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Exencephaly | Exencephaly is a type of cephalic disorder wherein the brain is located outside of the skull. This condition is usually found in embryos as an early stage of anencephaly. As an exencephalic pregnancy progresses, the neural tissue gradually degenerates.The prognosis for infants born with exencephaly is extremely poor. It is rare to find an infant born with exencephaly, as most cases that are not early stages of anencephaly are usually stillborn. Those infants who are born with the condition usually die within hours or minutes. Caused by the failure of cranial neuropore to properly fuse, between the 3rd and 4th week post conception. The calvarium doesnt develop/fuse properly, therefore the brain extrudes from the cranium.
Pathophysiology
Until recently, the medical literature did not indicate a connection among many genetic disorders, both genetic syndromes and genetic diseases, that are now being found to be related. As a result of new genetic research, some of these are, in fact, highly related in their root cause despite the widely varying set of medical symptoms that are clinically visible in the disorders. Exencephaly is one disease that has recently been identified as part of an emerging class of diseases called cilopathies. The underlying cause may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cell types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.
See also
Anencephaly
Notes
External links
NINDS Overview
Obgyn.net |
Lymphangiosarcoma | Lymphangiosarcoma is a rare cancer which occurs in long-standing cases of primary or secondary lymphedema. It involves either the upper or lower lymphedematous extremities but is most common in upper extremities. Although its name implies lymphatic origin, it is believed to arise from endothelial cells and may be more accurately referred to as angiosarcoma.
Signs and symptoms
Lymphangiosarcoma may present as a purple discoloration or a tender skin nodule in the extremity, typically on the anterior surface. It progresses to an ulcer with crusting to an extensive necrotic focus involving the skin and subcutaneous tissue. It metastasizes quickly.
Causes
It was previously a relatively common complication of the massive lymphedema of the arm which followed removal of axillary (arm pit) lymph nodes and lymphatic channels as part of the classical Halstedian radical mastectomy, as a treatment for breast cancer. The classical radical mastectomy was abandoned in most areas of the world in the late 1960s to early 1970s, being replaced by the much more conservative modified radical mastectomy and, more recently, by segmental breast tissue excision and radiation therapy. Because of this change in clinical practice lymphedema is now a rarity following breast cancer treatment—and post-mastectomy lymphangiosarcoma is now vanishingly rare. When it occurs following mastectomy it is known as Stewart–Treves syndrome. The pathogenesis of lymphangiosarcoma has not been resolved, however several vague mechanisms have been proposed. Stewart and Treves, proposed that a cancer causing agent is present in lymphedematous limbs. Schreiber et al. proposed that local immunodeficiency as a result of lymphedema results in a "immunologically privileged site" in which the sarcoma is able to develop.
Diagnosis
Treatment
The most successful treatment for lymphangiosarcoma is amputation of the affected limb if possible. Chemotherapy may be administered if there is evidence or suspicion of metastatic disease. Evidence supporting the effectiveness of chemotherapy is, in many cases, unclear due to a wide variety of prognostic factors and small sample size. However, there is some evidence to suggest that drugs such as paclitaxel, doxorubicin, ifosfamide, and gemcitabine exhibit antitumor activity.
See also
Angiosarcoma
Hemangiosarcoma
Lymphangioma
Sarcoma
Stewart–Treves syndrome
References
== External links == |
Familial male-limited precocious puberty | Familial male-limited precocious puberty, often abbreviated as FMPP, also known as familial sexual precocity or gonadotropin-independent testotoxicosis, is a form of gonadotropin-independent precocious puberty in which boys experience early onset and progression of puberty. Signs of puberty can develop as early as an age of 1 year.The spinal length in boys may be short due to a rapid advance in epiphyseal maturation. It is an autosomal dominant condition with a mutation of the luteinizing hormone (LH) receptor. As FMPP is a gonadotropin-independent form of precocious puberty, gonadotropin-releasing hormone agonists (GnRH agonists) are ineffective. Treatment is with drugs that suppress or block the effects of gonadal steroidogenesis, such as cyproterone acetate, ketoconazole, spironolactone, and testolactone. Alternatively, the combination of the androgen receptor antagonist bicalutamide and the aromatase inhibitor anastrozole may be used.Robert King Stone, personal physician to American president Abraham Lincoln, described the first case of FMPP in 1852.
See also
Follicle-stimulating hormone insensitivity
Gonadotropin-releasing hormone insensitivity
Hypergonadism, hyperandrogenism, and precocious puberty
Inborn errors of steroid metabolism
Leydig cell hypoplasia (or LH insensitivity)
References
External links
Testotoxicosis at NIHs Office of Rare Diseases |
Vulvodynia | Vulvodynia is a chronic pain syndrome that affects the vulvar area and occurs without an identifiable cause. Symptoms typically include a feeling of burning or irritation. It has been established by the ISSVD that for the diagnosis to be made symptoms must last at least three months.The exact cause is unknown but is believed to involve a number of factors, including genetics, immunology, and possibly diet. Diagnosis is by ruling out other possible causes. This may or may not include a biopsy of the area.Treatment may involve a number of different measures; however, none is universally effective, and the evidence to support their effectiveness is often poor. Some of these measures include improved vulvar care, dietary changes, medications, counselling, and, if conservative treatment is not effective, surgery. It is estimated to affect up to 16% of women.
Signs and symptoms
Pain is the most notable symptom of vulvodynia, and can be characterized as a burning, stinging, irritation or sharp pain that occurs in the vulva and entrance to the vagina. It may be constant, intermittent or happen only when the vulva is touched, but vulvodynia usually has a long duration.Symptoms may occur in one place or the entire vulvar area. It can occur during or after sexual activity, when tampons are inserted, or when prolonged pressure is applied to the vulva, such as during sitting, bike riding, or horseback riding. Some cases of vulvodynia are idiopathic where no particular cause can be determined.
Vulvar vestibulitis
Vulvar vestibulitis syndrome (VVS), vestibulodynia, or simply vulvar vestibulitis or "localized (to the vestibule) provoked vulvodynia" refers to pain localized to the vestibular region. It tends to be associated with a highly localized "burning" or "cutting" type of pain. The pain of vulvodynia may extend into the clitoris; this is referred to as clitorodynia.Vulvar vestibulitis syndrome is the most common subtype of vulvodynia that affects premenopausal women – the syndrome has been cited as affecting about 10%–15% of women seeking gynecological care.
Causes
A wide variety of possible causes and treatments for vulvodynia are currently being explored. Moreover, there are probably several causes of vulvodynia, and some may be individual to the patient.Possible causes include Sjögren syndrome, the symptoms of which include chronic vaginal dryness. Others include genetic predisposition to inflammation, allergy or other sensitivity (for example: oxalates in the urine), an autoimmune disorder similar to lupus erythematosus or to eczema or to lichen sclerosus, infection (e.g., yeast infections, bacterial vaginosis, HPV, HSV), injury, and neuropathy—including an increased number of nerve endings in the vaginal area. Some cases seem to be negative outcomes of genital surgery, such as a labioplasty. Initiation of hormonal contraceptives that contain low- dose estrogen before the age of 16 could predispose women to vulvar vestibulitis syndrome. A significantly lower pain threshold, especially in the posterior vestibulum, has also been associated with the use of hormonal contraceptives in women without vulvar vestibulitis syndrome. Pelvic floor dysfunction may be the underlying cause of some womens pain.
Diagnosis
The condition is one of exclusion and other vulvovaginal problems should be ruled out. The diagnosis is based on the typical complaints of the patient, essentially normal physical findings, and the absence of identifiable causes per the differential diagnosis. Cotton swab testing is used to differentiate between generalized and localized pain and delineate the areas of pain and categorize their severity. Patients often will describe the touch of a cotton ball as extremely painful, like the scraping of a knife. A diagram of pain locations may be helpful in assessing the pain over time. The vagina should be examined, and tests, including wet mount, vaginal pH, fungal culture, and Gram stain, should be performed as indicated. Fungal culture may identify resistant strains.It is estimated that only half of affected women will seek medical help, among whom many will see several doctors before a correct diagnosis is made. Only 2% of the people that seek help do obtain a diagnostic. Many gynecologists are not familiar with this family of conditions, but awareness has spread with time. Affected women are also often hesitant to seek treatment for chronic vulvar pain, especially since many women begin experiencing symptoms around the same time they become sexually active. Moreover, the absence of any visible symptoms means that before being successfully diagnosed many patients have been told that the pain is "in their head" (a medical stance more associated with the 1970s than with modern medicine).
Differential diagnosis
Infections: urinary tract infection, candidiasis, herpes, HPV
Inflammation: lichen planus
Neoplasm: Pagets disease, vulvar carcinoma
Neurologic disorder: neuralgia secondary to herpes virus, spinal nerve injury
Treatment
There are a number of possible treatments with none being uniformly effective. Treatments include:
Lifestyle
A number of lifestyle changes are often recommended such as using cotton underwear, not using substances that may irritate the area, and using lubricant during sex. The use of alternative medicine has not been sufficiently studied to make recommendations.
Counseling
Education and accurate information about vestibulodynia: Gynaecologist-led educational seminars delivered in a group format have a significant positive impact on psychological symptoms and sexual functioning in women who have provoked (caused by a stimulus such as touch or sexual activity) vestibulodynia. Provoked vestibulodynia, whilst similar in some respects, is different to vulvodynia which this article refers to.
Biofeedback, physical therapy and relaxation: Biofeedback, often done by physical therapists, involves inserting a vaginal sensor to get a sense of the strength of the muscles and help a patient get greater control of her muscles to feel the difference between contraction and relaxation. Sessions are linked with at-home recommendations including often Kegel exercises (e.g., hold for 9 seconds, relax for 30 seconds, for 10–15 sets), and relaxation.
Medications
A number of medications have been used to treat vulvodynia. Evidence to support their use, however, is often poor. These include creams and ointments containing lidocaine, estrogen or tricyclic antidepressants. Antidepressants and anticonvulsants in pill form are sometimes tried but have been poorly studied. Injectable medications included steroids and botulinum toxin have been tried with limited success.
Surgery
Vestibulectomy, during which the nerve fibers to the area are cut out, may be recommended if other treatments have not been found to be effective. There have been no high quality studies looking at surgery as a treatment. While improvement has been noted in 60% to 90%, those who were treated without surgery improved in 40 to 80% of cases.
Epidemiology
The percentage of women affected is not entirely clear, but estimates range as high as 16%. Many other conditions that are not truly vulvodynia (diagnosis is made by ruling out other causes of vulvar pain) could be confused with it. Vulvar pain is a quite frequent complaint in womens health clinics. Vulvodynia is a new term in the medical literature.
References
External links
Vulvodynia at Curlie |
Amnesic shellfish poisoning | Amnesic shellfish poisoning (ASP) is an illness caused by consumption of shellfish that contain the marine biotoxin called domoic acid. In mammals, including humans, domoic acid acts as a neurotoxin, causing permanent short-term memory loss, brain damage, and death in severe cases.
This toxin is produced naturally by marine diatoms belonging to the genus Pseudo-nitzschia and the species Nitzschia navis-varingica. When accumulated in high concentrations by shellfish during filter feeding, domoic acid can then be passed on to birds, marine mammals, and humans by consumption of the contaminated shellfish.Although human illness due to domoic acid has only been associated with shellfish, the toxin can bioaccumulate in many marine organisms that consume phytoplankton, such as anchovies and sardines. Intoxication by domoic acid in nonhuman organisms is frequently referred to as domoic acid poisoning.
Symptoms and treatment
In the brain, domoic acid especially damages the hippocampus and amygdaloid nucleus. It damages the neurons by activating AMPA and kainate receptors, causing an influx of calcium. Although calcium flowing into cells is a normal event, the uncontrolled increase of calcium causes the cell to degenerate.Gastrointestinal symptoms can appear 24 hours after ingestion of affected molluscs. They may include vomiting, nausea, diarrhea, abdominal cramps, and haemorrhagic gastritis. In more severe cases, neurological symptoms can take several hours or up to 3 days to develop. These include headache, dizziness, disorientation, vision disturbances, loss of short-term memory, motor weakness, seizures, profuse respiratory secretions, hiccups, unstable blood pressure, abnormal heart rhythms, and coma.
People poisoned with very high doses of the toxin or displaying risk factors such as old age and kidney failure can die. Death has occurred in four of 107 confirmed cases. In a few cases, permanent sequelae included short-term memory loss and peripheral polyneuropathy.
No antidote for domoic acid is known, so if symptoms fit the description, immediate medical attention is advised. Cooking or freezing affected fish or shellfish tissue does not lessen the toxicity. Domoic acid is a heat-resistant and very stable toxin which can damage kidneys at concentrations that are 1/100th of those that cause neurological effects.
Discovery
ASP was first discovered in humans late in 1987, when a serious outbreak of food poisoning occurred in eastern Canada. Three elderly patients died and other victims suffered long-term neurological problems. Because the victims suffered from memory loss, the term "amnesic" shellfish poisoning is used.Epidemiologists from Health Canada quickly linked the illnesses to restaurant meals of cultured mussels harvested from one area in Prince Edward Island, a place never before affected by toxic algae. Mouse bioassays on aqueous extracts of the suspect mussels caused death with some unusual neurotoxic symptoms very different from those of paralytic shellfish poisoning toxins and other known toxins. On December 12, 1987, a team of scientists was assembled at the National Research Council of Canada laboratory in Halifax, Nova Scotia. Integrating bioassay-directed fractionation with chemical analysis, the team identified the toxin on the afternoon of December 16, only four days after the start of the concerted investigation.
Possible animal effects
On June 22, 2006, a California brown pelican, possibly under the influence of domoic acid, flew through the windshield of a car on the Pacific Coast Highway. The phycotoxin is found in the local coastal waters.
Since March 2007, marine mammal and seabird strandings and deaths off the Southern California coast have increased markedly. These incidents have been linked to the recent and dramatic increase of a naturally occurring toxin produced by algae. Most of the animals found dead tested positive for domoic acid.
According to the Channel Islands Marine and Wildlife Institute, "It is generally accepted that the incidence of problems associated with toxic algae is increasing. Possible reasons to explain this increase include natural mechanisms of species dispersal (currents and tides) to a host of human-related phenomena such as nutrient enrichment (agricultural run-off), climate shifts, or transport of algae species via ship ballast water."
In popular culture
In the TV series Elementary episode "The Red Team" (original air date January 31, 2013), a witness is intentionally poisoned with domoic acid.
In the "Bad Fish" episode of Get a Life (original air date: February 2, 1992), Sharon and Gus get amnesia after eating bad shellfish, and Chris seizes the opportunity to convince them that they are his best friends.
Domoic acid poisoning may have caused an August 18, 1961, invasion of thousands of frantic seabirds in Capitola and Santa Cruz, California. Director Alfred Hitchcock heard about this invasion while working on his adaptation of the Daphne du Maurier novelette "The Birds" for his feature film The Birds (1963), and asked the Santa Cruz Sentinel for any further news copy as "research for his new thriller."
See also
Diarrhetic shellfish poisoning (DSP)
Neurotoxic shellfish poisoning (NSP)
Paralytic shellfish poisoning (PSP)
Harmful algal blooms (HABs)
References
External links
Amnesic Shellfish Poisoning at Woods Hole Oceanographic Institution
Domoic acid and Pseudo-nitzschia references at Fisheries and Oceans Canada
Amnesic Shellfish Poisoning, Domoic Acid, and Pseudo-nitzschia links at the ISSHA website
Domoic acid at International Programme on Chemical Safety
DOMOIC ACID — A MAJOR CONCERN TO WASHINGTON STATE’S SHELLFISH LOVERS at Washington Department of Fish and Wildlife
Crisis off our coast at the International Bird Rescue Research Center
Domoic Acid Poisoning Linked to Recent Marine Strandings and Deaths at Heal the Bay
Domoic Acid Information and History at the Channel Islands Marine and Wildlife Institute |
Neutrophil immunodeficiency syndrome | Neutrophil immunodeficiency syndrome is a condition caused by mutations in the Rac2 gene.
See also
Immunodeficiency with hyper-IgM
List of cutaneous conditions
Chronic granulomatous disease
References
== External links == |
Camptocormia | Camptocormia, also known as bent spine syndrome (BSS), is a symptom of a multitude of diseases that is most commonly seen in the elderly. It is identified by an abnormal thoracolumbar spinal flexion, which is a forward bending of the lower joints of the spine, occurring in a standing position. In order to be classified as BSS, the anterior flexion (the lower back bending) must be of 45 degrees anteriorly. This classification differentiates it from a similar syndrome known as kyphosis. Although camptocormia is a symptom of many diseases, there are two common origins: neurological and muscular. Camptocormia is treated by alleviating the underlying condition causing it through therapeutic measures or lifestyle changes.
History and society
Camptocormia comes from two Greek words, meaning "to bend" (κάμπτω, kamptō) and "trunk" (κόρμος, kormos), and was coined by Alexandre-Achille Souques and B. Rosanoff-Saloff. These two men also created the definition of the disease that is widely accepted today.When the disorder was first clinically studied around the time of First World War, it was believed to be a psychogenic conversion disorder that resulted from the severe trauma of war. Souques and others treated patients with psychological therapy and early versions of electrotherapy. Samuel A. Sandler used a similar approach to treat soldiers during the Second World War. The view of BSS as a conversion disorder led to a lack of awareness about the conditions and few diagnoses by physicians.
As time progressed and advances were made in knowledge of neuroscience and physiology, biological mechanisms behind the irregular bending were identified. The current medically preferred term for the condition is bent spine syndrome, because of the psychological origin associated with camptocormia.
Camptocormia in the elderly
BSS is not limited to the elderly but has an average age of onset of 66 years and is more common amongst men. This late age of onset is largely due to the increased preponderance of the conditions causing the symptom in older individuals – such as muscular weakness and neurological disorders like Parkinsons disease. While BSS does not have any negative stigma in and of itself, those affected by it may be perceived differently due to the condition. For example, an elderly individual with the condition may be viewed as very physically weak, because of the severe bending of the back caused by the condition.
Symptoms
The primary symptom of camptocormia is abnormal forward bending of the torso. This bending becomes worse while walking but does not appear when the affected individual is lying down in a horizontal position. This alleviation of the condition indicates that it is a manifestation of another disease or ailment and is not due to a spine that is actually bent. This is somewhat ironic, since the medically accepted name for the condition is bent spine syndrome.
In an affected individual, the abnormal bending consists of an anterior flexion greater than 45 degrees. Because of this bending and the physical limitations caused by the conditions associated with the disease, it is usually impossible for an affected person to achieve a fully erect position. In addition, patients with camptocormia often experience low back pain as a result of the condition. BSS often appears in individuals with Parkinsons disease, muscular dystrophies, endocrine disorders, inflammatory conditions (myositis), or mitochondrial myopathies. As previously mentioned, the disease is more common in older individuals.
Pathology
When initially identified, camptocormia was classified as a psychogenic disease. Although the condition is sometimes a psychogenic manifestation, camptocormia typically originates from either muscular or neurological diseases. However, due to the wide variety of pathologies resulting in camptocormia, there is no singular cause that is most influential for the condition.
Muscular origin
Myopathic origin BSS can be secondary to various muscular disorders or occur as a primary idiopathy. These etiologies are termed secondary and primary BSS respectively. Idiopathic primary BSS is a late-onset myopathy with progressive muscular weakness that is detected on the spinal extensor muscles in elderly patients and is more predominant in females. The pathogenesis of primary BSS is typically related to fibrosis and fatty infiltration of muscular tissues and to mitochondrial changes due to the aging process. Specifically, weakening occurs in the paravertebral muscles of patients. These paravertebral muscles have a great influence over the walking stance and gait of a patient, so fatty infiltration and degradation of these muscle lead to the characteristics that easily define BSS, such as the anterior flexion of the back combined with an ability to keep upright with any kind of support (e.g., holding onto a table).Secondary BSS can have a multitude of causes, making it hard to pinpoint to a specific muscular disorder. Some examples of diseases that have secondary BSS as a symptom are myopathies caused by muscular dystrophies, neuromuscular disorders, and inflammatory muscle diseases; metabolic or endocrine disorders; and mitochondrial myopathies. A muscle biopsy can clearly demonstrate whether primary BSS or secondary BSS is affecting a patient, because primary BSS is much more identifiable.
Neurological origin
A multitude of neurological disorders cause BSS, including motor neuron disease, CNS disorders, and early amyotrophic lateral sclerosis. Usually, the bent spine is caused by dysfunctioning extensor spinal muscles with a neurological cause.
Neurological origin BSS may also result from damage to the basal ganglia nuclei that are a part of the cerebral cortex, which play a major role in bodily positioning. Damage to this part of the brain can inhibit proper flexion and extension in the muscles necessary for maintaining an upright position. Additionally, the neurotransmitter dopamine plays a key role in the operation of basal ganglia. An abnormally low dopamine concentration, such as that associated with Parkinsons disease, causes dysfunction in the basal ganglia and the associated muscle groups, leading to BSS. Studies have estimated the prevalence of BSS in people affected by Parkinsons to be between 3% and 18%.
Gene mutations
Several gene mutations have been identified in patients with camptocormia. These include the RYR1 gene in axial myopathy, the DMPK gene in myotonic dystrophy, and genes related to dysferlinopathy and Parkinsons disease. These genes could serve as targets for gene therapy to treat the condition in the years to come.
Diagnosis
In order to qualify a patients condition as BSS, the bending angle must be greater than 45 degrees. While the presence of the condition is very easy to note, the cause of the condition is much more difficult to discern. Conditions not considered to be BSS include vertebral fractures, previously existing conditions, and ankylosing spondylitis. Lower-back CT scans and MRIs can typically be used to visualize the cause of the disease. Further identification of the cause can be done by histochemical or cellular analysis of muscle biopsy.
Camptocormia is becoming progressively found in patients with Parkinsons disease.
The diagnosis of Parkinsons-associated camptocormia includes the use of imaging of the brain and the spinal cord, along with electromyography or muscle biopsies.
Muscle biopsies are also a useful tool to diagnose camptocormia. Muscle biopsies found to have variable muscle fiber sizes and even endomysial fibrosis may be markers of bent spine syndrome. In addition, disorganized internal architecture and little necrosis or regeneration is a marker of camptocormia.
Patients with camptocormia present with reduced strength and stooped posture when standing due to weakened paraspinous muscles (muscles parallel to the spine). Clinically, limb muscles show fatigue with repetitive movements. Paraspinous muscles undergo fat infiltration. Electromyography may be used as well in diagnosis. On average, the paraspinous muscles of affected individuals were found to be 75% myopathic, while limb muscles were 50% percent myopathic. Creatine kinase activity levels in skeletal muscle are a diagnostic indicator that can be identifiable through blood tests.
Treatment
Treatment and management
Due to the wide range of causes of camptocormia, there is no one treatment that suits all patients. In addition, there is no specific pharmacological treatment for primary BSS. The use of analgesic drugs depends entirely on the intensity of the back pain. Muscular-origin BSS can be alleviated by positive lifestyle changes, including physical activity, walking with a cane, a nutritious diet, and weight loss. Worsening of symptoms is possible but rare in occurrence.Treatment of the underlying cause of the disease can alleviate the condition in some individuals with secondary BSS. Other treatment options include drugs, injections of botulinum toxin, electroconvulsive therapy, deep brain stimulation, and surgical correction. Unfortunately, many of the elderly individuals affected by the BSS are not treated surgically due to age-related physical ailments and the long postoperative recovery period.
Prognosis
This condition can lead to excess pressure on the spine, causing pain and discomfort. If the spine is bent too far, a patient may have difficulties breathing because of the pressure of the spine pressed against the lungs. Camptocormia may also lead to muscle weakness in the upper back and to arthritis and other bone-degeneration diseases. Because of loss of bone strength, injury to the spine and slipped discs become increasingly significant. Camptocormia can lead to infection, tumors, and diseases of the endocrine system and connective tissues. The success of the treatment method is largely dependent on the patient, but response to therapeutic methods is generally low.
Research directions
Clinical studies have revealed that camptocormia may be hereditary; however, the inheritance mechanism remains unclear. Current areas of research include molecular and genetic studies aimed at elucidating a possible inheritance model along with molecular pathological mechanisms and proteins responsible for BSS. This research will help will facilitate improvement in the classification, diagnosis, and treatment of the condition. In addition, new technologies and animal models of postural abnormalities are being developed to understand camptocormia and design more effective treatment methods.
Deep brain stimulation
One treatment methodogy that is very promising for the treatment of camptocormia is deep brain stimulation. Previously, deep brain stimulation and bilateral stimulation of the subthalamic nucleus and/or globus pallidus internus have been used to treat patients with Parkinsons disease. Studies have shown that similar treatments could be used on patients with severe camptocormia. By using the Burke-Fahn-Marsden Dystonia Rating Scale before and after treatment, it was found that patients experienced significant functional improvement in the ability to walk.
== References == |
Leiomyoma | A leiomyoma, also known as a fibroid, is a benign smooth muscle tumor that very rarely becomes cancer (0.1%). They can occur in any organ, but the most common forms occur in the uterus, small bowel, and the esophagus. Polycythemia may occur due to increased erythropoietin production as part of a paraneoplastic syndrome.
The word is from leio- + myo- + -oma, "smooth-muscle tumor". The plural form can be either the English leiomyomas or the classical leiomyomata.
Uterus
Uterine fibroids are leiomyomata of the uterine smooth muscle. As other leiomyomata, they are benign, but may lead to excessive menstrual bleeding (menorrhagia), often cause anemia and may lead to infertility.
A rare form of these tumors is uterine lipoleiomyoma—benign tumors consisting of a mixture of adipocytes and smooth muscle cells. Uterine lipoleiomyomata have been observed together with ovarian and other pathologies and some of them may develop into liposarcoma. These tumors are monoclonal, and non-random chromosomal abnormalities have been seen in 40% of the tumors.
Gallbladder
Mesenchymal neoplasms of the gallbladder are rare and in particular leiomyomas of the gallbladder have been rarely reported, all of them in patients with immune system disorders. However, a case was reported in absence of associated immunodeficiency at Monash Hospital in Melbourne, Australia, in a healthy 39-year-old woman with no symptoms.
Skin
Leiomyomas of the skin are generally (1) acquired, and (2) divided into several categories:
Solitary cutaneous leiomyoma
Multiple cutaneous (or pilar) leiomyomas arising from the arrectores pilorum muscles
Angioleiomyomas (vascular leiomyomas) that are thought to arise from vascular smooth muscle
Dartoic (or genital) leiomyomas originating in the dartos muscles of the genitalia, areola, and nipple
Angiolipoleiomyoma
Esophagus, stomach and small intestines
Leiomyoma is the most common benign mesenchymal tumor of esophagus and second most common benign tumor of the small bowel (with gastrointestinal stromal tumor as most common). Although leiomyoma is the most common benign esophageal tumor, malignant carcinoma is still 50 times more likely. Approximately 50% of cases are found in the jejunum, followed by the ileum in 31% of cases. Almost one half of all lesions are less than 5 centimeters.
Other locations, metastatic leiomyoma
Metastatic leiomyoma are an extremely rare complication after surgery to remove the uterus for uterine fibroids. The most frequent sites of occurrence are the lungs and pelvis. The lesions are hormonally responsive.
Fibromyoma of the breast is an extremely rare benign breast neoplasm. Most reports in literature mention a history of hysterectomy for uterine fibroids, although the question of whether these fibromyomas are possibly metastases of the uterine fibroids has not been investigated. An alternative hypothesis is an origin from the smooth muscle of the nipple.
Leiomyoma may spontaneously occur in any muscle. Depending on the location of the tumor, identification may not be timely until overall mass becomes undeniably noticeable. The symptoms for a 30-year-old male with a 10 cm leiomyoma included "dead leg" pains. Tumor was intertwined with quadriceps muscles, making identification and excision difficult. Tumor was successfully excised with only minor rehabilitation required.
Familial leiomyoma
Associated with papillary variant of renal cell carcinoma and multiple cutaneous leiomyoma. Defect is in the fumarate hydratase gene in the long arm of chromosome 1.
See also
Leiomyosarcoma
Elagolix/estradiol/norethindrone acetate
References
External links
Esophageal Leiomyoma at eMedicine |
Myocardial stunning | Myocardial stunning or transient post-ischemic myocardial dysfunction is a state of mechanical cardiac dysfunction that can occur in a portion of myocardium without necrosis after a brief interruption in perfusion, despite the timely restoration of normal coronary blood flow. In this situation, even after ischemia has been relieved (by for instance angioplasty or coronary artery bypass surgery) and myocardial blood flow (MBF) returns to normal, myocardial function is still depressed for a variable period of time, usually days to weeks. This reversible reduction of function of heart contraction after reperfusion is not accounted for by tissue damage or reduced blood flow, but rather, its thought to represent a perfusion-contraction "mismatch". Myocardial stunning was first described in laboratory canine experiments in the 1970s where LV wall abnormalities were observed following coronary artery occlusion and subsequent reperfusion.
Cause
Clinical situations associated with myocardial stunning include:
acute myocardial infarction (AMI) with early reperfusion
unstable angina
after percutaneous transluminal coronary angioplasty (PTCA)
after cardiac surgery
neurogenic stunned myocardium following an acute cerebrovascular event such as a subarachnoid hemorrhage
in patients undergoing chronic hemodialysis, chronic myocardial stunning may lead to heart failureMyocardial stunning has been implicated in the development of Takotsubo (Stress) cardiomyopathy.
Pathophysiology
The underlying mechanisms of myocardial stunning have remained the subject of debate for several decades. Two leading hypotheses implicate reperfusion-induced oxygen free-radical damage and altered calcium flux resulting in intracellular hypercalcemia and desensitization of myofilaments. After total ischemia occurs, the myocardium switches immediately from aerobic glycolysis to anaerobic glycolysis resulting in the reduced ability to produce high energy phosphates such as ATP and Creatinine Phosphate. At this point, the lack of the energy and lactate accumulation results in cessation of contraction within 60 seconds of ischemia (i.e. Vessel Occlusion). Subsequent to this is a period of "myocardial stunning," in which reversible ischemic damage is taking place. At approximately 30 minutes after the onset of total ischemia the damage becomes irreversible, thereby ending the phase of myocardial stunning. The generation of oxygen-derived [free radicals] during the initial period of reperfusion after ischemia is believed to contribute to the pathogenesis of myocardial stunning.Some evidence suggests that brief, repetitive episodes of myocardial ischemia may result in chronic myocardial stunning and ventricular contractile impairment.
Diagnosis
Imaging techniques such as echocardiography, ventriculography, and nuclear imaging can be used to detect a contractile dysfunction following reperfusion after an episode of ischemia. The area of dysfunction should also maintain normal perfusion, detected via Positron Emission Tomography, echocardiography with contrast, and/or thallium scintigraphy in order for a diagnosis of myocardial stunning to be considered. However, there are many practical challenges to diagnosing myocardial stunning using these methods. Accurate detection of regional myocardial blood flow and contraction function abnormalities must be detected at levels of high sensitivity. The diagnosis of myocardial stunning must also be differentiated from other conditions such as hibernating myocardium and persistent (silent) subendocardial ischemia, which can also co-exist with superimposed stunning.
Management
Treatment considerations for myocardial stunning should be determined based on the clinical judgment of the cardiologist or physician, the degree of LV impairment and symptoms, and the wishes of the person.Some evidence supports the use of inotropic drugs in the case of severe myocardial dysfunction.Results from canine experimental trials investigating the oxygen free-radical hypothesis for myocardial stunning have shown a reduction in free radical generation and improvement in myocardial function following anti-oxidant infusion.
References
Further reading
"Myocardial “stunning” in man"
Baker C, Rimoldi O, Camici P, Barnes E, Chacon M, Huehns T, Haskard D, Polak J, Hall R (1999). "Repetitive myocardial stunning in pigs is associated with the increased expression of inducible and constitutive nitric oxide synthases". Cardiovasc. Res. 43 (3): 685–97. doi:10.1016/S0008-6363(99)00149-2. PMID 10690340.
Wittstein IS, Thiemann DR, Lima JA, et al. (February 2005). "Neurohumoral features of myocardial stunning due to sudden emotional stress". N. Engl. J. Med. 352 (6): 539–48. doi:10.1056/NEJMoa043046. PMID 15703419.
== External links == |
Paracoccidioidomycosis | Paracoccidioidomycosis (PCM), also known as South American blastomycosis, is a fungal infection that can occur as a mouth and skin type, lymphangitic type, multi-organ involvement type (particularly lungs), or mixed type. If there are mouth ulcers or skin lesions, the disease is likely to be widespread. There may be no symptoms, or it may present with fever, sepsis, weight loss, large glands, or a large liver and spleen.The cause is fungi in the genus Paracoccidioides, including Paracoccidioides brasiliensis and Paracoccidioides lutzii, acquired by breathing in fungal spores.Diagnosis is by sampling of blood, sputum, or skin. The disease can appear similar to tuberculosis, leukaemia, and lymphoma Treatment is with antifungals; itraconazole. For severe disease, treatment is with amphotericin B followed by itraconazole, or trimethoprim/sulfamethoxazole as an alternative.It is endemic to Central and South America, and is considered a type of neglected tropical disease. In Brazil, the disease causes around 200 deaths per year.
Signs and symptoms
Asymptomatic lung infection is common, with fewer than 5% of infected individuals developing clinical disease.It can occur as a mouth and skin type, lymphangitic type, multi-organ involvement type (particularly lungs), or mixed type. If there are mouth ulcers or skin lesions, the disease is likely to be widespread. There may be no symptoms, or it may present with fever, sepsis, weight loss, large glands, or a large liver and spleen. If there are mouth ulcers or skin lesions, the disease is likely to be widespread.Two presentations are known, firstly the acute or subacute form, which predominantly affects children and young adults, and the chronic form, predominantly affecting adult men. Most cases are infected before age 20, although symptoms may present many years later.
Juvenile (acute/subacute) form
The juvenile, acute form is characterised by symptoms, such as fever, weight loss and feeling unwell together with enlarged lymph nodes and enlargement of the liver and spleen. This form is most often disseminated, with symptoms manifesting depending on the organs involved. Skin and mucous membrane lesions are often present, and bone involvement may occur in severe cases. This acute, severe presentation may mimic tuberculosis, lymphoma or leukaemia.
Adult (chronic) form
The chronic form presents months to years after the initial infection occurs and most frequently presents with dry cough and shortness of breath. Other symptoms include excess salivation, difficulty swallowing, and difficulties with voice control. Upper respiratory tract mucosal lesions may be present, as well as increased mucus production and coughing up blood. Both pulmonary and extrapulmonary involvement is common.Up to 70% of cases have mucosal involvement, with lesions often found in the mouth, oropharynx, larynx, and palate. Classic lesions are superficial painful granular ulcers, with small spots of bleeding.
Cause
Paracoccidioidomycosis is caused by two species of fungi that can exist as a mold or yeast depending on temperature, P. brasiliensis and P. lutzii. In protected soil environments, near water sources, that are disturbed either naturally or by human activity, P. brasiliensis has been epidemiologically observed (although not isolated). A known animal carrier is the armadillo. In the natural environment, the fungi are found as filamentous structures, and they develop infectious spores known as conidia.Human to human transmission has never been proven.
Mechanism
Primary infection, although poorly understood due to lack of data, is thought to occur through inhalation of the conidia through the respiratory tract, after inhaling fungal conidia produced by the mycelial form of P. brasiliensis. This occurs predominantly in childhood and young adulthood, after exposure to agricultural activity. Infection may occur through direct skin inoculation, although this is rare.After inhalation into the alveoli, there is rapid multiplication of the organism in the lung tissue, sometimes spreading via the venous and lymphatic systems. Approximately 2% of people develop clinical features after the initial asymptomatic infection.The type of immune response determines the clinical manifestation of the infection, with children and HIV co-infected individuals most commonly developing the acute/subacute disseminated disease. Most of those infected develop a Type 1 T-cell (Th1) mediated immune response, resulting in fibrosing alveolitis and compact granuloma formation that control fungal replication, and latent or asymptomatic infection. It then is thought to remain dormant in residual lung lesions and mediastinal lymph nodes. A deficient Th1 cell response results in the severe forms of the disease. In these individuals, granulomas do not form, and the affected person develops Th2 and Th9 responses, resulting in activation of B lymphocytes, high levels of circulating antibodies, eosinophilia, and hypergammaglobulinemia.Lung involvement subsequently occurs after a dormant phase, manifesting in upper respiratory tract symptoms, and lung infiltrates on imaging. The commonest, chronic form, is almost certainly a reactivation of the disease, and may develop into progressive scarring of the lungs (pulmonary fibrosis).It can cause disease in those with normal immune function, although immunosuppression increases the aggressiveness of the fungus. It rarely causes disease in fertile-age women, probably due to a protective effect of estradiol.
Diagnosis
More than 90% of cases can be diagnoses with direct histological examination of tissue, such as sputum, bronchial lavage fluid, exudates and biopsies. Histopathological study with Gomori methenamine silver (GMS) stain or hematoxylin and eosin (H&E) stain revealing large yeast cells with translucent cell walls with multiple buds.In the juvenile form, lung abnormalities are shown in high-resolution CT scans of the lungs, whereas in the chronic form plain X-rays may show interstitial and alveolar infiltrates in the central and lower lung fields.Culture of P. brasiliensis takes between 20 and 30 days, requiring multiple samples and culture media. Initial culture can occur at room temperature, however after growth is noted, confirmation occurs by incubating at to 36-37 degrees to transform the fungus into yeast cells.Antibody detection is useful both for acute diagnosis and monitoring. Gel immunodiffusion is commonly used in endemic areas, diagnoses 95% of cases with high specificity. Complement fixation allows for a measure of severity of cases by quantifying the antibody level, and is thus useful for monitoring treatment response. It is however only sensitive for 85% of cases, and cross-reacts with H. capsulatum.
Differential diagnosis
The disease can appear similar to tuberculosis, leukaemia, and lymphoma
Treatment
Both P. brasiliensis and P. lutzii are in-vitro susceptible to most antifungal agents, unlike other systemic fungal infections. Mild and moderate forms are treated with itraconazole for 9 to 18 months, as this has been shown to be more effective, has a shorter treatment duration and is more tolerated. Acidic beverages have been shown to reduce absorption of itraconazole. Co-trimoxazole is a second line agent, and is preferred for those with brain involvement, and during pregnancy. For severe cases, intravenous treatment with amphotericin B is indicated, for an average of 2 to 4 weeks.Prednisolone prescribed at the same time may reduce inflammation during treatment. Patients should be treated until stabilisation of symptoms, and increase in body weight. Advice in regards to nutritional support, as well as smoking and alcohol intake should be provided. Adrenal insufficiency, if found, is treated with corticosteroids. Clinical criteria for cure includes the absence or healing of lesions, stabilisation of body weight, negative as well as negative autoantibody tests. There is insufficient data to support the benefits of above drugs to treat the disease.
Epidemiology
Paracoccidioidomycosis is endemic in rural areas of Latin America, from southern Mexico to Argentina, and is also found in Brazil, Colombia, Venezuela, Ecuador and Paraguay. An epidemic outbreak has never been observed. It has the highest prevalence of all systemic mycoses (fungal infections) in the area. As many as 75% of people in endemic areas have been estimated to be infected with the asymptomatic form (up to 10 million people), with 2% developing clinically significant disease. Morbidity and mortality is strongly associated with patients socioeconomic background, with most adult patients being male agricultural workers. Other risk factors include smoking, alcohol use, HIV co-infection or other immunosuppression.
80% of reported cases are in Brazil, in the southeast, midwest, and south, spreading in the 1990s to the Amazon area. Most of the remaining infections are in Argentina, Colombia and Venezuela. Most epidemiological reports have focused on P. brasliensis, with P. lutzii epidemiology poorly understood as of 2015.Rising cases have been linked to agriculturalization and deforestation in Brazil, urbanisation to peripheral city areas with poor infrastructure, as well as increased soil and air humidity. One Brazilian indigenous tribe, the Surui, after changing from subsistence agriculture to coffee farming showed higher infection rates than surrounding tribes.There have also been reports in non-endemic areas with the rise of eco-tourism, in the United States, Europe and Japan. All reported cases were returned travellers from endemic regions.
History
Lutz-Splendore-de Almeida disease is named for the physicians Adolfo Lutz, Alfonso Splendor (1871–1953), an Italo-Brazilian Parasitologist and Floriano Paulo de Almeida (1898–1977), a Brazilian Pathologist specializing in Pathologic Mycology (Study of Infectious Fungi), who first characterized the disease in Brazil in the early 20th century.
See also
North American blastomycosis
References
== External links == |
Congenital disorder of glycosylation | A congenital disorder of glycosylation (previously called carbohydrate-deficient glycoprotein syndrome) is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. Congenital disorders of glycosylation are sometimes known as CDG syndromes. They often cause serious, sometimes fatal, malfunction of several different organ systems (especially the nervous system, muscles, and intestines) in affected infants. The most common sub-type is PMM2-CDG (formally known as CDG-Ia) where the genetic defect leads to the loss of phosphomannomutase 2 (PMM2), the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate.
Presentation
The specific problems produced differ according to the particular abnormal synthesis involved. Common manifestations include ataxia; seizures; retinopathy; liver disease; coagulopathies; failure to thrive (FTT); dysmorphic features (e.g., inverted nipples and subcutaneous fat pads), pericardial effusion, and hypotonia. If an MRI is obtained; cerebellar hypoplasia is a common finding.Ocular abnormalities of CDG-Ia include: myopia, infantile esotropia, delayed visual maturation, peripheral neuropathy (PN), strabismus, nystagmus, optic disc pallor, and reduced rod function on electroretinography.Three subtypes PMM2-CDG, PMI-CDG, ALG6-CDG can cause congenital hyperinsulinism with hyperinsulinemic hypoglycemia in infancy.
N-Glycosylation and known defects
A biologically very important group of carbohydrates is the asparagine (Asn)-linked, or N-linked, oligosaccharides. Their biosynthetic pathway is very complex and involves a hundred or more glycosyltransferases, glycosidases, transporters and synthases. This plethora allows for the formation of a multitude of different final oligosaccharide structures, involved in protein folding, intracellular transport/localization, protein activity, and degradation/half-life. A vast amount of carbohydrate binding molecules (lectins) depend on correct glycosylation for appropriate binding; the selectins, involved in leukocyte extravasation, is a prime example. Their binding depends on a correct fucosylation of cell surface glycoproteins. Lack thereof leads to leukocytosis and increase sensitivity to infections as seen in SLC35C1-CDG(CDG-IIc); caused by a GDP-fucose (Fuc) transporter deficiency.All N-linked oligosaccharides originate from a common lipid-linked oligosaccharide (LLO) precursor, synthesized in the ER on a dolichol-phosphate (Dol-P) anchor. The mature LLO is transferred co-translationally to consensus sequence Asn residues in the nascent protein, and is further modified by trimming and re-building in the Golgi.
Deficiencies in the genes involved in N-linked glycosylation constitute the molecular background to most of the CDGs.
Type I defects involve the synthesis and transfer of the LLO
Type II defects impair the modification process of protein-bound oligosaccharides.
Type I
Type II
The mature LLO chain is next transferred to the growing protein chain, a process catalysed by the oligosaccharyl transferase (OST) complex.
Once transferred to the protein chain, the oligosaccharide is trimmed by specific glycosidases. This process is vital since the lectin chaperones calnexin and calreticulin, involved in protein quality, bind to the Glc1Man9GlcNAc-structure and assure proper folding. Lack of the first glycosidase (GCS1) causes CDG-IIb.
Removal of the Glc residues and the first Man residue occurs in the ER.
The glycoprotein then travels to the Golgi, where a multitude of different structures with different biological activities are formed.
Mannosidase I creates a Man5GlcNAc2-structure on the protein, but note that this has a different structure than the one made on LLO.
Next, a GlcNAc residue forms GlcNAc1Man5GlcNAc2, the substrate for a-mannosidase II (aManII).
aManII then removes two Man residues, creating the substrate for GlcNAc transferase II, which adds a GlcNAc to the second Man branch. This structure serves as substrate for additional galactosylation, fucosylation and sialylation reactions. Additionally, substitution with more GlcNAc residues can yield tri- and tetra-antennary molecules.Not all structures are fully modified, some remain as high-mannose structures, others as hybrids (one unmodified Man branch and one modified), but the majority become fully modified complex type oligosaccharides.In addition to glycosidase I, mutations have been found:
in MGAT2, in GlcNAc transferase II (CDG-IIa)
in SLC35C1, the GDP-Fuc transporter (CDG-IIc)
in B4GALT1, a galactosyltransferase (CDG-IId)
in COG7, the conserved oligomeric Golgi complex-7 (CDG-IIe)
in SLC35A1, the CMP-sialic acid (NeuAc) transporter (CDG-IIf)However, the use of >100 genes in this process, presumably means that many more defects are to be found.
Diagnosis
Classification
Historically, CDGs are classified as Types I and II (CDG-I and CDG-II), depending on the nature and location of the biochemical defect in the metabolic pathway relative to the action of oligosaccharyltransferase. The most commonly used screening method for CDG, analysis of transferrin glycosylation status by isoelectric focusing, ESI-MS, or other techniques, distinguish between these subtypes in so called Type I and Type II patterns.Currently, twenty-two CDG Type-I and fourteen Type-II subtypes of CDG have been described.Since 2009, most researchers use a different nomenclature based on the gene defect (e.g. CDG-Ia = PMM2-CDG, CDG-Ib = PMI-CDG, CDG-Ic = ALG6-CDG etc.). The reason for the new nomenclature was the fact that proteins not directly involved in glycan synthesis (such as members of the COG-family and vesicular H+-ATPase) were found to be causing the glycosylation defect in some CDG patients.
Also, defects disturbing other glycosylation pathways than the N-linked one are included in this classification. Examples are the α-dystroglycanopathies (e.g. POMT1/POMT2-CDG (Walker-Warburg syndrome and Muscle-Eye-Brain syndrome)) with deficiencies in O-mannosylation of proteins; O-xylosylglycan synthesis defects (EXT1/EXT2-CDG (hereditary multiple exostoses) and B4GALT7-CDG (Ehlers-Danlos syndrome, progeroid variant)); O-fucosylglycan synthesis (B3GALTL-CDG (Peters plus syndrome) and LFNG-CDG (spondylocostal dysostosis III)).
Type I
Type I disorders involve disrupted synthesis of the lipid-linked oligosaccharide precursor (LLO) or its transfer to the protein.Types include:
Type II
Type II disorders involve malfunctioning trimming/processing of the protein-bound oligosaccharide chain.Types include:
Disorders of O-mannosylation
Disorders with deficient α-dystroglycan O-mannosylation.Mutations in several genes have been associated with the traditional clinical syndromes, termed muscular dystrophy-dystroglycanopathies (MDDG). A new nomenclature based on clinical severity and genetic cause was recently proposed by OMIM. The severity classifications are A (severe), B (intermediate), and C (mild). The subtypes are numbered one to six according to the genetic cause, in the following order: (1) POMT1, (2) POMT2, (3) POMGNT1, (4) FKTN, (5) FKRP, and (6) LARGE.Most common severe types include:
Treatment
No treatment is available for most of these disorders. Mannose supplementation relieves the symptoms in MPI-CDG for the most part, even though the hepatic fibrosis may persist. Fucose supplementation has had a partial effect on some SLC35C1-CDG patients.
History
The first CDG patients (twin sisters) were described in 1980 by Jaeken et al. Their main features were psychomotor retardation, cerebral and cerebellar atrophy and fluctuating hormone levels (e.g.prolactin, FSH and GH). During the next 15 years the underlying defect remained unknown but since the plasmaprotein transferrin was underglycosylated (as shown by e.g. isoelectric focusing), the new syndrome was named carbohydrate-deficient glycoprotein syndrome (CDGS) Its "classical" phenotype included psychomotor retardation, ataxia, strabismus, anomalies (fat pads and inverted nipples) and coagulopathy.In 1994, a new phenotype was described and named CDGS-II. In 1995, Van Schaftingen and Jaeken showed that CDGS-I (now PMM2-CDG) was caused by the deficiency of the enzyme phosphomannomutase. This enzyme is responsible for the interconversion of mannose-6-phosphate and mannose-1-phosphate, and its deficiency leads to a shortage in GDP-mannose and dolichol (Dol)-mannose (Man), two donors required for the synthesis of the lipid-linked oligosaccharide precursor of N-linked glycosylation.In 1998, Niehues described a new CDG syndrome, MPI-CDG, which is caused by mutations in the enzyme metabolically upstream of PMM2, phosphomannose isomerase (PMI). A functional therapy for MPI-CDG, alimentary mannose was also described.
The characterization of new defects took increased and several new Type I and Type II defects were delineated.In 2012, Need described the first case of a congenital disorder of deglycosylation, NGLY1 deficiency. A 2014 study of NGLY1 deficient patients found similarities with traditional congenital disorders of glycosylation.
See also
Inborn error of metabolism
Leukocyte adhesion deficiency
PMM2 deficiency
References
External links
GeneReviews/NIH/NCBI/UW entry on PMM2-CDG (CDG-Ia)Carbohydrate-Deficient Glycoprotein Syndrome, Type 1a; Congenital Disorder of Glycosylation Type 1a; Jaeken Syndrome
OMIM entries on Carbohydrate-Deficient Glycoprotein Syndrome, Type 1a; Congenital Disorder of Glycosylation Type 1a; Jaeken Syndrome
GeneReviews/NIH/NCBI/UW entry on Congenital Disorders of Glycosylation Overview |
First-degree atrioventricular block | First-degree atrioventricular block (AV block) is a disease of the electrical conduction system of the heart in which electrical impulses conduct from the cardiac atria to the ventricles through the atrioventricular node (AV node) more slowly than normal. First degree AV block does not generally cause any symptoms, but may progress to more severe forms of heart block such as second- and third-degree atrioventricular block. It is diagnosed using an electrocardiogram, and is defined as a PR interval greater than 200 milliseconds. First degree AV block affects 0.65-1.1% of the population with 0.13 new cases per 1000 persons each year.
Causes
The most common causes of first-degree heart block are AV nodal disease, enhanced vagal tone (for example in athletes), myocarditis, acute myocardial infarction (especially acute inferior MI), electrolyte disturbances and medication. The medications that most commonly cause first-degree heart block are those that increase the refractory time of the AV node, thereby slowing AV conduction. These include calcium channel blockers, beta-blockers, cardiac glycosides, and anything that increases cholinergic activity such as cholinesterase inhibitors.
Diagnosis
In normal individuals, the AV node slows the conduction of electrical impulses through the heart. This is manifest on a surface electrocardiogram (ECG) as the PR interval. The normal PR interval is from 120 ms to 200 ms in length. This is measured from the initial deflection of the P wave to the beginning of the QRS complex.In first-degree heart block, the diseased AV node conducts the electrical activity more slowly. This is seen as a PR interval greater than 200 ms in length on the surface ECG. It is usually an incidental finding on a routine ECG.First-degree heart block does not require any particular investigations except for electrolyte and drug screens, especially if an overdose is suspected.
Treatment
The management includes identifying and correcting electrolyte imbalances and withholding any offending medications. This condition does not require admission unless there is an associated myocardial infarction. Even though it usually does not progress to higher forms of heart block, it may require outpatient follow-up and monitoring of the ECG, especially if there is a comorbid bundle branch block. If there is a need for treatment of an unrelated condition, care should be taken not to introduce any medication that may slow AV conduction. If this is not feasible, clinicians should be very cautious when introducing any drug that may slow conduction; and regular monitoring of the ECG is indicated.
Prognosis
Isolated first-degree heart block has no direct clinical consequences. There are no symptoms or signs associated with it. It was originally thought of as having a benign prognosis. In the Framingham Heart Study, however, the presence of a prolonged PR interval or first degree AV block doubled the risk of developing atrial fibrillation, tripled the risk of requiring an artificial pacemaker, and was associated with a small increase in mortality. This risk was proportional to the degree of PR prolongation.A subset of individuals with the triad of first-degree heart block, right bundle branch block, and either left anterior fascicular block or left posterior fascicular block (known as trifascicular block) may be at an increased risk of progression to complete heart block.
See also
Atrioventricular block
Second-degree atrioventricular block
Third-degree atrioventricular block
References
== External links == |
Cerebral atrophy | Cerebral atrophy is a common feature of many of the diseases that affect the brain. Atrophy of any tissue means a decrement in the size of the cell, which can be due to progressive loss of cytoplasmic proteins. In brain tissue, atrophy describes a loss of neurons and the connections between them. Brain atrophy can be classified into two main categories: generalized and focal atrophy. Generalized atrophy occurs across the entire brain whereas focal atrophy affects cells in a specific location. If the cerebral hemispheres (the two lobes of the brain that form the cerebrum) are affected, conscious thought and voluntary processes may be impaired.
Some degree of cerebral shrinkage occurs naturally with the dynamic process of aging. The human brain completes growth and attains its full maturity at 25 years of age. Structural changes continue during adulthood as brain shrinkage commences after the age of 35, at a rate of 0.2% per year. The rate of decline is accelerated when individuals reach 70 years old. By the age of 90, the human brain will have experienced a 15% loss of its initial peak weight. Besides brain atrophy, aging has also been associated with cerebral microbleeds.
Symptoms
Many diseases that cause cerebral atrophy are associated with dementia, seizures, and a group of language disorders called the aphasias. Dementia is characterized by a progressive impairment of memory and intellectual function that is severe enough to interfere with social and work skills. Memory, orientation, abstraction, ability to learn, visual-spatial perception, and higher executive functions such as planning, organizing and sequencing may also be impaired. Seizures can take different forms, appearing as disorientation, strange repetitive movements, loss of consciousness, or convulsions. Aphasias are a group of disorders characterized by disturbances in speaking and understanding language. Receptive aphasia causes impaired comprehension. Expressive aphasia is reflected in odd choices of words, the use of partial phrases, disjointed clauses, and incomplete sentences.
Causes
The pattern and rate of progression of cerebral atrophy depends on the disease involved.
Injury
Stroke, loss of brain function due to a sudden interruption of blood supply in the brain
Moderate-to-severe traumatic brain injury
Diseases and disorders
Alzheimers disease (High resolution MRI scans have shown the progression of cerebral atrophy in Alzheimers disease)
Cerebral palsy, in which lesions (damaged areas) may impair motor coordination
Senile dementia, fronto-temporal dementia, and vascular dementia
Picks disease, causes progressive destruction of nerve cells in the brain
Huntingtons disease, and other genetic disorders that cause build-up of toxic levels of proteins in neurons
Leukodystrophies, such as Krabbe disease, which destroy the myelin sheath that protects axons
Multiple sclerosis, which causes inflammation, myelin damage, and lesions in cerebral tissue
Epilepsy, in which lesions cause abnormal electrochemical discharges that result in seizures
Anorexia nervosa, bulimia nervosa, and other eating disorders
Malnutrition, caused by lack or excess of nutrition from foods
Type II diabetes, where the body does not use insulin properly resulting in high blood sugar
Bipolar disorder, significant loss of brain tissue during manic episodes; however its not verified whether the episodes cause brain tissue loss or vice versa
Schizophrenia
Mitochondrial encephalomyopathies, such as Kearns–Sayre syndrome, which interfere with the basic functions of neurons
Posterior cortical atrophy: In the most posterior area of the brain lies the visual cortex, the area of the brain where visual information is received and processed. When cortical atrophy occurs in this brain area due to neurodegeneration, the first symptom is impairment in vision. A common vision impairment seen in patients with posterior cortical atrophy is simultanagnosia, where a person is unable to see multiple locations at once or to quickly shift attention between these locations. When looking at images of a brain with posterior cortical atrophy, one can see a loss in volume of the dorsal and ventral visual pathways, where visual stimuli is brought to the visual cortex and integrated information is sent back out to other areas of the brain. Because this disorder results in visual impairments, there is often a missed or delayed diagnosis, as the assumption is that there is a problem is in the eyes when the reality is that the problem is all the way in the back of the brain.
Prion diseases, a group of invariably fatal encephalopathies that cause the progressive death of neurons.
Infections
Where an infectious agent or the inflammatory reaction to it destroys neurons and their axons, these include...
Encephalitis, acute inflammation in the brain
Neurosyphilis, an infection in the brain or spinal chord
AIDS, disease of the immune system
Drug-induced
Alcohol (partially reversible): Standardized MRI evidence suggest chronic alcoholism (alcohol use disorder) is associated with widespread cortical atrophy and major brain changes. In contrast to healthy controls, macrostructural findings indicate alcoholic brains are smaller in mass and volume. Neuroimaging studies also show that cortical shrinkage in "uncomplicated alcoholism" is most severe in the frontal lobe in comparison to the other divisions of the cerebral cortex. In addition, neurological diseases that co-occur with excessive alcohol consumption—such as Wernicke-Korsakoff syndrome (WKS)—are characterized by substantial volume deficits of the diencephalon structures. In comparison to unaffected, non-alcoholic participants, tissue degeneration in WKS patients is found in specific white matter structures including the corpus callosum, the hippocampus, the subcortical basal ganglia (hypothalamus, thalamus, putamen), and the mammillary bodies.
Antipsychotic
Corticosteroid use (There appears to be correlations between degree of dosing with corticosteroids and cerebral atrophy)
Diagnosis
Neurofilament light chain
Cerebrospinal fluid (CSF) is a fluid that is found exclusively in the brain and spinal cord that circulates between sections of the brain offering an extra layer of protection. Studies have shown that biomarkers in the CSF and plasma can be tracked for their presence in different parts of the brain—and their presence can tell us about cerebral atrophy. One study took advantage of biomarkers, namely one called neurofilament light chain (NFL), in patients with Alzheimers Disease. Neurofilament light chain is a protein that is important in the growth and branching of neurons—cells found in the brain. In Alzheimers Disease, neurons will stop working or die in a process called neurodegeneration. By tracking NFL, researchers can see this neurodegeneration, which this study showed was associated with brain atrophy and later cognitive decline in Alzheimers patients. Other biomarkers like Ng – a protein important in long-term potentiation and memory – have been tracked for their associations with brain atrophy as well, but NFL had the greatest association.
Measures
CT and MRI are most commonly used to observe the brain for cerebral atrophy. A CT scan takes cross sectional images of the brain using X-rays, while an MRI uses a magnetic field. With both measures, multiple images can be compared to see if there is a loss in brain volume over time.
Difference from hydrocephalus
Cerebral atrophy can be hard to distinguish from hydrocephalus because both cerebral atrophy and hydrocephalus involve an increase in cerebrospinal fluid (CSF) volume. In cerebral atrophy, this increase in CSF volume comes as a result of the decrease in cortical volume. In hydrocephalus, the increase in volume happens due to the CSF itself.
Treatment
Cerebral atrophy is not usually preventable. However, there are steps that can be taken to reduce the risk:
controlling blood pressure
a healthy balanced diet including omega-3s and antioxidants
staying active mentally, physically, and socially.
Reversibility of cerebral atrophy
While most cerebral atrophy is said to be irreversible, recent studies that show this is not always the case. A child who was treated with ACTH originally showed atrophy, but four months after treatment the brain was seemingly normal again.As previously mentioned, chronic alcoholism is known to be associated with significant brain damage. The pronounced shrinkage in the frontal lobes and cerebellum of alcoholics correlates with serious impairments in executive and psychomotor functions. However, longitudinal studies suggest that some of these brain damages are partially reversible with abstinence. In response to drinking cessation, bodies of gray and white matter including the cerebral cortex, the limbic system (amygdala, hippocampus, thalamus), the cerebellum, and the brainstem all showed a general increase in brain volume. Similarly, ventricular enlargement—which reflects atrophy of surrounding brain regions—is also reduced in abstinent alcoholics. Following extended sobriety, the volume of the lateral and third ventricles was decreased, and abstainers showed an improvement in working memory and balance. Finally, evidence for the recovery of brain volume with continued sobriety is supported by the improvement in neuropsychological performance. Compared to the control participants, abstinent alcoholic patients scored significantly better on tests measuring cognitive, sensory, and motor functions including abstract reasoning, memory, visuospatial ability, and gait and balance. That being said, while short-term abstinence suffices to produce structural and functional recovery, some alcohol-induced brain changes may persist even after long-term sobriety.
See also
Cerebral atherosclerosis
Neurodegeneration
Traumatic brain injury
Neuroimmunology
Neuroendocrinology
Comorbidity
Migraine
== References == |
Essential fructosuria | Essential fructosuria, caused by a deficiency of the enzyme hepatic fructokinase, is a clinically benign condition characterized by the incomplete metabolism of fructose in the liver, leading to its excretion in urine. Fructokinase (sometimes called ketohexokinase) is the first enzyme involved in the degradation of fructose to fructose-1-phosphate in the liver.This defective degradation does not cause any clinical symptoms, fructose is either excreted unchanged in the urine or metabolized to fructose-6-phosphate by alternate pathways in the body, most commonly by hexokinase in adipose tissue and muscle.
Cause
Essential fructosuria is a genetic condition that is inherited in an autosomal recessive manner. Mutations in the KHK gene, located on chromosome 2p23.3-23.2 are responsible. The incidence of essential fructosuria has been estimated at 1:130,000. The actual incidence is likely higher, because those affected are asymptomatic.
Diagnosis
A diagnosis of essential fructosuria is typically made after a positive routine test for reducing sugars in the urine. An additional test with glucose oxidase must also be carried out (with a negative result indicating essential fructosuria) as a positive test for reducing sugars is most often a result of glucosuria secondary to diabetes mellitus. The excretion of fructose in the urine is not constant, it depends largely on dietary intake.
Treatment
No treatment is indicated for essential fructosuria, while the degree of fructosuria depends on the dietary fructose intake, it does not have any clinical manifestations. The amount of fructose routinely lost in urine is quite small. Other errors in fructose metabolism have greater clinical significance. Hereditary fructose intolerance, or the presence of fructose in the blood (fructosemia), is caused by a deficiency of aldolase B, the second enzyme involved in the metabolism of fructose.This enzyme deficiency results in an accumulation of fructose-1-phosphate, which inhibits the production of glucose and results in diminished regeneration of adenosine triphosphate. Clinically, patients with hereditary fructose intolerance are much more severely affected than those with essential fructosuria, with elevated uric acid, growth abnormalities and can result in coma if untreated.
References
== External links == |
Myoma | A myoma is a type of tumor that involves muscle cells. There are two main types of myoma:
Leiomyomas which occur in smooth muscle. They most commonly occur as uterine fibroids, but may also form in other locations.
Rhabdomyomas which occur in striated muscle. They are rare tumors, occur in childhood and often become malignant.Whether or not angiomyomas are a type of leiomyoma or a separate entity is disputed as of 2014.Myomas are benign tumors of the uterus that can affect the fertility of a woman depending mainly on three factors:
Size (cut off value 4-5 cm)
Number
Location (they can be intramural, subserous or submucous). Submucous ones are worst from a fertility point of view, while subserous are less dangerous.Some of the most common symptoms are: abundant menstrual bleeding, longer menstrual periods, pelvic pressure, constipation, a need to urinate continuously.
References
== External links == |
Methylmalonic acidemia | Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.Methylmalonic acidemia stems from several genotypes, all forms of the disorder usually diagnosed in the early neonatal period, presenting progressive encephalopathy, and secondary hyperammonemia. The disorder can result in death if undiagnosed or left untreated. It is estimated that this disorder has a frequency of 1 in 48,000 births, though the high mortality rate in diagnosed cases make exact determination difficult. Methylmalonic acidemias are found with an equal frequency across ethnic boundaries.
Symptoms and signs
Depending on the affected gene(s), this disorder may present symptoms that range from mild to life-threatening.
Stroke
Progressive encephalopathy
Seizure
Kidney failure
Vomiting
Dehydration
Failure to thrive and developmental delays
Lethargy
Repeated yeast infections
Acidosis
Hepatomegaly
Hypotonia
Pancreatitis
Respiratory distress
Cause
Genetic
The inherited forms of methylmalonic acidemia cause defects in the metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinyl-CoA by the enzyme methylmalonyl-CoA mutase.Vitamin B12 is also needed for the conversion of methylmalonyl-CoA to succinyl-CoA. Mutations leading to defects in vitamin B12 metabolism or in its transport frequently result in the development of methylmalonic acidemia.This disorder has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene—one from each parent—must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.
Nutritional
Though not always grouped together with the inherited versions, a severe nutritional deficiency of vitamin B12 can also result in syndrome with identical symptoms and treatments as the genetic methylmalonic acidemias. Methylmalonyl-CoA requires vitamin B12 to form succinyl-CoA. When the amount of B12 is insufficient for the conversion of cofactor methylmalonyl-CoA into succinyl-CoA, the buildup of unused methylmalonyl-CoA eventually leads to methylmalonic acidemia. This diagnosis is often used as an indicator of vitamin B12 deficiency in serum.
Mechanism
Pathophysiology
In methylmalonic acidemia, the body is unable to break down the amino acids methionine, threonine, isoleucine and valine; as a result methylmalonic acid builds up in the blood and tissues. Those afflicted with this disorder are either lacking functional copies or adequate levels of one or more of the following enzymes: methylmalonyl-CoA mutase, methylmalonyl-CoA epimerase, or those involved in adenosylcobalamin synthesis.
Methylmalonyl-CoA mutase
It is estimated that as many as 60% of cases are the result of a mutated MUT gene which encodes the protein methylmalonyl-CoA mutase. This enzyme is responsible for the digestion of potentially toxic derivatives of the breakdown of the above-mentioned amino acids and fats, primarily cholesterol, particularly this enzyme converts methylmalonyl-CoA into succinyl-CoA. Without this enzyme, the body has no means to neutralize or remove methylmalonic acid and related compounds. The action of this enzyme can also be crippled by mutations in the MMAA, MMAB, and MMADHC genes, each of which encodes a protein required for normal functioning of methylmalonyl-CoA mutase.
Methylmalonyl-CoA epimerase
Mutations in the MCEE gene, which encodes the methylmalonyl-CoA epimerase protein, also referred to as methylmalonyl racemase, will cause a much more mild form of the disorder than the related methylmalonyl-CoA mutase variant. Like the mutase, the epimerase also functions in breaking down the same substances, but to a significantly lesser extent than the mutase does. The phenotypic differences caused by a deficiency of the epimerase as opposed to the mutase are so mild that there is debate within the medical community as to whether or not this genetic deficiency can be considered a disorder or clinical syndrome.
Adenosylcobalamin
Also known as vitamin B12, this form of cobalamin is a required cofactor of methylmalonyl-CoA mutase. Even with a functional version of the enzyme at physiologically normal levels, if B12 cannot be converted to this active form, the mutase will be unable to function.
Progression
Though there are not distinct stages of the disease, methylmalonic acidemia is a progressive condition; the symptoms of this disorder are compounded as the concentration of methylmalonic acid increases. If the triggering proteins and fats are not removed from the diet, this buildup can lead to irreparable kidney or liver damage and eventually death.
Diagnosis
One of, if not the most common form of organic acidemia, methylmalonic acidemia is not apparent at birth as symptoms usually do not present themselves until proteins are added to the infants diet. Because of this, symptoms typically manifest anytime within the first year of life. Due to the severity and rapidity in which this disorder can cause complications when left undiagnosed, screening for methylmalonic acidemia is often included in the newborn screening exam.Because of the inability to properly break down amino acids completely, the byproduct of protein digestion, the compound methylmalonic acid, is found in a disproportionate concentration in the blood and urine of those afflicted. These abnormal levels are used as the main diagnostic criteria for diagnosing the disorder. This disorder is typically determined through the use of a urine analysis or blood panel. The presence of methylmalonic acidemia can also be suspected through the use of a CT or MRI scan or ammonia test, however these tests are by no means specific and require clinical and metabolic/correlation. Elevated levels of ammonia, glycine, and ketone bodies may also be present in the blood and urine.
Types
Methylmalonic acidemia has varying diagnoses, treatment requirements and prognoses, which are determined by the specific genetic mutation causing the inherited form of the disorder. The following are the known genotypes responsible for methylmalonic acidemia:
The mut type can further be divided into mut0 and mut- subtypes, with mut0 characterized by a complete lack of methylmalonyl-CoA mutase and more severe symptoms and mut- characterized by a decreased amount of mutase activity.Mut-, cblB, and cblA versions of methylmalonic acidemia have been found to be cobalamin responsive. Mut0 is a nonresponsive variant.
Treatment
Dietary
Treatment for all forms of this condition primarily relies on a low-protein diet, and depending on what variant of the disorder the individual suffers from, various dietary supplements. All variants respond to the levo isomer of carnitine as the improper breakdown of the affected substances results in sufferers developing a carnitine deficiency. The carnitine also assists in the removal of acyl-CoA, buildup of which is common in low-protein diets by converting it into acyl-carnitine which can be excreted in urine. Some forms of methylmalonyl acidemia are responsive to cobalamin although cyanocobalamin supplements could prove detrimental to some forms. If the individual proves responsive to both cobalamin and carnitine supplements, then it may be possible for them to ingest substances that include small amounts of the problematic amino acids isoleucine, threonine, methionine, and valine without causing an attack.
Surgical
A more extreme treatment includes kidney or liver transplant from a donor without the condition. The foreign organs will produce a functional version of the defective enzymes and digest the methylmalonic acid, however all of the disadvantages of organ transplantation are of course applicable in this situation. There is evidence to suggest that the central nervous system may metabolize methylmalonyl-CoA in a system isolated from the rest of the body. If this is the case, transplantation may not reverse the neurological effects of methylmalonic acid previous to the transplant or prevent further damage to the brain by continued build up.
Prognosis
The prognosis will vary depending on the severity of the condition and the individuals response to treatment. Prognosis is typically better for those with cobalamin-responsive variants and not promising in those suffering from noncobalamin-responsive variants. Milder variants have a higher frequency of appearance in the population than the more severe ones. Even with dietary modification and continued medical care, it may not be possible to prevent neurological damage in those with a nonresponsive acidemia. Without proper treatment or diagnosis, it is not uncommon for the first acidemic attack to be fatal.Despite these challenges, since it was first identified in 1967, treatment and understanding of the condition has improved to the point where it is not unheard of for even those with unresponsive forms of methylmalonic acidemia to be able to reach adulthood and even carry and deliver children safely.
Research
Nosologic history
MMA was first characterized by Oberholzer et al. in 1967.
Neurologic effects
That MMA can have disastrous effects on the nervous system has been long reported; however, the mechanism by which this occurs has never been determined. Published on June 15, 2015, research performed on the effects of methylmalonic acid on neurons isolated from fetal rats in an in vitro setting using a control group of neurons treated with an alternate acid of similar pH. These tests have suggested that methylmalonic acid causes decreases in cellular size and increase in the rate of cellular apoptosis in a concentration dependent manner with more extreme effects being seen at higher concentrations. Furthermore, micro-array analysis of these treated neurons have also suggested that on an epigenetic-level methylmalonic acid alters the transcription rate of 564 genes, notably including those involved in the apoptosis, p53, and MAPK signaling pathways.
Mitochondrial dysfunction
As the conversion of methylmalonyl-CoA to succinyl-CoA takes place inside the mitochondria, mitochondrial dysfunction as a result of diminished electron transport chain function has long been suspected as a feature in MMA. Recent research has found that in rat models mitochondria of rats affected by the disorder grow to unusual size, dubbed megamitochondria. These megamitochondria also appear to have deformed internal structures and a loss in electron richness in their internal matrix. These megamitochondria also showed signs of decreased respiratory chain function, particularly in respiratory complex IV which only functioned at about 50% efficiency. Similar changes were identified in the mitochondria of a liver sample removed during transplant from a 5-year-old boy suffering from MMA.
Benign mut phenotype
Recent case studies in several patients presenting nonresponsive mut0 MMA with a specific mutation designated p.P86L have suggest the possibility of further subdivision in mut type MMA might exist. Though currently unclear if this is due to the specific mutation or early detection and treatment, despite complete nonresponse to cobalamin supplements, these individuals appeared to develop a largely benign and near completely asymptomatic version of MMA. Despite consistently showing elevated methylmalonic acid in the blood and urine, these individuals appeared for the large part developmentally normal.
Notable cases
Ryan Stallings, a St. Louis infant, was mistakenly diagnosed with ethylene glycol poisoning instead of MMA in 1989, leading to a wrongful murder conviction and life sentence for his mother, Patricia Stallings.
See also
Combined malonic and methylmalonic aciduria (CMAMMA)
Isovaleric acidemia
Propionic acidemia
Maple syrup urine disease
Notes
References
Further reading
== External links == |
Hemopericardium | Hemopericardium refers to blood in the pericardial sac of the heart. It is clinically similar to a pericardial effusion, and, depending on the volume and rapidity with which it develops, may cause cardiac tamponade.The condition can be caused by full-thickness necrosis (death) of the myocardium (heart muscle) after myocardial infarction, chest trauma, and by over-prescription of anticoagulants. Other causes include ruptured aneurysm of sinus of Valsalva and other aneurysms of the aortic arch.Hemopericardium can be diagnosed with a chest X-ray or a chest ultrasound, and is most commonly treated with pericardiocentesis. While hemopericardium itself is not deadly, it can lead to cardiac tamponade, a condition that is fatal if left untreated.
Symptoms and signs
Symptoms of hemopericardium often include difficulty breathing, abnormally rapid breathing, and fatigue, each of which can be a sign of a serious medical condition not limited to hemopericardium. In many cases, patients also report feeling chest pressure and have an abnormally elevated heart rate.
Cause
Hemopericardium has been reported to result from various afflictions including chest trauma, free wall rupture after a myocardial infarction, bleeding into the pericardial sac following a type A aortic dissection, and as a complication of invasive cardiac procedures. Acute leukemia has also been reported as a cause of the condition. Several cases of hemopericardium have also been reported as a side-effect of anticoagulants. Patients should be made aware of this fact when prescribed these drugs.
Mechanism
Hemopericardium is a condition that affects the cardiovascular system. It typically begins with blood accumulating in the pericardial sac posterior to the heart, and eventually expands to surround the entire heart. The fluid build-up then causes pressure within the pericardial sac to increase. If the pressure becomes greater than the intracardiac pressure of the heart, compression of the adjacent cardiac chambers can occur. This compression, called cardiac tamponade, is often associated with hemopericardium and can be fatal if not diagnosed and treated promptly. Early signs of this compression include right atrial inversion during ventricular systole followed by diastolic compression of the right ventricular outflow tract.There have also been cases reported in which hemopericardium was noted as an initial manifestation of essential thrombocythemia.
Diagnosis
Hemopericardium can be diagnosed using echocardiography, a cardiac ultrasound. Chest X-rays are also often taken when hemopericardium is suspected and would reveal an enlarged heart. Other observable signs include rapid heart rate, jugular venous distension, low blood pressure, and pulsus paradoxus.
Treatment
When discovered, hemopericardium is usually treated by pericardiocentesis, a procedure wherein a needle is used to remove the fluid from the pericardial sac. This procedure typically utilizes an 8-cm, 18-gauge needle that is inserted between the xiphoid process and the left costal margin until it enters the pericardial sac, when it can then be used to drain the fluid from the sac. A catheter is often left in the pericardium to continue draining any remaining fluid after the initial procedure. The catheter can be removed when the hemopericardium no longer persists. The underlying causes of the condition, such as over-prescription of anticoagulants, must be addressed as well so that the hemopericardium does not return.While hemopericardium itself is not fatal, it may lead to cardiac tamponade, which can be deadly if not treated promptly. One study found that cardiac tamponade was fatal in 13.3% of cases in which it was not caused by a malignant disease.
Research
Studies have shown that hemopericardium can occur spontaneously in people with essential thrombocythemia, although this is relatively rare. It is a more common occurrence in patients who have been over-prescribed anticoagulants. Regardless of the underlying cause of the hemopericardium, pericardiocentesis has shown to be the best treatment method for the condition.
References
== External links == |
Autoimmune polyendocrine syndrome | Autoimmune polyendocrine syndromes (APSs), also called polyglandular autoimmune syndromes (PGASs) or polyendocrine autoimmune syndromes (PASs), are a heterogeneous group of rare diseases characterized by autoimmune activity against more than one endocrine organ, although non-endocrine organs can be affected. There are three types of APS, and there are a number of other diseases which involve endocrine autoimmunity.
Types
Autoimmune polyendocrine syndrome type 1, an autosomal recessive syndrome due to mutation of the AIRE gene resulting in hypoparathyroidism, adrenal insufficiency, hypogonadism, vitiligo, candidiasis and others.
Autoimmune polyendocrine syndrome type 2, an autosomal dominant syndrome due to multifactorial gene involvement resulting in adrenal insufficiency plus hypothyroidism and/or type 1 diabetes.
Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX syndrome) is X-linked recessive due to mutation of the FOXP3 gene on the X chromosome. Most patients develop diabetes and diarrhea and many die due to autoimmune activity against many organs. Boys are affected, while girls are carriers and might experience mild disease.
Cause
Each "type" of this condition has a different genetic cause. IPEX syndrome is inherited in males by an X-linked recessive process. The FOXP3 gene, whose cytogenetic location is Xp11.23, is involved in the mechanism of the IPEX condition.
Diagnosis
Diagnosis for type 1 of this condition for example, sees that the following methods/tests are available:
Endoscopic
CT scan
Histologic test
Differential diagnosis
For this condition, differential diagnosis sees that the following should be considered:
CD25 deficiency
STAT5B deficiency
Severe combined immunodeficiency
X linked thrombocytopenia
Management
Immunosuppressive therapy may be used in type I of this condition. Ketoconazole can also be used for type I under certain conditions.The component diseases are managed as usual; the challenge is to detect the possibility of any of the syndromes and to anticipate other manifestations. For example, in a person with known type 2 autoimmune polyendocrine syndrome but no features of Addisons disease, regular screening for antibodies against 21-hydroxylase may prompt early intervention and hydrocortisone replacement to prevent characteristic crises
See also
Immunosuppression
References
Further reading
Improda, Nicola; Capalbo, Donatella; Cirillo, Emilia; Cerbone, Manuela; Esposito, Andrea; Pignata, Claudio; Salerno, Mariacarolina (1 November 2014). "Cutaneous vasculitis in patients with autoimmune polyendocrine syndrome type 1: report of a case and brief review of the literature". BMC Pediatrics. 14: 272. doi:10.1186/1471-2431-14-272. ISSN 1471-2431. PMC 4286916. PMID 25361846.
Shoenfeld, Yehuda; Cervera, Ricard; Gershwin, M. Eric (2008). Diagnostic Criteria in Autoimmune Diseases. Springer Science & Business Media. ISBN 9781603272858.
External links
Diseases Database (DDB): 29690
PubMed |
Vesicouterine fistula | Vesicouterine fistula refers to an abnormal communication between the bladder and uterus. The first case of vesicouterine fistula was reported in 1908. It was however first described in 1957 by Abdel Fattah Youssef, an obstetrician and gynaecologist in Kasr el-Aini hospital, Cairo, Egypt. It is characterized by a vesicouterine fistula above the level of the internal os, absence of menstrual bleeding, cyclical presence of blood in urine and absence of urinary incontinence with a patent cervical canal following a lower segment caesarean section. Six of such cases had been reported by other clinicians before the term Menouria was coined by Youssef.
Pathology
Vesicouterine fistula is the least common type of urogenital fistula accounting for 1-4% of urogenital fistulas. It occurs following lower segment caesarean section and the incidence is increasing due to the increasing incidence of caesarean deliveries. The occurrence of menoruria in the absence of vaginal bleeding or passage of urine from the vagina is attributed to a sphincteric mechanism of the uterine isthmus.Jozwik and Jozwik classified vesicouterine fistula into three types based on the route of menstrual flow;I - Menstrual flow from the bladder only without urinary incontinence
II - Menstrual flow from both the bladder and vagina with urinary incontinence
III - Normal menstrual flow from the vagina only (no menouria) with urinary incontinence
Youssef syndrome corresponds to a type I vesicouterine fistula.
Causes
Vesicouterine fistulas occur most commonly after lower segment caesarean sections (about 83-93% of cases). The possible mechanisms by which vesicouterine fistulas occur following caesarean sections include undetected bladder injury during caesarean section, inadvertent placement of a suture through the bladder during the repair of the uterus and abnormal blood vessel connections following multiple caesarean sections.It may also present following use of obstetric forceps, manual placenta removal, external cephalic version, morbidly adherent placenta, surgical removal of fibroids, rupture of the uterus, perforation of the uterus and radiation therapy in the treatment of cervical cancer.Vesicouterine fistula can also occur as a birth defect in conjunction with vaginal atresia.
Diagnosis
The diagnosis of a vesicouterine fistula is made by demonstrating an abnormal connection between the cavities of the bladder and uterus. It can be diagnosed using hysterosalpingography, hysterography, cystography, magnetic resonance imaging (MRI) and computerised tomography. MRI has been found to have 100% accuracy in the diagnosis of vesicouterine fistula. It is also less invasive than other modalities and is considered the gold standard for diagnosis.
Treatment
The options of treatment include watchful waiting for spontaneous resolution of the fistula, use of medications that can stop menstrual periods such as oral contraceptive pills, progesterone and gonadotropin releasing hormone analogs. Surgery can be carried out through the vagina, bladder or peritoneum and can be done via laparoscopic or robotic surgery.Watchful waiting is the treatment of choice in case of small fistulas. The bladder is catheterised for a period of 4 to 8 weeks in order to allow spontaneous closure of the vesicouterine fistula. Fulguration of the fistula can also be done via cystoscopy in cases of small fistulas.
Differential diagnosis
Endometriosis
See also
Obstetric Fistula
== References == |
Cyclic vomiting syndrome | Cyclic vomiting syndrome (CVS) is a chronic functional condition of unknown pathogenesis. CVS is characterized as recurring episodes lasting a single day to multiple weeks. Each episode is divided into four phases: inter-episodic, prodrome, vomiting, and recovery. Inter-episodic phase (symptom free phase), is characterized as no discernible symptoms, normal everyday activities can occur, and this phase typically lasts one week to one month. The prodrome phase is known as the pre-emetic phase, characterized by the initial feeling of an approaching episode, still able to keep down oral medication. Emetic or vomiting phase is characterized as intense persistent nausea, and repeated vomiting typically lasting hours to days. Recovery phase is typically the phase where vomiting ceases, nausea diminishes or is absent, and appetite returns. This syndrome is most commonly seen in children usually between ages 3 and 7, however adult diagnosis is quite common. This disorder is thought to be closely related to migraines and family history of migraines.
Signs and symptoms
Affected individuals may vomit or retch 6–12 times in an hour and an episode may last from a few hours to over three weeks and in some cases months, with a median episode duration of 41 hours. Stomach acid, bile and, if the vomiting is severe, blood may be vomited. Some with the condition will ingest water to reduce the irritation of bile and acid on the esophagus during emesis. Between episodes, the affected individual is usually normal and healthy otherwise but can be in a weak state of fatigue or experience muscle pain. In approximately half of cases the attacks, or episodes, occur in a time-related manner. Each attack is stereotypical; that is, in any given individual, the timing, frequency and severity of attacks is similar. Some affected people experience episodes that progressively get worse when left untreated, occurring more frequently with reduced symptom free phase.Episodes may happen every few days, every few weeks or every few months, for some happening at common uniform times, typically mornings. For other affected people, there is not a pattern in time that can be recognized. Some with the condition have a warning of an episodic attack; they may experience a prodrome, some documented prodromal symptoms include: unusually intense nausea and pallor, excess salivation, sweating, flushing, rapid/irregular heartbeat, diarrhea, anxiety/panic, food aversion, restlessness/insomnia, irritability, depersonalization, fatigue/listlessness, intense feelings of being hot or chilled, intense thirst, shivering/shaking, retching, tachypnea, abdominal pain/cramping, limb paresthesias, hyperesthesia, photophobia, phonophobia, headache, and dyspnea, heightened sensitivity, especially to light, though sensitivity to smell, sound, pressure, and temperature, as well as oncoming muscle pain and fatigue, are also reported by some patients. Many experiences a full panic attack when nausea begins and continue to panic once the vomiting has begun. Medications like Lorazepam, Alprazolam, and other benzodiazepines are prescribed by their doctors and instructed to take immediately at the onset of any of their CVS symptoms and/or triggers. Some prodromal symptoms are present inter-episodically as well as during acute phases of illness. The majority of affected people can identify triggers that may precede an attack. The most common are various foods, infections (such as colds), menstruation, extreme physical exertion, lack of sleep, and psychological stresses, both positive and negative.An affected person may also be light-sensitive (photophobic), sound-sensitive (phonophobic) or, less frequently, temperature- or pressure-sensitive during an attack. Some people also have a strong urge to bathe in warm or cold water. In fact, many people with CVS experience a compulsion to be submerged in hot water, and end up taking several baths during the duration of an episode. For some the psychological compulsion to be in hot water is so extreme that they cannot stop themselves from taking very long baths in near scalding hot water several times per day. For some of these people, they may have just finished taking a lengthy bath in extremely hot water and immediately feel this compulsion again and end up taking another bath right after drying off. Some people with the condition experience insomnia, diarrhea (GI complications), hot and cold flashes, and excessive sweating before an episode. Some report that they experience a restless sensation or stinging pain along the spine, hands, and feet followed by weakness in both legs. Some of these symptoms may be due to dehydration or hypokalemia from excessive vomiting, rather than the underlying cause of CVS.
Genetics
There is no known genetic pathogenesis for CVS. Recent studies suggest many affected individuals have a family history of related conditions, such as migraines, psychiatric disorders and gastrointestinal disorders. Inheritance is thought to be maternal, a possible genetic mitochondrial inheritance. Adolescents show higher possible mitochondrial inheritance and maternal inheritance than found in adults. Single base-pair and DNA rearrangements in the mitochondrial DNA (mtDNA) have been associated with these traits.
Diagnosis
The cause of CVS has not been determined and there are no diagnostic tests for CVS. Several other medical conditions, such as cannabinoid hyperemesis syndrome (CHS), can mimic the same symptoms, and it is important to rule these out. If all other possible causes have been excluded, a diagnosis of CVS using Rome criteria by a physician may be appropriate.Once formal investigations to rule out gastrointestinal or other causes have been conducted, these tests do not need to be repeated in the event of future episodes.
Diagnostic criteria
Due to the lack of specific biomarkers available for the disorder, and if all other possible causes can be ruled out (such as intestinal malrotation), physicians rely on the Rome IV process criteria in order to diagnose patients. Patients must meet all three of the following criteria to receive diagnosis:
Stereotypical episodes of acute vomiting each with a duration of less than 1 week
A history of at least three discrete episodes in the prior year and at least two episodes in the past 6 months, each occurring at least 1 week apart
An absence of vomiting between episodes, but other milder symptoms can be present between cyclesCriteria must be fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis. A history of family history of migraine headaches can also be used in facilitating diagnosis.
Treatment
Treatment for cyclic vomiting syndrome depends on the evident phase of the disorder.Because the symptoms of CVS are similar (or perhaps identical) to those of the disease well-identified as "abdominal migraine," prophylactic migraine medications, such as topiramate and amitriptyline, have seen recent success in treatment for the prodrome and vomiting phases, reducing the duration, severity, and frequency of episodes.Therapeutic treatment for the prodromal phase, characterized by the anticipation of an episode, consists of sumatriptan (nasal or oral) an anti-migraine medication, anti-inflammatory drugs to reduce abdominal pain, and possible anti-emetic drugs. These options may be helpful in preventing an episode or reducing the severity of an attack.The most common therapeutic strategies for those already in the vomiting phase are maintenance of salt balance by appropriate intravenous fluids and, in some cases, sedation. Having vomited for a long period prior to attending a hospital, patients are typically severely dehydrated. For a number of patients, potent anti-emetic drugs such as ondansetron (Zofran) or granisetron (Kytril), and dronabinol (Marinol) may be helpful in either preventing an attack, aborting an attack, or reducing the severity of an attack. Many patients seek comfort during episodes by taking prolonged showers and baths typically quite hot. The use of a heating pad may also help reduce abdominal pain.Lifestyle changes may be recommended, such as extended rest, reduction of stress, frequent small meals, and to abstain from fasting. A diet change may be recommended avoid food allergens, eliminating trigger foods such as chocolates, cheese, beer, and red wine.Some patients experience relief from inhaled isopropyl alcohol.
Prognosis
Fitzpatrick et al. (2007) identified 41 children with CVS. The mean age of the sample was 6 years at the onset of the syndrome, 8 years at first diagnosis, and 13 years at follow-up. As many as 39% of the children had resolution of symptoms immediately or within weeks of the diagnosis. Vomiting had resolved at the time of follow-up in 61% of the sample. Many children, including those in the remitted group, continued to have somatic symptoms such as headaches (in 42%) and abdominal pain (in 37%).Most children who have this disorder miss on average 24 school days a year. The frequency of episodes is higher for some people during times of excitement. Charitable organizations to support affected people and their families and to promote knowledge of CVS exist in several countries.
A 2005 study by Fleisher et al. identified 41 adults who had been previously seen for complaints compatible with CVS. The average age at presentation of the sample was 34 years, and the mean age at onset was 21 years. The mean duration of the CVS at the time of consultation was 12 years. Of the 39 patients surveyed, 85% had episodes that were fairly uniform in length. Most patients reported these attacks in the morning hours. Of those 39 patients, 32% were completely disabled and required financial support due to CVS. Despite this, data suggests that the prognosis for CVS is generally favorable.Complications can include dehydration, dental caries, or an esophageal tear.
Epidemiology
The average age at onset is 3–7 years, with described cases as young as 6 days and as old as 73 years. Typical delay in diagnosis from onset of symptoms is 3 years. Females show a slight predominance over males.One study found that 3 in 100,000 five-year-olds are diagnosed with the condition. Two studies on childhood CVS suggest nearly 2% of school-age children may have CVS.
History
Cyclic vomiting syndrome was first described in France by Swiss physician Henri Clermond Lombard and first described in the English language by pediatrician Samuel Gee in 1882.It has been suggested that Charles Darwins adult illnesses may have been due to this syndrome.
See also
Migraine
References
Further reading
External links
Cyclic Vomiting Syndrome Emedicine article
CVS page at the US National Digestive Diseases Clearinghouse, NIH Publication No. 04-4548
Cyclic Vomiting Syndrome on rarediseases.org |
Torsion dystonia | Torsion dystonia, also known as dystonia musculorum deformans, is a disease characterized by painful muscle contractions resulting in uncontrollable distortions. This specific type of dystonia is frequently found in children, with symptoms starting around the ages of 11 or 12. It commonly begins with contractions in one general area such as an arm or a leg that continue to progress throughout the rest of the body. It takes roughly 5 years for the symptoms to completely progress to a debilitating state.
Causes
The disease is caused by a genetic disorder which results in a defect in a protein called Torsin A. A mutation in the DYT1 gene causes the loss of an amino acid, glutamic acid, in the Torsin A protein. Torsin A is an evolutionarily conserved AAA+ ATPase. The defective protein creates a disruption in communication in neurons that control muscle movement and muscle control. This mutation is most usually inherited from a parent, but can occur sporadically. The disease is caused by a dominant allele, meaning that the person affected needs only one copy of the mutated DYT1 gene to have symptoms. However, only 30 to 40 percent of those that do have the gene actually have symptoms, leading researchers to believe that there are other factors involved.
Diagnosis
Classification
There are several types of torsion dystonia that affect different areas of the body. However, it is unknown if the gene that causes Early Onset Torsion Dystonia is responsible for the other dystonias as well.
Cervical dystonia (spasmodic torticollis): A type of dystonia that affects the head, neck and spine. It can create problems by the characteristic turning of the head and neck from side to side.
Blepharospasm: This type of dystonia causes involuntary contraction of the eyelids. The main concern for this dystonia is that it can cause the eyelids to close involuntarily and for indefinite periods of time.
Oromandibular dystonia: A dystonia of the jaw, lips, and/or the tongue. It can make eating and swallowing very complicated due to the jaw being held open or shut for periods of time.
Spasmodic dysphonia: A dystonia of the vocal cords. The complications surrounding this form of dystonia are speech related and can cause symptoms such as speech that wavers, speech that sounds like a whisper, or speech that is hesitant.
Writers cramp (occupational dystonia): A dystonia that affects the muscles of the hand and forearm. It is triggered by attempting to write or execute other fine-motor hand functions.
Orofacial-Buccal dystonia (Meiges or Brueghals Syndrome): A combination of blepharospasm and oromandibular dystonia.
Early-onset torsion dystonia: The most severe type of dystonia, it begins in an arm or leg and progresses to the rest of the body until the person — in most cases, a child — is reliant on a wheelchair.
Treatment
There is no cure for torsion dystonia. However, there are several medical approaches that can be taken in order to lessen the symptoms of the disease. The treatment must be patient specific, taking into consideration all of the previous and current health complications. The doctor that creates the treatment must have intimate knowledge of the patients health and create a treatment plan that covers all of the symptoms focusing on the most chronic areas.
The first step for most with the disorder begins with some form of physical therapy in order for the patient to gain more control over the affected areas. The therapy can help patients with their posture and gain control over the areas of their body that they have the most problems with.
The second step in the treatment process is medication. The medications focus on the chemicals released by neurotransmitters in the nervous system, which control muscle movement. The medications on the market today are anticholinergics, benzodiazepines, baclofen, dopaminergic agents/dopamine-depleting agents, and tetrabenazine. Each medication is started on a low dosage and gradually increased to higher doses as the disease progresses and the side effects are known for the individual.
A more site-specific treatment is the injection of botulinum toxin. It is injected directly into the muscle and works much the same way the oral medications do—by blocking neurotransmitters. The injections are not a treatment for the disease, but are a means to control its symptoms.
A fourth option in the treatment for the symptoms of torsion dystonia is surgery. Surgery is performed only if the patient does not respond to the oral medications or the injections. The type of surgery performed is specific to the type of dystonia that the patient has. A systematic review found that some patients benefit from deep brain stimulation (DBS) surgery, but the studies may have been subject to financial bias.
Prevalence
The disease is more commonly found amongst Ashkenazi Jews. The occurrence of torsion dystonia in the Ashkenazi Jewish population as stated by the Department of Epidemiology and Public Health of Yale University School of Medicine in New Haven, Connecticut; "Reports dating to the beginning of this century describe Ashkenazi Jewish (AJ) families with multiple cases of ITD either in siblings (Schwalbe 1908; Bernstein 1912; Abrahamson 1920) or in parents and offspring (Wechsler and Brock 1922; Mankowsky and Czerny 1929; Regensberg 1930). The first comprehensive evaluation of the mode of inheritance of ITD in Jewish and non-Jewish families was described by Zeman and Dyken (1967), who concluded that the disorder was inherited as an autosomal dominant with incomplete penetrance in both populations. Although they concluded that the gene frequency was higher in the AJ population than in non-Jews, no difference in mode of inheritance or disease mechanism was construed."
Research
A 1969 study of torsion dystonia patients found an average IQ 10 points higher than controls matched for age, sex and ethnic background.
References
Further reading
https://web.archive.org/web/20060903085219/http://www.biochem.arizona.edu/classes/bioc461/Biochem499/AngelaPulsifer/dystonia1.htm
Risch, N. J.; Bressman, S. B.; Deleon, D; Brin, M. F.; Burke, R. E.; Greene, P. E.; Shale, H; Claus, E. B.; Cupples, L. A.; Fahn, S (1990). "Segregation analysis of idiopathic torsion dystonia in Ashkenazi Jews suggests autosomal dominant inheritance". American Journal of Human Genetics. 46 (3): 533–8. PMC 1683634. PMID 2309703.
== External links == |
Piblokto | Piblokto, also known as pibloktoq and Arctic hysteria, is a condition most commonly appearing in Inughuit (Northwest Greenlandic Inuit) societies living within the Arctic Circle. Piblokto is a culture-specific hysterical reaction in Inuit, especially women, who may perform irrational or dangerous acts, followed by amnesia for the event. Piblokto may be linked to repression of the personality of Inuit women. The condition appears most commonly in winter. It is considered to be a form of a culture-bound syndrome, although more recent studies (see Skepticism section) question whether it exists at all. Piblokto is also part of the glossary of cultural bound syndromes found in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
History
Piblokto was first documented in 1892 and reports by European explorers describe the phenomenon as common to all Arctic regions. Explorers were the first to record piblokto in writing. Among these, Admiral Robert Peary provided a detailed look into the disorder during an expedition to Greenland. Peary and his men found the acts they witnessed among the Inuit women entertaining, and, having sent the womens male counterparts out on missions, became sexually involved with the remaining women. Piblokto is not limited to the indigenous people; reports of stranded sailors during the 1800s exhibiting the same symptoms have been found. The disorder is said to have existed before Western contact and still occurs today. However, as discussed below, many scholars now hold that culture bound disorders may often be an artifact of colonial encounters, and contemporary discussions of piblokto in medical anthropology and cross-cultural psychiatry consider it to be an example of the suspect nature of culture bound syndromes.
Origin
Piblokto is most often found in but not confined to the Inughuit culture in the polar regions of northern Greenland. Similar symptoms have been reported in European sailors stranded in Arctic regions in the 1800s. Among the Inughuit, the attacks are not considered out of the ordinary. No native theory of the disorder is currently reported. This condition is most often seen in Inughuit women. Piblokto is most common during long Arctic nights.
Symptoms
Piblokto is an abrupt dissociative episode with four phases: social withdrawal, excitement, convulsions and stupor, and recovery. In his book Handbook of Cultural Psychiatry, Wen-Shing Tseng provides the following example adapted from Foulks:
Mrs. A is a 30-year-old woman who has had periodic episodes of "strange experiences" in the past 3 years (since her mothers death). Three years ago, in the winter, during her first episode, she was acutely assaultive and tried to harm herself. The attack lasted about 15 min and she remembered nothing about it afterward. Two years ago, she had her second attack, which lasted about half an hour, during which time she ran from her home into the snow, tearing off her clothing.
Causes
Although there is no known cause for piblokto, Western scientists have attributed the disorder to the lack of sun, the extreme cold, and the desolate state of most villages in the region. A cause for this disorder present in this culture may be the isolation of their cultural group.This culture-bound syndrome is possibly linked to vitamin A toxicity (hypervitaminosis A). The native Inughuit diet or Eskimo nutrition provides rich sources of vitamin A through the ingestion of livers, kidneys, and fat of arctic fish and mammals and is possibly the cause or a causative factor. This causative factor is through the toxicity that has been reported for males, females, adults, children, and dogs. The ingestion of organ meats, particularly the livers of some Arctic mammals, such as the polar bear and bearded seal, in whom the vitamin is stored at levels toxic to humans, can be fatal to most people.
Inughuit tradition states that it is caused by evil spirits possessing the living. Shamanism and animism are dominant themes in Inughuit traditional beliefs with the angakkuq (healer) acting as a mediator with the supernatural forces. Angakkuit use trance states to communicate with spirits and carry out faith healing. There is a view among the Inughuit that individuals entering trance states should be treated with respect, given the possibility of a new "revelation" emerging as a result. Treatment in piblokto cases usually involves allowing the episode to run its course without interference. While piblokto can often be confused with other conditions (including epilepsy), in which failure to intervene can lead to the victim coming to harm, most cases tend to be benign.
Skepticism
Although piblokto has a place in the historical record and official medical canons, a number of Arctic researchers and Arctic residents doubt its existence. The phenomenon, they suggest, may be more rooted in the experience and behavior of the early European explorers than the Inuit themselves.In 1988 Parks Canada historian Lyle Dick began a substantial challenge to the concept that piblokto exists at all. Dick examined the original records of the European Arctic explorers, and ethnographic and linguistic reports on Inughuit societies, and discovered that not only is the majority of academic speculation into piblokto based on reports of only eight cases, but the word "piblokto" / "pibloktoq" does not exist within Inuktun (the Inughuit language); possibly, Dick concluded, this may have been the result of errors in phonetic transcription. In a 1995 paper published in the journal Arctic Anthropology, and in his 2001 book Muskox land: Ellesmere Island in the Age of Contact, Dick suggests that piblokto is a "phantom phenomenon", arising more from the Inuhuit reaction to European explorers in their midst.Similarly, Hughes and Simons have described piblokto as a "catch-all rubric under which explorers lumped various Inuhuit anxiety reactions, expressions of resistance to patriarchy or sexual coercion, and shamanistic practice". Simply put, rather than understanding piblokto as a strange cultural phenomenon, some critical scholars now understand it to be an expression of trauma of colonial violence, including rape. For example, transcultural psychiatry scholar Laurence Kirmayer writes:
Most comprehensive psychiatric texts mention pibloktoq as a culture-bound syndrome characterized by sudden wild and erratic behaviour. Recently, the historian Lyle Dick collected all the published accounts of pibloktoq, of which there are only about 25. It seems that psychiatric case description transformed a situation of sexual exploitation of Inuit women by explorers into a discrete disorder worthy of a new diagnostic label. With hindsight, we can see how insensitivity to the impact of exploration on other peoples distorted the picture when vital information on social context was not included. The legacy of these colonialist blinkers is still with us ...
See also
Wendigo
Cabin fever
Kayak angst
Prairie madness
Menerik (ru) (sometimes meryachenie) – a condition similar to piblokto found in Siberia among Yakuts, Yukagirs, and Evenks. Sidorov and Davydov draw a distinction between piblokto-like menerik and latah-like meryachenie. Others use meryachenie as an umbrella term for both piblokto-like and latah-like states.
Culture-bound syndrome
Notes
References
Further reading
Landy D (1985). "Pibloktoq (hysteria) and Inuit nutrition: possible implication of hypervitaminosis A". Soc Sci Med. 21 (2): 173–85. doi:10.1016/0277-9536(85)90087-5. PMID 4049004.
Parker, S (1962). "Eskimo psychopathology in the context of Eskimo personality and culture". American Anthropologist. 64: 76–96. doi:10.1525/aa.1962.64.1.02a00080.
Higgs, Rachel D. (2011) "Pibloktoq - A study of a culture-bound syndrome in the circumpolar region," The Macalester Review: Vol. 1: Iss. 1, Article 3. |
Gastric lymphoma | Primary gastric lymphoma (lymphoma that originates in the stomach itself) is an uncommon condition, accounting for less than 15% of gastric malignancies and about 2% of all lymphomas. However, the stomach is a very common extranodal site for lymphomas (lymphomas originate elsewhere and metastasise to the stomach). It is also the most common source of lymphomas in the gastrointestinal tract.
Signs and symptoms
Symptoms include epigastric pain, early satiety, fatigue and weight loss. Most people affected by primary gastric lymphoma are over 60 years old.
Risk factors
Risk factors for gastric lymphoma include the following:
Helicobacter pylori
Long-term immunosuppressant drug therapy
HIV infection
Pathophysiology
The majority of gastric lymphomas are non-Hodgkins lymphoma of B-cell origin. These tumors may range from well-differentiated, superficial involvements (MALT) to high-grade, large-cell lymphomas. Sometimes, its hard to differentiate poorly differentiated high grade B-cell gastric lymphoma from gastric adenocarcinoma clinically or radiologically, yet histopathology with immunohistochemistry is recommended to stain specific markers on the malignant cell that favor the diagnosis of lymphoma. Immunohistochemistry stains specific clusters of differentiation that are present on B-cells like CD20. Cytokeratin is also a surface marker that is presented on epithelial cells, is stained histochemically and favors the diagnosis of epithelial tumors like adenocarcinoma.
Differentiating poor gastric lymphoma from adenocarcinoma is essential because the prognosis and modalities of treatment differ significantly.
Other lymphomas involving the stomach include mantle cell lymphoma and T-cell lymphomas which may be associated with enteropathy; the latter usually occur in the small bowel but have been reported in the stomach.
Diagnosis
These lymphomas are difficult to differentiate from gastric adenocarcinoma. The lesions are usually ulcers with a ragged, thickened mucosal pattern on contrast radiographs.
The diagnosis is typically made by biopsy at the time of endoscopy. Several endoscopic findings have been reported, including solitary ulcers, thickened gastric folds, mass lesions and nodules. As there may be infiltration of the submucosa, larger biopsy forceps, endoscopic ultrasound guided biopsy, endoscopic submucosal resection, or laparotomy may be required to obtain tissue.
Imaging investigations including CT scans or endoscopic ultrasound are useful to stage disease. Hematological parameters are usually checked to assist with staging and to exclude concomitant leukemia. An elevated LDH level may be suggestive of lymphoma.
Treatment
Diffuse large B-cell lymphomas of the stomach are primarily treated with chemotherapy with CHOP (cyclophosphamide+doxorubicine+vincristine+prednisone) with or without rituximab being a usual first choice.Antibiotic treatment to eradicate H. pylori is indicated as first line therapy for MALT lymphomas. About 80% of MALT lymphomas completely regress with eradication therapy. Radiation treatment for H. pylori negative gastric malt lymphoma, has a high success rate, 90% or better after 5 years. Second line therapy for MALT lymphomas is usually chemotherapy with a single agent, and complete response rates of greater than 70% have been reported.Subtotal gastrectomy, with post-operative chemotherapy is undertaken in refractory cases, or in the setting of complications, including gastric outlet obstruction.
See also
Lymphoepithelial lesion
== References == |
Chronic prostatitis | Chronic prostatitis may refer to:
Chronic prostatitis/chronic pelvic pain syndrome (about 90-95% of cases)
Chronic bacterial prostatitis
Asymptomatic inflammatory prostatitis |
Telogen effluvium | Telogen effluvium is a scalp disorder characterized by the thinning or shedding of hair resulting from the early entry of hair in the telogen phase (the resting phase of the hair follicle). It is in this phase that telogen hairs begin to shed at an increased rate, where normally the approximate rate of hair loss (having no effect on ones appearance) is 125 hairs per day.There are 5 potential alterations in the hair cycle that could lead to this shedding: immediate anagen release, delayed anagen release, short anagen syndrome, immediate telogen release, and delayed telogen release.
Immediate anagen release occurs when follicles leave anagen and are stimulated to enter telogen prematurely. The effects become visible 2–3 months later with increased telogen effluvium.
Delayed anagen release, most commonly associated with pregnancy, involves the prolongation of anagen under the effect of pregnancy hormones, resulting in delayed but synchronous and heavy postpartum hair shedding.
Short anagen syndrome is characterized by an idiopathic and persistent telogen hair shedding, as well as the inability to grow hair long. This is a result of the shortening of the duration of anagen, meaning a greater number of telogen hairs at any given time, and is responsible for the majority of chronic TE cases.
Immediate telogen release generally occurs with drug-induced shortening of telogen leading to the premature reentrance of follicles to anagen, which causes a massive release of club (telogen) hairs. Drugs such as minoxidil can precipitate immediate telogen release.
Delayed telogen release involves a prolonged telogen phase followed by a delayed transition to anagen. This occurs in animals with synchronous hair cycles that shed their hair or winter coats seasonally. This is also sometimes responsible for seasonal hair loss in humans.Emotional or physiological stress may result in an alteration of the normal hair cycle and cause the disorder, with potential causes including eating disorders, crash diets, pregnancy and childbirth, chronic illness, major surgery, anemia, severe emotional disorders, hypothyroidism, and drugs.Diagnostic tests, which may be performed to verify the diagnosis, include a trichogram, trichoscopy and biopsy. Effluvium can present with similar appearance to alopecia totalis, with further distinction by clinical course, microscopic examination of plucked follicles, or biopsy of the scalp. Histology would show telogen hair follicles in the dermis with minimal inflammation in effluvium, and dense peribulbar lymphocytic infiltrate in alopecia totalis.Vitamin D levels may also play a role in the normal hair cycle.Many new cosmetic treatments have been reported, including stemoxydine, Nioxin, minoxidil, and a leave-on technology combination: caffeine, niacinamide, panthenol, dimethicone, and an acrylate polymer (CNPDA). This treatment has shown to increase the diameter of existing, individual scalp hair fibres by 2–5 μm, yielding a significant increase of approximately 10% in the cross-sectional area of each hair. Additionally, CNPDA-thickened hairs also demonstrate altered mechanical properties of thicker fibres; increased suppleness/pliability, and increased ability to withstand force without breaking.
See also
Anagen effluvium
Noncicatricial alopecia
References
== External links == |
Ring chromosome | A ring chromosome is an aberrant chromosome whose ends have fused together to form a ring. Ring chromosomes were first discovered by Lilian Vaughan Morgan in 1926. A ring chromosome is denoted by the symbol r in human genetics and R in Drosophila genetics. Ring chromosomes may form in cells following genetic damage by mutagens like radiation, but they may also arise spontaneously during development.
Formation
In order for a chromosome to form a ring, both ends of the chromosome are usually missing, enabling the broken ends to fuse together. In rare cases, the telomeres at the ends of a chromosome fuse without any loss of genetic material, which results in a normal phenotype.Complex rearrangements, including segmental microdeletions and microduplications, have been seen in numerous ring chromosomes, providing important clues regarding the mechanisms of their formation.Small supernumary rings can also form, resulting in a partial trisomy.Ring chromosomes are unstable during cell division and can form interlocking or fused rings.
Associated syndromes
Human genetic disorders can be caused by ring chromosome formation. Although ring chromosomes are very rare, they have been found in all human chromosomes. Symptoms seen in patients carrying ring chromosomes are more likely to be caused by the deletion of genes in the telomeric regions of affected chromosomes, rather than by the formation of a ring structure itself. Almost all ring chromosome syndromes feature marked growth delay.Ring chromosomes can be inherited or sporadic. Mosaicism is common and affects the severity of the condition. Location of fusion also affects severity due to loss of differing amounts of genetic material from the ends of chromosomes.
Disorders arising from the formation of a ring chromosome include:
See also
Chromosome abnormalities
References
External links
Atlas of Genetics and Cytogenetics in Oncology and Haematology, explains HOW the ring formation causes abnormalities. |
Schnitzler syndrome | Schnitzler syndrome or Schnitzlers syndrome is a rare disease characterised by onset around middle age of chronic hives (urticaria) and periodic fever, bone pain and joint pain (sometimes with joint inflammation), weight loss, malaise, fatigue, swollen lymph glands and enlarged spleen and liver.Schnitzler syndrome is considered an autoinflammatory disorder and is generally treated with anakinra, which inhibits interleukin 1. This treatment controls the condition but does not cure it. Around 15% of people develop complications, but the condition generally does not shorten life.
Classification
Schnitzler syndrome is a late-onset autoinflammatory disorder.
Signs and symptoms
The typical onset is at around 55 years old, and the symptoms are recurrent hives, mostly on the torso and limbs, often with recurring fever, joint pain, bone pain, muscle pain, headache, fatigue, and loss of weight.
Cause
As of 2017 the cause of the disease was not understood.
Diagnosis
Blood tests show a high concentration of specific gamma-globulins (monoclonal gammopathy) of the IgM type. It almost always has light chains of the κ-type. A variant in which IgG is raised has been described, which appears to be one-tenth as common. The immunoglobulins may show up in the urine as Bence Jones proteins. Signs of inflammation are often present: these include an increased white blood cell count (leukocytosis) and a raised erythrocyte sedimentation rate and C-reactive protein. There can be anemia of chronic disease. Bone abnormalities can be seen on radiological imaging (often increased density or osteosclerosis) or biopsy.There are two sets of diagnostic criteria, the Lipsker criteria published in 2001 and the Strasbourg criteria that were produced at a meeting in that city in 2012.The Lipsker criteria require hives, the presence of monoclonal IgM, and at least 2 of the following: fever, joint pain or arthritis, bone pain, swollen lymph nodes, enlarged spleen or liver, elevated erythrocyte sedimentation rate, high levels of white blood cells, and findings of problems in bone imaging.In the Strasbourg criteria, the person must have hives and the presence of monoclonal IgM or IgG. Schnitzlers is diagnosed if the person has IgM and two of the following, or IgG and three of the following: recurrent fevers, abnormalities in bone imaging, with or without bone pain, findings of neutrophil infiltration in a skin biopsy, high levels of white blood cells or C-reactive protein.Other conditions which can cause periodic fevers, paraproteins or chronic hives that should be ruled out, include (and are not limited to) autoimmune or autoinflammatory disorders such as adult-onset Stills disease, angioedema, hematological disorders such as lymphoma or monoclonal gammopathy of undetermined significance (MGUS), other causes of hives, cryoglobulinemia, mastocytosis, chronic neonatal onset multisystem inflammatory disease or Muckle–Wells syndrome.
Treatment
As of 2017 no drug was approved to treat Schnitzlers. Drugs that inhibit interleukin 1 activity have been the preferred treatment since they emerged in 2005; since 2012 a consensus guideline has recommended treatment with anakinra. Immunosuppressant drugs such as corticosteroids, cyclooxygenase inhibitors, interferon alpha may be effective. A 2020 review reported that canakinumab was "an effective long-term treatment with a favorable safety profile in patients with Schnitzler syndrome".In June 2018 NHS England published a Clinical Commissioning Policy: Anakinra to treat periodic fevers and autoinflammatory disorders (all ages) which stated that "Anakinra
may be used as a first line treatment in patients with a documented diagnosis of Schnitzler syndrome".Because anakinra is so highly and rapidly effective for inducing complete remission of Schnitzler syndrome, it has been suggested that in patients who do not respond to anakinra, the diagnosis should be reconsidered. Anakinra is not curative, however; symptoms recur soon after treatment stops.
Outcomes
Generally treatment with anakinra prevents outbreaks but they resume if treatment is stopped. In around 15-20% of people, a lymphoproliferative disorder as a complication, most commonly Waldenströms macroglobulinemia, develops. AA amyloidosis has also been reported in people with Schnitzler syndrome.The life span in patients with Schnitzler syndrome has not been shown to differ much from the general population.
Epidemiology
It is a rare condition; as of September 2014, 281 cases had been reported and as of 2017 around 300 cases had been reported.
History
The disease is named after the French dermatologist Liliane Schnitzler who first described this syndrome in 1972. A Delphi study on the taxonomy and definition of auto-inflammatory diseases, published in 2018, considered the alternative name "late onset gammopathy with recurrent urticaria and fever" but this received little support.
See also
List of skin conditions
References
== External links == |
Apparent mineralocorticoid excess syndrome | Apparent mineralocorticoid excess is an autosomal recessive disorder causing hypertension (high blood pressure), hypernatremia (increased blood sodium concentration) and hypokalemia (decreased blood potassium concentration). It results from mutations in the HSD11B2 gene, which encodes the kidney isozyme of 11β-hydroxysteroid dehydrogenase type 2. In an unaffected individual, this isozyme inactivates circulating cortisol to the less active metabolite cortisone. The inactivating mutation leads to elevated local concentrations of cortisol in the aldosterone sensitive tissues like the kidney. Cortisol at high concentrations can cross-react and activate the mineralocorticoid receptor due to the non-selectivity of the receptor, leading to aldosterone-like effects in the kidney. This is what causes the hypokalemia, hypertension, and hypernatremia associated with the syndrome. Patients often present with severe hypertension and end-organ changes associated with it like left ventricular hypertrophy, retinal, renal and neurological vascular changes along with growth retardation and failure to thrive. In serum both aldosterone and renin levels are low.
Signs and symptoms
This disorder presents similarly to hyperaldosteronism, leading to feedback inhibition of aldosterone. Common symptoms include hypertension, hypokalemia, metabolic alkalosis, and low plasma renin activity.DOC excess syndrome is an excessive secretion of 21-hydroxyprogesterone also called 11-Deoxycorticosterone from adrenal glands and may cause mineralocorticoid hypertension.
Genetics
AME 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
Other conditions such as Liddles Syndrome can mimic the clinical features of AME, so diagnosis can be made by calculating the ratio of free urinary cortisol to free urinary cortisone. Since AME patients create less cortisone, the ratio will much be higher than non-affected patients. Alternatively, one could differentiate between the two syndromes by administering a potassium-sparing diuretic. Patients with Liddles syndrome will only respond to a diuretic that binds the ENaC channel, whereas those with AME will respond to a diuretic that binds to ENaC or the mineralcorticoid receptor.
Treatment
The treatment for AME is based on the blood pressure control with Aldosterone antagonist like Spironolactone which also reverses the hypokalemic metabolic alkalosis and other anti-hypertensives. Renal transplant is found curative in almost all clinical cases.AME is exceedingly rare, with fewer than 100 cases recorded worldwide.Liquorice consumption may also cause a temporary form of AME due to its ability to block 11β-hydroxysteroid dehydrogenase type 2, in turn causing increased levels of cortisol. Cessation of licorice consumption will reverse this form of AME.
See also
Inborn errors of steroid metabolism
11β-Hydroxylase I deficiency
Hyperaldosteronism
Pseudohyperaldosteronism
Glucocorticoid-remediable aldosteronism
Aldosterone and aldosterone synthase
Maria New
References
External links
Apparent mineralocorticoid excess at NIHs Office of Rare Diseases |
Choriovitelline placenta | A choriovitelline placenta is a placenta formed by the yolk sac and chorion. In a choriovitelline placenta, the yolk sac fuses with the chorion and, subsequently, wrinkles develop that hold the embryo to the uterine wall, thus forming the choriovitelline placenta. The chorionic blood vessels are connected with the vitelline blood vessel of the yolk sac. It is a primitive type of placenta found in all marsupials. (However, bandicoots also have a chorioallantoic placenta.) A choriovitelline placenta also forms early in the development of some placental mammals before the chorioallantoic placenta forms and the choriovitelline placenta is resorbed.
== References == |
Nasopharyngeal carcinoma | Nasopharyngeal carcinoma (NPC), or nasopharynx cancer, is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess (fossa of Rosenmüller), accounting for 50% of cases. NPC occurs in children and adults. NPC differs significantly from other cancers of the head and neck in its occurrence, causes, clinical behavior, and treatment. It is vastly more common in certain regions of East Asia and Africa than elsewhere, with viral, dietary and genetic factors implicated in its causation. It is most common in males. It is a squamous cell carcinoma of an undifferentiated type. Squamous epithelial cells are a flat type of cell found in the skin and the membranes that line some body cavities. Undifferentiated cells are cells that do not have their mature features or functions.
Signs and symptoms
NPC may present as a lump or a mass on both sides towards the back of the neck. These lumps usually are not tender or painful but appear as a result of the metastatic spread of the cancer to the lymph nodes, thus causing the lymph nodes to swell. Lymph nodes are defined as glands that function as part of the immune system and can be found throughout the body. Swelling of the lymph nodes in the neck is the initial presentation in many people, and the diagnosis of NPC is often made by lymph node biopsy. Signs of nasopharyngeal cancer may appear as headaches, a sore throat, and trouble hearing, breathing, or speaking. Additional symptoms of NPC include facial pain or numbness, blurred or double vision, trouble opening the mouth, or recurring ear infections. If the ear infection does not present with an upper respiratory tract infection, then an examination should be done on the nasopharynx. This is due to the fact that, in adults, ear infections are less common than in children. Signs and symptoms related to the primary tumor include trismus, pain, otitis media, nasal regurgitation due to paresis (loss of or impaired movement) of the soft palate, hearing loss and cranial nerve palsy (paralysis). Larger growths may produce nasal obstruction or bleeding and a "nasal twang". Metastatic spread may result in bone pain or organ dysfunction. Rarely, a paraneoplastic syndrome of osteoarthropathy (diseases of joints and bones) may occur with widespread disease.
Causes
NPC is caused by a combination of factors: viral, environmental influences, and heredity. The viral influence is associated with infection with Epstein–Barr virus (EBV). The Epstein-Barr virus is one of the most common viruses. 95% of all people in the U.S. are exposed to this virus by the time they are 30–40 years old. The World Health Organization does not have set preventative measures for this virus because it is so easily spread and is worldwide. Very rarely does Epstein-Barr virus lead to cancer, which suggests a variety of influencing factors. Other likely causes include genetic susceptibility, consumption of food (in particular salted fish) containing carcinogenic volatile nitrosamines. Various mutations that activate NF-κB signalling have been reported in almost half of NPC cases investigated.The association between Epstein-Barr virus and nasopharyngeal carcinoma is unequivocal in World Health Organization (WHO) types II and III tumors but less well-established for WHO type I (WHO-I) NPC, where preliminary evaluation has suggested that human papillomavirus (HPV) may be associated. EBV DNA was detectable in the blood plasma samples of 96% of patients with non-keratinizing NPC, compared with only 7% in controls. The detection of nuclear antigen associated with Epstein-Barr virus (EBNA) and viral DNA in NPC type 2 and 3, has revealed that EBV can infect epithelial cells and is associated with their transformation. The cause of NPC (particularly the endemic form) seems to follow a multi-step process, in which EBV, ethnic background, and environmental carcinogens all seem to play an important role. More importantly, EBV DNA levels appear to correlate with treatment response and may predict disease recurrence, suggesting that they may be an independent indicator of prognosis. The mechanism by which EBV alters nasopharyngeal cells is being elucidated to provide a rational therapeutic target.It is also being investigated as to whether or not chronic sinusitis could be a potential cause of cancer of the nasopharynx. It is hypothesised that this may happen in a way similar to how chronic inflammatory conditions in other parts of the body, such as esophagitis sometimes leading to Barretts esophagus because of conditions such as gastroesophageal reflux disease.
Diagnosis
Classification
The World Health Organization (WHO) has identified three subtypes of nasopharyngeal carcinoma:
type 1: squamous cell carcinoma, typically found in older adults
type 2: non-keratinizing carcinoma
type 3: undifferentiated carcinomaType 3 is most commonly found among younger children and adolescents, with a few type 2 cases. Both type 2 and 3 have been found to be associated with elevated levels of Epstein-Barr virus titers, but not type 1. Additionally, type 2 and type 3 may be followed with an influx of inflammatory cells, including lymphocytes, plasma cells, and eosinophils, generating the term lymphoepithelioma.Nasopharyngeal carcinoma, also known as nasopharyngeal cancer, is classified as a malignant neoplasm, or cancer, arising from the mucosal epithelium of the nasopharynx, most often within the lateral nasopharyngeal recess or fossa of Rosenmüller (a recess behind the entrance of the eustachian tube opening). The World Health Organization classifies nasopharyngeal carcinoma in three types, in order of frequency: Non-keratinizing squamous cell carcinoma; keratinizing squamous cell carcinoma; and basaloid squamous cell carcinoma. The tumor must show evidence of squamous differentiation, with the non-keratinizing type (also known as lymphoepithelioma) the tumor most strongly associated with Epstein–Barr virus infection of the cancerous cells.
Staging
Staging of nasopharyngeal carcinoma is based on clinical and radiologic examination. Most patients present with Stage III or IV disease.
Stage I is a small tumor confined to nasopharynx.
Stage II is a tumor extending in the local area, or that with any evidence of limited neck (nodal) disease.
Stage III is a large tumor with or without neck disease, or a tumor with bilateral neck disease.
Stage IV is a large tumor involving intracranial or infratemporal regions, an extensive neck disease, and/or any distant metastasis.
Risk factors
Nasopharyngeal carcinoma, classified as a squamous cell cancer, has not been linked to excessive use of tobacco. However, there are certain risk factors that can predispose an individual to NPC if exposed to them. These risk factors include: having Chinese, or Asian, ancestry, exposure to Epstein- Barr virus (EBV), unknown factors that result in rare familial clusters, and heavy alcohol consumption.
EBV
Epstein- Barr virus infects and persists in more than 90% of world population. Transmission of this virus occurs through saliva and is more commonly seen in developing countries where there are living areas are more packed together and less hygienic. Replication of this virus can occur in the oropharyngeal epithelial tissue and nasopharyngeal tissue. EBV primarily targets B lymphocytes. Patients diagnosed with NPC were found to show elevated levels of the antibodies against the EBV antigen than in individuals not diagnosed with NPC.
Smoking
Individuals that are exposed to cigarette smoking have an increased risk of developing NPC by 2- to 6-fold. Approximately two-thirds of patients with type 1 NPC was attributed to smoking in the United States. However the declining rates of smoking in the US can be associated with less prevalence of type 1 NPC. In southern China and North Africa, it has been suggested that high smoking rates come from wood fires in the country rather than cigarette smoking.
Treatment
NPC can be treated by surgery, by chemotherapy, or by radiotherapy. There are different forms of radiation therapy, including 3D conformal radiation therapy, intensity-modulated radiation therapy, particle beam therapy and brachytherapy, which are commonly used in the treatments of cancers of the head and neck. The expression of EBV latent proteins within undifferentiated nasopharyngeal carcinoma can be potentially exploited for immune-based therapies. Generally, there are three different types or treatment methods that can be used for patients with nasopharyngeal carcinoma. These three treatments are radiation therapy, chemotherapy, and surgery. Although there are currently three treatment methods, there are clinical trials taking place that may develop more effective treatments for NPC. A clinical trial is research study that works to develop new treatment techniques or to gain more information about or improve current methods. If an effective treatment comes out of the clinical trial, then this method may become a new standard treatment method. During the course of, or following, treatment, tests may be done in order to determine if the treatment is working, or if treatment needs to be dropped or changed. Tests that are done after treatment to determine the condition of patient after completing treatment are called follow-up tests and tell the doctor if the patients condition has changed or if the cancer has come back.
Radiation therapy
Radiation therapy uses high energy x-rays or other types of radiation aimed to prevent cancer cells from growing or kill them altogether. This kind of therapy can be administered to the patient externally or internally. With external radiation, a machine is used to send targeted radiation to the cancer site. A mesh mask is used on the patenting order to keep their head and neck still while the machine rotates to send out beams of radiation. In undergoing this kind of treatment, healthy cells may also be damaged during the process. Therefore, there are 2 other forms of radiation therapy that decreases the likelihood of damaging nearby healthy cells: intensity-modulated radiation therapy and stereotactic radiation therapy. Intensity-modulated radiation therapy (IMRT) uses 3D images of the size and shape of the tumor to then direct thin beams of radiation at different intensities from multiple angles. In stereotactic radiation therapy, radiation is aimed directly at the tumor. in this therapy, the total amount of radiation is divided into smaller does that will be given over the course of several days.Using radiation therapy as a cancer treatment method depends on the type and stage of cancer, however, internal and external radiation therapies can be used to treat NPC. If external radiation therapies are being aimed at the thyroid, then this could affect the way the thyroid works. For that reason, blood tests are done before and after radiation to check thyroid hormone levels.
Chemotherapy
Chemotherapy works as cancer treatment by using drugs that stop the growth of cancer cells, by either killing the cells or preventing them from dividing. This kind of therapy can be administered systemically or regionally. Systemic chemotherapy is when the chemotherapy is taken orally or is injected into a vein or muscle. In this method, the drug circulates through the blood system and can reach cancer cells throughout the body. Regional chemotherapy is when chemotherapy is administered directly into the cerebrospinal fluid, an organ, or a body cavity, for example, the abdomen. In this way, the drugs will mainly affect cancer cells in that area. However, the type of chemotherapy that is administered to the patient depends on the type and stage of the cancer. Additionally, chemotherapy can be used as an adjuvant therapy after radiation to lower the risk of recurrence in the patient. If given after radiation, chemotherapy can be used to kill any cancer cells that may have remained.
Surgery
Surgery can be used as a method to determine whether there is cancer present or to remove cancer from the body. If the tumor does not respond to radiation therapy, then the patient may undergo an operation to have it removed. Cancers that may have spread to the lymph nodes may require the doctor to remove lymph nodes or other tissue in the neck.
Epidemiology
As of 2010, NPC resulted in 65,000 deaths globally up from 45,000 in 1990.NPC is uncommon in the United States and most other nations, representing less than 1 case per 100,000 in most populations. but is extremely common in southern regions of China, particularly in Guangdong, accounting for 18% of all cancers in China. It is sometimes referred to as Cantonese cancer (廣東癌) because it occurs in about 25 cases per 100,000 people in this region, 25 times higher than the rest of the world. It is also quite common in Taiwan. This could be due to the Southeast Asian diet or that Southern Chinese people such as the Cantonese and Taiwanese have Southeast Asian ancestry (such as the proto-Kra-Dai speaking peoples and proto-Austronesian peoples) via ancient intermarriages with Han Chinese from Northeast Asia which led to the transmission of a genetic risk for nasopharynx cancer. While NPC is seen primarily in middle-aged persons in Asia, a high proportion of African cases appear in children. The cause of increased risk for NPC in these endemic regions is not clear. In low-risk populations, such as in the United States, a bimodal peak is observed. The first peak occurs in late adolescence/early adulthood (ages 15–24 years), followed by a second peak later in life (ages 65–79 years).
See also
Endoscopic nasopharyngectomy
Lymphoepithelioma-like carcinoma
References
External links
Cancer Management Handbook: Head and Neck Tumors
Clinically reviewed nasopharyngeal cancer information for patients from Cancer Research UK |
Korsakoff syndrome | Korsakoff syndrome (KS) is a disorder of the central nervous system characterized by amnesia, deficits in explicit memory, and confabulation. This neurological disorder is caused by a deficiency of thiamine (vitamin B1) in the brain, and it is typically associated with and exacerbated by the prolonged, excessive ingestion of alcohol. Korsakoff syndrome is often accompanied by Wernicke encephalopathy; this combination is called Wernicke–Korsakoff syndrome.Korsakoff syndrome is named after Sergei Korsakoff, the Russian neuropsychiatrist who described it during the late 19th century.
Signs and symptoms
There are seven major symptoms of Korsakoff syndrome, an amnestic-confabulatory syndrome:
anterograde amnesia, memory loss for events after the onset of the syndrome
retrograde amnesia, memory loss extends back for some time before the onset of the syndrome
amnesia of fixation, also known as fixation amnesia (loss of immediate memory, a person being unable to remember events of the past few minutes)
confabulation, that is, invented memories which are then taken as true, due to gaps in memory, with such gaps sometimes associated with blackouts
minimal content in conversation
lack of insight
apathy – interest in things is quickly lost, and there is an indifference to changeBenon R. and LeHuché R. (1920) described the characteristic signs of Korsakoff syndrome with some additional features including: confabulation (false memories), fixation amnesia, paragnosia or false recognition of places, mental excitation, and euphoria.Thiamine is essential for the decarboxylation of pyruvate, and deficiency during this metabolic process is thought to cause damage to the medial thalamus and mammillary bodies of the posterior hypothalamus, as well as generalized cerebral atrophy. These brain regions are all parts of the limbic system, which is heavily involved in emotion and memory.
KS involves neuronal loss, that is, damage to neurons; gliosis, which is a result of damage to supporting cells of the central nervous system, and bleeding also occurs in mammillary bodies. Damage to the medial dorsal nucleus or anterior nuclei of the thalamus (limbic-specific nuclei) is also associated with this disorder. Cortical dysfunction may have arisen from thiamine deficiency, alcohol neurotoxicity, and/or structural damage in the diencephalon.Originally, it was thought that a lack of initiative and a flat affect were important characteristics of emotional presentation in those affected. Studies have questioned this, proposing that neither is necessarily a symptom of KS. Research suggesting that people with Korsakoff syndrome are emotionally unimpaired has made this a controversial topic. It can be argued that apathy, which is a usual characteristic, reflects a deficit of emotional expressions, without affecting the experience or perception of emotion.KS causes deficits in declarative memory in most people, but leaves implicit spatial, verbal, and procedural memory functioning intact. People with KS have deficits in the processing of contextual information. Context memories refers to the where and when of experiences, and is an essential part of recollection. The ability to store and retrieve this information, such as spatial location or temporal order information, is impaired.
Research has also suggested that people with Korsakoff syndrome have impaired executive functions, which can lead to behavioral problems and interfere with daily activities. It is unclear, however, which executive functions are affected most. Nonetheless, IQ is usually not affected by the brain damage associated with Korsakoffs syndrome.At first it was thought that those with KS used confabulation to fill in memory gaps. However, it has been found that confabulation and amnesia do not necessarily co-occur. Studies have shown that there is dissociation between provoked confabulation, spontaneous confabulation (which is unprovoked), and false memories. That is, people affected could be led to believe certain things had happened which actually had not, but so could people without Korsakoff syndrome.
Causes
Conditions resulting in thiamine deficiency and its effects include chronic alcoholism and severe malnutrition. Alcoholism may co-occur with poor nutrition, which in addition to inflammation of the stomach lining, causes thiamine deficiency. Other causes include dietary deficiencies, prolonged vomiting, eating disorders, and the effects of chemotherapy. It can also occur in pregnant women who have a form of extreme morning sickness known as hyperemesis gravidarum. Mercury poisoning can also lead to Korsakoff syndrome. Though it does not always co-occur, this disorder can emerge frequently as a consequential result of Wernickes encephalopathy.PET scans show that there is a decrease of glucose metabolism in the frontal, parietal and cingulated regions of the brain in those with Korsakoff syndrome. This may contribute to memory loss and amnesia. Structural neuroimaging has also shown the presence of midline diencephalic lesions and cortical atrophy.Structural lesions of the central nervous system, though rare, can also contribute to symptoms of KS. Severe damage to the medial dorsal nucleus inevitably results in memory deficit. Additionally, autopsies of people who had KS have showed lesions in both the midline and anterior thalamus, and thalamic infarctions. Bilateral infarctions to the thalamus can result in Korsakoff-induced amnesia as well. These findings imply damage to anterior thalamic nuclei can result in disruptive memory.
Risk factors
A number of factors may increase a persons risk to develop Korsakoff syndrome. These factors are often related to general health and diet.
Age
Alcoholism
Chemotherapy
Dialysis
Extreme dieting
Genetic factors
Diagnosis
KS is primarily a clinical diagnosis; imaging and lab tests are not necessary.
Prevention
The most effective method of preventing AKS is to avoid thiamine deficiency. In Western nations, the most common causes of such a deficiency are alcoholism and eating disorders. Because these are behavioral-induced causes, Korsakoff syndrome is essentially considered a preventable disease. Thus, fortifying foods with thiamine, or requiring companies that sell alcoholic beverages to supplement them with B vitamins in general or thiamine in particular, could avert many cases.
Treatment
It was once assumed that anyone with KS would eventually need full-time care. This is still often the case, but rehabilitation can help regain some, albeit often limited, level of independence. Treatment involves the replacement or supplementation of thiamine by intravenous or intramuscular injection, together with proper nutrition and hydration. However, the amnesia and brain damage caused by the disease does not always respond to thiamine replacement therapy. In some cases, drug therapy is recommended. Treatment typically requires taking thiamine orally for 3 to 12 months, though only about 20 percent of cases are reversible. If treatment is successful, improvement will become apparent within two years, although recovery is slow and often incomplete.As an immediate form of treatment, a pairing of intravenous or intramuscular thiamine with a high concentration of B-complex vitamins can be administered three times daily for 2–3 days. In most cases, an effective response will be observed. A single dose of 1 gram of thiamine can also be administered to achieve a clinical response. In those who are seriously malnourished, the sudden availability of glucose without proper bodily levels of thiamine to metabolize is thought to cause damage to cells. Thus, the administration of thiamine along with an intravenous form of glucose is often good practice.Treatment for the memory aspect of KS can also include domain-specific learning, which when used for rehabilitation is called the method of vanishing cues. Such treatments aim to use intact memory processes as the basis for rehabilitation. Those who used the method of vanishing cues in therapy were found to learn and retain information more easily.People diagnosed with KS are reported to have a normal life expectancy, presuming that they abstain from alcohol and follow a balanced diet. Empirical research has suggested that good health practices have beneficial effects in Korsakoff syndrome.
Epidemiology
Rates varies between countries, but it is estimated to affect around 12.5% of heavy drinkers.
References
== External links == |
Nodular vasculitis | Nodular vasculitis is a skin condition characterized by crops of small, tender, erythematous nodules on the legs, mostly on the calves and shins. Miroscopically there are epithelioid granulomas and vasculitis in the subcutaneous tissue, making it a form of panicullitis. Most of these cases are now thought to be manifestation of tuberculosis and indeed they respond well to anti-tuberculous treatment.
See also
Panniculitis
List of cutaneous conditions
References
== External links == |
Plagiocephaly | Plagiocephaly, also known as flat head syndrome, is a condition characterized by an asymmetrical distortion (flattening of one side) of the skull. A mild and widespread form is characterized by a flat spot on the back or one side of the head caused by remaining in a supine position for prolonged periods.Plagiocephaly is a diagonal asymmetry across the head shape. Often it is a flattening which is to one side at the back of the head and there is often some facial asymmetry. Depending on whether synostosis is involved, plagiocephaly divides into two groups: synostotic, with one or more fused cranial sutures, and non-synostotic (deformational). Surgical treatment of these groups includes the deference method; however, the treatment of deformational plagiocephaly is controversial. Brachycephaly describes a very wide head shape with a flattening across the whole back of the head.
Causes
Slight plagiocephaly is routinely diagnosed at birth and may be the result of a restrictive intrauterine environment giving a "diamond" shaped head when seen from above. If there is premature union of skull bones, this is more properly called craniosynostosis.The incidence of plagiocephaly has increased dramatically since the advent of anti-sudden infant death syndrome recommendations for parents to keep their babies on their backs.Data also suggest that the rates of plagiocephaly are higher for twins and multiple births, premature babies, babies who were positioned in the breech position or back-to-back, as well as for babies born after a prolonged labour.
Diagnosis
A developmental and physical assessment performed by a physician or a pediatric specialist is recommended. Often imaging is obtained if the diagnosis is questionable to see if the babys sutures are present or not. If the sutures are not present, craniosynostosis may be ruled into question.It is also common for an infant with positional plagiocephaly to have misaligned ears (the ear on the affected side may be pulled forward and down and be larger or protrude more than the unaffected ear).
Prevention
Prevention methods include carrying the infant and giving the infant time to play on their stomach (tummy time), which may prevent the baby from progressing into moderate or severe plagiocephaly.Letting babies crawl may also prove to be crucial in preventing plagiocephaly as it strengthens babies spine and neck muscles. Crawling also boosts gross and fine motor skills (large and refined movements), balance, hand-eye-coordination and overall strength.In addition, specialized mattresses are available to prevent plagiocephaly. The design of these mattresses is characterized by an ergonomic design that reduces pressure on the babys head. It is very important that these mattresses are certified to guarantee their effectiveness.
Treatment
The condition may improve to some extent as the baby grows, but in some cases, home treatment or physical therapy treatment can improve the shape of a baby’s head.Early interventions (based on the severity) are of importance to reduce the severity of the degree of the plagiocephaly. Diagnosis is most commonly determined through clinical examination. In order to assess the severity of the condition and determine the best course of treatment, practitioners often use the Plagiocephaly Severity Scale. This is a scale that can help practitioners evaluate the condition in a standardized way.The course of treatment is typically based on the age of the child when the diagnosis is made in conjunction with the severity of the diagnosis. If a diagnosis of mild to moderate plagiocephaly occurs before four months of age, repositioning therapy may be helpful. If the diagnosis is determined to be severe, practitioners will likely prescribe a cranial molding orthosis (helmet), which has the best results when prescribed between five to six months of age.
Repositioning
Initially, treatment usually takes the form of reducing the pressure on the affected area through repositioning of the baby onto their abdomen for extended periods of time throughout the day.This may include repositioning the childs head throughout the day so that the rounded side of the head is placed against the mattress, re-positioning cribs and other areas that infants spend time in so that they will have to look in a different direction to see their parents or others in the room, re-positioning mobiles and other toys for similar reasons, and avoiding extended time sleeping in car-seats (when not in a vehicle), bouncy seats, or other supine seating which is thought to exacerbate the problem. If the child appears to have discomfort or cries when they are re-positioned, a neck problem should be ruled out.
Helmets
High quality evidence is lacking for cranial remolding orthosis (baby helmet) for the positional condition and use for this purpose is controversial. If conservative treatment is unsuccessful, helmets may help to correct abnormal head shapes. These helmets are used to treat deformational plagiocephaly, brachycephaly, scaphocephaly and other head shape deformities in infants 3–18 months of age by gently allowing the head shape to grow back into a normal shape. This type of treatment has been used for severe deformations.
Prognosis
Preliminary research indicates that some babies with plagiocephaly may comprise a high-risk group for developmental difficulties. Plagiocephaly is associated with motor and language developmental delays. While developmental delay is more commonplace among babies with plagiocephaly, it cannot be inferred that plagiocephaly is the cause of the delay.
Etymology
Ancient Greek πλάγιος (plagios) oblique, slanting, from PIE plag- flat, spread, from *plak, and Modern Latin cephal- head, skull, brain, (from Greek κεφαλή) together means flat head.
See also
Artificial cranial deformation
Yakovlevian torque
References
== External links == |
Central core disease | Central core disease (CCD), also known as central core myopathy, is an autosomal dominantly inherited muscle disorder present from birth that negatively affects the skeletal muscles. It was first described by Shy and Magee in 1956. It is characterized by the appearance of the myofibril under the microscope.
Signs and symptoms
The symptoms of CCD are variable, but usually involve hypotonia (decreased muscle tone) at birth, mild delay in child development (highly variable between cases), weakness of the facial muscles, and skeletal malformations such as scoliosis and hip dislocation.CCD is usually diagnosed in infancy or childhood, but some patients remain asymptomatic until adulthood to middle age. While generally not progressive, there appears to be a growing number of people who do experience a slow clinically significant progression of symptomatology. These cases may be due to the large number of mutations of ryanodine receptor malfunction, and with continued research may be found to be clinical variants.
Pathophysiology
Central core disease is inherited in an autosomal dominant fashion. Most cases have demonstrable mutations in the ryanodine receptor type 1 (RYR1) gene, which are often de novo (newly developed). People with CCD are at increased risk for developing malignant hyperthermia (MH) when receiving general anesthesia.
Diagnosis
The diagnosis is made based on the combination of typical symptoms and the appearance on biopsy (tissue sample) from muscle. The name derives from the typical appearance of the biopsy on light microscopy, where the muscle cells have cores that are devoid of mitochondria and specific enzymes.Respiratory insufficiency develops in a small proportion of cases. Creatine kinase tend to be normal and electromyography (EMG) shows short duration, short amplitude motor unit action potentials.
Treatment
There is no specific treatment but triggering anesthetics are avoided and relatives are screened for RYR1 mutations as these may make them susceptible to MH.
References
== External links == |
Transient ischemic attack | A transient ischemic attack (TIA), commonly known as a mini-stroke, is a minor stroke whose noticeable symptoms usually end in less than an hour. TIA causes the same symptoms associated with strokes, such as weakness or numbness on one side of the body, sudden dimming or loss of vision, difficulty speaking or understanding language, slurred speech, or confusion.
All forms of stroke, including TIA, result from a disruption in blood flow to the central nervous system. A TIA is caused by a temporary disruption in blood flow to the brain, or cerebral blood flow (CBF). The primary difference between a major stroke and the TIAs minor stroke is how much tissue death (infarction) can be detected afterwards through medical imaging. While a TIA must by definition be associated with symptoms, strokes can also be symptomatic or silent. In silent stroke, also known as silent cerebral infarct (SCI), there is permanent infarction detectable on imaging, but there are no immediately observable symptoms. The same person can have major strokes, minor strokes, and silent strokes, in any order.The occurrence of a TIA is a risk factor for having a major stroke, and many people with TIA have a major stroke within 48 hours of the TIA. All forms of stroke are associated with increased risk of death or disability. Recognition that a TIA has occurred is an opportunity to start treatment, including medications and lifestyle changes, to prevent future strokes.
Signs and symptoms
Signs and symptoms of TIA are widely variable and can mimic other neurologic conditions, making the clinical context and physical exam crucial in ruling in or out the diagnosis. The most common presenting symptoms of TIA are focal neurologic deficits, which can include, but are not limited to:
Amaurosis fugax (painless, temporary loss of vision)
One-sided facial droop
One-sided motor weakness
Diplopia (double vision)
Problems with balance and spatial orientation or dizziness
Visual field deficits, such as homonymous hemianopsia or monocular blindness
Sensory deficits in one or more limbs and of the face
Loss of ability to understand or express speech (aphasia)
Difficulty with articulation of speech (dysarthria)
Unsteady gait
Difficulties with swallowing (dysphagia)Numbness or weakness generally occur on the opposite side of the body from the affected hemisphere of the brain.
A detailed neurologic exam, including a thorough cranial nerve exam, is important to identify these findings and to differentiate them from mimickers of TIA. Symptoms such as unilateral weakness, amaurosis fugax, and double vision have higher odds of representing TIA compared to memory loss, headache, and blurred vision. Below is a table of symptoms at presentation, and what percentage of the time they are seen in TIAs versus conditions that mimic TIA. In general, focal deficits make TIA more likely, but the absence of focal findings do not exclude the diagnosis and further evaluation may be warranted if clinical suspicion for TIA is high (see "Diagnosis" section below).
TIA versus mimics
Non-focal symptoms such as amnesia, confusion, incoordination of limbs, unusual cortical visual symptoms (such as isolated bilateral blindness or bilateral positive visual phenomena), headaches and transient loss of consciousness are usually not associated with TIA, however patient assessment is still needed. Public awareness on the need to seek a medical assessment for these non-focal symptoms is also low, and can result in a delay by patients to seek treatmentSymptoms of TIAs can last on the order of minutes to one–two hours, but occasionally may last for a longer period of time. TIAs used to be defined as ischemic events in the brain that last less than 24 hours, but given the variation in duration of symptoms, this definition holds less significance. A pooled study of 808 patients with TIAs from 10 hospitals showed that 60% lasted less than one hour, 71% lasted less than two hours, and 14% lasted greater than six hours. Importantly, patients with symptoms that last more than one hour are more likely to have permanent neurologic damage, making prompt diagnosis and treatment important to maximize recovery.
Cause
The most common underlying pathology leading to TIA and stroke is a cardiac condition called atrial fibrillation, where poor coordination of contraction leads to a formation of a clot in the atrial chamber that can become dislodged and travel to a cerebral artery. Unlike in stroke, the blood flow can become restored prior to infarction which leads to the resolution of neurologic symptoms. Another common culprit of TIA is an atherosclerotic plaque located in the common carotid artery, typically by the bifurcation between the internal and external carotids, that becomes an embolism to the brain vasculature similar to the clot in the prior example. A portion of the plaque can become dislodged and lead to embolic pathology in the cerebral vessels.In-situ thrombosis, an obstruction that forms directly in the cerebral vasculature unlike the remote embolism previously mentioned, is another vascular occurrence with possible presentation as TIA. Also, carotid stenosis secondary to atherosclerosis narrowing the diameter of the lumen and thus limiting blood flow is another common cause of TIA. Individuals with carotid stenosis may present with TIA symptoms, thus labeled symptomatic, while others may not experience symptoms and be asymptomatic.
Risk factors
Risk factors associated with TIA are categorized as modifiable or non-modifiable. Non-modifiable risk factors include age greater than 55, sex, family history, genetics, and race/ethnicity. Modifiable risk factors include cigarette smoking, hypertension (elevated blood pressure), diabetes, hyperlipidemia, level of carotid artery stenosis (asymptomatic or symptomatic) and activity level. The modifiable risk factors are commonly targeted in treatment options to attempt to minimize risk of TIA and stroke.
Pathogenesis
There are three major mechanisms of ischemia in the brain: embolism traveling to the brain, in situ thrombotic occlusion in the intracranial vessels supplying the parenchyma of the brain, and stenosis of vessels leading to poor perfusion secondary to flow-limiting diameter. Globally, the vessel most commonly affected is the middle cerebral artery. Embolisms can originate from multiple parts of the body.
Common mechanisms of stroke and TIA:
Diagnosis
The initial clinical evaluation of a suspected TIA involves obtaining a history and physical exam (including a neurological exam). History taking includes defining the symptoms and looking for mimicking symptoms as described above. Bystanders can be very helpful in describing the symptoms and giving details about when they started and how long they lasted. The time course (onset, duration, and resolution), precipitating events, and risk factors are particularly important.
The definition, and therefore the diagnosis, has changed over time. TIA was classically based on duration of neurological symptoms. The current widely accepted definition is called "tissue-based" because it is based on imaging, not time. The American Heart Association and the American Stroke Association (AHA/ASA) now define TIA as a brief episode of neurological dysfunction with a vascular cause, with clinical symptoms typically lasting less than one hour, and without evidence of significant infarction on imaging.
Laboratory workup
Laboratory tests should focus on ruling out metabolic conditions that may mimic TIA (e.g. hypoglycemia causing altered mental status), in addition to further evaluating a patients risk factors for ischemic events. All patients should receive a complete blood count with platelet count, blood glucose, basic metabolic panel, prothrombin time/international normalized ratio, and activated partial thromboplastin time as part of their initial workup. These tests help with screening for bleeding or hypercoagulable conditions. Other lab tests, such as a full hypercoagulable state workup or serum drug screening, should be considered based on the clinical situation and factors, such as age of the patient and family history. A fasting lipid panel is also appropriate to thoroughly evaluate the patients risk for atherosclerotic disease and ischemic events in the future. Other lab tests may be indicated based on the history and presentation; such as obtaining inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) to evaluate for giant cell arteritis (which can mimic a TIA) in those presenting with headaches and monocular blindness.
Cardiac rhythm monitoring
An electrocardiogram is necessary to rule out abnormal heart rhythms, such as atrial fibrillation, that can predispose patients to clot formation and embolic events. Hospitalized patients should be placed on heart rhythm telemetry, which is a continuous form of monitoring that can detect abnormal heart rhythms. Prolonged heart rhythm monitoring (such as with a Holter monitor or implantable heart monitoring) can be considered to rule out arrhythmias like paroxysmal atrial fibrillation that may lead to clot formation and TIAs, however this should be considered if other causes of TIA have not been found.
Imaging
According to guidelines from the American Heart Association and American Stroke Association Stroke Council, patients with TIA should have head imaging "within 24 hours of symptom onset, preferably with magnetic resonance imaging, including diffusion sequences". MRI is a better imaging modality for TIA than computed tomography (CT), as it is better able to pick up both new and old ischemic lesions than CT. CT, however, is more widely available and can be used particularly to rule out intracranial hemorrhage. Diffusion sequences can help further localize the area of ischemia and can serve as prognostic indicators. Presence of ischemic lesions on diffusion weighted imaging has been correlated with a higher risk of stroke after a TIA.Vessels in the head and neck may also be evaluated to look for atherosclerotic lesions that may benefit from interventions, such as carotid endarterectomy. The vasculature can be evaluated through the following imaging modalities: magnetic resonance angiography (MRA), CT angiography (CTA), and carotid ultrasonography/transcranial doppler ultrasonography. Carotid ultrasonography is often used to screen for carotid artery stenosis, as it is more readily available, is noninvasive, and does not expose the person being evaluated to radiation. However, all of the above imaging methods have variable sensitivities and specificities, making it important to supplement one of the imaging methods with another to help confirm the diagnosis (for example: screen for the disease with ultrasonography, and confirm with CTA). Confirming a diagnosis of carotid artery stenosis is important because the treatment for this condition, carotid endarterectomy, can pose significant risk to the patient, including heart attacks and strokes after the procedure. For this reason, the U.S. Preventive Services Task Force (USPSTF) "recommends against screening for asymptomatic carotid artery stenosis in the general adult population". This recommendation is for asymptomatic patients, so it does not necessarily apply to patients with TIAs as these may in fact be a symptom of underlying carotid artery disease (see "Causes and Pathogenesis" above). Therefore, patients who have had a TIA may opt to have a discussion with their clinician about the risks and benefits of screening for carotid artery stenosis, including the risks of surgical treatment of this condition.
Cardiac imaging can be performed if head and neck imaging do not reveal a vascular cause for the patients TIA (such as atherosclerosis of the carotid artery or other major vessels of the head and neck). Echocardiography can be performed to identify patent foramen ovale (PFO), valvular stenosis, and atherosclerosis of the aortic arch that could be sources of clots causing TIAs, with transesophageal echocardiography being more sensitive than transthoracic echocardiography in identifying these lesions.
Differential diagnosis
Prevention
Although there is a lack of robust studies demonstrating the efficacy of lifestyle changes in preventing TIA, many medical professionals recommend them. These include:
Avoiding smoking
Cutting down on fats to help reduce the amount of plaque buildup
Eating a healthy diet including plenty of fruits and vegetables
Limiting sodium in the diet, thereby reducing blood pressure
Exercising regularly
Moderating intake of alcohol, stimulants, sympathomimetics, etc.
Maintaining a healthy weightIn addition, it is important to control any underlying medical conditions that may increase the risk of stroke or TIA, including:
Hypertension
High cholesterol
Diabetes mellitus
Atrial fibrillation
Treatment
By definition, TIAs are transient, self-resolving, and do not cause permanent impairment. However, they are associated with an increased risk of subsequent ischemic strokes, which can be permanently disabling. Therefore, management centers on the prevention of future ischemic strokes and addressing any modifiable risk factors. The optimal regimen depends on the underlying cause of the TIA.
Lifestyle modification
Lifestyle changes have not been shown to reduce the risk of stroke after TIA. While no studies have looked at the optimal diet for secondary prevention of stroke, some observational studies have shown that a Mediterranean diet can reduce stroke risk in patients without cerebrovascular disease. A Mediterranean diet is rich in fruits, vegetables and whole grains, and limited in red meats and sweets. Vitamin supplementation has not been found to be useful in secondary stroke prevention.
Antiplatelet medications
The antiplatelet medications, aspirin and clopidogrel, are both recommended for secondary prevention of stroke after high-risk TIAs. The clopidogrel can generally be stopped after 10 to 21 days. An exception is TIAs due to blood clots originating from the heart, in which case anticoagulants are generally recommended. After TIA or minor stroke, aspirin therapy has been shown to reduce the short-term risk of recurrent stroke by 60–70%, and the long-term risk of stroke by 13%.The typical therapy may include aspirin alone, a combination of aspirin plus extended-release dipyridamole, or clopidogrel alone. Clopidogrel and aspirin have similar efficacies and side effect profiles. Clopidogrel is more expensive and has a slightly decreased risk of GI bleed. Another antiplatelet, ticlopidine, is rarely used due to increased side effects.
Anticoagulant medications
Anticoagulants may be started if the TIA is thought to be attributable to atrial fibrillation. Atrial fibrillation is an abnormal heart rhythm that may cause the formation of blood clots that can travel to the brain, resulting in TIAs or ischemic strokes. Atrial fibrillation increases stroke risk by five times, and is thought to cause 10-12% of all ischemic strokes in the US. Anticoagulant therapy can decrease the relative risk of ischemic stroke in those with atrial fibrillation by 67% Warfarin is a common anticoagulant used, but direct acting oral anticoagulants (DOACs), such as apixaban, have been shown to be equally effective while also conferring a lower risk of bleeding. Generally, anticoagulants and antiplatelets are not used in combination, as they result in increased bleeding risk without a decrease in stroke risk. However, combined antiplatelet and anticoagulant therapy may be warranted if the patient has symptomatic coronary artery disease in addition to atrial fibrillation.
Sometimes, myocardial infarction ("heart attack") may lead to the formation of a blood clot in one of the chambers of the heart. If this is thought to be the cause of the TIA, people may be temporarily treated with warfarin or other anticoagulant to decrease the risk of future stroke.
Blood pressure control
Blood pressure control may be indicated after TIA to reduce the risk of ischemic stroke. About 70% of patients with recent ischemic stroke are found to have hypertension, defined as systolic blood pressure (SBP) > 140 mmHg, or diastolic blood pressure (DBP) > 90 mmHg. Until the first half of the 2010s, blood pressure goals have generally been SBP < 140 mmHg and DBP < 90 mmHg. However, newer studies suggest that a goal of SBP <130 mmHg may confer even greater benefit. Blood pressure control is often achieved using diuretics or a combination of diuretics and angiotensin converter enzyme inhibitors, although the optimal treatment regimen depends on the individual.Studies that evaluated the application of Blood pressure‐lowering drugs in people who had a TIA or stroke, concluded that this type of medication helps to reduce the possibility of a recurrent stroke, of a major vascular event and dementia. The effects achieved in stroke recurrence were mainly obtained through the ingestion of angiotensin-converting enzyme (ACE) inhibitor or a diuretic.
Cholesterol control
There is inconsistent evidence regarding the effect of LDL-cholesterol levels on stroke risk after TIA. Elevated cholesterol may increase ischemic stroke risk while decreasing the risk of hemorrhagic stroke. While its role in stroke prevention is currently unclear, statin therapy has been shown to reduce all-cause mortality and may be recommended after TIA.
Diabetes control
Diabetes mellitus increases the risk of ischemic stroke by 1.5-3.7 times, and may account for at least 8% of first ischemic strokes. While intensive glucose control can prevent certain complications of diabetes such as kidney damage and retinal damage, there has previously been little evidence that it decreases the risk of stroke or death. However, data from 2017 suggests that metformin, pioglitazone and semaglutide may reduce stroke risk.
Surgery
If the TIA affects an area that is supplied by the carotid arteries, a carotid ultrasound scan may demonstrate stenosis, or narrowing, of the carotid artery. For people with extra-cranial carotid stenosis, if 70-99% of the carotid artery is clogged, carotid endarterectomy can decrease the five-year risk of ischemic stroke by approximately half. For those with extra-cranial stenosis between 50 and 69%, carotid endarterectomy decreases the 5-year risk of ischemic stroke by about 16%. For those with extra-cranial stenosis less than 50%, carotid endarterectomy does not reduce stroke risk and may, in some cases, increase it. The effectiveness of carotid endarterectomy or carotid artery stenting in reducing stroke risk in people with intra-cranial carotid artery stenosis is currently unknown.In carotid endarterectomy, a surgeon makes an incision in the neck, opens up the carotid artery, and removes the plaque occluding the blood vessel. The artery may then be repaired by adding a graft from another vessel in the body, or a woven patch. In patients who undergo carotid endarterectomy after a TIA or minor stroke, the 30-day risk of death or stroke is 7%.Carotid artery stenting is a less invasive alternative to carotid endarterectomy for people with extra-cranial carotid artery stenosis. In this procedure, the surgeon makes a small cut in the groin and threads a small flexible tube, called a catheter, into the patients carotid artery. A balloon is inflated at the site of stenosis, opening up the clogged artery to allow for increased blood flow to the brain. To keep the vessel open, a small wire mesh coil, called a stent, may be inflated along with the balloon. The stent remains in place, and the balloon is removed.
For people with symptomatic carotid stenosis, carotid endarterectomy is associated with fewer perioperative deaths or strokes than carotid artery stenting. Following the procedure, there is no difference in effectiveness if you compare carotid endarterectomy and carotid stenting procedures, however, endarterectomy is often the procedure of choice as it is a safer procedure and is often effective in the longer term for preventing recurrent stroke. For people with asymptomatic carotid stenosis, the increased risk of stroke or death during the stenting procedure compared to an endarterectomy is less certain.People who undergo carotid endarterectomy or carotid artery stenting for stroke prevention are medically managed with antiplatelets, statins, and other interventions as well.
Prognosis
Without treatment, the risk of an ischemic stroke in the three months after a TIA is about 20% with the greatest risk occurring within two days of the TIA. Other sources cite that 10% of TIAs will develop into a stroke within 90 days, half of which will occur in the first two days following the TIA. Treatment and preventative measures after a TIA (for example treating elevated blood pressure) can reduce the subsequent risk of an ischemic stroke by about 80%. The risk of a stroke occurring after a TIA can be predicted using the ABCD² score. One limitation of the ABCD² score is that it does not reliably predict the level of carotid artery stenosis, which is a major cause of stroke in TIA patients. The patients age is the most reliable risk factor in predicting any level of carotid stenosis in transient ischemic attack. The ABCD2 score is no longer recommended for triage (to decide between outpatient management versus hospital admission) of those with a suspected TIA due to these limitations.
Epidemiology
With the difficulty in diagnosing a TIA due to its nonspecific symptoms of neurologic dysfunction at presentation and a differential including many mimics, the exact incidence of the disease is unclear. It is currently estimated to have an incidence of approximately 200,000 to 500,000 cases per year in the US according to the American Heart Association. TIA incidence trends similarly to stroke, such that incidence varies with age, gender, and different race/ethnicity populations. Associated risk factors include age greater than or equal to 60, blood pressure greater than or equal to 140 systolic or 90 diastolic, and comorbid diseases, such as diabetes, hypertension, atherosclerosis, and atrial fibrillation. It is thought that approximately 15 to 30 percent of strokes have a preceding TIA episode associated.
References
== External links == |
Porokeratotic eccrine ostial and dermal duct nevus | Porokeratotic eccrine ostial and dermal duct nevus is a skin lesion that resembles a comedonal nevus, but it occurs on the palms and soles where pilosebaceous follicles are normally absent. It is probably transmitted by paradominant transmission.
See also
Prominent inferior labial artery
List of cutaneous conditions
== References == |
Ureteritis | Ureteritis is a medical condition of the ureter that involves inflammation. One form is known as "ureteritis cystica".Eosinophilic ureteritis has been observed.Ureteritis is often considered part of a urinary tract infection.
References
== External links == |
Colorado tick fever | Colorado tick fever (CTF) is a viral infection (Coltivirus) transmitted from the bite of an infected Rocky Mountain wood tick (Dermacentor andersoni). It should not be confused with the bacterial tick-borne infection, Rocky Mountain spotted fever. Colorado tick fever is probably the same disease that American pioneers referred to as "mountain fever".Colorado tick fever virus (CTFV) infects haemopoietic cells, particularly erythrocytes, which explains how the virus is transmitted by ticks and also accounts for the incidence of transmission by blood transfusion.
Signs and symptoms
First signs or symptoms can occur about three to six days after the initial tick bite, although it can have incubation periods of up to 20 days. Patients usually experience a two-staged fever and illness which can continue for three days, diminish, and then return for another episode of one to three days. The virus has the ability to live in the bloodstream for up to 120 days; therefore, coming in contact without proper precautions and the donation of blood are prohibited.
Initial symptoms include fever, chills, headaches, pain behind the eyes, light sensitivity, muscle pain, generalized malaise, abdominal pain, hepatosplenomegaly, nausea and vomiting, and a flat or pimply rash. During the second phase of the virus, a high fever can return with an increase in symptoms. CTF can be very severe in cases involving children and can even require hospitalization. Complications with this disease have included aseptic meningitis, encephalitis, and hemorrhagic fever, but these are rare.
CTF is seasonal, mostly occurring in the Rocky Mountain region of the United States and usually in altitudes from 4,000 to 10,000 feet (1.600 to 3.000 meters). Patients with CTF are mostly campers and young males, who most likely have been bitten because of their activities.
Cause
Virology
The virus particle, like other coltiviruses, is about 80 nm in diameter and is generally not enveloped. The double-stranded RNA viral genome is about 20,000 bp long and is divided into 12 segments, which are termed Seg-1 to Seg-12. Viral replication in infected cells is associated with characteristic cytoplasmic granular matrices. Evidence suggests the viral presence in mature erythrocytes is a result of replication of the virus in hematopoetic erythrocyte precursor cells and simultaneous maturation of the infected immature cells rather than of direct entry and replication of CTFV in mature erythrocytes.
Tick
The Rocky Mountain wood tick is usually found attached to a host, but when it is without a host, it hides in cracks and crevices, as well as soil. If for some reason the tick is not able to find a host before the winter, it will stay under groundcover until spring, when it can resume its search. The wood tick does not typically seek hosts in the hottest summer months. Adult ticks tend to climb to the tops of grasses or low shrubs, attaching themselves to a host wandering by. They secure the attachment by secreting a cement-like substance from their mouths, inserting it into the host.
Transmission
Colorado tick fever is acquired by tick bite. No evidence of natural person-to-person transmission has been found. However, rare cases of transmission from blood transfusions have been reported. The virus which causes Colorado tick fever may stay in the blood for as long as four months after onset of the illness.
Diagnosis
A combination of clinical signs, symptoms, and laboratory tests can confirm the likelihood of having CTF. Some tests include complement fixation to Colorado tick virus, immunofluorescence for Colorado tick fever, and some other common laboratory findings suggestive of CTF, including leucopenia, thrombocytopenia, and mildly elevated liver enzyme levels.
Detection of viral antibodies on red blood cells is possible.
Prevention
To avoid tick bites and infection, experts advise:
Avoid tick-infested areas, especially during the warmer months.
Wear light-colored clothing so ticks can be easily seen. Wear a long sleeved shirt, hat, long pants, and tuck pant legs into socks.
Walk in the center of trails to avoid overhanging grass and brush.
Clothing and body parts should be checked every few hours for ticks when spending time outdoors in tick-infested areas. Ticks are most often found on the thigh, arms, underarms, and legs. Ticks can be very small (no bigger than a pinhead). Look carefully for new "freckles".
The use of insect repellents containing DEET on skin or permethrin on clothing can be effective. Follow the directions on the container and wash off repellents when going indoors.
Remove attached ticks immediately.Contracting the CTF virus is thought to provide long-lasting immunity against reinfection. However, it is always wise to be on the safe side and try to prevent tick bites.
Treatment
No specific treatment for CTF is yet available. The first action is to make sure the tick is fully removed from the skin, then acetaminophen and analgesics can be used to help relieve the fever and pain. Aspirin is not recommended for children, as it has been linked to Reye’s syndrome in some viral illnesses. Salicylates should not be used because of thrombocytopenia, and the rare occurrence of bleeding disorders. People who suspect they have been bitten by a tick or are starting to show signs of CTF should contact their physicians immediately.
Tick removal
Ticks should be removed promptly and carefully with tweezers and by applying gentle, steady traction. The ticks body should not be crushed when it is removed and the tweezers should be placed as close to the skin as possible to avoid leaving tick mouthparts in the skin. Mouthparts left in the skin can allow secondary infections. Ticks should not be removed with bare hands. Hands should be protected by gloves or tissues and thoroughly washed with soap and water after the removal process.
A match or flame should not be used to remove a tick. This method, once thought safe, can cause the tick to regurgitate expelling any disease it may be carrying into the bite wound.
Epidemiology
The disease develops from March to September, with the highest infections occurring in June. The disease is found almost exclusively in the western United States and Canada, mostly in high mountain areas such as Colorado and Idaho. The CTFV was first isolated from human blood in 1944.
References
== External links == |
Mucolipidosis | Mucolipidosis is a group of inherited metabolic disorders that affect the bodys ability to carry out the normal turnover of various materials within cells.When originally named, the mucolipidoses derived their name from the similarity in presentation to both mucopolysaccharidoses and sphingolipidoses. A biochemical understanding of these conditions has changed how they are classified. Four conditions (types I, II, III, and IV) were historically labeled as mucolipidoses. However, type I (sialidosis) is now classified as a glycoproteinosis, and type IV (Mucolipidosis type IV) is now classified as a gangliosidosis.
ML II and III
The other two types are closely related.
Mucolipidosis types II and III (ML II and ML III) result from a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase, which phosphorylates target carbohydrate residues on N-linked glycoproteins. Without this phosphorylation, the glycoproteins are not destined for lysosomes, and they escape outside the cell.
Genetics
The mucolipidoses are inherited in an autosomal recessive manner, that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry a defective gene, each of their children faces a one in four chance of developing one of the MLs. At the same time, each child also faces a one in two chance of inheriting only one copy of the defective gene. People who have only one defective gene are known as carriers. These individuals do not develop the disease but they can pass the defective gene on to their own children. Because the defective genes involved in certain forms of ML are known, tests can identify people who are carriers in some instances.
Diagnosis
The diagnosis of ML is based on clinical symptoms, a complete medical history, and certain laboratory tests. Symptoms of the disease are usually present at birth or begin in early childhood. Early symptoms can include skeletal abnormalities, vision problems, and developmental delays. Poor mental capacities, and difficulty reaching physical developmental milestones may also be result of mucolipidosis.
Treatment
There is currently no known treatment or specific therapy to cure this disease. However, there are multiple therapy techniques that can be used to help with some of the symptoms. Speech therapy and physical therapy may aid in a diagnosed childs motor and speech delays. Nutritional supplements such as iron and vitamin B12 may also be required if the patient needs them.
See also
Medical genetics of Ashkenazi Jews
mucolipidoses at NINDS
References
== External links == |
Alimentary toxic aleukia | Alimentary toxic aleukia is a mycotoxin-induced condition characterized by nausea, vomiting, diarrhea, leukopenia (aleukia), hemorrhaging, skin inflammation, and sometimes death. Alimentary toxic aleukia almost always refers to the human condition associated with presence of T-2 toxin.
History
Alimentary toxic aleukia was first characterized in the early 20th century after affecting a large population in the Orenburg Oblast of the former USSR during World War II. The sick people had eaten overwintered grain colonized with Fusarium sporotrichioides and Fusarium poae.
== References == |
Sparganosis | Sparganosis is a parasitic infection caused by the plerocercoid larvae of the genus Spirometra including S. mansoni, S. ranarum, S. mansonoides and S. erinacei. It was first described by Patrick Manson from China in 1882, and the first human case was reported by Charles Wardell Stiles from Florida in 1908. The infection is transmitted by ingestion of contaminated water, ingestion of a second intermediate host such as a frog or snake, or contact between a second intermediate host and an open wound or mucous membrane. Humans are the accidental hosts in the life cycle, while dogs, cats, and other mammals are definitive hosts. Copepods (freshwater crustaceans) are the first intermediate hosts, and various amphibians and reptiles are second intermediate hosts.Once a human becomes infected, the plerocercoid larvae migrate to a subcutaneous location, where they typically develop into a painful nodule. Migration to the brain results in cerebral sparganosis, while migration to the eyes results in ocular sparganosis. Sparganosis is most prevalent in Eastern Asia, although cases have been described in countries throughout the world. In total, approximately 300 cases have been described in the literature up to 2003. Diagnosis is typically not made until the sparganum larva has been surgically removed. Praziquantel is the drug of choice, although its efficacy is unknown and surgical removal of the sparganum is generally the best treatment. Public health interventions should focus on water and dietary sanitation, as well as education about the disease in rural areas and discouragement of the use of poultices.
Symptoms
Clinical presentation of sparganosis most often occurs after the larvae have migrated to a subcutaneous location. The destination of the larvae is often a tissue or muscle in the chest, abdominal wall, extremities, or scrotum, although other sites include the eyes, brain, urinary tract, pleura, pericardium, and spinal canal. The early stages of disease in humans are often asymptomatic, but the spargana typically cause a painful inflammatory reaction in the tissues surrounding the subcutaneous site as they grow. Discrete subcutaneous nodules develop that may appear and disappear over a period of time. The nodules usually itch, swell, turn red, and migrate, and are often accompanied by painful edema. Seizures, hemiparesis, and headaches are also common symptoms of sparganosis, especially cerebral sparganosis, and eosinophilia is a common sign. Clinical symptoms also vary according to the location of the sparganum; possible symptoms include elephantiasis from location in the lymph channels, peritonitis from location in the intestinal perforation, and brain abscesses from location in the brain. In genital sparganosis, subcutaneous nodules are present in the groin, labia, or scrotum and may appear tumor-like.Ocular sparganosis a particularly well-described type of sparganosis. Early signs of the ocular form include eye pain, epiphora (excessive watering of the eye), and/or ptosis (drooping of the upper eyelid). Other signs include periorbital edema and/or edematous swelling that resembles Romanas sign in Chagas disease, lacrimation, orbital cellulitis, exophthalmos (protrusion of the eyeball), and/or an exposed cornea ulcer. The most common sign at presentation is a mass lesion in the eye. If untreated, ocular sparganosis can lead to blindness.In one case of brain infestation by Spirometra erinaceieuropaei, a man sought treatment for headaches, seizures, memory flashbacks and strange smells. Magnetic resonance imaging (MRI) scans showed a cluster of rings, initially in the right medial temporal lobe, but moving over time to the other side of the brain. The cause was not determined for four years; ultimately a biopsy was performed and a 1 cm-long tapeworm was found and removed. The patient continued to have symptoms.
Transmission
The parasite is transmitted to humans in three different ways. First, humans may acquire the infection by drinking water that is contaminated with copepods housing Spirometra larvae. Second, humans may acquire the infection by consuming the raw flesh of one of the second intermediate hosts, such as frogs or snakes. For example, humans consume raw snakes or tadpoles for medicinal purposes in some Asian cultures; if the snakes or tadpoles are infected, the larvae may be transmitted to humans. Third, humans may acquire the infection by placing raw poultices of the second intermediate hosts on open wounds, lesions, or the eyes for medicinal or ritualistic reasons. If the poultice is infected with plerocercoid larvae, the human may become infected. According to Zunt et al., human infection most often occurs following ingestion of infected raw snake, frog, or pig, although contact with infected flesh of an intermediate host can also cause infection. The high prevalence in Korea may be explained by the ingestion of dog meat. In the Western hemisphere, the most common cause of infection is drinking contaminated water.
Hosts, reservoirs, and vectors
Definitive hosts of Spirometra include dogs, cats, birds, and wild carnivores, while humans are accidental hosts. First intermediate hosts include copepods and other fresh-water crustaceans, while second intermediate hosts include birds, reptiles, and amphibians. The intermediate hosts are also the reservoirs of Spirometra. There are no vectors of Spirometra.
Incubation period
The incubation period of Spirometra is 20 days to 3 years.
Morphology
The sparganum larvae are white, wrinkled, and ribbon-shaped. They range from a few millimeters in length to several centimeters. The anterior end can invaginate and bears suggestions of the sucking grooves that are present in the scolex of the mature worm. The absence of a scolex or protoscolex in Spirometra is a key difference in differentiating between Taenia solium and Spirometra. The worms body is also characterized by a stromal network of smooth muscle. In general, plerocercoids in the East (S. mansoni) are described as larger and more delicate than those in the West.The eggs of S. mansonoides provide an example of the general morphological characteristics of Spirometra eggs. S. mansonoides eggs resemble the eggs of D. latum, with some specific differences. S. mansonoides eggs measure 57-66 µm by 33-37 µm, which is smaller than the eggs of D. latum. The eggs of S. mansonoides are also ellipsoidal and have a conical, prominent operculum.
Life cycle
The adult Spirometra live in the small intestine of the definitive host—a dog, cat, raccoon, or other mammal—for up to 9 years, where they produce many eggs. When the host defecates, the unembryonated eggs leave the body in the feces and hatch when they reach fresh water. The eggs are eaten by copepods (crustaceans of the genus Cyclops), which are the first intermediate hosts. In the copepods, the eggs develop into procercoid larvae that live in the body cavity. The second intermediate hosts include fish, reptiles, or amphibians that consume the copepods. The larvae penetrate the intestinal tract of the second intermediate host, where they become plerocercoid larvae and proliferate to the subcutaneous tissues and muscles. The second intermediate host is eventually eaten by a definitive host predator, such as a dog, and the cycle begins again. Humans are accidental hosts in the cycle, becoming infected with the plerocercoid larvae by contact with or ingestion of the first or second intermediate hosts. The larvae migrate to the subcutaneous tissues in humans; however, no development takes place and the human is not capable of transmitting the disease. In S. proliferum, many larvae, rather than just a few, proliferate throughout the subcutaneous tissues of humans.
Diagnosis
Sparganosis is typically diagnosed following surgical removal of the worms, although the infection may also be diagnosed by identification of eosinophilia or identification of the parasite in a tissue specimen. If such biopsy and excision procedures are not feasible, the antisparganum ELISA test may be used. In theory, a pre-operative diagnosis could be made by identification of exposure history and a painful, migratory, subcutaneous nodule. Sparganosis usually presents as a single nodule, while other cestode infections such as cysticercosis typically present as multiple nodules. Preoperative diagnosis, however, is rare.CT and MRI scans are especially useful for diagnosis of cerebral sparganosis, as they reveal lesions in the brain. Through a retrospective analysis of 25 cases of cerebral sparganosis from 2000 to 2006, Song et al. found a number of characteristic signs that could be used in the future to diagnose cerebral sparganosis without performing an excision or tissue biopsy. The most characteristic finding was the "tunnel sign" on MRI images, showing the migrating track of the worm, while the most common finding was multiple conglomerated ring-shaped enhancements, seen as bead-shaped, usually with 3 to 6 rings. These findings led Song et al. to suggest that clinical history, ELISA, and either MRI or CT scans could be sufficient to make a sparganosis diagnosis. These lesions, however, are sometimes mistaken for tuberculosis lesions. In one case cerebral sparganosis was not diagnosed for four years, during which scans showed a cluster of rings moving from the right to the left side of the brain; ultimately the worm was found on biopsy.
Prevention
Because sparganosis is a rare infection, public health strategies have not made its prevention a priority. Public health strategies focusing on providing basic access to clean water may help to reduce future sparganosis infections. In their retrospective study of 25 cases of cerebral sparganosis, Song et al. found that 12 patients (48%) had eaten raw or uncooked frog or snake that was infected with sparganum, 5 patients (20%) had applied an animals flesh as a poultice to an open wound, 4 patients had drunk contaminated water, and the cause of infection was not known for 4 patients. As a result of these findings, Song et al. conclude that health education about sparganosis and the importance of food sanitation should be implemented in all rural endemic areas. It has been recommended that water consumed in endemic areas should be boiled or treated to prevent ingestion of Cyclops or Spirometra larvae. Especially in areas where ponds or ditches provide potential habitats for infected copepods, public health strategies should include education campaigns about how to identify drinking water that could potentially be infected. Strategies should warn people against ingesting the raw flesh of the intermediate hosts, such as snakes and frogs, and against using them as poultices.
Management
One treatment for sparganosis is praziquantel, administered at a dose of 120 to 150 mg/kg body weight over 2 days; however, praziquantel has had limited success. In general, infestation by one or a few sparganum larvae is often best treated by surgical removal.DNA analysis of rare worms removed surgically can provide genome information to identify and characterise each parasite; treatments for the more common tapeworms can be cross-checked to see whether they are also likely to be effective against the species in question.
Epidemiology
Sparganosis is endemic or potentially endemic in 48 countries, and although rare, cases have been described in Asia, Africa, Australia, South America, and the United States. The majority of cases occur in Southeast Asia and Eastern Africa. Ocular sparganosis is especially prevalent in China and Vietnam. The highest numbers of cases occur in Korea and Japan. As of 2003, only seven cases of sparganosis had ever been described in Europe.
History of discovery
Diesing first named the Sparganum genus of cestodes in 1854. Patrick Manson first reported sparganosis and the species Sparganum mansoni in China in 1882, while making the post-mortem examination of a man in Amoy, China. The first case of sparganosis in the United States was reported by Stiles in 1908; this was a case of infection by Spirometra proliferum. Mueller first described Spirometra mansonoides in the United States in 1935.
References
== External links == |
Indigestion | Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier than expected when eating. Indigestion is relatively common, affecting 20% of people at some point during their life, and is frequently caused by gastroesophageal reflux disease (GERD) or gastritis.Indigestion is subcategorized as "organic" or "functional", but making the diagnosis can prove challenging for physicians. Organic indigestion is the result of an underlying disease, such as gastritis, peptic ulcer disease (an ulcer of the stomach or duodenum), or cancer. Functional indigestion (previously called nonulcer dyspepsia) is indigestion without evidence of underlying disease. Functional indigestion is estimated to affect about 15% of the general population in western countries and accounts for a majority of dyspepsia cases.In elderly patients (60 years of age or older) or with worrisome symptoms such as trouble swallowing, weight loss, or blood loss, an endoscopy (a procedure whereby a camera attached to a flexible tube is inserted down the throat and into the stomach) is recommended to further assess and find a potential cause. In patients younger than 60 years of age, testing for the bacteria H. pylori and if positive, treatment of the infection is recommended. More details about how indigestion is diagnosed and treated can be found below.
Signs and symptoms
Symptoms
Patients experiencing indigestion likely report one, a combination of, or all of the following symptoms:
upper abdominal pain or discomfort
bloating
early satiety
postprandial fullness
nausea with or without vomiting
anorexia
regurgitation
belching
Signs
There may be abdominal tenderness, but this finding is nonspecific and is not required to make a diagnosis. However, there are physical exam signs that may point to a different diagnosis and underlying cause for a patients reported discomfort. A positive Carnett sign (focal tenderness that increases with abdominal wall contraction and palpation) suggests an etiology involving the abdominal wall musculature. Cutaneous dermatomal distribution of pain may suggest a thoracic polyradiculopathy. Tenderness to palpation over the right upper quadrant, or Murphys sign, may suggest cholecystitis or gallbladder inflammation.
Alarm symptoms
Also known as Alarm features, alert features, red flags, or warning signs in gastrointestinal (GI) literature.
Alarm features are thought to be associated with serious gastroenterologic disease and include:
chronic gastrointestinal bleeding
progressive unintentional weight loss
progressive difficulty swallowing (dysphagia)
persistent vomiting
Iron deficiency anemia
Vitamin B12 deficiency (Pernicious anemia)
epigastric mass
Cause
Indigestion is a diagnosis related to a combination of symptoms that can be attributed to "organic" or "functional" causes. Organic dyspepsia should have pathological findings upon endoscopy, like an ulcer in the stomach lining in peptic ulcer disease. Functional dyspepsia is unlikely to be detected on endoscopy but can be broken down into two subtypes, epigastric pain syndrome (EPS) and post-prandial distress syndrome (PDS). In addition, indigestion could be caused by medications, food, or other disease processes.
Psychosomatic and cognitive factors are important in the evaluation of people with chronic dyspepsia. Studies have shown a high occurrence of mental disorders, notably anxiety and depression, amongst patients with dyspepsia; however, there is little evidence to prove causation.
Organic Dyspepsia
Esophagitis
Esophagitis is an inflammation of the esophagus, most commonly caused by gastroesophageal reflux disease (GERD). It is defined by the sensation of "heartburn" or a burning sensation in the chest as a result of inappropriate relaxation of the lower esophageal sphincter at the site where the esophagus connects to the stomach. It is often treated with proton pump inhibitors. If left untreated, the chronic damage to the esophageal tissues poses a risk of developing cancer. A meta-analysis showed risk factors for developing GERD included age equal to or greater than 50, smoking, the use of non-steroid anti-inflammatory medications, and obesity.
Gastritis
Common causes of gastritis include peptic ulcer disease, infection, or medications.
Peptic Ulcer Disease
Gastric and/or duodenal ulcers are the defining feature of peptic ulcer disease (PUD). PUD is most commonly caused by an infection with H. pylori or NSAID use.
Helicobacter pylori (H.pylori) infection
The role of H. pylori in functional dyspepsia is controversial, and treatment for H. pylori may not lead to complete improvement of a patients dyspepsia. However, a recent systemic review and meta-analysis of 29 studies published in 2022 suggests that successful treatment of H. pylori modestly improves indigestion symptoms.
Pancreatobiliary Disease
These include cholelithiasis, chronic pancreatitis, and pancreatic cancer.
Duodenal micro-inflammation
Duodenal micro-inflammation caused by an altered duodenal gut microbiota, reactions to foods (mainly gluten proteins) or infections may induce dyspepsia symptoms in a subset of people.
Functional Dyspepsia
Functional dyspepsia is a common cause of chronic heartburn. More than 70% of people have no obvious organic cause for their symptoms after evaluation. Symptoms may arise from a complex interaction of increased visceral afferent sensitivity, gastric delayed emptying (gastroparesis) or impaired accommodation to food. Diagnostic criteria for functional dyspepsia categorize it into two subtypes by symptom: epigastric pain syndrome and post-prandial distress syndrome. Anxiety is also associated with functional dyspepsia. In some people, it appears before the onset of gut symptoms; in other cases, anxiety develops after onset of the disorder, which suggests that a gut-driven brain disorder may be a possible cause. Although benign, these symptoms may be chronic and difficult to treat.
Epigastric Pain Syndrome (EPS)
Defined by stomach pain and/or burning that interferes with daily life, without any evidence of organic disease.
Post-Prandial Distress Syndrome (PDS)
Defined by post-prandial fullness or early satiation that interferes with daily life, without any evidence of organic disease.
Food, herb, or drug intolerance
Acute, self-limited dyspepsia may be caused by overeating, eating too quickly, eating high-fat foods, eating during stressful situations, or drinking too much alcohol or coffee. Many medications cause dyspepsia, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics (metronidazole, macrolides), bronchodilators (theophylline), diabetes drugs (acarbose, metformin, Alpha-glucosidase inhibitor, amylin analogs, GLP-1 receptor antagonists), antihypertensive medications (angiotensin converting enzyme [ACE] inhibitors, Angiotensin II receptor antagonist), cholesterol-lowering agents (niacin, fibrates), neuropsychiatric medications (cholinesterase inhibitors [donepezil, rivastigmine]), SSRIs (fluoxetine, sertraline), serotonin-norepinephrine-reuptake inhibitors (venlafaxine, duloxetine), Parkinson drugs (Dopamine agonist, monoamine oxidase [MAO]-B inhibitors), weight-loss medications (orlistat), corticosteroids, estrogens, digoxin, iron, and opioids. Common herbs have also been show to cause indigestion, like white willow berry, garlic, ginkgo, chaste tree berry, saw palmetto, and feverfew. Studies have shown that wheat and dietary fats can contribute to indigestion and suggest foods high in short-chain carbohydrates (FODMAP) may be associated with dyspepsia. This suggests reducing or consuming a gluten-free, low-fat, and/or FODMAP diet may improve symptoms. Additionally, some people may experience dyspepsia when eating certain spices or spicy food as well as foods like peppers, chocolate, citrus, and fish.
Systemic Diseases
There are a number of systemic diseases that may involve dyspepsia, including coronary disease, congestive heart failure, diabetes mellitus, hyperparathyroidism, thyroid disease, and chronic kidney disease.
Post-infectious Causes of Dyspepsia
Gastroenteritis increases the risk of developing chronic dyspepsia. Post-infectious dyspepsia is the term given when dyspepsia occurs after an acute gastroenteritis infection. It is believed that the underlying causes of post-infectious IBS and post-infectious dyspepsia may be similar and represent different aspects of the same pathophysiology.
Pathophysiology
The pathophysiology for indigestion is not well understood; however, there are many theories. For example, there are studies that suggest a gut-brain interaction, as patients who received an antibiotic saw a reduction in their indigestion symptoms. Other theories propose issues with gut motility, a hypersensitivity of gut viscera, and imbalance of the microbiome. A genetic predisposition is plausible, but there is limited evidence to support this theory.
Diagnosis
A diagnosis for indigestion is based on symptoms, with a possible need for more diagnostic tests. In younger patients (less than 60 years of age) without red flags (e.g., weight loss), it is recommended to test for H. pylori noninvasively, followed by treatment with antibiotics in those who test positively. A negative test warrants discussing additional treatments, like proton pump inhibitors, with your doctor. An upper GI endoscopy may also be recommended. In older patients (60 or older), an endoscopy is often the next step in finding out the cause of newly onset indigestion regardless of the presence of alarm symptoms. However, for all patients regardless of age, an official diagnosis requires symptoms to have started at least 6 months ago with a frequency of at least once a week over the last 3 months.
Treatment
Functional and organic dyspepsia have similar treatments. Traditional therapies used for this diagnosis include lifestyle modification (e.g., diet), antacids, proton-pump inhibitors (PPIs), H2-receptor antagonists (H2-RAs), prokinetic agents, and antiflatulents. PPIs and H2-RAs are often first-line therapies for treating dyspepsia, having shown to be better than placebo medications. Anti-depressants, notably tricyclic antidepressants, have also been shown to be effective treatments for patients who do not respond to traditional therapies.
Diet
A lifestyle change that may help with indigestion is a change in diet, such as a stable and consistent eating schedule and slowing the pace of eating. Additionally, there are studies that support a reduction in the consumption of fats may also alleviate dyspepsia. While some studies suggest a correlation between dyspepsia and celiac disease, not everyone with indigestion needs to refrain from gluten in their diet. However, a gluten-free diet can relieve the symptoms in some patients without celiac disease. Lastly, a FODMAPs diet or diet low/free from certain complex sugars and sugar alcohols has also been shown to be potentially beneficial in patients with indigestion.
Acid suppression
Proton pump inhibitors (PPIs) were found to be better than placebo in a literature review, especially when looking at long-term symptom reduction. H2 receptor antagonists (H2-RAs) have similar effect on symptoms reduction when compared to PPIs. However, there is little evidence to support prokinetic agents are an appropriate treatment for dyspepsia.Currently, PPIs are FDA indicated for erosive esophagitis, gastroesophageal reflux disease (GERD), Zollinger-Ellison syndrome, eradication of H. pylori, duodenal and gastric ulcers, and NSAID-induced ulcer healing and prevention, but not functional dyspepsia.
Prokinetics
Prokinetics (medications focused on increasing gut motility), such as metoclopramide or erythromycin, has a history of use as a secondary treatment for dyspepsia. While multiple studies show that it is more effective than placebo, there are multiple concerns about the side effects surrounding the long-term use of these medications.
Alternative medicine
A 2021 meta-analysis concluded that herbal remedies, like menthacarin (a combination of peppermint and caraway oils), ginger, artichoke, licorice, and jollab (a combination of rose water, saffron, and candy sugar), may be as beneficial as conventional therapies when treating dyspepsia symptoms. However, it is important to note that herbal products are not regulated by the FDA and therefore it is difficult to assess the quality and safety of the ingredients found in alternative medications.
Epidemiology
Indigestion is a common problem and frequent reason for primary care physicians to refer patients to GI specialists. Worldwide, dyspepsia affects about a third of the population. It can affect a persons quality of life even if the symptoms within themselves are usually not life-threatening. Additionally, the financial burden on the patient and healthcare system is costly - patients with dyspepsia were more likely to have lower work productivity and higher healthcare costs compared to those without indigestion. Risk factors include NSAID-use, H. pylori infection, and smoking.
See also
Functional bowel disorder
References
== External links == |
Sydenhams chorea | Sydenhams chorea, also known as chorea minor and historically and occasionally referred to as St Vitus dance, is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet. Sydenhams chorea is an autoimmune disease that results from childhood infection with Group A beta-haemolytic Streptococcus. It is reported to occur in 20–30% of people with acute rheumatic fever and is one of the major criteria for it, although it sometimes occurs in isolation. The disease occurs typically a few weeks, but up to 6 months, after the acute infection, which may have been a simple sore throat (pharyngitis).
Sydenhams chorea is more common in females than males and most cases affect children between the ages of 5 and 15 years of age. Adult onset of Sydenhams chorea is comparatively rare, and the majority of the adult cases are recurrences following childhood Sydenhams chorea.
Signs and symptoms
Sydenhams chorea is characterized by the abrupt onset (sometimes within a few hours) of neurologic symptoms, classically chorea, which are non-rhythmic, writhing or explosive involuntary movements. Usually all four limbs are affected, but there are cases reported where just one side of the body is affected (hemichorea). Typical chorea includes repeated wrist hyperextension, grimacing, lip pouting. The fingers can move as if playing the piano. There may be tongue fasciculations ("bag of worms") and motor impersistence for example the "milk maid sign" (grip strength fluctuates, as if hand milking), or inability to sustain tongue protrusion or eye closure. There is usually loss of fine motor control, particularly obvious in handwriting if the child is of school age. Speech is often affected (dysarthria), as is walking; legs will suddenly give way or flick out to one side, giving an irregular gait and the appearance of skipping or dancing. Underlying the abnormal movements is often low tone (hypotonia) which may not become obvious until treatment is started to suppress the chorea. In severe cases, the loss of tone and weakness predominate (chorea paralyticum).
The severity of the condition can vary from just some instability on walking and difficulty with hand writing, to the extreme of being wholly unable to walk, talk, or eat.
Movements cease during sleep. The eye muscles are not affected, curiously.It is a neuropsychiatric disorder, so besides the motor problems there is classically emotional lability (mood swings, or inappropriate mood), anxiety, attention deficit. These can precede the motor symptoms.Non-neurologic manifestations of acute rheumatic fever may be present, namely carditis (up to 70% of cases, often subclinical, so echocardiography required), arthritis, erythema marginatum, and subcutaneous nodules.
Differentiating these signs from other involuntary movements such as tics and stereotypies can be difficult, and since these things are not uncommon they can potentially co-exist. Diagnosis is often delayed and attributed to another condition such as tic disorder or conversion disorder. The controversial PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) hypothesis has overlapping clinical features but Sydenhams chorea is one of the exclusion criteria. PANDAS can present with chorea but more typically there are tics, stereotypies with a psychological component (e.g., OCD).
Differential diagnosis
Other disorders that may be accompanied by chorea include benign hereditary chorea, bilateral striatal necrosis, abetalipoproteinemia, ataxia–telangiectasia, biotin-thiamine-responsive basal ganglia disease, Fahr disease, familial dyskinesia–facial myokymia (Bird–Raskind syndrome) due to an ADCY5 gene mutation, glutaric aciduria, Lesch–Nyhan syndrome, mitochondrial disorders, Huntingtons disease, Wilson disease, hyperthyroidism, lupus erythematosus, pregnancy (chorea gravidarum), drug intoxication and side effects of certain anticonvulsants (e.g. phenytoin) or psychotropic agents. Although some of these can similarly present in an acute way, there will typically be other neurological signs (such as ataxia or cognitive impairment), or other disease manifestations, or positive family history, which will help distinguish between them.
Pathology
One of the important manifestations of acute rheumatic fever, Sydenhams chorea is similarly caused by an autoimmune response following infection by group A β-hemolytic streptococci.Two cross reactive streptococcal antigens have been identified, the M protein and N-acetyl-beta-D-glucosamine, whereby infection leads to autoantibodies being produced against host tissues (molecular mimicry) causing a variety of streptococcal related diseases including Sydenhams chorea but also rheumatic heart disease and nephritic syndrome. Autoantibodies against basal ganglia proteins have been found in Sydenhams chorea but these are non-specific. Dopamine receptor autoantibodies have been reported to correlate with clinical symptoms. Whether these antibodies represent an epi-phenomenon or are pathogenic, remains to be proven.
Epidemiology
As with rheumatic fever, Sydenhams chorea is seen more often in less affluent communities, whether in the developing world or in aboriginal communities in the global North. High rates of impetigo are a marker for widespread streptococcal transmission.
Diagnosis
Chorea is distinctive, if the health care provider is familiar with it. The diagnosis is then made by the typical acute onset in the weeks following a sore throat or other minor infection, plus evidence of inflammation (raised CRP and/or ESR) and evidence of recent streptococcal infection.
To confirm recent streptococcal infection:
Throat culture
Anti-DNAse B titre (peaks at 8–12 weeks after infection)
Anti-streptolysin O titre (peaks at 3–5 weeks)None of these tests are 100% reliable, particularly when the infection was some months previously.
Further testing is directed more towards alternative diagnoses and other manifestations of rheumatic fever:
Echocardiography
EEG
Lumbar puncture
Magnetic resonance imaging or computed tomography scan of the brain (alterations in caudate nucleus and putaminal enlargement have been described in some patients)
Management
Management of Sydenhams chorea is based on the following principles:
Eliminate the streptococcus – it may not be of any use for the index patient but further spread of that specific clone will be prevented.
Treat the movement disorder
Immunosuppression
Prevention of relapses and further cardiac damage
Manage the disabilityThere is a UFMG rating scale for Sydenhams chorea, from Brazilian Universidade Federal de Minas Gerais (UFMG), for research purposes, but it only looks at motor function not psychiatric/behavioural symptoms.
Occupational therapy and physiotherapy is useful for maintaining function and muscle tone.
Treatment with sodium valproate is effective for controlling symptoms, but it doesn’t speed up recovery. Haloperidol was used previously, but caused serious side effects e.g. tardive dyskinesia. Case reports exist to support carbamazepine and levetiracetam; other drugs tried include pimozide, clonidine, and phenobarbitone.
Immunosuppression
Immunosuppression is used inconsistently in Sydenhams chorea. The model of an autoimmune disorder would support its use. One randomized controlled trial of steroids from Paz, Brazil in 2006 (22 cases) showed remission reduced to 54 days from 119 days. Various other reports of use of oral or IV steroids from Israel, Italy and Brazil . Immunoglobulin has been used in Holland and South Africa. Some improvement can be seen within a few days of IV steroids. In Italy, prednisolone reduced average duration of symptoms from 9 weeks to 4 weeks, and these were severe cases. South African group found less neuropsychiatric complications at 6 months with IVIG treatment (IVIG preferred due to fear of TB reactivation).A course of penicillin is usually given at diagnosis to definitively clear any remaining streptococci, but there is no evidence that this is an effective treatment. Active infection is usually cleared by diagnosis. Penicillin prophylaxis, on the other hand, is essential to treat cardiac features of rheumatic fever, even if subclinical (American Heart Association guideline). If the case is of isolated chorea, it is arguable whether cardiac risk justifies prophylaxis or not, however it is likely to reduce recurrence.
There are several historical case series reporting successful treatment of Sydenhams chorea by inducing fever.
Prognosis
Motor problems including chorea settle within an average of 2–3 months.
Recurrence seen in 16–40% of cases. Recurrence is more likely with poor compliance with penicillin prophylaxis. Intramuscular penicillin is given every 2–3 weeks superior to 4 weekly regime, and oral penicillin is also prescribed. Recurrences are sometimes associated with rise in ASO titre or other evidence of new streptococcal infection. There is no obvious clinical parameter that might predict those at risk of recurrence. More likely if failure to remit in initial 6 months, can recur with pregnancy (chorea gravidorum).
Higher recurrence rates seen in longest follow up – can recur up to 10 years after the initial episode, so might be underestimated by series with shorter follow up.
Recurrence is usually only chorea, even if the original case was associated with rheumatic fever. There are two total reports of heart disease worsening after recurrence of chorea. The Thailand study also had 2 cases where carditis, which had improved after initial diagnosis, came back again. Some suggest that recurrent chorea is a different disease altogether.10% reported long term tremor in one study (10 years follow up). Long term neuropsychiatric difficulties are increasingly recognized (49 studies so far, especially obsessive-compulsive disorder but also attention-deficit hyperactivity disorder, affective disorders, tic disorders, executive function disturbances, psychotic features, and language impairment).Heart involvement improves in about a third of cases (whether silent or not).[PMID 22734303]
Family support
Sydenhams Chorea Association
History
The incidence of acute rheumatic fever and rheumatic heart disease is not declining. Recent figures quote the incidence of Acute Rheumatic Fever as 0.6–0.7/1,000 population in the United States and Japan compared with 15–21/1,000 population in Asia and Africa. The prevalence of Acute Rheumatic Fever and Sydenhams Chorea has declined progressively in developed countries over the last decades.
Etymology
It is named after British physician Thomas Sydenham (1624–1689). The alternate eponym, "Saint Vitus Dance", is in reference to Saint Vitus, a Christian saint who was persecuted by Roman emperors and died as a martyr in AD 303. Saint Vitus is considered to be the patron saint of dancers, with the eponym given as homage to the manic dancing that historically took place in front of his statue during the feast of Saint Vitus in Germanic and Latvian cultures.
References
Further reading
Martino D, Tanner A, Defazio G, et al. (May 2005). "Tracing Sydenhams chorea: historical documents from a British paediatric hospital". Archives of Disease in Childhood. 90 (5): 507–11. doi:10.1136/adc.2004.057679. PMC 1720385. PMID 15851434.
== External links == |
Alacrima | Alacrima refers to an abnormality in tear production that could mean reduced tear production or absent tear production. Because a lack of tears presents in only in a few rare disorders, it aids in diagnosis of these disorders, including Triple-A syndrome and NGLY1 deficiency.Alacrima can be formally diagnosed through a Schirmers test.
References
== External links == |
Dyskinetic cerebral palsy | Dyskinetic cerebral palsy (DCP) is a subtype of cerebral palsy (CP) and is characterized by impaired muscle tone regulation, coordination and movement control. Dystonia and choreoathetosis are the two most dominant movement disorders in patients with DCP.
Presentation
In dyskinetic cerebral palsy, both motor and non-motor impairments are present. Motor impairments, such as impaired muscle tone regulations, lack of muscle control and bone deformations are often more severe compared to the other subtypes of CP. Non-motor impairments increase with motor severity. Half of the DCP group shows severe learning disabilities, 51% has epilepsy. Hearing and visual impairments occur frequently, respectively 11% and 45%. Dysarthria or anarthria are also common, so alternative and augmentative communication tools are needed.
Dystonia and choreoathetosis
Dystonia and choreoathetosis mostly occur concurrently in DCP, but they are two independent motor disorders with their own characteristics. Dystonia predominates in most patients.
Dystonia (DYS) is defined by twisting and repetitive movements, abnormal postures due to sustained muscle contractions, and hypertonia. Dystonia is aggravated by voluntary movements and postures, or with stress, emotion or pain. A video of dystonia in a patient with dyskinetic cerebral palsy can be seen here: Dyskinetic cerebral palsy: dystonia on YouTubeChoreoathetosis (CA) is characterized by hyperkinesia (chorea i.e. rapid involuntary, jerky, often fragmented movements) and hypokinesia (athetosis i.e. slower, constantly changing, writhing or contorting movements). A video of choreoathetosis in a patient with dyskinetic cerebral palsy can be seen here: Dyskinetic cerebral palsy: choreoathetosis on YouTube
Clinical patterns
Patients with DCP are more likely to obtain a high level of functional disability. Respectively 12,7% and 49% of the patients were assigned in level IV and V of the Gross Motor Function Classification System (GMFCS). The same trend appeared in manual ability with 21,8% in level IV and 43,6% in level V of the Manual Ability Classification System (MACS). A good correlation between the functional classification scales and the total dystonia level was found, meaning that a higher level of functional disability correlates with a higher dystonia level. The same study showed no associations with choreoathetosis. These results suggest that dystonia typically has a bigger impact on functionality and a larger effect on activity, participation and quality of life than choreoathetosis.As previously mentioned, dystonia predominates in most patients, partly because dystonia is often more noticeable and severe than choreoathetosis. Both increase with activity and are generalized over all body regions with a higher severity in the upper limbs than in the lower limbs. Dystonia has a significantly higher level of severity in the distal parts of the extremities, whereas choreoathetosis is more equally distributed.
Causes
Dyskinetic cerebral palsy could have multiple causes. The majority of the children are born at term and experience perinatal adverse events which can be supported by neuroimaging. Possible causes are perinatal hypoxic-ischaemia and neonatal shock in children born at term or near term. Hyperbilirubinaemia used to be a common contributing factor, but is now rare in high-income countries due to preventive actions. Other aetiological factors are growth retardation, brain maldevelopment, intracranial haemorrhage, stroke or cerebral infections.
Diagnosis
Multiple classification systems using Magnetic Resonance Imaging (MRI) have been developed, linking brain lesions to time of birth, cerebral palsy subtype and functional ability. The overall goal of these studies is to elucidate etiology, timing of injury and pathogenesis of cerebral palsy.Around 70% of patients with DCP show lesions in the cortical and deep grey matter of the brain, more specifically in the basal ganglia and thalamus. However, other brain lesions and even normal-appearing MRI findings can occur, for example white matter lesions and brain maldevelopments. Patients with pure basal ganglia and thalamus lesions are more likely to show more severe choreoathetosis whereas dystonia may be associated with other brain lesions, such as the cerebellum. These lesions occur mostly during the peri- and postnatal period since these regions have a high vulnerability during the late third trimester of the pregnancy. Unfortunately, contemporary imaging is not sophisticated enough to detect all subtle brain deformities and network disorders in dystonia. Research with more refined imaging techniques including diffusion tensor imaging and functional MRI is required.
Prevention
Prevention strategies have been developed for the different risk factors of the specific cerebral palsy subtypes. Primary prevention consists of reducing the possible risk factors. However, when multiple risk factors cluster together, prevention is much more difficult. Secondary preventions may be more appropriate at that time, e.g. prevention of prematurity. Studies showed a reduced risk of cerebral palsy when administering magnesium sulfate to women at risk of preterm delivery.Cooling or therapeutic hypothermia for 72 hours immediately after birth has a significant clinical effect on reducing mortality and severity of neurodevelopmental disabilities in neonates with birth asphyxia. This has been documented for newborns with hypoxic-ischemic encephalopathy.
Management
Measurement
Measuring dystonia and choreoathetosis can be very challenging. It is however crucial to have reliable measurements for the evaluation and effects of targeted management. So far, measurements involved the usage of clinical qualitative assessment scales judged by video observation. The Barry-Albright Dystonia Rating Scale (BADS), the Burke-Fahn-Marsden Dystonia Rating Scale (BFMS) and the Dyskinesia Impairment Scale (DIS) are most commonly used.The BADS was developed and validated to assess secondary dystonia in patients with CP. The BFMS has been validated for use in primary dystonia and is clinically the most used scale in both primary and secondary dystonia. Both the BADS and BFMS do not include scoring for choreoathetosis. The DIS is currently stated as the most sensitive, valid and reliable scale. It has been validated for use in secondary dystonia, as it occurs in patients with DCP. The value lays in its detailed full-body consideration and the differentiation action-rest, proximal-distal limb and duration-amplitude. Moreover, the DIS includes both the evaluation of dystonia and choreoathetosis. Although this scale is currently seen as the gold standard to evaluate patients with DCP in research, substantial time and experience with the current CA and DYS definitions is needed from the rater in scoring dystonia and choreoathetosis.Both the DIS and BFMS can be used as outcome measure in intervention studies such as deep brain stimulation (DBS) or intrathecal baclofen.
Aim of treatment interventions
Dyskinetic cerebral palsy is a non-progressive, non-reversible disease. The current management is symptomatic, since there is no cure. The main goal is to improve daily activity, quality of life and autonomy of the children by creating a timed and targeted management.
The many management options for patients with DCP are not appropriate as standalone treatment but must be seen within an individualized multidisciplinary rehabilitation program.
Medical and rehabilitation interventions
Management options can be subdivided into medical treatment and rehabilitation interventions.
Medical treatment consists of oral medication and surgery. Before using oral drugs, it is important to differentiate between spasticity, dystonia and choreoathetosis since each motor disorder has a specific approach. In general, many oral drugs have low efficacy, unwanted side-effects and variable effects. Oral baclofen and trihexyphenidyl are commonly used to decrease dystonia, although its efficacy is relatively low in most patients. Adverse effects of the latter can include worsening of choreoathetosis. Since dystonia predominates over choreoathetosis in most patients, reducing dystonia allows the possibility of a full expression of choreoathetosis. This suggests that the discrimination of dystonia and choreoathetosis is crucial, since misinterpretations in diagnosing can contribute to the administration of inappropriate medication, causing unwanted effects. Intrathecal baclofen pump (ITB) is often used as an alternative to reduce side-effects of the oral dystonic medication over the whole body and botulinum toxin injections are applied to decrease dystonia in specific muscles or muscle groups. Research on the effects of ITB and botulinum toxin on choreoathetosis is lacking.
Regarding surgical treatment in patients with DCP, deep brain stimulation (DBS) has shown to decrease dystonia. However, the responsiveness is less beneficial and the effects are more variable than in patients with inherited or primary dystonia. The effects on choreoathetosis have not been investigated.
Orthopedic surgery is performed to correct musculoskeletal deformities, but it is recommended that all other alternatives are considered first.The previous management options need to be combined with rehabilitation programs, adapted to the specific needs of each individual. Unfortunately, evidence for rehabilitation strategies is scarce and is based on clinical expertise. The team of caregivers can consist of physiotherapists, occupational therapists and speech/communication therapists. The therapy mainly focusses on the motor problems by using principles of neuroplasticity, patterning, postural balance, muscle strengthening and stretching. Non-motor impairments such as epilepsy require specific treatment.
Prevalence
Dyskinetic cerebral palsy is the second most common subtype of cerebral palsy, after spastic CP. A European Cerebral Palsy study reported a rate of 14,4% of patients with DCP which is similar to the rate of 15% reported in Sweden. The rate appeared lower in Australia, where data from states with full population-based ascertainment listed DCP as the predominant motor type in only 7% of the cases. The differences reported from various registers and countries may relate to under-identification of dyskinetic CP due to a lack of standardization in definition and classification based on predominant type.
== References == |
Mitochondrial myopathy | Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. On biopsy, the muscle tissue of patients with these diseases usually demonstrate "ragged red" muscle fibers. These ragged-red fibers contain mild accumulations of glycogen and neutral lipids, and may show an increased reactivity for succinate dehydrogenase and a decreased reactivity for cytochrome c oxidase. Inheritance was believed to be maternal (non-Mendelian extranuclear). It is now known that certain nuclear DNA deletions can also cause mitochondrial myopathy such as the OPA1 gene deletion. There are several subcategories of mitochondrial myopathies.
Signs and symptoms
Signs and symptoms include (for each of the following causes):
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS)
Varying degrees of cognitive impairment and dementia
Lactic acidosis
Strokes
Transient ischemic attacks
Hearing loss
Weight loss
Myoclonic epilepsy and ragged-red fibers (MERRF)
Progressive myoclonic epilepsy
Clumps of diseased mitochondria accumulate in muscle fibers and appear as "ragged-red fibers" when muscle is stained with modified Gömöri trichrome stain
Short stature
Kearns–Sayre syndrome (KSS)
External ophthalmoplegia
Cardiac conduction defects
Sensorineural hearing loss
Chronic progressive external ophthalmoplegia (CPEO)
Progressive ophthalmoparesis
Symptomatic overlap with other mitochondrial myopathies
Cause
Zidovudine, an HIV medication can cause red ragged fiber myopathy.
Diagnosis
Muscle biopsy: ragged red fibers in Gömöri trichrome stain.
Treatment
Although no cure currently exists, there is hope in treatment for this class of hereditary diseases with the use of an embryonic mitochondrial transplant.
References
== External links == |
Cornelia de Lange syndrome | Cornelia de Lange syndrome (CdLS) is a genetic disorder. People with this syndrome experience a range of physical, cognitive, and medical challenges ranging from mild to severe. The syndrome has a widely varied phenotype, meaning people with the syndrome have varied features and challenges. The typical features of CdLS include thick or long eyebrows, a small nose, small stature, developmental delay, long or smooth philtrum, thin upper lip and downturned mouth.The syndrome is named after Dutch pediatrician Cornelia Catharina de Lange, who described it in 1933.
It is often termed Brachmann de Lange syndrome or Bushy syndrome and is also known as Amsterdam dwarfism. Its exact incidence is unknown, but it is estimated at 1 in 10,000 to 30,000.
Signs and symptoms
The phenotype of CdLS is highly varied and is described as a spectrum; from Classic CdLS (with a greater number of key features) to mild variations with only a few features. Some people will have a small number of features but dont have CdLS.Key features:
Long and/or thick eyebrows
Short nose
Concave nasal ridge and/or upturned nasal tip
Long and/or smooth philtrum
Thin upper lip vermilion and/or downturned corners of mouth
Missing fingers or toes
Congenital diaphragmatic herniaOther suggestive features:
Developmental delay and/or intellectual disability
Small prenatal and birth size / weight
Small stature
Microcephaly (prenatally and/or postnatally)
Small hands and/or feet
Short fifth finger
HirsutismThe following health conditions are more common in people with CdLS than in the general population.
Respiratory illness
Heart defects (e.g., pulmonary stenosis, VSD, ASD, coarctation of the aorta)
Hearing impairment
Vision abnormalities (e.g., ptosis, nystagmus, high myopia, hypertropia)
Partial joining of the second and third toes
Incurved 5th fingers (clinodactyly)
Gastroesophageal reflux
Gastrointestinal abnormalities
Musculoskeletal problems
Scoliosis
Social anxiety
Seizures
Cleft palate
Feeding problemsChildren with this syndrome are often found to have long eyelashes, bushy eyebrows and synophrys (joined eyebrows). Body hair can be excessive and affected individuals are often shorter than their immediate family members. They present a characteristic facial phenotype.Children with CdLS often have gastrointestinal tract difficulties, particularly gastroesophageal reflux. Vomiting, intermittent poor appetite, constipation, diarrhea or gaseous distention are known to be a regularity in cases where the GI tract problems are acute. Symptoms may range from mild to severe.
People with CdLS may exhibit behaviours that have been described as "autistic-like," including self-stimulation, aggression, self-injury or strong preference to a structured routine. Behavior problems in CdLS are not inevitable. Many behaviour issues associated with CdLS are reactive (i.e., something happens within the persons body or environment to bring on the behavior) and cyclical (comes and goes). Often, an underlying medical issue, pain, social anxiety, environmental or caregiver stress can be associated with a change behaviour. If pain or a medical issue is the cause, once treated, the behaviour diminishes.
There is evidence for some features of premature aging including the early development of Barrett’s esophagus, osteoporosis present in the teenage years, premature greying of hair and some changes to the skin of the face causing a more aged appearance compared to chronological age.
Causes
The vast majority of cases are thought to be due to spontaneous genetic mutations. It can be associated with mutations affecting the cohesin complex.As of 2018, it was confirmed that 500 genetic mutations have been associated with the condition; occurring on 7 different genes. In around 30% of cases of CdLS the genetic cause remains undiscovered. The wide variation in phenotype is attributed to a high degree of somatic mosaicism in CdLS as well as the different genes and type of mutations. For this reason people with CdLS can have very different appearance, abilities, and associated health issues.
The latter two genes seem to correlate with a milder form of the syndrome.In 2004, researchers at the Childrens Hospital of Philadelphia (United States) and the University of Newcastle upon Tyne (England) identified a gene (NIPBL) on chromosome 5 that causes CdLS when it is mutated. Since then, additional genes have been found (SMC1A, SMC3 and HDAC8, RAD21) that cause CdLS when changed. In July 2012, the fourth "CdLS gene"—HDAC8—was announced. HDAC8 is an X-linked gene, meaning it is located on the X chromosome. Individuals with CdLS who have the gene change in HDAC8 make up just a small portion of all people with CdLS. Evidence of a linkage at chromosome 3q26.3 is mixed.Genetic alterations associated with CdLS have been identified in genes NIPBL, SMC1A and SMC3 as well as the more recently identified genes RAD21 and HDAC8. All of these genetic alterations occurring in CdLS patients affect proteins that function in the cohesin pathway. SMC1A, SMC3 and RAD21 proteins are structural components of the cohesin ring complex. NIPBL is involved in the loading of the cohesin ring onto chromosomes, and HDAC8 deacylates SMC3 to facilitate its function. The cohesin pathway is involved in cohesion of sister chromatids during mitosis, DNA repair, chromosome segregation and the regulation of developmental gene expression. Defects in these functions are theorised to underlie some of the features of CdLS. In particular, defective DNA repair may underlie the features of premature aging.
Diagnosis
The diagnosis of CdLS is primarily based on clinical findings by a clinical geneticist; and in some cases may be confirmed through laboratory testing.
Treatment
Often, an interdisciplinary approach is recommended to treat the issues associated with CdLS. A team for promoting the childs well-being often includes speech, occupational and physical therapists, teachers, physicians, and parents.Cornelia de Lange syndrome (CdLS) affects many different systems of the body, medical management is often provided by a team of doctors and other healthcare professionals. Treatment for this condition varies based on the signs and symptoms present in each person. It may include: [4] [5]
Supplemental formulas and/or gastrostomy tube placement to meet nutritional needs and improve the growth delay,Ongoing physical, occupational, and speech therapies,Surgery to treat skeletal abnormalities, gastrointestinal problems, congenital heart defects and other health problems, and,
Medications to prevent or control seizures.Research into CdLS ongoing
History
The first documented case was in 1916 by Winfried Robert Clemens Brachmann (1888–1969), a German physician who wrote about the distinct features of the disease from his 19-year-old patient, followed in 1933 by Cornelia Catharina de Lange (1871–1950), a Dutch pediatrician after whom the disorder has been named. CdLS was formerly known as Brachmann-de Lange Syndrome.
References
External links
GeneReviews/NCBI/UW/NIH entry on Cornelia de Lange syndrome
Malik, Lamees Mahmood; Khan, Ghazala Aziz; Azfar, Nadia Ali; Jahangir, Muhammad (2011). "Cornelia de Lange Syndrome - a cause of hypertrichosis in children: case report and review of literature". Journal of Pakistan Association of Dermatologists. 21 (3): 211–214. Gale A270898918. |
Hereditary gingival fibromatosis | Hereditary gingival fibromatosis (HGF), also known as idiopathic gingival hyperplasia, is a rare condition of gingival overgrowth. HGF is characterized as a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of keratinized gingiva. It can cover teeth in various degrees, and can lead to aesthetic disfigurement. Fibrous enlargement is most common in areas of maxillary and mandibular tissues of both arches in the mouth. Phenotype and genotype frequency of HGF is 1:175,000 where males and females are equally affected but the cause is not entirely known. It mainly exists as an isolated abnormality but can also be associated with a multi-system syndrome.
Signs and symptoms
There may or may not be any evidence of history of HGF in the family nor any usage of taking long-term medicines for any particular disease when it comes to diagnosing HGF. There also may or may not be any signs of medical and/or family history of mental retardation, hypertrichosis, nor clinical symptoms that can be associated with gingival enlargement. Although, enlargement of gingiva, interdental papilla, hindered speech, and secondary inflammatory changes taking place in the mouth commonly at the marginal gingiva are all very indicative of this condition. Commonly the patient will have mandibular and maxilliary inflammation and overgrowth as opposed to the traditional pink, firm, and fleshy consistency of healthy gingiva. The patients jaw may also appear distorted because of the gingiva enlargements. Overgrowth of the gingiva can range from slightly covering the surface of teeth or it can even completely cover the surrounding teeth. The patient can also experience damage or loss of teeth.
Obvious signs
Most obvious sign is gingival overgrowth (overgrowth of the gums)
Hindered chewing efficiency and difficulties eating
Increasing mobility of teeth
Abnormally shaped teeth and abnormal movement of teeth
Inflammation and/or swelling of the gums/gingiva
Not necessarily any signs of pain but experiencing pain is possible
Difficulties in speaking, oftentimes can lead to speech disorders
Other dental and oral problems
In some cases, Hereditary Gingival Fibromatosis may cause bleeding from the gums, or gum ulcerations.
Cause
Though much more research needs to be done, researchers have mostly agreed that a mutation in SOS1, son-of-sevenless gene, is responsible for this disease. SOS1 is a guanine nucleotide-exchange factor that functions in the transduction of signals that control cell growth and differentiation. A mutation in the SOS1 gene results in a single nucleotide insertion. Specific linkage studies have localized the mutation for isolated, nonsyndromic autosomal dominant forms of gingival fibromatosis to chromosomes 2 and 5, more specifically 2p21-p22 and 5q13-q22.
Genetic
HGF1 - Caused by a mutation in the SOS1 gene localized on chromosome 2p21-p22HGF2 - Caused by a mutation in the SOS1 gene localized on chromosome 5q13-q22Mutations in the RE1-silencing transcription factor (REST) gene can also cause this syndrome.
Non genetic
HGF may also be caused by unwanted side effects of pharmacological agents like phenytoin, ciclosporin, and some calcium-channel blockers, meaning HGF is a disease that can be drug-induced. However, there is little next to no research done in this area to support the claim.
Inflammation
Hormonal Imbalance
Neoplasia
More commonly associated with an autosomal dominant gene inheritance
Multi-system syndromes: Zimmerman-Laband syndrome, Jones syndrome, Ramon syndrome, Rutherford syndrome, juvenile hyaline fibromatosis, systemic infantile hyalinosis, and mannosidosis
Some unknown causes
Mechanism
Genetic linkage studies are among the most popular methods of study to look at the mechanism of this HGF. Genetic linkage studies have found to localize genetic loci for autosomal dominant forms of HGF to chromosome 2p21-p22 (indicative of HGF1) and chromosome 5q13-q22 (indicative of HGF2). Chromosome 2p21-p22 has been refined to an interval of ~2.3 Mb to construct an integrated physical and genetic map of the 16 genes interval. Here, a mutation is found in sequencing these 16 genes.There is an insertion of a cytosine between nucleotides 126,142 and 126,143 in codon 1083 of the SOS1 gene, meaning there is a mutation in SOS1. This causes a problem because SOS1 introduces a frameshift mutation and creates a premature stop codon. Also, it can segregate over generations, most commonly four. Once it causes a premature stop codon, the chromosome loses four important proline-rich SH-3 binding domains in the carboxyl-terminal region of the SOS1 protein. As a result, the N-terminal amino acids for SOS1 is fused into a 22–amino acid carboxyl terminus. Researchers claim that this mutation in the SOS1 gene is a probable primary cause of this disease but limited information supports the mechanism of this claim.
Diagnosis
There are very few ways to test a patient for HGF. Currently, the most common way to diagnose a patient is by means of a physical evaluation. The physician can make a physical evaluation of the patient and send them to a dentist or better yet a specialist like a periodontist to evaluate signs of gingival overgrowth, quality of gingiva, inflammation, mechanical difficulties of the mouth, tooth conditions, and any sort of discomfort.Aside from obvious physical symptoms seen in a physical evaluation, molecular tests can be run to check if there is a mutation in the SOS1 gene to confirm the diagnosis. If there is indeed a mutation in this gene coupled with the typical physical symptoms, then it is quite probable that a patient suffers from this disease. Also, looking at family history is also becoming more prominent in aiding to diagnose the patient. Otherwise, researchers are working to find new and better ways to test for the presence of HGF.
Prevention
Since this condition is generally agreed upon to be hereditary, nothing can be done to prevent HGF. However, in some cases where it can develop as a result of rare multi-system syndromes, such as: Zimmerman-Laband, Jones, Ramon Syndrome, Rutherford Syndrome, Juvenile Hyaline Fibromatosis, Systemic Infantile Hyalinosis, and Mannosidosis, it is best for one to simply monitors the possible progression for HGF with regular dental check-ups.If the patients disease is treated by means of surgery, it is recommended that the patient undergoes post-surgical therapies for maintenance and periodic monitoring of gums for the sake of the possibility of re-occurrence of HGF.
Treatment
This disease has not been shown to be life-threatening or the cause of death in patients. However, treatment is necessary to maintain a healthy lifestyle.
If left untreated
The following can occur if left untreated:
Too much gingiva exposure
Oral morbidity
Chronic infection of areas between the gums and teeth, or at the gum line
various degrees of Periodontitis - most likely due to the inability and difficulty of keeping the gingival margin and surrounding tissue clean due to the overgrowth
Improper tooth eruption and/or complete prevention of tooth eruption as a result of too much gingiva exposure
Systemic every-day troubles including functional and aesthetic problems of the mouth
Malocclusion
Treatment
Most recent methods of treatment take the form of surgeries such as oral prophylaxis, followed by post-surgical therapies to monitor, provide proper oral hygiene, and correct the deformity. Although, the nature of recurrence post-treatment is virtually unknown, let alone what type of treatment is most effective for HGF. (SOURCE 2) In some cases, there is re-growth after surgical removal of the excess gingival tissues, in others there is minimal. No cases yet have shown any particular treatment or form of medicine to permanently remove HGF.One type of procedure that can be executed is as follows: Removal of excess tissue under anesthesia through an internal bevel gingivectomy or undisplaced flap followed by gingivoplasty and continuous sling suture placements and periodontal dressing; after about a week of recovery after the surgery, remove sutures and periodically do observational evaluations to look for any signs of re-occurrence.
Recent research
Some researchers suggest that HGF is transmitted as a Mendelian trait since both autosomal dominant and autosomal recessive transmission has been reported since the early 1970s. (SOURCE 1) In more recent scientific literature, there is evidence in which pedigree analyses confirm autosomal dominant, autosomal recessive or even as X-linked inherited cases of the HGF trait.In 2002, researchers described the SOS1 gene and proved for the first time that a single-nucleotide–insertion mutation of the SOS1 gene on codon 1083 is the preliminary cause of HGF1 in humans. (Source 1) Later on in 2010, there was a case study done on a 16-year-old male with severe gingival overgrowth, almost covering all teeth. Researchers approached this issue with periodontics - a partial gingivectomy and flap surgery. This case study concluded that surgery followed by regular follow-ups is a good way to treat HGF despite the fact that the risks of re-occurrence of the condition remain high.Even more recently, a study was done in 2013 on a family that showed history of autosomal recessive inheritance of HGF. The study did not dismiss the return of HGF after treatment but did claim that general surgical intervention after scaling and root planning of teeth supplemented with good oral hygiene is good enough to prevent the re-occurrence of HGF. This case study also acknowledged how HGF can be part of a multi-system syndrome associated with disorders such as Zimmermann Laband syndrome (ear, nose, bone, and nail defects with hepatosplenomegaly), Rutherford syndrome (microphthalmia, mental retardation, athetosis, and hypopigmentation), Murray-Puretic Drescher syndrome and Ramon syndrome.
See also
Chronic periodontitis
Epidemiology of periodontal diseases
Gingivitis
Gum graft
Periodontist
Tooth loss
Gingival recession
References
External links
American Academy of Periodontology Home Page
Periodontal Disease as a Specific, albeit Chronic, Infection: Diagnosis and Treatment |
Zinc | Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic table. In some respects, zinc is chemically similar to magnesium: both elements exhibit only one normal oxidation state (+2), and the Zn2+ and Mg2+ ions are of similar size. Zinc is the 24th most abundant element in Earths crust and has five stable isotopes. The most common zinc ore is sphalerite (zinc blende), a zinc sulfide mineral. The largest workable lodes are in Australia, Asia, and the United States. Zinc is refined by froth flotation of the ore, roasting, and final extraction using electricity (electrowinning).
Zinc is an essential trace element for humans and other animals, for plants and for microorganisms and is necessary for prenatal and postnatal development. It is the second most abundant trace metal in humans after iron and it is the only metal which appears in all enzyme classes. Zinc deficiency affects about two billion people in the developing world and is associated with many diseases. In children, deficiency causes growth retardation, delayed sexual maturation, infection susceptibility, and diarrhea. Enzymes with a zinc atom in the reactive center are widespread in biochemistry, such as alcohol dehydrogenase in humans. Consumption of excess zinc may cause ataxia, lethargy, and copper deficiency.
Brass, an alloy of copper and zinc in various proportions, was used as early as the third millennium BC in the Aegean area and the region which currently includes Iraq, the United Arab Emirates, Kalmykia, Turkmenistan and Georgia. In the second millennium BC it was used in the regions currently including West India, Uzbekistan, Iran, Syria, Iraq, and Israel. Zinc metal was not produced on a large scale until the 12th century in India, though it was known to the ancient Romans and Greeks. The mines of Rajasthan have given definite evidence of zinc production going back to the 6th century BC. To date, the oldest evidence of pure zinc comes from Zawar, in Rajasthan, as early as the 9th century AD when a distillation process was employed to make pure zinc. Alchemists burned zinc in air to form what they called "philosophers wool" or "white snow".
The element was probably named by the alchemist Paracelsus after the German word Zinke (prong, tooth). German chemist Andreas Sigismund Marggraf is credited with discovering pure metallic zinc in 1746. Work by Luigi Galvani and Alessandro Volta uncovered the electrochemical properties of zinc by 1800. Corrosion-resistant zinc plating of iron (hot-dip galvanizing) is the major application for zinc. Other applications are in electrical batteries, small non-structural castings, and alloys such as brass. A variety of zinc compounds are commonly used, such as zinc carbonate and zinc gluconate (as dietary supplements), zinc chloride (in deodorants), zinc pyrithione (anti-dandruff shampoos), zinc sulfide (in luminescent paints), and dimethylzinc or diethylzinc in the organic laboratory.
Characteristics
Physical properties
Zinc is a bluish-white, lustrous, diamagnetic metal, though most common commercial grades of the metal have a dull finish. It is somewhat less dense than iron and has a hexagonal crystal structure, with a distorted form of hexagonal close packing, in which each atom has six nearest neighbors (at 265.9 pm) in its own plane and six others at a greater distance of 290.6 pm. The metal is hard and brittle at most temperatures but becomes malleable between 100 and 150 °C. Above 210 °C, the metal becomes brittle again and can be pulverized by beating. Zinc is a fair conductor of electricity. For a metal, zinc has relatively low melting (419.5 °C) and boiling points (907 °C). The melting point is the lowest of all the d-block metals aside from mercury and cadmium; for this reason among others, zinc, cadmium, and mercury are often not considered to be transition metals like the rest of the d-block metals.Many alloys contain zinc, including brass. Other metals long known to form binary alloys with zinc are aluminium, antimony, bismuth, gold, iron, lead, mercury, silver, tin, magnesium, cobalt, nickel, tellurium, and sodium. Although neither zinc nor zirconium is ferromagnetic, their alloy ZrZn2 exhibits ferromagnetism below 35 K.
Occurrence
Zinc makes up about 75 ppm (0.0075%) of Earths crust, making it the 24th most abundant element. Typical background concentrations of zinc do not exceed 1 μg/m3 in the atmosphere; 300 mg/kg in soil; 100 mg/kg in vegetation; 20 μg/L in freshwater and 5 μg/L in seawater. The element is normally found in association with other base metals such as copper and lead in ores. Zinc is a chalcophile, meaning the element is more likely to be found in minerals together with sulfur and other heavy chalcogens, rather than with the light chalcogen oxygen or with non-chalcogen electronegative elements such as the halogens. Sulfides formed as the crust solidified under the reducing conditions of the early Earths atmosphere. Sphalerite, which is a form of zinc sulfide, is the most heavily mined zinc-containing ore because its concentrate contains 60–62% zinc.Other source minerals for zinc include smithsonite (zinc carbonate), hemimorphite (zinc silicate), wurtzite (another zinc sulfide), and sometimes hydrozincite (basic zinc carbonate). With the exception of wurtzite, all these other minerals were formed by weathering of the primordial zinc sulfides.Identified world zinc resources total about 1.9–2.8 billion tonnes. Large deposits are in Australia, Canada and the United States, with the largest reserves in Iran. The most recent estimate of reserve base for zinc (meets specified minimum physical criteria related to current mining and production practices) was made in 2009 and calculated to be roughly 480 Mt. Zinc reserves, on the other hand, are geologically identified ore bodies whose suitability for recovery is economically based (location, grade, quality, and quantity) at the time of determination. Since exploration and mine development is an ongoing process, the amount of zinc reserves is not a fixed number and sustainability of zinc ore supplies cannot be judged by simply extrapolating the combined mine life of todays zinc mines. This concept is well supported by data from the United States Geological Survey (USGS), which illustrates that although refined zinc production increased 80% between 1990 and 2010, the reserve lifetime for zinc has remained unchanged. About 346 million tonnes have been extracted throughout history to 2002, and scholars have estimated that about 109–305 million tonnes are in use.
Isotopes
Five stable isotopes of zinc occur in nature, with 64Zn being the most abundant isotope (49.17% natural abundance). The other isotopes found in nature are 66Zn (27.73%), 67Zn (4.04%), 68Zn (18.45%), and 70Zn (0.61%).Several dozen radioisotopes have been characterized. 65Zn, which has a half-life of 243.66 days, is the least active radioisotope, followed by 72Zn with a half-life of 46.5 hours. Zinc has 10 nuclear isomers, of which 69mZn has the longest half-life, 13.76 h. The superscript m indicates a metastable isotope. The nucleus of a metastable isotope is in an excited state and will return to the ground state by emitting a photon in the form of a gamma ray. 61Zn has three excited metastable states and 73Zn has two. The isotopes 65Zn, 71Zn, 77Zn and 78Zn each have only one excited metastable state.The most common decay mode of a radioisotope of zinc with a mass number lower than 66 is electron capture. The decay product resulting from electron capture is an isotope of copper.
n30Zn + e− → n29CuThe most common decay mode of a radioisotope of zinc with mass number higher than 66 is beta decay (β−), which produces an isotope of gallium.
n30Zn → n31Ga + e− + νe
Compounds and chemistry
Reactivity
Zinc has an electron configuration of [Ar]3d104s2 and is a member of the group 12 of the periodic table. It is a moderately reactive metal and strong reducing agent. The surface of the pure metal tarnishes quickly, eventually forming a protective passivating layer of the basic zinc carbonate, Zn5(OH)6(CO3)2, by reaction with atmospheric carbon dioxide.Zinc burns in air with a bright bluish-green flame, giving off fumes of zinc oxide. Zinc reacts readily with acids, alkalis and other non-metals. Extremely pure zinc reacts only slowly at room temperature with acids. Strong acids, such as hydrochloric or sulfuric acid, can remove the passivating layer and the subsequent reaction with the acid releases hydrogen gas.The chemistry of zinc is dominated by the +2 oxidation state. When compounds in this oxidation state are formed, the outer shell s electrons are lost, yielding a bare zinc ion with the electronic configuration [Ar]3d10. In aqueous solution an octahedral complex, [Zn(H2O)6]2+ is the predominant species. The volatilization of zinc in combination with zinc chloride at temperatures above 285 °C indicates the formation of Zn2Cl2, a zinc compound with a +1 oxidation state. No compounds of zinc in positive oxidation states other than +1 or +2 are known. Calculations indicate that a zinc compound with the oxidation state of +4 is unlikely to exist. Zn(III) is predicted to exist in the presence of strongly electronegative trianions; however, there exists some doubt around this possibility. But in 2021 another compound was reported with more evidence that had the oxidation state of +3 with the formula ZnBeB11(CN)12.Zinc chemistry is similar to the chemistry of the late first-row transition metals, nickel and copper, though it has a filled d-shell and compounds are diamagnetic and mostly colorless. The ionic radii of zinc and magnesium happen to be nearly identical. Because of this some of the equivalent salts have the same crystal structure, and in other circumstances where ionic radius is a determining factor, the chemistry of zinc has much in common with that of magnesium. In other respects, there is little similarity with the late first-row transition metals. Zinc tends to form bonds with a greater degree of covalency and much more stable complexes with N- and S- donors. Complexes of zinc are mostly 4- or 6- coordinate, although 5-coordinate complexes are known.
Zinc(I) compounds
Zinc(I) compounds are very rare. The [Zn2]2+ ion is implicated by the formation of a yellow diamagnetic glass by dissolving metallic zinc in molten ZnCl2. The [Zn2]2+ core would be analogous to the [Hg2]2+ cation present in mercury(I) compounds. The diamagnetic nature of the ion confirms its dimeric structure. The first zinc(I) compound containing the Zn–Zn bond, (η5-C5Me5)2Zn2.
Zinc(II) compounds
Binary compounds of zinc are known for most of the metalloids and all the nonmetals except the noble gases. The oxide ZnO is a white powder that is nearly insoluble in neutral aqueous solutions, but is amphoteric, dissolving in both strong basic and acidic solutions. The other chalcogenides (ZnS, ZnSe, and ZnTe) have varied applications in electronics and optics. Pnictogenides (Zn3N2, Zn3P2, Zn3As2 and Zn3Sb2), the peroxide (ZnO2), the hydride (ZnH2), and the carbide (ZnC2) are also known. Of the four halides, ZnF2 has the most ionic character, while the others (ZnCl2, ZnBr2, and ZnI2) have relatively low melting points and are considered to have more covalent character.In weak basic solutions containing Zn2+ ions, the hydroxide Zn(OH)2 forms as a white precipitate. In stronger alkaline solutions, this hydroxide is dissolved to form zincates ([Zn(OH)4]2−). The nitrate Zn(NO3)2, chlorate Zn(ClO3)2, sulfate ZnSO4, phosphate Zn3(PO4)2, molybdate ZnMoO4, cyanide Zn(CN)2, arsenite Zn(AsO2)2, arsenate Zn(AsO4)2·8H2O and the chromate ZnCrO4 (one of the few colored zinc compounds) are a few examples of other common inorganic compounds of zinc.Organozinc compounds are those that contain zinc–carbon covalent bonds. Diethylzinc ((C2H5)2Zn) is a reagent in synthetic chemistry. It was first reported in 1848 from the reaction of zinc and ethyl iodide, and was the first compound known to contain a metal–carbon sigma bond.
Test for zinc
Cobalticyanide paper (Rinnmanns test for Zn) can be used as a chemical indicator for zinc. 4 g of K3Co(CN)6 and 1 g of KClO3 is dissolved on 100 ml of water. Paper is dipped in the solution and dried at 100 °C. One drop of the sample is dropped onto the dry paper and heated. A green disc indicates the presence of zinc.
History
Ancient use
The Charaka Samhita, thought to have been written between 300 and 500 AD, mentions a metal which, when oxidized, produces pushpanjan, thought to be zinc oxide. Zinc mines at Zawar, near Udaipur in India, have been active since the Mauryan period (c. 322 and 187 BCE). The smelting of metallic zinc here, however, appears to have begun around the 12th century AD. One estimate is that this location produced an estimated million tonnes of metallic zinc and zinc oxide from the 12th to 16th centuries. Another estimate gives a total production of 60,000 tonnes of metallic zinc over this period. The Rasaratna Samuccaya, written in approximately the 13th century AD, mentions two types of zinc-containing ores: one used for metal extraction and another used for medicinal purposes.
Various isolated examples of the use of impure zinc in ancient times have been discovered. Zinc ores were used to make the zinc–copper alloy brass thousands of years prior to the discovery of zinc as a separate element. Judean brass from the 14th to 10th centuries BC contains 23% zinc.Knowledge of how to produce brass spread to Ancient Greece by the 7th century BC, but few varieties were made. Ornaments made of alloys containing 80–90% zinc, with lead, iron, antimony, and other metals making up the remainder, have been found that are 2,500 years old. A possibly prehistoric statuette containing 87.5% zinc was found in a Dacian archaeological site.The oldest known pills were made of the zinc carbonates hydrozincite and smithsonite. The pills were used for sore eyes and were found aboard the Roman ship Relitto del Pozzino, wrecked in 140 BC.The manufacture of brass was known to the Romans by about 30 BC. They made brass by heating powdered calamine (zinc silicate or carbonate), charcoal and copper together in a crucible. The resulting calamine brass was then either cast or hammered into shape for use in weaponry. Some coins struck by Romans in the Christian era are made of what is probably calamine brass.Strabo writing in the 1st century BC (but quoting a now lost work of the 4th century BC historian Theopompus) mentions "drops of false silver" which when mixed with copper make brass. This may refer to small quantities of zinc that is a by-product of smelting sulfide ores. Zinc in such remnants in smelting ovens was usually discarded as it was thought to be worthless.The Berne zinc tablet is a votive plaque dating to Roman Gaul made of an alloy that is mostly zinc.
Early studies and naming
Zinc was distinctly recognized as a metal under the designation of Yasada or Jasada in the medical Lexicon ascribed to the Hindu king Madanapala (of Taka dynasty) and written about the year 1374. Smelting and extraction of impure zinc by reducing calamine with wool and other organic substances was accomplished in the 13th century in India. The Chinese did not learn of the technique until the 17th century.
Alchemists burned zinc metal in air and collected the resulting zinc oxide on a condenser. Some alchemists called this zinc oxide lana philosophica, Latin for "philosophers wool", because it collected in wooly tufts, whereas others thought it looked like white snow and named it nix album.The name of the metal was probably first documented by Paracelsus, a Swiss-born German alchemist, who referred to the metal as "zincum" or "zinken" in his book Liber Mineralium II, in the 16th century. The word is probably derived from the German zinke, and supposedly meant "tooth-like, pointed or jagged" (metallic zinc crystals have a needle-like appearance). Zink could also imply "tin-like" because of its relation to German zinn meaning tin. Yet another possibility is that the word is derived from the Persian word سنگ seng meaning stone. The metal was also called Indian tin, tutanego, calamine, and spinter.German metallurgist Andreas Libavius received a quantity of what he called "calay" of Malabar from a cargo ship captured from the Portuguese in the year 1596. Libavius described the properties of the sample, which may have been zinc. Zinc was regularly imported to Europe from the Orient in the 17th and early 18th centuries, but was at times very expensive.
Isolation
Metallic zinc was isolated in India by 1300 AD, much earlier than in the West. Before it was isolated in Europe, it was imported from India in about 1600 CE. Postlewayts Universal Dictionary, a contemporary source giving technological information in Europe, did not mention zinc before 1751 but the element was studied before then.Flemish metallurgist and alchemist P. M. de Respour reported that he had extracted metallic zinc from zinc oxide in 1668. By the start of the 18th century, Étienne François Geoffroy described how zinc oxide condenses as yellow crystals on bars of iron placed above zinc ore that is being smelted. In Britain, John Lane is said to have carried out experiments to smelt zinc, probably at Landore, prior to his bankruptcy in 1726.In 1738 in Great Britain, William Champion patented a process to extract zinc from calamine in a vertical retort-style smelter. His technique resembled that used at Zawar zinc mines in Rajasthan, but no evidence suggests he visited the Orient. Champions process was used through 1851.German chemist Andreas Marggraf normally gets credit for discovering pure metallic zinc, even though Swedish chemist Anton von Swab had distilled zinc from calamine four years previously. In his 1746 experiment, Marggraf heated a mixture of calamine and charcoal in a closed vessel without copper to obtain a metal. This procedure became commercially practical by 1752.
Later work
William Champions brother, John, patented a process in 1758 for calcining zinc sulfide into an oxide usable in the retort process. Prior to this, only calamine could be used to produce zinc. In 1798, Johann Christian Ruberg improved on the smelting process by building the first horizontal retort smelter. Jean-Jacques Daniel Dony built a different kind of horizontal zinc smelter in Belgium that processed even more zinc.
Italian doctor Luigi Galvani discovered in 1780 that connecting the spinal cord of a freshly dissected frog to an iron rail attached by a brass hook caused the frogs leg to twitch. He incorrectly thought he had discovered an ability of nerves and muscles to create electricity and called the effect "animal electricity". The galvanic cell and the process of galvanization were both named for Luigi Galvani, and his discoveries paved the way for electrical batteries, galvanization, and cathodic protection.Galvanis friend, Alessandro Volta, continued researching the effect and invented the Voltaic pile in 1800. Voltas pile consisted of a stack of simplified galvanic cells, each being one plate of copper and one of zinc connected by an electrolyte. By stacking these units in series, the Voltaic pile (or "battery") as a whole had a higher voltage, which could be used more easily than single cells. Electricity is produced because the Volta potential between the two metal plates makes electrons flow from the zinc to the copper and corrode the zinc.The non-magnetic character of zinc and its lack of color in solution delayed discovery of its importance to biochemistry and nutrition. This changed in 1940 when carbonic anhydrase, an enzyme that scrubs carbon dioxide from blood, was shown to have zinc in its active site. The digestive enzyme carboxypeptidase became the second known zinc-containing enzyme in 1955.
Production
Mining and processing
Zinc is the fourth most common metal in use, trailing only iron, aluminium, and copper with an annual production of about 13 million tonnes. The worlds largest zinc producer is Nyrstar, a merger of the Australian OZ Minerals and the Belgian Umicore. About 70% of the worlds zinc originates from mining, while the remaining 30% comes from recycling secondary zinc. Commercially pure zinc is known as Special High Grade, often abbreviated SHG, and is 99.995% pure.Worldwide, 95% of new zinc is mined from sulfidic ore deposits, in which sphalerite (ZnS) is nearly always mixed with the sulfides of copper, lead and iron.: 6 Zinc mines are scattered throughout the world, with the main areas being China, Australia, and Peru. China produced 38% of the global zinc output in 2014.Zinc metal is produced using extractive metallurgy.: 7 The ore is finely ground, then put through froth flotation to separate minerals from gangue (on the property of hydrophobicity), to get a zinc sulfide ore concentrate: 16 consisting of about 50% zinc, 32% sulfur, 13% iron, and 5% SiO2.: 16 Roasting converts the zinc sulfide concentrate to zinc oxide:
2
ZnS
+
3
O
2
→
t
o
2
ZnO
+
2
SO
2
{\displaystyle {\ce {2ZnS + 3O2 ->[t^o] 2ZnO + 2SO2}}}
The sulfur dioxide is used for the production of sulfuric acid, which is necessary for the leaching process. If deposits of zinc carbonate, zinc silicate, or zinc-spinel (like the Skorpion Deposit in Namibia) are used for zinc production, the roasting can be omitted.For further processing two basic methods are used: pyrometallurgy or electrowinning. Pyrometallurgy reduces zinc oxide with carbon or carbon monoxide at 950 °C (1,740 °F) into the metal, which is distilled as zinc vapor to separate it from other metals, which are not volatile at those temperatures. The zinc vapor is collected in a condenser. The equations below describe this process:
ZnO
+
C
→
950
o
C
Zn
+
CO
{\displaystyle {\ce {ZnO + C ->[950^oC] Zn + CO}}}
ZnO
+
CO
→
950
o
C
Zn
+
CO
2
{\displaystyle {\ce {ZnO + CO ->[950^oC] Zn + CO2}}}
In electrowinning, zinc is leached from the ore concentrate by sulfuric acid and impurities are precipitated:
ZnO
+
H
2
SO
4
⟶
ZnSO
4
+
H
2
O
{\displaystyle {\ce {ZnO + H2SO4 -> ZnSO4 + H2O}}}
Finally, the zinc is reduced by electrolysis.
2
ZnSO
4
+
2
H
2
O
⟶
2
Zn
+
O
2
+
2
H
2
SO
4
{\displaystyle {\ce {2ZnSO4 + 2H2O -> 2Zn + O2 + 2H2SO4}}}
The sulfuric acid is regenerated and recycled to the leaching step.
When galvanised feedstock is fed to an electric arc furnace, the zinc is recovered from the dust by a number of processes, predominantly the Waelz process (90% as of 2014).
Environmental impact
Refinement of sulfidic zinc ores produces large volumes of sulfur dioxide and cadmium vapor. Smelter slag and other residues contain significant quantities of metals. About 1.1 million tonnes of metallic zinc and 130 thousand tonnes of lead were mined and smelted in the Belgian towns of La Calamine and Plombières between 1806 and 1882. The dumps of the past mining operations leach zinc and cadmium, and the sediments of the Geul River contain non-trivial amounts of metals. About two thousand years ago, emissions of zinc from mining and smelting totaled 10 thousand tonnes a year. After increasing 10-fold from 1850, zinc emissions peaked at 3.4 million tonnes per year in the 1980s and declined to 2.7 million tonnes in the 1990s, although a 2005 study of the Arctic troposphere found that the concentrations there did not reflect the decline. Man-made and natural emissions occur at a ratio of 20 to 1.Zinc in rivers flowing through industrial and mining areas can be as high as 20 ppm. Effective sewage treatment greatly reduces this; treatment along the Rhine, for example, has decreased zinc levels to 50 ppb. Concentrations of zinc as low as 2 ppm adversely affects the amount of oxygen that fish can carry in their blood.
Soils contaminated with zinc from mining, refining, or fertilizing with zinc-bearing sludge can contain several grams of zinc per |
Zinc | kilogram of dry soil. Levels of zinc in excess of 500 ppm in soil interfere with the ability of plants to absorb other essential metals, such as iron and manganese. Zinc levels of 2000 ppm to 180,000 ppm (18%) have been recorded in some soil samples.
Applications
Major applications of zinc include (numbers are given for the US)
Galvanizing (55%)
Brass and bronze (16%)
Other alloys (21%)
Miscellaneous (8%)
Anti-corrosion and batteries
Zinc is most commonly used as an anti-corrosion agent, and galvanization (coating of iron or steel) is the most familiar form. In 2009 in the United States, 55% or 893,000 tons of the zinc metal was used for galvanization.Zinc is more reactive than iron or steel and thus will attract almost all local oxidation until it completely corrodes away. A protective surface layer of oxide and carbonate (Zn5(OH)6(CO3)2) forms as the zinc corrodes. This protection lasts even after the zinc layer is scratched but degrades through time as the zinc corrodes away. The zinc is applied electrochemically or as molten zinc by hot-dip galvanizing or spraying. Galvanization is used on chain-link fencing, guard rails, suspension bridges, lightposts, metal roofs, heat exchangers, and car bodies.The relative reactivity of zinc and its ability to attract oxidation to itself makes it an efficient sacrificial anode in cathodic protection (CP). For example, cathodic protection of a buried pipeline can be achieved by connecting anodes made from zinc to the pipe. Zinc acts as the anode (negative terminus) by slowly corroding away as it passes electric current to the steel pipeline. Zinc is also used to cathodically protect metals that are exposed to sea water. A zinc disc attached to a ships iron rudder will slowly corrode while the rudder stays intact. Similarly, a zinc plug attached to a propeller or the metal protective guard for the keel of the ship provides temporary protection.
With a standard electrode potential (SEP) of −0.76 volts, zinc is used as an anode material for batteries. (More reactive lithium (SEP −3.04 V) is used for anodes in lithium batteries ). Powdered zinc is used in this way in alkaline batteries and the case (which also serves as the anode) of zinc–carbon batteries is formed from sheet zinc. Zinc is used as the anode or fuel of the zinc–air battery/fuel cell. The zinc-cerium redox flow battery also relies on a zinc-based negative half-cell.
Alloys
A widely used zinc alloy is brass, in which copper is alloyed with anywhere from 3% to 45% zinc, depending upon the type of brass. Brass is generally more ductile and stronger than copper, and has superior corrosion resistance. These properties make it useful in communication equipment, hardware, musical instruments, and water valves.
Other widely used zinc alloys include nickel silver, typewriter metal, soft and aluminium solder, and commercial bronze. Zinc is also used in contemporary pipe organs as a substitute for the traditional lead/tin alloy in pipes. Alloys of 85–88% zinc, 4–10% copper, and 2–8% aluminium find limited use in certain types of machine bearings. Zinc has been the primary metal in American one cent coins (pennies) since 1982. The zinc core is coated with a thin layer of copper to give the appearance of a copper coin. In 1994, 33,200 tonnes (36,600 short tons) of zinc were used to produce 13.6 billion pennies in the United States.Alloys of zinc with small amounts of copper, aluminium, and magnesium are useful in die casting as well as spin casting, especially in the automotive, electrical, and hardware industries. These alloys are marketed under the name Zamak. An example of this is zinc aluminium. The low melting point together with the low viscosity of the alloy makes possible the production of small and intricate shapes. The low working temperature leads to rapid cooling of the cast products and fast production for assembly. Another alloy, marketed under the brand name Prestal, contains 78% zinc and 22% aluminium, and is reported to be nearly as strong as steel but as malleable as plastic. This superplasticity of the alloy allows it to be molded using die casts made of ceramics and cement.Similar alloys with the addition of a small amount of lead can be cold-rolled into sheets. An alloy of 96% zinc and 4% aluminium is used to make stamping dies for low production run applications for which ferrous metal dies would be too expensive. For building facades, roofing, and other applications for sheet metal formed by deep drawing, roll forming, or bending, zinc alloys with titanium and copper are used. Unalloyed zinc is too brittle for these manufacturing processes.As a dense, inexpensive, easily worked material, zinc is used as a lead replacement. In the wake of lead concerns, zinc appears in weights for various applications ranging from fishing to tire balances and flywheels.Cadmium zinc telluride (CZT) is a semiconductive alloy that can be divided into an array of small sensing devices. These devices are similar to an integrated circuit and can detect the energy of incoming gamma ray photons. When behind an absorbing mask, the CZT sensor array can determine the direction of the rays.
Other industrial uses
Roughly one quarter of all zinc output in the United States in 2009 was consumed in zinc compounds; a variety of which are used industrially. Zinc oxide is widely used as a white pigment in paints and as a catalyst in the manufacture of rubber to disperse heat. Zinc oxide is used to protect rubber polymers and plastics from ultraviolet radiation (UV). The semiconductor properties of zinc oxide make it useful in varistors and photocopying products. The zinc zinc-oxide cycle is a two step thermochemical process based on zinc and zinc oxide for hydrogen production.Zinc chloride is often added to lumber as a fire retardant and sometimes as a wood preservative. It is used in the manufacture of other chemicals. Zinc methyl (Zn(CH3)2) is used in a number of organic syntheses. Zinc sulfide (ZnS) is used in luminescent pigments such as on the hands of clocks, X-ray and television screens, and luminous paints. Crystals of ZnS are used in lasers that operate in the mid-infrared part of the spectrum. Zinc sulfate is a chemical in dyes and pigments. Zinc pyrithione is used in antifouling paints.Zinc powder is sometimes used as a propellant in model rockets. When a compressed mixture of 70% zinc and 30% sulfur powder is ignited there is a violent chemical reaction. This produces zinc sulfide, together with large amounts of hot gas, heat, and light.Zinc sheet metal is used to make zinc bars.64Zn, the most abundant isotope of zinc, is very susceptible to neutron activation, being transmuted into the highly radioactive 65Zn, which has a half-life of 244 days and produces intense gamma radiation. Because of this, zinc oxide used in nuclear reactors as an anti-corrosion agent is depleted of 64Zn before use, this is called depleted zinc oxide. For the same reason, zinc has been proposed as a salting material for nuclear weapons (cobalt is another, better-known salting material). A jacket of isotopically enriched 64Zn would be irradiated by the intense high-energy neutron flux from an exploding thermonuclear weapon, forming a large amount of 65Zn significantly increasing the radioactivity of the weapons fallout. Such a weapon is not known to have ever been built, tested, or used.65Zn is used as a tracer to study how alloys that contain zinc wear out, or the path and the role of zinc in organisms.Zinc dithiocarbamate complexes are used as agricultural fungicides; these include Zineb, Metiram, Propineb and Ziram. Zinc naphthenate is used as wood preservative. Zinc in the form of ZDDP, is used as an anti-wear additive for metal parts in engine oil.
Organic chemistry
Organozinc chemistry is the science of compounds that contain carbon-zinc bonds, describing the physical properties, synthesis, and chemical reactions. Many organozinc compounds are important. Among important applications are
The Frankland-Duppa Reaction in which an oxalate ester (ROCOCOOR) reacts with an alkyl halide RX, zinc and hydrochloric acid to form the α-hydroxycarboxylic esters RRCOHCOOR
On the downside, organozincs are much less nucleophilic than Grignards, and they are expensive and difficult to handle. Commercially available diorganozinc compounds are dimethylzinc, diethylzinc and diphenylzinc. In one study, the active organozinc compound is obtained from much cheaper organobromine precursors.Zinc has found many uses as a catalyst in organic synthesis including asymmetric synthesis, being cheap and easily available alternative to precious metal complexes. The results (yield and enantiomeric excess) obtained with chiral zinc catalysts are comparable to those achieved with palladium, ruthenium, iridium and others, and zinc becomes a metal catalyst of choice.
Dietary supplement
In most single-tablet, over-the-counter, daily vitamin and mineral supplements, zinc is included in such forms as zinc oxide, zinc acetate, zinc gluconate, or zinc amino acid chelate.Generally, zinc supplement is recommended where there is high risk of zinc deficiency (such as low and middle income countries) as a preventive measure. Although zinc sulfate is a commonly used zinc form, zinc citrate, gluconate and picolinate may be valid options as well. These forms are better absorbed than zinc oxide.
Gastroenteritis
Zinc is an inexpensive and effective part of treatment of diarrhea among children in the developing world. Zinc becomes depleted in the body during diarrhea and replenishing zinc with a 10- to 14-day course of treatment can reduce the duration and severity of diarrheal episodes and may also prevent future episodes for as long as three months. Gastroenteritis is strongly attenuated by ingestion of zinc, possibly by direct antimicrobial action of the ions in the gastrointestinal tract, or by the absorption of the zinc and re-release from immune cells (all granulocytes secrete zinc), or both.
Common cold
Weight gain
Zinc deficiency may lead to loss of appetite. The use of zinc in the treatment of anorexia has been advocated since 1979. At least 15 clinical trials have shown that zinc improved weight gain in anorexia. A 1994 trial showed that zinc doubled the rate of body mass increase in the treatment of anorexia nervosa. Deficiency of other nutrients such as tyrosine, tryptophan and thiamine could contribute to this phenomenon of "malnutrition-induced malnutrition".
A meta-analysis of 33 prospective intervention trials regarding zinc supplementation and its effects on the growth of children in many countries showed that zinc supplementation alone had a statistically significant effect on linear growth and body weight gain, indicating that other deficiencies that may have been present were not responsible for growth retardation.
Other
A Cochrane review stated that people taking zinc supplement may be less likely to progress to age-related macular degeneration. Zinc supplement is an effective treatment for acrodermatitis enteropathica, a genetic disorder affecting zinc absorption that was previously fatal to affected infants. Zinc deficiency has been associated with major depressive disorder (MDD), and zinc supplements may be an effective treatment.
Topical use
Topical preparations of zinc include those used on the skin, often in the form of zinc oxide. Zinc oxide can be formulated into a sunscreen to mitigate sunburn. Applied thinly to a babys diaper area (perineum) with each diaper change, it can protect against diaper rash.Chelated zinc is used in toothpastes and mouthwashes to prevent bad breath; zinc citrate helps reduce the build-up of calculus (tartar).Zinc pyrithione is widely included in shampoos to prevent dandruff.Topical zinc has also been shown to effectively treat, as well as prolong remission in genital herpes.
Biological role
Zinc is an essential trace element for humans and other animals, for plants and for microorganisms. Zinc is required for the function of over 300 enzymes and 1000 transcription factors, and is stored and transferred in metallothioneins. It is the second most abundant trace metal in humans after iron and it is the only metal which appears in all enzyme classes.In proteins, zinc ions are often coordinated to the amino acid side chains of aspartic acid, glutamic acid, cysteine and histidine. The theoretical and computational description of this zinc binding in proteins (as well as that of other transition metals) is difficult.Roughly 2–4 grams of zinc are distributed throughout the human body. Most zinc is in the brain, muscle, bones, kidney, and liver, with the highest concentrations in the prostate and parts of the eye. Semen is particularly rich in zinc, a key factor in prostate gland function and reproductive organ growth.Zinc homeostasis of the body is mainly controlled by the intestine. Here, ZIP4 and especially TRPM7 were linked to intestinal zinc uptake essential for postnatal survival.In humans, the biological roles of zinc are ubiquitous. It interacts with "a wide range of organic ligands", and has roles in the metabolism of RNA and DNA, signal transduction, and gene expression. It also regulates apoptosis. A review from 2015 indicated that about 10% of human proteins (~3000) bind zinc, in addition to hundreds more that transport and traffic zinc; a similar in silico study in the plant Arabidopsis thaliana found 2367 zinc-related proteins.In the brain, zinc is stored in specific synaptic vesicles by glutamatergic neurons and can modulate neuronal excitability. It plays a key role in synaptic plasticity and so in learning. Zinc homeostasis also plays a critical role in the functional regulation of the central nervous system. Dysregulation of zinc homeostasis in the central nervous system that results in excessive synaptic zinc concentrations is believed to induce neurotoxicity through mitochondrial oxidative stress (e.g., by disrupting certain enzymes involved in the electron transport chain, including complex I, complex III, and α-ketoglutarate dehydrogenase), the dysregulation of calcium homeostasis, glutamatergic neuronal excitotoxicity, and interference with intraneuronal signal transduction. L- and D-histidine facilitate brain zinc uptake. SLC30A3 is the primary zinc transporter involved in cerebral zinc homeostasis.
Enzymes
Zinc is an efficient Lewis acid, making it a useful catalytic agent in hydroxylation and other enzymatic reactions. The metal also has a flexible coordination geometry, which allows proteins using it to rapidly shift conformations to perform biological reactions. Two examples of zinc-containing enzymes are carbonic anhydrase and carboxypeptidase, which are vital to the processes of carbon dioxide (CO2) regulation and digestion of proteins, respectively.In vertebrate blood, carbonic anhydrase converts CO2 into bicarbonate and the same enzyme transforms the bicarbonate back into CO2 for exhalation through the lungs. Without this enzyme, this conversion would occur about one million times slower at the normal blood pH of 7 or would require a pH of 10 or more. The non-related β-carbonic anhydrase is required in plants for leaf formation, the synthesis of indole acetic acid (auxin) and alcoholic fermentation.Carboxypeptidase cleaves peptide linkages during digestion of proteins. A coordinate covalent bond is formed between the terminal peptide and a C=O group attached to zinc, which gives the carbon a positive charge. This helps to create a hydrophobic pocket on the enzyme near the zinc, which attracts the non-polar part of the protein being digested.
Signalling
Zinc has been recognized as a messenger, able to activate signalling pathways. Many of these pathways provide the driving force in aberrant cancer growth. They can be targeted through ZIP transporters.
Other proteins
Zinc serves a purely structural role in zinc fingers, twists and clusters. Zinc fingers form parts of some transcription factors, which are proteins that recognize DNA base sequences during the replication and transcription of DNA. Each of the nine or ten Zn2+ ions in a zinc finger helps maintain the fingers structure by coordinately binding to four amino acids in the transcription factor.In blood plasma, zinc is bound to and transported by albumin (60%, low-affinity) and transferrin (10%). Because transferrin also transports iron, excessive iron reduces zinc absorption, and vice versa. A similar antagonism exists with copper. The concentration of zinc in blood plasma stays relatively constant regardless of zinc intake. Cells in the salivary gland, prostate, immune system, and intestine use zinc signaling to communicate with other cells.Zinc may be held in metallothionein reserves within microorganisms or in the intestines or liver of animals. Metallothionein in intestinal cells is capable of adjusting absorption of zinc by 15–40%. However, inadequate or excessive zinc intake can be harmful; excess zinc particularly impairs copper absorption because metallothionein absorbs both metals.The human dopamine transporter contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro. The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites. Some EF-hand calcium binding proteins such as S100 or NCS-1 are also able to bind zinc ions.
Nutrition
Dietary recommendations
The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for zinc in 2001. The current EARs for zinc for women and men ages 14 and up is 6.8 and 9.4 mg/day, respectively. The RDAs are 8 and 11 mg/day. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy is 11 mg/day. RDA for lactation is 12 mg/day. For infants up to 12 months the RDA is 3 mg/day. For children ages 1–13 years the RDA increases with age from 3 to 8 mg/day. As for safety, the IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of zinc the adult UL is 40 mg/day (lower for children). Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the United States. For people ages 18 and older the PRI calculations are complex, as the EFSA has set higher and higher values as the phytate content of the diet increases. For women, PRIs increase from 7.5 to 12.7 mg/day as phytate intake increases from 300 to 1200 mg/day; for men the range is 9.4 to 16.3 mg/day. These PRIs are higher than the U.S. RDAs. The EFSA reviewed the same safety question and set its UL at 25 mg/day, which is much lower than the U.S. value.For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For zinc labeling purposes 100% of the Daily Value was 15 mg, but on May 27, 2016, it was revised to 11 mg. A table of the old and new adult daily values is provided at Reference Daily Intake.
Dietary intake
Animal products such as meat, fish, shellfish, fowl, eggs, and dairy contain zinc. The concentration of zinc in plants varies with the level in the soil. With adequate zinc in the soil, the food plants that contain the most zinc are wheat (germ and bran) and various seeds, including sesame, poppy, alfalfa, celery, and mustard. Zinc is also found in beans, nuts, almonds, whole grains, pumpkin seeds, sunflower seeds, and blackcurrant.Other sources include fortified food and dietary supplements in various forms. A 1998 review concluded that zinc oxide, one of the most common supplements in the United States, and zinc carbonate are nearly insoluble and poorly absorbed in the body. This review cited studies that found lower plasma zinc concentrations in the subjects who consumed zinc oxide and zinc carbonate than in those who took zinc acetate and sulfate salts. For fortification, however, a 2003 review recommended cereals (containing zinc oxide) as a cheap, stable source that is as easily absorbed as the more expensive forms. A 2005 study found that various compounds of zinc, including oxide and sulfate, did not show statistically significant differences in absorption when added as fortificants to maize tortillas.
Deficiency
Nearly two billion people in the developing world are deficient in zinc. Groups at risk include children in developing countries and elderly with chronic illnesses. In children, it causes an increase in infection and diarrhea and contributes to the death of about 800,000 children worldwide per year. The World Health Organization advocates zinc supplementation for severe malnutrition and diarrhea. Zinc supplements help prevent disease and reduce mortality, especially among children with low birth weight or stunted growth. However, zinc supplements should not be administered alone, because many in the developing world have several deficiencies, and zinc interacts with other micronutrients. While zinc deficiency is usually due to insufficient dietary intake, it can be associated with malabsorption, acrodermatitis enteropathica, chronic liver disease, chronic renal disease, sickle cell disease, diabetes, malignancy, and other chronic illnesses.In the United States, a federal survey of food consumption determined that for women and men over the age of 19, average consumption was 9.7 and 14.2 mg/day, respectively. For women, 17% consumed less than the EAR, for men 11%. The percentages below EAR increased with age. The most recent published update of the survey (NHANES 2013–2014) reported lower averages – 9.3 and 13.2 mg/day – again with intake decreasing with age.Symptoms of mild zinc deficiency are diverse. Clinical outcomes include depressed growth, diarrhea, impotence and delayed sexual maturation, alopecia, eye and skin lesions, impaired appetite, altered cognition, impaired immune functions, defects in carbohydrate utilization, and reproductive teratogenesis. Zinc deficiency depresses immunity, but excessive zinc does also.Despite some concerns, western vegetarians and vegans do not suffer any more from overt zinc deficiency than meat-eaters. Major plant sources of zinc include cooked dried beans, sea vegetables, fortified cereals, soy foods, nuts, peas, and seeds. However, phytates in many whole-grains and fibers may interfere with zinc absorption and marginal zinc intake has poorly understood effects. The zinc chelator phytate, found in seeds and cereal bran, can contribute to zinc malabsorption. Some evidence suggests that more than the US RDA (8 mg/day for adult women; 11 mg/day for adult men) may be needed in those whose diet is high in phytates, such as some vegetarians. The European Food Safety Authority (EFSA) guidelines attempt to compensate for this by recommending higher zinc intake when dietary phytate intake is greater. These considerations must be balanced against the paucity of adequate zinc biomarkers, and the most widely used indicator, plasma zinc, has poor sensitivity and specificity.
Soil remediation
Species of Calluna, Erica and Vaccinium can grow in zinc-metalliferous soils, because translocation of toxic ions is prevented by the action of ericoid mycorrhizal fungi.
Agriculture
Zinc deficiency appears to be the most common micronutrient deficiency in crop plants; it is particularly common in high-pH soils. Zinc-deficient soil is cultivated in the cropland of about half of Turkey and India, a third of China, and most of Western Australia. Substantial responses to zinc fertilization have been reported in these areas. Plants that grow in soils that are zinc-deficient are more susceptible to disease. Zinc is added to the soil primarily through the weathering of rocks, but humans have added zinc through fossil fuel combustion, mine waste, phosphate fertilizers, pesticide (zinc phosphide), limestone, manure, sewage sludge, and particles from galvanized surfaces. Excess zinc is toxic to plants, although zinc toxicity is far less widespread.
Precautions
Toxicity
Although zinc is an essential requirement for good health, excess zinc can be harmful. Excessive absorption of zinc suppresses copper and iron absorption. The free zinc ion in solution is highly toxic to plants, invertebrates, and even vertebrate fish. The Free Ion Activity Model is well-established in the literature, and shows that just micromolar amounts of the free ion kills some organisms. A recent example showed 6 micromolar killing 93% of all Daphnia in water.The free zinc ion is a powerful Lewis acid up to the point of being corrosive. Stomach acid contains hydrochloric acid, in which metallic zinc dissolves readily to give corrosive zinc chloride. Swallowing a post-1982 American one cent piece (97.5% zinc) can cause damage to the stomach lining through the high solubility of the zinc ion in the acidic stomach.Evidence shows that people taking 100–300 mg of zinc daily may suffer induced copper deficiency. A 2007 trial observed that elderly men taking 80 mg daily were hospitalized for urinary complications more often than those taking a placebo. Levels of 100–300 mg may interfere with the utilization of copper and iron or adversely affect cholesterol. Zinc in excess of 500 ppm in soil interferes with the plant absorption of other essential metals, such as iron and manganese. A condition called the zinc shakes or "zinc chills" can be induced by inhalation of zinc fumes while brazing or welding galvanized materials. Zinc is a common ingredient of denture cream which may contain between 17 and 38 mg of zinc per gram. Disability and even deaths from excessive use of these products have been claimed.The U.S. Food and Drug Administration (FDA) states that zinc damages nerve receptors in the nose, causing anosmia. Reports of anosmia were also observed in the 1930s when zinc preparations were used in a failed attempt to prevent polio infections. On June 16, 2009, the FDA ordered removal of zinc-based intranasal cold products from store shelves. The FDA said the loss of smell can be life-threatening because people with impaired smell cannot detect leaking gas or smoke, and cannot tell if food has spoiled before they eat it.Recent research suggests that the topical antimicrobial zinc pyrithione is a potent heat shock response inducer that may impair genomic integrity with induction of PARP-dependent energy crisis in cultured human keratinocytes and melanocytes.
Poisoning
In 1982, the US Mint began minting pennies coated in copper but containing primarily zinc. Zinc pennies pose a risk of zinc toxicosis, which can be fatal. One reported case of chronic ingestion of 425 pennies (over 1 kg of zinc) resulted in death due to gastrointestinal bacterial and fungal sepsis. Another patient who ingested 12 grams of zinc showed only lethargy and ataxia (gross lack of coordination of muscle movements). Several other cases have been reported of humans suffering zinc intoxication by the ingestion of zinc coins.Pennies and other small coins are sometimes ingested by dogs, requiring veterinary removal of the foreign objects. The zinc content of some coins can cause zinc toxicity, commonly fatal in dogs through severe hemolytic anemia and liver or kidney damage; vomiting and diarrhea are possible symptoms. Zinc is highly toxic in parrots and poisoning can often be fatal. The consumption of fruit juices stored in galvanized cans has resulted in mass parrot poisonings with zinc.
See also
List of countries by zinc production
Spelter
Wet storage stain
Zinc alloy |
Zinc | electroplating
Metal fume fever
Piotr Steinkeller
Notes
Citations
Bibliography
External links
Zinc Fact Sheet from the U.S. National Institutes of Health
History & Etymology of Zinc
Statistics and Information from the U.S. Geological Survey
Reducing Agents > Zinc
American Zinc Association Information about the uses and properties of zinc.
ISZB International Society for Zinc Biology, founded in 2008. An international, nonprofit organization bringing together scientists working on the biological actions of zinc.
Zinc-UK Founded in 2010 to bring together scientists in the United Kingdom working on zinc.
Zinc at The Periodic Table of Videos (University of Nottingham)
ZincBind – a database of biological zinc binding sites. |
Pleomorphic lipoma | Pleomorphic lipomas, like spindle-cell lipomas, occur for the most part on the backs and necks of elderly men, and are characterized by floret giant cells with overlapping nuclei.: 625
See also
Lipoma
Skin lesion
List of cutaneous conditions
References
== External links == |
Gitelman syndrome | Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. The disorder is caused by genetic mutations resulting in improper function of the thiazide-sensitive sodium-chloride symporter (SLC12A3, also known as NCC, NCCT, or TSC) located in the distal convoluted tubule of the kidney. The distal convoluted tubule of the kidney plays an important homoestatic role in sodium and chloride absorption as well as of the reabsorption of magnesium and calcium.Genetic mutations of NCC, lead to loss of function and subsequently, reduced transport of sodium and chloride via NCC. Secondary derangement of calcium, magnesium, and potassium concentrations are caused by secondary effects in the distal tubule and collecting duct. The effect is an electrolyte imbalance similar to that seen with thiazide diuretic therapy (which causes pharmacological inhibition of NCC activity).Gitelman syndrome was formerly considered a subset of Bartter syndrome until the distinct genetic and molecular bases of these disorders were identified. Bartter syndrome is also an autosomal recessive cause of hypokalemic metabolic alkalosis, but it derives from a mutations of a number of genes that reduce NKCC2 activity. NKCC2 is found in the thick ascending limb of the loop of Henle.
Signs and symptoms
Affected individuals may not have symptoms in some cases. Symptomatic individuals present with symptoms identical to those of patients who are on thiazide diuretics, given that the affected transporter is the exact target of thiazides, (unlike in Bartter syndrome, in which patients present as though on loop diuretics).
Clinical signs of Gitelman syndrome include a high blood pH in combination with low levels of chloride, potassium, and magnesium in the blood and decreased calcium excretion in the urine. In contrast to people with Gordons syndrome, those affected by Gitelman syndrome generally have low or normal blood pressure. Individuals affected by Gitelman syndrome often complain of severe muscle cramps or weakness, numbness, thirst, waking up at night to urinate, salt cravings, abnormal sensations, chondrocalcinosis, or weakness expressed as extreme fatigue or irritability. Though cravings for salt are most common and severe, cravings for sour foods (e.g. vinegar, lemons, and sour figs) have been noted in some persons affected. More severe symptoms such as seizures, tetany, and paralysis have been reported. Abnormal heart rhythms and a prolonged QT interval can be detected on electrocardiogram and cases of sudden cardiac death have been reported due to low potassium levels. Quality of life is decreased in Gitelman syndromePhenotypic variations observed among patients probably result from differences in their genetic background and may depend on which particular amino acid in the NCCT protein has been mutated. A study by Riviera-Munoz et al. identified a subset of individuals with Gitelman syndrome with a severe phenotypic expression. The clinical manifestations observed in this group were neuromuscular manifestations, growth retardation, and ventricular arrhythmias. The patients were mostly male and were found to have at least one allele of a splice defect on the SLC12A3 gene.
Cause
The sodium chloride symporter is a protein made up of 1021 amino acids and 12 transmembrane domains. Mutations that occur on the SLC12A3 gene range from missense, nonsense, frame-shift and splice-site mutations which occur throughout the gene.Most cases of Gitelman syndrome are linked to inactivating mutations in the SLC12A3 gene, resulting in a loss of function of the thiazide-sensitive sodium-chloride co-transporter (NCCT). This genetic mutation in SLC12A3 is present in 80% of adults with Gitelman syndrome. More than 180 mutations of this transporter protein have been described. This cell membrane protein participates in the control of ion homeostasis at the distal convoluted tubule portion of the nephron. Loss of this transporter also has the indirect effect of increasing calcium reabsorption in a transcellular fashion. This has been suggested to be the result of a putative basolateral Na+/Ca2+ exchanger and apical calcium channel.When the sodium-chloride cotransporter (NCCT) is inactivated, continued action of the basolateral Na+/K+-ATPase creates a favourable sodium gradient across the basolateral membrane. This increases the reabsorption of divalent cations by secondary active transport. It is currently unknown why calcium reabsorption is increased while magnesium absorption is decreased, often leading to a low level of magnesium in the blood .A secondary effect of the inactivated sodium-chloride cotransporter is the subsequent activation of the renin-angiotensin aldosterone system (RAAS). RAAS activation is a byproduct of the failure of the distal convoluted tubule in reuptaking electrolytes specifically sodium and chloride leading to cellular dehydration. RAAS attempts to compensate for this dehydration resulting in low serum blood potassium.A small percentage of Gitelman syndrome cases can be attributed to mutations in the CLCNKB gene. This gene is related to the function of the renal chloride channel CLC-Kb located at the basolateral membrane of cells in the thick ascending limb of the Henles loop. Genetic variations or mutations in the CLCNKB was initially linked to classic Bartter Syndrome. When mutations are not found within the SLC12A3 gene, screening can be done to rule out involvement of CLCNKB gene.Gitelman syndrome is inherited in an autosomal-recessive manner: one defective allele has to be inherited from each parent.In 2021, mutations in the tRNAs encoding Isoleucine (MT-TI) and Phenylalanine (MT-TF) in the mitochondrial DNA were described to cause Gitelman syndrome. These homomplasmic mtDNA mutations are maternally inherited.
Diagnosis
Diagnosis of Gitelman syndrome can be confirmed after eliminating other common pathological sources of hypokalemia and metabolic alkalosis. A complete metabolic panel (CMP) or basic metabolic panel (BMP) can be used to evaluate serum electrolyte levels. Renin and aldosterone can be tested in the blood. Electrolyte measurement and aldosterone levels can be done via urine. The pathognomonic clinical markers include low serum levels of potassium, sodium, chloride, and magnesium in the blood as a result of urinary excretion. Urinary fractional excretion potassium is high or inappropriately normal in the context of hypokalaemia, and high levels of urinary sodium and chloride are observed. Other clinical indicators include elevated serum renin and aldosterone in the bloodstream, and metabolic alkalosis. The symptomatic features of this syndrome are highly variable ranging from asymptomatic to mild manifestations (weakness, cramps) to severe symptoms (tetany, paralysis, rhabdomyolysis). Symptom severity is multi-factorial, with phenotypic expression varying amongst individuals within the same family. Genetic testing is another measure of identifying the underlying mutations which cause the pathologic symptoms of the disease. This mode of testing is available at select laboratories.Work-up to exclude the differential diagnosis of the electrolyte abnormalities is key.
In Gitelman syndrome hypocalciuria is present, and a urine calcium:creatinine ratio may help distinguish it from Bartter syndrome as the two disorders can be clinically indistinguishable. Additionally in Bartter syndrome maximal urine concentrating ability is lost.
Laxative abuse can mimic the serum electrolyte abnormalities, but fractional excretion of potassium will be low
Diuretic abuse could be suspected if urinary chloride excretion varies by time of day but may require a diuretic assay to detect
Surreptitious vomiting can cause metabolic alkalosis and hypokalaemia, but urinary chloride levels will be low
Medication history; Proton-pump inhibitors can cause an isolated hypomagnesaemia phenotype, and aminoglycosides such as gentamicin can cause a transient metabolic alkalosis with hypokalaemia and hypomagnesaemia that resolves 2–6 weeks after drug termination.
Primary aldosteronism will cause metabolic alkalosis and hypokalaemia, but hypertension will be present and serum renin will be low
EAST syndrome, though neurological features will predominate
Renal cysts and diabetes syndrome can cause hypomagnesaemia and hypocalcuria, but is distinguished by early onset chronic kidney disease and an autosomal dominant inheritance pattern of renal cysts and/or diabetes
Treatment
Most asymptomatic individuals with Gitelman syndrome can be monitored without medical treatment. Dietary modification of a high salt diet incorporated with, potassium and magnesium supplementation to normalize blood levels is the mainstay of treatment. Large doses of potassium and magnesium are often necessary to adequately replace the electrolytes lost in the urine. Diarrhea is a common side effect of oral magnesium which can make replacement by mouth difficult but dividing the dose to 3-4 times a day is better tolerated. Severe deficits of potassium and magnesium require intravenous replacement. If low blood potassium levels are not sufficiently replaced with replacement by mouth, aldosterone antagonists (such as spironolactone or eplerenone) or epithelial sodium channel blockers such as amiloride can be used to decrease urinary wasting of potassium.In patients with early onset of the disease such as infants and children, indomethacin is the drug of choice utilized to treat growth disturbances. Indomethacin in a study by Blanchard et al. 2015 was shown to increase serum potassium levels, and decrease renin concentration. Adverse effects of indomethacin include a decrease in the glomerular filtration rate, and gastrointestinal disturbances.Cardiac evaluation is promoted in the prevention of dysrhythmias and monitoring of QT interval activity. Medications that extend or prolong the QT interval (macrolides, antihistamines, beta-2 agonists) should be avoided in these patients to prevent cardiac death.
Epidemiology
Gitelman syndrome is estimated to have a prevalence of 1 in 40,000 homozygous people . The ratio of men to women affected is 1:1. This disease is encountered typically past the 1st decade of life, during adolescence or adulthood but can occur in the neonatal period. Heterozygous carriers of the SLC12A3 gene mutations are 1% of the population. Parents with Gitelman syndrome have a low probability of passing the disorder to their offspring roughly 1 in 400 unless they are both carriers of the disease.
History
The condition is named for Hillel Jonathan Gitelman (1932– January 12, 2015), an American nephrologist working at University of North Carolina School of Medicine. He first described the condition in 1966, after observing a pair of sisters with the disorder. Gitelman and his colleagues later identified and isolated the gene responsible (SLC12A3) by molecular cloning.
References
External links
"Gitelman syndrome". MedlinePlus. U.S. National Library of Medicine. |
Rachischisis | Rachischisis (Greek: "rhachis - ῥάχις" - spine, and "schisis - σχίσις" - split) is a developmental birth defect involving the neural tube. This anomaly occurs in utero, when the posterior neuropore of the neural tube fails to close by the 27th intrauterine day. As a consequence the vertebrae overlying the open portion of the spinal cord do not fully form and remain unfused and open, leaving the spinal cord exposed. Patients with rachischisis have motor and sensory deficits, chronic infections, and disturbances in bladder function. This defect often occurs with anencephaly.
Craniorachischisis is a variant of rachischisis that occurs when the entire spinal cord and brain are exposed – simultaneous complete rachischisis and anencephaly. It is incompatible with life; affected pregnancies often end in miscarriage or stillbirth. Infants born alive with craniorachischisis die soon after birth.
Presentation
Interactions with other developmental deformities
Rachischisis is a complex condition and presents itself along with other deformities. Other deformities are typically those of the face, neck, spine and head. It is extremely common for rachischisis to develop in conjunction with aplasia (a condition in which a tissue or organ does not develop fully).Acrania is a developmental defect in which the bones with the cranial vault do not develop correctly and brain does not develop fully. Rachischisis can develop in conjunction with acrania, causing further damage to the brain and spinal regions. In the absence of acrania, patients with rachischisis still have a high mortality rate.Anencephaly is a condition in which the baby develops with an open skull in some region. Rachischisis can develop in conjunction with anencephaly, increasing the amount of area that is exposed. Although these conditions closely resemble one another, cases of rachischisis are morphologically different from cases of anencephaly, so they are indeed two separate conditions.
Rachischisis is also a contributing factor to the onset of iniencephaly – a condition in which the spine is malformed.
Further abnormalities such as rib malformations can occur with rachischisis. Stomach deformities can also develop with rachischisis.
Risk factors
If a sibling of the fetus has been affected by rachischisis, there is increased risk that another child will develop the condition. There is also a slightly higher chance that females will develop the condition over males.Folate deficiency is also a well-accepted risk factor of all neural tube defects, including rachischisis. It is this reason that has caused many health policies regarding folic acid during pregnancy to be developed.
Diagnosis
Initial diagnosis is typically by ultrasonography to reveal any congenital abnormalities. Fetuses affected typically show cranial abnormalities and deformities in brain tissue as well as spinal abnormalities. Following ultrasonography, magnetic resonance imaging (MRI) is commonly used to confirm the diagnosis. The presence of rachischisis is indicated in imaging by the absence of an arch-cranial line.Other neural tube defect diagnostic tools such as assays of α-fetoprotein or acetylcholinesterase may also be helpful in determining any other conditions that can lead to development of rachischisis.
Classification
Rachischisis occurs most commonly in utero during the development of the child. Rachischisis is a neural tube defect characterised by a complete or severe defect in the spine. The defect can be located anywhere from the cervical region to the sacrum, or through the entire length of the spine. Typical defects are clefts or splits that open the spine to the exterior environment. Rachischisis occurs around 3–4 weeks after conception when the posterior neuropore of the neural tube does not close completely. It is a multifactorial aetiology and is most typically accompanied by other defects. Rachischisis is often described as a severe form of spina bifida, with the spine not only being exposed to the exterior environment, but with the opening being large enough to allow the neural plate to spread out of the opening and to the surface.
Treatment
Rachischisis is a severe condition and survival rates for fetuses are extremely low. Babies that are born with the condition have high mortality rates and extreme developmental defects. Fetuses with the condition often spontaneously abort. Babies that are born with rachischisis are stillborn or die within a few hours to a few days of birth. Typically, medical termination of pregnancy is presented as an option to the mother once a diagnosis of rachischisis has been confirmed. As the condition is often accompanied by other deformities that not only need to be treated themselves, but also complicate the condition of rachischisis, it is difficult to treat fetuses affected. Treatments for neural tube defects such as spina bifida do not work as the child is not stable enough to receive them, or they are complicated by other accompanying conditions that have developed alongside rachischisis.There has, however, been one reported successful treatment of rachischisis. The fetus was able to have the spinal shunt closed surgically. However, during this treatment several resuscitations were required and these caused trauma to the chest. Despite the closing of the shunt, extreme developmental inhibition was expected, and the prognosis was still extremely poor. This sparked questions as to whether this sort of treatment was ethical on fetuses. The fetus in this case had developed rachischisis without any indications of acrania. This is not typical of most cases, so this treatment would not be possible in the majority of cases of the condition.Due to the lack of treatments available for rachischisis, there is a focus on prevention of the disease. Folate supplementation is recommended before conception (if possible) and through to early pregnancy. There are many products on the market to assist with this. Products marketed towards reducing the risk of spina bifida and other neural tube defects are recommended to reduce the risk of rachischisis.
See also
Cranioschisis
Spina bifida
References
== External links == |
Vitreous membrane | The vitreous membrane (or hyaloid membrane or vitreous cortex) is a layer of collagen separating the vitreous humour from the rest of the eye. At least two parts have been identified anatomically. The posterior hyaloid membrane separates the rear of the vitreous from the retina. It is a false anatomical membrane. The anterior hyaloid membrane separates the front of the vitreous from the lens. Bernal et al. describe it "as a delicate structure in the form of a thin layer that runs from the pars plana to the posterior lens, where it shares its attachment with the posterior zonule via Weigerts ligament, also known as Eggers line".
References
External links
Image at ivy-rose.co.uk |
Hypochondroplasia | Hypochondroplasia (HCH) is a developmental disorder caused by an autosomal dominant genetic defect in the fibroblast growth factor receptor 3 gene (FGFR3) that results in a disproportionately short stature, micromelia and a head that appears large in comparison with the underdeveloped portions of the body. It is classified as short-limbed dwarfism.
Signs and symptoms
Individuals affected by this disorder appear normal at birth. As the infant grows, however, their arms and legs do not develop properly, and their body becomes thicker and shorter than normal. The following are characteristics consistent with this condition:
Brachydactyly
Short stature
Micromelia
Skeletal dysplasia
Abnormality of femur
Cause
Hypochondroplasia is transmitted as an autosomal dominant trait affecting the FGFR3 gene on chromosome 4p16.3. There is currently no cure for this condition.
Pathophysiology
This disorder results from mutations in the proximal tyrosine kinase domain of the FGFR3 gene. This gene plays an important role in embryonic development, playing a part in regulating activities such as cell division, migration and differentiation.Hypochondroplasia can result from p. Lys650Asn as well. In FGFR3, some 20 different mutations have been associated to hypochondroplasia, and it seems to have a role in skeletal dysplasia.
Diagnosis
The diagnosis of this condition can be done via X-rays (with lack of normal distance L1 to L5), and additionally genetic testing is available to ascertain hypochondroplasia. However, the physical characteristics are one of the most important in determining the condition.
Treatment
Treatment of hypochondroplasia usually takes the form of orthopedic surgery and physical therapy. Genetic counseling is advised for individuals and their families. Specifically in the case of spinal stenosis, one option is laminectomy.
Prognosis
Life expectancy for individuals with hypochondroplasia is normal; height is about 132–147 centimetres (4 ft 4 in – 4 ft 10 in).
See also
Achondroplasia
List of congenital disorders
References
Further reading
ed, Sally Radovick; MacGillivray, Margaret H. (2010). Pediatric Endocrinology a Practical Clinical Guide, Second Edition (2nd ed.). Dordrecht: Springer. ISBN 9781607613954. Retrieved 21 December 2016.
Kelly, Evelyn B. (2013). Encyclopedia of human genetics and disease. Santa Barbara, Calif.: Greenwood. ISBN 9780313387142. Retrieved 21 December 2016.
== External links == |
Myofascial pain syndrome | Myofascial pain syndrome (MPS), also known as chronic myofascial pain (CMP), is a syndrome characterized by chronic pain in multiple myofascial trigger points ("knots") and fascial (connective tissue) constrictions. It can appear in any body part. Symptoms of a myofascial trigger points include: focal point tenderness, reproduction of pain upon trigger point palpation, hardening of the muscle upon trigger point palpation, pseudo-weakness of the involved muscle, referred pain, and limited range of motion following approximately 5 seconds of sustained trigger point pressure.The cause is believed to be muscle tension or spasms within the affected musculature. Diagnosis is based on the symptoms and possible sleep studies.Treatment may include pain medication, physical therapy, mouth guards, and occasionally benzodiazepine. It is a relatively common cause of temporomandibular pain.
Signs and symptoms
Myofascial pain is pain in muscles or fascia (a type of connective tissue that surrounds muscles). It can occur in distinct, isolated areas of the body. Because any muscle or fascia in the body may be affected, this may cause a variety of localized symptoms.Generally speaking, the muscular pain is steady, aching, and deep. Depending on the case and location the intensity can range from mild discomfort to excruciating and "lightning-like". Knots may be visible or felt beneath the skin. The pain does not resolve on its own, even after typical first-aid self-care such as ice, heat, and rest. Myofascial pain syndromes are characterized by localized pain in an area of repetitive use or trauma with resultant trigger points that cause non-dermatomal pain radiation upon palpation. Autonomic dysfunction and spontaneous EMG activity can be seen in the affected region.
Causes
The causes of MPS are not fully documented or understood. At least one study rules out trigger points: "The theory of myofascial pain syndrome (MPS) caused by trigger points (TrPs) ... has been refuted. This is not to deny the existence of the clinical phenomena themselves, for which scientifically sound and logically plausible explanations based on known neurophysiological phenomena can be advanced." Some systemic diseases, such as connective tissue disease, can cause MPS. Poor posture and emotional disturbance might also instigate or contribute to MPS.
Diagnosis
Diagnosis is generally based on the symptoms and possible sleep studies.
Treatment
Massage therapy using trigger-point release techniques may be effective in short-term pain relief. Physical therapy involving gentle stretching and exercise maybe useful for recovering full range of motion and motor coordination. Once the trigger points are gone, muscle strengthening exercise can begin, supporting long-term health of the local muscle system.Myofascial release, which involves gentle fascia manipulation and massage, may improve or remediate the condition.A systematic review concluded that dry needling for the treatment of myofascial pain syndrome in the lower back appeared to be a useful adjunct to standard therapies, but that clear recommendations could not be made because the published studies were small and of low quality.Posture evaluation and ergonomics may provide relief in the early stages of treatment. Gentle, sustained stretching exercises within a comfortable range of motion have been shown to lessen symptoms. Regular, non-intense activity is also encouraged.
References
Sources
Starlanyl, Devin J.; Copeland, Mary Ellen (2001). Fibromyalgia & Chronic Myofascial Pain: A Survival Manual (2nd ed.). Oakland, CA: New Harbinger Publications. ISBN 978-1-57224-238-8.
== External links == |
Hennekam syndrome | Hennekam syndrome also known as intestinal lymphagiectasia–lymphedema–mental retardation syndrome, is an autosomal recessive disorder consisting of intestinal lymphangiectasia, facial anomalies, peripheral lymphedema, and mild to moderate levels of growth and intellectual disability.It is also known as "lymphedema-lymphangiectasia-mental retardation syndrome".Hennekam Syndrome is subdivided according to the causative genetic lesion, most (or all) of which are affecting the VEGF-C/VEGFR-3 signaling pathway:
Type 1 (mutations in CCBE1)
Type 2 (mutations in FAT4)
Type 3 (mutations in ADAMTS3)The first recognition of a genetic association was with CCBE1, published by its namesake, Raoul Hennekam. The molecular mechanism of the lymphedema phenotype in CCBE1-associated cases was identified as a diminished ability of the mutated CCBE1 to accelerate and focus the activation of the primary lymphangiogenic growth factor VEGF-C. Mutations in the FAT4 gene had previously been only associated with van Maldergem syndrome, but the pathogenetic molecular mechanism and the function of FAT4 within lymphangiogenesis are still unknown.
References
== External links == |
Neurodevelopmental disorder | Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental disorders tend to last for a persons lifetime.
Types
Neurodevelopmental disorders are impairments of the growth and development of the brain and/or central nervous system. A narrower use of the term refers to a disorder of brain function that affects emotion, learning ability, self-control and memory which unfolds as an individual develops and grows.According to the DSM-5, the neurodevelopmental disorders include the following:
Attention deficit hyperactivity disorder (ADHD)
DLD - Developmental language disorder (formerly known as SLI- Specific Language Impairment)
Communication, speech, or language disorders, expressive language disorder, fluency disorder, social (pragmatic) communication disorder, and speech sound disorder.
Autism spectrum disorder (ASD)
Intellectual disabilities (IDs) or intellectual development disorder (IDD, previously called mental retardation) and global developmental delay (GDD)
Motor disorders including developmental coordination disorder, stereotypic movement disorder, and tic disorders (such as Tourettes syndrome), and CAS - Apraxia of speech
Neurogenetic disorders, such as Fragile X syndrome, Down syndrome, Rett syndrome, hypogonadotropic hypogonadal syndromes
Specific learning disorders, like dyslexia or dyscalculia.
Traumatic brain injury (including congenital injuries such as those that cause cerebral palsy) and disorders due to neurotoxicants including Minamata disease caused by mercury, behavioral disorders including conduct disorder etc. caused by other heavy metals, such as lead, chromium, platinum etc., hydrocarbons like dioxin, PBDEs and PCBs, medications and illegal drugs, like cocaine, radioactive metals like Po210(which is found in cigarettes), and others.
Fetal Alcohol Spectrum Disorders (FASD) can exhibit a combination of the above, most commonly ADHD, because of this, FASD is usually under-diagnosed, yet it is estimated that about 1 in 20 people may be affected.
Currently being researched
There are neurodevelopmental research projects examining potential new classifications of disorders including:
Nonverbal learning disorder (NLD or NVLD), a neurodevelopmental disorder thought to be linked to white matter in the right hemisphere of the brain and generally considered to include (a) low visuospatial intelligence; (b) discrepancy between verbal and visuospatial intelligence; (c) visuoconstructive and fine-motor coordination skills; (d) visuospatial memory tasks; (e) reading better than mathematical achievement; and (f) socioemotional skills. While Nonverbal learning disorder is not categorized in the ICD or DSM as an discrete classification, "the majority of researchers and clinicians agree that the profile of NLD clearly exists (but see Spreen, 2011, for an exception), but they disagree on the need for a specific clinical category and on the criteria for its identification."
Presentation
Consequences
The multitude of neurodevelopmental disorders span a wide range of associated symptoms and severity, resulting in different degrees of mental, emotional, physical, and economic consequences for individuals, and in turn families, social groups, and society.
Causes
The development of the nervous system is tightly regulated and timed; it is influenced by both genetic programs and the environment. Any significant deviation from the normal developmental trajectory early in life can result in missing or abnormal neuronal architecture or connectivity. Because of the temporal and spatial complexity of the developmental trajectory, there are many potential causes of neurodevelopmental disorders that may affect different areas of the nervous system at different times and ages. These range from social deprivation, genetic and metabolic diseases, immune disorders, infectious diseases, nutritional factors, physical trauma, and toxic and environmental factors. Some neurodevelopmental disorders, such as autism and other pervasive developmental disorders, are considered multifactorial syndromes which have many causes that converge to a more specific neurodevelopmental manifestation.
Social deprivation
Deprivation from social and emotional care causes severe delays in brain and cognitive development. Studies with children growing up in Romanian orphanages during Nicolae Ceauşescus regime reveal profound effects of social deprivation and language deprivation on the developing brain. These effects are time-dependent. The longer children stayed in negligent institutional care, the greater the consequences. By contrast, adoption at an early age mitigated some of the effects of earlier institutionalization (abnormal psychology).
Genetic disorders
A prominent example of a genetically determined neurodevelopmental disorder is Trisomy 21, also known as Down syndrome. This disorder usually results from an extra chromosome 21, although in uncommon instances it is related to other chromosomal abnormalities such as translocation of the genetic material. It is characterized by short stature, epicanthal (eyelid) folds, abnormal fingerprints, and palm prints, heart defects, poor muscle tone (delay of neurological development), and intellectual disabilities (delay of intellectual development).Less commonly known genetically determined neurodevelopmental disorders include Fragile X syndrome. Fragile X syndrome was first described in 1943 by Martin and Bell, studying persons with family history of sex-linked "mental defects". Rett syndrome, another X-linked disorder, produces severe functional limitations. Williams syndrome is caused by small deletions of genetic material from chromosome 7.
The most common recurrent Copy Number Variant disorder is 22q11.2 deletion syndrome (formerly DiGeorge or velocardiofacial syndrome), followed by Prader-Willi syndrome and Angelman syndrome.
Immune dysfunction
Immune reactions during pregnancy, both maternal and of the developing child, may produce neurodevelopmental disorders. One typical immune reaction in infants and children is PANDAS, or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection. Another disorder is Sydenhams chorea, which results in more abnormal movements of the body and fewer psychological sequellae. Both are immune reactions against brain tissue that follow infection by Streptococcus bacteria. Susceptibility to these immune diseases may be genetically determined, so sometimes several family members may have one or both of them following an epidemic of Strep infection.
Infectious diseases
Systemic infections can result in neurodevelopmental consequences, when they occur in infancy and childhood of humans, but would not be called a primary neurodevelopmental disorder. For example HIV Infections of the head and brain, like brain abscesses, meningitis or encephalitis have a high risk of causing neurodevelopmental problems and eventually a disorder. For example, measles can progress to subacute sclerosing panencephalitis.
A number of infectious diseases can be transmitted congenitally (either before or at birth), and can cause serious neurodevelopmental problems, as for example the viruses HSV, CMV, rubella (congenital rubella syndrome), Zika virus, or bacteria like Treponema pallidum in congenital syphilis, which may progress to neurosyphilis if it remains untreated. Protozoa like Plasmodium or Toxoplasma which can cause congenital toxoplasmosis with multiple cysts in the brain and other organs, leading to a variety of neurological deficits.
Some cases of schizophrenia may be related to congenital infections, though the majority are of unknown causes.
Metabolic disorders
Metabolic disorders in either the mother or the child can cause neurodevelopmental disorders. Two examples are diabetes mellitus (a multifactorial disorder) and phenylketonuria (an inborn error of metabolism). Many such inherited diseases may directly affect the childs metabolism and neural development but less commonly they can indirectly affect the child during gestation. (See also teratology).
In a child, type 1 diabetes can produce neurodevelopmental damage by the effects of excess or insufficient glucose. The problems continue and may worsen throughout childhood if the diabetes is not well controlled. Type 2 diabetes may be preceded in its onset by impaired cognitive functioning.A non-diabetic fetus can also be subjected to glucose effects if its mother has undetected gestational diabetes. Maternal diabetes causes excessive birth size, making it harder for the infant to pass through the birth canal without injury or it can directly produce early neurodevelopmental deficits. Usually the neurodevelopmental symptoms will decrease in later childhood.Phenylketonuria, also known as PKU, can induce neurodevelopmental problems and children with PKU require a strict diet to prevent intellectual disability and other disorders. In the maternal form of PKU, excessive maternal phenylalanine can be absorbed by the fetus even if the fetus has not inherited the disease. This can produce intellectual disability and other disorders.
Nutrition
Nutrition disorders and nutritional deficits may cause neurodevelopmental disorders, such as spina bifida, and the rarely occurring anencephaly, both of which are neural tube defects with malformation and dysfunction of the nervous system and its supporting structures, leading to serious physical disability and emotional sequelae. The most common nutritional cause of neural tube defects is folic acid deficiency in the mother, a B vitamin usually found in fruits, vegetables, whole grains, and milk products. (Neural tube defects are also caused by medications and other environmental causes, many of which interfere with folate metabolism, thus they are considered to have multifactorial causes.) Another deficiency, iodine deficiency, produces a spectrum of neurodevelopmental disorders ranging from mild emotional disturbance to severe intellectual disability. (see also congenital iodine deficiency syndrome).Excesses in both maternal and infant diets may cause disorders as well, with foods or food supplements proving toxic in large amounts. For instance in 1973 K.L. Jones and D.W. Smith of the University of Washington Medical School in Seattle found a pattern of "craniofacial, limb, and cardiovascular defects associated with prenatal onset growth deficiency and developmental delay" in children of alcoholic mothers, now called fetal alcohol syndrome, It has significant symptom overlap with several other entirely unrelated neurodevelopmental disorders.
Physical trauma
Brain trauma in the developing human is a common cause (over 400,000 injuries per year in the US alone, without clear information as to how many produce developmental sequellae) of neurodevelopmental syndromes. It may be subdivided into two major categories, congenital injury (including injury resulting from otherwise uncomplicated premature birth) and injury occurring in infancy or childhood. Common causes of congenital injury are asphyxia (obstruction of the trachea), hypoxia (lack of oxygen to the brain), and the mechanical trauma of the birth process itself.
Placenta
Although it not clear yet as strong is the correlation between placenta and brain, a growing number of studies are linking placenta to fetal brain development.
Diagnosis
Neurodevelopmental disorders are diagnosed by evaluating the presence of characteristic symptoms or behaviors in a child, typically after a parent, guardian, teacher, or other responsible adult has raised concerns to a doctor.Neurodevelopmental disorders may also be confirmed by genetic testing. Traditionally, disease related genetic and genomic factors are detected by karyotype analysis, which detects clinically significant genetic abnormalities for 5% of children with a diagnosed disorder. As of 2017, chromosomal microarray analysis (CMA) was proposed to replace karyotyping because of its ability to detect smaller chromosome abnormalities and copy-number variants, leading to greater diagnostic yield in about 20% of cases. The American College of Medical Genetics and Genomics and the American Academy of Pediatrics recommend CMA as standard of care in the US.
See also
Developmental disability
Epigenetics
Microcephaly
Teratology
References
Further reading
External links
Neurodevelopmental Disorders at Curlie
A Review of Neurodevelopmental Disorders - Medscape review |
Hematosalpinx | Hematosalpinx (sometimes also hemosalpinx) is a medical condition involving bleeding into the fallopian tubes.
Symptoms
A hematosalpinx from a tubal pregnancy may be associated with pelvic pain and uterine bleeding. A gynecologic ultrasound will show the hematosalpinx. A hematosalpinx from other conditions may be painless but could lead to uterine bleeding.
Causes
A number of causes may account for a hematosalpinx, by far the most common being a tubal pregnancy. Blood may also escape into the peritoneal cavity leading to a hemoperitoneum.
A hematosalpinx can also be associated with endometriosis or tubal carcinoma. Further, if menstrual blood flow is obstructed (cryptomenorrhea), caused for instance by a transverse vaginal septum, and gets backed up it may lead to a hematosalpinx.
Diagnosis
Diagnosis may include, but is not limited to, ultrasound, magnetic resonance imaging (MRI) and laparoscopy.
Treatment
Treatment is directed at the underlying condition and is usually surgical.
See also
Hydrosalpinx
References
== External links == |
Lobar pneumonia | Lobar pneumonia is a form of pneumonia characterized by inflammatory exudate within the intra-alveolar space resulting in consolidation that affects a large and continuous area of the lobe of a lung.It is one of three anatomic classifications of pneumonia (the other being bronchopneumonia and atypical pneumonia). In children round pneumonia develops instead because the pores of Kohn which allow the lobar spread of infection are underdeveloped.
Mechanism
The invading organism starts multiplying, thereby releasing toxins that cause inflammation and edema of the lung parenchyma. This leads to the accumulation of cellular debris within the lungs. This leads to consolidation or solidification, which is a term that is used for macroscopic or radiologic appearance of the lungs affected by pneumonia.
Bacterial pneumonia is mainly classified into lobar and diffuse depending on the degree of lung irritation or damage.
Stages
Lobar pneumonia usually has an acute progression.
Classically, the disease has four stages:
Congestion in the first 24 hours: This stage is characterized histologically by vascular engorgement, intra-alveolar fluid, small numbers of neutrophils, often numerous bacteria. Grossly, the lung is heavy and hyperemic.
Red hepatization or consolidation: Vascular congestion persists, with extravasation of red blood cells into alveolar spaces, along with increased numbers of neutrophils and fibrin. The filling of airspaces by the exudate leads to a gross appearance of solidification, or consolidation, of the alveolar parenchyma. This appearance has been likened to that of the liver, hence the term "hepatization".
Grey hepatization: Red blood cells disintegrate, with persistence of the neutrophils and fibrin. The alveoli still appear consolidated, but grossly the color is paler and the cut surface is drier. This is when death typically occurs in severe cases.
Resolution (complete recovery): The exudate is digested by enzymatic activity, and cleared by macrophages or by cough mechanism. Enzymes produced by neutrophils will liquify exudates, and this will either be coughed up in sputum or be drained via lymph.
In children
The openings between the alveoli known as the pores of Kohn, and the collateral airways of the canals of Lambert, are undeveloped in children. Spread of infection that would otherwise occur is prevented and can result in round pneumonia, most commonly caused by S. pneumoniae. This clinically presents with an initial mild respiratory infection, followed by fever. On imaging it presents an opaque pulmonary consolidation which is unusually round, and can resemble a lung mass. However it quickly resolves with antibiotics.
Diagnosis
The most common organisms which cause lobar pneumonia are Streptococcus pneumoniae, also called pneumococcus, Haemophilus influenzae and Moraxella catarrhalis. Mycobacterium tuberculosis, the tubercle bacillus, may also cause lobar pneumonia if pulmonary tuberculosis is not treated promptly. Other organisms that cause lobar pneumonia are Legionella pneumophila and Klebsiella pneumoniae.Like other types of pneumonia, lobar pneumonia can present as community acquired, in immune suppressed patients or as nosocomial infection. However, most causative organisms are of the community acquired type.
Pathological specimens to be obtained for investigations include:
Sputum for culture, AAFBS and gram stain
Blood for full hemogram/complete blood count, ESR and other acute phase reactants
Procalcitonin test, more specificOn a posteroanterior and lateral chest radiograph, an entire lobe will be radiopaque, which is indicative of lobar pneumonia.
The identification of the infectious organism (or other cause) is an important part of modern treatment of pneumonia. The anatomical patterns of distribution can be associated with certain organisms, and can help in selection of an antibiotic while waiting for the pathogen to be cultured.
References
External links
Media related to Lobar pneumonia at Wikimedia Commons |
Benzodiazepine withdrawal syndrome | Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal or BZD withdrawal —is the cluster of signs and symptoms that emerge when a person who has been taking benzodiazepines, either medically or recreationally, and has developed a physical dependence, undergoes dosage reduction or discontinuation.
Development of physical dependence and the resulting withdrawal symptoms, some of which may last for years, may result from taking the medication as prescribed. Benzodiazepine withdrawal is characterized by sleep disturbance, irritability, mast cell activation, increased tension and anxiety, panic attacks, hand tremor, shaking, sweating, difficulty with concentration, confusion and cognitive difficulty, memory problems, dry retching and nausea, weight loss, palpitations, headache, muscular pain and stiffness, a host of perceptual changes, hallucinations, seizures, psychosis, and increased risk of suicide (see "signs and symptoms" section below for full list). Further, these symptoms are notable for the manner in which they wax and wane and vary in severity from day to day or week by week instead of steadily decreasing in a straightforward monotonic manner. This phenomenon is often referred to as "waves" and "windows".
It is a potentially serious condition, and is complex and often protracted in its course. Long-term benzodiazepine use, defined as daily use for at least three months, is not desirable because of the associated increased risk of dependence, dose escalation, loss of efficacy, increased risk of accidents and falls, particularly for the elderly, as well as cognitive, neurological, and intellectual impairments. Use of short-acting hypnotics, while being effective at initiating sleep, worsens the second half of sleep due to withdrawal effects.Benzodiazepine withdrawal can be severe and provoke life-threatening withdrawal symptoms, such as seizures, particularly with abrupt or overly rapid dosage reduction from high doses or long-time use. A severe withdrawal response can nevertheless occur despite gradual dose reduction, or from relatively low doses in short-time users; even after a single large dose in animal models. A minority of individuals will experience a protracted withdrawal syndrome, whose symptoms may persist at a sub-acute level for months or years after cessation of benzodiazepines. The likelihood of developing a protracted withdrawal syndrome can be minimized by a slow, gradual reduction in dosage.Chronic exposure to benzodiazepines causes neural adaptations that counteract the drugs effects, leading to tolerance and dependence. Despite taking a constant therapeutic dose, long-term use of benzodiazepines may lead to the emergence of withdrawal-like symptoms, particularly between doses, when patients are treated with shorter-acting benzodiazepines. When the drug is discontinued or the dosage reduced, withdrawal symptoms may appear and remain until the body has reversed the long-term physiological adaptations. These rebound symptoms may be identical to the symptoms for which the drug was initially taken, or may be part of discontinuation symptoms. In severe cases, the withdrawal reaction may exacerbate or resemble serious psychiatric and medical conditions, such as mania, schizophrenia, and, especially at high doses, seizure disorders. Failure to recognize discontinuation symptoms can lead to false evidence for the need to take benzodiazepines, which in turn leads to withdrawal failure and reinstatement of benzodiazepines, often at higher doses.Awareness of the withdrawal reactions, individualized taper strategies according to withdrawal severity, the addition of alternative strategies such as reassurance and referral to benzodiazepine withdrawal support groups, all increase the success rate of withdrawal.
Signs and symptoms
Withdrawal effects caused by sedative-hypnotics discontinuation, such as benzodiazepines, barbiturates, or alcohol, can cause serious medical complications. They are cited to be more hazardous to withdraw from than opioids. Users typically receive little advice and support for discontinuation. Some withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed, and can be acute or protracted in duration. Onset of symptoms from long half-life benzodiazepines might be delayed for up to three weeks, although withdrawal symptoms from short-acting ones often present early, usually within 24–48 hours. There may be no fundamental differences in symptoms from either high or low dose discontinuation, but symptoms tend to be more severe from higher doses.Daytime reemergence and rebound withdrawal symptoms, sometimes confused with interdose withdrawal, may occur once dependence has set in. Reemergence is the return of symptoms for which the drug was initially prescribed, in contrast, rebound symptoms are a return of the symptoms for which the benzodiazepine was initially taken, but at a more intense level than before; whereas interdose withdrawal is when a prior dosage of drug wears off and beginnings of an entirely new cycle of withdrawal sets in, the symptoms of which dissipate upon taking the next dosage but after which yet another entirely new cycle of withdrawal begins when that dosage wears off, a new onset of withdrawal between each dosage thus called interdose withdrawal and if not properly treated can recur indefinitely in a vicious circle (for which a benzo with a long half life, e.g. diazepam, can be substituted so the drug does not wear off between doses).Withdrawal symptoms may appear for the first time during dose reduction, and include insomnia, anxiety, distress, weight loss, dizziness, night sweats, shakes, muscle twitches, aphasia, panic attacks, depression, derealization, paranoia, indigestion, diarrhea, photophobia etc., and are more commonly associated with short-acting benzodiazepines discontinuation, like triazolam. Daytime symptoms can occur after a few days to a few weeks of administration of nightly benzodiazepines or z-drugs such as zopiclone; withdrawal-related insomnia rebounds worse than baseline, and for rapidly eliminated benzodiazepines, including triazolam and temazepam, this may occur even when used briefly and intermittently, according to a small 1991 study (n=18).The following symptoms may emerge during gradual or abrupt dosage reduction:
Rapid discontinuation may result in a more serious syndrome
As withdrawal progresses, patients often find their physical and mental health improves with improved mood and improved cognition.
Mechanism
The neuroadaptive processes involved in tolerance, dependence, and withdrawal mechanisms implicate both the GABAergic and the glutamatergic systems. Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system; roughly one-quarter to one-third of synapses use GABA. GABA mediates the influx of chloride ions through ligand-gated chloride channels called GABAA receptors. When chloride enters the nerve cell, the cell membrane potential hyperpolarizes thereby inhibiting depolarization, or reduction in the firing rate of the post-synaptic nerve cell. Benzodiazepines potentiate the action of GABA, by binding a site between the α and γ subunits of the 5-subunit receptor thereby increasing the frequency of the GABA-gated chloride channel opening in the presence of GABA.When potentiation is sustained by long-term use, neuroadaptations occur which result in decreased GABAergic response. What is certain is that surface GABAA receptor protein levels are altered in response to benzodiazepine exposure, as is receptor turnover rate. The exact reason for the reduced responsiveness has not been elucidated but down-regulation of the number of receptors has only been observed at some receptor locations including in the pars reticulata of the substantia nigra; down-regulation of the number of receptors or internalization does not appear to be the main mechanism at other locations. Evidence exists for other hypotheses including changes in the receptor conformation, changes in turnover, recycling, or production rates, degree of phosphorylation and receptor gene expression, subunit composition, decreased coupling mechanisms between the GABA and benzodiazepine site, decrease in GABA production, and compensatory increased glutamatergic activity. A unified model hypothesis involves a combination of internalization of the receptor, followed by preferential degradation of certain receptor sub-units, which provides the nuclear activation for changes in receptor gene transcription.It has been postulated that when benzodiazepines are cleared from the brain, these neuroadaptations are "unmasked", leading to unopposed excitability of the neuron. Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Increased glutamate excitatory activity during withdrawal may lead to sensitization or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse. Those who have a prior history of withdrawing from benzodiazepines are found to be less likely to succeed the next time around.
Diagnosis
In severe cases, the withdrawal reaction or protracted withdrawal may exacerbate or resemble serious psychiatric and medical conditions, such as mania, schizophrenia, agitated depression, panic disorder, generalised anxiety disorder, and complex partial seizures and, especially at high doses, seizure disorders. Failure to recognize discontinuation symptoms can lead to false evidence for the need to take benzodiazepines, which in turn leads to withdrawal failure and reinstatement of benzodiazepines, often to higher doses. Pre-existing disorder or other causes typically do not improve, whereas symptoms of protracted withdrawal gradually improve over the ensuing months.Symptoms may lack a psychological cause and can fluctuate in intensity with periods of good and bad days until eventual recovery.
Prevention
According to the British National Formulary, it is better to withdraw too slowly rather than too quickly from benzodiazepines. The rate of dosage reduction is best carried out so as to minimize the symptoms intensity and severity. Anecdotally, a slow rate of reduction may reduce the risk of developing a severe protracted syndrome.
Long half-life benzodiazepines like diazepam or chlordiazepoxide are preferred to minimize rebound effects and are available in low dose forms. Some people may not fully stabilize between dose reductions, even when the rate of reduction is slowed. Such people sometimes simply need to persist as they may not feel better until they have been fully withdrawn from them for a period of time.
Management
Management of benzodiazepine dependence involves considering the persons age, comorbidity and the pharmacological pathways of benzodiazepines. Psychological interventions may provide a small but significant additional benefit over gradual dose reduction alone at post-cessation and at follow-up. The psychological interventions studied were relaxation training, cognitive-behavioral treatment of insomnia, and self-monitoring of consumption and symptoms, goal-setting, management of withdrawal and coping with anxiety.There is no standard approach to managing benzodiazepine withdrawal.
With sufficient motivation and the proper approach, almost anyone can successfully withdraw from benzodiazepines. However, a prolonged and severe withdrawal syndrome can cause profound disability, which may lead to breakdown of relationships, loss of employment, financial difficulties, as well as more serious adverse effects such as hospitalization and suicide. As such, long-term users should not be forced to discontinue against their will.Over-rapid withdrawal, lack of explanation, and failure to reassure individuals that they are experiencing temporary withdrawal symptoms led some people to experience increased panic and fears they are going mad, with some people developing a condition similar to post-traumatic stress disorder as a result. A slow withdrawal regimen, coupled with reassurance from family, friends, and peers improves the outcome. According to a 2015 Cochrane review, cognitive behavior therapy plus taper was effective in achieving discontinuation in the short-term but the effect was not certain after six months.
Medications
While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use. Some studies found that the abrupt substitution of substitutive pharmacotherapy was actually less effective than gradual dose reduction alone, and only three studies found benefits of adding melatonin, paroxetine, trazodone, or valproate in conjunction with a gradual dose reduction.
Antipsychotics are generally ineffective for benzodiazepine withdrawal-related psychosis. Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions. Some antipsychotic agents may be riskier than others during withdrawal, especially clozapine, olanzapine or low potency phenothiazines (e.g., chlorpromazine), as they lower the seizure threshold and can worsen withdrawal effects; if used, extreme caution is required.
Barbiturates are cross tolerant to benzodiazepines and should generally be avoided; however phenobarbital can be used, as it is relatively safe, see below.
Benzodiazepines or cross tolerant drugs should be avoided after discontinuation, even occasionally. These include the nonbenzodiazepines Z-drugs, which have a similar mechanism of action. This is because tolerance to benzodiazepines has been demonstrated to be still present at four months to two years after withdrawal depending on personal biochemistry. Re-exposures to benzodiazepines typically resulted in a reactivation of the tolerance and benzodiazepine withdrawal syndrome.
Bupropion, which is used primarily as an antidepressant and smoking cessation aid, is contraindicated in persons experiencing abrupt withdrawal from benzodiazepines or other sedative-hypnotics (e.g. alcohol), due to an increased risk of seizures.
Buspirone augmentation was not found to increase the discontinuation success rate.
Caffeine may worsen withdrawal symptoms because of its stimulatory properties. At least one animal study has shown some modulation of the benzodiazepine site by caffeine, which produces a lowering of seizure threshold.
Carbamazepine, an anticonvulsant, appears to have some beneficial effects in the treatment and management of benzodiazepine withdrawal; however, research is limited and thus the ability of experts to make recommendations on its use for benzodiazepine withdrawal is not possible at present.
Ethanol, the primary alcohol in alcoholic beverages, even mild to moderate use, has been found to be a significant predictor of withdrawal failure, probably because of its cross tolerance with benzodiazepines.
Flumazenil has been found to stimulate the reversal of tolerance and the normalization of receptor function. However, further research is needed in the form of randomised trials to demonstrate its role in the treatment of benzodiazepine withdrawal. Flumazenil stimulates the up-regulation and reverses the uncoupling of benzodiazepine receptors to the GABAA receptor, thereby reversing tolerance and reducing withdrawal symptoms and relapse rates. Because of limited research and experience compared to the possible risks involved, the flumazenil detoxification method is controversial and can only be done as an inpatient procedure under medical supervision.Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.A study into the effects of the benzodiazepine receptor antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting after withdrawal was carried out by Lader and Morton. Study subjects had been benzodiazepine-free for between one month and five years, but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, depersonalisation, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles feeling, burning skin, pain and subjective sensations of bodily distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo-controlled study. This is of interest as benzodiazepine receptor antagonists are neutral and have no clinical effects. The author of the study suggested the most likely explanation is past benzodiazepine use and subsequent tolerance had locked the conformation of the GABA-BZD receptor complex into an inverse agonist conformation, and the antagonist flumazenil resets benzodiazepine receptors to their original sensitivity. Flumazenil was found in this study to be a successful treatment for protracted benzodiazepine withdrawal syndrome, but further research is required. A study by Professor Borg in Sweden produced similar results in patients in protracted withdrawal. In 2007, Hoffmann–La Roche the makers of flumazenil, acknowledged the existence of protracted benzodiazepine withdrawal syndromes, but did not recommended flumazenil to treat the condition.Fluoroquinolone antibiotics have been noted to increase the incidence of a CNS toxicity from 1% in the general population, to 4% in benzodiazepine-dependent population or in those undergoing withdrawal from them. This is probably the result of their GABA antagonistic effects as they have been found to competitively displace benzodiazepines from benzodiazepine receptor sites. This antagonism can precipitate acute withdrawal symptoms, that can persist for weeks or months before subsiding. The symptoms include depression, anxiety, psychosis, paranoia, severe insomnia, paresthesia, tinnitus, hypersensitivity to light and sound, tremors, status epilepticus, suicidal thoughts and suicide attempt. Fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal. NSAIDs have some mild GABA antagonistic properties and animal research indicate that some may even displace benzodiazepines from their binding site. However, NSAIDs taken in combination with fluoroquinolones cause a very significant increase in GABA antagonism, GABA toxicity, seizures, and other severe adverse effects.
Imidazenil has received some research for management of benzodiazepine withdrawal, but is not currently used in withdrawal.
Imipramine was found to statistically increase the discontinuation success rate.
Melatonin augmentation was found to statistically increase the discontinuation success rate for people with insomnia.
Phenobarbital, (a barbiturate), is used at "detox" or other inpatient facilities to prevent seizures during rapid withdrawal or cold turkey. The phenobarbital is followed by a one- to two-week taper, although a slow taper from phenobarbital is preferred. In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper.
Pregabalin may help reduce the severity of benzodiazepine withdrawal symptoms, and reduce the risk of relapse.
Propranolol was not found to increase the discontinuation success rate.
SSRI antidepressants have been found to have little value in the treatment of benzodiazepine withdrawal.
Trazodone was not found to increase the discontinuation success rate.
Inpatient treatment
Inpatient drug detox or rehabilitation facilities may be inappropriate for those who have become tolerant or dependent while taking the drug as prescribed, as opposed to recreational use. Such inpatient referrals may be traumatic for these individuals.
Prognosis
A 2006 meta-analysis found evidence for the efficacy of stepped care: minimal intervention (e.g. send an advisory letter, or meet a large number of patients to advise discontinuation), followed by systematic tapered discontinuation alone without augmentation if the first try was unsuccessful. Cognitive behavioral therapy improved discontinuation success rates for panic disorder, melatonin for insomnia, and flumazenil or sodium valproate for general long-term benzodiazepine use. A ten-year follow-up found that more than half of those who had successfully withdrawn from long-term use were still abstinent two years later and that if they were able to maintain this state at two years, they were likely to maintain this state at the ten-year follow-up. One study found that after one year of abstinence from long-term use of benzodiazepines, cognitive, neurological and intellectual impairments had returned to normal.Those who had a prior psychiatric diagnosis had a similar success rate from a gradual taper at a two-year follow-up. Withdrawal from benzodiazepines did not lead to an increased use of antidepressants.
Withdrawal process
It can be too difficult to withdraw from short- or intermediate-acting benzodiazepines because of the intensity of the rebound symptoms felt between doses. Moreover, short-acting benzodiazepines appear to produce a more intense withdrawal syndrome. For this reason, discontinuation is sometimes carried out by first substituting an equivalent dose of a short-acting benzodiazepine with a longer-acting one like diazepam or chlordiazepoxide. Failure to use the correct equivalent amount can precipitate a severe withdrawal reaction. Benzodiazepines with a half-life of more than 24 hours include chlordiazepoxide, diazepam, clobazam, clonazepam, chlorazepinic acid, ketazolam, medazepam, nordazepam, and prazepam. Benzodiazepines with a half-life of less than 24 hours include alprazolam, bromazepam, brotizolam, flunitrazepam, loprazolam, lorazepam, lormetazepam, midazolam, nitrazepam, oxazepam, and temazepam. The resultant equivalent dose is then gradually reduced.
The consensus is to reduce dosage gradually over several weeks, e.g. 4 or more weeks for diazepam doses over 30 mg/day,
with the rate determined by the persons ability to tolerate symptoms.
The recommended reduction rates range from 50% of the initial dose every week or so,
to 10-25% of the daily dose every 2 weeks.
For example, the reduction rate used in the Heather Ashton protocol calls for eliminating 10% of the remaining dose every two to four weeks, depending on the severity and response to reductions with the final dose at 0.5 mg dose of diazepam or 2.5 mg dose of chlordiazepoxide.
For most people, discontinuation over 4–6 weeks or 4–8 weeks is suitable.
A prolonged period of reduction for longer than six months should be avoided to prevent the withdrawal process from becoming a "morbid focus" for the person.
Duration
After the last dose has been taken, the acute phase of the withdrawal generally lasts for about two months although withdrawal symptoms, even from low-dose use, can persist for six to twelve months gradually improving over that period, however, clinically significant withdrawal symptoms may persist for years, although gradually declining.
A clinical trial of patients taking the benzodiazepine alprazolam for as short as eight weeks triggered protracted symptoms of memory deficits which were still present up to eight weeks after cessation of alprazolam.
Protracted withdrawal syndrome
Protracted withdrawal syndrome refers to symptoms persisting for months or even years. A significant minority of people withdrawing from benzodiazepines, perhaps 10% to 15%, experience a protracted withdrawal syndrome which can sometimes be severe. Symptoms may include tinnitus, psychosis, cognitive deficits, gastrointestinal complaints, insomnia, paraesthesia (tingling and numbness), pain (usually in limbs and extremities), muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, dizziness and blepharospasm and may occur even without a pre-existing history of these symptoms. Tinnitus occurring during dose reduction or discontinuation of benzodiazepines is alleviated by recommencement of benzodiazepines. Dizziness is often reported as being the withdrawal symptom that lasts the longest.
A study testing neuropsychological factors found psychophysiological markers differing from normals, and concluded that protracted withdrawal syndrome was a genuine iatrogenic condition caused by the long-term use. The causes of persisting symptoms are a combination of pharmacological factors such as persisting drug induced receptor changes, psychological factors both caused by the drug and separate from the drug and possibly in some cases, particularly high dose users, structural brain damage or structural neuronal damage. Symptoms continue to improve over time, often to the point where people eventually resume their normal lives, even after years of incapacity.A slow withdrawal rate significantly reduces the risk of a protracted or severe withdrawal state. Protracted withdrawal symptoms can be punctuated by periods of good days and bad days. When symptoms increase periodically during protracted withdrawal, physiological changes may be present, including dilated pupils as well as an increase in blood pressure and heart rate. The change in symptoms has been proposed to be due to changes in receptor sensitivity for GABA during the process of tolerance reversal. A meta-analysis found cognitive impairments in many areas due to benzodiazepine use show improvements after six months of withdrawal, but significant impairments in most areas may be permanent or may require more than six months to reverse.Protracted symptoms continue to fade over a period of many months or several years. There is no known cure for protracted benzodiazepine withdrawal syndrome except time, however, the medication flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
Epidemiology
The severity and length of the withdrawal syndrome is likely determined by various factors, including rate of tapering, length of use and dosage size, and possible genetic factors. Those who have a prior history of withdrawing from benzodiazepines may have a sensitized or kindled central nervous system leading to worsening cognition and symptomatology, and making each subsequent withdrawal period worse.
Special populations
Pediatrics
A neonatal withdrawal syndrome, sometimes severe, can occur when the mother had taken benzodiazepines, especially during the third trimester. Symptoms include hypotonia, apnoeic spells, cyanosis, impaired metabolic responses to cold stress, and seizures. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hours to months after birth.A withdrawal syndrome is seen in about 20% of pediatric intensive care unit children after infusions with benzodiazepines or opioids. The likelihood of having the syndrome correlates with total infusion duration and dose, although duration is thought to be more important. Treatment for withdrawal usually involves weaning over a 3- to 21-day period if the infusion lasted for more than a week. Symptoms include tremors, agitation, sleeplessness, inconsolable crying, diarrhea and sweating. In total, over fifty withdrawal symptoms are listed in this review article. Environmental measures aimed at easing the symptoms of neonates with severe abstinence syndrome had little impact, but providing a quiet sleep environment helped in mild cases.
Pregnancy
Discontinuing benzodiazepines or antidepressants abruptly due to concerns of teratogenic effects of the medications has a high risk of causing serious complications, so is not recommended. For example, abrupt withdrawal of benzodiazepines or antidepressants has a high risk of causing extreme withdrawal symptoms, including suicidal ideation and a severe rebound effect of the return of the underlying disorder if present. This can lead to hospitalisation and potentially, suicide. One study reported one-third of mothers who suddenly discontinued or very rapidly tapered their medications became acutely suicidal due to unbearable symptoms. One woman had a medical abortion, as she felt she could no longer cope, and another woman used alcohol in a bid to combat the withdrawal symptoms from benzodiazepines. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications, including benzodiazepines. The study reported physicians generally are not aware of the severe consequences of abrupt withdrawal of psychotropic medications such as benzodiazepines or antidepressants.
Elderly
A study of the elderly who were benzodiazepine dependent found withdrawal could be carried out with few complications and could lead to improvements in sleep and cognitive abilities. At 52 weeks after successful withdrawal, a 22% improvement in cognitive status was found, as well as improved social functioning. Those who remained on benzodiazepines experienced a 5% decline in cognitive abilities, which seemed to be faster than that seen in normal aging, suggesting the longer the intake of benzodiazepines, the worse the cognitive effects become. Some worsening of symptoms were seen in the first few months of benzodiazepine abstinence, but at a 24-week follow-up, elderly subjects were clearly improved compared to those who remained on benzodiazepines. Improvements in sleep were seen at the 24- and 52-week follow-ups. The authors concluded benzodiazepines were not effective in the long term for sleep problems except in suppressing withdrawal-related rebound insomnia. Improvements were seen between 24 and 52 weeks after withdrawal in many factors, including improved sleep and several cognitive |
Benzodiazepine withdrawal syndrome | and performance abilities. Some cognitive abilities, which are sensitive to benzodiazepines, as well as age, such as episodic memory, did not improve. The authors, however, cited a study in younger patients who at a 3.5-year follow-up showed no memory impairments and speculated that certain memory functions take longer to recover from chronic benzodiazepine use and further improvements in elderly peoples cognitive function may occur beyond 52 weeks after withdrawal. The reason it took 24 weeks for improvements to be seen after cessation of benzodiazepine use was due to the time it takes the brain to adapt to the benzodiazepine-free environment.At 24 weeks, significant improvements were found, including accuracy of information processing improved, but a decline was seen in those who remained on benzodiazepines. Further improvements were noted at the 52-week follow-up, indicating ongoing improvements with benzodiazepine abstinence. Younger people on benzodiazepines also experience cognitive deterioration in visual-spatial memory but are not as vulnerable as the elderly to the cognitive effects. Improved reaction times were noted at 52 weeks in elderly patients free from benzodiazepines. This is an important function in the elderly, especially if they drive a car due to the increased risk of road traffic accidents in benzodiazepine users. At the 24-week follow-up, 80% of people had successfully withdrawn from benzodiazepines. Part of the success was attributed to the placebo method used for part of the trial which broke the psychological dependence on benzodiazepines when the elderly patients realised they had completed their gradual reduction several weeks previously and had only been taking placebo tablets. This helped reassure them they could sleep without their pills.The authors also warned of the similarities in pharmacology and mechanism of action of the newer nonbenzodiazepine Z drugs.The elimination half-life of diazepam and chlordiazepoxide, as well as other long half-life benzodiazepines, is twice as long in the elderly compared to younger individuals. Many doctors do not adjust benzodiazepine dosage according to age in elderly patients.
See also
References
External links
Benzodiazepines: How they work and how to withdraw by Professor Heather Ashton
The Minor Tranquilliser Project, For support, Camden, UK
Benzodiazepine withdrawal syndrome at Curlie |
Chronic inflammatory demyelinating polyneuropathy | Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is sometimes called chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculoneuropathy (because it involves the nerve roots). CIDP is closely related to Guillain–Barré syndrome and it is considered the chronic counterpart of that acute disease. Its symptoms are also similar to progressive inflammatory neuropathy. It is one of several types of neuropathy.
Types
Several variants have been reported. Specially important are:
An asymmetrical variant of CIDP is known as Lewis-Sumner Syndrome. or MADSAM (multifocal acquired demyelinating sensory and motor neuropathy)
A variant with CNS involvement named combined central and peripheral demyelination (CCPD)Currently there is one special variant in which the CNS is also affected. It is termed "combined central and peripheral demyelination" (CCPD) and is special because it belongs at the same time to the CDIP syndrome and to the multiple sclerosis spectrum. These cases seem to be related to the presence of anti-neurofascin autoantibodies.
Causes
Chronic inflammatory demyelinating polyneuropathy (or polyradiculoneuropathy) is considered an autoimmune disorder destroying myelin, the protective covering of the nerves. Typical early symptoms are "tingling" (sort of electrified vibration or paresthesia) or numbness in the extremities, frequent (night) leg cramps, loss of reflexes (in knees), muscle fasciculations, "vibration" feelings, loss of balance, general muscle cramping and nerve pain. CIDP is extremely rare but under-recognized and under-treated due to its heterogeneous presentation (both clinical and electrophysiological) and the limitations of clinical, serologic, and electrophysiologic diagnostic criteria. Despite these limitations, early diagnosis and treatment is favoured in preventing irreversible axonal loss and improving functional recovery.There is a lack of awareness and treatment of CIDP. Although there are stringent research criteria for selecting patients for clinical trials, there are no generally agreed-upon clinical diagnostic criteria for CIDP due to its different presentations in symptoms and objective data. Application of the present research criteria to routine clinical practice often misses the diagnosis in a majority of patients, and patients are often left untreated despite progression of their disease.CIDP has been associated with diabetes mellitus, HIV infection, and paraproteinemias.
Variants with paranodal autoantibodies
Some variants of CIDP present autoimmunity against proteins of the node of Ranvier. These variants comprise a subgroup of inflammatory neuropathies with IgG4 autoantibodies against the paranodal proteins neurofascin-155, contactin-1 and caspr-1.These cases are special not only because of their pathology, but also because they are non-responsive to the standard treatment. They are responsive to Rituximab instead.Also some cases of combined central and peripheral demyelination (CCPD) could be produced by neurofascins.
Autoantibodies of the IgG3 Subclass in CIDP
Autoantibodies to components of the Ranvier nodes, specially autoantibodies the Contactin-associated protein 1 (CASPR), cause a form of CIDP with an acute "Guillain-Barre-like" phase, followed by a chronic phase with progressive symptoms. Different IgG subclasses are associated with the different phases of the disease. IgG3 Caspr autoantibodies were found during the acute GBS-like phase, while IgG4 Caspr autoantibodies were present during the chronic phase of disease.
Diagnosis and symptoms
Diagnosis is typically made on the basis of presenting symptoms in tandem with electrodiagnostic testing or a nerve biopsy. Doctors may use a lumbar puncture to verify the presence of increased cerebrospinal fluid protein.
Differential diagnosis
CIBP variants are among several types of immune-mediated neuropathies recognised. These include:
Chronic inflammatory demyelinating polyneuropathy (CIDP) with subtypes:
Classical CIDP
CIDP with diabetes
CIDP/monoclonal gammopathy of undetermined significance
Sensory CIDP
Multifocal motor neuropathy
Multifocal acquired demyelinating sensory and motor neuropathy (Lewis-Sumner syndrome)
Multifocal acquired sensory and motor neuropathy
Distal acquired demyelinating sensory neuropathy
Guillain–Barré syndrome with subtypes:
Acute inflammatory demyelinating polyradiculoneuropathy
Acute motor axonal neuropathy
Acute motor and sensory axonal neuropathy
Acute pandysautonomia
Miller Fisher syndrome
IgM monoclonal gammopathies with subtypes:
Waldenströms macroglobulinemia
Mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome
Myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome (POEMS)Other possible diagnoses are
Bickerstaff brainstem encephalitis
Fisher syndrome
Guillain–Barré syndromeFor this reason a diagnosis of chronic inflammatory demyelinating polyneuropathy needs further investigations. The diagnosis is usually provisionally made through a clinical neurological examination.
Symptoms
Symptoms such as diminished or absent deep-tendon reflexes and sensory ataxia are common. Other symptoms include proximal and distal muscle weakness in the limbs.Patients usually present with a history of weakness, numbness, tingling, pain and difficulty in walking. They may additionally present with fainting spells while standing up or burning pain in extremities. Some patients may have sudden onset of back pain or neck pain radiating down the extremities, usually diagnosed as radicular pain. These symptoms are usually progressive and may be intermittent.Autonomic system dysfunction can occur; in such a case, the patient would complain of orthostatic dizziness, problems breathing, eye, bowel, bladder and cardiac problems. The patient may also present with a single cranial nerve or peripheral nerve dysfunction.On examination the patients may have weakness, and loss of deep tendon reflexes (rarely increased or normal). There may be atrophy (shrinkage) of muscles, fasciculations (twitching) and loss of sensation. Patients may have multi-focal motor neuropathy, as they have no sensory loss.Most experts consider the necessary duration of symptoms to be greater than 8 weeks for the diagnosis of CIDP to be made.
Fatigue has been identified as common in CIDP patients, but it is unclear how much this is due to primary (due to the disease action on the body) or secondary effects (impacts on the whole person of being ill with CIDP).
Tests
Typical diagnostic tests include:
Electrodiagnostics – electromyography (EMG) and nerve conduction study (NCS). In usual CIDP, the nerve conduction studies show demyelination. These findings include:a reduction in nerve conduction velocities;
the presence of conduction block or abnormal temporal dispersion in at least one motor nerve;
prolonged distal latencies in at least two nerves;
absent F waves or prolonged minimum F wave latencies in at least two motor nerves. (In some case EMG/NCV can be normal).
Serum test to exclude other autoimmune diseases.
Lumbar puncture and serum test for anti-ganglioside antibodies. These antibodies are present in the branch of CIDP diseases comprised by anti-GM1, anti-GD1a, and anti-GQ1b.
Sural nerve biopsy; biopsy is considered for those patients in whom the diagnosis is not completely clear, when other causes of neuropathy (e.g., hereditary, vasculitic) cannot be excluded, or when profound axonal involvement is observed on EMG.
Ultrasound of the peripheral nerves may show swelling of the affected nerves.
Magnetic resonance imaging can also be used in the diagnostic workup.In some cases electrophysiological studies fail to show any evidence of demyelination. Though conventional electrophysiological diagnostic criteria are not met, the patient may still respond to immunomodulatory treatments. In such cases, presence of clinical characteristics suggestive of CIDP are critical, justifying full investigations, including sural nerve biopsy.
Treatment
First-line treatment for CIDP is currently intravenous immunoglobulin and other treatments include corticosteroids (e.g., prednisone), and plasmapheresis (plasma exchange) which may be prescribed alone or in combination with an immunosuppressant drug. Recent controlled studies show subcutaneous immunoglobulin appears to be as effective for CIDP treatment as intravenous immunoglobulin in most patients, and with fewer systemic side effects.Intravenous immunoglobulin and plasmapheresis have proven benefit in randomized, double-blind, placebo-controlled trials. Despite less definitive published evidence of efficacy, corticosteroids are considered standard therapies because of their long history of use and cost effectiveness. Intravenous immunoglobulin is probably the first-line CIDP treatment, but is extremely expensive. For example, in the U.S., a single 65 g dose of Gamunex brand in 2010 might be billed at the rate of $8,000 just for the immunoglobulin—not including other charges such as nurse administration.Immunosuppressive drugs are often of the cytotoxic (chemotherapy) class, including rituximab (Rituxan) which targets B cells, and cyclophosphamide, a drug which reduces the function of the immune system. Ciclosporin has also been used in CIDP but with less frequency as it is a newer approach. Ciclosporin is thought to bind to immunocompetent lymphocytes, especially T-lymphocytes.Non-cytotoxic immunosuppressive treatments usually include the anti-rejection transplant drugs azathioprine (Imuran/Azoran) and mycophenolate mofetil (Cellcept). In the U.S., these drugs are used "off-label", meaning that they do not have an indication for the treatment of CIDP in their package inserts. Before azathioprine is used, the patient should first have a blood test that ensures that azathioprine can safely be used.Anti-thymocyte globulin, an immunosuppressive agent that selectively destroys T lymphocytes is being studied for use in CIDP. Anti-thymocyte globulin is the gamma globulin fraction of antiserum from animals that have been immunized against human thymocytes. It is a polyclonal antibody. Although chemotherapeutic and immunosuppressive agents have shown to be effective in treating CIDP, significant evidence is lacking, mostly due to the heterogeneous nature of the disease in the patient population in addition to the lack of controlled trials.A review of several treatments found that azathioprine, interferon alpha and methotrexate were not effective. Cyclophosphamide and rituximab seem to have some response. Mycophenolate mofetil may be of use in milder cases. Immunoglobulin and steroids are the first line choices for treatment.In severe cases of CIDP, when second-line immunomodulatory drugs are not efficient, autologous hematopoietic stem cell transplantation is sometimes performed. The treatment may induce long-term remission even in severe treatment-refractory cases of CIDP. To improve outcome, it has been suggested that it should be initiated before irreversible axonal damage has occurred. However, a precise estimation of its clinical efficacy for CIDP is not available, as randomized controlled trials have not been performed.Physical therapy and occupational therapy may improve muscle strength, activities of daily living, mobility, and minimize the shrinkage of muscles and tendons and distortions of the joints.
Prognosis
As in multiple sclerosis, another demyelinating condition, it is not possible to predict with certainty how CIDP will affect patients over time. The pattern of relapses and remissions varies greatly with each patient. A period of relapse can be very disturbing, but many patients make significant recoveries.If diagnosed early, initiation of early treatment to prevent loss of nerve axons is recommended. However, many individuals are left with residual numbness, weakness, tremors, fatigue and other symptoms which can lead to long-term morbidity and diminished quality of life.It is important to build a good relationship with doctors, both primary care and specialist. Because of the rarity of the illness, many doctors will not have encountered it before. Each case of CIDP is different, and relapses, if they occur, may bring new symptoms and problems. Because of the variability in severity and progression of the disease, doctors will not be able to give a definite prognosis. A period of experimentation with different treatment regimens is likely to be necessary in order to discover the most appropriate treatment regimen for a given patient.
Epidemiology
In 1982 Lewis et al. reported a group of patients with a chronic asymmetrical sensorimotor neuropathy mostly affecting the arms with multifocal involvement of peripheral nerves. Also in 1982 Dyck et al reported a response to prednisolone to a condition they referred to as chronic inflammatory demyelinating polyradiculoneuropathy. Parry and Clarke in 1988 described a neuropathy which was later found to be associated with IgM autoantibodies directed against GM1 gangliosides. This latter condition was later termed multifocal motor neuropathy This distinction is important because multifocal motor neuropathy responds to intravenous immunoglobulin alone, while chronic inflammatory demyelinating polyneuropathy responds to intravenous immunoglobulin, steroids and plasma exchange. It has been suggested that multifocal motor neuropathy is distinct from chronic inflammatory demyelinating polyneuropathy and that Lewis-Sumner syndrome is a distinct variant type of chronic inflammatory demyelinating polyneuropathy.The Lewis-Sumner form of this condition is considered a rare disease with only 50 cases reported up to 2004. A total of 90 cases had been reported by 2009.
Vaccine injury compensation for CIDP
The National Vaccine Injury Compensation Program has awarded money damages to patients who came down with CIDP after receiving one of the childhood vaccines listed on the Federal Governments vaccine injury table. These Vaccine Court awards often come with language stating that the Court denies that the specific vaccine "caused petitioner to suffer CIDP or any other injury. Nevertheless, the parties agree to the joint stipulation, attached hereto as Appendix A. The undersigned finds said stipulation reasonable and adopts it as the decision of the Court in awarding damages, on the terms set forth therein." A keyword search on the Court of Federal Claims "Opinions/Orders" database for the term "CIDP" returns 202 opinions related to CIDP and vaccine injury compensation.
See also
Autoimmune disease
Neurology
References
External links
CIDP at NINDS
CIDP at GBS|CIDP Foundation International |
Postoperative cognitive dysfunction | Postoperative cognitive dysfunction (POCD) is a decline in cognitive function (especially in memory and executive functions) that may last from 1–12 months after surgery, or longer. In some cases, this disorder may persist for several years after major surgery. POCD is distinct from emergence delirium. Its causes are under investigation and occurs commonly in older patients and those with pre-existing cognitive impairment.The causes of POCD are not understood. It does not appear to be caused by lack of oxygen or impaired blood flow to the brain and is equally likely under regional and general anesthesia. It may be mediated by the bodys inflammatory response to surgery.
Causes
The bodys inflammatory response to surgery likely plays an important role, at least in elderly patients. Various research initiatives during recent years have evaluated whether actions taken before, during and after surgery can lessen the possible deleterious effects of inflammation. For example, anti-inflammatory agents can be given before surgery. During surgery, inflammation can be modulated by temperature control, use of regional rather than general anesthesia or the use of beta blockers. After surgery, optimal pain management and infection control is important. Several studies have shown variable-significance positive effects when a multidisciplinary, multifactorial approach to elderly patient is followed during pre, peri and post-operative care.A Cochrane review explored whether inhalation anaesthetics or intravenous anaesthetics were more likely to cause POCD when used in the elderly for non-cardiac surgery. Seven studies (869 participants) included in the review led to the conclusion that fewer people experienced POCD with total intravenous anaesthesia (TIVA) compared to inhalational anaesthesia. The conclusions, however, rated "low" on GRADE scoring (confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect).
Assessment
Cognitive tests are given prior to operations to establish a baseline. The same tests are again given post-operatively to determine the extent and duration of the decline for POCD. "A project examining adults 55 and older who have major non-cardiac surgeries is finding that upward of 30 percent of patients is testing significantly worse than their baseline 3 months later".
Epidemiology
POCD is common after cardiac surgery, and recent studies have now verified that POCD also exists after major non-cardiac surgery, although at a lower incidence. The risk of POCD increases with age, and the type of surgery is also important because there is a very low incidence associated with minor surgery. POCD is common in adult patients of all ages at hospital discharge after major noncardiac surgery, but only the elderly (aged 60 years or older) are at significant risk for long-term cognitive problems. Patients with POCD are at an increased risk of death in the first year after surgery. Research interest has increased since early 2000, especially as more elderly patients are able to undergo successful minor and major surgeries.POCD has been studied through various institutions since the inception of the IPOCDS-I study centred in Eindhoven, Netherlands and Copenhagen, Denmark. This study found no causal relationship between cerebral hypoxia and low blood pressure and POCD. Age, duration of anaesthesia, introperative complications, and postoperative infections were found to be associated with POCD.
POCD is just as likely to occur after operations under regional anesthesia as under general anesthesia.
More likely after major operations than minor operations.
More likely after heart operations than other types of surgery.
More likely in aged than in younger patients.
More likely in older patients with high alcohol intake.
People with higher preoperative ASA physical status scores are more likely to develop POCD.
People with lower educational level are more likely to develop POCD than those with a higher educational level.
People with prior history of a stroke, even though there is complete functional recovery, are more likely to develop POCD.
More likely in the elderly with pre-existing declining mental functions, termed mild cognitive impairment (MCI). MCI is a transitional zone between normal mental function and evident Alzheimers disease or other forms of dementia. It is insidious, and seldom recognized, except in retrospect after affected persons are evidently demented.
Delirium and severe worsening of mental function is very likely in those with clinically evident Alzheimers disease or other forms of dementia, as well as those with a history of delirium after previous operations.
Footnotes
Further reading
"Postoperative cognitive dysfunction" (PDF). {{cite journal}}: Cite journal requires |journal= (help)
Muñoz-Corsini L, Gómez-Arnau J, Porras MC, Galindo S, Jiménez R (May 1997). "Postoperative cognitive dysfunction". Rev Esp Anestesiol Reanim. 44 (5): 191–200. PMID 9280997.
Crosby, Gregory; Culley, Deborah J. (2011). "Surgery and anesthesia: healing the body but harming the brain?". Anesthesia & Analgesia. 112 (5): 999–1001. doi:10.1213/ANE.0b013e3182160431. PMC 3092153. PMID 21515644.
Rasmussen, L. S. (November 1998). "Defining postoperative cognitive dysfunction". European Journal of Anaesthesiology. 15 (6): 761–764. doi:10.1097/00003643-199811000-00026. PMID 9884870.
Deiner, S.; Silverstein, J.H. (2009). "Postoperative delirium and cognitive dysfunction". British Journal of Anaesthesia. 103: i41–i46. doi:10.1093/bja/aep291. PMC 2791855. PMID 20007989.
External links
International Study of Post-Operative Cognitive Dysfunction (ISPOCD) |
Pneumoretroperitoneum | Pneumoretroperitoneum is the presence of air in the retroperitoneum. It is always a pathological condition and can be caused by a perforation of a retroperitoneal hollow organ such as the duodenum, colon or rectum. Pneumoretroperitoneum can best be identified by CT scan.
See also
Pneumoperitoneum
== References == |
Self-healing juvenile cutaneous mucinosis | Self-healing juvenile cutaneous mucinosis is a skin condition caused by fibroblasts producing abnormally large amounts of mucopolysaccharides, and is characterized by the sudden onset of skin lesions and polyarthritis.: 185
See also
Lichen myxedematosus
Skin lesion
References
== External links == |
Warthins tumor | Warthins tumor, also known as papillary cystadenoma lymphomatosum, is a benign cystic tumor of the salivary glands containing abundant lymphocytes and germinal centers (lymph node-like stroma). It is named for pathologist Aldred Scott Warthin, who described two cases in 1929.
Signs and symptoms
Warthins tumor primarily affects older individuals (age 60–70 years). There is a slight male predilection according to recent studies. The tumor is slow growing, painless, and usually appears in the tail of the parotid gland near the angle of the mandible. In 5–14% of cases, Warthins tumor is bilateral, but the two masses usually are at different times. Warthins tumor is highly unlikely to become malignant.
Locations
The gland most likely affected is the parotid gland. In fact, it is the only tumor virtually restricted to the parotid gland. Warthins tumor is the second most common benign parotid tumor after pleomorphic adenoma, but its prevalence is steadily increasing.
Cause
Its cause is unknown, but there is a strong association with cigarette smoking. Smokers are at 8 times greater risk of developing Warthins tumor than the general population.
Diagnosis
The appearance of this tumor under the microscope is unique. There are cystic spaces surrounded by two uniform rows of oncocytes, which are epithelial cells with abundant, granular, eosinophilic cytoplasm. The cystic spaces have epithelium referred to as papillary infoldings that protrude into them. Additionally, the epithelium has lymphoid stroma with germinal center formation.The differential diagnosis includes sebaceous lymphadenoma and oncocytoma.
Treatment
Most of these tumors are treated with surgical removal called parotidectomy. Contrary to pleomorphic adenoma, it is non recurrent.
See also
Pleomorphic adenoma
References
Additional sources
Kahn, Michael A. Basic Oral and Maxillofacial Pathology. Volume 1. 2001.
== External links == |
Pleuropulmonary blastoma | Pleuropulmonary blastoma (PPB) is a rare cancer originating in the lung or pleural cavity. It occurs most often in infants and young children but also has been reported in adults. In a retrospective review of 204 children with lung tumors, pleuropulmonary blastoma and carcinoid tumor were the most common primary tumors (83% of the 204 children had secondary tumors spread from cancers elsewhere in the body). Pleuropulmonary blastoma is regarded as malignant. The male:female ratio is approximately one.
Signs and symptoms
Symptoms may include coughing, an upper respiratory tract infection, shortness of breath, and chest pain. These symptoms are very non-specific, and can be caused by other types of tumor in the lung or mediastinum more generally, and by other conditions. Imaging (X-ray, CT, MRI) may be used to determine the presence and precise location of a tumor, but not a specific diagnosis of PPB or other tumor.
Doctors are unable to tell if a child has PPB right away, and not upper respiratory tract infection, until more test are taken and they show that there is no infection. Another symptom is pneumothorax.
Genetics
A number of PPBs have shown trisomy 8 (17 out of 23 cases studied per the PPB registry). Trisomy 2 and p53 mutations/deletions have also been described.An association with mutations in the DICER1 gene has been reported. Mutations in this gene are found in 2/3 cases.
Diagnosis
The most common way to test someone for PPB is to take a biopsy. Other tests like x-rays, CAT scans, and MRIs can suggest that cancer is present, but only an examination of a piece of the tumor can make a definite diagnosis.
Types
Pleuropulmonary blastoma is classified into 3 types:
Type I is multicystic
Type II shows thickening areas (nodules) within this cystic lesion
Type III shows solid masses.Type I PPB is made up of mostly cysts, and may be hard to distinguish from benign lung cysts, and there is some evidence that not all type I PPB will progress to types II and III. Types II and III are aggressive, and cerebral metastasis is more frequent in PPB than in other childhood sarcomas.
Treatment
Treating PPB depends on the size and location of the tumor, whether the cancer has spread, and the childs overall health. Surgery is the main treatment for PPB. The main goal of surgery is to remove the tumor. If the tumor is too large to be completely removed, or if its not possible to completely remove the tumor, surgery may be performed after chemotherapy. Because PPB can return after treatment, regular screening for possible recurrence should continue for 48 to 60 months, after diagnosis.
History
Pleuropulmonary blastoma was first described in 1988.An international registry has been established.
See also
Lung cancer
References
== External links == |
Susto | Susto (Spanish pronunciation: [ˈsusto], Portuguese pronunciation: [ˈsuʃtu]) is a cultural illness primarily among Latin American cultures. It is described as a condition of "chronic somatic suffering stemming from emotional trauma or from witnessing traumatic experiences lived by others".
Symptoms
Among the indigenous peoples of Latin America, in which this illness is most common, susto may be conceptualized as a case of spirit attack. Symptoms of susto are thought to include nervousness, anorexia, insomnia, listlessness, fever, depression, and diarrhea.
Treatment
Treatments among indigenous people are natural. Some natural treatments to susto consist of using plants as medicine; sweating out the toxins; and massaging to encourage blood flow. Prayer is a big part of the treatment of susto. In addition to prayer, healing rituals are also used, some of which include sweeping and giving gifts.
Classification
Susto may be a culturally dependent variation of the symptoms of a panic attack, which is distinct from anxiety and depressive disorders.
See also
Psychological trauma
References
Further reading
Rubel, Arthur J (July 1964). "The Epidemiology of a Folk Illness: Susto in Hispanic America". Ethnology. 3 (3): 268–283. doi:10.2307/3772883. JSTOR 3772883. Also published as Chapter 12 in Landy, David, ed. (1977). Culture, Disease, and Healing: Studies in Medical Anthropology. New York: Macmillan Press. ISBN 0-02-367390-7.
Susto: The context of community morbidity patterns
Rubel, Arthur J; ONell, Carl W; Collado-Ardon, Rolando (1991). Susto A Folk Illness. University of California Press. ISBN 9780520076341.
ONeil, Dennis. "Explanations of Illness". Medical Anthropology. ONeil. Retrieved 6 March 2013. |
Drug-induced pigmentation | Drug induced pigmentation may take on many different appearances, one of the most common being a change in the color, or pigmentation, of the skin.
Presentation
Cause
Drug-induced pigmentation of the skin may occur as a consequence of drug administration, and the mechanism may be postinflammatory hyperpigmentation in some cases, but frequently is related to actual deposition of the offending drug in the skin.: 125–6 The incidence of this change varies, and depends on the type of medication involved. Some of the most common drugs involved are NSAIDs, antimalarials, psychotropic drugs, Amiodarone, cytotoxic drugs, tetracyclines, and heavy metals such as silver and gold (which must be ingested, not just worn).
Pathophysiology
There are 4 possible mechanisms to how this change may occur:
Accumulation of melanin, the skin pigment
Accumulation of drug or one of its products under any layer of the skin (usually the dermis or epidermis)
Accumulation of iron throughout the dermis from drug-induced post-inflammatory changes
The synthesis of special pigments, under direct influence of the drug
See also
Skin lesion
References
== External links == |
Colles fracture | A Colles fracture is a type of fracture of the distal forearm in which the broken end of the radius is bent backwards. Symptoms may include pain, swelling, deformity, and bruising. Complications may include damage to the median nerve.It typically occurs as a result of a fall on an outstretched hand. Risk factors include osteoporosis. The diagnosis may be confirmed via X-rays. The tip of the ulna may also be broken.Treatment may include casting or surgery. Surgical reduction and casting is possible in the majority of cases in people over the age of 50. Pain management can be achieved during the reduction with procedural sedation and analgesia or a hematoma block. A year or two may be required for healing to occur.About 15% of people have a Colles fracture at some point in their life. They occur more commonly in young adults and older people than in children and middle-aged adults. Women are more frequently affected than men. The fracture is named after Abraham Colles who described it in 1814.
Causes
The fracture is most commonly caused by people falling onto a hard surface and breaking their fall with outstretched hand (FOOSH)–falling with wrists flexed would lead to a Smiths fracture. Originally it was described in elderly and/or post-menopausal women. It usually occurs about three to five centimetres proximal to the radio-carpal joint with posterior and lateral displacement of the distal fragment resulting in the characteristic "dinner fork" or "bayonet" like deformity. Colles fracture is a common fracture in people with osteoporosis, second only to vertebral fractures.
Diagnosis
Diagnosis can be made upon interpretation of anteroposterior and lateral views alone.The classic Colles fracture has the following characteristics:
Transverse fracture of the radius
2.5 cm (0.98 inches) proximal to the radio-carpal joint
dorsal displacement and dorsal angulation, together with radial tiltOther characteristics:
Radial shortening
Loss of ulnar inclination≤
Radial angulation of the wrist
Comminution at the fracture site
Associated fracture of the ulnar styloid process in more than 60% of cases.
Classification
The term Colles fracture is classically used to describe a fracture at the distal end of the radius, at its cortico-cancellous junction. However, the term now tends to be used loosely to describe any fracture of the distal radius, with or without involvement of the ulna, that has dorsal displacement of the fracture fragments. Colles himself described it as a fracture that “takes place at about an inch and a half (38mm) above the carpal extremity of the radius” and “the carpus and the base of metacarpus appears to be thrown backward”. The fracture is sometimes referred to as a "dinner fork" or "bayonet" deformity due to the shape of the resultant forearm.Colles fractures can be categorized according to several systems including Frykman, Gartland & Werley, Lidström, Nissen-Lie and the Olders classifications.
Treatment
Management depends on the severity of the fracture. An undisplaced fracture may be treated with a cast alone. The cast is applied with the distal fragment in palmar flexion and ulnar deviation. A fracture with mild angulation and displacement may require closed reduction. There is some evidence that immobilization with the wrist in dorsiflexion as opposed to palmarflexion results in less redisplacement and better functional status. Significant angulation and deformity may require an open reduction and internal fixation or external fixation. The volar forearm splint is best for temporary immobilization of forearm, wrist and hand fractures, including Colles fracture.
There are several established instability criteria:
dorsal tilt >20°,
comminuted fracture,
abruption of the ulnar styloid process,
intraarticular displacement >1mm,
loss of radial height >2mm.
A higher amount of instability criteria increases the likelihood of operative treatment.
Treatment modalities differ in the elderly.Repeat Xrays are recommended at one, two, and six weeks to verify proper healing.
Prognosis
Recovery time depends on the degree of bone displacement, the number of bone fragments, whether or not the break is "intra-articular" (involves the wrist joint), as well as the persons age, gender, and medical history, and may range from two months to a year or more for complete recovery.
Epidemiology
Colles fractures occur in all age groups, although certain patterns follow an age distribution.
In the elderly, because of the weaker cortex, the fracture is more often extra-articular.
Younger individuals tend to require a higher energy force to cause the fracture and tend to have more complex intra-articular fractures. In children with open epiphyses, an equivalent fracture is the "epiphyseal slip", as can be seen in other joints, such as a slipped capital femoral epiphysis in the hip. This is a Salter I or II fracture with the deforming forces directed through the weaker epiphyseal plate.
More common in women because of post-menopausal osteoporosis.
History
The Colles fracture is named after Abraham Colles (1773–1843), an Irish surgeon, from Kilkenny who first described it in 1814 by simply looking at the classic deformity before the advent of X-rays. Ernest Amory Codman was the first to study it using X-rays. His article, published in the Boston Medical and Surgical Journal, now known as The New England Journal of Medicine, also developed the classification system.It is sometimes said that Claude Pouteau was the first to describe the Colles fracture (which is sometimes called the Pouteau-Colles fracture), but, according to P. Liverneaux, it is not the case.
See also
Smiths fracture
References
External links
00913 at CHORUSColles Fracture Wheeless Textbook |
Self-defeating personality disorder | Self-defeating personality disorder (also known as masochistic personality disorder) was a proposed personality disorder. As a descriptor for Other personality disorder it was mentioned in the DSM-III in 1980. It was discussed in an appendix of the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) in 1987, but was never formally admitted into the manual. Because of its significant overlap with other personality disorders (borderline, avoidant and dependent) the distinction was not seen as clinically valuable. It was entirely excluded from the DSM-IV. Since the DSM-5, the diagnoses other specified personality disorder and unspecified personality disorder have mostly replaced its use.
Diagnosis
Definition proposed in DSM III-R for further review
Self-defeating personality disorder is:
A) A pervasive pattern of self-defeating behavior, beginning by early adulthood and present in a variety of contexts. The person may often avoid or undermine pleasurable experiences, be drawn to situations or relationships in which they will suffer, and prevent others from helping them, as indicated by at least five of the following:chooses people and situations that lead to disappointment, failure, or mistreatment even when better options are clearly available
rejects or makes ineffective the attempts of others to help them
following positive personal events (e.g., new achievement), responds with depression, guilt, or a behavior that produces pain (e.g., an accident)
incites angry or rejecting responses from others and then feels hurt, defeated, or humiliated (e.g., makes fun of spouse in public, provoking an angry retort, then feels devastated)
rejects opportunities for pleasure, or is reluctant to acknowledge enjoying themselves (despite having adequate social skills and the capacity for pleasure)
fails to accomplish tasks crucial to their personal objectives despite having demonstrated ability to do so (e.g., helps fellow students write papers, but is unable to write their own)
is uninterested in or rejects people who consistently treat them well
engages in excessive self-sacrifice that is unsolicited by the intended recipients of the sacrifice
The person may often avoid or undermine pleasurable experiences [...][and] rejects opportunities for pleasure, or is reluctant to acknowledge enjoying themself
B) The behaviors in A do not occur exclusively in response to, or in anticipation of, being physically, sexually, or psychologically abused.C) The behaviors in A do not occur only when the person is depressed.
Exclusion from DSM-IV
Historically, masochism has been associated with feminine submissiveness. This disorder became politically controversial when associated with domestic violence which was considered to be mostly caused by males. However a number of studies suggest that the disorder is common. In spite of its exclusion from DSM-IV in 1994, it continues to enjoy widespread currency amongst clinicians as a construct that explains a great many facets of human behaviour.Sexual masochism that "causes clinically significant distress or impairment in social, occupational, or other important areas of functioning" is still in DSM-IV.
Millons subtypes
Theodore Millon has proposed four subtypes of masochist. Any individual masochist may fit into none, one or more of the following subtypes:
See also
Sadistic personality disorder
Self-handicapping
Self-preservation
Setting up to fail
Autosadism
Algolagnia
Learned helplessness
Notes
References
External links
http://www.psychnet-uk.com/x_new_site/personality_psychology/personality_disorders_self_defeating.html
https://www.scribd.com/doc/55533833/The-Riddle-of-Masochism |
Fitz-Hugh–Curtis syndrome | Fitz-Hugh–Curtis syndrome is a rare complication of pelvic inflammatory disease (PID) involving liver capsule inflammation leading to the creation of adhesions. The condition is named after the two physicians, Thomas Fitz-Hugh, Jr and Arthur Hale Curtis who first reported this condition in 1934 and 1930 respectively.
Signs and symptoms
The major symptom and signs include an acute onset of right upper quadrant (RUQ) abdominal pain aggravated by breathing, coughing or laughing, which may be referred to the right shoulder. There is usually also tenderness on palpation of the right upper abdomen and tenderness to percussion of the lower ribs which protect the liver. Surprisingly there is often no or only minimal pelvic pain, vaginal discharge or cervical motion tenderness, which may lead to the diagnosis being missed. This may be due to infectious bacteria bypassing pelvic structures on the way to the liver capsule.
Pathophysiology
Fitz-Hugh–Curtis syndrome occurs almost exclusively in women. It is usually caused by Chlamydia trachomatis (Chlamydia) or Neisseria gonorrhoeae (Gonorrhea) though other bacteria such as Bacteroides, Gardnerella, E. coli and Streptococcus have also been found to cause Fitz-Hugh-Curtis syndrome on occasion. These bacterial pathogens cause a thinning of cervical mucus and allow bacteria from the vagina into the uterus and fallopian tubes, causing infection and inflammation. Occasionally, this inflammation can cause scar tissue to form on Glissons capsule, a thin layer of connective tissue surrounding the liver.(Bailey&Love)
Diagnosis
Abdominal ultrasound will typically be normal. Liver function tests will typically be normal or unchanged from baseline as the infection does not involve the liver parenchyma. If a D-dimer is ordered, which it often is when there is pleuritic torso pain, it will usually be markedly elevated but other testing for pulmonary embolism will be normal. CT of the abdomen with IV contrast may show subtle enhancement of the liver capsule, but this may be missed by radiologists if they are not advised to look for it. Testing for gonorrhea and chlamydia should be performed to make the diagnosis. An endocervical or low vaginal swab should be taken to test for these organisms. Antibody testing is rarely required but may be considered if other tests are non-diagnostic and suspicion is high.Laparoscopy is also rarely required, but may be performed when the diagnosis is uncertain and may reveal "guitar string" adhesions of parietal peritoneum to liver.
Treatment
Treatment involves a course of antibiotics to cover the appropriate organisms, typically ceftriaxone plus azithromycin. Laparoscopy for lysis of adhesions may be performed for refractory pain.
References
Further reading
Pregerson, Brady (2010). Quick Essentials: Emergency Medicine (4th ed.). ISBN 978-0-9761552-3-2.
Pregerson, D. Brady (2012). Tarascon Emergency Department Quick Reference Guide. Jones & Bartlett. ISBN 978-0-7637-8789-9.
== External links == |
Ornithine transcarbamylase deficiency | Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder is the final enzyme in the proximal portion of the urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.
In severely affected individuals, ammonia concentrations increase rapidly causing ataxia, lethargy and death without rapid intervention. OTC deficiency is diagnosed using a combination of clinical findings and biochemical testing, while confirmation is often done using molecular genetics techniques.
Once an individual has been diagnosed, the treatment goal is to avoid precipitating episodes that can cause an increased ammonia concentration. The most common treatment combines a low protein diet with nitrogen scavenging agents. Liver transplant is considered curative for this disease. Experimental trials of gene therapy using adenoviral vectors resulted in the death of one participant, Jesse Gelsinger, and have been discontinued.
Signs and symptoms
As with several other metabolic conditions, OTC deficiency can have variable presentations, regarding age of onset and the severity of symptoms. This compounded when considering heterozygous females and the possibility of non-random X-inactivation. In the classic and most well-known presentation, a male infant appears well initially, but by the second day of life they are irritable, lethargic and stop feeding. A metabolic encephalopathy develops, and this can progress to coma and death without treatment. Ammonia is only toxic to the brain, other tissues can handle elevated ammonia concentrations without problems.Later onset forms of OTC deficiency can have variable presentations. Although late onset forms of the disease are often considered milder than the classic infantile presentation, any affected individual is at risk for an episode of hyperammonemia that could still be life-threatening, if presented with the appropriate stressors. These patients will often present with headaches, nausea, vomiting, delayed growth and a variety of psychiatric symptoms (confusion, delirium, aggression, or self-injury). A detailed dietary history of an affected individual with undiagnosed OTC deficiency will often reveal a history of protein avoidance.The prognosis of a patient with severe OTC deficiency is well correlated with the length of the hyperammonemic period rather than the degree of hyperammonemia or the presence of other symptoms, such as seizures. Even for patients with late onset forms of the disease, their overall clinical picture is dependent on the extent of hyperammonemia they have experienced, even if it has remained unrecognized.
Genetics
OTC deficiency is caused by mutations in the OTC gene, which is located on the X chromosome. OTC codes for the mitochondrial enzyme ornithine transcarbamylase, which is expressed only in liver. The functional enzyme consists of three identical subunits. OTC is the last enzyme in the proximal portion of the urea cycle, which consists of the reactions that take place in the mitochondria. The substrates of the reaction catalyzed by ornithine transcarbamylase are ornithine and carbamyl phosphate, while the product is citrulline.There are no common mutations that cause disease, however 10 - 15% of disease causing mutations are deletions. It is inherited in an X-linked recessive manner, meaning males are more commonly affected than females. Females who carry a defective copy of the gene can be severely affected or asymptomatic, largely depending on the random nature of X-inactivation. There is some degree of genotype - phenotype correlation with OTC deficiency, but this depends on a number of situations. Individuals with milder mutations, often associated with late onset disease can still present with severe illness when exposed to sufficient metabolic stress. Correlations are more difficult to ascertain in females, since the residual activity of OTC in the liver is impacted not only by the nature of the mutation, but also by the random pattern of X-inactivation. OTC deficiency is estimated to be the most common urea cycle disorder. An exact incidence is difficult to calculate, due to the varying clinical presentations of later onset forms of the disease. Early estimates of the incidence were as high as 1:14,000 live births, however later studies have decreased these estimates to approximately 1:60,000 - 1:72,000.
Diagnosis
In individuals with marked hyperammonemia, a urea cycle disorder is usually high on the list of possible causes. While the immediate focus is lowering the patients ammonia concentrations, identifying the specific cause of increased ammonia levels is key as well.
Diagnostic testing for OTC deficiency, or any individual with hyperammonemia involves plasma and urine amino acid analysis, urine organic acid analysis (to identify the presence or absence of orotic acid, as well as rule out an organic acidemia) and plasma acylcarnitines (will be normal in OTC deficiency, but can identify some other causes of hyperammonemia). An individual with untreated OTC deficiency will show decreased citrulline and arginine concentrations (because the enzyme block is proximal to these intermediates) and increased orotic acid. The increased orotic acid concentrations result from the buildup of carbamoyl phosphate. This biochemical phenotype (increased ammonia, low citrulline and increased orotic acid) is classic for OTC deficiency, but can also be seen in neonatal presentations of ornithine aminotransferase deficiency. Only severely affected males consistently demonstrate this classic biochemical phenotype.
Heterozygous females can be difficult to diagnose. With the rise of sequencing techniques, molecular testing has become preferred, particularly when the disease causing mutations in the family are known. Historically, heterozygous females were often diagnosed using an allopurinol challenge. In a female with reduced enzyme activity, an oral dose of allopurinol would be metabolized to oxypurinol ribonucleotide, which blocks the pyrimidine biosynthetic pathway. When this induced enzymatic block is combined with reduced physiologic enzyme activity as seen in heterozygotes, the elevation of orotic acid could be used to differentiate heterozygotes from unaffected individuals. This test was not universally effective, as it had both false negative and false positive results.Ornithine transcarbamylase is only expressed in the liver, thus performing an enzyme assay to confirm the diagnosis requires a liver biopsy. Before molecular genetic testing was commonly available, this was one of the only methods for confirmation of a suspected diagnosis. In cases where prenatal diagnosis was requested, a fetal liver biopsy used to be required to confirm if a fetus was affected. Modern molecular techniques have eliminated this need, and gene sequencing is now the preferred method of diagnosis in asymptomatic family members after the diagnosis has been confirmed in a proband.
Treatment
The treatment goal for individuals affected with OTC deficiency is the avoidance of hyperammonemia. This can be accomplished through a strictly controlled low-protein diet, as well as preventative treatment with nitrogen scavenging agents such as sodium benzoate. The goal is to minimize the nitrogen intake while allowing waste nitrogen to be excreted by alternate pathways. Arginine is typically supplemented as well, in an effort to improve the overall function of the urea cycle. If a hyperammonemic episode occurs, the aim of treatment is to reduce the individuals ammonia levels as soon as possible. In extreme cases, this can involve hemodialysis.Gene therapy had been considered a possibility for curative treatment for OTC deficiency, and clinical trials were taking place at the University of Pennsylvania in the late 1990s. These were halted after the death of Jesse Gelsinger, a young man taking part in a phase I trial using an adenovirus vector. Currently, the only option for curing OTC deficiency is a liver transplant, which restores normal enzyme activity. A 2005 review of 51 patients with OTC deficiency who underwent liver transplant estimated 5-year survival rates of greater than 90%. Severe cases of OTC deficiency are typically evaluated for liver transplant by 6 months of age.
Prognosis
A 1999 retrospective study of 74 cases of neonatal onset found that 32 (43%) patients died during their first hyperammonemic episode. Of those who survived, less than 20% survived to age 14. Few of these patients received liver transplants.
References
External links
http://www.nucdf.orghttp://www.otcdeficiency.com |
Perifollicular fibroma | Perifollicular fibroma is a cutaneous condition, a benign tumor usually skin colored, most often affecting the face and upper trunk.: 674
See also
Birt–Hogg–Dubé syndrome
List of skin conditions
== References == |
Spinal muscular atrophy with lower extremity predominance | Spinal muscular atrophy with lower extremity predominance, sometimes called lower extremity-predominant spinal muscular atrophy, may refer to:
Spinal muscular atrophy with lower extremity predominance 1
Spinal muscular atrophy with lower extremity predominance 2A
Spinal muscular atrophy with lower extremity predominance 2B
See also
Spinal muscular atrophies |
Shunt nephritis | Shunt nephritis is a rare disease of the kidney that can occur in patients being treated for hydrocephalus with a cerebral shunt. It usually results from an infected shunt that produces a long-standing blood infection, particularly by the bacterium Staphylococcus epidermidis. Kidney disease results from an immune response that deposits immune complexes in the kidney. The most common signs and symptoms of the condition are blood and protein in the urine, anemia, and high blood pressure. Diagnosis is based on these findings in the context of characteristic laboratory values. Treatment includes antibiotics and the prompt removal of the infected shunt. Over half of individuals with shunt nephritis recover completely; most of the remainder have some degree of persistent kidney disease.
Presentation
The clinical presentation of shunt nephritis is variable, but the most common manifestations of shunt nephritis include blood in the urine, protein in the urine, anemia, and high blood pressure. Recurrent fever, enlarged liver and spleen, and a skin rash may also be present. Rarely, the major complaint may be arthritis.
Pathophysiology
Shunt nephritis occurs when a shunt becomes infected with bacteria, most commonly Staphylococcus epidermidis. Bacteria from this infected shunt seed the bloodstream, leading to blood infection (bacteremia). In response to long-standing infection (months to years), the body mounts an immune response that results in deposition of immune complexes in the kidney, leading to nephritis.
Diagnosis
Urinalysis typically demonstrates hematuria and proteinuria. Levels of the complement protein C3 are low, while levels of C-reactive protein and cryoglobulins may be modestly elevated. Blood cultures and cerebrospinal fluid cultures demonstrate Staphylococcus epidermidis, a coagulase-negative species of Staphylococcus. Biopsy of the kidney frequently demonstrates membranoproliferative glomerulonephritis, with deposits of C3, IgM, and IgG.
Treatment
Management is focused on removing the infectious source. The shunt is removed immediately and antibiotics are begun. The infected shunt, typically a ventriculoatrial shunt, may be replaced with a ventriculoperitoneal shunt.
Prognosis
In one review, over half of individuals with shunt nephritis made a complete recovery. An additional 40% of individuals had persistent urine abnormalities or end-stage renal disease. Death occurred in 9%.
Epidemiology
Shunt nephritis is a rare condition affecting males and females of all ages. It occurs in approximately 0.7-2.3% of patients with shunt infections. Approximately 12% of ventriculoatrial shunts become infected, with Staphylococcus epidermidis being the infectious agent in 75% of cases.
History
Shunt nephritis was first described by Black in 1965. Early cases and most cases since then are associated with infections of shunts that connect the ventricular system of the brain to the atria of the heart (ventriculoatrial shunts). Less commonly, shunt nephritis has been reported to arise from infections of shunts connecting the ventricular system to the abdominal cavity (ventriculoperitoneal shunts).
== References == |
Fountain syndrome | Fountain syndrome is an autosomal recessive congenital disorder characterized by mental retardation, deafness, skeletal abnormalities and a coarse face with full lips. The abnormal swelling of the cheeks and lips are due to the excessive accumulation of body fluids under the skin. The deafness is due to malformation of the cochlea structure within the inner ear.
Signs and symptoms
Cause
The exact cause of the disorder is unknown, but it is believed to be inherited in an autosomal recessive manner.
Diagnosis
Fountain syndrome is usually diagnosed in infancy or early childhood. It can be diagnosed by thorough clinical evaluation, characteristic physical findings, and specialized tests such as audiological tests and scans of the inner ear and brain.
Treatment
Unfortunately, there is not one specific treatment option that can rid a person of this syndrome. However, there are many routes one can take to make living with this disease a lot easier. For example, there are many treatment programs that doctors can specialize for patients and their needs. Meeting with a doctor is very crucial and these specializations can be very useful. Also, one can seek help from pediatricians, EENT doctors, audiologists, and orthopedists. Brace fittings, hearing aids, and physical therapy can also be pushed by ones doctor, so that a patient can live normally. Additionally, anticonvulsant drugs can be used to stop seizures.
References
Fountain RB (1974). "Familial bone abnormalities, deaf mutism, mental retardation and skin granuloma". Proc R Soc Med. 67 (9): 878–879. PMC 1645940. PMID 4431800.
Fryns JP (1989). "Fountains syndrome: mental retardation, sensorineural deafness, skeletal abnormalities, and coarse face with full lips". J Med Genet. 26 (11): 722–724. doi:10.1136/jmg.26.11.722. PMC 1015742. PMID 2585470.
Fryns JP, Dereymaeker A, Hoefnagels M, Van den Berghe H (1987). "Mental retardation, deafness, skeletal abnormalities, and coarse face with full lips: confirmation of the Fountain syndrome". Am J Med Genet. 26 (3): 551–555. doi:10.1002/ajmg.1320260307. PMID 3565469.
Dunkle Mary (1996). "Fountain Syndrome". NORD. Retrieved 26 April 2012.
"Fountain syndrome". Ailments.com. 2000. Retrieved 29 April 2012.
"Childrens Health:Fountain syndrome". WebMD. 2011. Retrieved 30 April 2012.
External links
Online Mendelian Inheritance in Man (OMIM): 229120 |
Nasopharyngeal angiofibroma | Nasopharyngeal angiofibroma is an angiofibroma also known as juvenile nasal angiofibroma, fibromatous hamartoma, and angiofibromatous hamartoma of the nasal cavity. It is a histologically benign but locally aggressive vascular tumor of the nasopharynx that arises from the superior margin of the sphenopalatine foramen and grows in the back of the nasal cavity. It most commonly affects adolescent males (because it is a hormone-sensitive tumor).
Though it is a benign tumor, it is locally invasive and can invade the nose, cheek, orbit (frog face deformity), or brain. Patients with nasopharyngeal angiofibroma usually present with one-sided nasal obstruction with profuse epistaxis.
Signs and symptoms
Frequent chronic epistaxis or blood-tinged nasal discharge
Nasal obstruction and rhinorrhea
Facial dysmorphism (when locally invasive)
Conductive hearing loss from eustachian-tube obstruction
Diplopia, which occurs secondary to erosion into superior orbital fissure and due to third and sixth nerve palsy.
Proptosis when having intraorbital extension.
Rarely anosmia, recurrent otitis media, and eye pain.
Diagnosis
If nasopharyngeal angiofibroma is suspected based on physical examination (a smooth vascular submucosal mass in the posterior nasal cavity of an adolescent male), imaging studies such as CT or MRI should be performed. Biopsy should be avoided as to avoid extensive bleeding since the tumor is composed of blood vessels without a muscular coat.Antral sign or Holman-Miller sign (forward bowing of posterior wall of maxilla) is pathognomic of angiofibroma.DSA (digital subtraction angiography) of carotid artery to see the extension of tumors and feeding vessels
Differential diagnosis
Antro-choanal polyp (benign non neoplastic growth)
Rhinosporidiosis (as bleeding point is here too)
Malignancy—nasopharyngeal carcinoma, lymphoma, plasmacytoma, rhabdomyosarcoma
Chordoma
Nasopharyngeal cyst
Pyogenic granuloma
Staging
There are many different staging- systems published. One of the most used is that of Radkowsky:
Treatment
Treatment for Nasopharyngeal angiofibroma (JNA) is primarily surgical. The tumor is primarily excised by external or endoscopic approach. Medical treatment and radiation therapy are only of historical interest.External approaches:
transpalatine approach
transpalatine + sublabial (Sardanas) Approach
infratemporal Approach
nasal endoscopic Approach
transmaxillary Approach
maxillary swing Approach or Facial translocationEndoscopic approach is an excellent tool in primary and recurrent JNA, it allows visualisation and precise removal of the lesion. Preoperative embolisation of tumour may be of some use in reducing intraoperative bleeding.Direct visualization is not common-
If the tumor is limited to nasopharynx and nose, for endoscopic approach or Wilsons transpalatal approach is used. It can be extended into Sardanas approach if the tumor extends laterally.
For tumors of infratemporal fossa, Maxillary Swing approach is used.
Transmaxillary Le Fort 1 approach is used for tumors extending into maxillary and ethmoid sinuses and pterygopalatine fossa.
If the tumor extend up to the cheek, for Weber–Ferguson approach should be used.
Prognosis
Prognosis for nasopharyngeal angiofibroma is favorable. Because these tumors are benign, metastasis to distal sites does not occur. However, these tumors are highly vascularized and grow rapidly. Removal is important in preventing nasal obstruction and recurrent epistaxis. Mortality is not associated with nasopharyngeal angiofibroma.
References
== External links == |
Marburg virus disease | Marburg virus disease (MVD; formerly Marburg hemorrhagic fever) is a viral hemorrhagic fever in humans and primates caused by either of the two Marburgviruses: Marburg virus (MARV) and Ravn virus (RAVV). Its clinical symptoms are very similar to those of Ebola virus disease (EVD).Egyptian fruit bats are believed to be the normal carrier in nature and Marburg virus RNA has been isolated from them.
Signs and symptoms
The most detailed study on the frequency, onset, and duration of MVD clinical signs and symptoms was performed during the 1998–2000 mixed MARV/RAVV disease outbreak. A maculopapular rash, petechiae, purpura, ecchymoses, and hematomas (especially around needle injection sites) are typical hemorrhagic manifestations. However, contrary to popular belief, hemorrhage does not lead to hypovolemia and is not the cause of death (total blood loss is minimal except during labor). Instead, death occurs due to multiple organ dysfunction syndrome (MODS) due to fluid redistribution, hypotension, disseminated intravascular coagulation, and focal tissue necroses.Clinical phases of Marburg Hemorrhagic Fevers presentation are described below. Note that phases overlap due to variability between cases.
Incubation: 2–21 days, averaging 5–9 days.
Generalization Phase: Day 1 up to Day 5 from the onset of clinical symptoms. MHF presents with a high fever 104 °F (~40˚C) and a sudden, severe headache, with accompanying chills, fatigue, nausea, vomiting, diarrhea, pharyngitis, maculopapular rash, abdominal pain, conjunctivitis, and malaise.
Early Organ Phase: Day 5 up to Day 13. Symptoms include prostration, dyspnea, edema, conjunctival injection, viral exanthema, and CNS symptoms, including encephalitis, confusion, delirium, apathy, and aggression. Hemorrhagic symptoms typically occur late and herald the end of the early organ phase, leading either to eventual recovery or worsening and death. Symptoms include bloody stools, ecchymoses, blood leakage from venipuncture sites, mucosal and visceral hemorrhaging, and possibly hematemesis.
Late Organ Phase: Day 13 up to Day 21+. Symptoms bifurcate into two constellations for survivors and fatal cases. Survivors will enter a convalescence phase, experiencing myalgia, fibromyalgia, hepatitis, asthenia, ocular symptoms, and psychosis. Fatal cases continue to deteriorate, experiencing continued fever, obtundation, coma, convulsions, diffuse coagulopathy, metabolic disturbances, shock and death, with death typically occurring between days 8 and 16.
Causes
MVD is caused by two viruses; Marburg virus (MARV) and Ravn virus (RAVV), family Filoviridae.Marburgviruses are endemic in arid woodlands of equatorial Africa. Most marburgvirus infections were repeatedly associated with people visiting natural caves or working in mines. In 2009, the successful isolation of infectious MARV and RAVV was reported from healthy Egyptian fruit bat caught in caves. This isolation strongly suggests that Old World fruit bats are involved in the natural maintenance of marburgviruses and that visiting bat-infested caves is a risk factor for acquiring marburgvirus infections. Further studies are necessary to establish whether Egyptian rousettes are the actual hosts of MARV and RAVV or whether they get infected via contact with another animal and therefore serve only as intermediate hosts. Another risk factor is contact with nonhuman primates, although only one outbreak of MVD (in 1967) was due to contact with infected monkeys.Contrary to Ebola virus disease (EVD), which has been associated with heavy rains after long periods of dry weather, triggering factors for spillover of marburgviruses into the human population have not yet been described.
Diagnosis
MVD is clinically indistinguishable from Ebola virus disease (EVD), and it can also easily be confused with many other diseases prevalent in Equatorial Africa, such as other viral hemorrhagic fevers, falciparum malaria, typhoid fever, shigellosis, rickettsial diseases such as typhus, cholera, gram-negative sepsis, borreliosis such as relapsing fever or EHEC enteritis. Other infectious diseases that ought to be included in the differential diagnosis include leptospirosis, scrub typhus, plague, Q fever, candidiasis, histoplasmosis, trypanosomiasis, visceral leishmaniasis, hemorrhagic smallpox, measles, and fulminant viral hepatitis. Non-infectious diseases that can be confused with MVD are acute promyelocytic leukemia, hemolytic uremic syndrome, snake envenomation, clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura, hereditary hemorrhagic telangiectasia, Kawasaki disease, and even warfarin intoxication. The most important indicator that may lead to the suspicion of MVD at clinical examination is the medical history of the patient, in particular the travel and occupational history (which countries and caves were visited?) and the patients exposure to wildlife (exposure to bats or bat excrements?). MVD can be confirmed by isolation of marburgviruses from or by detection of marburgvirus antigen or genomic or subgenomic RNAs in patient blood or serum samples during the acute phase of MVD. Marburgvirus isolation is usually performed by inoculation of grivet kidney epithelial Vero E6 or MA-104 cell cultures or by inoculation of human adrenal carcinoma SW-13 cells, all of which react to infection with characteristic cytopathic effects. Filovirions can easily be visualized and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot differentiate the various filoviruses alone despite some overall length differences. Immunofluorescence assays are used to confirm marburgvirus presence in cell cultures. During an outbreak, virus isolation and electron microscopy are most often not feasible options. The most common diagnostic methods are therefore RT-PCR in conjunction with antigen-capture ELISA, which can be performed in field or mobile hospitals and laboratories. Indirect immunofluorescence assays (IFAs) are not used for diagnosis of MVD in the field anymore.
Classification
Marburg virus disease (MVD) is the official name listed in the World Health Organizations International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg, where MARV was first discovered.
Transmission
The details of the initial transmission of MVD to humans remain incompletely understood. Transmission most likely occurs from Egyptian fruit bats or another natural host, such as non-human primates or through the consumption of bush meat, but the specific routes and body fluids involved are unknown. Human-to-human transmission of MVD occurs through direct contact with infected bodily fluids such as blood.
Prevention
There are currently no Food and Drug Administration-approved vaccines for the prevention of MVD. Many candidate vaccines have been developed and tested in various animal models. Of those, the most promising ones are DNA vaccines or based on Venezuelan equine encephalitis virus replicons, vesicular stomatitis Indiana virus (VSIV) or filovirus-like particles (VLPs) as all of these candidates could protect nonhuman primates from marburgvirus-induced disease. DNA vaccines have entered clinical trials. Marburgviruses are highly infectious, but not very contagious. They do not get transmitted by aerosol during natural MVD outbreaks. Due to the absence of an approved vaccine, prevention of MVD therefore relies predominantly on quarantine of confirmed or high probability cases, proper personal protective equipment, and sterilization and disinfection.
Endemic zones
The natural maintenance hosts of marburg viruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source.
During outbreaks
Since marburgviruses are not spread via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids, and any possibly contaminated materials and utensils. Patients should be isolated, but still are safe to be visited by family members. Medical staff should be trained in and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers.
In the laboratory
Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment, laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.
Treatment
There is currently no effective marburgvirus-specific therapy for MVD. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration, administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation, administration of procoagulants late in infection to control hemorrhaging, maintaining oxygen levels, pain management, and administration of antibiotics or antifungals to treat secondary infections.
Prognosis
Prognosis is generally poor. If a patient survives, recovery may be prompt and complete, or protracted with sequelae, such as orchitis, hepatitis, uveitis, parotitis, desquamation, or alopecia. Importantly, MARV is known to be able to persist in some survivors and to either reactivate and cause a secondary bout of MVD or to be transmitted via sperm, causing secondary cases of infection and disease.Of the 252 people who contracted Marburg during the 2004–2005 outbreak of a particularly virulent serotype in Angola, 227 died, for a case fatality rate of 90%.
Although all age groups are susceptible to infection, children are rarely infected. In the 1998–2000 Congo epidemic, only 8% of the cases were children less than 5 years old.
Epidemiology
Below is a table of outbreaks concerning MVD from 1967 to 2021:
1967 outbreak
MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main, and in Belgrade, Yugoslavia. The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines. The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine, Emil von Behring. The company, which at the time was owned by Hoechst, was originally set up to develop sera against tetanus and diphtheria. Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment. Secondary cases involved two physicians, a nurse, a post-mortem attendant, and the wife of a veterinarian. All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients. A popular science account of this outbreak can be found in Laurie Garrett’s book The Coming Plague.
1975 cases
In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe). He died in a hospital in Johannesburg, South Africa. His girlfriend and an attending nurse were subsequently infected with MVD, but survived.
1980 cases
A case of MARV infection occurred in 1980 in Kenya. A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma) at the base of Mount Elgon (which contains Kitum Cave), became infected by unknown means and died on 15 January shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston’s book The Hot Zone (the French man is referred to under the pseudonym “Charles Monet”, whereas the physician is identified under his real name, Shem Musoke).
1987 case
In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu, Kenya. He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa, where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston’s book The Hot Zone (the boy is referred to under the pseudonym “Peter Cardinal”).
1988 laboratory infection
In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs. The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor") in Koltsovo, USSR (today Russia). Very little information is publicly available about this MVD case because Ustinovs experiments were classified. A popular science account of this case can be found in Ken Alibek’s book Biohazard.
1990 laboratory infection
Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor") in Koltsovo, USSR, when a scientist contracted MARV by unknown means.
1998–2000 outbreak
A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa, Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine.
2004–2005 outbreak
In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola, which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, pointing out that there were only approximately 1,200 doctors in the entire country, with some provinces having as few as two. Health care workers also complained about a shortage of personal protective equipment such as gloves, gowns, and masks. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity. Contact tracing was complicated by the fact that the countrys roads and other infrastructure were devastated after nearly three decades of civil war and the countryside remained littered with land mines. Americo Boa Vida Hospital in the Angolan capital Luanda set up a special isolation ward to treat infected people from the countryside. Unfortunately, because MVD often results in death, some people came to view hospitals and medical workers with suspicion and treated helpers with hostility. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy", which entailed distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD during outbreak, 227 died.
2007 cases
In 2007, four miners became infected with marburgviruses in Kamwenge District, Uganda. The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection.
2008 cases
On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda had MVD due to MARV infection, and had been admitted to a hospital in the Netherlands. The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin. At the time, serologic testing was negative for viral hemorrhagic fever. She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA.
2017 Uganda outbreak
In October 2017 an outbreak of Marburg virus disease was detected in Kween District, Eastern Uganda. All three initial cases (belonging to one family – two brothers and one sister) had died by 3 November. The fourth case – a health care worker – developed symptoms on 4 November and was admitted to a hospital. The first confirmed case traveled to Kenya before the death. A close contact of the second confirmed case traveled to Kampala. It is reported that several hundred people may have been exposed to infection.
2021 Guinean cases
In August 2021, two months after the re-emergent Ebola epidemic in the Guéckédou prefecture was declared over, a case of the Marburg disease was confirmed by health authorities through laboratory analysis. Other potential case of the disease in a contact awaits official results. These are the first cases of the Marburg hemorrhagic fever confirmed to happen in West Africa. The cases of Marburg also have been identified in Guéckédou.
On August 10, the WHO said health authorities in Guinea have confirmed one death from Marburg virus.
2022 Ghanaian cases
In July 2022, preliminary analysis of samples taken from two patients – both deceased – in Ghana indicated the cases were positive for Marburg. However, per standard procedure, the samples were sent to the Pasteur Institute of Dakar for confirmation. On 17 July 2022 the two cases were confirmed by Ghana, which caused the country to declare a Marburg virus disease outbreak. An additional case was identified, bringing the total to three.
Research
Experimentally, recombinant vesicular stomatitis Indiana virus (VSIV) expressing the glycoprotein of MARV has been used successfully in nonhuman primate models as post-exposure prophylaxis. A vaccine candidate has been effective in nonhuman primates. Experimental therapeutic regimens relying on antisense technology have shown promise, with phosphorodiamidate morpholino oligomers (PMOs) targeting the MARV genome New therapies from Sarepta and Tekmira have also been successfully used in humans as well as primates.
See also
List of other Filoviridae outbreaks
References
Further reading
External links
ViralZone: Marburg virus
Centers for Disease Control, Infection Control for Viral Haemorrhagic Fevers In the African Health Care Setting.
Center for Disease Control, Marburg Haemorrhagic Fever.
Center for Disease Control, Known Cases and Outbreaks of Marburg Haemorrhagic Fever
Ebola and Marburg haemorrhagic fever (10 July 2008) factsheet from European Centre for Disease Prevention and Control
World Health Organization, Marburg Haemorrhagic Fever.
Red Cross PDF
Virus Pathogen Database and Analysis Resource (ViPR): Filoviridae |
Berlins edema | Berlins edema (commotio retinae) a common condition caused by blunt injury to the eye. It is characterized by decreased vision in the injured eye a few hours after the injury. Under examination the retina appears opaque and white in colour in the periphery but the blood vessels are normally seen along with "cherry red spot" in the foveal region. This whitening is indicative of cell damage, which occurs in the retinal pigment epithelium and outer segment layer of photoreceptors. Damage to the outer segment often results in photoreceptor death through uncertain mechanisms. Usually there is no leakage of fluid and therefore it is not considered a true edema. The choroidal fluorescence in fluorescent angiography is absent. Visual acuity ranges from 20/20 to 20/400.
The prognosis is excellent except in case of complications of choroidal rupture, hemorrhage or pigment epithelial damage, but damage to the macula will result in poorer recovery. The outcome can be worsened in the case of retinal detachment, atrophy or hyperplasia. Visual field defects can occur. In late cases cystoid macular edema sometimes develops which can further lead to macular destruction.
Commotio retinae is usually self limiting and there is no treatment as such. It usually resolves in 3–4 weeks without any complications and sequelae.
== References == |
Localized granuloma annulare | Localized granuloma annulare is a skin condition of unknown cause, tending to affect children and young to middle-aged adults, usually appearing on the lateral or dorsal surfaces of the fingers or hands, elbows, dorsal feet, and ankles.: 703
See also
Granuloma annulare
Skin lesion
== References == |
Sarcopenia | Sarcopenia is a type of muscle loss (muscle atrophy) that occurs with aging and/or immobility. It is characterized by the degenerative loss of skeletal muscle mass, quality, and strength. The rate of muscle loss is dependent on exercise level, co-morbidities, nutrition and other factors. The muscle loss is related to changes in muscle synthesis signalling pathways. It is distinct from cachexia, in which muscle is degraded through cytokine-mediated degradation, although both conditions may co-exist. Sarcopenia is considered a component of frailty syndrome. Sarcopenia can lead to reduced quality of life, falls, fracture, and disability.Sarcopenia is a factor in changing body composition associated with aging populations; and certain muscle regions are expected to be affected first, specifically the anterior thigh and abdominal muscles. In population studies, body mass index (BMI) is seen to decrease in aging populations while bioelectrical impedance analysis (BIA) shows body fat proportion rising.The term sarcopenia is from Greek σάρξ sarx, "flesh" and πενία penia, "poverty". This was first proposed by Rosenberg in 1989, who wrote that "there may be no single feature of age-related decline that could more dramatically affect ambulation, mobility, calorie intake, and overall nutrient intake and status, independence, breathing, etc."
Signs and symptoms
The hallmark sign of sarcopenia is loss of lean muscle mass, or muscle atrophy. The change in body composition may be difficult to detect due to obesity, changes in fat mass, or edema. Changes in weight, limb or waist circumference are not reliable indicators of muscle mass changes. Sarcopenia may also cause reduced strength, functional decline and increased risk of falling. Sarcopenia may also have no symptoms until it is severe and is often unrecognized. Research has shown, however, that hypertrophy may occur in the upper parts of the body to compensate for this loss of lean muscle mass Therefore, one early indicator of the onset of sarcopenia can be significant loss of muscle mass in the anterior thigh and abdominal muscles.
Causes
There are many proposed causes of sarcopenia and it is likely the result of multiple interacting factors. Understanding of the causes of sarcopenia is incomplete, however changes in hormones, immobility, age-related muscle changes, nutrition and neurodegenerative changes have all been recognized as potential causative factors.The degree of sarcopenia is determined by two factors: initial amount of muscle mass and rate at which muscle mass declines. Due to variations in these factors across the population, the rate of progression and the threshold at which muscle loss becomes apparent is variable. Immobility dramatically increases the rate of muscle loss, even in younger people. Other factors that can increase rate of progression of sarcopenia include decreased nutrient intake, low physical activity, or chronic disease. Additionally, epidemiological research has indicated that early environmental influences may have long-term effects on muscle health. For example, low birth weight, a marker of a poor early environment, is associated with reduced muscle mass and strength in adult life.
Pathophysiology
There are multiple theories proposed to explain the mechanisms of muscle changes of sarcopenia including changes in satellite cell recruitment, changes in anabolic signalling, protein oxidation, inflammation, and developmental factors. The pathologic changes of sarcopenia include a reduction in muscle tissue quality as reflected in the replacement of muscle fibers with fat, an increase in fibrosis, changes in muscle metabolism, oxidative stress, and degeneration of the neuromuscular junction.The distribution of muscle fibers types also changes in sarcopenic muscle causing a decrease in type II muscle fibers, or "fast twitch," with little to no decrease in type I muscle fibers, or "slow-twitch" muscle fibers. Deinervated type II fibers are often converted to type I fibers by reinnervation by slow type I fiber motor nerves.The failure to activate satellite cells upon injury or exercise is also thought to contribute to the pathophysiology of sarcopenia. Additionally, oxidized proteins can lead to a buildup of lipofuscin and cross-linked proteins causing an accumulation of non-contractile material in the skeletal muscle and contribute to sarcopenic muscle.An apparent protective factor is sufficient levels of the protein BNIP3, which prevents cells buildup of damaged mitochondria. Deficiency of BNIP3 leads to muscle inflammation and atrophy.
Diagnosis
Multiple diagnostic criteria have been proposed by various expert groups and continues to be an area of research and debate. Despite the lack of a widely accepted definition, sarcopenia was assigned an ICD-10 code (M62.84) in 2016, recognizing it as a disease state.Sarcopenia can be diagnosed when a patient has muscle mass that is at least two standard deviations below the relevant population mean and has a slow walking speed. The European Working Group on Sarcopenia in Older People (EWGSOP) developed a broad clinical definition for sarcopenia, designated as the presence of low muscle mass and either low muscular strength or low physical performance. Other international groups have proposed criteria that include metrics on walking speed, distance walked in 6 minutes, or grip strength. Hand grip strength alone has also been advocated as a clinical marker of sarcopenia that is simple and cost effective and has good predictive power, although it does not provide comprehensive information.There are screening tools for sarcopenia that assess patient reported difficulty in doing daily activities such as walking, climbing stairs or standing from a chair and have been shown to predict sarcopenia and poor functional outcomes.
Management
Exercise
Exercise remains the intervention of choice for sarcopenia, but translation of research findings into clinical practice is challenging. The type, duration and intensity of exercise are variable between studies, preventing a standardized exercise prescription for sarcopenia. Lack of exercise is a significant risk factor for sarcopenia and exercise can dramatically slow the rate of muscle loss. Exercise can be an effective intervention because aging skeletal muscle retains ability to synthesize proteins in response to short-term resistance exercise. Progressive resistance training in older adults can improve physical performance (gait speed) and muscular strength.
Medication
There are currently no approved medications for the treatment of sarcopenia. Testosterone or other anabolic steroids have also been investigated for treatment of sarcopenia, and seem to have some positive effects on muscle strength and mass, but cause several side effects and raise concerns of prostate cancer in men and virilization in women. Additionally, recent studies suggest testosterone treatments may induce adverse cardiovascular events.DHEA and human growth hormone have been shown to have little to no effect in this setting. Growth hormone increases muscle protein synthesis and increases muscle mass, but does not lead to gains in strength and function in most studies. This, and the similar lack of efficacy of its effector insulin-like growth factor 1 (IGF-1), may be due to local resistance to IGF-1 in aging muscle, resulting from inflammation and other age changes.Other medications under investigation as possible treatments for sarcopenia include ghrelin, vitamin D, angiotensin converting enzyme inhibitors, and eicosapentaenoic acid.
Nutrition
Intake of calories and protein are important stimuli for muscle protein synthesis. Older adults may not utilize protein so efficiently as younger people and may require higher amounts to prevent muscle atrophy. A number of expert groups have proposed an increase in dietary protein recommendations for older age groups to 1.0-1.2 g/kg body weight per day.
Ensuring adequate nutrition in older adults is of interest in the prevention of sarcopenia and frailty, since it is a simple, low-cost treatment approach without major side effects.
Supplements
A component of sarcopenia is the loss of ability for aging skeletal muscle to respond to anabolic stimuli such as amino acids, especially at lower concentrations. However, aging muscle retains the ability of an anabolic response to protein or amino acids at larger doses. Supplementation with larger doses of amino acids, particularly leucine has been reported to counteract muscle loss with aging. Exercise may work synergistically with amino acid supplementation.β-hydroxy β-methylbutyrate (HMB) is a metabolite of leucine that acts as a signalling molecule to stimulate protein synthesis. It is reported to have multiple targets, including stimulating mTOR and decreasing proteasome expression. Its use to prevent the loss of lean body mass in older adults is consistently supported in clinical trials. More research is needed to determine the precise effects of HMB on muscle strength and function in this age group.
Epidemiology
The prevalence of sarcopenia depends on the definition used in each epidemiological study. Estimated prevalence in people between the ages of 60-70 is 5-13% and increases to 11-50% in people more than 80 years of age. This equates to >50 million people and is projected to affect >200 million in the next 40 years given the rising population of older adults.
Public health impact
Sarcopenia is emerging as a major public health concern given the increased longevity of industrialized populations and growing geriatric population. Sarcopenia is a predictor of many adverse outcomes including increased disability, falls and mortality. Immobility or bed rest in populations predisposed to sarcopenia can cause dramatic impact on functional outcomes. In the elderly, this often leads to decreased biological reserve and increased vulnerability to stressors known as the "frailty syndrome". Loss of lean body mass is also associated with increased risk of infection, decreased immunity, and poor wound healing. The weakness that accompanies muscle atrophy leads to higher risk of falls, fractures, physical disability, need for institutional care, reduced quality of life, increased mortality, and increased healthcare costs. This represents a significant personal and societal burden and its public health impact is increasingly recognized.
Research directions
There are significant opportunities to better understand the causes and consequences of sarcopenia and help guide clinical care. This includes elucidation of the molecular and cellular mechanisms of sarcopenia, further refinement of reference populations by ethnic groups, validation of diagnostic criteria and clinical tools, as well as tracking of incidence of hospitalization admissions, morbidity, and mortality. Identification and research on potential therapeutic approaches and timing of interventions is also needed.New pharmaceutical therapies in clinical development include myostatin and the selective androgen receptor modulators (SARMs). Nonsteriodal SARMs are of particular interest, given they exhibit significant selectivity between the anabolic effects of testosterone on muscle, but with little to no evidence of androgenic effects (such as prostate stimulation in men).
See also
Cachexia
Ageing
Frailty syndrome
Geriatrics
Dynapenia
References
Further reading
Fujita S, Volpi E (January 2006). "Amino acids and muscle loss with aging". The Journal of Nutrition (Review). 136 (1 Suppl): 277S–80S. doi:10.1093/jn/136.1.277S. PMC 3183816. PMID 16365098.
Roubenoff R (December 2007). "Physical activity, inflammation, and muscle loss". Nutrition Reviews. 65 (12 Pt 2): S208-12. doi:10.1111/j.1753-4887.2007.tb00364.x. PMID 18240550.
Sharlo K, Tyganov SA, Tomilovskaya E, Popov DV, Saveko AA, Shenkman BS. (December 2021) "Effects of Various Muscle Disuse States and Countermeasures on Muscle Molecular Signaling". International Journal of Molecular Sciences. 23(1):468. PMID 35008893 PMC 8745071 doi:10.3390/ijms23010468
== External links == |
Transvestic fetishism | Transvestic fetishism is a psychiatric diagnosis applied to men who are thought to have an excessive sexual or erotic interest in cross-dressing; this interest is often expressed in autoerotic behavior. It differs from cross-dressing for entertainment or other purposes that do not involve sexual arousal. Under the name transvestic disorder, it is categorized as a paraphilia in the DSM-5.
Description
The DSM-5 states that adolescent and adult males with late-onset gender dysphoria "frequently engage in transvestic behavior with sexual excitement." "Habitual fetishistic transvestism developing into autogynephilia" is given as a risk factor for gender dysphoria to develop.
According to DSM-IV, this fetishism was limited to heterosexual men; however, the DSM-5 does not have this restriction, and opens it to women and men with this interest, regardless of their sexual orientation. It is, however, usually documented in males.There are two key criteria before a psychiatric diagnosis of "transvestic fetishism" is made:
Individuals must be sexually aroused by the act of cross-dressing.
Individuals must experience significant distress or impairment – socially or occupationally – because of their behavior.
Types
Some male transvestic fetishists collect womens clothing, e.g. panties, nightgowns, babydolls, bridal gowns, slips, petticoats, brassieres, and other types of nightwear, lingerie, stockings, pantyhose, shoes, and boots, items of a distinct feminine look and feel, especially of silk, satin and lace. They may dress in these feminine garments and take photographs of themselves while living out their fantasies.
See also
Dual-role transvestism
Feminization
Hair fetishism
List of transgender-related topics
List of paraphilias
Pinafore eroticism
Transgender
Transvestism
References
Citations
SourcesLaws, Richard D.; ODonohue, William T., eds. (2008). Sexual Deviance: Theory, Assessment, and Treatment (2 ed.). New York: Guilford Press. ISBN 978-1-59385-605-2. |
Megalencephaly | Megalencephaly (or macrencephaly; abbreviated MEG) is a growth development disorder in which the brain is abnormally large. It is characterized by a brain with an average weight that is 2.5 standard deviations above the mean of the general population. Approximately 1 out of 50 children (2%) are said to have the characteristics of megalencephaly in the general population.A mutation in the PI3K-AKT pathway is believed to be the primary cause of brain proliferation and ultimately the root cause of megalencephaly. This mutation has produced a classification of brain overdevelopment that consists of two syndromes including megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH). Megalencephaly is usually diagnosed at birth and is confirmed with an MRI.
There are several neuropsychiatric disorders linked with megalencephaly; however, studies have shown that autism is the most prevalent association with the malformation of MEG. Although no treatment currently exists for megalencephaly, management methods are focused at reducing deficits linked with autism. Most recent research is targeted at creating inhibitors to reduce the mutational pathway that causes megalencephaly.
Classification
Macrocephaly
Macrocephaly is a term used to refer to a person who has an abnormally large head. The circumference of the head must be above the 95th percentile or at least 2.5 standard deviations from the mean of normal weight and gender groups in the United States. A person with macrocephaly does not necessarily indicate that megalencephaly is also present. Large skulls usually exhibit no neurodevelopment conditions at all, meaning most individuals with macrocephaly are healthy.
Hemimegalencephaly
Hemimegalencephaly is an extremely rare form of macrocephaly and is characterized by uneven development of brain hemispheres (one-half of brain is larger than other). The syndrome can be presented by itself or in association with phakomatosis or hemigigantism. Additionally, hemimegalencephaly will frequently cause severe epilepsy, focal neuro-logical deficits, macrocrania, and mild to severe intellectual disability.
MCAP
Megalencephaly-capillary (MCAP) is one of the two major syndromes of megalencephaly. Typically, MCAP and MPPH can be distinguished by somatic features. MCAP includes many characteristics that are observed at birth including: cutaneous vascular malformations, especially capillary malformations of the face and cutis marmorata, polydactyly, connective tissue dysplasia, and focal or segmental body overgrowth. Furthermore, MCAP can occasionally be linked with asymmetric brain overgrowth (hemimegalencephaly) as well as segmental overgrowth of the body (hemihypertrophy).
MPPH
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) is one of the two major syndromes contributing to megalencephaly. Typically MCAP and MPPH can be distinguished by somatic features. In differentiation to MCAP, MPPH lacks consistent somatic features other than postaxial polydactyly. Furthermore, brain and body development is normally symmetric in the majority of patients that appear to have MPPH symptoms.
Presentation
Autism
There is an extremely high association between megalencephaly and autism. Approximately 20% of autistic children have megalencephaly, making it the most common physical characteristic of autism. People who present both megalencephaly and autistic characteristics usually also show signs of hyperactivity as a major symptom. However, there is no definitive evidence that autism is the primary cause/result of megalencephaly.Since most children with megalencephaly also have autism, the goal of treatment for MEG is focused on managing the signs and symptoms associated with autism.
Other associations
Achondroplasia
Beckwith–Wiedemann syndrome
Neurofibromatosis type I (NF1)
Tuberous sclerosis (TS)
Klippel–Trénaunay syndrome
Epidermal nevus syndrome
Causes
Although very little is still known as to the direct cause of megalencephaly, recent studies have begun to provide early indications of possible sources for its formation. Recent research has shown that there is a strong link between genetic pathways that cause brain develop and mutations in that pathway that result in brain overgrowth.
PI3K-AKT
Recent studies have shown that mutations in phosphoinositide 3-kinase (PI3K) and AKT (also known as protein kinase B) pathway have been identified in MCAP and MPPH. This pathway has proven to be an integral part of brain growth and development and is an area of interest to many researchers who study the cause of megalencephaly. Mutations in this pathway have been shown to cause a gain of function in the activation of the PI3K-AKT pathway. This cellular pathway is critical in the regulation of diverse cell functions including, cell growth, proliferation, metabolism, survival, apoptosis, angiogenesis, tumorigenesis and most importantly in regards to megalencephaly, brain development. AKT is a crucial signaling molecule part of the PI3K pathway and is also involved in many cellular functions. These functions include, brain development, synaptic plasticity and neurodevelopment. Loss of function in AKT can cause microcephaly in humans while inactivation of the pathway can cause hemimegalencephaly. There are also several cancers that have been shown to be linked with mutations in the AKT pathway, including melanoma and lung cancer.
Pur-alpha
Pur-alpha (purα) is a sequence-specific single-stranded DNA and RNA-binding protein. Studies have shown that the protein is primarily active during early development and is believed to have a role in brain enlargement. Although the exact function is still controversial, it is believed that pur-alpha is responsible for neuronal proliferation during neurogenesis as well as the maturation of dendrites. Thus, pur-alpha is also considered a potential root cause of megalencephaly and brain overgrowth.
Pathophysiology
One impact of megalencephaly is the complete lack of motor development. One medical study assessed three patients presenting megalencephaly who showed severely impaired motor and speech development as well as distinct facial abnormalities including skull bossing, a low nasal bridge and large eyes.
Diagnoses
Diagnosis of megalencephaly has changed over the years, however, with the development of more advanced equipment, physicians have been able to confirm the disorder with better accuracy. Usually, a physical exam is first performed when characteristics of megalencephaly have appeared. This typically occurs at birth or during early child development. A physician will then take head measurements in order to determine the circumference. This is known as the head circumference. Then a family background will be recorded in order to determine if there has been a history of megalencephaly in the family.A neurological exam will then be performed using the technology of an MRI machine in order to confirm the diagnosis of megalencephaly. These imaging tests give detailed information regarding brain size, volume asymmetry and other irregular developments linked with MCAP, MPPH and hemimegalencephaly.There is also a strong correlation of epilepsy and megalencephaly and this can aid doctors in their diagnosis.If a diagnosis of megalencephaly is confirmed, the child is referred to a specialist who focuses on managing the symptoms and improving lifestyle. Since megalencephaly is usually presented with autism, the goal of treatment is to improve deficiencies associated with autistic causes. Additionally, since each patient has unique symptoms, there is no one specific treatment method and therefore is heavily reliant on symptoms associated with an individual.
Prevention
Since there are very few treatment methods focused on managing megalencephaly, future research is targeted at inhibiting mutation of the pathway. However, this next step could be met with several complications as understanding the underlying mechanism of the mutation is a difficult task. The genetic coding that initiates a single mutation is sporadic and patterns are hard to detect in many cases.
Even though very little research has been done to create inhibitors of the PI3K-AKT pathway, several pharmaceutical companies have begun to focus their interests in designing a prevention method for this purpose.
Treatment
There is currently no specific treatment for megalencephaly, however periodic head measurements may be assessed to determine the rate of brain growth.
Those individuals who develop neurological disorders may be prescribed anti-epileptic drugs for seizures. Studies have shown that reducing epilepsy can increase cell apoptosis and reduce the proliferation of neurons that ultimately leads to brain overgrowth.
Prognosis
The prognosis of megalencephaly depends heavily on the underlying cause and associated neurological disorders. Because the majority of megalencephaly cases are linked with autism, the prognosis is equivalent to the corresponding condition.
Since hemimegalencephaly is associated with severe seizures, hemiparesis and intellectual disability, the result is a poor prognosis. In most cases, those diagnosed with this type of megalencephaly usually do not survive through adulthood.
Epidemiology
Approximately one out of every 50 (2%) children in the general population are said to have megalencephaly. Additionally, it is said that megalencephaly affects 3–4 times more males than females.
Those individuals that are classified with macrocephaly, or general head overgrowth, are said to have megalencephaly at a rate of 10–30% of the time.
History
It is believed that megalencephaly was discovered in 1972. Prior to diagnoses that used MRI scanning as a way to confirm brain overgrowth, cases of megalencephaly were diagnosed by autopsy in which the physical brain was measured and weighed.
Research
Future research is targeted at further understanding mutations and how they lead to MCAP and MPPH syndromes. The majority of studies of megalencephaly have included mice who present brain abnormalities and overgrowth. The next step is to move to clinical trials involving humans in order to determine the exact genetic mutation causing the sequences. Additionally, scientists and pharmaceutical companies have begun to show interest in mutation inhibition and designing preventative methods to eliminate the underlying cause of megalencephaly altogether.
Other relations
Intracranial volume also affects this pathology, since it is related with the size of the brain.
References
External links
Megalencephaly information page (provided by National Institute of Neurological Disorders and Stroke) |
Spinal muscular atrophy with progressive myoclonic epilepsy | Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), sometimes called Jankovic–Rivera syndrome, is a very rare neurodegenerative disease whose symptoms include slowly progressive muscle (atrophy), predominantly affecting proximal muscles, combined with denervation and myoclonic seizures. Only 12 known human families are described in scientific literature to have SMA-PME.SMA-PME is associated with a missense mutation (c.125C→T) or deletion in exon 2 of the ASAH1 gene and is inherited in an autosomal recessive manner. SMA-PME is closely related to a lysosomal disorder disease called Farber lipogranulomatosis. As with many genetic disorders, there is no known cure for SMA-PME.
The condition was first described in 1979 by American researchers Joseph Jankovic and Victor M. Rivera.
ASAH1 gene
The ASAH1 gene codes for acid ceramidase, an enzyme found in lysosomes. The lysosome breaks down acid ceramidase; the fatty acid component is then used to produce myelin. Myelin is an insulating coating around the neurons in the body which helps to contain bioelectrical signals along a nerve cells axon and increase transmission rate. In patients with SMA-PME, the ceramidase function decreases to 33.33% effective. The lack of myelin resulting from the lack of acid ceramidase breakdown leads to nerve cell dysfunction.
See also
Spinal muscular atrophies
Progressive myoclonus epilepsy
References
Further reading
National Institutes of Health (December 2013). "Genetics Home Reference: Spinal muscular atrophy with progressive myoclonic epilepsy".
== External links == |
Onychophosis | Onychophosis is a localized or diffuse hyperkeratotic tissue that develops on the lateral or proximal nailfolds, within the space between the nailfolds and the nail plate, and is a common finding in the elderly. Onychophosis may involve the subungual area, as a direct result of repeated minor trauma, and most frequently affects the first and fifth toe.
== References == |
Congestive hepatopathy | Congestive hepatopathy, is liver dysfunction due to venous congestion, usually due to congestive heart failure. The gross pathological appearance of a liver affected by chronic passive congestion is "speckled" like a grated nutmeg kernel; the dark spots represent the dilated and congested hepatic venules and small hepatic veins. The paler areas are unaffected surrounding liver tissue. When severe and longstanding, hepatic congestion can lead to fibrosis; if congestion is due to right heart failure, it is called cardiac cirrhosis.
Signs and symptoms
Signs and symptoms depend largely upon the primary lesions giving rise to the condition. In addition to the heart or lung symptoms, there will be a sense of fullness and tenderness in the right hypochondriac region. Gastrointestinal catarrh is usually present, and vomiting of blood may occur. There is usually more or less jaundice. Owing to portal obstruction, ascites occurs, followed later by generalised oedema. The stools are light or clay-colored, and the urine is colored by bile. On palpation, the liver is found enlarged and tender, sometimes extending several inches below the costal margin of the ribs.
Pathophysiology
Increased pressure in the sublobular branches of the hepatic veins causes an engorgement of venous blood, and is most frequently due to chronic cardiac lesions, especially those affecting the right heart (e.g., right-sided heart failure), the blood being dammed back in the inferior vena cava and hepatic veins. Central regions of the hepatic lobules are red–brown and stand out against the non-congested, tan-coloured liver. Centrilobular necrosis occurs.Macroscopically, the liver has a pale and spotty appearance in affected areas, as stasis of the blood causes pericentral hepatocytes (liver cells surrounding the central venule of the liver) to become deoxygenated compared to the relatively better-oxygenated periportal hepatocytes adjacent to the hepatic arterioles. This retardation of the blood also occurs in lung lesions, such as chronic interstitial pneumonia, pleural effusions, and intrathoracic tumors.
Diagnosis
It is diagnosed with laboratory testing, including liver function tests, and radiology imaging, including ultrasounds.
Treatment
Treatment is directed largely to removing the cause, or, where that is impossible, to modifying effects of the heart failure. Thus, therapy aimed at improving right heart function will also improve congestive hepatopathy. True nutmeg liver is usually secondary to left-sided heart failure, causing congestive right heart failure, so treatment options are limited.Treatments for heart failure include medications, an intra-aortic balloon pump, a ventricular assist device, heart valve replacements, extracorporeal membrane oxygenation (if the heart failure worsens suddenly and especially if an infection was the cause), an artificial heart, or a heart transplant (from a deceased human donor, or from a pig). Some patients may need a liver transplant; an artificial liver can be used for a short period of time (about two weeks or so) as a bridge to a transplant, or until the liver recovers.
See also
Ischemic hepatitis
References
== External links == |
Erythema gyratum repens | Erythema gyratum repens is a figurate erythema that is rapidly moving and usually a marker of underlying cancer,: 143 usually from the lung.
See also
Annular erythema of infancy
List of cutaneous conditions
List of cutaneous conditions associated with internal malignancy
List of migrating cutaneous conditions
References
Further reading
Prouty, Megan; Liu, Deede (2019). "Erythema Gyratum Repens Associated with Anal Cancer". New England Journal of Medicine. 380 (3): e3. doi:10.1056/NEJMicm1805833. ISSN 0028-4793. PMID 30650327. Illustration of the condition
== External links == |
Thrombin | Thrombin (EC 3.4.21.5, fibrinogenase, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, blood-coagulation factor IIa, factor IIa, E thrombin, beta-thrombin, gamma-thrombin) is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.
History
After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.Prothrombin was discovered by Pekelharing in 1894.
Physiology
Synthesis
Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is co-translationally modified in a vitamin K-dependent reaction that converts 10-12 glutamic acids in the N terminus of the molecule to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.
In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life.
Mechanism of action
In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa. In the conversion of fibrinogen into fibrin, thrombin catalyzes the cleavage of fibrinopeptides A and B from the respective Aα and Bβ chains of fibrinogen to form fibrin monomers.Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Thrombin interacts with thrombomodulin.As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet.
Negative feedback
Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. Thrombin is also inactivated by antithrombin, a serine protease inhibitor.
Structure
The molecular weight of prothrombin is approximately 72,000 Da. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36,000 Da. Structurally, it is a member of the large PA clan of proteases.
Prothrombin is composed of four domains; an N-terminal Gla domain, two kringle domains and a C-terminal trypsin-like serine protease domain.
Factor Xa with factor V as a cofactor leads to cleavage of the Gla and two Kringle domains (forming together a fragment called fragment 1.2) and leave thrombin, consisting solely of the serine protease domain.As is the case for all serine proteases, prothrombin is converted to active thrombin by proteolysis of an internal peptide bond, exposing a new N-terminal Ile-NH3. The historic model of activation of serine proteases involves insertion of this newly formed N-terminus of the heavy chain into the β-barrel promoting the correct conformation of the catalytic residues. Contrary to crystal structures of active thrombin, hydrogen-deuterium exchange mass spectrometry studies indicate that this N-terminal Ile-NH3 does not become inserted into the β-barrel in the apo form of thrombin. However, binding of the active fragment of thrombomodulin appears to allosterically promote the active conformation of thrombin by inserting this N-terminal region.
Gene
The thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12).There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency, which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.Prothrombin G20210A is not usually accompanied by other factor mutations (i.e., the most common is factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), and is not related to gender or blood type. Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i.e., Crohns disease or ulcerative colitis) and prothrombin G20210A or factor V Leiden mutation have been contradicted by research.
Role in disease
Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant (also known as antiphospholipid syndrome). Hyperprothrombinemia can be caused by the G20210A mutation.
Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke).
Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis.Thrombin is implicated in the physiology of blood clots. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated iron oxide attached to "reporter chemicals". When a peptide binds to a thrombin molecule, the report is released and appears in the urine where it can be detected. Human testing has not been conducted.
Applications
Research tool
Due to its high proteolytic specificity, thrombin is a valuable biochemical tool. The thrombin cleavage site (Leu-Val-Pro-Arg-Gly-Ser) is commonly included in linker regions of recombinant fusion protein constructs. Following purification of the fusion protein, thrombin can be used to selectively cleave between the arginine and glycine residues of the cleavage site, effectively removing the purification tag from the protein of interest with a high degree of specificity.
Medicine and surgery
Prothrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Indications include intractable bleeding due to warfarin.
Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site.
Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding.
Food production
Thrombin, combined with fibrinogen, is sold under the brand name Fibrimex for use as a binding agent for meat. Both proteins in Fibrimex derives from porcine or bovine blood. According to the manufacturer it can be used to produce new kinds of mixed meats (for example combining beef and fish seamlessly). The manufacturer also states that it can be used to combine whole muscle meat, form and portion these, thus cutting down on production costs without a loss in quality.General secretary Jan Bertoft of Swedish Consumers Association has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat".
See also
Cerastocytin
Fibrin glue
Fibrinogen
PA clan of proteases
The Proteolysis Map
Thrombin generation assay
References
Further reading
External links
The MEROPS online database for peptidases and their inhibitors: S01.217
Kujovich JL (February 2021). Adam MP, Ardinger HH, Pagon RA, et al. (eds.). "Prothrombin Thrombophilia". GeneReviews. Seattle WA: University of Washington, Seattle. PMID 20301327. NBK1148.
Anti-coagulation & proteases on YouTube by The Proteolysis Map-animation
[1] PMAP: The Proteolysis Map/Thrombin
Thrombin: RCSB PDB Molecule of the Month Archived 2013-10-05 at the Wayback Machine
Prothrombin Structure
PDBe-KB provides an overview of all the structure information available in the PDB for Human Thrombin.
PDBe-KB provides an overview of all the structure information available in the PDB for Mouse Thrombin. |
Vitreous hemorrhage | Vitreous hemorrhage is the extravasation, or leakage, of blood into the areas in and around the vitreous humor of the eye. The vitreous humor is the clear gel that fills the space between the lens and the retina of the eye. A variety of conditions can result in blood leaking into the vitreous humor, which can cause impaired vision, floaters, and photopsia.
Symptoms
Common symptoms of vitreous hemorrhage include:
Blurred vision
Floaters – faint cobweb-like apparitions floating through the field of vision
Reddish tint to vision
Photopsia – brief flashes of light in the peripheral visionSmall vitreous hemorrhage often manifests itself as "floaters." A moderate case will often result in dark streaks in the vision, while dense vitreous hemorrhage can significantly inhibit vision.
Causes
There are many factors known to cause vitreous hemorrhage.
Diabetic retinopathy
The most common cause found in adults is diabetic retinopathy. Abnormal blood vessels can form in the back of the eye of a person with diabetes. These new blood vessels are weaker and prone to breaking and causing hemorrhage. Diabetic retinopathy accounts for 31.5–54% of all cases of vitreous hemorrhage in adults in the United States.
Trauma
Some injuries can cause blood vessels in the back of the eye to bleed. Trauma is the leading cause of vitreous hemorrhage in young people, and accounts for 12–18.8% of cases in adults.
Retinal tear or detachment
A tear in the retina can allow fluids from the eye to leak in behind the retina, which causes retinal detachment. When this occurs, blood from the retinal blood vessels can bleed into the vitreous. Retinal tear accounts for 11.4–44% of vitreous hemorrhage cases.
Posterior vitreous detachment
As one gets older, pockets of fluid can develop in the vitreous. When these pockets develop near the back of the eye, the vitreous can pull away from the retina and possibly tear it. Posterior vitreous detachment accounts for 3.7–11.7% of vitreous hemorrhage cases.
Other causes
Less common causes of vitreous hemorrhage make up 6.4–18% of cases, and include:
Proliferative sickle cell retinopathy
Macroaneurysms
Age-related macular degeneration
Terson syndrome
Retinal neovascularization as a result of branch or central retinal vein occlusion
Other
Diagnosis
Vitreous hemorrhage is diagnosed by identifying symptoms, examining the eye, and performing tests to identify the cause. Some common tests include:
Examination of the eye with a microscope
Pupil dilation and examination
An ultrasound examination may be used if the doctor does not have a clear view of the back of the eye
Blood tests to check for specific causes such as diabetes
A CT scan to check for injury around the eye
Referral to a retinal specialist
Complications
Ghost cell glaucoma: Secondary open angle glaucoma caused by degenerated red blood cells.
Treatments
The treatment method used depends on the cause of the hemorrhage. In most cases, the patient is advised to rest with the head elevated 30–45°, and sometimes to put patches over the eyes to limit movement prior to treatment in order to allow the blood to settle. The patient is also advised to avoid taking medications that cause blood thinning (such as aspirin or similar medications).
The goal of the treatment is to fix the cause of the hemorrhage as quickly as possible. Retinal tears are closed by laser treatment or cryotherapy, and detached retinas are reattached surgically.Even after treatment, it can take months for the body to clear all of the blood from the vitreous. In cases of vitreous hemorrhage due to detached retina, long-standing vitreous hemorrhage with a duration of more than 2–3 months, or cases associated with rubeosis iridis or glaucoma, a vitrectomy may be necessary to remove the standing blood in the vitreous.
References
== External links == |
Poroma | Poromas are rare, benign, cutaneous adnexal tumors. Cutaneous adnexal tumors are a group of skin tumors consisting of tissues that have differentiated (i.e. matured from stem cells) towards one or more of the four primary adnexal structures found in normal skin: hair follicles, sebaceous sweat glands, apocrine sweat glands, and eccrine sweat glands. Poromas are eccrine or apocrine sweat gland tumors derived from the cells in the terminal portion of these glands ducts. This part of the sweat gland duct is termed the acrosyringium and had led to grouping poromas in the acrospiroma class of skin tumors (syringofibroadenomas and syringoacanthomas are classified as acrospiromas). Here, poromas are regarded as distinct sweat gland tumors that differ from other sweat gland tumors by their characteristic clinical presentations, microscopic histopathology, and the genetic mutations that their neoplastic cells have recently been found to carry.As currently viewed, there are 4 poroma variants based on their predominant cell types and extent of the their tumor tissues presence in the epidermis and dermis: 1) Hidroacanthoma simplex poromas are confined to the epidermis, i.e. uppermost layer of the skin. 2) Dermal duct poromas are confined to the dermis, i.e. layer of skin between the epidermis and subcutaneous tissues. 3) Hidradenomas have recently been sub-classified into two groups; 95% are termed clear cell hidradenomas and have features suggesting that they derive from apocrine sweat glands while the remaining 5% are termed poroid hidradenomas and have features suggesting that they derive from eccrine sweat glands. And 4) eccrine poromas are eccrine sweat gland tumors that consist of three cell types (see Histopathology section).Poromas usually occur as single, small, skin tumors that develop in middle aged to elderly individuals. They may occur anywhere on the body, but are most commonly seen on the head, neck, and extremities. They seldom cause symptoms. While benign, long-standing poromas have, in very rare cases, progressed to malignant forms termed porocarcinomas. Poromas are treated by excision; their removal is almost always curative.
Presentation
Poromas are rare tumors that in two large review studies represented 0.0058% and 0.134% of all skin tumors; dermal duct tumors are the rarest form of the poromas, representing only 3.3% of these tumors in 3 studies examining 675 poroid neoplasms. They usually occur in the elderly population (mean age 65.1–66.6 in different studies) as small (<2 centimeters), solitary dome-shaped papules, plaques, or nodules, that are skin-colored, pink, red, white, or blue and range from smooth to wart-like, ulcerative, or pyogenic granuloma-like lesions. They may be located on the palms of the hands, soles of the feet, trunk, face, neck, or other cutaneous surfaces such as the areola, nipple, or other areas of the breast, on the scrotum, or on the vulva. Rarely, individuals present with multiple poromas either in one or widespread areas; these cases are termed poromatosis.Poromas present more commonly in: pregnancy; patients treated with electron therapy for mycosis fungoides; sites of chronic radiation dermatitis caused by long-term radiation exposure; patients who received chemotherapy with or with radiation therapy (these patients have often presented with poromatosis); individuals with underlying skin conditions such as hypohidrotic ectodermal dysplasia and Bowen’s disease (i.e. a form of squamous cell carcinoma that is localized to the outermost layer of the skin); and skin plaques of individuals with the congenital disease, nevus sebaceous.Poromas are usually slow growing and asymptomatic but some individuals report that their lesions are itchy, mildly tender, or painful. An existing poroma that develops spontaneous bleeding, ulceration, sudden itching, pain, or rapid growth over a short period of time may indicate that it has become a cancerous porocarcinoma. These cancers may metastasize to local lymph nodes, nearby or distal skin sites, bones, bladder, breast, retroperitoneum, ovary, liver, lung, brain, or stomach. However, the progression of a poroma to a porocarcinoma is very rare, i.e. less than 1% of cases.
Histopathology
Microscopic histopathological examinations of the tumor tissues of all poroma variants stained with hematoxylin and eosin dyes reveal: a) basophilic "poroid cells" (i.e. small, cuboid-shaped cells with oval nuclei which resemble cells in the peripheral layer of the distal portion of eccrine sweat gland ducts) that may form cords and broad columns extending downward from the epidermis; b) larger cuticular cells (i.e. squamous epithelial-like eosinophilic cells that resemble the luminal cells lining eccrine sweat gland ducts); and in some cases c) clear cells (i.e. cells with small nuclei surrounded by pale cytoplasm). Poroma tumor tissues may appear highly vascularized and/or have areas of necrosis, i.e. dead or dying cells. Hidroacanthoma simplex variants are mainly composed of poroid cells, few cuticular cells, and no clear cells and are confined to the epidermis; dermal ductal variants are mostly confined to the superficial dermis and are composed of small solid and cystic nodular aggregates of poroid, cuticular, and clear cells; poroid hidradenoma variants have large aggregates of solid and cystic components and extend deeper into the dermis or even subcutis; and eccrine poroma variants are composed of all three cell types but are primarily located in the epidermis and superficial dermis. Poromas may have 2 or more of these variants in the same tumor tissue and the variants typically have histopathology findings that are not clearly distinguishable from each other.
Immunohistochemistry
As detected by immunohistochemical analyses, the poroma tumor cells, regardless of variant type, test positive when probed with the AE1/AE3 antibody cocktail that detects various cytokeratin proteins. Tumor cells of the four variants also commonly express carcinoembryonic antigen (i.e. CEA) or MUC1 (also termed EMA) and, except for the hidroacanthoma simplex variant, the carcinoembryonic antigen and MUC1 protein.
Gene abnormalities
The four poroma variants contain at least one of two YAP1 fusion genes, i.e. abnormal genes caused by a mutation which merges a part of the YAP1 gene fused to part of either the Nuclear protein in testis gene (also termed the NUTM1 gene) or the MAML2 gene to form the YAP1::NUTM1 and YAP::MAML2 fusion genes, respectively. Rarely, they may also contain a WWTR1::NUTM1 fusion gene. The YAP1::MAML2 fusion gene is detected in ~63% of poromas, the YAP1::NUTM1 fusion in 20.2% to 66% of poromas, and the WWTR1::NUTM1 fusion gene in 1% of poromas. YAP1 and WNTR1 fusion genes have been implicated in the initiation, aggressiveness, metastasis, and/or therapy resistance of various neoplasms. Studies are needed to determine if they play a role in the development and/or progression of poromas.
Diagnosis
The great diversity, rarity, and complex terminology of poromas make their diagnosis challenging. They have been misdiagnosed as other types of skin tumors including porocarcinomas, basal cell carcinomas, pyogenic granulomas, skin tags, plantar warts (i.e. warts on the palms or soles), fibromas, hemangiomas, pigmented moles, seborrheic keratosis, trichilemmomas, melanomas, Kaposi sarcomas, and other adnexal tumors. Poromas are typically diagnosed based on their clinical presentation; microscopic histopathology showing tumor tissues consisting of poroid, cuticular, and/or clear cells; and, in unclear cases, the presence of tumor cells that express a YAP1::NUTM1, YAP::MAML2, and/or WWTR1::NUTM1 fusion gene. However, these fusion genes also occur in porocarcinomas and cannot be used to differentiate poromas from their malignant counterpart. Poromas and porocarcinomas are distinguished based on their clinical findings and histopathology, e.g. a higher Ki67 labeling index and aberrant expression of p53, RB, and p16 proteins are more frequent in porocarcinoma (see Diagnosis of porcarcinomas). Dermatoscopy, particularly when revealing a "leaf- and flower-like pattern" in a skin tumor, has been used as a strong indicator that the lesion is a poroma, but confirmation of this diagnosis ultimately relies on histopathological analyses.There is no clear-cut evidence that diagnosing a poromas variant type carries any clinical or therapeutic significance.
Treatment
Superficial poroma tumors have been treated by shaving (i.e. removal using a sharp razor) or electrosurgical destruction. Deeper lesions have been removed by excisional biopsy (i.e. a procedure in which an entire tumorous or suspicious area is removed) or simple surgical excision. Since poromas are almost always benign tumors and rarely recur after their removal, these treatments are in general curative.
See also
Porocarcinoma
Hidradenoma
== References == |
Tyrosinemia type I | Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. Clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe.Tyrosinemia type I is an autosomal recessive disorder caused by mutations in both copies of the gene encoding the enzyme fumarylacetoacetate hydrolase (FAH). FAH is a metabolic enzyme that catalyzes the conversion of fumarylacetoacetate to fumarate and acetoacetate. It is expressed primarily in the liver and kidney. Loss of FAH activity results in the accumulation of certain metabolic intermediates in the tyrosine catabolic pathway. These compounds are toxic to cells and lead to differential gene expression and apoptosis in high concentrations. HT1 is diagnosed when elevated levels of succinylacetone (SA), one of the metabolites in this pathway, is detected in blood and urine samples.While there is no cure for tyrosinemia type I, management of the disease is possible utilizing dietary restrictions and medications. A diet low in tyrosine and phenylalanine is utilized indefinitely once a diagnosis is suspected or confirmed. Additionally, the drug nitisinone (brand name Orfadin) is prescribed and continued indefinitely in order to combat liver and kidney damage, promoting normal function of these organs. Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1.Tyrosinemia type I is especially prevalent in the Saguenay-Lac Saint-Jean region of Quebec, where the prevalence is 1 in 1,850 births. It is most common among those with French-Canadian ancestry and this frequency of infliction has been attributed to the founder effect. There are five other known types of tyrosinemia, all of which derange the metabolism of tyrosine in the human body. They are distinguished by their symptoms and genetic cause.
Signs and symptoms
Type 1 tyrosinemia typically presents in infancy as failure to thrive and hepatomegaly. The primary effects are progressive liver and kidney dysfunction. The liver disease causes cirrhosis, conjugated hyperbilirubinemia, elevated AFP, hypoglycemia and coagulation abnormalities. This can lead to jaundice, ascites and hemorrhage. There is also an increased risk of hepatocellular carcinoma.The kidney dysfunction presents as Fanconi syndrome: Renal tubular acidosis, hypophosphatemia and aminoaciduria. Cardiomyopathy, neurologic and dermatologic manifestations are also possible. The urine has an odor of cabbage or rancid butter.The presentation of symptoms of tyrosinemia type 1 in terms of timing is broken into three categories: acute, sub-acute, and chronic.The acute classification typically is presented clinically between birth and 6 months of age. The common presentation in an acute case is synthetic liver failure, marked by the lack of formation of coagulation factors in blood. Patients are prone to infections at this stage accompanied by fever, vomiting, increased tendency to bleed, and diarrhea along with bloody feces as manifestations of sepsis. Other symptoms include enlarged liver, jaundice, and excess abdominal fluid.Sub-acute cases present between 6 months and the first year of life and the severity of liver disease is lessened to an extent. Again, synthetic function of the liver in terms of blood coagulation factors is impaired in addition to enlargement of the liver and spleen. The infant may also display a failure to thrive as their growth is limited by the disease. This growth impairment can manifest itself in rickets, which is the softening of bones.The final classification, chronic HT1, is detected with presentations occurring after one year of life. The course of the disease up to this point can lead to different ailments affecting the liver. Cirrhosis, liver failure, or cancer of the liver may present as a result of chronic liver disease. Additional symptoms common in this classification include cardiomyopathy, renal disease, and acute neurological crises.
Liver
The liver is the organ affected most by Tyrosinemia Type I due to the high level of expression of the gene for fumarylacetoacetate hydrolase (FAH) in liver cells. The production of blood coagulation factors by the liver is disrupted, causing hemophiliac-like symptoms. Acute liver failure is common, especially in early life. Additionally, the synthesis of albumin in the liver may be defective, therefore leading to hypoalbuminemia. As the disease progresses, cirrhosis is common. This can lead to a fatty liver and the development of tumors in areas affected by this scarring of liver tissue. These scars are known as nodules. There is a 37% chance of developing a hepatocellular carcinoma (HCC) for untreated patients.
Renal and neurological manifestations
Many patients display impaired kidney function and neurological symptoms. In addition to liver cells, kidney cell expression involves expression of the gene for FAH. Kidney failure is a potential result of impaired kidney function, but the most common symptom associated with renal dysfunction is hypophosphatemic rickets. Neurological manifestations are characterized by acute neurological crises due to overaccumulation of porphyrin. These crises are characterized by porphyria. They typically follow an infection. Patients can present with a variety of varied symptoms including paresthesias, abdominal pain, pain-induced seizures, and can result in self-mutilation in response to this pain. Episodes can last for 1–7 days and can lead to neuropathy.
Genetics
Tyrosinemia type I is an autosomal recessive inherited condition. Mutant alleles in the gene are inherited from both parents. The genetic mutation occurs to the fumarylacetoacetate hydrolase (FAH) enzyme gene, located on chromosome 15. The most common mutation is IVS12+5(G->A) which is a mutation in the splice site consensus sequence of intron 12, therefore affecting exon 12. A second allele is the IVS6-1(G-T) mutation. This mutation results in a nonfunctional enzyme.Type 1 tyrosinemia is inherited in an autosomal recessive pattern.
Pathophysiology
Fumarylacetoacetate hydrolase catalyzes the final step in the degradation of tyrosine - fumarylacetoacetate to fumarate, acetoacetate and succinate. Fumarylacetoacetate accumulates in hepatocytes and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death and dysfunctional gene expression which alters metabolic processes like protein synthesis and gluconeogenesis. The increase in fumarylacetoacetate inhibits previous steps in tyrosine degradation leading to an accumulation of tyrosine in the body. Tyrosine is not directly toxic to the liver or kidneys but causes dermatologic and neurodevelopmental problems.
Tyrosine metabolic pathway
Fumarylacetoacetate hydrolase (FAH) is the final enzyme in the tyrosine metabolic pathway. The mutation of FAH enzyme results in nonfunctional FAH in all cells expressing this gene and thus metabolizing tyrosine is impaired. FAH catalyzes the conversion of fumarylacetoacetate to fumarate and acetoacetate. Loss of FAH results in the accumulation of upstream compounds in the catabolic pathway. These include maleylacetoacetate (MAA) and fumarylacetoacetate (FAA). MAA and FAA are converted to succinylacetoacetate (SAA) which is then catabolized to succinylacetone (SA).The accumulation of MAA, FAA, and SA in cells inhibits the breakdown of thiol derivatives, leading to post-translational modifications to the antioxidant glutathione. This inhibits the antioxidant activity of glutathione, leading to reactive oxygen species (ROS) damaging cell components. Over time, the combined effect of accumulation of toxic metabolic intermediates and elevated ROS levels in liver and kidney cells leads to apoptosis in these tissues which ultimately results in organ failure. Accumulated SA in liver and kidney cells results in its release into the bloodstream, which leads to secondary effects. SA inhibits the enzyme 5-ALA dehydratase which converts aminolevulinic acid (5-ALA) into porphobilinogen, a precursor to porphyrin. Consequently, porphyrin deposits form in the bloodstream and cause neuropathic pain, leading to the acute neurological crises experienced by some patients. Additionally. SA can function to inhibit renal tubular function, the synthesis of heme, and the immune system.The accumulation of unprocessed tyrosine itself in the blood stream as a consequence of deficient catabolism can also lead to disruption of hormonal signaling and neurotransmission. Tyrosine is a precursor molecule required for synthesis of several neurotransmitters and hormones, mainly Dopamine, norepinephrine, and thryoxine. Excessive synthesis of these molecules due to elevated tyrosine levels can impair physical growth, motor function, and speech development.
Diagnosis
Beyond the identification of physical clinical symptoms outlined above, the definitive criterion for diagnostic assessment of Tyrosinemia Type I is elevated succinylacetone (SA) in blood and urine. Elevated SA levels are not associated with any other known medical condition, so there is minimal risk of misdiagnosis. Quantitation of tyrosine levels is also used as a diagnostic but is less reliable due to high false positive and false negative rates. Newborns are not generally screened for HT1 due to rarity of the condition and lack of apparent symptoms at time of birth. However, prompt assessment upon the manifestation of physical symptoms such as fever, vomiting, increased tendency to bleed, diarrhea along with bloody feces, and jaundice is critical for improving long term prognosis.
Management
The primary treatment for type 1 tyrosinemia is nitisinone and restriction of tyrosine in the diet. Nitisinone inhibits the conversion of 4-OH phenylpyruvate to homogentisic acid by 4-Hydroxyphenylpyruvate dioxygenase, the second step in tyrosine degradation. By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Previously, liver transplantation was the primary treatment option and is still used in patients in whom nitisinone fails.Clinical treatment of HT1 relies on medications and strict regulation of diet. Nitisinone and dietary restrictions that decrease the amount of tyrosine and phenylalaine absorbed from the GI tract during protein digestion are used in combination as therapeutic measures that control the disease state if they are continued indefinitely. If not, there is a lack of control over the disease, resulting in continued liver and kidney damage, contributing to organ failure and death. In this case, a liver transplant may be required. Levels of SA are monitored throughout treatment in order to assess treatment effectiveness.
Diet
The prescribed diet for treatment of HT1 is low in protein. Patients received amino acid supplements lacking tyrosine and phenylalanine in order to acquire sufficient protein. It is recommended that tyrosine levels remain below 500 μmol/L. Phenylalnine is the precursor to tyrosine. The ideology behind maintaining low tyrosine levels is two-fold. Firstly, it prevents the toxic metabolic intermediates from accumulating as a result of the dysfunctional tyrosine metabolic pathway. Prior to the introduction of nitisinone, this was the main treatment measure. Secondly, the mechanism of action of nitisinone is prevention of any tyrosine metabolism, thus it is important to prevent tyrosine from accumulating. Dietary protein consumption while taking nitisinone can also lead to side effects affecting the ocular system, which are easily reversed by removing protein from the diet.
Medication
Nitisinone is prescribed ultimately to reduce the accumulation of toxic metabolic intermediates, such as succinylacetate, which are toxic to cells. It modifies the function of 4-hydrooxyphenylpyruvate dioxygenase by acting as a competitive inhibitor. 4-hydrooxyphenylpyruvate dioxygenase functions to convert 4-hydroxyphenylpyruvate to homogentisate as the second enzymatic reaction in the tyrosine catabolic pathway. This prevents the further catabolism of tyrosine. It is recommended that nitisinone treatment begins immediately following a confirmed or suspected case of HT1. It is supplied orally as a capsule or suspension in dose increments of 2 mg, 5 mg, 10 mg, or 20 mg or 4 mg/mL respectively. The starting dose is 1 mg/kg one time daily or 2 mg/kg one time daily for 48 hours if the patient is experiencing acute liver failure. Patient responsiveness to nitisinone is assessed by measuring blood coagulation activity and SA levels in blood and urine. Patients should display a positive response within 24–48 hours of first dose. Establishment of the long-term dosage will vary from patient to patient. It is recommended that nitisinone levels be maintained at 30-50 μM in the blood stream.
Prognosis
Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1. A study regarding the efficacy of treatment with nitisinone and dietary restrictions found that 93% of people survived at two years, four years, and six years indicating the prognosis of stabilizing the HT1 disease state is positive.
Epidemiology
Tyrosinemia type I affects males and females in equal numbers. Its prevalence has been estimated to be 1 in 100,000 to 120,000 births worldwide. HT1 is especially prevalent in the Saguenay-Lac Saint-Jean region of Quebec is one in 1,850 births. The elevated frequency of this disorder within individuals of French-Canadian ancestry in Quebec is believed to be due to reduced genetic heterogeneity within the original founder population for the Saguenay-Lac Saint-Jean region. The initial settlement of Saguenay Lac-Saint-Jean (SLSJ) occurred between 1838 and 1911. From a total of 28,656 settlers, 75 percent originated from the neighboring Charlevoix region. The settling of the Charlevoix region itself started in 1675 when 599 founders of mostly French descent moved to this region from the Quebec City area.Worldwide, type I tyrosinemia affects about 1 person in 100,000. This type of tyrosinemia is much more common in Quebec, Canada. The overall incidence in Quebec is about 1 in 16,000 individuals. In the Saguenay-Lac-Saint-Jean region of Quebec, type 1 tyrosinemia affects 1 person in 1,846. The carrier rate has been estimated to be between 1 in 20 and 1 in 31.
History
Nitisinone was first used to clinically treat tyrosinemia type I in 1991. Nitisinone was approved by the European Medicine Agency (EMA) under exceptional circumstances in 2005. Originally, nitisinone was developed as a weed-killer by Zeneca Agrochemicals. It was epidemiologically observed that the growth of plants and weeds was inhibited under the bottlebrush plant (Callistemon citrinus). It became clear that neither the shade nor the litterfall of these plants was responsible for the suppression of plant and weed growth. Rather, a substance – which was identified as leptospermone – in the soil under the bottlebrush plant was shown to have bleaching activity on the emerging plants. The allelochemical leptospermone was extracted from the bottlebrush plant and chemically characterized. Leptospermone belongs to the triketone family and inhibits chloroplast development due to a lack of plastoquinone secondary to hepatic 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition; thus, it served as a blueprint for the synthesis of nitisinone.In 1932, Grace Medes first described "a new disorder of tyrosine metabolism," She coined the condition "tyrosinosis" after observing 4-hydroxyphenylpyruvate in the urine of a 49-year-old man with myasthenia gravis. She proposed that the metabolic defect in this patient was a deficiency of 4-hydroxyphenylpyruvate dioxygenase, but her case remains puzzling and has since been assigned a separate OMIM number. The first typical patient with hepatorenal tyrosinemia was described in 1956 by Margaret D Baber at Edgware General Hospital in Middlesex, England. Starting the following year, Kiyoshi Sakai and colleagues, at the Jikei University School of Medicine in Tokyo, published 3 reports describing the clinical, biochemical, and pathological findings of a 2-year-old boy with hepatorenal tyrosinemia who was then thought to have an "atypical" case of tyrosinosis. Between 1963 and 1965, Swedish pediatrician Rolf Zetterström and colleagues at the Karolinska Institute in Sweden published the first detailed clinical account of hepatorenal tyrosinemia and its variants. Shortly thereafter, a Canadian group also described the clinical and laboratory findings of hepatorenal tyrosinemia. Both the Scandinavian and Canadian groups suggested that the Japanese patients described earlier by Sakai and colleagues had the same disorder, ie, hepatorenal tyrosinemia. In 1965, doubts emerged that the underlying biochemical cause of hepatorenal tyrosinemia was a defective form of the 4-hydroxyphenylpyruvate dioxygenase enzyme. In 1977, Bengt Lindblad and colleagues at the University of Gothenburg in Sweden demonstrated that the actual defect in causing hepatorenal tyrosinemia involved the fumarylacetoacetate hydrolase enzyme. This was subsequently confirmed using direct enzyme assays.
Research directions
As of April 2020, two new clinical trials, are underway in the USA for a Mass Spectrometry-based biomarker for the early and sensitive diagnosis of Tyrosinemia type 1 from blood plasma.
References
External links
Reference, Genetics Home. "Tyrosinemia". Genetics Home Reference. Retrieved 2020-05-01.
"Tyrosinemia Type 1". NORD (National Organization for Rare Disorders). Retrieved 2020-05-01. |
Cervical lymphadenopathy | Cervical lymphadenopathy refers to lymphadenopathy of the cervical lymph nodes (the glands in the neck). The term lymphadenopathy strictly speaking refers to disease of the lymph nodes, though it is often used to describe the enlargement of the lymph nodes. Similarly, the term lymphadenitis refers to inflammation of a lymph node, but often it is used as a synonym of lymphadenopathy.
Cervical lymphadenopathy is a sign or a symptom, not a diagnosis. The causes are varied, and may be inflammatory, degenerative, or neoplastic. In adults, healthy lymph nodes can be palpable (able to be felt), in the axilla, neck and groin. In children up to the age of 12 cervical nodes up to 1 cm in size may be palpable and this may not signify any disease. If nodes heal by resolution or scarring after being inflamed, they may remain palpable thereafter. In children, most palpable cervical lymphadenopathy is reactive or infective. In individuals over the age of 50, metastatic enlargement from cancers (most commonly squamous cell carcinomas) of the aerodigestive tract should be considered.
Classification
Cervical lymphadenopathy can be thought of as local where only the cervical lymph nodes are affected, or general where all the lymph nodes of the body are affected.
Causes
Infection
Pericoronitis
Staphylococcal lymphadenitis
Mycobacterial lymphadenitis
Rubella
Cat scratch fever
Infectious mononucleosis
Streptococcal pharyngitis
Viral respiratory infection
Toxoplasmosis
Tuberculosis
Brucellosis
Primary herpes simplex infection (primary herpetic gingivostomatitis)
Syphilis (secondary)
Cytomegalovirus
Human immunodeficiency virus
Histoplasmosis
Chicken pox
Malignancy
Lymph nodes may become enlarged in malignant disease. This cervical lymphadenopathy may be reactive or metastatic. Alternatively, enlarged lymph nodes may represent a primary malignancy of the lymphatic system itself, such as lymphoma (both Hodgkins and non-Hodgkins), lymphocytic leukemia, Lymphadenopathy that lasts less than two weeks or more than one year with no progressive size increase has a very low likelihood of being neoplastic.Metastatic lymph nodes are enlarged because tumor cells have detached from the primary tumor and started growing in the lymph node ("seeded"). Since cancer generally occurs more frequently in older people, this kind of lymphadenopathy is more common in older persons. Metastatic lymph nodes tend to feel hard and may be fixed to underlying tissues and may or may not be tender. Usually the lymph nodes that directly drain the area of the cancer are affected by the spread (e.g. Sometimes metastatic cervical lymph node is detected before the main cancer). In such cases, this discovery leads to a search for the primary malignancy, firstly in the nearby area with endoscopy, "blind" biopsies, and tonsillectomy on the side of the lymphadenopathy. If no tumor is found, then the rest of the body is examined, looking for lung cancer or other possible sites. If still no primary tumor is detected, the term "occult primary" is used.In lymphoma, usually there are multiple enlarged nodes which feel rubbery to palpation.
Rhabdomyosarcoma
Neuroblastoma
Other causes
Surgical trauma, e.g. following a biopsy in the mouth
Kawasaki disease,
Kikuchi-Fujimoto disease
Rosai-Dorfman disease
Castleman disease
Sarcoidosis
Lupus erythematosus
Cyclic neutropenia
Orofacial granulomatosis
Diagnosis
In possible malignancy, it is routine to perform a throat examination including mirror and/or endoscopy.On ultrasound, B-mode imaging depicts lymph node morphology, whilst power Doppler can assess the vascular pattern. B-mode imaging features that can distinguish metastasis and lymphoma include size, shape, calcification, loss of hilar architecture, as well as intranodal necrosis. Soft tissue edema and nodal matting on B-mode imaging suggests tuberculous cervical lymphadenitis or previous radiation therapy. Serial monitoring of nodal size and vascularity are useful in assessing treatment response.Fine needle aspiration cytology (FNAC) has a sensitivity and specificity percentages of 81% and 100%, respectively, in the histopathology of malignant cervical lymphadenopathy. PET-CT has proven to be helpful in identifying occult primary carcinomas of the head and neck, especially when applied as a guiding tool prior to panendoscopy, and may induce treatment related clinical decisions in up to 60% of cases.
== References == |
African tick bite fever | African tick bite fever (ATBF) is a bacterial infection spread by the bite of a tick. Symptoms may include fever, headache, muscle pain, and a rash. At the site of the bite there is typically a red skin sore with a dark center. The onset of symptoms usually occurs 4–10 days after the bite. Complications are rare but may include joint inflammation. Some people do not develop symptoms.Tick bite fever is caused by the bacterium Rickettsia africae. The bacterium is spread by ticks of the Amblyomma type. These generally live in tall grass or bush rather than in cities. The diagnosis is typically based on symptoms. It can be confirmed by culture, PCR, or immunofluorescence.There is no vaccine. Prevention is by avoiding tick bites by covering the skin, using DEET, or using permethrin treated clothing. Evidence regarding treatment, however, is limited. The antibiotic doxycycline appears useful. Chloramphenicol or azithromycin may also be used. The disease will also tend to resolve without treatment.The disease occurs in sub-Saharan Africa, the West Indies, and Oceania. It is relatively common among travelers to sub-Saharan Africa. Most infections occur between November and April. Outbreaks of the disease may occur. The earliest descriptions of the condition are believed to be from 1911. African tick bite fever is a type of spotted fever. It has previously been confused with Mediterranean spotted fever.
Signs and symptoms
African tick bite fever is often asymptomatic or mild in clinical presentation and complications are rare. The onset of illness is typically 5–7 days after the tick bite, although in some cases it may take up to 10 days for symptoms to occur. Symptoms can persist for several days to up to three weeks. Common presenting symptoms include:
Fever
Headache
Muscle aches
Inoculation eschar, which is dead, often black, tissue around a bite site (see photo above)
Eschars may or may not be present. Amblyomma ticks actively attack cattle or humans and can bite more than once. In African tick bite fever, unlike what is typically seen with other Rickettsial spotted fevers when only one eschar is identified, multiple eschars may be seen and are considered pathognomonic.
Swollen lymph nodes near the site of the bite
Maculopapular and/or vesicular rash
Complications
Complications are rare and are not life-threatening. No deaths due to African tick bite fever have been reported. Reported complications include:
Prolonged fever > 3 weeks in duration
Reactive arthritis
Moderate to severe headache
Cause
Bacteriology
Rickettsia africae is a gram-negative, obligate intracellular, pleomorphic bacterium. It belongs to the genus Rickettsia, which includes many bacterial species that are transmitted to humans by arthropods.
Vectors
Two species of hard ticks, Amblyoma variegatum and Amblyomma hebraeum are the most common vectors of R. africae. Typically, Amblyomma hebraeum transmits the bacteria in South Africa while Amblyoma variegatum carries R. africae throughout West, Central and East Africa and through the French West Indies. Other species of Amblyomma in sub-Saharan Africa can also transmit R. africae and it may be that up to 100% of Amblyomma ticks in sub-Saharan Africa carry R. africae. Amblyomma ticks are most active from November to April. These tick species frequently feed on cattle and other livestock, but can also be found feeding on wild animals in areas where farm animals are not found. Unlike other hard tick species, which passively seek hosts by clinging to plants and waiting for a potential host to brush by in passing, the Amblyomma hard ticks actively seek out hosts.Groups of tourists visiting Africa have returned to their own countries and were diagnosed there as having been infected.Up until 1998, it was thought that only ticks in sub-Saharan Africa carried R. africae. However, a case of locally transmitted African tick bite fever in the French West Indies led to the discovery of R. africae carried by Amblyomma varigatum ticks introduced through cattle shipped from Senegal to Gaudeluope more than a century ago. R. africae has been isolated from ticks on several Caribbean islands, though the only cases in humans in the Caribbean have occurred in the French West Indies. R. africae has also been found in Amblyomma loculosum ticks in Oceania.
Pathogenesis
After the rickettsia bacteria infects humans through a tick bite, it invades endothelial cells in the circulatory system (veins, arteries, capillaries). The body then releases chemicals that cause inflammation, resulting in the characteristic symptoms like headache and fever. The hallmark of all rickettsial diseases is a histology (cellular) finding called lymphohistiocytic vasculitis that involves immune cell deposition into the endothelial cells that make up vessels. This occurs secondary to the chemicals mentioned above, as well as damage from the infection, and involves signals to immune cells (T cells and macrophages) to come to the site of the infection.Rickettsia bacteria species like R. africae replicate around the area of the initial tick bite, causing necrosis (cell death) and lymph node inflammation. This is the cause of the characteristic eschar.
Diagnosis
Many patients with ATBF who live in areas with a high number of infections (Africa and the West Indies) do not visit a doctor, as most patients only have mild symptoms. This disease can, however, cause more serious symptoms in travelers who have never been exposed to the Rickettsia africae bacterium before and are not immune. Travelers who present to a doctor after a trip to affected areas can be hard to diagnose, as many tropical diseases cause a fever similar to that of ATBF. Other diseases that may look similar are malaria, dengue fever, tuberculosis, acute HIV and respiratory infections. In addition to questions about symptoms, doctors will ask patients for an accurate travel history and whether he/she was near animals or ticks. Microbiological tests are available for doctors, but are expensive and often must be done by special laboratories.The antibiotic treatment available for rickettsiae infections has very few side effects, so if a doctor has a high suspicion of the disease, he or she may simply treat without doing more laboratory tests.
Blood tests
Diagnosis of ATBF is mostly based on symptoms, as many laboratory tests are not specific for ATBF. Common laboratory test signs of ATBF are a low white blood cell count (lymphopenia) and low platelet count (thrombocytopenia), a high C-reactive protein, and mildly high liver function tests.
Microbiological tests
Biopsies or cultures of a persons tick wound (eschar) are used to diagnose ATBF. However, this requires special culture media and can only be done by a laboratory with biohazard protection. There are more specialized laboratory tests available that use quantitative polymerase chain reactions (qPCR), but can only be done by laboratories with special equipment. Immunofluorescence assays can also be used, but are hard to interpret because of cross-reactions with other rickettsiae bacteria.
Prevention
Prevention of ATBF centers around protecting oneself from tick bites by wearing long pants and shirt, and using insecticides like DEET on the skin. Travelers to rural areas in Africa and the West Indies should be aware that they may come in contact with ATBF tick vectors. Infection is more likely to occur in people who are traveling to rural areas or plan to spend time participating in outdoor activities. Extra caution should be taken in November - April, when Amblyomma ticks are more active. Inspection of the body, clothing, gear, and any pets after time outdoors can help to identify and remove ticks early.
Treatment
African tick bite fever is usually mild, and most patients do not need more than at-home treatment with antibiotics for their illness. However, because so few patients with this infection visit a doctor, the best antibiotic choice, dose and length of treatment are not well known. Typically doctors treat this disease with antibiotics that have been used effectively for the treatment of other diseases caused by bacteria of similar species, such as Rocky Mountain Spotted Fever.
For mild cases, people are usually treated with one of the following:
doxycycline
chloramphenicol
ciprofloxacinIf a person has more severe symptoms, like a high fever or serious headache, the infection can be treated with doxycycline for a longer amount of time. Pregnant women should not use doxycycline or ciprofloxacin as both antibiotics can cause problems in fetuses. Josamycin has been used effectively for treatment of pregnant women with other rickettsial diseases, but it is unclear if it has a role in the treatment of ATBF.
Epidemiology
Cases of African tick bite fever have been more frequently reported in the literature among international travelers. Data examining rates in local populations are limited. Among locals who live in endemic areas, exposure at a young age and mild symptoms or lack of symptoms, as well as decreased access to diagnostic tools, may lead to decreased diagnosis. In Zimbabwe, where R. africae is endemic, one study reported an estimated yearly incidence of 60-80 cases per 10,000 patients.Looking at published data over the past 35 years, close to 200 confirmed cases of African tick bite fever in international travelers have been reported. The majority (~80%) of these cases occurred in travelers returning from South Africa.
See also
Boutonneuse fever
Rocky Mountain spotted fever
Flea-borne spotted fever
References
== External links == |
Acute zonal occult outer retinopathy | Acute zonal occult outer retinopathy (AZOOR) is an inflammatory retinopathy in the category of white dot syndromes typified by acute loss of one or more zones of outer retinal function associated with photopsia, minimal funduscopic changes and abnormal electroretinography findings.This retinal disease was first described by Donald Gass in 1992. Relatively little is known about the condition.
Risk factors
Caucasian females in their mid-thirties appear to be most susceptible but the disease may affect anyone regardless of age, sex or race.
Pathophysiology
The disease mechanism is unknown but it is believed that it may be caused by a virus, or an auto immune response.
References
== External links == |
Friedreichs ataxia | Friedreichs ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years of age. Many develop hypertrophic cardiomyopathy and require a mobility aid such as a cane, walker, or wheelchair in their teens. As the disease progresses, some affected people lose their sight and hearing. Other complications may include scoliosis and diabetes mellitus.
The condition is caused by mutations in the FXN gene on chromosome 9, which makes a protein called frataxin. In FRDA, cells produce less frataxin. Degeneration of nerve tissue in the spinal cord causes the ataxia; particularly affected are the sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum. The spinal cord becomes thinner, and nerve cells lose some myelin sheath.
No effective treatment is known, but several therapies are in trials. FRDA shortens life expectancy due to heart disease, but some people can live into their 60s or older.
FRDA affects one in 50,000 people in the United States and is the most common inherited ataxia. Rates are highest in people of Western European descent. The condition is named after German physician Nikolaus Friedreich, who first described it in the 1860s.
Symptoms
Symptoms typically start between the ages of 5 and 15, but in late-onset FRDA, they may occur after age 25 years. The symptoms are broad, but consistently involve gait and limb ataxia, dysarthria and loss of lower limb reflexes.
Classical symptoms
There is some variability in symptom frequency, onset and progression. All individuals with FRDA develop neurological symptoms, including dysarthria and loss of lower limb reflexes, and more than 90% present with ataxia. Cardiac issues are very common with early onset FRDA . Most individuals develop heart problems such as enlargement of the heart, symmetrical hypertrophy, heart murmurs, atrial fibrillation, tachycardia, hypertrophic cardiomyopathy, and conduction defects. Scoliosis is present in about 60%. 7% of people with FRDA also have diabetes and having diabetes has an adverse impact on people with FA, especially those that show symptoms when young.
Other symptoms
People who have been living with FRDA for a long time may develop other complications. 36.8% experience decreased visual acuity, which may be progressive and could lead to functional blindness. Hearing loss is present in about 10.9% of cases. Some patients report bladder and bowel symptoms. Advanced stages of disease are associated with supraventricular tachyarrhythmias, most commonly atrial fibrillation.Other later stage symptoms can include, cerebellar effects such as nystagmus, fast saccadic eye movements, dysmetria and loss of coordination (truncal ataxia, and stomping gait). Symptoms can involve the dorsal column such as the loss of vibratory sensation and proprioceptive sensation.The progressive loss of coordination and muscle strength leads to the full-time use of a wheelchair. Most young people diagnosed with FRDA require mobility aids such as a cane, walker, or wheelchair by early 20s.
The disease is progressive, with increasing staggering or stumbling gait and frequent falling. By the third decade, affected people lose the ability to stand or walk without assistance and require a wheelchair for mobility.
Early-onset cases
Non-neurological symptoms such as scoliosis, pes cavus, cardiomyopathy and diabetes are more frequent amongst the early-onset cases.
Genetics
FRDA is an autosomal-recessive disorder that affects a gene (FXN) on chromosome 9, which produces an important protein called frataxin.In 96% of cases, the mutant FXN gene has 90–1,300 GAA trinucleotide repeat expansions in intron 1 of both alleles. This expansion causes epigenetic changes and formation of heterochromatin near the repeat. The length of the shorter GAA repeat is correlated with the age of onset and disease severity. The formation of heterochromatin results in reduced transcription of the gene and low levels of frataxin. People with FDRA might have 5-35% of the frataxin protein compared to healthy individuals. Heterozygous carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms.In about 4% of cases, the disease is caused by a (missense, nonsense, or intronic) point mutation, with an expansion in one allele and a point mutation in the other. A missense point mutation can have milder symptoms. Depending on the point mutation, cells can produce no frataxin, nonfunctional frataxin, or frataxin that is not properly localized to the mitochondria.
Pathophysiology
FRDA affects the nervous system, heart, pancreas, and other systems.Degeneration of nerve tissue in the spinal cord causes ataxia. The sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum are particularly affected. The disease primarily affects the spinal cord and peripheral nerves.
The spinal cord becomes thinner and nerve cells lose some myelin sheath. The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia. The motor neurons of the spinal cord are affected to a lesser extent than sensory neurons. In peripheral nerves, a loss of large myelinated sensory fibers occurs.Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum. The heart often develops some fibrosis, and over time, develops left-ventricle hypertrophy and dilatation of the left ventricle.
Frataxin
The exact role of frataxin remains unclear. Frataxin assists iron-sulfur protein synthesis in the electron transport chain to generate adenosine triphosphate, the energy molecule necessary to carry out metabolic functions in cells. It also regulates iron transfer in the mitochondria by providing a proper amount of reactive oxygen species (ROS) to maintain normal processes. One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism.Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage. Low frataxin levels lead to insufficient biosynthesis of iron–sulfur clusters that are required for mitochondrial electron transport and assembly of functional aconitase and iron dysmetabolism of the entire cell.
Diagnosis
Balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems are common signs from a physical examination. Diagnostic tests are made to confirm a physical examination such as electromyogram, nerve conduction studies, electrocardiogram, echocardiogram, blood tests for elevated glucose levels and vitamin E levels, and scans such as X-ray radiograph for scoliosis. MRI and CT scans of brain and spinal cord are done to rule out other neurological conditions. Finally, a genetic test is conducted to confirm.Other diagnoses might include Charcot-Marie-Tooth types 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia types 1 and 2, and other early-onset ataxias.
Management
Physical therapists play a critical role in educating on correct posture, muscle use, and the identification and avoidance of features that aggravate spasticities such as tight clothing, poorly adjusted wheelchairs, pain, and infection.
Rehabilitation
Physical therapy typically includes intensive motor coordination, balance, and stabilization training to preserve gains. Low intensity strengthening exercises are incorporated to maintain functional use of the upper and lower extremities. Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities. Other physical therapy goals include increased transfer and locomotion independence, muscle strengthening, increased physical resilience, "safe fall" strategy, learning to use mobility aids, learning how to reduce the bodys energy expenditure, and developing specific breathing patterns. Speech therapy can improve voice quality.
Devices
Well-fitted orthoses can promote correct posture, support normal joint alignment, stabilize joints during walking, improve range of motion and gait, reduce spasticity, and prevent foot deformities and scoliosis.Functional electrical stimulation or transcutaneous nerve stimulation devices may alleviate symptoms.As progression of ataxia continues, assistive devices such as a cane, walker, or wheelchair may be required for mobility and independence. A standing frame can help reduce the secondary complications of prolonged use of a wheelchair.
Medication and surgery
Cardiac abnormalities can be controlled with ACE inhibitors such as enalapril, ramipril, lisinopril, or trandolapril, sometimes used in conjunction with beta blockers. Affected people who also have symptomatic congestive heart failure may be prescribed eplerenone or digoxin to keep cardiac abnormalities under control.Surgery may correct deformities caused by abnormal muscle tone. Titanium screws and rods inserted in the spine help prevent or slow the progression of scoliosis. Surgery to lengthen the Achilles tendon can improve independence and mobility to alleviate equinus deformity. An automated implantable cardioverter-defibrillator can be implanted after a severe heart failure.
Prognosis
The disease evolves differently in different people. In general, those diagnosed at a younger age or with longer GAA triplet expansions tend to have more severe symptoms.Congestive heart failure and abnormal heart rhythms are the leading causes of death, but people with fewer symptoms can live into their 60s or older.
Epidemiology
FRDA affects Indo-European populations. It is rare in East Asians, sub-Saharan Africans, and Native Americans. FRDA is the most prevalent inherited ataxia, affecting approximately 1 in 40,000 with European descent. Males and females are affected equally. The estimated carrier prevalence is 1:100. A 1990–1996 study of Europeans calculated the incidence rate was 2.8:100,000. The prevalence rate of FRDA in Japan is 1:1,000,000.FRDA follows the same pattern as haplogroup R1b. Haplogroup R1b is the most frequently occurring paternal lineage in Western Europe. FRDA and Haplogroup R1b are more common in northern Spain, Ireland, and France, rare in Russia and Scandinavia, and follow a gradient through central and eastern Europe. A population carrying the disease went through a population bottleneck in the Franco-Cantabrian region during the last ice age.
History
The condition is named after the 1860s German pathologist and neurologist, Nikolaus Friedreich. Friedreich reported the disease in 1863 at the University of Heidelberg. Further observations appeared in a paper in 1876.Frantz Fanon wrote his medical thesis on FRDA, in 1951.A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France in 1634.FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996.
Research
Active research is ongoing to find a treatment. Patients can enroll in a registry to make clinical trial recruiting easier. The Friedreichs Ataxia Global Patient Registry is the only worldwide registry of Friedreichs ataxia patients to characterize the symptoms and establish the rate of disease progression. The Friedreichs Ataxia App is the only global community app which enables novel forms of research.As of May 2021, research continues along the following paths.
Improve mitochondrial function and reduce oxidative stress
Reata Pharmaceuticals developed RTA 408 (Omaveloxolone or Omav) to target activation of a transcriptional factor, Nrf2. Nrf2 is decreased in FRDA cells.
PTC-743 (formerly EPI-743) is being developed by PTC Therapeutics. PTC-743 is a para-benzoquinone and targets the NAD(P)H dehydrogenase (quinone 1) (NQO1) enzyme to increase the biosynthesis of glutathione.
Retrotope is advancing RT001. RT001 is a deuterated synthetic homologue of ethyl linoleate, an essential omega-6 polyunsaturated fatty acid which is one of the major components of lipid membranes, particularly in mitochondria. Oxidation damage might be reduced if the polyunsaturated fatty acids in the lipids were made more rigid and less susceptible to oxidation by the replacement of hydrogen atoms with the heavy hydrogen isotope deuterium.
Modulation of frataxin controlled metabolic pathways
Dimethyl fumarate has been shown to increase frataxin levels in FRDA cells, mouse models, and humans. DMF showed an 85% increase in frataxin expression over 3 months in multiple sclerosis .
Frataxin replacements or stabilizers
EPO mimetics are orally available peptide imitations of erythropoietin. They are small molecules erythropoietin receptor agonists designed to activate the tissue-protective erythropoietin receptor.
Etravirine, an antiviral drug used to treat HIV, was found in a drug repositioning screening to increase frataxin levels in peripheral cells. Fratagene Therapeutics is developing a small molecule called RNF126 to inhibit an enzyme which degrades frataxin.
Increase frataxin gene expression
Resveratrol might improve mitochondrial function.
Nicotinamide (vitamin B3) was found effective in preclinical FRDA models and well tolerated.
An RNA-based approach might unsilence the FXN gene and increase the expression of frataxin. Non-coding RNA (ncRNA) could be responsible for directing the localized epigenetic silencing of the FXN gene.
Lentivirus-mediated delivery of the FXN gene has been shown to increase frataxin expression and prevent DNA damage in human and mouse fibroblasts.
CRISPR Therapeutics received a grant from the Friedreichs Ataxia Research Alliance to investigate gene editing as a potential treatment for the disease in 2017.
Society and culture
The Cake Eaters is a 2007 independent drama film that stars Kristen Stewart as a young woman with FRDA.The Ataxian is a documentary that tells the story of Kyle Bryant, an athlete with FRDA who completes a long-distance bike race in an adaptive "trike" to raise money for research.Dynah Haubert spoke at the 2016 Democratic National Convention about supporting Americans with disabilities.Geraint Williams in an athlete affected by FRDA who is known for scaling Mount Kilimanjaro in an adaptive wheelchair.Shobhika Kalra is an activist with FRDA who helped build over 1000 wheelchair ramps across the United Arab Emirates in 2018 to try to make Dubai fully wheelchair-friendly by 2020.
References
External links
Friedreichs Ataxia Global Patient Registry
NIHs FRDA information page |
Choline | Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). To maintain health, it must be obtained from the diet as choline or as choline phospholipids, like phosphatidylcholine. Humans, as well as most other animal species, do make choline de novo; however, production is generally insufficient. Choline is often not classified as a vitamin, but as a nutrient with an amino acid–like metabolism. In most animals, choline phospholipids are necessary components in cell membranes, in the membranes of cell organelles, and in very low-density lipoproteins. Choline is required to produce acetylcholine – a neurotransmitter – and S-adenosylmethionine (SAM), a universal methyl donor. Upon methylation SAM is transformed into homocysteine.
Symptomatic choline deficiency – rare in humans – causes nonalcoholic fatty liver disease and muscle damage. Excessive consumption of choline (greater than 7.5 g/day) can cause low blood pressure, sweating, diarrhea and fish-like body odor due to trimethylamine, which forms in its metabolism. Rich dietary sources of choline and choline phospholipids include organ meats and egg yolks, dairy products, peanuts, certain beans, nuts, seeds and vegetables with pasta and rice also contributing to choline intake in the American diet.
Chemistry
The cholines are a family of water-soluble quaternary ammonium compounds. Choline is the parent compound of the cholines class, consisting of ethanolamine having three methyl substituents attached to the amino function. Choline hydroxide is known as choline base. It is hygroscopic and thus often encountered as a colorless viscous hydrated syrup that smells of trimethylamine (TMA). Aqueous solutions of choline are stable, but the compound slowly breaks down to ethylene glycol, polyethylene glycols, and TMA.Choline chloride can be made by treating TMA with 2-chloroethanol:
(CH3)3N + ClCH2CH2OH → (CH3)3N+CH2CH2OH · Cl–The 2-chloroethanol can be generated from ethylene oxide. Choline has historically been produced from natural sources, such as via hydrolysis of lecithin.
Metabolism
Biosynthesis
In plants, the first step in de novo biosynthesis of choline is the decarboxylation of serine into ethanolamine, which is catalyzed by a serine decarboxylase. The synthesis of choline from ethanolamine may take place in three parallel pathways, where three consecutive N-methylation steps catalyzed by a methyl transferase are carried out on either the free-base, phospho-bases, or phosphatidyl-bases. The source of the methyl group is S-adenosyl-L-methionine and S-adenosyl-L-homocysteine is generated as a side product.
In humans and most other animals, de novo synthesis of choline is via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, but biosynthesis is not enough to meet human requirements. In the hepatic PEMT route, 3-phosphoglycerate (3PG) receives 2 acyl groups from acyl-CoA forming a phosphatidic acid. It reacts with cytidine triphosphate to form cytidine diphosphate-diacylglycerol. Its hydroxyl group reacts with serine to form phosphatidylserine which decarboxylates to ethanolamine and phosphatidylethanolamine (PE) forms. A PEMT enzyme moves three methyl groups from three S-adenosyl methionines (SAM) donors to the ethanolamine group of the phosphatidylethanolamine to form choline in the form of a phosphatidylcholine. Three S-adenosylhomocysteines (SAHs) are formed as a byproduct.Choline can also be released from more complex choline containing molecules. For example, phosphatidylcholines (PC) can be hydrolyzed to choline (Chol) in most cell types. Choline can also be produced by the CDP-choline route, cytosolic choline kinases (CK) phosphorylate choline with ATP to phosphocholine (PChol). This happens in some cell types like liver and kidney. Choline-phosphate cytidylyltransferases (CPCT) transform PChol to CDP-choline (CDP-Chol) with cytidine triphosphate (CTP). CDP-choline and diglyceride are transformed to PC by diacylglycerol cholinephosphotransferase (CPT).In humans, certain PEMT-enzyme mutations and estrogen deficiency (often due to menopause) increase the dietary need for choline. In rodents, 70% of phosphatidylcholines are formed via the PEMT route and only 30% via the CDP-choline route. In knockout mice, PEMT inactivation makes them completely dependent on dietary choline.
Absorption
In humans, choline is absorbed from the intestines via the SLC44A1 (CTL1) membrane protein via facilitated diffusion governed by the choline concentration gradient and the electrical potential across the enterocyte membranes. SLC44A1 has limited ability to transport choline: at high concentrations part of it is left unabsorbed. Absorbed choline leaves the enterocytes via the portal vein, passes the liver and enters systemic circulation. Gut microbes degrade the unabsorbed choline to trimethylamine, which is oxidized in the liver to trimethylamine N-oxide.Phosphocholine and glycerophosphocholines are hydrolyzed via phospholipases to choline, which enters the portal vein. Due to their water solubility, some of them escape unchanged to the portal vein. Fat-soluble choline-containing compounds (phosphatidylcholines and sphingomyelins) are either hydrolyzed by phospholipases or enter the lymph incorporated into chylomicrons.
Transport
In humans, choline is transported as a free molecule in blood. Choline–containing phospholipids and other substances, like glycerophosphocholines, are transported in blood lipoproteins. Blood plasma choline levels in healthy fasting adults is 7–20 micromoles per liter (μmol/L) and 10 μmol/L on average. Levels are regulated, but choline intake and deficiency alters these levels. Levels are elevated for about 3 hours after choline consumption. Phosphatidylcholine levels in the plasma of fasting adults is 1.5–2.5 mmol/L. Its consumption elevates the free choline levels for about 8–12 hours, but does not affect phosphatidylcholine levels significantly.Choline is a water-soluble ion and thus requires transporters to pass through fat-soluble cell membranes. Three types of choline transporters are known:
SLC5A7
CTLs: CTL1 (SLC44A1), CTL2 (SLC44A2) and CTL4 (SLC44A4)
OCTs: OCT1 (SLC22A1) and OCT2 (SLC22A2)SLC5A7s are sodium- (Na+) and ATP-dependent transporters. They have high binding affinity for choline, transport it primarily to neurons and are indirectly associated with the acetylcholine production. Their deficient function causes hereditary weakness in the pulmonary and other muscles in humans via acetylcholine deficiency. In knockout mice, their dysfunction results easily in death with cyanosis and paralysis.CTL1s have moderate affinity for choline and transport it in almost all tissues, including the intestines, liver, kidneys, placenta and mitochondria. CTL1s supply choline for phosphatidylcholine and trimethylglycine production. CTL2s occur especially in the mitochondria in the tongue, kidneys, muscles and heart. They are associated with the mitochondrial oxidation of choline to trimethylglycine. CTL1s and CTL2s are not associated with the acetylcholine production, but transport choline together via the blood–brain barrier. Only CTL2s occur on the brain side of the barrier. They also remove excess choline from the neurons back to blood. CTL1s occur only on the blood side of the barrier, but also on the membranes of astrocytes and neurons.OCT1s and OCT2s are not associated with the acetylcholine production. They transport choline with low affinity. OCT1s transport choline primarily in the liver and kidneys; OCT2s in kidneys and the brain.
Storage
Choline is stored in the cell membranes and organelles as phospholipids, and inside cells as phosphatidylcholines and glycerophosphocholines.
Excretion
Even at choline doses of 2–8 g, little choline is excreted into urine in humans. Excretion happens via transporters that occur within kidneys (see transport). Trimethylglycine is demethylated in the liver and kidneys to dimethylglycine (tetrahydrofolate receives one of the methyl groups). Methylglycine forms, is excreted into urine, or is demethylated to glycine.
Function
Choline and its derivatives have many functions in humans and in other organisms. The most notable function is that choline serves as a synthetic precursor for other essential cell components and signalling molecules, such as phospholipids that form cell membranes, the neurotransmitter acetylcholine, and the osmoregulator trimethylglycine (betaine). Trimethylglycine in turn serves as a source of methyl groups by participating in the biosynthesis of S-adenosylmethionine.
Phospholipid precursor
Choline is transformed to different phospholipids, like phosphatidylcholines and sphingomyelins. These are found in all cell membranes and the membranes of most cell organelles. Phosphatidylcholines are structurally important part of the cell membranes. In humans 40–50% of their phospholipids are phosphatidylcholines.Choline phospholipids also form lipid rafts in the cell membranes along with cholesterol. The rafts are centers, for example for receptors and receptor signal transduction enzymes.Phosphatidylcholines are needed for the synthesis of VLDLs: 70–95% of their phospholipids are phosphatidylcholines in humans.Choline is also needed for the synthesis of pulmonary surfactant, which is a mixture consisting mostly of phosphatidylcholines. The surfactant is responsible for lung elasticity, that is for lung tissues ability to contract and expand. For example, deficiency of phosphatidylcholines in the lung tissues has been linked to acute respiratory distress syndrome.Phosphatidylcholines are excreted into bile and work together with bile acid salts as surfactants in it, thus helping with the intestinal absorption of lipids.
Acetylcholine synthesis
Choline is needed to produce acetylcholine. This is a neurotransmitter which plays a necessary role in muscle contraction, memory and neural development, for example. Nonetheless, there is little acetylcholine in the human body relative to other forms of choline. Neurons also store choline in the form of phospholipids to their cell membranes for the production of acetylcholine.
Source of trimethylglycine
In humans, choline is oxidized irreversibly in liver mitochondria to glycine betaine aldehyde by choline oxidases. This is oxidized by mitochondrial or cytosolic betaine-aldehyde dehydrogenases to trimethylglycine. Trimethylglycine is a necessary osmoregulator. It also works as a substrate for the BHMT-enzyme, which methylates homocysteine to methionine. This is a S-adenosylmethionine (SAM) precursor. SAM is a common reagent in biological methylation reactions. For example, it methylates guanidines of DNA and certain lysines of histones. Thus it is part of gene expression and epigenetic regulation. Choline deficiency thus leads to elevated homocysteine levels and decreased SAM levels in blood.
Content in foods
Choline occurs in foods as a free molecule and in the form of phospholipids, especially as phosphatidylcholines. Choline is highest in organ meats and egg yolks though it is found to a lesser degree in non-organ meats, grains, vegetables, fruit and dairy products. Cooking oils and other food fats have about 5 mg/100 g of total choline. In the United States, food labels express the amount of choline in a serving as a percentage of daily value (%DV) based on the adequate intake of 550 mg/day. 100% of the daily value means that a serving of food has 550 mg of choline. "Total choline" is defined as the sum of free choline and choline-containing phospholipids, without accounting for mass fraction.Human breast milk is rich in choline. Exclusive breastfeeding corresponds to about 120 mg of choline per day for the baby. Increase in a mothers choline intake raises the choline content of breast milk and low intake decreases it. Infant formulas may or may not contain enough choline. In the EU and the US, it is mandatory to add at least 7 mg of choline per 100 kilocalories (kcal) to every infant formula. In the EU, levels above 50 mg/100 kcal are not allowed.Trimethylglycine is a functional metabolite of choline. It substitutes for choline nutritionally, but only partially. High amounts of trimethylglycine occur in wheat bran (1,339 mg/100 g), toasted wheat germ (1,240 mg/100 g) and spinach (600–645 mg/100 g), for example.
Daily values
The following table contains updated sources of choline to reflect the new Daily Value and the new Nutrition Facts and Supplement Facts Labels. It reflects data from the U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019.
DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for choline is 550 mg for adults and children age 4 years and older. The FDA does not require food labels to list choline content unless choline has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.
The U.S. Department of Agricultures (USDAs) FoodData Central lists the nutrient content of many foods and provides a comprehensive list of foods containing choline arranged by nutrient content.
Dietary recommendations
Recommendations are in milligrams per day (mg/day). The European Food Safety Authority (EFSA) recommendations are general recommendations for the EU countries. The EFSA has not set any upper limits for intake. Individual EU countries may have more specific recommendations. The National Academy of Medicine (NAM) recommendations apply in the United States, Australia and New Zealand.
Intake in populations
Twelve surveys undertaken in 9 EU countries between 2000 and 2011 estimated choline intake of adults in these countries to be 269–468 milligrams per day. Intake was 269–444 mg/day in adult women and 332–468 mg/day in adult men. Intake was 75–127 mg/day in infants, 151–210 mg/day in 1- to 3-year-olds, 177–304 mg/day in 3- to 10-year-olds and 244–373 mg/day in 10- to 18-year-olds. The total choline intake mean estimate was 336 mg/day in pregnant adolescents and 356 mg/day in pregnant women.A study based on the NHANES 2009–2012 survey estimated the choline intake to be too low in some US subpopulations. Intake was 315.2–318.8 mg/d in 2+ year olds between this time period. Out of 2+ year olds, only 15.6±0.8% of males and 6.1±0.6% of females exceeded the adequate intake (AI). AI was exceeded by 62.9±3.1% of 2- to 3-year-olds, 45.4±1.6% of 4- to 8-year-olds, 9.0±1.0% of 9- to 13-year-olds, 1.8±0.4% of 14–18 and 6.6±0.5% of 19+ year olds. Upper intake level was not exceeded in any subpopulations.A 2013–2014 NHANES study of the US population found the choline intake of 2- to 19-year-olds to be 256±3.8 mg/day and 339±3.9 mg/day in adults 20 and over. Intake was 402±6.1 mg/d in men 20 and over and 278 mg/d in women 20 and over.
Deficiency
Signs and symptoms
Symptomatic choline deficiency is rare in humans. Most obtain sufficient amounts of it from the diet and are able to biosynthesize limited amounts of it. Symptomatic deficiency is often caused by certain diseases or by other indirect causes. Severe deficiency causes muscle damage and non-alcoholic fatty liver disease, which may develop into cirrhosis.Besides humans, fatty liver is also a typical sign of choline deficiency in other animals. Bleeding in the kidneys can also occur in some species. This is suspected to be due to deficiency of choline derived trimethylglycine, which functions as an osmoregulator.
Causes and mechanisms
Estrogen production is a relevant factor which predisposes individuals to deficiency along with low dietary choline intake. Estrogens activate phosphatidylcholine producing PEMT enzymes. Women before menopause have lower dietary need for choline than men due to womens higher estrogen production. Without estrogen therapy, the choline needs of post-menopausal women are similar to mens. Some single-nucleotide polymorphisms (genetic factors) affecting choline and folate metabolism are also relevant. Certain gut microbes also degrade choline more efficiently than others, so they are also relevant.In deficiency, availability of phosphatidylcholines in the liver are decreased – these are needed for formation of VLDLs. Thus VLDL-mediated fatty acid transport out of the liver decreases leading to fat accumulation in the liver. Other simultaneously occurring mechanisms explaining the observed liver damage have also been suggested. For example, choline phospholipids are also needed in mitochondrial membranes. Their inavailability leads to the inability of mitochondrial membranes to maintain proper electrochemical gradient, which, among other things, is needed for degrading fatty acids via β-oxidation. Fat metabolism within liver therefore decreases.
Excess intake
Excessive doses of choline can have adverse effects. Daily 8–20 g doses of choline, for example, have been found to cause low blood pressure, nausea, diarrhea and fish-like body odor. The odor is due to trimethylamine (TMA) formed by the gut microbes from the unabsorbed choline (see trimethylaminuria).The liver oxidizes TMA to trimethylamine N-oxide (TMAO). Elevated levels of TMA and TMAO in the body have been linked to increased risk of atherosclerosis and mortality. Thus, excessive choline intake has been hypothetized to increase these risks in addition to carnitine, which also is formed into TMA and TMAO by gut bacteria. However, choline intake has not been shown to increase the risk of dying from cardiovascular diseases. It is plausible that elevated TMA and TMAO levels are just a symptom of other underlying illnesses or genetic factors that predispose individuals for increased mortality. Such factors may have not been properly accounted for in certain studies observing TMA and TMAO level related mortality. Causality may be reverse or confounding and large choline intake might not increase mortality in humans. For example, kidney dysfunction predisposes for cardiovascular diseases, but can also decrease TMA and TMAO excretion.
Health effects
Neural tube closure
Some human studies showed low maternal intake of choline to significantly increase the risk of neural tube defects (NTDs) in newborns. Folate deficiency also causes NTDs. Choline and folate, interacting with vitamin B12, act as methyl donors to homocysteine to form methionine, which can then go on to form SAM (S-adenosylmethionine). SAM is the substrate for almost all methylation reactions in mammals. It has been suggested that disturbed methylation via SAM could be responsible for the relation between folate and NTDs. This may also apply to choline. Certain mutations that disturb choline metabolism increase the prevalence of NTDs in newborns, but the role of dietary choline deficiency remains unclear, as of 2015.
Cardiovascular diseases and cancer
Choline deficiency can cause fatty liver, which increases cancer and cardiovascular disease risk. Choline deficiency also decreases SAM production, which partakes in DNA methylation – this decrease may also contribute to carcinogenesis. Thus, deficiency and its association with such diseases has been studied. However, observational studies of free populations have not convincingly shown an association between low choline intake and cardiovascular diseases or most cancers. Studies on prostate cancer have been contradictory.
Cognition
Studies observing the effect between higher choline intake and cognition have been conducted in human adults, with contradictory results. Similar studies on human infants and children have been contradictory and also limited.
Perinatal development
Both pregnancy and lactation increase demand for choline dramatically. This demand may be met by upregulation of PEMT via increasing estrogen levels to produce more choline de novo, but even with increased PEMT activity, the demand for choline is still so high that bodily stores are generally depleted. This is exemplified by the observation that Pemt −/− mice (mice lacking functional PEMT) will abort at 9–10 days unless fed supplemental choline.While maternal stores of choline are depleted during pregnancy and lactation, the placenta accumulates choline by pumping choline against the concentration gradient into the tissue, where it is then stored in various forms, mostly as acetylcholine. Choline concentrations in amniotic fluid can be ten times higher than in maternal blood.
Functions in the fetus
Choline is in high demand during pregnancy as a substrate for building cellular membranes (rapid fetal and mother tissue expansion), increased need for one-carbon moieties (a substrate for methylation of DNA and other functions), raising choline stores in fetal and placental tissues, and for increased production of lipoproteins (proteins containing "fat" portions). In particular, there is interest in the impact of choline consumption on the brain. This stems from cholines use as a material for making cellular membranes (particularly in making phosphatidylcholine). Human brain growth is most rapid during the third trimester of pregnancy and continues to be rapid to approximately five years of age. During this time, the demand is high for sphingomyelin, which is made from phosphatidylcholine (and thus from choline), because this material is used to myelinate (insulate) nerve fibers. Choline is also in demand for the production of the neurotransmitter acetylcholine, which can influence the structure and organization of brain regions, neurogenesis, myelination, and synapse formation. Acetylcholine is even present in the placenta and may help control cell proliferation and differentiation (increases in cell number and changes of multiuse cells into dedicated cellular functions) and parturition.Choline uptake into the brain is controlled by a low-affinity transporter located at the blood–brain barrier. Transport occurs when arterial plasma choline concentrations increase above 14 μmol/L, which can occur during a spike in choline concentration after consuming choline-rich foods. Neurons, conversely, acquire choline by both high- and low-affinity transporters. Choline is stored as membrane-bound phosphatidylcholine, which can then be used for acetylcholine neurotransmitter synthesis later. Acetylcholine is formed as needed, travels across the synapse, and transmits the signal to the following neuron. Afterwards, acetylcholinesterase degrades it, and the free choline is taken up by a high-affinity transporter into the neuron again.
Uses
Choline chloride and choline bitartrate are used in dietary supplements. Bitartrate is used more often due to its lower hygroscopicity. Certain choline salts are used to supplement chicken, turkey and some other animal feeds. Some salts are also used as industrial chemicals: for example, in photolithography to remove photoresist. Choline theophyllinate and choline salicylate are used as medicines, as well as structural analogs, like methacholine and carbachol. Radiolabeled cholines, like 11C-choline, are used in medical imaging. Other commercially used salts include tricholine citrate and choline bicarbonate.
Antagonists and inhibitors
Hundreds of choline antagonists and enzyme inhibitors have been developed for research purposes. Aminomethylpropanol is among the first ones used as a research tool. It inhibits choline and trimethylglycine synthesis. It is able to induce choline deficiency that in turn results in fatty liver in rodents. Diethanolamine is another such compound, but also an environmental pollutant. N-cyclohexylcholine inhibits choline uptake primarily in brains. Hemicholinium-3 is a more general inhibitor, but also moderately inhibits choline kinases. More specific choline kinase inhibitors have also been developed. Trimethylglycine synthesis inhibitors also exist: carboxybutylhomocysteine is an example of a specific BHMT inhibitor.The cholinergic hypothesis of dementia has not only lead to medicinal acetylcholinesterase inhibitors, but also to a variety of acetylcholine inhibitors. Examples of such inhibiting research chemicals include triethylcholine, homocholine and many other N-ethyl derivates of choline, which are false neurotransmitter analogs of acetylcholine. Choline acetyltransferase inhibitors have also been developed.
History
Discovery
In 1849, Adolph Strecker was the first to isolate choline from pig bile. In 1852, L. Babo and M. Hirschbrunn extracted choline from white mustard seeds and named it sinkaline. In 1862, Strecker repeated his experiment with pig and ox bile, calling the substance choline for the first time after the Greek word for bile, chole, and identifying it with the chemical formula C5H13NO. In 1850, Theodore Nicolas Gobley extracted from the brains and roe of carps a substance he named lecithin after the Greek word for egg yolk, lekithos, showing in 1874 that it was a mixture of phosphatidylcholines.In 1865, Oscar Liebreich isolated "neurine" from animal brains. The structural formulas of acetylcholine and Liebreichs "neurine" were resolved by Adolf von Baeyer in 1867. Later that year "neurine" and sinkaline were shown to be the same substances as Streckers choline. Thus, Bayer was the first to resolve the structure of choline. The compound now known as neurine is unrelated to choline.
Discovery as a nutrient
In the early 1930s, Charles Best and colleagues noted that fatty liver in rats on a special diet and diabetic dogs could be prevented by feeding them lecithin |
Choline | , proving in 1932 that choline in lecithin was solely responsible for this preventive effect. In 1998, the US National Academy of Medicine reported their first recommendations for choline in the human diet.
== References == |
Subsets and Splits