvature is abnormally rounded), discitits (an inflammation of the intervertebral disc space caused by infection) and benign juvenile lordosis. Other factors may also include those with rare diseases, as is the case with Ehlers Danlos Syndrome (EDS), where hyper-extensive and usually unstable joints (e.g. joints that are problematically much more flexible, frequently to the point of partial or full dislocation) are quite common throughout the body. With such hyper-extensibility, it is also quite common (if not the norm) to find the muscles surrounding the joints to be a major source of compensation when such instability exists.
Excessive lordotic curvature – lumbar hyperlordosis, is also called "hollow back", and "saddle back" (after a similar condition that affects some horses); swayback usually refers to a nearly opposite postural misalignment that can initially look quite similar. Common causes of lumbar hyperlordosis include tight low back muscles, excessive visceral fat, and pregnancy. Rickets, a vitamin D deficiency in children, can cause lumbar hyperlordosis.
Lumbar hypolordosis
Being less common than lumbar hyperlordosis, hypolordosis (also known as flatback) occurs when theres less of a curve in the lower back or a flattening of the lower back. This occurs because the vertebrae are oriented toward the back of the spine, stretching the disc towards the back and compressing it in the front. This can cause a narrowing of the opening for the nerves, potentially pinching them.
Signs and symptoms
Lumbar hyperlordosis (also known as anterior pelvic tilt) has a noticeable impact on the height of individuals with this medical issue, a height loss of 0.5–2.5 inches (1.27–6.35 centimeters) is common.For example, the height loss was measured by measuring the patients height while he or she is standing straight (with exaggerated curves in the upper and lower back) and again after he or she fixed this issue (with no exaggerated curves), both of these measurements were taken in the morning with a gap of 6 months and the growth plates of the patient were checked to make sure that they were closed to rule out natural growth. The height loss occurs in the torso region and once the person fixes his or her back, the persons Body Mass Index will reduce since he or she is taller and the stomach will also appear to be slimmer.A similar impact has also been noticed in transfeminine people who have weaker muscles in the lower back due to increased estrogen intake and other such treatments.However, the cause of height loss in both situations is a little different even though the impact is similar. In the first scenario, it can be due to a genetic condition, trauma to the spine, pregnancy in women, increased abdominal fat or a sedentary lifestyle (sitting too much causes muscle imbalances and is the most common reason for this issue) and in the second scenario, the estrogen weakens the muscles in the area.Merely slouching doesnt cause height loss even though it may make a person look shorter, slouching may lead to perceived height loss whereas lumbar hyperlordosis leads to actual and measured height loss. To make it easier to understand the difference, if a person loses a vertebra (which is around 2 inches or 5 centimeters in height) in his or her spine, it doesnt matter if he or she slouches or not, he or she will be shorter regardless of his or her posture. Lumbar hyperlordosis, of course, doesnt make you lose a vertebra but it bends them in such a way that your spines vertical height is reduced.Although lumbar hyperlordosis gives an impression of a stronger back, it can lead to moderate to severe lower back pain. The most problematic symptom is that of a herniated disc where the individual has put so much strain on the back that the discs between the vertebrae have been damaged or have ruptured. Technical problems with dancing such as difficulty in the positions of attitude and arabesque can be a sign of weak iliopsoas. Tightness of the iliopsoas results in a dancer having difficulty lifting their leg into high positions. Abdominal muscles being weak and the rectus femoris of the quadriceps being tight are signs that improper muscles are being worked while dancing which leads to lumbar hyperlordosis. The most obvious signs of lumbar hyperlordosis is lower back pain in dancing and pedestrian activities as well as having the appearance of a swayed back.
Causes
Possible causes that lead to the condition of lumbar hyperlordosis are the following:
Spines – Natural factors of how spines are formed greatly increase certain individuals likelihood to experience a strain or sprain in their back or neck. Factors such as having more lumbar vertebrae allowing for too much flexibility, and then in cases of less lumbar the individual not reaching their necessity for flexibility and then pushing their bodies to injury.
Legs – Another odd body formation is when an individual has a leg shorter than the other, which can be immediate cause for imbalance of hips then putting strain on the posture of the back which an individual has to adjust into vulnerable positions to meet aesthetic appearances. This can lead to permanent damage in the back. Genu recurvatum (sway back knees) is also a factor that forces a dancer to adjust into unstable postures.
Hips – Common problems in the hips are tight hip flexors, which causes for poor lifting posture, hip flexion contracture, which means the lack of postural awareness, and thoracic hyperkyphosis, which causes the individual to compensate for limited hip turn out (which is essential to dances such as ballet). Weak psoas (short for iliopsoas-muscle that controls the hip flexor) force the dancer to lift from strength of their back instead of from the hip when lifting their leg into arabesque or attitude. This causes great stress and risk of injury, especially because the dancer will have to compensate to obtain the positions required.
Muscles – One of the greatest contributors is uneven muscles. Because all muscles have a muscle that works in opposition to it, it is imperative that to keep all muscles protected, the opposite muscle is not stronger than the muscle at risk. In the situation of lumbar lordosis, abdominal muscles are weaker than the muscles in the lumbar spine and the hamstring muscles. The muscular imbalance results in pulling down the pelvis in the front of the body, creating the swayback in the spine.
Growth spurt – Younger dancers are more at risk for development of lumbar hyperlordosis because the lumbar fascia and hamstrings tighten when a child starts to experience a growth spurt into adolescence.Technical factors
Improper lifts – When male dancers are performing dance lifts with another dancer they are extremely prone to lift in the incorrect posture, pushing their arms up to lift the other dancer, while letting their core and spine curve which is easy to then hyperlordosis in a dancers back.
Overuse – Over 45% of anatomical sites of injury in dancers are in the lower back. This can be attributed to the strains of repetitive dance training which may lead to minor trauma. If the damaged site is not given time to heal the damage of the injury will increase. Abrupt increases in dance intensity or sudden changes in dance choreography do not allow the body to adapt to the new stresses. New styles of dance, returning to dance, or increasing dance time by a great deal will result in exhaustion of the body.
Diagnosis
Measurement and diagnosis of lumbar hyperlordosis can be difficult. Obliteration of vertebral end-plate landmarks by interbody fusion may make the traditional measurement of segmental lumbar lordosis more difficult. Because the L4–L5 and L5–S1 levels are most commonly involved in fusion procedures, or arthrodesis, and contribute to normal lumbar lordosis, it is helpful to identify a reproducible and accurate means of measuring segmental lordosis at these levels. A visible sign of hyperlordosis is an abnormally large arch of the lower back and the person appears to be puffing out his or her stomach and buttocks.
Scanning
X-ray
Precise diagnosis is done by looking at a complete medical history, physical examination and other tests of the patient. X-rays are used to measure the lumbar curvature. On a lateral X-ray, a normal range of the lordotic curvature of between 20° and 60° has been proposed by Stagnara et al., as measured from the inferior endplate of T12 to the inferior endplate of L5. The Scoliosis Research Society has proposed a range of 40° and 60° as measured between the upper endplate of Th12 and the upper endplate of S1. Individual studies, although using other reference points, have found normal ranges up to approximately 85°. It is generally more pronounced in females. It is relatively constant through adolescence and young adulthood, but decreases in the elderly.
MRI and CT
Bone scans are conducted in order to rule out possible fractures and infections, magnetic resonance imaging (MRI) is used to eliminate the possibility of spinal cord or nerve abnormalities, and computed tomography scans (CT scans) are used to get a more detailed image of the bones, muscles and organs of the lumbar region.
Treatment
Exercises
Some corrective exercises can be done to alleviate this issue, it may take several months to fix (provided that the person sits less, stands with a neutral pelvis and sleeps on their back).Since lumbar hyperlordosis is usually caused by habitual poor posture, rather than by an inherent physical defect like scoliosis or hyperkyphosis, it can be reversed. This can be accomplished by stretching the lower back, hip-flexors, quads and strengthening the abdominal muscles, hamstrings and glutes. Strengthening the gluteal complex is a commonly accepted practice to reverse excessive lumbar lordosis, as an increase in gluteals muscle tone assist in the reduction excessive anterior pelvic tilt and lumbar hyperlordosis. Local intra-articular hip pain has been shown to inhibit gluteal contraction potential, meaning that hip pain could be a main contributing factor to gluteal inhibition. Dancers should ensure that they dont strain themselves during dance rehearsals and performances. To help with lifts, the concept of isometric contraction, during which the length of muscle remains the same during contraction, is important for stability and posture.Lumbar hyperlordosis may be treated by strengthening the hip extensors on the back of the thighs, and by stretching the hip flexors on the front of the thighs.
Only the muscles on the front and on the back of the thighs can rotate the pelvis forward or backward while in a standing position because they can discharge the force on the ground through the legs and feet. Abdominal muscles and erector spinae cant discharge force on an anchor point while standing, unless one is holding his hands somewhere, hence their function will be to flex or extend the torso, not the hip.
Back hyper-extensions on a Roman chair or inflatable ball will strengthen all the posterior chain and will treat hyperlordosis. So too will stiff legged deadlifts and supine hip lifts and any other similar movement strengthening the posterior chain without involving the hip flexors in the front of the thighs. Abdominal exercises could be avoided altogether if they stimulate too much the psoas and the other hip flexors.
Controversy regarding the degree to which manipulative therapy can help a patient still exists. If therapeutic measures reduce symptoms, but not the measurable degree of lordotic curvature, this could be viewed as a successful outcome of treatment, though based solely on subjective data. The presence of measurable abnormality does not automatically equate with a level of reported symptoms.
Braces
The Boston brace is a plastic exterior that can be made with a small amount of lordosis to minimize stresses on discs that have experienced herniated discs. In the case where Ehlers Danlos syndrome (EDS) is responsible, being properly fitted with a customized brace may be a solution to avoid strain and limit the frequency of instability.
Tai chi
While not really a treatment, the art of tai chi chuan calls for adjusting the lower back curvature (as well as the rest of the spinal curvatures) through specific re-alignments of the pelvis to the thighs, its referred to in shorthand as dropping the tailbone. The specifics of the structural change are school specific, and are part of the jibengong (essential technique) of these schools. The adjustment is referred to in tai chi chuan literature as when the lowest vertebrae are plumb erect...
See also
Hyperkyphosis
Kyphoscoliosis
Lordosis behavior
Potts disease
Footnotes
References
Gabbey, Amber. "Lordosis". Healthline Networks Incorporated. Retrieved 10 December 2013.
Gylys, Barbara A.; Mary Ellen Wedding (2005), Medical Terminology Systems, F.A. Davis Company
"Osteoporosis-overview". A.D.A.M. Retrieved 8 December 2013.
External links
What is Lordosis?
Lordosis - MedlinePlus definition
Lordosis - SpineUniverse
Ways To Treat Lordosis |
Paraphilia | Paraphilia (previously known as sexual perversion and sexual deviation) is the experience of intense sexual arousal to atypical objects, situations, fantasies, behaviors, or individuals. It has also been defined as sexual interest in anything other than a consenting human partner.There is no scientific consensus for any precise border between unusual sexual interests and paraphilic ones. There is debate over which, if any, of the paraphilias should be listed in diagnostic manuals, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases (ICD).
The number and taxonomy of paraphilia is under debate; one source lists as many as 549 types of paraphilia. The DSM-5 has specific listings for eight paraphilic disorders. Several sub-classifications of the paraphilias have been proposed, and some argue that a fully dimensional, spectrum or complaint-oriented approach would better reflect the evidence.
Terminology
History
Many terms have been used to describe atypical sexual interests, and there remains debate regarding technical accuracy and perceptions of stigma. Sexologist John Money popularized the term paraphilia as a non-pejorative designation for unusual sexual interests. Money described paraphilia as "a sexuoerotic embellishment of, or alternative to the official, ideological norm." Psychiatrist Glen Gabbard writes that despite efforts by Stekel and Money, "the term paraphilia remains pejorative in most circumstances."Coinage of the term paraphilia (paraphilie) has been credited to Friedrich Salomon Krauss in 1903 and it was used with some regularity by Wilhelm Stekel in the 1920s. The term comes from the Greek παρά (para) "beside" and φιλία (-philia) "friendship, love".
In the late 19th century, psychologists and psychiatrists started to categorize various paraphilias as they wanted a more descriptive system than the legal and religious constructs of sodomy and perversion. Before the introduction of the term paraphilia in the DSM-III (1980), the term sexual deviation was used to refer to paraphilias in the first two editions of the manual. In 1981, an article published in American Journal of Psychiatry described paraphilia as "recurrent, intense sexually arousing fantasies, sexual urges, or behaviors generally involving" the following:
Non-human objects
The suffering or humiliation of oneself or ones partner
Children
Non-consenting persons
Homosexuality and non-heterosexuality
Homosexuality, now widely accepted as a variant of human sexuality, was at one time discussed as a sexual deviation. Sigmund Freud and subsequent psychoanalytic thinkers considered homosexuality and paraphilias to result from psychosexual non-normative relations to the Oedipal complex. As such, the term sexual perversion or the epithet pervert have historically referred to gay men, as well as other non-heterosexuals (people who fall outside the perceived norms of sexual orientation).By the mid-20th century, mental health practitioners began formalizing "deviant sexuality" classifications into categories. Originally coded as 000-x63, homosexuality was the top of the classification list (Code 302.0) until the American Psychiatric Association removed homosexuality from the DSM in 1973. Martin Kafka writes, "Sexual disorders once considered paraphilias (e.g., homosexuality) are now regarded as variants of normal sexuality."A 2012 literature study by clinical psychologist James Cantor, when comparing homosexuality with paraphilias, found that both share "the features of onset and course (both homosexuality and paraphilia being life-long), but they appear to differ on sex ratio, fraternal birth order, handedness, IQ and cognitive profile, and neuroanatomy". The research then concluded that the data seemed to suggest paraphilias and homosexuality as two distinct categories, but regarded the conclusion as "quite tentative" given the current limited understanding of paraphilias.
Causes
The causes of paraphilias in people are unclear, but some research points to a possible prenatal neurodevelopmental correlation. A 2008 study analyzing the sexual fantasies of 200 heterosexual men by using the Wilson Sex Fantasy Questionnaire exam determined that males with a pronounced degree of fetish interest had a greater number of older brothers, a high 2D:4D digit ratio (which would indicate excessive prenatal estrogen exposure), and an elevated probability of being left-handed, suggesting that disturbed hemispheric brain lateralization may play a role in paraphilic attractions.Behavioral explanations propose that paraphilias are conditioned early in life, during an experience that pairs the paraphilic stimulus with intense sexual arousal. Susan Nolen-Hoeksema suggests that, once established, masturbatory fantasies about the stimulus reinforce and broaden the paraphilic arousal.
Diagnosis
There is scientific and political controversy regarding the continued inclusion of sex-related diagnoses such as the paraphilias in the DSM, due to the stigma of being classified as a mental illness.Some groups, seeking greater understanding and acceptance of sexual diversity, have lobbied for changes to the legal and medical status of unusual sexual interests and practices. Charles Allen Moser, a physician and advocate for sexual minorities, has argued that the diagnoses should be eliminated from diagnostic manuals.
Typical versus atypical interests
Albert Eulenburg (1914) noted a commonality across the paraphilias, using the terminology of his time, "All the forms of sexual perversion...have one thing in common: their roots reach down into the matrix of natural and normal sex life; there they are somehow closely connected with the feelings and expressions of our physiological erotism. They are...hyperbolic intensifications, distortions, monstrous fruits of certain partial and secondary expressions of this erotism which is considered normal or at least within the limits of healthy sex feeling."The clinical literature contains reports of many paraphilias, only some of which receive their own entries in the diagnostic taxonomies of the American Psychiatric Association or the World Health Organization. There is disagreement regarding which sexual interests should be deemed paraphilic disorders versus normal variants of sexual interest. For example, as of May 2000, per DSM-IV-TR, "Because some cases of Sexual Sadism may not involve harm to a victim (e.g., inflicting humiliation on a consenting partner), the wording for sexual sadism involves a hybrid of the DSM-III-R and DSM-IV wording (i.e., "the person has acted on these urges with a non-consenting person, or the urges, sexual fantasies, or behaviors cause marked distress or interpersonal difficulty")".The DSM-IV-TR also acknowledges that the diagnosis and classification of paraphilias across cultures or religions "is complicated by the fact that what is considered deviant in one cultural setting may be more acceptable in another setting”. Some argue that cultural relativism is important to consider when discussing paraphilias, because there is wide variance concerning what is sexually acceptable across cultures.Consensual adult activities and adult entertainment involving sexual roleplay, novel, superficial, or trivial aspects of sexual fetishism, or incorporating the use of sex toys are not necessarily paraphilic. Paraphilial psychopathology is not the same as psychologically normative adult human sexual behaviors, sexual fantasy, and sex play.
Intensity and specificity
Clinicians distinguish between optional, preferred and exclusive paraphilias, although the terminology is not completely standardized. An "optional" paraphilia is an alternative route to sexual arousal. In preferred paraphilias, a person prefers the paraphilia to conventional sexual activities, but also engages in conventional sexual activities.
The literature includes single-case studies of very rare and idiosyncratic paraphilias. These include an adolescent male who had a strong fetishistic interest in the exhaust pipes of cars, a young man with a similar interest in a specific type of car, and a man who had a paraphilic interest in sneezing (both his own and the sneezing of others).
Diagnostic and Statistical Manual of Mental Disorders
DSM-I and DSM-II
In American psychiatry, prior to the publication of the DSM-I, paraphilias were classified as cases of "psychopathic personality with pathologic sexuality". The DSM-I (1952) included sexual deviation as a personality disorder of sociopathic subtype. The only diagnostic guidance was that sexual deviation should have been "reserved for deviant sexuality which [was] not symptomatic of more extensive syndromes, such as schizophrenic or obsessional reactions". The specifics of the disorder were to be provided by the clinician as a "supplementary term" to the sexual deviation diagnosis; there were no restrictions in the DSM-I on what this supplementary term could be. Researcher Anil Aggrawal writes that the now-obsolete DSM-I listed examples of supplementary terms for pathological behavior to include "homosexuality, transvestism, pedophilia, fetishism, and sexual sadism, including rape, sexual assault, mutilation."The DSM-II (1968) continued to use the term sexual deviations, but no longer ascribed them under personality disorders, but rather alongside them in a broad category titled "personality disorders and certain other nonpsychotic mental disorders". The types of sexual deviations listed in the DSM-II were: sexual orientation disturbance (homosexuality), fetishism, pedophilia, transvestitism (sic), exhibitionism, voyeurism, sadism, masochism, and "other sexual deviation". No definition or examples were provided for "other sexual deviation", but the general category of sexual deviation was meant to describe the sexual preference of individuals that was "directed primarily toward objects other than people of opposite sex, toward sexual acts not usually associated with coitus, or toward coitus performed under bizarre circumstances, as in necrophilia, pedophilia, sexual sadism, and fetishism." Except for the removal of homosexuality from the DSM-III onwards, this definition provided a general standard that has guided specific definitions of paraphilias in subsequent DSM editions, up to DSM-IV-TR.
DSM-III through DSM-IV
The term paraphilia was introduced in the DSM-III (1980) as a subset of the new category of "psychosexual disorders."
The DSM-III-R (1987) renamed the broad category to sexual disorders, renamed atypical paraphilia to paraphilia NOS (not otherwise specified), renamed transvestism as transvestic fetishism, added frotteurism, and moved zoophilia to the NOS category. It also provided seven nonexhaustive examples of NOS paraphilias, which besides zoophilia included exhibitionism, necrophilia, partialism, coprophilia, klismaphilia, and urophilia.The DSM-IV (1994) retained the sexual disorders classification for paraphilias, but added an even broader category, "sexual and gender identity disorders," which includes them. The DSM-IV retained the same types of paraphilias listed in DSM-III-R, including the NOS examples, but introduced some changes to the definitions of some specific types.
DSM-IV-TR
The DSM-IV-TR describes paraphilias as "recurrent, intense sexually arousing fantasies, sexual urges or behaviors generally involving nonhuman objects, the suffering or humiliation of oneself or ones partner, or children or other nonconsenting persons that occur over a period of six months" (criterion A), which "cause clinically significant distress or impairment in social, occupational, or other important areas of functioning" (criterion B). DSM-IV-TR names eight specific paraphilic disorders (exhibitionism, fetishism, frotteurism, pedophilia, sexual masochism, sexual sadism, voyeurism, and transvestic fetishism, plus a residual category, paraphilia—not otherwise specified). Criterion B differs for exhibitionism, frotteurism, and pedophilia to include acting on these urges, and for sadism, acting on these urges with a nonconsenting person. Sexual arousal in association with objects that were designed for sexual purposes is not diagnosable.Some paraphilias may interfere with the capacity for sexual activity with consenting adult partners.In the current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), a paraphilia is not diagnosable as a psychiatric disorder unless it causes distress to the individual or harm to others.
DSM-5
The DSM-5 adds a distinction between paraphilias and paraphilic disorders, stating that paraphilias do not require or justify psychiatric treatment in themselves, and defining paraphilic disorder as "a paraphilia that is currently causing distress or impairment to the individual or a paraphilia whose satisfaction has entailed personal harm, or risk of harm, to others".The DSM-5 Paraphilias Subworkgroup reached a "consensus that paraphilias are not ipso facto psychiatric disorders", and proposed "that the DSM-V make a distinction between paraphilias and paraphilic disorders. [...] One would ascertain a paraphilia (according to the nature of the urges, fantasies, or behaviors) but diagnose a paraphilic disorder (on the basis of distress and impairment). In this conception, having a paraphilia would be a necessary but not a sufficient condition for having a paraphilic disorder." The Rationale page of any paraphilia in the electronic DSM-5 draft continues: "This approach leaves intact the distinction between normative and non-normative sexual behavior, which could be important to researchers, but without automatically labeling non-normative sexual behavior as psychopathological. It also eliminates certain logical absurdities in the DSM-IV-TR. In that version, for example, a man cannot be classified as a transvestite—however much he cross-dresses and however sexually exciting that is to him—unless he is unhappy about this activity or impaired by it. This change in viewpoint would be reflected in the diagnostic criteria sets by the addition of the word Disorder to all the paraphilias. Thus, Sexual Sadism would become Sexual Sadism Disorder; Sexual Masochism would become Sexual Masochism Disorder, and so on."Bioethics professor Alice Dreger interpreted these changes as "a subtle way of saying sexual kinks are basically okay – so okay, the sub-work group doesnt actually bother to define paraphilia. But a paraphilic disorder is defined: thats when an atypical sexual interest causes distress or impairment to the individual or harm to others." Interviewed by Dreger, Ray Blanchard, the Chair of the Paraphilias Sub-Work Group, stated, "We tried to go as far as we could in depathologizing mild and harmless paraphilias, while recognizing that severe paraphilias that distress or impair people or cause them to do harm to others are validly regarded as disorders."Charles Allen Moser stated that this change is not really substantive, as the DSM-IV already acknowledged a difference between paraphilias and non-pathological but unusual sexual interests, a distinction that is virtually identical to what was being proposed for DSM-5, and it is a distinction that, in practice, has often been ignored. Linguist Andrew Clinton Hinderliter argued that "including some sexual interests—but not others—in the DSM creates a fundamental asymmetry and communicates a negative value judgment against the sexual interests included," and leaves the paraphilias in a situation similar to ego-dystonic homosexuality, which was removed from the DSM because it was no longer recognized as a mental disorder.The DSM-5 acknowledges that many dozens of paraphilias exist, but only has specific listings for eight that are forensically important and relatively common. These are voyeuristic disorder, exhibitionistic disorder, frotteuristic disorder, sexual masochism disorder, sexual sadism disorder, pedophilic disorder, fetishistic disorder, and transvestic disorder. Other paraphilias can be diagnosed under the Other Specified Paraphilic Disorder or Unspecified Paraphilic Disorder listings, if accompanied by distress or impairment.
International Classification of Diseases
ICD-6, ICD-7, ICD-8
In the ICD-6 (1948) and ICD-7 (1955), a category of “sexual deviation” was listed with “other Pathological personality disorders”. In the ICD-8 (1965), “sexual deviations” were categorized as homosexuality, fetishism, pedophilia, transvestism, exhibitionism, voyeurism, sadism and masochism.
ICD-9
In the ICD-9 (1975), the category of sexual deviations and disorders was expanded to include transsexualism, sexual dysfunctions, and psychosexual identity disorders. The list contained homosexuality, bestiality, pedophilia, transvestism, exhibitionism, transexualism, Disorders of psychosexual identity, frigidity and impotence, Other sexual deviations and disorders (including fetishism, masochism, and sadism).
ICD-10
In the ICD-10 (1990), the category "sexual deviations and disorders" was divided into several subcategories. Paraphilias were placed in subcategory of "sexual preference disorders". The list included fetishism, fetishistic transvestism, exhibitionism, voyeurism, pedophilia, sadomasochism and other disorders of sexual preference (including frotteurism, necrophilia, and zoophilia). Homosexuality was removed from the list, but ego-dystonic sexual orientation was still considered a deviation which was placed in subcategory "psychological and behavioural disorders associated with sexual development and orientation".
ICD-11
In the ICD-11 (2022), "paraphilia" has been replaced with "paraphilic disorder". Any paraphilia and any other arousal pattern by itself no longer constitutes a disorder. To date, the diagnosis must meet criteria of paraphilia and one of the following:
1) a marked distress associated with arousal pattern (but not one that comes from rejection or fear of rejection);
2) the person has acted on the arousal pattern towards unwilling others or others considered as unable to give consent;
3) a serious risk of injury or death.
The list of the paraphilic disorders includes: Exhibitionistic Disorder, Voyeuristic Disorder, Pedophilic Disorder, Coercive Sexual Sadism Disorder, Frotteuristic Disorder, Other Paraphilic Disorder Involving Non-Consenting Individuals, and Other Paraphilic Disorder Involving Solitary Behaviour or Consenting Individuals. As of now, disorders associated with sexual orientation have been removed from the ICD. Gender issues have been removed from the mental health category and have been placed under "Conditions related to sexual health".
Management
Most clinicians and researchers believe that paraphilic sexual interests cannot be altered, although evidence is needed to support this. Instead, the goal of therapy is normally to reduce the persons discomfort with their paraphilia and limit any criminal behavior. Both psychotherapeutic and pharmacological methods are available to these ends.Cognitive behavioral therapy, at times, can help people with paraphilias develop strategies to avoid acting on their interests. Patients are taught to identify and cope with factors that make acting on their interests more likely, such as stress. It is currently the only form of psychotherapy for paraphilias supported by randomized double-blind trials, as opposed to case studies and consensus of expert opinion.
Medications
Pharmacological treatments can help people control their sexual behaviors, but do not change the content of the paraphilia. They are typically combined with cognitive behavioral therapy for best effect.
SSRIs
Selective serotonin reuptake inhibitors (SSRIs) are used, especially with exhibitionists, non-offending pedophiles, and compulsive masturbators. They are proposed to work by reducing sexual arousal, compulsivity, and depressive symptoms. They have been well received and are considered an important pharmacological treatment of paraphilia.
Antiandrogens
Antiandrogens are used in more severe cases. Similar to physical castration, they work by reducing androgen levels, and have thus been described as chemical castration. The antiandrogen cyproterone acetate has been shown to substantially reduce sexual fantasies and offending behaviors. Medroxyprogesterone acetate and gonadotropin-releasing hormone agonists (such as leuprorelin) have also been used to lower sex drive. Due to the side effects, the World Federation of Societies of Biological Psychiatry recommends that hormonal treatments only be used when there is a serious risk of sexual violence, or when other methods have failed. Surgical castration has largely been abandoned because these pharmacological alternatives are similarly effective and less invasive.
Epidemiology
Research has shown that paraphilias are rarely observed in women. However, there have been some studies on females with paraphilias. Sexual masochism has been found to be the most commonly observed paraphilia in women, with approximately 1 in 20 cases of sexual masochism being female.Many acknowledge the scarcity of research on female paraphilias. The majority of paraphilia studies are conducted on people who have been convicted of sex crimes. Since the number of male convicted sex offenders far exceeds the number of female convicted sex offenders, research on paraphilic behavior in women is consequently lacking. Some researchers argue that an underrepresentation exists concerning pedophilia in females. Due to the low number of women in studies on pedophilia, most studies are based from "exclusively male samples". This likely underrepresentation may also be attributable to a "societal tendency to dismiss the negative impact of sexual relationships between young boys and adult women". Michele Elliott has done extensive research on child sexual abuse committed by females, publishing the book Female Sexual Abuse of Children: The Last Taboo in an attempt to challenge the gender-biased discourse surrounding sex crimes. John Hunsley states that physiological limitations in the study of female sexuality must also be acknowledged when considering research on paraphilias. He states that while a mans sexual arousal can be directly measured from his erection (see penile plethysmograph), a womans sexual arousal cannot be measured as clearly (see vaginal photoplethysmograph), and therefore research concerning female sexuality is rarely as conclusive as research on men.
Legal issues
In the United States, since 1990 a significant number of states have passed sexually violent predator laws. Following a series of landmark cases in the Supreme Court of the United States, persons diagnosed with paraphilias, particularly pedophilia (Kansas v. Hendricks, 1997) and exhibitionism (Kansas v. Crane, 2002), with a history of anti-social behavior and related criminal history (that includes at a determination of at least "some lack-of-control" by the person), can be held indefinitely in civil confinement under various state legislation generically known as sexually violent predator laws and the federal Adam Walsh Act (United States v. Comstock, 2010).
See also
-phil- (list of philias)
Courtship disorder
Dorian Gray syndrome
Erotic target location error
Human sexuality
List of paraphilias
Lovemap
Object sexuality
Perversion
Psychosexual development
Sex and the law
Sexual ethics
Richard von Krafft-Ebing
References
Citations
General bibliography
D. Richard Laws, William T. ODonohue (ed.), Sexual Deviance: Theory, Assessment, and Treatment, 2nd ed., Guilford Press, 2008, ISBN 978-1-59385-605-2
Further reading
Kenneth Plummer, Sexual stigma: an interactionist account, Routledge, 1975, ISBN 0-7100-8060-3
Elisabeth Roudinesco, Our Dark Side, a History of Perversion, Polity Press, 2009, ISBN 0-7456-4593-3
David Morgan (psychoanalyst), Married to the Eiffel Tower. Married to the Eiffel Tower, a post on the blog Documentary Heaven.
Castellini, Giovanni; Alessandra H. Rellini, PhD; Cristina Appignanesi, MD; Irene Pinucci, MD; Matteo Fattorini, BA; Elisa Grano, BA; Alessandra D. Fisher, PhD; Emanuele Cassioli, MD; Lorenzo Lelli, MD; Mario Maggi, MD; Valdo Ricca, MD (1 September 2018). "Deviance or Normalcy? The Relationship Among Paraphilic Thoughts and Behaviors, Hypersexuality, and Psychopathology in a Sample of University Students". Journal of Sexual Medicine. 15 (9): 1322–1335. doi:10.1016/j.jsxm.2018.07.015. PMID 30224020. S2CID 52290404. Archived (PDF) from the original on 24 March 2020.
External links
DSM-IV and DSM-IV-TR list of paraphilias
Proposed diagnostic criteria for sex and gender section of DSM5 |
Hyperhomocysteinemia | Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of homocysteine in the blood, conventionally described as above 15 μmol/L.As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of
vitamin B6, folic acid (vitamin B9), and vitamin B12 can lead to high homocysteine levels. Other possible causes of hyperhomocysteinemia include genetics, excessive methionine intake, and other diseases. Hyperhomocysteinemia is typically managed with vitamin B6, vitamin B9 and vitamin B12 supplementation. Hyperhomocysteinemia is a risk factor for cardiovascular disease; however, supplements of these vitamins may not improve cardiovascular disease outcomes.
Signs and symptoms
Elevated levels of homocysteine have been associated with a number of disease states.
Cardiovascular risks
Elevated homocysteine is a known risk factor for cardiovascular disease as well as thrombosis. It has also been shown to be associated with microalbuminuria which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Homocysteine degrades and inhibits the formation of the three main structural components of arteries: collagen, elastin and proteoglycans. In proteins, homocysteine permanently degrades cysteine disulfide bridges and lysine amino acid residues, affecting structure and function.
Neuropsychiatric illness
Evidence exists linking elevated homocysteine levels with vascular dementia and Alzheimers disease. There is also evidence that elevated homocysteine levels and low levels of vitamin B6 and B12 are risk factors for mild cognitive impairment and dementia. Oxidative stress induced by homocysteine may also play a role in schizophrenia.
Bone health
Elevated levels of homocysteine have also been linked to increased fractures in elderly persons. Homocysteine auto-oxidizes and reacts with reactive oxygen intermediates, damaging endothelial cells and increasing the risk of thrombus formation.
Ectopia lentis
Homocystinuria is the second most common cause of heritable ectopia lentis. Homocystinuria is an autosomal recessive metabolic disorder most often caused by a near absence of cystathionine b-synthetase. It is associated with intellectual disability, osteoporosis, chest deformities, and increased risk of thrombotic episodes. Lens dislocation occurs in 90% of patients, and is thought to be due to decreased zonular integrity due to the enzymatic defect. Lens dislocation in homocystinuria is usually bilateral and in 60% of cases occurs in the inferior or nasal direction.
Causes
Vitamin deficiency
Deficiencies of vitamins B6, B9 and B12 can lead to high homocysteine levels. Vitamin B12 acts as a cofactor for the enzyme methionine synthase (which forms part of the S-adenosylmethionine (SAM) biosynthesis and regeneration cycle). Vitamin B12 deficiency prevents the 5-methyltetrahydrofolate (5-MTHF) form of folate from being converted into THF due to the "methyl trap". This disrupts the folate pathway and leads to an increase in homocysteine which damages cells (for example, damage to endothelial cells can result in increased risk of thrombosis).
Alcohol
Chronic consumption of alcohol may also result in increased plasma levels of homocysteine.
Tobacco
Smokeless tobacco is implicated as risk factor for hyperhomocysteinemia. Smoking also causes hyperhomocysteinemia
Genetic
Homocysteine is a non-protein amino acid, synthesized from methionine and either recycled back into methionine or converted into cysteine with the aid of the B-group vitamins.
About 50% of homocysteine is converted back to methionine by remethylation via the methionine synthase major pathway. This requires active folate and vitamin B12, in order to donate a methyl group. Active folate is known as 5-methyltetrahydrofolate (5-MTHF).
Another pathway for the conversion of homocysteine back to methionine also exists, involving methylation with trimethylglycine (also called betaine or abbreviated to TMG) as a methyl donor.
The remaining homocysteine is transsulfurated to cysteine, with vitamin B6 as the co-factor.Genetic defects in 5-MTHF reductase can consequently lead to hyperhomocysteinemia. The most common polymorphisms are known as MTHFR C677T and MTR A2756G. These polymorphisms occur in about 10% of the worlds population. Elevations of homocysteine can also occur in the rare hereditary disease homocystinuria.
Diagnosis
A blood test can be performed to quantify total homocysteine concentration in the plasma, of which approximately 80% is generally protein-bound. Classification of hyperhomocysteinemia is defined with respect to serum concentration as follows:
Moderate: 15–30 nmol/mL (or μmol/L)
Intermediate: 30–100 nmol/mL
Severe: > 100 nmol/mLIf total homocysteine concentration is not found to be elevated, but clinical suspicion is still high, an oral methionine loading challenge several hours prior to quantification of homocysteine concentration may be used to increased sensitivity for marginal abnormalities of homocysteine metabolism.Fasting for 10 hours is sometimes recommended prior to measurement of homocysteine levels, but this may not be necessary for diagnostic yield.
Treatment
Vitamins B6, B9, or B12 supplements (alone or combined), while they lower homocysteine level, do not change the risk of heart disease or prevent death in people who have heart disease when compared to standard care or to an inactive supplement in a clinical trial. When combined with medicine to reduce blood pressure (antihypertensive drugs), it is not clear if treatments that lower homocysteine can help prevent a stroke in some people. Hypotheses have been offered to address the failure of homocysteine-lowering therapies to reduce cardiovascular events. When folic acid is given as a supplement, it may increase the build-up of arterial plaque. A second hypothesis involves the methylation of genes in vascular cells by folic acid and vitamin B12, which may also accelerate plaque growth. Finally, altered methylation may catalyse l-arginine to asymmetric dimethylarginine, which is known to increase the risk of vascular disease.
See also
Homocystinuria
Kilmer S. McCully
References
== External links == |
Idiopathic granulomatous hepatitis | Idiopathic granulomatous hepatitis is a rare medical condition characterised by granulomas in the liver, recurrent fever, myalgia, and fatigue. The condition is not a true hepatitis, and some experts believe it is a variant of sarcoidosis.
== References == |
Congenital amegakaryocytic thrombocytopenia | Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited disorder.
Presentation
The primary manifestations are thrombocytopenia and megakaryocytopenia, or low numbers of platelets and megakaryocytes. There is an absence of megakaryocytes in the bone marrow with no associated physical abnormalities.
Cause
The cause for this disorder appears to be a mutation in the gene for the TPO receptor, c-mpl, despite high levels of serum TPO. In addition, there may be abnormalities with the central nervous system including the cerebrum and cerebellum which could cause symptoms.
Diagnosis
Treatment
The primary treatment for CAMT is bone marrow transplantation.Bone Marrow/Stem Cell Transplant is the only thing that ultimately cures this genetic disease. Frequent platelet transfusions are required to ensure that platelet levels do not fall to dangerous levels, although this is not always the case. It is known for patients to continue to create very small numbers of platelets over time.
See also
Thrombopoietin
Myeloproliferative leukemia virus oncogene
References
External links
Amegakaryocytic Thrombocytopenia research study of Inherited Bone Marrow Failure Syndromes (IBMFS) |
Hemiplegic migraine | == Symptoms and signs ==
Hemiplegia (Greek hemi = Half), is condition that affects one side of the body. Signs of a hemiplegic migraine attack are similar to what would be presented in a stroke that typically includes sudden severe headache on one side of the brain, weakness of half the body, ataxia and aphasia which can last for hours, days or weeks.
Cause
Diagnosis
Classification
The ICHD classification and diagnosis of migraine distinguish 6 subtypes of hemiplegic migraine. Familial hemiplegic migraine (FHM) can be loosely divided into two categories: with and without cerebellar signs. Cerebellar signs refer to ataxia, sometimes episodic and other times progressive, that can accompany FHM1 mutations and is caused by degeneration of the cerebellum. These cerebellar signs result in a phenotypic overlap between FHM and both episodic ataxia and spinocerebellar ataxia. This is unsurprising as subtypes of these disorders (FHM1, EA2 and SCA6) are allelic, i.e., they result from mutations in the same gene. The other forms of FHM seem to be distinguishable only on the basis of their genetic cause.
Familial hemiplegic migraine
Familial hemiplegic migraine is a form of hemiplegic migraine headache that runs in families. Hemiplegic migraine is inherited via autosomal dominant manner.
Sporadic hemiplegic migraine
There are also non-familial cases of hemiplegic migraine, termed sporadic hemiplegic migraine. These cases seem to have the same causes as the familial cases and represent de novo mutations. Sporadic cases are also clinically identical to familial cases with the exception of a lack of family history of attacks.
Screening
Prenatal screening is not typically done for FHM, however it may be performed if requested. As penetrance is high, individuals found to carry mutations should be expected to develop signs of FHM at some point in life.
Management
See the equivalent section in the main migraine article.
People with FHM are encouraged to avoid activities that may trigger their attacks. Minor head trauma is a common attack precipitant, so FHM sufferers should avoid contact sports. Acetazolamide or standard drugs are often used to treat attacks, though those leading to vasoconstriction should be avoided due to the risk of stroke.
Epidemiology
Migraine itself is a very common disorder, occurring in 15–20% of the population. Hemiplegic migraine, be it familial or spontaneous, is less prevalent, 0.01% prevalence according to one report. Women are three times more likely to be affected than males.
References
== External links == |
Brazilian hemorrhagic fever | Brazilian hemorrhagic fever (BzHF) is an infectious disease caused by Brazilian mammarenavirus, an arenavirus. Brazilian mammarenavirus is one of the arenaviruses from South America to cause hemorrhagic fever. It shares a common progenitor with Argentinian mammarenavirus, Machupo mammarenavirus, Tacaribe mammarenavirus, and Guanarito mammarenavirus. It is an enveloped RNA virus and is highly infectious and lethal. Very little is known about this disease, but it is thought to be transmitted by the excreta of rodents. This virus has also been implicated as a means for bioterrorism, as it can be spread through aerosols.As of 2019, there had only been four documented infections of Brazilian mammarenavirus: two occurred naturally, and the other two cases occurred in the clinical setting. The first naturally occurring case was in 1990, when a female agricultural engineer who was staying in the neighborhood of Jardim Sabiá in the municipality of Cotia, a suburb of São Paulo, Brazil contracted the disease (The virus is also known as "Sabiá Virus"). She presented with hemorrhagic fever and died. Her autopsy showed liver necrosis. A virologist who was studying the womans disease contracted the virus but survived. Ribavirin was not given in these first two cases. Four years later, in 1994, a researcher was exposed to the virus in a level 3 biohazard facility at Yale University when a centrifuge bottle cracked, leaked, and released aerosolized virus particles. He was successfully treated with ribavirin.A fifth case, also naturally acquired in upstate São Paulo, was reported in January 2020. The patient died 12 days after the onset of symptoms.
Treatment
Ribavirin is thought to be effective in treating the illness, similar to other arenaviruses. Compared to the patients who did not receive ribavirin, the patient who was treated with it had a shorter and less severe clinical course. Symptomatic control such as fluids to address dehydration and bleeding may also be required.Brazilian mammarenavirus is a biosafety Level 4 pathogen.
References
== External links == |
Digitate wart | Digitate or Filiform warts are warts that often appear on the eyelids, lips, face, or neck.
The warts tend to grow directly outwards from the skin. They have a spiky, thread-like or finger-like appearance. They sometimes look and feel like tiny brushes, making them especially uncomfortable for the patient.As with other wart types, a number of treatments are available, including laser therapy, cryotherapy, salicylic acid, and other topical treatments.
== References == |
Psychogenic non-epileptic seizure | Psychogenic non-epileptic seizures (PNES) are events resembling an epileptic seizure, but without the characteristic electrical discharges associated with epilepsy. PNES fall under the category of disorders known as functional neurological disorders (FND), also known as conversion disorders. A more recent term to describe these events is dissociative non-epileptic seizures. These are typically treated by psychologists or psychiatrists. PNES has previously been called pseudoseizures, psychogenic seizures, and hysterical seizures, but these terms have fallen out of favor.
Incidence
The number of people with PNES ranges from 2 to 33 per 100,000. PNES are most common in young adults, particularly women. The prevalence for PNES is estimated to make up 5–20% of outpatient epilepsy clinics; 75–80% of these diagnoses are given to female patients and 83% are to individuals between 15 and 35 years old.
Children
PNES are seen in children after the age of eight, and occur equally among boys and girls before puberty. Diagnostic and treatment principles are similar to those for adults, except that in children there is a broader differential diagnosis of seizures so that other possible diagnoses specific to children may be considered.
Signs and symptoms
Individuals with PNES present with episodes that resemble epileptic seizures, and most have received a diagnosis of epilepsy and treatment for it. PNES episodes are nearly indistinguishable from epileptic seizures. The main differences between a PNES episode and an epileptic seizure is the duration of episodes. Epileptic seizures typically last between 30 and 120 seconds depending on the type, while PNES episodes typically last for two to five minutes.
Causes and risk factors
The cause of PNES has not yet been established. One hypothesis is that they are a learned physical reaction or habit the body develops, similar to a reflex. The individual does not have control of the learned reaction, but this can be retrained to allow the patient to control the physical movements again. The production of seizure-like symptoms is not under voluntary control, meaning that the person is not faking; symptoms which are feigned or faked voluntarily would fall under the categories of factitious disorder or malingering.Risk factors for PNES include having a history of head injury, and having a diagnosis of epilepsy. Approximately 10–30% of people diagnosed with PNES also have an epilepsy diagnosis. People diagnosed with PNES commonly report physical, sexual, or emotional trauma, but the reported incidence of these events may not differ between PNES and epilepsy.
Diagnosis
According to the Diagnostic and Statistical Manual of Mental Disorders (version 5) the criteria for receiving a diagnosis of PNES are:
One or more symptoms of altered voluntary motor or sensory function.
Clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions.
The symptom or deficit is not better explained by another medical or mental disorder.
The symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.Additionally, the specific symptom type must be reported "with attacks or seizures".Some individuals with PNES have carried an erroneous diagnosis of epilepsy. On average, it takes seven years to receive a proper diagnosis. The differential diagnosis of PNES firstly involves ruling out epilepsy as the cause of the seizure episodes, along with other organic causes of non-epileptic seizures, including syncope, migraine, vertigo, anoxia, hypoglycemia, and stroke. However, 5–20% of people with PNES also have epilepsy. Frontal lobe seizures can be mistaken for PNES, though these tend to have shorter duration, stereotyped patterns of movements, and occurrence during sleep. Next, an exclusion of factitious disorder (a subconscious somatic symptom disorder, where seizures are caused by psychological reasons) and malingering (simulating seizures intentionally for conscious personal gain – such as monetary compensation or avoidance of criminal punishment) is conducted. Finally other psychiatric conditions that may superficially resemble seizures are eliminated, including panic disorder, schizophrenia, and depersonalisation disorder.The most definitive test to distinguish epilepsy from PNES is long term video-EEG monitoring, with the aim of capturing one or two episodes on both video recording and EEG simultaneously (some clinicians may use suggestion to attempt to trigger an episode). Additional clinical criteria are usually considered in addition to video-EEG monitoring when diagnosing PNES. By recording the event in question on video and EEG simultaneously, a clear diagnosis can usually be obtained.Laboratory testing can detect rising blood levels of serum prolactin if samples are taken in the right time window after most tonic-clonic or complex partial epileptic seizures. However, due to false positives and variability in results, this test is relied upon less frequently.
Distinguishing features
Some features are more or less likely to suggest PNES but they are not conclusive and should be considered in the broader clinical picture. Features that are common in PNES but rarer in epilepsy include: biting the tip of the tongue, seizures lasting more than two minutes (easiest factor to distinguish), seizures having a gradual onset, a fluctuating course of disease severity, the eyes being closed during a seizure, and side to side head movements. Features that are uncommon in PNES include automatisms (automatic complex movements during the seizure), severe tongue biting, biting the inside of the mouth, and incontinence.If a person with suspected PNES has an episode during a clinical examination, there are a number of signs that can be elicited to help support or refute the diagnosis of PNES. Compared to people with epilepsy, people with PNES will tend to resist having their eyes forced open (if they are closed during the seizure), will stop their hands from hitting their own face if the hand is dropped over the head, and will fixate their eyes in a way suggesting an absence of neurological interference.
Treatment
Patient understanding of the new diagnosis is crucial for their treatment, which requires their active participation. There are a number of recommended steps to explain to people their diagnosis in a sensitive and open manner. A negative diagnosis experience may cause frustration and could cause a person to reject any further attempts at treatment. Eight points recommended to explain the diagnosis to the person and their caregivers are:
Reasons for concluding they do not have epilepsy
What they do have (describe FND)
Emphasize they are not suspected of "putting on" the attacks, and the symptoms are not "all in their head"
There may be no triggering "stresses"
Maintaining factors
May improve after correct diagnosis
Caution that anticonvulsant drug withdrawal should be done in conjunction with their physician
Describe treatment to help regain control of symptomsPsychotherapy is the most frequently used treatment, which might include cognitive behavioral therapy or therapy to retrain the physical symptoms and allow the individual to regain control of the attacks (ReACT). There is also some evidence supporting selective serotonin reuptake inhibitor antidepressants.Cognitive behavioral therapy
Cognitive behavioral therapy (CBT) treatments for PNES typically target fear avoidance and work to reattribute patients symptoms to psychosocial issues.
Retraining and Control Therapy (ReACT)
ReACT, while new and understudied, has shown extremely promising outcomes for reduction of PNES episodes in pediatric patients. This therapy focuses on the idea that PNES are caused by a learned physical reaction or habit the body develops, similar to a reflex. ReACT aims to retrain the learned reaction (PNES episodes) by targeting symptom catastrophizing and restoring sense of control over symptoms.
Prognosis
Though there is limited evidence, outcomes appear to be relatively poor with a review of outcome studies finding that two thirds of people with PNES continue to experience episodes and more than half are dependent on the Social Security program at three-year follow-up. This outcome data was obtained in a referral-based academic epilepsy center and loss to follow-up was considerable; the authors point out ways in which this may have biased their outcome data. Outcome was shown to be better in people with higher IQ, social status, greater educational attainments, younger age of onset and diagnosis, attacks with less dramatic features, and fewer additional somatoform complaints.For individuals who pursue treatment for PNES, CBT has shown varying rates of success but it has been established as one of the most promising treatments to date. ReACT has shown reduction in symptoms by 100% seven days after treatment and 82% of individuals who completed the therapy remained symptom free for 60 days. A follow-up has not been done to see if the therapy retained its reduction of symptoms beyond the 60 days. The largest trial of CBT for PNES though found no significant reduction in monthly seizures compared to the control arm at 12 months, however there were significant improvements on a number of secondary outcomes, such as psychosocial functioning, and self-rated and clinician-rated global change.
History
Hystero-epilepsy is a historical term that refers to a condition described by 19th-century French neurologist Jean-Martin Charcot where people with neuroses "acquired" symptoms resembling seizures as a result of being treated on the same ward as people who genuinely had epilepsy.
The etiology of FND was historically explained in the context of psychoanalytic theory as a physical manifestation of psychological distress and repressed trauma. There is very little supporting evidence for this theory, as there is little research.The DSM-IV lists conversion disorders instead of the current FND. Additionally, in revision, the DSM-5 was updated to add emphasis to the positive physical signs inconsistent with recognized diseases. The requirement of a history of psychological stressors and that the symptom is not fake was removed as well.
Society and culture
PNES rates and presenting symptoms are somewhat dependent on the culture and society. In some cultures, they, like epilepsy, are thought of as a curse or a demonic possession. In cultures with a solid establishment of evidence-based medicine, they are considered a subtype of a larger category of psychiatric disease.
Terminology
The use of older terms including pseudoseizures and hysterical seizures are discouraged. In the English language, the word "seizure" usually refers to epileptic events, so some prefer to use more general terms like "events", "attacks", or "episodes", as the term "seizures" may cause confusion with epilepsy.PNES may also be referred to as "non-epileptic attack disorder" "functional seizures", "dissociative convulsions" or "dissociative non-epileptic seizures". These terms are more neutral as to cause, and given that a psychological cause cannot be identified in many cases, they may be more appropriate. Within DSM 5, patients presenting with PNES may meet the criteria for functional neurological disorder and in some cases, somatic symptom disorder, whilst in ICD 10 it may meet the criteria for a conversion disorder.
References
== External links == |
Combat stress reaction | Combat stress reaction (CSR) is acute behavioral disorganization as a direct result of the trauma of war. Also known as "combat fatigue", "battle fatigue", or "battle neurosis", it has some overlap with the diagnosis of acute stress reaction used in civilian psychiatry. It is historically linked to shell shock and can sometimes precurse post-traumatic stress disorder.
Combat stress reaction is an acute reaction that includes a range of behaviors resulting from the stress of battle that decrease the combatants fighting efficiency. The most common symptoms are fatigue, slower reaction times, indecision, disconnection from ones surroundings, and the inability to prioritize. Combat stress reaction is generally short-term and should not be confused with acute stress disorder, post-traumatic stress disorder, or other long-term disorders attributable to combat stress, although any of these may commence as a combat stress reaction. The US Army uses the term/acronym COSR (Combat Stress Reaction) in official medical reports. This term can be applied to any stress reaction in the military unit environment. Many reactions look like symptoms of mental illness (such as panic, extreme anxiety, depression, and hallucinations), but they are only transient reactions to the traumatic stress of combat and the cumulative stresses of military operations.In World War I, shell shock was considered a psychiatric illness resulting from injury to the nerves during combat. The horrors of trench warfare meant that about 10% of the fighting soldiers were killed (compared to 4.5% during World War II) and the total proportion of troops who became casualties (killed or wounded) was about 57%. Whether a person with shell-shock was considered "wounded" or "sick" depended on the circumstances. When faced with the phenomenon of a minority of soldiers mentally breaking down, there was an expectation that the root of this problem lay in character of the individual soldier, not because of what they experienced on the front lines during the war. The large proportion of World War I veterans in the European population meant that the symptoms were common to the culture.
Signs and symptoms
Combat stress reaction symptoms align with the symptoms also found in psychological trauma, which is closely related to post-traumatic stress disorder (PTSD). CSR differs from PTSD (among other things) in that a PTSD diagnosis requires a duration of symptoms over one month, which CSR does not.
Fatigue-related symptoms
The most common stress reactions include:
Autonomic nervous system – Autonomic arousal
Battle casualty rates
The ratio of stress casualties to battle casualties varies with the intensity of the fighting. With intense fighting, it can be as high as 1:1. In low-level conflicts, it can drop to 1:10 (or less).
Modern warfare embodies the principles of continuous operations with an expectation of higher combat stress casualties.The World War II European Army rate of stress casualties of 1 in 10 (101:1,000) troops per annum is skewed downward from both its norm and peak by data by low rates during the last years of the war.
Diagnosis
The following PIE principles were in place for the "not yet diagnosed nervous" (NYDN) cases:
Proximity – treat the casualties close to the front and within sound of the fighting.
Immediacy – treat them without delay and not wait until the wounded were all dealt with.
Expectancy – ensure that everyone had the expectation of their return to the front after a rest and replenishment.United States medical officer Thomas W. Salmon is often quoted as the originator of these PIE principles. However, his real strength came from going to Europe and learning from the Allies and then instituting the lessons. By the end of the war, Salmon had set up a complete system of units and procedures that was then the "worlds best practice". After the war, he maintained his efforts in educating society and the military. He was awarded the Distinguished Service Medal for his contributions.Effectiveness of the PIE approach has not been confirmed by studies of CSR, and there is some evidence that it is not effective in preventing PTSD.US services now use the more recently developed BICEPS principles:
Brevity
Immediacy
Centrality or contact
Expectancy
Proximity
Simplicity
Between the wars
The British government produced a Report of the War Office Committee of Inquiry into "Shell-Shock", which was published in 1922. Recommendations from this included:
In forward areas
No soldier should be allowed to think that loss of nervous or mental control provides an honorable avenue of escape from the battlefield, and every endeavor should be made to prevent slight cases leaving the battalion or divisional area, where treatment should be confined to provision of rest and comfort for those who need it and to heartening them for return to the front line.
In neurological centers
When cases are sufficiently severe to necessitate more scientific and elaborate treatment they should be sent to special Neurological Centers as near the front as possible, to be under the care of an expert in nervous disorders. No such case should, however, be so labelled on evacuation as to fix the idea of nervous breakdown in the patients mind.
In base hospitals
When evacuation to the base hospital is necessary, cases should be treated in a separate hospital or separate sections of a hospital, and not with the ordinary sick and wounded patients. Only in exceptional circumstances should cases be sent to the United Kingdom, as, for instance, men likely to be unfit for further service of any kind with the forces in the field. This policy should be widely known throughout the Force.
Forms of treatment
The establishment of an atmosphere of cure is the basis of all successful treatment, the personality of the physician is, therefore, of the greatest importance. While recognizing that each individual case of war neurosis must be treated on its merits, the Committee are of opinion that good results will be obtained in the majority by the simplest forms of psycho-therapy, i.e., explanation, persuasion and suggestion, aided by such physical methods as baths, electricity and massage. Rest of mind and body is essential in all cases.The committee are of opinion that the production of deep hypnotic sleep, while beneficial as a means of conveying suggestions or eliciting forgotten experiences are useful in selected cases, but in the majority they are unnecessary and may even aggravate the symptoms for a time.
They do not recommend psycho-analysis in the Freudian sense.In the state of convalescence, re-education and suitable occupation of an interesting nature are of great importance. If the patient is unfit for further military service, it is considered that every endeavor should be made to obtain for him suitable employment on his return to active life.
Return to the fighting line
Soldiers should not be returned to the fighting line under the following conditions:(1) If the symptoms of neurosis are of such a character that the soldier cannot be treated overseas with a view to subsequent useful employment.
(2) If the breakdown is of such severity as to necessitate a long period of rest and treatment in the United Kingdom.
(3) If the disability is anxiety neurosis of a severe type.
(4) If the disability is a mental breakdown or psychosis requiring treatment in a mental hospital.
It is, however, considered that many of such cases could, after recovery, be usefully employed in some form of auxiliary military duty.
Part of the concern was that many British veterans were receiving pensions and had long-term disabilities.
By 1939, some 120,000 British ex-servicemen had received final awards for primary psychiatric disability or were still drawing pensions – about 15% of all pensioned disabilities – and another 44,000 or so were getting pensions for soldiers heart or Effort Syndrome. There is, though, much that statistics do not show, because in terms of psychiatric effects, pensioners were just the tip of a huge iceberg."War correspondent Philip Gibbs wrote:
Something was wrong. They put on civilian clothes again and looked to their mothers and wives very much like the young men who had gone to business in the peaceful days before August 1914. But they had not come back the same men. Something had altered in them. They were subject to sudden moods, and queer tempers, fits of profound depression alternating with a restless desire for pleasure. Many were easily moved to passion where they lost control of themselves, many were bitter in their speech, violent in opinion, frightening.
One British writer between the wars wrote:
There should be no excuse given for the establishment of a belief that a functional nervous disability constitutes a right to compensation. This is hard saying. It may seem cruel that those whose sufferings are real, whose illness has been brought on by enemy action and very likely in the course of patriotic service, should be treated with such apparent callousness. But there can be no doubt that in an overwhelming proportion of cases, these patients succumb to shock because they get something out of it. To give them this reward is not ultimately a benefit to them because it encourages the weaker tendencies in their character. The nation cannot call on its citizens for courage and sacrifice and, at the same time, state by implication that an unconscious cowardice or an unconscious dishonesty will be rewarded.
World War II
American
At the outbreak of World War II, most in the United States military had forgotten the treatment lessons of World War I. Screening of applicants was initially rigorous, but experience eventually showed it to lack great predictive power.
The US entered the war in December 1941. Only in November 1943 was a psychiatrist added to the table of organization of each division, and this policy was not implemented in the Mediterranean Theater of Operations until March 1944. By 1943, the US Army was using the term "exhaustion" as the initial diagnosis of psychiatric cases, and the general principles of military psychiatry were being used. General Pattons slapping incident was in part the spur to institute forward treatment for the Italian invasion of September 1943. The importance of unit cohesion and membership of a group as a protective factor emerged.
John Appel found that the average American infantryman in Italy was "worn out" in 200 to 240 days and concluded that the American soldier "fights for his buddies or because his self respect wont let him quit". After several months in combat, the soldier lacked reasons to continue to fight because he had proven his bravery in battle and was no longer with most of the fellow soldiers he trained with. Appel helped implement a 180-day limit for soldiers in active combat and suggested that the war be made more meaningful, emphasizing their enemies plans to conquer the United States, encouraging soldiers to fight to prevent what they had seen happen in other countries happen to their families. Other psychiatrists believed that letters from home discouraged soldiers by increasing nostalgia and needlessly mentioning problems soldiers could not solve. William Menninger said after the war, "It might have been wise to have had a nation-wide educational course in letter writing to soldiers", and Edward Strecker criticized "moms" (as opposed to mothers) who, after failing to "wean" their sons, damaged morale through letters.Airmen flew far more often in the Southwest Pacific than in Europe, and although rest time in Australia was scheduled, there was no fixed number of missions that would produce transfer out of combat, as was the case in Europe. Coupled with the monotonous, hot, sickly environment, the result was bad morale that jaded veterans quickly passed along to newcomers. After a few months, epidemics of combat fatigue would drastically reduce the efficiency of units. Flight surgeons reported that the men who had been at jungle airfields longest were in bad shape:
Many have chronic dysentery or other disease, and almost all show chronic fatigue states. … They appear listless, unkempt, careless, and apathetic with almost mask-like facial expression. Speech is slow, thought content is poor, they complain of chronic headaches, insomnia, memory defect, feel forgotten, worry about themselves, are afraid of new assignments, have no sense of responsibility, and are hopeless about the future.
British
Unlike the Americans, the British leaders firmly held the lessons of World War I. It was estimated that aerial bombardment would kill up to 35,000 a day, but the Blitz killed only 40,000 in total. The expected torrent of civilian mental breakdown did not occur. The Government turned to World War I doctors for advice on those who did have problems. The PIE principles were generally used. However, in the British Army, since most of the World War I doctors were too old for the job, young, analytically trained psychiatrists were employed. Army doctors "appeared to have no conception of breakdown in war and its treatment, though many of them had served in the 1914–1918 war." The first Middle East Force psychiatric hospital was set up in 1942. With D-Day for the first month there was a policy of holding casualties for only 48 hours before they were sent back over the Channel. This went firmly against the expectancy principle of PIE.Appel believed that British soldiers were able to continue to fight almost twice as long as their American counterparts because the British had better rotation schedules and because they, unlike the Americans, "fight for survival" – for the British soldiers, the threat from the Axis powers was much more real, given Britains proximity to mainland Europe, and the fact that Germany was concurrently conducting air raids and bombarding British industrial cities. Like the Americans, British doctors believed that letters from home often needlessly damaged soldiers morale.
Canadian
The Canadian Army recognized combat stress reaction as "Battle Exhaustion" during the Second World War and classified it as a separate type of combat wound. Historian Terry Copp has written extensively on the subject. In Normandy, "The infantry units engaged in the battle also experienced a rapid rise in the number of battle exhaustion cases with several hundred men evacuated due to the stress of combat. Regimental Medical Officers were learning that neither elaborate selection methods nor extensive training could prevent a considerable number of combat soldiers from breaking down."
Germans
In his history of the pre-Nazi Freikorps paramilitary organizations, Vanguard of Nazism, historian Robert G. L. Waite describes some of the emotional effects of World War I on German troops, and refers to a phrase he attributes to Göring: men who could not become "de-brutalized".In an interview, Dr Rudolf Brickenstein stated that:
... he believed that there were no important problems due to stress breakdown since it was prevented by the high quality of leadership. But, he added, that if a soldier did break down and could not continue fighting, it was a leadership problem, not one for medical personnel or psychiatrists. Breakdown (he said) usually took the form of unwillingness to fight or cowardice.
However, as World War II progressed there was a profound rise in stress casualties from 1% of hospitalizations in 1935 to 6% in 1942. Another German psychiatrist reported after the war that during the last two years, about a third of all hospitalizations at Ensen were due to war neurosis. It is probable that there was both less of a true problem and less perception of a problem.
Finns
The Finnish attitudes to "war neurosis" were especially tough. Psychiatrist Harry Federley, who was the head of the Military Medicine, considered shell shock as a sign of weak character and lack of moral fibre. His treatment for war neurosis was simple: the patients were to be bullied and harassed until they returned to front line service.Earlier, during the Winter War, several Finnish machine gun operators on the Karelian Isthmus theatre became mentally unstable after repelling several unsuccessful Soviet human wave assaults on fortified Finnish positions.
Post-World War II developments
Simplicity was added to the PIE principles by the Israelis: in their view, treatment should be brief, supportive, and could be provided by those without sophisticated training.
Peacekeeping stresses
Peacekeeping provides its own stresses because its emphasis on rules of engagement contains the roles for which soldiers are trained. Causes include witnessing or experiencing the following:
Constant tension and threat of conflict.
Threat of land mines and booby traps.
Close contact with severely injured and dead people.
Deliberate maltreatment and atrocities, possibly involving civilians.
Cultural issues.
Separation and home issues.
Risk of disease including HIV.
Threat of exposure to toxic agents.
Mission problems.
Return to service.
Pathophysiology
SNS activation
Many of the symptoms initially experienced by people with CSR are effects of an extended activation of the human bodys fight-or-flight response. The fight-or-flight response involves a general sympathetic nervous system discharge in reaction to a perceived stressor and prepares the body to fight or run from the threat causing the stress. Catecholamine hormones, such as adrenaline or noradrenaline, facilitate immediate physical reactions associated with a preparation for violent muscular action. Although the flight-or-fight-response normally ends with the removal of the threat, the constant mortal danger in combat zones likewise constantly and acutely stresses soldiers.
General adaptation syndrome
The process whereby the human body responds to extended stress is known as general adaptation syndrome (GAS). After the initial fight-or-flight response, the body becomes more resistant to stress in an attempt to dampen the sympathetic nervous response and return to homeostasis. During this period of resistance, physical and mental symptoms of CSR may be drastically reduced as the body attempts to cope with the stress. Long combat involvement, however, may keep the body from homeostasis and thereby deplete its resources and render it unable to normally function, sending it into the third stage of GAS: exhaustion. Sympathetic nervous activation remains in the exhaustion phase and reactions to stress are markedly sensitized as fight-or-flight symptoms return. If the body remains in a state of stress, then such more severe symptoms of CSR as cardiovascular and digestive involvement may present themselves. Extended exhaustion can permanently damage the body.
Treatment
7 Rs
The British Army treated Operational Stress Reaction according to the 7 Rs:
Recognition – identify that the individual has an Operational Stress Reaction
Respite – provide a short period of relief from the front line
Rest – allow rest and recovery
Recall – give the individual the chance to recall and discuss the experiences that have led to the reaction
Reassurance – inform them that their reaction is normal and they will recover
Rehabilitation – improve the physical and mental health of the patient until they no longer show symptoms
Return – allow the soldier to return to their unit
BICEPS
Modern front-line combat stress treatment techniques are designed to mimic the historically used PIE techniques with some modification. BICEPS is the current treatment route employed by the U.S. military and stresses differential treatment by the severity of CSR symptoms present in the service member. BICEPS is employed as a means to treat CSR symptoms and return soldiers quickly to combat.
The following subsections on the BICEPS program are adapted from the USMC combat stress handbook:
Brevity
Critical Event Debriefing should take 2 to 3 hours. Initial rest and replenishment at medical CSC (Combat Stress Control) facilities should last no more than 3 or 4 days. Those requiring further treatment are moved to the next level of care. Since many require no further treatment, military commanders expect their service members to return to duty rapidly.
Immediacy
CSC should be done as soon as possible when operations permit. Intervention is provided as soon as symptoms appear.
Centrality/Contact
Service members requiring observation or care beyond the unit level are evacuated to facilities in close proximity to, but separate from the medical or surgical patients at the BAS, surgical support company in a central location (Marines) or forward support/division support or area support medical companies (Army) nearest the service members unit. It is best to send service members who cannot continue their mission and require more extensive respite to a central facility other than a hospital, unless no other alternative is possible. The service member must be encouraged to continue to think of themselves as a war fighter, rather than a patient or a sick person. The chain of command remains directly involved in the service members recovery and return to duty. The CSC team coordinates with the units leaders to learn whether the over-stressed individual was a good performer prior to the combat stress reaction, or whether they were always a marginal or problem performer whom the team would rather see replaced than returned. Whenever possible, representatives of the unit, or messages from the unit, tell the casualty that they are needed and wanted back. The CSC team coordinates with the unit leaders, through unit medical personnel or chaplains, any special advice on how to assure quick reintegration when the service member returns to their unit.
Expectancy
The individual is explicitly told that he is reacting normally to extreme stress and is expected to recover and return to full duty in a few hours or days. A military leader is extremely effective in this area of treatment. Of all the things said to a service member experiencing combat stress, the words of his small-unit leader have the greatest impact due to the positive bonding process that occurs during combat. Simple statements from the small-unit leader to the service member that he is reacting normally to combat stress and is expected back soon have positive impact. Small-unit leaders should tell service members that their comrades need and expect them to return. When they do return, the unit treats them as every other service member and expects them to perform well. Service members suffering and recovering from combat stress disorder are no more likely to become overloaded again than are those who have not yet been overloaded. In fact, they are less likely to become overloaded than inexperienced replacements.
Proximity
In mobile war requiring rapid and frequent movement, treatment of many combat stress cases takes place at various battalion or regimental headquarters or logistical
units, on light duty, rather than in medical units, whenever possible. This is a key factor and another area where the small-unit leader helps in the treatment. CSC and follow-up care for combat stress casualties are held as close as possible to and maintain close association with the members unit, and are an integral part of the entire healing process. A visit from a member of the individuals unit during restoration is effective in keeping a bond with the organization. A service member experiencing combat stress reaction is having a crisis, and there are two basic elements to that crisis working in opposite directions. On the one hand, the service member is driven by a strong desire to seek safety and to get out of an intolerable environment. On the other hand, the service member does not want to let their comrades down. They want to return to their unit. If a service member starts to lose contact with their unit when he enters treatment, the impulse to get out of the war and return to safety takes over. They feel that theyve failed their comrades who have already rejected them as unworthy. The potential is for the service member to become more and more emotionally invested in keeping their symptoms so they can stay in a safe environment. Much of this is done outside the service members conscious awareness, but the result is the same. The more out of touch the service member is with their unit, the less likely they will recover. They are more likely to develop a chronic psychiatric illness and get evacuated from the war.
Simplicity
Treatment is kept simple. CSC is not therapy. Psychotherapy is not done. The goal is to rapidly restore the service members coping skills so that he functions and returns to duty again. Sleep, food, water, hygiene, encouragement, work details, and confidence-restoring talk are often all that is needed to restore a service member to full operational readiness. This can be done in units in reserve positions, logistical units or at medical companies. Every effort is made to reinforce service members identity. They are required to wear their uniforms and to keep their helmets, equipment, chemical protective gear, and flak jackets with them. When possible, they are allowed to keep their weapons after the weapons have been cleared. They may serve on guard duty or as members of a standby quick reaction force.
Predeployment preparation
Screening
Historically, screening programs that have attempted to preclude soldiers exhibiting personality traits thought to predispose them to CSR have been a total failure. Part of this failure stems from the inability to base CSR morbidity on one or two personality traits. Full psychological work-ups are expensive and inconclusive, while pen and paper tests are ineffective and easily faked. In addition, studies conducted following WWII screening programs showed that psychological disorders present during military training did not accurately predict stress disorders during combat.
Cohesion
While it is difficult to measure the effectiveness of such a subjective term, soldiers who reported in a WWII study that they had a "higher than average" sense of camaraderie and pride in their unit were more likely to report themselves ready for combat and less likely to develop CSR or other stress disorders. Soldiers with a "lower than average" sense of cohesion with their unit were more susceptible to stress illness.
Training
Stress exposure training or SET is a common component of most modern military training. There are three steps to an effective stress exposure program.
Providing knowledge of the stress environmentSoldiers with a knowledge of both the emotional and physical signs and symptoms of CSR are much less likely to have a critical event that reduces them below fighting capability. Instrumental information, such as breathing exercises that can reduce stress and suggestions not to look at the faces of enemy dead, is also effective at reducing the chance of a breakdown.
Skills acquisitionCognitive control strategies can be taught to soldiers to help them recognize stressful and situationally detrimental thoughts and repress those thoughts in combat situations. Such skills have been shown to reduce anxiety and improve task performance.
Confidence building through application and practiceSoldiers who feel confident in their own abilities and those of their squad are far less likely to develop combat stress reaction. Training in stressful conditions that mimic those of an actual combat situation builds confidence in the abilities of themselves and the squad. As this training can actually induce some of the stress symptoms it seeks to prevent, stress levels should be increased incrementally as to allow the soldiers time to adapt.
Prognosis
Figures from the 1982 Lebanon war showed that with proximal treatment, 90% of CSR casualties returned to their unit, usually within 72 hours. With rearward treatment, only 40% returned to their unit. It was also found that treatment efficacy went up with the application of a variety of front line treatment principles versus just one treatment. In Korea, similar statistics were seen, with 85% of US battle fatigue casualties returned to duty within three days and 10% returned to limited duties after several weeks.Though these numbers seem to promote the claims that proximal PIE or BICEPS treatment is generally effective at reducing the effects of combat stress reaction, other data suggests that long term PTSD effects may result from the hasty return of affected individuals to combat. Both PIE and BICEPS are meant to return as many soldiers as possible to combat, and may actually have adverse effects on the long-term health of service members who are rapidly returned to the front-line after combat stress control treatment. Although the PIE principles were used extensively in the Vietnam War, the post traumatic stress disorder lifetime rate for Vietnam veterans was 30% in a 1989 US study and 21% in a 1996 Australian study. In a study of Israeli Veterans of the 1973 Yom Kippur War, 37% of veterans diagnosed with CSR during combat were later diagnosed with PTSD, compared with 14% of control veterans.
Controversy
There is significant controversy with the PIE and BICEPS principles. Throughout a number of wars, but notably during the Vietnam War, there has been a conflict among doctors about sending distressed soldiers back to combat. During the Vietnam War this reached a peak with much discussion about the ethics of this process. Proponents of the PIE and BICEPS principles argue that it leads to a reduction of long-term disability but opponents argue that combat stress reactions lead to long-term problems such as post-traumatic stress disorder.
The use of psychiatric drugs to treat people with CSR has also attracted criticism, as some military psychiatrists have come to question the efficacy of such drugs on the long-term health of veterans. Concerns have been expressed as to the effect of pharmaceutical treatment on an already elevated substance abuse rate among former people with CSR.Recent research has caused an increasing number of scientists to believe that there may be a physical (i.e., neurocerebral damage) rather than psychological basis for blast trauma. As traumatic brain injury and combat stress reaction have very different causes yet result in similar neurologic symptoms, researchers emphasize the need for greater diagnostic care.
See also
Acute stress disorder
Eye movement desensitization and reprocessing (modern treatment)
Lack of Moral Fibre
Shell shock
Social alienation – among returning war veterans
References
Further reading
West, Rebecca (1918). The Return of the Soldier. Garden City, NY: Garden City Pub. Co.
Woolf, Virginia (1925). Mrs Dalloway.
Barker, Pat (1991). Regeneration. Dutton. ISBN 978-0525934271.
Holden, Wendy (1998). Shell Shock. (Channel 4 Books).
Grabenhorst, Georg (1928 |
Combat stress reaction | ). Zero Hour.
Roth, Joseph (1924). Die Rebellion.
A Review on the Disarm Doctumentary
Corns, Cathryn and Hughes-Wilson, John (2001) Blindfold and Alone – British Military Executions in the Great War (Cassell)
Lamprecht, Friedhelm and Sack, Martin, "Posttraumatic Stress Disorder Revisited"
Dispatches: Lessons learned for Soldiers; Stress Injury and Operational Deployments, The Army Lessons Learned Centre, Canadian Forces Base Kingston, Vol. 10, No. 1, February 2004.
Tyquin, M. Madness and the Military: Australias Experience in the Great War. AMHP, Sydney, 2006.
External links
Glossary of Traumatology
DCoE National Center for Telehealth and Technology
Mortar attacks becoming routine for troops in Afghanistan
A Matter of Duty: The Continuing War Against PTSD Documentary produced by the Maine Public Broadcasting Network |
Cholestatic pruritus | Cholestatic pruritus is the sensation of itch due to nearly any liver disease, but the most commonly associated entities are primary biliary cholangitis, primary sclerosing cholangitis, obstructive choledocholithiasis, carcinoma of the bile duct, cholestasis (also see drug-induced pruritus), and chronic hepatitis C viral infection and other forms of viral hepatitis.
Cause
Cholestasis means "the slowing or stopping of bile flow" which can be caused by any number of diseases of the liver (which produces the bile), the gallbladder (which stores the bile), or biliary tract (also known as the biliary tree, the conduit that allows the bile to leave the liver and gallbladder and enter the small intestine). When this occurs, conjugated bilirubin and the waste products that usually would be cleared in bile reflux back into the bloodstream. This causes a primarily conjugated hyperbilirubinemia and jaundice; the liver conjugates the bile to make it water-soluble and because the bile has already been processed by the liver, when it gets backed up because of a blockage and is refluxed into the blood, the blood will have high levels of conjugated bilirubin. This is in contrast to primarily unconjugated hyperbilirubinemia which is the water-insoluble form that is bound to serum albumin; the liver has not had a chance to conjugate the bilirubin yet and can be caused either because too much unconjugated bilirubin is made (such as in massive hemolysis or ineffective erythropoiesis) or because too little is conjugated (Gilberts disease or Crigler–Najjar syndrome). Unconjugated hyperbilirubinemia does not typically cause pruritus.
It is thought that bile salts that deposit into the skin are responsible for the pruritus (itching) because the levels of bilirubin in the bloodstream and the severity of the pruritus does not appear to be highly correlated. Patients that have been administered bile salt chelating agents do report some relief, however, and patients that have complete liver cell failure (and therefore cannot make these products to begin with) do not have pruritus. This suggests that products made by the liver must have some role in pruritus although it is not known exactly which product is responsible.
See also
Intrahepatic cholestasis of pregnancy
List of cutaneous conditions
References
== External links == |
Pili bifurcati | Pili bifurcati is characterized by bifurcation found in short segments along the shafts of several hairs, with each branch of the bifurcation being covered with its own cuticle.: 768
See also
List of cutaneous conditions
Pili multigemini – multiple hairs growing from the same source.
Ringed hair
References
== External links == |
Double outlet right ventricle | Double outlet right ventricle (DORV) is a form of congenital heart disease where both of the great arteries connect (in whole or in part) to the right ventricle (RV). In some cases it is found that this occurs on the left side of the heart rather than the right side.
Cause
Pathogenesis
DORV occurs in multiple forms, with variability of great artery position and size, as well as of ventricular septal defect (VSD) location. It can occur with or without transposition of the great arteries. The clinical manifestations are similarly variable, depending on how the anatomical defects affect the physiology of the heart, in terms of altering the normal flow of blood from the RV and left ventricle (LV) to the aorta and pulmonary artery. For example:
in DORV with a subaortic VSD, blood from the LV flows through the VSD to the aorta and blood from the RV flows mainly to the pulmonary artery, yielding physiology similar to ventricular septal defect
in DORV with a subpulmonic VSD (called Taussig-Bing syndrome), blood from the LV flows through the VSD to the pulmonary artery and blood from the RV flows mainly to the aorta, yielding physiology similar to Transposition of the Great Arteries
but if there is pulmonic stenosis in addition, physiology resembles Tetralogy of Fallot
in other forms of DORV, blood from both ventricles is substantially mixed in the RV, yielding physiology that resembles a large VSD
but again, if there is pulmonic stenosis, physiology resembles Tetralogy of Fallot
Treatment
DORV is treated with surgery.
Epidemiology
DORV affects between 1% and 3% of people born with congenital heart defects.Chromosomal abnormalities were reported in about 40% of reported cases in the medical literature.
References
== External links == |
Lentigo simplex | Lentigo simplex is the most common form of lentigo.: 29 A single lesion or multiple lesions (lentigines) may be present at birth or more commonly first develop in early childhood. Lentigo simplex is not induced by sun exposure, and it is not associated with any medical diseases or conditions. It is also referred to as simple lentigo and juvenile lentigo. This condition also affects cats, those with orange coloration most often, and can appear on the nose, lips, and eyes as the cat ages.
See also
Balloon cell nevus
List of cutaneous conditions
References
== External links == |
Pleomorphism (cytology) | Pleomorphism is a term used in histology and cytopathology to describe variability in the size, shape and staining of cells and/or their nuclei. Several key determinants of cell and nuclear size, like ploidy and the regulation of cellular metabolism, are commonly disrupted in tumors. Therefore, cellular and nuclear pleomorphism is one of the earliest hallmarks of cancer progression and a feature characteristic of malignant neoplasms and dysplasia. Certain benign cell types may also exhibit pleomorphism, e.g. neuroendocrine cells, Arias-Stella reaction.
A rare type of rhabdomyosarcoma that is found in adults is known as pleomorphic rhabdomyosarcoma.Despite the prevalence of pleomorphism in human pathology, its role in disease progression is unclear. In epithelial tissue, pleomorphism in cellular size can induce packing defects and disperse aberrant cells. But the consequence of atypical cell and nuclear morphology in other tissues is unknown.
See also
Anaplasia
Cell growth
Cytopathology
Giant cell carcinoma of the lung
Nuclear atypia
== References == |
Lycoperdonosis | Lycoperdonosis is a respiratory disease caused by the inhalation of large amounts of spores from mature puffballs. It is classified as a hypersensitivity pneumonitis (also called extrinsic allergic alveolitis)—an inflammation of the alveoli within the lung caused by hypersensitivity to inhaled natural dusts. It is one of several types of hypersensitivity pneumonitis caused by different agents that have similar clinical features. Typical progression of the disease includes symptoms of a cold hours after spore inhalation, followed by nausea, rapid pulse, crepitant rales (a sound like that made by rubbing hairs between the fingers, heard at the end of inhalation), and dyspnea. Chest radiographs reveal the presence of lung nodules. The early symptoms presented in combination with pulmonary abnormalities apparent on chest radiographs may lead to misdiagnosis of the disease as tuberculosis, histiocytosis, or pneumonia caused by Pneumocystis carinii. Lycoperdonosis is generally treated with corticosteroids, which decrease the inflammatory response; these are sometimes given in conjunction with antimicrobials.The disease was first described in the medical literature in 1967 by R.D. Strand and colleagues in the New England Journal of Medicine. In 1976, a 4-year-old was reported developing the disease in Norway after purposely inhaling a large quantity of Lycoperdon spores to stop a nosebleed. Lycoperdon species are sometimes used in folk medicine in the belief that their spores have haemostatic properties. A 1997 case report discussed several instances of teenagers inhaling the spores. In one severe case, the individual inhaled enough spores so as to be able to blow them out of his mouth. He underwent bronchoscopy and then had to be on life support before recovering in about four weeks. In another instance, a teenager spent 18 days in a coma, had portions of his lung removed, and suffered severe liver damage. In Wisconsin, eight teenagers who inhaled spores at a party presented clinical symptoms such as cough, fever, shortness of breath, myalgia, and fatigue within a week. Five of the eight required hospitalization; of these, two required intubation to assist in breathing. The disease is rare, possibly because of the large quantity of spores that need to be inhaled for clinical effects to occur. Lycoperdonosis also occurs in dogs; in the few reported cases, the animals had been playing or digging in areas known to contain puffballs. Known species of puffballs implicated in the etiology of the published cases include the widespread Lycoperdon perlatum (the "devils snuff-box", L. gemmatum) and Calvatia gigantea, both of the family Lycoperdaceae.
== References == |
Acne keloidalis nuchae | Acne keloidalis nuchae (also known as "acne keloidalis", "dermatitis papillaris capillitii", "folliculitis keloidalis", "folliculitis keloidis nuchae", and "nuchal keloid acne": 526 ) is a destructive scarring folliculitis that occurs almost exclusively on the occipital scalp of people of African descent, primarily men.AKN is characterized by firm pink or flesh-colored hyperpigmented bumps in the skin, which are usually located on the back of the neck. This is mainly because men often cut their hair very low as opposed to women, allowing the hair to prick the occipital scalp thereby causing irritation. Acne keloidalis nuchae most commonly presents itself in individuals aged 13 to 25. The disease is closely related to pseudofolliculitis barbae and both occur frequently in black men in the military, where it is so common that the US Army has developed official protocols for management. Prolonged cases of AKN can cause keloid formation due to chronic irritation from folliculitis. Bacterial folliculitis and acne can mimic the appearance of AKN; however, unlike acne, comedones are not seen with AKN.
Treatments for AKN aim to reduce inflammation and prevent infections and scarring. Therapies for AKN may include topical antibiotics, topical or intralesional corticosteroids, and laser hair removal. Recommended modifications to shaving habits include liberal use of shaving cream, avoidance of stretching the skin while shaving, and use of a single-blade razor rather than a razor with multiple blades.
See also
List of cutaneous conditions
References
== External links == |
Half and half nail | Half and half nails (also known as "Lindsays nails") show the proximal portion of the nail white and the distal half red, pink, or brown, with a sharp line of demarcation between the two halves.: 785 Seventy percent of hemodialysis patients and 56% of renal transplant patients have at least one type of nail abnormality. Absence of lunula, splinter hemorrhage, and half and half nails were significantly more common in hemodialysis patients, while leukonychia was significantly more common in transplant patients.: 785 : 659
See also
List of cutaneous conditions
References
== External links == |
Ductus venosus | In the fetus, the ductus venosus (Arantius duct after Julius Caesar Aranzi) shunts a portion of umbilical vein blood flow directly to the inferior vena cava. Thus, it allows oxygenated blood from the placenta to bypass the liver. Compared to the 50% shunting of umbilical blood through the ductus venosus found in animal experiments, the degree of shunting in the human fetus under physiological conditions is considerably less, 30% at 20 weeks, which decreases to 18% at 32 weeks, suggesting a higher priority of the fetal liver than previously realized. In conjunction with the other fetal shunts, the foramen ovale and ductus arteriosus, it plays a critical role in preferentially shunting oxygenated blood to the fetal brain. It is a part of fetal circulation.
Anatomic course
The pathway of fetal umbilical venous flow is umbilical vein to left portal vein to ductus venosus to inferior vena cava and eventually the right atrium. This anatomic course is important in the assessment of neonatal umbilical venous catheterization, as failure to cannulate through the ductus venosus results in malpositioned hepatic catheterization via the left or right portal veins. Complications of such positioning can include hepatic hematoma or abscess.
Postnatal closure
The ductus venosus is open at the time of birth and that is the reason why umbilical vein catheterization works. The ductus venosus naturally closes during the first week of life in most full-term neonates; however, it may take much longer to close in pre-term neonates. Functional closure occurs within minutes of birth. Structural closure in term babies occurs within 3 to 7 days.
After it closes, the remnant is known as ligamentum venosum.
If the ductus venosus fails to occlude after birth, it remains patent (open), and the individual is said to have a patent ductus venosus and thus an intrahepatic portosystemic shunt (PSS). This condition is hereditary in some dog breeds (e.g. Irish Wolfhound). The ductus venosus shows a delayed closure in preterm infants, with no significant correlation to the closure of the ductus arteriosus or the condition of the infant. Possibly, increased levels of dilating prostaglandins leads to a delayed occlusion of the vessel.
== References == |
Double inlet left ventricle | A double inlet left ventricle (DILV) or "single ventricle", is a congenital heart defect appearing in 5 in 100,000 newborns, where both the left atrium and the right atrium feed into the left ventricle. The right ventricle is hypoplastic or does not exist.
Both atria communicate with the ventricle by a single atrio-ventricular valve. There is a big shunt left-right with a quickly evolutive pulmonary hypertension. Without life-prolonging interventions, the condition is fatal, but with intervention, the newborn may survive. Even if there is no foetal sickness, the diagnosis can be made in utero by foetal echocardiography.
Presentation
Infants born with DILV cannot feed normally (breathlessness) and have difficulty gaining weight. The mixed blood in systemic circulation leads to hypoxia (lack of oxygen to the body and organs), so infants develop cyanosis and breathlessness early.
Diagnosis
Treatment
In the first few days, if there is no pulmonary valve stenosis, a pulmonary valve banding is necessary to prevent pulmonary hypertension and the ductus must be kept open to allow blood-flow using medication containing prostaglandin. At same time, if necessary, the atrial and ventricular septum communications must be enlarged.
When possible Glenn procedure is done.
Later, surgical options include the Damus–Kaye–Stansel procedure, the Fontan procedure, and the Norwood procedure. The goal of all of these is separating the pulmonary and the systemic circulation.Usually, DILV is associated with other cardiac malformations.
Prognosis
Mortality is very high in the first 2 years, 85%, but after it decreases and between 2 and 15 years old the mortality is only around 9%. Few reach middle age.
Diagnosis must be made within few days or even hours to prevent death.
References
== External links == |
Cryoglobulinemic purpura | Cryoglobulinemic purpura is a skin condition characterized by purpura and occurring most frequently in multiple myeloma and macroglobulinemia.: 822
See also
Cryoglobulinemia
Skin lesion
== References == |
Gestational choriocarcinoma | Gestational choriocarcinoma is a form of gestational trophoblastic neoplasia, which is a type of gestational trophoblastic disease (GTD), that can occur during pregnancy. It is a rare disease where the trophoblast, a layer of cells surrounding the blastocyst, undergoes abnormal developments, leading to trophoblastic tumors. The choriocarcinoma can metastasize to other organs, including the lungs, kidney, and liver. The amount and degree of choriocarcinoma spread to other parts of the body can vary greatly from person to person.Gestational choriocarcinoma can happen during and after any type of pregnancy event, though risk of the disease is higher in and after complete or partial molar pregnancies. Risk of disease may also be higher in those experiencing pregnancy at younger or older ages that average, such as below 15 years old or above 45 years old. Those with gestational choriocarcinoma may experience abnormal vaginal bleeding, abdominal pain, and have high levels of human chorionic gonadotropin (hCG), in addition to history of molar pregnancy or other metastatic cancer. A combination of history, symptoms, human chorionic gonadotropin levels, and imaging can be used in the diagnosis process, with ultrasonography being commonly used to image. Approximately 50% of those with gestational choriocarcinoma have experienced molar pregnancy, approximately 25% developed the disease after a regular, term pregnancy, and other situations have included history of ectopic pregnancy, where the pregnancy does not occur in the uterus.Guidelines from the Federation of Gynecologists and Obstetricians (FIGO), Royal College of Obstetricians and Gynaecologists (RCOG), European Society for Medical Oncology (ESMO), and Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) exist to evaluate risk and treatment of the disease. There are generally three levels of risk: low risk, high risk, and ultrahigh risk. The primary form of treatment is chemotherapy with one or more agents. Duration can go upwards of six weeks following return of human chorionic gonadotropin levels to the normal range. Depending on the risk of gestational trophoblastic disease (GTD) development, such as in certain people with mole pregnancies, chemotherapy has been used in a preventative manner in the past. However, this type of use is now advised against due to risk of toxicity and resistance to agents that may be needed in future treatment of the disease, on top of medical costs. Guidelines also detail options for salvage therapies in the situation of resistance to preferred choice of chemotherapy and surgical procedures possible in the situation of drug-resistant tumors.
Signs and symptoms
Vaginal bleeding is a common symptom of gestational choriocarcinoma. In the event the gestational choriocarcinoma has already spread to other parts of the body, bleeding events in other organs may be the first symptom. If the choriocarcinoma has metastasized to the lungs, one of the most common organs of metastasis, then symptoms may include abnormally quick breathing, coughing, and chest pain. However, it is also possible for there to be none of these symptoms and only a difference in biomarkers in an individual instead.Uterine enlargement as seen in an ultrasound can be a presenting sign of gestational choriocarcinoma. Transvaginal ultrasounds may also be used in screening for the disease, with the positron emission tomography (PET) scan, computed tomography (CT), and magnetic resonance imaging (MRI) in locations such as the abdomen, pelvis, and brain being other imaging options. Chest x-rays may also be used to see if gestational choriocarcinoma has potentially spread to the lungs.Human chorionic gonadotropin is a hormone produced by the trophoblast and can be measured in both urine and blood. Another option of measuring this biomarker level is through lumbar puncture, which can show fluid-to-serum ratio of human chorionic gonadotropic and reflect whether the disease has potentially spread to the central nervous system. Elevated or rising human chorionic gonadotropin can be a sign of gestational choriocarcinoma, though it is also used as a biomarker in other types of gestational trophoblastic diseases (GTD). It is useful not only for diagnosis but also for monitoring disease progression, treatment response, and potential of recurring gestational choriocarcinoma.
Causes
Gestational choriocarcinoma (GC) is the most aggressive form of trophoblastic tumor; it most commonly arises from certain fertilization defects, such as molar pregnancy, which results in increased level of growth factors and uncontrolled proliferation of trophoblasts in the uterus. Statistics from clinical cases have shown that GC is associated with any pregnancy events, with 50% of GC arise from hydatidiform moles, 25% from gestation, and 25% from abortion or tubal pregnancy.
Risk factors
The exact underlying causes for this disease are still not fully elucidated, part of the reasons being that this condition is very rare and it is clinically hard to distinguish it from invasive mole, which are other type of trophoblastic tumor that present some similarities as GC. But several risk factors have been reported to have association with gestational choriocarcinoma.
Maternal age. This is one of the two well-established risk factors for GC. Many studies have shown that the risk of developing GC increased very rapidly in gestational women older than 40 years old.
Prior history of complete hydatidiform mole. This is another well-established risk factor for GC. It has been showed that the risk of having GC after a complete hydatidiform mole is significantly higher than after a live birth.
Others risk factors such as reproductive factors, use of oral contraceptives, diet and environmental factors were also reported. But because of data inconsistency, such associations are still questionable. For example, there is a case-control study showed that theres a significant association of GC in women having more than 5 births. But other studies had showed no association when corrected for age.
Pathogenesis
At the cellular level, any abnormalities in the placental trophoblastic proliferation could potentially contribute to molar pregnancy and tumor development. There are three different types of trophoblasts: cytotrophoblasts, syncytiotrophoblasts, and intermediate trophoblasts. Each of them possesses distinct specialized functions to support a developing embryo. Cytotrophoblasts are the germinating cells that forms the chorion villi and can be differentiated into syncytiotrophoblasts which produce hCG and can intrude to the inner muscle layer of the uterus to help embed the developing embryo, and intermediate trophoblasts which spread throughout the chorion villi to support maternal-fetal circulation. Malignant cellular transformation of all of these three trophoblastic cells contribute to the development of gestational choriocarcinoma. Common pathological features of GC include abnormal trophoblastic enlargement, loss of trophoblastic specialized features and functions, absence of villi in the placenta, abnormal bleeding, and necrosis.Many efforts have been made to try to understand the mechanism of how non-malignant mole could become invasive. It is suspected that activation of certain oncogenes (such as up-regulations of MDM2, c-ERB2, and BLC2) and inactivation of tumor suppressor genes (such as up-regulations of p53, p21) were involved in the processes of genetic changes in this malignant transformation. But trophoblastic cells, by nature, are highly active in cell division, the increased activities of those genes are also necessary to maintain their normal cell function. Therefore, it is still unclear how significantly these genetic changes are in the pathogenesis of gestational choriocarcinoma.
Recent research in the role of long non-coding RNAs (lncRNAs) in the GC development is believed to bring hope in this field. Long non-coding RNAs are groups of RNAs that do not code for protein expression and are usually over 200 nucleotides long; they are increasingly recognized to have essential role in many aspects of cellular function, like transcriptional regulation, sub-cellular protein localization, and epigenetic remodeling. To date, several types of lncRNAs are reported to have role in GC pathogenesis, which are metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), H19, maternally expressed gene 3 (MEG3), prostate cancer antigen 3 (PCA3), the long intergenic non-coding RNA 00261 (LINC00261), etc.. However, as many of these studies are still in the preliminary stages, more investigation is needed to fully understand the underlying mechanism.
Diagnosis
Common characteristic manifestations of gestational choriocarcinoma include irregular vaginal bleeding and hydatidiform moles. A hydatidiform mole is a red hemorrhagic mass with various sizes in the uterus. Often, diagnosis is presumptive. It is based on clinical findings and the identification of a malignant trophoblast. One prevalent symptom is vaginal bleeding after a pregnancy, abortion, or hydatidiform mole. In the presence of choriocarcinoma, a pregnancy test will be positive even if there is no embryo/fetus.A confirmed diagnosis usually happens after the disease has progressed to a late clinical stage. This is partly due to the wide spectrum and rare clinical presentations of the disease. Individuals presented with the disease are mostly in their reproductive years.Similar to other non-gestational tumors, gestational choriocarcinoma can be reflected via an elevated level in serum hCG concentration. Besides the change in serum hCG levels, the diagnosis of gestational choriocarcinoma also focuses on the presence of metastases after any types of pregnancy events. Based on the International Federation of Gynecology and Obstetrics (FIGO)s updated guidelines on gestational trophoblastic disease management, the diagnostic criteria of a post-gestational trophoblastic neoplasia (GTN) is as follows:
Over a period of 3 weeks or longer (day 1, 7, 14, 21), there are 4 or more plateaued hCG levels.
Over a period of 2 weeks or longer (day 1, 7, 14), there are 3 consecutive weekly measurements of rising hCG levels.
A histological diagnosis of choriocarcinoma.There are currently different guidelines available in terms of diagnosing and recommending treatment options for gestational trophoblastic neoplasia (GTN). The 4 guidelines identified are: the Royal College of Obstetricians and Gynecologists (RCOG), the International Federation of Gynecology and Obstetrics (FIGO), the European Society for Medical Oncology (ESMO), and the Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG). The differences in GTN diagnosis between the guidelines are as follows:
To differentiate gestational choriocarcinoma from other tumors such as lung or brain cancers, a genetic test is usually completed on top of a pathological diagnosis. DNA genotyping is a powerful tool that helps with the differentiation. The technique can accurately determine the time that it takes to develop the observed tumor and the type of index gestation, which includes term pregnancy, molar gestation, or non-molar abortion.
Treatment
Due to the susceptability of choriocarcinomas to chemotherapy, it is the first line treatment for this disease. Treatment course depends on the FIGO Scoring System for GTN, which has various prognostic factors, and categorizes based on low risk with a score of 0-6 and high risk with a score of 7 and above.
Low risk
Individuals with low risk GTN are usually treated with single agent chemotherapy, such as methotrexate and folinic acid (MTX/FA) or actinomycin D (ActD). Other treatment options for those with low risk include hysterectomy and surgical removal of the tumor if possible.
High risk
Those with high risk GTN receive a multi-agent chemotherapy regimen, usually consisting of a weekly rotation of etopside, methotrexate, and actinomycin D given one week and cyclophosphamide and vincristine given the following week, with variations to treatment occurring on a patient-specific basis. In individuals who relapse, secondary chemotherapy is needed where treatment may vary from the original regimen. The treatment includes a platinum-etopside combination given with other chemotherapy medications, such as methotrexate and actinomycin D (EMA-EP), bleomycin (BEP), or ifosfamide (VIP, ICE). Additional treatment also consists of surgery and radiotherapy if deemed appropriate for the individual. This condition can also result in resistance to the medications used to treat it and failure of their success in the individuals. If this occurs, individuals usually undergo a more intensive medication regimen than what was originally given to them.
Immune checkpoint inhibitors
New treatment options designed to reduce the risk of resistance are currently being researched, such as immune checkpoint inhibitors. Studies of gestational choriocarcinoma demonstrate an increased expression of the ligand PD-L1 and its corresponding receptor PD-1, leading to drug research and development into medications that can block the PD-1 receptor, such as Pembrolizumab. In individuals requiring more intensive chemotherapy options, using an immune checkpoint inhibitor may be preferable to long-term use of multi-agent chemotherapy to prevent prolonged toxicity to the body.
Prognosis
The survival rate following treatment with chemotherapy is approximately at least 90%. If gestational choriocarcinoma has spread to the liver in an individual, survival rate may be lower. Overall survival rate is also higher when management of gestational choriocarcinoma occurs in a setting with physicians familiar with the condition. Earlier diagnosis and treatment intervention can lead to greater success in preserving potential of future pregnancy in those seeking it.Return of human chorionic gonadotropic levels to within the bounds of normal values lowers the chance of recurring gestational choriocarcinoma. These levels can be checked monthly as follow-up. If an individual is interested in pregnancy following chemotherapy treatment for gestational choriocarcinoma, it is recommended that they wait a minimum of one year following chemotherapy before they plan to have a child to minimize the chance of miscarriage.
== References == |
Microcephaly | Microcephaly (from New Latin microcephalia, from Ancient Greek μικρός mikrós "small" and κεφαλή kephalé "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it may develop in the first few years of life. Since brain growth is correlated with head growth, people with this disorder often have an intellectual disability, poor motor function, poor speech, abnormal facial features, seizures and dwarfism.The disorder is caused by a disruption to the genetic processes that form the brain early in pregnancy, though the cause is not identified in most cases. Many genetic syndromes can result in microcephaly, including chromosomal and single-gene conditions, though almost always in combination with other symptoms. Mutations that result solely in microcephaly (primary microcephaly) exist but are less common. External toxins to the embryo, such as alcohol during pregnancy or vertically transmitted infections, can also result in microcephaly. Microcephaly serves as an important neurological indication or warning sign, but no uniformity exists in its definition. It is usually defined as a head circumference (HC) more than two standard deviations below the mean for age and sex. Some academics advocate defining it as head circumference more than three standard deviations below the mean for the age and sex.There is no specific treatment that returns the head size to normal. In general, life expectancy for individuals with microcephaly is reduced, and the prognosis for normal brain function is poor. Occasional cases develop normal intelligence and grow normally (apart from persistently small head circumference). It is reported that in the United States, microcephaly occurs in 2 to 12 babies per 10,000 births.
Signs and symptoms
There are a variety of symptoms that can occur in children. Infants with microcephaly are born with either a normal or reduced head size. Subsequently, the head fails to grow, while the face continues to develop at a normal rate, producing a child with a small head and a receding forehead, and a loose, often wrinkled scalp. As the child grows older, the smallness of the skull becomes more obvious, although the entire body also is often underweight and dwarfed.Severely impaired intellectual development is common, but disturbances in motor functions may not appear until later in life. Affected newborns generally have striking neurological defects and seizures. Development of motor functions and speech may be delayed. Hyperactivity and intellectual disability are common occurrences, although the degree of each varies. Convulsions may also occur. Motor ability varies, ranging from clumsiness in some to spastic quadriplegia in others.
Causes
Microcephaly is a type of cephalic disorder. It has been classified in two types based on the onset:
Congenital
Isolated
Familial (autosomal recessive) microcephaly
Autosomal dominant microcephaly
X-linked microcephaly
Chromosomal (balanced rearrangements and ring chromosome)
Syndromes
Chromosomal
Poland syndrome
Down syndrome
Edward syndrome
Patau syndrome
Unbalanced rearrangements
Contiguous gene deletion
4p deletion (Wolf–Hirschhorn syndrome)
5p deletion (Cri-du-chat)
7q11.23 deletion (Williams syndrome)
22q11 deletion (DiGeorge syndrome)
Single gene defects
Smith–Lemli–Opitz syndrome
Seckel syndrome
Cornelia de Lange syndrome
Holoprosencephaly
Primary microcephaly 4
Wiedemann-Steiner syndrome
Acquired
Disruptive injuries
Ischemic stroke
Hemorrhagic stroke
Death of a monozygotic twin
Vertically transmitted infections
Congenital cytomegalovirus infection
Toxoplasmosis
Congenital rubella syndrome
Congenital Varicella Syndrome
Zika virus (see Zika fever#Microcephaly)
Drugs
Fetal hydantoin syndrome
Fetal alcohol syndrome
Other
Radiation exposure to mother
Maternal malnutrition
Maternal phenylketonuria
Poorly controlled gestational diabetes
Hyperthermia
Maternal hypothyroidism
Placental insufficiency
Craniosynostosis
Postnatal onset
Genetic
Inborn errors of metabolism
Congenital disorder of glycosylation
Mitochondrial disorders
Peroxisomal disorder
Glucose transporter defect
Menkes disease
Congenital disorders of amino acid metabolism
Organic acidemia
Syndromes
Contiguous gene deletion
17p13.3 deletion (Miller–Dieker syndrome)
Single gene defects
Rett syndrome (primarily girls)
Nijmegen breakage syndrome
X-linked lissencephaly with abnormal genitalia
Aicardi–Goutières syndrome
Ataxia telangiectasia
Cohen syndrome
Cockayne syndrome
Acquired
Disruptive injuries
Traumatic brain injury
Hypoxic-ischemic encephalopathy
Ischemic stroke
Hemorrhagic stroke
Infections
Congenital HIV encephalopathy
Meningitis
Encephalitis
Toxins
Chronic kidney failure
Deprivation
Hypothyroidism
Anemia
Congenital heart disease
MalnutritionGenetic mutations cause most cases of microcephaly. Relationships have been found between autism, duplications of genes and macrocephaly on one side. On the other side, a relationship has been found between schizophrenia, deletions of genes and microcephaly. Several genes have been designated "MCPH" genes, after microcephalin (MCPH1), based on their role in brain size and primary microcephaly syndromes when mutated. In addition to microcephalin, these include WDR62 (MCPH2), CDK5RAP2 (MCPH3), KNL1 (MCPH4), ASPM (MCPH5), CENPJ (MCPH6), STIL (MCPH7), CEP135 (MCPH8), CEP152 (MCPH9), ZNF335 (MCPH10), PHC1 (MCPH11) and CDK6 (MCPH12). Moreover, an association has been established between common genetic variants within known microcephaly genes (such as MCPH1 and CDK5RAP2) and normal variation in brain structure as measured with magnetic resonance imaging (MRI)—i.e., primarily brain cortical surface area and total brain volume.The spread of Aedes mosquito-borne Zika virus has been implicated in increasing levels of congenital microcephaly by the International Society for Infectious Diseases and the US Centers for Disease Control and Prevention. Zika can spread from a pregnant woman to her fetus. This can result in other severe brain malformations and birth defects. A study published in The New England Journal of Medicine has documented a case in which they found evidence of the Zika virus in the brain of a fetus that displayed the morphology of microcephaly.
Microlissencephaly
Microlissencephaly is microcephaly combined with lissencephaly (smooth brain surface due to absent sulci and gyri). Most cases of microlissencephaly are described in consanguineous families, suggesting an autosomal recessive inheritance.
Historical causes of microcephaly
After the dropping of atomic bombs "Little Boy" on Hiroshima and "Fat Man" on Nagasaki, several women close to ground zero who had been pregnant at the time gave birth to children with microcephaly. Microcephaly was present in 7 children from a group of 11 pregnant women at 11–17 weeks of gestation who survived the blast at less than 1.2 km (0.75 mi) from ground zero. Due to their proximity to the bomb, the pregnant womens in utero children received a biologically significant radiation dose that was relatively high due to the massive neutron output of the lower explosive-yielding Little Boy. Researchers studied 286 additional children who were in utero during the atomic bombings, and after a year they found these children had a higher incidence of microcephaly and mental retardation.
Other relations
Intracranial volume also affects this pathology, as it is related with the size of the brain.
Pathophysiology
Microcephaly generally is due to the diminished size of the largest part of the human brain, the cerebral cortex, and the condition can arise during embryonic and fetal development due to insufficient neural stem cell proliferation, impaired or premature neurogenesis, the death of neural stem cells or neurons, or a combination of these factors. Research in animal models such as rodents has found many genes that are required for normal brain growth. For example, the Notch pathway genes regulate the balance between stem cell proliferation and neurogenesis in the stem cell layer known as the ventricular zone, and experimental mutations of many genes can cause microcephaly in mice, similar to human microcephaly. Mutations of the abnormal spindle-like microcephaly-associated (ASPM) gene are associated with microcephaly in humans and a knockout model has been developed in ferrets that exhibits severe microcephaly. In addition, viruses such as cytomegalovirus (CMV) or Zika have been shown to infect and kill the primary stem cell of the brain—the radial glial cell, resulting in the loss of future daughter neurons. The severity of the condition may depend on the timing of infection during pregnancy.Microcephaly is a feature common to several different genetic disorders arising from a deficiency in the cellular DNA damage response. Individuals with the following DNA damage response disorders exhibit microcephaly: Nijmegen breakage syndrome, ATR-Seckel syndrome, MCPH1-dependent primary microcephaly disorder, xeroderma pigmentosum complementation group A deficiency, Fanconi anemia, ligase 4 deficiency syndrome and Bloom syndrome. These findings suggest that a normal DNA damage response is critical during brain development, perhaps to protect against induction of apoptosis by DNA damage occurring in neurons.
Treatment
There is no known cure for microcephaly. Treatment is symptomatic and supportive. Because some cases of microcephaly and its associated symptoms may be a result of amino acid deficiencies, treatment with amino acids in these cases has been shown to improve symptoms such as seizures and motor function delays.
History
People with small heads were displayed as a public spectacle in ancient Rome.People with microcephaly were sometimes sold to freak shows in North America and Europe in the 19th and early 20th centuries, where they were known by the name "pinheads". Many of them were presented as different species (e.g., "monkey man") and described as being the missing link. Famous examples include Zip the Pinhead (although he may not have had microcephaly), Maximo and Bartola, and Schlitzie the Pinhead,. Zip the Pinhead and Schlitzie the Pinhead, also stars of the 1932 film Freaks, were cited as influences on the development of the long-running comic strip character Zippy the Pinhead, created by Bill Griffith.
Notable cases
A dwarf of Punt (ancient Somalia) was given by the Chief clans as partial tribute to the last ruler of Ancient Egypts Old Kingdom, Pepi II Neferkare (6th Dynasty, circa 2125–2080 BC); it could be inferred that this person was also microcephalic. In a letter preserved at the British Museum, the young king gives instructions by letter, "Harkhuf! The men in your service [escorts; soldiers; sailors; guards, etc.] ought pay sincere care with the dwarfs head while sleeping during the voyage to the palace" (so that it does not fall off). At the same time, it could be for other reasons unrelated to microcephaly, etc.
Triboulet, a jester of duke René of Anjou (not to be confused with the slightly later Triboulet at the French court).
Jenny Lee Snow and Elvira Snow, whose stage names were Pip and Flip, respectively, were sisters with microcephaly who acted in the 1932 film Freaks.
Schlitze "Schlitzie" Surtees, possibly born Simon Metz, was a widely known sideshow performer and actor, who also appeared in Freaks.
Lester "Beetlejuice" Green, a member of radio host Howard Sterns Wack Pack.
See also
Anencephaly (Usually rapidly fatal)
Cerebral rubicon
Hydrocephaly
Macrocephaly
Seckel syndrome
Achalasia microcephaly
References
External links
Microcephaly at NINDS
NINDS Overview |
Couvade | Couvade is a term which was coined by anthropologist E. B. Tylor in 1865 to refer to certain rituals in several cultures that fathers adopt during pregnancy.
Couvade can be traced to Ancient Egypt as a "sacred birth custom, of when a child is born, the man experiences the ritual of "labor" in which he takes to his bed, and undergoes periods of fasting and purification, and the observance of certain taboos".The term "couvade" is borrowed from French (where it is derived from the verb couver "to brood, hatch"); the use in the modern sense derives from a misunderstanding of an earlier idiom faire la couvade, which meant "to sit doing nothing."An example of couvade is that the Cantabri people had a custom in which the father, during or immediately after the birth of a child, took to bed, complained of having labour pains, and was accorded the treatment usually shown to women during pregnancy or after childbirth. Similarly, in Papua New Guinea, fathers built a hut outside the village and mimicked the pains of labour until the baby is born. Similar rituals occur in other cultural groups in Thailand, Russia, China, India and many indigenous groups in the Americas.
In some cultures, "sympathetic pregnancy" is attributed to efforts to ward off demons or spirits from the mother or seek favour of supernatural beings for the child. Couvade has been reported by travelers throughout history, including the Greek geographer Strabo (3.4.17).
According to Claude Levi-Strauss, the custom of couvade reinforces the institution of the family in some societies by "welding" together men and their wives and future children.
See also
Couvade syndrome
References
External links
Chisholm, Hugh, ed. (1911). "Couvade" . Encyclopædia Britannica. Vol. 7 (11th ed.). Cambridge University Press. pp. 337–338.
Couvade in Tribal Cultures |
Ullrich congenital muscular dystrophy | Ullrich congenital muscular dystrophy is a form of congenital muscular dystrophy. It is associated with variants of type VI collagen, it is commonly associated with muscle weakness and respiratory problems, though cardiac issues are not associated with this type of CMD. It is named after Otto Ullrich, who is also known for the Ullrich-Turner syndrome.
Signs and symptoms
The presentation of Ullrich congenital muscular dystrophy in an affected individual is as follows:
Muscle weakness
Difficulty walking
Contractures (predominantly in proximal muscles, e.g. neck)
Joint looseness (predominantly in distal joints)
Genetics
In terms of the genetics of Ullrich congenital muscular dystrophy, there are mutations in the genes COL6A1, COL6A2, and COL6A3. This sub-type of muscular dystrophy is autosomal recessive in nature.COL6A1 plays an important part in maintaining the human bodys integrity of various tissues. Alpha 1 subunit of type VI collagen is the encoded protein.
Diagnosis
In terms of the diagnosis of Ullrich congenital muscular dystrophy upon inspection follicular hyperkeratosis, may be a dermatological indicator, additionally also serum creatine kinase may be mildly above normal. Other exams/methods to ascertain if the individual has Ullrich congenital muscular dystrophy are:
MRI
Biopsy muscle
Genetic testing
Differential diagnosis
This includes
Treatment
Treatment for Ullrich congenital muscular dystrophy can consist of physical therapy and regular stretching to prevent and reduce contractures. Respiratory support may be needed at some point by the affected individual.Though cardiac complications are not a concern in this type of CMD, in regards to respiratory issues ventilation via a tracheostomy is a possibility in some cases.
Prognosis
The prognosis of this sub-type of MD indicates that the affected individual may eventually have feeding difficulties. Surgery, at some point, might be an option for scoliosis.Scoliosis, which is a sideways curve of the persons vertebrate, is determined by a variety of factors, including the degree (mild or severe), in which case if possible a brace might be used by the individual.
Research
In terms of possible research for Ullrich congenital muscular dystrophy one source indicates that cyclosporine A might be of benefit to individuals with this CMD type.According to a review by Bernardi, et al., cyclosporin A (CsA) used to treat collagen VI muscular dystrophies demonstrates a normalization of mitochondrial reaction to rotenone.
See also
Muscular dystrophy
Congenital muscular dystrophy
References
Further reading
Ph.D, Evelyn B. Kelly (2013-01-07). Encyclopedia of Human Genetics and Disease [2 volumes]. ABC-CLIO. ISBN 9780313387142.
Carakushansky, Gerson; Ribeiro, Marcia Gonçalves; Kahn, Evelyn (2011). "Moderately progressive Ullrich congenital muscular dystrophy". Jornal de Pediatria. 88 (1): 93–96. doi:10.2223/JPED.2112. ISSN 0021-7557. PMID 22016142.
"National Guideline Clearinghouse | Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular and Electrodiagnostic Medicine". www.guideline.gov. Archived from the original on 2016-04-08. Retrieved 2016-05-12.
Hicks, D.; Lampe, A. K.; Laval, S. H.; Allamand, V.; Jimenez-Mallebrera, C.; Walter, M. C.; Muntoni, F.; Quijano-Roy, S.; Richard, P.; Straub, V.; Lochmuller, H.; Bushby, K. M. D. (16 November 2008). "Cyclosporine A treatment for Ullrich congenital muscular dystrophy: a cellular study of mitochondrial dysfunction and its rescue" (PDF). Brain. 132 (1): 147–155. doi:10.1093/brain/awn289. PMID 19015158. Retrieved 12 May 2016.
== External links == |
Periapical cyst | Commonly known as a dental cyst, the periapical cyst is the most common odontogenic cyst. It may develop rapidly from a periapical granuloma, as a consequence of untreated chronic periapical periodontitis.Periapical is defined as "the tissues surrounding the apex of the root of a tooth" and a cyst is "a pathological cavity lined by epithelium, having fluid or gaseous content that is not created by the accumulation of pus."Most frequently located in the maxillary anterior region, the cyst is caused by pulpal necrosis secondary to dental caries or trauma. Its lining is derived from the epithelial cell rests of Malassez which proliferate to form the cyst. Such cysts are very common. Although initially asymptomatic, they are clinically significant because secondary infection can cause pain and damage. In radiographs, the cyst appears as a radiolucency (dark area) around the apex of a tooths root.
Signs and symptoms
Periapical cysts begin as asymptomatic and progress slowly. Subsequent infection of the cyst causes swelling and pain. Initially, the cyst swells to a round hard protrusion, but later on the body resorbs some of the cyst wall, leaving a softer accumulation of fluid underneath the mucous membrane.Secondary symptoms of periapical cysts include inflammation and infection of the pulp causing dental caries. This infection is what causes necrosis of the pulp.Larger cysts may cause bone expansion or displace roots. Discoloration of the affected tooth may also occur. Patient will present negative results to electric and ice test of the affected tooth but will be sensitive to percussion. Surrounding gingival tissue may experience lymphadenopathy. The alveolar plate may exhibit crepitus when palpated.
Complications
Expansion of the cyst causes erosion of the floor of the maxillary sinus. As soon as it enters the maxillary antrum, the expansion rate increases due to available space for expansion. Performing a percussion test by tapping the affected teeth will cause shooting pain. This is often clinically diagnostic of pulpal infection.
Causes
Dental cysts are usually caused due to root infection involving tooth decay. Untreated dental caries then allow bacteria to reach the level of the pulp, causing infection. The bacteria gains access to the periapical region of the tooth through deeper infection of the pulp, traveling through the roots. The resulting pulpal necrosis causes proliferation of epithelial rests of Malassez which release toxins at the apex of the tooth. The bodys inflammatory response will attack the source of the toxins, leading to periapical inflammation. The many cells and proteins that rush to an area of infection create osmotic tension in the periapex which is the source of internal pressure increase at the cyst site.
These lesions can grow large because they apply pressure over the bone, causing resorption. The toxins released by the breakdown of granulation tissue are one of the common causes of bone resorption.
There are two schools of thought regarding cyst expansion.
Complementary response to inflammation
Chemical reaction with Interleukin and Prostaglandin
Mechanisms
Periapical cysts develop due to an inflammatory stimulus in 3 stages:
Initial stage: Epithelial cells from the rests of Malassez at the apex of the roots of a non-vital tooth (one where the nerve and blood supply in the tooth have degenerated and no longer exist) become stimulated due to the bodys inflammatory response to bacterial endotoxins infecting the pulp or as a direct response to necrotic pulp tissue, therefore re-entering the growth phase. Bacterial byproducts then are able to seep into the periapical region through the infected pulp.
Cyst development stage: Epithelial cells form strands and are attracted to the area which contains exposed connective tissue and foreign substances. Several strands from each rest converge and surround the abscess or foreign body.
Cyst growth stage: Fluid flows into the cavity where the forming cyst is growing due to the increased osmolality of the cavity in relation to surrounding serum in capillaries. Pressure and size increase.The definitive mechanism by which cysts grow is under debate; several theories exist.
Biomechanical theory
Pressure and concentration differences between the cystic cavity and the growth surroundings influence fluid movement into the cyst, causing size increase.
Biochemical theories
a. Collagenase (breakdown of collagen) in the jaw bone leads to bone degeneration, providing room for cysts to develop. Substances released by the bodys immune system as a result of the connective tissue breakdown, such as cytokines and growth factors, contribute to the mobilization and proliferation of epithelial cells in the area.
b. Bone resorption caused by metabolism of acidic substances produced by cysts contributes to cyst growth. Such substances include Prostaglandin-2 and Interleukin-1 which are both produced by the cyst itself.
Nutritional deficiency theory
Epithelial cells will form a mass inside the cavity and the innermost cells become deprived of nutrients because they are far from the source of nutrients (the blood vessels). The innermost cells die and form an aggregate of dead tissue. The inner cells undergo ischemic liquefactive necrosis which creates the cavity space surrounded by growing epithelial cells. This theory is unlikely in the absence of malignant transformation of epithelial cells as it does not follow the existing relationship between connective tissue and epithelium.
Abscess theory
Epithelial cells have an inherent quality to reproduce and cover any connective tissue that is not already lined with epithelia. Formation of an abscess must precede the epithelial proliferation in order for the cells to carry out this tendency. This theory explains why cysts are lined in epithelia but not why the initial cysts itself forms.
Diagnosis
A non-vital tooth is necessary for the diagnosis of a periapical cyst, meaning the nerve has been removed by root canal therapy.
Oral examination
The surrounding intraoral anatomical structures should be palpated to identify the presence of bone expansion or displacement of tooth roots as well as crepitus noises during examination, indicating extensive bone damage. Bulging of the buccal or lingual cortical plates may be present. Age of occurrence in the patient, the location of the cyst, the edges of cystic contours, and the impact that the cyst has on adjacent structures must all be considered for proper diagnosis.
Radiology
Several lesions can appear similarly in radiographic appearance. Intraoral X-rays or a 3-D cone beam scan of the affected area can be used to obtain radiological images and confirm diagnosis of cysts in the periapical area. Circular or ovoid radiolucency surrounding the root tip of approximately 1-1.5 cm in diameter is indicative of the presence of a periapical cyst. The border of the cyst is seen as a narrow opaque margin contiguous with the lamina dura. In cysts that are actively enlarging, peripheral areas of the margin may not be present. Periapical cysts have a characteristic unilocular shape on radiographs. There is also a severe border of cortication between the cyst and surrounding bone. Pseudocysts, on the other hand, have a fluid filled cavity but are not lined by epithelium, therefore they have a less severe and more blurred border between the fluid and bony surroundings.
Histopathology
In light microscopy, periapical cysts show:
Stratified squamous epithelium of variable thickness, except when originating in a maxillary sinus where there is respiratory epithelium (pseudostratified ciliated columnar epithelium).
A fibrous capsule of varying thickness, with chronic inflammatory cells, wherein a plasma cells may be abundantThey sometimes have the following features:
Rushton hyaline bodies, which are amorphic, eosinophilic, linear to crescent-shaped bodies in the cyst epithelium, present in 10% of periapical cysts.
Scattered ciliated cells
Cholesterol clefts in the cyst lining.
Classification
Periapical cysts exist in two structurally distinct classes:
Periapical true cysts - cysts containing cavities entirely surrounded in epithelial lining. Resolution of this type of cyst requires surgical treatment such as a cystectomy.
Periapical pocket cysts - epithelium lined cavities that have an opening to the root canal of the affected tooth. Resolution may occur after traditional root canal therapy.
Differentiation
Radiographically, it is virtually impossible to differentiate granuloma from a cyst. If the lesion is large it is more likely to be a cyst. Radiographically, both granulomas and cysts appear radiolucent. Many lesions of the mandible in particular appear cystlike in appearance. It is often necessary to obtain a biopsy and evaluate the tissue under a microscope to accurately identify the lesion.
Treatment
The infected tissue of the periapical cyst must be entirely removed, including the epithelium of the cyst wall; otherwise, a relapse is likely to occur. Root canal treatment should be performed on the tooth if it is determined that previous therapy was unsuccessful. Removal of the necrotic pulp and the inflamed tissue as well as proper sealing of the canals and an appropriately fitting crown will allow the tooth to heal under uninfected conditions.Surgical options for previously treated teeth that would not benefit from root canal therapy include cystectomy and cystostomy. This route of treatment is recommended upon discovery of the cyst after inadequate root canal treatment. A cystectomy is the removal of a cyst followed by mucosa and wound closure to reduce chances of cyst regeneration. This type of treatment is more ideal for small cysts.
A cystostomy is recommended for larger cysts that compromise important adjacent anatomy. The cyst is tamponaded to allow for the cyst contents to escape the bone. Over time, the cyst decreases in size and bone regenerates in the cavity space.
Marsupialization could also be performed, which involves suturing the edges of the gingiva surrounding the cyst to remain open. The cyst then drains its contents and heal without being prematurely closed. The end result is the same as the cystostomy, bone regeneration. For both a cystostomy and marsupialization, root resectioning may also be required in cases where root resorption has occurred.
Epidemiology
Periapical cysts comprise approximately 75% of the types of cysts found in the oral region. The ratio of individuals diagnosed with periapical cysts is 3:2 male to female, as well as individuals between 20 and 60 years old. Periapical cysts occur worldwide.
Types of Periapical cysts:
Apical: 70%
Lateral: 20%
Residual: 10%
References
== External links == |
Autoimmune neutropenia | Autoimmune neutropenia (AIN) is a form of neutropenia which is most common in infants and young children where the body identifies the neutrophils as enemies and makes antibody to destroy them.
Primary autoimmune neutropenia, another name for autoimmune neutropenia, is an autoimmune disease first reported in 1975 that primarily occurs in infancy. In autoimmune neutropenia, the immune system produces autoantibodies directed against the neutrophilic protein antigens in white blood cells known as granulocytic neutrophils, granulocytes, segmented neutrophils, segs, polysegmented neutrophils, or polys. These antibodies, IgG antibodies, destroy granulocytic neutrophils. Consequently, patients with autoimmune neutropenia have low levels of granulocytic neutrophilic white blood cells causing a condition of neutropenia. Neutropenia causes an increased risk of infection from organisms that the body could normally fight easily.
Primary autoimmune neutropenia has been reported as early as the second month of life although most cases are diagnosed in children between 5 and 15 months of age. Girls have a slightly higher risk of developing AIN than boys as well as do people of Caucasian background. In neutropenia discovered at birth or shortly after birth, a diagnosis of allo-immune neutropenia (from maternal white blood cell antibodies passively transferred to the infant) is more likely.
In infants neutropenia is defined by absolute neutrophil counts less than 1000/uL. After the first year of life neutropenia is defined by absolute counts less than 1500/uL. Neutropenia may be primary in which it is the only blood abnormality seen. In secondary neutropenia, other primary conditions occur, including other autoimmune diseases, infections, and cancers. Neutropenia is considered chronic when it persists for more than 6 months.
Signs and symptoms
Neutropenia, which may be discovered on routine blood tests, typically causes benign infections even when the condition is severe. Ear infections (otitis media) are the most common infection seen in autoimmune neutropenia and typically infection responds to antibiotic treatment alone. Infections associated with primary AIN are usually mild and limited, including skin infections such as impetigo, gastroenteritis, upper respiratory tract infections, and ear infections. Rarely, cellulitis and abscesses may occur.
Studies of children studied for up to six years showed that most cases of autoimmune neutropenia resolved spontaneously after a median of 17 months. In 95 percent of patients, neutropenia persisted for 7 to 24 months.
Diagnosis
The diagnosis of autoimmune neutropenia is based on blood tests demonstrating neutropenia and the presence of granulocyte-specific antibodies. In some cases, tests for granulocyte-specific antibodies must be repeated several times before a positive result is seen. Bone marrow aspiration, if performed, is typically normal or it can show increased cell production with a variably diminished number of segmented granulocytes.An association with prior parvovirus B19 has been made, but this hasn’t been confirmed.
Treatment
Treatment consists of corticosteroids to reduce autoantibody production and antibiotics to prevent infection.
Granulocyte colony-stimulating factor (G-CSF) is recommended to temporarily increase neutrophil counts in patients with absolute neutrophil counts (ANC) of less than 0.5 x 109/l and recurrent fever or infections.In cases of severe infection or the need for surgery, intravenous immunoglobulin therapy may be used.
Prognosis
This form of neutropenia disappears in two to three years of a childs life in 95% of cases.The use of prophylactic antibiotics has been successfully demonstrated to reduce infection incidence without causing adverse effects among the 5% of children whose condition does not resolve itself.
References
== External links == |
Knuckle pads | Knuckle pads (also known as "Heloderma", meaning similar to the skin of the Gila monster lizard for which it is named) are circumscribed, keratotic, fibrous growths over the dorsa of the interphalangeal joints. They are described as well-defined, round, plaque-like, fibrous thickening that may develop at any age, and grow to be 10 to 15mm in diameter in the course of a few weeks or months, then go away over time.Knuckle pads are sometimes associated with Dupuytrens contracture and camptodactyly,: 595 and histologically, the lesions are fibromas.: 595 Knuckle pads are generally non-responsive to treatment, including corticosteroids, and tend to recur after surgery; however, there has been some effectiveness with intralesional fluorouracil.
See also
Skin lesion
List of cutaneous conditions
Garrods pad
References
Further reading
Guberman D; et al. (1996). ""Knuckle pads-a forgotten skin condition " report of a case and review of the literature". Cutis. 57 (4): 241–242. PMID 8727774.
Ly Y; et al. (2003). "A novel mutation of keratin 9 in epidermolytic palmoplantar keratoderma combined with knuckle pads". Am J Med Genet. 120A (3): 345–9. doi:10.1002/ajmg.a.20090. PMID 12838553.
Peterson CM; et al. (2000). "Knuckle pads: does knuckle cracking play an etiologic role?". Pediatr Dermatol. 17 (6): 450–2. doi:10.1046/j.1525-1470.2000.01819.x. PMID 11123776.
== External links == |
Antisynthetase syndrome | Anti-synthetase syndrome is an autoimmune disease associated with interstitial lung disease, dermatomyositis, and polymyositis.
Signs and symptoms
As a syndrome, this condition is poorly defined. Diagnostic criteria require one or more antisynthetase antibodies (which target tRNA synthetase enzymes), and one or more of the following three clinical features: interstitial lung disease, inflammatory myopathy, and inflammatory polyarthritis affecting small joints symmetrically. Other supporting features may include fever, Raynauds phenomenon and "mechanics hands"-thick, cracked skin usually on the palms and radial surfaces of the digits.The disease, rare as it is, is more prevalent in women than in men. Early diagnosis is difficult, and milder cases may not be detected. Also, interstitial lung disease may be the only manifestation of the disease. Severe disease may develop over time, with intermittent relapses.
Pathogenesis
It is postulated that autoantibodies are formed against aminoacyl-tRNA synthetases. The synthethases may be involved in recruiting antigen-presenting and inflammatory cells to the site of muscle or lung injury. The specific molecular pathway of the process awaits elucidation.
Antisynthetase antibodies
The most common antibody is "Anti-Jo-1" named after John P, a patient with polymyositis and interstitial lung disease detected in 1980. This anti-histidyl tRNA Synthetase antibody is commonly seen in patients with pulmonary manifestations of the syndrome.
The following are other possible antibodies that may be seen in association with antisynthetase syndrome: Anti-PL-7, Anti-PL-12, Anti-EJ, Anti-OJ, Anti-KS, Anti-Zo, Anti-Ha-YRS, and Anti-SRP.
Diagnosis
In the presence of suspicious symptoms a number of test are helpful in the diagnosis:
Muscle enzymes are often elevated, i.e. creatine kinase
Anti-Jo-1 antibody testing
Electromyography
Muscle biopsy
Pulmonary function testing
Lung biopsy
Imaging such as High Resolution computed tomography In certain situations, testing of other antibodies, specific imaging (MRI, thoracic high resolution computed tomography), and swallowing evaluation may be needed.
Treatment
Unfortunately, treatment for the anti-synthetase syndrome is limited, and usually involves immunosuppressive drugs such as glucocorticoids. For patients with pulmonary involvement, the most serious complication of this syndrome is pulmonary fibrosis and subsequent pulmonary hypertension.Additional treatment with azathioprine and/or methotrexate may be required in advanced cases.
Prognosis
Prognosis is largely determined by the extent of pulmonary damage.
References
== External links == |
Aggressive fibromatosis | Aggressive fibromatosis or desmoid tumor is a rare condition. Desmoid tumors arise from cells called fibroblasts, which are found throughout the body and provide structural support, protection to the vital organs, and play a critical role in wound healing. These tumors tend to occur in women in their thirties, but can occur in anyone at any age. They can be either relatively slow-growing or malignant. However, aggressive fibromatosis is locally aggressive and can cause life-threatening problems or even death when they compress vital organs such as intestines, kidneys, lungs, blood vessels, or nerves. Most cases are sporadic, but some are associated with familial adenomatous polyposis (FAP). Approximately 10% of individuals with Gardners syndrome, a type of FAP with extracolonic features, have desmoid tumors.The World Health Organization reclassified desmoid tumors (termed desmoid-type fibromatosis) as a specific type of tumor in the category of intermediate (locally aggressive) fibroblastic and myofibroblastic tumors.Histologically they resemble very low-grade fibrosarcomas, but they are very locally aggressive and tend to recur even after complete resection. There is a tendency for recurrence in the setting of prior surgery; in one study, two-thirds of patients with desmoid tumors had a history of prior abdominal surgery.
Risk factor
Risk factors for desmoid disease amongst FAP patients include female sex, a 3 APC mutation, a positive family history, and a history of previous abdominal surgery.
Diagnosis
Classification
Desmoid tumors may be classified as extra-abdominal, abdominal wall, or intra-abdominal (the last is more common in patients with FAP). It is thought that the lesions may develop in relation to estrogen levels or trauma/operations.A 3 APC mutation is the most significant risk factor for intra-abdominal desmoid development amongst FAP patients. FAP patients presenting with an abdominal wall desmoid pre-operatively are at an increased risk of developing an intra-abdominal desmoid post-operatively.Desmoid tumours of the breast are rare. Although benign, they can mimic breast cancer
on physical examination, mammography and breast ultrasound and can also be locally invasive. Even
though they occur sporadically, they can also be seen as a part of Gardners syndrome. A high index of suspicion and a thorough triple examination protocol is necessary to detect rare lesions like a desmoid tumour which can masquerade as breast carcinoma. Desmoid tumour of the breast may present a difficulty in the diagnosis especially where imaging studies are not conclusive and suggest a more ominous diagnosis.
Treatment
Treatment may consist of watchful waiting, complete surgical removal, radiation therapy, antiestrogens (e.g. Tamoxifen), NSAIDs, chemotherapy, or ablation (cold, heat, ultrasound). Treatment with oral tyrosine kinase inhibitor drugs (e.g. imatinib, sorafenib, pazopanib) show promising success rates.Patients with desmoid tumors should be evaluated by a multi-disciplinary team of surgeons, medical oncologists, radiation oncologists, and geneticists. There is no cure for desmoid tumors; when possible, patients are encouraged to enlist in clinical trials.A biopsy is always indicated as the definitive method to determine nature of the tumour. Management of these lesions is complex, the main problem being the high rates of recurrence in FAP associated disease. Conversely, for intra-abdominal fibromatosis without evidence of FAP, although extensive surgery may still be required for local symptoms, the risk of recurrence appears to be lower. Wide surgical resection with clear margins is the most widely practiced technique with radiation, chemotherapy, or hormonal therapy being used to reduce the risk of recurrence.Intestinal transplant is a treatment option for those patients with complicated desmoid tumor, such as those involving the mesenteric root, or those with intestinal failure resulting from the tumor or prior interventions.
References
== External links == |
Copper deficiency | Copper deficiency, or hypocupremia, is defined either as insufficient copper to meet the needs of the body, or as a serum copper level below the normal range. Symptoms may include fatigue, decreased red blood cells, early greying of the hair, and neurological problems presenting as numbness, tingling, muscle weakness, and ataxia. The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback". Copper deficiency can manifest in parallel with vitamin B12 and other nutritional deficiencies.
Overview
The most common cause of copper deficiency is a remote gastrointestinal surgery, such as gastric bypass surgery, due to malabsorption of copper, or zinc toxicity. On the other hand, Menkes disease is a genetic disorder of copper deficiency involving a wide variety of symptoms that is often fatal.Copper is required for the functioning of many enzymes, such as cytochrome c oxidase, which is complex IV in the mitochondrial electron transport chain, ceruloplasmin, Cu/Zn superoxide dismutase, and in amine oxidases. These enzyme catalyze reactions for oxidative phosphorylation, iron transportation, antioxidant and free radical scavenging and neutralization, and neurotransmitter synthesis, respectively. Diets vary in the amount of copper they contain, but may provide about 5 mg/day, of which only 20-50% is absorbed. The diet of the elderly may have a lower copper content than the recommended daily intake. Dietary copper can be found in whole grain cereals, legumes, oysters, organ meats (particularly liver), cherries, dark chocolate, fruits, leafy green vegetables, nuts, poultry, prunes, and soybean products like tofu.Copper deficiency can have many hematological consequences, such as myelodysplasia, anemia, low white blood cell count, and low count of neutrophils (a type of white blood cell that is often called "the first line of defense" of the immune system). Copper deficiency has long been known as a cause of myelodysplasia (when a blood profile has indicators of possible future leukemia development), but it was not until 2001 that copper deficiency was associated with neurological manifestations like sensory ataxia (irregular coordination due to proprioceptive loss), spasticity, muscle weakness, and more rarely visual loss due to damage in the peripheral nerves, myelopathy (disease of the spinal cord), and rarely optic neuropathy.
Signs and symptoms
Blood symptoms
The characteristic hematological (blood) effects of copper deficiency are anemia (which may be microcytic, normocytic or macrocytic) and neutropenia. Thrombocytopenia (low blood platelets) is unusual.The peripheral blood and bone marrow aspirate findings in copper deficiency can mimic myelodysplastic syndrome. Bone marrow aspirate in both conditions may show dysplasia of blood cell precursors and the presence of ring sideroblasts (erythroblasts containing multiple iron granules around the nucleus). Unlike most cases of myelodysplastic syndrome, the bone marrow aspirate in copper deficiency characteristically shows cytoplasmic vacuoles within red and white cell precursors, and karyotyping in cases of copper deficiency does not reveal cytogenetic features characteristic of myelodysplastic syndrome.Anemia and neutropenia typically resolve within six weeks of copper replacement.
Neurological symptoms
Copper deficiency can cause a wide variety of neurological problems including myelopathy, peripheral neuropathy, and optic neuropathy.
Myelopathy
Copper deficiency myelopathy in humans was discovered and first described by Schleper and Stuerenburg in 2001. They described a patient with a history of gastrectomy and partial colonic resection who presented with severe tetraparesis and painful paraesthesias and who was found on imaging to have dorsomedial cervical cord T2 hyperintensity. Upon further analysis, it was found that the patient had decreased levels of serum coeruloplasmin, serum copper, and CSF copper. The patient was treated with parenteral copper and the patients paraesthesias did resolve. Since this discovery, there has been heightened and increasing awareness of copper-deficiency myelopathy and its treatment, and this disorder has been reviewed by Kumar.
Patients typically present difficulty walking (gait difficulty) caused by sensory ataxia (irregular muscle coordination) due to dorsal column dysfunction or degeneration of the spinal cord (myelopathy). Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing sideways jerks and lunges.In brain MRI, there is often an increased T2 signalling at the posterior columns of the spinal cord in patients with myelopathy caused by copper deficiency. T2 signalling is often an indicator of some kind of neurodegeneration. There are some changes in the spinal cord MRI involving the thoracic cord, the cervical cord or sometimes both. Copper deficiency myelopathy is often compared to subacute combined degeneration (SCD). Subacute combined degeneration is also a degeneration of the spinal cord, but instead vitamin B12 deficiency is the cause of the spinal degeneration. SCD also has the same high T2 signalling intensities in the posterior column as copper deficient patient in MRI imaging.
Peripheral neuropathy
Another common symptom of copper deficiency is peripheral neuropathy, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso. In an Advances in Clinical Neuroscience & Rehabilitation (ACNR) published case report, a 69-year-old patient had progressively worsened neurological symptoms. These symptoms included diminished upper limb reflexes with abnormal lower limb reflexes, sensation to light touch and pin prick was diminished above the waist, vibration sensation was lost in the sternum, and markedly reduced proprioception or sensation about the selfs orientation. Many people with the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient. This numbness and tingling poses danger for the elderly because it increases their risk of falling and injuring themselves. Peripheral neuropathy can become very disabling leaving some patients reliant on wheelchairs or walking canes for mobility if there is a lack of correct diagnosis. Rarely can copper deficiency cause major disabling symptoms. The deficiency will have to be present for an extensive amount of time until such disabling conditions manifest.
Optic neuropathy
Some patients with copper deficiency have shown signs of vision and color loss. The vision is usually lost in the peripheral views of the eye. The bilateral vision loss is usually very gradual. An optical coherence tomography (OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary to optic neuropathy or neurodegeneration.
Causes
Surgery
Bariatric surgery is a common cause of copper deficiency. Bariatric surgery, such as gastric bypass surgery, is often used for weight control of the morbidly obese. The disruption of the intestines and stomach from the surgery can cause absorption difficulties not only as regards copper but also for iron and vitamin B12 and many other nutrients. The symptoms of copper deficiency myelopathy may take up to decades to develop.
Zinc toxicity
Increased consumption of zinc is another cause of copper deficiency. Zinc is often used for the prevention or treatment of common colds and sinusitis (inflammation of sinuses due to an infection), ulcers, sickle cell disease, celiac disease, memory impairment, and acne. Zinc is found in many common vitamin supplements and is also found in denture creams. Recently, several cases of copper deficiency myeloneuropathy were found to be caused by prolonged use of denture creams containing high quantities of zinc. A literature review found two cases of copper deficiency myelopathy secondary to parenteral zinc supplementation during chronic dialysis.Metallic zinc is the core of all United States currency coins, including copper-coated pennies. People who ingest a large number of coins will have elevated zinc levels, leading to zinc-toxicity-induced copper deficiency and the associated neurological symptoms. This was the case for a 57-year-old woman diagnosed with schizophrenia. The woman consumed over 600 coins, and started to show neurological symptoms such as unsteady gait and mild ataxia.
Hereditary disorders
Menkes disease is a congenital disease that is a cause of copper deficiency. Menkes disease is a hereditary condition caused by a defective gene involved with the metabolism of copper in the body. Menkes disease involves a wide variety of symptoms including floppy muscle tone, seizures, abnormally low temperatures, and a peculiar steel color hair that feels very rough. Menkes disease is usually a fatal disease with most children dying within the first ten years of life.
Other
It is rarely suggested that excess iron supplementation causes copper deficiency myelopathy.
Another rarer cause of copper deficiency is celiac disease, probably due to malabsorption in the intestines.
Still, a large percentage, around 20%, of cases have unknown causes.
Pathophysiology
Copper functions as a prosthetic group, which permits electron transfers in key enzymatic pathways like the electron transport chain. Copper is integrated in the enzymes cytochrome c oxidase, which is involved in cellular respiration and oxidative phosphorylation, Cu/Zn dismutase, which is involved in antioxidant defense, and many more listed in the table below.
Neurological
Cytochrome c oxidase
There have been several hypotheses about the role of copper and some of its neurological manifestations. Some suggest that disruptions in cytochrome c oxidase, also known as Complex IV, of the electron transport chain is responsible for the spinal cord degeneration.
Methylation cycle
Another hypothesis is that copper deficiency myelopathy is caused by disruptions in the methylation cycle. The methylation cycle causes a transfer of a methyl group (-CH3) from methyltetrahydrofolate to a range of macromolecules by the suspected copper dependent enzyme methionine synthase. This cycle is able to produce purines, which are a component of DNA nucleotide bases, and also myelin proteins. The spinal cord is surrounded by a layer of protective protein coating called myelin (see figure). When this methionine synthase enzyme is disrupted, the methylation decreases and myelination of the spinal cord is impaired. This cycle ultimately causes myelopathy.
Hematological cause
Iron transportation
The anemia caused by copper deficiency is thought to be caused by impaired iron transport. Hephaestin is a copper containing ferroxidase enzyme located in the duodenal muscosa that oxidizes iron and facilitates its transfer across the basolateral membrane into circulation. Another iron transporting enzyme is ceruloplasmin. This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma. Ceruloplasmin also oxidizes iron from its ferrous state to the ferric form that is required for iron binding. Impairment in these copper dependent enzymes that transport iron may cause the secondary iron deficiency anemia. Another speculation for the cause of anemia is involving the mitochondrial enzyme cytochrome c oxidase (complex IV in the electron transport chain). Studies have shown that animal models with impaired cytochrome c oxidase failed to synthesize heme from ferric iron at the normal rate. The lower rate of the enzyme might also cause the excess iron to clump, giving the heme an unusual pattern. This unusual pattern is also known as ringed sideroblastic anemia cells.
Cell growth halt
The cause of neutropenia is still unclear; however, the arrest of maturing myelocytes, or neutrophil precursors, may cause the neutrophil deficiency.
Zinc intoxication
Zinc intoxication may cause anemia by blocking the absorption of copper from the stomach and duodenum. Zinc also upregulates the expression of chelator metallothionein in enterocytes, which are the majority of cells in the intestinal epithelium. Since copper has a higher affinity for metallothionein than zinc, the copper will remain bound inside the enterocyte, which will be later eliminated through the lumen. This mechanism is exploited therapeutically to achieve negative balance in Wilsons disease, which involves an excess of copper.
Diagnosis
The diagnosis of copper deficiency may be supported by a persons report of compatible signs and symptoms, findings from a thorough physical examination, and supportive laboratory evidence. Low levels of copper and ceruloplasmin in the serum are consistent with the diagnosis as is a low 24 hour urine copper level. Additional supportive bloodwork findings also include neutropenia and anemia. MRI imaging may demonstrate increased T2 signal of the dorsal column–medial lemniscus pathways.
Treatment
Copper deficiency is a very rare disease and is often misdiagnosed several times by physicians before concluding the deficiency of copper through differential diagnosis (copper serum test and bone marrow biopsy are usually conclusive in diagnosing copper deficiency). On average, patients are diagnosed with copper deficiency around 1.1 years after their first symptoms are reported to a physician.
Copper deficiency can be treated with either oral copper supplementation or intravenous copper. If zinc intoxication is present, discontinuation of zinc may be sufficient to restore copper levels back to normal, but this usually is a very slow process. People with zinc intoxication will usually have to take copper supplements in addition to ceasing zinc consumption. Hematological manifestations are often quickly restored back to normal. The progression of the neurological symptoms will be stopped and sometimes improved with appropriate treatment, but residual neurological disability is common.
See also
Copper in health
Copper deficiency and excess health conditions (non-genetic)
References
== External links == |
Monocephalus | Monocephalus is a genus of dwarf spiders that was first described by F. P. Smith in 1906.
Species
As of May 2019 it contains two species:
Monocephalus castaneipes (Simon, 1884) – Europe
Monocephalus fuscipes (Blackwall, 1836) (type) – Europe
See also
List of Linyphiidae species (I–P)
== References == |
Osteochondropathy | Osteochondropathy refers to a disease ("-pathy") of the bone and cartilage.
However, it is more common to refer to these conditions as one of the following:
chondropathy (disease of the cartilage)
A bone disease is also called an "osteopathy", but because the term osteopathy is often used to describe a healthcare approach, use of the term can cause some confusion.
See also
Osteochondrosis
Osteochondritis
References
== External links == |
Neurasthenia | Neurasthenia (from the Ancient Greek νεῦρον neuron "nerve" and ἀσθενής asthenés "weak") is a term that was first used at least as early as 1829 for a mechanical weakness of the nerves and became a major diagnosis in North America during the late nineteenth and early twentieth centuries after neurologist George Miller Beard reintroduced the concept in 1869.
As a psychopathological term, the first to publish on neurasthenia was Michigan alienist E. H. Van Deusen of the Kalamazoo asylum in 1869, followed a few months later by New York neurologist George Beard, also in 1869, to denote a condition with symptoms of fatigue, anxiety, headache, heart palpitations, high blood pressure, neuralgia, and depressed mood. Van Deusen associated the condition with farm wives made sick by isolation and a lack of engaging activity, while Beard connected the condition to busy society women and overworked businessmen.
Neurasthenia was a diagnosis in the World Health Organizations ICD-10, but is no more diagnosed in ICD-11, marked as deprecated. It also is no longer included as a diagnosis in the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders. The condition is, however, described in the Chinese Society of Psychiatrys Chinese Classification of Mental Disorders.
Americans were said to be particularly prone to neurasthenia, which resulted in the nickname "Americanitis" (popularized by William James). Another, rarely used, term for neurasthenia is nervosism.
Symptoms
The condition was explained as being a result of exhaustion of the central nervous systems energy reserves, which Beard attributed to modern civilization. Physicians in the Beard school of thought associated neurasthenia with the stresses of urbanization and with stress suffered as a result of the increasingly competitive business environment. Typically, it was associated with upper class people and with professionals working in sedentary occupations, but really can apply to anyone who lives within the monetary system.
Freud included a variety of physical symptoms into this category, including fatigue, dyspepsia with flatulence, and indications of intra-cranial pressure and spinal irritation. In common with some other people of the time, he believed this condition to be due to "non-completed coitus" or the non-completion of the higher cultural correlate thereof, or to "infrequency of emissions" or the infrequent practice of the higher cultural correlate thereof. Later, Freud formulated that in cases of coitus interruptus as well as in cases of masturbation, there was "an insufficient libidinal discharge" that had a poisoning effect on the organism, in other words, neurasthenia was the result of (auto‑)intoxication. Eventually he separated it from anxiety neurosis, though he believed that a combination of the two conditions existed in many cases.In 19th-century Britain and, by extension, across the British Empire, neurasthenia was also used to describe mental exhaustion or fatigue in “brain workers” or in the context of “overstudy”. This use was often synonymous with the term “brain fag”.
Diagnosis
From 1869, neurasthenia became a "popular" diagnosis, expanding to include such symptoms as weakness, dizziness and fainting. A common treatment promoted by neurologist S. Weir Mitchell was the rest cure, especially for women. Data from this period gleaned from the Annual Reports of Queen Square Hospital, London, indicates that the diagnosis was balanced between the sexes and had a presence within Europe. Virginia Woolf was known to have been forced to have rest cures, which she describes in her book On Being Ill. Charlotte Perkins Gilmans protagonist in The Yellow Wallpaper also suffers under the auspices of rest cure doctors, much as Gilman herself did. Marcel Proust was said to suffer from neurasthenia. To capitalize on this epidemic, the Rexall drug company introduced a medication called Americanitis Elixir which claimed to be a soother for any bouts related to neurasthenia.
Treatment
Beard, with his partner A.D. Rockwell, advocated first electrotherapy and then increasingly experimental treatments for people with neurasthenia, a position that was controversial. An 1868 review posited that Beards and Rockwells knowledge of the scientific method was suspect and did not believe their claims to be warranted.
William James was diagnosed with neurasthenia, which he nicknamed Americanitis, and was quoted as saying, "I take it that no man is educated who has never dallied with the thought of suicide."In 1895, Sigmund Freud reviewed electrotherapy and declared it a "pretense treatment." He emphasized the example of Elizabeth von Rs note that "the stronger these were the more they seemed to push her own pains into the background."
Nevertheless, neurasthenia was a common diagnosis during World War I for "shell shock", but its use declined a decade later. Soldiers who deserted their post could be executed even if they had a medical excuse, but officers who had neurasthenia were not executed.
Current opinion
This concept remained popular well into the 20th century, eventually coming to be seen as a behavioural rather than physical condition, with a diagnosis that excluded postviral syndromes. Neurasthenia has largely been abandoned as a medical diagnosis. The ICD-10 system of the World Health Organization categorizes neurasthenia under "F48 - Other neurotic disorders".One modern opinion of neurasthenia is that it was actually dysautonomia, an "imbalance" of the autonomic nervous system.Barbara Ehrenreich, restating Jamess view, considers that neurasthenia was caused by the Calvinist gloom, and it was helped by the New Thought, through replacing the "puritanical demand for perpetual effort and self-examination to the point of self-loathing" with a more hopeful faith.
In Asia
The medical term neurasthenia is translated as Chinese shenjing shuairuo (simplified Chinese: 神经衰弱; traditional Chinese: 神經衰弱; pinyin: shénjīng shuāiruò; Cantonese Yale: sàhngīng sēuiyeuhk) or Japanese shinkei-suijaku (神経衰弱), both of which also translate the common term nervous breakdown. This loanword combines shenjing (神經) or shinkei (神経) "nerve(s); nervous" and shuairuo or suijaku (衰弱) "weakness; feebleness; debility; asthenia".
Despite being omitted by the American Psychiatric Associations DSM in 1980, neurasthenia is listed in an appendix as the culture-bound syndrome shenjing shuairuo as well as appearing in the ICD-10. The condition is thought to persist in Asia as a culturally acceptable diagnosis that avoids the social stigma of a diagnosis of mental disorder.
In Japan, shinkei-suijaku is treated with Morita therapy involving mandatory rest and isolation, followed by progressively more difficult work, and a resumption of a previous social role. The diagnosis is sometimes used as a disguise for serious mental illnesses such as schizophrenia and mood disorders.In China, traditional Chinese medicine describes shenjingshuairuo as a depletion of qi "vital energy" and reduction of functioning in the wuzang "five internal organs" (heart, liver, spleen, lungs, kidneys). The modern CCMD classifies it as a persistent mental disorder diagnosed with three of these five symptoms: "weakness symptoms, emotional symptoms, excitement symptoms, tension-induced pain, and sleep disturbances" not caused by other conditions. Arthur Kleinman described Chinese neurasthenia as a "biculturally patterned illness experience (a special form of somatization), related to depression or other diseases or to culturally sanctioned idioms of distress and psychosocial coping."
See also
Combat stress reaction
Newyorkitis
Placebo effect
Psychogenic disease
References
Further reading
Brown, EM (1980). "An American Treatment for the American Nervousness". American Association of the History of Medicine. Archived from the original on 2008-09-07. Retrieved 2008-09-11.
Gijswijt-Hofstra, Marijke (2001). Cultures of Neurasthenia: From Beard to the First World War (Clio Medica 63) (Clio Medica). Rodopi Bv Editions. ISBN 978-90-420-0931-8.
Gosling, F. G. Before Freud: Neurasthenia and the American Medical Community, 1870-1910. Urbana: University of Illinois Press, 1987.
Weir Mitchell, S (1884). Fat and Blood: an essay on the treatment of certain types of Neurasthenia and hysteria. Philadelphia: J. D. Lippincott & Co. Retrieved 2008-09-11.
Farmer A, Jones I, Hillier J, Llewelyn M, Borysiewicz L, Smith A (October 1995). "Neuraesthenia revisited: ICD-10 and DSM-III-R psychiatric syndromes in chronic fatigue patients and comparison subjects". Br J Psychiatry. 167 (4): 503–6. doi:10.1192/bjp.167.4.503. PMID 8829720. S2CID 45684552.
Schuster, David G. Neurasthenic Nation: Americas Search for Health, Comfort, and Happiness, 1869-1920. New Brunswick, NJ: Rutgers University Press, 2011.
Lutz, Tom. American Nervousness, 1903. Ithaca, NY: Cornell University Press, 1991.
== External links == |
Orthostatic purpura | Orthostatic purpura is a skin condition that results from prolonged standing or even sitting with the legs lowered (as in a bus, airplane, or train), which produced edema and a purpuric eruption on the lower extremities.: 827
See also
Skin lesion
== References == |
Congenital stationary night blindness | Congenital stationary night blindness (CSNB) is a rare non-progressive retinal disorder. People with CSNB often have difficulty adapting to low light situations due to impaired photoreceptor transmission. These patients may also have reduced visual acuity, myopia, nystagmus, and strabismus. CSNB has two forms -- complete, also known as type-1 (CSNB1), and incomplete, also known as type-2 (CSNB2), which are distinguished by the involvement of different retinal pathways. In CSNB1, downstream neurons called bipolar cells are unable to detect neurotransmission from photoreceptor cells. CSNB1 can be caused by mutations in various genes involved in neurotransmitter detection, including NYX. In CSNB2, the photoreceptors themselves have impaired neurotransmission function; this is caused primarily by mutations in the gene CACNA1F, which encodes a voltage-gated calcium channel important for neurotransmitter release. CSNB has been identified in horses and dogs as the result of mutations in TRPM1 (Horse, "LP"), GRM6 (Horse, "CSNB2"), and LRIT3 (Dog, CSNB).
Congenital stationary night blindness (CSNB) can be inherited in an X-linked, autosomal dominant, or autosomal recessive pattern, depending on the genes involved.
Two forms of CSNB can also affect horses, one linked to the leopard complex of equine coat colors and the other found in certain horse breeds. Both are autosomal recessives.
Symptoms and signs
The X-linked varieties of congenital stationary night blindness (CSNB) can be differentiated from the autosomal forms by the presence of myopia, which is typically absent in the autosomal forms. Patients with CSNB often have impaired night vision, myopia, reduced visual acuity, strabismus and nystagmus. Individuals with the complete form of CSNB (CSNB1) have highly impaired rod sensitivity (reduced ~300x) as well as cone dysfunction. Patients with the incomplete form can present with either myopia or hyperopia.
Cause
CSNB is caused by malfunctions in neurotransmission from rod and cone photoreceptors to bipolar cells in the retina. At this first synapse, information from photoreceptors is divided into two channels: ON and OFF. The ON pathway detects light onset, while the OFF pathway detects light offset. The malfunctions in CSNB1 specifically affect the ON pathway, by hindering the ability of ON-type bipolar cells to detect neurotransmitter released from photoreceptors. Rods, which are responsible for low-light vision, make contacts with ON-type bipolar cells only, while, cones, which are responsible for bright-light vision, make contacts with bipolar cells of both ON an OFF subtypes. Because the low-light sensing rods feed only into the ON pathway, individuals with CSNB1 typically have problems with night vision, while vision in well-lit conditions is spared. In CSNB2, release of neurotransmitter from photoreceptors is impaired, leading to involvement of both ON and OFF pathways.
The electroretinogram (ERG) is an important tool for diagnosing CSNB. The ERG a-wave, which reflects the function of the phototransduction cascade in response to a light flashes, is typically normal in CSNB patients, although in some cases phototransduction is also affected, leading to a reduced a-wave. The ERG b-wave, which primarily reflects the function of ON-bipolar cells, is greatly reduced in CSNB2 cases, and completely absent in CSNB1 cases.
Genetics
Only three rhodopsin mutations have been found associated with congenital stationary night blindness (CSNB). Two of these mutations are found in the second transmembrane helix of rhodopsin at Gly-90 and Thr-94. Specifically, these mutations are the Gly90Asp and the Thr94Ile, which has been the most recent one reported. The third mutation is Ala292Glu, and it is located in the seventh transmembrane helix, in proximity to the site of retinal attachment at Lys-296. Mutations associated with CSNB affect amino acid residues near the protonated Schiff base (PSB) linkage. They are associated with changes in conformational stability and the protonated status of the PSB nitrogen.
Pathophysiology
CSNB1
The complete form of X-linked congenital stationary night blindness, also known as nyctalopia, is caused by mutations in the NYX gene (Nyctalopin on X-chromosome), which encodes a small leucine-rich repeat (LRR) family protein of unknown function. This protein consists of an N-terminal signal peptide and 11 LRRs (LRR1-11) flanked by cysteine-rich LRRs (LRRNT and LRRCT). At the C-terminus of the protein there is a putative GPI anchor site. Although the function of NYX is yet to be fully understood, it is believed to be located extracellularly. A naturally occurring deletion of 85 bases in NYX in some mice leads to the "nob" (no b-wave) phenotype, which is highly similar to that seen in CSNB1 patients. NYX is expressed primarily in the rod and cone cells of the retina. There are currently almost 40 known mutations in NYX associated with CSNB1, Table 1., located throughout the protein. As the function of the nyctalopin protein is unknown, these mutations have not been further characterized. However, many of them are predicted to lead to truncated proteins that, presumably, are non-functional.
CSNB2
The incomplete form of X-linked congenital stationary night blindness (CSNB2) is caused by mutations in the CACNA1F gene, which encodes the voltage-gated calcium channel CaV1.4 expressed heavily in retina. One of the important properties of this channel is that it inactivates at an extremely low rate. This allows it to produce sustained Ca2+ entry upon depolarization. As photoreceptors depolarize in the absence of light, CaV1.4 channels operate to provide sustained neurotransmitter release upon depolarization. This has been demonstrated in CACNA1F mutant mice that have markedly reduced photoreceptor calcium signals. There are currently 55 mutations in CACNA1F located throughout the channel, Table 2 and Figure 1. While most of these mutations result in truncated and, likely, non-functional channels, it is expected that they prevent the ability of light to hyperpolarize photoreceptors. Of the mutations with known functional consequences, 4 produce channels that are either completely non-functional, and two that result in channels which open at far more hyperpolarized potentials than wild-type. This will result in photoreceptors that continue to release neurotransmitter even after light-induced hyperpolarization.
Diagnosis
Footnotes
External links
GeneReview/NCBI/NIH/UW entry on X-Linked Congenital Stationary Night Blindness |
Subsets and Splits