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Colorectal adenoma | The colorectal adenoma is a benign glandular tumor of the colon and the rectum. It is a precursor lesion of the colorectal adenocarcinoma (colon cancer). They often manifest as colorectal polyps.
Comparison table
Tubular adenoma
In contrast to hyperplastic polyps, these display dysplasia.
Tubulovillous adenoma
Tubulovillous adenoma, TVA are considered to have a higher risk of becoming malignant (cancerous) than tubular adenomas.
Villous adenoma
These adenomas may become malignant (cancerous). Villous adenomas have been demonstrated to contain malignant portions in about 15–25% of cases, approaching 40% in those over 4 cm in diameter. Colonic resection may be required for large lesions. These can also lead to secretory diarrhea with large volume liquid stools with few formed elements. They are commonly described as secreting large amounts of mucus, resulting in hypokalaemia in patients. On endoscopy, a "cauliflower like mass is described due to villi stretching. Being an adenoma, the mass is covered in columnar epithelial cells.
Sessile serrated adenoma
Sessile serrated adenomas are characterized by (1) basal dilation of the crypts, (2) basal crypt serration, (3) crypts that run horizontal to the basement membrane (horizontal crypts), and (4) crypt branching. The most common of these features is basal dilation of the crypts.
See also
Colorectal cancer
Colorectal polyp
== References == |
Fuchs heterochromic iridocyclitis | Fuchs heterochromic iridocyclitis (FHI) is a chronic unilateral uveitis appearing with the triad of heterochromia, predisposition to cataract and glaucoma, and keratitic precipitates on the posterior corneal surface. Patients are often asymptomatic and the disease is often discovered through investigation of the cause of the heterochromia or cataract. Neovascularisation (growth of new abnormal vessels) is possible and any eye surgery, such as cataract surgery, can cause bleeding from the fragile vessels in the atrophic iris causing accumulation of blood in the anterior chamber of the eye, also known as hyphema.
Presentation
This condition is usually unilateral, and its symptoms vary from none to mild blurring and discomfort. Signs include diffuse iris atrophy and small white keratic precipitates (deposits on the inner surface of the cornea), cells presenting in the anterior chamber as well as the anterior vitreous. Glaucoma and cataract occur frequently.
Complications
Glaucoma
Cataract
Decreased visual acuity (vision loss)
Iris atrophy
Causes
According to recent research, not a single theory is able to explain the cause fully. However current plausible theories include infection with Toxoplasma gondii, Herpes simplex virus, Rubella, neurogenic causes, and autoimmune pathology.
Diagnosis
Diagnosis is made by an ophthalmologist or optometrist based on the clinical presentation. One indication can be the Amsler sign, which is the presence of blood (hyphema) in the aspirated vitreous fluid, in paracentesis of the anterior chamber. This is caused due to iris atrophy usually seen in FHI and exposure of the fragile iris vasculature to the vitreous fluid. The sudden change of pressure in the anterior chamber upon suction induced by the paracentesis, or during cataract surgery, causes bursting of the fragile superficial iris capillaries resulting in micro-bleeding. This is one clinical diagnostic sign of FHI slit-lamp examination shows stringy keratic precipitates
Treatment
Patients usually do not require treatment due to the benign nature of the disease. In case a cataract develops, patients generally do well with cataract surgery.
History
First described using available patient presentations observed, by an Austrian ophthalmologist, Ernst Fuchs in 1906.
Sources
== External links == |
Beckers nevus | Beckers nevus (also known as "Beckers melanosis", "Beckers pigmentary hamartoma", "nevoid melanosis", and "pigmented hairy epidermal nevus") is a benign skin disorder predominantly affecting males.: 687 The nevus can be present at birth, but more often shows up around puberty. It generally first appears as an irregular pigmentation (melanosis or hyperpigmentation) on the torso or upper arm (though other areas of the body can be affected), and gradually enlarges irregularly, becoming thickened and often hairy (hypertrichosis). The nevus is due to an overgrowth of the epidermis, pigment cells (melanocytes), and hair follicles. This form of nevus was first documented in 1948 by American dermatologist Samuel William Becker (1894–1964).
Clinical information
Medical knowledge and documentation of this disorder is poor, likely due to a combination of factors including recent discovery, low prevalence, and the more or less aesthetic nature of the effects of the skin disorder. Thus the pathophysiology of Beckers nevus remains unclear. While it is generally considered an acquired rather than congenital disorder, there exists at least one case report documenting what researchers claim is a congenital Beckers nevus with genetic association: a 16-month-old boy with a hyperpigmented lesion on his right shoulder whose father has a similar lesion on his right shoulder.
Prevalence
The most extensive study to date, a 1981 survey of nearly 20,000 French males aged 17 to 26, served to disprove many commonly held beliefs about the disorder. In the French study, 100 subjects were found to have Beckers nevi, revealing a prevalence of 0.52%. Nevi appeared in one half the subjects before the age of 10, and between ages 10 and 20 in the rest. In one quarter of cases sun exposure seems to have played a role, a number apparently lower than that expected by researchers. Also surprising to researchers was the low incidence (32%) of Beckers nevi above the nipples, for it had generally been believed that the upper chest and shoulder area was the predominant site of occurrence. Pigmentation was light brown in 75% of cases (note: subjects were Caucasian), and average size of the nevus was 125 cm2 (19 in2).
Malignancy
A 1991 report documented the cases of nine patients with both Beckers nevus and malignant melanoma. Of the nine melanomas, five were in the same body area as the Beckers nevus, with only one occurring within the nevus itself. As this was apparently the first documented co-occurrence of the two diseases, there is so far no evidence of higher malignancy rates in Beckers nevi versus normal skin. Nonetheless, as with any abnormal skin growth, the nevus should be monitored regularly and any sudden changes in appearance brought to the attention of ones doctor.
Treatment
As Beckers nevus is considered a benign lesion, treatment is generally not necessary except for cosmetic purposes. Shaving or trimming can be effective in removing unwanted hair, while electrology or laser hair removal may offer a longer-lasting solution. Different types of laser treatments may also be effective in elimination or reduction of hyperpigmentation, though the results of laser treatments for both hair and pigment reduction appear to be highly variable.
See also
List of cutaneous conditions
References
== External links == |
Darwins tubercle | Darwins tubercle (or auricular tubercle) is a congenital ear condition which often presents as a thickening on the helix at the junction of the upper and middle thirds.
History
This atavistic feature is so called because its description was first published by Charles Darwin in the opening pages of The Descent of Man, and Selection in Relation to Sex, as evidence of a vestigial feature indicating common ancestry among primates which have pointy ears. However, Darwin himself named it the Woolnerian tip, after Thomas Woolner, a British sculptor who had depicted it in one of his sculptures and had first theorised that it was an atavistic feature.
Prevalence
The feature is present in approximately 10.4% of the Spanish adult population, 40% of adults in India, and 58% of Swedish school children. This acuminate nodule represents the point of the mammalian ear. The trait can potentially be bilateral, meaning present on both ears, or unilateral, where it is present on only one ear. There is mixed evidence in regard to whether the bilateral or unilateral expression is related to population, or other factors. Some populations express full bilateral, while others may express either unilateral or bilateral. However, bilateral appears to be more common than unilateral as it pertains to the expression of the trait.
Inheritance
The gene for Darwins tubercle was once thought to be inherited in an autosomal dominant pattern with incomplete penetrance, meaning that those who possess the allele (version of a gene) will not necessarily present with the phenotype. However, genetic and family studies have demonstrated that the presence of Darwins tubercle may be more likely to be influenced by ones environment or developmental accidents than it is by genetics alone. There is no clear argument for whether the trait has significance in sexual dimorphism studies or age related studies. In some studies, there is clear data that Darwins tubercle is not associated with sex. In contrast, others indicate that there is a correlation with sexual dimorphism between men and women, where men tend to have the tubercle more than women in some populations. Two studies indicate that older men tend to have greater expression of Darwins tubercle than do older women.
See also
Human vestigiality
References
== External links == |
Nummular keratitis | Nummular keratitis is a feature of viral keratoconjunctivitis. It is a common feature of adenoviral keratoconjunctivitis (an ocular adenovirus infection), as well as approximately 1/3rd of cases of Herpes Zoster Ophthalmicus infections. It represents the presence of anterior stromal infiltrates. Unilateral or bilateral subepithelial lesions of the cornea may be present. Slit lamp examination reveals multiple tiny granular deposits surrounded by a halo of stromal haze. After healing, residual nummular scars often remain. Disciform keratitis occurs in 50% of individuals with Nummular keratitis, but Nummular keratitis always precedes Disciform keratitis.
Treatment
Lubricating eye drops
Topical dilute steroid drops in tapering doses (debatable, see: Adenoviral keratoconjunctivitis)
== References == |
Middle cerebral artery syndrome | Middle cerebral artery syndrome is a condition whereby the blood supply from the middle cerebral artery (MCA) is restricted, leading to a reduction of the function of the portions of the brain supplied by that vessel: the lateral aspects of frontal, temporal and parietal lobes, the corona radiata, globus pallidus, caudate and putamen. The MCA is the most common site for the occurrence of ischemic stroke.Depending upon the location and severity of the occlusion, signs and symptoms may vary within the population affected with MCA syndrome. More distal blockages tend to produce milder deficits due to more extensive branching of the artery and less ischemic response. In contrast, the most proximal occlusions result in widespread effects that can lead to significant cerebral edema, increased intracranial pressure, loss of consciousness and could even be fatal. In such occasions, mannitol (osmotic diuretic) or hypertonic saline are given to draw fluid out of the edematous cerebrum to minimise secondary injury. Hypertonic saline is better than mannitol, as mannitol being a diuretic will decrease the mean arterial pressure and since cerebral perfusion is mean arterial pressure minus intracranial pressure, mannitol will also cause a decrease in cerebral perfusion.
Contralateral hemiparesis and hemisensory loss of the face, upper and lower extremities is the most common presentation of MCA syndrome. Lower extremity function is more spared than that of the faciobrachial region. The majority of the primary motor and somatosensory cortices are supplied by the MCA and the cortical homunculus can, therefore, be used to localize the defects more precisely. Middle cerebral artery lesions mostly affect the dominant hemisphere i.e. the left cerebral hemisphere.
Signs and Symptoms
Hemiparesis or hemiplegia of the lower half of the contralateral face
Hemiparesis or hemiplegia of the contralateral upper and lower extremities*
Sensory loss of the contralateral face, arm and leg*
Ataxia of contralateral extremities*
Speech impairments/aphasia: Brocas area, Wernickes or Global aphasia as a result of a dominant hemisphere lesion (usually the left brain)
Perceptual deficits: hemispatial neglect, anosognosia, apraxia, and spatial disorganization as a result of a non-dominant hemisphere lesion (usually the right brain)
Visual disorders: déviation conjuguée, a gaze preference towards the side of the lesion; contralateral homonymous hemianopsiaNote: *faciobrachial deficits greater than that of the lower limb
Diagnosis
Diagnosis can be confirmed by CT Scan or MRI for advanced investigations.
References
== External links == |
Periorbital cellulitis | Periorbital cellulitis, or preseptal cellulitis (not to be confused with orbital cellulitis, which is posterior to the orbital septum), is an inflammation and infection of the eyelid and portions of skin around the eye anterior to the orbital septum. It may be caused by breaks in the skin around the eye, and subsequent spread to the eyelid; infection of the sinuses around the nose (sinusitis); or from spread of an infection elsewhere through the blood.
Signs and symptoms
Periorbital cellulitis must be differentiated from orbital cellulitis, which is an emergency and requires intravenous (IV) antibiotics. In contrast to orbital cellulitis, patients with periorbital cellulitis do not have bulging of the eye (proptosis), limited eye movement (ophthalmoplegia), pain on eye movement, or loss of vision. If any of these features is present, one must assume that the patient has orbital cellulitis and begin treatment with IV antibiotics. CT scan may be done to delineate the extension of the infection.
Affected individuals may experience: swelling,
redness,
discharge,
pain,
shut eye,
conjunctival infection,
fever (mild), slightly blurred vision, teary eyes, and some reduction in vision.
Typical signs include periorbital erythema, induration, tenderness and warmth.
Causes
Staphylococcus aureus, Streptococcus pneumoniae, other streptococci, and anaerobes are the most common causes, depending on the origin of the infection.The advent of the Haemophilus influenzae vaccine has dramatically decreased the incidence.
Diagnosis
Tests include blood work (CBC) to rule out infectious cause. Also perform a CT scan, x ray of the anterior skull to view the sinuses, MRI scan and finally a soft tissue ultrasound of the orbital region.
Treatment
Antibiotics are aimed at gram positive bacteria. Medical attention should be sought if symptoms persist beyond 2–3 days.
There is inadequate evidence to draw conclusions about the adjunctive corticosteroid therapy in the treatment of periorbital cellulitis. More research is needed to inform decision making.
See also
Orbital cellulitis
Cellulitis
References
== External links == |
Shwachman–Diamond syndrome | Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities and short stature. After cystic fibrosis (CF), it is the second most common cause of exocrine pancreatic insufficiency in children.
Signs and symptoms
The syndrome shows a wide range of abnormalities and symptoms. The main characteristics of the syndrome are exocrine pancreatic dysfunction, hematologic abnormalities and growth retardation. Only the first two of these are included in the clinical diagnostic criteria.
Hematologic abnormalities: neutropenia may be intermittent or persistent and is the most common hematological finding. Low neutrophil counts leave patients at risk of developing severe recurrent infections that may be life-threatening. Anemia (low red blood cell counts) and thrombocytopenia (low platelet counts) may also occur. Bone marrow is typically hypocellular, with maturation arrest in the myeloid lineages that give rise to neutrophils, macrophages, platelets and red blood cells. Patients may also develop progressive marrow failure or transform to acute myelogenous leukemia.
Exocrine pancreatic dysfunction: Pancreatic exocrine insufficiency arises due to a lack of acinar cells that produce digestive enzymes. These are extensively depleted and replaced by fat. A lack of pancreatic digestive enzymes leaves patients unable to digest and absorb fat. However, pancreatic status may improve with age in some patients.
Growth retardation: More than 50% of patients are below the third percentile for height, and short stature appears to be unrelated to nutritional status. Other skeletal abnormalities include metaphyseal dysostosis (45% of patients), thoracic dystrophy (rib cage abnormalities in 46% of patients) and costochondral thickening (shortened ribs with flared ends in 32% of patients). Skeletal problems are one of the most variable components of SDS, with 50% affected siblings from the same family discordant for clinical presentation or type of abnormality. Despite this, a careful review of radiographs from 15 patients indicated that all of them had at least one skeletal anomaly, though many were subclinical.
Other features include metaphysial dysostosis, mild hepatic dysfunction, increased frequency of infections.
Genetics
Shwachman–Diamond syndrome is characterized by an autosomal recessive mode of inheritance. The gene that is mutated in this syndrome, SBDS, lies on the long arm of chromosome 7 at cytogenetic position 7q11. It is composed of five exons and has an associated mRNA transcript that is 1.6 kilobase pairs in length. The SBDS gene resides in a block of genomic sequence that is locally duplicated on the chromosome. The second copy contains a non-functional version of the SBDS gene that is 97% identical to the original gene, but has accumulated inactivating mutations over time. It is considered to be a pseudogene. In a study of 158 SDS families, 75% of disease-associated mutations appeared to be the result of gene conversion, while 89% of patients harbored at least one such mutation. Gene conversion occurs when the intact SBDS gene and its pseudogene copy aberrantly recombine at meiosis, leading to an incorporation of pseudogene-like sequences into the otherwise functional copy of the SBDS gene, thereby inactivating it.Two gene conversion mutations predominate in SDS patients. One is a splice site mutation affecting the 5 splice site of intron two, while the second is an exon two nonsense mutation. The marked absence of patients homozygous for the otherwise common nonsense mutation suggested that the SBDS gene is essential. Consistent with this, knockout of the mouse gene leads to early embryonic lethality. This, in turn, suggests that the common splice site mutation seen in patients may be hypomorphic, i.e. that it results in only a partial loss of function, whereas the complete loss of SBDS function is likely to be lethal.
Mechanisms
The SBDS gene is expressed in all tissues and encodes a protein of 250 amino acid residues. A great deal of indirect evidence suggested that the SBDS protein may be involved in an aspect of cellular RNA metabolism or ribosome assembly or function. The wide occurrence of the gene in all archaea and eukaryotes supported a role for this protein in a very fundamental and evolutionarily conserved aspect of cellular biology. The homologous genes in archaea also tend to be present in conserved cluster enriched for RNA processing and ribosomal genes. A specific function for SBDS in RNA metabolism or ribosome assembly or function is further supported by its localization to the nucleolus, the nuclear subdomain where these processes occur. In line with this, the yeast homologue, SdoI, has been shown to be critical for maturation of pre-60S ribosomes, by effecting release and recycling of the nucleolar shuttling factor Tif6. This is required for 60S maturation and translational activation of ribosomes. It has also been shown that the Dictyostelium discoideum homologue catalyzes the removal of eukaryotic initiation factor 6 (eIF6), which is required for the translational activation of ribosomes. Cells from SDS patients were shown to have a defect in assembly of ribosome subunits.At present, it is not obvious how disruption of the basic cellular process of translation leads to the tissue- and organ-specific manifestations seen in SDS. However, unusual and combinations of tissues and organs are also affected in Diamond–Blackfan anemia, X-linked dyskeratosis congenita, and cartilage–hair hypoplasia—three diseases that may also be linked to defective ribosome function. Pleiotropic disease features may be the result of cell-specific effects of reduced levels of SBDS activity provided by hypomorphic mutations.
Diagnosis
Initially, the clinical presentation of SDS may appear similar to cystic fibrosis. However, CF can be excluded with a normal chloride in sweat test but faecal elastase as a marker of pancreatic function will be reduced. The variation, intermittent nature, and potential for long-term improvement of some clinical features make this syndrome difficult to diagnose. SDS may present with either malabsorption, or hematological problems. Rarely, SDS may present with skeletal defects, including severe rib cage abnormalities that lead to difficulty in breathing. Diagnosis is generally based on evidence of exocrine pancreatic dysfunction and neutropenia. Skeletal abnormalities and short stature are characteristics that can be used to support the diagnosis. The gene responsible for the disease has been identified and genetic testing is now available.
Management
Pancreatic exocrine insufficiency may be treated through pancreatic enzyme supplementation, while severe skeletal abnormalities may require surgical intervention. Neutropenia may be treated with granulocyte-colony stimulating factor (GCSF) to boost peripheral neutrophil counts. However, there is ongoing and unresolved concern that this drug could contribute to the development of leukemia. Signs of progressive marrow failure may warrant bone marrow transplantation (BMT). This has been used successfully to treat hematological aspects of disease. However, SDS patients have an elevated occurrence of BMT-related adverse events, including graft-versus-host disease (GVHD) and toxicity relating to the pre-transplant conditioning regimen. In the long run, study of the gene that is mutated in SDS should improve understanding of the molecular basis of disease. This, in turn, may lead to novel therapeutic strategies, including gene therapy and other gene- or protein-based approaches.
Research
A major goal of curative therapy for SDS is to reduce the risk of bone marrow failure and halt the progression of malignant transformation toward myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the most detrimental complications of SDS. Currently, there is no such therapy. However, several emerging therapeutic strategies, including gene therapy and antisense oligonucleotides (ASOs), could potentially slow or prevent malignant transformation, at least in theory. These new therapies have been proven effective for several rare diseases, including metachromatic leukodystrophy and spinal muscular atrophy. Several SDS patient groups are advocating for better therapies for SDS, and one organization is focused on driving the therapy development efforts. The challenge is whether the SDS community can come together to support the required research, and whether the organizations can successfully execute a strategy that coordinates the efforts for new therapy development.
Epidemiology
It is thought to have an estimated incidence of 1 in 75,000 people.
History
The disease was first described as a coherent clinical entity in May 1964 by Bodian, Sheldon, and Lightwood. It was subsequently described by Shwachman, Diamond, Oski, and Khaw in November of the same year. In 2001, linkage analysis in SDS families indicated that affected gene mapped to a large region of human chromosome seven. In 2002, this interval was refined to a region on the long arm of the chromosome next to the centromere.In 2003, a team of researchers led by Johanna Rommens at the Hospital of Sick Children (SickKids) in Toronto, Canada, discovered mutations in the SBDS gene (Shwachman–Bodian–Diamond syndrome) were associated with disease.
Eponym
Shwachman–Diamond syndrome, less commonly known as Shwachman–Bodian–Diamond syndrome, is named for Harry Shwachman (1910 – September 12, 1986), an American physician, Martin Bodian (1912 – May 12, 1994), a British ophthalmologist who worked in New York City, and Louis Klein Diamond (May 11, 1902 – June 14, 1999), an American pediatrician.
References
Further reading
Foerster (2014). "Ch 37. Inherited Aplastic Anemia Syndromes". In John P. Greer; Daniel A. Arber; Bertil Glader; Alan F. List; Robert T. Means Jr.; Frixos Paraskevas; George M. Rodgers; John Foerster (eds.). Wintrobes clinical hematology (13th ed.). p. Shwachman-Diamond Syndrome. ISBN 978-1451172683.
GeneReviews/NCBI/NIH/UW entry on Shwachman–Diamond Syndrome
== External links == |
Vocal cord cyst | Vocal fold cysts (also known as vocal cord cysts) are benign masses of the membranous vocal folds. These cysts are enclosed, sac-like structures that are typically of a yellow or white colour. They occur unilaterally on the midpoint of the medial edge of the vocal folds. They can also form on the upper/superior, surface of the vocal folds. There are two types of vocal fold cysts:
Sub-epithelial vocal fold cysts- located in the superficial lamina propria of the vocal folds.
Ligament vocal fold cysts- located within the deeper layers of the lamina propria or on the vocal ligament.The symptoms of vocal fold cysts vary but most commonly include a hoarse voice and problems with the pitch of the voice. Vocal fold cysts are diagnosed based on gathering a case history, perceptual examination, and laryngeal imaging. Practicing good vocal hygiene is recommended to prevent vocal fold cysts. Initial treatment of the cysts involves voice therapy to reduce harmful vocal behaviours. If symptoms remain after voice therapy, patients may require surgery to remove the cyst. Surgery is typically followed by vocal rest and further voice therapy to improve voice function. Cysts may also be treated using vocal fold steroid injection.
Histology
The vocal folds consist of 3 primary layers; the Epithelium, the Lamina Propria (containing superficial, intermediate and deep layers) and the Thyroarytenoid Muscle. Vocal fold cysts commonly appear in the Superficial portion of the Lamina Propria, the cyst size impacts the nature of this layer making it more rigid. The border of vocal fold cysts contains squamous or epithelial cells. In the case of retention cysts, the border consists of glandular epithelium. Epidermoid cysts closely resemble epidermal cysts that can occur anywhere in the body.
Types of Vocal Cord Cysts
Sub-epithelial cysts (also known as mucous retention cysts) are closed lesions that occur from a build-up of tissue on the vocal folds. They are typically found in the middle portion of the upper lamina propria of the vocal folds. Sub-epithelial cysts are small and white in colour. Their presence on the vocal folds usually does not disrupt the vibration of the vocal folds for speech (known as the "mucosal wave").Ligament cysts (also known as epidermoid cysts) are closed lesions that occur near the vocal ligament in the deep layers of the lamina propria. Ligament cysts are usually larger in size than sub-epithelial cysts. They are yellow in colour and unlike sub-epithelial cysts, their presence is usually observed to disrupt the mucosal wave of the vocal folds in the region around the cyst.
Signs and Symptoms
Sub-epithelial vocal fold cysts and ligament vocal fold cysts are characterized by similar symptoms. The presence and severity of symptoms may be influenced by the location and size of the cyst.Common symptoms include:
Hoarse voice
Inability to produce high pitch notes
Fatigue when speaking
Limited pitch range
Pain near the larynx
Variations in pitch when speakingSigns and symptoms of vocal fold cysts may remain stable or increase over time. In rare cases it is also possible for symptoms to improve if the cyst ruptures spontaneously. Symptoms affecting quality of voice tend to worsen after speaking for long periods of time, or when speaking with increased volume. Many individuals who use their voice professionally find even a slight presence of symptoms to be problematic. However, some voice professionals are not impacted by the presence of vocal cysts.
Vocal Dynamics
Vocal fold cysts cause the properties of the vocal folds to change. When a cyst is present on a vocal fold, the cover of the vocal fold becomes more stiff and increases in mass. The increased mass and stiffness tends to result in hyperkinetic muscular movement during phonation. Hyperkinetic movement is characterized by increased rigidity in the affected vocal fold(s). This hyperkinetic movement results in the voice being perceived as hoarse. (see Signs and Symptoms) Specifically, the presence of a vocal fold cyst leads to an asynchronous mucosal wave of the vocal folds during phonation.
Causes
There are several possible causes of vocal fold cysts:
They can be congenital.
They can result from the blockage of a mucous glands excretory duct. In this case, they are sometimes referred to as retention cysts.
They can be the result of phonotrauma. Phonotrauma refers to behaviours that can lead to vocal fold injuries, such as vocal overuse (i.e. too much speaking), vocal misuse (i.e. speaking in an unnaturally high or low pitch), or vocal abuse (i.e. yelling or whispering for prolonged periods). Vocal folds vibrate during phonation resulting in repeated collisions of the right and left vocal folds. Phonotrauma subjects the vocal folds to excessive mechanical forces during these vibratory cycles, which can lead to the development of a wound. It is the healing of these wounds, which leads to tissue re-structuring, that can result in a vocal fold cyst.
Diagnosis
There are generally four components included in the full diagnosis of a vocal cord cyst: a medical and voice history, a head and neck exam, a perceptual assessment of the voice and imaging of the vocal folds. A medical and voice history can help distinguish patterns of misuse and phonotrauma to assist in diagnosis. The primary perceptual sign of vocal fold cysts is hoarseness of the voice. Diagnosis through perceptual means alone is difficult, therefore in the fourth component of diagnosis the patient often undergoes an imaging procedure. Imaging is most commonly done with laryngeal videostroboscopy. A videostroboscopy is an examination of the vocal folds using flashes of light to slow down the image of the vocal fold movement enough to provide a sharp picture of the phases of the movement cycle (mucosal wave.) This procedure provides information about vocal fold vibrations during speech, vocal intensity and vocal frequency. Imaging shows the reduced movement of the vocal folds (mucosal wave) when a vocal fold cyst is present. Further, videostroboscopy tends to show increased submucosal swelling in the affected areas of the vocal fold(s) More recently, other technologies have been introduced to assist with obtaining imaging of the vocal folds, including the use of Narrow-band imaging (NBI.) Narrow-band imaging involves the use of blue and yellow lights to improve the picture quality of an image and accentuate blood vessel visibility. NBI has been found to help improve visual identification of vocal fold cysts in some cases.Vocal fold cysts can be differentiated from other vocal fold growths as they are usually unilateral. The two types of vocal fold cysts (sub-epithelial and ligament cysts) can be differentiated by colour, size and location. (See section on Types of vocal cord cysts for more information.)
If the vocal fold cyst(s) are presumed to be congenital, the patient should have a history of presenting with a hoarse voice.Patients with vocal fold cysts are considered for surgery when presenting with:
Dysphonia
Lack of improvement through voice therapy
Prevention
A key aspect of preventing vocal fold cysts is good vocal hygiene. Good vocal hygiene promotes the healthy use of the vocal apparatus and the avoidance of phonotrauma. Good vocal hygiene practices involve the avoidance of:
Shouting
Whispering loudly or for long periods of time
Frequently of talking over loud background noise
Talking while yawning
Continual clearing of the throat
Speaking in an unnatural voice (i.e. too high or low)
Talking with a cold or laryngitis
Smoking tobacco or marijuana
The consumption of alcohol and coffee
The use of antihistamines, aspirin, steroids, tricyclic antidepressants, or any substance that alters perception (i.e. sleeping pills)
Foul airIn addition, good vocal hygiene involves getting enough rest and drinking sufficient water. It is important to keep the vocal fold tissue healthy and hydrated, and when possible to limit the quantity of speaking in order to avoid damage.
Treatment
Vocal fold cysts are treated using a multidisciplinary approach. Vocal fold cysts are most responsive when surgical intervention is supplemented with voice therapy. Applying vocal therapy techniques in isolation has not yet been proven to remediate and decrease the actual size of the vocal fold cyst.Voice therapy to address harmful vocal behaviours is recommended as the first treatment option. Voice therapy may involve reducing tension in the larynx, reducing loudness, reducing the amount of speech produced, and modifying the environment. If symptoms are significant, treatment usually involves microsurgery to remove the cyst. Although voice therapy is useful for preventing vocal fold cysts caused by phonotrauma and for promoting safe vocal practices, vocal fold cysts tend not to respond to therapy alone and typically require surgery for full repair.During surgery, attempts are made to preserve as much vocal fold tissue as possible, given that glottal insufficiency (a gap in the vocal folds) is a possible consequence of surgery. Vocal fold tissue can be preserved during surgery by raising a micro-flap, removing the cyst, then laying the flap back down. This is intended to lead to minimal scarring and improved voice function. However, if any epithelium from the cyst sac is left behind during surgery, the cyst may regrow. Surgery of the larynx may also be conducted using a CO2 laser, which was reported as early as the 1970s. Congenital ductal cysts (those caused by blockage of a glandular duct) may be treated by marsupialization.Following surgery, patients are recommended to take 2 to 14 days of vocal rest. In absolute vocal rest, activities such as talking, whispering, whistling, straining, coughing, and sneezing are restricted. Once adequate healing has occurred, the patient may be transitioned to relative vocal rest, which typically involves 5 to 10 minutes of breathy voicing per hour. Voice therapy is then required to restore as much function as possible. Post-operative voice therapy may include addressing harmful vocal behaviours, exercises to restrengthen the larynx, and reintegration into normal voice activities.
Professional voice users who do not experience substantial limitations due to their cysts may choose to forego surgery. Considering that some cysts remain stable over long periods of time, voice therapy alone may be an option for those who are resistant to surgery. Another option for those who are unwilling to undergo surgery is vocal fold steroid injection (VFSI). Injection of the vocal folds may be done transorally or percutaneously, through the thyrohyoid membrane, thyroid cartilage, or cricothyroid membrane. After VFSI, patients are recommended to take 1 to 7 days of vocal rest. VFSI may also be used to delay surgery, or as a treatment method when the risks associated with surgery are deemed to be too high.
Prognosis
Following diagnosis, voice therapy should be implemented to optimize vocal hygiene. Vocal fold cysts tend not to improve solely through vocal rest or vocal therapy.Patients with sub-epithelial cysts have a better prognosis for timely recovery of vocal abilities than patients with ligament vocal fold cysts. Typically, patients can resume speaking activities in 7–30 days following surgery, and singing activities 30–90 days post-surgery.Up to 20% of patients show scarring, polyps or vascular changes of the vocal folds following surgery. In severe cases, these resulting symptoms may require further surgery. The patient must always be aware of the impact and potential complications of surgery on their voice, especially if the voice is heavily used occupationally. In these cases, post-operative therapy should be discussed.
See also
Vocal fold nodule
References
External links
Vocal Cord / Voice Disorder Community - Online Support
VoiceInfo.org
Photo Library at VoiceInfo.org |
Pemphigoid nodularis | Pemphigoid nodularis is a cutaneous condition that is a variant of bullous pemphigoid that has skin lesions mimicking prurigo nodularis.The antibody involved is IgG.
See also
Adult linear IgA disease
List of cutaneous conditions
== References == |
Far-sightedness | Far-sightedness, also known as long-sightedness, hypermetropia, or hyperopia, is a condition of the eye where distant objects are seen clearly but near objects appear blurred. This blurred effect is due to incoming light being focused behind, instead of on, the retina wall due to insufficient accommodation by the lens. Minor hypermetropia in young patients is usually corrected by their accommodation, without any defects in vision. But, due to this accommodative effort for distant vision, people may complain of asthenopic symptoms during prolonged reading. Some hypermetropes can see clear at distance, but near vision may be blurred due to insufficient accommodation. For this reason, this defect is referred as far-sightedness. If the hypermetropia is high, there will be defective vision for both distance and near. People may also experience accommodative dysfunction, binocular dysfunction, amblyopia, and strabismus. Newborns are almost invariably hypermetropic, but it gradually decreases as the newborn gets older.There are many causes for this condition. It may occur when the axial length of eyeball is too short or if the lens or cornea is flatter than normal. Changes in refractive index of lens, alterations in position of the lens or absence of lens are the other main causes. Risk factors include a family history of the condition, diabetes, certain medications, and tumors around the eye. It is a type of refractive error. Diagnosis is based on an eye exam.Management can occur with eyeglasses, contact lenses, or refractive corneal surgeries. Glasses are easiest while contact lenses can provide a wider field of vision. Surgery works by changing the shape of the cornea. Far-sightedness primarily affects young children, with rates of 8% at 6 years and 1% at 15 years. It then becomes more common again after the age of 40, known as presbyopia, affecting about half of people. Best treatment option to correct hypermetropia due to aphakia is IOL implantation.Other common types of refractive errors are near-sightedness, astigmatism, and presbyopia.
Signs and symptoms
In young patients, mild hypermetropia may not produce any symptoms. The signs and symptoms of far-sightedness include blurry vision, frontal or fronto temporal headaches, eye strain, tiredness of eyes etc. The common symptom is eye strain. Difficulty seeing with both eyes (binocular vision) may occur, as well as difficulty with depth perception. The asthenopic symptoms and near blur are usually seen after close work, especially in the evening or night.
Complications
Far-sightedness can have rare complications such as strabismus and amblyopia. At a young age, severe far-sightedness can cause the child to have double vision as a result of "over-focusing".Hypermetropic patients with short axial length are at higher risk of developing primary angle closure glaucoma, so, routine gonioscopy and glaucoma evaluation is recommended for all hypermetropic adults.
Causes
Simple hypermetropia, the most common form of hypermetropia, is caused by normal biological variations in the development of eyeball. Aetiologically, causes of hypermetropia can be classified as:
Axial: Axial hypermetropia occur when the axial length of eyeball is too short. About 1 mm decrease in axial length cause 3 diopters of hypermetropia. One condition that cause axial hypermetropia is nanophthalmos.
Curvatural: Curvatural hypermetropia occur when curvature of lens or cornea is flatter than normal. About 1 mm increase in radius of curvature results in 6 diopters of hypermetropia. Cornea is flatter in microcornea and cornea plana.
Index: Age related changes in refractive index (cortical sclerosis) can cause hypermetropia. Another cause of index hypermetropia is diabetes. Occasionally, mild hypermetropic shift may be seen in association with cortical or subcapsular cataract also.
Positional: Positional hypermetropia occur due to posterior dislocation of Lens or IOL. It may occur due to trauma.
Consecutive: Consecutive hypermetropia occur due to surgical over correction of myopia or surgical under correction in cataract surgery.
Functional: Functional hypermetropia results from paralysis of accommodation as seen in internal ophthalmoplegia, CN III palsy etc.
Absence of lens: Congenital or acquired aphakia cause high degree hypermetropia.Far-sightedness is often present from birth, but children have a very flexible eye lens, which helps to compensate. In rare instances hyperopia can be due to diabetes, and problems with the blood vessels in the retina.
Diagnosis
A diagnosis of far-sightedness is made by utilizing either a retinoscope or an automated refractor-objective refraction; or trial lenses in a trial frame or a phoropter to obtain a subjective examination.
Ancillary tests for abnormal structures and physiology can be made via a slit lamp test, which examines the cornea, conjunctiva, anterior chamber, and iris.In severe cases of hyperopia from birth, the brain has difficulty in merging the images that each individual eye sees. This is because the images the brain receives from each eye are always blurred. A child with severe hyperopia can never see objects in detail. If the brain never learns to see objects in detail, then there is a high chance of one eye becoming dominant. The result is that the brain will block the impulses of the non-dominant eye. In contrast, the child with myopia can see objects close to the eye in detail and does learn at an early age to see objects in detail.
Classification
Hyperopia is typically classified according to clinical appearance, its severity, or how it relates to the eyes accommodative status.
Clinical classification
There are three clinical categories of hyperopia.
Simple hyperopia: Occurs naturally due to biological diversity.
Pathological hyperopia: Caused by disease, trauma, or abnormal development.
Functional hyperopia: Caused by paralysis that interferes eyes ability to accommodate.
Classification according to severity
There are also three categories severity:
Low: Refractive error less than or equal to +2.00 diopters (D).
Moderate: Refractive error greater than +2.00 D up to +5.00 D.
High: Refractive error greater than +5.00 D.
Components of hypermetropia
Accommodation has significant role in hyperopia. Considering accommodative status, hyperopia can be classified as:
Total hypermetropia: It is the total amount of hyperopia which is obtained after complete relaxation of accommodation using cycloplegics like atropine.
Latent hyperopia: It is the amount of hyperopia normally corrected by ciliary tone (approximately 1 diopter).
Manifest hyperopia: It is the amount of hyperopia not corrected by ciliary tone. Manifest hyperopia is further classified into two, facultative and absolute.
Facultative hyperopia: It is the part of hyperopia corrected by patients accommodation.
Absolute hyperopia: It is the residual part of hyperopia which causes blurring of vision for distance.So, Total hyperopia= latent hyperopia + manifest hyperopia (facultative + absolute)
Treatment
Corrective lenses
The simplest form of treatment for far-sightedness is the use of corrective lenses, i.e. eyeglasses or contact lenses. Eyeglasses used to correct far-sightedness have convex lenses.
Surgery
There are also surgical treatments for far-sightedness:
Laser procedures
Photorefractive keratectomy (PRK): This is a refractive technique that is done by removal of a minimal amount of the corneal surface. Hyperopic PRK has many complications like regression effect, astigmatism due to epithelial healing, and corneal haze. Post operative epithelial healing time is also more for PRK.
Laser assisted in situ keratomileusis (LASIK): Laser eye surgery to reshape the cornea, so that glasses or contact lenses are no longer needed. Excimer laser LASIK can correct hypermetropia up to +6 diopters. LASIK is contraindicated in patients with lupus and rheumatoid arthritis.
Laser epithelial keratomileusis (LASEK): Resembles PRK, but uses alcohol to loosen the corneal surface.
Epi-LASIK: Epi-LASIK is also used to correct hyperopia. In this procedure, use of epikeratome eliminates the use of alcohol.
Laser thermal keratoplasty (LTK): Laser thermal keratoplasty is a laser based non-destructive refractive procedure used to correct hyperopia and presbyopia. It uses Thallium-Holmium-Chromium (THC): YAG laser.IOL implantation
Aphakia correction: High degree hypermetropia due to absence of lens (aphakia) is best corrected using intraocular lens implantation.
Refractive lens exchange (RLE): A variation of cataract surgery where the natural crystalline lens is replaced with an artificial intraocular lens; the difference is the existence of abnormal ocular anatomy which causes a high refractive error.
Phakic IOL: Phakic intraocular lens are lenses that implanted inside eye without removing the normal crystalline lens. Phakic IOLs can be used to correct hypermetropia up to +20 diopters.Non laser procedures
Conductive keratoplasty (CK): Conductive keratoplasty is a non laser refractive procedure used to correct presbyopia and low hypermetropia (+0.75D to +3.25D) with or without astigmatism (up to 0.75D). It uses radiofrequency energy to heat and shrink corneal collagen tissue. CK is contraindicated in pregnant/breastfeeding women, central corneal dystrophies and scarring, history of herpetic keratitis, type 1 diabetes etc.
Automated lamellar keratoplasty (ALK): Hyperopic automated lamellar keratoplasty (H-ALK) and Homoplastic ALK are ALK procedures that corrects low to moderate hyperopia. Poor predictability and the risk of complications limits usefulness of these procedures.
Keratophakia and epi-keratophakia are another two non laser surgical procedures used to correct hypermetropia. Keratophakia is a surgical technique developed by Barraquer for treating high hypermetropia and aphakia. Poor predictability and induced irregular astigmatism are complications of these procedures.
Etymology
The term hyperopia comes from Greek ὑπέρ hyper "over" and ὤψ ōps "sight" (GEN ὠπός ōpos).
References
== External links == |
Macrodontia | Macrodontia may refer to:
Macrodontia (tooth), a tooth disorder where the teeth are larger than normal
Macrodontia (beetle), a genus of beetles
See also
Macrodonta (disambiguation) |
Nephrogenic systemic fibrosis | Nephrogenic systemic fibrosis is a rare syndrome that involves fibrosis of skin, joints, eyes, and internal organs. NSF is caused by exposure to gadolinium in gadolinium-based MRI contrast agents (GBCAs) in patients with impaired kidney function. Epidemiological studies suggest that the incidence of NSF is unrelated to gender or ethnicity and it is not thought to have a genetic basis. After GBCAs were identified as a cause of the disorder in 2006, and screening and prevention measures put in place, it is now considered rare.
Signs and symptoms
Clinical features of NSF develop within days to months and, in some cases, years following exposure to some GBCAs. The main symptoms are the thickening and hardening of the skin associated with brawny hyperpigmentation, typically presenting in a symmetric fashion. The skin gradually becomes fibrotic and adheres to the underlying fascia. The symptoms initiate distally in the limbs and progress proximally, sometimes involving the trunk. Joint contractures of the fingers, elbows and knees can develop secondary to skin involvement and can severely impair physical function. While skin involvement is on the foreground, the process may involve any organ, e.g., the eye, heart, diaphragm, pleura, pericardium, and kidneys, as well as the lungs and liver.
Causes
NSF is an iatrogenic disease caused by exposure to gadolinium-based contrast agents used in magnetic resonance imaging.
Risk factors
Impaired kidney function reduces the clearance of GBCAs and is the major risk factor for the development of NSF. The etiology or duration of renal failure seems not to be relevant, but NSF risk greatly depends on the residual kidney function. The majority of NSF cases have been identified in patients with stage 5 CKD, but NSF has also developed in patients with stage 4 and 3 CKD, and those with acute kidney injury, even if kidney function subsequently returned to normal following GBCA administration. Thus NSF should be considered as a differential diagnosis in any patient who has been exposed to a GBCA, regardless of the kidney function level.Three GBCAs have been principally implicated in NSF: gadodiamide, gadopentetate dimeglumine, and gadoversetamide, though cases have been reported with majority of GBCAs on the market. High doses in individual GBCA administrations and high cumulative doses of GBCA over the lifetime of patients with renal dysfunction are associated with increased risk of NSF.
Mechanism
De-chelation of Gd(III) is responsible for the toxicity associated with gadolinium complexes such as GBCAs, and the toxicity appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallation in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd(III) complexes, all become lethally toxic when they release precisely the same quantity of Gd(III). It is also supported by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn2+ deficiency. Under the transmetallation hypothesis, we can expect that subtle changes in formulation can affect the intrinsic safety of gadolinium complexes, which is indeed observed.
Diagnosis
There is no specific imaging finding for NSF, and the diagnosis is a clinicopathological one, based on presentation and histological findings.
Microscopic pathology
At the microscopic level, NSF shows a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and deposits of mucin. More recent case reports have described the presence of sclerotic bodies (also known as elastocollagenous balls) in skin biopsies from NSF patients. While not universally present, this finding is believed to be unique to patients exposed to gadolinium, although not necessarily limited to areas involved by NSF.
Differential diagnosis
The differential diagnoses for NSF include diffuse cutaneous or limited cutaneous systemic sclerosis, scleromyxedema, lipodermatosclerosis, scleroedema diabeticorum, graft versus host disease, eosinophilic fasciitis; eosinophilia-myalgia syndrome; porphyria cutanea tarda, and other disorders. The nearly universal absence of facial skin involvement in NSF, presence of yellow plaques on the sclera of the eyes, absence of Raynauds phenomenon, and other differences in presentation can aid the proper diagnosis. History of exposure to GBCAs would favor NSF as the differential diagnosis.
Prevention
The only known measure for prevention of NSF is the non-use or cautious use of GBCAs in patients with renal impairment, including preferential use of safer, macrocyclic GBCAs. Performing dialysis immediately after the MRI exam is recommended for patients already in dialysis treatment, but there is no evidence for introducing dialysis in non-dialytic patients for prevention of NSF. Screening for impaired kidney function is routinely conducted and has drastically reduced the incidence of NSF.
Treatment
Multiple therapies for NSF have been attempted, with variable clinical improvement. None have been as effective as restoration of kidney function. Restoration of kidney function by treating the underlying disease process, recovery from acute kidney injury (AKI), or performing a kidney transplant can slow or hold the progression of NSF. A few cases of curative kidney transplantation have been reported, and it is appropriate to consider transplantation as treatment.
Epidemiology
NSF affects males and females in approximately equal numbers and has been reported in patients of different ethnic and geographic regions. It most often affects middle-aged individuals, but there are reports of cases occurring from childhood to senescence.
History
This condition was originally termed "nephrogenic fibrosing dermopathy" as initially only skin involvement in patients with impaired kidney function was observed, and later renamed "nephrogenic systemic fibrosis" to better describe its systemic nature. The term "gadolinium-associated systemic fibrosis" has also been proposed to reflect the fact that impaired kidney function is not in itself the cause of NSF.The first cases of NSF were identified in 1997, but it was first described as an independent disease entity in 2000. In 2006, the link between NSF and gadolinium-based MRI contrast agents was made. As a result, restrictions on use of GBCAs in patients with an estimated glomerular filtration rate (a measure of kidney function) under 60 and especially under 30 mL/min/1.73 m2 have been recommended and NSF is now considered rare.After several years of controversy, during which up to 100 Danish patients developed gadolinium poisoning after use of the contrast agent Omniscan, the Norwegian medical company Nycomed admitted that they were aware of some dangers from using gadolinium-based agents in their product.With both Gadopentetic acid (gadopentetate dimegulumine (Magnevist)) and Gadodiamide (Omniscan) the risk was considered to outweigh the benefits and, as a result, the EMA recommended the licence for intravenous gadopentetic acid and Gadodiamide be suspended.Following a legally binding decision issued by The European Commission and applicable in all EU Member States (Commission decision date: 23/11/2017), Intravenous Magnevist and Omniscan is now no longer authorised for use in Europe. Magnavist is, however, still authorised in Europe as an intra-articular MR contrast medium. The authorised indication for the use of linear chelated media gadobenic acid (also known as gadobenate dimeglumine; MultiHance) and gadoxetic acid (Primovist) has been limited to delayed phase liver imaging only.
References
Further reading
== External links == |
Bigeminy | Bigeminy is a cardiac arrhythmia in which there is a single ectopic beat, or irregular heartbeat, following each regular heartbeat. Most often this is due to ectopic beats occurring so frequently that there is one after each sinus beat, or normal heartbeat. The two beats are figuratively similar to two twins (hence bi- + gemini). For example, in ventricular bigeminy, a sinus beat is shortly followed by a premature ventricular contraction (PVC), a pause, another normal beat, and then another PVC. In atrial bigeminy, the other "twin" is a premature atrial contraction (PAC).
Cause
After any PVC there is a pause that can lead to the development of bigeminy. A PVC wavefront often encounters a refractory AV node that does not conduct the wavefront retrograde. Thus the atrium is not depolarized and the sinus node is not reset. Since the sinus P wave to PVC interval is less than the normal P–P interval, the interval between the PVC and the next P wave is prolonged to equal the normal time elapsed during two P–P intervals. This is called a "compensatory" pause. The pause after the PVC leads to a longer recovery time, which is associated with a higher likelihood of myocardium being in different stages of repolarization. This then allows for re-entrant circuits and sets up the ventricle for another PVC after the next sinus beat. The constant interval between the sinus beat and PVC suggests a reentrant etiology rather than spontaneous automaticity of the ventricle.Premature atrial contractions by contrast do not have a compensatory pause, since they reset the sinus node, but atrial or supraventricular bigeminy can occur. If the PACs are very premature, the wavefront can encounter a refractory AV node and not be conducted. This can be mistaken for sinus bradycardia if the PAC is buried in the T wave since the PAC will reset the SA node and lead to a long P–P interval.
Diagnosis
Rule of bigeminy
When the atrial rhythm is irregular (as in atrial fibrillation or sinus arrythmia) the presence of bigeminy depends on the length of the P–P interval and happens more frequently with a longer interval. As with post PVC pauses, a longer P–P interval leads to a higher chance of re-entrant circuits and thus PVCs. The term "rule of bigeminy" is used to refer to the dependence of bigeminy on the ventricular cycle length in irregular rhythms.
Classification
There can be similar patterns depending on the frequency of abnormal beats. If every other beat is abnormal, it is described as bigeminal. If every third beat is aberrant, it is trigeminal; every fourth would be quadrigeminal. Typically, if every fifth or more beat is abnormal, the aberrant beat would be termed occasional.Bigeminy is contrasted with couplets, which are paired abnormal beats. Groups of three abnormal beats are called triplets and are considered a brief run of non-sustained ventricular tachycardia (NSVT), and if the grouping lasts for more than 30 seconds, it is ventricular tachycardia (VT).
Treatment
In people without underlying heart disease and who do not have any symptoms, bigeminy in itself does not require any treatment. If it does become symptomatic, beta-blockers can be used to try and suppress ventricular ectopy. Class I and III agents are generally avoided as they can provoke more serious arrhythmias.
== References == |
Chondrodysplasia punctata | Chondrodysplasia punctata is a clinically and genetically diverse group of rare diseases, first described by Erich Conradi (1882–1968), that share the features of stippled epiphyses and skeletal changes.: 500 : 549
Types
Rhizomelic chondrodysplasia punctata 215100, 222765, 600121
X-linked recessive chondrodysplasia punctata 302950
Conradi–Hünermann syndrome (chondrodysplasia punctata 2, x-linked dominant) 302960
Autosomal dominant chondrodysplasia punctata 118650
See also
List of cutaneous conditions
List of radiographic findings associated with cutaneous conditions
References
== External links == |
Acidosis | Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma.
The term acidemia describes the state of low blood pH, while acidosis is used to describe the processes leading to these states. Nevertheless, the terms are sometimes used interchangeably. The distinction may be relevant where a patient has factors causing both acidosis and alkalosis, wherein the relative severity of both determines whether the result is a high, low, or normal pH.
Acidemia is said to occur when arterial pH falls below 7.35 (except in the fetus – see below), while its counterpart (alkalemia) occurs at a pH over 7.45. Arterial blood gas analysis and other tests are required to separate the main causes.
The rate of cellular metabolic activity affects and, at the same time, is affected by the pH of the body fluids. In mammals, the normal pH of arterial blood lies between 7.35 and 7.50 depending on the species (e.g., healthy human-arterial blood pH varies between 7.35 and 7.45). Blood pH values compatible with life in mammals are limited to a pH range between 6.8 and 7.8. Changes in the pH of arterial blood (and therefore the extracellular fluid) outside this range result in irreversible cell damage.
Signs and symptoms
Nervous system involvement may be seen with acidosis and occurs more often with respiratory acidosis than with metabolic acidosis. Signs and symptoms that may be seen in acidosis include headaches, confusion, feeling tired, tremors, sleepiness, flapping tremor, and dysfunction of the cerebrum of the brain which may progress to coma if there is no intervention.
Metabolic acidosis
Metabolic acidosis may result from either increased production of metabolic acids, such as lactic acid, or disturbances in the ability to excrete acid via the kidneys, such as either renal tubular acidosis or the acidosis of kidney failure, which is associated with an accumulation of urea and creatinine as well as metabolic acid residues of protein catabolism.
An increase in the production of other acids may also produce metabolic acidosis. For example, lactic acidosis may occur from:
severe (PaO2 <36mm Hg) hypoxemia causing a fall in the rate of oxygen diffusion from arterial blood to tissues.
hypoperfusion (e.g., hypovolemic shock) causing an inadequate blood delivery of oxygen to tissues.A rise in lactate out of proportion to the level of pyruvate, e.g., in mixed venous blood, is termed "excess lactate", and may also be an indicator of fermentation due to anaerobic metabolism occurring in muscle cells, as seen during strenuous exercise. Once oxygenation is restored, the acidosis clears quickly. Another example of increased production of acids occurs in starvation and diabetic ketoacidosis. It is due to the accumulation of ketoacids (via excessive ketosis) and reflects a severe shift from glycolysis to lipolysis for energy needs.
Acid consumption from poisoning such as methanol ingestion, elevated levels of iron in the blood, and chronically decreased production of bicarbonate may also produce metabolic acidosis.
Metabolic acidosis is compensated for in the lungs, as increased exhalation of carbon dioxide promptly shifts the buffering equation to reduce metabolic acid. This is a result of stimulation to chemoreceptors, which increases alveolar ventilation, leading to respiratory compensation, otherwise known as Kussmaul breathing (a specific type of hyperventilation). Should this situation persist, the patient is at risk of exhaustion leading to respiratory failure.
Mutations to the V-ATPase a4 or B1 isoforms result in distal renal tubular acidosis, a condition that leads to metabolic acidosis, in some cases with sensorineural deafness.
Arterial blood gases will indicate low pH, low blood HCO3, and normal or low PaCO2.
In addition to arterial blood gas, an anion gap can also differentiate between possible causes.
The Henderson-Hasselbalch equation is useful for calculating blood pH, because blood is a buffer solution. In the clinical setting, this equation is usually used to calculate HCO3 from measurements of pH and PaCO2 in arterial blood gases. The amount of metabolic acid accumulating can also be quantitated by using buffer base deviation, a derivative estimate of the metabolic as opposed to the respiratory component. In hypovolemic shock for example, approximately 50% of the metabolic acid accumulation is lactic acid, which disappears as blood flow and oxygen debt are corrected.
Treatment
Treatment of uncompensated metabolic acidosis is focused upon correcting the underlying problem. When metabolic acidosis is severe and can no longer be compensated for adequately by the lungs or kidneys, neutralizing the acidosis with infusions of bicarbonate may be required.
Fetal metabolic acidemia
In the fetus, the normal range differs based on which umbilical vessel is sampled (umbilical vein pH is normally 7.25 to 7.45; umbilical artery pH is normally 7.18 to 7.38). Fetal metabolic acidemia is defined as an umbilical vessel pH of less than 7.20 and a base excess of less than −8.
Respiratory acidosis
Respiratory acidosis results from a build-up of carbon dioxide in the blood (hypercapnia) due to hypoventilation. It is most often caused by pulmonary problems, although head injuries, drugs (especially anaesthetics and sedatives), and brain tumors can cause this acidemia. Pneumothorax, emphysema, chronic bronchitis, asthma, severe pneumonia, and aspiration are among the most frequent causes. It can also occur as a compensatory response to chronic metabolic alkalosis.
One key to distinguish between respiratory and metabolic acidosis is that in respiratory acidosis, the CO2 is increased while the bicarbonate is either normal (uncompensated) or increased (compensated). Compensation occurs if respiratory acidosis is present, and a chronic phase is entered with partial buffering of the acidosis through renal bicarbonate retention.
However, in cases where chronic illnesses that compromise pulmonary function persist, such as late-stage emphysema and certain types of muscular dystrophy, compensatory mechanisms will be unable to reverse this acidotic condition. As metabolic bicarbonate production becomes exhausted, and extraneous bicarbonate infusion can no longer reverse the extreme buildup of carbon dioxide associated with uncompensated respiratory acidosis, mechanical ventilation will usually be applied.
Fetal respiratory acidemia
In the fetus, the normal range differs based on which umbilical vessel is sampled (umbilical vein pH is normally 7.25 to 7.45; umbilical artery pH is normally 7.20 to 7.38). In the fetus, the lungs are not used for ventilation. Instead, the placenta performs ventilatory functions (gas exchange). Fetal respiratory acidemia is defined as an umbilical vessel pH of less than 7.20 and an umbilical artery PCO2 of 66 or higher or umbilical vein PCO2 of 50 or higher.
See also
References
Notes
== External links == |
Ecthyma gangrenosum | Ecthyma gangrenosum is a type of skin lesion characterized by vesicles or blisters which rapidly evolve into pustules and necrotic ulcers with undermined tender erythematous border. "Ecthyma" means a pus forming infection of the skin with an ulcer, "gangrenosum" refers to the accompanying gangrene or necrosis. It is classically associated with Pseudomonas aeruginosa bacteremia, but it is not pathognomonic. Pseudomonas aeruginosa is a gram negative, aerobic bacillus.This type of skin lesion was first described in association with Pseudomonas aeruginosa by L. Barker in 1897. It was given the name "ecthyma gangrenosum" by Hitschmann and Kreibich.It mostly occurs in patients with underlying immunocompromise (e.g. malignancy or HIV). Although most cases are due to Pseudomonas aeruginosa infection, there are recent reports of this skin lesion in association with other microorganisms, such as Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, various other Pseudomonas species, and Morganella morganii.
Signs and symptoms
The primary skin lesion usually starts with a macule that is painless, round and erythematous. Then, it develops into a pustule, and then a bulla with central hemorrhagic focus. The bulla progresses into an ulcer which extends laterally. Finally it becomes a gangrenous ulcer with a central black eschar surrounded by an erythematous halo.The lesions may be single or multiple. They are most commonly seen in perineum and under arm pit. However, they can occur in any part of the body.
Mechanism
The organism enters directly through the breakdown of mechanical defense barriers such as mucosa or skin. Conditions which lead to the development of an immunocompromised state make the patient more susceptible to ecthyma gangrenosum and sepsis. In case of sepsis, the bacteria reaches the skin via the bloodstream. Defective humoral or cellular immunity increases risk, as the organism is not cleared from the bloodstream as usual. The main mechanism of the organism that is causing the typical skin lesions is the invasion of the organism into the arteries and veins in the dermis and subcutaneous tissues of the skin. This perivascular invasion leads to nodular formation, ulceration, vasculitis and necrosis due to impaired blood supply. Perivascular involvement is achieved by direct entry of bacteria through the skin or hematogenous spreading in case of sepsis.
Diagnosis
Diagnosis is made by clinical observation and the following tests.(1) Gram stain of the fluid from pustules or bullae, and tissue swab.
(2) Blood culture
(3) Urine culture
(4) Skin biopsy
(5) Tissue culture
Magnetic resonance imaging can be done in case of ecthyma gangrenosum of plantar foot to differentiate from necrotizing fasciitis.
Prevention
The main organism associated with ecthyma gangrenosum is Pseudomonas aeruginosa. However, multi-bacterial cases are reported as well. Prevention measures include practicing proper hygiene, educating the immunocompromised patients for awareness to avoid possible conditions and seek timely medical treatment.
Treatments
Treatments involve antibiotics that cover for Pseudomonas aeruginosa. antipseudomonal penicillins, aminoglycosides, fluoroquinolones, third generation cephalosporins or ceftriaxone aztreonam can be given. Usually, the antibiotics are changed according to the culture and sensitivity result. In patients with very low white blood cell counts, granulocyte-macrophage colony-stimulating factor may be given. Depending on the causal agents, antivirals or antifungals can be added.Surgery will be needed if there is extensive necrosis not responding to medical treatments.
Recent research
A recent retrospective study of all cases of ecthyma gangrenosum from 2004 to 2010 in a university hospital in Mexico shows that neutropenia in immunocompromised patients is the most common risk factor for ecthyma gangrenosum.
References
== External links == |
Pentosuria | Pentosuria is a condition where the sugar xylitol, a pentose, presents in the urine in unusually high concentrations. It was characterized as an inborn error of carbohydrate metabolism in 1908. It is associated with a deficiency of L-xylulose reductase, necessary for xylitol metabolism. L-Xylulose is a reducing sugar, so it may give false diagnosis of diabetes, as it is found in high concentrations in urine. However glucose metabolism is normal in people with pentosuria, and they are not diabetic. Patients of pentosuria have a low concentration of the sugar d-xyloketose. Using phenyl pentosazone crystals, phloroglucin reaction, and absorption spectrum, pentose can be traced back as the reducing substance in urine, with those that have pentosuria.Research has shown that pentosuria appears in 3 forms. The most widely studied is essential pentosuria, where a couple of grams of L-xylusol are released into a persons system daily. L-xylulose reductase, contained in red blood cells, is composed of both a major and minor isozyme. For those diagnosed with essential pentosuria, the major isozyme appears to be the same as the minor one. Alimentary pentosuria can be acquired through fruits high in pentose. Finally, drug-induced pentosuria can be developed by those exposed to morphine, fevers, allergies, and some hormones.Those diagnosed with Pentosuria are predominantly of Jewish root. However, it is a harmless defect, and no cure is needed.
References
== External links == |
Phantom limb | A phantom limb is the sensation that an amputated or missing limb is still attached. Approximately 80 to 100% of individuals with an amputation experience sensations in their amputated limb. However, only a small percentage will experience painful phantom limb sensation. These sensations are relatively common in amputees and usually resolve within two to three years without treatment. Research continues to explore the underlying mechanisms of phantom limb pain (PLP) and effective treatment options.
Signs and symptoms
Most (80% to 100%) amputees experience a phantom limb, with some of them having non-painful sensations. The amputee may feel very strongly that the phantom limb is still part of the body.People will sometimes feel as if they are gesturing, feel itches, twitch, or even try to pick things up. The missing limb often feels shorter and may feel as if it is in a distorted and painful position. Occasionally, the pain can be made worse by stress, anxiety and weather changes. Exposure to extreme weather conditions, especially below freezing temperatures, can cause increased sensitivity to the sensation. Phantom limb pain is usually intermittent, but can be continuous in some cases. The frequency and intensity of attacks usually declines with time.Repressed memories in phantom limbs could potentially explain the reason for existing sensations after amputation. Specifically, there have been several reports from patients of painful clenching spasms in the phantom hand with the feeling of their nails digging into their palms. The motor output is amplified due to the missing limb; therefore, the patient may experience the overflow of information as pain. The patient contains repressed memories from previous motor commands of clenching the hand and sensory information from digging their nails into their palm. These memories remain due to previous neural connections in the brain.
Phantom limb syndrome
The term "phantom limb" was coined by physician Silas Weir Mitchell in 1871. For many years, the dominant hypothesis for the cause of phantom limbs was irritation in the peripheral nervous system at the amputation site (neuroma). By the late 1980s, Ronald Melzack had recognized that the peripheral neuroma account could not be correct, because many people born without limbs also experienced phantom limbs. According to Melzack the experience of the body is created by a wide network of interconnecting neural structures, which he called the "neuromatrix".Pons and colleagues (1991) at the National Institutes of Health (NIH) showed that the primary somatosensory cortex in macaque monkeys undergoes substantial reorganization after the loss of sensory input.Hearing about these results, Vilayanur S. Ramachandran hypothesized that phantom limb sensations in humans could be due to reorganization in the human brains somatosensory cortex. Ramachandran and colleagues illustrated this hypothesis by showing that stroking different parts of the face led to perceptions of being touched on different parts of the missing limb. Later brain scans of amputees showed the same kind of cortical reorganization that Pons had observed in monkeys.Maladaptive changes in the cortex may account for some but not all phantom limb pain. Pain researchers such as Tamar Makin (Oxford) and Marshall Devor (Hebrew University, Jerusalem) argue that phantom limb pain is primarily the result of "junk" inputs from the peripheral nervous system.Despite a great deal of research on the underlying neural mechanisms of phantom limb pain there is still no clear consensus as to its cause. Both the brain and the peripheral nervous system may be involved.Research continues into more precise mechanisms and explanations.
Neural mechanisms
Pain, temperature, touch, and pressure information are carried to the central nervous system via the anterolateral system (spinothalamic tracts, spinoreticular tract, spinomesencefalic tract), with pain and temperature information transferred via lateral spinothalamic tracts to the primary sensory cortex, located in the postcentral gyrus in the parietal lobe, where sensory information is represented somatotropically, forming the sensory homunculus.In phantom limb syndrome, there is sensory input indicating pain from a part of the body that is no longer existent. This phenomenon is still not fully understood, but it is hypothesized that it is caused by activation of the somatosensory cortex.
Treatment
Most approaches to treatment over the past two decades have not shown consistent symptom improvement. Treatment approaches have included medication such as antidepressants, spinal cord stimulation, vibration therapy, acupuncture, hypnosis, and biofeedback. Reliable evidence is lacking on whether any treatment is more effective than the others.
Most treatments are not very effective. Ketamine or morphine may be useful around the time of surgery. Morphine may be helpful for longer periods of time. Evidence for gabapentin is mixed. Perineural catheters that provide local anesthetic agents have poor evidence of success when placed after surgery in an effort to prevent phantom limb pain.One approach that has received public interest is the use of a mirror box. The mirror box provides a reflection of the intact hand or limb that allows the patient to "move" the phantom limb, and to unclench it from potentially painful positions.Although mirror therapy was introduced by VS Ramachandran in the early 1990s, little research was done on it before 2009, and much of the subsequent research has been of poor quality, according to a 2016 review. A 2018 review, which also criticized the scientific quality of many reports on mirror therapy (MT), found 15 good-quality studies conducted between 2012 and 2017 (out of a pool of 115 publications), and concluded that "MT seems to be effective in relieving PLP, reducing the intensity and duration of daily pain episodes. It is a valid, simple, and inexpensive treatment for PLP."
Other phantom sensations
Phantom sensations may also occur after the removal of body parts other than the limbs, e.g. after amputation of the breast, extraction of a tooth (phantom tooth pain) or removal of an eye (phantom eye syndrome).Some people who have undergone gender reassignment surgery have reported the sensation of phantom genitals. The reports were less common among post-operative transgender women, but did occur in transgender men. Similarly, subjects who had undergone mastectomy reported experiencing phantom breasts; these reports were substantially less common among post-operative transgender men.
See also
Neuropathic pain
Supernumerary phantom limb, where sensations are felt in a limb that never existed
Synesthesia
Visual release hallucinations
References
Further reading
External links
Phantom limb syndrome: A review M.E.J. ANESTH 19 (2), 2007 |
Langerhans cell sarcoma | Langerhans cell sarcoma (LCS) is a rare form of malignant histiocytosis. It should not be confused with Langerhans cell histiocytosis, which is cytologically benign. It can present most commonly in the skin and lymphatic tissue, but may also present in the lung, liver, and bone marrow. Treatment is most commonly with surgery or chemotherapy.
Classification
Dendritic cell neoplasms are classified by the World Health Organization as follows:
Langerhans cell histiocytosis
Langerhans cell sarcoma
Interdigitating dendritic cell sarcoma/tumor
Follicular dendritic cell sarcoma/tumor
Dendritic cell sarcoma
Epidemiology
The exact incidence of LCS is unknown due to the rarity of the condition. The related condition, Langerhans Cell Histiocytosis (LCH) is estimated to have an incidence of around 5 cases per 1 million people per year. In one review of Japanese patients with confirmed LCS, patients were a median age of 41 years. Patients were twice as likely to be female than male. In another systematic review, the median age of presentation was 50 years, but with a slight predilection for males.
Pathophysiology
Throughout the body in locations such as mucous membranes, skin, lymph nodes, thymus, and spleen are cells known as antigen-presenting cells. These cells are surveillance cells that take foreign antigens and present them to antigen-processing cells, such as T-cells, protecting the body from potential harm. Antigen-presenting cells are also termed Dendritic cells, of which Langerhans cells are a subtype. There are four main types that make up the structure and functions of lymphoid tissue, such as lymph nodes and splenic tissue. By definition, Langerhans Cell Sarcoma (LCS) is a cancerous disease caused by the uncontrolled overproliferation of Langerhans cells.Because Langerhans cells are most commonly found in the mucosa and the skin, LCS is thought to usually begin here with further spread to other areas of the body via the lymphatic system.Langerhans cell sarcoma can occur de novo, or can occur as a malignant transformation of Langerhans cell histiocytosis.
Clinical Manifestations
The related condition, LCH, presents with various clinical features depending on the bodily organs involved. LCS shares most of these clinical presentations. Most commonly, these patients will present with generalized signs and symptoms such as fever and weight loss. Blood tests will commonly show pancytopenia, an overall reduction in blood cell counts. Additionally, these patients may display lymphadenopathy, hepatosplenomegaly, skin lesions, bone lesions, and lung lesions. Most common site presentations are the skin and lymphatics. Other common sites of involvement include the lung, liver, and spleen.LCS will present with a varied gross appearance. When involving the skin, LCS will present as a patches of erythema, with nodules and ulceration present as well. Skin lesions will most commonly involve the trunk, scalp, and legs. Tumor size may range from 1-6 cm, but may be larger. Usually the tumor is well circumscribed with a surface covered in small nodules or protuberances. Most are of a solid consistency and are of a pink, white, or tan color. LCS tumors may present with much larger sizes and aggressive features, even causing some bleeding and necrosis of the surrounding tissue.
Diagnosis
Diagnosis of Langerhans Cell Sarcoma is predominantly a pathologic diagnosis. Cells from these tumor samples will display features characteristic of Langerhans cells, but with additional signs of malignancy, such as increased mitoses, cellular atypia, and pleomorphic nuclei.CD-207 is a cellular marker associated with Birbeck granules than can be used for confirmation of cell type. LCS will also stain positive for CD-68, CD-68R, CD-21, CD-35, S-100, CD1a, lysozyme, HLA-DR, CD4, fascin, Factor XIIIa, and cyclin D1, which are cellular markers typically used in the characterization of various pathology specimens. Positive staining with CD1a and S-100 are required for diagnosis of LCS. Positive staining with CD-207 (Langerin) is an additional confirmation marker of malignancy in LCS. Other cellular markers have been reported to be positive in LCS, but have are not as routinely used.Histologically, Langerhans cells characteristically display Birbeck granules and nuclei with a longitudinal groove. Birbeck granules are currently a poorly understood cellular structure, but are commonly used for cell-type identification. Previously, the presence of Birbeck granules was necessary for diagnosis, but this is no longer considered diagnostic.Currently, there appears to be no relation of LCS with chromosomal abnormalities.The diagnosis of LCS can be difficult, especially due to its rarity. It has previously been mistaken with metastatic melanoma and metastatic large-cell carcinoma.
Treatment
Treatment for this rare disease consists of a variety of approaches, with none displaying any increased efficacy over another. There are currently three broad treatment strategies for LCS: surgery, chemotherapy, and combination with radiation therapy. When the LCS tumor is readily accessible, the best treatment method is usually surgical removal. There is, however, an observed increased risk of tumor relapse following surgical resection. Both chemotherapy and radiation therapy are useful as treatments, either as monotherapy or in conjunction with other treatments. Chemotherapy is currently the most common treatment method, either alone or in combination. The most common chemotherapeutic regimen consisted of cyclophosphamide, doxorubicin, vincristine, and prednisolone (otherwise known as CHOP therapy). Other common chemotherapeutic regimens include MAID (mesna, doxorubicin, ifosfamide, and dacarbazine), ESHAP (etoposide, carboplatin, cytarabine, and methylprednisolone), EPIG (etoposide, cisplatin, ifosfamide, mesna, and gemcitabine), and AIM (doxorubicin, ifosfamide, and mesna). Other regimens have been used with mixed levels of success. In an effort to prevent recurrence, sometimes combination therapy is used. Following surgical resection, additional radiation therapy or chemotherapy may be performed to prevent relapse. Patients receiving combined chemotherapy and radiation therapy has only shown limited benefit.There are a variety of other therapies under research with varying levels of reported success. These include high-dose chemotherapy, bone marrow transplants, and somatostatin analogues.When there is only one site of LCS involvement, monotherapy may be sufficient treatment. But when the disease has multiple sites or has metastasized, combination therapy will be necessary to achieve any level of adequate treatment.
Prognosis
Overall prognosis of patients with LCS depends heavily on the bodily organ involved and the extent of involvement of the tumor. Organs associated with a poor prognosis include the liver, lungs, and bone marrow. In patients with a single site of involvement, survivability tends to be very favorable. However, those with multi-organ involvement have a mortality rate of 50-66%. One systematic review calculated the disease-specific survival as 27.2 months, or 58% at one year. One group found the death rate to be 50% in patients with LCS, compared to 31% in patients who had the related condition LCH. Survivability decreases dramatically with increased disease burden and spread. LCS may be associated with other malignancies as well, such as follicular lymphoma, adenocarcinoma, and germ cell tumors. Evidence of metastatic disease or relapse from a previously treated LCS usually signifies a worsened prognosis. Treatment of these metastatic lesions or relapsed tumors may improve the patients prognosis, but there is limited evidence as to a preferred therapy.
See also
Langerhans cell histiocytosis
Sarcoma
References
== External links == |
Fetal distress | Fetal distress, also known as non-reassuring fetal status, is a condition during pregnancy or labor in which the fetus shows signs of inadequate oxygenation. Due to its imprecision, the term "fetal distress" has fallen out of use in American obstetrics. The term "non-reassuring fetal status" has largely replaced it. It is characterized by changes in fetal movement, growth, heart rate, and presence of meconium stained fluid.Risk factors for fetal distress/non-reassuring fetal status include anemia, restriction of fetal growth, maternal hypertension or cardiovascular disease, low amniotic fluid or meconium in the amniotic fluid, or a post-term pregnancy. The condition is detected most often with electronic fetal heart rate (FHR) monitoring through cardiotocography (CTG), which allows clinicians to measure changes in the fetal cardiac response to declining oxygen. Specifically, heart rate decelerations detected on CTG can represent danger to the fetus and to delivery.Treatment primarily consists of intrauterine resuscitation, the goal of which is to restore oxygenation of the fetus. This can involve improving the position, hydration, and oxygenation of the mother, as well as amnioinfusion to restore sufficient amniotic fluid, delaying preterm labor contractions with tocolysis, and correction of fetal acid-base balance. An algorithm is used to treat/resuscitate babies in need of respiratory support post-birth.
Signs and symptoms
Generally it is preferable to describe specific signs in lieu of declaring fetal distress that include:
Decreased movement felt by the mother
Meconium in the amniotic fluid ("meconium stained fluid")
Non-reassuring patterns seen on cardiotocography:
increased or decreased fetal heart rate (tachycardia and bradycardia), especially during and after a contraction
decreased variability in the fetal heart rate
late decelerations
Biochemical signs, assessed by collecting a small sample of babys blood from a scalp prick through the open cervix in labor
fetal metabolic acidosis
elevated fetal blood lactate levels (from fetal scalp blood testing) indicating the baby has a lactic acidosisSome of these signs are more reliable predictors of fetal compromise than others. For example, cardiotocography can give high false positive rates, even when interpreted by highly experienced medical personnel. Metabolic acidosis is a more reliable predictor, but is not always available.
Complications
Complications are primarily those associated with insufficient fetal oxygenation, most notably increased mortality risk. Other complications include fetal encephalopathy, seizures, cerebral palsy, and neurodevelopmental delay.
Causes
Several conditions and risk factors can lead to fetal distress or non-reassuring fetal status, including:
Low amniotic fluid (oligohydramnios)
If there is too little amniotic fluid around the baby in the uterus, the baby can have trouble moving around in the uterus and its growth and temperature can be impacted. Low amniotic fluid can be caused by placental issues, high gestational blood pressure, some medications, as well as problems with the fetal kidney or urinary tract.
Meconium in the amniotic fluid
If a fetus has meconium in their lungs when they are born, this prevents the pressure in their lungs from falling, which normally facilitates the transition to independent breathing. Since aspiration of meconium can lead to improper oxygenation due to obstruction and carries the potential risk for inflammatory pneumonitis, this is an important diagnosis to make in the setting of newborn respiratory distress.
Gestational Hypertension
If hypertension in the mother occurs after the 20th week and meets certain criteria, this is considered preeclampsia/eclampsia. The mechanism of preeclampsia/eclampsia is unknown, but consequences if left untreated can include fetal growth restriction or death, as well as pose medical risks to the mother. Signs and symptoms of preeclampsia can include swelling, protein in the urine, headaches, vomiting, and abnormal labs that assess kidney and liver function, some of which may be considered severe preeclampsia or eclampsia.
Post-term pregnancy
Breathing problems
Anemia
Abnormal position and presentation of the fetus
Multiple births
Shoulder dystocia
Umbilical cord prolapse
Nuchal cord
Placental abruption
Premature closure of the fetal ductus arteriosus
Uterine rupture
Intrahepatic cholestasis of pregnancy, a liver disorder during pregnancy
Maternal diabetes (Type 1 or 2) or gestational diabetes (GDM)
Prevention
Monitoring of the mother and fetus prior to birth is critical to avoid complications after birth. This is often done via electronic fetal heart rate (FHR) monitoring, which helps providers monitor the fetus heart rate to ensure it is receiving enough oxygen, monitor the mothers contractions, and monitor the mothers blood pressure and systemic symptoms for gestational hypertension, preeclampsia, or eclampsia.
Treatment
Instead of referring to "fetal distress", current recommendations hold to look for more specific signs and symptoms, assess them, and take the appropriate steps to remedy the situation through the implementation of intrauterine resuscitation. Traditionally the diagnosis of "fetal distress" led the obstetrician to recommend rapid delivery by instrumental delivery or by caesarean section if vaginal delivery is not advised.An algorithm is used to treat/resuscitate babies in need of respiratory support post-birth. The algorithm steps include: clearing the airways and warming, stimulating, and drying the baby, positive-pressure ventilation (PPV), supplementary oxygen, intubation, chest compressions, and pharmacological therapy. The order of these interventions is set, and each step is done for 30 seconds with heart rate monitoring and assessment of chest movement prior to escalating to the next step in the algorithm.
References
== External links == |
Nijmegen breakage syndrome | Nijmegen breakage syndrome (NBS) is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the double Holliday junction DNA repair mechanism and/or the synthesis dependent strand annealing mechanism for repairing double strand breaks in DNA (see Homologous recombination).NBS1 codes for a protein (nibrin) that has two major functions: (1) to stop the cell cycle in the S phase, when there are errors in the cell DNA (2) to interact with FANCD2 that can activate the BRCA1/BRCA2 pathway of DNA repair. This explains why mutations in the NBS1 gene lead to higher levels of cancer (see Fanconi anemia, Cockayne syndrome.)
The name derives from the Dutch city Nijmegen, where the condition was first described.Most people with NBS have West Slavic origins. The largest number of them live in Poland.
Presentation
It is characterized by microcephaly, a distinct facial appearance, short stature, immunodeficiency, radiation sensitivity and a strong predisposition to lymphoid malignancy. NBS is caused by a mutation in the NBS1 gene. Unsurprisingly, many of the features are similar to ataxia telangiectasia (AT) and this syndrome was sometimes termed AT-variant 1, as the protein mutated in AT, ATM, interacts with the MRE11/RAD50/NBS1 (MRN) complex. Other syndromes with clinical features similar to Nijmegen Breakage Syndrome include RAD50 deficiency and Cernunnos/NHEJ deficiency.
Cause
NBS is caused by a mutation in the NBS1 gene, located at human chromosome 8q21. The disease is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome (chromosome 8 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.Two adult siblings, both heterozygous for two particular NBS1 nonsense mutations displayed cellular sensitivity to radiation, chromosome instability and fertility defects, but not the developmental defects that are typically found in other NBS patients. These individuals appear to be primarily defective in homologous recombination, a process that accurately repairs double-strand breaks, both in somatic cells and during meiosis.
Diagnosis
Treatment
There is no treatment for NBS; however in those with agammaglobulinemia, intravenous immunoglobulin may be started. Prophylactic antibiotics are considered to prevent urinary tract infections as those with NBS often have congenital kidney malformations. In the treatment of malignancies, radiation therapy, alkylating antineoplastic agents, and epipodophyllotoxins are not used, and methotrexate can be used only with caution; the dose should be limited. Bone marrow transplants and hematopoietic stem cell transplants are also considered in the treatment of NBS. The supplementation of vitamin E is also recommended. A ventriculoperitoneal shunt can be placed in patients with hydrocephalus, and surgical intervention for congenital deformities is also attempted.
Prognosis
A review from 2000 stated that life expectancy was reduced because of a tendency to develop cancer relatively early as well as deaths due to infections related to immunodeficiency.
References
External links
nijmegen at NIH/UW GeneTests
Nijmegen Breakage Syndrome at NIHs Office of Rare Diseases |
Fatal insomnia | Fatal familial insomnia is an extremely rare genetic (and even more rarely, sporadic) disorder that results in trouble sleeping as its hallmark symptom. The problems with sleeping typically start out gradually and worsen over time. Other symptoms may include speech problems, coordination problems, and dementia. It results in death within a few months to a few years.Fatal familial insomnia is a prion disease of the brain. It is usually caused by a mutation to the gene encoding protein PrPC. It has two forms: fatal familial insomnia (FFI), which is autosomal dominant, and sporadic fatal insomnia (sFI), which lacks the gene mutation. Diagnosis is suspected based on symptoms and can be supported by a sleep study, a PET scan, and genetic testing if the patients family has a history of the disease. Similar to other prion diseases, the diagnosis can only be confirmed by a brain autopsy at post-mortem.Fatal insomnia has no known cure and involves progressively worsening insomnia, which leads to hallucinations, delirium, and confusional states like that of dementia, until the patient slips into a stupor and eventually dies. The average survival time from onset of symptoms is 18 months. The first recorded case was an Italian man who died in Venice in 1765.
Signs and symptoms
The disease has four stages:
Characterized by worsening insomnia, resulting in panic attacks, paranoia, and phobias. This stage lasts for about four months.
Hallucinations and panic attacks become noticeable, continuing for about five months.
Complete inability to sleep is followed by rapid loss of weight. This lasts for about three months.
Dementia, during which the person becomes unresponsive or mute over the course of six months, is the final stage of the disease, after which death follows.Other symptoms include: profuse sweating, miosis (pinpoint pupils), sudden entrance into menopause or impotence, neck stiffness, and elevation of blood pressure and heart rate. The sporadic form of the disease often presents with double vision. Constipation is common as well. As the disease progresses, the person becomes stuck in a state of pre-sleep limbo, or hypnagogia, which is the state just before sleep in healthy individuals. During these stages, people commonly and repeatedly move their limbs as if dreaming.The age of onset is variable, ranging from 13 to 60 years, with an average of 50. The disease can be detected prior to onset by genetic testing. Death usually occurs between 6–36 months from onset. The presentation of the disease varies considerably from person to person, even among people within the same family; in the sporadic form, for example, sleep problems are not commonly reported and early symptoms are ataxia, cognitive impairment, and double vision.
Cause
The gene PRNP that provides instructions for making the prion protein PrPC is located on the short (p) arm of chromosome 20 at position p13. Both people with FFI and those with familial Creutzfeldt–Jakob disease (fCJD) carry a mutation at codon 178 of the prion protein gene. FFI is also invariably linked to the presence of the methionine codon at position 129 of the mutant allele, whereas fCJD is linked to the presence of the valine codon at that position. "The disease is where there is a change of amino acid at position 178 when an asparagine (N) is found instead of the normal aspartic acid (D). This has to be accompanied with a methionine at position 129."
Pathophysiology
In itself, the presence of prions causes reduced glucose use by the thalamus and a mild hypo-metabolism of the cingulate cortex. The extent of this symptom varies between two variations of the disease, these being those presenting methionine homozygotes at codon 129 and methionine/valine heterozygotes being the most severe in the latter one. Given the relationship between the involvement of the thalamus in regulating sleep and alertness, a causal relationship can be drawn, and is often mentioned as the cause.
Diagnosis
Diagnosis is suspected based on symptoms. Further work up often include a sleep study and PET scan. Confirmation of the familial form is by genetic testing.
Differential diagnosis
Other diseases involving the mammalian prion protein are known. Some are transmissible (TSEs, including FFI) such as kuru, bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle, and chronic wasting disease in American deer and American elk in some areas of the United States and Canada, as well as Creutzfeldt–Jakob disease (CJD). Until recently, prion diseases were only thought to be transmissible by direct contact with infected tissue, such as from eating infected tissue, transfusion, or transplantation; research suggests that prions can be transmitted by aerosols, but that the general public is not at risk of airborne infection.
Treatments
Treatment involves palliative care. There is conflicting evidence over the use of sleeping pills, including barbiturates, as a treatment for the disease.
Prognosis
Similar to other prion diseases, the disease is invariably fatal. Life expectancy ranges from seven months to six years, with an average of 18 months.
Epidemiology
In 1998, 40 families were known to carry the gene for FFI globally: eight German, five Italian, four American, two French, two Australian, two British, one Japanese, and one Austrian. In the Basque Country, Spain, 16 family cases of the 178N mutation were seen between 1993 and 2005 related to two families with a common ancestor in the 18th century. In 2011, another family was added to the list when researchers found the first man in the Netherlands with FFI. While he had lived in the Netherlands for 19 years, he was of Egyptian descent. Other prion diseases are similar to FFI and could be related, but are missing the D178N gene mutation.As of 2016, 24 cases of sporadic fatal insomnia have been diagnosed. Unlike in FFI, those with sFI do not have the D178N mutation in the PRNP-prion gene; they all have a different mutation in the same gene causing methionine homozygosity at codon 129.
Nonetheless, the methionine presence in lieu of the valine (Val129) is what causes the sporadic form of disease. The targeting of this mutation is another strategy that has been suggested as possible for treatment, or hopefully as cure for the disease.
Silvano, 1983, Bologna, Italy
In late 1983, Italian neurologist/sleep expert Dr. Ignazio Roiter received a patient at the University of Bologna hospitals sleep institute. The man, known only as Silvano, decided in a rare moment of consciousness to be recorded for future studies and to donate his brain for research in hopes of finding a cure for future victims.
Unnamed American patient, 2001
In a 2006 published article, Schenkein and Montagna wrote of a 52-year-old American man who was able to exceed the average survival time by nearly one year with various strategies that included vitamin therapy and meditation, different stimulants and hypnotics, and even complete sensory deprivation in an attempt to induce sleep at night and increase alertness during the day. He managed to write a book and drive hundreds of miles in this time, but nonetheless, over the course of his trials, the man succumbed to the classic four-stage progression of the illness.
Egyptian man, 2011, Netherlands
In 2011, the first reported case in the Netherlands was of a 57-year-old man of Egyptian descent. The man came in with symptoms of double vision and progressive memory loss, and his family also noted he had recently become disoriented, paranoid, and confused. While he tended to fall asleep during random daily activities, he experienced vivid dreams and random muscular jerks during normal slow-wave sleep. After four months of these symptoms, he began to have convulsions in his hands, trunk, and lower limbs while awake. The person died at age 58, seven months after the onset of symptoms. An autopsy revealed mild atrophy of the frontal cortex and moderate atrophy of the thalamus. The latter is one of the most common signs of FFI.
Research
Still with unclear benefit in humans, a number of treatments have had tentative success in slowing disease progression in animal models, including pentosan polysulfate, mepacrine, and amphotericin B. As of 2016, a study investigating doxycycline is being carried out.In 2009, a mouse model was made for FFI. These mice expressed a humanized version of the PrP protein that also contains the D178N FFI mutation. These mice appear to have progressively fewer and shorter periods of uninterrupted sleep, damage in the thalamus, and early deaths, similar to humans with FFI.The Prion Alliance was established by husband and wife duo Eric Minikel and Sonia Vallabh after Vallabhs mother was diagnosed with the fatal disease. They conduct research at the Broad Institute to develop therapeutics for human prion diseases. Other research interests involve identifying biomarkers to track the progression of prion disease in living people.
References
External links
"AFIFF Fatal Familial Insomnia Families Association". |
Accessory breast | Accessory breasts, also known as polymastia, supernumerary breasts, or mammae erraticae, is the condition of having an additional breast. Extra breasts may appear with or without nipples or areolae. It is a condition and a form of atavism which is most prevalent in male humans, and often goes untreated as it is mostly harmless. In recent years, many affected women have had a plastic surgery operation to remove the additional breasts, for purely aesthetic reasons.
A related condition, in which extra nipples form, is called "supernumerary nipple" or "polythelia".
Presentation
In some cases, the accessory breast may not be visible at the surface. In these cases, it may be possible to distinguish their appearance from normal breast tissue with MRI. In other cases, accessory breasts have been known to lactate, as illustrated in a drawing showing a child nursing at ectopic breast tissue on the lateral thigh.
There is some evidence that the condition may be more common in Native American populations.
Cause
Polymastia typically occurs in the womb during the development. During normal development, breast tissue will develop along the milk line, and additional tissue will disintegrate and be absorbed into the body. Polymastia occurs when the additional tissue does not disintegrate before birth. This condition can be inherited.
See also
Artemis § As the Lady of Ephesus (fertility goddess with many breasts)
Fleischers syndrome
References
A Paper on the Appearance of Multiple Mammaries in Humans, R. Eghardt, Oxford University Press (1923)
Weird Diseases, B. Hargreaves and M. Wallette, Emu Publishing (2007)
== External links == |
Youngs syndrome | Youngs syndrome, also known as azoospermia sinopulmonary infections, sinusitis-infertility syndrome and Barry-Perkins-Young syndrome, is a rare condition that encompasses a combination of syndromes such as bronchiectasis, rhinosinusitis and reduced male fertility. In individuals with this syndrome the functioning of the lungs is usually normal but the mucus is abnormally viscous. The reduced fertility (obstructive azoospermia) is due to functional obstruction of sperm transport down the genital tract at the epididymis, where the sperm is found in viscous, lipid-rich fluid. The syndrome was named after Donald Young, the urologist who first made observations of the clinical signs of the syndrome in 1972. Possible causes include genetics, and exposure to mercury during childhood, but the cause is unknown.
Causes
Youngs syndrome is caused by helminthiasis where specific parasites are attacking the reproductive organs.
See also
Infertility
Cystic fibrosis
References
Lau KY, Lieberman J (June 1986). "Youngs syndrome. An association between male sterility and bronchiectasis". West. J. Med. 144 (6): 744–6. PMC 1306774. PMID 3727536.
== External links == |
Ghost sickness | Ghost sickness is a cultural belief among some traditional indigenous peoples in North America, notably the Navajo, and some Muscogee and Plains cultures, as well as among Polynesian peoples. People who are preoccupied and/or consumed by the deceased are believed to suffer from ghost sickness. Reported symptoms can include general weakness, loss of appetite, suffocation feelings, recurring nightmares, and a pervasive feeling of terror. The sickness is attributed to ghosts or, occasionally, to witches or witchcraft.
Cultural background
In the Muscogee (Creek) culture, it is believed that everyone is a part of an energy called Ibofanga. This energy supposedly results from the flow between mind, body, and spirit. Illness can result from this flow being disrupted. Therefore, their "medicine is used to prevent or treat an obstruction and restore the peaceful flow of energy within a person". Purification rituals for mourning "focus on preventing unnatural or prolonged emotional and physical drain."The traditional Native American grief resolution process is qualitatively different from those usually seen in mainstream Western cultures. In 1881, there was a federal ban on some of the traditional mourning rituals practised by the Lakota and other tribes. Lakota expert Maria Yellow Horse Brave Heart proposes that the loss of these rituals may have caused the Lakota to be "further predisposed to the development of pathological grief". Some manifestations of unresolved grief include seeking visions of the spirits of deceased relatives, obsessive reminiscing about the deceased, longing for and believing in a reunion with the deceased, fantasies of reappearance of the deceased, and belief in ones ability to project oneself to the past or to the future.
Cause
There are a variety of mainstream psychological theories about Ghost Sickness. Putsch states that "Spirits or ghosts may be viewed as being directly or indirectly linked to the cause of an event, accident, or illness". retrieved on May 22, 2008 Both Erikson and Macgregor report substantiating evidence of psychological trauma response in ghost sickness, with features including withdrawal and psychic numbing, anxiety and hypervigilance, guilt, identification with ancestral pain and death, and chronic sadness and depression.
Treatment
Religious leaders within the Navajo tribe repeatedly perform ceremonies to eliminate the all-consuming thoughts of the dead.
See also
Complicated grief disorder
Vengeful ghost
== References == |
Osteochondrodysplasia | Osteochondrodysplasia is a general term for a disorder of the development (dysplasia) of bone ("osteo") and cartilage ("chondro"). Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Nonetheless, if taken collectively, genetic skeletal dysplasias or osteochondrodysplasias comprise a recognizable group of genetically determined disorders with generalized skeletal affection. Osteochondrodysplasias can result in marked functional limitation and even mortality.
Osteochondrodysplasias subtypes can overlap in clinical aspects, therefore plain radiography is absolutely necessary to establish an accurate diagnosis. Magnetic resonance imaging can provide further diagnostic insights and guide treatment strategies especially in cases of spinal involvement. Early diagnosis, and timely management of skeletal dysplasia are important to combat functional deterioration.
Types
Achondroplasia
Achondroplasia is a type of autosomal dominant genetic disorder that is the most common cause of dwarfism. It is also the most common type of non-lethal osteochondrodysplasia or skeletal dysplasia. The prevalence is approximately 1 in 25,000 births. Achondroplastic dwarfs have short stature, with an average adult height of 131 cm (4 feet, 3 inches) for males and 123 cm (4 feet, 0 inches) for females. In achondroplasia the dwarfism is readily apparent at birth. likewise, craniofacial abnormalities in the form of macrocephaly and mid-face hypoplasia are present at birth. The previous clinical findings differentiate between achondroplasia and pseudoachondroplasia in which dwarfism is not recognizable at birth and craniofacial abnormalities are not considered a disease feature. Plain radiography plays an additional and important role in the differential diagnosis of achondroplasia.
Pseudoachondroplasia
Pseudoachondroplasia is an osteochondrodysplasia made distinctive by disproportionate short stature, hip and knee deformities, brachydactyly (short fingers) and ligamentous laxity. It affects at least 1 in 20,000 individuals. Pseudoachondroplasia is inherited in an autosomal dominant manner and is caused solely by mutations in the cartilage oligomeric matrix protein COMP gene. It’s distinguished by a moderate to severe form of disproportionate short-limb short stature. The limb shortening is fundamentally confined to the proximal limb segments i.e. Femurs and humeri. A known presenting feature is a waddling gait, noticed at the onset of walking. A prompt diagnosis of a skeletal dysplasia in general and Pseudoachondroplasia in specific is still based upon a comprehensive clinical and radiographic correlation. A detailed radiographic examination of the axial and appendicular skeleton is invaluable for the differential diagnosis of Pseudoachondroplasia. Coxa vara (reduced neck shaft angle), broad femoral necks, short femurs and humeri, and bullet-shaped vertebrae are noticeable radiographic features. Additionally, the presence of metaphyseal broadening, cupping and dense line of ossification about the knee can simulate rachitic changes. These radiographic features are collectively known as rachitic-like changes. The presence of epiphyseal changes serves as an important differentiating feature from achondroplasia.
Osteogenesis imperfecta
COL1A1/2-related osteogenesis imperfecta is inherited in an autosomal dominant manner. The proportion of cases caused by a De novo COL1A1 or COL1A2 mutations are the cause of osteogenesis imperfecta in the vast majority of perinatally lethal osteogenesis imperfecta, and progressively deforming osteogenesis imperfecta. In classic non-deforming osteogenesis imperfecta with blue sclerae or common variable osteogenesis imperfecta with normal sclerae, nearly 60% of cases are de novo. COL1A1/2-related osteogenesis imperfecta is identified by repeated fractures with trivial trauma, defective dentinogenesis imperfecta (DI), and hearing loss. The clinical features of COL1A1/2-related osteogenesis imperfecta can be highly variable ranging from severe and lethal perinatal fractures to individuals with minimal tendency to repeated fractures and skeletal deformities and with a normal stature and life span. In between the clinical spectrum may include individuals with various degrees of disabling skeletal deformities and short stature. The radiographic findings of osteogenesis imperfecta include; long bone deformations such as bowing of the tibias and femurs, pencil-like deformity and tapering of bones, cortical thinning and rarefaction, pathologic fractures at various degrees of healing, bone shortening and vertebral wedging. Accordingly, COL1A1/2-related osteogenesis imperfecta has been classified into four sub-types (I, II, III, and IV) built upon the diversity of the radioclinical features.
OI type I: classic non-deforming OI with blue sclerae
OI type II: perinatally lethal OI
OI type III: progressively deforming OI
OI type IV: common variable OI with normal sclerae
Muocopolysachariodosis
Mucopolysaccharidoses (MPS) constitute a commonly seen group of osteochondrodysplasias. Mucopolysaccharidosis can cause a wide spectrum of clinical and radiologic manifestations ranging from mild skeletal and systemic involvement to severe life-threatening manifestations. It is caused by a contiguous gene duplication or deletion syndrome in which multiple genes are involved. All forms of MPS are inherited in an autosomal recessive pattern, except fir of MPS II; Hunter syndrome which is X-linked. They are caused by an abnormal function of the lysosomal enzymes, which blocks degradation of mucopolysaccharides and leads to accumulation of harmful byproducts, namely, heparan sulfate, dermatan sulfate, and keratan sulfate. The resulting cellular malfunction can lead to a diverse array of skeletal and visceral manifestations. MPS have been subcategorized according to the type of enzyme inadequacy and glycoprotein accumulated.
Cleidocranial dysostosis
Cleidocranial dysostosis is a general skeletal condition named for the collarbone (cleido-) and cranium deformities which people with it often have. Common features include:
Partly or completely missing collarbones.
A soft spot or larger soft area in the top of the head where the fontanelle failed to close.
Bones and joints are underdeveloped.
The permanent teeth include supernumerary teeth.
Permanent teeth not erupting
Bossing (bulging) of the forehead.
Hypertelorism
Fibrous dysplasia
Fibrous dysplasia causes bone thinning and growths or lesions in one or more bones of the human body.
These lesions are tumor-like growths that consist of replacement of the medullary bone with fibrous tissue, causing the expansion and weakening of the areas of bone involved. Especially when involving the skull or facial bones, the lesions can cause externally visible deformities. The skull is often, but not necessarily, affected, and any other bones can be involved.
Langer–Giedion syndrome
Langer–Giedion syndrome is a very rare genetic disorder caused by a deletion of chromosomal material. Diagnosis is usually made at birth or in early childhood. The features associated with this condition include mild to moderate learning difficulties, short stature, unique facial features, small head and skeletal abnormalities including bony growths projecting from the surfaces of bones.
Maffucci syndrome
Maffucci syndrome is a sporadic disease characterized by the presence of multiple enchondromas associated with multiple simple or cavernous soft tissue hemangiomas. Also lymphangiomas may be apparent.Patients are normal at birth and the syndrome manifests during childhood and puberty. The enchondromas affect the extremities and their distribution is asymmetrical.
Osteosclerosis
Osteosclerosis, an elevation in bone density, is normally detected on an X-ray as an area of whiteness, and is where the bone density has significantly increased. Localized osteosclerosis can be caused by injuries that compress the bone, by osteoarthritis, and osteoma.
Other
Deformity type Erlenmeyer flask gives a distal femur similar to an Erlenmeyer flask. It may result from Gaucher disease.
Kashin–Beck disease
Melnick–Needles syndrome
Ovine chondrodysplasia
Familial osteodysplasia, Anderson type
Diagnosis
The diagnosis is mainly based upon delineating the specific clinical and radiographic pattern of skeletal involvement. However, the different types of skeletal dysplasia can overlap considerably in their clinical presentation. Molecular or genetic analysis may be required to resolve diagnostic difficulties. Molecular analysis is also of importance to the phenotype genotype correlations and to disease classifications.
Differential diagnosis
Juvenile idiopathic arthritis may closely resemble the clinical presentation of some osteochondrodysplasias or genetic skeletal dysplsias. In that, both conditions can present with swollen, stiff and deformed joints.
Treatment
Emerging therapies for genetic skeletal dysplasias include enzyme replacement therapy, hematopoietic stem cell transplantation and gene therapy. These therapies aim at preventing disease progression and thus improving quality of life. Examples of the use of enzyme replacement therapy are Mucopolysaccharidoses and Gaucher disease. Results have shown effectivity of enzyme replacement therapy. In some instances as malignant infantile osteopetrosis, hematopoietic stem cell transplantation can be life-saving.
References
== External links == |
Acrofrontofacionasal dysostosis | Acrofrontofacionasal dysostosis is an extremely rare disorder, characterized by intellectual disability, short stature, hypertelorism, broad notched nasal tip, cleft lip/palate, postaxial camptobrachypolysyndactyly, fibular hypoplasia, and anomalies of foot structure.An association with mutations in the neuroblastoma amplified sequence gene (NBAS) has been reported. This gene is located on the short arm of chromosome 2. Mutations in this gene have been associated with the Short Stature, Optic Nerve Atrophy, and Pelger-Huet Anomaly syndrome and Infantile Liver Failure Syndrome.
References
Richieri-Costa A, Colletto GM, Gollop TR, Masiero D (April 1985). "A previously undescribed autosomal recessive multiple congenital anomalies/mental retardation (MCA/MR) syndrome with fronto-nasal dysostosis, cleft lip/palate, limb hypoplasia, and postaxial poly-syndactyly: acro-fronto-facio-nasal dysostosis syndrome". Am. J. Med. Genet. 20 (4): 631–8. doi:10.1002/ajmg.1320200409. PMID 2986457.
== External links == |
Melanonychia | Melanonychia is a black or brown pigmentation of the normal nail plate, and may be present as a normal finding on many digits in Afro-Caribbeans, as a result of trauma, systemic disease, or medications, or as a postinflammatory event from such localized events as lichen planus or fixed drug eruption.: 790 : 665 There are two types, longitudinal and transverse melanonychia.: 671 Longitudinal melanonychia may be a sign of subungual melanoma (acral lentiginous melanoma), although there are other diagnoses such as chronic paronychia, onychomycosis, subungual hematoma, pyogenic granuloma, glomus tumour, subungual verruca, mucous cyst, subungual fibroma, keratoacanthoma, carcinoma of the nail bed, and subungual exostosis.
See also
Nail anatomy
List of cutaneous conditions
== References == |
Tinea faciei | Tinea faciei is a fungal infection of the skin of the face. It generally appears as a photosensitive painless red rash with small bumps and a raised edge appearing to grow outwards, usually over eyebrows or one side of the face. It may feel wet or have some crusting, and overlying hairs may fall out easily. There may be a mild itch.
Treatment
Most infections can be treated with topical antifungal medication. Rarely, more extensive or long-standing infections may require treatment with oral antifungals. The infection will still be contagious between 24 and 48 hours of the first treatment.
The ringworm should go away within 4–6 weeks after using effective treatment.
See also
Tinea corporis
Antifungal drug
List of cutaneous conditions
References
== External links == |
Spinal epidural hematoma | Spinal extradural haematoma or spinal epidural hematoma (SEH) is bleeding into the epidural space in the spine. These may arise spontaneously (e.g. during childbirth), or as a rare complication of epidural anaesthesia or of surgery (such as laminectomy). Symptoms usually include back pain which radiates to the arms or the legs. They may cause pressure on the spinal cord or cauda equina, which may present as pain, muscle weakness, or dysfunction of the bladder and bowel.
Pathophysiology
The anatomy of the epidural space is such that spinal epidural hematoma has a different presentation from intracranial epidural hematoma. In the spine, the epidural space contains loose fatty tissue and a network of large, thin-walled veins, referred to as the epidural venous plexus. The source of bleeding in spinal epidural hematoma is likely to be this venous plexus.
Diagnosis
The best way to confirm the diagnosis is MRI. Risk factors include anatomical abnormalities and bleeding disorders.
Treatment
Treatment is generally with emergency surgery. The risk following epidural anaesthesia is difficult to quantify; estimates vary from 1 per 10,000 to 1 per 100,000 epidural anaesthetics.
== References == |
Oculocutaneous albinism type I | Oculocutaneous albinism type I or type 1A is an autosomal recessive skin disease. This subtype of oculocutaneous albinism is caused when the gene for tyrosinase (symbol TYR or OCA1) does not function properly.
The location of OCA1 may be written as "11q1.4-q2.1", meaning it is on chromosome 11, long arm, somewhere in the range of band 1, sub-band 4, and band 2, sub-band 1. Since the disorder is autosomal recessive, genetic counseling can be used to determine if both parents are heterozygous for the condition when considering having children. If both parents are heterozygous, their child has a 25% chance of inheriting both recessive copies of OCA1 and having the skin disease.This symptoms in this disease include absence of pigmentation, due to a mutation that affects melanin levels in the eyes, hair, and skin. This rare disease is found in 1 out of 20,000 people around the world, being much more prevalent in Caucasians. There is no known cure for this disease as of present, but there are various ways to manage this disease, including safety around the sun and regular checks for other skin diseases such as skin cancer.
Signs and Symptoms
OCA is characterized by the absence of pigmentation caused by the mutation that effects the production of tyrosinase that causes partial or total absence of melanin in the hair, skin, and eyes. Reduction in melanin production specifically in the peripheral retina during embryonic development can trigger other symptoms such as abnormal nerve fiber projection that causes defects in neuronal migration that interrupts visual pathways and creates reduced visual acuity in the range of 20/60 to 20/400. This vision acuity is dependent upon the amount of pigmentation in the eye. Acuity is usually better in individuals with greater amounts of pigment. Aside from decreased pigment in the iris and retina, optic changes include decreased visual acuity, misrouting of the optic nerves at the chiasm, and nystagmus.OCA1 is one of the more extreme types of albinism where the iris is translucent and the eye appears pink or red in ambient light and have white skin with slight to no pigmentation when other types may have residual pigmentation. OCA1 is caused by mutations in the TYR gene, where there is a complete lack of tyrosinase activity.
Genetics
The tyrosinase (TYR) gene is located on chromosome 11q14. This protein coding gene produces tyrosinase, an enzyme which catalyzes a total of three steps in the conversion of tyrosine to the end product, melanin. This enzyme and conversion process takes place within melanocytes, which are specialized cells for melanin production. Melanin is a large group of molecules that give skin, eyes, and hair their respective colors. It is also partially responsible for vision, as it protects the light sensitive portion of the eye, the retina, through absorbing light. OCA Type 1A is an autosomal recessive condition, meaning there is a homozygous or compound heterozygous mutation related to the TYR gene. There are many different types of albinism, differing due to the effects of various mutations. Oculocutaneous albinism type IA is the most severe type of albinism, as it is characterized by no melanin production. Other types of albinism have limited melanin production. Because type IA Albinism has no functioning copies of the gene, it is the most severe type of albinism. The mutations on this gene lead to a complete lack of tyrosinase activity as the inactive enzyme is produced. An inactive enzyme can be caused by a missense or nonsense mutation. Due to the lack of enzymes needed to catalyze the production of melanin, patients do not have melanin protecting them from the sun, resulting in sensitive eyes, skin, and other symptoms mentioned in the signs and symptoms of OCA1A. The different forms of albinism and range of severity is dependent upon the level of melanin production, which depends on the level of tyrosinase activity.
Diagnosis
Because albinism is autosomal recessive, prenatal genetic screening and genetic counseling can be performed to diagnose OCA early on. When pathogenic variants are known to be present in an affected family, carrier testing can also be conducted. The level of expression can be variable depending on the pigmentation background, so phenotypically, OCA can be expressed on a spectrum. OCA is heterogenous, with OCA1 being caused by a mutation in the TYR gene. The separate subdivisions are categorized by the genes that they effect. The seven types are not evenly distributed amongst ethnic groups with OCA1 being the subtype most prominent in Caucasians - "accounting for approximately 50% of cases worldwide."Previously, diagnosis was done from observation of hypopigmentation which is obvious at birth, but this is now insufficient early on to distinguish between the seven major types of OCA.Prenatal testing has been achieved through fetal skin biopsy followed by subsequent histologic and electron microscope examination for melanin levels. Clinical findings have established that molecular genetic testing of TYR, the gene encoding tyrosinase, can distinguish between 1A and 1B because the phenotypes can be identical during the first year of life. OCA1A results in complete loss of tyrosinase enzyme activity. Individuals with 1B will experience increased pigmentation with age because they have a very low level of melanin production that can increase. The histological approach for prenatal diagnosis is useful for all families at risk for OCA1 whereas the molecular genetic test is only helpful when at least one mutation is known.
Management
There is currently no treatment for this disease. The extremely hypopigmented skin that is characteristic in OCA1 particularly leads to risk of skin damage and non-melanotic skin cancers due to increased sensitivity to UV rays. In OCA1B, because there is some presence of melanin, it grows with age and pigmentation can increase; the same cannot be said for OCA1A. Individuals affected by OCA1A should be attentive to the amount of sun exposure they experience and wear proper protection such as clothing that covers the skin. Additionally, individuals may need corrective visual aids for their visual acuity of 1/10 or less with intense photophobia. Visual aids can both improve vision or protect eyes from bright lights. These visual aids can be adjusted for based on individual needs.
Individuals should receive annual skin evaluation to access for damage or skin cancers that can be induced from sun exposure. In some situations, therapy or surgery can correct crossed eyes (strabismus) or rapid eye movements (nystagmus).
Epidemiology
The highest frequency of Albinism type IA is in Northern Ireland, with a phenotype frequency of around 1: 10,000. First cousin - marriages accounted for 4.5% of the parents of patients. Additionally, symptoms that could be heterozygous mutations, such as abnormal iris translucency occurred in 70% of the parents and children of individuals affected with this condition. In general, the phenotypical appearance of OCA1A is associated with northern and western Europe. This is because over 50% of OCA1 subjects are Caucasians. OCA1 is also the most common form of Albinism in China and Japan. The overall frequency is 1: 20,000 people in the world.
References
== External links == |
Klinefelter syndrome | Klinefelter syndrome (KS), also known as 47,XXY, is a syndrome where a male has an additional copy of the X chromosome. The primary features are infertility and small, poorly functioning testicles. Usually, symptoms are subtle and subjects do not realize they are affected. Sometimes, symptoms are more evident and may include weaker muscles, greater height, poor motor coordination, less body hair, breast growth, and less interest in sex. Often, these symptoms are noticed only at puberty. Intelligence is usually normal, but reading difficulties and problems with speech are more common.Klinefelter syndrome occurs randomly. The extra X chromosome comes from the father and mother nearly equally. An older mother may have a slightly increased risk of a child with KS. The syndrome is defined by the presence of at least one extra X chromosome in addition to a Y chromosome yielding a total of 47 or more chromosomes rather than the usual 46. KS is diagnosed by the genetic test known as a karyotype.While no cure is known, a number of treatments may help. Physical therapy, occupational therapy, speech and language therapy, counselling, and adjustments of teaching methods may be useful. Testosterone replacement may be used in those who have significantly lower levels. Enlarged breasts may be removed by surgery. About half of affected males have a chance of fathering children with the help of assisted reproductive technology, but this is expensive and not risk free. XXY males have a ~15-fold higher risk of developing breast cancer than typical, but still lower than that of females. People with the condition have a nearly normal life expectancy.Klinefelter syndrome is one of the most common chromosomal disorders, occurring in one to two per 1,000 live male births. It is named after American endocrinologist Harry Klinefelter, who identified the condition in the 1940s. In 1956, the extra X chromosome was identified as the cause. Mice can also have the XXY syndrome, making them a useful research model.
Signs and symptoms
The primary features are infertility and small, poorly functioning testicles. Often, symptoms may be subtle and many people do not realize they are affected. Sometimes, symptoms are more prominent and may include weaker muscles, greater height, poor coordination, less body hair, breast growth, and low libido. Often, these symptoms are noticed only at puberty.
Prenatal
An estimated 60% of fetuses with Klinefelter syndrome end in miscarriage.
Physical
As babies and children, XXY males may have weaker muscles and reduced strength. As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys of their age.During puberty, the physical traits of the syndrome become more evident; because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may develop breast tissue and also have weaker bones, and a lower energy level than other males.By adulthood, XXY males look similar to males without the condition, although they are often taller. In adults, possible characteristics vary widely and include little to no sign of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue). Gynecomastia is present in about a third of affected individuals, a slightly higher percentage than in the XY population. About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic surgery.Affected males are often infertile, or have reduced fertility. Advanced reproductive assistance is sometimes possible. An estimated 50% of males with Klinefelter syndrome can produce sperm.The term "hypogonadism" in XXY symptoms is often misinterpreted to mean "small testicles", when it instead means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum testosterone level, but high serum follicle-stimulating hormone and luteinizing hormone levels, hypergonadotropic hypogonadism. Despite this misunderstanding of the term, however, XXY men may also have microorchidism (i.e., small testicles).The testicles of affected males are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4 ml in volume.XXY males are more likely than other men to have certain health problems, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis. In contrast to these potentially increased risks, rare X-linked recessive conditions are thought to occur less frequently in XXY males than in XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.
Cognitive and developmental
Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions, although these deficits can often be overcome through early intervention. Also, delays in motor development may occur, which can be addressed through occupational and physical therapies. XXY males may sit up, crawl, and walk later than other infants; they may also struggle in school, both academically and with sports. It is estimated that 10% of those with Klinefelter syndrome are autistic.Additional abnormalities may include impaired attention, reduced organizational and planning abilities, deficiencies in judgment (often presented as a tendency to interpret non-threatening stimuli as threatening), and dysfunctional decision processing.Compared to individuals with a normal number of chromosomes, males affected by Klinefelters syndrome may display behavioral abnormalities. These are phenotypically displayed as higher level of anxiety and depression, and mood dysregulation. These neurocognitive abnormalities are most likely due to the presence of the extra X chromosome, as indicated by studies carried out on animal models carrying an extra X chromosome.
Cause
Klinefelter syndrome is not an inherited condition. Maternal age is the only known risk factor. Women at 40 years have a four times higher risk for a child with Klinefelter syndrome than women aged 24 years.The extra chromosome is retained because of a nondisjunction event during paternal meiosis I, maternal meiosis I, or maternal meiosis II (gametogenesis). The relevant nondisjunction in meiosis I occurs when homologous chromosomes, in this case the X and Y or two X sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome or an egg with two X chromosomes. Fertilizing a normal (X) egg with this sperm produces an XXY offspring (Klinefelter). Fertilizing a double X egg with a normal sperm also produces an XXY offspring (Klinefelter).Another mechanism for retaining the extra chromosome is through a nondisjunction event during meiosis II in the egg. Nondisjunction occurs when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced, which when fertilized with a Y sperm, yields an XXY offspring. This XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about one in 500 live male births. See also Triple X syndrome.
In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males, as well as normal XX females. However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes have corresponding genes on their Y chromosome and are capable of being expressed.
Variations
The condition 48,XXYY or 48,XXXY occurs in one in 18,000–50,000 male births. The incidence of 49,XXXXY is one in 85,000 to 100,000 male births. These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic, and other anomalies.About 15–20% of males with KS may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Often, symptoms are milder in mosaic cases, with regular male secondary sex characteristics and testicular volume even falling within typical adult ranges. Another possible mosaicism is 47,XXY/46,XX with clinical features suggestive of KS and male phenotype, but this is very rare. Thus far, only about 10 cases of 47,XXY/46,XX have been described in literature.Analogous XXY syndromes are known to occur in cats—specifically, the presence of calico or tortoiseshell markings in male cats is an indicator of the relevant abnormal karyotype. As such, male cats with calico or tortoiseshell markings are a model organism for KS, because a color gene involved in cat tabby coloration is on the X chromosome.
Random X-inactivation
Women typically have two X chromosomes, with half of their X chromosomes switching off early in embryonic development. The same happens with people with Klinefelters, including in both cases a small proportion of individuals with a skewed ratio between the two Xs.
Diagnosis
The standard diagnostic method is the analysis of the chromosomes karyotype on lymphocytes. A small blood sample is sufficient as test material. In the past, the observation of the Barr body was common practice, as well. To investigate the presence of a possible mosaicism, analysis of the karyotype using cells from the oral mucosa is performed. Physical characteristics of a Klinefelter syndrome can be tall stature, low body hair, and occasionally an enlargement of the breast. Usually, a small testicle volume of 1–5 ml per testicle (standard values: 12–30 ml) occurs. During puberty and adulthood, low testosterone levels with increased levels of the pituitary hormones FSH and LH in the blood can indicate the presence of Klinefelter syndrome. A spermiogram can also be part of the further investigation. Often. an azoospermia is present, or rarely an oligospermia. Furthermore, Klinefelter syndrome can be diagnosed as a coincidental prenatal finding in the context of invasive prenatal diagnosis (amniocentesis, chorionic villus sampling). About 10% of KS cases are found by prenatal diagnosis.The symptoms of KS are often variable, so a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long arms/legs, developmental delay, speech/language deficits, learning disabilities/academic issues, and/or behavioral issues are present in an individual.
Treatment
As the genetic variation is irreversible, no causal therapy is available. From the onset of puberty, the existing testosterone deficiency can be compensated by appropriate hormone-replacement therapy. Testosterone preparations are available in the form of syringes, patches, or gel. If gynecomastia is present, the surgical removal of the breast may be considered for both the psychological reasons and to reduce the risk of breast cancer.The use of behavioral therapy can mitigate any language disorders, difficulties at school, and socialization. An approach by occupational therapy is useful in children, especially those who have dyspraxia.
Infertility treatment
Methods of reproductive medicine, such as intracytoplasmic sperm injection (ICSI) with previously conducted testicular sperm extraction (TESE), have led to men with Klinefelter syndrome producing biological offspring. By 2010, over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from males with KS.
Prognosis
The lifespan of individuals with Klinefelter syndrome appears to be reduced by around 2.1 years compared to the general male population. These results are still questioned data, are not absolute, and need further testing.
Epidemiology
This syndrome, evenly distributed in all ethnic groups, has a prevalence of approximately four subjects per every 10,000 (0.04%) males in the general population. However, it is estimated that only 25% of the individuals with Klinefelter syndrome are diagnosed throughout their lives. The rate of Klinefelter syndrome among infertile males is 3.1%. The syndrome is also the main cause of male hypogonadism.
History
The syndrome was named after American endocrinologist Harry Klinefelter, who in 1942 worked with Fuller Albright and E. C. Reifenstein at Massachusetts General Hospital in Boston, Massachusetts, and first described it in the same year. The account given by Klinefelter came to be known as Klinefelter syndrome as his name appeared first on the published paper, and seminiferous tubule dysgenesis was no longer used. Considering the names of all three researchers, it is sometimes also called Klinefelter–Reifenstein–Albright syndrome. In 1956, Klinefelter syndrome was found to result from an extra chromosome. Plunkett and Barr found the sex chromatin body in cell nuclei of the body. This was further clarified as XXY in 1959 by Patricia Jacobs and John Anderson Strong. The first published report of a man with a 47,XXY karyotype was by Patricia Jacobs and John Strong at Western General Hospital in Edinburgh, Scotland, in 1959. This karyotype was found in a 24-year-old man who had signs of KS. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.In August 2022, a team of scientists published a study of a skeleton found at Torre Velha, Municipality of Bragança in north-eastern Portugal. The male was buried in a cut grave around 1,000CE, and found from DNA tests to be the earliest known person with this syndrome.
See also
Aneuploidy
Intersex
Turner syndrome
XYY syndrome
XXYY syndrome
Taurodontism
Trisomy X
References
Further reading
Virginia Isaacs Cover (2012). Living with Klinefelter Syndrome, Trisomy X and 47,XYY: A Guide for Families and Individuals Affected by Extra X and Y Chromosomes. ISBN 978-0-615-57400-4.
External links
Klinefelter syndrome at Curlie |
Rachitic rosary | The prominent knobs of bone at the costochondral joints of rickets patients are known as a rachitic rosary or beading of the ribs. The knobs create the appearance of large beads under the skin of the rib cage, hence the name by analogy with the beads of a Catholic Christian rosary.
Causes
Causes include:
Rickets : Nodularity at costochondral junction (rachitic rosary).
Scurvy : More angular costochondral junction with a sharper step-off (scorbutic rosary) and depressed sternum.
Chondrodystrophy
Pathophysiology
Rachitic rosary is due to a deficiency of calcium resulting in lack of mineralization and an overgrowth of costochondral joint cartilage. The calcium deficiency may be caused by rickets or other causes of calcium deficiency such as hypoparathyroidism.
Diagnosis
Management
== References == |
Hypodysfibrinogenemia | Hypodysfibrinogenemia, also termed congenital hypodysfibrinogenemia, is a rare hereditary fibrinogen disorder cause by mutations in one or more of the genes that encode a factor critical for blood clotting, fibrinogen. These mutations result in the production and circulation at reduced levels of fibrinogen at least some of which is dysfunctional. Hypodysfibrinogenemia exhibits reduced penetrance, i.e. only some family members with the mutated gene develop symptoms.The disorder is similar to a form of dysfibrinogenemia termed congenital dysfibrinogenemia. However, congenital dysfibrinogenemia differs form hypodysfibrinogenemia in four ways. Congenital dysfibrinogenemia involves: the circulation at normal levels of fibrinogen at least some of which is dysfunctional; a different set of causative gene mutations; a somewhat different mix of clinical symptoms; and a much lower rate of penetrance.Hypodysfibrinogenemia causes episodes of pathological bleeding and thrombosis due not only to low levels of circulating fibrinogen but also to the dysfunction of a portion of the circulating fibrinogen. The disorder can lead to very significant bleeding during even minor surgical procedures and women afflicted with the disorderoften suffer significant bleeding during and after giving child birth, higher rates of miscarriages, and menorrhagia, i.e. abnormally heavy bleeding during the menstrual period.
Presentation
In a study of 32 individuals diagnosed with hypodysfibrinogenemia, 41% presented with episodic bleeding, 43% presented with episodic thrombosis, and 16% were asymptomatic, being detected by abnormal blood tests. Bleeding and thrombosis generally begin in adulthood with the average age at the time of presentation and diagnosis being 32 years. Bleeding is more frequent and severe in women of child-bearing age; these women may suffer miscarriages, menometrorrhagia, and excessive bleeding during child birth and/or the postpartum period. Excessive bleeding following major or minor surgery, including dental extractions, occurs in both females and males with the disorder. Thrombotic complications of the disorder are often (~50%) recurrent and can involve central and peripheral arteries, deep and superficial veins. Thrombotic events may be serious and involve occlusion of a cerebral artery leading to stroke, splanchnic venous thrombosis, and pulmonary thrombosis presumptively secondary to deep vein thrombosis.
Fibrinogen
Circulating fibrinogen is a glycoprotein made of two trimers each of which is composed of three polypeptide chains, Aα (also termed α) encoded by the FGA gene, Bβ (also termed β) encoded by the FGB gene, and γ encoded by the FGG gene. All three genes are located on the long or "q" arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively) and are the sites where mutations occur that code for a dysfunctional fibrinogen and/or reduced fibrinogen levels which are the cause of congenital hypodysfibrinogenemia.
Pathophysiology
Congenital hypodysfibrinogenemia is inherited as an autosomal dominant disorder caused by at least 32 different types of single mutations. Ten of these mutations are in the fibrinogen alpha chain gene (also termed the FGA gene), 5 in the fibrinogen beta chain gene (also termed the FGB gene), and 17 in the fibrinogen gamma chain gene (also termed the FGG gen). The mutations are mainly missense mutations with nonsense and Frameshift mutations each occurring in 12.5% of cases. The causes of two fibrinogen abnormalities that characterize hypodysfibrinogenemia, i.e. circulation at reduced levels of fibrinogen at least some of which is dysfunctional, reflect different molecular mechanisms:
A heterozygous mutation in one of the two copies of either the FGA, FGB, or FGG gene leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen Vlissingen, fibrinogen Philadelphia, and fibrinogen Freiburg.
A homozygous mutation in both copies of one of the cited genes leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen Otago, fibrinogen Marburg, and fibrinogen Sfax.
Two different mutations (see Compound heterozygosity) occur in each of the two copies of one of the cited genes, with one mutation coding for reduced formation of a functionally normal circulating fibrinogen and the second mutation coding for the circulation of a dysfunctional fibrinogen, e.g. fibrinogen Leipzig.
Two different mutations occur in one copy of the cited genes, with one mutation causing hypofibrinogenemia and the other mutation coding for a dysfunctional fibrinogen, e.g. fibrinogen Keokuk.The following Table adds further information on the just cited examples of hypodysfibrinogenemias. The Table gives: a) each mutated proteins trivial name; b) the gene mutated (i.e. FGA, FGB, or FGG), its mutation site (i.e. numbered nucleotide in the cloned gene), and name of the nucleotides (i.e. C, T, A, G) at these sites before>after the mutation; c) the name of the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using standard abbreviations) occurring before-after the mutation at the numbered amino acid(s) sites in the circulating mutated fibrinogen; d) the pathophysiology for the mutated fibrinogens misfunction(s); and e) the clinical consequence(s) of the mutation. Unless noted as a deletion (del) or frame shift (fs), all mutations are missense or nonsense mutations. A nonsense mutation causing a premature stop codon and thereby a shorten polypeptide chain is notated by an X (PSC) after the altered amino acid codon.
Diagnosis
Hypodysfibrinogenemia is usually diagnosed in individuals who: have a history of abnormal bleeding or thrombosis or are a close blood relative of such an individual. Initial laboratory findings include a decrease in serum fibrinogen mass levels as measured by immunoassay plus a reduction in inducible blood clot formation so that the ratio of functionally-detected fibrinogen mass (i.e. detected in induced clots) to immunoassay-detected fibrinogen mass is abnormally low, i.e. <0.7. This contrast with individuals with congenital dysfibrinogenemia who exhibit normal levels of fibrinogen as measured by immunoassay but low functionally-detected to immunoassay-detected fibrinogen mass ratios, i.e. <0.7. Where available, specialized laboratories can conduct studies to define the exact gene mutation(s) and fibrinogen abnormalities underlying the disorder.
Treatment
Blood relatives of the proband case should be evaluated for the presence of hypodysfibrinogenemia. Individuals with the disorder need to be advised on its inheritance, complications, and preventative measures that can be taken to avoid bleeding and/or thrombosis. Since >80% of individuals may develop bleeding or thrombosis complications of the disorder, asymptomatic individuals diagnosed with hydposyfibrinogenemia are best handled at a specialized center in order to benefit from multidisciplinary management.Measures to prevent and/or treat complications of hypodysfibrinogenemia should be tailored to the personal and family history of the individual by a specialized center. Individuals with a personal or family history of bleeding are considered to be of low risk of bleeding when their functional fibrinogen levels are >1 gram/liter for major surgery, >0.5 gram/liter for minor surgery, >0.5 to 1-2 gram/liter for spontaneous bleeding (depending on its severity), >0.5 to > 1 gram/liter for the first two trimesters of pregnancy, and >1 to <2 gram/liter for the last trimester of pregnancy and postpartum period. Functional fibrinogen below these levels should be treated preferably with fibrinogen concentrate or if not available, fibrinogen-rich cryoprecipitate or plasma to attain low risk levels of functional fibrinogen. Antifibrinolytic drugs such as tranexamic acid or (ε-aminocaproic acid) may be considered as an alternative preventative or therapeutic treatments in cases of minor surgery, dental extractions, mucosal bleeding, or other episodes of mild bleeding. In individuals with a personal or family history of thrombosis, should be considered for long-term anticoagulation drugs such as low molecular weight heparin, coumadin, or rivaroxaban.
References
== External links == |
Ulcer | An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbinss pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing out of inflamed necrotic tissue." Common forms of ulcers recognized in medicine include:
Ulcer (dermatology), a discontinuity of the skin or a break in the skin.
Pressure ulcers, also known as bedsores
Genital ulcer, an ulcer located on the genital area
Ulcerative dermatitis, a skin disorder associated with bacterial growth often initiated by self-trauma
Anal fissure, a.k.a. an ulcer or tear near the anus or within the rectum
Diabetic foot ulcer, a major complication of the diabetic foot
Corneal ulcer, an inflammatory or infective condition of the cornea
Mouth ulcer, an open sore inside the mouth.
Aphthous ulcer, a specific type of oral ulcer also known as a canker sore
Peptic ulcer, a discontinuity of the gastrointestinal mucosa (stomach ulcer)
Venous ulcer, a wound thought to occur due to improper functioning of valves in the veins
Stress ulcer, an ulcer located within the stomach and proximal duodenum
Ulcerative sarcoidosis, a cutaneous condition affecting people with sarcoidosis
Ulcerative lichen planus, a rare variant of lichen planus
Ulcerative colitis, a form of inflammatory bowel disease (IBD).
Ulcerative disposition, a disorder or discomfort that causes severe abdominal distress, often associated with chronic gastritis
References
== External links == |
Osteodystrophy | Osteodystrophy is any dystrophic growth of the bone. It is defective bone development that is usually attributable to renal disease or to disturbances in calcium and phosphorus metabolism.One form is renal osteodystrophy.
See also
List of radiographic findings associated with cutaneous conditions
References
== External links == |
Pituicytoma | Pituicytoma is a rare brain tumor. It grows at the base of the brain from the pituitary gland. This tumor is thought to be derived from the parenchymal cells of the posterior lobe of the pituitary gland, called pituicytes. Some researchers believe that they arise from the folliculostellate cells in the anterior lobe of the pituitary. As such, it is a low-grade glioma. It occurs in adults and symptoms include visual disturbance and endocrine dysfunction. They are often mistaken for pituitary adenomas which have a similar presentation and occur in the same location. The treatment consists of surgical resection, which is curative in most cases.
References
Further reading
== External links == |
Ichthyosis linearis circumflexa | Ichthyosis linearis circumflexa is a distinctive skin condition of generalized hyperkeratosis and polycyclic and serpiginous erythematous plaques with a characteristic, migratory, double-edged scale at the margins, and is the typical cutaneous manifestation of Nethertons syndrome.: 496 : 563
See also
Ichthyosis prematurity syndrome
List of cutaneous conditions
== References == |
Macrognathism | Macrognathism is an abnormally large or protruding jaw. The opposite condition is called micrognathia.
Causes
Heredity
Pituitary gigantism
Pagets disease of bone
Acromegaly
Fetal alcohol syndrome
Leontiasis ossea
Cleidocranial dysplasia
Treatment
Treatment is surgical. Osteotomy may be done in case of maxillary macrognathia. Mandibular macrognathia is generally managed by resection of a portion of the mandible.
== References == |
Physical urticaria | Physical urticaria is a distinct subgroup of the urticaria that are induced by an exogenous physical stimulus rather than occurring spontaneously. There are seven subcategories that are recognized as independent diseases. Physical urticaria is known to be painful, itchy and physically unappealing; it can recur for months to years of a persons life.
Signs and symptoms
Urticaria are characterized by dermal edema (wheal, swollen) and erythema (flare, red), also known as hives. Hive lesions typically last less than 24 hours and are usually itchy (pruritic). Hives can appear anywhere on the body and they may change shape, move around, disappear and reappear over short periods of time.
Types of hives
Acute urticaria (short-term): can develop suddenly and will last less than 6 weeks. About 1 in 6 people will have acute hives at one point in their life.Chronic urticaria (long-term): can develop suddenly and will persist more than 6 weeks. This type of urticaria is uncommon and occurs in only 0.1% of the population. 20% of people with chronic urticaria report still having problems 10 years after its onset.
Causes
The cause of physical urticaria is unknown but it has been suggested to be an autoimmune disease. Suggesting that antibodies, which are produced by the immune system to protect humans from foreign microbes, are binding to body tissue; damaging body tissue.In some cases physical urticaria can be a symptom of an underlying health issue such as:
Thyroid disease
Hepatitis
Infection
Cancer
Food allergies
Atopy
Diagnosis
Sub-categories
There are seven sub-categories of physical urticaria:
delayed pressure urticaria (DPU)
cholinergic urticaria (ChU)
cold urticaria (CU)
solar urticaria (SU)
Acute pressure urticaria (AU)
chronic idiopathic urticaria (CIU)
symptomatic dermatographism urticaria (SDU) (most common)
Treatment
Antihistamine agents are the typically prescribed drug for the treatment of physical urticaria. They block the effect of histamine, a compound produced by the body which forms a part of the local immune response consequently causing inflammation. Some research has suggested that the use antihistamines and antagonist in synergy are better for the treatment of physical urticarias.The cascade of events that link the autoantibody-antigen reaction with the production and release of histamine is not well characterized. Therefore, the focus of treatment for physical urticaria has been on characterizing the effectiveness of antihistamines rather than analysis of receptor binding or the pathomechanisms.
See also
Urticarial syndromes
Acquired C1 esterase inhibitor deficiency
List of cutaneous conditions
== References == |
Lafora disease | Lafora disease is a rare, adult-onset and autosomal recessive genetic disorder which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of inclusion bodies, known as Lafora bodies, within the cytoplasm of the cells in the heart, liver, muscle, and skin.: 545 Lafora disease is also a neurodegenerative disease that causes impairment in the development of cerebral cortical neurons and is a glycogen metabolism disorder.
Lafora disease (LD) was described by the Spanish Neuropathologist Gonzalo Rodríguez Lafora (1886-1971) in 1911, while directing the Neuropathology Section at the Government Hospital for Mental Insane (current NIH, USA)
Gonzalo Rodríguez Lafora was a disciple of Santiago Ramón y Cajal (Nobel laureate in Physiology or Medicine 1906) and one of the most brilliant exponents of the Cajal School or the Spanish Neurological School.
Typically Lafora is very rare in children, adolescents and adults worldwide. However, Lafora disease has a higher incidence among children and adolescents with ancestry from regions where incestuous relationships are common, namely the Mediterranean (North Africa, Southern Europe), the Middle East, India, and Pakistan. Dogs can also have the condition. In canines, Lafora disease can spontaneously occur in any breed, but the Miniature Wire Haired Dachshund, Bassett Hound, and the Beagle are predisposed to LD.Most human patients with this disease do not live past the age of twenty-five, and death within ten years of symptoms is usually inevitable. Late onset symptoms of this disease can begin at any age depending on the genes affected. At present, there is no cure for this disease but there are ways to deal with symptoms through treatments and medications.
Signs and symptoms
Symptoms of Lafora disease begin to develop during the early adolescent years, and symptoms progress as time passes. In the years before then, there is generally no indication of the presence of the disease, though in a few cases, the disease presents as a learning disorder around 5 years of age. In extremely rare cases, symptoms may not show at all until as late as the 3rd decade of life, though these cases have slower progression than typical LD. The most common feature of Lafora disease is seizures that have been reported mainly as occipital seizures and myoclonic seizures with some cases of generalized tonic-clonic seizures, atypical absence seizures, and atonic and complex partial seizures. Other symptoms common with the seizures are drop attacks, ataxia, temporary blindness, visual hallucinations, and a quickly-developing and dramatic dementia.Other common signs and symptoms associated with Lafora disease are behavioral changes due to the frequency of seizures. Over time those affected with Lafora disease have brain changes that cause confusion, speech difficulties, depression, decline in intellectual function, impaired judgement and impaired memory. If areas of the cerebellum are affected by seizures, it is common to see problems with speech, coordination, and balance in Lafora patients.For dogs that are affected with Lafora disease, common symptoms are rapid shuddering, shaking, or jerking of the canines head backwards, high pitched vocalizations that could indicate the dog is panicking, seizures, and as the disease progresses dementia, blindness, and loss of balance.Within ten years of developing symptoms, life expectancy has known to go down. People who advance to adulthood tend to lose their ability to do daily tasks by themselves, which can lead them to having to have comprehensive care. If their symptoms have become onset extremely fast or at an early age, comprehensive care allows one to get treatment in ways that are not only regarding receiving their medication, but it also includes both physical and mental health towards the daily activities that one would normally perform by themselves.
Genetics
Lafora disease is an autosomal recessive disorder, caused by loss of function mutations in either laforin glycogen phosphatase gene (EPM2A) or malin E3 ubiquitin ligase gene (NHLRC1). These mutations in either of these two genes lead to polyglucosan formation or lafora body formation in the cytoplasm of heart, liver, muscle, and skin.Graph 1 shows the data for 250 families that have been affected by Lafora Disease and the distribution of cases around the world. The graph shows that there is a very large number of cases in Italy because of the EPM2A gene mutation compared to any other country in the world.
Graph 2 shows the percentage distribution of the cases from either an EPM2A gene mutation or an EPM2B (NHLRC1) gene mutation. 42% of the cases are caused by EPM2A and 58% are caused by EPM2B (NHLRC1). The most common mutation on the EPM2A gene is the R241X mutation. This genetic mutation is the cause for 17% of the EPM2A caused Lafora Disease cases.EPM2A codes for the protein laforin, a dual-specificity phosphatase that acts on carbohydrates by taking phosphates off.NHLRC1 encodes the protein malin, an E3 ubiquitin ligase, that regulates the amount of laforin.Laforin is essential for making the normal structure of a glycogen molecule. When the mutation occurs on the EPM2A gene, laforin protein is down-regulated and less amount of this protein is present or none is made at all. If there is also a mutation in the NHLRC1 gene that makes the protein malin, then laforin cannot be regulated and thus less of it is made.
Less Laforin means more phosphorylation of glycogen, causing conformational changes, rendering it insoluble, leading to an accumulation of misformed glycogen, which has neurotoxic effects.
In a laforin mutation, glycogen would be hyperphosphorylated; this has been confirmed in laforin knock-out mice.Research literature also suggests that over-activity of glycogen synthase, the key enzyme in synthesizing glycogen, can lead to the formation of polyglucosans and it can be inactivated by phosphorylation at various amino acid residues by many molecules, including GSK-3beta, Protein phosphatase 1, and malin.As defective enzyme molecules participate in the production of these molecules (GSK-3beta, PP1, and malin), excessive glycogen synthase activity occurs in combination with mutations in laforin that phosphorylates the excess glycogen being made, rendering it insoluble. The key player missing is ubiquitin. It is not able to degrade the excess amount of the insoluble lafora bodies. Since mutations arise in malin, an e3 ubiquitin ligase, this directly interferes with the degradation of laforin, causing the laforin not to be degraded; it can then hyperphosphorylate.
Lafora bodies
Lafora disease is distinguished by the presence of inclusions called Lafora bodies within the cytoplasm of cells. Lafora bodies are aggregates of polyglucosans or abnormally shaped glycogen molecules. Glycogen in Lafora disease patients has abnormal chain lengths, which causes them to be insoluble, accumulate, and have a neurotoxic effect.For glycogen to be soluble, there must be short chains and a high frequency of branching points, but this is not found in the glycogen in Lafora patients. LD patients have longer chains that have clustered arrangement of branch points that form crystalline areas of double helices making it harder for them to clear the blood-brain barrier. The glycogen in LD patients also has higher phosphate levels and is present in greater quantities.
Diagnosis
Lafora Disease is diagnosed by conducting a series of tests by a neurologist, epileptologist (person who specializes in epilepsy), or geneticist. To confirm the diagnosis, an EEG, MRI, and genetic testing are needed. A biopsy may be necessary as well to detect and confirm the presence of Lafora bodies in the skin. Typically, if a patient comes to a doctor and has been having seizures, as patients with LD characteristically have, these are the standard screening tests.
Epidemiology
All the reports that have been published on Lafora Disease have shown that the overall prevalence of the disease is about 4 cases per million individuals around the world. Due to Laforas disease (LD) being so rare, there have been very few case series documented. The prevalence of Lafora Disease varies throughout the world because of the differing customs of each country that it is present in. It is much more prevalent in countries that have higher cases of inbreeding. Usually, these locations are generally more isolated from the world at large. In the western countries the prevalence of Lafora Disease is much lower because of the greater city size and less isolated communities that would participate in inbreeding.
Treatment
Unfortunately there is no cure for Lafora Disease with treatment being limited to controlling seizures through anti-epileptic and anti-convulsant medications. The treatment is usually based on the individuals specific symptoms and the severity of those symptoms. Some examples of medications include valproate, levetiracetam, topiramate, benzodiazepines, or perampanel. Although the symptoms and seizures can be controlled for a long period by using anti-epileptic drugs, the symptoms will progress and patients lose their ability to perform daily activities leading to the survival rate of approximately 10 years after symptoms begin. Quality of life worsens as the years go on, with some patients requiring a feeding tube so that they can get the nutrition and medication they need in order to keep living, but not necessarily functioning. Recently Metformin is approved for the treatment.
Due to the severity of Laforas disease being exceedingly rare, it is recommended to contact a specialist, such as one specialized in genetics, as well as looking into universities and other medical centers around because they will have the most up to date technology.
Research
The disease is named after Gonzalo Rodríguez Lafora (1886–1971), a Spanish neuropathologist who first recognized small inclusion bodies in Lafora patients. Since the discovery of Lafora Disease in early to mid 1900s there has not been too much research into it, until more recent years.
An approach to studying this rare disease would be performing a case-control study. This is done by following a group of people to accrue person years to evaluate historical associated factors. These historical factors can then help researchers deduce new cases and consider the discrepancies of various risk factors. This leads to potentially faster recognition of exposures when there are outbreaks of the disease. The added benefits of a case control study are that they take less time to complete, and cost quite a bit less to facilitate, with no follow-up necessary. They can also be used to establish association between different variables, which can then lead into more focused, long-term studies.Recent research is looking into how inhibition of glycogen synthesis, since increased glucose uptake causes increased glycogen, could potentially stop the formation of the Lafora Bodies in neurons in laforin-deficient mice models while also reducing the chances of seizures. The adipocyte hormone Leptin is what this research targeted by blocking the leptin signaling to reduce glucose uptake and stop Lafora bodies from forming.Other researchers are looking into the ways in which Lafora bodies are being regulated at the level of gene expression. There is specific research looking into how Laforin, a glycogen dephosphatase, gene expression is potentially being downregulated or mutations are arising in the DNA in LD allowing more phosphates to be present helping to render glycogen insoluble.During the past two years (2015-2017), researchers in U.S., Canada, and Europe have formed the (LECI) Lafora Epilepsy Cure Initiative to try and find a cure for Lafora Disease with funding from the National Institutes of Health (NIH) led by Dr. Matthew Gentry at the University of Kentucky. Since researchers have found the two genes that cause LD, they are currently aiming to interrupt the process of how these mutations in those genes interfere with normal carbohydrate metabolism in mice models. They predict they will have one or more drugs ready for human clinical trials within the next few years.
References
External links
GeneReview/NCBI/NIH/UW entry on Progressive Myoclonus Epilepsy, Lafora Type |
Necrolytic acral erythema | Necrolytic acral erythema is a cutaneous condition that is a manifestation of hepatitis C viral infection or zinc deficiency.It is a papulosquamous and sometimes vesiculobullous eruption bearing clinical and histologic similarity to other necrolytic erythemas such as necrolytic migratory erythema, pseudoglucagonoma and nutritional deficiency syndromes.
See also
List of cutaneous conditions
References
== External links == |
Leber congenital amaurosis | Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.It affects about 1 in 40,000 newborns. LCA was first described by Theodor Leber in the 19th century. It should not be confused with Lebers hereditary optic neuropathy, which is a different disease also described by Theodor Leber.
One form of LCA was successfully treated with gene therapy in 2008.
Signs and symptoms
The term congenital refers to a condition present from birth (not acquired) and amaurosis refers to a loss of vision not associated with a lesion. However, beyond these general descriptions, the presentation of LCA can vary, because it is associated with multiple genes.LCA is typically characterized by nystagmus, sluggish or absent pupillary responses, and severe vision loss or blindness.
Genetics
It is usually autosomal recessive; however, importantly for family planning, it is sometimes autosomal dominant. It is a disorder thought to be caused by abnormal development of photoreceptor cells.OMIM currently recognizes 18 types of LCA.
The gene CEP290 has been associated with Joubert syndrome, as well as type 10 LCA.
Diagnosis
Genetic tests and related research are currently being performed at Centogene AG in Rostock, Germany; John and Marcia Carver Nonprofit Genetic Testing Laboratory in Iowa City, IA; GENESIS Center for Medical Genetics in Poznan, Poland; Miraca Genetics Laboratories in Houston, TX; Asper Biogene in Tartu, Estonia; CGC Genetics in Porto, Portugal; CEN4GEN Institute for Genomics and Molecular Diagnostics in Edmonton, Canada; and Reference Laboratory Genetics - Barcelona, Spain.
Treatment
One form of LCA, in patients with LCA2 bearing a mutation in the RPE65 gene, has been successfully treated in clinical trials using gene therapy. The results of three early clinical trials were published in 2008 demonstrating the safety and efficacy of using adeno-associated virus to deliver gene therapy to restore vision in LCA patients. In all three clinical trials, patients recovered functional vision without apparent side effects. These studies, which used adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease.The results of a phase 1 trial conducted by the University of Pennsylvania and Children’s Hospital of Philadelphia and published in 2009 showed sustained improvement in 12 subjects (ages 8 to 44) with RPE65-associated LCA after treatment with AAV2-hRPE65v2, a gene replacement therapy. Early intervention was associated with better results. In that study, patients were excluded based on the presence of particular antibodies to the vector AAV2 and treatment was only administered to one eye as a precaution. A 2010 study testing the effect of administration of AAV2-hRPE65v2 in both eyes in animals with antibodies present suggested that immune responses may not complicate use of the treatment in both eyes. On 19 December 2017, the U.S. Food and Drug Administration approved voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy for children and adults with biallelic RPE65 gene mutations responsible for retinal dystrophy, including Leber congenital amaurosis. Patients must have viable retinal cells as a prerequisite for the intraocular administration of Luxturna.Retina surgeon Dr. Albert Maguire and gene therapy expert Dr. Jean Bennett developed the technique used by the Childrens Hospital.Dr. Sue Semple-Rowland at the University of Florida has recently restored sight in an avian model using gene therapy.In March 2020, doctors at the Casey Eye Institute of the Oregon Health & Science University injected a CRISPR-modified virus into a patients eye in an attempt to treat LCA10.
Popular culture
In the episode "The Blackout in the Blizzard" (season 6, episode 16) of the television drama Bones, Dr. Jack Hodgins and his pregnant wife Angela Montenegro, who is an LCA carrier, have to wait during a citywide blackout for Hodginss genetic test results, to see if he is also an LCA carrier. He does indeed turn out to be a carrier, giving their unborn child a 25% chance of having LCA.
In the television series ER (season 14, episode 12 "Believe the Unseen") Dr. Abby Lockhart diagnoses a young foster girl with Leber congenital amaurosis. The girl to this point hid her condition from her foster families. The episode contains some information about symptoms, clinical diagnosis and mentions gene replacement therapy and clinical trials as hope for help in managing the condition.
In the Korean drama The King of Dramas (episode 16, "In Search of Lost Time") Anthony Kim, played by Kim Myung-min, is diagnosed with Leber congenital amaurosis, the same disease that made his mother blind.
Four-year-old Gavin who suffers from a form of LCA was made famous in 2013 by a YouTube video showing him using his white cane for the first time to navigate down a curb. He later appeared on the TV show Little Big Shots.
See also
Visual cycle
References
Further reading
Gambino, Megan (December 17, 2008). "Jocelyn Kaiser on Gene Therapy in a New Light". Science & Nature. Smithsonian. p. 124. Retrieved 22 May 2021.
Lewis, Ricki (2012). The Forever Fix: Gene Therapy and the Boy Who Saved It. New York: St. Martins Press. ISBN 978-0-312-68190-6. OCLC 740628904.
External links
GeneReview/NIH/UW entry on Leber Congenital Amaurosis |
Nevus anemicus | Nevus anemicus is a congenital disorder characterized by macules of varying size and shape that are paler than the surrounding skin and cannot be made red by trauma, cold, or heat. The paler area is due to the blood vessels within the area which are more sensitive to the body’s normal vasoconstricting chemicals.
Signs and symptoms
This benign patch appears on the skin at birth or in early childhood. In most people these are under 10 centimeters (3.9 in) in size. If there is doubt about the diagnosis, rubbing the area causes the skin around the lesion to become red while the lesion itself does not change in color. Often the patches are difficult to see against the background color of the patient’s skin, but if sunburn develops, then the white area stands out prominently. The involved area is lighter than the normal skin, not because of a loss of pigment occurs, but because blood vessels are constricted, producing a permanent blanching of the area. This blanching is a functional rather than a structural abnormality, presumed to be caused by local increased sensitivity to catecholamines. Although the cutaneous vasculature appears normal histologically, the blood vessels within the nevus do not respond to injection of vasodilators. It has been postulated that the persistent pallor may represent a sustained localized adrenergic vasoconstriction. Results of a skin biopsy would be interpreted as normal and only physiological testing can reveal the nevus in contrast to normal skin. Stroking the patch elicits no red flare. Only the normal skin would react with a characteristic erythematous response. Examination under a Wood lamp can also reveal the nevus anemicus patch will not emphasize as a patch of vitiligo would.
Diagnosis
Treatment
Since the histopathology of nevus anemicus is normal, nevus anemicus is a pharmacologic nevus and not an anatomic one. In most people a nevus anemicus is on a covered area and so light in appearance that no treatment is needed.
See also
List of cutaneous conditions
Melanism
Nevus
Skin lesion
== References == |
Carneys triad | Carney triad (CT) is characterized by the coexistence of three types of neoplasms, mainly in young women, including gastric gastrointestinal stromal tumor, pulmonary chondroma, and extra-adrenal paraganglioma. The underlying genetic defect remains elusive. CT is distinct from Carney complex, and the Carney-Stratakis syndrome.
Background
Carney triad (CT), named for J Aidan Carney, is considered to be a specific type of multiple endocrine neoplasia (MEN). The three classically associated tumors are a subset of gastric epithelioid leiomyosarcoma (it is now known that this subset is actually gastrointestinal stromal tumor arising from the interstitial cells of Cajal), pulmonary chondroma, and extra-adrenal paraganglioma.The condition manifests more commonly in females. Multiple tumors in multiple organs in young patients, with occasional sibling involvement, suggested an inherited disorder, but the underlying genetic basis has not been identified.In addition to these three classical tumors, there is an increased incidence of pheochromocytoma, esophageal leiomyoma and adrenocortical adenoma.The original description employed the then-prevailing terminology of gastric epithelioid leiomyosarcoma. Subsequent advances in molecular biology have led to the current terminology of gastrointestinal stromal tumors (GISTs). However, there is limited evidence to suggest that the gastrointestinal stromal tumors (GIST) in Carney triad lack CD117 (c-kit) mutations (i.e., they are wild-type), and hence these GISTs may prove unresponsive to Imatinib.
Taxonomy
Carney triad is distinct from two other multiple neoplasia syndromes, also described by J. Aidan Carney.
Carney complex
The Carney complex is a distinct entity, characterized by myxomatous neoplasms (cardiac, endocrine, cutaneous and neural), and a host of pigmented lesions of the skin and mucosae, including the rarely occurring epitheloid blue nevus.
Carney–Stratakis syndrome
A third condition, the Carney–Stratakis syndrome (CSS), describes the dyad of hereditary gastrointestinal stromal tumor (GIST) and paraganglioma, that is caused by germline mutations in the mitochondrial tumor suppressor gene pathway involving the succinate dehydrogenase subunits SDHD, SDHC and SDHB.
== References == |
Pelvic girdle pain | Pelvic girdle pain (abbreviated PGP) can be described as a pregnancy discomfort for some women and a severe disability for others. PGP can cause pain, instability and limitation of mobility and functioning in any of the three pelvic joints. PGP has a long history of recognition, mentioned by Hippocrates and later described in medical literature by Snelling.
The affection appears to consist of relaxation of the pelvic articulations, becoming apparent suddenly after parturition or gradually during pregnancy and permitting a degree of mobility of the pelvic bones which effectively hinders locomotion and gives rise to the most peculiar and alarming sensations.
Classification
Prior to the 20th century, specialists of pregnancy-related PGP used varying terminologies. It is now referred to as Pregnancy Related Pelvic Girdle Pain that may incorporate the following conditions:
Diastasis of the symphysis pubis (DSP)
Symphysis pubis dysfunction (SPD)
Pelvic Joint Syndrome
Physiological Pelvic Girdle Relaxation
Symptom Giving Pelvic Girdle Relaxation
Posterior Pelvic Pain
Pelvic Arthropathy
Inferior Pubic Shear/ Superior Pubic Shear /Symphyseal Shear
Symphysiolysis
Osteitis pubis (usually postpartum)
Sacroiliitis
One-sided Sacroiliac Syndrome /Double Sided Sacroiliac Syndrome
Hypermobility"The classification between hormonal and mechanical pelvic girdle instability is no longer used. For treatment and/or prognosis it makes no difference whether the complaints started during pregnancy or after childbirth." Mens (2005)
Signs and symptoms
A combination of postural changes, baby, unstable pelvic joints under the influence of pregnancy hormones, and changes in the centre of gravity can all add to the varying degrees of pain or discomfort. In some cases it can come on suddenly or following a fall, sudden abduction of the thighs (opening too wide too quickly) or an action that has strained the joint.
PGP can begin as early as the first trimester of pregnancy. Pain is usually felt low down over the symphyseal joint, and this area may be extremely tender to the touch. Pain may also be felt in the hips, groin and lower abdomen and can radiate down the inner thighs. Women with PGP may begin to waddle or shuffle, and may be aware of an audible clicking sound coming from the pelvis. PGP can develop slowly during pregnancy, gradually gaining in severity as the pregnancy progresses.
During pregnancy and postpartum, the symphyseal gap can be felt moving or straining when walking, climbing stairs or turning over in bed; these activities can be difficult or even impossible. The pain may remain static, e.g., in one place such as the front of the pelvis, producing the feeling of having been kicked; in other cases it may start in one area and move to other areas. It is also possible that a woman may experience a combination of symptoms.
Any weight bearing activity has the potential of aggravating an already unstable pelvis, producing symptoms that may limit the ability of the woman to carry out many daily activities. She may experience pain involving movements such as dressing, getting in and out of the bath, rolling in bed, climbing the stairs or sexual activity. Pain may also be present when lifting, carrying, pushing or pulling.
The symptoms (and their severity) experienced by women with PGP vary, but include:
Present swelling and/or inflammation over joint.
Difficulty lifting leg.
Pain pulling legs apart.
Inability to stand on one leg.
Inability to transfer weight through pelvis and legs.
Pain in hips and/or restriction of hip movement.
Transferred nerve pain down leg.
Can be associated with bladder and/or bowel dysfunction.
A feeling of the symphysis pubis giving way.
Stooped back when standing.
Malalignment of pelvic and/or back joints.
Struggle to sit or stand.
Pain may also radiate down the inner thighs.
Waddling or shuffling gait.
Audible clicking sound coming from the pelvis.
Severity
The severity and instability of the pelvis can be measured on a three level scale.
Pelvic type 1:The pelvic ligaments support the pelvis sufficiently. Even when the
muscles are used incorrectly, no complaints will occur when performing everyday activities. This is the most common situation in persons who have never been pregnant, who have never been in an accident, and who are not hypermobile.
Pelvic type 2:The ligaments alone do not support the joint sufficiently. A
coordinated use of muscles around the joint will compensate for ligament weakness. In case the muscles around the joint do not function, the patient will experience pain and weakness when performing everyday activities. This type often occurs after giving birth to a child weighing 3000 grams or more, in cases of hypermobility, and sometimes after an accident involving the pelvis. Type 2 is the most common form of pelvic instability. Treatment is based on learning how to use the muscles around the pelvis more efficiently.
Pelvic type 3:The ligaments do not support the joint sufficiently. This is a serious
situation whereby the muscles around the joint are unable to compensate for ligament weakness. This type of pelvic instability usually only occurs after an accident, or occasionally after a (small) accident in combination with giving birth. Sometimes a small accident occurring long before giving birth is forgotten so that the pelvic instability is attributed only to the childbirth. Although the difference between Type 2 and 3 is often difficult to establish, in case of doubt an exercise program may help the patient. However, if Pelvic Type 3 has been diagnosed then invasive treatment is the only option: in this case parts of the pelvis are screwed together. (Mens 2005)
Psychosocial impact
PGP in pregnancy seriously interferes with participation in society and activities of daily life; the average sick leave due to posterior pelvic pain during pregnancy is 7 to 12 weeks.In some cases women with PGP may also experience emotional problems such as anxiety over the cause of pain, resentment, anger, lack of self-esteem, frustration and depression; she is three times more likely to develop postpartum depressive symptoms. Other psychosocial risk factors associated with woman experiencing PGP include higher level of stress, low job satisfaction and poorer relationship with spouse.
Causes
Sometimes there is no obvious explanation for the cause of PGP but usually there is a combination of factors such as:
The pelvic joints moving unevenly.
A change in the activity of the muscles in the pelvis, hip, abdomen, back and pelvic floor.
A history of pelvic trauma.
The position of the baby altering the loading stresses on the pelvic ligaments and joints.
Strenuous work.
Previous lower back pain.
Previous pelvic girdle pain during pregnancy.
Hypermobility, genetical ability to stretch joints beyond normal range.
An event during the pregnancy or birth that caused injury or strain to the pelvic joints or rupture of the fibrocartilage.
The occurrence of PGP is associated with twin pregnancy, first pregnancy and a higher age at first pregnancy.
Mechanism
Pregnancy related Pelvic Girdle Pain (PGP) can be either specific (trauma or injury to pelvic joints or genetical i.e. connective tissue disease) and non-specific. PGP disorder is complex and multi-factorial and likely to be also represented by a series of sub-groups driven by pain varying from peripheral or central nervous system,
altered laxity/stiffness of muscles, laxity to injury of tendinous/ligamentous structures to mal-adaptive body mechanics.Pregnancy begins the physiological changes through a pattern of hormonal secretion and signal transduction thus initiating the remodelling of soft tissues, cartilage and ligaments. Over time, the ligaments could be stretched either by injury or excess strain and in turn may cause PGP.
Anatomy
The pelvis is the largest bony part of the skeleton and contains three joints: the pubic symphysis, and two sacroiliac joints. A highly durable network of ligaments surrounds these joints giving them tremendous strength.
The pubic symphysis has a fibrocartilage joint which may contain a fluid filled cavity and is avascular; it is supported by the superior and arcuate ligaments. The sacroiliac joints are synovial, but their movement is restricted throughout life and they are progressively obliterated by adhesions. The nature of the bony pelvic ring with its three joints determines that no one joint can move independently of the other two.
Relaxin hormone
Relaxin is a hormone produced mainly by the corpus luteum of the ovary and breast, in both pregnant and non-pregnant females. During pregnancy it is also produced by the placenta, chorion, and decidua. The body produces relaxin during menstruation that rises to a peak within approximately 14 days of ovulation and then declines. In pregnant cycles, rather than subsiding, relaxin secretion continues to rise during the first trimester and then again in the final weeks. During pregnancy relaxin has a diverse range of effects, including the production and remodelling of collagen thus increasing the elasticity of muscles, tendons, ligaments and tissues of the birth canal in view of delivery.
Although relaxins main cellular action in pregnancy is to remodel collagen by biosynthesis (thus facilitating the changes of connective tissue) it does not seem to generate musculoskeletal problems. European Research has determined that relaxin levels are not a predictor of PGP during pregnancy.
Gait changes
The pregnant woman has a different pattern of "gait". The step lengthens as the pregnancy progresses due to weight gain and changes in posture. Both the length and height of the footstep shortens with PGP. Sometimes the foot can turn inwards due to the rotation of the hips when the pelvic joints are unstable. On average, a womans foot can grow by a half size or more during pregnancy. Pregnancy hormones that are released to adapt the bodily changes also remodel the ligaments in the foot. In addition, the increased body weight of pregnancy, fluid retention and weight gain lowers the arches, further adding to the foots length and width. There is an increase of load on the lateral side of the foot and the hind foot. These changes may also be responsible for the musculoskeletal complaints of lower limb pain in pregnant women.
During the motion of walking, an upward movement of the pelvis, one side then the other, is required to let the leg follow through. The faster or longer each step the pelvis adjusts accordingly. The flexibility within the knees, ankles and hips are stabilized by the pelvis. Normal gait tends to minimize displacement of centre of gravity whereas abnormal gait through pelvic instability tends to amplify displacement. During pregnancy there may be an increased demand placed on hip abductor, hip extensor, and ankle plantar flexor muscles during walking. To avoid pain on weight bearing structures a very short stance phase and limp occurs on the injured side(s), this is called Antalgic Gait.
Treatment
A number of treatments have some evidence for benefits include an exercise program. Paracetamol (acetaminophen) has not been found effective but is safe. NSAIDs are sometimes effective but should not be used after 30 weeks of pregnancy. There is tentative evidence for acupuncture.Some pelvic joint trauma will not respond to conservative type treatments and orthopedic surgery might become the only option to stabilize the joints.
Prognosis and epidemiology
For most women, PGP resolves in weeks after delivery but for some it can last for years resulting in a reduced tolerance for weight bearing activities. PGP can take from 11 weeks, 6 months or even up to 2 years postpartum to subside. However, some research supports that the average time to complete recovery is 6.25 years, and the more severe the case is, the longer recovery period.Overall, about 45% of all pregnant women and 25% of all women postpartum have PGP. During pregnancy, serious pain occurs in about 25%, and severe disability in about 8% of patients. After pregnancy, problems are serious in about 7%. There is no correlation between age, culture, nationality and numbers of pregnancies that determine a higher incidence of PGP.If a woman experiences PGP during one pregnancy, she is more likely to experience it in subsequent pregnancies; but the severity cannot be determined.
References
Further reading
Recommendations for the Nomenclature of Receptors for Relaxin Family Peptides Pharmacol Rev 58:7-31,2006 Ross A. Bathgate, Richard Ivell, Barbara M. Sanborn, O. David Sherwood and Roger J. Summers |
Painful bruising syndrome | Painful bruising syndrome (also known as "autoerythrocyte sensitization", "Gardner–Diamond syndrome", and "psychogenic purpura") is an idiopathic trauma-induced condition seen in young to middle-aged women who sometimes manifest personality disorders.: 829 It is characterized by a distinctive localized purpuric reaction occurring primarily on the legs, face and trunk, with recurring painful ecchymoses variably accompanied by syncope, nausea, vomiting, gastrointestinal and intracranial bleeding.Patients with this condition can experience frequent painful bruising around joints and muscles. Because of the rarity of the disorder, there are few methods of support in place for patients.Many patients are labelled with the stigma of having a psychological condition without this having a specifically proven link. There have been cases of painful bruising syndrome reported where there are no additional psychological disorders. This has been known to be put into remission with chemotherapy. It was characterized in 1955 by Frank Gardner and Louis Diamond.Patient may present with a history of intermittent purpura mostly precipitated by stress.
See also
List of cutaneous conditions
References
Further reading
Panconesi, E., & Hautmann, G. (1995). Stress, Stigmatization and Psychosomatic Purpuras. International Angiology 14: 130–137.
Yuecel, B., Kiziltan, E., & Aktan, M. (2000). Dissociative Identity Disorder Presenting With Psychogenic Purpura. Psychosomatics 41: 279–281.
== External links == |
Internuclear ophthalmoplegia | Internuclear ophthalmoplegia (INO) is a disorder of conjugate lateral gaze in which the affected eye shows impairment of adduction. When an attempt is made to gaze contralaterally (relative to the affected eye), the affected eye adducts minimally, if at all. The contralateral eye abducts, however with nystagmus. Additionally, the divergence of the eyes leads to horizontal diplopia. That is if the right eye is affected the patient will "see double" when looking to the left, seeing two images side-by-side. Convergence is generally preserved.
Causes
The disorder is caused by injury or dysfunction in the medial longitudinal fasciculus (MLF), a heavily myelinated tract that allows conjugate eye movement by connecting the paramedian pontine reticular formation (PPRF)-abducens nucleus complex of the contralateral side to the oculomotor nucleus of the ipsilateral side.
In young patients with bilateral INO, multiple sclerosis is often the cause. In older patients with one-sided lesions a stroke is a distinct possibility. Other causes are possible.
Variants
A rostral lesion within the midbrain may affect the convergence center thus causing bilateral divergence of the eyes which is known as the WEBINO syndrome (Wall Eyed Bilateral INO) as each eye looks at the opposite "wall".
If the lesion affects the PPRF (or the abducens nucleus) and the MLF on the same side (the MLF having crossed from the opposite side), then the "one and a half syndrome" occurs, with paralysis of all conjugate horizontal eye movements other than abduction of the eye on the opposite side to the lesion.
Diagnosis
Can be seen in multiple sclerosis, stroke, and other pathologies. Accompanying symptoms include scanning speech, intention tremor, incontinence, and nystagmus.
See also
Multiple sclerosis
One and a half syndrome
References
== External links == |
Rheumatoid neutrophilic dermatitis | Rheumatoid neutrophilic dermatitis (also known as "Rheumatoid neutrophilic dermatosis") is a cutaneous condition associated with rheumatoid arthritis.
See also
Sweets syndrome-like dermatosis
List of cutaneous conditions
== References == |
Asthma | Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath. These may occur a few times a day or a few times per week. Depending on the person, asthma symptoms may become worse at night or with exercise.Asthma is thought to be caused by a combination of genetic and environmental factors. Environmental factors include exposure to air pollution and allergens. Other potential triggers include medications such as aspirin and beta blockers. Diagnosis is usually based on the pattern of symptoms, response to therapy over time, and spirometry lung function testing. Asthma is classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate. It may also be classified as atopic or non-atopic, where atopy refers to a predisposition toward developing a type 1 hypersensitivity reaction.There is no known cure for asthma, but can be controlled. Symptoms can be prevented by avoiding triggers, such as allergens and respiratory irritants, and suppressed with the use of inhaled corticosteroids. Long-acting beta agonists (LABA) or antileukotriene agents may be used in addition to inhaled corticosteroids if asthma symptoms remain uncontrolled. Treatment of rapidly worsening symptoms is usually with an inhaled short-acting beta-2 agonist such as salbutamol and corticosteroids taken by mouth. In very severe cases, intravenous corticosteroids, magnesium sulfate, and hospitalization may be required.In 2019 asthma affected approximately 262 million people and caused approximately 461,000 deaths. Most of the deaths occurred in the developing world. Asthma often begins in childhood, and the rates have increased significantly since the 1960s. Asthma was recognized as early as Ancient Egypt. The word "asthma" is from the Greek ἆσθμα, âsthma, which means "panting".
Signs and symptoms
Asthma is characterized by recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing. Sputum may be produced from the lung by coughing but is often hard to bring up. During recovery from an asthma attack (exacerbation), it may appear pus-like due to high levels of white blood cells called eosinophils. Symptoms are usually worse at night and in the early morning or in response to exercise or cold air. Some people with asthma rarely experience symptoms, usually in response to triggers, whereas others may react frequently and readily and experience persistent symptoms.
Associated conditions
A number of other health conditions occur more frequently in people with asthma, including gastroesophageal reflux disease (GERD), rhinosinusitis, and obstructive sleep apnea. Psychological disorders are also more common, with anxiety disorders occurring in between 16 and 52% and mood disorders in 14–41%. It is not known whether asthma causes psychological problems or psychological problems lead to asthma. Current asthma, but not former asthma, is associated with increased all-cause mortality, heart disease mortality, and chronic lower respiratory tract disease mortality. Asthma, particularly severe asthma, is strongly associated with development of chronic obstructive pulmonary disease (COPD). Those with asthma, especially if it is poorly controlled, are at increased risk for radiocontrast reactions.Cavities occur more often in people with asthma. This may be related to the effect of beta 2 agonists decreasing saliva. These medications may also increase the risk of dental erosions.
Causes
Asthma is caused by a combination of complex and incompletely understood environmental and genetic interactions. These influence both its severity and its responsiveness to treatment. It is believed that the recent increased rates of asthma are due to changing epigenetics (heritable factors other than those related to the DNA sequence) and a changing living environment. Asthma that starts before the age of 12 years old is more likely due to genetic influence, while onset after age 12 is more likely due to environmental influence.
Environmental
Many environmental factors have been associated with asthmas development and exacerbation, including, allergens, air pollution, and other environmental chemicals. Smoking during pregnancy and after delivery is associated with a greater risk of asthma-like symptoms. Low air quality from environmental factors such as traffic pollution or high ozone levels has been associated with both asthma development and increased asthma severity. Over half of cases in children in the United States occur in areas when air quality is below the EPA standards. Low air quality is more common in low-income and minority communities.Exposure to indoor volatile organic compounds may be a trigger for asthma; formaldehyde exposure, for example, has a positive association. Phthalates in certain types of PVC are associated with asthma in both children and adults. While exposure to pesticides is linked to the development of asthma, a cause and effect relationship has yet to be established.The majority of the evidence does not support a causal role between acetaminophen (paracetamol) or antibiotic use and asthma. A 2014 systematic review found that the association between acetaminophen use and asthma disappeared when respiratory infections were taken into account. Acetaminophen use by a mother during pregnancy is also associated with an increased risk of the child developing asthma. Maternal psychological stress during pregnancy is a risk factor for the child to develop asthma.Asthma is associated with exposure to indoor allergens. Common indoor allergens include dust mites, cockroaches, animal dander (fragments of fur or feathers), and mold. Efforts to decrease dust mites have been found to be ineffective on symptoms in sensitized subjects. Weak evidence suggests that efforts to decrease mold by repairing buildings may help improve asthma symptoms in adults. Certain viral respiratory infections, such as respiratory syncytial virus and rhinovirus, may increase the risk of developing asthma when acquired as young children. Certain other infections, however, may decrease the risk.
Hygiene hypothesis
The hygiene hypothesis attempts to explain the increased rates of asthma worldwide as a direct and unintended result of reduced exposure, during childhood, to non-pathogenic bacteria and viruses. It has been proposed that the reduced exposure to bacteria and viruses is due, in part, to increased cleanliness and decreased family size in modern societies. Exposure to bacterial endotoxin in early childhood may prevent the development of asthma, but exposure at an older age may provoke bronchoconstriction. Evidence supporting the hygiene hypothesis includes lower rates of asthma on farms and in households with pets.Use of antibiotics in early life has been linked to the development of asthma. Also, delivery via caesarean section is associated with an increased risk (estimated at 20–80%) of asthma – this increased risk is attributed to the lack of healthy bacterial colonization that the newborn would have acquired from passage through the birth canal. There is a link between asthma and the degree of affluence which may be related to the hygiene hypothesis as less affluent individuals often have more exposure to bacteria and viruses.
Genetic
Family history is a risk factor for asthma, with many different genes being implicated. If one identical twin is affected, the probability of the other having the disease is approximately 25%. By the end of 2005, 25 genes had been associated with asthma in six or more separate populations, including GSTM1, IL10, CTLA-4, SPINK5, LTC4S, IL4R and ADAM33, among others. Many of these genes are related to the immune system or modulating inflammation. Even among this list of genes supported by highly replicated studies, results have not been consistent among all populations tested. In 2006 over 100 genes were associated with asthma in one genetic association study alone; more continue to be found.Some genetic variants may only cause asthma when they are combined with specific environmental exposures. An example is a specific single nucleotide polymorphism in the CD14 region and exposure to endotoxin (a bacterial product). Endotoxin exposure can come from several environmental sources including tobacco smoke, dogs, and farms. Risk for asthma, then, is determined by both a persons genetics and the level of endotoxin exposure.
Medical conditions
A triad of atopic eczema, allergic rhinitis and asthma is called atopy. The strongest risk factor for developing asthma is a history of atopic disease; with asthma occurring at a much greater rate in those who have either eczema or hay fever. Asthma has been associated with eosinophilic granulomatosis with polyangiitis (formerly known as Churg–Strauss syndrome), an autoimmune disease and vasculitis. Individuals with certain types of urticaria may also experience symptoms of asthma.There is a correlation between obesity and the risk of asthma with both having increased in recent years. Several factors may be at play including decreased respiratory function due to a buildup of fat and the fact that adipose tissue leads to a pro-inflammatory state.Beta blocker medications such as propranolol can trigger asthma in those who are susceptible. Cardioselective beta-blockers, however, appear safe in those with mild or moderate disease. Other medications that can cause problems in asthmatics are angiotensin-converting enzyme inhibitors, aspirin, and NSAIDs. Use of acid suppressing medication (proton pump inhibitors and H2 blockers) during pregnancy is associated with an increased risk of asthma in the child.
Exacerbation
Some individuals will have stable asthma for weeks or months and then suddenly develop an episode of acute asthma. Different individuals react to various factors in different ways. Most individuals can develop severe exacerbation from a number of triggering agents.Home factors that can lead to exacerbation of asthma include dust, animal dander (especially cat and dog hair), cockroach allergens and mold. Perfumes are a common cause of acute attacks in women and children. Both viral and bacterial infections of the upper respiratory tract can worsen the disease. Psychological stress may worsen symptoms – it is thought that stress alters the immune system and thus increases the airway inflammatory response to allergens and irritants.Asthma exacerbations in school‐aged children peak in autumn, shortly after children return to school. This might reflect a combination of factors, including poor treatment adherence, increased allergen and viral exposure, and altered immune tolerance. There is limited evidence to guide possible approaches to reducing autumn exacerbations, but while costly, seasonal omalizumab treatment from four to six weeks before school return may reduce autumn asthma exacerbations.
Pathophysiology
Asthma is the result of chronic inflammation of the conducting zone of the airways (most especially the bronchi and bronchioles), which subsequently results in increased contractability of the surrounding smooth muscles. This among other factors leads to bouts of narrowing of the airway and the classic symptoms of wheezing. The narrowing is typically reversible with or without treatment. Occasionally the airways themselves change. Typical changes in the airways include an increase in eosinophils and thickening of the lamina reticularis. Chronically the airways smooth muscle may increase in size along with an increase in the numbers of mucous glands. Other cell types involved include T lymphocytes, macrophages, and neutrophils. There may also be involvement of other components of the immune system, including cytokines, chemokines, histamine, and leukotrienes among others.
Diagnosis
While asthma is a well-recognized condition, there is not one universal agreed upon definition. It is defined by the Global Initiative for Asthma as "a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment".There is currently no precise test for the diagnosis, which is typically based on the pattern of symptoms and response to therapy over time. Asthma may be suspected if there is a history of recurrent wheezing, coughing or difficulty breathing and these symptoms occur or worsen due to exercise, viral infections, allergens or air pollution. Spirometry is then used to confirm the diagnosis. In children under the age of six the diagnosis is more difficult as they are too young for spirometry.
Spirometry
Spirometry is recommended to aid in diagnosis and management. It is the single best test for asthma. If the FEV1 measured by this technique improves more than 12% and increases by at least 200 milliliters following administration of a bronchodilator such as salbutamol, this is supportive of the diagnosis. It however may be normal in those with a history of mild asthma, not currently acting up. As caffeine is a bronchodilator in people with asthma, the use of caffeine before a lung function test may interfere with the results. Single-breath diffusing capacity can help differentiate asthma from COPD. It is reasonable to perform spirometry every one or two years to follow how well a persons asthma is controlled.
Others
The methacholine challenge involves the inhalation of increasing concentrations of a substance that causes airway narrowing in those predisposed. If negative it means that a person does not have asthma; if positive, however, it is not specific for the disease.Other supportive evidence includes: a ≥20% difference in peak expiratory flow rate on at least three days in a week for at least two weeks, a ≥20% improvement of peak flow following treatment with either salbutamol, inhaled corticosteroids or prednisone, or a ≥20% decrease in peak flow following exposure to a trigger. Testing peak expiratory flow is more variable than spirometry, however, and thus not recommended for routine diagnosis. It may be useful for daily self-monitoring in those with moderate to severe disease and for checking the effectiveness of new medications. It may also be helpful in guiding treatment in those with acute exacerbations.
Classification
Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate. Asthma may also be classified as atopic (extrinsic) or non-atopic (intrinsic), based on whether symptoms are precipitated by allergens (atopic) or not (non-atopic). While asthma is classified based on severity, at the moment there is no clear method for classifying different subgroups of asthma beyond this system. Finding ways to identify subgroups that respond well to different types of treatments is a current critical goal of asthma research.Although asthma is a chronic obstructive condition, it is not considered as a part of chronic obstructive pulmonary disease, as this term refers specifically to combinations of disease that are irreversible such as bronchiectasis and emphysema. Unlike these diseases, the airway obstruction in asthma is usually reversible; however, if left untreated, the chronic inflammation from asthma can lead the lungs to become irreversibly obstructed due to airway remodeling. In contrast to emphysema, asthma affects the bronchi, not the alveoli. The combination of asthma with a component of irreversible airways obstruction has been termed the asthma-chronic obstructive disease (COPD) overlap syndrome (ACOS). Compared to other people with "pure" asthma or COPD, people with ACOS exhibit increased morbidity, mortality and possibly more comorbidities.
Asthma exacerbation
An acute asthma exacerbation is commonly referred to as an asthma attack. The classic symptoms are shortness of breath, wheezing, and chest tightness. The wheezing is most often when breathing out. While these are the primary symptoms of asthma, some people present primarily with coughing, and in severe cases, air motion may be significantly impaired such that no wheezing is heard. In children, chest pain is often present.Signs occurring during an asthma attack include the use of accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck), there may be a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest. A blue color of the skin and nails may occur from lack of oxygen.In a mild exacerbation the peak expiratory flow rate (PEFR) is ≥200 L/min, or ≥50% of the predicted best. Moderate is defined as between 80 and 200 L/min, or 25% and 50% of the predicted best, while severe is defined as ≤ 80 L/min, or ≤25% of the predicted best.Acute severe asthma, previously known as status asthmaticus, is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators and corticosteroids. Half of cases are due to infections with others caused by allergen, air pollution, or insufficient or inappropriate medication use.Brittle asthma is a kind of asthma distinguishable by recurrent, severe attacks. Type 1 brittle asthma is a disease with wide peak flow variability, despite intense medication. Type 2 brittle asthma is background well-controlled asthma with sudden severe exacerbations.
Exercise-induced
Exercise can trigger bronchoconstriction both in people with or without asthma. It occurs in most people with asthma and up to 20% of people without asthma. Exercise-induced bronchoconstriction is common in professional athletes. The highest rates are among cyclists (up to 45%), swimmers, and cross-country skiers. While it may occur with any weather conditions, it is more common when it is dry and cold. Inhaled beta2-agonists do not appear to improve athletic performance among those without asthma, however, oral doses may improve endurance and strength.
Occupational
Asthma as a result of (or worsened by) workplace exposures is a commonly reported occupational disease. Many cases, however, are not reported or recognized as such. It is estimated that 5–25% of asthma cases in adults are work-related. A few hundred different agents have been implicated, with the most common being: isocyanates, grain and wood dust, colophony, soldering flux, latex, animals, and aldehydes. The employment associated with the highest risk of problems include: those who spray paint, bakers and those who process food, nurses, chemical workers, those who work with animals, welders, hairdressers and timber workers.
Aspirin-induced asthma
Aspirin-exacerbated respiratory disease (AERD), also known as aspirin-induced asthma, affects up to 9% of asthmatics. AERD consists of asthma, nasal polyps, sinus disease, and respiratory reactions to aspirin and other NSAID medications (such as ibuprofen and naproxen). People often also develop loss of smell and most experience respiratory reactions to alcohol.
Alcohol-induced asthma
Alcohol may worsen asthmatic symptoms in up to a third of people. This may be even more common in some ethnic groups such as the Japanese and those with aspirin-induced asthma. Other studies have found improvement in asthmatic symptoms from alcohol.
Non-atopic asthma
Non-atopic asthma, also known as intrinsic or non-allergic, makes up between 10 and 33% of cases. There is negative skin test to common inhalant allergens. Often it starts later in life, and women are more commonly affected than men. Usual treatments may not work as well. The concept that "non-atopic" is synonymous with "non-allergic" is called into question by epidemiological data that the prevalence of asthma is closely related to the serum IgE level standardized for age and sex (P<0.0001), indicating that asthma is almost always associated with some sort of IgE-related reaction and therefore has an allergic basis, although not all the allergic stimuli that cause asthma appear to have been included in the battery of aeroallergens studied (the "missing antigen(s)" hypothesis). For example, an updated systematic review and meta-analysis of population-attributable risk (PAR) of Chlamydia pneumoniae biomarkers in chronic asthma found that the PAR for C. pneumoniae-specific IgE was 47%.
Infectious asthma
When queried, asthma patients may report that their first asthma symptoms began after an acute lower respiratory tract illness. This type of history has been labelled the "infectious asthma" (IA) syndrome, or as "asthma associated with infection" (AAWI) to distinguish infection-associated asthma initiation from the well known association of respiratory infections with asthma exacerbations. Reported prevalences of IA for adults range from around 40% in a primary care practice to 70% in a specialty practice treating mainly severe asthma patients. The true population prevalence of IA in adult-onset asthma is unknown because clinicians are not trained to elicit this type of history routinely, and recollection in child-onset asthma is challenging.
Differential diagnosis
Many other conditions can cause symptoms similar to those of asthma. In children, symptoms may be due to other upper airway diseases such as allergic rhinitis and sinusitis, as well as other causes of airway obstruction including foreign body aspiration, tracheal stenosis, laryngotracheomalacia, vascular rings, enlarged lymph nodes or neck masses. Bronchiolitis and other viral infections may also produce wheezing. In adults, COPD, congestive heart failure, airway masses, as well as drug-induced coughing due to ACE inhibitors may cause similar symptoms. In both populations vocal cord dysfunction may present similarly.Chronic obstructive pulmonary disease can coexist with asthma and can occur as a complication of chronic asthma. After the age of 65, most people with obstructive airway disease will have asthma and COPD. In this setting, COPD can be differentiated by increased airway neutrophils, abnormally increased wall thickness, and increased smooth muscle in the bronchi. However, this level of investigation is not performed due to COPD and asthma sharing similar principles of management: corticosteroids, long-acting beta-agonists, and smoking cessation. It closely resembles asthma in symptoms, is correlated with more exposure to cigarette smoke, an older age, less symptom reversibility after bronchodilator administration, and decreased likelihood of family history of atopy.
Prevention
The evidence for the effectiveness of measures to prevent the development of asthma is weak. The World Health Organization recommends decreasing risk factors such as tobacco smoke, air pollution, chemical irritants including perfume, and the number of lower respiratory infections. Other efforts that show promise include: limiting smoke exposure in utero, breastfeeding, and increased exposure to daycare or large families, but none are well supported enough to be recommended for this indication.Early pet exposure may be useful. Results from exposure to pets at other times are inconclusive and it is only recommended that pets be removed from the home if a person has allergic symptoms to said pet.Dietary restrictions during pregnancy or when breast feeding have not been found to be effective at preventing asthma in children and are not recommended. Omega-3 consumption, mediterranean diet and anti-oxidants have been suggested by some studies that might help preventing crisis but the evidence is still inconclusive.Reducing or eliminating compounds known to sensitive people from the work place may be effective. It is not clear if annual influenza vaccinations affects the risk of exacerbations. Immunization, however, is recommended by the World Health Organization. Smoking bans are effective in decreasing exacerbations of asthma.
Management
While there is no cure for asthma, symptoms can typically be improved. The most effective treatment for asthma is identifying triggers, such as cigarette smoke, pets, or aspirin, and eliminating exposure to them. If trigger avoidance is insufficient, the use of medication is recommended. Pharmaceutical drugs are selected based on, among other things, the severity of illness and the frequency of symptoms. Specific medications for asthma are broadly classified into fast-acting and long-acting categories. The medications listed below have demonstrated efficacy in improving asthma symptoms, however "real world" use-effectiveness is limited as around half of people with asthma worldwide remain sub-optimally controlled, even when treated. People with asthma may remain sub-optimally controlled either because optimum doses of asthma medications do not work (called "refractory" asthma) or because individuals are either unable (e.g. inability to afford treatment, poor inhaler technique) or unwilling (e.g., wish to avoid side effects of corticosteroids) to take optimum doses of prescribed asthma medications (called "difficult to treat" asthma). In practice, it is not possible to distinguish "refractory" from "difficult to treat" categories for patients who have never taken optimum doses of asthma medications. A related issue is that the asthma efficacy trials upon which the pharmacological treatment guidelines are based have systematically excluded the majority of people with asthma. For example, asthma efficacy treatment trials always exclude otherwise eligible people who smoke, and smoking blunts the efficacy of inhaled corticosteroids, the mainstay of asthma control management.Bronchodilators are recommended for short-term relief of symptoms. In those with occasional attacks, no other medication is needed. If mild persistent disease is present (more than two attacks a week), low-dose inhaled corticosteroids or alternatively, a leukotriene antagonist or a mast cell stabilizer by mouth is recommended. For those who have daily attacks, a higher dose of inhaled corticosteroids is used. In a moderate or severe exacerbation, corticosteroids by mouth are added to these treatments.People with asthma have higher rates of anxiety, psychological stress, and depression. This is associated with poorer asthma control. Cognitive behavioral therapy may improve quality of life, asthma control, and anxiety levels in people with asthma.Improving peoples knowledge about asthma and using a written action plan has been identified as an important component of managing asthma. Providing educational sessions that include information specific to a persons culture is likely effective. More research is necessary to determine if increasing preparedness and knowledge of asthma among school staff and families using home-based and school interventions results in long term improvements in safety for children with asthma. School-based asthma self-management interventions, which attempt to improve knowledge of asthma, its triggers and the importance of regular practitioner review, may reduce hospital admissions and emergency department visits. These interventions may also reduce the number of days children experience asthma symptoms and may lead to small improvements in asthma-related quality of life. More research is necessary to determine if shared-decision-making is helpful for managing adults with asthma or if a personalized asthma action plan is effective and necessary. Some people with asthma use pulse oximeters to monitor their own blood oxygen levels during an asthma attack. However, there is no evidence regarding the use in these instances.
Lifestyle modification
Avoidance of triggers is a key component of improving control and preventing attacks. The most common triggers include allergens, smoke (from tobacco or other sources), air pollution, non selective beta-blockers, and sulfite-containing foods. Cigarette smoking and second-hand smoke (passive smoke) may reduce the effectiveness of medications such as corticosteroids. Laws that limit smoking decrease the number of people hospitalized for asthma. Dust mite control measures, including air filtration, chemicals to kill mites, vacuuming, mattress covers and others methods had no effect on asthma symptoms. There is insufficient evidence to suggest that dehumidifiers are helpful for controlling asthma.Overall, exercise is beneficial in people with stable asthma. Yoga could provide small improvements in quality of life and symptoms in people with asthma. More research is necessary to determine how effective weight loss is on improving quality of life, the usage of health care services, and adverse effects for people of all ages with asthma.
Medications
Medications used to treat asthma are divided into two general classes: quick-relief medications used to treat acute symptoms; and long-term control medications used to prevent further exacerbation. Antibiotics are generally not needed for sudden worsening of symptoms or for treating asthma at any time.
Medications of asthma exacerbations
Short-acting beta2-adrenoceptor agonists (SABA), such as salbutamol (albuterol USAN) are the first line treatment for asthma symptoms. They are recommended before exercise in those with exercise induced symptoms.
Anticholinergic medications, such as ipratropium, provide additional benefit when used in combination with SABA in those with moderate or severe symptoms and may prevent hospitalizations. Anticholinergic bronchodilators can also be used if a person cannot tolerate a SABA. If a child requires admission to hospital additional ipratropium does not appear to help over a SABA. For children over 2 years old with acute asthma symptoms, inhaled anticholinergic medications taken alone is safe but is not as effective as inhaled SABA or SABA combined with inhaled anticholinergic medication. Adults who receive combined inhaled medications that |
Asthma | includes short-acting anticholinergics and SABA may be at risk for increased adverse effects such as experiencing a tremor, agitation, and heart beat palpitations compared to people who are treated with SABA by itself.
Older, less selective adrenergic agonists, such as inhaled epinephrine, have similar efficacy to SABAs. They are however not recommended due to concerns regarding excessive cardiac stimulation.
Corticosteroids can also help with the acute phase of an exacerbation because of their antiinflamatory properties. The benefit of systemic and oral corticosteroids is well established. Inhaled or nebulized corticosteroids can also be used. For adults and children who are in the hospital due to acute asthma, systemic (IV) corticosteroids improve symptoms. A short course of corticosteroids after an acute asthma exacerbation may help prevent relapses and reduce hospitalizations.
Other remedies, less established, are intravenous or nebulized magnesium sulfate and helium mixed with oxygen. Aminophylline could be used with caution as well.
Mechanical ventilation is the last resort in case of severe hypoxemia.
Intravenous administration of the drug aminophylline does not provide an improvement in bronchodilation when compared to standard inhaled beta-2 agonist treatment. Aminophylline treatment is associated with more adverse effects compared to inhaled beta-2 agonist treatment.
Long–term control
Corticosteroids are generally considered the most effective treatment available for long-term control. Inhaled forms are usually used except in the case of severe persistent disease, in which oral corticosteroids may be needed. Dosage depends on the severity of symptoms. High dosage and long term use might lead to the appearance of common adverse effects which are growth delay, adrenal suppression, and osteoporosis. Continuous (daily) use of an inhaled corticosteroid, rather than its intermitted use, seems to provide better results in controlling asthma exacerbations. Commonly used corticosteroids are budesonide, fluticasone, mometasone and ciclesonide.
Long-acting beta-adrenoceptor agonists (LABA) such as salmeterol and formoterol can improve asthma control, at least in adults, when given in combination with inhaled corticosteroids. In children this benefit is uncertain. When used without steroids they increase the risk of severe side-effects, and with corticosteroids they may slightly increase the risk. Evidence suggests that for children who have persistent asthma, a treatment regime that includes LABA added to inhaled corticosteroids may improve lung function but does not reduce the amount of serious exacerbations. Children who require LABA as part of their asthma treatment may need to go to the hospital more frequently.
Leukotriene receptor antagonists (anti-leukotriene agents such as montelukast and zafirlukast) may be used in addition to inhaled corticosteroids, typically also in conjunction with a LABA. For adults or adolescents who have persistent asthma that is not controlled very well, the addition of anti-leukotriene agents along with daily inhaled corticosteriods improves lung function and reduces the risk of moderate and severe asthma exacerbations. Anti-leukotriene agents may be effective alone for adolescents and adults, however there is no clear research suggesting which people with asthma would benefit from anti-leukotriene receptor alone. In those under five years of age, anti-leukotriene agents were the preferred add-on therapy after inhaled corticosteroids. A 2013 Cochrane systematic review concluded that anti-leukotriene agents appear to be of little benefit when added to inhaled steroids for treating children. A similar class of drugs, 5-LOX inhibitors, may be used as an alternative in the chronic treatment of mild to moderate asthma among older children and adults. As of 2013 there is one medication in this family known as zileuton.
Mast cell stabilizers (such as cromolyn sodium) are safe alternatives to corticosteroids but not preferred because they have to be administered frequently.
Oral Theophyllines are sometimes used for controlling chronic asthma, but their used is minimized because of their side effects.
Omalizumab, a monoclonal Antibody Against IgE, is a novel way to lessen exacerbations by lessening the levels of circulating IgE that play a significant role at allergic asthma.
Anticholinergic medications such as ipratropium bromide have not been shown to be beneficial for treating chronic asthma in children over 2 years old, but is not suggested for routine treatment of chronic asthma in adults.
There is no strong evidence to recommend chloroquine medication as a replacement for taking corticosteroids by mouth (for those who are not able to tolerate inhaled steroids). Methotrexate is not suggested as a replacement for taking corticosteriods by mouth ("steroid sparing") due to the adverse effects associated with taking methotrexate and the minimal relief provided for asthma symptoms.
Macrolide antibiotics, particularly the azalide macrolide azithromycin, are a recently added GINA-recommended treatment option for both eosinophilic and non-eosinophilic severe, refractory asthma based on azithromycins efficacy in reducing moderate and severe exacerbations combined. Azithromycins mechanism of action is not established, and could involve pathogen- and/or host-directed anti-inflammatory activities. Limited clinical observations suggest that some patients with new-onset asthma and with "difficult-to-treat" asthma (including those with the asthma-COPD overlap syndrome - ACOS) may respond dramatically to azithromycin. However, these groups of asthma patients have not been studied in randomized treatment trials and patient selection needs to be carefully individualized.For children with asthma which is well-controlled on combination therapy of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA), the benefits and harms of stopping LABA and stepping down to ICS-only therapy are uncertain. In adults who have stable asthma while they are taking a combination of LABA and inhaled corticosteroids (ICS), stopping LABA may increase the risk of asthma exacerbations that require treatment with corticosteroids by mouth. Stopping LABA probably makes little or no important difference to asthma control or asthma-related quality of life. Whether or not stopping LABA increases the risk of serious adverse events or exacerbations requiring an emergency department visit or hospitalisation is uncertain.
Delivery methods
Medications are typically provided as metered-dose inhalers (MDIs) in combination with an asthma spacer or as a dry powder inhaler. The spacer is a plastic cylinder that mixes the medication with air, making it easier to receive a full dose of the drug. A nebulizer may also be used. Nebulizers and spacers are equally effective in those with mild to moderate symptoms. However, insufficient evidence is available to determine whether a difference exists in those with severe disease. For delivering short-acting beta-agonists in acute asthma in children, spacers may have advantages compared to nebulisers, but children with life-threatening asthma have not been studied. There is no strong evidence for the use of intravenous LABA for adults or children who have acute asthma. There is insufficient evidence to directly compare the effectiveness of a metered-dose inhaler attached to a homemade spacer compared to commercially available spacer for treating children with asthma.
Adverse effects
Long-term use of inhaled corticosteroids at conventional doses carries a minor risk of adverse effects. Risks include thrush, the development of cataracts, and a slightly slowed rate of growth. Rinsing the mouth after the use of inhaled steroids can decrease the risk of thrush. Higher doses of inhaled steroids may result in lower bone mineral density.
Others
Inflammation in the lungs can be estimated by the level of exhaled nitric oxide. The use of exhaled nitric oxide levels (FeNO) to guide asthma medication dosing may have small benefits for preventing asthma attacks but the potential benefits are not strong enough for this approach to be universally recommended as a method to guide asthma therapy in adults or children.When asthma is unresponsive to usual medications, other options are available for both emergency management and prevention of flareups. Additional options include:
Humidified Oxygen to alleviate hypoxia if saturations fall below 92%.
Corticosteroid by mouth are recommended with five days of prednisone being the same 2 days of dexamethasone. One review recommended a seven-day course of steroids.
Magnesium sulfate intravenous treatment increases bronchodilation when used in addition to other treatment in moderate severe acute asthma attacks. In adults intravenous treatment results in a reduction of hospital admissions. Low levels of evidence suggest that inhaled (nebulised) magnesium sulfate may have a small benefit for treating acute asthma in adults. Overall, high quality evidence do not indicate a large benefit for combining magnesium sulfate with standard inhaled treatments for adults with asthma.
Heliox, a mixture of helium and oxygen, may also be considered in severe unresponsive cases.
Intravenous salbutamol is not supported by available evidence and is thus used only in extreme cases.
Methylxanthines (such as theophylline) were once widely used, but do not add significantly to the effects of inhaled beta-agonists. Their use in acute exacerbations is controversial.
The dissociative anesthetic ketamine is theoretically useful if intubation and mechanical ventilation is needed in people who are approaching respiratory arrest; however, there is no evidence from clinical trials to support this.
For those with severe persistent asthma not controlled by inhaled corticosteroids and LABAs, bronchial thermoplasty may be an option. It involves the delivery of controlled thermal energy to the airway wall during a series of bronchoscopies. While it may increase exacerbation frequency in the first few months it appears to decrease the subsequent rate. Effects beyond one year are unknown.
Monoclonal antibody injections such as mepolizumab, dupilumab, or omalizumab may be useful in those with poorly controlled atopic asthma. However, as of 2019 these medications are expensive and their use is therefore reserved for those with severe symptoms to achieve cost-effectiveness. Monoclonal antibodies targeting interleukin-5 (IL-5) or its receptor (IL-5R), including mepolizumab, reslizumab or benralizumab, in addition to standard care in severe asthma is effective in reducing the rate of asthma exacerbations. There is limited evidence for improved health-related quality of life and lung function.
Evidence suggests that sublingual immunotherapy in those with both allergic rhinitis and asthma improve outcomes.
It is unclear if non-invasive positive pressure ventilation in children is of use as it has not been sufficiently studied.
Alternative medicine
Many people with asthma, like those with other chronic disorders, use alternative treatments; surveys show that roughly 50% use some form of unconventional therapy. There is little data to support the effectiveness of most of these therapies.
Evidence is insufficient to support the usage of vitamin C or vitamin E for controlling asthma. There is tentative support for use of vitamin C in exercise induced bronchospasm. Fish oil dietary supplements (marine n-3 fatty acids) and reducing dietary sodium do not appear to help improve asthma control. In people with mild to moderate asthma, treatment with vitamin D supplementation may reduce the risk of asthma exacerbations, however, it is not clear if this is only helpful for people who have low vitamin D levels to begin with (low baseline vitamin D). There is no strong evidence to suggest that vitamin D supplements improve day-to-day asthma symptoms or a persons lung function. There is no strong evidence to suggest that adults with asthma should avoid foods that contain monosodium glutamate (MSG). There have not been enough high-quality studies performed to determine if children with asthma should avoid eating food that contains MSG.Acupuncture is not recommended for the treatment as there is insufficient evidence to support its use. Air ionisers show no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators. Manual therapies, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic maneuvers, have insufficient evidence to support their use in treating asthma. The Buteyko breathing technique for controlling hyperventilation may result in a reduction in medication use; however, the technique does not have any effect on lung function. Thus an expert panel felt that evidence was insufficient to support its use. There is no clear evidence that breathing exercises are effective for treating children with asthma.
Prognosis
The prognosis for asthma is generally good, especially for children with mild disease. Mortality has decreased over the last few decades due to better recognition and improvement in care. In 2010 the death rate was 170 per million for males and 90 per million for females. Rates vary between countries by 100 fold.Globally it causes moderate or severe disability in 19.4 million people as of 2004 (16 million of which are in low and middle income countries). Of asthma diagnosed during childhood, half of cases will no longer carry the diagnosis after a decade. Airway remodeling is observed, but it is unknown whether these represent harmful or beneficial changes. Early treatment with corticosteroids seems to prevent or ameliorates a decline in lung function. Asthma in children also has negative effects on quality of life of their parents.
Epidemiology
In 2019, approximately 262 million people worldwide were affected by asthma and approximately 461,000 people died from the disease. Rates vary between countries with prevalences between 1 and 18%. It is more common in developed than developing countries. One thus sees lower rates in Asia, Eastern Europe and Africa. Within developed countries it is more common in those who are economically disadvantaged while in contrast in developing countries it is more common in the affluent. The reason for these differences is not well known. Low and middle income countries make up more than 80% of the mortality.While asthma is twice as common in boys as girls, severe asthma occurs at equal rates. In contrast adult women have a higher rate of asthma than men and it is more common in the young than the old. In 2010, children with asthma experienced over 900,000 emergency department visits, making it the most common reason for admission to the hospital following an emergency department visit in the US in 2011.Global rates of asthma have increased significantly between the 1960s and 2008 with it being recognized as a major public health problem since the 1970s. Rates of asthma have plateaued in the developed world since the mid-1990s with recent increases primarily in the developing world. Asthma affects approximately 7% of the population of the United States and 5% of people in the United Kingdom. Canada, Australia and New Zealand have rates of about 14–15%.The average death rate from 2011 to 2015 from asthma in the UK was about 50% higher than the average for the European Union and had increased by about 5% in that time. Children are more likely see a physician due to asthma symptoms after school starts in September.Population-based epidemiological studies describe temporal associations between acute respiratory illnesses, asthma, and development of severe asthma with irreversible airflow limitation (known as the asthma-chronic obstructive pulmonary disease "overlap" syndrome, or ACOS). Additional prospective population-based data indicate that ACOS seems to represent a form of severe asthma, characterised by more frequent hospitalisations, and to be the result of early-onset asthma that has progressed to fixed airflow obstruction.
Economics
From 2000 to 2010, the average cost per asthma-related hospital stay in the United States for children remained relatively stable at about $3,600, whereas the average cost per asthma-related hospital stay for adults increased from $5,200 to $6,600. In 2010, Medicaid was the most frequent primary payer among children and adults aged 18–44 years in the United States; private insurance was the second most frequent payer. Among both children and adults in the lowest income communities in the United States there is a higher rate of hospital stays for asthma in 2010 than those in the highest income communities.
History
Asthma was recognized in ancient Egypt and was treated by drinking an incense mixture known as kyphi. It was officially named as a specific respiratory problem by Hippocrates circa 450 BC, with the Greek word for "panting" forming the basis of our modern name. In 200 BC it was believed to be at least partly related to the emotions. In the 12th century the Jewish physician-philosopher Maimonides wrote a treatise on asthma in Arabic, based partly on Arabic sources, in which he discussed the symptoms, proposed various dietary and other means of treatment, and emphasized the importance of climate and clean air.In 1873, one of the first papers in modern medicine on the subject tried to explain the pathophysiology of the disease while one in 1872, concluded that asthma can be cured by rubbing the chest with chloroform liniment. Medical treatment in 1880 included the use of intravenous doses of a drug called pilocarpine. In 1886, F. H. Bosworth theorized a connection between asthma and hay fever. Epinephrine was first referred to in the treatment of asthma in 1905. Oral corticosteroids began to be used for this condition in the 1950s while inhaled corticosteroids and selective short acting beta agonist came into wide use in the 1960s.A well-documented case in the 19th century was that of young Theodore Roosevelt (1858–1919). At that time there was no effective treatment. Roosevelts youth was in large part shaped by his poor health partly related to his asthma. He experienced recurring nighttime asthma attacks that felt as if he was being smothered to death, terrifying the boy and his parents.During the 1930s to 1950s, asthma was known as one of the "holy seven" psychosomatic illnesses. Its cause was considered to be psychological, with treatment often based on psychoanalysis and other talking cures. As these psychoanalysts interpreted the asthmatic wheeze as the suppressed cry of the child for its mother, they considered the treatment of depression to be especially important for individuals with asthma.In January 2021, an appeal court in France overturned a deportation order against a 40-year-old Bangladeshi man, who was a patient of asthma. His lawyers had argued that the dangerous levels of pollution in Bangladesh could possibly lead to worsening of his health condition, or even premature death.
Notes
References
External links
Asthma at Curlie |
Lutembachers syndrome | Lutembachers syndrome is a very rare form of congenital heart disease that affects one of the chambers of the heart (commonly the atria) as well as a valve (commonly the mitral valve). It is commonly known as both congenital atrial septal defect (ASD) and acquired mitral stenosis (MS). Congenital (at birth) atrial septal defect refers to a hole being in the septum or wall that separates the two atria; this condition is usually seen in fetuses and infants. Mitral stenosis refers to mitral valve leaflets (or valve flaps) sticking to each other making the opening for blood to pass from the atrium to the ventricles very small. With the valve being so small, blood has difficulty passing from the left atrium into the left ventricle. Septal defects that may occur with Lutembachers syndrome include: Ostium primum atrial septal defect or ostium secundum which is more prevalent.Lutembachers syndrome affects females more often than males. It can affect children or adults; the person can either be born with the disorder or develop it later in life. The syndrome was first described by René Lutembacher (1884–1968) of Paris in 1916.To correct Lutembachers syndrome, surgery is often done. There are several types of surgeries depending on the cause of Lutembachers syndrome (ASD Primum or ASD Ostium Secundum with Mitral Stenosis):
Suturing (stitching) or placing a patch of tissue (similar to skin grafting) over the hole to completely close the opening
Reconstructing of the mitral and tricuspid valve while patching any holes in the heart
Device closure of ASD (e.g. Amplatzer umbrella or CardioSEAL to seal the hole)
Percutaneous transcatheter therapy
Transcatheter therapy of balloon valvuloplasty to correct MS
Symptoms and signs
As Lutembachers syndrome is known for ASD and MS, most of the symptoms experienced will be associated with ASD and MS. For most people, they will remain asymptomatic (experience no symptoms) but when symptoms are shown, they are due mainly to ASD and will vary depending on the size of the hole in the atria. If the patient has a large ASD, pulmonary congestion (blood or fluid buildup in the lungs) will happen later but if the patient has a small ASD, symptoms will appear early in the disorder. In general, unless the ASD and mitral stenosis causing Lutembachers syndrome is severe, symptoms may not appear until the second and third decade of the patients life. As many of the patients are asymptomatic and symptoms may not appear until later in life, the duration or frequency of the symptoms varies. For symptoms such as palpitations, ventricular overload, heart failure, and pulmonary congestion, these symptoms may be sudden and not that frequent as they are very severe symptoms. For symptoms such as loud mitral S1, pulmonary S2, mid-diastolic murmur, fatigue, reduced exercise tolerance, weight gain, ankle edema, and right upper quadrant pain, and ascities, these symptoms may be less frequent and severe; their duration may be only a few seconds, minutes, or even months.
Major symptoms
Major symptoms of Lutembachers syndrome as a result of ASD and MS can range from heart failure to pulmonary congestion.
Right ventricular overload and Right-sided heart failure: Both are caused by a large ASD and MS (moderate to severe).
Palpitations: This is caused by blood flowing from left atrium to the right atrium causing a higher left atrial pressure and leading to mitral stenosis. Both atria will be dilated (stretched or open) leading to future atrial arrhythmias or atrial fibrillation (Riaz).
Pulmonary congestion: When blood or fluid pools within the lungs; this is usually a symptom of mitral stenosis and a small ASD.
Loud mitral S1 and wide fixed split of pulmonary S2: The loud sound of the mitral S1 and the wide fixed split of pulmonary S2 is a symptoms of mitral stenosis. The sounds often are caused by a reduced pressure gradient in the mitral area that was caused from decompression of the left atrium from the ASD and a displacement (moving from normal position) of the left ventricular lower portion of the heart to the a large right ventricle. The second heart sound (S2) split is caused by the increase right heart blood flow through the ASD causing a late closing of the pulmonary component of the S2 as well as decreased left ventricular and aortic blood flow.
III/IV mid diastolic murmur, early systolic murmur: This heart murmur is caused by an increase blood flow through the tricuspid valve due to ASD; it is heard best in the left lower sternal area or the bottom of the heart (apex).
Minor symptoms
Fatigue: symptoms is caused by decreased systemic (oxygenated blood to the rest of the body) flow. When the patient has MS and the blood flows from the left atrium to the right atrium causes the forward blood flow into the left ventricle to reduce leading to a reduction of systemic blood flow; this causes tiredness.
Reduced exercise tolerance: symptoms also caused by decreased systemic (oxygenated blood to the rest of the body) flow. Just as with fatigue, when the patient has MS and the blood flows from the left atrium to the right atrium, the forward blood flow into the left ventricle is reduced leading to a reduction of systemic blood flow; this causes tiredness and hence a reduced exercise tolerance.
Weight gain: this is commonly found in patients with large ASD and can be a symptom of developing right-sided heart failure. As there is a chronically increased left-to-right blood flow through the atria, this will lead in the future to right-sided heart failure.
Ankle edema: This is also caused by a large ASD and has the same symptoms and causes as seen in weight gain and right upper quadrant pain. As blood flow is not happening correctly and the heart is pumping under strain, pooling of blood and fluid will happen in the ankles.
Right upper quadrant pain: Also caused by large ASD; has same symptoms and underlying causes as weight gain and ankle edema.
Ascites: Ascite is known as abnormal buildup of fluid in spaces between abdomen lining and abdominal organs. Same symptoms and causes as weight, gain, ankle edema, and right upper quadrant pain.
Less common symptoms
Paroxysmal nocturnal dyspnea, orthopnea, and hemoptysis (sign of pulmonary venous congestion): this symptoms are less frequent in Lutembachers syndrome and are more associated with MS and small ASD or patients who develop reverse Lutembachers syndrome. This symptom is caused by mitral stenosis.
Related disorders
Eisenmenger syndrome
Ventricular Septal Defect
Mitral regurgitation
Ebstein disease
Causes
Lutembacher is caused indirectly by heart damage or disorders. Lutembachers syndrome is caused by either birth defects where the heart fails to close all holes in the walls between the atria or from an episode of rheumatic fever where damage is done to the heart valves such as the mitral valve and resultant in an opening of heart wall between atria. With Lutembachers syndrome, a fetus or infant is usually seen to have a hole in their heart wall (interatrial) separating their right and left atria. Normally during fetal development, blood bypasses the lungs and is oxygenated from the placenta. Blood passes from the umbilical cord and flows into the left atrium through an opening called the foramen ovale; the foramen ovale is a hole between the two atria. Once a baby is born and the lungs begin to fill with air and the blood flow of the heart changes, a tissue flap (somewhat like a trap door) called the septum primum closes the foramen ovale or hole between the two atria and becomes part of the atrial wall. The failure of the hole between the two atria to close after birth leads to a disorder called ASD primum. The most common problems with an opening found in the heart with Lutembachers syndrome is Ostium Secundum. Ostium Secundum is a hole that is found within the flap of tissue (septum primum) that will eventually close the hole between the two atria after birth. With either type of ASD, ASD will usually cause the blood flow from the right atrium to skip going to the right ventricle and instead flow to the left atrium. If mitral stenosis (the hardening of flap of tissue known as a valve which opens and closes between the left atrium and ventricle to control blood flow) is also present, blood will flow into the right atrium through the hole between the atria wall instead of flowing into the left ventricle and systemic circulation. Eventually this leads to other problems such as the right ventricle failing and a reduced blood flow to the left ventricle.In addition to the ASD, MS can either be acquired (present either from an episode of rheumatic fever or the mother has or had rheumatic fever during the pregnancy) or congenital (the child being born with the disorder). With the combination of both ASD and MS, the heart can be under severe strain as it tries to move blood throughout the heart and lungs.
Mechanism
There is no exact mechanism for Lutembachers syndrome but instead a combination of disorders as the result of Atrial septal defect (ASD) and/or Mitral valve stenosis.It is thought ASD is caused by the failure to close the hole (foramen ovale) between the right and left atrium normally found within the heart during fetal development; the creation of a hole between the atrium may also be acquired. There are two types of ASD: Ostium secundum and ASD Primum.
Atrial Septal Defect Primum
The failure of the hole between the right and left atrium to close shortly after birth is the cause behind ASD primum. During fetal development blood will pass from the umbilical cord and flow into the left atrium through a hole between the two atria. Once a baby is born and the lungs begin to fill with air, the blood flow of the heart changes; a tissue flap (septum primum) normally closes the hole (foramen ovale) between the two atria and becomes part of the atrial wall. During ASD primum, after birth the hole is not completely closed allowing blood to flow into the right atria from the left atria. Then blood pass to right ventricle this will increase pulmonary artery pressure Due to the incorrect blood flow, symptoms such as fatigue (from decreased systemic blood flow), palpitations (from blood flowing from left atria to right atria), weight gain, edema, right upper chest pain (all caused from the left to right atria blood flow), and paroxysmal nocturnal dyspnea (shortness of breath during sleep), orthopnea (difficulty in breathing while lying down), and hemoptysis or coughing up blood (all caused by small ASD that cause blood flow from left to right atria).
Atrial Septal Defect Ostium secundum
During the more common form of Lutembachers syndrome, ASD Ostium secundum, a hole will form in the flap of tissue (septum primum) that should close between the two atria after birth. With the onset of a hole created in the tissue flap that closes the larger hole between the left and right atrium, blood can again flow from the left atrium to the right. Ostium secundum causes many of the same symptoms seen in ASD primum. With either type of ASD, blood will flow from the right atrium skipping the right ventricle (or very little flowing into the ventricle) and instead flow to the left atrium introducing the possibility of blood lacking oxygen to go the rest of the body. Sometimes, the direction of blood flow is largely determined by the left and right ventricle ability to squeeze (contract) and relax (compliance).Apart from congential or birth defects causing ASD, ASD is thought to be also acquired. During percutaneous interventional procedures such as mitral valvuloplasty (a surgical process done to repair a mitral valve), 11-12% of individuals will develop ASD allowing blood to flow from the left atrium to the right.
Mitral Valve Stenosis
The second cause of Lutembachers syndrome is mitral stenosis (MS). MS can be caused by birth defects, rheumatic fever, or just stress to the heart due to ASD; because MS can be caused by several things, there is no exact mechanism but many mechanisms or causes. If mitral valve stenosis is a result of birth defects during development stemming from rheumatic fever, several things may occur in the heart. Rheumatic fever causes the immune system to attack its own protein tissues leading to lesions forming on the mitral valve flaps. As the flaps heals over time, the flaps lose their filmy and floppiness resulting in solid, stiff flaps. The loss of proper flappy mitral valves makes it harder for the valves to open and allow blood to flow through. As a result of blood flow being stopped or slowed by the faulty valve, pressure begins to build in the heart. It was once thought an ASD is not already present, could form because of MS, but it is now thought the ASD is either a birth defect or acquired from surgical procedures.Overall, Lutembachers syndrome has no certain mechanism but a combination as the result of ASD and MS.
Diagnosis
Lutembachers syndrome is diagnosis primarily by physical examinations for heart sounds, electrocardiograms, chest radiogram, transthoracic or transesophageal echocardiography, color flow mapping, and Doppler imaging. Use of the various test can help to differentiate other possible conditions such as mitral regurgitation, Ebstein disease, ventricular septal defect (VSD).
Physical examinations
A physical examination will be done to check for abnormal heart sounds, condition of heart, blood pressure, lungs, palpitations, edema, weight gain, ascites, or any other abnormal symptoms. Blood may also be drawn to help determine the cause of fatigue, determination of ascites, other health problems that maybe closely related to cause the symptoms such as kidney, liver, immune (signs of rheumatic fever), abnormal glucose levels.
Electrocardiograms
Electrocardiogram (ECG) is used for determination of the location, size, direction of blood flow through the atrial hole, hemodynamic of the right ventricle (blood circulation), tricuspid valve, and functioning of left ventricle. The ECG can also be used to determine the rhythm of the heart to determine if there is an indication of sinus rhythm or atrial fibrillation. In the ECG, the p wave morphology will be study for any abnormalities. If during the ECG, the P-wave (atrial depolarization) is tall, broad, or split waves in lead II and accompanied with a deep negative force in V1, this would be considered to be abnormal; only one wave should be associated with the P-wave. Additionally, in an ECG the QRS morphology and axis will be examined for any abnormalities. If the ECG shows a right axis deviation which is abnormal or a right bundle-branch block (this would mean there was no signal going through the atrium to instruct the ventricle to contract or squeeze blood out of the ventricle).
Chest radiogram
A chest radiogram can be given to a patient to determine:
Pulmonary plethora: the test will help to determine if there is a left-to-right shunt meaning the blood is flowing from the left atrium to the right through a hole between the two atria.
Mild left atrial enlargement: the test will help to determine if the left atrium is enlarged due to alternate blood flows
Right ventricular enlargement: the test will help to determine if the ventricle is enlarged due to a surge of blood above normal or if the ventricle is having to work harder than normal to pump blood out of the ventricle.
Pulmonary artery enlargement: the test will help to determine if there is a large volume of blood in the pulmonary veins and arteries than normal
Mitral Valve calcification late in life: the test will help to determine if the mitral valve or flaps are becoming hardened and losing their floppiness.
pulmonary vascular congestion, marked left atrial enlargement: the test will help to determine if there is a sign of MS and small ASD and how severe both are.
Transthoracic or Transesophageal echocardiography
Transthoracic or Transesophageal echocardiography two dimensional images that can be made of the heart. They can be used to determine the stages of Lutembachers syndrome. They are used to determine:
Large left atrium: the test can help to determine if the left atrium is enlarged to a large blood flow then unusually
Large right atrium and ventricle: the test will help to determine if the right atrium and ventricle are enlarged due to a greater blood flow
ASD: the test will help to determine if there is a hole between the two atria and if blood is flowing through both
Stenotic mital valve: the test will help to determine if the blood flow through the mitral valve is normal or if the mitral valve is stiff, has a reduced opening, and constricting blood flow through it.
Color flow mapping and Doppler imaging
A color flow and doppler imaging is used to help confirm the presence as well as evaluate the severity of ASD and MS.
Chest X-ray
A chest x-ray will be given to determine the size of the heart and the blood vessels supplying blood to the lungs.
Cardiac catheterization
Cardiac catheterization is done to confirm a diagnosis; it is not routinely done prior. It can also be used to evaluate the severity of ASD and measure the mitral valve area. To determine the presence ASD, a catheter is passed through the suspected hole between the atrium into the left atrium.
Treatments
To treat Lutembachers syndrome, the underlying causes of the disorder must first be treated: mitral stenosis and atrial septal defect. Lutembachers syndrome is usually treated surgically with treatments such as:
percutaneous transcatheter therapy for MS
Device closure of ASDPercutaneous transcatheter treatment for the MS can include transcatheter therapies of such as balloon valvuloplasty.
Percutaneous transcatheter therapy
Percutaneous transcatheter therapy is used to repair the mitral valve and sometimes the septum. In percutaneous balloon mitral valvuloplasty, using a catheter, a ballon such as the Inoue ballon is placed into blood vessels in the groin area and the balloon guided to the heart. If a hole is not already present, a small hole may need to be inserted the atria and inserted into the mitral valve through the left atrium; the balloon is then inflated. The balloon inside the mitral valve will be inflated and deflated several times to wide the valve opening until the opening is satisfactory; the balloon will then be deflated and removed.The advantage to using percutaneous procedures instead of open-heart surgery is not needing general anesthesia, blood transfusions, and the recovery time is quicker. The drawback to this procedure is the lack of repeating and transseptal procedures if they are needed later. Also if the patient later develops a relapse of MS, surgery will need to be performed where using more evasive techniques. Additionally, if a hole is needed to be inserted into the atria to obtain access to the mitral valve, there is a risk of developing ASD secondarily.
Side effects
Possible side effects from this non-invasive procedure could be:
fever
Chest pain
Shortness of breath
Unusual swelling or weight gain
Swelling, bleeding, change in skin color at site of initial catheterization in groin, or pain in the groin.If any of the above symptoms occur, it is important to contact your doctor to prevent another lapse of mitral stenosis. To ensure good health, routine doctors visits, diet, weight loss, doctor-approved exercise, and use of antibiotics in dental and other procedures are recommended.
Device closure
To treat ASD a device closure can be used. In fact an ASD closure is often recommended for certain cases such as with a patient who has significant left-to-right shunt with a pulmonary and/or systemic flow fraction of Qp/Qs >1.5. It is best to perform this procedure/surgery between the ages of 2–4 years. The closure is done by two methods: interventionally or surgically.
Interventionally
This procedure is done by placing a device such as Amplatzer "umbrella", CardioSEAL similar to percutaneous transcatheter therapy. A catheter is inserted in the vessels and threaded to the heart and inserted into the ASD closing the defect. Other closure device that have been used is the GORE HELEX Septal Occluder. After the device has been inserted and covers the defect, over time tissue will grow over the implant device to make it become part of the heart. Anticoagulant medication will be given to the patient for the first six months following the surgery: aspirin, clopidogrel or warfarin (Coumadin).
Surgically
This procedure is done through open heart surgery (sternotomy or thoracotomy) using an ECC where the heart is stopped to allow a system of special cannulas to be placed. The hole is closed by a direct suture (sewing) if the hole is small enough or if the hole is larger, suturing (sewing) a small patch of pericardium (heart tissue or skin) or fabric to close the hole.To increase quality life following ASD procedures/surgeries, patients should have a physical exam and ECG every 3, 6, and 12 months with their cardiologist. For many patients with secundum ASD closure repair, they can return to their normal activities unless their procedure was heart catheterization which in this case they should rest for a few days. All patients should remain on blood thinner medication for at least 6 months and up to a year unless the patient had a stroke in which they would always be on blood thinners. Patients with coronary artery disease or pulmonary hypertension will take additional medicines described by their physician. For patients who had heart surgery to repair the defect or received a transcatheter closure device, they will need to take some form of antibiotics to prevent infections such as endocarditis for at least 6 months following the procedure.Success with ASD closure is very high, 96% for percutaneous procedures and 100% of ASD surgeries as found by one research group. No patient was found to have died from either interventional or surgical treatments and only 7.2% of patients
who received a device and 24.0% of patients who had surgery had complications. The hospital stay for each group also varied, the surgical group was 3.4 ± 1.2 days and device group 1.0 ± 0.3 days. As seen by this study, prognosis was good and quality of life could be excellent.
Side effects
Side effects with interventional device closure have not been extensively supported as yet.Possible side effects from the ASD device closure procedure could be:
fever
Chest pain
Swelling
Swelling, bleeding, change in skin color at site of initial catheterization in groin, or pain in the groinWith surgically closure, the normal risk of infection, fevers, and blood clots are among the risks. If any signs of infection such as swelling, pain, or fever are present, the patient should seek medical attention. Patients who have ASD repaired later in life are also at a higher risk of developing atrial fibrillation especially if the device is not stable.
Recent research
Through examining the benefits of using percutaneous treatment as an alternative to surgically means to correct MS and ASD, it was found that combined percutaneous treatment (including balloon valvuloplasty for MS and Amplatzer septal occluder for closure of the ASD) has improved the patients planimetric mitral valve area to 2.1 cm (as compared to the previous 1.5 cm), maximum diastolic gradient to 9 mmHg (compared to previous 17 mmHg), and mean diastolic gradient to 4 mmHg (as compared to previous 9 mmHg).In another study, surgeons developed a way to use percanteous therapy in difficult situations. In this study they developed a technique to use the Inoue balloon in valvuloplasty but to insert a wire into the left atrium prior to inserting the balloon. This enabled the surgeons to be more precise in treating the mitral valve and not have the balloon to slip out of place; the wire served as a guide to inserting the balloon.Other Percutaneous procedures beside balloon valvuloplasty for MS have been looked into. Percutaneous Leaflet Plication (Edge-to-Edge Leaflet Repair) is being explored as a way to increase the opening of the mitral valve by clamping down mitral leaflets. The clamps are delivered to the mitral through a catheter as with the balloon, and then clamped onto the mitral valve. Of the patients that received this treatment, 74% patients achieved surgical success, and at 1-year, 68% were saved from dying, 90% from having to have surgery or dying from the lack thereof, a 76.3% prognosis at three years.Given the many possible treatments that are to come, future research is continuing to find better methods of treating Lutembacher patients non-invasively as with percutaneous therapy. Without successfully treating Lutembachers more serious complications can occur such as heart failure or even disorders such as Eisenmenger syndrome.
References
Additional references
Goldman, Lee (2011). Goldmans Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. ISBN 978-1437727883.
External links
00732 at CHORUS |
Leontiasis ossea | Leontiasis ossea, also known as leontiasis, lion face or lion face syndrome, is a rare medical condition, characterized by an overgrowth of the facial and cranial bones. It is not a disease in itself, but a symptom of other diseases, including Pagets disease, fibrous dysplasia, hyperparathyroidism and renal osteodystrophy.The common form is that in which one or other maxilla is affected, its size progressively increasing, and thus encroaching on the cavities of the orbit, the mouth, the nose and its accessory sinuses. Exophthalmos gradually develops, going on later to a complete loss of sight due to compression of the optic nerve by the overgrowth of bone. There may also be interference with the nasal respiration and with the taking of food. In the somewhat less common form of this rare disease the overgrowth of bone affects all the cranial bones as well as those of the face, the senses being lost one by one and death finally resulting from cerebral pressure. There is no treatment other than exposing the overgrown bone, and chipping away pieces, or excising entirely where possible.
Great Sphinx
Surgeon Hutan Ashrafian from Imperial College London has analysed the Great Sphinx to identify that it may have represented an individual suffering from prognathism which may have been a reflection of a disease suffered by the sculptures human inspiration. Furthermore, as the Sphinx represented a lion, the same person may have suffered from leontiasis ossea.
See also
Lionitis
References
This article incorporates text from a publication now in the public domain: Chisholm, Hugh, ed. (1911). "Leontiasis Ossea". Encyclopædia Britannica. Vol. 16 (11th ed.). Cambridge University Press. p. 455.
Lee VS, Webb MS Jr, Martinez S, McKay CP, Leight GS Jr (April 1996). "Uremic leontiasis ossea: "bighead" disease in humans? Radiologic, clinical, and pathologic features". Radiology. 199 (1): 233–240. doi:10.1148/radiology.199.1.8633151. PMID 8633151.{{cite journal}}: CS1 maint: multiple names: authors list (link) |
T-cell prolymphocytic leukemia | T-cell-prolymphocytic leukemia (T-PLL) is a mature T-cell leukemia with aggressive behavior and predilection for blood, bone marrow, lymph nodes, liver, spleen, and skin involvement. T-PLL is a very rare leukemia, primarily affecting adults over the age of 30. It represents 2% of all small lymphocytic leukemias in adults. Other names include T-cell chronic lymphocytic leukemia, "knobby" type of T-cell leukemia, and T-prolymphocytic leukemia/T-cell lymphocytic leukemia.
Signs and symptoms
People affected by T-cell prolymphocytic leukemia typically have systemic disease at presentation, including enlargement of the liver and spleen, widespread enlargement of the lymph nodes, and skin infiltrates.Due to the systemic nature of this disease, leukemic cells can be found in peripheral blood, lymph nodes, bone marrow, spleen, liver, and skin. A high lymphocyte count (> 100 x 109/L) along with low amounts of red blood cells and platelets in the blood are common findings. HTLV-1 serologies are negative, and serum immunoglobins are within normal limits with no paraproteins present.
Causes
It is postulated that the originating cell line for this disease is a mature (post-thymic) T-cell.
Diagnosis
Morphology
In the peripheral blood, T-PLL consists of medium-sized lymphocytes with single nucleoli and basophilic cytoplasm with occasional blebs or projections. The nuclei are usually round to oval in shape, with occasional patients having cells with a more irregular nuclear outline that is similar to the cerebriform nuclear shape seen in Sézary syndrome. A small cell variant comprises 20% of all T-PLL cases, and the Sézary cell-like (cerebriform) variant is seen in 5% of cases.Marrow involvement is typically diffuse with morphology similar to what is observed in peripheral blood. In the spleen, the leukemic cell infiltrate both the red pulp and white pulp, and lymph node involvement is typically diffuse through the paracortex. Skin infiltrates are seen in 20% of patients, and the infiltrates are usually dense and confined to the dermis and around the skin appendages.
Immunophenotype
T-PLL has the immunophenotype of a mature (post-thymic) T-lymphocyte, and the neoplastic cells are typically positive for pan-T antigens CD2, CD3, and CD7 and negative for TdT and CD1a. The immunophenotype CD4+/CD8- is present in 60% of cases, the CD4+/CD8+ immunophenotype is present in 25%, and the CD4-/CD8+ immunophenotype is present in 15% of cases.
Genetic findings
Clonal TCR gene rearrangements for the γ and δ chains are typically found. The most frequent chromosomal abnormality is the inversion of chromosome 14, specifically inv 14(q11;q32). This is found in 80% of cases, while 10% of cases show a reciprocal translocation of chromosome 14 (t(14;14)(q11;q32)). Also, abnormalities of chromosome 8 are seen approximately 75% of patients, including idic (8p11), t(8;8)(p11-12;q12), and trisomy 8.
Treatment
Most patients with T-cell prolymphocytic leukemia require immediate treatment.T-cell prolymphocytic leukemia is difficult to treat, and it does not respond to most available chemotherapeutic drugs. Many different treatments have been attempted, with limited success in certain patients: purine analogues (pentostatin, fludarabine, cladribine), chlorambucil, and various forms of combination chemotherapy regimens, including cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), etoposide, bleomycin (VAPEC-B).
Alemtuzumab (Campath), an anti-CD52 monoclonal antibody that attacks white blood cells, has been used in treatment with greater success than previous options. In one study of previously treated people with T-PLL, people who had a complete response to alemtuzumab survived a median of 16 months after treatment.Some patients who successfully respond to treatment also undergo stem cell transplantation to consolidate the response.
Prognosis
T-PLL is an extremely rare aggressive disease, and patients are not expected to live normal lifespans. Before the recent introduction of better treatments, such as alemtuzumab, the median survival time was 7.5 months after diagnosis. More recently, some patients have survived five years and more, although the median survival is still low.
Epidemiology
About four men are diagnosed with this disease for every three women. Despite its overall rarity, it is also the most common type of mature T cell leukemia.
References
== External links == |
Non-alcoholic fatty liver disease | Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), with the latter also including liver inflammation. Non-alcoholic fatty liver is less dangerous than NASH and usually does not progress to NASH or liver cirrhosis. When NAFL does progress to NASH, it may eventually lead to complications such as cirrhosis, liver cancer, liver failure, or cardiovascular disease.Obesity and type 2 diabetes are strong risk factors for NAFLD. Other risks include being overweight, metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum HDL cholesterol), a diet high in fructose, and older age. NAFLD and alcoholic liver disease are types of fatty liver disease. Obtaining a sample of the liver after excluding other potential causes of fatty liver can confirm the diagnosis.Treatment for NAFLD is weight loss by dietary changes and exercise. There is tentative evidence for pioglitazone and vitamin E; bariatric surgery can improve or resolve severe cases. Those with NASH have a 2.6% increased risk of dying per year.NAFLD is the most common liver disorder worldwide and is present in approximately 25% of the worlds population. It is also very common in developed nations, such as the United States, and affected about 75 to 100 million Americans in 2017. Over 90% of obese, 60% of diabetic, and up to 20% of normal-weight people develop it. NAFLD is the leading cause of chronic liver disease and the second most common reason for liver transplantation in the US and Europe as of 2017. NAFLD affects about 20 to 25% of people in Europe. In the United States, estimates suggest between 30 and 40% of adults have NAFLD, and about 3 to 12% of adults have NASH. The annual economic burden was approximately US$103 billion in the US in 2016.
Definition
An abnormal accumulation of fat in the liver in the absence of secondary causes of fatty liver, such as significant alcohol use, viral hepatitis, or medications that can induce fatty liver characterizes non-alcoholic fatty liver disease (NAFLD). The term NAFLD encompasses a continuum of liver abnormalities, from non-alcoholic fatty liver (NAFL, simple steatosis) to non-alcoholic steatohepatitis (NASH). These diseases begin with fatty accumulation in the liver (hepatic steatosis). A liver can remain fatty without disturbing liver function (NAFL), but by various mechanisms and possible insults to the liver, it may also progress into non-alcoholic steatohepatitis (NASH), a state in which steatosis is combined with inflammation and sometimes fibrosis (steatohepatitis). NASH can then lead to complications such as cirrhosis and hepatocellular carcinoma.A new name, metabolic dysfunction associated fatty liver disease, was proposed after 70% of a panel of experts expressed support for this name.
Signs and symptoms
People with NAFLD often have no noticeable symptoms, and NAFLD is often only detected during routine blood tests or unrelated abdominal imaging or liver biopsy. In some cases, NAFLD can cause symptoms related to liver dysfunction such as fatigue, malaise, and dull right-upper-quadrant abdominal discomfort. Mild yellow discoloration of the skin may occur, although this is rare. NASH can severely impair liver function, leading to cirrhosis, liver failure, and liver cancer.
Comorbidities
NAFLD is strongly associated with or caused by type 2 diabetes, insulin resistance, and metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein). It is also associated with hormonal disorders (panhypopituitarism, hypothyroidism, hypogonadism, polycystic ovary syndrome), persistently elevated transaminases, increasing age and hypoxia caused by obstructive sleep apnea, with some of these conditions predicting disease progression.The majority of normal-weight people affected by NAFLD ("lean NAFLD") have impaired insulin sensitivity, are sedentary, and have increased cardiovascular disease risk and increased liver lipid levels. These are the consequences of a decreased capacity for storing fat and reduced mitochondrial function in adipose tissue and increased hepatic de novo lipogenesis. A recent systematic review has reported an increased risk of severe COVID-19 infection in NAFLD patients; however, no difference in mortality was observed between NAFLD and non-NAFLD patients.
Risk factors
Genetics
Two-thirds of families with a history of diabetes type 2 report more than one family member having NAFLD. There is a higher risk of fibrosis for family members where someone was diagnosed with NASH. Asian populations are more susceptible to metabolic syndrome and NAFLD than their western counterparts. Hispanic persons have a higher prevalence of NAFLD than white individuals, whereas the lowest prevalence is observed in black individuals. NAFLD is twice as prevalent in men compared to women, which might be explained by lower levels of estrogen in men.Genetic variations in two genes are associated with NAFLD: non-synonymous single-nucleotide polymorphisms (SNPs) in PNPLA3 and TM6SF2. Both correlate with NAFLD presence and severity, but their roles for diagnosis remain unclear. Although NAFLD has a genetic component, the American Association for the Study of Liver Diseases (AASLD) does not recommend screening family members as there is not enough confirmation of heritability, although there is some evidence from familial aggregation and twin studies.
Diet
According to the Asia-Pacific Working Group (APWG) on NAFLD, overnutrition is a major factor of NAFLD and NASH, particularly for lean NAFLD. Diet composition and quantity, in particular omega-6 fatty acid and fructose, have important roles in disease progression from NAFL to NASH and fibrosis. Choline deficiency can lead to the development of NAFLD.
Lifestyle
Habitual snoring may be a risk factor for NAFLD, even after accounting for established risk factors in individuals. Severe cases of snoring lead to airway blockage or difficulty breathing when sleeping, and usually signals the presence of obstructive sleep apnea (OSAS), a much more serious breathing condition. Blockage or narrowing of the airways, even temporarily, can cause the body to experience lowered oxygen levels in the blood, and these conditions of hypoxia are recurring in those with obstructive sleep apnea (OSAS). Constant hypoxia may cause a variety of changes within the body, such as tissue inflammation, increased insulin resistance, and liver injury. A prospective cohort study found the association between habitual snoring and NAFLD development to be significant, and the trend was noted to be most prominent in lean individuals.
Pathophysiology
The primary characteristic of NAFLD is the accumulation of lipids in the liver, largely in the form of triglycerides. However, the mechanisms by which triglycerides accumulate and the reasons that accumulation can lead to liver dysfunction are complex and incompletely understood. NAFLD can include steatosis along with varied signs of liver injury: either lobular or portal inflammation (a form of liver injury) or ballooning degeneration. Similarly, NASH can include histological features such as portal inflammation, polymorphonuclear cell infiltrates, Mallory bodies, apoptotic bodies, clear vacuolated nuclei, microvesicular steatosis, megamitochondria, and perisinusoidal fibrosis. NASH increases hepatocyte death via apoptosis or necroptosis is increased in NASH compared with simple steatosis, and inflammation is a hallmark of NASH.One debated mechanism proposes that hepatic steatosis progresses to steatosis with inflammation following some further injury, or second hit. Oxidative stress, hormonal imbalances, and mitochondrial abnormalities are potential causes of this "second hit" phenomenon. A further nutrigenomics model named multiple hit extends the second hit model, suggesting that multiple disease biomarkers and factors such as genes and nutrition influence NAFLD and NASH progression. This model attempts to use these factors to predict the impact of lifestyle changes and genetics for the evolution of the NAFLD pathology. Many researchers describe NAFLD as a multisystem disease, as it impacts and is influenced by organs and regulatory pathways other than the liver.The accumulation of senescent cells in the liver is seen in persons with NAFLD. In mice, liver senescent hepatocytes result in increased liver fat deposition. Treatment of NAFLD mice with senolytic agents has been shown to reduce hepatic steatosis.Based on gene knockout studies in murine models, it has been suggested that, among many other pathogenic factors, TGF beta signals may be crucially involved in promoting the progression of NASH.
Fructose consumption
Non-alcoholic and alcoholic fatty liver disease share similar histological features, which suggests that they might share common pathogenic pathways. Fructose can cause liver inflammation and addiction similarly to ethanol by using similar metabolic pathways, unlike glucose. Therefore, some researchers argue that non-alcoholic and alcoholic fatty liver diseases are more alike than previously thought. Furthermore, high fructose consumption promotes fat accumulation in the liver by stimulating de novo lipogenesis in the liver and reducing the beta-oxidation of fat. Unlike the sugar glucose, the enzyme fructokinase rapidly metabolizes fructose. This leads to a decreased level of intracellular adenosine triphosphate (ATP). The decrease in ATP increases oxidative stress and impairments in proper protein synthesis and mitochondrial function in the liver.
Insulin resistance
Insulin resistance contributes to the accumulation of toxic fat in the liver in several ways. First, it promotes the release of free fatty acids (FFAs) from adipose tissue into the blood. Typically, adipose tissue stores lipids in the form of triglycerides, slowly releasing them into the bloodstream when insulin is low. In insulin-resistant adipose tissue, such as in people with obesity and type 2 diabetes, more triglycerides are broken down into FFAs and released into the bloodstream, promoting uptake by the liver. Second, insulin promotes the production of new FFAs in the liver via de novo lipogenesis; this production of liver fats continues to be stimulated by insulin, even when other tissues are insulin-resistant. These FFAs are combined back into triglycerides in the liver, forming the major constituent of the accumulated fat in the liver. The three sources of free fatty acids that contribute to liver triglyceride accumulation include FFAs circulating in the bloodstream (59%), FFAs derived from carbohydrates such as fructose and glucose (26%), and diet (14%). Despite the accumulation of triglycerides in the liver, they are not directly toxic to liver tissue. Instead, alteration of the profile of the other lipid subtypes present in the liver, such as diacylglycerols, phospholipids, ceramides, and free cholesterol, have a more significant role in the pathogenesis of NAFLD.Once NAFLD progresses in severity to the point of NASH, this promotes further insulin resistance in the adipose tissue and liver, which results in a harmful cycle of insulin resistance, liver fat accumulation, and inflammation. Adipose tissue dysfunction also decreases secretion of the insulin-sensitizing adipokine adiponectin in people with NAFLD. Adiponectin has several properties that protect the liver. These properties include improved liver fat metabolism, decreased de novo lipogenesis, decreased glucose production in the liver, anti-inflammatory properties, and anti-fibrotic properties. Skeletal muscle insulin resistance may also play a role in NAFLD. Insulin-resistant skeletal muscle is not as efficient at taking up glucose from the bloodstream after a meal. This inefficient glucose uptake promotes the redistribution of consumed carbohydrates from glucose destined for use in glycogen stores in the skeletal muscles to being used as a substrate for de novo lipogenesis in the liver.
Dysbiosis
Disruptions in the intestinal microbiota seem to influence NAFLD risk in several ways. People with NASH can have elevated levels of blood ethanol and Pseudomonadota (which produce alcohol), with dysbiosis proposed as a mechanism for this elevation. Alterations in the composition of the intestinal microbiota may influence NAFLD risk in several ways. These changes appear to increase the permeability of intestinal tissue, thereby facilitating increased liver exposure to harmful substances (e.g., translocated bacteria, bacterial toxins, and inflammatory chemical signals). The increased transport of these harmful substances to the liver promotes liver inflammation, enhances nutrient and calorie absorption, and alters choline metabolism. Higher levels of intestinal bacteria that produce butyrate may be protective.Excessive macronutrient intake contributes to gut inflammation and perturbation of homeostasis, and micronutrients may also be involved. In addition to reducing weight and risk factors, lifestyle changes may prompt positive changes in the gut microbiota. In particular, diet diversity may play a role that was overlooked in animal studies, since they often compare a Western high-fat, low-diversity diet against a low-fat but higher-diversity chow. The health benefits after bariatric surgery may also involve changes in the gut microbiota by increasing gut permeability.
Diagnosis
NAFLD is defined by evidence of fatty liver without another factor that could explain the liver fat accumulation, such as excessive alcohol use (>21 standard drinks/week for men and >14 for women in the USA; >30 g daily for men and >20 g for women in UK and EU, >140 g/week for men and >70 g/week for women in Asia-Pacific and most NIH clinical studies), drug-induced steatosis, chronic hepatitis C, heredity or by deficiencies in parenteral nutrition such as choline and endocrine conditions. If any of these factors are observed, an investigation into alternative causes of fatty liver unrelated to NAFLD is recommended. A history of chronic alcohol usage is an important consideration.NAFLD comprises two histological categories: NAFL, and the more aggressive form NASH. The presence of at least 5% fatty liver is common to both NAFL and NASH, but the features of substantial lobular inflammation and hepatocyte injuries such as ballooning or Mallory hyaline only occur in NASH. The majority of NAFL cases show minimal or no inflammation. Pericentral and perisinusoidal fibrosis occur more often in adult-onset NASH, whereas portal fibrosis is more common in children with the disorder. NASH represents a more advanced stage of NAFL and is associated with poor outcomes such as cardiovascular events, cirrhosis, or hepatocellular carcinoma. ICD-11 does not use the term NAFL as it was deemed confusing with the family of disorders NAFLD. The preferred descriptions are instead: NAFLD without NASH or simple steatosis and "NASH". Also, the modifier with or without fibrosis or cirrhosis completes the diagnostic description.
Blood tests
Elevated liver enzymes are common. According to National Institute for Health and Care Excellence (NICE) guidelines, it is disadvised to test enzymes levels to rule out NAFLD, as they are often within the normal range even in advanced disease.Blood tests that are useful to confirm diagnosis or rule out others include erythrocyte sedimentation rate, glucose, albumin, and kidney function. Because the liver is important for making proteins used in blood clotting, coagulation-related studies are often carried out, especially the INR (international normalized ratio). In people with fatty liver with associated inflammatory injury (steatohepatitis) blood tests are usually used to rule out viral hepatitis (hepatitis A, B, C and herpesviruses such as Epstein–Barr virus or cytomegalovirus), rubella, and autoimmune diseases. Low thyroid activity is more prevalent in people with NASH, which would be detected by determining the thyroid-stimulating hormone. Some biomarker-based blood tests have been developed and may be useful for diagnosis.Although blood tests cannot diagnose NAFLD, circulating serum biomarkers of liver fibrosis can give moderate estimates in the diagnosis of liver fibrosis and cirrhosis. The ratio of the transaminase liver enzyme aspartate aminotransferase (AST) to platelets in the blood, known as the AST/platelet ratio index (APRI score), and Fibrotest are recommended as the preferred noninvasive tests for cirrhosis by the Asian-Pacific Association for Study of the Liver (APASL). Several other scores such as FIB-4 score and NAFLD fibrosis score can also reflect the burden of the fibrosis in the liver, and previous studies have confirmed that these score can predict future development of mortality and liver cancer.
Imaging
A liver ultrasound scan or magnetic resonance imaging (MRI) can diagnose steatosis, but not fibrosis and confirmation of early cirrhosis detection by ultrasound by other diagnostic methods is recommended. The European Association for the Study of the Liver (EASL) recommends screening for steatosis whenever NAFLD is suspected as this is a strong predictor of the disease evolution and predicts future type 2 diabetes, cardiovascular events, and hypertension. These non-invasive methods can be used for NAFLD screening but are not accepted as a substitute for liver biopsy in NAFLD nor NASH clinical trials, as only a liver biopsy can define liver pathology.Ultrasound presented average sensitivity and specificity for diagnosing the disease in children, while in the adult population, sensitivity and specificity were significantly higher. Proton density fat fraction magnetic resonance imaging has been increasingly used for the diagnosis of steatosis in pediatric patients. Elastography is an effective tool for staging liver fibrosis and discriminating NASH from NAFLD in children.CT scans and MRIs are more accurate in detecting cirrhosis than conventional ultrasound. Transient elastography is recommended for the initial assessment of liver fibrosis and cirrhosis and helps to predict complications and prognosis, but the interpretation of results is carefully weighed in the presence of limiting factors, such as steatosis, high BMI, lower degrees of hepatic fibrosis and narrow spaces between the ribs (intercostal spaces). However, transient elastography can fail for people with pre-hepatic portal hypertension. Transient elastography is not considered to be a replacement for liver biopsy.Magnetic resonance elastography (MRE) is an emerging method that can accurately assess hepatic fibrosis and is recommended by the APASL. MRE possesses a good sensitivity to quantify hepatic fat and excellent accuracy to detect fibrosis in NAFLD regardless of BMI and inflammation and is suggested as a more reliable alternative to diagnose NAFLD and its progression to NASH compared to ultrasound and blood tests.
Liver biopsy
A liver biopsy (tissue examination) is the only test widely accepted (gold standard) as definitively diagnosing and distinguishing NAFLD (including NAFL and NASH) from other forms of liver disease and can be used to assess the severity of the inflammation and resultant fibrosis. However, since most people affected by NAFLD are likely to be asymptomatic, liver biopsy presents too high a risk for routine diagnosis, so other methods are preferred, such as liver ultrasonography or liver MRI. For young people, guidelines recommend liver ultrasonography, but biopsy remains the best evidence. Liver biopsy is also the gold standard to detect hepatic fibrosis and assess its progression. Routine liver function blood tests are not sensitive enough to detect NAFLD, and biopsy is the only procedure that can reliably differentiate NAFL from NASH.There are several liver biopsy techniques available to obtain liver tissue. Percutaneous liver biopsy remains the most common practice. Biopsies can also be performed via the transvenous route, either during surgery or by laparoscopy, especially for people with contraindications to a percutaneous approach. The liver biopsy can also be image-guided, in real-time or not, which is recommended for some clinical situations such as people with known intra-hepatic lesions, previous intra-abdominal surgery who may have adhesions, a small liver that is difficult to percuss, obese people and people with evident ascites. Vital signs must be monitored frequently afterward (at least every 15 minutes in the hour following the biopsy).According to AASLD guidelines, a liver biopsy may be considered in people with NAFLD who are at increased risk of having steatohepatitis with or without advanced fibrosis, but only when all other competing chronic liver diseases are excluded (such as alcoholic liver disease). The presence of metabolic syndrome, NAFLD Fibrosis Score (FIB-4), or liver stiffness (as measured by Vibration-controlled transient elastography or MRE) can identify the individuals who are at higher risk of steatohepatitis or advanced fibrosis.The AASLD and ICD-11 consider that clinically useful pathology reporting distinguishes "between NAFL (steatosis), NAFL with inflammation and NASH (steatosis with lobular and portal inflammation and hepatocellular ballooning)" with the presence or absence of fibrosis being described and optionally comment on severity. The EASL recommends the Fatty Liver Inhibition of Progression (FLIP) algorithm to grade the ballooning and classify NAFLD-associated liver injury, and the use of the NAFLD Activity Score (NAS) to grade the severity of NASH rather than for its diagnosis. They also consider the steatosis, activity, and fibrosis (SAF) score to be an accurate and reproducible scoring system. The AASLD recommends the use of the NAS scoring system with or without the SAF score if deemed appropriate. The Asia-Pacific Working Group on NAFLD disadvises the use of NAS, as it is considered uninformative for NAFLD and inappropriate to diagnose NASH.For liver fibrosis assessment, percutaneous liver biopsy, with or without image guidance, is contraindicated in uncooperative people. Transjugular liver biopsy is indicated for any person with diffuse liver disease who needs a biopsy but has a contraindication to percutaneous biopsy or needs a hemodynamic evaluation for diagnostic purposes. A transvenous liver biopsy is recommended instead of a percutaneous approach in people with clinically evident ascites, although percutaneous biopsy is an acceptable alternative approach after the removal of ascites.
Management
NAFLD warrants treatment regardless of whether the affected person is overweight or not. NAFLD is a preventable cause of death. Guidelines are available from the American Association for the Study of Liver Diseases (AASLD), American Association of Clinical Endocrinologists (AACE) National Institute for Health and Care Excellence (NICE), the European Association for the Study of the Liver (EASL), and the Asia-Pacific Working Party on NAFLD.
Lifestyle
Weight loss is the most effective treatment for NAFLD. A loss of 4% to 10% body weight is recommended, with 10% to 40% weight loss completely reversing NASH without cirrhosis. A structured weight loss program helps people with NAFLD lose more weight compared with advice alone. This type of program also leads to improvements in NAFLD measured using blood tests, ultrasound, imaging, or liver biopsies. Although fibrosis improves with lifestyle interventions and weight loss, there is limited evidence for cirrhosis improvement.A combination of improved diet and exercise, rather than either alone, appears to best help manage NAFLD and reduce insulin resistance. Motivational support, such as with cognitive behavioral therapy, is helpful, as most people with NAFLD do not perceive their condition as a disease, and thus have a low motivation to change.Higher-intensity behavioral weight loss therapies (diet and exercise combined) may produce more weight loss than lower-intensity ones. Weight loss is associated with improvements in biomarkers, NAFLD grade, and reduced chances of NASH, but their impact on long-term health is yet unknown. A 2019 systematic review thus suggests a change of guidelines to recommend these therapies for NAFLD management.
As of 2021, there is limited evidence to indicate that lifestyle modifications and nutritional supplementation have an effect on mortality, liver cirrhosis, liver decompensation, liver transplantation, and hepatocellular carcinoma in people with nonalcohol-related fatty liver disease.
Diet
Treatment of NAFLD typically involves counseling to improve nutrition and calorie restriction. People with NAFLD can benefit from a moderate to low-carbohydrate diet and a low-fat diet. The Mediterranean diet also showed promising results in a 6-week study with a reduction of NASH induced inflammation and fibrosis, independently from weight loss. Tentative evidence supports dietary interventions in individuals with fatty liver who are not overweight.The EASL recommends energy restriction of 500–1000 kcal per week less than the normal daily diet, a target of 7–10% weight loss for obese/overweight NAFLD, a low- to moderate-fat, and moderate- to high-carbohydrate diet, or a low-carbohydrate ketogenic or high-protein diet such as the Mediterranean diet, and avoiding all beverages and food containing fructose.Alcohol is an aggravating factor, and the AASLD recommends that people with NAFLD or NASH avoid alcohol consumption. The EASL allows alcohol consumption below 30g/day for men and 20g/day for women. The role of coffee consumption for NAFLD treatment is unclear though some studies indicate that regular coffee consumption may have protective effects.Herbal compounds such as silymarin (a milk thistle seed extract), curcumin, a turmeric extract, and green tea appear to improve NAFLD biomarkers and reduce the grade of NAFLD. Studies suggest an association between microscopic organisms that inhabit the gut (microbiota) and NAFLD. Reviews reported the use of probiotics and synbiotics (combinations of probiotics and prebiotics) were associated with improvement in liver-specific markers of hepatic inflammation, measurements of liver stiffness, and steatosis in persons with NAFLD.
Vitamin E
Vitamin E does not improve established liver fibrosis in those with NAFLD but seems to improve certain markers of liver function and reduces inflammation and fattiness of the liver in some people with NAFLD. The Asia-Pacific Work Group advises that Vitamin E may improve liver condition and aminotransferase levels, but only in adults without diabetes or cirrhosis who have NASH. The NICE guidelines recommend Vitamin E as an option for children and adults with NAFLD with advanced liver fibrosis, regardless of whether the person has diabetes mellitus.
Red Yeast Rice
The genum of mold Aspergillus and/or Monascus are used in the fabrication of Red yeast rice to stimulate the production of lovastatin, where lovastatin and other statins inhibit the total cholesterol and LDL cholesterol synthesis by blocking action of the enzyme HMG-CoA reductase.
The safety of red yeast rice has not yet been established as studies found that some commercial supplements contain high levels of toxin citrinin.There are reports in the literature of muscle myopathy and liver damage resulting from red yeast rice usage.
Essential phospholipids
Research shows that essential phospholipids from soy lecithin (Latin: phospholipida sojae praeparata), polyenylphosphatidylcholine being the active component, has a well-established mode of action, therapeutic effectiveness, and lack of toxicity, which ensures clinically relevant efficacy-to-safety ratio. It influences membrane- dependent cellular functions and shows anti-inflammatory, antioxidant, antifibrogenic, anti apoptotic, membrane-protective, and lipid-regulating effects. Due to its positive effects on membrane composition and functions, it accelerates the improvement or normalization of subjective symptoms; pathological, clinical, and biochemical findings; hepatic imaging; and liver histology. It is justified to administer EPL together with other therapeutic measurements in the liver.The usual dosage for adults and children older than 12 years of age (and of at least 43 kg of weight) is 600 mg three times a day.
Coffee
Allegedly seems to inverse and prevent fatty liver disease.
Choline
Low choline intake is significantly associated with the increased prevalence of NAFLD.
Physical activity
Weight loss may improve NAFLD and is recommended particularly for obese or overweight people; similar physical activities and diets are advisable for overweight people with NAFLD as for |
Non-alcoholic fatty liver disease | other obese and overweight people. Although physical activity is less important for weight loss than dietary adaptations (to reduce caloric intake), the NICE advises physical activity to reduce liver fat even if there is no overall bodyweight reduction. Weight loss, through exercise or diet, is the most effective way to reduce liver fat and help NASH and fibrosis remission. Exercise alone can prevent or reduce hepatic steatosis, but it remains unknown whether it can improve all other aspects of the liver; hence a combined approach with diet and exercise is advised. Aerobic exercise may be more effective than resistance training, although there are contradictory results. Vigorous training is preferable to moderate training, as only the high-intensity exercise reduced the chances of NAFLD developing into NASH or advanced fibrosis. The EASL recommends between 150 and 200 min/week in 3 to 5 sessions of moderate-intensity aerobic physical activity or resistance training. Since both effectively reduce liver fat, a pragmatic approach to the choice of physical activity that accounts for the individuals preferences for what they can maintain in the long-term is preferred. Any engagement in physical activity or increase over previous levels is better than remaining sedentary.
Medication
Treatment with medications is primarily aimed at improving liver disease and is generally limited to those with biopsy-proven NASH and fibrosis.No medicines specifically for NAFLD or NASH had received approval, as of 2018, although anti-diabetic medications may help in liver fat loss. While many treatments appear to improve biochemical markers such as alanine transaminase levels, most do not reverse histological abnormalities or improve outcomes.Insulin sensitizers (metformin and thiazolidinediones, such as pioglitazone) and liraglutide are not specifically recommended for NAFLD as they do not directly improve the liver condition. They can be indicated for diabetic individuals, after a careful assessment of risks, to reduce insulin resistance and risks of complications. Indeed, the side effects associated with thiazolidinedione medications, which include osteopenia, increased fracture risk, fluid retention, congestive heart failure, bladder cancer, and long-term weight gain, have limited their adoption. Due to these side effects, the AASLD recommends the use of pioglitazone only for individuals with biopsy-proven NASH, and the Asia-Pacific Work Group recommends them only for individuals with NAFLD with known diabetic issues. However, the AASLD advises against the use of metformin as studies were inconclusive about the improvement of the livers histological condition. Although there was an improvement in insulin resistance and serum aminotransferases, this did not translate into NASH improvements. The NICE provides similar guidelines to the AASLD regarding pioglitazone and recommends it be administered in secondary care to adults with advanced liver fibrosis irrespective of whether or not they have diabetes.Statin medications appear to improve liver histology and markers of liver biochemistry in people with NAFLD. Since people with NAFLD are at a higher risk of cardiovascular disease, statin treatment is indicated. People with NAFLD are not at higher risk for serious liver injury from statins, according to AASLD and EASL. However, even if statins are safe to use in people with NASH cirrhosis, the AASLD suggests avoiding them in people with decompensated cirrhosis. Guidelines recommend statins to treat dyslipidemia for people with NAFLD. According to NICE guidelines, statins can continue unless liver enzyme levels double within three months of starting statins. Treatment with pentoxifylline is not recommended.As of 2018, neither the AASLD nor the Asia-Pacific Working Group recommends obeticholic acid or elafibranor due to inconsistent results for NASH treatment and concerns about safety.Omega-3 fatty acids may reduce liver fat and improve blood lipid profile but do not seem to improve liver histology (fibrosis, cirrhosis, cancer). The NICE does not recommend omega-3 fatty acid supplementation since randomized trials were inconclusive. Previous systematic reviews found that omega-3 fatty acid supplementation in those with NAFLD/NASH using doses of one gram daily or more (median dose four grams/day with median treatment duration six months) has been associated with improvements in liver fat. According to AASLD guidelines, "omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH, but they may be considered to treat hypertriglyceridemia for patients with NAFLD".
Surgery
Bariatric surgery is an effective method for obese and diabetic individuals with NAFLD to induce weight loss and reduce or resolve NASH inflammation, including fibrosis, and improve longevity. For the AASLD, bariatric surgery can be considered only for NASH on a case-by-case basis by an experienced bariatric surgery program. Indeed, some individuals might develop new or worsened features of NAFLD.About 92% of people with NAFLD saw an improvement in steatosis and 70% a complete resolution after bariatric surgery.A preoperative diet such as a low-calorie diet or a very-low-calorie diet is usually recommended to reduce liver volume by 16–20%. Preoperative weight loss is the only factor associated with postoperative weight loss. Preoperative weight loss can reduce operative time and hospital stay, although there is insufficient evidence whether preoperative weight loss reduces long-term morbidity or complications. Weight loss and decreases in liver size may be independent of the amount of calorie restriction.The APWG on NAFLD recommends bariatric surgery as a treatment option for those with class II obesity (BMI >32.5 kg/m2 for Asians, 35 kg/m2 for Caucasians). They consider its effects on improving liver-related complications as unproven yet, but it effectively increases longevity by improving cardiovascular factors.Surgery carries more risks for individuals with NASH cirrhosis, with a review estimating overall morbidity to be 21%. For people with NAFLD who have undifferentiated cirrhosis, the APWG recommends an investigation to determine the cause of the cirrhosis as well as the persons liver function and whether they have portal hypertension.
Screening
Cardiovascular system screening is considered mandatory by the EASL, as NAFLD outcomes often result in cardiovascular complications, which can manifest as subclinical atherosclerosis, the cause of the majority of NAFLD-related deaths. People with NAFLD are at high risk for cardiovascular morbidity and mortality, and "aggressive modification of cardiovascular disease risk factors is warranted in all patients with NAFLD," according to AASLD.The AASLD further recommends for people with a cirrhotic NASH to be systematically screened for gastric and esophageal varices and liver cancer. They do not recommend routine liver biopsies and screening for liver cancer for non-cirrhotic people with NASH, but such screening sometimes occurs on a case-by-case basis.Also, people with NAFLD may be considered for screening for hepatocellular carcinoma (liver cancer) and gastroesophageal varices. The NICE advises regular screening of NAFLD for advanced liver fibrosis every three years to adults and every two years for children using the enhanced liver fibrosis (ELF) blood test. Follow-up is recommended for people with obesity and insulin resistance using the homeostasis model assessment of insulin resistance (HOMA-IR). People with NASH with fibrosis and hypertension merit closer monitoring as there is a higher risk of disease progression.
Transplantation
NAFLD is the second most common indication for liver transplantation in the US and Europe as of 2017. NAFLD/NASH is expected to become the leading cause of liver transplantation by 2020.For people with NASH and end-stage liver disease, liver failure, or liver cancer, liver transplantation is an accepted procedure according to the EASL. People with NASH cirrhosis NASH who are being considered for a liver transplant warrant systematic evaluation for cardiovascular diseases (whether the symptoms are apparent or not).The overall survival is comparable to transplantation following other diseases. People with NASH cirrhosis who undergo liver transplantation are more likely to die post-transplant because of cardiovascular disease or chronic kidney disease. These people with NASH are often older and are thus more prone to these complications. For these reasons and others, individuals with morbid obesity (BMI ≥ 40 kg/m2) and NASH with cirrhosis may be considered unfit for liver transplantation until they follow lifestyle modifications to reduce bodyweight. Diabetic people with poor glycemic control are at similar risks, and optimal glycemic control is essential before attempting transplantation.The Asia Pacific Working Group guidelines recommend healthcare providers discuss lifestyle modifications before and after transplantation to reduce potential surgery risks and to assist with NAFLD management after the transplant.Simultaneous bariatric surgery and liver transplantation were performed in exceptional circumstances.After transplantation, liver biopsy is the best method to monitor the evolution of post-transplant fibrosis, with significant fibrosis or portal hypertension one year after transplantation predicting rapid progression and graft loss and indicating the need for urgent intervention.
Related complications
There is no special treatment for liver cancer associated with NAFLD/NASH and are treated according to general guidelines on liver cancers.
Prognosis
The average progression rate from one stage of liver fibrosis to the next in humans with NASH is estimated to be seven years, compared to 14 years with NAFLD. The course of progression varies with different clinical manifestations among individuals. Fibrosis in humans with NASH progressed more rapidly than in humans with NAFLD. Obesity predicts a worse long-term outcome than for lean individuals. In the Asia-Pacific region, about 25% of NAFLD cases progress to NASH under three years, but only a low proportion (3.7%) develop advanced liver fibrosis. An international study showed that people with NAFLD had a 10-year survival rate of 81.5%.NAFLD is a risk factor for fibrosis, hypertension, chronic kidney disease, atrial fibrillation, myocardial infarction, ischemic stroke, and death from cardiovascular causes based on very-low to low-quality evidence from observational studies. Although NAFLD can cause cirrhosis and liver failure and liver cancer, most deaths among people with NAFLD are attributable to cardiovascular disease. According to a meta-analysis of 34,000 people with NAFLD over seven years, these individuals have a 65% increased risk of developing fatal or nonfatal cardiovascular events when compared to those without NAFLD.NAFLD and NASH increase the risk of liver cancer. Cirrhosis and liver cancer induced by NAFLD were the second cause of liver transplantation in the US in 2017. Liver cancer develops in NASH in the absence of cirrhosis in 45% in the cases, and people with NASH cirrhosis have an increased risk of liver cancer. The rate of liver cancer associated with NASH increased fourfold between 2002 and 2012 in the US, which is more than any other cause of liver cancer. NAFLD constitutes the third most common risk factor for liver cancer. NAFLD and NASH were found to worsen with cirrhosis in respectively 2–3% and 15–20% of the people over a 10–20 year period. Cirrhosis is found in only about 50% of people with NAFLD and with liver cancer, so that liver cancer and cirrhosis are not always linked.NAFLD may be a precursor of metabolic syndrome, although a bidirectional influence is possible. The presence and stage of fibrosis are the strongest prognostic factors for liver-related events and mortality, in particular for NAFLD.
Epidemiology
NAFLD incidence is rapidly rising, along with obesity and diabetes, and has become the most common cause of liver disease in developed countries, for adults, teenagers, and children. The percentage of people with NAFLD ranges from 9 to 36.9% in different parts of the world. Approximately 20% of the United States and 25% of the Asia-Pacific populations have non-alcoholic fatty liver. Similar prevalence can be found in Europe, although less data is available. NAFLD is the most common in the Middle East (32%) and South America (30%), while Africa has the lowest rates (13%). Compared to the 2000s, NAFL and NASH respectively increased 2-fold and 2.5-fold in the 2010s in the USA.NAFLD and NASH are more prevalent in Hispanics - which can be attributed to high rates of obesity and type 2 diabetes in Hispanic populations, intermediate in Whites, and lowest in Blacks. NAFLD was observed to be twice as prevalent in men as women. For severely obese individuals, the prevalence of NAFLD rises over 90%, and for those with diabetes, over 60%, and up to 20% for normal-weight people. NAFLD is present in 65% to 90% of people that had bariatric surgery, and up to 75% of them have NASH. Ultrasonography and proton NMR spectroscopy studies suggest about 25% of the population seems to be affected by NAFLD or NASH.Although the disease is commonly associated with obesity, a significant proportion of those affected are normal weight or lean. Lean NAFLD affects between 10 and 20% of Americans and Europeans, and approximately 25% of the Asians, although some countries have a higher incidence (e.g., India has a very high proportion of lean NAFLD and almost no obese NAFLD). PNPLA3 may be relevant for the progression of NAFLD in lean people. Thus, people with NAFLD deserve consideration for treatment regardless of the presence or absence of obesity.In children ages 1 to 19, the prevalence was found to be approximately 8% in the general population up to 34% in studies with data from child obesity clinics.The majority of cryptogenic cirrhosis is believed to be due to NASH. NAFLD prevalence is expected to increase steadily, from 25% in 2018 to a projected 33.5% of people with NAFLD globally in 2030, and from 20% to a projected 27% of those with NAFLD will progress to NASH.
History
The first acknowledged case of obesity-related non-alcoholic fatty liver was observed in 1952 by Samuel Zelman. Zelman started investigating after observing a fatty liver in a hospital employee who drank more than twenty bottles of Coca-Cola a day. He then went on to design a trial for a year and a half on 20 obese people who were not alcoholic, finding that about half of them had substantially fatty livers. Fatty liver was, however, linked to diabetes since at least 1784 — an observation picked up again in the 1930s. Studies in experimental animals implicated choline inadequacy in the 1920s and excess sugar consumption in 1949.The name "non-alcoholic steatohepatitis" (NASH) was later defined in 1980 by Jurgen Ludwig and his colleagues from the Mayo Clinic to raise awareness of the existence of this pathology, as similar reports previously were dismissed as "patients lies". This paper was mostly ignored at the time but eventually came to be seen as a landmark paper, and starting in the mid-1990s, the condition began to be intensively studied, with a series of international meetings being held on the topic since 1998. The broader NAFLD term started to be used around 2002. Diagnostic criteria began to be worked out, and in 2005 the Pathology Committee of the NIH NASH Clinical Research Network proposed the NAS scoring system.
Society and culture
Political recommendations
EASL recommends Europes public health authorities to "restrict advertising and marketing of sugar-sweetened beverages and industrially processed foods high in saturated fat, sugar, and salt", as well as "fiscal measures to discourage the consumption of sugar-sweetened beverages and legislation to ensure that the food industry improves labeling and the composition of processed foods", as well as "public awareness campaigns on liver disease, highlighting that it is not only linked to excessive consumption of alcohol".
Lobbying
In France, the French syndicate of non-alcoholic beverages "Boissons Rafraîchissantes de France" (that included soft drink producers such as Coca-Cola France, Orangina, PepsiCo France) was denounced by the French journal fr:Canard Enchainé for misleading consumers using a communication on their website titled "Better understanding the NASH pathology", explaining that "NASH pathology is sometimes called the soda illness by language abuse or an unfortunate semantic shortcut, as it is not directly linked to the consumption of non-alcoholic beverages". This page and others on the same website, such as one titled "Say no to disinformation," were since then removed.
Children
Pediatric NAFLD was first reported in 1983. It is the most common chronic liver disease among children and adolescents since at least 2007, affecting 10 to 20% of them in the US in 2016. NAFLD is associated with metabolic syndrome, which is a cluster of risk factors that contribute to the development of cardiovascular disease and type 2 diabetes mellitus. Studies have demonstrated that abdominal obesity and insulin resistance, in particular, are significant contributors to the development of NAFLD. Coexisting liver diseases, such as hepatitis C and cardiovascular diseases such as atherosclerosis, are also associated with an increased risk of NAFLD. Some children were diagnosed as early as two years old, with a mean age of diagnosis between 11 and 13 years old. The mean age is usually above 10 years, as children can also report non-specific symptoms and are thus difficult to diagnose for NAFLD.Boys are more likely to be diagnosed with NAFLD than girls. Overweight, or even weight gain, in childhood and adolescence, is associated with an increased risk of NAFLD later in life, with adult NAFLD predicted in a 31-year follow-up study by risk factors during childhood including BMI, plasma insulin levels, male sex, genetic background (PNPLA3 and TM6SF2 variants) and low birth weight, an emerging risk factor for adulthood NAFLD. In a study, simple steatosis was present in up to 45% in children with a clinical suspicion of NAFLD. Children with simple steatosis have a worse prognosis than adults, with significantly more of them progressing from NAFLD to NASH compared to adults. Indeed, 17-25% of children with NAFLD develop a NASH in general, and up to 83% for children with severe obesity (versus 29% for adults), further suggesting that hepatic fibrosis seems to follow a more aggressive clinical course in children compared to adults.Early diagnosis of NAFLD in children may help prevent the development of liver disease during adulthood. This is challenging as most children with NAFLD are asymptomatic, with only 42-59% showing abdominal pain. Other symptoms might be present, such as right upper quadrant pain or acanthosis nigricans, the latter of which is often present in children with NASH. An enlarged liver occurs in 30–40% of children with NAFLD.The AASLD recommends a diagnostic liver biopsy in children when the diagnosis is unclear or before starting a potentially hepatotoxic medical therapy. The EASL suggests using fibrosis tests such as elastography, acoustic radiation force impulse imaging, and serum biomarkers to reduce the number of biopsies. In follow up, NICE guidelines recommend that healthcare providers offer children regular NAFLD screening for advanced liver fibrosis every two years using the enhanced liver fibrosis (ELF) blood test. Several studies also suggest magnetic resonance elastography as an alternative to the less reliable ultrasonography.Intensive lifestyle modifications, including physical activity and dietary changes, are the first line of treatment according to AASLD and EASL as it improves the liver histology and aminotransferase levels. In terms of pharmacological treatment, the AASLD and EASL do not recommend metformin, but vitamin E may improve liver health for some children. The NICE advises the use of vitamin E for children with advanced liver fibrosis, whether they have diabetes or not. The only treatment shown to be effective in childhood NAFLD is weight loss.Some evidence indicates that maternal undernutrition or overnutrition increases a childs susceptibility to NASH and hastens its progression.
Research
Diagnosis and biomarkers
Since a NAFLD diagnosis based on a liver biopsy is invasive and makes it difficult to estimate epidemiology, it is a high research priority to find accurate, inexpensive, and noninvasive methods of diagnosing and monitoring NAFLD disease and its progression. The search for these biomarkers of NAFLD, NAFL, and NASH involves lipidomics, medical imaging, proteomics, blood tests, and scoring systems.According to a review, proton density fat fraction estimation by magnetic resonance imaging (MRI-PDFF) may be considered the most accurate and even gold standard test to quantify hepatic steatosis. They recommend ultrasound-based transient elastography to accurately diagnose both fibrosis and cirrhosis in a routine clinical setting, with more objectivity than ultrasonography but with lower accuracy than magnetic resonance elastography; and plasma cytokeratin 18 (CK18) fragment levels to be a moderately accurate biomarker of steatohepatitis. However, transient elastography can fail for people with pre-hepatic portal hypertension.
Medication development
Medication development for NASH is very active and advancing rapidly. New medications are being designed to target various intrahepatic sites, from regulating lipids and glucose homeostasis to oxidant stress and mitochondrial targets in hepatocytes, inflammatory signals on hepatocytes, and intracellular targets related to hepatic stellate cell activation and fibrogenesis. As of 2021, pivotal trials are underway for obeticholic acid (FXR agonist), Resmetirom (THRβ agonist), belapectin (Galectin-3 inhibitor), and Aramchol (SCD1 inhibitor).
See also
Foie gras, fatty liver induced in poultry, with pathophysiology homologous to that of NAFLD in humans
References
External links
NIH page on non-alcoholic steatohepatitis
Mayo Clinic page on NAFLD |
Proximal subungual onychomycosis | Proximal subungual onychomycosis is an infection of the nail plate by fungus, primarily affecting the proximal nailfold.: 305
See also
Onychomycosis
Skin lesion
== References == |
Dyskeratosis congenita | Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, but these components do not always occur. DKC is characterized by short telomeres. Some of the manifestations resemble premature ageing (similar to progeria). The disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.
Presentation
DKC can be characterized by cutaneous pigmentation, premature graying, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in the male carriers, and predisposition to cancer. Many of these symptoms are characteristic of geriatrics, and those carrying the more serious forms of the disease often have significantly shortened lifespans. Also, liver abnormalities are associated with this syndrome, Nodular Regenerative Hypoplasia of the liver, although rare, it is one of many manifestations of liver disorders short telomeres can cause.
Predisposition to cancer
Susceptibility to cancer seems counterintuitive because in many known cancers reactivation of telomerase is actually a required step for malignancy to evolve (see telomere). In a disease where telomerase is affected, it does not seem to follow that cancer would be a complication to result. The authors note the paradoxical nature of cancer predisposition in individuals who seem to lack one of the required components for cancer to form. It is thought that without functional telomerase, chromosomes will likely be attached together at their ends through the non-homologous end joining pathway. If this proves to be a common enough occurrence, malignancy even without telomerase present is possible. Myelodysplastic Syndrome is associated with this syndrome usually presenting as a Hypoplastic Bone Marrow that can resemble Aplastic Anemia, but can be differentiated with >10% dysplasia in affected cell lines, sometimes not possible though because of the Hypoplastic marrow reducing blood cells to be observed, genetic clones are usually not present more often than not with Hypoplastic Myelodysplastic Disorder associated with Dyskeratosis Congenita.
Genetics
Of the components of the telomerase RNA component (TERC), one of key importance is the box H/ACA domain. This H/ACA domain is responsible for maturation and stability of TERC and therefore of telomerase as a whole. The mammalian H/ACA ribonucleoprotein contains four protein subunits: dyskerin, Gar1, Nop10, and Nhp2. Mutations in Nop10, Nhp2 and dyskerin1 have all been shown to lead to DKC-like symptoms.
X-linked
The best characterized form of dyskeratosis congenita is a result of one or more mutations in the long arm of the X chromosome in the gene DKC1. This results in the X-linked recessive form of the disease wherein the major protein affected is dyskerin. Of the five mutations described by Heiss and colleagues in Nature Genetics, four were single nucleotide polymorphisms all resulting in the change of highly conserved amino acids. One case was an in-frame deletion resulting in the loss of a leucine residue, also conserved in mammals. In three of the cases, the specific amino acids affected (phenylalanine, proline, glycine) are found in the same locus in humans as they are in yeast (S. Cerevisiae) and the brown rat (R. Norvegicus). This establishes the sequence conservation and importance of dyskerin within the eukaryotes. The relevant nature of dyskerin throughout most species is to catalyze the post-transcriptional pseudouridylation of specific uridines found in non-coding RNAs, such as ribosomal RNA (rRNA). Cbf5, the yeast analog of human dyskerin, is indeed known to be associated with the processing and maturation of rRNA. In humans, this role can be attributed to dyskerin. Thus, the X-linked form of this disease may result in specific issues related to dysfunctional RNA and perhaps a graver phenotype. Within the vertebrates, as opposed to single celled eukaryotes, dyskerin is a key component of the telomerase RNA component (TERC) in the form of the H/ACA motif. This X-linked variety, like the Nop10 and Nhp2 mutations, demonstrates shortened telomeres as a result of lower TERC concentrations.
Autosomal dominant
3 genes: TERC, TERT, TINF2
The evidence supporting the importance of the H/ACA domain in human telomerase is abundant. At least one study has shown that these mutations affect telomerase activity by negatively affecting pre-RNP assembly and maturation of human telomerase RNA. Nonetheless, mutations that directly affect the telomerase RNA components would presumably exist and should also cause premature aging or DKC-like symptoms. Indeed, three families with mutations in the human TERC gene have been studied with intriguing results. In two of these families, two family-specific single nucleotide polymorphisms were present while in the other there persisted a large-scale deletion (821 base pairs of DNA) on chromosome 3 which includes 74 bases coding for a section of the H/ACA domain. These three different mutations result in a mild form of dyskeratosis congenita which uniquely follows an autosomal dominant pattern of inheritance. Premature graying, early dental loss, predisposition to skin cancer, as well as shortening of telomere length continue to be characteristic of this disease.
Autosomal recessive
6 genes:
The true phenotype of DKC individuals may depend upon which protein has incurred a mutation. One documented autosomal recessive mutation in a family that carries DKC has been found in NOP10. Specifically, the mutation is a change of base from cytosine to thymine in a highly conserved region of the NOP10 sequence. This mutation, on chromosome 15, results in an amino acid change from arginine to tryptophan. Homozygous recessive individuals show the symptoms of dyskeratosis congenita in full. As compared to age-matched normal individuals, those suffering from DKC have telomeres of a much shorter length. Furthermore, heterozygotes, those who have one normal allele and one coding for the disease, also show relatively shortened telomeres. The cause of this was determined to be a reduction in TERC levels in those with the Nop10 mutation. With TERC levels down, telomere maintenance, especially in development, would be presumed to suffer accordingly. This would lead to the telomere shortening described.NHP2 mutations are similar in characterization to NOP10. These mutations are also autosomal recessive with three specific single-nucleotide polymorphisms being recognized which result in dyskeratosis congenita. Also, like NOP10, individuals with these NHP2 mutations have a reduction in the amount of telomerase RNA component (TERC) present in the cell. Again, it can be presumed that a reduction in TERC results in aberrant telomere maintenance and thus shortened telomeres. Those homozygous recessive for mutations in NHP2 do show shorter telomeres when compared with age-matched normal individuals.
Pathophysiology
Dyskeratosis congenita is a disorder of poor telomere maintenance mainly due to a number of gene mutations that give rise to abnormal ribosome function, termed ribosomopathy. Specifically, the disease is related to one or more mutations which directly or indirectly affect the vertebrate telomerase RNA component (TERC). Telomerase is a reverse transcriptase which maintains a specific repeat sequence of DNA, the telomere, during development. Telomeres are placed by telomerase on both ends of linear chromosomes as a way to protect linear DNA from general forms of chemical damage and to correct for the chromosomal end-shortening that occurs during normal DNA replication. This end-shortening is the result of the eukaryotic DNA polymerases having no mechanism for synthesizing the final nucleotides present on the end of the "lagging strand" of double stranded DNA. DNA polymerase can only synthesize new DNA from an old DNA strand in the 5→3 direction. Given that DNA has two strands that are complementary, one strand must be 5→3 while the other is 3→5. This inability to synthesize in the 3→5 directionality is compensated with the use of Okazaki fragments, short pieces of DNA that are synthesized 5→3 from the 3→5 as the replication fork moves. As DNA polymerase requires RNA primers for DNA binding in order to commence replication, each Okazaki fragment is thus preceded by an RNA primer on the strand being synthesized. When the end of the chromosome is reached, the final RNA primer is placed upon this nucleotide region, and it is inevitably removed. Unfortunately once the primer is removed, DNA polymerase is unable to synthesize the remaining bases.Sufferers of DKC have been shown to have a reduction in TERC levels invariably affecting the normal function of telomerase which maintains these telomeres. With TERC levels down, telomere maintenance during development suffers accordingly. In humans, telomerase is inactive in most cell types after early development (except in extreme cases such as cancer). Thus, if telomerase is not able to efficiently affect the DNA in the beginning of life, chromosomal instability becomes a grave possibility in individuals much earlier than would be expected. A study shows that proliferative defects in DC skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 of the telomerase RNA component, TERC.
Diagnosis
Since the disease has a wide variety of symptoms due to involvement of multiple systems of the body, diagnostic testing depends on the clinical findings in each individual patient. Commonly used tests include a complete blood count (CBC), bone marrow examination, leukocyte telomere length test (e.g. Flow FISH), pulmonary function test, and genetic testing.
Management
The mainstay of treatment in dyskeratosis congenita is hematopoietic stem cell transplantation, best outcome with sibling donor. Short term therapy in initial stages is with anabolic steroids [oxymetholone, danazol] or with erythropoietin-like hormones or with granulocyte-colony stimulating factor [filgrastim) all these therapies are directed to cope with effects of bone marrow failure which manifests as low red and white blood cell counts. These medications help to increase the blood components and make up for the deficiencies caused due to bone marrow failure. Dyskeratosis Congenita in regards to stem cell transplantation have to be very carefully treated with low intensity radiation/chemo to avoid potentially catastrophic effects of Host versus graft disease and toxicity to other organs affected by short telomeres which makes them very sensitive to any radiation especially the lungs, and liver.
Prognosis
DC is associated with shorter life expectancy, but many live to at least age 60.
Main cause of mortality in these patients are related to bone marrow failure. Nearly 80% of the patients of dyskeratosis congenita develop bone marrow failure.
Research
Recent research has used induced pluripotent stem cells to study disease mechanisms in humans, and discovered that the reprogramming of somatic cells restores telomere elongation in dyskeratosis congenita (DKC) cells despite the genetic lesions that affect telomerase. The reprogrammed DKC cells were able to overcome a critical limitation in TERC levels and restored function (telomere maintenance and self-renewal). Therapeutically, methods aimed at increasing TERC expression could prove beneficial in DKC.
See also
Cutaneous conditions
List of cutaneous conditions
References
External links
GeneReviews/NCBI/NIH/UW entry on Dyskeratosis Congenita
Dyskeratosis Congenita research study of Inherited Bone Marrow Failure Syndromes (IBMFS) |
Patulous Eustachian tube | Patulous Eustachian tube (PET) is the name of a physical disorder where the Eustachian tube, which is normally closed, instead stays intermittently open. When this occurs, the person experiences autophony, the hearing of self-generated sounds. These sounds, such as ones own breathing, voice, and heartbeat, vibrate directly onto the ear drum and can create a "bucket on the head" effect. PET is a form of eustachian tube dysfunction (ETD), which is said to be present in about 1 percent of the general population.
Signs and symptoms
With patulous Eustachian tube, variations in upper airway pressure associated with respiration are transmitted to the middle ear through the Eustachian tube. This causes an unpleasant fullness feeling in the middle ear and alters the auditory perception. Complaints seem to include muffled hearing and autophony. In addition, patulous Eustachian tube generally feels dry with no clogged feeling or sinus pressure.
Patients hear their own voice or its echo from inside. They describe it as being amplified and unpleasant. Lying head down may help since it increases venous blood pressure and congestion of the mucosa.
Causes
Patulous Eustachian tube is a physical disorder. The exact causes may vary depending on the person. Weight loss is a commonly cited cause of the disorder due to the nature of the Eustachian tube itself and is associated with approximately one-third of reported cases. Fatty tissues hold the tube closed most of the time in healthy individuals. When circumstances cause overall body fat to diminish, the tissue surrounding the Eustachian tube shrinks and this function is disrupted.Activities and substances which dehydrate the body have the same effect and are also possible causes of patulous Eustachian tube. Examples are stimulants (including caffeine) and exercise. Exercise may have a more short-term effect than caffeine or weight loss in this regard.
Pregnancy can also be a cause of patulous Eustachian tube due to the effects of pregnancy hormones on surface tension and mucus in the respiratory system.Granulomatosis with polyangiitis can also be a cause of this disorder. It is yet unknown why.
PET can occur as a result of liquid residue in the Eustachian tube, after suffering a middle ear infection (otitis media).
Radiation therapy
High levels of estrogen
Nasal decongestants
Stress
Sudden weight loss
Neurological disorders
Diagnosis
Upon examination of a suspected case of patulous Eustachian tube, a doctor can directly view the tympanic membrane with a light and observe that it vibrates with every breath taken by the patient. A tympanogram may also help with the diagnosis. Patulous Eustachian tube is likely if brisk inspiration causes a significant pressure shift.
Patulous Eustachian tube is frequently misdiagnosed as standard congestion due to the similarity in symptoms and rarity of the disorder. Audiologists are more likely to recognize the disorder, usually with tympanometry or nasally delivered masking noise during a hearing assessment, which is highly sensitive to this condition.When misdiagnosis occurs, a decongestant medication is sometimes prescribed. This type of medication aggravates the condition, as the Eustachian tube relies on sticky fluids to keep closed and the drying effect of a decongestant would make it even more likely to remain open and cause symptoms. The misdiagnosed patient may also have tubes surgically inserted into the eardrum, which increases the risk of ear infection and will not alleviate patulous Eustachian tube. If these treatments are tried and failed, and the doctor is not aware of the actual condition, the symptoms may even be classified as psychological.
Incidentally, patients who instead suffer from the even rarer condition of superior canal dehiscence are at risk for misdiagnosis of patulous Eustachian tube due to the similar autophony in both conditions.
Treatment
Estrogen nasal drops or saturated potassium iodide have been used to induce edema of the eustachian tube opening. Nasal medications containing diluted hydrochloric acid, chlorobutanol, and benzyl alcohol have been reported to be effective in some patients, with few side effects. Food and Drug Administration approval is still pending, however. Nasal sprays have also been a very effective temporary treatment for this disease, as well.In extreme cases surgical intervention may attempt to restore the Eustachian tube tissues with fat, gel foam, or cartilage or scar it closed with cautery. These methods are not always successful. For example, there is the case of the early attempts at surgical correction involving injections of tetrafluoroetheylene (Teflon) paste but although this treatment was able to give transient relief, it was discontinued due to several deaths that resulted from inadvertent intracarotid injections.Although a temporary solution, surgical ventilation tube placement in the ear drum has also proven to be an effective treatment option. This treatment is known as either a unilateral or bilateral myringotomy. 50% of patients reported relief of PET symptoms when given this treatment.
References
== External links == |
Cushing ulcer | A Cushing ulcer, named after Harvey Cushing, is a gastric ulcer associated with elevated intracranial pressure. It is also called von Rokitansky–Cushing syndrome. Apart from the stomach, ulcers may also develop in the proximal duodenum and distal esophagus.
Causes
The mechanism of development of Cushing ulcers is thought to be due to direct stimulation of vagal nuclei as a result of increased intracranial pressure. Brain tumors, traumatic head injury, and other intracranial processes including infections, can cause increased intracranial pressure and lead to overstimulation of the vagus nerve. Efferent fibers of the vagus nerve then release acetylcholine onto gastric parietal cell M3 receptors, causing insertion of hydrogen potassium ATPase vesicles into the apical plasma membrane. The end result is increased secretion of gastric acid with eventual ulceration of the gastric mucosa.
Diagnosis
As Cushing ulcers have a higher incidence of developing after shock, sepsis or trauma, diagnosis should include recent medical history evaluation. Both endoscopy and angiography can be used to locate the lesion or ulcer, though endoscopy is more commonly used as a first-line diagnosis procedure.
Treatment
Most episodes of Cushing ulceration resolve on medical intervention, consisting primarily of rinsing the area with saline and the administration of antacids.Patients should also be put on proton pump inhibitors during the course of treatment until their intracranial pressure lowers to a normal level. As it is caused due to vagal stimulation, vagotomy is considered as last treatment resort..
See also
Curling ulcer
References
== External links == |
Trifascicular block | Trifascicular block is a problem with the electrical conduction of the heart, specifically the three fascicles of the bundle branches that carry electrical signals from the atrioventricular node to the ventricles. The three fascicles are one in the right bundle branch, and two in the left bundle branch the left anterior fascicle and the left posterior fascicle. A block at any of these levels can cause an abnormality to show on an electrocardiogram
The most literal meaning of trifascicular block is complete heart block: all three fascicles are blocked. A second, and clinically distinct, definition of trifascicular block is a circumstance in which right bundle branch block (RBBB) and left bundle branch block occur in the same patient, but at distinct points in time. For example, a patient that is found to have a RBBB one day and a LBBB another can be said to have "alternating bundle branch blocks". In this context, because all three fascicles show evidence of block at different points in time, the term trifascicular block is often used.
Finally, the third meaning of trifascicular block refers to a specific finding on an electrocardiogram in which bifascicular block is observed in a patient with a prolonged PR interval (first degree AV block).
The treatment of trifascicular block is highly dependent on which clinical entity (one of the three above) is being described.
Diagnosis
An electrophysiology study of the conduction system can help discern the severity of conduction system disease. In an electrophysiology study, trifascicular block due to AV nodal disease is represented by a prolonged AH interval (denoting prolonged time from impulse generation in the atria and conduction to the bundle of His) with a relatively preserved HV interval (denoting normal conduction from the bundle of His to the ventricles). Trifascicular block due to distal conduction system disease is represented by a normal AH interval and a prolonged HV interval. In the absence of symptoms, a prolonged AH interval is likely benign while a prolonged HV interval is almost always pathologic.
Treatment
An implantable cardiac pacemaker or permanent pacemaker is recommended in the following clinical circumstances. Class 1 recommendation is the strongest recommendation. Level A evidence is the highest level of evidence.Class I
Bifascicular block + complete heart block, even in the absence of symptoms (1b)
Bifascicular block + 2nd degree AV Block Type 2, even in the absence of symptoms (1b)
Alternating bundle branch blocks, even in the absence of symptoms (1c)Class II
Bifascicular block + syncope + alternative causes ruled out (e.g. orthostasis, arrhythmia) (2a)Class III (i.e. pacemaker not recommended)
Bifascicular block without symptoms
Bifascicular block + 1st degree AV Block, without symptoms
References
External links
http://www.ecglibrary.com/trifas.html
http://circ.ahajournals.org/content/97/13/1325.long - new guidelines in which trifascicular block terminology continues to be used. |
Trigeminal autonomic cephalgia | Trigeminal autonomic cephalalgia (TAC) is the name for a type of primary headache that occurs with pain on one side of the head in the trigeminal nerve area and symptoms in autonomic systems on the same side, such as eye watering and redness or drooping eyelids. TACs include
Cluster headache
Paroxysmal hemicrania (chronic or episodic)
Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)
Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA)
Long-lasting autonomic symptoms with hemicrania (LASH)TACs can be differentiated by the length and frequency of recurrence of the headaches.Treatment for TACs varies depending on the exact type, but can include medication such as Indomethacin (in the case of chronic paroxysmal hemicrania) or acute and prophylactic therapy (in the case of cluster headache).
== References == |
Angiokeratoma | Angiokeratoma is a benign cutaneous lesion of capillaries, resulting in small marks of red to blue color and characterized by hyperkeratosis. Angiokeratoma corporis diffusum refers to Fabrys disease, but this is usually considered a distinct condition.
Signs and symptoms
Presentation includes telangiectasia, acanthosis, and hyperkeratosis.Presentation can be solitary or systemic.Multiple angiokeratomas, especially on the trunk in young people, are typical for Fabry disease, genetic disorder connected with systemic complications.
Complications
In some instances nodular angiokeratomas can produce necrotic tissue and valleys that can harbor fungal, bacterial and viral infections. Infections can include staphylococcus. If the lesion becomes painful, begins draining fluids or pus, or begins to smell, consult a physician. In these instance a doctor may recommend excision and grafting.
Pathophysiology
Histology
Angiokeratomas characteristically have large dilated blood vessels in the superficial dermis and hyperkeratosis (overlying the dilated vessels).
Diagnosis
Due to the rarity of different types of vascular conditions, angiokeratomas may be misdiagnosed. A biopsy of the lesion can produce a more accurate diagnosis.
Classification
Angiokeratoma may be classified as:
Angiokeratoma of Mibelli (also known as "Mibellis angiokeratoma," "Telangiectatic warts") consists of 1- to 5-mm red vascular papules, the surfaces of which become hyperkeratotic in the course of time.: 589 The disease is named after Italian dermatologist Vittorio Mibelli (1860-1910).
Angiokeratoma of Fordyce (also known as "Angiokeratoma of the scrotum and vulva," though not to be confused with Fordyces spots) is a skin condition characterized by red to blue papules on the scrotum or vulva.
Solitary angiokeratoma is a small, bluish-black, warty papule that occurs predominantly on the lower extremities.: 590
Verrucous vascular malformation (also known as "Angiokeratoma circumscriptum naeviforme") is a malformation of dermal and subcutaneous capillaries and veins, a congenital vascular malformation, which, over time, a verrucous component appears.: 584
Treatment
Outpatient treatments such as interventional radiology, lasers, and physical therapy are employed to reduce the severity of the vascular lesions. However, in some cases lasers have caused a reaction in the tissue causing it to expand and become exposed to infection. Excision and grafting may be necessary to remove the lesion. Recovery time on such an operation ranges from 3 to 12 weeks depending on location of the graft, healing time and the possibility of complications.
See also
Fabry disease
List of cutaneous conditions
References
== External links == |
Jaw abnormality | A jaw abnormality is a disorder in the formation, shape and/or size of the jaw. In general abnormalities arise within the jaw when there is a disturbance or fault in the fusion of the mandibular processes. The mandible in particular has the most differential typical growth anomalies than any other bone in the human skeleton. This is due to variants in the complex symmetrical growth pattern which formulates the mandible.The mandible in particular plays a significant role in appearance as it is the only moving part of the facial skeleton. This has a large impact upon an individuals’ ability speak, masticate and also influence their overall aesthetic and expressive features of the face. In turn the maxilla faces the same issues if any abnormalities in size or position were to occur. The obvious functional disabilities that arise from jaw abnormalities are very much physically seen as previously stated, but when considering these individuals it must be kept in mind that these conditions may well affect them psychologically; making them feel as though they are handicapped. It is also of the utmost importance when correcting these mandibular anomalies that the teeth result in a good occlusion with the opposing dentition of the maxilla. If this is not done satisfactorily occlusal instability may be created leading to a plethora of other issues. In order to correct mandibular anomalies it is common for a complex treatment plan which would involve surgical intervention and orthodontic input.
Signs and symptoms
Individuals with jaw abnormalities have both functional and aesthetic impairment.Misalignment of teeth creates difficulties in head and neck functions related to chewing, swallowing, breathing, speech articulation and lip closure/posture.Affected individuals may also experience TMJ pain and dysfunction, which negatively affect the quality of life.A proportion of affected individuals also have psychological problems.
Diagnosis
Diagnosis of a jaw deformity is a structured process, linking the undertaking of a history, physical examination of the patient, and appraisal of diagnostic studies. This process may involve more than a single discipline of Dentistry – in addition to orthodontic and surgical needs, some patients may also require periodontal, endodontic, complex restorative, and prosthetic considerations.It involves the chief presenting complaint of the patient, which allows the clinician to understand the patients perception of the problem – what they think the problem is and what they would like corrected. The patient may find eating difficult or may have problems with speech or the appearance of the teeth or face. However, patients may be hesitant to discuss dissatisfaction with their appearance because they may feel that it is more acceptable to present a functional problem to the clinician. For this reason it is important to reassure patients that their aesthetic problems and the effects of these are perfectly valid concerns. In children, psychological development can be affected due to teasing if they have abnormal appearance of teeth or face. Correction of the abnormality can be extremely beneficial to the patient. The benefits can manifest themselves in many ways including improved peer relationships and social confidence. Motivation on the patients part is necessary if they are going to undergo lengthy orthodontic treatment and major surgery. In addition, they need to be well informed so that they may give valid consent. In terms of history, the family history and perhaps obstetric history may be relevant, especially when features of a syndrome are present.: 200 A medical and dental history is obtained for completeness. The medical history includes questions on the general health of the patient, to assess contraindications to treatment of jaw abnormality. Special emphasis is placed on diseases and medication which cause altered metabolism, that may affect growth and tissue reactions. Allergies are checked (specifically nickel allergies), so that treatment appliances with nickel-containing materials like stainless steel can be replaced with other materials to avoid the risk of allergic reactions. Questions on family history are also relevant, as malocclusions, growth and development may be expressions of genetic patterns. The dental history investigates if the patient has had any previous dental trauma, or past dental experiences, which can serve as a gauge to patient compliance with treatment.
Examination
The assessment of facial form includes the evaluation of facial soft tissue and dentition. As the human skeleton is not visibly perceptible, bone deformity is inferred and evaluated by facial appearance and dentition. To obtain a 3D assessment of the patient, the skeletal pattern must be measured in different planes: anterior-posterior, vertical, and transverse. This allows for an accurate assessment of the size, position, orientation, shape, and symmetry of the jaws.
The anterior-posterior skeletal pattern measures the relationship of the lower jaw to the upper jaw. This is judged with the patient seated upright, head in a neutral horizontal position, and teeth in gentle occlusion. It can be classified into the following classes:
Class I: The ideal relationship whereby the upper jaw lies 2-4mm in front of the lower jaw
Class II: Upper jaw lies more than 4mm in front of the lower jaw
Class III: Upper jaw lies less than 2mm in front of the lower jaw, or in more severe cases, the lower jaw may be in front of the upper jaw. The vertical dimension can be measured by facial thirds, with ideal facial aesthetics showing equality between each vertical third. The face is divided into thirds – hairline to glabella; glabella to subnasale; and subnasale to the lowest part of the chin. Two other clinical indicators can be assessed when analysing vertical dimensions, namely the Frankfort Mandibular Planes Angle (FMPA) and the Lower Facial Height (LFH) – both of which are each recorded as either average, increased, or decreased.
FMPA: This is estimated by the point of intersection between the lower border of the mandible and the Frankfort Horizontal plane.
LFH: The face is divided into thirds, and the proportion of the lower third of the face is compared to the rest.The transverse relationship is a measure of jaw or facial asymmetry. It checks for the alignment of the soft tissue nasion, the middle part of the upper lip at the vermillion border, and the chin point. If present, it is necessary to distinguish between a false and true asymmetry. A false asymmetry arises due to occlusal interferences, which results in a lateral displacement of the mandible, producing a cross-bite in the anterior/buccal region. Elimination of the displacement will return the mandible to a centric position. On the other hand, a true asymmetry indicates unequal facial growth on the left or right side of the jaws. Elimination of any occlusal cross-bites is not only difficult, but unlikely to improve the facial asymmetry. The assessment of the transverse components of the facial width is best described by the "rule of fifths", which sagittally divides the face into five equal parts:
Each transverse fifth should be an eye distance in width.
The middle fifth is marked by the inner canthus of both eyes.
The medial three-fifths of the face is marked from the outer canthus of the eye frames
The outer two-fifths of the face is measured from the lateral canthus to lateral helix of the ear, which represents the width of the ears.
Tests
It is insufficient to derive at a diagnosis of jaw deformity solely based on the clinical examination. Hence, additional information is gathered from diagnostic tests, which may include dental model analyses and radiographic imaging studies.
Dental Model Analyses - Study models for analysis can be made by taking dental impressions, or by 3D intra-oral scanning. They allow for the appraisal of shape and size of jaws and teeth. This can be valuable for the long-term evaluation of development and for the follow up of treatment results. Depending on the type of jaw abnormality, a face bow record for transfer on to the articulator, can sometimes be appropriate for the patient.
Radiographs - Radiographic investigations should be based on individual needs and used in conjunction to the clinical examination. As with all other dental radiographs, the benefit gained for the patient with the radiograph must be weighed against the radiation dosage of taking it. In the assessment of jaw abnormalities, the most common radiographs taken used to be the dental panoramic tomography and lateral cephalometry. With the advancement in technology, the use of 3D imaging e.g. Cone Beam Computed Tomography (CBCT) has gained popularity for the use of radiographic examinations of facial bones for purpose of planning complex orthognathic surgery, especially involving significant facial asymmetry. A 3D facial construction model can be utilised in more complex malocclusion to help plan management.
Classification
Size
MicrognathiaMandibular micrognathia is the condition when lower jaw is smaller than normal. Failure of the ramus to develop will give rise to micrognathia. Micrognathia can be classified as either congenital or acquired. Clinical appearance of some patients with congenital type of mandibular micrognathia can have a severe retrusion of the chin but by actual measurements, the mandible maybe be found to be within the normal limits of variation. This maybe because a posterior placing of the condylar head with regard to the skull or to a steep mandibular angle resulting in an evident jaw retrusion. The acquired type of micrognathia occurs after birth and usually is an effect of a disturbance to temporomandibular joint. Growth of mandible depends on the normally developing condyles and the muscle function For example, trauma or infection that affect mastoid, middle ear or the joint will result in ankylosis of temporomandibular joint leading to mandibular micrognathia.
MacronagthiaMacronagthia is a condition of abnormally large jaws. The jaw size is usually proportion to the increase in skeleton size. It is usually due to excessive growth of the mandible and can have features including reverse maxillary to mandibular relationship, reverse overjet or absence of overbite. It can also be clinically presented when the glenoid fossa and condylar head is more anteriorly placed, causing mandibular prognathism. Macronagthism can be associated with other medical conditions :-
1. Pagets disease where there is overgrowth of the maxilla, cranium and mandible2. Acromegaly, an endocrine disease, can present with enlargement of bones with growth potential such as the mandible, thickened soft tissues and facial features and spade-like hands
Macrogenia or MicrogeniaMacrogenia and microgenia occur when there is a normal skeletal relationship but the chin, skeletal and soft tissue components, failed to develop in proportion to the skeletal base, resulting in marked protrusive (macrogenia) or retrusive (microgenia) facial profile. Microgenia can be presented when there is inadequate bone depth at the apex of lower anteriors or the base of mandible and vice versa.
Position
TransverseA transverse jaw position is known as Laterognathia. This term describes a lateral bite in the lower jaw and is often associated with a unilateral crossbite at an early age This can lead to bone development of an asymmetrical mandibular ramus resulting in asymmetry in the whole of the lower face. Treatment of laterognathism is either possible with orthodontic tooth movement or a surgical relocation of the lower jaw.
VerticalOne of the ways in which a jaw can develop abnormally is in the vertical dimension. Abnormal growth can occur in the maxilla and the mandible. The jaw is usually loosely used to refer to the mandible (considered the lower jaw). However, the maxilla is also a jaw and should thus be referred to in this respect as well.
The vertical jaw abnormalities relating to the mandible are in relation to excessive vertical growth and excessive horizontal growth, measured by the maxillary-mandibular plane angle (MMPA). The vertical jaw abnormalities relating to the maxilla are in relation to excessive downward displacement (EDD) and insufficient downward displacement (IDD). These terms used to previously be known as vertical maxillary excess and deficiency. This nomenclature changed because excess and deficiency typically refer to size. Whereas when assessing this clinically, one would measure the distance between the central incisors and the upper lip, which, in fact, denotes position rather than size. Therefore, in order to ‘harmonize with geometry’, EDD and IDD are now used widely.Vertical and Horizontal Mandibular Excess:
Simply put, excessive vertical growth is the term used for when the mandible is considered ‘too far down. Whereas in excessive horizontal growth the opposite applies, where the mandible is growing in a more horizontal pattern, in relation to the maxilla. The primary cause of the above two abnormalities in adolescents is due to accelerated and slow mandibular growth. Resulting in either a longer lower face height appearance (vertical growth) or a shorter one (horizontal growth). The length between the columella (base of the nose) and menton (base of the chin) is the variable measurement. This is in relation to the length between the glabella (between eyebrows) and the columella. In a normal case, these lengths would be equal or without a major discrepancy. However, in excess vertical and horizontal growth, the proportions vary and do not equal.
The development of the mandible is such that it ossifies in two primary ways; endochondrally and intramembranously. Almost the entire mandible is formed via intramembranous ossification, with just the condyle ossifying endochondrally. This allows the condyle to resist forces exerted on it. One way in which a vertical jaw abnormality can occur is if the condylar growth process is damaged, and thus the intramembranous growth continues along the posterior condylar margin, becoming predominant, thus resulting in a high angle type.Assessing a patient for vertical and horizontal excess
The Maxillary Mandibular Plane Angle (MMPA) is important in assessing a patient for vertical jaw abnormality. The important landmarks are the Frankfurt plane and the Mandibular plane. The Frankfurt plane is a line charted from the upper border of external auditory meatus to the lower border of the orbit. It is similar to the ala-tragus line however should not be confused with it. Whereas the Mandibular angle is a line measured along the natural lower border of the patients mandible. The intersection of the Frankfurt and Mandibular plane is what determines the pattern of vertical growth. If the intersection occurs behind the occiput i.e. decreased angle, then the patient is considered to have horizontal growth. On the other hand, if the intersection occurs in front of the occiput, then the patient is considered to have vertical growth. The normal range is considered to be between 25 and 30 degrees in a typical Caucasian person. Those with excess vertical jaw growth are most often seen having an anterior open bite, as the mandible is growing away from the maxilla. Whereas those with excessive horizontal growth are seen as having an overbite.
Excessive Downward Displacement and Insufficient Downward Displacement
Here on, we will use interchangeably the terms vertical maxillary excess and deficiency with excessive and insufficient downward displacement. In order to understand its manifestations, we need to account for key landmarks such as:· Columella (CM)– The tissue that links the nasal tip to the nasal base, separating the nares. The inferior margin of the nasal septum
· Subnasale (SN) – the junction of the upper lip and the columella
· Stomion Superios (Sts) – the lower most point on the vermillion of the upper lip
· Stomion (Sto) – The point of contact, when lips are competent, in the midline, between the top and bottom lip
· Stomion Inferious (Sti) – the upper most point on the vermillion of the lower lip
· Soft tissue mention (Me) – The most inferior point on the soft tissue outline of the chin
The measurements of the upper lip and lower lip for each patient are ascertained by using the aforementioned landmarks. The length of the upper lip is measured from Sn to Sts. In a typical male and female this measures to 24mm and 21mm respectively (REF). The length of the lower lip is measured from Sti to Me. In a typical male and female this measures to 50mm and 46.5mm respectively.When considering EDD and IDD, the class of the skeletal base is a good adjunct. In other words, EDD and IDD can either appear camouflaged or apparent given the skeletal base and the soft tissue profile accompanying it. For example, the drape of the upper lip can mask the maxillary deficiency to such an extent that it presents as a normal soft tissue profile (REF). Para-nasal hollowing is a key indicator of underlying maxillary deficiency. It is most common in class III patients, but can also present in some class II cases, with bilateral maxillary retrusion.Assessing a patient for vertical and horizontal excess:
Arguably the main observation to carry out in a patient to assess maxillary excess or deficiency is the upper incisor/gum show when at rest and smiling. In other words, the relationship between the upper lip and upper central incisors when at rest and smiling. Ensure the patients head posture is correct and the lips are at rest to establish the resting lip line. Similarly, to assess the incisor/gum show on smiling, the patient needs to fully smile to allow the upper lip to rise to its maximum height. The average showing of the incisors when the lips are at rest is 1/3 of its clinical crown height. With maxillary excess, more than 1/3 of the incisors would show. When the patient smiles, maxillary excess would manifest as the entire clinical crown and a portion of the gums showing as well. This is regarded as a ‘gummy smile.’
As alluded to previously, the paranasal region is important to consider when assessing a patient for IDD or EDD. Observing the patient from the side view allows a clearer perspective. A lack of bony support for the soft tissues in this region will subsequently produce the depression, known as paranasal hollowing. This indicates a low level antero-posterior maxillary deficiency. Maxillary deficiency usually manifests as an increased naso-labial angle, although this is not a credible indication due to factors such as a short upper lip and/or proclined incisors.
Another method to predict if a patient has maxillary deficiency is by the ‘scleral show and eyelid shape.’ The lower eyelid normally rests at the inferior border of the iris, without any sclera showing. If there is any sclera showing, then this is a good sign of infraorbital rim deficiency and maxillary antero-posterior deficiency, two manifestations that are usually seen in Class III patients.
Orientation
When a jaw is abnormally oriented, malrotations occur. These malrotations are classified according to the axis on which the abnormal rotation occurs. When a jaw is malrotated around the transverse facial axis, it is said to have abnormal pitch. When malrotated around the anteroposterior axis, the jaw has an abnormal roll, a condition also known as cant. Finally, when a jaw is malrotated around the vertical axis, it has abnormal yaw. It can occur in maxilla and/or mandible and could result due to abnormal growth of the jaws in itself or as compensatory growth.
Shape
Shape refers to figure, the geometric characteristic of an object that is not size, position, or orientation 5. A jaw with abnormal shape is said be distorted.
Completeness
Completeness means the wholeness of the jaw. When failure of tissues to fuse together that are forming early in pregnancy, defect can happen and jaw is incomplete. For example, cleft lip and palate when one of the jaws embryological processes failed to fuse together or the agenesis of the condylar process of the mandible, which may be seen in hemifacial microsomia. Clinically, cleft palate presents as opening in the palate that can affect the front palate only or extending from the front to the back palate. Cleft lip is presented clinically with opening of the upper lip which can be a small slit on the upper lip or large opening connected to the nose. The cleft can be unilateral on the upper lip or bilaterally. Cleft lip can happen together with cleft palate.Palatal clefts are one of the most common congenital abnormalities which occur in 1:2500 live births. Embryologically, palate formation takes place in two stages, with the primary palate formed after 6th week followed by secondary palate formation between sixth and eighth weeks. The palate will fuse with the medial nasal process to form the roof of the mouth in order to complete the developmental process. However, if this process is incomplete that is when developmental defect occur. Initially, it is just a common oro-nasal cavity within the embryo with nothing to separate the nose and mouth cavity. This space is occupied with tongue. The primary palate formed when medial nasal prominences fused together to form the intermaxillary segment to demarcate the oral from the nasal components. The formation of secondary palate starts with the growing of tissues vertically and mesially forming the right and left lateral palatal shelves. On the week 8, the tongue will be withdrawn downwards and the right and left lateral palatal shelves will be rapidly elevated, flipped into a horizontal orientation and fuse together from the front to the back two. The right and left lateral palatal shelves contact or fuse with each other at the midline to form the secondary palate two.A lot of growth factors are actively involved in the signalling to the tissues during craniofacial development. These growth factors function to control the cells proliferation, survival and apoptosis. Some of the growth factors that can be implicated in the facial development resulting in craniofacial defect are BMP, FGF, Shh, Wnt and endothelins. One of the environmental factors that has been identified in mice study to have link to cleft lip is teratogen which can interfere the molecular signalling between the growth factors. However, the exact mechanism is still not clear. Another environmental factors that has been actively involved in studies to prevent cleft lip and palate occurrences is the intake of folic acid during pregnancy. 0.4 mg folic acid intake per day has been shown to reduce one third risk of cleft lip (with or without cleft palate) in babies. However, it seems had no apparent effect on the risk of cleft palate alone. There are also studies in mice and dogs reported the protective effect of folic acid supplementation to prevent cleft lip palate occurrence.
Treatment
Jaw abnormalities are commonly treated with combined surgical (orthognathic surgery) and orthodontic treatment. The procedure is carried out by oral and maxillofacial surgeons and orthodontists in close collaboration.In most cases, the orthodontist will first align the teeth with braces or other appliances, which may worsen the occlusion until after the surgery. This is carried out to show the full degree of abnormality, and to create sufficient space for full correction in the bones.Orthognathic surgery, also known as corrective jaw surgery, is performed to normalise dentofacial deformity and reposition part/all of the upper and/or lower jaws to improve occlusion stability and facial proportions. It is the mainstay treatment for patients who are too old for growth modification and for dentofacial conditions that are too severe for either surgical or orthodontic camouflage.The surgery usually involves gaining access to the bone from inside the mouth, revealing and moving the bone into a correct functional position, and fixing it in position with metal plates and screws. These plates are most often left in the bone, but at times require removal due to infection, which would require another operation. Most orthognathic surgeries are performed inside the mouth without any external scarring.
Mandibular surgery
There are numerous surgical techniques available to correct the position of the mandible. The most popular of these techniques is the sagittal split osteotomy which "enables the body of mandible to be moved forwards or backwards by sliding the split ramus and angle".: 203 This provides a lot of bone overlap for healing. Damage to the inferior alveolar bundle is avoided by sectioning the buccal and retromolar cortex of the mandible and the cancellous bone is carefully split. After the mandible has been repositioned, screws or mini-plates can be used to fix the mandible directly. This is instead of fixing it indirectly with intermaxillary fixation (IMF).: 203
Genioplasty
Reduction or augmentation of the chin may be carried out either on its own or as part of a mandibular or maxillary orthognathic operation.: 203
Maxillary surgery
The Le Fort classification (which is used for fracture description) generally describes the surgical techniques which are used for maxillary surgery.: 203
References
== External links == |
Minor depressive disorder | Minor depressive disorder, also known as minor depression, is a mood disorder that does not meet the full criteria for major depressive disorder but at least two depressive symptoms are present for a long time. These symptoms can be seen in many different psychiatric and mental disorders, which can lead to more specific diagnoses of an individuals condition. However, some of the situations might not fall under specific categories listed in the Diagnostic and Statistical Manual of Mental Disorders. Minor depressive disorder is an example of one of these nonspecific diagnoses, as it is a disorder classified in the DSM-IV-TR under the category Depressive Disorder Not Otherwise Specified (DD-NOS). The classification of NOS depressive disorders is up for debate. Minor depressive disorder as a term was never an officially accepted term, but was listed in Appendix B of the DSM-IV-TR. This is the only version of the DSM that contains the term, as the prior versions and the most recent edition, DSM-5, does not mention it.A person is considered to have minor depressive disorder if they experience 2 to 4 depressive symptoms, with one of them being either depressed mood or loss of interest or pleasure, during a 2-week period. The person must not have experienced the symptoms for 2 years and there must not have been one specific event that caused the symptoms to arise. Although not all cases of minor depressive disorder are deemed in need of treatment, some cases are treated similarly to major depressive disorder. This treatment includes cognitive behavioral therapy (CBT), anti-depressant medication, and combination therapy. A lot of research supports the notion that minor depressive disorder is an early stage of major depressive disorder, or that it is simply highly predictive of subsequent major depressive disorder.
Signs and symptoms
Minor depressive disorder is very similar to major depressive disorder in the symptoms present. Generally, a persons mood is affected by thoughts and feelings of being sad or down on themself or by a loss of interest in nearly all activities. People can experience ups and downs in their life everyday where an event, action, stress or many other factors can affect their feelings on that day. However, depression occurs when those feelings of sadness persist for longer than a few weeks.A person is considered to have minor depressive disorder if they experience 2 to 4 depressive symptoms during a 2-week period. The Diagnostic and Statistical Manual of Mental Disorders lists the major depressive symptoms. Depressed mood most of the day and/or loss of interest or pleasure in normal activities must be experienced by the individual to be considered to have minor depressive disorder. Without either of these two symptoms, the disorder is not classified as minor depressive disorder. Other depressive symptoms include significant weight loss or weight gain without trying to diet (an increase/decrease in appetite can provide clues as well), insomnia or hypersomnia, psychomotor agitation or psychomotor retardation, fatigue or loss of energy, and feelings of worthlessness or excessive guilt.
All of these signs can compound on each other to create the last major symptom group of minor depressive disorder: thoughts of death, suicidal thoughts, plans to commit suicide, or a suicide attempt.Minor depressive disorder differs from major depressive disorder in the number of symptoms present with 5 or more symptoms necessary for a diagnosis of major depressive disorder. Both disorders require either depressed mood or loss of interest or pleasure in normal activities to be one of the symptoms and the symptoms need to be present for two weeks or longer. Symptoms also must be present for the majority of the length of a day and present for a majority of the days in the two-week period. Diagnosis can only occur if the symptoms cause "clinically significant distress or impairment". Dysthymia consists of the same depressive symptoms, but its main differentiable feature is its longer-lasting nature as compared to minor depressive disorder. Dysthymia was replaced in the DSM-5 by persistent depressive disorder, which combined dysthymia with chronic major depressive disorder.
Treatment
Treatment of minor depressive disorder has not been studied as extensively as major depressive disorder. Although there are often similarities in the treatments used, there are also differences in what may work better for the treatment of minor depressive disorder. Some third-party payers do not pay to cover treatment for minor depressive disorder.The leading treatment techniques for minor depressive disorder are the use of antidepressants and therapy. Typically, patients with minor depression were treated by watchful waiting, prescribed antidepressants, and given brief supportive counseling, but Problem-Solving Treatment for Primary Care (PST-PC) is a Cognitive-Behavioral Therapy that has gained popularity. In one study, PST-PC and Paroxetine, an antidepressant, were shown to be equally effective in significantly reducing symptoms. In another study, PST-PC was compared with the more typical care of the time and shown to reduce symptoms more quickly. Although the use of antidepressants has been widely used, not all agree that it is an appropriate treatment for some minor depression disorder settings.Another alternative that has been researched is the use of St. Johns wort (Hypericum perforatum). This herbal treatment has been studied by various groups with various results. Some studies show evidence of the treatment being helpful to treat minor depression, but others show that it does no better than the placebo.
History
At its core, minor depressive disorder is the same illness as major depressive disorder with its symptoms being less pronounced. This ties its history closely to that of major depressive disorder. Depression in the past has largely been shrouded in mystery, as its causes and appropriate treatment were largely unknown. By the 1950s, it was clear that depression could be both a mental and largely physical disease, thus being able to be treated through both psychotherapy and medication. When the DSM-IV-TR was created and major depressive disorder was spelled out more clearly, there still seemed to be an uncategorized range of depression. People in this category did not have a complete set of symptoms in order to be diagnosed with major depression, but still were undoubtedly depressed. The DSM-IV-TR solution to this uncatergorized range of depression was to create Depressive Disorder Not Otherwise Specified (NOS). This group of not specified disorders included minor depressive disorder. In the recent switch to the current DSM-5, minor depressive disorder was dropped from the list of depression disorders.
With the disappearance of minor depressive disorder from the DSM-5, there has been confusion between dysthymic disorder, persistent depressive disorder, and minor depressive disorder. Dysthymic disorder was a subsection in the DSM-IV-TR under mood disorders. In the DSM-5, dysthymia is relabeled as "Persistent Depressive Disorder (Dysthymia)". There are differences between persistent depressive disorder and minor depressive disorder including: length of symptom presence, the number of symptoms present, and recurrent periods. The diagnosis of minor depressive disorder has historically been harder to outline, which could have perhaps lead to the disappearance of the disorder. The DSM-IV-TR includes a statement detailing the difficulty of diagnosis, "symptoms meeting research criteria for minor depressive disorder can be difficult to distinguish from periods of sadness that are an inherent part of everyday life".
== References == |
Hereditary haemochromatosis | Hereditary haemochromatosis type 1 (HFE-related Hemochromatosis) is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no means to excrete excess iron, with the exception of menstruation which, for the average woman, results in a loss of 3.2 mg of iron.Excess iron accumulates in tissues and organs, disrupting their normal function. The most susceptible organs include the liver, heart, pancreas, skin, joints, gonads, thyroid and pituitary gland; patients can present with cirrhosis, polyarthropathy, hypogonadism, heart failure, or diabetes.There are 5 types of hereditary hemochromatosis: type 1, 2 (2A, 2B), 3, 4 and 5, all caused by mutated genes. Hereditary hemochromatosis is the most frequent, and unique related to the HFE gene. It is most common among those of Northern European ancestry, in particular those of Celtic descent. The disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not express signs or symptoms of the condition. In this situation, the otherwise unaffected parents are referred to as carriers.
Signs and symptoms
Haemochromatosis is protean in its manifestations, i.e., often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon, and most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they have premature morbidity, if they are diagnosed early, but, more often than not, the condition is diagnosed only at autopsy.Presently, the classic triad of cirrhosis, bronze skin, and diabetes is less common because of earlier diagnosis.The more common clinical manifestations include:
Fatigue
Malaise
Joint pain (mainly knee and hand)
Abdominal pain
Bronze or gray skin color (for this the illness was named "bronze diabetes" when it was first described by Armand Trousseau in 1865)
Liver fibrosis or cirrhosis (with an increased risk of hepatocellular carcinoma): Liver disease is always preceded by evidence of liver dysfunction, including elevated serum enzymes specific to the liver, clubbing of the fingers, leuconychia, asterixis, hepatomegaly, palmar erythema, and spider naevi. Cirrhosis can also present with jaundice (yellowing of the skin) and ascites.
Diabetes mellitus type 2: HH patients have insulin resistance for liver disease, and poor insulin secretion due to pancreatic damage from iron deposition.
Erectile dysfunction and hypogonadism, resulting in decreased libido, amenorrhea
Congestive heart failure, abnormal heart rhythms, or pericarditis
Arthritis of the hands (especially the second and third metacarpophalangeal joints), but also the knee and shoulder joints
Weight lossLess common findings including:
Memory loss
Hair loss
Splenomegaly
adrenal insufficiency
Deafness
Dyskinesias, including Parkinsonian symptoms
Dysfunction of certain endocrine organs:
Parathyroid gland (leading to hypocalcaemia)
Pituitary gland: secondary hypothyroidism, secondary hypogonadism
Adrenal gland
An increased susceptibility to certain infectious diseases caused by siderophilic microorganisms:
Vibrio vulnificus infections from eating seafood or wound infection
Listeria monocytogenes
Yersinia enterocolica
Salmonella enterica (serotype Typhymurium)
Klebsiella pneumoniae
Escherichia coli
Rhizopus arrhizus
Mucor species
Aspergillus fumigatus
Cytomegalovirus
Hepatitis B virus
Hepatitis C virusIn the hereditary hemochromatosis (HH or HHC), males are usually diagnosed after their forties and fifties, and women some decades later, during menopause. The severity of clinical disease varies considerably. Some evidence suggests that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease have worse liver disease than those with either condition alone. Also, juvenile form of primary haemochromatosis (Hemochromatosis type 2) present in childhood with the same consequences of iron overload.
End-organ damage
Iron is stored in the liver, pancreas and heart.
Long-term effects of haemochromatosis on these organs can be serious, even fatal when untreated.Since the liver is a primary storage area for iron and naturally accumulates excess iron over time, it is likely to be damaged by iron overload.
Toxins may accumulate in the blood and eventually affect mental functioning due to increased risk of hepatic encephalopathy.
Together, they can increase the risk of liver cancer to one in three persons.
If excess iron in the heart interferes with its ability to circulate enough blood, a number of problems can occur, including (potentially fatal) congestive heart failure. The condition may be reversible when haemochromatosis is treated and excess iron stores are reduced. Arrhythmia or abnormal heart rhythm can cause heart palpitations, chest pain, and light-headedness, and is occasionally life-threatening. This condition can often be reversed with treatment.The pancreas, which also stores iron, is very important in the bodys mechanisms for sugar metabolism. Diabetes affects the way the body uses blood sugar (glucose), and diabetes is, in turn, the leading cause of new blindness in adults and may be involved in kidney failure.Haemochromatosis may lead to cirrhosis and its complications, including bleeding from dilated veins in the esophagus (esophageal varices) and stomach (gastric varices) and severe fluid retention in the abdomen (ascites).
Severity of periodontal disease is associated with high transferrin saturation in haemochromatosis patients.
Genetics
The regulation of dietary iron absorption is complex and understanding is incomplete. One of the better-characterized genes responsible for hereditary haemochromatosis is HFE on chromosome 6, which codes for hepcidin, a protein that participates in the regulation of iron absorption. The HFE gene has three often observed genetic variants:
rs1799945, c.187C>G, p.His63Asp (H63D);
rs1800562, c.845G>A, p. Cys282Tyr (C282Y);
rs1800730, c.193A>T, p.Ser65Cys (S65C).The worldwide prevalence rates for H63D, C282Y and S65C (minor allele frequencies) are 10%, 3% and 1% respectively.The C282Y allele is a transition point mutation from guanine to adenine at nucleotide 845 in HFE, resulting in a missense mutation that replaces the cysteine residue at position 282 with a tyrosine amino acid. Heterozygotes for either allele can manifest clinical iron overload, if they have two of any alleles. This makes them compound heterozygous for haemochromatosis and puts them greatly at risk of storing excess iron in the body. Homozygosity for the C282Y genetic variant is the most common genotype responsible for clinical iron accumulation, though heterozygosity for C282Y/H63D variants, so-called compound heterozygotes, results in clinically evident iron overload. Considerable debate exists regarding the penetrance—the probability of clinical expression of the trait given the genotype— for clinical disease in homozygotes. Most males homozygous for HFE C282Y show at least one manifestation of iron-storage disease by middle age. Individuals with the relevant genetic variants may never develop iron overload. Phenotypic expression is present in 70% of C282Y homozygotes with less than 10% going on to experience severe iron overload and organ damage.
The H63D variant is just a gene polymorphism, and if there are no other changes, it may not have clinical significance. In a 2014 study, H63D homozygosity was associated with an elevated mean ferritin level, but only 6.7% had documented iron overload at follow-up. As about the people with one copy of the H63D alteration (heterozygous carriers), this genotype is very unlikely to cause a clinical presentation, there is no predictable risk of iron overload. Besides that, two 2020 studies revealed that the frequency of homozygous or heterozygous H63D variant is significantly higher in elite endurance athletes comparing to ethnically matched controls, and is associated with high V̇O2max in male athletes.
.
Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the genetic variant, and the presence of other insults to the liver, such as alcohol and viral disease. As such, the degree to which the liver and other organs are affected is highly variable and is dependent on these factors and co-morbidities, as well as age at which they are studied for manifestations of disease. Penetrance differs between populations.
Disease-causing genetic variants of the HFE gene account for 90% of the cases of non-transfusion iron overload.This gene is closely linked to the HLA-A3 locus.
Pathophysiology
Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available. A working model describes the defect in the HFE gene, where a mutation puts the intestinal absorption of iron into overdrive. Normally, HFE facilitates the binding of transferrin, which is irons carrier protein in the blood. Transferrin levels are typically elevated at times of iron depletion (low ferritin stimulates the release of transferrin from the liver). When transferrin is high, HFE works to increase the intestinal release of iron into the blood. When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron. This leads to maximal iron absorption from ingested foods and iron overload in the tissues. However, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype. A possible explanation is the fact that HFE normally plays a role in the production of hepcidin in the liver, a function that is impaired in HFE mutations.People with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body. Thus, the iron stores of the body increase. As they increase, the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress. Iron is a pro-oxidant. Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilsons disease, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs. The latter also experience "bronzing".
Diagnosis
The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or elevation of the transferrin saturation or elevated serum ferritin.. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint.
Blood tests
Serum ferritin and fasting transferrin saturation are commonly used as screening for haemochromatosis. Transferrin binds iron and is responsible for iron transport in the blood. Measuring ferritin provides a crude measure of iron stores in the body. Fasting transferrin saturation values in excess of 45%, and the serum ferritin more than 250 ug/L in males and 200 ug/L in females are recognized as a threshold for further evaluation of haemochromatosis. Other source says that the normal values for males are 12-300 ng/mL and for female, 12-150 ng/mL. Fasting transferrin saturation is a better test to detect HH. Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the HFE gene.Ferritin, a protein synthesized by the liver, is the primary form of iron storage within cells and tissues. Measuring ferritin provides a crude estimate of whole-body iron stores, though many conditions, particularly inflammatory conditions, infection, chronic alcohol consumption (mainly >20g/day), liver disease, cancer, porphyria, Hemophagocytic lymphohistiocytosis, hyperthyroidism, obesity, metabolic syndrome, diabetes, several blood transfusions, too many iron supplements, aceruloplasminemia, atransferrinemia, hyperferritinemia cataract syndrome and others, can elevate serum ferritin, which can account for up to 90% of cases where elevated levels are observed. Measuring iron in the body</ref> Serum ferritin in excess of 1000 ng/mL of blood is almost always attributable to haemochromatosis.Other blood tests routinely performed include blood count, renal function, liver enzymes, electrolytes, and glucose (and/or an oral glucose tolerance test).
Liver biopsy
Liver biopsies involve taking a sample of tissue from the liver, using a thin needle. The amount of iron in the sample is then quantified and compared to normal, and evidence of liver damage, especially cirrhosis, is measured microscopically. Formerly, this was the only way to confirm a diagnosis of haemochromatosis, but measures of transferrin and ferritin along with a history are considered adequate in determining the presence of the malady. Risks of biopsy include bruising, bleeding, and infection. Now, when a history and measures of transferrin or ferritin point to haemochromatosis, whether a liver biopsy is still necessary to quantify the amount of accumulated iron is debatable.
MRI
MRI-based testing is a noninvasive and accurate alternative to measure liver iron concentrations.
Other imaging
Clinically, the disease may be silent, but characteristic radiological features may point to the diagnosis. The increased iron stores in the organs involved, especially in the liver and pancreas, result in characteristic findings on unenhanced CT and a decreased signal intensity in MRI scans. Haemochromatosis arthropathy includes degenerative osteoarthritis and chondrocalcinosis. The distribution of the arthropathy is distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand. The arthropathy can, therefore, be an early clue as to the diagnosis of haemochromatosis.
Functional testing
Based on the history, a physician might consider specific tests to monitor organ dysfunction, such as an echocardiogram for heart failure, or blood glucose monitoring for patients with haemochromatosis diabetes.
Stages
The American Association for the Study of Liver Diseases suggests the following three stages for the condition (identified by the European Association for the Study of Liver Diseases):
Genetic susceptibility but no iron overload. Individuals who have the genetic disorder only.
Iron overload but no organ or tissue damage.
Organ or tissue damage as a result of iron deposition.Individuals at each stage do not necessarily progress on to the next stage, and end stage disease is more common in males.
Differential diagnosis
Other causes of excess iron accumulation exist, which have to be considered before haemochromatosis type 1 is diagnosed.
Haemochromatosis type 2.
Haemochromatosis type 3.
Haemochromatosis type 4.
Haemochromatosis type 5.
African iron overload, formerly known as Bantu siderosis, was first observed among people of African descent in Southern Africa. Originally, this was blamed on ungalvanised barrels used to store home-made beer, which led to increased oxidation and increased iron levels in the beer. Further investigation has shown that only some people drinking this sort of beer get iron overload syndrome, and that a similar syndrome occurred in people of African descent who have had no contact with this kind of beer (e.g., African Americans). This led investigators to the discovery of a gene polymorphism in the gene for ferroportin, which predisposes some people of African descent to iron overload.
Secondary haemochromatosis: its main cause is the Transfusional haemosiderosis. It is the accumulation of iron, mainly in the liver, in patients who receive frequent blood transfusions (such as those with thalassaemia). Other causes are: chronic hemolytic anemia, chronic liver disease (hepatitis B, hepatitis C, cirrhosis, fatty liver disease), dysmetabolic hyperferritinemia, overdose of oral iron pills or iron injections, long-time kidney dialysis, and dyserythropoeisis, also known as myelodysplastic syndrome. It is a disorder in the production of red blood cells that leads to increased iron recycling from the bone marrow and accumulation in the liver.
Aceruloplasminemia.
Atransferrinemia.
Neonatal hemochromatosis
GRACILE syndrome
Porphyria cutanea tarda
Screening
Standard diagnostic measures for haemochromatosis, transferrin saturation and ferritin tests, are not a part of routine medical testing. Screening for haemochromatosis is recommended if the patient has a parent, child, or sibling with the disease.Routine screening of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the U.S. Preventive Services Task Force, among other groups, which recommended against genetic screening of the general population for hereditary haemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than one in 1,000. Although strong evidence shows that treatment of iron overload can save lives in patients with transfusional iron overload, no clinical study has shown that for asymptomatic carriers of hereditary haemochromatosis treatment with venesection (phlebotomy) provides any clinical benefit. Recently, patients are suggested to be screened for iron overload using serum ferritin as a marker. If serum ferritin exceeds 1000 ng/mL, iron overload is very likely the cause.
Treatment
Phlebotomy
Early diagnosis is vital, as the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations.Phlebotomy (or bloodletting) is usually done at a weekly or each two weeks interval until ferritin levels are 50 μg/L or less. To prevent iron reaccumulation, subsequent phlebotomies are normally carried out about once every three to four months for males, and twice a year for females to keep the serum ferritin between 50 and 100 ug/L
Iron chelation therapy
Where venesection is not possible, long-term administration of an iron chelator as Deferoxamine (or Desferrioxamine), Deferasirox and Deferiprone is useful. Deferoxamine is an iron-chelating compound, and excretion induced by deferoxamine is enhanced by administration of vitamin C. It cannot be used during pregnancy or breast-feeding due to risk of defects in the child.
Organ damage
Treatment of organ damage (heart failure with diuretics and ACE inhibitor therapy). Hepatic transplantation in patients with liver failure.
Diet
Limiting intake of alcoholic beverages, vitamin C (increases iron absorption in the gut), red meat (high in iron), and potential causes of food poisoning (shellfish, raw seafood)
Increasing intake of substances that inhibit iron absorption, such as high-tannin tea, calcium, and foods containing oxalic and phytic acids (such as collard greens, which must be consumed at the same time as the iron-containing foods to be effective)
Chelating polymers
A novel experimental approach to the hereditary haemochromatosis treatment is the maintenance therapy with polymeric chelators. These polymers or particles have a negligible or null systemic biological availability and they are designed to form stable complexes with Fe2+ and Fe3+ in the GIT and thus limiting the uptake of these ions and their long-term accumulation. Although this method has only a limited efficacy, unlike small-molecular chelators, such an approach has virtually no side effects in sub-chronic studies. Interestingly, the simultaneous chelation of Fe2+ and Fe3+ increases the treatment efficacy.
Prognosis
Persons with symptomatic haemochromatosis have somewhat reduced life expectancy compared to the general population, mainly due to excess mortality from cirrhosis and liver cancer. Patients who were treated with phlebotomy lived longer than those who were not. Patients without liver disease or diabetes had similar survival rate to the general population.
Epidemiology
Haemochromatosis is one of the most common heritable genetic conditions in people of Northern Europe, with a prevalence of 1:200. The disease has a variable penetration, and about one in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism. In the U.S., the frequency of the C282Y and H63D mutations is 5.4% and 13.5%, respectively. Whereas, the worldwide frequency of the C282Y and H63D mutations is about 1.9% and 8.1%, respectively, so mutation in H63D allele are more than C282Y allele. The prevalence of mutations in iron-metabolism genes varies in different populations. A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0.5% were homozygous for an HFE mutation, and only 0.25% of the study population had clinically relevant iron overload. Most patients who are homozygous for HFE mutations do not manifest clinically relevant haemochromatosis (see Genetics above). Other populations have a lower prevalence of both the genetic mutation and the clinical disease. It is the most frequent genetic disease in the U.S. with a prevalence of 1:300 in the non-Hispanic white population, It is 2-3 times most common in males.Genetics studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60–70 generations ago. At that time, when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided an evolutionary advantage by maintaining higher iron levels in the blood.The distribution of the C282Y variant was noted in various countries. Non-HFE associated hemochromatosis, as Haemochromatosis type 2, Haemochromatosis type 3, Haemochromatosis type 4 and Haemochromatosis type 5, were discovered in Mediterranean countries. On the other side, Northern European ancestry is closely linked to hereditary hemochromatosis disease (HFE). In one study, over 93% of Irish patients with HFE C282Y mutation were homozygotic. The G320V mutation in the HJV gene, which produces hemojuvelin protein, is widely distributed in central Europe and Greece.
Terminology
The term "haemochromatosis" is used by different sources in many different ways.
It is often used to imply an association with the HFE gene. For many years, HFE was the only known gene associated with haemochromatosis, and the term "hereditary haemochromatosis" was used to describe haemochromatosis type 1. However, many different genetic associations with this condition are now known. The older the text, or the more general the audience, the more likely that HFE is implied. "Haemochromatosis" has also been used in contexts where a genetic cause for iron accumulation had not been known. In some cases, however, a condition that was thought to be due to diet or environment was later linked to a genetic polymorphism, as in African iron overload.
History
In 1847, Virchow described a golden brown granular pigment that was soluble in sulfuric acid and produced red ash on ignition. The disease was first described in 1865 by Armand Trousseau in a report on diabetes in patients presenting with a bronze pigmentation of their skin. Two years later, Perls developed the first practical method for the analysis of iron in tissue. Despite Trousseau did not associate diabetes with iron accumulation, the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen in 1890. In 1935, English gerontologist Joseph Sheldon described the cases of haemochromatosis. He established this as the name of the disorder and his detailed monograph. Despite lacking the modern molecular techniques accessible today, he came to accurate conclusions that describe haemochromatosis disease as an inborn error of metabolism where this inherited disorder can increase the absorption of iron and thus cause tissue damage due to iron deposition. Moreover, he rejected theories that alcohol, drug, and other factors contribute to the disorder.The clinical case series from 1935 to 1955 indicated that haemochromatosis was more common than had been acknowledged. During the 1960s, MacDonald, a pathologist at Boston City Hospital, diverted attention away from the true cause of haemochromatosis. He believed that haemochromatosis was a nutritional condition because he observed many drunken patients of Irish ancestry. During this period of time, other investigators reported additional evidence suggesting that a genetic factor could play a central role in the absorption of iron in people with haemochromatosis. However, alcohol consumption is known to increase the risk of liver injury in haemochromatosis. This finding is consistent with the concept that excess iron metabolism is a primary cause of haemochromatosis disease.Finally, in 1976, Marcel Simon and his collaborators confirmed that haemochromatosis is an autosomal recessive disorder that has a link to the human leukocyte antigen (HLA) region of the genome. It took 20 years for researchers at Mercator Genetics to effectively identify and clone the haemochromatosis genes using a positional cloning approach.In 1996, Feder et al. identified HFE, which is a major histocompatibility complex (MHC) gene. They found that 83% of patients have homozygosity for a missense mutation (C282Y) in the HFE gene. Finally, several groups reported their findings in a series of patients with haemmochromatosis where they discovered the existence of the C282Y mutation in about 85-90% of the cases. The discovery has led to improved clinical medicine and liver disease evaluation.
References
External links
GeneReview/NIH/UW entry on HFE-Associated Hereditary Hemochromatosis
Hereditary haemochromatosis at Curlie |
Brodie abscess | A Brodie abscess is a subacute osteomyelitis, which may persist for years before progressing to a chronic, frank osteomyelitis. Classically, this may present after progression to a draining abscess extending from the tibia out through the skin. Occasionally acute osteomyelitis may be contained to a localized area and walled off by fibrous and granulation tissue.
The most frequent causative organism is Staphylococcus aureus.
Presentation
Localized pain, often nocturnal, alleviated by aspirin. Often mimics the symptoms of osteoid osteoma, which is typically less than 1 cm in diameter.
Location
Usually occurs at the metaphysis of long bones.
Distal tibia,
proximal tibia,
distal femur,
proximal or distal fibula, and
distal radius.
Diagnosis
Radiographic features
Oval, elliptical, or serpentine radiolucency usually greater than 1 cm surrounded by a heavily reactive sclerosis, granulation tissue, and a nidus often less than 1 cm. The margins often appear scalloped on radiograph. Brodies abscess is best visualized using computed tomography (CT) scan.
Associated atrophy of soft tissue near the site of infection and shortening of the affected bone. Osteoblastoma may be a classic sign for Brodies abscess.
Treatment
In the majority of cases, surgery has to be performed.
If the cavity is small then surgical evacuation and curettage is performed under antibiotic cover.
If the cavity is large then the abscess space may need packing with cancellous bone chips after evacuation.
History
Brodie abscess is named after Sir Benjamin Collins Brodie, 1st Baronet. In the 1830s, he initially described a chronic inflammatory condition affecting the tibia without obvious acute etiology. It was later discovered that this was caused by infection.
References
== External links == |
POEMS syndrome | POEMS syndrome (also termed osteosclerotic myeloma, Crow–Fukase syndrome, Takatsuki disease, or PEP syndrome) is a rare paraneoplastic syndrome caused by a clone of aberrant plasma cells. The name POEMS is an acronym for some of the diseases major signs and symptoms (polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes), as is PEP (polyneuropathy, endocrinopathy, plasma cell dyscrasia).
The signs and symptoms of most neoplasms are due to their mass effects caused by the invasion and destruction of tissues by the neoplasms cells. Signs and symptoms of a cancer causing a paraneoplastic syndrome result from the release of humoral factors such as hormones, cytokines, or immunoglobulins by the syndromes neoplastic cells and/or the response of the immune system to the neoplasm. Many of the signs and symptoms in POEMS syndrome are due at least in part to the release of an aberrant immunoglobulin, i.e. a myeloma protein, as well as certain cytokines by the malignant plasma cells.POEMS syndrome typically begins in middle age – the average age at onset is 50 – and affects up to twice as many men as women.
Signs and symptoms
The signs and symptoms of POEMS syndrome are highly variable. This often leads to long delays (e.g. 13–18 months) between the onset of initial symptoms and diagnosis. In addition to the signs and symptoms indicated by the POEMS acronym, the PEST acronym is used to describe some of the other signs and symptoms of the disease. PEST stands for Papilledema, evidence of Extravascular volume overload (ascites, pleural effusion, pericardial effusion, and lower extremity edema), Sclerotic bone lesions, and Thrombocytosis/erythrocytosis (i.e. increased in blood platelets and red blood cells). Other features of the disease include a tendency toward leukocytosis, blood clot formation, abnormal lung function (restrictive lung disease, pulmonary hypertension, and impaired lung diffusion capacity), very high blood levels of the cytokine vascular endothelial growth factor (VEGF), and an overlap with the signs and symptoms of multicentric Castleman disease.
Common features
The more common features of the disease are summarized in the acronym POEMS:
Papilledema (swelling of the optic disc) often but not always due to increased intracranial pressure) is the most common ocular sign of POEMS syndrome, occurring in ≥29% of cases. Less frequent ocular findings include cystoid macular edema, serous macular detachment, infiltrative orbitopathy, and venous sinus thrombosis.Pulmonary disease/ Polyneuropathy: The lungs are often affected at more severe stages of the illness, although since by then physical exertion is usually limited by neuropathy, shortness of breath is unusual. Pulmonary hypertension is the most serious effect on the lungs, and there may also be restriction of chest expansion or impaired gas exchange.Organomegaly: The liver may be enlarged, and less often the spleen or lymph nodes, though these organs usually function normally.Edema: Leakage of fluid into the tissues is a common and often severe problem. This may take several forms, including dependent peripheral edema, pulmonary edema, effusions such as pleural effusion or ascites, or generalized capillary leakage (anasarca).Endocrinopathy: In women, amenorrhea, and in men, gynecomastia, erectile dysfunction and testicular atrophy, are common early symptoms due to dysfunction of the gonadal axis. Other hormonal problems occurring in at least a quarter of patients include type 2 diabetes, hypothyroidism, and adrenal insufficiency.Monoclonal paraprotein: In most cases a serum myeloma protein can be detected, although this is not universal. This may represent IgG or IgA, but the light chain type is almost always lambda. This is in contrast to most paraproteinemic neuropathies, in which the paraprotein is usually an IgM antibody.Skin changes: A very wide variety of skin problems have been reported in association with POEMS syndrome. The most common is non-specific hyperpigmentation. The fingernails may be clubbed or white. There may be thickening of the skin, excess hair or hair in unusual places (hypertrichosis), skin angiomas or hemangiomas, or changes reminiscent of scleroderma.
Possible features
Some features have been observed in patients with POEMS syndrome but are not yet certain to form part of the syndrome itself. These include a predisposition to forming blood clots, joint pain, cardiomyopathy (systolic dysfunction), fever, low vitamin B12 levels, and diarrhea.
Pathogenesis
While the main features of this paraneoplastic disease have been described, the exact mechanism behind its development, progression, and manifestations remain elusive. Overproduction of the myeloma protein and VEGF may underlie some, but are insufficient to explain all, of the multi-organ features of the disease. It is suggested that various other cytokines produced by the clonal plasma cells, perhaps working in concert with each other as well as with VEGF and the myeloma proteins, mediate many of the features of POEMS syndrome. The other cytokines detected in, and suspected of contributing to, POEMS syndrome include interleukin 1β, interleukin 6, and TNFα. Nonetheless, it seems likely that some of these paraneoplastic factors, operating individually, make a major contribution to certain features of the disease. For example, VEGF, given its ability to stimulate blood vessel formation, would seem likely to be the major contributor to the pathologic hyper-vascularization changes seem in many tissues, such as lymph nodes, affected by POEMS syndrome.
Diagnosis
The diagnosis of POEMS syndrome is based on meeting its two mandatory criteria, meeting at least one of its 3 other major criteria, and meeting at least one of its 6 minor criteria. These criteria are:
Mandatory major criteria
Plasma cell dyscrasia: This is evidenced by 1) the presence of a serum myeloma protein, typically an IgG or IgA isotype (occurs in nearly 100% of cases; in >95% of instances the myeloma proteins contain a λ chain that is restricted to either of two V lambda 1 subfamily members viz., IGLV1-40*01 and IGLV1-44*01 (see V lambda family); 2) any, but often a small, increase above the normal value of <1.5% in the percentage of nucleated bone marrow cells that are clonal plasma cells (occurs ~67% of cases); and/or 3) presence of a plasma cell tumor (i.e. plasmacytoma) usually in bone (occurs in ~33% of cases).
Polyneuropathy: The nerve damage is usually symmetrical, located in distal extremities, and due to the nerve losing its fatty myelin coating and axonal damage. Neurons of the Sensory, motor and autonomic nervous systems are all affected. The typical symptoms are therefore numbness, tingling, and weakness in the feet, later affecting the legs and hands. Pain is unusual, but the weakness may eventually become severe and disabling. The autonomic neuropathy may cause excessive sweating and erectile dysfunction; hormonal changes may also contribute to the latter. It is usually the symptoms of neuropathy which prompt a person with POEMS syndrome to seek medical attention.
Other major criteria
Castleman disease: The lymphoproliferative disorder Castleman disease associated with POEMS syndrome is multicentric and occurs in ~15 of cases. It is characterized by a morphology in lymph nodes termed angiofollicular lymph node hyperplasia; an overly activate immune system; excessive production of cytokines including particularly IL-6 and to lesser extents, proliferation of immune B cells and T cells, enlarged lymph nodes, enlarged liver and spleen, capillary leak syndrome, anasarca, evidence of extravascular fluid overload, and organ failure. Patients with Castleman disease without a plasma cell dyscrasia and peripheral neuropathy but having other signs and symptoms of POEMS syndrome can be classified as a Castleman disease variant of POEMS syndrome.
Sclerotic bone lesions: These lesions consist of plasma cell tumors encased within or associated with abnormally dense bone structures; in different studies, they have been observed to occur in 27% to 97% of cases.
Elevated VEGF: VEGF is a cytokine that stimulates angiogenesis (i.e. capillary formation), increases capillary permeability, and contributes to polyneuropathy. It is elevated in almost all cases of POEMS syndrome and has become a clinically useful marker for the syndromes presence, severity, and response to treatment. However, its role in mediating the symptoms of this disease are unclear. A second cytokine, IL-12, is similar to VEGF in being highly correlated with the disease activity level in POEMS syndrome.
Minor criteria
Organomegaly: Enlargement spleen, liver, and/or lymph nodes occurs in 45% to 85% of cases.
Extravascular volume overload: Ascites, pleural effusions, pericardial effusions, and/or lower extremity edema occur in 27% to 89% of cases.
Endocrinopathy: Gynecomastia occurs in 12% to 18% of cases; endocrine abnormalities involving the regulation of gonadotrophins, adrenal gland corticosteroids, and prolactin occur in 55% to 89%, 16% to 33%, and 55 to 20% of cases, respectively. Diabetes and hypothyroidism also occur in 3% to 36% and 9% to 67%, respectively, of cases but are not considered to be criteria for the presence of POEMS syndrome because of their frequent occurrence in the general population.
Skin changes: Skin changes occur in 68% to 89% of POEMS syndrome patients. These changes most commonly are hyperpigmentation and/or hypertrichosis (abnormal amount of hair growth over the body) but less commonly include glomeruloid hemangioma, signs or symptoms of Hypervolemia (e.g. edema and ascites), acrocyanosis (blue discoloration of the extremities due to blood flow abnormalities), flushing, and/or white nails.
Papilledema: Papilledema (swelling of retinal optical discs) occurs in 29% to 64% of cases. Papilledema in POEMS syndrome patients may occur with or without visual disturbances, increased intracranial pressure, or changes in cerebral spinal fluid protein levels.
Thrombocytosis/polycythemia: Thrombocytosis (increase in blood platelet count) and polycythemia (increase in red blood cells) occurs 54% to 88% and 12% to 19%, respectively, of POEMS syndrome patients and may be may underlying causes of these patients to experience thrombosis events.
Laboratory findings
In addition to tests corresponding to the above findings, such as EMG for neuropathy, CT scan, bone marrow biopsy to detect clonal plasma cells, plasma or serum protein electrophoresis to myeloma proteins, other tests can give abnormal results supporting the diagnosis of POEMS syndrome. These included raised blood levels of VEGF, thrombocytes, and/or erythrocyte parameters.
Differential diagnosis
Patients diagnosed as having Castleman disease but also exhibiting many of the symptoms and signs of POEMS syndrome but lacking evidence of a peripheral neuropathy and/or clonal plasma cells should not be diagnosed as having POEMS syndrome. They are better classified as having Castleman disease variant of POEMS syndrome. These patients may exhibit high blood levels of the interleukin-6 cytokine and have an inferior overall survival compared to POEMS syndrome patients. Treatment of patients with this POEMS syndrome variant who have evidence of bone lesions and/or myeloma proteins are the same as those for POEMS syndrome patients. In the absence of these features, treatment with rituximab, a monoclonal antibody preparation directed against B cells bearing the CD20 antigen, or siltuximab, a monoclonal antibody preparation directed against interleukin-6, may be justified.
Treatment
As reported by Dispenzieri et al. Mayo Clinic treatment regimens are tailored to treat the clinical manifestations and prognosis for the rate of progression of the POEMS syndrome in each patient. In rare cases, patients may have minimal or no symptoms at presentation or after successful treatment of their disorder. These patients may be monitored every 2–3 months for symptoms and disease progression. Otherwise, treatment is divided based on the local versus systemic spread of its clonal plasma cells. Patients with one or two plasmacytoma bone lesions and no clonal plasma cells in their bone marrow biopsy specimens are treated by surgical removal or radiotherapy of their tumors. These treatments can relieve many of the syndromes clinical manifestations including neuropathies, have a 10-year overall survival of 70% and a 6-year progression-free survival of 62%. Patients with >2 plasmacytoma bone lesions and/or increases in bone marrow clonal plasma cells are treated with a low-dose or high-dose chemotherapy regimen, i.e. a corticosteroid such as dexamethasone plus an alkylating agents such as melphalan. Dosage regimens are selected on the basis of patient tolerance. Hematological response rates to the dexamethasone/melphalan regimens have been reported to be in the 80% range with neurological response rates approaching 100%. Patients successfully treated with the high-dose dexamethasone/melphalan regimen have been further treated with autologous stem cell transplantation. In 59 patients treated with the chemotherapy/transplantation regimen, the Mayo Clinic reported progression-free survival rates of 98%, 94%, and 75% at 1, 2, and 5 years, respectively.Other treatment regiments are being studied. Immunomodulatory imide drugs such as thalidomide and lenalidomide have been used in combination with dexamethasone to treat POEMS syndrome patients. While the mechanism of action of these immunomodulators are not clear, they do inhibit the production of cytokines suspected of contributing to POEMS syndrome such as VEGF, TNFα, and IL-6 and stimulate T cells and NK cells to increase their production of interferon gamma and interleukin 2 (see immunomodulatory imide drugs mechanism of action). A double blind study of 25 POEMS syndrome patients found significantly better results (VEGF reduction, neuromuscular function improvement, quality of life improvement) in patients treated with thalidomide plus dexamethasone compared to patients treated with a thalidomide placebo plus dexamethasone.Since VEGF plays a central role in the symptoms of POEMS syndrome, some have tried bevacizumab, a monoclonal antibody directed against VEGF. While some reports were positive, others have reported capillary leak syndrome suspected to be the result of overly rapid lowering of VEGF levels. It therefore remains doubtful as to whether this will become part of standard treatment for POEMS syndrome.
History
R. S. Crow, working in Bristol, first described the combination of osteosclerotic myeloma, polyneuropathy and various unusual features (such as pigmentation and clubbing) in two patients aged 54 and 67.
References
== External links == |
Saddle sore | A saddle sore in humans is a skin ailment on the buttocks due to, or exacerbated by, horse riding or cycling on a bicycle saddle. It often develops in three stages: skin abrasion, folliculitis (which looks like a small, reddish acne), and finally abscess.
Because it most commonly starts with skin abrasion, it is desirable to reduce the factors which lead to skin abrasion. Some of these factors include:
Reducing the friction. In equestrian activities, friction is reduced with a proper riding position and using properly fitting clothing and equipment. In cycling, friction from bobbing or swinging motion while pedaling is reduced by setting the appropriate saddle height. Angle and fore/aft position can also play a role, and different cyclists have different needs and preferences in relation to this.
Selecting an appropriate size and design of horse riding saddle or bicycle saddle.
Wearing proper clothing. In bicycling, this includes cycling shorts, with chamois padding. For equestrian activity, long, closely fitted pants such as equestrian breeches or jodhpurs minimize chafing. For western riding, closely fitted jeans with no heavy inner seam, sometimes combined with chaps, are preferred. Padded cycling shorts worn under riding pants helps some equestrians, and extra padding, particularly sheepskin, on the seat of the saddle may help in more difficult situations such as long-distance endurance riding.
Using petroleum jelly, chamois cream or lubricating gel to further reduce friction.If left untreated over an extended period of time, saddle sores may need to be drained by a physician.
In animals such as horses and other working animals, saddle sores often form on either side of the withers, which is the area where the front of a saddle rests, and also in the girth area behind the animals elbow, where they are known as a girth gall. Saddle sores can occur over the loin, and occasionally in other locations. These sores are usually caused by ill-fitting gear, dirty gear, lack of proper padding, or unbalanced loads. Reducing friction is also of great help in preventing equine saddle sores. Where there is swelling but not yet open sores, the incidence of sore backs may be reduced by loosening the girth without immediately removing the saddle after a long ride, thus allowing normal circulation to return slowly.
See also
Bicycling
Pack saddle
== References == |
Polymelia | Polymelia is a birth defect in which an affected individual has more than the usual number of limbs. It is a type of dysmelia. In humans and most land-dwelling vertebrates, this means having five or more limbs. The extra limb is most commonly shrunken and/or deformed. The term is from Greek πολυ- "many", μέλεα "limbs".
Sometimes an embryo started as conjoined twins, but one twin degenerated completely except for one or more limbs, which end up attached to the other twin.
Sometimes small extra legs between the normal legs are caused by the body axis forking in the dipygus condition.
Notomelia (from Greek for "back-limb-condition") is polymelia where the extra limb is rooted along or near the midline of the back. Notomelia has been reported in Angus cattle often enough to be of concern to farmers.Cephalomelia (from Greek for "head-limb-condition") is polymelia where the extra limb is rooted on the head.
Origin
Tetrapod legs evolved in the Devonian or Carboniferous geological period from the pectoral fins and pelvic fins of their crossopterygian fish ancestors.
Fish fins develop along a "fin line", which runs from the back of the head along the midline of the back, round the end of the tail, and forwards along the underside of the tail, and at the cloaca splits into left and right fin lines which run forwards to the gills. In the paired ventral part of the fin line, normally only the pectoral and pelvic fins survive (but the Devonian acanthodian fish Mesacanthus developed a third pair of paired fins); but along the non-paired parts of the fin line, other fins develop.
In tetrapods, only the four paired fins normally persisted, and became the four legs. Notomelia and cephalomelia are atavistic reappearances of dorsal fins. Some other cases of polymelia are extra development along the paired part of the fin lines, or along the ventral posterior non-paired part of the fin line.
Notable cases
Humans
1995: Somali baby girl born with three right arms.
In the summer of 2005, a baby girl named Destiny was born with a fully formed extra leg in Detroit. This was the result of a conjoined twin scenario.
In March 2006, a baby boy identified only as Jie-jie was born in Shanghai with a fully formed third arm: he had two full-sized left arms, one ventral to the other. This is the only documented case of a child born with a fully formed supernumerary arm. It is an example of an extra limb on a normal body axis.
In July 2007 a child was born with four legs at the Lebowakgomo hospital outside Polokwane (South Africa)
On November 6, 2007, doctors at Bangalores Sparsh Hospital in Bangalore, India successfully completed surgery on a two-year-old girl named Lakshmi Tatma who was born with four arms and four legs; this was not true polymelia but a case of ischiopagus Siamese twinning where one twins head had disappeared during development.
Frank Lentini had a third leg, as well as a fourth foot and two sets of genitals.
A boy named Gaurav, born in Tanahun district in Nepal with an extra arm growing out of his upper back between his shoulder blades, two years ago was published on 2016.
Other animals
A four-legged chicken was born at Brendle Farms in Somerset, Pennsylvania, in 2005. The story was carried on the major TV network news programs and USA Today. The bird was found living normally among the rest of the chickens after 18 months. She was adopted and named Henrietta by the farm owners 13-year-old daughter, Ashley, who refuses to sell the chicken. The second (hind) legs are fully formed but non-functional.
Four-legged ducks are occasionally hatched, such as Stumpy, an individual born in February 2007 on a farm in Hampshire, England.
Frogs in the US sometimes are affected by polymelia when attacked in the tadpole stage by the Ribeiroia parasite.
A puppy, known as Lilly, was born in the United States with a fully formed fifth leg jutting out between her hind legs. She was initially set to be sold to a freak show, but was instead bought by a dog lover who had the extra leg removed.
An eight-legged lamb has been reported on at least two occasions including in 1898 and 2018.
In mythology
Many mythological creatures like dragons, winged horses, and griffins have six limbs: four legs and two wings. The dragons science is discussed in Dragons: A Fantasy Made Real.
In Greek Mythology:
The Hekatonkheires were said to each have one hundred hands.
The Gegenees were a race of giants with six arms.
The centaurs had six limbs: four horse legs and two human arms.Sleipnir, Odins horse in Norse mythology, has eight normal horse legs, and is usually depicted with limbs twinned at the shoulder or hip.
Several Hindu deities are depicted with multiple arms and sometimes also multiple legs.
In popular culture
Edward Albees stage play The Man Who Had Three Arms tells the story of a fictional individual who was normal at birth but eventually sprouted a third functional arm, protruding from between his shoulder blades. After several years of living with three arms, the extra limb was reabsorbed into his body and the man became physically normal again. In Albees play, the title character is extremely angry that we (the audience) seem to be much more interested in the period of his life when he had three arms, rather than his normal life before and after that interval.
Monty Pythons Flying Circus performed a skit about a man with three buttocks. He believes that he has been invited to be interviewed on television because he is a nice person, and is dismayed to learn that he has only been invited because the interviewer is curious about his unusual condition.
The Dark Backward is a 1991 comedy film directed and written by Adam Rifkin, which features Judd Nelson as an unfunny garbage man who pursues a stand-up comedy career. When the "comedian" grows a third arm out of his back, he becomes an overnight hit.
Justice, the main antagonist in the cartoon Afro Samurai, has a fully formed extra arm protruding from his right shoulder.
Paco, a playable character in Brawlout, is a four-armed frog- and shark-like creature.
Spiral, character in the X-Men stories of Marvel Comics, has six arms.
A 6-armed Spider-Man frequently appears as an alternate reality incarnation of the character, and is sometimes referred to as "Polymelian".
In the Mortal Kombat series, the Shokan is a race of humanoids known to have four arms.
Ibid: A Life is a fictional biography of Jonathan Blashette, a man with three legs.
Zaphod Beeblebrox, a character in Douglas Adams Hitchhikers Guide to the Galaxy, has a third arm as well as a second head.
See also
Dipygus
Dysmelia
Polydactyly
Polysyndactyly
Supernumerary body parts
References
Sources
Avian Diseases, 1985 Jan-Mar; 29(1): pp. 244-5. Polymelia in a broiler chicken., Anderson WI, Langheinrich KA, McCaskey PC.: "A polymelus monster was observed in a 7-week-old slaughterhouse chicken. The supernumerary limbs were smaller than the normal appendages but contained an equal number of digits.".
Kim C, Yeo S, Cho G, Lee J, Choi M, Won C, Kim J, Lee S (2001). "Polymelia with two extra forelimbs at the right scapular region in a male Korean native calf". J. Vet. Med. Sci. 63 (10): 1161–4. doi:10.1292/jvms.63.1161. PMID 11714039.
"Polymelia in the toad Bufo melanostictus" (PDF). Ias.ac.in. Retrieved 2016-12-22.
External links
2013: child with two left legs
Youtube video of child with notomelia |
Transient neonatal pustular melanosis | Transient neonatal pustular melanosis (TNPM), also known as pustular melanosis, is a transient rash common in newborns. It is vesiculopustular and made up of 1–3 mm fluid-filled lesions that rupture, leaving behind a collarette of scale and a brown macule.[3] This rash occurs only in the newborn stage, usually appearing a few days after birth[2], but is sometimes already present at birth[3]. The rash usually fades over three to four weeks but may linger for up to three months after birth.[3] It can occur anywhere on the body, including the palms and soles.[1][2][3]The cause of TNPM is unknown. No treatment is needed except for parental reassurance.
Causes
The cause of TNPM is unknown but it is a common rash in newborns.[3]
Histopathology
Gram, Wright, or Giemsa staining of the pustular contents will show polymorphic neutrophils and occasional eosinophils.[2][3] On histopathology, the pigmented macules will show basal and supra-basal increase in pigmentation without any pigmentary incontinence.[3] Bacterial culture will be negative.[4]It has been suggested that TNPM is merely a precocious form of erythema toxicum neonatorum based on the similar histopathology.[4]
Diagnosis
Transient neonatal pustular melanosis is diagnosed clinically, based on appearance alone, with no need for special testing. Proper identification is important to distinguish it from other serious, infectious neonatal diseases[3] and to help avoid unnecessary diagnostic testing and treatments.
Treatment
No treatment is needed except for parental reassurance. The rash spontaneously resolves, usually in three to four weeks, but may linger for up to three months after birth.[3]
Epidemiology
Transient neonatal pustular melanosis occurs in as much as 15% of black newborns.[3] but in less than 1% of white newborns. [2]
See also
List of cutaneous conditions
References
1. OConnor NR, McLaughlin, MR, Ham P (2008). "Newborn Skin: Part I. Common Newborn Rashes". American Family Physician. 77 (1): 47–52.
2. Patrizi A, Neri I, Virid A, Gurioli C.(2016). "Frequent newborn skin diseases". Clinical Dermatology. 4 (3-4): 82–86. doi: 10.11138/cderm/2016.4.3.082.
3. Ghosh S. (2015). "Neonatal Pustular Dermatosis: An Overview". Indian Journal of Dermatology. 60 (2): 211. doi: 10.4103/0019-5154.152558
4. Ferrándiz C, Coroleu W, Ribera M, Lorenzo JC, Natal A (1992). "Sterile transient neonatal pustulosis is a precocious form of erythema toxicum neonatorum". Dermatology. 185:18–22.
5. Mebazaa A, Khaddar-Kort R, Cherif M, Mokni S, Haouet A, Osman B (2011). "Transient pustular eruption in neonates". Archives de Pediatrie. 18 (3) 291–293. |
X-linked agammaglobulinemia | X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the bodys ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies (also called immunoglobulins), which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Brutons tyrosine kinase (Btk) gene that leads to a severe block in B cell development (at the pre-B cell to immature B cell stage) and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.XLA is caused by a mutation on the X chromosome (Xq21.3-q22) of a single gene identified in 1993 which produces an enzyme known as Brutons tyrosine kinase, or Btk. XLA was first characterized by Dr. Ogden Bruton in a ground-breaking research paper published in 1952 describing a boy unable to develop immunities to common childhood diseases and infections. It is the first known immune deficiency, and is classified with other inherited (genetic) defects of the immune system, known as primary immunodeficiency disorders.
Signs and symptoms
Affects males 50% of the time if mother is a carrier for the gene. Children are generally asymptomatic until 6–9 months of age when maternal IgG decreases. Present with recurrent infections with Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, hepatitis virus, and enterovirus CNS infections. Examination shows lymphoid hypoplasia (tonsils and adenoids, no splenomegaly or lymphadenopathy). There is significant decrease in all immunoglobulins.
Genetics
Most antibodies are gamma globulins. Antibodies are made mainly by plasma cells, which are daughter cells of the B cell line. The Btk enzyme plays an essential role in the maturation of B cells in the bone marrow, and when mutated, immature pro-B lymphocytes are unable to develop into pre-B lymphocytes, which normally develop into mature (naive) B cells that leave the bone marrow into the blood stream.The disorder is inherited in an X-linked recessive fashion (as the gene linked to it is on the X chromosome) and is almost entirely limited to the sons of asymptomatic female carriers. This is because males have only one copy of the X chromosome, while females have two copies; one normal copy of an X chromosome can compensate for mutations in the other X chromosome, so they are less likely to be symptomatic.There is 30–50% chance of XLA patients having a positive family history of genetic inheritance. The rest of the cases occur as random mutations. If a carrier female gives birth to a male child, there is a 50% chance that the male will have XLA. A carrier female has a 25% chance overall of giving birth to an affected male child. An XLA patient will pass on the gene, and all of his daughters will be XLA carriers, meaning that any male grandchildren from an XLA patients daughters have a 50% chance of inheriting XLA. A female XLA patient can arise only as the child of an XLA patient and a carrier mother. XLA can also rarely result from a spontaneous mutation in the fetus of a non-carrier mother.
Diagnosis
XLA diagnosis usually begins due to a history of recurrent infections, mostly in the respiratory tract, through childhood. This is due to humoral immunodeficiency. The diagnosis is probable when blood tests show the complete lack of circulating B cells (determined by the B cell marker CD19 and/or CD20), as well as low levels of all antibody classes, including IgG, IgA, IgM, IgE and IgD.When XLA is suspected, it is possible to do a Western Blot test to determine whether the Btk protein is being expressed. Results of a genetic blood test confirm the diagnosis and will identify the specific Btk mutation, however its cost prohibits its use in routine screening for all pregnancies. Women with an XLA patient in their family should seek genetic counseling before pregnancy. Although the symptoms of a XLA and other primary immune diseases (PID) include repeated and often severe infections, the average time for a diagnosis of a PID can be up to 10 years.
Treatment
The most common treatment for XLA is an intravenous infusion of immunoglobulin (IVIg, human IgG antibodies) every week, for life. IVIg is a human product extracted and pooled from thousands of blood donations. IVIg does not cure XLA but increases the patients lifespan and quality of life, by generating passive immunity, and boosting the immune system. With treatment, the number and severity of infections is reduced. With IVIg, XLA patients may live a relatively healthy life. A patient should attempt reaching a state where his IgG blood count exceeds 800 mg/kg. The dose is based on the patients weight and IgG blood-count.Muscle injections of immunoglobulin (IMIg) were common before IVIg was prevalent, but are less effective and much more painful; hence, IMIg is now uncommon. Subcutaneous treatment (SCIg) was recently approved by the U.S. Food and Drug Administration (FDA), which is recommended in cases of severe adverse reactions to the IVIg treatment.Antibiotics are another common supplementary treatment. Local antibiotic treatment (drops, lotions) are preferred over systemic treatment (pills) for long-term treatment, if possible. One of the future prospects of XLA treatment is gene therapy, which could potentially cure XLA. Gene therapy technology is still in its infancy and may cause severe complications such as cancer and even death. Moreover, the long-term success and complications of this treatment are, as yet, unknown.
Other considerations
It is not recommended and dangerous for XLA patients to receive live attenuated vaccines such as live polio, or the measles, mumps, rubella (MMR vaccine). Special emphasis is given to avoiding the oral live attenuated SABIN-type polio vaccine that has been reported to cause polio to XLA patients. Furthermore, it is not known if active vaccines in general have any beneficial effect on XLA patients as they lack normal ability to maintain immune memory.XLA patients are specifically susceptible to viruses of the Enterovirus family, and mostly to: polio virus, coxsackie virus (hand, foot, and mouth disease) and Echoviruses. These may cause severe central nervous system conditions as chronic encephalitis, meningitis and death. An experimental anti-viral agent, pleconaril, is active against picornaviruses. XLA patients, however, are apparently immune to the Epstein-Barr virus (EBV), as they lack mature B cells (and so HLA co-receptors) needed for the viral infection. Patients with XLA are also more likely to have a history of septic arthritis.It is not known if XLA patients are able to generate an allergic reaction, as they lack functional IgE antibodies. There is no special hazard for XLA patients in dealing with pets or outdoor activities. Unlike in other primary immunodeficiencies XLA patients are at no greater risk for developing autoimmune illnesses.
Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder Hypogammaglobulinemia (CVID), and their clinical conditions and treatment are almost identical. However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood. In addition, to X-linked agammaglobulinemia a couple of autosomal recessive agammaglobulinemia gene mutations have been described including mutations in IGHM, IGLL1, CD79A/B, BLNK and deletion of the deletion of the terminal 14q32.33 chromosom.XLA was also historically mistaken as Severe Combined Immunodeficiency (SCID), a much more severe immune deficiency ("Bubble boys").A strain of laboratory mouse, XID, is used to study XLA. These mice have a mutated version of the mouse Btk gene, and exhibit a similar, yet milder, immune deficiency as in XLA.
See also
Hypogammaglobulinemia (CVID)
Intravenous immunoglobulin (IVIg)
References
External links
GeneReviews/NCBI/NIH/UW entry on X-Linked Agammaglobulinemia |
Dentin | Dentin () (American English) or dentine ( or ) (British English) (Latin: substantia eburnea) is a calcified tissue of the body and, along with enamel, cementum, and pulp, is one of the four major components of teeth. It is usually covered by enamel on the crown and cementum on the root and surrounds the entire pulp. By volume, 45% of dentin consists of the mineral hydroxyapatite, 33% is organic material, and 22% is water. Yellow in appearance, it greatly affects the color of a tooth due to the translucency of enamel. Dentin, which is less mineralized and less brittle than enamel, is necessary for the support of enamel. Dentin rates approximately 3 on the Mohs scale of mineral hardness. There are two main characteristics which distinguish dentin from enamel: firstly, dentin forms throughout life; secondly, dentin is sensitive: 125 and can become hypersensitive to changes in temperature due to the sensory function of odontoblasts, especially when enamel recedes and dentin channels become exposed.
Dentinal sclerosis
Dentinal sclerosis or transparent dentin sclerosis of primary dentin is a change in the structure of teeth characterized by calcification of dentinal tubules. It can occur as a result of injury to dentin by caries or abrasion, or as part of the normal aging process.
Development
Prior to enamel formation, dentine formation begins through a process known as dentinogenesis, and this process continues throughout a persons life even after the tooth has fully developed. Events such as tooth decay and tooth wear can also initiate dentine formation.Dentinogenesis is initiated by the odontoblasts of the pulp. Odontoblasts are specialised cells that lay down an organic matrix known as pre-dentine. This pre-dentine is subsequently mineralised into dentine. Mineralisation of pre-dentine begins at the dentino-enamel junction during tooth development and progresses towards the pulp of the tooth. After growth of pre-dentine and maturation into dentine, the cell bodies of the odontoblasts remain in the pulp, along its outer wall, and project into tiny tubules in the dentine.
Pre-dentine is composed of 90% type I collagen and 10% non-collagenous proteins (including phosphoproteins, proteoglycans, growth factors, phosphatases such as alkaline phosphatase, and matrix metalloproteinases (MMPs)), and this composition is significantly altered when it is mineralised into dentine. See the Structure section for information about the composition of dentine.
Structure
Unlike enamel, dentin may be demineralized and stained for histological study. Dentin consists of microscopic channels, called dentinal tubules, which radiate outward through the dentin from the pulp to the exterior cementum or enamel border. The dentinal tubules extend from the dentinoenamel junction (DEJ) in the crown area, or dentinocemental junction (DCJ) in the root area, to the outer wall of the pulp. From the outer surface of the dentin to the area nearest the pulp, these tubules follow an S-shaped path. The diameter and density of the tubules are greatest near the pulp.: 152 Tapering from the inner to the outermost surface, they have a diameter of 2.5 μm near the pulp, 1.2 μm in the middle of the dentin, and 0.9 μm at the dentino-enamel junction. Their density is 59,000 to 76,000 per square millimeter near the pulp, whereas the density is only half as much near the enamel. Within the tubules, there is an odontoblast process, which is an extension of an odontoblast, and dentinal fluid, which contains a mixture of albumin, transferrin, tenascin and proteoglycans. In addition, there are branching canalicular systems that connect to each other. These branches have been categorized by size, with major being 500-1000 nm in diameter, fine being 300-700 nm, and micro being less than 300 nm.: 155 The major branches are the terminal ends of the tubules. About every 1-2 μm, there are fine branches diverging from dentinal tubules at 45 degree angles. The microtubules diverge at 90 degree angles. The dentinal tubules contain the cytoplasmic extensions of odontoblasts that once formed the dentin and maintain it. The cell bodies of the odontoblasts are aligned along the inner aspect of dentin against a layer of predentin where they also form the peripheral boundary of the dental pulp Because of dentinal tubules, dentin has a degree of permeability, which can increase the sensation of pain and the rate of tooth decay. The strongest held theory of dentinal hypersensitivity suggests that it is due to changes in the dentinal fluid associated with the processes, a type of hydrodynamic mechanism.Dentin is a bone-like matrix that is porous and yellow-hued material. It is made up, by weight, of 70-72% inorganic materials (mainly hydroxylapatite and some non-crystalline amorphous calcium phosphate), 20% organic materials (90% of which is collagen type 1 and the remaining 10% ground substance, which includes dentin-specific proteins), and 8-10% water (which is adsorbed on the surface of the minerals or between the crystals). Because it is softer than enamel, it decays more rapidly and is subject to severe cavities if not properly treated, but due to its elastic properties, it is good support for enamel. Its flexibility prevents the brittle enamel fracturing.
In areas where both primary and secondary mineralization have occurred with complete crystalline fusion, these appear as lighter rounded areas on a stained section of dentin and are considered globular dentin. In contrast, the darker arc-like areas in a stained section of dentin are considered interglobular dentin. In these areas, only primary mineralization has occurred within the predentin, and the globules of dentin do not fuse completely. Thus, interglobular dentin is slightly less mineralized than globular dentin. Interglobular dentin is especially evident in coronal dentin, near the dentinoenamel junction (DEJ), and in certain dental anomalies, such as in dentinogenesis imperfecta.
Regional variations in dentin structure and composition
The different regions in dentin can be recognized due to their structural differences. The outermost layer, known as the mantle dentin layer, is found in the crown of the tooth. It can and can be identified by the presence of various characteristics, including collagen fibres found perpendicular to the enamel-dentin junction and it is slightly less mineralized (by approximately 5%, compared to the enamel. The dentin undergoes mineralization in the presence of matrix vesicles ("hydroxyapatite-containing, membrane-enclosed vesicles secreted by odontoblasts, osteoblasts, and some chondrocytes; believed to serve as nucleation centers for the mineralization process in dentin, bone, and calcified cartilage.") The dentinal tubules in this region branch profusely.
In the root of the tooth there are two morphologically distinguishable outer layers: the hyaline layer on the periphery of dentin and the granular layer of Tomes beneath this. The granular layer has a dark, granular appearance which occurs due to the branching and looping back of dentinal tubules in this region. This appearance, specific to root dentin, is possibly due to differences in the rates of formation of coronal and root dentin. The hyaline layer, which has an obscure origin, is a clear layer, unlike the granular layer, with a width of up to 20μm. It can have clinical significance during periodontal regeneration.
Circumpulpal dentin forms the majority of the dentin and is generally constant in structure. Peripherally, mineralization can be seen to be incomplete, whereas centrally the mineralizing front shows ongoing mineralizing.
The innermost layer of dentin is known as predentin, and is the initial dentin matrix that is laid down prior to mineralization. It can be distinguished by its pale color when stained with haematoxylin and eosin. The presence of odontoblastic processes here allows the secretion of matrix components. Predentin can be 10-40μm in width, depending on its rate of deposition.: 134–137
Types
There are three types of dentin, primary, secondary and tertiary. Secondary dentin is a layer of dentin produced after the root of the tooth is completely formed. Tertiary dentin is created in response to a stimulus, such as a carious attack or wear.
Primary dentin
Primary dentin, the most prominent dentin in the tooth, lies between the enamel and the pulp chamber (near dentinoenamel junction). The outer layer closest to enamel is known as mantle dentin. This layer is unique to the rest of primary dentin. Mantle dentin is formed by newly differentiated odontoblasts and forms a layer consistently 15-20 micrometers (µm) wide. Unlike primary dentin, mantle dentin lacks phosphorylation, has loosely packed collagen fibrils and is less mineralized. Below it lies the circumpulpal dentin, more mineralized dentin which makes up most of the dentin layer and is secreted after the mantle dentin by the odontoblasts. Circumpulpal dentin is formed before the root formation is completed.
Newly secreted dentin is unmineralized and is called predentin. It is easily identified in hematoxylin and eosin stained sections since it stains less intensely than dentin. It is usually 10-47μm and lines the innermost region of the dentin. It is unmineralized and consists of collagen, glycoproteins, and proteoglycans. It is similar to osteoid in bone and is thickest when dentinogenesis is occurring.
Secondary dentin
Secondary dentin (adventitious dentin) is formed after root formation is complete, normally after the tooth has erupted and is functional. It grows much more slowly than primary dentin but maintains its incremental aspect of growth. It has a similar structure to primary dentin, although its deposition is not always even around the pulp chamber. It appears greater in amounts on the roof and floor of the coronal pulp chamber, where it protects the pulp from exposure in older teeth. The secondary dentin formed is not in response to any external stimuli, and it appears very much similar to the primary dentine. It is the growth of this dentin that causes a decrease in the size of the pulp chamber with age. This is clinically known as pulp recession; cavity preparation in young patients, therefore, carries a greater risk of exposing the pulp. If this occurs, the pulp can be treated by different therapies such as direct pulp capping. Previously it was thought that Pulp capping was most successful if followed by a stainless steel crown, however this procedure is most of the times unnecessary in children. it requires the unnecessary removal of enamel which is key to the life of the tooth. Adhesive dentistry allows for conservative restoration techniques that minimize the loss of tooth structure and should be used. In order to maintain space in the primary dentition, attempts are made not to extract a pulpal exposure.
Tertiary dentin (including reparative dentin or sclerotic dentin) – pathologic
Tertiary dentin is dentin formed as a reaction to external stimulation such as cavities and wear. It is of two types, either reactionary, where dentin is formed from a pre-existing odontoblast, or reparative, where newly differentiated odontoblast-like cells are formed due to the death of the original odontoblasts, from a pulpal progenitor cell. Tertiary dentin is only formed by an odontoblast directly affected by a stimulus; therefore, the architecture and structure depend on the intensity and duration of the stimulus, e.g., if the stimulus is a carious lesion, there is extensive destruction of dentin and damage to the pulp, due to the differentiation of bacterial metabolites and toxins. Thus, tertiary dentin is deposited rapidly, with a sparse and irregular tubular pattern and some cellular inclusions; in this case, it is referred to as "osteodentin". Osteodentin is seen in Vit.A deficiency during development. However, if the stimulus is less active, it is laid down less rapidly with a more regular tubular pattern and hardly any cellular inclusions. The speed at which tertiary dentin forms also varies substantially among primate species.
Animal dentin
Elephant ivory is solid dentin. The structure of the dentinal tubules contributes to both its porosity and its elasticity. Elephant tusks are formed with a thin cap of enamel, which soon wears away, leaving the dentin exposed. Exposed dentin in humans causes the symptom of sensitive teeth. Dentin is best known for its occurrence in teeth, but in early vertebrates, it was an important part of the dermal skeleton that covered most of the body, and it persists today in a few taxa such as the coelacanth.Because dentin is softer than enamel, it wears away more quickly than enamel. Some mammalian teeth exploit this phenomenon, especially herbivores such as horses, deer or elephants. In many herbivores, the occlusal (biting) surface of the tooth is composed of alternating areas of dentin and enamel. Differential wearing causes sharp ridges of enamel to be formed on the surface of the tooth (typically a molar), and to remain during the working life of the tooth. Herbivores grind their molars together as they chew (masticate), and the ridges help to shred tough plant material.
A material similar to dentin forms the hard material that makes up dermal denticles in sharks and other cartilaginous fish.
See also
Dentinogenesis
Dentinogenesis imperfecta
Odontoblast
Tooth development
References
== External links == |
Scott syndrome | Scott syndrome is a rare congenital bleeding disorder that is due to a defect in a platelet mechanism required for blood coagulation.Normally when a vascular injury occurs, platelets are activated and phosphatidylserine (PS) in the inner leaflet of the platelet membrane is transported to the outer leaflet of the platelet membrane, where it provides a binding site for plasma protein complexes that are involved in the conversion of prothrombin to thrombin, such as factor VIIIa-IXa (tenase) and factor Va-Xa (prothrombinase).In Scott syndrome, the mechanism for translocating PS to the platelet membrane is defective, resulting in impaired thrombin formation. A similar defect in PS translocation has also been demonstrated in Scott syndrome red blood cells and Epstein–Barr virus transformed lymphocytes, suggesting that the defect in Scott syndrome reflects a mutation in a stem cell that affects multiple hematological lineages.The basis for the defect in PS translocation is, at present, unknown. A candidate protein, scramblase, that may be involved in this process appears to be normal in Scott syndrome platelets. Other possible defects in PS translocation, reported in some patients, require further study. The initially reported patient with Scott Syndrome has been found to have a mutation at a splice-acceptor site of the gene encoding anoctamin 6 (ANO6, transmembrane protein 16F, TMEM16F). At present, the only treatment for episodes of bleeding is the transfusion of normal platelets.
References
Further reading
Heemskerk JWM, Bevers EM, Lindhout T. Platelet activation and blood coagulation, Thromb Haem 2002; 88:186–194
Martinez MC, Martin S, Toti F, Fressinaud E, Dachary-Prigent J, Meyer D, et al. Significance of capacitative Ca2+ entry to the regulation of phoshatidylserine expression at the surface of stimulated cells. Biochemistry 1999; 38:10092–10098
Munnix ICA, Harmsma M, Diddings JC, Collins PW, Feijge P, Comfurius JWM, et al. Store-mediated Ca2+ entry in the regulation of phoshatidylserine exposure in blood cells from Scott patients. Thromb Haemost 2003; 89:687–695
Weiss HJ, Vicic WJ, Lages BA, Rogers J. Isolated deficiency of platelet procoagulant activity. Am J Med 1979; 67:206–213
Miletich JP, Kane WH, Hofmann SL, Stanford N, Majerus PW. Deficiency of factor Xa-factor Va binding sites on the platelets of a patient with a bleeding disorder. Blood 1979; 54:1015–1022
Bevers EM, Wiedmer T, Comfurius P, Shattil SJ, Weiss HJ, Zwaal RFA, et al. Defective Ca2+ induced microvesiculation and deficient expression of procoagulant activity in erythrocytes from a patient with a bleeding disorder: a study of the red blood cells of Scott syndrome. Blood 1992;79:380–388
Kojima H, Newton-Nash D, Weiss HJ, Sims PJ, Zhao J, Wiedmer T. Production and characterization of transformed B-lymphocytes expressing the membrane defect of Scott Syndrome. J Clin Invest 1994; 94:2237–2244
Stout JG, Basse F, Luhm RA, Weiss HJ, Wiedmer T, Sims PJ. Scott syndrome erythrocytes contain a membrane protein capable of mediating Ca2+-dependent transbilayer migration of membrane phospholipids. J Clin Invest 1997; 99:2232–2238
Albrecht C, McVey JH, Elliott JI, Sardini A, Kasza I, Mumford AD, et al. A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome. Blood 2005; 106:542–549
Brooks MB, Catalfamo JL, Alex Brown H, Ivanova P, Lovaglio J. A hereditary bleeding disorder of dogs caused by a lack of platelet procoagulant activity. Blood 2002; 99:2434–2441
== External links == |
Fibromyalgia | Fibromyalgia (FM) is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hypersensitivity.The cause of fibromyalgia is unknown, but is believed to involve a combination of genetic and environmental factors. Environmental factors may include psychological stress, trauma, and certain infections. The pain appears to result from processes in the central nervous system and the condition is referred to as a "central sensitization syndrome".The treatment of fibromyalgia is symptomatic and multidisciplinary. The European Alliance of Associations for Rheumatology strongly recommends aerobic and strengthening exercise. Weak recommendations are given to mindfulness, psychotherapy, acupuncture, hydrotherapy, and meditative exercise such as qigong, yoga, and tai chi. The use of medication in the treatment of fibromyalgia is debated, although antidepressants can improve quality of life. The medications duloxetine, milnacipran, or pregabalin have been approved by the US Food and Drug Administration (FDA) for the management of fibromyalgia. Other common helpful medications include serotonin-noradrenaline reuptake inhibitors (SNRI), non-steroidal anti-inflammatory drugs (NSAIDs), and muscle relaxants. Q10 coenzyme and vitamin D supplements may improve pain and quality of life. While fibromyalgia is persistent in nearly all patients, it does not result in death or tissue damage.Fibromyalgia is estimated to affect 2–4% of the population. Women are affected about twice as often as men. Rates appear similar in different areas of the world and among different cultures. Fibromyalgia was first defined in 1990, with updated criteria in 2011, 2016, and 2019. The term "fibromyalgia" is from New Latin fibro-, meaning "fibrous tissues", Greek μυο- myo-, "muscle", and Greek άλγος algos, "pain"; thus, the term literally means "muscle and fibrous connective tissue pain".
Classification
Fibromyalgia is classed as a disorder of pain processing due to abnormalities in how pain signals are processed in the central nervous system. The International Classification of Diseases (ICD-11) includes fibromyalgia in the category of "Chronic widespread pain", code MG30.01.
Signs and symptoms
The defining symptoms of fibromyalgia are chronic widespread pain, fatigue, and sleep disturbance. Other symptoms may include heightened pain in response to tactile pressure (allodynia), cognitive problems, musculoskeletal stiffness, environmental sensitivity, hypervigilance, sexual dysfunction, and visual symptoms.
Pain
Fibromyalgia is predominantly a chronic pain disorder. According to the NHS, widespread pain is one major symptom, which could feel like: an ache, a burning sensation, or a sharp, stabbing pain.
Fatigue
Fatigue is one of the defining symptoms of fibromyalgia. Patients may experience physical or mental fatigue. Physical fatigue can be demonstrated by a feeling of exhaustion after exercise or by a limitation in daily activities.
Sleep problems
Sleep problems are a core symptom in fibromyalgia. These include a difficulty to fall asleep or stay asleep, awakening while sleeping and waking up feeling unrefreshed. A meta-analysis compared objective and subjective sleep metrics in people with fibromyalgia and healthy people. Individuals with fibromyalgia had lower sleep quality and efficiency, as well as longer wake time after sleep start, shorter sleep duration, lighter sleep, and greater trouble initiating sleep when objectively assessed, and more difficulty initiating sleep when subjectively assessed. Sleep problems may contribute to pain by decreased release of IGF-1 and human growth hormone, leading to decreased tissue repair. Improving sleep quality can help people with fibromyalgia minimize pain.
Cognitive problems
Many people with fibromyalgia experience cognitive problems (known as "fibrofog" or "brainfog"). One study found that approximately 50% of fibromyalgia patients had subjective cognitive dysfunction and that it was associated with higher levels of pain and other fibromyalgia symptoms. The American Pain Society recognizes these problems as a major feature of fibromyalgia, characterized by trouble concentrating, forgetfulness and disorganized or slow thinking. About 75% of fibromyalgia patients report significant problems with concentration, memory, and multitasking. A 2018 meta-analysis found that the largest differences between fibromyalgia patients and healthy subjects were for inhibitory control, memory, and processing speed. It is hypothesized that the increased pain compromises attention systems, resulting in cognitive problems.
Hypersensitivity
In addition to a hypersensitivity to pain, patients with fibromyalgia show hypersensitivity to other stimuli, such as bright lights, loud noises, perfumes and cold. A review article found that they have a lower cold pain threshold. Other studies documented an acoustic hypersensitivity.
Comorbidity
Fibromyalgia as a stand-alone diagnosis is uncommon, as most fibromyalgia patients often have other chronic overlapping pain problems or mental disorders. Fibromyalgia is associated with mental health issues like anxiety, posttraumatic stress disorder, bipolar disorder, and depression. Patients with fibromyalgia are five times more likely to have major depression than the general population.Fibromyalgia and numerous chronic pain conditions frequently coexist. These include chronic tension headaches, myofascial pain syndrome, and temporomandibular disorders. Multiple sclerosis, post-polio syndrome, neuropathic pain, and Parkinsons disease are four neurological disorders that have been linked to pain or fibromyalgia. Fibromyalgia largely overlaps with chronic fatigue syndrome and may share the same pathogenetic mechanisms.Comorbid fibromyalgia has been reported to occur in 20–30% of individuals with rheumatic diseases. It has been reported in people with noninflammatory musculoskeletal diseases.The prevalence of fibromyalgia in gastrointestinal disease has been described mostly for celiac disease and irritable bowel syndrome (IBS). Fibromyalgia has also been linked with obesity. Other conditions that are associated with fibromyalgia include an overactive bladder.
Risk factors
The cause of fibromyalgia is unknown. However, several risk factors, genetic and environmental, have been identified.
Genetics
Genetics play a major role in fibromyalgia, and may explain up to 50% of the disease susceptibility. Fibromyalgia is potentially associated with polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems. Several genes have been suggested as candidates for susceptibility to fibromyalgia. These include SLC64A4, TRPV2, MYT1L, NRXN3, and the 5-HT2A receptor 102T/C polymorphism. The heritability of fibromyalgia is estimated to be higher in patients younger than 50.Neuropathic pain and major depressive disorder often co-occur with fibromyalgia – the reason for this comorbidity appears to be due to shared genetic abnormalities, which leads to impairments in monoaminergic, glutamatergic, neurotrophic, opioid and proinflammatory cytokine signaling. In these vulnerable individuals, psychological stress or illness can cause abnormalities in inflammatory and stress pathways that regulate mood and pain. Eventually, a sensitization and kindling effect occurs in certain neurons leading to the establishment of fibromyalgia and sometimes a mood disorder.
Stress
Stress may be an important precipitating factor in the development of fibromyalgia. A 2021 meta-analysis found psychological trauma to be strongly associated with fibromyalgia. People who suffered abuse in their lifetime were three times more likely to have fibromyalgia, people who suffered medical trauma or other stressors in their lifetime were about twice as likely.Some authors have proposed that, because exposure to stressful conditions can alter the function of the hypothalamic-pituitary-adrenal (HPA) axis, the development of fibromyalgia may stem from stress-induced disruption of the HPA axis.
Personality
Although some have suggested that fibromyalgia patients are more likely to have specific personality traits, when depression is statistically controlled for, it appears that their personality is no different than that of people in the general population.
Other risk markers
Other risk markers for fibromyalgia include premature birth, female sex, cognitive influences, primary pain disorders, multiregional pain, infectious illness, hypermobility of joints, iron deficiency and small-fiber polyneuropathy. Metal-induced allergic inflammation has also been linked with fibromyalgia, especially in response to nickel but also inorganic mercury, cadmium, and lead.
Pathophysiology
As of 2022, the pathophysiology of fibromyalgia has not yet been elucidated and several theories have been suggested.
Nervous system
Pain processing abnormalities
Chronic pain can be divided into three categories. Nociceptive pain is pain caused by inflammation or damage to tissues. Neuropathic pain is pain caused by nerve damage. Nociplastic pain (or central sensitization) is less understood and is the common explanation of the pain experienced in fibromyalgia. Because the three forms of pain can overlap, fibromyalgia patients may experience nociceptive (e.g., rheumatic illnesses) and neuropathic (e.g., small fiber neuropathy) pain, in addition to nociplastic pain.
Nociplastic pain (central sensitization)
Fibromyalgia can be viewed as a condition of nociplastic pain. Nociplastic pain is caused by an altered function of pain-related sensory pathways in the periphery and the central nervous system, resulting in hypersensitivity.Nociplastic pain is commonly referred to as "Nociplastic pain syndrome" because it is coupled with other symptoms. These include fatigue, sleep disturbance, cognitive disturbance, hypersensitivity to environmental stimuli, anxiety, and depression. Nociplastic pain is caused by either (1) increased processing of pain stimuli or (2) decreased suppression of pain stimuli at several levels in the nervous system, or both.
Neuropathic pain
An alternative hypothesis to nociplastic pain views fibromyalgia as a stress-related dysautonomia with neuropathic pain features. This view highlights the role of autonomic and peripheral nociceptive nervous systems in the generation of widespread pain, fatigue, and insomnia. The description of small fiber neuropathy in a subgroup of fibromyalgia patients supports the disease neuropathic-autonomic underpinning. However, others claim that small fiber neuropathy occurs only in small groups of those with fibromyalgia.
Autonomic nervous system
Some suggest that fibromyalgia is caused or maintained by a decreased vagal tone, which is indicated by low levels of heart rate variability, signaling a heightened sympathetic response. Accordingly, several studies show that clinical improvement is associated with an increase in heart rate variability. Some examples of interventions that increase the heart rate variability and vagal tone are meditation, yoga, mindfulness and exercise.
Neurotransmitters
Some neurochemical abnormalities that occur in fibromyalgia also regulate mood, sleep, and energy, thus explaining why mood, sleep, and fatigue problems are commonly co-morbid with fibromyalgia. Serotonin is the most widely studied neurotransmitter in fibromyalgia. It is hypothesized that an imbalance in the serotoninergic system may lead to the development of fibromyalgia. There is also some data that suggests altered dopaminergic and noradrenergic signaling in fibromyalgia. Supporting the monoamine related theories is the efficacy of monoaminergic antidepressants in fibromyalgia.
Neurophysiology
Neuroimaging studies have observed decreased grey matter of the default mode network in people with fibromyalgia. These deficits are associated with pain processing.
Neuroendocrine system
Studies on the neuroendocrine system and HPA axis in fibromyalgia have been inconsistent. One study found fibromyalgia patients exhibited higher plasma cortisol, more extreme peaks and troughs, and higher rates of dexamethasone non-suppression. However, other studies have only found correlations between a higher cortisol awakening response and pain, and not any other abnormalities in cortisol. Increased baseline ACTH and increase in response to stress have been observed, hypothesized to be a result of decreased negative feedback.
Immune system
Inflammation has been suggested to have a role in the pathogenesis of fibromyalgia. People with fibromyalgia tend to have higher levels of inflammatory cytokines IL-6, and IL-8. There are also increased levels of the pro-inflammatory cytokines IL-1 receptor antagonist. Increased levels of pro-inflammatory cytokines may increase sensitivity to pain, and contribute to mood problems. Anti-inflammatory interleukins such as IL-10 have also been associated with fibromyalgia.A repeated observation shows that autoimmunity triggers such as traumas and infections are among the most frequent events preceding the onset of fibromyalgia. Neurogenic inflammation has been proposed as a contributing factor to fibromyalgia.
Digestive system
Gut microbiome
Gut bacteria may play a role in fibromyalgia. People with fibromyalgia are more likely to show dysbiosis, a decrease in microbiota diversity. There is a bidirectional interplay between the gut and the nervous system. Therefore, the gut can affect the nervous system, but the nervous system can also affect the gut. Neurological effects mediated via the autonomic nervous system as well as the hypothalamic pituitary adrenal axis are directed to intestinal functional effector cells, which in turn are under the influence of the gut microbiota.
Gut-brain axis
The gut-brain axis, which connects the gut microbiome to the brain via the enteric nervous system, is another area of research. Fibromyalgia patients have less varied gut flora and altered serum metabolome levels of glutamate and serine, implying abnormalities in neurotransmitter metabolism.
Diagnosis
There is no single pathological feature, laboratory finding, or biomarker that can diagnose fibromyalgia and there is debate over what should be considered diagnostic criteria and whether an objective diagnosis is possible. In most cases, people with fibromyalgia symptoms may have laboratory test results that appear normal and many of their symptoms may mimic those of other rheumatic conditions such as arthritis or osteoporosis. The specific diagnostic criteria for fibromyalgia have evolved over time.
American College of Rheumatology 1990
The first widely accepted set of classification criteria for research purposes was elaborated in 1990 by the Multicenter Criteria Committee of the American College of Rheumatology. These criteria, which are known informally as "the ACR 1990", defined fibromyalgia according to the presence of the following criteria:
A history of widespread pain lasting more than three months – affecting all four quadrants of the body, i.e., both sides, and above and below the waist.
Tender points – there are 18 designated possible tender points (although a person with the disorder may feel pain in other areas as well).The ACR criteria for the classification of patients were originally established as inclusion criteria for research purposes and were not intended for clinical diagnosis but have later become the de facto diagnostic criteria in the clinical setting. A controversial study was done by a legal team looking to prove their clients disability based primarily on tender points and their widespread presence in non-litigious communities prompted the lead author of the ACR criteria to question now the useful validity of tender points in diagnosis. Use of control points has been used to cast doubt on whether a person has fibromyalgia, and to claim the person is malingering.
American College of Rheumatology 2010 provisional criteria
In 2010, the American College of Rheumatology approved provisional revised diagnostic criteria for fibromyalgia that eliminated the 1990 criterias reliance on tender point testing. The revised criteria used a widespread pain index (WPI) and symptom severity scale (SSS) in place of tender point testing under the 1990 criteria. The WPI counts up to 19 general body areas in which the person has experienced pain in the preceding week. The SSS rates the severity of the persons fatigue, unrefreshed waking, cognitive symptoms, and general somatic symptoms, each on a scale from 0 to 3, for a composite score ranging from 0 to 12. The revised criteria for diagnosis were:
WPI ≥ 7 and SSS ≥ 5 OR WPI 3–6 and SSS ≥ 9,
Symptoms have been present at a similar level for at least three months, and
No other diagnosable disorder otherwise explains the pain.: 607
American College of Rheumatology 2016 revisions
In 2016, the provisional criteria of the American College of Rheumatology from 2010 were revised. The new diagnosis required all of the following criteria:
"Generalized pain, defined as pain in at least 4 of 5 regions, is present."
"Symptoms have been present at a similar level for at least 3 months."
"Widespread pain index (WPI) ≥ 7 and symptom severity scale (SSS) score ≥ 5 OR WPI of 4–6 and SSS score ≥ 9."
"A diagnosis of fibromyalgia is valid irrespective of other diagnoses. A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses."
American Pain Society 2019
In 2019, the American Pain Society in collaboration with the U.S. Food and Drug Administration developed a new diagnostic system using two dimensions. The first dimension included core diagnostic criteria and the second included common features. In accordance to the 2016 diagnosis guidelines, the presence of another medical condition or pain disorder does not rule out the diagnosis of fibromyalgia. Nonetheless, other conditions should be ruled out as the main explaining reason for the patients symptoms. The core diagnostic criteria are:
Multisite pain defined as six or more pain sites from a total of nine possible sites, for at least three months
Moderate to severe sleep problems or fatigue, for at least three monthsCommon features found in fibromyalgia patients can assist the diagnosis process. These are tenderness (sensitivity to light pressure), dyscognition (difficulty to think), musculoskeletal stiffness, and environmental sensitivity or hypervigilance.
Self-report questionnaires
Some research has suggested using a multidimensional approach taking into consideration somatic symptoms, psychological factors, psychosocial stressors and subjective belief regarding fibromyalgia. These symptoms can be assessed by several self-report questionnaires.
Widespread Pain Index (WPI)
The Widespread Pain Index (WPI) measures the number of painful body regions.
Symptom Severity Scale (SSS)
The Symptom Severity Scale (SSS) assesses the severity of the fibromyalgia symptoms.
Fibromyalgia Impact Questionnaire (FIQ)
The Fibromyalgia Impact Questionnaire (FIQ) and the Revised Fibromyalgia Impact Questionnaire (FIQR) assess three domains: function, overall impact and symptoms. It is considered a useful measure of disease impact.
Other questionnaires
Other measures include the Hospital Anxiety and Depression Scale, Multiple Ability Self-Report Questionnaire, Multidimensional Fatigue Inventory, and Medical Outcomes Study Sleep Scale.
Differential diagnosis
As of 2009, as many as two out of every three people who are told that they have fibromyalgia by a rheumatologist may have some other medical condition instead. Fibromyalgia could be misdiagnosed in cases of early undiagnosed rheumatic diseases such as preclinical rheumatoid arthritis, early stages of inflammatory spondyloarthritis, polymyalgia rheumatica, myofascial pain syndromes and hypermobility syndrome. Neurological diseases with an important pain component include multiple sclerosis, Parkinsons disease and peripheral neuropathy. Other medical illnesses that should be ruled out are endocrine disease or metabolic disorder (hypothyroidism, hyperparathyroidism, acromegaly, vitamin D deficiency), gastro-intestinal disease (celiac and non-celiac gluten sensitivity), infectious diseases (Lyme disease, hepatitis C and immunodeficiency disease) and the early stages of a malignancy such as multiple myeloma, metastatic cancer and leukemia/lymphoma. Other systemic, inflammatory, endocrine, rheumatic, infectious, and neurologic disorders may cause fibromyalgia-like symptoms, such as systemic lupus erythematosus, Sjögren syndrome, ankylosing spondylitis, Ehlers-Danlos syndromes, psoriatic-related polyenthesitis, a nerve compression syndrome (such as carpal tunnel syndrome), and myasthenia gravis. In addition, several medications can also evoke pain (statins, aromatose inhibitors, biophosphonates, and opioids).The differential diagnosis is made during the evaluation on the basis of the persons medical history, physical examination, and laboratory investigations. The patients history can provide some hints to a fibromyalgia diagnosis. A family history of early chronic pain, a childhood history of pain, an emergence of broad pain following physical and/or psychosocial stress, a general hypersensitivity to touch, smell, noise, taste, hypervigilance, and various somatic symptoms (gastrointestinal, urology, gynecology, neurology), are all examples of these signals Extensive laboratory tests are usually unnecessary in the differential diagnosis of fibromyalgia. Common tests that are conducted include complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, C-reactive protein, and thyroid function test.
Management
As with many other medically unexplained syndromes, there is no universally accepted treatment or cure for fibromyalgia, and treatment typically consists of symptom management and improving patient quality of life. A personalized, multidisciplinary approach to treatment that includes both non-pharmacologic and pharmacologic therapy and begins with effective patient education is most beneficial. Developments in the understanding of the pathophysiology of the disorder have led to improvements in treatment, which include prescription medication, behavioral intervention, and exercise.
A number of associations have published guidelines for the diagnosis and management of fibromyalgia. The European League Against Rheumatism (EULAR; 2017) recommends a multidisciplinary approach, allowing a quick diagnosis and patient education. The recommended initial management should be non-pharmacological, later pharmacological treatment can be added. The European League Against Rheumatism gave the strongest recommendation for aerobic and strengthening exercise. Weak recommendations were given to a number of treatments, based on their outcomes. Qigong, yoga, and tai chi were weakly recommended for improving sleep and quality of life. Mindfulness was weakly recommended for improving pain and quality of life. Acupuncture and hydrotherapy were weakly recommended for improving pain. A weak recommendation was also given to psychotherapy. It was more suitable for patients with mood disorders or unhelpful coping strategies. Chiropractic was strongly recommended against, due to safety concerns. Some medications were weakly recommended for severe pain (duloxetine, pregabalin, tramadol) or sleep disturbance (amitriptyline, cyclobenzaprine, pregabalin). Others were not recommended due to a lack of efficacy (nonsteroidal anti-inflammatory drugs, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors). Growth hormone, sodium oxybate, opioids and steroids were strongly recommended against due to lack of efficacy and side effects.
The guidelines published by the Association of the Scientific Medical Societies in Germany inform patients that self-management strategies are an important component in managing the disease. The Canadian Pain Society also published guidelines for the diagnosis and management of fibromyalgia.
Exercise
Exercise is the only fibromyalgia treatment which has been given a strong recommendation by the European Alliance of Associations for Rheumatology (EULAR). There is strong evidence indicating that exercise improves fitness, sleep and quality of life and may reduce pain and fatigue for people with fibromyalgia. Exercise has an added benefit in that it does not cause any serious adverse effects.Exercise may diminish fibromyalgia symptoms through a number of hypothesized biological mechanisms. Exercise may improve pain modulation through serotoninergic pathways. It may reduce pain by altering the hypothalamic-pituitary-adrenal axis and reducing cortisol levels. It also has anti-inflammatory effects that may improve fibromyalgia symptoms. Aerobic exercise can improve muscle metabolism and pain through mitochondrial pathways.When comparing different exercise programs, aerobic exercise is capable of modulating the autonomic nervous function of fibromyalgia patients, whereas resistance exercise does not show such effects. A 2022 meta-analysis found that aerobic training showed a high effect size while strength interventions showed moderate effects. Meditative exercise seems preferable for improving sleep, with no differences between resistance, flexibility and aquatic exercise in their favorable effects on fatigue.Despite its benefits, exercise is a challenge for patients with fibromyalgia, due to the chronic fatigue and pain they experience. They perceive it as more effortful than healthy adults. Exercise may intimidate them, in fear that they will be asked to do more than they are capable of. They may also feel that those who recommend or deliver exercise interventions do not fully understand the possible negative impact of exercise on fatigue and pain. This is especially true for non-personalized exercise programs. Adherence is higher when the exercise program is recommended by doctors or supervised by nurses. A recommended approach to a graded exercise program begins with small, frequent exercise periods and builds up from there. In order to reduce pain, it is recommended to use an exercise program of 13 to 24 weeks, with each session lasting 30 to 60 minutes.
Aerobic
Aerobic exercise for fibromyalgia patients is the most investigated type of exercise. It includes activities such as walking, jogging, spinning, cycling, dancing and exercising in water. A 2017 cochrane summary concluded that aerobic exercise probably improves quality of life, slightly decreases pain and improves physical function and makes no difference in fatigue and stiffness. A 2019 meta-analysis showed that exercising aerobically can reduce autonomic dysfunction and increase heart rate variability. This happens when patients exercise at least twice a week, for 45–60 minutes at about 60%-80% of the maximum heart rate. Aerobic exercise also decreases anxiety and depression and improves the quality of life.
Flexibility
Combinations of different exercises such as flexibility and aerobic training may improve stiffness. However, the evidence is of low-quality. It is not clear if flexibility training alone compared to aerobic training is effective at reducing symptoms or has any adverse effects.
Resistance
In resistance exercise, participants apply a load to their body using weights, elastic band, body weight or other measures.
Two meta-analyses on fibromyalgia have shown that resistance training can reduce anxiety and depression and one found that it improves quality of life.The dosage of resistance exercise for women with fibromyalgia was studied in a 2022 meta-analysis. Effective dosages were found when exercising twice a week, for at least eight weeks. Symptom improvement was found for even low dosages such as 1–2 sets of 4–20 repetitions. Most studies use moderate exercise intensity of 40% to 85% one-repetition maximum. This level of intensity was effective in reducing pain. Some treatment regimes increase the intensity over time (from 40% to 80%), whereas others increase it when the participant is able to perform 12 repetitions. High-intensity exercises may cause lower treatment adherence.
Meditative
A 2021 meta-analysis found that meditative exercise programs (tai chi, yoga, qigong) were superior to other forms of exercise (aerobic, flexibility, resistance) in improving sleep quality. Other meta-analyses also found positive effects of tai chi for sleep, fibromyalgia symptoms, and pain, fatigue, depression and quality of life. These tai chi interventions frequently included 1-hour sessions practiced 1-3 times a week for 12 weeks. Meditative exercises, as a whole, may achieve desired outcomes through biological mechanisms such as antioxidation, anti-inflammation, reduction in sympathetic activity and modulation of glucocorticoid receptor sensitivity.
Aquatic
Several reviews and meta-analyses suggest that aquatic training can improve symptoms and wellness in people with fibromyalgia.
Other
Limited evidence suggests vibration training in combination with exercise may improve pain, fatigue, and stiffness.
Medications
A few countries have published guidelines for the management and treatment of fibromyalgia. As of 2018, all of them emphasize that medications are not required, only optional. The German guidelines outlined parameters for drug therapy termination and recommended considering drug holidays after six months.
Approved medications
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Fibromyalgia | Health Canada and the US Food and Drug Administration (FDA) have approved pregabalin and duloxetine for the management of fibromyalgia. The FDA also approved milnacipran, but the European Medicines Agency refused marketing authority.
Antidepressants
Antidepressants are one of the common drugs for fibromyalgia. A 2021 meta-analysis concluded that antidepressants can improve the quality of life for fibromyalgia patients in the medium-term. As of 2018, the only tricyclic antidepressant (TCA) that has sufficient evidence is amitriptyline.For most people with fibromyalgia, the potential benefits of treatment with the serotonin and noradrenaline reuptake inhibitors (SNRI) duloxetine and milnacipran and the TCAs, such as amitriptyline, are outweighed by significant adverse effects (more adverse effects than benefits), however, a small number of people may experience relief from symptoms with these medications. In addition, while amitriptyline has been used as a first line treatment, the quality of evidence to support this use and comparison between different medications is poor. Very weak evidence indicates that a very small number of people may benefit from treatment with the tetracyclic antidepressant mirtazapine, however, for most, the potential benefits are not great and the risk of adverse effects and potential harm outweighs any potential for benefit.The length of time that antidepressant medications take to be effective at reducing symptoms can vary. Any potential benefits from the antidepressant amitriptyline may take up to three months to take effect and it may take between three and six months for duloxetine, milnacipran, and pregabalin to be effective at improving symptoms. Some medications have the potential to cause withdrawal symptoms when stopping so gradual discontinuation may be warranted particularly for antidepressants and pregabalin.There is tentative evidence that the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) appear to be similar. SSRIs may be used to treat depression in people diagnosed with fibromyalgia.Tentative evidence suggests that monoamine oxidase inhibitors (MAOIs) such as pirlindole and moclobemide are moderately effective for reducing pain. Very low-quality evidence suggests pirlindole as more effective at treating pain than moclobemide. Side effects of MAOIs may include nausea and vomiting.
Central nervous system depressants
Central nervous system depressants include drug categories such as sedatives, tranquilizers, and hypnotics. A 2021 meta-analysis concluded that such drugs can improve the quality of life for fibromyalgia patients in the medium-term.
Anti-seizure medication
The anti-convulsant medications gabapentin and pregabalin may be used to reduce pain. There is tentative evidence that gabapentin may be of benefit for pain in about 18% of people with fibromyalgia. It is not possible to predict who will benefit, and a short trial may be recommended to test the effectiveness of this type of medication. Approximately 6/10 people who take gabapentin to treat pain related to fibromyalgia experience unpleasant side effects such as dizziness, abnormal walking, or swelling from fluid accumulation. Pregabalin demonstrates a benefit in about 9% of people. Pregabalin reduced time off work by 0.2 days per week.
Cannabinoids
Cannabinoids may have some benefits for people with fibromyalgia. However, as of 2022, the data on the topic is still limited. Cannabinoids may also have adverse effects and may negatively interact with common rheumatological drugs.
Opioids
The use of opioids is controversial. As of 2015, no opioid is approved for use in this condition by the FDA. A 2016 Cochrane review concluded that there is no good evidence to support or refute the suggestion that oxycodone, alone or in combination with naloxone, reduces pain in fibromyalgia. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) in 2014 stated that there was a lack of evidence for opioids for most people. The Association of the Scientific Medical Societies in Germany in 2012 made no recommendation either for or against the use of weak opioids because of the limited amount of scientific research addressing their use in the treatment of FM. They strongly advise against using strong opioids. The Canadian Pain Society in 2012 said that opioids, starting with a weak opioid like tramadol, can be tried but only for people with moderate to severe pain that is not well-controlled by non-opioid painkillers. They discourage the use of strong opioids and only recommend using them while they continue to provide improved pain and functioning. Healthcare providers should monitor people on opioids for ongoing effectiveness, side effects, and possible unwanted drug behaviors.A 2015 review found fair evidence to support tramadol use if other medications do not work. A 2018 review found little evidence to support the combination of paracetamol (acetaminophen) and tramadol over a single medication. Goldenberg et al suggest that tramadol works via its serotonin and norepinephrine reuptake inhibition, rather than via its action as a weak opioid receptor agonist.A large study of US people with fibromyalgia found that between 2005 and 2007 37.4% were prescribed short-acting opioids and 8.3% were prescribed long-acting opioids, with around 10% of those prescribed short-acting opioids using tramadol; and a 2011 Canadian study of 457 people with FM found 32% used opioids and two-thirds of those used strong opioids.
Topical treatment
Capsaicin has been suggested as a topical pain reliever. Preliminary results suggest that it may improve sleep quality and fatigue, but there are not enough studies to support this claim.
Unapproved or unfounded
Sodium oxybate increases growth hormone production levels through increased slow-wave sleep patterns. However, this medication was not approved by the FDA for the indication for use in people with fibromyalgia due to the concern for abuse.The muscle relaxants cyclobenzaprine, carisoprodol with acetaminophen and caffeine, and tizanidine are sometimes used to treat fibromyalgia; however, as of 2015 they are not approved for this use in the United States. The use of NSAIDs is not recommended as first line therapy. Moreover, NSAIDs cannot be considered as useful in the management of fibromyalgia.Very low-quality evidence suggests quetiapine may be effective in fibromyalgia.No high-quality evidence exists that suggests synthetic THC (nabilone) helps with fibromyalgia.
Others
A 2013 review found moderate-level evidence on the usage of acupuncture with electrical stimulation for improvement of the overall well-being. Acupuncture alone will not have the same effects, but will enhance the influence of exercise and medication in pain and stiffness.
Nutrition and dietary supplements
Nutrition is related to fibromyalgia in several ways. Some nutritional risk factors for fibromyalgia complications are obesity, nutritional deficiencies, food allergies and consuming food additives. The consumption of fruits and vegetables, low-processed foods, high-quality proteins, and healthy fats may have some benefits. Low-quality evidence found some benefits of a vegetarian or vegan diet.Although dietary supplements have been widely investigated in relation to fibromyalgia, most of the evidence, as of 2021, is of poor quality. It is therefore difficult to reach conclusive recommendations. It appears that Q10 coenzyme and vitamin D supplements can improve pain and quality of life for fibromyalgia patients. Q10 coenzyme has beneficial effects on fatigue in fibromyalgia patients, with most studies using doses of 300 mg per day for three months. Q10 coenzyme is hypothesized to improve mitochondrial activity and decrease inflammation. Vitamin D has been shown to improve some fibromyalgia measures, but not others.A review article including four studies with 98 patients found that melatonin treatment has several positive effects on fibromyalgia patients, including the improvement of sleep quality, pain, and disease impact. No major adverse events were reported.
Psychotherapy
Due to the uncertainty about the pathogenesis of FM, current treatment approaches focus on management of symptoms to improve quality of life, using integrated pharmacological and non-pharmacological approaches. There is no single intervention shown to be effective for all patients. In a 2020 Cochrane review cognitive behavioral therapy (CBT) was found to have a small but beneficial effect for reducing pain and distress but adverse events were not well evaluated. CBT and related psychological and behavioural therapies have a small to moderate effect in reducing symptoms of fibromyalgia. Effect sizes tend to be small when CBT is used as a stand-alone treatment for FM patients, but these improve significantly when CBT is part of a wider multidisciplinary treatment program.A 2010 systematic review of 14 studies reported that CBT improves self-efficacy or coping with pain and reduces the number of physician visits at post-treatment, but has no significant effect on pain, fatigue, sleep, or health-related quality of life at post-treatment or follow-up. Depressed mood was also improved but this could not be distinguished from some risks of bias. A 2022 meta-analysis found that CBT reduces insomnia in people with chronic pain, including people with fibromyalgia. Sleep hygiene interventions, however, were not as effective.
Patient education
Patient education is recommended by the European League Against Rheumatism (EULAR) as an important treatment component. As of 2022, there is only low-quality evidence showing that patient education can decrease pain and fibromyalgia impact.Sleep hygiene interventions show low effectiveness in improving insomnia.
Manual therapy
A 2021 meta-analysis concluded that massage and myofascial release diminish pain in the medium-term. As of 2015, there was no good evidence for the benefit of other mind-body therapies.
Transcutaneous electrical nerve stimulation (TENS)
Transcutaneous electrical nerve stimulation (TENS) is the delivery of pulsed electrical currents to the skin to stimulate peripheral nerves. TENS is widely used to treat pain and is considered to be a low-cost, safe, and self-administered treatment. As such, it is commonly recommended by clinicians to people suffering from pain. On 2019, an overview of eight Cochrane reviews was conducted, covering 51 TENS-related randomized controlled trials. The review concluded that the quality of the available evidence was insufficient to make any recommendations. A later review concluded that transcutaneous electrical nerve stimulation may diminish pain in the short-term, but there was uncertainty about the relevance of the results.Preliminary findings suggest that electrically stimulating the vagus nerve through an implanted device can potentially reduce fibromyalgia symptoms. However, there may be adverse reactions to the procedure.
Noninvasive brain stimulation
Noninvasive brain stimulation includes methods such as transcranial direct current stimulation and high-frequency repetitive transcranial magnetic stimulation (TMS). Both methods have been found to improve pain scores in neuropathic pain and fibromyalgia.A 2021 meta-analysis of multiple intervention types concluded that magnetic field therapy and transcranial magnetic stimulation may diminish pain in the short-term, but conveyed an uncertainty about the relevance of the result. Several 2022 meta-analyses focusing on transcranial magnetic stimulation found positive effects on fibromyalgia. Repetitive transcranial magnetic stimulation improved pain in the short-term and quality of life after 5–12 weeks. Repetitive transcranial magnetic stimulation did not improve anxiety, depression, and fatigue. Transcranial magnetic stimulation to the left dorsolateral prefrontal cortex was also ineffective.
Hyperbaric oxygen therapy
Hyperbaric oxygen therapy (HBOT) has shown beneficial effects in treating chronic pain. However, treating fibromyalgia with hyperbaric oxygen therapy is still controversial, in light of the scarcity of large-scale clinical trials. In addition, hyperbaric oxygen therapy raises safety concerns due to the oxidative damage that may follow it.
Prognosis
Although in itself fibromyalgia is neither degenerative nor fatal, the chronic pain of fibromyalgia is pervasive and persistent. Most people with fibromyalgia report that their symptoms do not improve over time. However, most patients learn to adapt to the symptoms over time. The German guidelines for patients explain that:
The symptoms of fibromyalgia are persistent in nearly all patients.
Total relief of symptoms is seldom achieved.
The symptoms do not lead to disablement and do not shorten life expectancy.An 11-year follow-up study on 1,555 patients found that most remained with high levels of self-reported symptoms and distress. However, there was a great deal of patient heterogeneity accounting for almost half of the variance. At the final observation, 10% of the patients showed substantial improvement with minimal symptoms. An additional 15% had moderate improvement. This state, though, may be transient, given the fluctuations in symptom severity.A study of 97 adolescents diagnosed with fibromyalgia followed them for eight years. After eight years, the majority of youth still experienced pain and disability in physical, social, and psychological areas. At the last follow-up, all participants reported experiencing one or more fibromyalgia symptoms such pain, fatigue, and/or sleep problems, with 58% matching the complete ACR 2010 criteria for fibromyalgia. Based on the WPI and SS score cut-points, the remaining 42% exhibited subclinical symptoms. Pain and emotional symptom trajectories, on the other hand, displayed a variety of longitudinal patterns. The study concluded that while most patients fibromyalgia symptoms endure, the severity of their pain tends to reduce over time.Baseline depressive symptoms in adolescents appear to predict worse pain at follow-up periods.
Epidemiology
Fibromyalgia is estimated to affect 2–4% of the population.Females are affected about twice as often as males based on criteria as of 2014.
History
Chronic widespread pain had already been described in the literature in the 19th century but the term fibromyalgia was not used until 1976 when Dr P.K. Hench used it to describe these symptoms. Many names, including "muscular rheumatism", "fibrositis", "psychogenic rheumatism", and "neurasthenia" were applied historically to symptoms resembling those of fibromyalgia. The term fibromyalgia was coined by researcher Mohammed Yunus as a synonym for fibrositis and was first used in a scientific publication in 1981. Fibromyalgia is from the Latin fibra (fiber) and the Greek words myo (muscle) and algos (pain).Historical perspectives on the development of the fibromyalgia concept note the "central importance" of a 1977 paper by Smythe and Moldofsky on fibrositis. The first clinical, controlled study of the characteristics of fibromyalgia syndrome was published in 1981, providing support for symptom associations. In 1984, an interconnection between fibromyalgia syndrome and other similar conditions was proposed, and in 1986, trials of the first proposed medications for fibromyalgia were published.A 1987 article in the Journal of the American Medical Association used the term "fibromyalgia syndrome" while saying it was a "controversial condition". The American College of Rheumatology (ACR) published its first classification criteria for fibromyalgia in 1990. Later revisions were made in 2010, 2016, and 2019.
Society and culture
Economics
People with fibromyalgia generally have higher healthcare costs and utilization rates. A review of 36 studies found that fibromyalgia causes a significant economic burden on health care systems. Annual costs per patient were estimated to be up to $35,920 in the US and $8,504 in Europe.
Controversies
Fibromyalgia was defined relatively recently. In the past, it was a disputed diagnosis. Frederick Wolfe, lead author of the 1990 paper that first defined the diagnostic guidelines for fibromyalgia, stated in 2008 that he believed it "clearly" not to be a disease but instead a physical response to depression and stress. In 2013 Wolfe added that its causes "are controversial in a sense" and "there are many factors that produce these symptoms – some are psychological and some are physical and it does exist on a continuum". Some members of the medical community did not consider fibromyalgia a disease because of a lack of abnormalities on physical examination and the absence of objective diagnostic tests.In the past, some psychiatrists have viewed fibromyalgia as a type of affective disorder, or a somatic symptom disorder. These controversies do not engage healthcare specialists alone; some patients object to fibromyalgia being described in purely somatic terms.As of 2022, neurologists and pain specialists tend to view fibromyalgia as a pathology due to dysfunction of muscles and connective tissue as well as functional abnormalities in the central nervous system. Rheumatologists define the syndrome in the context of "central sensitization" – heightened brain response to normal stimuli in the absence of disorders of the muscles, joints, or connective tissues. Because of this symptomatic overlap, some researchers have proposed that fibromyalgia and other analogous syndromes be classified together as central sensitivity syndromes.
Notes
References
External links
Arthritis – Types – Fibromyalgia by the CDC
Fibromyalgia by the National Institute of Arthritis and Musculoskeletal and Skin Diseases
Fibromyalgia by the American College of Rheumatology
Fibromyalgia by the NHS |
Persistent thyroglossal duct | A persistent thyroglossal duct is a usually benign medical condition in which the thyroglossal duct, a structure usually only found during embryonic development, fails to atrophy. The duct persists as a midline structure forming an open connection between the back of the tongue and the thyroid gland. This opening can lead to fluid accumulation and infection, which necessitate the removal of the duct.
Signs and symptoms
Studies done on cadavers claim persistent thyroglossal ducts can be completely asymptomatic and found in 7% of the human adult population. However, the continued presence of the duct can often lead to complications due to infections and fluid buildup. The glands in the mucosa of the duct will continue their secretions until the fluid forms a cyst or exit the duct via the opening in the foramen cecum. Local infections, such as colds, tonsillitis, or inflammation of the lymph nodes in the area can also lead to the accumulation of fluid within the duct. Even if the cyst forms as secondary to another infection and improved after antibiotics, it will often reoccur and require treatment.
Three-fourths of abnormalities within a persistent thyroglossal duct involve the formation of a cyst. If a persistent thyroglossal duct becomes fluid filled it will form a thyroglossal duct cyst, which accounts for 70% of congenital neck masses and is the most likely diagnosis if the mass is along the midline of the neck. These cysts are often diagnosed in children under the age of ten and have no particular gender prevalence. The cysts are normally asymptomatic at this age and are noticed because of the swelling that will move if the patient swallows. Over 80% of these cysts are located at or below the hyoid bone.Very rarely, the persistent duct can become cancerous, called thyroglossal duct carcinoma. In the case of thyroglossal duct carcinoma, the cancerous cells are ectopic thyroid tissue that has been deposited along the thyroglossal duct and will present as a papillary carcinoma. However, the cells are less likely to metastasize in the cyst, than if they were present in the actual thyroid gland.The other fourth of abnormalities presents as draining abscess. This is from an infection that will rupture through the skin to allow for adequate drainage of the infected area.
Anatomy
The tongue develops after the thyroid primordium so the foramen cecum becomes buried at the base of the tongue. The thyroglossal duct then continues through the neck and lies anterior to the laryngeal cartilage. The duct then passes anteriorly to the developing hyoid bone; however, as the bone continues to grow it can continue to grow posteriorly, become anterior, or even grow to surround the duct. The duct is found very close to the medial line of the neck. The duct continues in front of the thyrohyoid membrane, sternothyroid muscle, and sternohyoid muscle, before terminating in the inferior segment of the neck at the thyroid.Failures of duct removal surgeries have proven that the suprahyoid region of the duct can have many microscopic branches that connect to the base of the tongue. They exhibit variability between different cases; however, it is believed they are associated with the pharyngeal mucosa and muscles of the tongue.
Embryological origin
During the third week of development, the thyroid gland begins to develop from the floor of the pharynx. This primordium begins as an evagination between the first and second pharyngeal grooves, relatively where the anterior two-thirds of the tongue ends. This area is known as the foramen cecum and marks the origin of the thyroglossal duct. As the developing thyroid begins to travel to its intended destination, it remains connected to the tongue via the thyroglossal duct. By the seventh week of fetal development, the thyroid reaches its final position in the neck after growing through the mesoderm and musculature of the tongue, mouth, and neck. During the eighth to tenth week, the cells of the duct normally begin growing inwards and fill the previously hollow tube, beginning from the inferior end. This inferior end of the duct will then become the pyramidal lobe of the thyroid gland. The dividing cellular cords of the tubular duct become the isthmus and lateral lobes of the gland to complete the formation of the rest of the gland.Once the thyroglossal duct involutes, the cells will begin to degenerate and disappear. However, in the case of a persistent thyroglossal duct, the tube remains hollow and continues to connect the foramen cecum to the thyroid gland.
Histology
The cells of the thyroglossal duct are epithelial in origin. The cell shapes can range from columnar, to squamous, to transitional epithelium. Thyroid-like masses can also be seen in close relation along the duct. Enclosed vesicles and cysts can also be seen while studying the tissue of the duct. A persistent thyroglossal duct in a rabbit showed resemblance to the layout of the alimentary canal; with its external fibrous connective tissue, muscular layers, submucosal glands, and convoluted epithelium.
Diagnosis
Ultrasound is the often chosen to examine the duct and determine the presence and size of any cysts or abnormalities. Fine-needle aspiration cytology can also be used to confirm the diagnosis.
Treatment
In order to prevent further cysts and infections from forming, the thyroglossal duct and all of its branches are removed from the throat and neck area. A procedure, known as the Sistrunk procedure, is considered to be the standard procedure and involves removal of portions of the hyoid bone and core tissue of the suprahyoid region. Cysts will often reoccur if the entire duct is not removed, so reoccurrence requires a wider range of tissue to be removed in a subsequent surgery.Delaying the surgical procedure almost always leads to recurrent infections, which will continue to delay the needed treatment. The Sistrunk procedure has a reoccurrence rate of less than 5%, proving it is extremely effective at removing the majority of traces of the persistent thyroglossal duct.
References
External links
ent/323 at eMedicine |
Mycobacterium avium-intracellulare infection | Mycobacterium avium-intracellulare infection (MAI) is an atypical mycobacterial infection, i.e. one with nontuberculous mycobacteria or NTM, caused by Mycobacterium avium complex (MAC), which is made of two Mycobacterium species, M. avium and M. intracellulare. This infection causes respiratory illness in birds, pigs, and humans, especially in immunocompromised people. In the later stages of AIDS, it can be very severe. It usually first presents as a persistent cough. It is typically treated with a series of three antibiotics for a period of at least six months.
M. avium, M. intracellulare, and M. chimaera are each saprotrophic organisms present in soil and water; entry into hosts is usually via the gastrointestinal tract, but also can be via the lungs.
MAC infections can cause fevers, diarrhea, malabsorption, as well as loss of appetite and weight loss, and can disseminate to the bone marrow. MAI is typically resistant to standard mycobacterial therapies.
Signs and symptoms
Pulmonary involvement symptoms are similar to tuberculosis (TB), and include fever, fatigue, weight loss, and coughing up blood. Diarrhea and abdominal pain are associated with gastrointestinal involvement.
Children
M. avium and M. haemophilum infections in children form a distinct clinical entity, not associated with abnormalities of the immune system. M. avium typically causes unilateral swelling of one of the lymph nodes of the neck. This node is firm at the beginning, but a collar-stud abscess is formed eventually, which is a characteristic blue-purple in colour with multiple discharging sinuses. The treatment of choice is surgical excision of the affected lymph nodes, with antibiotic treatment (usually clarithromycin and rifabutin for 18 to 24 months) reserved for those patients who cannot have surgery.
Cause
MAC bacteria are common in the environment and cause infection when inhaled or swallowed. Recently, M. avium has been found to deposit and grow in bathroom shower heads from which it may be easily aerosolized and inhaled.
Bacteria
Mycobacterium avium complex (MAC), also called Mycobacterium avium-intracellulare complex, is a microbial complex of three Mycobacterium species (i.e. M. avium, M. intracellulare, and M. chimaera). It causes Mycobacterium avium-intracellulare infection. Some sources also include Mycobacterium avium subspecies paratuberculosis (MAP).
Risk factors
MAI is common in immunocompromised individuals, including senior citizens and those with HIV/AIDS or cystic fibrosis. Bronchiectasis, the bronchial condition which causes pathological enlargement of the bronchial tubes, is commonly found with MAI infection. Whether the bronchiectasis leads to the MAC infection or is the result of it is not always known.The Mycobacterium avium complex (MAC) includes common atypical bacteria, i.e. nontuberculous mycobacteria (NTM), found in the environment which can infect people with HIV and low CD4 cell count (below 100/microliter); mode of infection is usually inhalation or ingestion.MAC causes disseminated disease in up to 40% of people with HIV in the United States, producing fever, sweats, weight loss, and anemia. Disseminated MAC (DMAC) characteristically affects people with advanced HIV disease and peripheral CD4 cell counts less than 50 cells/uL. Effective prevention and therapy of MAC has the potential to contribute substantially to improved quality of life and duration of survival for HIV-infected persons.
Pathophysiology
MAC is the most commonly found form of NTM.Immunodeficiency is not a requirement for MAI.MAC usually affects patients with abnormal lungs or bronchi. However, Jerome Reich and Richard Johnson describe a series of six patients with MAC infection of the right middle lobe or lingula who did not have any predisposing lung disorders.The right middle lobe and lingula of the lungs are served by bronchi that are oriented downward when a person is in the upright position. As a result, these areas of the lung may be more dependent upon vigorous voluntary expectoration (cough) for clearance of bacteria and secretions.Since the six patients in their retrospective case series were older females, Reich and Johnson proposed that patients without a vigorous cough may develop right middle lobe or left lingular infection with MAC. They proposed this syndrome be named Lady Windermere syndrome, after the character Lady Windermere in Oscar Wildes play Lady Windermeres Fan. However, little research has confirmed this speculative cause.
Diagnosis
Diagnosis can be achieved through blood cultures or cultures of other bodily fluids such as sputum. Bone marrow culture can often yield an earlier diagnosis but is usually avoided as an initial diagnostic step because of its invasiveness. Many people will have anemia and neutropenia if the bone marrow is involved. MAC bacteria should always be considered in a person with HIV infection presenting with diarrhea.The diagnosis requires consistent symptoms with two additional signs:
Chest X-ray or CT scan showing evidence of right middle lobe (or left lingular lobe) lung infection
Sputum culture or bronchoalveolar lavage culture demonstrating the infection is caused by MACDisseminated MAC is most readily diagnosed by one positive blood culture. Blood cultures should be performed in patients with symptoms, signs, or laboratory abnormalities compatible with mycobacterium infection. Blood cultures are not routinely recommended for asymptomatic persons, even for those who have CD4+ T-lymphocyte counts less than 100 cells/uL.
HIV infection
MAC in patients with HIV disease is theorized to represent recent acquisition rather than latent infection reactivating (which is the case in many other opportunistic infections in immunocompromised patients).The risk of MAC is inversely related to the patients CD4 count and increases significantly when the CD4 count decreases below 50 cells/mm³. Other risk factors for acquisition of MAC infection include using an indoor swimming pool, consumption of raw or partially cooked fish or shellfish, bronchoscopy and treatment with granulocyte stimulating factor. Disseminated disease was previously the common presentation prior to the advent of highly active antiretroviral therapy (HAART). Today, in regions where HAART is the standard of care, localized disease presentation is more likely. This generally includes a focal lymphadenopathy/lymphadenitis.
Prevention
People with AIDS are given macrolide antibiotics such as azithromycin for prophylactic treatment.People with HIV infection and less than 50 CD4 cells/uL should be administered prophylaxis against MAC. Prophylaxis should be continued for the patients lifetime unless multiple drug therapy for MAC becomes necessary because of the development of MAC disease.Clinicians must weigh the potential benefits of MAC prophylaxis against the potential for toxicities and drug interactions, the cost, the potential to produce resistance in a community with a high rate of tuberculosis, and the possibility that the addition of another drug to the medical regimen may adversely affect patients compliance with treatment. Because of these concerns, therefore, in some situations rifabutin prophylaxis should not be administered.Before prophylaxis is administered, patients should be assessed to ensure that they do not have the active disease due to MAC, M. tuberculosis, or any other mycobacterial species. This assessment may include a chest radiograph and tuberculin skin test.Rifabutin, by mouth daily, is recommended for the peoples lifetime unless disseminated MAC develops, which would then require multiple drug therapy. Although other drugs, such as azithromycin and clarithromycin, have laboratory and clinical activity against MAC, none has been shown in a prospective, controlled trial to be effective and safe for prophylaxis. Thus, in the absence of data, no other regimen can be recommended at this time. The 300-mg dose of rifabutin has been well tolerated. Adverse effects included neutropenia, thrombocytopenia, rash, and gastrointestinal disturbances.
Treatment
Postinfection treatment involves a combination of antituberculosis antibiotics, including rifampicin, rifabutin, ciprofloxacin, amikacin, ethambutol, streptomycin, clarithromycin or azithromycin.NTM infections are usually treated with a three-drug regimen of either clarithromycin or azithromycin, plus rifampicin and ethambutol. Treatment typically lasts at least 12 months.Although studies have not yet identified an optimal regimen or confirmed that any therapeutic regimen produces sustained clinical benefit for patients with disseminated MAC, the Task Force concluded that the available information indicated the need for treatment of disseminated MAC. The Public Health Service, therefore, recommends that regimens be based on the following principles:
Treatment regimens outside a clinical trial should include at least two agents.
Every regimen should contain either azithromycin or clarithromycin; many experts prefer ethambutol as a second drug. Many clinicians have added one or more of the following as second, third, or fourth agents: clofazimine, rifabutin, rifampin, ciprofloxacin, and in some situations amikacin. Isoniazid and pyrazinamide are not effective for the therapy of MAC.
Therapy should continue for the lifetime of the patient if the clinical and microbiologic improvement is observed.Clinical manifestations of disseminated MAC—such as fever, weight loss, and night sweats—should be monitored several times during the initial weeks of therapy. The microbiologic response, as assessed by blood culture every 4 weeks during initial therapy, can also be helpful in interpreting the efficacy of a therapeutic regimen. Most patients who ultimately respond show substantial clinical improvement in the first 4–6 weeks of therapy. Elimination of the organism from blood cultures may take somewhat longer, often requiring 4–12 weeks.
HIV-infected children
HIV-infected children less than 12 years of age also develop disseminated MAC. Some age adjustment is necessary when clinicians interpret CD4+ T-lymphocyte counts in children less than 2 years of age. Diagnosis, therapy, and prophylaxis should follow recommendations similar to those for adolescents and adults.
Society and culture
Terminology
"Lady Windermere syndrome" is one term to describe infection in the lungs due to MAC. It is named after a character in Oscar Wildes 1892 play Lady Windermeres Fan.In recent years, some have described the eponym as inappropriate, and some have noted that it would have been unlikely that Lady Windermere had the condition to which her name was assigned.The more commonly used term is nontuberculous mycobacteria (NTM) infection, or non-tuberculous mycobacterial infection (NMI). There is no evidence that a persons reluctance to spit has any causal role in NTM infection, the chief reason for the term having been applied to older women presenting with the condition.Lady Windermere syndrome is a type of mycobacterial lung infection.
Literary reference
The original Chest article proposing the existence and pathophysiology of the Lady Windermere syndrome suggested the character Lady Windermere in Oscar Wildes Victorian-era play Lady Windermeres Fan is a good example of the fastidious behavior believed to cause the syndrome. The article states:
We offer the term, Lady Windermeres Syndrome, from the Victorian-era play, Lady Windermeres Fan, to convey the fastidious behavior hypothesized: "How do you do, Lord Darlington. No, I cant shake hands with you. My hands are all wet with the roses."Victorian women presumably believed "ladies dont spit," and consequently might have been predisposed to develop lung infection.
Shortly after the Lady Windermere syndrome was proposed, a librarian wrote a letter to the editor of Chest challenging the use of Lady Windermere as the eponymous ancestor of the proposed syndrome. In the play, Lady Windermere is a vivacious young woman, married only two years, who never coughs or displays any other signs of illness. While her avoidance of shaking hands might be interpreted as "fastidiousness", two alternative explanations may be just as probable:
1) Lady Windermere actually is in the midst of arranging flowers and consequently cannot properly greet her guest:[LADY WINDERMERE is at table R., arranging roses in a blue bowl.]2) Lady Windermere wishes to discourage the flirtatious advances of her would-be suitor Lord Darlington and cites her wet hands as an excuse to keep him from touching her:LADY WINDERMERE. Lord Darlington, you annoyed me last night at the Foreign Office. I am afraid you are going to annoy me again. . . .LORD DARLINGTON. [Takes chair and goes across L.C.] I am quite miserable, Lady Windermere. You must tell me what I did. [Sits down at table L.]LADY WINDERMERE. Well, you kept paying me elaborate compliments the whole evening.]The scholars highlight the literary malapropism, but some in the medical community have adopted the term regardless, and peer-reviewed medical journals still sometimes mention the Lady Windermere syndrome, although it is increasingly viewed as a limiting and sexist term for a serious bacterial infection.
See also
Paratuberculosis
References
External links
Media related to Mycobacterium avium-intracellulare infection at Wikimedia Commons
Mycobacterium avium-intracellulare Infection at the US National Library of Medicine Medical Subject Headings (MeSH) |
Sucrose intolerance | Sucrose intolerance or genetic sucrase-isomaltase deficiency (GSID) is the condition in which sucrase-isomaltase, an enzyme needed for proper metabolism of sucrose (sugar) and starch (e.g., grains), is not produced or the enzyme produced is either partially functional or non-functional in the small intestine. All GSID patients lack fully functional sucrase, while the isomaltase activity can vary from minimal functionality to almost normal activity. The presence of residual isomaltase activity may explain why some GSID patients are better able to tolerate starch in their diet than others with GSID.
Signs and symptoms
Abdominal cramps and bloating
Diarrhea and constipation
Vomiting
Hypoglycemia and headaches
Poor weight gain and growth
Upper respiratory tract and viral diseases
Anxiety and heart palpitations
Excess gas production
Cause
Sucrose intolerance can be caused by genetic mutations in which both parents must contain this gene for the child to carry the disease (so-called primary sucrose intolerance). Sucrose intolerance can also be caused by irritable bowel syndrome, aging, or small intestine disease (secondary sucrose intolerance). There are specific tests used to help determine if a person has sucrose intolerance. The most accurate test is the enzyme activity determination, which is done by biopsying the small intestine. This test is a diagnostic for GSID. Other tests which can aid in the diagnosis of GSID but which are not truly diagnostic for the disease are the sucrose breath test, and a genetic test which tests for the absence of certain genes which are thought to be responsible for GSID.Sucrose (also called saccharose) is a disaccharide and is a two-sugar chain composed of glucose and fructose which are bonded together. A more familiar name is table, beet, or cane sugar. It was believed that most cases of sucrose intolerance were due to an autosomal recessive, genetic, metabolic disease. Based on new data patients with heterozygous and compound heterozygous genotypes can have symptom presentation as well. GSID involves deficiency in the enzyme sucrase-isomaltase, which breaks the bond between the glucose and fructose molecules. When disaccharides are consumed, they must be broken down into monosaccharides by enzymes in the intestines before they can be absorbed. Monosaccharides, or single sugar units, are absorbed directly into the blood.A deficiency of sucrase may result in malabsorption of sugar, which can lead to potentially serious symptoms. Since sucrase-isomaltase is involved in the digestion of starches, some GSID patients may not be able to absorb starches as well. It is important for those with sucrose intolerance to minimize sucrose consumption as much as possible. Dietary supplements or medications may be taken as a substitute for the missing enzyme or to introduce healthy bacteria into the immune system.
Diagnosis
Chronic gastrointestinal symptoms that are fairly common but difficult to diagnose may be caused by congenital sucrase-isomaltase deficiency (CSID). CSID is an inherited condition characterized by a dysfunctional digestive enzyme.The purpose of the digestive enzyme, sucrase-isomaltase, is to break down the compound sugars sucrose (table sugar) and starch sugars so they will be small enough to be absorbed from the gastrointestinal tract.In addition to CSID, a primary gastrointestinal disorder such as a gastrointestinal infection, celiac disease or Crohn’s disease, can transiently suppress the digestive function of sucrase-isomaltase, causing an acquired form of sucrase-isomaltase deficiency (SID). Once the underlying disorder is treated and resolved, the symptoms of SID usually go away.A deficiency or absence of sucrase-isomaltase function is likely to cause chronic gastrointestinal symptoms whenever a person eats food containing sucrose or starch sugars, which are very common in carbohydrates. In fact, the sucrase-isomaltase enzyme is responsible for the digestion of all foods containing sucrose and approximately 60% to 80% of all foods containing starch sugars. When sucrose or starch sugars are not absorbed from the gastrointestinal tract, they travel to the large intestine (colon) where two things happen:
The food draws in excess water by a process called osmosis, creating watery diarrhea.
The food is broken down by the normal bacteria that reside in the colon by a process called fermentation; byproducts of all fermentation include the production of excess gas and an acidic environment.The timing of gastrointestinal symptoms associated with CSID is distinctive. CSID symptoms are frequent, daily events; they are lifelong, and they are postprandial (occurring after eating food). These symptoms can range from mild to severe and include chronic, watery, acidic diarrhea; intestinal gas and bloating; nausea; and abdominal pain.Infants may not show symptoms of CSID until they begin to eat sucrose- and starch-containing foods such as juices, solid foods, and medications sweetened with sucrose. Chronic, watery diarrhea and failure to thrive are the most common symptoms in infants and toddlers. Other symptoms include abdominal distention, gassiness, colic, irritability, excoriated buttocks, severe diaper rash due to acidic diarrhea, indigestion, and vomiting.Adults with CSID are usually lean, with a low body-mass index and an aversion to eating carbohydrates and “sweets.” Because CSID is an inherited condition, patients with CSID often have close relatives who also experience chronic diarrhea.
Determining the cause of chronic gastrointestinal symptoms may take a long time because the symptoms can be common to many gastrointestinal conditions. One diagnostic method, considered the gold standard for diagnosing CSID, measures the level of activity of four intestinal enzymes that digest compound sugars, also called disaccharides. The four disaccharides digested in the small intestine are lactose, sucrose, maltose, and isomaltose.This diagnostic method, called a disaccharidase assay, is conducted on tissue samples taken from the small intestine during an endoscopic procedure, also called an upper GI (gastrointestinal) examination. If the level of sucrase activity is below the level considered necessary for normal sucrase function, the patient will be diagnosed with CSID.Noninvasive diagnostic methods include two breath tests, which can be useful screening tools but are not specific enough for a confirmed diagnosis of CSID.The first of these is the hydrogen/methane breath test, which measures the amount of hydrogen and methane gases a person exhales after consuming sugary water. The exhaled breath is collected in sealed test tubes at 30-minute intervals over a three-hour period after drinking the sugary water. If a person has CSID and there are little or no working sucrase-isomaltase enzymes in the intestines, greater than normal levels of hydrogen and/or methane are generated and exhaled in the breath. However, there may be other reasons why the person is exhaling excess hydrogen and/or methane gas, such as an overgrowth of bacteria in the small intestine, called small intestinal bacterial overgrowth (SIBO).The second breath test is called the carbon-13 (13C) breath test. Carbon-13 is a stable isotope of carbon that occurs naturally in sucrose, making it possible to track a person’s ability to digest and absorb sucrose by measuring the amount of 13CO2 exhaled after drinking a sugar-water solution. In this breath test, the exhaled breath is collected in sealed test tubes at 30-minute intervals over a 90-minute period after drinking the sugar-water solution. If the cumulative amount of 13CO2 exhaled is below the normal level that occurs when sucrose is digested by sucrase, the person may have CSID and the person should undergo further examination by their doctor.The findings from a 13C-breath test are believed to be more definitive for CSID than the hydrogen/methane breath test although neither test is validated to provide, by themselves, a diagnosis for CSID. In both breath tests, the consumption of sugar may cause severe gastrointestinal symptoms in those who have CSID. For this reason, these breath tests should be conducted under the supervision of a healthcare professional.
A relatively new, noninvasive test that shows promise is a genetic test for the gene SI, which codes for the enzyme sucrase-isomaltase. This test requires a swab of tissue from the inside of the cheek. So far, 37 aberrant variations of the SI gene have been found in patients who have been diagnosed with CSID.A positive genetic test for one or more of the 37 SI gene variations known to cause CSID can help confirm a diagnosis of CSID. However, a negative genetic test cannot rule out a diagnosis of CSID. There are more than 2,000 different variations of the SI gene, and many of these variations have not yet been investigated for their ability to cause CSID. Therefore, a negative genetic test only means that the person does not carry one of the 37 SI gene variations that are known to be associated with CSID, but they may have an SI gene variation that has not yet been identified as one that can cause CSID.
While the breath tests and genetic test have not been validated to be diagnostic for CSID, they may become important tests that help in identifying patients with CSID. As with all diagnoses, a diagnosis of CSID depends on combining a doctor’s clinical findings with results from objective tests. A physical examination, medical history, and other secondary tests, such as stool pH test for acidic stool, can aid in the diagnosis of CSID.If it is clinically inappropriate or difficult to perform a biopsy or if a CSID diagnosis is in doubt, a physician may suggest a two-week therapeutic trial with an enzyme replacement. If the patient shows a reduction of symptoms it is considered diagnostic for CSID.
Treatment
The two ways to manage the gastrointestinal symptoms associated with CSID are:
Diet modification that eliminates or restricts the consumption of foods containing sucrose (table sugar) or starch sugarsThe use of enzyme replacement therapy to replace the action of the sucrase enzyme that is deficient. This medication requires a prescription from a doctor.
Diet modification
The level of ability to digest sucrose or starch sugars is unique to each person who is living with CSID and depends on many factors, including the following:
The individual level of function of the digestive enzyme sucrase-isomaltase
How well the other functions of the gastrointestinal tract are working
How much sucrose and starch sugars are consumed
If a person has any other health issues that may affect digestionFor these reasons, a restriction diet needs to be specific for each patient who has CSID. Before making any changes to the diet, it is important for a patient to speak with a healthcare provider, especially if the patient is underweight or not gaining weight as would be expected.
It is also advised that the patient work with a registered dietitian or nutritionist who can help identify the foods that can be tolerated and those that cannot be tolerated. A registered dietitian or nutritionist can also help the patient plan a diet that will meet the nutritional needs for normal growth and development. Vitamins, minerals, and additional supplements may be needed to meet all nutritional needs.
Epidemiology
The highest prevalence rates are seen in the Inuit populations of Greenland (5–10%), Alaska (3–7%), and Canada (about 3%). European descent prevalence ranges from 0.2% to 0.05%. There is a lower prevalence reported in African Americans and Hispanics compared to Caucasians.
See also
Fructose malabsorption
Digestive system diseases
Lactose intolerance
References
External links
"Congenital sucrase-isomaltase deficiency". Genetic Home Reference. US National Library of Medicine. |
Pachydermodactyly | Pachydermodactyly is a superficial dermal fibromatosis that presents as a poorly circumscribed symmetric, infiltrative, asymptomatic soft-tissue hypertrophy of the proximal fingers, typically sparing the thumbs and fifth fingers and rarely extending proximally to the wrists or occurring distally.: 990
See also
Skin lesion
References
External links
A Case of Pachydermodactyly |
Schneckenbecken dysplasia | Schneckenbecken dysplasia is a rare pre-natally fatal hereditary autosomal recessive condition which affects the bones and pre-natal growth.
Signs and symptoms
Fetuses with the condition typically have a hypoplastic iliac bone which resembles a snail, short ribs, short neck, shortened and widened (dysplastic) fibula bones, premature ossification of the tarsus, shortened and broadened long bones which resemble a dumbbell, hypoplastia and flattening vertebrae, macrocephaly, dolichocephaly, toenail hypoplasia, flattening of the malar prominence, and micromelic (short-limbed) dwarfism.
Complications
Fetuses homozygous for this condition typically die before being born, and because of this they dont usually live to experience the complications of the disease.
Genetics
This condition is typically caused by loss-of-function mutations in the SLC35D1 gene, located in chromosome 1. These mutations are inherited in an autosomal recessive manner.
Diagnosis
This condition can be diagnosed through the following methods:
Ultrasound (due to its prenatally fatal nature)
Whole genome sequencing
Physical examination
Post-mortem autopsy
Treatment
There is no cure for this disorder, and attempted treatment will always be ineffective due to this conditions lethal nature.
Prevalence
According to OrphaNet, less than 20 cases have been reported.
History
This condition was first discovered in 1986 by Knowles et al. when they described 5 fetuses born to a consanguineous, first-cousin Asian couple. The couple in question went through 13 pregnancies, these pregnancies consisted of 4 successful pregnancies which resulted in healthy children, 5 pregnancies which resulted in dead dwarf babies, 3 pregnancies which ended in miscarriage, and 1 pregnancy which was clinically aborted after the pre-natal detection of dwarfism.
Eponym
This condition is named after the German translation for "snail-pelvis" (Schneckenbecken), this name was first used by Borochowitz et al. when they described a Californian fetus with the symptoms of the disorder and referred to said symptoms as "Schneckenbecken dysplasia".
Mouse knockout model
In 2007, Hiraoka et al. created an SLC35D1-knockout mouse model, said experiment revealed that while mice heterozygous for the genetic mutation were born normally without any associated complications, mice homozygous for said mutation died during their neo-natal life. The latter mice had micromelia, craniofacial bone hypoplasia, vertebrae flattening, severely short long bones and iliac bones, Hiraoka noted these symptoms to be similar to those experienced by human fetuses with Schenckenbecken dysplasia, and concluded that this gene must be important for normal ante-natal skeletal formation in mice.
See also
Achondroplasia
== References == |
Pneumocephalus | Pneumocephalus is the presence of air or gas within the cranial cavity. It is usually associated with disruption of the skull: after head and facial trauma, tumors of the skull base, after neurosurgery or otorhinolaryngology, and rarely, spontaneously. Pneumocephalus can occur in scuba diving, but is very rare in this context.
If there is a valve mechanism which allows air to enter the skull but prevents it from escaping, a tension pneumocephalus can occur (similar to what can happen in a tension pneumothorax).
CT scans of patients with a tension pneumocephalus typically show air that compresses the frontal lobes of the brain, which results in a tented appearance of the brain in the skull known as the Mount Fuji sign.
The name is derived from the resemblance of the brain to Mount Fuji in Japan, a volcano known for its symmetrical cone. In typical cases, there is a symmetrical depression near the midline (such as the crater of a volcano), due to intact bridging veins. Its occurrence seems to be limited to tension pneumocephalus (not occurring in pneumocephalus without tension). The sign was first described by a team of Japanese neurosurgeons.Pneumocephalus has also been shown to follow neurosurgical procedures such as deep brain stimulation and hematoma evacuation (e.g., chronic subdural hematoma), where while seemingly innocuous to the patient, may cause brain shift, subsequent stereotactic inaccuracy, and even another surgical intervention. Regarding chronic subdural hematoma (CSDH) surgery, a postoperative volume of pneumocephalus greater than 15mL puts a patient at increased risk of CSDH recurrence; in fact, for every milliliter of air entering the cranial cavity after CSDH evacuation, the recurrence risk increases by 4%. Efforts are made by neurosurgeons to reduce pneumocephalus volume during surgery, and thus, subsequent brain shift.
Additional images
Footnotes
== External links == |
Acute megakaryoblastic leukemia | Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.AMKL is commonly regarded as a subtype of acute myeloid leukemia (AML). More formally, it is classified under the AML-M7 category of the French-American-British classification and by the World Health Organization of 2016 in the AML-Not Otherwise Specified subcategory.Acute megakaryoblastic leukemia falls into three distinct groups which differ in underlying causes, ages of presentation, responses to therapy, and prognoses. These groups are: AMKL occurring in young children with Down syndrome, i.e. DS-AMKL; AMKL occurring in children who do not have Down syndrome, i.e. non-DS-AMKL (also termed pediatric acute megakaryoblastic leukemia or pediatric AMKL); and AMKL occurring in non-DS adults, i.e. adult-AMKL. AMKL, while rare, is the most common form of AML in DS-AMKL, occurring ~500-fold more commonly in Down syndrome children than in children without Down syndrome; non-DS-AMKL and adult-AMLK are rare, accounting for <1% of all individuals diagnosed as in the AML-M7 category of leukemia.
DS-AMKL
Pathophysiology
Individuals with Down syndrome almost always have three instead of the normal two copies of chromosome 21. The extra copies of key chromosome 21 genes underlie their increased susceptibility to AMKL by promoting the development of a certain type of inactivating mutation in the GATA1 gene. The GATA1 gene resides on the X chromosome and codes for two transcription factors, GATA1 and a shorter version, GATA1-S. GATA1 and GATA1-S contribute to regulating the expression of genes that control the maturation of megakaryoblasts to promegakaryocytes, megakaryocytes, and platelets as well as the maturation of erythroblasts to red blood cells. GATA1-S appears less active than GATA1 in controlling some of the genes that promote megakaryoblast maturation but more active than GATA1 in stimulating megakaryoblast proliferation. Various GATA1 mutations that cause this gene to make GATA1-S but unable to make GATA1 result in the excessive proliferation of platelet precursor cells, reductions in the levels of circulating blood platelets, mild reductions in the levels of circulating red blood cells, and the development of transient myeloproliferative disease (TMD). TMD is a disorder involving the excessive proliferation of non-malignant megakaryoblasts and descendent cells due to the cited truncating mutations in the GATA1 gene. TMD is a necessary predecessor to DS-AMKL.Down syndrome fetuses and neonates with one of the cited types of GATA1 truncating mutations are in rare cases asymptomatic (i.e. silent TMD) but more commonly exhibit in utero or during the first months of live accumulations of immature megakaryoblasts in, and sometimes life-threatening injury to, the fetal blood-forming organ, the liver, and other tissues. While fatal in up to 20% of cases, ~80 of infants with TMD fully recover from the diseases within 4 months. However, ~10% of individuals with a history of symptomatic or silent TMD develop DS-AMKL within 4 years. During this interval, these individuals may acquire somatic mutations in those of their megakaryoblasts that bear the original truncating GATA1 mutation. These newly acquired mutations appear to result from the interactions of GATAT1 truncating mutations with excessive copies of chromosome 21 genes. The genes with these mutations include TP53, FLT3, ERG, DYRK1A, CHAF1B, HLCS, RUNX1, MIR125B2 (which is the gene for microRNA MiR125B2CTCF, STAG2, RAD21, SMC3, SMC1A, NIPBL, SUZ12, PRC2, JAK1, JAK2, JAK3, MPL, KRAS, NRAS, and SH2B3. At least one but probably several of these mutations, whether occurring in individuals with silent or symptomatic TMD, are presumed responsible for or to contribute to the development of DS-AMKL.Rare cases of transient myeloproliferative disease and DS-AMKL occur in individuals who do not have Down syndrome. These individuals usually have a history of TMD and invariably have megakaryoblasts which bear extra copies of key chromosome 21 genes, truncating mutations in GATA1, and somatic mutations in one or more of the genes listed in the previous section. These individuals have extra copies of only a portion of the genes on chromosome 21. This duplication of only some chromosome 21 genes results from: a) Robertsonian translocations, wherein part of chromosome 21 is duplicated on another chromosome; b) partial trisomy 21, wherein only part of chromosome 21 is duplicated); c) an isochromosome, wherein chromosome 21 contains two long but no short arms); or d) duplications, wherein extra chromosome 21 genes are on this or other chromosomes. AMKL occurring in these individuals is classified as DS-AMKL.
Presentation
DS-AMKL most often presents in children 1–2 years old but almost always less than 4 years old who have a history of TMD. Given this history, these children are usually followed-up medically with complete blood count tests. and therefore often present with elevated blood levels of abnormally appearing platelets and platelet precursor cells, particularly megakaryoblasts, and reduced blood levels of red blood cells. DS-AMKL usually progresses slowly with affected children gradually developing increasingly more severe changes in their blood counts as well as slowly developing symptoms of these developments such as fatigue and shortness of breath due to anemia. In cases of advanced disease, individuals with DS-AMKL may present with signs and symptoms that are more typical of acute myeloid leukemic diseases such as liver enlargement, spleen enlargement, leukemia cutis (i.e. skin nodules caused by leukemic infiltrates), or leukostasis (i.e. an emergency situation in which excessive elevations in circulating blast (i.e. early precursor) cells plug the microcirculation to cause life-threatening heart, lung, and neurological dysfunctions).
Diagnosis
The diagnosis of DS-AMKL in young children is indicated by: a history of TMD; findings of increased presence of blast cells (e.g. ≥20% of nucleated cells) that have the megakaryoblast phenotype in blood and/or bone marrow as defined by the morphology of these cells in blood or bone marrow smears; failure to obtain a bone marrow aspirate because of marrow fibrosis; and immunophenotyping analyses of platelet precursor cells lineage as determined by flow cytometry and immunohistochemistry. Malignant megakaryoblasts are usually medium-sized to large cells with a high nuclear-cytoplasmic ratio. Nuclear chromatin is dense and homogeneous. There is scanty, variable basophilic cytoplasm which may be excessively vacuolated. An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present. Megakaryoblasts lack myeloperoxidase (MPO) activity and stain negatively with Sudan Black B. They are alpha naphthyl butyrate esterase negative and manifest variable alpha naphthyl acetate esterase activity usually in scattered clumps or granules in the cytoplasm. PAS diastase staining varies from negative to focal or granular positivity to strongly positive. Immunochemical analyses, often conducted by flow cytometry, of the surface antigens on leukemic blast cells are positive for CD41, CD42b, CD51, and Von Willebrand factor in AMKL but not leukemia involving non-platelet malignant cells.Where indicated and available, the diagnosis of DS-AMKL is further supported by; immunophenotyping analysis using monoclonal antibody directed against megakaryocyte restricted antigen (CD41 and CD61) and DNA sequencing to detect GATA1 mutations that are projected to cause the gene to make GATA1-S but not GATA1 transcription factors.
Treatment
The chemotherapy regimens used for all types of AMKL are similar to those used for AML. A final confirmation of safety and efficacy phase 3 study consisted of 4 cycles of induction therapy with cytarabine and daunorubicin followed by a single course of intensification therapy consisting of cytarabine and L-asparaginase, and concluded with a central nervous system consolidation course of 3 additional doses of intrathecal cytarabine. The dosages of cytarabine in this study were kept low because DS-AMKL patients proved highly susceptible to the toxic effects of the regimen which used a higher cytarabine dosage to treat AML. The low-dose cytarabine regimen achieved excellent results in DS-AMKL with relatively reduced overall toxicity and is currently recommended as a preferred treatment regimen for the disease.Autologous hematopoietic stem cell transplantation (i.e. transplantation of stem cells derived from the individual being transplanted) did not improve relapse-free survival in one large study of DS-AMKL. Allogenic hematopoietic stem cell transplantation (i.e. transplantation of stem cells derived another individual) has given better disease-free survival results than autologous transplantation and, based on recent uncontrolled studies, should be considered in DS-AMKL cases that have relapsed after their first chemotherapy-induced complete remission.
Prognosis
The 5-year event free survival, disease-free survival, and overall survival rate in the phase 3 clinical study in DS-AMKL were 79, 89, 84 percent, respectively. Other studies that use a treatment regimen similar to that used in the phase 3 clinical study report overall survival rates of ~80% and long-term survivals of 74-91%. However, DS-AMKL patients who relapse following chemotherapy have a far poorer outlook with 3 year overall survival rate in one study of only 26%. There also appears to be little role for stem cell transplantation in DS-AMKL given the success of initial chemotherapy and the relatively poor results in DS-AMKL patients given this transplantation.
Non-DS-AMKL
Pathophysiology
The most common genetic abnormality occurring in non-Down-AMKL is a nonreciprocal translocation between the short or p arm at position 13 on chromosome 1 (i.e. 1p13) and the p arm at position 13 on chromosome 22 (i.e. 22p13). Nonreciprocal translocations are exchanges of genes between two chromosomes that are not homologs, i.e. that are not maternal and paternal copies of the same chromosome. This particular translocation, designated t(1;22)(p13;q13), occurs mainly in infants but also is seen in children up to the age of 7 years with non-DS-AMKL. This translocation involves the RBM15 gene on chromosome 1 and the MKL1 gene (also termed MRTFA) on chromosome 22 to create a RBM15-MKL1 fusion gene. Studies in mice indicate that the Mkl1 gene (only the first letter of a mouse gene is capitalized) product, MKL1, interacts with the transcription factor SRF to stimulate the expression of various genes. MKLl is required for the maturation of mouse megakaryoblasts: in its absence, megakaryoblasts and promegakaryocytes proliferate abnormally while megakaryocytes are few in number and have an abnormal morphology. Mouse studies also indicate that the product of Rbm15, RMB15, interacts with Nuclear receptor co-repressor 1, Nuclear receptor co-repressor 2 (also termed SMRT), and RBPJ nuclear proteins to suppress the expression of various genes that are involved in the maturation of platelet, myeloid and lymphocyte precursor cells. In consequence, the RBM15-MKL1 fusion protein acts in an unregulated fashion to suppress MKL1 targeted genes while stimulating RPBJ target genes. This causes an over-active Notch signaling pathway and, among other abnormalities, expansion of fetal hematopoiesis and development of AMKL in a small percentage of adult mice. It is assumed that these events must be accompanied by other, as yet undefined, oncogenic (i.e., cancer causing) events to explain the development of human non-Down AMKL. A large number of other genetic abnormalities are associated with the development of non-DS-AMLK. These include complex chromosomal rearrangements and increases in copy number of various genes. Besides the t(1;22)(p13;q13) translocation, common genetic abnormalities in a study of 372 individuals diagnosed with non-DS-AMKL include: rearrangements of genes at position 23 on the long (i.e. q) arm of chromosome 11; inversion of chromosome 16 occurring between p13.3 and q24.3 denoted as inv(16)(p13.3q24.3) that results in the production of a CBFA2T3-GLIS2 fusion protein; and increases in chromosome numbers from a normal of 46 to anywhere from 47 to >50. The relationships of these and the many other genetic abnormalities detected in non-Down-AMKL to the diseases development require further investigations.
Presentation
Non-DS-AMKL occurs in neonates, infants, and children of all ages. Except for the lack of Down syndrome, no history of TMD, and occurrences in children that can be >4 years of age, individuals with non-DS-AMKL present with many of the symptoms, signs, and hematological findings seen in DS-AMKL. However, non-DS-AMKL is a more aggressive and rapidly progressing disorder than DS-AMKL. Nonetheless, the presentation of non-DS-AMKL is also like DS-AMKL in that it is not often accompanied by one or more extramedullary signs or symptoms of the disease such as liver enlargement, spleen enlargement, leukemia cutis, and leukostasis.
Diagnosis
The diagnosis of non-DS-AMKL is made in children who do not have Down syndrome but exhibit the same clinical symptoms, signs, hematological abnormalities, and specialized laboratory findings seen in DS-AMKL. These children should bear one or more of the genetic aberrations associated with the disease but not the inactivating GATA1 mutations, extra copies of chromosome 21 genes, or other genetic abnormalities associated with DS-AMKL. Non-DS-AMKL has many clinical and laboratory features similar to and must be distinguished from Acute panmyelosis with myelofibrosis, a disorder characterized by bone marrow fibrosis, abnormal megakaryocytes, macrocytic erythropoiesis, defects in neutrophil production, reduced blood levels of most circulating cells (i.e. pancytopenia), and low levels of circulating blast cells. Analyses of circulating and bone marrow blast cells for features of AMKL (see Diagnosis section of DS-AMKL) and genetic aberrations is helpful in distinguishing the two diseases.
Treatment
In a review of 153 patients treated for non-DS-AMKL between 1990 and 2014 with various intensive chemotherapy protocols that included cytarabine, an anthracycline (e.g. daunorubicin, doxorubicin), and in 25% of cases human stem cell transplantation, the probability of overall 4 year survival rate, probability of 4 year event-free survival, and probability of 4 year cumulative relapse rate were 56, 51, and 29%, respectively. A more recent treatment regimen that is similar to that used to treat DS-AMKL as described above (except it employs the high dose of cytarabine used to treat AML) gives better results and has been recommended for non-DS-AMKL. The response to this regimen approached that seen in non-DS-AMKL, i.e. its complete remission and estimated 10 year survival rates were both 76%. Similar to DS-AMKL treatment regimens, allogenic rather than autologous stem cell bone marrow transplantation should be considered in non-DS-AMKL cases that have relapsed following their first chemotherapy-induced complete remission. Further studies may indicate that this recent cancer chemotherapy regimen plus allogenic bone marrow transplantation in cases which relapse after the first remission are the preferred treatment for non-DS-AMKL.
Prognosis
In a review of 153 patients treated for non-DS-AMKL between 1990 and 2014 with various intensive chemotherapy protocols that included cytarabine, an anthracycline (e.g. daunorubicin, doxorubicin), and in 25% of cases human stem cell transplantation, the probability of overall 4 year survival rate, probability of 4 year event-free survival, and probability of 4 year cumulative relapse rate were 56, 51, and 29%, respectively. Patients with non-DS-AMKL given the treatment regimen described for DS-AMKL above had a much better prognosis than patients treated with earlier-devised treatment regimens: their overall survival rate using these regimen was estimated to be 76%.
Adult-AMKL
Pathophysiology
Adult-AMKL can result from the progression of other myeloproliferative neoplasms (MPN) viz., chronic myelogenous leukemia, polycythemia vera, essential thrombocytosis, and primary myelofibrosis. In one review of adult-AMKL, 25% of 49 cases were considered as secondary to one of these MPN. The mechanism behind these cases of secondary AMKL are unknown although an inversion in chromosome 3 at positions q21 and q26, i.e. inv(3)(q21q26), is often seen in these secondary cases of adult-AMKL.Rare cases of adult-AMKL also have mediastinal germ cell tumors. These tumors are malignancies of germ cells, i.e. primitive cells that give rise to sperm and ovum cells. In adult-AMKL, mediastinal germ cell tumors that are associated with adult-AMKL are not seminomas (i.e. do not originate from the sperm cell line) and occur before or concomitantly with but not after the diagnosis AMKL is made. The three most common genetic aberrations in the bone marrow cells of these individuals (representing ~65% of all cases) were inversions in the p arm of chromosome 12, trisomy 8, and an extra X chromosome. In several of these cases, the genetic aberrations in the malignant platelet precursor cells were similar to those in the malignant mediastinal germ cells. These results and those of other analyses suggest that the two malignancies derive from a common founding clone of cells (i.e. a set of genetically identical cells).Overall, the most common genetic aberrations occurring in adult-AMKL are the previously described inv((3)(q21q26) inversion, translocation between the q arm of chromosome 9 at position 34 and the q arm of chromosome 22 at position 11, i.e. (t(9:22)(q34:q11), and various aberrations in chromosome 5 or chromosome 7. Aberrations in the latter two chromosomes are also commonly seen in an AML that is associated with myelodydplastic-related changes (i.e. predominance of immature blood cells in the bone marrow). The underlying malignancy-causing mechanism, if any, behind these genetic aberrations requires further study.
Presentation
Adult-AMKL may occur in individuals who have a prior diagnosis of and/or present with chronic myelogenous leukemia, polycythemia vera, essential thrombocytosis, primary myelofibrosis, or mediastinal germ cell tumor. AMKL associated with mediastinal germ cell tumors typically occurs in younger adults, i.e. ages 13–36 (average age 24). Cases occurring in children aged ≤18 years, which represent ~20% of all cases, could be regarded in the non-DS-AMKL category. Cases of the disease not associated with mediastinal germ cell tumors occur in adults who as a group have older median age centering around those 50–70 years old. The disorder is far more fulminant than non-DS-AMKL and DS-AMKL and generally presents with more serious hematological symptoms (e.g. anemia-related) and a much higher incidence of extramedullary manifestations (e.g. organ enlargement, leukemia cutis) than seen in the other two forms of AMKL.
Diagnosis
Adult-AMKL commonly occurs in adults in their sixties and seventies but may be seen in adolescents as young as 13. Its diagnosis can be suspected in cases that have either a prior history of MPN or a history or current findings indicating the presence of mediastinal blast cell tumor. In all cases, the diagnosis adult-AMKL rests upon the same determinations used to diagnose DS-AMKL, e.g. increased blast cells in blood and/or bone marrow, immunochemical evidence that these blast cells bear platelet line-specific markers, and occurrence of the genetic aberrations in these blast cells that have been associated with the disease.
Treatment
Adult-AMKL has remained poorly responsive to the treatment regiments used in DS-AMKL and non-DS-AMKL. These treatments have given complete remission rates of 43-50%.
Prognosis
The prognosis of adult-AMKL in patients treated for the disease is far below that of other forms of AMKL. Their median overall survival times are only 18 to 41 weeks with 5 year survival rates of only 10-11 percent. Major improvements in these statistics will likely require new approaches directed at the underlying mechanisms driving the disease.
See also
List of hematologic conditions
References
External links
Histology at University of Virginia
Images at Nagoya University
https://rarediseases.info.nih.gov/diseases/524/acute-megakaryoblastic-leukemia (NIH Genetic and Rare Diseases Information Center) |
Paruresis | Paruresis, also known as shy bladder syndrome, is a type of phobia in which a person is unable to urinate in the real or imaginary presence of others, such as in a public restroom. The analogous condition that affects bowel movement is called parcopresis or shy bowel.
Signs and symptoms
Some people have brief, isolated episodes of urinary difficulty in situations where other people are in close proximity. Paruresis, however, goes beyond simple shyness, embarrassment, fear of exposure, or fear of being judged for not being able to urinate. Other people may find that they are unable to urinate while in moving vehicles, or are fixated on the sounds of their urination in quiet restrooms or residential settings. In severe cases, a person with paruresis can urinate only when alone at home or through the process of catheterization.
Causes
A possible cause of paruresis is undergoing a voiding cystourethrography (VCUG) in the past. "Complications that can occur in both sexes include UTI, hematuria, cystitis as well as urinary dysfunction following a catheterization, phobia of urination, nocturia, and stopping urination. In the literature, psychological trauma resulting from VCUG was considered the same as from a violent rape, especially in girls."
Pathophysiology
It appears that paruresis involves a tightening of the sphincter or bladder neck due to a sympathetic nervous system response. The adrenaline rush that produces the involuntary nervous system response probably has peripheral and central nervous system involvement. The internal urethral sphincter (smooth muscle tissue) or the external urethral sphincter (striated muscle), levator ani (especially the pubococcygeus) muscle area, or some combination of the above, may be involved. It is possible that there is an inhibition of the detrusor command through a reflex pathway as well. The pontine micturition center (Barringtons nucleus) also may be involved, as its inhibition results in relaxation of the detrusor and prevents the relaxation of the internal sphincter.
Diagnosis
The condition is catered for in the rules for mandatory urine testing for drugs in UK prisons, and UK Incapacity Benefit tribunals also recognise it. It is listed in the NHS on-line encyclopaedia of conditions and disorders. It is now reported to have been accepted as a valid reason for jury service excusal. From 1 August 2005, the guidance on the rules relating to the testing of those on probation in the UK cites paruresis as a valid reason for inability to produce a sample which is not to be construed as a refusal.The condition is recognised by the American Urological Association, who include it in their on-line directory of conditions.Paruresis was described in section 300.23 of the DSM-IV-TR as "performance fears . . . using a public restroom" but it was not mentioned by name. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) mentions paruresis by name.Kaplan & Sadocks Synopsis of Psychiatry states, "Persons with social phobias (also called social anxiety disorder) have excessive fears of humiliation or embarrassment in various social settings, such as in speaking in public, urinating in a public rest room (also called shy bladder), and speaking to a date." The Synopsis describes shy bladder as "inability to void in a public bathroom" and notes that relaxation exercises are an application of behavior therapy for dealing with this disorder. Some paruretics experience delayed urination and must wait for their need to void to overcome their anxiety, while others are unable to urinate at all.
Treatment
In terms of treating the mental aspect of paruresis, such treatment can be achieved by graduated exposure therapy and cognitive behavioral therapy. In graduated exposure therapy, the subject has a trusted person stand outside the restroom at first, and once the fear is overcome the observer is brought closer in, until step by step the phobia is vanquished. The International Paruresis Association provides a detailed discussion of this method on its website.
In addition to gradual exposure therapy, cognitive behavioral therapy is used to change a patients mental approach to the condition, from one of a person who cannot urinate, to a person who can urinate or is not overly fearful when they cant publicly urinate.
History
The term paruresis was coined by Williams and Degenhart (1954) in their paper "Paruresis: a survey of a disorder of micturition" in the Journal of General Psychology 51:19-29. They surveyed 1,419 college students and found 14.4% had experienced paruresis, either incidentally or continuously.
Other names
Paruresis is also known by many colloquial terms, including bashful bladder, bashful kidneys, stage fright, pee-shyness, and shy bladder syndrome.
Society and culture
Drug testing
Some drug testing authorities find paruresis a nuisance, and some implement "shy bladder procedures" which pay no more than lip service to the condition, and where there is no evidence that they have conducted any real research into the matter. In the U.S. Bureau of Prisons, the Code of Federal Regulations provides that "An inmate is presumed to be unwilling if the inmate fails to provide a urine sample within the allotted time period. An inmate may rebut this presumption during the disciplinary process." Although U.S. courts have ruled that failure to treat properly diagnosed paruresis might violate prisoners constitutional rights, the courts have also "routinely rejected suspicious or unsubstantiated attempts to invoke it in defense of failure to complete drug testing," particularly when there were no medical record or physician testimony to back up the claim of paruresis.The International Paruresis Association stresses the importance of medical documentation of ones condition since "[t]he person who is unable to produce a urine sample is presumed guilty in the absence of any evidence." Some prisons have offered the use of a "dry cell"—i.e., a cell with no toilet facilities, but only a container for the prisoners waste—as an accommodation to inmates who are hindered by paruresis from providing an observed urine sample.FBOP Program Statement 6060.08 states, "Ordinarily, an inmate is expected to provide a urine sample within two hours of the request, but the Captain (or Lieutenant) may extend the time if warranted by specific situations (for example, the inmate has a documented medical or psychological problem, is dehydrated, etc.). Staff may consider supervising indirectly an inmate who claims to be willing but unable to provide a urine sample under direct visual supervision. For example, this might be accomplished by allowing the inmate to provide the sample in a secure, dry room after a thorough search has been made of both the inmate and the room." At least six state prison systems—Florida, Massachusetts, Maryland, Michigan, New York and Tennessee—have modified their drug testing regulations to provide accommodations for prisoners with paruresis.Per the Handbook of Correctional Mental Health, "No definitive or objective test is available to confirm or refute the presence of paruresis. The absence of prior treatment or the ability to void in some social situations but not in others does not rule it out. Although modalities associated with the treatment of social phobias help some individuals, no universally effective medication or other treatment exists. Coercive interventions, such as forcing fluids while observing a person with paruresis, are ineffective and can cause serious medical complications. Alternatives to observed urine specimen collection for individuals who self-report paruresis include unobserved collections in a dry room, testing of hair specimens, sweat testing with a patch, and blood testing (Test for Drugs of Abuse 2002). These alternatives preclude the need for futile attempts to differentiate inmates with true paruresis from those who fabricate complaints."
Popular culture
The condition has been occasionally portrayed in popular culture, sometimes for comedic effect or parody. Examples of this include:
In the 2005 comedy Waiting..., a nerdy character with paruresis is one of many bathroom jokes.
In 2015, the International Paruresis Association protested a DirecTV ad starring Rob Lowe that portrayed a paruretic as goofy, wearing a fanny pack, and having his hair parted in the middle.
In the American sitcom The Big Bang Theory the character Penny is revealed to suffer from bladder shyness.
See also
The Sound Princess
References
External links
International Paruresis Association
United Kingdom Paruresis Trust (UKPT) |
Autoimmune hepatitis | Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the bodys immune system attacks liver cells, causing the liver to be inflamed. Common initial symptoms may include fatigue, nausea, muscle aches, or weight loss or signs of acute liver inflammation including fever, jaundice, and right upper quadrant abdominal pain. Individuals with autoimmune hepatitis often have no initial symptoms and the disease may be detected by abnormal liver function tests and increased protein levels during routine bloodwork or the observation of an abnormal-looking liver during abdominal surgery.Anomalous presentation of MHC class II receptors on the surface of liver cells, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated immune response against the bodys own liver, resulting in autoimmune hepatitis. This abnormal immune response results in inflammation of the liver, which can lead to further symptoms and complications such as fatigue and cirrhosis. The disease is most often diagnosed in patients in their late teens or early 20s and between the ages of 40 and 50. It affects women more commonly than men.
Signs and symptoms
Autoimmune hepatitis may present completely asymptomatic (12–35% of the cases), with signs of chronic liver disease, or acute or even fulminant hepatic failure.People usually present with one or more nonspecific, long-lasting symptoms such as fatigue, general ill health, lethargy, weight loss, mild right upper quadrant abdominal pain, malaise, anorexia, itching, nausea, jaundice or joint pain especially affecting the small joints. Rarely, rash or unexplained fever may appear. In women, the absence of menstruation (amenorrhoea) is a frequent feature. Physical examination may be normal, but it may also reveal signs and symptoms of chronic liver disease. Many people have only laboratory abnormalities as their initial presentation, as unexplained increase in transaminases and are diagnosed during an evaluation for other reasons. Others have already developed cirrhosis at diagnosis. Of note, alkaline phosphatase and bilirubin are usually normal.
Autoimmune hepatitis may overlap with other autoimmune conditions, mainly type 1 diabetes mellitus, ulcerative colitis, lupus, celiac disease, vasculitis, and autoimmune thyroiditis.
Cause
The prevailing theory for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger (virus, drugs, herbs, immunizations), and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver.There is no specific evidence of the cause. Sixty percent of patients have findings associated with chronic hepatitis but without serologic evidence of a viral infection. The disease is strongly associated with anti-smooth muscle autoantibodies.The exact genes and triggers responsible remain undefined, but studies show association of early-onset, severe disease with the HLA-DR3 serotype and late-onset disease with the HLA-DR4 serotype.
Diagnosis
The diagnosis of autoimmune hepatitis is best achieved with a combination of clinical, laboratory, and histological findings after excluding other etiological factors (e.g. viral, hereditary, metabolic, cholestatic, and drug-induced liver diseases). The requirement for histological examination necessitates a liver biopsy, typically performed with a needle by the percutaneous route, to provide liver tissue.
Autoantibodies
A number of specific antibodies found in the blood (antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver kidney microsomal antibodies (LKM-1, LKM-2, LKM-3), anti soluble liver antigen (SLA), liver–pancreas antigen (LP), and anti-mitochondrial antibody (AMA)) are of use, as is finding an increased immunoglobulin G level. The presence of anti-mitochondrial antibody is more suggestive of primary biliary cholangitis. Hypergammaglobulinemia is also of diagnostic value.
Histology
Autoimmune hepatitis can be characterized histologically by the following nonspecific findings:
Portal mononuclear cell infiltrate that invades the boundary surrounding the portal triad and infiltrates the surrounding lobule.
Periportal lesions, also known as interface hepatitis, that spare the biliary tree (may include centrizonal necrosis).
Bile duct abnormalities (cholangitis, ductal injury, ductular reaction) can be seen and should prompt evaluation for primary biliary cholangitis or sarcoidosis if granulomas are observed.
Plasma cell infiltrate, rosettes of hepatocytes, and multinucleated giant cells.
Varying degrees of fibrosis (except in the mildest form of autoimmune hepatitis). Bridging fibrosis that connects the portal and central areas can distort the structure of the hepatic lobule and result in cirrhosis.
Diagnostic scoring
The Internal Autoimmune Hepatitis Group developed a standardized scoring system for clinical diagnosis in population studies but lacks value in individualized cases. A simplified scoring system for clinical use incorporates titers of autoantibodies, total IgG levels, liver histology, and the exclusion of viral hepatitis for diagnostic scoring.
Classification
On the basis of detected autoantibodies, autoimmune hepatitis can be classified into three subtypes but have no distinct clinical presentations.
Type 1 autoimmune hepatitis. Positive antibodies include:Antinuclear antibody (ANA)
Anti-smooth muscle antibody (ASMA) - 65% of people
Anti-actin antibodies
Anti-mitochondrial antibodies - rare except for overlap syndromes with primary biliary cholangitis
Anti-soluble liver antigen/liver pancreas antibody antigen - 20% of people
Anti-double stranded DNA - 30% of people
Atypical perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA)
Type 2 autoimmune hepatitis. Positive antibodies include:Liver Kidney Microsomal antibody (LKM-1)
Anti-liver cytosol antibody-1 (SLC-1)
Autoantibody negative autoimmune hepatitis.Lack positive ANA, ASMA, LKM-1, etc. antibody panels but present with clinical features of autoimmune hepatitis that resolve with standard treatment.
Differential diagnosis
Other diagnoses to consider include conditions that may cause acute hepatitis or chronic liver inflammation that may be accompanied by cirrhosis:
Other autoimmune diseases that involve the liver:
Primary biliary cholangitis - the presence of isolated elevated AMA antibodies usually signifies primary biliary cholangitis rather than autoimmune hepatitis and further diagnostic evaluation is needed.
Overlap syndromes - autoimmune hepatitis may present similarly to primary sclerosing cholangitis but people with primary sclerosing cholangitis have stricturing and dilatation of intra/extra-hepatic ducts while people with autoimmune hepatitis generally have a spared biliary tree.
Other causes of hepatitis:
Viral hepatitis - it is necessary to distinguish autoimmune hepatitis from acute hepatitis caused by Hepatitis A/B/C/D/E, herpes simplex, varicella zoster, EBV, CMV virus
Drug-induced liver injury - portal neutrophils are more prevalent in drug-induced liver injury on liver biopsy and can help distinguish the two
Nonalcoholic steatohepatitis - related medical history and liver biopsy showing fatty infiltration and the presence of neutrophils and central fibrosis can distinguish the two
Lupus-associated liver disease - rarely presents with elevated ASMA or AMA antibodies
Acute liver failure - people with acute liver failure may have elevated autoantibodies but the antibodies alone are not enough for the diagnosis of autoimmune hepatitis
Iron overload - elevated iron in the body can cause liver inflammation
Treatment
The choice for medical treatment should be based on the individuals severity of symptoms, quantitative elevation of liver enzymes and antibody levels, findings on liver biopsy, and ability to tolerate side effects of medical therapy.
Generally, treatment is not required in asymptomatic patients with normal liver enzyme and antibody levels and liver biopsies that do not demonstrate inflammation because these patients are at a low risk of disease progression. In symptomatic individuals with evidence of interface hepatitis and necrosis on liver biopsy, it is recommended to offer treatment especially if the patient is young and can tolerate the side effects of medical therapy.The mainstay of treatment involves the use of immunosuppressive glucocorticoids such as prednisone during acute episodes and resolution of symptoms can be achieved in up to 60–80% of cases, although many will eventually experience a relapse. In individuals with moderate to severe disease who may not tolerate glucocorticoids, lower dose prednisone monotherapy or combination with azathioprine is a reasonable alternative. Budesonide has been shown to be more effective in inducing remission than prednisone, but evidence is scarce and more data is needed before it can be routinely recommended. Those with autoimmune hepatitis who do not respond to glucocorticoids and azathioprine may be given other immunosuppressives like mycophenolate, ciclosporin, tacrolimus, or methotrexate.Liver cirrhosis can develop in about 7% to 40% of treated patients. People with the highest risk for progression to cirrhosis are those with incomplete response to treatment, treatment failure, and multiple relapses. Once cirrhosis develops, management of liver cirrhosis in autoimmune hepatitis is standard regardless of etiology. Liver transplantation is the standard of care in people presenting with fulminant liver failure or those with the progression of disease despite multiple lines of therapy.
Prognosis
Without treatment, the ten-year survival rate for individuals with symptomatic autoimmune hepatitis is 50%. However, with treatment, the ten-year survival rate is above 90%. Despite the benefits of treatment, people with autoimmune hepatitis generally have a lower transplant-free survival than the general population. Outcomes with liver transplant are generally favorable with a five-year survival greater than 80 percent.Presentation and response to therapy may differ according to race. African Americans appear to present with a more aggressive disease that is associated with worse outcomes.There has been strong evidence that patients with autoimmune hepatitis can develop mental health disorders like schizophrenia and bipolar disorder later in their life.
Epidemiology
Autoimmune hepatitis can develop in people of any race or age but occurs most frequently in women. Eighty percent of cases are the type 1 subtype with women being affected 4 times more often than men; for the type 2 subtype, women are affected 10 times more often than men.European studies suggest a disease incidence of 1 to 2 people affected per 100,000 population with a prevalence of 10 to 25 people per 100,000 population.The disease has a bimodal peak occurring between the ages of 10 to 20 and then later in life between the ages of 40 to 50.
History
Autoimmune hepatitis was previously called "lupoid" hepatitis due to people having an associated autoimmune disease like system lupus erythematosus at time of diagnosis, which was believed to be its cause. It was originally described in the early 1950s.
References
== External links == |
Vascular headache | A vascular headache is an outdated term to describe certain types of headache which were thought to be related to blood vessel swelling and hyperemia as cause of pain.There is no doubt that some headaches are caused by vascular effects. However, it is no longer a recognized term and not mentioned in the Headache classification of the International Headache society (IHS), although it is still used by some physicians and still mentioned in some medical classification systems. There are many types of vascular headaches. Other types of vascular headaches include headaches produced by fever, cluster headaches, and headaches from a rise in blood pressure (OSU Wexner Medical Center, 2012).
Headaches that were described as being vascular headaches include:
Cluster headache
Migraine
Toxic headache
References
== External links == |
Spondylocostal dysostosis | Spondylocostal dysostosis, also known as Jarcho-Levin syndrome (JLS), is a rare, heritable axial skeleton growth disorder. It is characterized by widespread and sometimes severe malformations of the vertebral column and ribs, shortened thorax, and moderate to severe scoliosis and kyphosis. Individuals with Jarcho-Levin typically appear to have a short trunk and neck, with arms appearing relatively long in comparison, and a slightly protuberant abdomen. Severely affected individuals may have life-threatening pulmonary complications due to deformities of the thorax. The syndrome was first described by Saul Jarcho and Paul M. Levin at Johns Hopkins University in 1938.
Genetics
Types include:
Diagnosis
Subtypes and characteristics
In 1968, Dr. David Rimoin and colleagues in Baltimore first distinguished between the two major presentations of Jarcho-Levin. Both conditions were characterized as failures of proper vertebral segmentation. However, the condition within the family described in their article appeared to be inherited in an autosomal dominant fashion and had a less severe course than that reported by other investigators. They specified their condition as spondylocostal dysplasia, which has since become known as spondylocostal dysostosis. The subtype of Jarcho-Levin with which they contrasted their reported cases to is now known as spondylothoracic dysplasia.
Spondylothoracic dysplasia
Spondylothoracic dysplasia, or STD, has been repeatedly described as an autosomal recessively inherited condition that results in a characteristic fan-like configuration of the ribs with minimal intrinsic rib anomalies. Infants born with this condition typically died early in life due to recurrent respiratory infections and pneumonia due to their restricted thorax. Recently, a report has documented that actual mortality associated with STD is only about 50%, with many survivors leading healthy, independent lives.
Spondylocostal dysostosis
In contrast to STD, the subtype spondylocostal dysostosis, or SCD features intrinsic rib anomalies, in addition to vertebral anomalies. Intrinsic rib anomalies include defects such as bifurcation, broadening and fusion that are not directly related to the vertebral anomalies (such as in STD, where extensive posterior rib fusion occurs due to segmentation defects and extreme shortening of the thoracic vertebral column). In both subtypes, the pulmonary restriction may result in pulmonary hypertension, and have other potential cardiac implications.
Management
Prognosis
Babies born with Jarcho-Levin may be very healthy and grow up to lead normal lives. However, many individuals with Jarcho-Levin suffer from problems of respiratory insufficiency secondary to volume-restricted thoraces. These individuals will often develop pulmonary complications and die in infancy or early childhood. The disparity in outcomes of those with the syndrome is related to the fact that Jarcho-Levin actually encompasses two or more distinct syndromes, each with its own range of prognoses. The syndromes currently recognized as subtypes of Jarcho-Levin are termed spondylothoracic dysplasia and spondylocostal dysostosis. The disease is related to the SRRT gene.
Epidemiology
To date about 20 cases of Spondylocostal dysostosis have been reported in literature.
Terminology
"Type 1" is also known as "Jarcho-Levin syndrome", or "JLS".
While clinicians almost unanimously refer to the syndrome as "Jarcho-Levin", reports have variously labelled or referred to the condition as all of the following: Hereditary malformations of the vertebral bodies, hereditary multiple hemivertebrae, syndrome of bizarre vertebral anomalies, spondylocostal dysplasia, spondylothoracic dysplasia, costovertebral anomalies, costovertebral dysplasia, spondylothoracic dysplasia, occipito-facial-cervico-thoracic-abdomino-digital dysplasia (deemed "ridiculously long" and "unwarranted" by OMIM), and spondylocostal dysostosis.A closely related condition termed "Costovertebral segmentation defect with mesomelia and peculiar facies", or Covesdem syndrome, was first described in 1978 in India.
References
Further reading
GeneReviews/NIH/NCBI/UW entry on Spondylocostal Dysostosis, Autosomal Recessive.
== External links == |
Idiopathic scrotal calcinosis | Idiopathic scrotal calcinosis is a cutaneous condition characterized by calcification of the skin resulting from the deposition of calcium and phosphorus occurring on the scrotum.: 528 However, the levels of calcium and phosphate in the blood are normal. Idiopathic scrotal calcinosis typically affects young males, with an onset between adolescence and early adulthood. The scrotal calcinosis appears, without any symptoms, as yellowish nodules that range in size from 1 mm to several centimeters.
Presentation
Single or multiple hard, marble-like nodules of varying size affecting scrotal skin.
Nodules vary in size from a few millimeters to a few centimeters.
Usually start to appear in childhood or early adult life
Over time, nodules increase in number and size
Nodules may break down and discharge chalky material
Rarely, lesions may be polypoid
Usually asymptomatic
Etiology
The cause is not well defined. Originally considered idiopathic condition. Now accepted that majority of cases develop from dystrophic calcification of cyst contents.
Diagnostic
Clinically Relevant Pathologic FeaturesLesions slowly progress throughout life
They slowly increase in number and size
Nodules are mobile and do not attach to underlying structuresPathologic Interpretation Pearls
Globular and granular purple deposits within dermis surrounded by giant cell granulomatous reaction
Sometimes remnants of cystic lesion can be identified
Very distinctive appearance with almost no histologic differential diagnosis.
Treatment
Treatment may involve surgery, which is currently the only recommended intervention. Surgery should include the removal of even small nodules, to prevent the recurrence of the scrotal calcinosis.
Prognosis
Benign conditionSlow progression throughout lifeLesions remain discrete and do not become confluent
Epidemiology
Incidence: uncommon
Age: children and young adults
History
Scrotal calcinosis was first described in 1883 by Lewinski.
See also
Calcinosis cutis
Skin lesion
List of cutaneous conditions
== References == |
Monosomy | Monosomy is a form of aneuploidy with the presence of only one chromosome from a pair. Partial monosomy occurs when a portion of one chromosome in a pair is missing.
Human monosomy
Human conditions due to monosomy:
Turner syndrome – People with Turner syndrome typically have one X chromosome instead of the usual two X chromosomes. Turner syndrome is the only full monosomy that is seen in humans — all other cases of full monosomy are lethal and the individual will not survive development.
Cri du chat syndrome – (French for "cry of the cat" after the persons malformed larynx) a partial monosomy caused by a deletion of the end of the short arm of chromosome 5
1p36 deletion syndrome – a partial monosomy caused by a deletion at the end of the short arm of chromosome 1
17q12 microdeletion syndrome - a partial monosomy caused by a deletion of part of the long arm of chromosome 17
See also
Anaphase lag
Miscarriage
References
== External links == |
Human back | The human back, also called the dorsum, is the large posterior area of the human body, rising from the top of the buttocks to the back of the neck. It is the surface of the body opposite from the chest and the abdomen. The vertebral column runs the length of the back and creates a central area of recession. The breadth of the back is created by the shoulders at the top and the pelvis at the bottom.
Back pain is a common medical condition, generally benign in origin.
Structure
The central feature of the human back is the vertebral column, specifically the length from the top of the thoracic vertebrae to the bottom of the lumbar vertebrae, which houses the spinal cord in its spinal canal, and which generally has some curvature that gives shape to the back. The ribcage extends from the spine at the top of the back (with the top of the ribcage corresponding to the T1 vertebra), more than halfway down the length of the back, leaving an area with less protection between the bottom of the ribcage and the hips. The width of the back at the top is defined by the scapula, the broad, flat bones of the shoulders.
Muscles
The muscles of the back can be divided into three distinct groups; a superficial group, an intermediate group and a deep group.
Superficial group
The superficial group, also known as the appendicular group, is primarily associated with movement of the appendicular skeleton. It is composed of trapezius, latissimus dorsi, rhomboid major, rhomboid minor and levator scapulae. It is innervated by anterior rami of spinal nerves, reflecting its embryological origin outside the back.
Intermediate group
The intermediate group is also known as respiratory group as it may serve a respiratory function. It is composed of serratus posterior superior and serratus posterior inferior. Like the superficial group, it is innervated by anterior rami of spinal nerves.
Deep group
The deep group, also known as the intrinsic group due to its embryological origin in the back, can be further subdivided into four groups:
Spinotransversales - composed of splenius capitis and splenius cervicis.
Erector spinae - composed of iliocostalis, longissismus and spinalis
Transversospinales - composed of semispinalis, multifidus and rotatores
Segmental muscles - composed of levatores costarum, interspinales and intertransversariiThe deep group is innervated by the posterior rami of spinal nerves.
Organs near the back
The lungs are within the ribcage, and extend to the back of the ribcage making it possible for them to be listened into through the back. The kidneys are situated beneath the muscles in the area below the end of the ribcage, loosely connected to the peritoneum. A strike to the lower back can damage the kidneys of the person being hit.
Surface of the back
The skin of the human back is thicker and has fewer nerve endings than the skin on any other part of the torso. With some notable exceptions (see, e.g. George "The Animal" Steele), it tends to have less hair than the chest on men. The upper-middle back is also the one area of the body which a typical human under normal conditions might be unable to physically touch.
The skin of the back is innervated by the dorsal cutaneous branches, as well as the lateral abdominal cutaneous branches of intercostal nerves.
Movement
The intricate anatomy of the back provides support for the head and trunk of the body, strength in the trunk of the body, as well as a great deal of flexibility and movement. The upper back has the most structural support, with the ribs attached firmly to each level of the thoracic spine and very limited movement. The lower back (lumbar vertebrae) allows for flexibility and movement in back bending (extension) and forward bending (flexion). It does not permit twisting.
Clinical significance
Back pain
The back comprises interconnecting nerves, bones, muscles, ligaments, and tendons, all of which can be a source of pain. Back pain is the second most common type of pain in adults (the most common being headaches). By far the most common cause of back pain is muscle strain. The back muscles can usually heal themselves within a couple of weeks, but the pain can be intense and debilitating. Other common sources of back pain include disc problems, such as degenerative disc disease or a lumbar disc herniation, many types of fractures, such as spondylolisthesis or an osteoporotic fracture, or osteoarthritis.
Society and culture
The curvature of the female back is a frequent theme in paintings, because the sensibilities of many cultures permit the back to be shown nude - implying full nudity without actually displaying it. Indeed, the practice of showing explicitness on the lower back has been performed for centuries. Certain articles of clothing, such as the haltertop and the backless dress, are designed to expose the back in this manner. The lower back is typically exposed frequently by many types of shirts in womans fashion, and even the more conservative shirts and blouses will reveal the lower back. This happens for a variety of reasons- the lower waist area is a pivot point for the body and lengthens and arches as a person sits or bends. Secondly, womans fashion typically favors tops that are waist length, allowing the back to be left bare during slight movement, bending or sitting. The back also serves as the largest canvas for body art on the human body. Because of its size and the relative lack of hair, the back presents an ideal canvas on the human body for lower back tattoos, mostly among young women. Indeed, some individuals have tattoos that cover the entirety of the back. Others have smaller tattoos at significant locations, such as the shoulder blade or the bottom of the back.
Many English idioms mention the back, usually highlighting it as an area of vulnerability; one must "watch ones back", or one may end up "with ones back up against the wall"; worse yet, someone may "stab one in the back", but hopefully a friend "has got ones back". The back is also a symbol of strength and hard work, with those seeking physical labor looking for "strong backs", and workers being implored to "put their back into it".
Historically, flagellation of a person across the back with a whip was both a common form of punishment of criminals, and a common means of forcing slaves to work. As well, self-flagellation, as in self punishment, may include the use of whipping oneself. This is one method of mortification, the practice of inflicting physical suffering on oneself with the religious belief that it will serve as penance for ones own sins or those of others. While more moderate forms of mortification are widely practiced—particularly in the Catholic Church—self flagellation is not encouraged by mainstream religions or religious leaders. A well-known instrument used for flagellations is the infamous Cat o Nine Tails, a nine-corded whip with one handle enabling a much more effective whipping than would be possible with only one lashing at a time.
== References == |
Chest injury | A chest injury, also known as chest trauma, is any form of physical injury to the chest including the ribs, heart and lungs. Chest injuries account for 25% of all deaths from traumatic injury. Typically chest injuries are caused by blunt mechanisms such as direct, indirect, compression, contusion, deceleration, or blasts- caused by motor vehicle collisions or penetrating mechanisms such as stabbings.
Classification
Chest injuries can be classified as blunt or penetrating. Blunt and penetrating injuries have different pathophysiologies and clinical courses.
Specific types of injuries include:
Injuries to the chest wall
Chest wall contusions or hematomas.
Rib fractures
Flail chest
Sternal fractures
Fractures of the shoulder girdle
Pulmonary injury (injury to the lung) and injuries involving the pleural space
Pulmonary contusion
Pulmonary laceration
Pneumothorax
Hemothorax
Hemopneumothorax
Injury to the airways
Tracheobronchial tear
Cardiac injury
Pericardial tamponade
Myocardial contusion
Traumatic arrest
Hemopericardium
Blood vessel injuries
Traumatic aortic rupture
Thoracic aorta injury
Aortic dissection
And injuries to other structures within the torso
Esophageal injury (Boerhaave syndrome)
Diaphragm injury
Diagnosis
Most blunt injuries are managed with relatively simple interventions like tracheal intubation and mechanical ventilation and chest tube insertion. Diagnosis of blunt injuries may be more difficult and require additional investigations such as CT scanning. Penetrating injuries often require surgery, and complex investigations are usually not needed to come to a diagnosis. Patients with penetrating trauma may deteriorate rapidly, but may also recover much faster than patients with blunt injury.
See also
Transmediastinal gunshot wound
Commotio thoracis
References
== External links == |
Eosinophilic folliculitis | Eosinophilic folliculitis is an itchy rash with an unknown cause that is most common among individuals with HIV, though it can occur in HIV-negative individuals where it is known by the eponym Ofuji disease. EF consists of itchy red bumps (papules) centered on hair follicles and typically found on the upper body, sparing the abdomen and legs. The name eosinophilic folliculitis refers to the predominant immune cells associated with the disease (eosinophils) and the involvement of the hair follicles.
Pathophysiology
The cause of EF is unknown. A variety of microorganisms have been implicated, including the mite Demodex, the yeast Pityrosporum, and bacteria. An autoimmune process has what is this also been investigated.
Diagnosis
Eosinophilic folliculitis may be suspected clinically when an individual with HIV exhibits the classic symptoms. The diagnosis can be supported by the finding of eosinophilia but a skin biopsy is necessary to establish it. Skin biopsies reveal lymphocytic and eosinophilic inflammation around the hair follicles.
Treatment
Treatment of eosinophilic folliculitis in people with HIV typically begins with the initiation of Highly Active Anti-Retroviral Therapy in order to help reconstitute the immune system. Direct treatment of the EF itself focuses on decreasing the inflammation and itching. Topical corticosteroids and oral antihistamines can alleviate the itching and decrease the size and number of lesions. Treatment with the antifungal drug itraconazole, the antibiotic metronidazole, and the anti-mite drug permethrin may lead to some improvement of symptoms. Other therapies include PUVA, topical tacrolimus, and isotretinoin.
Epidemiology
Eosinophilic folliculitis associated with HIV infection typically affects individuals with advanced HIV and low T helper cell counts. It affects both men and women as well as children with HIV and is found throughout the world.
EF may also affect individuals with hematologic disease such as leukemia and lymphoma. It may also affect otherwise normal infants in a self-limited form. HIV-negative individuals can also develop EF — this is more common in Japan.
See also
Eosinophilic pustular folliculitis of infancy
List of cutaneous conditions
References
== External links == |
Hymen | The hymen is a thin piece of mucosal tissue that surrounds or partially covers the external vaginal opening. It forms part of the vulva, or external genitalia, and is similar in structure to the vagina.In children, a common appearance of the hymen is crescent-shaped, although many shapes are possible. During puberty, estrogen causes the hymen to change in appearance and become very elastic. Normal variations of the post-pubertal hymen range from thin and stretchy to thick and somewhat rigid. Very rarely, it may be completely absent.The hymen can rip or tear during first penetrative intercourse, which usually results in pain and, sometimes, mild temporary bleeding or spotting. Sources differ on how common tearing or bleeding after first intercourse are. The state of the hymen is not a reliable indicator of virginity, though "virginity testing" remains a common practice in some cultures, sometimes accompanied by surgical restoration of hymen to give the appearance of virginity. Minor injuries to the hymen may heal on their own, and not require surgical intervention.
Development and histology
The genital tract develops during embryogenesis, from the third week of gestation to the second trimester, and the hymen is formed following the vagina. At week seven, the urorectal septum forms and separates the rectum from the urogenital sinus. At week nine, the Müllerian ducts move downwards to reach the urogenital sinus, forming the uterovaginal canal and inserting into the urogenital sinus. At week twelve, the Müllerian ducts fuse to create a primitive uterovaginal canal called unaleria. At month five, the vaginal canalization is complete and the fetal hymen is formed from the proliferation of the sinovaginal bulbs (where Müllerian ducts meet the urogenital sinus), and normally becomes perforate before or shortly after birth.The hymen has dense innervation. In newborn babies, still under the influence of the mothers hormones, the hymen is thick, pale pink, and redundant (folds in on itself and may protrude). For the first two to four years of life, the infant produces hormones that continue this effect. Their hymenal opening tends to be annular (circumferential).
Post neonatal stage, the diameter of the hymenal opening (measured within the hymenal ring) widens by approximately 1 mm for each year of age. During puberty, estrogen causes the hymen to become very elastic and fimbriated.
The hymen can stretch or tear as a result of various behaviors, by the use of tampons or menstrual cups, pelvic examinations with a speculum, sexual intercourse, insertion of multiple fingers or items into the vagina, and activities such as gymnastics (doing the splits), horseback riding or trauma caused by a "straddle injury". Remnants of the hymen are called carunculae myrtiformes.A glass or plastic rod of 6 mm diameter having a globe on one end with varying diameter from 10 to 25 mm, called a Glaister Keen rod, is used for close examination of the hymen or the degree of its rupture. In forensic medicine, it is recommended by health authorities that a physician who must swab near this area of a prepubescent girl avoid the hymen and swab the outer vulval vestibule instead. In cases of suspected rape or child sexual abuse, a detailed examination of the hymen may be performed, but the condition of the hymen alone is often inconclusive.
Anatomic variations
Normal variations of the hymen range from thin and stretchy to thick and somewhat rigid. An imperforate hymen occurs in 1-2 out of 1,000 infants. The only variation that may require medical intervention is the imperforate hymen, which either completely prevents the passage of menstrual fluid or slows it significantly. In either case, surgical intervention may be needed to allow menstrual fluid to pass or intercourse to take place at all.Prepubescent hymenal openings come in many shapes, depending on hormonal and activity level, the most common being crescentic (posterior rim): no tissue at the 12 oclock position; crescent-shaped band of tissue from 1–2 to 10–11 oclock, at its widest around 6 oclock. From puberty onwards, depending on estrogen and activity levels, the hymenal tissue may be thicker, and the opening is often fimbriated or erratically shaped. In younger children, a torn hymen will typically heal very quickly. In adolescents, the hymenal opening can naturally extend and variation in shape and appearance increases.Variations of the female reproductive tract can result from agenesis or hypoplasia, canalization defects, lateral fusion and failure of resorption, resulting in various complications.
Imperforate: hymenal opening nonexistent; will require minor surgery if it has not corrected itself by puberty to allow menstrual fluids to escape.
Cribriform, or microperforate: sometimes confused for imperforate, the hymenal opening appears to be nonexistent, but has, under close examination, small perforations.
Septate: the hymenal opening has one or more bands of tissue extending across the opening.
Trauma
Historically, it was believed that first sexual intercourse was necessarily traumatic to the hymen and always resulted in the hymen being "broken" or torn, causing bleeding. However, research on women in Western populations has found that bleeding during first intercourse does not invariably occur. In one cross-cultural study, slightly more than half of all women self-reported bleeding during first intercourse, with significantly different levels of pain and bleeding reported depending on their region of origin. Not all women experience pain, and one study found a correlation between the experience of strong emotions – such as excitement, nervousness, or fear – with experiencing pain during first intercourse.In several studies of adolescent female rape victims, where patients were examined at a hospital following sexual assault, half or fewer of virgin victims had any injury to the hymen. Tears of the hymen occurred in less than a quarter of cases. However, virgins were significantly more likely to have injuries to the hymen than non-virgins.In a study of adolescents who had previously had consensual sex, approximately half showed evidence of trauma to the hymen. Trauma to the hymen may also occur in adult non-virgins following consensual sex, although it is rare. Trauma to the hymen may heal without any visible sign of injury. An observational study of adolescent sexual assault victims found that majority of wounds to the hymen healed without any visible sign of injury having occurred.Trauma to the hymen is hypothesized to occur as a result of various other behaviors, such as tampon or menstrual cup use, pelvic examinations with a speculum, masturbation, gymnastics, or horseback riding, although the true prevalence of trauma as a result of these activities is unclear.
Cultural significance
The hymen is often attributed important cultural significance in certain communities because of its association with a womans virginity. In those cultures, an intact hymen is highly valued at marriage in the belief that this is a proof of virginity. Some women undergo hymenorrhaphy to restore their hymen for this reason.In October 2018, the UN Human Rights, UN Women and the World Health Organization (WHO) stated that virginity testing must end as "it is a painful, humiliating and traumatic practice, constituting violence against women".
Womb fury
In the 16th and 17th centuries, medical researchers mistakenly saw the presence or absence of the hymen as founding evidence of physical diseases such as "womb-fury", i.e., (female) hysteria. If not cured, womb-fury would, according to doctors practicing at the time, result in death.
Other animals
Due to similar reproductive system development, many mammals have hymens, including chimpanzees, elephants, manatees, whales, horses and llamas.
See also
Artificial hymen
References
External links
Magical Cups and Bloody Brides—the historical context of virginity
20 Questions About Virginity—Interview with Hanne Blank, author of Virgin: The Untouched History. Discusses relationship between hymen and concept of virginity.
Putting tampon in painlessly Radiology (US - ultrasound) of Hydrocolpos
Evaluating the Child for Sexual Abuse at the American Family Physician
My Corona: The Anatomy Formerly Known as the Hymen & the Myths That Surround It Scarleteen, Sex education for the real world
The Hymen Myth
Vaginal Corona |
Diamond–Blackfan anemia | Diamond–Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. DBA causes low red blood cell counts (anemia), without substantially affecting the other blood components (the platelets and the white blood cells), which are usually normal. This is in contrast to Shwachman–Bodian–Diamond syndrome, in which the bone marrow defect results primarily in neutropenia, and Fanconi anemia, where all cell lines are affected resulting in pancytopenia.
A variety of other congenital abnormalities may also occur in DBA.
Signs and symptoms
Diamond–Blackfan anemia is characterized by normocytic or macrocytic anemia (low red blood cell counts) with decreased erythroid progenitor cells in the bone marrow. This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.
Genetics
Most pedigrees suggest an autosomal dominant mode of inheritance with incomplete penetrance. Approximately 10–25% of DBA occurs with a family history of disease.
About 25-50% of the causes of DBA have been tied to abnormal ribosomal protein genes. The disease is characterized by genetic heterogeneity, affecting different ribosomal gene loci: Exceptions to this paradigm have been demonstrated, such as with rare mutations of transcription factor GATA1 and advanced alternative splicing of a gene involved in iron metabolism, SLC49A1 (FLVCR1).
In 1997, a patient was identified who carried a rare balanced chromosomal translocation involving chromosome 19 and the X chromosome. This suggested that the affected gene might lie in one of the two regions that were disrupted by this cytogenetic anomaly. Linkage analysis in affected families also implicated this region in disease, and led to the cloning of the first DBA gene. About 20–25% of DBA cases are caused by mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2. Some previously undiagnosed relatives of DBA patients were found to carry mutations, and also had increased adenosine deaminase levels in their red blood cells, but had no other overt signs of disease.A subsequent study of families with no evidence of RPS19 mutations determined that 18 of 38 families showed evidence for involvement of an unknown gene on chromosome 8 at 8p23.3-8p22. The precise genetic defect in these families has not yet been delineated.
Malformations are seen more frequently with DBA6 RPL5 and DBA7 RPL11 mutations.The genetic abnormalities underpinning the combination of DBA with Treacher Collins syndrome (TCS)/mandibulofacial dysostosis (MFD) phenotypes are heterogeneous, including RPS26 (the known DBA10 gene), TSR2 which encodes a direct binding partner of RPS26, and RPS28.
Molecular basis
The phenotype of DBA patients suggests a hematological stem cell defect specifically affecting the erythroid progenitor population. Loss of ribosomal function might be predicted to affect translation and protein biosynthesis broadly and impact many tissues. However, DBA is characterized by dominant inheritance, and arises from partial loss of ribosomal function, so it is possible that erythroid progenitors are more sensitive to this decreased function, while most other tissues are less affected.
Diagnosis
Typically, a diagnosis of DBA is made through a blood count and a bone marrow biopsy.
A diagnosis of DBA is made on the basis of anemia, low reticulocyte (immature red blood cells) counts, and diminished erythroid precursors in bone marrow. Features that support a diagnosis of DBA include the presence of congenital abnormalities, macrocytosis, elevated fetal hemoglobin, and elevated adenosine deaminase levels in red blood cells.Most patients are diagnosed in the first two years of life. However, some mildly affected individuals only receive attention after a more severely affected family member is identified.About 20–25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene.
Treatment
Corticosteroids can be used to treat anemia in DBA. In a large study of 225 patients, 82% initially responded to this therapy, although many side effects were noted. Some patients remained responsive to steroids, while efficacy waned in others. Blood transfusions can also be used to treat severe anemia in DBA. Periods of remission may occur, during which transfusions and steroid treatments are not required. Bone marrow transplantation (BMT) can cure hematological aspects of DBA. This option may be considered when patients become transfusion-dependent because frequent transfusions can lead to iron overloading and organ damage. However, adverse events from BMTs may exceed those from iron overloading. A 2007 study showed the efficacy of leucine and isoleucine supplementation in one patient. Larger studies are being conducted.
History
First noted by Hugh W. Josephs in 1936, the condition is however named for the pediatricians Louis K. Diamond and Kenneth Blackfan, who described congenital hypoplastic anemia in 1938. Responsiveness to corticosteroids was reported in 1951. In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an association with skeletal abnormalities. In 1997, a region on chromosome 19 was determined to carry a gene mutated in some DBA. In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients. In 2001, a second DBA gene was localized to a region of chromosome 8, and further genetic heterogeneity was inferred. Additional genes were subsequently identified.
See also
List of hematologic conditions
Pure red cell aplasia
References
External links
GeneReviews/NCBI/NIH/UW entry on Diamond–Blackfan Anemia
OMIM entries on Diamond–Blackfan Anemia
Diamond–Blackfan anemia Genetics Home Reference |
Neonatal hemochromatosis | Neonatal Hemochromatosis is a rare and severe liver disease of unknown origin, though research suggests that it may be alloimmune condition. Its characteristics are similar to hereditary hemochromatosis, where iron deposition causes damage to the liver and other organs and tissues.
Causes
The causes of neonatal hemochromatosis are still unknown, but recent research has led to the hypothesis that it is an alloimmune disease. Evidence supporting this hypothesis includes the high rate among siblings (>80%). This evidence along with other research indicates that neonatal hemochromatosis could be classified as a congenital alloimmune hepatitis.
Diagnosis
Differential diagnosis
The condition is sometimes confused with juvenile hemochromatosis, which is a hereditary hemochromatosis caused by mutations of a gene called hemojuvelin. While the symptoms and outcomes for these two diseases are similar, the causes appear to be different.
Treatment
Effective treatment of the disease has been confined to liver transplants. Success has also been reported with an antioxidant chelation cocktail, though its effectiveness cannot be confirmed. Based on the alloimmune cause hypothesis, a new treatment involving high-dose immunoglobulin to pregnant mothers who have had a previous pregnancy with a confirmed neonatal hemochromatosis outcome, has provided very encouraging results.
References
Further reading
Andrews N (1999). "Disorders of iron metabolism". New England Journal of Medicine. 341 (26): 1986–95. doi:10.1056/NEJM199912233412607. PMID 10607817. link
External links
Hemachromatosis page at the National Center for Biotechnology Information |
Descending perineum syndrome | Descending perineum syndrome (also known as levator plate sagging) refers to a condition where the perineum "balloons" several centimeters below the bony outlet of the pelvis during strain, although this descent may happen without straining. The syndrome was first described in 1966 by Parks et al.
Signs and symptoms
Abnormal descent of the perineum may be asymptomatic, but otherwise the following may feature:
perineodynia (perineal pain)
Colo-proctological symptoms, e.g. obstructed defecation, dyschesia (constipation), or degrees of fecal incontinence
gynaecological symptoms, e.g. cystocele (prolapse of the bladder into the vagina) and rectocele (prolapse of the rectum into the vagina)
lower urinary tract symptoms, e.g. dysuria (painful urination), dyspareunia (pain during sexual intercourse), urinary incontinence and urgencyOther researchers concluded that abnormal perineal descent did not correlate with constipation or perineal pain, and there are also conflicting reports of the correlation of fecal incontinence with this condition.
Cause
One of the main causes is suggested to be excessive and repetitive straining during defecation. Other causes include weakness of the pelvic floor muscles (secondary to age-related neuropathic degeneration or traumatic injury during pregnancy and labor.
Diagnosis
Diagnosis is by rectal examination. A specialized tool called a "Perineocaliper" can be used to measure the descent of the perineum. A retro anal ultrasound scan may demonstrate the condition. "Anti sagging tests", whereby the abnormal descent is corrected temporarily, may help to show whether symptoms are due to descending perineum syndrome or are in fact due to another condition.
Normally, the anal margin lies just below a line drawn between the coccyx (tailbone) and the pubic symphysis. In descending perineum syndrome the anal canal is situated several cm below this imaginary line, or it descends 3–4 cm during straining.
Defecography may also demonstrate abnormal perineal descent.
Treatment
Surgical treatments may be used to treat the condition, and include retro-rectal levatorplasty, post-anal repair, retro-anal levator plate myorrhaphy.
Epidemiology
The condition mainly occurs in women, and it is thought by some to be one of the main defects encountered problem in perineology.
== References == |
Pulmonary vein stenosis | Pulmonary vein stenosis is a rare cardiovascular disorder. It is recognized as being the stenosis of one or more of the four pulmonary veins that return blood from the lungs to the left atrium of the heart. In congenital cases, it is associated with poor prognosis and high mortality rate. In some people, pulmonary vein stenosis occurs after pulmonary vein ablation for the treatment of atrial fibrillation. Some recent research has indicated that it may be genetically linked in congenital cases.
== References == |
Keratosis pilaris atrophicans faciei | Keratosis pilaris atrophicans faciei begins in infancy as follicular papules with perifollicular erythema.: 762 Initially, the lesions are restricted to the lateral eyebrows, but with time spread to involve the cheeks and forehead, and may also be associated with keratosis pilaris on the extremities and buttocks.: 762 : 714
See also
Skin lesion
Cicatricial alopecia
Ulerythema
List of cutaneous conditions
References
== External links == |
Cornea plana | Cornea plana may refer to:
Cornea plana 1, an eye condition
Cornea plana 2, an eye condition |
Subsets and Splits