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Arteritic anterior ischemic optic neuropathy	Arteritic anterior ischemic optic neuropathy (AAION or arteritic AION) is the cause of vision loss that occurs in temporal arteritis (aka giant-cell arteritis). Temporal arteritis is an inflammatory disease of medium-sized blood vessels that happens especially with advancing age. AAION occurs in about 15-20 percent of patients with temporal arteritis. Damage to the blood vessels supplying the optic nerves leads to insufficient blood supply (ischemia) to the nerve and subsequent optic nerve fiber death. Most cases of AAION result in nearly complete vision loss first to one eye. If the temporal arteritis is left untreated, the fellow eye will likely suffer vision loss as well within 1–2 weeks. Arteritic AION falls under the general category of anterior ischemic optic neuropathy, which also includes non-arteritic AION. AION is considered an eye emergency, immediate treatment is essential to rescue remaining vision. An exhaustive review article published in March 2009 described the latest information on arteritic and non-arteritic ischemic optic neuropathy, both anterior (A-AION and NA-AION) and posterior (A-PION, NA-PION, and surgical). Symptoms There are several constitutional symptoms of temporal arteritis that may aid in diagnosis of AAION such as jaw claudication (spasms of the jaw muscle), scalp tenderness, unintentional weight loss, fatigue, myalgias and loss of appetite. However, many cases are asymptomatic. There are also elevations in three blood tests that help identify AAION: erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and platelet count (thrombocytosis). A relate rheumatic disease called polymyalgia rheumatica has a 15 percent incidence of giant cell arteritis. Cause Diagnosis Prompt diagnosis is critical, since the sudden blindness in the one eye is often followed, within days, by similar sudden blindness in the second eye. Treatment may prevent further damage (see below). Any patient diagnosed with non-arteritic AION over the age of 50 must be asked about the constitutional symptoms mentioned above. Furthermore, AION patients over the age of 75 should often be blood tested regardless. Treatment AAION requires urgent and critical intervention with a very long course of corticosteroids to prevent further damage. While this treatment is in itself problematic, non-treatment leads to bilateral blindness and strokes.There is much research currently underway looking at ways to protect the nerve (neuroprotection) or even regenerate new fibers within the optic nerve. References Myron Yanoff et al., Ophthalmology, 2nd ed. (C.V. Mosby, 2004), chapt. 191. UpToDate article "Clinical manifestations and diagnosis of giant cell (temporal) arteritis" External links The Use of Botulinum Toxin in a Case of Acquired Periodic Alternating Nystagmus
3q29 microdeletion syndrome	3q29 microdeletion syndrome is a rare genetic disorder resulting from the deletion of a segment of chromosome 3. This syndrome was first described in 2005. Presentation The clinical phenotype of 3q29 microdeletion syndrome is variable. Clinical features can include mild to moderate intellectual disability with mildly dysmorphic facial features (long and narrow face, short philtrum and a high nasal bridge). Of the 6 reported patients, additional features including autism, ataxia, chest-wall deformity and long, tapering fingers were found in at least two patients. A review of 14 children with interstitial deletions of 3q29, found 11 who had the common recurrent 1.6Mb deletion and displayed intellectual disability and microcephaly.The variability of phenotype is underscored by the report on a 6 and 9/12-year-old male patient with a de novo chromosome 3q29 microdeletion identified by BAC array comparative genomic hybridization assay (aCGH), with accompanying normal 46,XY high-resolution chromosome analysis. The patient has language-based learning disabilities and behavioral features consistent with diagnoses of autism and attention deficit hyperactivity disorder (ADHD) of the inattentive type. He also displays some other features previously associated with chromosome 3q29 microdeletion such as an elongated face, long fingers, and joint laxity. Most notably the patient, per formal IQ testing, did not have an intellectual disability. The patient demonstrated an average full-scale IQ result. This is notable because previously reported patients with chromosome 3q29 terminal deletion had intellectual disabilities. This report further expands the phenotypic spectrum to include the possibility of normal intelligence as corroborated by formal, longitudinal psycho-educational testing.The presence of two homologous low copy repeats either side of the deletion break-point suggests that non-allelic homologous recombination is the likely mechanism underlying this syndrome. Genetics The microdeletion, around 1.6 million base pairs, in length and encompasses 5 known genes and 17 uncharacterised transcripts. These include transferrin receptor, choline-phosphate cytidylyltransferase A, RNF168, serine/threonine-protein kinase, nuclear cap-binding protein complex, melanotransferrin, DLG1 and D-beta-hydroxybutyrate dehydrogenase Research Research on the risk for developing schizophrenia in Ashkenazi Jews and other populations showed that 3q29 microdeletion syndrome leads to a significant higher rate of schizophrenia. In addition, a deletion at 3q29 was found to confer an increase to the odds of developing schizophrenia in a study of copy number variants and their effect on that disorder. References External links DECIPHER database entry for 3q29 microdeletion syndrome
HIV	The human immunodeficiency viruses (HIV) are two species of Lentivirus (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype.In most cases, HIV is a sexually transmitted infection and occurs by contact with or transfer of blood, pre-ejaculate, semen, and vaginal fluids. Non-sexual transmission can occur from an infected mother to her infant during pregnancy, during childbirth by exposure to her blood or vaginal fluid, and through breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. Research has shown (for both same-sex and opposite-sex couples) that HIV is untransmittable through condomless sexual intercourse if the HIV-positive partner has a consistently undetectable viral load.HIV infects vital cells in the human immune system, such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through a number of mechanisms, including pyroptosis of abortively infected T cells, apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4+ T cells by CD8+ cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS. Virology Classification HIV is a member of the genus Lentivirus, part of the family Retroviridae. Lentiviruses have many morphologies and biological properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period. Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the target cell, the viral RNA genome is converted (reverse transcribed) into double-stranded DNA by a virally encoded enzyme, reverse transcriptase, that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded enzyme, integrase, and host co-factors. Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time. The HIV virus can remain dormant in the human body for up to ten years after primary infection; during this period the virus does not cause symptoms. Alternatively, the integrated viral DNA may be transcribed, producing new RNA genomes and viral proteins, using host cell resources, that are packaged and released from the cell as new virus particles that will begin the replication cycle anew. Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both lymphadenopathy associated virus (LAV) and human T-lymphotropic virus 3 (HTLV-III). HIV-1 is more virulent and more infective than HIV-2, and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2, compared to HIV-1, implies that fewer of those exposed to HIV-2 will be infected per exposure. Due to its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa. Structure and genome HIV is similar in structure to other retroviruses. It is roughly spherical with a diameter of about 120 nm, around 100,000 times smaller in volume than a red blood cell. It is composed of two copies of positive-sense single-stranded RNA that codes for the viruss nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein p24. The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as reverse transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.This is, in turn, surrounded by the viral envelope, that is composed of the lipid bilayer taken from the membrane of a human host cell when the newly formed virus particle buds from the cell. The viral envelope contains proteins from the host cell and relatively few copies of the HIV envelope protein, which consists of a cap made of three molecules known as glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure into the viral envelope. The envelope protein, encoded by the HIV env gene, allows the virus to attach to target cells and fuse the viral envelope with the target cells membrane releasing the viral contents into the cell and initiating the infectious cycle. As the sole viral protein on the surface of the virus, the envelope protein is a major target for HIV vaccine efforts. Over half of the mass of the trimeric envelope spike is N-linked glycans. The density is high as the glycans shield the underlying viral protein from neutralisation by antibodies. This is one of the most densely glycosylated molecules known and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic and Golgi apparatus. The majority of the glycans are therefore stalled as immature high-mannose glycans not normally present on human glycoproteins that are secreted or present on a cell surface. The unusual processing and high density means that almost all broadly neutralising antibodies that have so far been identified (from a subset of patients that have been infected for many months to years) bind to, or are adapted to cope with, these envelope glycans.The molecular structure of the viral spike has now been determined by X-ray crystallography and cryogenic electron microscopy. These advances in structural biology were made possible due to the development of stable recombinant forms of the viral spike by the introduction of an intersubunit disulphide bond and an isoleucine to proline mutation (radical replacement of an amino acid) in gp41. The so-called SOSIP trimers not only reproduce the antigenic properties of the native viral spike, but also display the same degree of immature glycans as presented on the native virus. Recombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising epitopes than recombinant monomeric gp120, which act to suppress the immune response to target epitopes. The RNA genome consists of at least seven structural landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS), and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and sometimes a tenth tev, which is a fusion of tat, env and rev), encoding 19 proteins. Three of these genes, gag, pol, and env, contain information needed to make the structural proteins for new virus particles. For example, env codes for a protein called gp160 that is cut in two by a cellular protease to form gp120 and gp41. The six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.The two tat proteins (p16 and p14) are transcriptional transactivators for the LTR promoter acting by binding the TAR RNA element. The TAR may also be processed into microRNAs that regulate the apoptosis genes ERCC1 and IER3. The rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the RRE RNA element. The vif protein (p23) prevents the action of APOBEC3G (a cellular protein that deaminates cytidine to uridine in the single-stranded viral DNA and/or interferes with reverse transcription). The vpr protein (p14) arrests cell division at G2/M. The nef protein (p27) down-regulates CD4 (the major viral receptor), as well as the MHC class I and class II molecules.Nef also interacts with SH3 domains. The vpu protein (p16) influences the release of new virus particles from infected cells. The ends of each strand of HIV RNA contain an RNA sequence called a long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell. The Psi element is involved in viral genome packaging and recognized by gag and rev proteins. The SLIP element (TTTTTT) is involved in the frameshift in the gag-pol reading frame required to make functional pol. Tropism The term viral tropism refers to the cell types a virus infects. HIV can infect a variety of immune cells such as CD4+ T cells, macrophages, and microglial cells. HIV-1 entry to macrophages and CD4+ T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells membrane and also with chemokine co-receptors.Macrophage-tropic (M-tropic) strains of HIV-1, or non-syncytia-inducing strains (NSI; now called R5 viruses) use the β-chemokine receptor, CCR5, for entry and are thus able to replicate in both macrophages and CD4+ T cells. This CCR5 co-receptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4+ cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the central nervous system. In the tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce huge amounts of virus. T-tropic strains of HIV-1, or syncytia-inducing strains (SI; now called X4 viruses) replicate in primary CD4+ T cells as well as in macrophages and use the α-chemokine receptor, CXCR4, for entry.Dual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry. The α-chemokine SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down-regulating the expression of CXCR4 on the surface of HIV target cells. M-tropic HIV-1 isolates that use only the CCR5 receptor are termed R5; those that use only CXCR4 are termed X4, and those that use both, X4R5. However, the use of co-receptors alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection and HIV can also infect a subtype of myeloid dendritic cells, which probably constitute a reservoir that maintains infection when CD4+ T cell numbers have declined to extremely low levels. Some people are resistant to certain strains of HIV. For example, people with the CCR5-Δ32 mutation are resistant to infection by the R5 virus, as the mutation leaves HIV unable to bind to this co-receptor, reducing its ability to infect target cells. Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal fluid, which enables the virus to be transmitted from a male to his sexual partner. The virions can then infect numerous cellular targets and disseminate into the whole organism. However, a selection process leads to a predominant transmission of the R5 virus through this pathway. In patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants that can infect a variety of T cells through CXCR4. These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS. HIV-positive patients acquire an enormously broad spectrum of opportunistic infections, which was particularly problematic prior to the onset of HAART therapies; however, the same infections are reported among HIV-infected patients examined post-mortem following the onset of antiretroviral therapies. Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of studies with subtype B-infected individuals have determined that between 40 and 50 percent of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes.HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution to West Africa. The adoption of "accessory genes" by HIV-2 and its more promiscuous pattern of co-receptor usage (including CD4-independence) may assist the virus in its adaptation to avoid innate restriction factors present in host cells. Adaptation to use normal cellular machinery to enable transmission and productive infection has also aided the establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host, but ultimately become a commensal organism. Having achieved a low pathogenicity, over time, variants that are more successful at transmission will be selected. Replication cycle Entry to the cell The HIV virion enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its surface to receptors on the target cell followed by fusion of the viral envelope with the target cell membrane and the release of the HIV capsid into the cell.Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) on the HIV viral envelope and both CD4 and a chemokine co-receptor (generally either CCR5 or CXCR4, but others are known to interact) on the target cell surface. Gp120 binds to integrin α4β7 activating LFA-1, the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1. The gp160 spike contains binding domains for both CD4 and chemokine receptors.The first step in fusion involves the high-affinity attachment of the CD4 binding domains of gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine receptor binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane. Repeat sequences in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin shape. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell. During the microtubule-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome. HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used. DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells when the virus is captured in the mucosa by DCs. The presence of FEZ-1, which occurs naturally in neurons, is believed to prevent the infection of cells by HIV. HIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at the plasma membrane. More recently, however, productive infection by pH-independent, clathrin-mediated endocytosis of HIV-1 has also been reported and was recently suggested to constitute the only route of productive entry. Replication and transcription Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the positive-sense single-stranded RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule. The process of reverse transcription is extremely error-prone, and the resulting mutations may cause drug resistance or allow the virus to evade the bodys immune system. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a sense DNA from the antisense cDNA. Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus. The integration of the viral DNA into the host cells genome is carried out by another viral enzyme called integrase.The integrated viral DNA may then lie dormant, in the latent stage of HIV infection. To actively produce the virus, certain cellular transcription factors need to be present, the most important of which is NF-κB (nuclear factor kappa B), which is upregulated when T cells become activated. This means that those cells most likely to be targeted, entered and subsequently killed by HIV are those actively fighting infection. During viral replication, the integrated DNA provirus is transcribed into RNA. The full-length genomic RNAs (gRNA) can be packaged into new viral particles in a pseudodiploid form. The selectivity in the packaging is explained by the structural properties of the dimeric conformer of the gRNA. The gRNA dimer is characterized by a tandem three-way junction within the gRNA monomer, in which the SD and AUG hairpins, responsible for splicing and translation respectively, are sequestered and the DIS (dimerization initiation signal) hairpin is exposed.The formation of the gRNA dimer is mediated by a kissing interaction between the DIS hairpin loops of the gRNA monomers. At the same time, certain guanosine residues in the gRNA are made available for binding of the nucleocapsid (NC) protein leading to the subsequent virion assembly. The labile gRNA dimer has been also reported to achieve a more stable conformation following the NC binding, in which both the DIS and the U5:AUG regions of the gRNA participate in extensive base pairing.RNA can also be processed to produce mature messenger RNAs (mRNAs). In most cases, this processing involves RNA splicing to produce mRNAs that are shorter than the full-length genome. Which part of the RNA is removed during RNA splicing determines which of the HIV protein-coding sequences is translated.Mature HIV mRNAs are exported from the nucleus into the cytoplasm, where they are translated to produce HIV proteins, including Rev. As the newly produced Rev protein is produced it moves to the nucleus, where it binds to full-length, unspliced copies of virus RNAs and allows them to leave the nucleus. Some of these full-length RNAs function as mRNAs that are translated to produce the structural proteins Gag and Env. Gag proteins bind to copies of the virus RNA genome to package them into new virus particles. HIV-1 and HIV-2 appear to package their RNA differently. HIV-1 will bind to any appropriate RNA. HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself. Recombination Two RNA genomes are encapsidated in each HIV-1 particle (see Structure and genome of HIV). Upon infection and replication catalyzed by reverse transcriptase, recombination between the two genomes can occur. Recombination occurs as the single-strand, positive-sense RNA genomes are reverse transcribed to form DNA. During reverse transcription, the nascent DNA can switch multiple times between the two copies of the viral RNA. This form of recombination is known as copy-choice. Recombination events may occur throughout the genome. Anywhere from two to 20 recombination events per genome may occur at each replication cycle, and these events can rapidly shuffle the genetic information that is transmitted from parental to progeny genomes.Viral recombination produces genetic variation that likely contributes to the evolution of resistance to anti-retroviral therapy. Recombination may also contribute, in principle, to overcoming the immune defenses of the host. Yet, for the adaptive advantages of genetic variation to be realized, the two viral genomes packaged in individual infecting virus particles need to have arisen from separate progenitor parental viruses of differing genetic constitution. It is unknown how often such mixed packaging occurs under natural conditions.Bonhoeffer et al. suggested that template switching by reverse transcriptase acts as a repair process to deal with breaks in the single-stranded RNA genome. In addition, Hu and Temin suggested that recombination is an adaptation for repair of damage in the RNA genomes. Strand switching (copy-choice recombination) by reverse transcriptase could generate an undamaged copy of genomic DNA from two damaged single-stranded RNA genome copies. This view of the adaptive benefit of recombination in HIV could explain why each HIV particle contains two complete genomes, rather than one. Furthermore, the view that recombination is a repair process implies that the benefit of repair can occur at each replication cycle, and that this benefit can be realized whether or not the two genomes differ genetically. On the view that recombination in HIV is a repair process, the generation of recombinational variation would be a consequence, but not the cause of, the evolution of template switching.HIV-1 infection causes chronic inflammation and production of reactive oxygen species. Thus, the HIV genome may be vulnerable to oxidative damage, including breaks in the single-stranded RNA. For HIV, as well as for viruses in general, successful infection depends on overcoming host defense strategies that often include production of genome-damaging reactive oxygen species. Thus, Michod et al. suggested that recombination by viruses is an adaptation for repair of genome damage, and that recombinational variation is a byproduct that may provide a separate benefit. Assembly and release The final step of the viral cycle, assembly of new HIV-1 virions, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi apparatus where it is cleaved by furin resulting in the two HIV envelope glycoproteins, gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. The budded virion is still immature as the gag polyproteins still need to be cleaved into the actual matrix, capsid and nucleocapsid proteins. This cleavage is mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of the protease inhibitor class. The various structural components then assemble to produce a mature HIV virion. Only mature virions are then able to infect another cell. Spread within the body The classical process of infection of a cell by a virion can be called "cell-free spread" to distinguish it from a more recently recognized process called "cell-to-cell spread". In cell-free spread (see figure), virus particles bud from an infected T cell, enter the blood or extracellular fluid and then infect another T cell following a chance encounter. HIV can also disseminate by direct transmission from one cell to another by a process of cell-to-cell spread, for which two pathways have been described. Firstly, an infected T cell can transmit virus directly to a target T cell via a virological synapse. Secondly, an antigen-presenting cell (APC), such as a macrophage or dendritic cell, can transmit HIV to T cells by a process that either involves productive infection (in the case of macrophages) or capture and transfer of virions in trans (in the case of dendritic cells). Whichever pathway is used, infection by cell-to-cell transfer is reported to be much more efficient than cell-free virus spread. A number of factors contribute to this increased efficiency, including polarised virus budding towards the site of cell-to-cell contact, close apposition of cells, which minimizes fluid-phase diffusion of virions, and clustering of HIV entry receptors on the target cell towards the contact zone. Cell-to-cell spread is thought to be particularly important in lymphoid tissues, where CD4+ T cells are densely packed and likely to interact frequently. Intravital imaging studies have supported the concept of the HIV virological synapse in vivo. The many dissemination mechanisms available to HIV contribute to the viruss ongoing replication in spite of anti-retroviral therapies. Genetic variability HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of about 1010 virions every day, coupled with a high mutation rate of approximately 3 x 10−5 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase.This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day. This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes. This recombination is most obvious when it occurs between subtypes.The closely related simian immunodeficiency virus (SIV) has evolved into many strains, classified by the natural host species. SIV strains of the African green monkey (SIVagm) and sooty mangabey (SIVsmm) are thought to have a long evolutionary history with their hosts. These hosts have adapted to the presence of the virus, which is present at high levels in the hosts blood, but evokes only a mild immune response, does not cause the development of simian AIDS, and does not undergo the extensive mutation and recombination typical of HIV infection in humans.In contrast, when these strains infect species that have not adapted to SIV ("heterologous" or similar hosts such as rhesus or cynomologus macaques), the animals develop AIDS and the virus generates genetic diversity similar to what is seen in human HIV infection. Chimpanzee SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host. SIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus. This virus has also lost a function of the nef gene that is present in most SIVs. For non-pathogenic SIV variants, nef suppresses T cell activation through the CD3 marker. Nefs function in non-pathogenic forms of SIV is to downregulate expression of inflammatory cytokines, MHC-1, and signals that affect T cell trafficking. In HIV-1 and SIVcpz, nef does not inhibit T-cell activation and it has lost this function. Without this function, T cell depletion is more likely, leading to immunodeficiency.Three groups of HIV-1 have been identified on the basis of differences in the envelope (env) region: M, N, and O. Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct. The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form
HIV	branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Co-infection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs. Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes. The existence of a fourth group, "P", has been hypothesised based on a virus isolated in 2009. The strain is apparently derived from gorilla SIV (SIVgor), first isolated from western lowland gorillas in 2006.HIV-2s closest relative is SIVsm, a strain of SIV found in sooty mangabees. Since HIV-1 is derived from SIVcpz, and HIV-2 from SIVsm, the genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsm. Diagnosis Many HIV-positive people are unaware that they are infected with the virus. For example, in 2001 less than 1% of the sexually active urban population in Africa had been tested, and this proportion is even lower in rural populations. Furthermore, in 2001 only 0.5% of pregnant women attending urban health facilities were counselled, tested or received their test results. Again, this proportion is even lower in rural health facilities. Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine and medical research are routinely screened for HIV.HIV-1 testing is initially done using an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a non-reactive result from the initial ELISA are considered HIV-negative, unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate. If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., a polymerase chain reaction (PCR), western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or PCR or reactive by western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person. Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. In general, a second specimen should be collected more than a month later and retested for persons with indeterminate western blot results. Although much less commonly available, nucleic acid testing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations. In addition, a few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection. Modern HIV testing is extremely accurate, when the window period is taken into consideration. A single screening test is correct more than 99% of the time. The chance of a false-positive result in a standard two-step testing protocol is estimated to be about 1 in 250,000 in a low risk population. Testing post-exposure is recommended immediately and then at six weeks, three months, and six months.The latest recommendations of the US Centers for Disease Control and Prevention (CDC) show that HIV testing must start with an immunoassay combination test for HIV-1 and HIV-2 antibodies and p24 antigen. A negative result rules out HIV exposure, while a positive one must be followed by an HIV-1/2 antibody differentiation immunoassay to detect which antibodies are present. This gives rise to four possible scenarios: 1. HIV-1 (+) & HIV-2 (−): HIV-1 antibodies detected 2. HIV-1 (−) & HIV-2 (+): HIV-2 antibodies detected 3. HIV-1 (+) & HIV-2 (+): both HIV-1 and HIV-2 antibodies detected 4. HIV-1 (−) or indeterminate & HIV-2 (−): Nucleic acid test must be carried out to detect the acute infection of HIV-1 or its absence. Research HIV/AIDS research includes all medical research that attempts to prevent, treat, or cure HIV/AIDS, as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV. Many governments and research institutions participate in HIV/AIDS research. This research includes behavioral health interventions, such as research into sex education, and drug development, such as research into microbicides for sexually transmitted diseases, HIV vaccines, and anti-retroviral drugs. Other medical research areas include the topics of pre-exposure prophylaxis, post-exposure prophylaxis, circumcision and HIV, and accelerated aging effects. Treatment and transmission The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs. In many parts of the world, HIV has become a chronic condition in which progression to AIDS is increasingly rare. HIV latency, and the consequent viral reservoir in CD4+ T cells, dendritic cells, as well as macrophages, is the main barrier to eradication of the virus.It is important to note that although HIV is highly virulent, transmission does not occur through sex when an HIV-positive person has a consistently undetectable viral load (<50 copies/ml) due to anti-retroviral treatment. This was first argued by the Swiss Federal Commission for AIDS/HIV in 2008 in the Swiss Statement, though the statement was controversial at the time. However, following multiple studies, it became clear that the chance of passing on HIV through sex is effectively zero where the HIV-positive person has a consistently undetectable viral load; this is known as U=U, "Undetectable=Untransmittable", also phrased as "cant pass it on". The studies demonstrating U=U are: Opposites Attract, PARTNER 1, PARTNER 2, (for male-male couples) and HPTN052 (for heterosexual couples) when "the partner living with HIV had a durably suppressed viral load." In these studies, couples where one partner was HIV positive and one partner was HIV negative were enrolled and regular HIV testing completed. In total from the four studies, 4097 couples were enrolled over four continents and 151,880 acts of condomless sex were reported; there were zero phylogenetically linked transmissions of HIV where the positive partner had an undetectable viral load. Following this, the U=U consensus statement advocating the use of "zero risk" was signed by hundreds of individuals and organisations, including the US CDC, British HIV Association and The Lancet medical journal. The importance of the final results of the PARTNER 2 study were described by the medical director of the Terrence Higgins Trust as "impossible to overstate", while lead author Alison Rodger declared that the message that "undetectable viral load makes HIV untransmittable... can help end the HIV pandemic by preventing HIV transmission. The authors summarised their findings in The Lancet as follows: Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV. This result is consistent with the conclusion presented by Anthony S. Fauci, the Director of the National Institute of Allergy and Infectious Diseases for the U.S. National Institutes of Health, and his team in a viewpoint published in the Journal of the American Medical Association, that U=U is an effective HIV prevention method when an undetectable viral load is maintained.Genital herpes (HSV-2) reactivation in those infected with the virus have an associated increase in CCR-5 enriched CD4+ T cells as well as inflammatory dendritic cells in the submucosa of the genital skin. Tropism of HIV for CCR-5 positive cells explains the two to threefold increase in HIV acquisition among persons with genital herpes. Daily antiviral (e.g. acyclovir) medication do not reduce the sub-clinical post reactivation inflammation and therefore does not confer reduced risk of HIV acquisition. History Discovery The first news story on "an exotic new disease" appeared May 18, 1981, in the gay newspaper New York Native.AIDS was first clinically observed in 1981 in the United States. The initial cases were a cluster of injection drug users and gay men with no known cause of impaired immunity who showed symptoms of Pneumocystis pneumonia (PCP or PJP, the latter term recognizing that the causative agent is now called Pneumocystis jirovecii), a rare opportunistic infection that was known to occur in people with very compromised immune systems. Soon thereafter, researchers at the NYU School of Medicine studied gay men developing a previously rare skin cancer called Kaposis sarcoma (KS). Many more cases of PJP and KS emerged, alerting U.S. Centers for Disease Control and Prevention (CDC) and a CDC task force was formed to monitor the outbreak. The earliest retrospectively described case of AIDS is believed to have been in Norway beginning in 1966.In the beginning, the CDC did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus. They also used Kaposis Sarcoma and Opportunistic Infections, the name by which a task force had been set up in 1981. In the general press, the term GRID, which stood for gay-related immune deficiency, had been coined. The CDC, in search of a name and looking at the infected communities, coined "the 4H disease", as it seemed to single out homosexuals, heroin users, hemophiliacs, and Haitians. However, after determining that AIDS was not isolated to the gay community, it was realized that the term GRID was misleading and AIDS was introduced at a meeting in July 1982. By September 1982 the CDC started using the name AIDS.In 1983, two separate research groups led by American Robert Gallo and French investigators Françoise Barré-Sinoussi and Luc Montagnier independently declared that a novel retrovirus may have been infecting AIDS patients, and published their findings in the same issue of the journal Science. Gallo claimed that a virus his group had isolated from a person with AIDS was strikingly similar in shape to other human T-lymphotropic viruses (HTLVs) his group had been the first to isolate. Gallo admitted in 1987 that the virus he claimed to have discovered in 1984 was in reality a virus sent to him from France the year before. Gallos group called their newly isolated virus HTLV-III. Montagniers group isolated a virus from a patient presenting with swelling of the lymph nodes of the neck and physical weakness, two classic symptoms of primary HIV infection. Contradicting the report from Gallos group, Montagnier and his colleagues showed that core proteins of this virus were immunologically different from those of HTLV-I. Montagniers group named their isolated virus lymphadenopathy-associated virus (LAV). As these two viruses turned out to be the same, in 1986 LAV and HTLV-III were renamed HIV.Another group working contemporaneously with the Montagnier and Gallo groups was that of Jay A. Levy at the University of California, San Francisco. He independently discovered the AIDS virus in 1983 and named it the AIDS associated retrovirus (ARV). This virus was very different from the virus reported by the Montagnier and Gallo groups. The ARV strains indicated, for the first time, the heterogeneity of HIV isolates and several of these remain classic examples of the AIDS virus found in the United States. Origins Both HIV-1 and HIV-2 are believed to have originated in non-human primates in West-central Africa, and are believed to have transferred to humans (a process known as zoonosis) in the early 20th century.HIV-1 appears to have originated in southern Cameroon through the evolution of SIVcpz, a simian immunodeficiency virus (SIV) that infects wild chimpanzees (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies Pan troglodytes troglodytes). The closest relative of HIV-2 is SIVsmm, a virus of the sooty mangabey (Cercocebus atys atys), an Old World monkey living in littoral West Africa (from southern Senegal to western Côte dIvoire). New World monkeys such as the owl monkey are resistant to HIV-1 infection, possibly because of a genomic fusion of two viral resistance genes.HIV-1 is thought to have jumped the species barrier on at least three separate occasions, giving rise to the three groups of the virus, M, N, and O. There is evidence that humans who participate in bushmeat activities, either as hunters or as bushmeat vendors, commonly acquire SIV. However, SIV is a weak virus, and it is typically suppressed by the human immune system within weeks of infection. It is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough time to mutate into HIV. Furthermore, due to its relatively low person-to-person transmission rate, it can only spread throughout the population in the presence of one or more high-risk transmission channels, which are thought to have been absent in Africa prior to the 20th century. Specific proposed high-risk transmission channels, allowing the virus to adapt to humans and spread throughout the society, depend on the proposed timing of the animal-to-human crossing. Genetic studies of the virus suggest that the most recent common ancestor of the HIV-1 M group dates back to circa 1910. Proponents of this dating link the HIV epidemic with the emergence of colonialism and growth of large colonial African cities, leading to social changes, including different patterns of sexual contact (especially multiple, concurrent partnerships), the spread of prostitution, and the concomitant high frequency of genital ulcer diseases (such as syphilis) in nascent colonial cities. While transmission rates of HIV during vaginal intercourse are typically low, they are increased manyfold if one of the partners has a sexually transmitted infection resulting in genital ulcers. Early 1900s colonial cities were notable for their high prevalence of prostitution and genital ulcers to the degree that as of 1928 as many as 45% of female residents of eastern Leopoldville (currently Kinshasa) were thought to have been prostitutes and as of 1933 around 15% of all residents of the same city were infected by one of the forms of syphilis.The earliest, well-documented case of HIV in a human dates back to 1959 in the Belgian Congo. The virus may have been present in the United States as early as the mid- to late 1960s, as a sixteen-year-old male named Robert Rayford presented with symptoms in 1966 and died in 1969.An alternative and likely complementary hypothesis points to the widespread use of unsafe medical practices in Africa during years following World War II, such as unsterile reuse of single-use syringes during mass vaccination, antibiotic, and anti-malaria treatment campaigns. Research on the timing of most recent common ancestor for HIV-1 groups M and O, as well as on HIV-2 groups A and B, indicates that SIV has given rise to transmissible HIV lineages throughout the twentieth century. The dispersed timing of these transmissions to humans implies that no single external factor is needed to explain the cross-species transmission of HIV. This observation is consistent with both of the two prevailing views of the origin of the HIV epidemics, namely SIV transmission to humans during the slaughter or butchering of infected primates, and the colonial expansion of sub-Saharan African cities. See also Antiviral drug Discovery and development of HIV-protease inhibitors HIV/AIDS denialism World AIDS Day References Further reading External links HIV/AIDS at Curlie
Arbovirus	Arbovirus is an informal name for any virus that is transmitted by arthropod vectors. The term arbovirus is a portmanteau word (arthropod-borne virus). Tibovirus (tick-borne virus) is sometimes used to more specifically describe viruses transmitted by ticks, a superorder within the arthropods. Arboviruses can affect both animals (including humans) and plants. In humans, symptoms of arbovirus infection generally occur 3–15 days after exposure to the virus and last three or four days. The most common clinical features of infection are fever, headache, and malaise, but encephalitis and viral hemorrhagic fever may also occur. Signs and symptoms The incubation period – the time between when infection occurs and when symptoms appear – varies from virus to virus, but is usually limited between 2 and 15 days for arboviruses. The majority of infections, however, are asymptomatic. Among cases in which symptoms do appear, symptoms tend to be non-specific, resembling a flu-like illness, and are not indicative of a specific causative agent. These symptoms include fever, headache, malaise, rash and fatigue. Rarely, vomiting and hemorrhagic fever may occur. The central nervous system can also be affected by infection, as encephalitis and meningitis are sometimes observed. Prognosis is good for most people, but is poor in those who develop severe symptoms, with up to a 20% mortality rate in this population depending on the virus. The very young, elderly, pregnant women, and people with immune deficiencies are more likely to develop severe symptoms. Cause Transmission Arboviruses maintain themselves in nature by going through a cycle between a host, an organism that carries the virus, and a vector, an organism that carries and transmits the virus to other organisms. For arboviruses, vectors are commonly mosquitoes, ticks, sandflies and other arthropods that consume the blood of vertebrates for nutritious or developmental purposes. Vertebrates which have their blood consumed act as the hosts, with each vector generally having an affinity for the blood of specific species, making those species the hosts.Transmission between the vector and the host occurs when the vector feeds on the blood of the vertebrate, wherein the virus that has established an infection in the salivary glands of the vector comes into contact with the hosts blood. While the virus is inside the host, it undergoes a process called amplification, where the virus replicates at sufficient levels to induce viremia, a condition in which there are large numbers of viruses present in the blood. The abundance of viruses in the hosts blood allows the host to transmit the virus to other organisms if its blood is consumed by them. When uninfected vectors become infected from feeding, they are then capable of transmitting the virus to uninfected hosts, resuming amplification of virus populations. If viremia is not achieved in a vertebrate, the species can be called a "dead-end host", as the virus cannot be transmitted back to the vector. An example of this vector-host relationship can be observed in the transmission of the West Nile virus. Female mosquitoes of the genus Culex prefer to consume the blood of passerine birds, making them the hosts of the virus. When these birds are infected, the virus amplifies, potentially infecting multiple mosquitoes that feed on its blood. These infected mosquitoes may go on to further transmit the virus to more birds. If the mosquito is unable to find its preferred food source, it will choose another. Human blood is sometimes consumed, but since the West Nile virus does not replicate that well in mammals, humans are considered a dead-end host. In humans Person-to-person transmission of arboviruses is not common, but can occur. Blood transfusions, organ transplantation, and the use of blood products can transmit arboviruses if the virus is present in the donors blood or organs. Because of this, blood and organs are often screened for viruses before being administered. Rarely, vertical transmission, or mother-to-child transmission, has been observed in infected pregnant and breastfeeding women. Exposure to used needles may also transmit arboviruses if they have been used by an infected person or animal. This puts intravenous drug users and healthcare workers at risk for infection in regions where the arbovirus may be spreading in human populations. Virology Arboviruses are a polyphyletic group, belonging to various viral genera and therefore exhibiting different virologic characteristics. Diagnosis Preliminary diagnosis of arbovirus infection is usually based on clinical presentations of symptoms, places and dates of travel, activities, and epidemiological history of the location where infection occurred. Definitive diagnosis is typically made in a laboratory by employing some combination of blood tests, particularly immunologic, serologic and/or virologic techniques such as ELISA, complement fixation, polymerase chain reaction, neutralization test, and hemagglutination-inhibition test. Classification In the past, arboviruses were organized into one of four groups: A, B, C, and D. Group A denoted members of the genus Alphavirus, Group B were members of the genus Flavivirus, and Group C remains as the Group C serogroup of the genus Orthobunyavirus. Group D was renamed in the mid-1950s to the Guama group and is currently the Guama serogroup in the genus Orthobunyavirus. Currently, viruses are jointly classified according to Baltimore classification and a virus-specific system based on standard biological classification. With the exception of the African swine fever virus, which belongs to the Asfarviridae family of viruses, all major clinically important arboviruses belong to one of the following four groups: Prevention Vector control measures, especially mosquito control, are essential to reducing the transmission of disease by arboviruses. Habitat control involves draining swamps and removal of other pools of stagnant water (such as old tires, large outdoor potted plants, empty cans, etc.) that often serve as breeding grounds for mosquitoes. Insecticides can be applied in rural and urban areas, inside houses and other buildings, or in outdoor environments. They are often quite effective for controlling arthropod populations, though use of some of these chemicals is controversial, and some organophosphates and organochlorides (such as DDT) have been banned in many countries. Infertile male mosquitoes have been introduced in some areas in order to reduce the breeding rate of relevant mosquito species. Larvicides are also used worldwide in mosquito abatement programs. Temefos is a common mosquito larvicide. People can also reduce the risk of getting bitten by arthropods by employing personal protective measures such as sleeping under mosquito nets, wearing protective clothing, applying insect repellents such as permethrin and DEET to clothing and exposed skin, and (where possible) avoiding areas known to harbor high arthropod populations. Arboviral encephalitis can be prevented in two major ways: personal protective measures and public health measures to reduce the population of infected mosquitoes. Personal measures include reducing time outdoors particularly in early evening hours, wearing long pants and long sleeved shirts and applying mosquito repellent to exposed skin areas. Public health measures often require spraying of insecticides to kill juvenile (larvae) and adult mosquitoes. Vaccination Vaccines are available for the following arboviral diseases: Japanese encephalitis Yellow fever Tick-borne encephalitis Rift Valley Fever (only veterinary use)Vaccines are in development for the following arboviral diseases: Zika Virus Dengue fever Eastern Equine encephalitis West Nile Chikungunya Rift Valley Fever Treatment Because the arboviral encephalitides are viral diseases, antibiotics are not an effective form of treatment and no effective antiviral drugs have yet been discovered. Treatment is supportive, attempting to deal with problems such as swelling of the brain, loss of the automatic breathing activity of the brain and other treatable complications like bacterial pneumonia.Aspirin and ibuprofen should not be taken in cases of dengue fever as it could increase the risk of bleeding and cause Dengue Shock Syndrome. Epidemiology Most arboviruses are located in tropical areas, however as a group they have a global distribution. The warm climate conditions found in tropical areas allows for year-round transmission by the arthropod vectors. Other important factors determining geographic distribution of arthropod vectors include rainfall, humidity, and vegetation.Mapping methods such as GIS and GPS have allowed for spatial and temporal analyses of arboviruses. Tagging cases or breeding sites geographically has allowed for deeper examination of vector transmission.To see the epidemiology of specific arboviruses, the following resources hold maps, fact sheets, and reports on arboviruses and arboviral epidemics. History Arboviruses were not known to exist until the rise of modern medicine, with the germ theory and an understanding that viruses were distinct from other microorganisms. The connection between arthropods and disease was not postulated until 1881 when Cuban doctor and scientist Carlos Finlay proposed that yellow fever may be transmitted by mosquitoes instead of human contact, a reality that was verified by Major Walter Reed in 1901. The primary vector, Aedes aegypti, had spread globally from the 15th to the 19th centuries as a result of globalization and the slave trade. This geographic spreading caused dengue fever epidemics throughout the 18th and 19th centuries, and later, in 1906, transmission by the Aedes mosquitoes was confirmed, making yellow fever and dengue fever the first two diseases known to be caused by viruses.Thomas Milton Rivers published the first clear description of a virus as distinct from a bacterium in 1927. The discovery of the West Nile virus came in 1937, and has since been found in Culex populations causing epidemics throughout Africa, the Middle East, and Europe. The virus was introduced into the Western Hemisphere in 1999, sparking a series of epidemics. During the latter half of the 20th century, Dengue fever reemerged as a global disease, with the virus spreading geographically due to urbanization, population growth, increased international travel, and global warming, and continues to cause at least 50 million infections per year, making Dengue fever the most common and clinically important arboviral disease.Yellow fever, alongside malaria, was a major obstacle in the construction of the Panama Canal. French supervision of the project in the 1880s was unsuccessful because of these diseases, forcing the abandonment of the project in 1889. During the American effort to construct the canal in the early 1900s, William C. Gorgas, the Chief Sanitary Officer of Havana, was tasked with overseeing the health of the workers. He had past success in eradicating the disease in Florida and Havana by reducing mosquito populations through draining nearby pools of water, cutting grass, applying oil to the edges of ponds and swamps to kill larvae, and capturing adult mosquitoes that remained indoors during the daytime. Joseph Augustin LePrince, the Chief Sanitary Inspector of the Canal Zone, invented the first commercial larvicide, a mixture of carbolic acid, resin, and caustic soda, to be used throughout the Canal Zone. The combined implementation of these sanitation measures led to a dramatic decline in the number of workers dying and the eventual eradication of yellow fever in the Canal Zone as well as the containment of malaria during the 10-year construction period. Because of the success of these methods at preventing disease, they were adopted and improved upon in other regions of the world. See also List of diseases spread by invertebrates List of insect-borne diseases Mosquito-borne disease Robovirus Tibovirus Tick-borne disease References External links Beran, G. W., ed. (1994). Handbook of Zoonoses. CRC Press. ISBN 9780849332067.
Priapism	Priapism is a condition in which a penis remains erect for hours in the absence of stimulation or after stimulation has ended. There are three types: ischemic (low-flow), nonischemic (high-flow), and recurrent ischemic (intermittent). Most cases are ischemic. Ischemic priapism is generally painful while nonischemic priapism is not. In ischemic priapism, most of the penis is hard; however, the glans penis is not. In nonischemic priapism, the entire penis is only somewhat hard. Very rarely, clitoral priapism occurs in women.Sickle cell disease is the most common cause of ischemic priapism. Other causes include medications such as antipsychotics, SSRIs, blood thinners and prostaglandin E1, as well as drugs such as cocaine. Ischemic priapism occurs when blood does not adequately drain from the penis. Nonischemic priapism is typically due to a connection forming between an artery and the corpus cavernosum or disruption of the parasympathetic nervous system resulting in increased arterial flow. Nonischemic priapism may occur following trauma to the penis or a spinal cord injury. Diagnosis may be supported by blood gas analysis of blood aspirated from the penis or an ultrasound.Treatment depends on the type. Ischemic priapism is typically treated with a nerve block of the penis followed by aspiration of blood from the corpora cavernosa. If this is not sufficient, the corpus cavernosum may be irrigated with cold, normal saline or injected with phenylephrine. Nonischemic priapism is often treated with cold packs and compression. Surgery may be done if usual measures are not effective. In ischemic priapism, the risk of permanent scarring of the penis begins to increase after four hours and definitely occurs after 48 hours. Priapism occurs in about 1 in 20,000 to 1 in 100,000 males per year. Classification Priapism is classified into three groups: ischemic (low-flow), nonischemic (high-flow), and recurrent ischemic. The majority of cases (19 out of 20) are ischemic in nature.Some sources give a duration of four hours as a definition of priapism, but others give six. "The duration of a normal erection before it is classifiable as priapism is still controversial. Ongoing penile erections for more than 6 hours can be classified as priapism."Priapism in females (continued, painful erection of the clitoris) is significantly rarer than priapism in men and is known as clitoral priapism or clitorism. It is associated with persistent genital arousal disorder (PGAD). Only a few case reports of women experiencing clitoral priapism exist. Signs and symptoms Complications Because ischemic priapism causes the blood to remain in the penis for unusually long periods of time, the blood becomes deprived of oxygen, which can cause damage to the penile tissue. Such damage can result in erectile dysfunction or disfigurement of the penis. In extreme cases, if the penis develops severe vascular disease, the priapism can result in penile gangrene. Low-flow priapism Causes of low-flow priapism include sickle cell anemia (most common in children), leukemia, and other blood dyscrasias such as thalassemia and multiple myeloma, and the use of various drugs, as well as cancers. A genome-wide association study on Brazilian patients with sickle cell disease identified four single nucleotide polymorphisms in LINC02537 and NAALADL2 significantly associated with priapism.Other conditions such as Fabrys disease, as well as neurologic disorders such as spinal cord lesions and spinal cord trauma (priapism has been reported in people who have been hanged; see death erection). Priapism can also be caused by reactions to medications. The most common medications that cause priapism are intra-cavernous injections for the treatment of erectile dysfunction (papaverine, alprostadil). Other medication groups reported are antihypertensives, antipsychotics (e.g., chlorpromazine, clozapine), antidepressants (most notably trazodone), anti-convulsant and mood stabilizer drugs such as sodium valproate. Anticoagulants, cantharides (Spanish Fly) and recreational drugs (alcohol, heroin and cocaine) have been associated. Priapism is also known to occur from bites of the Brazilian wandering spider. High-flow priapism Causes of high-flow priapism include: blunt trauma to the perineum or penis, with laceration of the cavernous artery, which can generate an arterial-lacunar fistula. Anticoagulants (heparin and warfarin). Antihypertensives (i.e., hydralazine, guanethidine and propranolol). Hormones (i.e., gonadotropin releasing hormone and testosterone). Diagnosis The diagnosis is often based on the history of the condition as well as a physical exam.Blood gas testing the blood from the cavernosa of the penis can help in the diagnosis. If the low-flow type of priapism is present, the blood typically has a low pH, while if the high-flow type is present, the pH is typically normal. Color Doppler ultrasound may also help differentiate the two. Testing a person to make sure they do not have a hemoglobinopathy may also be reasonable. Ultrasonography Penile ultrasonography with Doppler is the imaging method of choice, because it is noninvasive, widely available, and highly sensitive. By means of this method, it is possible to diagnose priapism and differentiate between its low- and high-flow forms.In low-flow (ischemic) priapism the flow in the cavernous arteries is reduced or absent. As the condition progresses, there is an increase in echogenicity of the corpora cavernosa, attributed to tissue edema. Eventually, changes in the echotexture of the corpora cavernosa can be observed due to the fibrotic transformation generated by tissue anoxia.In high-flow priapism normal or increased, turbulent blood flow in the cavernous arteries is seen. The area surrounding the fistula presents a hypoechoic, irregular lesion in the cavernous tissue. Treatment Medical evaluation is recommended for erections that last for longer than four hours. Pain can often be reduced with a dorsal penile nerve block or penile ring block. For those with nonischemic priapism, cold packs and pressure to the area may be sufficient. Pseudoephedrine Orally administered pseudoephedrine is a first-line treatment for priapism. Erection is largely a parasympathetic response, so the sympathetic action of pseudoephedrine may serve to relieve this condition. Pseudoephedrine is an alpha-agonist agent that exerts a constriction effect on smooth muscle of corpora cavernosum, which in turn facilitates venous outflow. Pseudoephedrine is no longer available in some countries. Aspiration For those with ischemic priapism, the initial treatment is typically aspiration of blood from the corpus cavernosum. This is done on either side. If this is not sufficiently effective, then cold normal saline may be injected and removed. Medications If aspiration is not sufficient, a small dose of phenylephrine may be injected into the corpus cavernosum. Side effects of phenylephrine may include: high blood pressure, slow heart rate, and arrhythmia. If this medication is used, it is recommended that people be monitored for at least an hour after. For those with recurrent ischemic priapism, diethylstilbestrol (DES) or terbutaline may be tried. Surgery Distal shunts, such as the Winters, involve puncturing the glans (the distal part of the penis) into one of the cavernosa, where the old, stagnant blood is held. This causes the blood to leave the penis and return to the circulation. This procedure can be performed by a urologist at the bedside. Winters shunts are often the first invasive technique used, especially in hematologically induced priapism, as it is relatively simple and repeatable.Proximal shunts, such as the Quackels, are more involved and entail operative dissection in the perineum where the corpora meet the spongiosum while making an incision in both and suturing both openings together. Shunts created between the corpora cavernosa and great saphenous vein called a Grayhack shunt can be done though this technique is rarely used.As the complication rates with prolonged priapism are high, early penile prosthesis implantation may be considered. As well as allowing early resumption of sexual activity, early implantation can avoid the formation of dense fibrosis and, hence, a shortened penis. Sickle cell anemia In sickle cell anemia, treatment is initially with intravenous fluids, pain medication, and oxygen therapy. The typical treatment of priapism may be carried out as well. Blood transfusions are not usually recommended as part of the initial treatment, but if other treatments are not effective, exchange transfusion may be done. History Persistent semi-erections and intermittent states of prolonged erections have historically been sometimes called semi-priapism. Terminology The name comes from the Greek god Priapus (Ancient Greek: Πρίαπος), a fertility god, often represented with a disproportionately large, permanent erection. References External links Guideline on the Management of Priapism (2003) - American Urological Association website - The unabridged 275-page version of this guideline. Media related to Priapism at Wikimedia Commons
Osteoporosis circumscripta	Osteoporosis circumscripta cranii refers to a highly circumscribed (focal) lytic lesion of the skull bone as seen on X-ray in patients with Pagets disease of bones. This focal lesion can be fairly large. This finding is highly specific for Pagets disease of bones. == References ==
CADASIL	CADASIL or CADASIL syndrome, involving cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3 gene on chromosome 19. The disease belongs to a family of disorders called the leukodystrophies. The most common clinical manifestations are migraine headaches and transient ischemic attacks or strokes, which usually occur between 40 and 50 years of age, although MRI is able to detect signs of the disease years prior to clinical manifestation of disease.The condition was identified and named by French researchers Marie-Germaine Bousser and Elisabeth Tournier-Lasserve in the 1990s. Together with two other researchers, Hugues Chabriat and Anne Joutel, they received the 2019 Brain Prize for their research into the condition. Signs and symptoms CADASIL may start with attacks of migraine with aura or subcortical transient ischemic attacks or strokes, or mood disorders between 35 and 55 years of age. The disease progresses to subcortical dementia associated with pseudobulbar palsy and urinary incontinence.Ischemic strokes are the most frequent presentation of CADASIL, with approximately 85% of symptomatic individuals developing transient ischemic attacks or stroke(s). The mean age of onset of ischemic episodes is approximately 46 years (range 30–70). A classic lacunar syndrome occurs in at least two-thirds of affected patients while hemispheric strokes are much less common. It is worthy of note that ischemic strokes typically occur in the absence of traditional cardiovascular risk factors. Recurrent silent strokes, with or without clinical strokes, often lead to cognitive decline and overt subcortical dementia. A case of CADASIL presenting as schizophreniform organic psychosis has been reported. Pathophysiology The underlying pathology of CADASIL is progressive hypertrophy of the smooth muscle cells in blood vessels. Autosomal dominant mutations in the Notch 3 gene (on the long arm of chromosome 19) cause an abnormal accumulation of Notch 3 at the cytoplasmic membrane of vascular smooth muscle cells both in cerebral and extracerebral vessels, seen as granular osmiophilic deposits on electron microscopy. Leukoencephalopathy follows. Depending on the nature and position of each mutation, a consensus significant loss of betasheet structure of the Notch3 protein has been predicted using in silico analysis. Diagnosis MRIs show hypointensities on T1-weighted images and hyperintensities on T2-weighted images, usually multiple confluent white matter lesions of various sizes, are characteristic. These lesions are concentrated around the basal ganglia, peri-ventricular white matter, and the pons, and are similar to those seen in Binswanger disease. These white matter lesions are also seen in asymptomatic individuals with the mutated gene. While MRI is not used to diagnose CADASIL, it can show the progression of white matter changes even decades before onset of symptoms.The definitive test is sequencing the whole Notch 3 gene, which can be done from a sample of blood. However, as this is quite expensive and CADASIL is a systemic arteriopathy, evidence of the mutation can be found in small and medium-size arteries. Therefore, skin biopsies are often used for the diagnosis. Treatment No specific treatment for CADASIL is available. While most treatments for CADASIL patients symptoms – including migraine and stroke – are similar to those without CADASIL, these treatments are almost exclusively empiric, as data regarding their benefit to CADASIL patients are limited. Antiplatelet agents such as aspirin, dipyridamole, or clopidogrel might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages. Control of high blood pressure is particularly important in CADASIL patients. Short-term use of atorvastatin, a statin-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients cerebral hemodynamic parameters, although treatment of comorbidities such as high cholesterol is recommended. Stopping oral contraceptive pills may be recommended. Some authors advise against the use of triptan medications for migraine treatment, given their vasoconstrictive effects, although this sentiment is not universal. In this regard, the advent of the "Ditans" such as Lasmiditan, lacking vasoconstrictive effect, and the "Gepants" such as Ubrogepant and Rimegepant, are attractive alternatives, albeit not yet field-tested in this condition. As with other individuals, people with CADASIL should be encouraged to quit smoking.In one small study, around 1/3 of patients with CADASIL were found to have cerebral microhemorrhages (tiny areas of old blood) on MRI.L-arginine, a naturally occurring amino acid, has been proposed as a potential therapy for CADASIL, but as of 2017 there are no clinical studies supporting its use. Donepezil, normally used for Alzheimers Disease, was not shown not to improve executive functioning in CADASIL patients. Society and culture John Ruskin has been suggested to have had CADASIL. Ruskin reported in his diaries having visual disturbances consistent with the disease, and it has also been suggested that it might have been a factor in causing him to describe James Whistlers Nocturne in Black and Gold – The Falling Rocket as "ask[ing] two hundred guineas for throwing a pot of paint in the publics face". This resulted in the famous libel trial that resulted in a jurys awarding Whistler one farthing damages.Recent research into the illness of philosopher Friedrich Nietzsche has suggested that his mental illness and death may have been caused by CADASIL rather than tertiary syphilis. Likewise, the early death of the composer Felix Mendelssohn, at age 37, from a stroke has been potentially linked to CADASIL. His sister, Fanny Mendelssohn, was similarly affected. And James Dewar, best known as vocalist for Robin Trower, died age 59 from complications of CADASIL.In the movie The Sea Inside, one of the characters is stated to have CADASIL. See also Proteopathy CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) References Further reading Lesnik Oberstein SA, Boon EM, Terwindt GM (June 28, 2012). CADASIL. University of Washington, Seattle. PMID 20301673. NBK1500. In Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A (1993). Pagon RA, Bird TD, Dolan CR, et al. (eds.). GeneReviews [Internet]. Seattle WA: University of Washington, Seattle. PMID 20301295. External links A patient story at The New York Times
Ring chromosome 18	Ring chromosome 18 is a genetic condition caused by a deletion of the two ends of chromosome 18 followed by the formation of a ring-shaped chromosome. It was first reported in 1964. Signs and symptoms Ring 18 causes a wide range of medical and developmental concerns. As discussed above, people with ring 18 can have features of both distal 18q- and 18p-. The features of distal 18q- and 18p- vary greatly because of the variability of the deletion size and breakpoint locations between people. Because ring 18 can involve unique deletions of both the p and q arms of the chromosome there is twice as much reason for the variability between individuals. This variation is also partly attributable to the incidence of mosaicism, which is relatively common in people with ring 18. Holoprosencephaly has been reported in some people with ring 18. This is due to the deletion of the TGIF gene on the short arm of chromosome 18 in some people with ring 18. Approximately 30-40% of people with ring 18 have a congenital heart anomaly. Septal defects are the most common type of defect reported in this population. Hypotonia is frequently seen in the ring 18 population. Seizures, though uncommon, have been reported in people with ring 18. In some children without “classic” holoprosencephaly, microforms of holoprosencephaly may be noted on MRI, including missing olfactory tracts and bulbs and absent or hypoplastic corpus callosum. Strabismus as well as nystagmus have both been reported in infants and children with ring 18. Hearing loss has been reported and may be related to ear canal atresia or stenosis. Umbilical and inguinal hernias have been reported in a small number of people with ring 18. Unilateral renal hypoplasia and aplasia have both been reported in individuals with ring 18. Hydronephrosis as well as pyelonephritis have also been reported in a few individuals. Cryptorchidism, hypospadias, and micropenis have been seen in males with ring 18, while females have been reported with hypoplastic labia. Foot abnormalities are common within the ring 18 population. Scoliosis as well as pectus excavatum have also been frequently reported. Several people with ring 18 have growth hormone deficiency. Hypothyroidism has also been reported in a minority of people. Cognitive ability varies; according to a literature review, the degree of impairment may fall anywhere between the mild and severe ends of the spectrum. Facial features of ring 18 include low-set, dysplastic ears, epicanthic folds, and hypertelorism. Micrognathia has also been reported. Genetic Individuals with ring 18 have one of their two copies of chromosome 18 that has formed the shape of a ring. The ring is formed when the caps on both the long arm (q) and the short arm (p) of one copy of chromosome 18 are lost and the new ends re-join to form the ring. Because the ring involves deletions of both the long arm (18q-) and the short arm (18p-) of chromosome 18, individuals with ring 18 can have features of both 18p- as well as distal 18q-. Diagnosis Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of ring 18 is usually made via a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible via amniocentesis or chorionic villus sampling. Treatment At present, treatment for ring 18 is symptomatic, meaning that the focus is on treating the signs and symptoms of the conditions as they arise. To ensure early diagnosis and treatment, it is suggested that people with ring 18 undergo routine screenings for thyroid, hearing, and vision problems. Research Currently, research is focusing on identifying the role of the genes on 18p and 18q in causing the signs and symptoms associated with deletions of 18p and/or 18q. This will ultimately enable predictive genotyping. Thus far, several genes on chromosome 18 have been linked with a phenotypic effect.TGIF - Mutations and deletions of this gene, which is located on18p, have been associated with holoprosencephaly. Penetrance is incomplete, meaning that a deletion of one copy of this gene is not in and of itself sufficient to cause holoprosencephaly. Ten to fifteen percent of people with 18p- have holoprosencephaly, suggesting that other genetic and environmental facts play a role in the etiology of holoprosencephaly in these individuals. TCF4 – In 2007, deletions of or point mutations in this gene, which is located on 18q, were identified as the cause of Pitt-Hopkins disease. This is the first gene that has been definitively shown to directly cause a clinical phenotype when deleted. If a deletion includes the TCF4 gene (located at 52,889,562-52,946,887), features of Pitt-Hopkins may be present, including abnormal corpus callosum; short neck; small penis; accessory and wide-spaced nipples; broad or clubbed fingers; and sacral dimple. Those with deletions inclusive of TCF4 have a significantly more severe cognitive phenotype. TSHZ1 - Point mutations and deletions of this gene, located on 18q, are linked with congenital aural atresia Individuals with deletions inclusive of this gene have a 78% chance of having aural atresia. Critical regions – Recent research has narrowed the critical regions for four features of the distal 18q- phenotype down to a small segment of distal 18q, although the precise genes responsible for those features remain to be identified. Haplolethal Regions - There are two regions on chromosome 18 that has never been found to be deleted. They are located between the centromere and 22,826,284 bp (18q11.2) and between 43,832,732 and 45,297,446 bp (18q21.1). It is hypothesized that there are genes in these regions that are lethal when deleted. Nomenclature The phrase “ring 18” refers to the shape that the normally linear chromosome assumes when one tip of the chromosome joins the other. A ring-shaped chromosome is the result. In the case of ring 18, one of the two copies of chromosome 18 has formed a ring. References == External links ==
Hibernating myocardium	In cardiology, hibernating myocardium is a state when some segments of the myocardium exhibit abnormalities of contractile function. These abnormalities can be visualised with echocardiography, cardiac magnetic resonance imaging (CMR), nuclear medicine (PET) or ventriculography. Echocardiography: A wall motion abnormality at rest which improves during a low-dose dobutamine stress test is classified as "hibernating myocardium." Low dose dobutamine stimulates contractile function and thus helps to predict functional recovery after revascularization. Cardiac magnetic resonance: The most frequently used MR contrast agents based on Gd-chelates accumulate in the extracellular space which is increased in scarred myocardium. This leads to a signal increase which can be visualised with the "late gadolinium enhancement technique." This is probably the most accurate way to visualise scarred myocardium. An alternative (or additional) technique with CMR is the use of low dose dobutamine similar to echocardiography. PET: The finding of a perfusion or metabolic mismatch between PET-FDG and PET-NH3 is indicative of decreased metabolism. The wall of the affected segments is hypo-, a-, or dyskinetic.The phenomenon is highly significant clinically because it usually manifests itself in the setting of chronic ischemia, that is potentially reversible by revascularisation via cardiac catheterization. The regions of myocardium are still viable and can return to normal function. There develops a new steady state between myocardial blood flow (MBF) and myocardial function, MBF reduced and in consequence function is reduced too. The clinical situations where one can expect hibernating myocardium are: chronic stable angina unstable angina silent ischemia after AMI See also Stunned myocardium Myocardial scarring == References ==
Cuboid syndrome	Cuboid syndrome or cuboid subluxation describes a condition that results from subtle injury to the calcaneocuboid joint and ligaments in the vicinity of the cuboid bone, one of seven tarsal bones of the human foot. This condition often manifests in the form of lateral (little toe side) foot pain and sometimes general foot weakness. Cuboid syndrome, which is relatively common but not well defined or recognized, is known by many other names, including lateral plantar neuritis, cuboid fault syndrome, peroneal cuboid syndrome, dropped cuboid, locked cuboid and subluxed cuboid. Signs and symptoms A patient with cuboid syndrome usually seeks medical advice and attention complaining of pain, discomfort, or weakness along the lateral aspect of the foot between the fourth and fifth metatarsals and the calcaneocuboid joint. The pain may radiate throughout the foot. Tenderness may be elicited over the tendon of the peroneus longus muscle and an antalgic gait may be observed. The pain may be observed in a controlled environment by standing on the toes or rolling the arches of the foot, as these motions tend to exercise the foots calcaneocuboid joint and ligament, which are characteristically strained in a patient suffering from cuboid syndrome. Also, the pain may come on suddenly or it may develop gradually and persist over time. Sometimes the pain is intermittent, subsiding partially or completely for a period of time before returning again. Causes A patient may develop Cuboid syndrome through either a single traumatic event (e.g., ankle sprain) or insidiously with repetitive strain over time. The exact etiology of Cuboid syndrome remains unclear but many ideas have been proposed. Such ideas include excessive pronation of the foot, overuse injury, and inversion ankle sprains. The favored idea is that the cuboid bone is forcefully everted while the calcaneus is inverted resulting in incongruity at the calcaneocuboid joint. The condition mainly affects athletes, especially those whose activities incur a significant amount of pressure on their feet from jumping or running (such as ballet dancers and runners) and those who place added strain on their feet during lateral maneuvering (such as tennis and basketball players). Cuboid syndrome may persist even if the patient is taking part in regular physical therapy. The patients foot type, such as the presence of overpronation or underpronation, may also play a factor in the condition. Risk factors Suspected risk factors for Cuboid syndrome include obesity, midtarsal instability, poorly fitting footwear, physical exercise, inadequate recovery from physical activity, physical training on uneven surfaces, and ankle sprains. Diagnosis Treatment Once diagnosed, a medical professional may treat cuboid syndrome by realigning (also known as reducing) the subluxed cuboid unless contraindications to manipulation are present such as gout, inflammatory arthritis, bony disease, neurovascular compromise, or a bone fracture. This form of manual manipulation of the foot should be done by a trained specialist, such as an orthopedic surgeon or podiatrist, or secondarily a chiropractor, osteopath, athletic trainer, osteopathic physician, or physical therapist. Further treatment may take into account other considerations, such as possible causes or aggravators (e.g. recommending that the patient be fit with custom orthotics if they are overprone). Fortunately, subluxed cuboids are generally quite treatable and most patients return to a normal level of activity once the pain is brought under control. See also Arthritis Physiatry Rheumatology Tarsal tunnel syndrome == References ==
Fleck corneal dystrophy	Fleck corneal dystrophy, also known as Francois-Neetens speckled corneal dystrophy, is a rare form of corneal dystrophy. It is caused by mutations in PIKFYVE gene. Small opacities, some of which resemble "flecks", are scattered in the stroma of the patients. Other opacities look more like snowflakes or clouds. The disease is non-progressive and in most cases asymptomatic, with mild photophobia reported by some patients. In a single case report, a corneal transplantation was performed for concurrent keratoconus, and at 10 years follow-up there was still no evidence of the inclusions in the stroma. References == External links ==
Epoophoron	The epoophoron or epoöphoron (also called organ of Rosenmüller or the parovarium) is a remnant of the mesonephric tubules that can be found next to the ovary and fallopian tube. Anatomy It may contain 10–15 transverse small ducts or tubules that lead to the Gartner’s duct (also longitudinal duct of epoophoron) that represents the caudal remnant of the mesonephric duct and passes through the broad ligament and the lateral wall of the cervix and vagina. The epoophoron is a homologue to the epididymis in the male. While the epoophoron is located in the lateral portion of the mesosalpinx and mesovarium, the paroophoron (residual remnant of that part of the mesonephric duct that forms the paradidymis in the male) lies more medially in the mesosalpinx. Histology It has a unique histological profile. Clinical significance Clinically the organ may give rise to a local paraovarian cyst or adenoma. See also List of homologues of the human reproductive system Vesicular appendages of epoophoron References External links figures/chapter_35/35-8.HTM: Basic Human Anatomy at Dartmouth Medical School genital-016a—Embryo Images at University of North Carolina Swiss embryology (from UL, UB, and UF) ugenital/genitinterne05
Airport malaria	Airport malaria, sometimes known as baggage, luggage or suitcase malaria, occurs when a malaria infected female Anopheles mosquito travels by aircraft from a country where malaria is common, arrives in a country where malaria is usually not found, and bites a person at or around the vicinity of the airport, or if the climate is suitable, travels in luggage and bites a person further away. The infected person usually presents with a fever in the absence of a recent travel history. There is often no suspicion of malaria, resulting in a delay in diagnosis. It is typically considered as a diagnosis after other explanations for symptoms have been ruled out.Most mosquitoes on aircraft do not carry malaria and the few that do are relatively inefficient invaders. The climate of the host country also offers natural protection. The detection and treatment is the same as of malaria in general. Prevention involves control of mosquitoes at and around airports in the countries of departure and on the aircraft.Studies of airport malaria have been largely observations of individual scenarios, all unique in timing, place of infection and problems, in addition to possibilities of error. The first cases of airport malaria were reported in 1969. Climate change, the rise in international travel, and less frequent aircraft disinsection, have likely played roles in the significant increase in cases between 2010 an 2020 as compared to the previous decade in Europe. Background Human malaria is native to 97 countries and is the worlds most prevalent vector-borne disease with 212 million new cases in 2015. Any occurrences outside endemic countries are largely imported cases or less commonly malaria with no recent travel history.Airport malaria is defined as malaria acquired at or near an airport through the bite of an infected tropical Anopheles mosquito by a person who has no history of being exposed to the mosquitoes in their natural habitat. Malaria transmission in-flight or on a stop-over is not considered airport malaria. Causes Although most imported malaria is due to travel by infected humans, airport malaria is specifically caused by the transmission of malaria parasites to a human through the bite of a malaria infected mosquito that has travelled by aircraft on an international flight from a country where malaria is usually found to a country where malaria is usually not found. It occurs at or around the vicinity of the airport. Very few mosquitoes however enter aircraft and of those that do, less than 5% are likely to carry malaria. Of the four different species of the protozoan parasite Plasmodium; Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax and Plasmodium ovale, airport malaria is most commonly the falciparum and less commonly the vivax type. These can only be transmitted by female Anopheles mosquitoes, which bite mainly between dusk and dawn.Five infection pathways have been described: inside the aircraft, inside the airport, around the airport, far from the airport and from luggage. Expansion of mosquito habitats Deforestation, and projects involving housing, agriculture and water can incidentally expand mosquito habitats. Economic necessity, disasters and conflicts, are known to affect the migration of people, which can also contribute to the movement of mosquitoes and hence risk of malaria. Failure to take this into account has previously resulted in failed attempts to control malaria. Air traffic and global warming With an increase in air traffic volume, higher climate temperatures and humidity, the summers of temperate climates are potentially favourable for mosquitoes. Should temperatures rise in Europe and the United States as a result of global climate change, conditions may become more ideal for mosquito survival, potentially leading to a rise in isolated outbreaks of airport and imported malaria. Uninfected mosquitoes that arrive by flight may also live for long in enough as to feed on an infected person, which could also result in the transmission of malaria in non-endemic countries. Airports, air routes and aircraft Airports The highest risk of airport malaria in Europe is from western and central Africa. A number of species have been found in these Western European airports, particularly Anopheles gambiae which breeds in Africas rainy season during summer, when conditions in Europe are more favourable for its survival.When the cabin and cargo hold doors are opened, ground personnel working on airstrips are at risk. Also, those who manipulate and open containers in warehouses, stores or the post office are exposed to bites of the mosquitoes which have travelled in containers. Air routes The increase in air routes from Africa potentially increase the risk of introducing airport malaria. Aircraft Mosquitoes have been found to be attracted to the illuminated cabins rather than to the baggage compartments. Diagnosis Mild cases may be missed. Due to the absence of a travel history in a person with fever, malaria is not usually expected, resulting in delays in diagnosis. Before the diagnosis of airport malaria can be made, other methods of transmission need to be excluded including blood transfusion, shared needles, prior exposure in endemic regions, and transmission by local mosquitoes. History taking requires information on where the person lives and works, in addition to the distance from the airport. Epidemiology Airport malaria is rare with most cases being reported sporadically and in the summer. It is not as well recognised as malaria in a person with a travel history to a place with endemic malaria. Europe Between 1969 and 1999, Europe saw up to 89 people diagnosed with airport malaria. The frequent flights from Sub-saharan Africa resulted in Belgium, France and the Netherlands being at highest risk.In the UK, at least 14 people with airport malaria were reported between 1969 and 1999. In 1983, 12 out of 67 aircraft flying from tropical countries to Gatwick Airport, London, contained mosquitoes. In the same year, falciparum malaria was reported in two people living 10 km (6.2 mi) and 15 km (9.3 mi) from Gatwick Airport. It was deduced that an infected mosquito accompanied aircrew to a pub near Gatwick and infected its landlord. It was also construed, according to an article in the BMJ by Donald Whitfield, that the same stowaway mosquito also transmitted malaria to a woman who rode through the same village on her motor scooter. High minimum temperatures and humidity were thought to have allowed the infected anopheline mosquitoes to enter the country via aircraft and facilitate their survival. Reports of transmission taking place on the aircraft occurred in the UK in 1984 and 1990, the only such reports on aircraft, leading to infection on aircraft being described as a "British speciality". In 2002, one report came from the vicinity of Heathrow airport.In France, most flights at risk arrive at Charles de Gaulle Airport, Paris, and to a much lesser extent at Marseille, Nice, Lyon, Bordeaux and Toulouse. In 1994, airport malaria was identified in and around Charles de Gaulle Airport in six people, of which four were airport workers, and the others lived 7.5 km (4.7 mi) away in Villeparisis. It was thought that the mosquitoes traveled in the cars of airport workers who lived next door to the two people. All were caused by P. falciparum.In 1989, two cases of falciparum malaria were identified in Italy in two people who lived in Geneva. Distance from the nearest airport ruled out airport malaria in one woman who developed malaria in Italy. A local mosquito (Anopheles labranchiae) had bitten a girl with malaria from India and passed it on. This species was a common malaria vector in Italy until the country was declared malaria free in 1970. Five cases of airport malaria were reported in Geneva in the hot summer of 1989.In Spain, 1964 marked the elimination of malaria following sanitary and socioeconomic developments. However, over the following 50 years, more than 10 000 cases of malaria were reported, of which 0.8% had no history of recent travel. Airport malaria was reported in two people. In 1984, a 76-year-old woman died from P. falciparum after visiting relatives less than 6 kilometres (3.7 mi) from Madrid airport. Suspected to have pneumonia, the diagnosis was not initially clear. In 2001, a second woman was diagnosed, treated and recovered. Other countries There have not been any confirmed reports of airport malaria in the US. However, between 1957 and 2003, there were 156 people reported with malaria who had no history of travel or other risk factors. Some were likely to be caused by airport malaria. A small number of airport malaria reports have come from Florida.Airport malaria was first reported in Australia in 1996. Prevention The WHO International Health Regulations give guidance on prevention of airport malaria. Mosquito control programmes also recommend procedures for aircraft coming from endemic areas and for the receiving airports, including the surrounding 400 metres (1,300 ft) of area.Routine aircraft disinsection of aircraft has been shown to reduce mosquitoes on aircraft. Insecticide can also be sprayed on the ground. However, these procedures are not totally efficient and they vary from country to country.Most mosquitos on aircraft do not carry malaria. The few that do are relatively inefficient invaders. In addition, further natural protection is offered by constraints of the hosting countrys climate.A list of airports at risk has been proposed. International sanitary regulations require the area of airports and the perimeter of 400 m (1,300 ft) around the airport to be made free of Aedes aegypti and Anopheles mosquitos. However, the application of disinsection varies from country to country. Outlook Airport malaria is not considered a serious public health problem but has a high fatality rate and poses a local threat. The prognosis is poor with fatality rates ranging from 16.9% to 26% with almost all the reports being of the falciparum type. History There were reports from as early as 1925 that diseases including cholera, plague, smallpox, typhus, yellow fever and malaria could make their way across countries within short periods of time on aircraft. Based on the International Sanitary Convention for Aerial Navigation (1933) (Hague), which came into force in 1935 to protect communities against diseases liable to be imported by aircraft, air-traffic health control administrations, dealt with by the Office International dHygiène Publique, Paris, were able to impose maximally excepted measures for this purpose, but left their actual application to each country concerned. Information regarding disease surveillance was supplied by "The Health Organization of the League of Nations" and updates were published and circulated regularly. Individual governments drew up their own regulations accordingly. To prevent the introduction of infectious diseases from abroad into the United Kingdom, the Public Health (Aircraft) Regulations 1938 was issued by the Ministry of Health. Its actions included the "disinsection of aircraft in the tropics and subtropics to prevent yellow fever and malaria-infected mosquitoes from being introduced into the country".In 1928, the first report of insects on aircraft came from the quarantine inspector of the dirigible Graf Zeppelin on its arrival in the United States. Airport malaria was later first documented in 1969. Until 1970, malaria was endemic in Europe. Research directions Epidemiological and entomological surveillance and research on the interconnection between malaria transmission and population movement requires attention, as to is improvement in living facilities to prevent forced movement of people, awareness of the connection between mosquitoes and malaria, in addition to adequate healthcare and the control of urbanization.Airport malaria poses a potential risk to the local spread of malaria. The UK is home to five species of anopheline mosquitoes, of which only Anopheles atroparvus breeds close enough in proximity to humans and in enough numbers to act as an efficient vector for malaria. A serious public health problem would arise if the introduction of infected mosquitoes led to the transmission of malaria by local mosquitoes, particularly if transmission were revived in an area where the disease had previously been endemic and then eradicated. == References ==
Motor speech disorders	Motor speech disorders are a class of speech disorders that disturb the bodys natural ability to speak due to neurologic impairments. These neurologic impairments make it difficult for individuals with motor speech disorders to plan, program, control, coordinate, and execute speech productions. Disturbances to the individuals natural ability to speak vary in their etiology based on the integrity and integration of cognitive, neuromuscular, and musculoskeletal activities. Speaking is an act dependent on thought and timed execution of airflow and oral motor / oral placement of the lips, tongue, and jaw that can be disrupted by weakness in oral musculature (dysarthria) or an inability to execute the motor movements needed for specific speech sound production (apraxia of speech or developmental verbal dyspraxia). Such deficits can be related to pathology of the nervous system (central and /or peripheral systems involved in motor planning) that affect the timing of respiration, phonation, prosody, and articulation in isolation or in conjunction. Dysarthria Dysarthria is the reduced ability to motor plan volitional movements needed for speech production as the result of weakness/paresis and/or paralysis of the musculature of the oral mechanism needed for respiration, phonation, resonance, articulation, and/or prosody. Apraxia There are two types of Apraxia. Developmental (or Childhood Apraxia of speech) or acquired Apraxia. Childhood apraxia of speech (CAS) is a neurological childhood speech sound disorder that involves impaired precision and consistency of movements required for speech production without any neuromuscular deficits (ASHA, 2007a, Definitions of CAS section, para. 1). Both are the inability to plan volitional motor movements for speech production in the absence of muscular weakness. Apraxia is not a result of sensory problems, or physical issues with the articulatory structures themselves, simply the way the brain plans to move them. Developmental verbal dyspraxia Developmental verbal dyspraxia is a developmental inability to motor plan volitional movement for the production of speech in the absence of muscular weakness. Research has suggested links to the FOXP2 gene. See also KE family References Duffy, Joseph (2013), Motor speech disorders (3rd ed.), St. Louis, MO: Elsevier Mosby
Erythema ab igne	Erythema ab igne (EAI), also known as hot water bottle rash, is a skin condition caused by long-term exposure to heat (infrared radiation). Prolonged thermal radiation exposure to the skin can lead to the development of reticulated erythema, hyperpigmentation, scaling, and telangiectasias in the affected area. Some people may complain of mild itchiness and a burning sensation, but often, unless a change in pigmentation is seen, it can go unnoticed. Causes Different types of heat sources can cause this condition such as: Repeated application of hot water bottles, heating blankets, or heat pads to treat chronic pain—e.g., chronic back pain. Repeated exposure to heated car seats, space heaters, or fireplaces. Repeated or prolonged exposure to a heater is a common cause of this condition in elderly individuals. Occupational hazards of silversmiths and jewelers (face exposed to heat), bakers, and chefs (arms, face) Resting a laptop computer on the thigh (laptop computer-induced erythema ab igne). In a 2012 review, Riahi and Cohen describe the characteristics of laptop computer-induced erythema ab igne. Temperatures between 43 and 47 °C can cause this skin condition; modern laptops can generate temperatures in this range. Indeed, laptops with powerful processors can reach temperatures of 50 °C and be associated with burns. Positioning the laptop on the thighs can allow for direct exposure to the heating elements of the laptop, which include the central processing unit (CPU) and the graphics processing unit (GPU). At least 15 cases have been reported by 2012 with the condition usually affecting the left anterior thigh. In these reports, 9 of the 15 patients were women (60%) with an average age of 25 years at diagnosis. In Kashmir, due to the use of a kanger which also causes kangri cancer. It is a classic finding in chronic pancreatitis and may also be seen in people with hypothyroidism or lymphedema Pathogenesis The pathogenesis of erythema ab igne remains unknown. It has been proposed that thermal radiation exposure can induce damage to superficial blood vessels that subsequently leads to epidermal vascular dilation. The dilation of vessels presents morphologically as the initially observed erythema. Red blood cell extravasation and deposition of hemosiderin that follows clinically appear as hyperpigmentation, which can occur in a reticular distribution. It has also been proposed that the distribution of affected blood vessels—predominantly in the superficial subcutaneous plexus (found in the papillary dermis)—results in the net-like pattern of erythema ab igne skin lesions. Diagnosis Differential diagnosis Livedo reticularis Vasculitis Treatment Discontinuing contact with the heat source is the initial treatment of erythema ab igne. If the area is only mildly affected with slight redness, the condition may resolve after a few months. If the condition is severe and the skin pigmented and atrophic, then it is unlikely to resolve. In this case, there is a possibility that a squamous cell carcinoma or a neuroendocrine carcinoma such as a Merkel cell carcinoma may form. If there is a persistent sore that does not heal or a growing lump within the rash, a skin biopsy should be performed to rule out the possibility of skin cancer. If the erythema ab igne lesions demonstrate pre-cancerous changes, the use of 5-fluorouracil cream has been recommended. Abnormally pigmented skin may persist for years. Treatment with topical tretinoin or laser treatment may improve the appearance. Epidemiology Erythema ab igne was once commonly seen in the elderly who stood or sat closely to open fires or electric heaters; however, erythema ab igne has been reported in both young and elderly individuals. Women have a higher incidence of erythema ab igne than men. Although wide use of central heating has reduced the overall incidence of erythema ab igne, it is still sometimes found in people exposed to heat from other sources such as heating pads, space heaters, hot water bottles, and electronic devices. References External links DermNet vascular/erythema-ab-igneNew England Journal of Medicine Image Challenge
Macular edema	Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye (a yellow central area of the retina) and causes it to thicken and swell (edema). The swelling may distort a persons central vision, because the macula holds tightly packed cones that provide sharp, clear, central vision to enable a person to see detail, form, and color that is directly in the centre of the field of view. Cause The causes of macular edema are numerous and different causes may be inter-related. It is commonly associated with diabetes. Chronic or uncontrolled diabetes type 2 can affect peripheral blood vessels including those of the retina which may leak fluid, blood and occasionally fats into the retina causing it to swell. Age-related macular degeneration may cause macular edema. As individuals age there may be a natural deterioration in the macula which can lead to the depositing of drusen under the retina sometimes with the formation of abnormal blood vessels. Replacement of the lens as treatment for cataract can cause pseudophakic macular edema. (‘pseudophakia’ means ‘replacement lens’) also known as Irvine-Gass syndrome The surgery involved sometimes irritates the retina (and other parts of the eye) causing the capillaries in the retina to dilate and leak fluid into the retina. Less common today with modern lens replacement techniques. Chronic uveitis and intermediate uveitis can be a cause. Blockage of a vein in the retina can cause engorgement of the other retinal veins causing them to leak fluid under or into the retina. The blockage may be caused, among other things, by atherosclerosis, high blood pressure and glaucoma. A number of drugs can cause changes in the retina that can lead to macular edema. The effect of each drug is variable and some drugs have a lesser role in causation. The principal medication known to affect the retina are:- latanoprost, epinephrine, rosiglitazone, timolol and thiazolidinediones among others. A few congenital diseases are known to be associated with macular edema for example retinitis pigmentosa and retinoschisis. Diagnosis Classification Cystoid macular edema (CME) involves fluid accumulation in the outer plexiform layer secondary to abnormal perifoveal retinal capillary permeability. The edema is termed "cystoid" as it appears cystic; however, lacking an epithelial coating, it is not truly cystic. The cause for CME can be remembered with the mnemonic "DEPRIVEN" (diabetes, epinepherine, pars planitis, retinitis pigmentosa, Irvine-Gass syndrome, venous occlusion, E2-prostaglandin analogues, nicotinic acid/niacin). Diabetic macular edema (DME) is similarly caused by leaking macular capillaries. DME is the most common cause of visual loss in both proliferative, and non-proliferative diabetic retinopathy. Treatment Macular edema sometimes occurs for a few days or weeks after cataract surgery, but most such cases can be successfully treated with NSAID or cortisone eye drops. Prophylactic use of Nonsteroidal anti-inflammatory drugs has been reported to reduce the risk of macular edema to some extent. Higher frequency use of topical steroids provides benefit in difficult to treat cases.Diabetic macular edema may be treated with laser photocoagulation, reducing the chance of vision loss.In 2010, the US FDA approved the use of Lucentis intravitreal injections for macular edema.Iluvien, a sustained release intravitreal implant developed by Alimera Sciences, has been approved in Austria, Portugal and the U.K. for the treatment of vision impairment associated with chronic diabetic macular edema (DME) considered insufficiently responsive to available therapies. Additional EU country approvals are anticipated.In 2013 Lucentis by intravitreal injection was approved by the National Institute for Health and Care Excellence in the UK for the treatment of macular edema caused by diabetes and/or retinal vein occlusion.On July 29, 2014, Eylea (aflibercept), an intravitreal injection produced by Regeneron Pharmaceuticals Inc., was approved to treat DME in the United States. Research In 2005, steroids were investigated for the treatment of macular edema due to retinal blood vessel blockage such as CRVO and BRVO.A 2014 Cochrane Systematic Review studied the effectiveness of two anti-VEGF treatments, ranibizumab and pegaptanib, on patients with macular edema caused by CRVO. Participants on both treatment groups showed a reduction in macular edema symptoms over six months.Another Cochrane Review examined the effectiveness and safety of two intravitreal steroid treatments, triamcinolone acetonide and dexamethasone, for patients with from CRVO-ME. The results from one trial showed that patients treated with triamcinolone acetonide were significantly more likely to show improvements in visual acuity than those in the control group, though outcome data was missing for a large proportion of the control group. The second trial showed that patients treated with dexamethasone implants did not show improvements in visual acuity, compared to patients in the control group. Intravitreal injections and implantation of steroids inside the eye may result in a small improvement of vision for people with chronic or refractory diabetic macular edema. There is low certainty evidence that there does not appear to be any additional benefit of combining anti-VEGF and intravitreal steroids when compared to either treatment alone.Anti‐tumour necrosis factor agents have been proposed as a treatment for macular oedema due to uveitis but a Cochrane Review published in 2018 found no relevant randomised controlled trials. See also Diabetic retinopathy Fuchs spot Intermediate uveitis Macular telangiectasia References == External links ==
Bacillary angiomatosis	Bacillary angiomatosis (BA) is a form of angiomatosis associated with bacteria of the genus Bartonella. Symptoms Cutaneous BA is characterised by the presence of lesions on or under the skin. Appearing in numbers from one to hundreds, these lesions may take several forms: papules or nodules which are red, globular and non-blanching, with a vascular appearance purplish nodules sufficiently similar to Kaposis sarcoma that a biopsy may be required to verify which of the two it is a purplish lichenoid plaque a subcutaneous nodule which may have ulceration, similar to a bacterial abscessWhile cutaneous BA is the most common form, it can also affect several other parts of the body, such as the brain, bone, bone marrow, lymph nodes, gastrointestinal tract, respiratory tract, spleen, and liver. Symptoms vary depending on which parts of the body are affected; for example, those whose livers are affected may have an enlarged liver and fever, while those with osseous BA experience intense pain in the affected area. Presentation BA is characterised by the proliferation of blood vessels, resulting in them forming tumour-like masses in the skin and other organs. Causes It is caused by either Bartonella henselae or B. quintana. B. henselae is most often transmitted through a cat scratch or bite, though ticks and fleas may also act as vectors. B. quintana is usually transmitted by lice.It can manifest in people with AIDS and rarely appears in those who are immunocompetent. Diagnosis Diagnosis is based on a combination of clinical features and biopsy. Neutrophilic infiltrate. Treatment and prevention While curable, BA is potentially fatal if not treated. BA responds dramatically to several antibiotics. Usually, erythromycin will cause the skin lesions to gradually fade away in the next four weeks, resulting in complete recovery. Doxycycline may also be used. However, if the infection does not respond to either of these, the medication is usually changed to tetracycline. If the infection is serious, then a bactericidal medication may be coupled with the antibioticsIf a cat is carrying Bartonella henselae, then it may not exhibit any symptoms. Cats may be bacteremic for weeks to years, but infection is more common in young cats. Transmission to humans is thought to occur via flea feces inoculated into a cat scratch or bite, and transmission between cats occurs only in the presence of fleas. Therefore, elimination and control of fleas in the cats environment are key to prevention of infection in both cats and humans. History The condition that later became known as bacillary angiomatosis was first described by Stoler and associates in 1983. Being unaware of its infectious origin, it was originally called epithelioid angiomatosis. Following documentation of bacilli in Warthin-Starry stains and by electron microscopy in a series of cases by LeBoit and colleagues, the term bacillary angiomatosis was widely adopted. See also Cat scratch fever Trench fever Angiomatosis References == External links ==
Hyperphenylalaninemia	Hyperphenylalaninemia is a medical condition characterized by mildly or strongly elevated concentrations of the amino acid phenylalanine in the blood. Phenylketonuria (PKU) can result in severe hyperphenylalaninemia. Phenylalanine concentrations ([phe]) are routinely screened in newborns by the neonatal heel prick (Guthrie test), which takes a few drops of blood from the heel of the infant. Standard [phe] concentrations in unaffected persons are about 60µM: [phe] concentrations in persons with untreated phenylketonuria may be many times that (600µM to 2400µM), which indicate that the child is at risk for severe intellectual disability. Phenylketonuria is classed as an autosomal recessive condition: in heterozygous form, [phe] shows a moderate elevation, perhaps two-fold over that of unaffected homozygotes, which is classified as hyperphenylalaninemia (hyper- + phenylalanine + -emia = high [phe] in blood). Symptoms and signs The coloration of the skin, hair, and eyes is different in children with PKU. This is caused by low levels of tyrosine, whose metabolic pathway is blocked by deficiency of PAH. Another skin alteration that might occur is the presence of irritation or dermatitis. The childs behaviour may be influenced as well due to augmented levels of phenethylamine which in turn affects levels of other amines in the brain. Psychomotor function may be affected and observed to worsen progressively. Cause People with the genotype for PKU are unaffected in utero, because maternal circulation prevents buildup of [phe]. After birth, PKU in newborns is treated by a special diet with highly restricted phenylalanine content. Persons with genetic predisposition to PKU have normal mental development on this diet. Previously, it was thought safe to withdraw from the diet in the late teens or early twenties, after the central nervous system was fully developed; recent studies suggest some degree of relapse, and a continued phenylalanine-restricted diet is now recommended.PKU or hyperphenylalaninemia may also occur in persons without the PKU genotype. If the mother has the PKU genotype but has been treated so as to be asymptomatic, high levels of [phe] in the maternal blood circulation may affect the non-PKU fetus during gestation. Mothers successfully treated for PKU are advised to return to the [phe]-restricted diet during pregnancy.A small subset of patients with hyperphenylalaninemia shows an appropriate reduction in plasma phenylalanine levels with dietary restriction of this amino acid; however, these patients still develop progressive neurologic symptoms and seizures and usually die within the first 2 years of life ("malignant" hyperphenylalaninemia). These infants exhibit normal phenylalanine hydroxylase (PAH) enzymatic activity but have a deficiency in dihydropteridine reductase (DHPR), an enzyme required for the regeneration of tetrahydrobiopterin (THB or BH4), a cofactor of PAH.Less frequently, DHPR activity is normal but a defect in the biosynthesis of THB exists. In either case, dietary therapy corrects the hyperphenylalaninemia. However, THB is also a cofactor for two other hydroxylation reactions required in the syntheses of neurotransmitters in the brain: the hydroxylation of tryptophan to 5-hydroxytryptophan and of tyrosine to L-dopa. It has been suggested that the resulting deficit in the CNS neurotransmitter activity is, at least in part, responsible for the neurologic manifestations and eventual death of these patients. Hyperphenylalaninemia most is commonly diagnosed by newborn screening and must be distinguished from classic PKU by confirmatory testing at an experienced center. Some cases in adult women have been detected using maternal screening programs or following birth of children with birth defects. Elevated phenylalanine levels are associated with neuropsychological effects. Diagnosis Treatment Maintain plasma phenylalanine values in therapeutic range of 120 to 360 mM using a diet that restricts phenylalanine but otherwise nutritionally complete. Treatment for life is recommended to reduce the risk of long term neuropsychiatric problems and reduce the risk of maternal PKU syndrome. Outcome With treatment the outcome is excellent. Most infants with classic PKU who are treated within the first 10 days of life achieve normal intelligence. However learning problems are more frequent than in unaffected peers. References == External links ==
Unverricht–Lundborg disease	Unverricht–Lundborg disease (abbreviated ULD or EPM1) is the most common form of an uncommon group of genetic epilepsy disorders called the progressive myoclonus epilepsies. It is caused due to a mutation in the cystatin B gene (CSTB). The disease is named after Heinrich Unverricht, who first described it in 1891, and Herman Bernhard Lundborg, who researched it in greater detail in 1901 and 1903. ULD onsets in children between the ages of 6 and 16; there are no known cases in which the person was older than 18. Most cases originate from the Baltic region of Europe, though many have been reported from countries in the Mediterranean.Onset of the disease is characterized by myoclonic jerks and tonic-clonic seizures. Early cases often resulted in the need of a wheelchair and death before the age of 24, but new treatments and medications have increased the life expectancy of individuals with ULD, in some cases even to near that of an unaffected individual. Signs and symptoms Patients with Unverricht–Lundborg disease exhibit myoclonic jerks and tonic-clonic seizures at a young age, between ages 6–16. The myoclonic jerks occur in the muscles of the arms and legs closest to the torso, and are triggered due to a variety of common external stimuli. Seizures begin at an average age of 10.8 years, with myoclonus beginning around 12.1 years. It is not currently possible to diagnose without a genetic test, and since early symptoms are general, it is often mistaken for another more common epilepsy, in many cases juvenile myoclonic epilepsy (JME). Causes The genetic cause of ULD is known, but research has led to new areas of study that may lead to an increase in knowledge of what causes ULD. Genetic factors The cause of ULD is known to be a mutation of the gene that produces cystatin B. The disease is autosomal recessive, so both parents of an individual must be carriers of the recessive CSTB gene for the individual to inherit it, and for an individual to show symptoms of ULD, they must have both recessive CSTB genes. Siblings of affected individuals who only have one recessive gene have been monitored and generally do not show the signs of ULD, though in some cases mild symptoms may be present. New developments New research shows that cystatin B may not be the only factor involved in Unverricht–Lundborg disease. In a study, it was determined that patients with ULD had more dopamine receptors in certain areas of their brain than unaffected individuals. The researchers chose to investigate dopamine receptors because they are known to be a factor in myoclonus, which are a significant part of the symptoms of ULD. The results of this study indicate that the cause of ULD may be more complex than currently thought. Mechanism While the genetic cause of Unverricht–Lundborg disease is known, the mechanism by which it works is not fully known. Current research has provided promising results that may lead to a confirmation of the mechanism. This research has been performed on mice with the gene for producing cystatin B removed, to provide a similar set of symptoms to individuals with ULD. The mechanism currently supported by research is very similar to another theory of epilepsy progression known as kindling. Onset Current research links cystatin B to production of inhibitory neurons known as GABAergic neurons. It has shown that a lack of cystatin B due to a mutation of the CSTB gene leads to a decrease in the number of inhibitory neurons, and this lack of inhibition makes the cells in the brain, particularly the hippocampus, more excitable. It is hypothesized that this increase in excitability is what causes the myoclonic jerks and tonic-clonic seizures in patients with ULD. Progression Research also gives evidence to support the idea that cystatin B may be a type of "protecting" molecule in the brain. Normally, after a seizure, the presence of cystatin B prevents the neurons from dying due to toxic levels of neurotransmitters. Studies suggest that the absence of cystatin B leads to the death of affected neurons, leading to a damaged portion of the brain. This damage coupled with the increased excitability of the cells then leads to more damage, which is what makes Unverricht–Lundborg disease progressive. Diagnosis The only currently available method to diagnose Unverricht–Lundborg disease is a genetic test to check for the presence of the mutated cystatin B gene. If this gene is present in an individual suspected of having the disease, it can be confirmed. However, genetic tests of this type are prohibitively expensive to perform, especially due to the rarity of ULD. The early symptoms of ULD are general and in many cases similar to other more common epilepsies, such as juvenile myoclonic epilepsy. For these reasons, ULD is generally one of the last options doctors explore when looking to diagnose patients exhibiting its symptoms. In most cases, a misdiagnosis is not detrimental to the patient, because many of the same medications are used to treat both ULD and whatever type of epilepsy the patient has been misdiagnosed with. However, there are a few epilepsy medications that increase the incidence of seizures and myoclonic jerks in patients with ULD, which can lead to an increase in the speed of progression, including phenytoin, fosphenytoin, sodium channel blockers, GABAergic drugs, gabapentin and pregabalin.Other methods to diagnose Unverricht–Lundborg disease are currently being explored. While electroencephalogram (EEG) is useful in identifying or diagnosing other forms of epilepsy, the location of seizures in ULD is currently known to be generalized across the entire brain. Without a specific region to pinpoint, it is difficult to accurately distinguish an EEG reading from an individual with ULD from an individual with another type of epilepsy characterized by generalized brain seizures. However, with recent research linking ULD brain damage to the hippocampus, the usefulness of EEG as a diagnostic tool may increase. Magnetic Resonance Imaging (MRI) is also often used during diagnosis of patients with epilepsy. While MRIs taken during the onset of the disease are generally similar to those of individuals without ULD, MRIs taken once the disease has progressed show characteristic damageWhile ULD is a rare disease, the lack of well defined cases to study and the difficulty in confirming diagnosis provide strong evidence that this disease is likely under diagnosed. Classification Unverricht–Lundborg disease is also known as EPM1, as it is a form of progressive myoclonic epilepsy (PME). Other progressive myoclonic epilepsies include myoclonus epilepsy and ragged red fibers (MERRF syndrome), Lafora disease (EPM2a or EMP2b), Neuronal ceroid lipofuscinosis (NCL) and sialidosis. Progressive myoclonic epilepsies generally constitute only a small percentage of epilepsy cases seen, and ULD is the most common form. While ULD can lead to an early death, it is considered to be the least severe form of progressive myoclonic epilepsy. Treatment While there is no current cure to repair the mutated CSTB gene, several antiepileptic drugs are effective in reducing seizures and helping patients with ULD to manage the symptoms. In addition, new research is being performed to examine the effectiveness of other types of treatments. Current methods Valproic acid is the first line drug choice for reducing generalised seizures and myoclonus. Levetiracetam is also effective for both generalised seizures and myoclonus. Clonazepam and high-dose piracetam can alleviate myoclonus. Phenytoin can worsen seizures and may speed up neurodegeneration; carbamazepine, oxcarbazepine, tiagabine, vigabatrin, gabapentin and pregabalin may worsen myoclonus and myoclonic seizures. Other common medications to treat ULD include topiramate and zonisamide. If an individual with Unverricht–Lundborg disease is particularly sensitive to a certain type of stimulus, it is also beneficial to reduce the patients exposure to that stimulus in order to reduce the likelihood of seizures. Since ULD is progressive and may not get better over time, depression has been documented in many cases, so providing a strong support group of friends, family, and even other individuals with ULD is very beneficial. Prognosis For early Unverricht–Lundborg disease patients, the disease would begin to progress early and lack of effective treatment meant a quick progression. In many cases the patient would require a wheelchair for mobility, and would die at a young age.However, increased knowledge about the disease and improved treatment and medication has led to a dramatic improvement in prognosis for individuals with ULD. Antiepileptic drugs reduce the occurrence of seizures and myoclonus, which leads to a decrease in the damage caused in the brain due to seizures and the body due to falls resulting from the seizures. As a result, individuals with Unverricht–Lundborg disease are now much less likely to end up in a wheelchair, which eliminates the chance of complications involved with being a wheelchair user. All these factors have increased the outlook for patients. Due to the progressive nature of the disease, depression is prevalent, but support of family and friends as well as proper treatment can help. While early patients with ULD had a life expectancy of around 24 years, there have recently been reported cases of individuals living to near-normal ages. Epidemiology The only country that Unverricht–Lundborg disease has a reported incidence is in Finland, where it is reported to occur in 4 in 100,000 individuals. However, ULD has only become well defined recently, and it is likely still under diagnosed, so the actual incidence may be different that what is currently known. Other countries with known cases include countries in the Mediterranean region including Italy, France, Tunisia, Algeria, and Morocco, next is Czech Republic as well as the United States. History Unverricht–Lundborg disease was first known as one of two different diseases, depending on the location of the individual who had it: Baltic myoclonus or Mediterranean myoclonus. The reason for the different names was partly regional but also because the prognosis of the disease was different for individuals with each due to the way that it was treated in that region. Eventually, both were realized to be the same disease, ULD. Research directions Many studies have been performed recently to investigate the cause, mechanism, and chemical basis of Unverricht–Lundborg disease. Cystatin B Characteristics A recent study has attempted to describe the behavior of normal and mutated cystatin B as it is expressed in the body. The results show that cystatin B has a polymeric structure, and that the mutated form of cystatin B, which is present in patients with Unverricht–Lundborg disease, is likely to attract other molecules of cystatin B and form clumps of the molecule. The researchers suggest that this clotting action of the cystatin B molecules may be one of the factors that cause progression of ULD. Study of Heterozygous Mice In humans, it is generally known that unless a patient has both recessive CSTB genes (are homozygous recessive), they will not express ULD symptoms. A recent study has attempted to characterize the effects, if any, seen in mice that carry only one recessive CSTB gene (are heterozygous). The researchers analyzed normal and heterozygous mice by having them perform various tasks. The study found that heterozygous mice performed similar to normal mice when the task was started, but as the task continued or became more complex they were more likely to fail. While the results for the heterozygous mice were not remarkably different from the normal mice, they do indicate that carrying just one recessive CSTB gene may have adverse effects, at least in mice. Analysis of EEG as ULD Progresses Currently, electroencephalography (EEG) is not very effective as a diagnostic tool for Unverricht–Lundborg disease. This study instead looks to characterize the change in EEG of ULD patients as the disease progresses. The researchers studied twenty-five patients with ULD and monitored their EEG over time. The results show that certain brain waves that are present at the beginning of ULD progression and are also present in unaffected individuals, including spontaneous generalized spike or polyspike wave discharges and photoparoxysmal response, tend to decrease after 10 to 15 years. References External links Genetics Home References GeneReviews
Glucocorticoid deficiency 1	Glucocorticoid deficiency 1 is an adrenocortical failure characterized by low levels of plasma cortisol produced by the adrenal gland despite high levels of plasma ACTH. This is an inherited disorder with several different causes which define the type.FGD type 1 (FGD1 or GCCD1) is caused by mutations in the ACTH receptor (melanocortin 2 receptor; MC2R). FGD type 2 is caused by mutations in the MC2R accessory protein (MRAP). These two types account for 45% of all cases of FGD.Some cases of FGD type 3 are caused by mutations in the steroidogenic acute regulatory protein (StAR), with similarity to the nonclassic form of lipoid congenital adrenal hyperplasia. In this case, a general impairment in not just adrenal steroid production, but gonadal steroid production can affect sexual development and fertility. The causes of other cases of FGD type 3 not due to StAR are currently unknown. References External links GCCD1 Online Mendelian Inheritance in Man (OMIM): 202200 GCCD2 Online Mendelian Inheritance in Man (OMIM): 607398 GCCD3 Online Mendelian Inheritance in Man (OMIM): 609197
High-functioning autism	High-functioning autism (HFA) is an autism classification where a person exhibits no intellectual disability, but may exhibit deficits in communication, emotion recognition and expression, and social interaction. HFA is not included in either the American Psychological Associations DSM-5 or the World Health Organizations ICD-10, neither of which subdivides autism based on intellectual capabilities. Characterization High-functioning autism is characterized by features similar to those of Asperger syndrome. The defining characteristic recognized by psychologists is a significant delay in the development of early speech and language skills, before the age of three years. The diagnostic criteria of Asperger syndrome exclude a general language delay.Further differences in features of people with high-functioning autism from those with Asperger syndrome include the following: Lower verbal reasoning ability Better visual/spatial skills (higher performance IQ) Less deviating locomotion (e.g. clumsiness) Problems functioning independently Curiosity and interest for many different things Not as good at empathizing with other people Male to female ratio (4:1) much smallerAs of 2013, Asperger Syndrome and High-functioning autism are no longer terms used by the American Psychological Association, and have instead both been merged into autism spectrum disorder (ASD). As of 2021, the World Health Organization also retired the terms and merged them into autism spectrum disorder. Comorbidities Individuals with autism spectrum disorders, including high-functioning autism, risk developing symptoms of anxiety. While anxiety is one of the most commonly occurring mental health symptoms, children and adolescents with high functioning autism are at an even greater risk of developing symptoms.There are other comorbidities, the presence of one or more disorders in addition to the primary disorder, associated with high-functioning autism. Some of these include bipolar disorder and obsessive–compulsive disorder (OCD). In particular the link between HFA and OCD, has been studied; both have abnormalities associated with serotonin.Observable comorbidities associated with HFA include ADHD and Tourette syndrome. HFA does not cause, nor include, intellectual disabilities. This characteristic distinguishes HFA from low-functioning autism; between 40 and 55% of individuals with autism also have an intellectual disability. Behavior An association between HFA and criminal behavior is not completely characterized. Several studies have shown that the features associated with HFA may increase the probability of engaging in criminal behavior. While there is still a great deal of research that needs to be done in this area, recent studies on the correlation between HFA and criminal actions suggest that there is a need to understand the attributes of HFA that may lead to violent behavior. There have been several case studies that link the lack of empathy and social naïveté associated with HFA to criminal actions.There is still a need for more research on the link between HFA and crimes, because many other studies point out that most people with ASD are more likely to be victims and less likely to commit crimes than the general population. But there are also small-subgroups of people with autism that commit crimes because they lack understanding of the laws they have broken. Misunderstandings are especially common regarding autism and sex offenses, since many people with autism do not receive sex education. Cause Although little is known about the biological basis of autism, studies have revealed structural abnormalities in specific brain regions. Regions identified in the "social" brain include the amygdala, superior temporal sulcus, fusiform gyrus area and orbitofrontal cortex. Further abnormalities have been observed in the caudate nucleus, believed to be involved in restrictive behaviors, as well as in a significant increase in the amount of cortical grey matter and atypical connectivity between brain regions. Diagnosis and IQ HFA is not a recognised diagnosis by the American Psychological Association (DSM-5) or the World Health Organization (ICD-10). HFA is often, however, used in clinical settings to describe a set of symptoms related to an autism spectrum disorder whereby they exhibit standard autism indicators although have an intelligence quotient (IQ) of 70 or greater.For modern IQ tests, the raw score is transformed to a normal distribution with mean 100 and standard deviation 15. This results in approximately two-thirds of the population scoring between IQ 85 and IQ 115 and about 2.5 percent each above 130 and below 70.IQ scales are ordinally scaled. The raw score of the norming sample is usually (rank order) transformed to a normal distribution with mean 100 and standard deviation 15. While one standard deviation is 15 points, and two SDs are 30 points, and so on, this does not imply that mental ability is linearly related to IQ, such that IQ 50 would mean half the cognitive ability of IQ 100. In particular, IQ points are not percentage points. A diagnosis of intellectual disability is in part based on the results of IQ testing. Borderline intellectual functioning is the categorization of individuals of below-average cognitive ability (an IQ of 71–85), although not as low as those with an intellectual disability (70 or below). People with high IQs are found at all levels of education and occupational categories. The biggest difference occurs for low IQs with only an occasional college graduate or professional scoring below 90. Treatment While there exists no single treatment or medicine for people with autism, there exists several strategies to help lessen the symptoms and effects of the condition. Augmentative and alternative communication Augmentative and alternative communication (AAC) is used for autistic people who cannot communicate orally. People who have problems speaking may be taught to use other forms of communication, such as body language, computers, interactive devices, and pictures. The Picture Exchange Communication System (PECS) is a commonly used form of augmentative and alternative communication with children and adults who cannot communicate well orally. People are taught how to link pictures and symbols to their feelings, desires and observation, and may be able to link sentences together with the vocabulary that they form. Speech-language therapy Speech–language therapy can help those with autism who need to develop or improve communication skills. According to the organization Autism Speaks, "speech-language therapy is designed to coordinate the mechanics of speech with the meaning and social use of speech". People with autism may have issues with communication, or speaking spoken words. Speech-language pathologists (SLP) may teach someone how to communicate more effectively with others or work on starting to develop speech patterns. The SLP will create a plan that focuses on what the child needs. Occupational therapy Occupational therapy helps autistic children and adults learn everyday skills that help them with daily tasks, such as personal hygiene and movement. These skills are then integrated into their home, school, and work environments. Therapists will oftentimes help people learn to adapt their environment to their skill level. This type of therapy could help autistic people become more engaged in their environment. An occupational therapist will create a plan based on a persons needs and desires and work with them to achieve their set goals. Applied behavioral analysis (ABA) Applied behavior analysis (ABA) is considered the most effective therapy for autism spectrum disorders by the American Academy of Pediatrics. ABA focuses on teaching adaptive behaviors like social skills, play skills, or communication skills and diminishing problematic behaviors such as self-injury by creating a specialized plan that uses behavioral therapy techniques, such as positive or negative reinforcement, to encourage or discourage certain behaviors over-time. However, ABA has been strongly criticised by the autistic community, who view it as abusive and detrimental to autistic childrens growth. Sensory integration therapy Sensory integration therapy helps people with autism adapt to different kinds of sensory stimuli. Many with autism can be oversensitive to certain stimuli, such as lights or sounds, causing them to overreact. Others may not react to certain stimuli, such as someone speaking to them. Many types of therapy activities involve a form of play, such as using swings, toys and trampolines to help engage people with sensory stimuli. Therapists will create a plan that focuses on the type of stimulation the person needs integration with. Medication There are no medications specifically designed to treat autism. Medication is usually used for symptoms associated with autism, such as depression, anxiety, or behavioral problems. Medicines are usually used after other alternative forms of treatment have failed. Criticism of functioning labels Many medical professionals, autistic people, and supporters of autistic rights disagree with the categorisation of individuals into "high-functioning autism" and "low-functioning autism", stating that the "low-functioning" label causes people to put low expectations on a child and view them as lesser. Furthermore, critics of functioning labels state that an individuals functioning can fluctuate from day to day, and categories do not take this into consideration. Levels of functioning are unrelated to intellectual disability. Additionally, individuals with "medium-functioning autism" are typically left out of the discussion entirely, and due to the non-linear nature of the autistic spectrum, individuals can be high-functioning in some areas while at the same time being medium or low functioning in other areas. See also Asperger syndrome and neuroscience Autism-spectrum quotient, a self-administered test for high-functioning autism Historical figures sometimes considered autistic Low-functioning autism Nonverbal learning disorder Lorna Wing References Further reading Robison, John Elder (2007). Look Me in the Eye: My Life with Aspergers. Three Rivers Press. ISBN 9780307395986.
Pervasive developmental disorder not otherwise specified	A pervasive developmental disorder not otherwise specified (Including atypical autism) (PDD-NOS) is one of the four autistic spectrum disorders in the DSM-5 and also was one of the five disorders classified as a pervasive developmental disorder (PDD) in the DSM-IV. According to the DSM-4, PDD-NOS is a diagnosis that is used for "severe or pervasive impairment in the development of reciprocal social interaction and/or verbal and nonverbal communication skills, or when stereotyped behavior, interests, and/or activities are present, but the criteria are not met for a specific PDD" or for several other disorders. PDD-NOS includes atypical autism, because the criteria for autistic disorder are not met, for instance because of late age of onset, atypical symptomatology, or subthreshold symptomatology, or all of these. Even though PDD-NOS is considered milder than typical autism, this is not always true. While some characteristics may be milder, others may be more severe. Signs and symptoms It is common for individuals with PDD-NOS to have more intact social skills and a lower level of intellectual deficit than individuals with other PDDs. Characteristics of many individuals with PDD-NOS are: Communication difficulties (e.g., using and understanding language) Difficulty with social behavior Paranoia, a characteristic form of social anxiety, derealization, transient psychosis, and unconventional beliefs if the environment changed without further notice Uneven skill development (strengths in some areas and delays in others) Unusual play with toys and other objects Repetitive body movements or behavior patterns Preoccupation with fantasies that interfere and that are not normal to have at a certain age depending on social, cultural and religious norms. Unconventional perception of the world Maladaptive daydreaming, excessive daydreaming interfering with daily life Diagnosis PDD-NOS is an old diagnostic category. It is not included as an option for an Autism Spectrum Disorder and is not part of the DSM-5, but is included in the ICD-10, as either "atypical autism" or "pervasive developmental disorder, unspecified".The diagnosis of a pervasive developmental disorder not otherwise specified is given to individuals with difficulties in the areas of social interaction, communication, and/or stereotypic behavior patterns or interests, but who do not meet the full DSM-4 criteria for autism or another PDD. This does not necessarily mean that PDD-NOS is a milder disability than the other PDDs. It only means that individuals who receive this diagnosis do not meet the diagnostic criteria of the other PDDs, but that there is still a pervasive developmental disorder that affects the individual in the areas of communication, socialization, and behavior.As for the other pervasive developmental disorders, the diagnosis of PDD-NOS requires the involvement of a team of specialists. The individual needs to undergo a full diagnostic evaluation, including a thorough medical, social, adaptive, motor skills and communication history. Other parts of an assessment can be behavioral rating scales, direct behavioral observations, psychological assessment, educational assessment, communication assessment, and occupational assessment.Description of PDD-NOS merely as a "subthreshold" category without a more specific case definition poses methodological problems for research regarding the relatively heterogeneous group of people who receive this diagnosis. While its true that children diagnosed with PDD-NOS, as a whole, show fewer intellectual deficits and are higher-functioning than autistic children, many others who fit the criteria for PDD-NOS have some autistic features but also have intellectual deficits that are so severe that its difficult or impossible to tell whether some of the deficits come from the autism or from the severe to profound degree of intellectual disability itself. Furthermore, some others who fit the criteria for PDD-NOS come to professional attention at a later age, compared to those diagnosed with autism. Subgroups Studies suggest that persons with PDD-NOS belong to one of three very different subgroups: A high-functioning group (around 25 percent) whose symptoms more or less overlap with that of Asperger syndrome, while also not meeting the criteria for autistic disorder, but who completely differ from those with Asperger syndrome in terms of having a lag in language development and/or mild cognitive impairment. (The criteria for Asperger syndrome excludes a speech delay or a cognitive delay in early life.) Another group (around 25 percent) whose symptoms more closely resemble those of autism, but do not fully meet all its diagnostic signs and symptoms. This is because either the symptoms were recognized at a later age or because they were too young or have cognitive deficits that are too severe to properly identify all the symptoms of autism that they may have. The biggest group (around 50 percent) consists of those who meet all the diagnostic criteria for autistic disorder but whose stereotypical and repetitive behaviors are noticeably mild. Treatment There is no known cure for PDD-NOS, but there are interventions that can have a positive influence. Some of the more common therapies and services include: Visual and environmental supports, visual schedules Social stories and comic strip conversations Speech therapy Physical and occupational therapy References == External links ==
Pathergy	Pathergy is a skin condition in which a minor trauma such as a bump or bruise leads to the development of skin lesions or ulcers that may be resistant to healing. Pathergy can also lead to ulcerations at the site of surgical incisions. Pathergy is seen with both Behçets disease and pyoderma gangrenosum. A highly similar phenomenon known as the Koebner phenomenon occurs in autoimmune diseases such as psoriasis and systemic lupus erythematosus, among others. Doctors looking toward a diagnosis of Behçets disease may attempt to induce a pathergy reaction with a test known as a "skin prick test". The inflammation and ulceration that occurs as a result of pathergy in pyoderma gangrenosum often responds to systemic steroid therapy. The pathergy reaction is a unique feature of Behçets disease and, according to the International Study Group for Behcets Disease, is among the major criteria required for the diagnosis. Different positive pathergy reaction rates in BD have been reported worldwide. When BD-positive groups are studied for pathergy reaction, the pathergy-positive and pathergy-negative BD groups showed a similar male: female ratio, age at disease onset, and mean disease duration. They also exhibited similar HLA-B51 levels and a similar frequency of oral ulcerations in close family members. The mucocutaneous manifestations, systemic disease expression, and severity score were similar in patients with and without the pathergy reaction. The presence of a positive pathergy reaction is not associated with an increased risk for specific mucocutaneous or systemic manifestations of the disease, and probably does not predict a more severe disease course.It is also important to note that, while a positive pathergy reaction helps to confirm a specific Behçets disease diagnosis, a negative reaction does not invalidate a BD diagnosis, because the disease process has to be active at the time of the skin prick test to produce a pathergy reaction. Differences in positive/negative pathergy and severity of the reaction depend on disease activity, ethnicity, type of needle used for the prick test, among other factors.Pathergy test is done both orally and cutaneous. Orally, the lower lip is the site of testing. Appearance of any ulcer or papule indicates a positive pathergy reaction. Cutaneous sites are the flexor forearm. Epidemiology See also Cutaneous conditions List of cutaneous conditions == References ==
Foix–Alajouanine syndrome	Foix–Alajouanine syndrome, also called subacute ascending necrotizing myelitis, is a disease caused by an arteriovenous malformation of the spinal cord. In particular, most cases involve dural arteriovenous malformations that present in the lower thoracic or lumbar spinal cord. The condition is named after Charles Foix and Théophile Alajouanine who first described the condition in 1926. Signs and symptoms The patients can present with symptoms indicating spinal cord involvement such as (paralysis of arms and legs, numbness and loss of sensation and sphincter dysfunction), and pathological examination reveals disseminated nerve cell death in the spinal cord. Diagnosis Clinically, the patient may present with neurological symptoms such as numbness, weakness, loss of reflexes, or even sudden or progressive paralysis. The affected portion of the body will correlate to where the lesion lies within the spinal cord. The disease typically has an insidious onset, but symptoms may manifest suddenly. A thorough physical exam may lead a physician toward targeted imaging, with MRI being the most appropriate imaging modality for initial diagnosis. A spinal MRA will serve as a superior imaging technique to visualize the extent of the arteriovenous malformation within the cord and may be especially useful if surgical treatment is attempted. Treatment Surgical treatment may be attempted with endovascular embolization or ligation of the arteriovenous malformation within the spinal cord.Corticosteroids may be used acutely to help slow the progression of symptoms or they may be used chronically in a poor surgical candidate. In either case, physical therapy will be an important part of the recovery process in helping the patient regain strength and coordination. See also Vascular myelopathy References External links synd/1526 at Who Named It? synd/1755 at Who Named It?
Adrenoleukodystrophy	Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome. It is a result of fatty acid buildup caused by peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the body. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes. The long chain fatty acid buildup causes damage to the myelin sheath of the nerves of the brain, resulting in seizures and hyperactivity. Other symptoms include problems in speaking, listening, and understanding verbal instructions. Clinically, ALD presents as a heterogeneous disorder, showing several distinct phenotypes, and no clear pattern of genotype–phenotype correlation. As an X-linked disorder, ALD presents most commonly in males; however, approximately 50% of heterozygote females show some symptoms later in life. Approximately two-thirds of ALD patients will present with the childhood cerebral form of the disease, which is the most severe form. It is characterized by normal development in early childhood, followed by rapid degeneration to a vegetative state. The other forms of ALD vary in timing of onset and in clinical severity, ranging from adrenal insufficiency alone to progressive paraparesis in early adulthood. ALD is caused by mutations in ABCD1, a gene located on the X chromosome that codes for ALD, a peroxisomal membrane transporter protein. The exact mechanism of the pathogenesis of the various forms of ALD is not known. Biochemically, individuals with ALD show very high levels of unbranched, saturated, very long chain fatty acids, particularly cerotic acid (26:0). The level of cerotic acid in plasma does not correlate with clinical presentation. Treatment options for ALD are limited. For the childhood cerebral form, stem cell transplant and gene therapy are options if the disease is detected early in the clinical course. Adrenal insufficiency in ALD patients can be successfully treated. ALD is the most common peroxisomal inborn error of metabolism, with an incidence estimated between 1:18,000 and 1:50,000. It does not have a significantly higher incidence in any specific ethnic group. Signs and symptoms ALD can present in different ways. The different presentations are complicated by the pattern of X-linked recessive inheritance. There have been seven phenotypes described in males with ABCD1 mutations and five in females. Initial symptoms in boys affected with the childhood cerebral form of ALD include emotional instability, hyperactivity and disruptive behavior at school. Older patients affected with the cerebral form will present with similar symptoms. Untreated, cerebral ALD is characterized by progressive demyelination leading to a vegetative state and death. Adult males with an adrenomyeloneuropathy presentation typically present initially with muscle stiffness, paraparesis and sexual dysfunction. All patients with clinically recognized ALD phenotypes are at risk for adrenal insufficiency. There is no reliable way to predict which form of the disease an affected individual will develop, with multiple phenotypes being demonstrated within families. Onset of adrenal insufficiency is often the first symptom, appearing as early as two years of age. Male adrenoleukodystrophy phenotypes Female adrenoleukodystrophy phenotypes Genetics ALD is caused by mutations in ABCD1, located at Xq28 and demonstrates X-linked recessive inheritance. The gene ABCD1 encodes a peroxisomal membrane transporter which is responsible for transporting very long chain fatty acid substrate into the peroxisomes for degradation. Mutations in this gene that interfere with this process cause this syndrome.Males with an ABCD1 mutation are hemizygous, as they only have a single X chromosome. Female carriers will typically avoid the most severe manifestations of the disease, but often become symptomatic later in life. Although the detection of an ABCD1 mutation identifies an individual who is affected with a form of ALD, there is no genotype–phenotype correlation. Within a family, there will often be several different phenotypes, despite the presence of the same causative mutation. In one case, a family with six affected members displayed five different phenotypes. There are no common mutations that cause ALD, most are private or familial. Almost 600 different mutations have been identified, approximately half are missense mutations, one quarter are frameshifts, with in-frame deletions and splicing defects making up the remainder. The incidence of new mutations in ALD (those occurring spontaneously, rather than being inherited from a carrier parent) is estimated at 4.1%, with the possibility that these are due to germline mosaicism. Pathogenesis The exact cause for the varied collection of symptoms found in the different ALD phenotypes is not clear. The white matter of the brain, the Leydig cells of the testes and the adrenal cortex are the most severely affected systems. The excess VLCFA can be detected in almost all tissues of the body, despite the localization of symptoms. The lack of Coenzyme A does not permit the disintegration of the VLCFA, accumulating the same in the white matter, adrenal glands, and the testes more specifically in the Leydig cells not allowing the proper function of these organs. Successful treatment of the demyelination process that affects the brain with either stem cell transplant or gene therapy does not immediately normalize the VLCFA levels in body tissues. The levels of VLCFA can be normalized by treatment with Lorenzos oil, but this does not alter the progression of the disease. It is unclear whether the accumulation of VLCFA is associated with the pathogenesis of the disease in a specific way, or if it is a biochemical phenotype, useful for identification. Diagnosis The clinical presentation of ALD can vary greatly, making diagnosis difficult. With the variety of phenotypes, clinical suspicion of ALD can result from a variety of different presentations. Symptoms vary based on the disease phenotype, and even within families or between twins. When ALD is suspected based on clinical symptoms, the initial testing usually includes plasma very long chain fatty acid (VLCFA) determination using gas chromatography-mass spectrometry. The concentration of unsaturated VLCFA, particularly 26 carbon chains is significantly elevated in males with ALD, even prior to the development of other symptoms. Confirmation of ALD after positive plasma VLCFA determination usually involves molecular genetic analysis of ABCD1. In females, where plasma VLCFA measurement is not always conclusive (some female carriers will have normal VLCFA in plasma), molecular analysis is preferred, particularly in cases where the mutation in the family is known. Although the clinical phenotype is highly variable among affected males, the elevations of VLCFA are present in all males with an ABCD1 mutation.Because the characteristic elevations associated with ALD are present at birth, well before any symptoms are apparent, there have been methods developed in the interests of including it in newborn screening programs. One of the difficulties with ALD as a disease included in universal newborn screening is the difficulty in predicting the eventual phenotype that an individual will express. The accepted treatment for affected boys presenting with the cerebral childhood form of the disease is a bone marrow transplant, a procedure which carries significant risks. However, because most affected males will demonstrate adrenal insufficiency, early discovery and treatment of this symptom could potentially prevent complications and allow these patients to be monitored for other treatment in the future, depending on the progression of their disease.The Loes score is a rating of the severity of abnormalities in the brain found on MRI. It ranges from 0 to 34, based on a point system derived from the location and extent of disease and the presence of atrophy in the brain, either localized to specific points or generally throughout the brain. A Loes score of 0.5 or less is classified as normal, while a Loes score of 14 or greater is considered severe. It was developed by neuroradiologist Daniel J. Loes MD and is an important tool in assessing disease progression and the effectiveness of therapy. Treatments Dietary therapy Initial attempts at dietary therapy in ALD involved restricting the intake of very-long chain fatty acids (VLCFA). Dietary intake is not the only source for VLCFA in the body, as they are also synthesized endogenously. This dietary restriction did not impact the levels of VLCFA in plasma and other body tissues. After the realization that endogenous synthesis was an important contribution to VLCFA in the body, efforts at dietary therapy shifted to inhibiting these synthetic pathways in the body. The parents of Lorenzo Odone, a boy with ALD, spearheaded efforts to develop a dietary treatment to slow the progression of the disease. They developed a mixture of unsaturated fatty acids (glycerol trioleate and glyceryl trierucate in a 4:1 ratio), known as Lorenzos oil that inhibits elongation of saturated fatty acids in the body. Supplementation with Lorenzos oil has been found to normalize the VLCFA concentrations in the body, although its effectiveness at treating the cerebral manifestations of the disease is still controversial and unproven. Trials with Lorenzos oil have shown that it does not stop the neurological degradation in symptomatic patients, nor does it improve adrenal function, but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of oleic and erucic acids in addition to VLCFA restriction. Lorenzos oil A solution of 4 parts glycerol trioleate and 1 part glycerol trierucate, which are the triacylglycerol forms of oleic acid and erucic acid, has been tested for ALD. Results are mixed, showing possible benefit for asymptomatic patients in conjunction with dietary therapy, but little or no benefit for those with symptomatic ALD. Transplant While dietary therapy has been shown to be effective to normalize the very-long chain fatty acid concentrations in the plasma of individuals with ALD, allogeneic hematopoietic stem cell transplants is the only treatment that can stop demyelination that is the hallmark of the cerebral forms of the disease. In order to be effective, the transplant must be done at an early stage of the disease; if the demyelination has progressed, transplant can worsen the outcome, and increase the rate of decline. While transplants have been shown to be effective at halting the demyelination process in those presenting with the childhood cerebral form of ALD, follow-up of these patients has shown that it does not improve adrenal function. Gene therapy For patients where an appropriate match for a transplant cannot be found, there have been investigations into the use of gene therapy. Appropriate vectors are selected and modified to express wild type ABCD1, which is then transplanted into the patients using a similar procedure as for a bone marrow or stem cell transplant. Gene therapy has only been tried on a small number of patients, mainly in France. These patients were only considered for gene therapy after there was no HLA match for a traditional transplant. In two reported cases, the gene therapy was successful, with a resolution of the demyelination process up to two years after the procedure. Although the gene therapy was successful in resolving the neurological symptoms, plasma VLCFA levels remained elevated.Elivaldogene autotemcel is pending authorization by the European Commission as of May 2021. Adrenal insufficiency Treatment of the adrenal insufficiency that can accompany any of the common male phenotypes of ALD does not resolve any of the neurological symptoms. Hormone replacement is standard for ALD patients demonstrating adrenal insufficiency. Adrenal insufficiency does not resolve with successful transplant; most patients still require hormone replacement. Epidemiology ALD has not been shown to have an increased incidence in any specific country or ethnic group. In the United States, the incidence of affected males is estimated at 1:21,000. Overall incidence of hemizygous males and carrier females is estimated at 1:16,800. The reported incidence in France is estimated at 1:22,000. Asymptomology There are documented asymptomatic males who present no ALD symptoms well into their 60s and 70s. Its not understood how they can have an ABCD1 gene variant and possess elevated VLCFAs and not exhibit either Cerebral ALD, Adrenal Insufficiency, or Adrenomyeloneuropathy symptoms. Daughters of asymptomatic males become obligate carriers, who may themselves be asymptomatic and who can pass the variant onto their children, which then silently perpetuates ALD. Sons of asymptomatic males only receive their fathers Y chromosome and therefore cant inherit ALD. References External links adrenoleukodystrophy at NINDS Adrenoleukodystrophy at National Center for Biotechnology Information
Juvenile primary lateral sclerosis	Juvenile primary lateral sclerosis, also known as primary lateral sclerosis (PLSJ), is a very rare genetic disorder, with a small number of reported cases, characterized by progressive weakness and stiffness of muscles in the arms, legs, and face. The disorder damages motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement. Symptoms and signs Symptoms of JPLS begin in early childhood and progress over a period of 15 to 20 years. Early symptoms include clumsiness, muscle spasms, weakness and stiffness in the legs, and difficulty with balance. As symptoms progress, they become more serious and include weakness and stiffness in the arms and hands, slurred speech, drooling, difficulty swallowing, and an inability to walk. Genetics juvenile primary lateral sclerosis is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, parents of affected individuals each carry one copy of the altered gene, but do not show any signs or symptoms.Mutations in the ALS2 gene, found on chromosome 2, are responsible for causing juvenile primary lateral sclerosis. The ALS2 gene provides instructions for making a protein called alsin. Alsin is abundant in motor neurons, but its function is not fully understood. Mutations in the ALS2 gene in this disorder disrupt the instructions for producing alsin. As a result, alsin is unstable and decays rapidly, or it is disabled and cannot function properly. It is currently unknown how the loss of functional alsin protein causes the death of motor neurons and the symptoms of juvenile primary lateral sclerosis. Diagnosis Treatment Treatment of ALS2-related disorders includes physical therapy and occupational therapy to promote mobility and independence and use of computer technologies and devices to facilitate writing and voice communication. See also List of genetic disorders References == External links ==
Hangnail	A hangnail is a tiny, torn piece of skin next to a fingernail or toenail, related to ingrown nails. The hangnails other scientific names are: eponychium or paronychium. Hangnails are typically caused by having dry skin, or by trauma to the fingers, such as paper cuts or nail biting. Presentation Complications Hangnails can become infected and cause paronychia, a type of skin infection that occurs around the nails. Treatments for paronychia vary with severity, but may include soaking in hot salty water, the use of oral antibiotic medication, or clinical lancing. Paronychia itself rarely results in further complications but can lead to abscess, permanent changes to the shape of the nail, or the spread of infection. Hangnails may also hurt if pulled, as they may remain firmly attached to living skin. Prevention Daily use of hand lotion (or hand cream) or cuticle oil may help prevent the formation of hangnails. Treatment For home treatment, the American Academy of Dermatology recommends washing the hands, clipping the loose piece of skin with a clean nail clipper or nail scissors, and applying over-the-counter antibiotic ointment if the area appears inflamed. Persistent hangnails should be evaluated by a physician. == References ==
Langerhans cell histiocytosis	Langerhans cell histiocytosis (LCH) is an abnormal clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. Symptoms range from isolated bone lesions to multisystem disease. LCH is part of a group of syndromes called histiocytoses, which are characterized by an abnormal proliferation of histiocytes (an archaic term for activated dendritic cells and macrophages). These diseases are related to other forms of abnormal proliferation of white blood cells, such as leukemias and lymphomas.The disease has gone by several names, including Hand–Schüller–Christian disease, Abt-Letterer-Siwe disease, Hashimoto-Pritzker disease (a very rare self-limiting variant seen at birth) and histiocytosis X, until it was renamed in 1985 by the Histiocyte Society. Classification The disease spectrum results from clonal accumulation and proliferation of cells resembling the epidermal dendritic cells called Langerhans cells, sometimes called dendritic cell histiocytosis. These cells in combination with lymphocytes, eosinophils, and normal histiocytes form typical LCH lesions that can be found in almost any organ. A similar set of diseases has been described in canine histiocytic diseases.LCH is clinically divided into three groups: unifocal, multifocal unisystem, and multifocal multisystem. Unifocal Unifocal LCH, also called eosinophilic granuloma (an older term which is now known to be a misnomer), is a disease characterized by an expanding proliferation of Langerhans cells in one organ, where they cause damage called lesions. It typically has no extraskeletal involvement, but rarely a lesion can be found in the skin, lungs, or stomach. It can appear as a single lesion in an organ, up to a large quantity of lesions in one organ. When multiple lesions are scattered throughout an organ, it can be called a multifocal unisystem variety. When found in the lungs, it should be distinguished from Pulmonary Langerhans cell hystiocytosis—a special category of disease most commonly seen in adult smokers. When found in the skin it is called cutaneous single system Langerhans cell LCH. This version can heal without therapy in some rare cases. This primary bone involvement helps to differentiate eosinophilic granuloma from other forms of Langerhans Cell Histiocytosis (Letterer-Siwe or Hand-Schüller-Christian variant). Multifocal unisystem Seen mostly in children, multifocal unisystem LCH is characterized by fever, bone lesions and diffuse eruptions, usually on the scalp and in the ear canals. 50% of cases involve the pituitary stalk, often leading to diabetes insipidus. The triad of diabetes insipidus, exophthalmos, and lytic bone lesions is known as the Hand-Schüller-Christian triad. Peak onset is 2–10 years of age. Multifocal multisystem Multifocal multisystem LCH, also called Letterer-Siwe disease, is an often rapidly progressing disease in which Langerhans Cell cells proliferate in many tissues. It is mostly seen in children under age 2, and the prognosis is poor: even with aggressive chemotherapy, the five-year survival is only 50%. Pulmonary Langerhans cell histiocytosis (PLCH) Pulmonary Langerhans cell histiocytosis (PLCH) is a unique form of LCH in that it occurs almost exclusively in cigarette smokers. It is now considered a form of smoking-related interstitial lung disease. PLCH develops when an abundance of monoclonal CD1a-positive Langerhans (immature histiocytes) proliferate the bronchioles and alveolar interstitium, and this flood of histiocytes recruits granulocytes like eosinophils and neutrophils and agranulocytes like lymphocytes further destroying bronchioles and the interstitial alveolar space that can cause damage to the lungs. It is hypothesized that bronchiolar destruction in PLCH is first attributed to the special state of Langerhans cells that induce cytotoxic T-cell responses, and this is further supported by research that has shown an abundance of T-cells in early PLCH lesions that are CD4+ and present early activation markers. Some affected people recover completely after they stop smoking, but others develop long-term complications such as pulmonary fibrosis and pulmonary hypertension. Signs and symptoms LCH provokes a non-specific inflammatory response, which includes fever, lethargy, and weight loss. Organ involvement can also cause more specific symptoms. Bone: The most-frequently seen symptom in both unifocal and multifocal disease is painful bone swelling. The skull is most frequently affected, followed by the long bones of the upper extremities and flat bones. Infiltration in hands and feet is unusual. Osteolytic lesions can lead to pathological fractures. Skin: Commonly seen are a rash which varies from scaly erythematous lesions to red papules pronounced in intertriginous areas. Up to 80% of LCH patients have extensive eruptions on the scalp. Bone marrow: Pancytopenia with superadded infection usually implies a poor prognosis. Anemia can be due to a number of factors and does not necessarily imply bone marrow infiltration. Lymph node: Enlargement of the liver in 20%, spleen in 30% and lymph nodes in 50% of Histiocytosis cases. Endocrine glands: Hypothalamic pituitary axis commonly involved. Diabetes insipidus is most common. Anterior pituitary hormone deficiency is usually permanent. Lungs: some patients are asymptomatic, diagnosed incidentally because of lung nodules on radiographs; others experience chronic cough and shortness of breath. Less frequently gastrointestinal tract, central nervous system, and oral cavity. Pathophysiology The pathogenesis of Langerhans cell histiocytosis (LCH) is a matter of debate. There are ongoing investigations to determine whether LCH is a reactive (non-cancerous) or neoplastic (cancerous) process. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as cytokine storm) in the lesional tissue, favorable prognosis and relatively good survival rate in patients without organ dysfunction or risk organ involvement.On the other hand, the infiltration of organs by monoclonal population of pathologic cells, and the successful treatment of subset of disseminated disease using chemotherapeutic regimens are all consistent with a neoplastic process. In addition, a demonstration, using X chromosome–linked DNA probes, of LCH as a monoclonal proliferation provided additional support for the neoplastic origin of this disease. While clonality is an important attribute of cancer, its presence does not prove that a proliferative process is neoplastic. Recurrent cytogenetic or genomic abnormalities would also be required to demonstrate convincingly that LCH is a malignancy.An activating somatic mutation of a proto-oncogene in the Raf family, the BRAF gene, was detected in 35 of 61 (57%) LCH biopsy samples with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%). This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding. Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder. Diagnosis Diagnosis is confirmed histologically by tissue biopsy. Hematoxylin-eosin stain of biopsy slide will show features of Langerhans Cell e.g. distinct cell margin, pink granular cytoplasm. Presence of Birbeck granules on electron microscopy and immuno-cytochemical features e. g. CD1 positivity are more specific. Initially routine blood tests e.g. full blood count, liver function test, U&Es, bone profile are done to determine disease extent and rule out other causes.Imaging may be evident in chest X-rays with micronodular and reticular changes of the lungs with cyst formation in advanced cases. MRI and High-resolution CT may show small, cavitated nodules with thin-walled cysts. MRI scan of the brain can show three groups of lesions such as tumourous/granulomatous lesions, nontumourous/granulomatous lesions, and atrophy. Tumourous lesions are usually found in the hypothalamic-pituitary axis with space-occupying lesions with or without calcifications. In non-tumourous lesions, there is a symmetrical hyperintense T2 signal with hypointense or hyperintense T1 signal extending from grey matter into the white matter. In the basal ganglia, MRI shows a hyperintense T1 signal in the globus pallidus.Assessment of endocrine function and bonemarrow biopsy are also performed when indicated. S-100 protein is expressed in a cytoplasmic pattern peanut agglutinin (PNA) is expressed on the cell surface and perinuclearly major histocompatibility (MHC) class II is expressed (because histiocytes are macrophages) CD1a langerin (CD207), a Langerhans Cell–restricted protein that induces the formation of Birbeck granules and is constitutively associated with them, is a highly specific marker. Treatment Guidelines for management of patients up to 18 years with Langerhans cell histiocytosis have been suggested. Treatment is guided by extent of disease. Solitary bone lesion may be amenable through excision or limited radiation, dosage of 5-10 Gy for children, 24-30 Gy for adults. However systemic diseases often require chemotherapy. Use of systemic steroid is common, singly or adjunct to chemotherapy. Local steroid cream is applied to skin lesions. Endocrine deficiency often require lifelong supplement e.g. desmopressin for diabetes insipidus which can be applied as nasal drop. Chemotherapeutic agents such as alkylating agents, antimetabolites, vinca alkaloids either singly or in combination can lead to complete remission in diffuse disease. Prognosis Excellent for single-focus disease. With multi-focal disease 60% have a chronic course, 30% achieve remission and mortality is up to 10%. Prevalence LCH usually affects children between 1 and 15 years old, with a peak incidence between 5 and 10 years of age. Among children under the age of 10, yearly incidence is thought to be 1 in 200,000; and in adults even rarer, in about 1 in 560,000. It has been reported in elderly but is vanishingly rare. It is most prevalent in Caucasians, and affects males twice as often as females. In other populations too the prevalence in males is slightly more than in females.LCH is usually a sporadic and non-hereditary condition but familial clustering has been noted in limited number of cases. Hashimoto-Pritzker disease is a congenital self-healing variant of Hand-Schüller-Christian disease. Culture In the 10th episode of season 3 of House entitled "Merry Little Christmas", the primary patient is a girl with dwarfism who has a variety of symptoms, who is ultimately diagnosed with Langerhans cell histiocytosis. Also in the 5th episode, season 1 of "The Good Doctor", Dr. Murphy tries to diagnose Langerhans cell histiocytosis in a boy with a previously diagnosed osteosarcoma.In an episode of Mystery Diagnosis, "The Woman Who Saw Pink", Brooke Rohrer has experiencing symptoms of abdominal pain, was diagnosed with Langerhans cell histiocytosis. Nomenclature Langerhans cell histiocytosis is occasionally misspelled as "Langerhan" or "Langerhans" cell histiocytosis, even in authoritative textbooks. The name, however, originates back to its discoverer, Paul Langerhans. References == External links ==
Snatiation	Snatiation is a term coined to refer to the a medical condition originally termed "stomach sneeze reflex", which is characterized by uncontrollable bursts of sneezing brought on by fullness of the stomach, typically immediately after a large meal. The type of food consumed does not appear to affect its occurrence. It is reported, based on a preliminary study, to be passed along genetically as an autosomal dominant trait, as first described by Ahmad Teebi and Qasem Al-Saleh in 1989. The term "snatiation", coined shortly thereafter in a humorous letter to the Journal of Medical Genetics by Judith G. Hall, is a portmanteau of the words sneeze and satiation. Similar in nature to this condition is gustatory rhinitis, which involves rhinorrhea induced by certain foods, such as spicy foods. See also Photic sneeze reflex References External links Online Mendelian Inheritance in Man (OMIM): Gastric Sneezing - 137130
Albinism	Albinism is the congenital absence of melanin in an animal or plant resulting in white hair, feathers, scales and skin and pink or blue eyes. Individuals with the condition are referred to as albino. Varied use and interpretation of the terms mean that written reports of albinistic animals can be difficult to verify. Albinism can reduce the survivability of an animal; for example, it has been suggested that albino alligators have an average survival span of only 24 hours due to the lack of protection from UV radiation and their lack of camouflage to avoid predators. It is a common misconception that all albino animals have characteristic pink or red eyes (resulting from the lack of pigment in the iris allowing the blood vessels of the retina to be visible), however this is not the case for some forms of albinism. Familiar albino animals include in-bred strains of laboratory animals (rats, mice and rabbits), but populations of naturally occurring albino animals exist in the wild, e.g. Mexican cave tetra. Albinism is a well-recognized phenomenon in molluscs, both in the shell and in the soft parts. It has been claimed by some, e.g. that albinism can occur for a number of reasons aside from inheritance, including genetic mutations, diet, living conditions, age, disease, or injury. However, this is contrary to definitions where the condition is inherited. Oculocutaneous albinism (OCA) is a clearly defined set of seven types of genetic mutations which reduce or completely prevent the synthesis of eumelanin or pheomelanin, resulting in reduced pigmentation. Type I oculocutaneous albinism (OCA1a) is the form most commonly recognised as albino as this results in a complete absence of melanin in the skin, hair/fur/feathers, and pink pupils, however this has led many to assume that all albinos are pure white with pink pupils, which is not the case.In plants, albinism is characterised by partial or complete loss of chlorophyll pigments and incomplete differentiation of chloroplast membranes. Albinism in plants interferes with photosynthesis, which can reduce survivability. Some plant variations may have white flowers or other parts. However, these plants are not totally devoid of chlorophyll. Terms associated with this phenomenon are "hypochromia" and "albiflora". Biological colouration Biological pigments are substances produced by living organisms that have a colour resulting from selective colour absorption. What is perceived as a plant or animals "colour" is the wavelengths of light that are not absorbed by the pigment, but instead are reflected. Biological pigments include plant pigments and flower pigments. Animal colouration Animals can appear coloured due to two mechanisms, pigments and structural colours. Animals may have both biological pigments and structural colours, for example, some butterflies with white wings. Pigments Many animal body-parts, such as skin, eyes, feathers, fur, hair, scales and cuticles, contain pigments in specialized cells called chromatophores. These cells are found in a wide range of animals including amphibians, fish, reptiles, crustaceans and cephalopods. Mammals and birds, in contrast, have a class of cells called melanocytes for colouration. The term chromatophore can also refer to coloured, membrane-associated vesicles found in some forms of photosynthetic bacteria. Chromatophores are largely responsible for generating skin and eye colour in poikilothermic animals and are generated in the neural crest during embryonic development. Mature chromatophores are grouped into subclasses based on their colour under white light: xanthophores (yellow): contain yellow pigments in the forms of carotenoids erythrophores (red): contain reddish pigments such as carotenoids and pteridine melanophores (black/brown): contain black and brown pigments such as the melanins cyanophores (blue): limited taxonomic range but found in some fish and amphibians Structural colours Animals can also appear coloured due to structural colour, the result of coherent scattering perceived as iridescence. The structures themselves are colourless. Light typically passes through multiple layers and is reflected more than once. The multiple reflections compound one another and intensify the colours. Structural colour differs according to the observers position whereas pigments appear the same regardless of the angle-of-view. Animals that show iridescence include mother of pearl seashells, fish, and peacocks. These are just a few examples of animals with this quality, but it is most pronounced in the butterfly family. iridophores (reflective/iridescent): sometimes called "guanophores", reflect light using plates of crystalline chemochromes made from guanine leucophores (reflective white): found in some fish, utilize crystalline purines (often guanine) to produce a reflective, shiny, white colour. Plant colouration The primary function of pigments in plants is photosynthesis, which uses the green pigment chlorophyll along with several red and yellow pigments including porphyrins, carotenoids, anthocyanins and betalains. Definition Definitions of albinism vary and are inconsistent. While they are clear and precise for humans and other mammals, this is because the majority of mammals have only one pigment, melanin. Many animals have pigments other than melanin, and some also have structural colours. Some definitions of albinism, whilst taking most taxa into account, ignore others. So, "a person or animal with very pale skin, white hair or fur, and pink eyes caused by a medical condition that they were born with" and "a person or animal with white skin and hair and pink eyes" do not include feathers, scales or cuticles of birds, fish and invertebrates, nor do they include plants. Some definitions are too broad to be of much use, e.g. "an animal or plant with a marked deficiency in pigmentation".Other definitions of albinism encompass most of the major animal taxa, but ignore the several other pigments that non-mammalian animals have and also structural colouration. For example, "Absence of the pigment melanin in the eyes, skin, hair, scales, or feathers." refers only to the pigment melanin. Because of the various uses of different terms applied to colouration, some authors have indicated that the colour of the eyes is the defining characteristic of albinism, e.g. "This leads to a good diagnostic feature with which to distinguish leucistic and albino individuals – the colour of the eye." However, there are multiple forms of albinism – currently seven types recognised for humans – most of which do not result in red or pink pupils.The term "partial albino" is sometimes used in the literature, however, it has been stated that "A common misnomer is partial albino – this is not possible since albinism affects the whole plumage of a bird, not just part" and the definition of albinism precludes the possibility of "partial albinism" in which a mostly white bird shows some form of melanin pigmentation. "It is simply impossible, just like being partially pregnant ". Conditions that are commonly termed "partial albino" include neural crest disorders such as piebaldism, Waardenburg syndrome, or other depigmentation conditions such as vitiligo. These conditions result from fundamentally different causes to the seven types of oculocutaneous albinism that have been identified in humans (and confirmed in some other animals) and the use of the term "partial albino" is therefore misleading.One definition states that "albinism, (from the Latin albus, meaning "white"), hereditary condition characterized by the absence of pigment in the eyes, skin, hair, scales, or feathers", however, this does not encompass invertebrates, nor does it include plants. Furthermore, it could be interpreted that "...absence of pigment..." does not include an absence of structural colours. The lack of clarity about the term is furthered when the name of an animal includes the term "albino" although the animals (clearly) do not have the condition. For example, the albino gaur has this name because it is ash-grey whereas other gaur are almost black. A clear definition appears to be – "Congenital absence of any pigmentation or colouration in a person, animal, or plant, resulting in white hair and pink eyes in mammals." Whilst this does not state specifically that non-mammalian albino animals (or plants) are white, this can be inferred from "...absence of any pigmentation or colouration..." Due to the varied use and interpretation of the term "albino", written reports of albinistic organisms can often not be verified. Mechanism and frequency Melanin is an organic pigment that produces most of the colour seen in mammals. Depending on how it is created, melanin comes in two colour ranges, eumelanin (producing dark browns and blacks) and pheomelanin (producing light reddish tans and blondes). The dark and light melanins have their influence either alone or in conjunction, making either plain or multi-coloured coats. Sometimes, in a condition called agouti, they make multi-coloured individual hairs. The production of melanin occurs in melanocytes in a complex process involving the enzyme tyrosinase. Mammals have a gene that codes for the presence of tyrosinase in cells – called the TYR gene. If this gene is altered or damaged, melanin cannot be reliably produced and the mammal becomes an albino. Besides the TYR gene, several other genes can cause albinism. This is because other hormones and proteins are involved in melanin production, the presence of which is genetically determined. In mice, a total of 100 genes are known to affect albinism.All the genetic traits for albinism are recessive traits. This means that their influence is hidden when paired with stronger traits. For the recessive albino trait to be expressed in a mammal, the offspring must inherit a recessive gene from both parents.Albinism occurs throughout the animal kingdom. The condition is most commonly seen in birds, reptiles and amphibians, but more rarely seen in mammals and other taxa. It is often difficult to explain occasional occurrences, especially when only one documented incidence has occurred, such as only one albino gorilla and one albino koala. In mammals, albinism occurs once in every 10,000 births, but in birds, the rate is once in every 1,764 births.Some species, such as white peacocks, swans and geese, are not believed to be true albinos, as they do not have red eyes, rather, their colouration is suggested to be the expression of a white fur or feather gene, not a lack of melanin. Consequences Melanin has several functions in most mammals and other animals; these are disrupted by albinism. Abnormal eye development and appearance Melanin functions in the normal development of various parts of the eye, including the iris, retina, eye muscles, and optic nerve. The absence of melanin results in abnormal development of eyes and leads to problems with focusing, and depth perception. The eyes of albino animals appear red because the colour of the red blood cells in the retina can be seen through the iris, which has no pigment to obscure this. Some albino animals may have pale-blue eyes due to other colour generating processes. Albino vertebrates exposed to intense light typically lose photoreceptors due to apoptosis. In all albino mammals studied, the centre of the retina is under-developed and there is a deficit of rod cells; the central ganglion cell density is approximately 25% below normal (except for the gray squirrel). In nearly all mammals, the overwhelming majority of photoreceptors are rods rather than cones. Albinism specifically affects the rod cells, but the number and distribution of the cones is unaffected. In contrast, the retinas of birds are cone rich meaning that the vision of albino birds is affected less than albino mammals. Reduced protection from sunlight in albino creatures Melanin protects the skin from ultra-violet radiation in sunlight. Melanosomes block harmful electromagnetic radiation from the sun while allowing beneficial frequencies to enter the body. This means some animals may die from UV radiation due to a lack of protection. Albino humans must use an excessive amount of sunscreen, even if the sun is hidden behind the clouds. Survival disadvantages Many animals with albinism lack their protective camouflage and are therefore less able to conceal themselves from their predators or prey: The survival rate of animals with albinism in the wild can be low, however, it has been stated that in studies where animals had many places to hide, predators captured albino and normally coloured animals at the same rate. Furthermore, albino animals may be excluded from families or other groups, or rejected as mates.The novelty of albino animals has occasionally led to their protection by groups such as the Albino Squirrel Preservation Society. They have also been protected in studies on their ecology, sociology and behaviour. Reduced viability Studies on medaka fish in the laboratory, i.e. with no predators, sufficient food supply, controlled temperatures, etc., found that albinos had considerably reduced viability; from 800 albino embryos, only 29 survived to full adulthood. Early studies on fish led some researchers to describe albinism as a "semi-lethal mutation". Hearing disorders Pigmentation disorders such as albinism are occasionally associated with hearing impairments in mice, rats, guinea pigs and cats. In mammals Artificially selected Intentionally bred albinistic strains of some animal species are commonly used as model organisms in biomedical research and also as pets. Examples include the BALB/c mouse and Wistar and Sprague Dawley rat strains, laboratory rabbits and ferrets. Albino axolotl (an amphibian) are also used widely in the laboratory as their transparent skin allows observation of the underlying tissues during limb regeneration. Some researchers have argued that albino animals are not always the best choice for scientific studies due to the consequences of albinism (e.g. hearing and visual impairments).Many individual albino mammals are in captivity and were caught while young. It is doubtful whether these individuals would have survived to become adults without the protection and care they receive in captivity. Naturally occurring It has been claimed that "Squirrels are the only known albino mammal to survive successfully in the wild". The retina of the squirrel (Sciurus carolinensis) is unusual for mammals as it is rich in cones. Central cell densities are less than 5% lower in albino squirrels than in pigmented individuals. This relatively minor disruption to vision is thought to assist in the survivability of albino squirrels in the wild. This is supported by observations that the behaviour of albinos in the wild, e.g. leaping from branch to branch, is similar to pigmented squirrels.A 2012 survey of the literature reported that in India, there were several records of albino mammals including the tiger, lesser mouse-tailed bat, chital, common palm civet, northern palm squirrel, five-striped palm squirrel and wild boar.Albino macaques have been reported in several occasions including a toque macaque (M. sinica), rhesus macaque (M. mulatta), and bonnet macaque (M. radiata).Albinism was observed in jungle cats (Felis chaus) and jackals (Canis aureus) along the coastline of the southern Western Ghats (Kerala and Kanyakumari coast, India). Albinism was observed in jungle cats from the Amaravila area of Trivandrum district in the Kerala State. Albinism in jackals was observed from the Polooni area in Malappuram district and Chaliyam area of Calicut district (Kerala). As albinism is observed in those areas where the density of these mammals is comparatively low, it is concluded that continuous inbreeding could be the reason for expression of albinism.A study on albinistic prairie voles (Microtus ochrogaster) found that albinism in this species conferred an advantage for the males compared to the wild-type; albino males had higher mount frequencies than wild-type males. In addition, the albinos had greater differential fertilizing capacity.Albinism can also occur in marsupials and monotremes as well such as echidnas, kangaroos, koalas, possums, wallabies and wombats as well. Marine mammals The costs of albinism for marine mammals may include reduced heat absorption in colder waters, poor camouflage from predators, increased sensitivity to sunlight, and impaired visual communication. Despite the costs, some individuals do reach adult age and breeding status.Albino dolphins were first sighted in the Gulf of Mexico in 1962. Since 1994, three further individuals have been seen. These tend to be pink in colour due to blood vessels showing through the blubber and unpigmented skin. A report published in 2008 stated that in marine mammals, "anomalously white" individuals have been reported for 21 cetacean species and 7 pinniped species but there were no known reports of anomalously white sea otters (Enhydra lutris) or sirenians.Whales and dolphins also may appear white if extensively scarred, or covered with a fungus, such as Lacazia loboi. Famous albino mammals Famous albino mammals include Migaloo, a humpback whale living off the coast of Australia; Pinky, a bottlenose dolphin living in and around in Calcasieu Lake, Louisiana; Carolina Snowball, a popular albino bottlenose dolphin displayed at the Miami Seaquarium in the early 1960s; Snowflake, a Barcelona Zoo gorilla, and Mahpiya Ska, (Sioux for White Cloud), a buffalo in Jamestown, North Dakota, and inspiration for Herman Melvilles novel Moby-Dick, a sperm whale known as Mocha Dick. In birds The most important pigments that determine plumage colouration in birds are melanines and carotenoids. The latter are ingested in food and transformed into colour pigments by enzymes. Aberrations in this pigmentation are mostly caused by food deficiencies and usually do not have a genetic basis. Well-known examples are flamingos, which owe their distinct pink colour to the presence of red carotenoids in their natural food. When these carotenoids are in short supply, these birds appear white after the next moult. Mutations causing changes in carotenoid-based colour pigments are rare; melanine mutations occur much more frequently. Two types of melanin, eumelanin and phaeomelanin, are present in birds. In the skin and eyes, only eumelanin is present. In some bird species, the colour is completely caused by eumelanin, however, both types of melanin are found in most species. In birds, albinism has been defined as "a total lack of both melanins in feathers, eyes and skin as a result of an inherited absence of tyrosinase", however, this ignores the effects of other pigments and structural colours. An albino bird has a white beak, white plumage, non-coloured skin, white talons and pink or red eyes. Albinism is only seen in about 1 of every 1,800 birds. The two most common species of albino birds are the common house martin and the American robin. Famous albino birds include "Snowdrop", a Bristol Zoo penguin.In one study, albinism in birds has been categorised according to the extent of pigment absence. – Total albinism – a simultaneous complete absence of melanin from the eyes, skin, and feathers. This is the rarest form. Only 7% of 1,847 cases of avian albinism examined was this type. Incomplete albinism – when melanin is not simultaneously absent from the eyes, skin and feathers. Imperfect albinism – when melanin is reduced in the eyes, skin and feathers. Partial albinism – when albinism is localized to certain areas of the body.However, it has been argued that the definition of albinism precludes the possibility of "partial albinism" in which a mostly white bird shows some form of melanin pigmentation. "It is simply impossible, just like being partially pregnant. In fish As with other animals, it has been stated that for fish to be properly described as "albino", they must have a white body and pink or red eyes. Artificially selected Zebrafish have three types of chromatophores—iridophores, melanophores, and xanthophores—which produce silver, black, and yellow pigmentation respectively. Zebrafish that lack iridophores are known as roy mutants, those that lack melanophores as albino mutants, and those which lack both melanophores and iridophores are ruby mutants. The gross eye morphology, feeding and swimming behaviours between wild-type and albino zebrafish were indistinguishable, except under dim or bright light or low contrast. In mammals, albinism is occasionally associated with hearing impairments. However, when tested, there was no differences in responses between wild-type and albinistic European wels catfish (Silurus glanis) and South American bronze catfish (Corydoras aeneus). Similarly, Mexican blind cave fish (Astyanax mexicanus) do not differ in hearing sensitivity from the normally pigmented and eyed surface-dwelling populations. Fish lack melanin in the inner ear, meaning that hearing in fishes is less likely to be affected by albinism than in mammals. Naturally occurring There are several reports of total albinism in both freshwater and marine fish, however, frequently captured albino fish are only reported in aquarium magazines and local newspapers.The incidence of albinism can be artificially increased in fish by exposing the eggs to heavy metals (e.g. arsenic, cadmium, copper, mercury, selenium, zinc).In the wild, albinism is reasonably common in the teleosts, especially the Pleuronectiformes (flatfish), however, it is rarely reported in the elasmobranchs. Albinism has been reported in hagfish, lampreys, sharks, rays and numerous teleost fishes, e.g. catfishes, grunts or cyprinids. In Actinopterygii Albino and normally pigmented channel catfish (Ictalurus punctatus) differ in their characteristics. Normal individuals of this species are superior to albinos in body weight and total length. Albinos crossed with other albinos require 11 days longer to spawn and produce smaller egg masses. These masses contain eggs of lighter weight with poorer hatchability than crosses of normal fish. The albino fish have lower survival rates than normal fish but dress-out percentages are nearly equal.Some wild cave fish have populations that are albinistic. The Mexican cave tetra is a species that has evolved specialized characteristics in a series of independent caves. One of these is albinism linked to the Oca2 gene, a known pigmentation gene, This trait has evolved independently in at least two caves. In Chondrichthyes In the class Chondrichthyes, several species of naturally occurring albino rays and sharks have been recorded. Furthermore, an albino individual spotted ratfish (Hydrolagus colliei) from the order Chimaeriformes has been reported.Albinistic individuals of the following shark species have been reported: Basking shark (Cetorhinus maximus) – 2 cases Broadnose sevengill shark (Notorynchus cepedianus) Great white shark (Carcharodon carcharias) Grey smooth-hound (Mustelus californicus) – 2 cases Japanese topeshark (Hemitriakis japanica) Japanese wobbegong (Orectolobus japonicus) Java shark (Carcharhinus amboinensis) Leopard shark (Triakis semifasciata) Narrownose smooth-hound (Mustelus schmitti) Pigeye shark (Carcharhinus amboinensis) Porbeagle (Lamna nasus) Scalloped hammerhead shark (Sphyrna lewini) Spiny dogfish (Squalus acanthias) Tawny nurse shark (Nebrius ferigineus) Tiger shark (Galeocerdo cuvier) – embryo Whale shark (Rhincodon typus) Whitespotted bamboo shark (Chiloscyllium plagiosum) Zebra shark (Stegostoma fasciatum)A study published in 2006 reported albinistic individuals of the following ray species: Bat ray (Myliobatis californica) Common skate (Raja batis) Common stingray (Dasyatis pastinaca) Common torpedo (Torpedo torpedo) Cownose ray (Rhinoptera bonasus) Giant electric ray (Narcine entemedor) Giant oceanic manta ray (Manta birostris) Ocellate spot skate (Okamejei kenojei) Southern stingray (Dasyatis americana) Thornback ray (Raja clavata) Cuckoo ray (Raja naevus) In Hyperoartia There are several reports of albino lampreys and it has been estimated that this occurs at a frequency of one in 100,000 normal individuals. In Sarcopterygii Albinism in the African lungfish has been reported on at least two occasions. In reptiles Many reptiles labeled as albino are, in fact, not completely lacking in all colour pigments. They are actually amelanistic, not albino. Reptiles often possess at least two pigments. Among the most common are xanthin (yellow) and erythrin (red). An amelanistic reptile therefore, may still have pale yellow, orange, or red pigmentation. The California Academy of Science, in the Steinhart Aquarium, as of 2015, has on display an albino American alligator named "Claude". The alligator is partially blind because of lack of pigment in its eyes. The albino alligator hatched from the egg in 1995 in Florida, and was brought to the academy in 2008. This alligator would not have survived in the wild because its whiteness would have made it too easy a prey object. The only known albino alligators are in captivity. While extremely rare, white-coloured crocodiles and alligators do exist in other places. However, most of these animals are leucistic given that they have a general loss of pigmentation with some colour tinges remaining on their bodies although looking at first like other albino creatures, thus creating the misconception that the reptiles are albino themselves when they are not. Four such alligators are kept at the Gatorland theme park in the U.S. state of Florida. In Australia, a crocodile believed to be "part-albino" and nicknamed by people in the area as "Michael Jackson", attacked and killed a man.In snakes, partial absence of pigment is more common than absolute albinism. For snakes that are usually patterned in colours, they appear as a faint blue, peach or yellowish. In these cases, there has been a genetic mutation in the melanin and pigment delivery. The appearance comes from the inability for full colours to be present, such as black, red, brown and others. The eyes of an albino snake are typically red or pink. Albino snakes can remain in the sunlight for several hours with minimal harm. Corn snakes and snakes of larger types, such as a boa or diamondback snakes, are the most commonly affected by albinism often appearing to be a pinkish or yellowish colour.Albino tortoises and turtles are uncommon; Sulcata tortoises are the most likely type of turtle to express albinism. The shells have an almost yellow colouration and they have pink eyes. For turtles, a pure white colour is nearly impossible, even with albinism. Albino turtles
Albinism	can have a longer lifespan than many other albino animals; their hard shells help to prevent predation and other environmental challenges. Vision and sensory organs are slightly affected.In 2012, an albino anole was reported and photographed. In 2007, it was reported that an albino stumpy-tail lizard (possibly a shingleback lizard), approximately 12 cm (4.7 in) long and roughly 1 year old, had been found in Victoria, Australia.There are three known "albino" strains of leopard gecko, however, breeders state that albinos are generally recognized by their lack of black pigment and having red eyes is not a requirement to be considered an albino. These three strains are called "tremper albinos", "rainwater albinos" and "bell albinos". In amphibians As with reptiles, many amphibians labeled as albino are, in fact, not completely lacking in all colour pigments. They are actually amelanistic, not albino. Amphibians have six types of chromatophore in their skin, i.e. melanophores, xanthophores, erythrophores, leucophores, cyanophores and iridophores. An amelanistic amphibian therefore, may still have various pigmentation. The incidence of albinism in frogs, salamanders, and newts is relatively higher than other taxa. It has been estimated that one in four hundred of these animals is albino. When albino tadpoles hatch, they are almost transparent. This may help camouflage them initially, however, after two weeks, when their hindlegs begin to emerge, they become milky white. A survey in 2001 found hundreds of tiny albino plains leopard frogs, but when the researcher returned a few months later, not a single albino adult could be found.In European Salamandridae, albinism has been recorded in the fire salamander (Salamandra salamandra), gold-striped salamander (Chioglossa lusitanica), Italian crested newt (Triturus carnifex), marbled newt (Triturus marmoratus), Iberian ribbed newt (Pleurodeles waltl), alpine newt (Ichthyosaura alpestris) and two sub-species of the smooth newt (Lissotriton vulgaris vulgaris and Lissotriton vulgaris meridionalis). Genetics Genetic studies of albinism in amphibians have focused on mutations in the tyrosinase gene. The albino phenotype of the leopard frog (Rana pipiens) has been attributed to a failure in post-translational control in a single recessive tyrosinase gene which still has some tyrosinase and DOPA oxidase activity. This is in contrast with mammals, some of which have mutations that show no tyrosinase or DOPA oxidase activity in albinos. The albino phenotype of the pond frog (Pelophylax nigromaculatus) has been attributed to one of three mutations that created a dysfunctional tyrosinase. Two of those mutations involve an insertion of a thymine (T), a frameshift mutation, resulting in a truncated isoform of the TYR protein that is defective. The other mutation involves the deletion of a codon, three nucleotides that code for a lysine (Lys). In the wrinkled frog (Glandirana rugosa) and in the rice frog (Fejervarya kawamurai), a substitution from a guanine (G) to an adenine (A) creates a missense mutation, in which a glycine (Gly) changes to an aspartic acid (Asp) and an arginine (Arg), respectively. These changes in the polypeptide chain causes a dysfunctional tyrosinase. In invertebrates Albinism in molluscs has been recognized to be a hereditary phenomenon at least since 1900. Albinism in molluscs can exist to a variable degree. Sometimes an individual snail has a normally pigmented body, but the shell is completely without the normal pigmentation because of a defect in the cells of the mantle. Shells of certain mollusc species can be translucent when they lack the normal pigmentation. In insects The neurohormone [His7]-corazonin induces darkening of the cuticle of Locusta migratoria. The Okinawa strain of this species is deficient in [His7]-corazonin and is albino. One of the typical features of Locusta migratoria is that they are gregarious locusts. However, the albino strain shows more solitarious behaviour.The yellow mutation in fruit flies is a mutation causing a congenital lack of normal pigment; it is a similar phenomenon to albinism in other organisms. In echinoderms The Japanese sea cucumber (Apostichopus japonicus) is an echinoderm that is caught in the wild or cultivated for food. Normal Japanese sea cucumbers start to develop pigmentation when they are about 1 cm long. The upperside becomes a dull, yellowish -brown to maroon and the underside a light brown. The body walls of adult, albino Japanese sea cucumbers contain only 0.24% melanin compared to 3.12% in normal adults. The difference in melanin content becomes visually apparent at 60 days of age. The epidermis is thinner in the albinos and contains fewer melanocytes. Albino individuals are similar to normal individuals in growth rate, digestion rate and fertility.Astaxanthin is the main carotenoid in marine crustaceans (and fish). It has been shown that adding astaxanthin to the feed can improve the skin and muscle colour of marine organisms and thereby increase their commercial and ornamental value. In arachnids "Depigmented" arthropods have been found, usually in cave populations. "Albino" individuals of normally red citrus red mites (Panonychus citri) occasionally appear in laboratory colonies, however, these still contain green and yellow pigments. This albinism does not affect mortality. Related pigment disorders In some animals, albinism-like conditions may affect other pigments or pigment-production mechanisms: "Whiteface," a condition that affects some parrot species, is caused by a lack of psittacins. Axanthism is a condition common in reptiles and amphibians, in which xanthophore metabolism is affected rather than synthesis of melanin, resulting in reduction or absence of red and yellow pteridine pigments. Leucism differs from albinism in that the melanin is, at least, partially absent but the eyes retain their usual colour. Some leucistic animals are white or pale because of chromatophore (pigment cell) defects, and do not lack melanin. Melanism is the direct opposite of albinism. An unusually high level of melanin pigmentation (and sometimes absence of other types of pigment in species that have more than one) results in an appearance darker than non-melanistic specimens from the same gene pool. In plants In plants, albinism is characterised by partial or complete loss of chlorophyll pigments and incomplete differentiation of chloroplast membranes. Albinism in plants interferes with photosynthesis, which can reduce survivability. Some plant variations may have white flowers or other parts. However, these plants are not totally devoid of chlorophyll. Terms associated with this phenomenon are "hypochromia" and "albiflora".Plants that are pale simply from being in the dark are termed etiolated. Albino redwoods are rare examples of an albino tree with white needles; despite its lack of chlorophyll it may grow to substantial size as a parasite, usually on the base of the (normal) redwood tree from which it first grew. Only about sixty examples of albino redwoods are known. Additionally, an even smaller number of "chimeric" redwood trees have both normal and white needles. Albinism has frequently occurred in progeny of Black Tartarian, Bing and Hedelfingen varieties of sweet cherry.Some herbicides (e.g. glyphosate and triazines) can cause partial chlorosis in plants, even several seasons or years after applicating. In human culture The Albino Squirrel Preservation Society was founded at the University of Texas at Austin in 2001. Members of the society at the University of North Texas petitioned for an election to name their albino squirrel as the universitys secondary mascot. The University of Louisville in Kentucky also has a documented population of albino squirrels.Albino animals are often kept as pets, for example, African clawed frog, guinea pigs and peacocks. See also == References ==
Menstrual migraine	Menstrual migraine (also called catamenial migraine) is term used to describe both true menstrual migraines and menstrually related migraines. About 7%–14% of women have migraines only at the time of menstruation, these are called true menstrual migraines. Most female migraneurs experience migraine attacks throughout the menstruation cycle with an increased number perimenstrually, these are referred to as menstrually related or menstrually triggered migraine.It used to believed that treatments for migraine would work in menstrual migraine but that has not proven to be the case because menstrual migraines are harder to treat. Because of this, menstrual migraines are now considered a separate medical disorder from migraine. In 2008, menstrual migraines were given ICD-9 codes (346.4-346.43) of their own which separate menstrual migraine from other types of migraine. About 40% of women and 20% of men will get a migraine at sometime in their life; most of them will get their first migraine before they are 35-years-old. Menstrual-related migraines happen in more than 50 percent of women who have migraine headaches. Menstrual migraine attacks usually last longer than other migraine attacks, and short-term treatments do not work as well with menstrual migraine as they do in other kinds of migraine. They are usually migraines without aura, but in 2012 a case of menstrual migraine with aura was reported, so it is possible. Auras are a kind of condition which affect certain parts of the brain, usually the parts that control vision but they can also affect the parts of the brain which control the other senses like touch, motor control (moving parts of the body) and the parts of the brain that control speech. Signs and symptoms Warning symptoms Warning symptoms also called prodrome symptoms often happen before a migraine attack. Sleepiness Fatigue Depression (feeling sad), euphoria (feeling very happy) or irritability Restlessness Excessive (too much) yawning Food cravings especially for sweet or salty foods or loss of appetite Increased thirst Diarrhea Nausea Bloating: the body retains (keeps) too much water Neck stiffness Talkativeness (talking too much) Feeling light-headed Uterine pain and cramping Headache A pounding throbbing headache with the pain being on one side of the head (unilateral). The side of the head that has the pain changes from one headache to the next. Associated conditions Often, having one medical condition makes it more likely a person will also have one or more other medical or psychiatric disorders. These other disorders are the "comorbid disorders" or "comorbidities". There are various comorbid medical and psychiatric conditions associated with migraines. The treatment and prognosis (if a disease gets better, worse or stays the same over time) of migraine is affected by the comorbid disorders which may be present and/or the chance of getting comorbid disorders. Asthma – Premenstrual asthma (PMA): is when asthma symptoms get worse during the premenstrual period. This condition may affect up to 40% of females with asthma. For a diagnosis of PMA to be made it is necessary to have a detailed history of the timing of menstrual cycles along with asthma symptoms experienced, and the peak expiratory flow rate (PMA may cause the PEF to be lowered in the premenstrual period). It is helpful in making a diagnosis to keep a diary of symptoms and peak expiratory flow (PEF) rates. Raynauds disease: is a circulatory disorder in which the smaller arteries that supply blood to the extremities – most often the hands, but it may also affect the, toes, the tip of the nose and the ears – become narrower reducing blood flow. This causes the extremities to become numb and to be cooler than the core body temperature. It can be triggered by exposure to stress and cold. Epilepsy FibromyalgiaIt is associated with a number of mental health conditions including Major depressive disorder Anxiety Bipolar disorder Causes The exact causes of menstrual migraine are not known for sure but there is a link between falling levels of the female hormone estrogen and the onset of a migraine attack. The estrogen level may fall after bleeding occurs during the menstrual cycle or when external sources of estrogen are no longer taken, like when a woman stops taking birth control pills or hormone pills in hormone replacement therapy. Diagnosis The diagnosis of a menstrual migraine is made by keeping track of when the migraines occur for a period of at least three months. Menstrually related migraine attacks occur usually between 2 days before and 3 days after the start of menstruation in at least 2 out of 3 menstrual cycles (periods) in a row. Pure menstrual migraine and menstrually related migraine are both migraines without auras with one exceptionally rare case with aura reported in 2012. The Menstrual Migraine Assessment Tool (MMAT) is a simple questionnaire with three questions, that has shown to be fairly accurate in diagnosing menstrual migraine (Tepper SJ, 2008). The three questions are: Do migraines occur in the space of time 2 days before the beginning of a womans period, until the third day after the start of the period. And does this happen in most months. Do headaches that happen during this time become very severe. Does the woman experience photophobia which is when a medical problem cause light to bother a persons eyes.The answer to the first question has to be yes and there has to be at least one yes answer to either question 2 or question 3.In order to keep track of what time of the month the migraines happen it is helpful to use a headache diary. A person uses the headache diary to write down information about their headaches, like when they started, what kind of symptoms they had and how bad the pain was etc. Prevention There are treatments which may decrease the severity or frequency of menstrual migraines. Preventative treatments for menstrual migraine should be tried for at least 3 menstruation cycles to determine effectiveness. Medications used may include: NSAIDS (nonsteroidal antiinflammatory drugs) such as naproxen Beta blockers—such as propranolol, nadolol, atenolol, and metoprolol Tricyclic antidepressants (TCAs) and other kinds of antidepressant medications are often used for migraine prevention. These include amitriptyline, nortriptyline, and doxepin. Treatment Acute treatments (short-term treatment) include drugs called Nonsteroidal anti-inflammatory drugs (NSAIDS) (drugs that help stop inflammation which is redness, swelling, pain, tenderness, heat in parts of the body), triptans such as Frovatriptan, ergotomines which are a kind of drug made from a fungus called ergot, and estrogen transdermal patches, which are patches worn on the skin that have estrogen in them which enters the body through the skin and then into the bloodstream. See also Catamenial epilepsy Catamenial pneumothorax References External links Optimizing Management of Menstrual Migraine
Irritant contact dermatitis	Irritant contact dermatitis is a form of contact dermatitis that can be divided into forms caused by chemical irritants and those caused by physical irritants. Chemical Chemical irritant contact dermatitis is either acute or chronic, which is usually associated with strong and weak irritants respectively. The following definition is provided by Mathias and Maibach (1978): The mechanism of action varies. Detergents, surfactants, extremes of pH, and organic solvents all directly affecting the barrier properties of the epidermis. These effects include removing fat emulsion, defatting of dermal lipids, inflicting cellular damage on the epithelium, and increasing the transepidermal water loss by damaging the horny layer water-binding mechanisms and damaging the DNA, which causes the layer to thin. Concentrated irritants have an acute effect, but this is not as common as the accumulative, chronic effect of irritants whose deleterious effects build up with subsequent doses (ESCD 2006). Chemical irritants are often strong alkalis as found in drain cleaners and soap with lye residues. Many other chemical compounds can also cause contact dermatitis. Physical Physical irritant contact dermatitis is a less-researched form of irritant contact dermatitis due to its various mechanisms of action and a lack of a test for its diagnosis. A complete patient history combined with negative allergic patch testing is usually necessary to reach a correct diagnosis. The simplest form of physical irritant contact dermatitis results from prolonged rubbing, although the diversity of implicated irritants is far wider. Examples include paper friction, fiberglass, and scratchy clothing. Low humidity Low humidity from air conditioning was found to be the most common cause of physical irritant contact dermatitis. To the lay person a definition of low humidity being a physical irritant can be confusing because low humidity is a deficit (or absence) of an elemental substance, whereas all other irritants implicated in contact dermatitis are in concentrations of relative abundance. So the irritant is actually a lack of water vapour. This confusion is further compounded with the use of the term contact implying touching (as is the case with all other forms of physical irritant contact dermatitis) whereas in the case of low humidity physical irritant contact dermatitis there is an absence of contact with water vapour. Plants Many plants cause irritant contact dermatitis through their spines or irritant hairs. Some plants such as the buttercup, spurge, and daisy act by chemical means. The sap of these plants contains a number of alkaloids, glycosides, saponins, anthraquinones, and (in the case of plant bulbs) irritant calcium oxalate crystals - all of which can cause crystal irritant contact dermatitis.Butternut squash and Acorn squash have been known to cause an allergic reaction in many individuals, especially in food preparation where the squash skin is cut and exposed to the epidermis. Food handlers and kitchen workers often take precautions to wear rubber or latex gloves when peeling butternut and acorn squash to avoid temporary Butternut squash (Cucurbita moschata) dermatitis A contact dermatitis reaction to butternut or acorn squash may result in orange and cracked skin, a sensation of "tightness", "roughness" or "rawness". Treatment A humidifier can be used to prevent low indoor humidity during winter (especially with indoor heating), and dry season. References == External links ==
Scarring hair loss	Scarring hair loss, also known as cicatricial alopecia, is the loss of hair which is accompanied with scarring. This is in contrast to non scarring hair loss. It can be caused by a diverse group of rare disorders that destroy the hair follicle, replace it with scar tissue, and cause permanent hair loss. A variety of distributions are possible. In some cases, hair loss is gradual, without symptoms, and is unnoticed for long periods. In other cases, hair loss is associated with severe itching, burning and pain and is rapidly progressive. The inflammation that destroys the follicle is below the skin surface and there is usually no "scar" seen on the scalp. Affected areas of the scalp may show little signs of inflammation, or have redness, scaling, increased or decreased pigmentation, pustules, or draining sinuses. Scarring hair loss occurs in otherwise healthy men and women of all ages and is seen worldwide. Signs and symptoms It is important to continue to watch for symptoms and signs of active disease during and after treatment to ensure that the disease is responding adequately and has not re-activated after therapy has been discontinued. Response to therapy may be indicated by the resolution of scalp symptoms such as itching, pain, tenderness, or burning, by improvement in the signs of scalp inflammation such as decreased redness, scaling or pustules, and by halting or slowing the progression of hair loss. A dermatologist can document and monitor a patients cicatricial alopecia using these guidelines, and with the pull test. Photographs of the scalp may be useful in monitoring the course of the disease and response to treatment. Causes The cause of the various cicatricial alopecias is poorly understood. However, all cicatricial alopecias involve inflammation directed at the upper part of the hair follicle where the stem cells and sebaceous gland (oil gland) are located. If the stem cells and sebaceous gland are destroyed, there is then no possibility for regeneration of the hair follicle, and permanent hair loss results. Cicatricial alopecias are not contagious. In general, cicatricial alopecias are not associated with other illnesses, and usually occur in otherwise healthy men and women. Cicatricial alopecias affect both men and women, most commonly adults, although all ages may be affected. Epidemiologic studies have not been performed to determine the incidence of cicatricial alopecias. In general, they are not common. The majority of patients with cicatricial alopecia have no family history of a similar condition. The one exception is Central centrifugal cicatricial alopecia, which primarily affects women of African ancestry and may occur in several women in the same family. While it is possible to have more than one type of hair loss condition, non-scarring forms of hair loss do not turn into scarring forms of hair loss. Diagnosis A scalp biopsy is essential for the diagnosis of cicatricial alopecia and is the necessary first step, as it can be hard to know the diagnosis for sure without a biopsy. Findings of the scalp biopsy, including the type of inflammation present, location and amount of inflammation, and other changes in the scalp, are necessary to diagnose the type of cicatricial alopecia, to determine the degree of activity, and to select appropriate therapy. Clinical evaluation of the scalp is also important. Symptoms of itching, burning, pain, or tenderness usually signal ongoing activity. Signs of scalp inflammation include redness, scaling, and pustules. However, in some cases there are few symptoms or signs and only the scalp biopsy demonstrates the active inflammation. The overall extent and pattern of hair loss is noted and sometimes photographed for future comparison. A hair "pull test" is performed to see if growing, or anagen, where hairs are pulled out easily. The pulled hairs are mounted on a slide and the hair bulbs are viewed with a light microscope to determine how many are growing hairs and how many are resting hairs. In addition, if pustules are present, cultures are taken to identify which microbes, if any, may be contributing to the inflammation. A thorough evaluation that includes all of these parameters is important in diagnosing a cicatricial alopecia and in identifying features in individual patients that will help the selection of therapy. New diagnostic techniques, such as trichoscopy may be used for non-invasive differential diagnosis of cicatricial alopecia. Diagnosis and treatment of cicatricial alopecias is often challenging. For this reason, it is helpful to be evaluated by a dermatologist with a special interest or expertise in scalp and hair disorders, and who is familiar with current diagnostic methods and therapies. Classification Cicatricial alopecias are classified as primary or secondary. This discussion is confined to the primary cicatricial alopecias in which the hair follicle is the target of the destructive inflammatory process. In secondary cicatricial alopecias, destruction of the hair follicle is incidental to a non-follicle-directed process or external injury, such as severe infections, burns, radiation, tumors, or traction. Primary cicatricial alopecias are further classified by the type of inflammatory cells that destroy the hair follicle during the active stage of the disease. The inflammation may predominantly involve lymphocytes or neutrophils. Cicatricial alopecias that predominantly involve lymphocytic inflammation include lichen planopilaris, frontal fibrosing alopecia, central centrifugal alopecia, and pseudopelade (Brocq). Cicatricial alopecias that are due to predominantly neutrophilic inflammation include folliculitis decalvans, tufted folliculitis, and dissecting cellulitis of the scalp. Sometimes the inflammation shifts from a predominantly neutrophilic process to a lymphocytic process. A cicatricial alopecia with a mixed inflammatory infiltrate is folliculitis keloidalis. Treatment As mentioned above, primary cicatricial alopecias are classified by the predominant type of inflammatory cells that attack the hair follicles, such as lymphocytes, neutrophils, or mixed inflammatory cells. Treatment strategies are different for each subtype and detailed treatment options are beyond the scope of this discussion. However, certain general principals are reviewed below. Treatment of the lymphocytic group of cicatricial alopecias (including lichen planopilaris, frontal fibrosing alopecia, central centrifugal alopecia, and pseudopelade (Brocq) involves use of anti-inflammatory medications. The goal of treatment is to decrease or eliminate the lymphocytic inflammatory cells that are attacking and destroying the hair follicle. Oral medications may include hydroxychloroquine, doxycycline, mycophenolate mofetil, cyclosporine, or corticosteroids. Topical medications may include corticosteroids, tacrolimus, pimecrolimus, or Derma-Smoothe/FS scalp oil. Triamcinolone acetonide, a corticosteroid, may be injected into inflamed, symptomatic areas of the scalp. Treatment of the neutrophilic group of cicatricial alopecias (folliculitis decalvans, tufted folliculitis) is directed at eliminating the predominant pathogenic microbes that are invariably involved in the inflammatory process. Oral antibiotics are the mainstay of therapy, and topical antibiotics may be used to supplement the oral antibiotics. In dissecting cellulitis, pathogenic microbes are not usually present. Isotretinoin in small doses may be helpful in treating dissecting cellulitis.Treatment of the mixed group of cicatricial alopecias (folliculitis keloidalis) may include antimicrobials, isotretinoin, and anti-inflammatory medications. Patients are recommended to discuss any treatment with a dermatologist, who also explains potential side effects, as well as laboratory tests that are needed before starting treatment and sometimes are monitored during treatment. The course of cicatricial alopecia is usually prolonged. Treatment is continued until the symptoms and signs of scalp inflammation are controlled, and progression of the condition has been slowed. In other words, itching, pain, tenderness, and burning have cleared, scalp redness, scaling, and/or pustules are no longer present, and the progression of the hair loss has been stopped or slowed. Treatment may then be stopped. Unfortunately, the cicatricial alopecias may reactivate after a quiet period and treatment may have to be repeated. Surgical treatment for cosmetic benefit is an option in some cases after the disease has been inactive for one to two or more years. Hair restoration surgery or scalp reduction may be considered in these instances. Hair regrowth Hair will not regrow once the follicle is destroyed. However, it may be possible to treat the inflammation in and around surrounding follicles before they are destroyed, and for this reason it is important to begin treatment as early as possible to halt the inflammatory process. Minoxidil solution (2% or 5%) applied twice daily to the scalp may be helpful to stimulate any small, remaining, unscarred follicles. The progression of hair loss is unpredictable. In some cases, progression is slow and there is always sufficient hair remaining to cover the affected scalp areas; in other cases, progression can be rapid and extensive. Hair care Hair care products and shampoos can generally be used with any frequency desired, as long as the products are gentle and non-irritating to the scalp. Hair pieces, wigs, hats, and scarves may be used freely. See also Noncicatricial alopecia List of cutaneous conditions References External links Cicatricial Alopecia Overview - US National Institute of Arthritis and Musculoskeletal and Skin Diseases
Conductive hearing loss	Conductive hearing loss (CHL) occurs when there is a problem transferring sound waves anywhere along the pathway through the outer ear, tympanic membrane (eardrum), or middle ear (ossicles). If a conductive hearing loss occurs in conjunction with a sensorineural hearing loss, it is referred to as a mixed hearing loss. Depending upon the severity and nature of the conductive loss, this type of hearing impairment can often be treated with surgical intervention or pharmaceuticals to partially or, in some cases, fully restore hearing acuity to within normal range. However, cases of permanent or chronic conductive hearing loss may require other treatment modalities such as hearing aid devices to improve detection of sound and speech perception. Causes Common causes of conductive hearing loss include: External ear Cerumen (earwax) or foreign body in the external auditory canal Otitis externa, infection or irritation of the outer ear Exostoses, abnormal growth of bone within the ear canal Tumor of the ear canal Congenital stenosis or atresia of the external auditory canal (narrow or blocked ear canal). Ear canal stenosis & atresia can exist independently or may result from congenital malformations of the auricle such as microtia or anotia. Acquired stenosis (narrowing) of the external auditory canal following surgery or radiotherapy Middle ear Fluid accumulation is the most common cause of conductive hearing loss in the middle ear, especially in children. Major causes are ear infections or conditions that block the eustachian tube, such as allergies or tumors. Blocking of the eustachian tube leads to decreased pressure in the middle ear relative to the external ear, and this causes decreased motion of both the ossicles and the tympanic membrane. Acute or Serous otitis media Chronic suppurative otitis media (CSOM) Perforated eardrum Tympanosclerosis or scarring of the eardrum Cholesteatoma Eustachian Tube Dysfunction, inflammation or mass within the nasal cavity, middle ear, or eustachian tube itself Otosclerosis, abnormal growth of bone in or near the middle ear Middle ear tumour Ossicular discontinuity as a consequence of infection or temporal bone trauma Congenital malformation of the ossicles. This can be an isolated phenomenon or can occur as part of a syndrome where development of the 1st and 2nd branchial arches is seen such as in Goldenhar syndrome, Treacher Collins syndrome, branchio-oto-renal syndrome etc. Barotrauma unequal air pressures in the external and middle ear. This can temporarily occur, for example, by the environmental pressure changes as when shifting altitude, or inside a train going into a tunnel. It is managed by any of various methods of ear clearing manoeuvres to equalize the pressures, like swallowing, yawning, or the Valsalva manoeuvre. More severe barotrauma can lead to middle ear fluid or even permanent sensorineural hearing loss. Inner ear Third window effect caused by: Superior canal dehiscence – which may require surgical correction. Enlarged vestibular aqueduct Labyrinthine fistula Presentation Conductive hearing loss makes all sounds seem faint or muffled. The hearing loss is usually worse in lower frequencies. Congenital conductive hearing loss is identified through newborn hearing screening or may be identified because the baby has microtia or other facial abnormalities. Conductive hearing loss developing during childhood is usually due to otitis media with effusion and may present with speech and language delay or difficulty hearing. Later onset of conductive hearing loss may have an obvious cause such as an ear infection, trauma or upper respiratory tract infection or may have an insidious onset related to chronic middle ear disease, otosclerosis or a tumour of the naso-pharynx. Earwax is a very common cause of a conductive hearing loss which may present suddenly when the wax blocks sound from getting through the external ear canal to the middle and inner ear. Diagnosis Diagnosis requires a detailed history, local examination of the ear, nose, throat and neck, and detailed hearing tests. In children a more detailed examination may be required if the hearing loss is congenital. Otoscopy Examination of the external ear canal and ear drum is important and may help identify problems located in the outer ear up to the tympanic membrane. Differential testing For basic screening, a conductive hearing loss can be identified using the Rinne test with a 256 Hz tuning fork. The Rinne test, in which a patient is asked to say whether a vibrating tuning fork is heard more loudly adjacent to the ear canal (air conduction) or touching the bone behind the ear (bone conduction), is negative indicating that bone conduction is more effective that air conduction. A normal, or positive, result, is when air conduction is more effective than bone conduction. With a one-sided conductive component the combined use of both the Weber and Rinne tests is useful. If the Weber test is used, in which a vibrating tuning fork is touched to the midline of the forehead, the person will hear the sound more loudly in the affected ear because background noise does not mask the hearing on this side. The following table compares sensorineural hearing loss to conductive: Tympanometry Tympanometry, or acoustic immitance testing, is a simple objective test of the ability of the middle ear to transmit sound waves from the outer ear to the middle ear and to the inner ear. This test is usually abnormal with conductive hearing loss. A type B tympanogram reveals a flat response, due to fluid in the middle ear (otitis media), or an eardrum perforation. A type C tympanogram indicates negative middle ear pressure, which is commonly seen in eustachian tube dysfunction. A type As tympanogram indicates a shallow compliance of the middle ear, which is commonly seen in otosclerosis. Audiometry Pure tone audiometry, a standardized hearing test over a set of frequencies from 250 Hz to 8000 Hz, may be conducted by a medical doctor, audiologist or audiometrist, with the result plotted separately for each ear on an audiogram. The shape of the plot reveals the degree and nature of hearing loss, distinguishing conductive hearing loss from other kinds of hearing loss. A conductive hearing loss is characterized by a difference of at least 15 decibels between the air conduction threshold and bone conduction threshold at the same frequency. On an audiogram, the "x" represents responses in the left ear at each frequency, while the "o" represents responses in right ear at each frequency. CT scan Most causes of conductive hearing loss can be identified by examination but if it is important to image the bones of the middle ear or inner ear then a CT scan is required. CT scan is useful in cases of congenital conductive hearing loss, chronic suppurative otitis media or cholesteatoma, ossicular damage or discontinuity, otosclerosis and third window dehiscence. Specific MRI scans can be used to identify cholesteatoma. Pathophysiology Management Management falls into three modalities: surgical treatment, pharmaceutical treatment, and supportive, depending on the nature and location of the specific cause. In cases of infection, antibiotics or antifungal medications are an option. Some conditions are amenable to surgical intervention such as middle ear fluid, cholesteatoma, and otosclerosis. If conductive hearing loss is due to head trauma, surgical repair is an option. If absence or deformation of ear structures cannot be corrected, or if the patient declines surgery, hearing aids which amplify sounds are a possible treatment option. Bone conduction hearing aids are useful as these deliver sound directly, through bone, to the cochlea or organ of hearing bypassing the pathology. These can be on a soft or hard headband or can be inserted surgically, a bone anchored hearing aid, of which there are several types. Conventional air conduction hearing aids can also be used. See also Hearing loss Sensorineural hearing loss References == External links ==
Intrahepatic cholestasis of pregnancy	Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, cholestasis of pregnancy, jaundice of pregnancy, and prurigo gravidarum, is a medical condition in which cholestasis occurs during pregnancy. It typically presents with itching and can lead to complications for both mother and baby. Pruritus (itching) is a common symptom of pregnancy, affecting around 23% of women. The majority of times, itching is a minor annoyance caused by changes to the skin, especially that of the abdomen. However, there are instances when itching may be a symptom of ICP. Although typically noticed on the palms of the hands and the soles of the feet, the itching can occur anywhere on the body. ICP occurs most commonly in the third trimester, but can begin at any time during the pregnancy. Signs and symptoms Most women with this condition present in the third trimester (although it can present as early as seven weeks) with itching without a rash. Typically, the itching is localized to the palms of the hands and soles of the feet, but can be anywhere on the body. Hallmarks of ICP include the following symptoms:Most common: Itching, in particular but not limited to that of the palms of the hands and soles of the feet, without presence of a rash Itching that is more noticeable in the evening Darker urineLess common: Lighter stools Increased clotting time (due to possibly associated vitamin K deficiency) Fatigue Increased nausea Decrease in appetite Jaundice (less than 10% of women) Upper right quadrant painNot all ICP sufferers have all of the above symptoms. Mechanism The causes of intrahepatic cholestasis of pregnancy are still not fully understood, but are thought to be caused through a combination of genetics, hormones and environment. Hormones, environmental and genetic factors are all thought to contribute to the condition. ICP commonly occurs in the third trimester at the time when hormone levels are at their highest. Twin and triplet pregnancies, which are associated with higher hormone levels, show a higher incidence of ICP. ICP resolves quickly after delivery, when placental hormone production ceases. Older high-dose estrogen oral contraceptive pills could cause features of ICP. Estrogens Estrogens, and particularly glucuronides such as estradiol-17β-D-glucuronide, have been shown to cause cholestasis in animal studies, by reducing bile acid uptake by hepatocytes. Progesterone Treatment with progesterone in the third trimester of pregnancy has been shown to be associated with the development of ICP, and levels of metabolites of progesterone, particularly sulfated progesterone, are higher in patients with ICP than unaffected women, suggesting that progesterone may have a bigger role than estrogen in ICP. Genetic factors Clustering of cases of ICP in families, geographic variation in rates of ICP, and recurrence of ICP in 45-70% of subsequent pregnancies all suggest a genetic component to the disease. Genetic mutations in the hepatocellular transport protein ABCB4 (MDR3), which controls secretion of phosphatidylcholine into bile, have been found in cases of ICP.Genetic mutations affecting hepatic bile salt transport molecules have also been found in patients with progressive familial intrahepatic cholestasis. It has been found that mothers of patients with this disease have a higher incidence of ICP, suggesting that heterozygote carriers of these mutations are also predisposed to ICP.In addition to genetic changes to bile salt transport molecules, high levels of estrogen glucuronides have been shown to inhibit the bile salt export pump (BSEP) ABCB11, and high levels of progesterone to inhibit the ABCB4 (MDR3) phospholipid transporter.Consequently, both genetic mutations in hepatocyte proteins involved in bile secretion together with inhibition of those proteins by high levels of hormone metabolites in pregnancy may have roles in the pathogenesis of ICP. Environmental factors A number of features of ICP suggest that environmental factors also have a role in the disease: It has been reported that the incidence of ICP is higher in winter than summer. The incidence of ICP in Chile has dropped from 14% of pregnancies before 1975 to 4% in 2016. ICP recurs in between 60% and 90% of subsequent pregnancies. Low serum selenium levels have been linked to ICP, although the role of selenium in bile secretion is not known. Diagnosis ICP is diagnosed by blood tests including a serum bile acid test and liver function test. While most pregnant women experience some itch from time to time, itching without a visible rash, or persistent or extensive itch symptoms should be reported to the midwife or obstetrician. It is important to note that as the level of itch does not correlate with bile acid levels (shown to be the most likely cause of stillbirth in ICP), the itch in ICP can range from being mild to severe.To obtain a diagnosis of ICP, a liver function test and a serum bile acid test should be requested. Although the ALT level may be raised, 20% of women with ICP will always have a normal LFT test result. This, plus pruritus of palms and soles, could be considered as potentially diagnostic of ICP but only with elevated bile acid levels (however LFTs are not always elevated in ICP patients). The serum bile acid blood test for ICP is a quantitative measurement of bile acids. Other problems with the liver that occur in pregnancy should be considered by the treating clinician. These include preeclampsia, the HELLP syndrome, and acute fatty liver of pregnancy. Furthermore, other causes of hepatitis, like hepatitis viruses, cancer and certain medications, should also be considered. Treatment Many providers will prescribe ursodeoxycholic acid. The most recent trial, PITCHES, did not show an overall beneficial effect, but some researchers believe that it may still be useful to offer ursodeoxycholic acid to women whose bile acids are > 40 μmol/litre. While there is no cure for ICP, and no way to guarantee a successful outcome, studies have shown a slightly better fetal and maternal outcome from administration of ursodeoxycholic acid, whereas cholestyramine appears to only relieve itching.There is no evidence that giving oral water-soluble Vitamin K may help to avoid the risk of hemorrhage at delivery. However, experts in ICP will prescribe this if the woman reports pale stools, has very severe ICP (bile acids > 100 μmol/litre) or has a known clotting problem. Delivery from 34 weeks may be important to reduce the risk of stillbirth, as a recent study identified the level of bile acids at which stillbirth risk rises. This research, published in The Lancet, also suggests that around 90% of women with ICP could wait until 39 weeks of pregnancy to be induced. However, this relies on regular bile acid testing with rapid return of results. Risks if untreated Maternal consequences include the following: Itching, which can become intense and debilitating Spontaneous premature labour when bile acids rise above 40 μmol/litreFetal consequences include: Fetal distress Meconium ingestion StillbirthIn most cases induction is typically recommended anywhere from 34–39 weeks.In the United States, some researchers have suggested that the risk of stillbirth is lower if induction occurs at 36 weeks. Whilst Ovadias research suggests differently, it is important to note that in the United States bile acid tests can take up to seven days to be processed, and this means that it may be more prudent to base delivery on the US research. See also Cholestasis Cholestatic pruritus List of cutaneous conditions Pruritic urticarial papules and plaques of pregnancy (PUPPP) an itchy condition of pregnancy that is associated with a rash. References External links E A Fagan "Intrahepatic cholestasis of pregnancy"
Intrauterine hypoxia	Intrauterine hypoxia (also known as fetal hypoxia) occurs when the fetus is deprived of an adequate supply of oxygen. It may be due to a variety of reasons such as prolapse or occlusion of the umbilical cord, placental infarction, maternal diabetes (prepregnancy or gestational diabetes) and maternal smoking. Intrauterine growth restriction may cause or be the result of hypoxia. Intrauterine hypoxia can cause cellular damage that occurs within the central nervous system (the brain and spinal cord). This results in an increased mortality rate, including an increased risk of sudden infant death syndrome (SIDS). Oxygen deprivation in the fetus and neonate have been implicated as either a primary or as a contributing risk factor in numerous neurological and neuropsychiatric disorders such as epilepsy, attention deficit hyperactivity disorder, eating disorders and cerebral palsy. Presentation Maternal Consequences Complications arising from intrauterine hypoxia are some of the leading causes of preeclampsia. Preeclampsia is a hypertensive disorder that occurs during the second trimester (after the 20th week of pregnancy) resulting from a poorly perfused placenta. Studies from the World Health Organization show that globally, about 14% (50,000- 750000 women) of maternal deaths annually are caused by preeclampsia and eclampsia.During pregnancy, women with preeclampsia faces serious risk of damage to vital organs such as the kidneys, liver, brain, and the blood system. This hypertensive disorder may also cause damage to the placenta leading to issues such as premature births, miscarriages, placental abruption, or even stillbirths. In some cases, preeclampsia can eventually lead to stroke and organ failure. Untreated, preeclampsia can progress and turn into eclampsia which is much more severe with the addition of seizures. Eclampsia seizures could lead to uncontrollable twitching and a loss of consciousness, which could potentially lead to the death of the mother and or the baby. Cause Intrauterine hypoxia can be attributed to maternal, placental, or fetal conditions. Kingdom and Kaufmann classifies three categories for the origin of fetal hypoxia: 1) pre-placental (both mother and fetus are hypoxic), 2) utero-placental (mother is normal but placenta and fetus is hypoxic), 3) post-placental (only fetus is hypoxic).Pre-placental hypoxia is most commonly caused by external hypoxic environments (such as high altitude). It can also be caused by maternal respiratory conditions (such as asthma), cardiovascular conditions (such as heart failure, pulmonary hypertension, and cyanotic heart disease), and hematological conditions (such as anemia). Conditions such as obesity, nutritional deficiencies, infections, chronic inflammations, and stress can also affect the maternal oxygen supply and fetal uptake.The most preventable cause is maternal smoking. Cigarette smoking by expectant mothers has been shown to have a wide variety of deleterious effects on the developing fetus. Among the negative effects are carbon monoxide induced tissue hypoxia and placental insufficiency which causes a reduction in blood flow from the uterus to the placenta thereby reducing the availability of oxygenated blood to the fetus. Placental insufficiency as a result of smoking has been shown to have a causal effect in the development of pre-eclampsia. While some previous studies have suggested that carbon monoxide from cigarette smoke may have a protective effect against preeclampsia, a recent study conducted by the Genetics of Pre-Eclampsia Consortium in the United Kingdom found that smokers were five times more likely to develop pre-eclampsia.Nicotine alone has been shown to be a teratogen which affects the autonomic nervous system, leading to increased susceptibility to hypoxia-induced brain damage. Maternal anemia in which smoking has also been implicated is another factor associated with IH/BA. Smoking by expectant mothers causes a decrease in maternal nucleated red blood cells, thereby reducing the amount of red blood cells available for oxygen transport.Utero-placental hypoxia is associated with abnormal placental implantation, impaired vascular remodeling and vascular diseases. It is also associated with pregnancies complicated by gestational hypertension, intrauterine growth restriction, and pre-eclampsia.Post-placental hypoxia is associated with mechanical obstructions of the umbilical cords, reduced uterine artery flow, progressive fetal cardiac failure, and genetic anomalies.The perinatal brain injury occurring as a result of birth asphyxia, manifesting within 48 hours of birth, is a form of hypoxic ischemic encephalopathy. Diagnosis Treatment Treatment of infants with birth asphyxia by lowering the core body temperature is now known to be an effective therapy to reduce mortality and improve neurological outcome in survivors, and hypothermia therapy for neonatal encephalopathy begun within 6 hours of birth significantly increases the chance of normal survival in affected infants.There has long been a debate over whether newborn infants with birth asphyxia should be resuscitated with 100% oxygen or normal air. It has been demonstrated that high concentrations of oxygen lead to generation of oxygen free radicals, which have a role in reperfusion injury after asphyxia. Research by Ola Didrik Saugstad and others led to new international guidelines on newborn resuscitation in 2010, recommending the use of normal air instead of 100% oxygen. Increasing the oxygen concentration to the mother has shown little effect on the fetus as hyperoxygenated blood does not perfuse the placental exchange site well.Underlying etiology of intrauterine hypoxia serves as a potential therapeutic target. If maternal preeclampsia is the underlying cause of fetal growth restriction (FGR) antihypertensive therapy and magnesium sulfate are potential therapies. Antihypertensive treatment is used to reduce blood pressure and prevent pulmonary edema and cerebral hemorrhages. An effective course of antihypertensive treatments should reduce blood pressure to below 160/110 mmHg. Magnesium sulfate acts as a vasodilator, reducing vascular resistance and protect the blood-brain barrier (BBB). The goal of these treatments is to prolong pregnancy and increase fetal survival. Each day gained by treatment in utero increases fetal survival and intact survival by 1%–2% up to 28 weeks gestation. Prevention Medical testing and care can be performed in order to prevent intrauterine hypoxia, though can be difficult. These tests dont directly detect hypoxia, but instead detects the general well-being of the baby and ensures that the baby is healthy since hypoxia causes a wide range of responses. These tests can include prenatal testing, such as fetal movement and amniotic fluid levels, Doppler examination, or fetal heart rate. Another risk factor is premature birth in which medical intervention, such as premature birth prevention or C-section delivery, can be used as prevention for intrauterine hypoxia.Studies have shown a connection between tetrahydrobiopterin (BH4) deficiency and hypoxia-ischemia brain injury, though further studies need to be done. Measuring fetal BH4 levels can be another way to look out for intrauterine hypoxia.During birth, birth asphyxia can occur in which cardiotocograph can be used to monitor the babys health during labor. Epidemiology In the United States, intrauterine hypoxia and birth asphyxia were listed together as the tenth leading cause of neonatal death. Society IH/BA is also a causative factor in cardiac and circulatory birth defects the sixth most expensive condition, as well as premature birth and low birth weight the second most expensive and it is one of the contributing factors to infant respiratory distress syndrome (RDS) also known as hyaline membrane disease, the most expensive medical condition to treat and the number one cause of infant mortality. Medicolegal In the United States the National Practitioner Data Bank 2006 Annual Report obstetrics-related cases accounted for 8.7 percent of all 2006 physician Malpractice Payment Reports and had the highest median payment amounts ($333,334). References == External links ==
Injury	An injury is any physiological damage to living tissue caused by immediate physical stress. An injury can occur intentionally or unintentionally and may be caused by blunt trauma, penetrating trauma, burning, toxic exposure, asphyxiation, or overexertion. Injuries can occur in any part of the body, and different symptoms are associated with different injuries. Treatment of a major injury is typically carried out by a health professional and varies greatly depending on the nature of the injury. Traffic collisions are the most common cause of accidental injury and injury-related death among humans. Injuries are distinct from chronic conditions, psychological trauma, infections, or medical procedures, though injury can be a contributing factor to any of these. Several major health organizations have established systems for the classification and description of human injuries. Occurrence Injuries may be intentional or unintentional. Intentional injuries may be acts of violence against others or self-harm against ones own person. Accidental injuries may be unforeseeable or they may be caused by negligence The most common types of unintentional injuries in order are traffic accidents, falls, drowning, burns, and accidental poisoning. Certain types of injuries are more common in developed countries or developing countries. Traffic injuries are more likely to kill pedestrians than drivers in developing countries. Scalding burns are more common in developed countries, while open-flame injuries are more common in developing countries.As of 2021, approximately 4.4 million people are killed due to injuries each year worldwide, constituting nearly 8% of all deaths. 3.16 million of these injuries are unintentional and 1.25 million are intentional. Traffic accidents are the most common form of deadly injury, causing about one-third of injury-related deaths. One-sixth are caused by suicide, and one-tenth are caused by homicide. Tens of millions of individuals require medical treatment for nonfatal injuries each year, and injuries are responsible for about 10% of all years lived with disability. Men are twice as likely to be killed through injury than women. In 2013, 367,000 children under the age of five died from injuries, down from 766,000 in 1990. Classification systems The World Health Organization (WHO) developed the International Classification of External Causes of Injury (ICECI). Under this system, injuries are classified by mechanism of injury, objects/substances producing injury, place of occurrence, activity when injured, the role of human intent, and additional modules. These codes allow the identification of distributions of injuries in specific populations and case identification for more detailed research on causes and preventive efforts.The United States Bureau of Labor Statistics developed the Occupational Injury and Illness Classification System (OIICS). Under this system injuries are classified by nature, part of body affected, source and secondary source, and event or exposure. The OIICS was first published in 1992 and has been updated several times since. The Orchard Sports Injury and Illness Classification System (OSIICS), previously OSICS, is used to classify injuries to enable research into specific sports injuries.The injury severity score (ISS) is a medical score to assess trauma severity. It correlates with mortality, morbidity, and hospitalization time after trauma. It is used to define the term major trauma (polytrauma), recognized when the ISS is greater than 15. The AIS Committee of the Association for the Advancement of Automotive Medicine designed and updates the scale. Mechanisms Trauma Traumatic injury is caused by an external object making forceful contact with the body, resulting in a wound. Major trauma is a severe traumatic injury that has the potential to cause disability or death. Serious traumatic injury most often occurs as a result of traffic collisions. Traumatic injury is the leading cause of death in people under the age of 45.Blunt trauma injuries are caused by the forceful impact of an external object. Injuries from blunt trauma may cause internal bleeding and bruising from ruptured capillaries beneath the skin, abrasion from scraping against the superficial epidermis, lacerated tears on the skin or internal organs, or bone fractures. Crush injuries are a severe form of blunt trauma damage that apply large force to a large area over a longer period of time. Penetrating trauma injuries are caused by external objects entering the tissue of the body through the skin. Low-velocity penetration injuries are caused by sharp objects, such as stab wounds, while high-velocity penetration injuries are caused by ballistic projectiles, such as gunshot wounds or injuries caused by shell fragments. Perforated injuries result in an entry wound and an exit wound, while puncture wounds result only in an entry wound. Puncture injuries result in a cavity in the tissue. Burns Burn injury is caused by contact with extreme temperature, chemicals, or radiation. The effects of burns vary depending on the depth and size. Superficial or first-degree burns only affect the epidermis, causing pain for a short period of time. Superficial partial-thickness burns cause weeping blisters and require dressing. Deep partial-thickness burns are dry and less painful due to the burning away of the skin and require surgery. Full-thickness or third-degree burns affect the entire dermis and is susceptible to infection. Fourth-degree burns reach deep tissues such as muscles and bones, causing loss of the affected area.Thermal burns are the most common type of burn, caused by contact with excessive heat, including contact with flame, contact with hot surfaces, or scalding burns caused by contact with hot water or steam. Frostbite is a type of burn caused by contact with excessive cold, causing cellular injury and deep tissue damage through the crystallization of water in the tissue. Friction burns are caused by friction with external objects, resulting in a burn and abrasion. Radiation burns are caused by exposure to ionizing radiation. Most radiation burns are sunburns caused by ultraviolet radiation or high exposure to radiation through medical treatments such as repeated radiography or radiation therapy.Electrical burns are caused by contact with electricity as it enters and passes through the body. They are often deeper than other burns, affecting lower tissues as electricity penetrates the skin, and the full extent of electrical burns are often obscured. They will also cause extensive destruction of tissue at the entry and exit points. Electrical injuries in the home are often minor, while high tension power cables cause serious electrical injuries in the workplace. Lightning strikes can also cause severe electrical injuries. Fatal electrical injuries are often caused by tetanic spasm inducing respiratory arrest or interference with the heart causing cardiac arrest.Chemical burns are caused by contact with corrosive substances such as acid or alkali. Chemical burns are rarer than most other burns, though there are many chemicals that can damage tissue. The most common chemical-related injuries are those caused by carbon monoxide, ammonia, chlorine, hydrochloric acid, and sulfuric acid. Some chemical weapons induce chemical burns, such as white phosphorus. Most chemical burns are treated with extensive application of water to remove the chemical contaminant, though some burn-inducing chemicals react with water to create more severe injuries. The ingestion of corrosive substances can cause chemical burns to the larynx and stomach. Other mechanisms Toxic injury is caused by the ingestion, inhalation, injection, or absorption of a toxin. This may occur through an interaction caused by a drug or the ingestion of a poison. Different toxins may cause different types of injuries, and many will cause injury to specific organs. Toxins in gases, dusts, aerosols, and smoke can be inhaled, potentially causing respiratory failure. Respiratory toxins can be released by structural fires, industrial accidents, domestic mishaps, or through chemical weapons. Some toxicants may affect other parts of the body after inhalation, such as carbon monoxide.Asphyxia causes injury to the body from a lack of oxygen. It can be caused by drowning, inhalation of certain substances, strangulation, blockage of the airway, traumatic injury to the airway, apnea, and other means. The most immediate injury caused by asphyxia is hypoxia, which can in turn cause acute lung injury or acute respiratory distress syndrome as well as damage to the circulatory system. The most severe injury associated with asphyxiation is cerebral hypoxia and ischemia, in which the brain receives insufficient oxygen or blood, resulting in neurological damage or death. Specific injuries are associated with water inhalation, including alveolar collapse, atelectasis, intrapulmonary shunting, and ventilation perfusion mismatch. Simple asphyxia is caused by a lack of external oxygen supply. Systemic asphyxia is caused by exposure to a compound that prevents oxygen from being transported or used by the body. This can be caused by azides, carbon monoxide, cyanide, smoke inhalation, hydrogen sulfide, methemoglobinemia-inducing substances, opioids, or other systemic asphyxiants. Ventilation and oxygenation are necessary for treatment of asphyxiation, and some asphyxiants can be treated with antidotes.Injuries of overuse or overexertion can occur when the body is strained through use, affecting the bones, muscles, ligaments, or tendons. Sports injuries are often overuse injuries such as tendinopathy. Over-extension of the ligaments and tendons can result in sprains and strains, respectively. Repetitive sedentary behaviors such as extended use of a computer or a physically repetitive occupation may cause a repetitive strain injury. Extended use of brightly lit screens may also cause eye strain. Locations Abdomen Abdominal trauma includes injuries to the stomach, intestines, liver, pancreas, kidneys, gallbladder, and spleen. Abdominal injuries are typically caused by traffic accidents, assaults, falls, and work-related injuries, and physical examination is often unreliable in diagnosing blunt abdominal trauma. Splenic injury can cause low blood volume or blood in the peritoneal cavity. The treatment and prognosis of splenic injuries are dependent on cardiovascular stability. The gallbladder is rarely injured in blunt trauma, occurring in about 2% of blunt abdominal trauma cases. Injuries to the gallbladder are typically associated with injuries to other abdominal organs. The intestines are susceptible to injury following blunt abdominal trauma. The kidneys are protected by other structures in the abdomen, and most injuries to the kidney are a result of blunt trauma. Kidney injuries typically cause blood in the urine.Due to its location in the body, pancreatic injury is relatively uncommon but more difficult to diagnose. Most injuries to the pancreas are caused by penetrative trauma, such as gunshot wounds and stab wounds. Pancreatic injuries occur in under 5% of blunt abdominal trauma cases. The severity of pancreatic injury depends primarily on the amount of harm caused to the pancreatic duct. The stomach is also well protected from injury due to its heavy layering, its extensive blood supply, and its position relative to the rib cage. As with pancreatic injuries, most traumatic stomach injuries are caused by penetrative trauma, and most civilian weapons do not cause long-term tissue damage to the stomach. Blunt trauma injuries to the stomach are typically caused by traffic accidents. Ingestion of corrosive substances can cause chemical burns to the stomach. Liver injury is the most common type of organ damage in cases of abdominal trauma. The livers size and location in the body makes injury relatively common compared to other abdominal organs, and blunt trauma injury to the liver is typically treated with nonoperative management. Liver injuries are rarely serious, though most injuries to the liver are concomitant with other injuries, particularly to the spleen, ribs, pelvis, or spinal cord. The liver is also susceptible to toxic injury, with overdose of paracetamol being a common cause of liver failure. Face Facial trauma may affect the eyes, nose, ears, or mouth. Nasal trauma is a common injury and the most common type of facial injury. Oral injuries are typically caused by traffic accidents or alcohol-related violence, though falls are a more common cause in young children. The primary concerns regarding oral injuries are that the airway is clear and that there are no concurrent injuries to other parts of the head or neck. Oral injuries may occur in the soft tissue of the face, the hard tissue of the mandible, or as dental trauma.The ear is susceptible to trauma in head injuries due to its prominent location and exposed structure. Ear injuries may be internal or external. Injuries of the external ear are typically lacerations of the cartilage or the formation of a hematoma. Injuries of the middle and internal ear may include a perforated eardrum or trauma caused by extreme pressure changes. The ear is also highly sensitive to blast injury. The bones of the ear are connected to facial nerves, and ear injuries can cause paralysis of the face. Trauma to the ear can cause hearing loss.Eye injuries often take place in the cornea, and they have the potential to permanently damage vision. Corneal abrasions are a common injury caused by contact with foreign objects. The eye can also be injured by a foreign object remaining in the cornea. Radiation damage can be caused by exposure to excessive light, often caused by welding without eye protection or being exposed to excessive ultraviolet radiation, such as sunlight. Exposure to corrosive chemicals can permanently damage the eyes, causing blindness if not sufficiently irrigated. The eye is protected from most blunt injuries by the infraorbital margin, but in some cases blunt force may cause an eye to hemorrhage or tear. Overuse of the eyes can cause eye strain, particularly when looking at brightly lit screens for an extended period. Heart Cardiac injuries affect the heart and blood vessels. Blunt cardiac injury in a common injury caused by blunt trauma to the heart. It can be difficult to diagnose, and it can have many effects on the heart, including contusions, ruptures, acute valvular disorders, arrhythmia, or heart failure. Penetrative trauma to the heart is typically caused by stab wounds or gunshot wounds. Accidental cardiac penetration can also occur in rare cases from a fractured sternum or rib. Stab wounds to the heart are typically survivable with medical attention, though gunshot wounds to the heart are not. The right ventricle is most susceptible to injury due to its prominent location. The two primary consequences of traumatic injury to the heart are severe hemorrhaging and fluid buildup around the heart. Musculoskeletal Musculoskeletal injuries affect the skeleton and the muscular system. Soft tissue injuries affect the skeletal muscles, ligaments, and tendons. Ligament and tendon injuries account for half of all musculoskeletal injuries. Ligament sprains and tendon strains are common injuries that do not require intervention, but the healing process is slow. Physical therapy can be used to assist reconstruction and use of injured ligaments and tendons. Torn ligaments or tendons typically require surgery. Skeletal muscles are abundant in the body and commonly injured when engaging in athletic activity. Muscle injuries trigger an inflammatory response to facilitate healing. Blunt trauma to the muscles can cause contusions and hematomas. Excessive tensile strength can overstretch a muscle, causing a strain. Strains may present with torn muscle fibers, hemorrhaging, or fluid in the muscles. Severe muscle injuries in which a tear extends across the muscle can cause total loss of function. Penetrative trauma can cause laceration to muscles, which may take an extended time to heal. Unlike contusions and strains, lacerations are uncommon in sports injuries.Traumatic injury may cause various bone fractures depending on the amount of force, direction of the force, and width of the area affected. Pathologic fractures occur when a previous condition weakens the bone until it can be easily fractured. Stress fractures occur when the bone is overused or suffers under excessive or traumatic pressure, often during athletic activity. Hematomas occur immediately following a bone fracture, and the healing process often takes from six weeks to three months to complete, though continued use of the fractured bone will prevent healing. Articular cartilage damage may also affect function of the skeletal system, and it can cause posttraumatic osteoarthritis. Unlike most bodily structures, cartilage cannot be healed once it is damaged. Nervous system Injuries to the nervous system include brain injury, spinal cord injury, and nerve injury. Trauma to the brain causes traumatic brain injury (TBI), causing "long-term physical, emotional, behavioral, and cognitive consequences". Mild TBI, including concussion, often occurs during athletic activity, military service, or as a result of untreated epilepsy, and its effects are typically short-term. More severe injuries to the brain cause moderate TBI, which may cause confusion or lethargy, or severe TBI, which may result in a coma or a secondary brain injury. TBI is a leading cause of mortality. Approximately half of all trauma-related deaths involve TBI. Non-traumatic injuries to the brain causeacquired brain injury (ABI). This can be caused by stroke, a brain tumor, poison, infection, cerebral hypoxia, drug use, or the secondary effect of a TBI.Injury to the spinal cord is not immediately terminal, but it is associated with concomitant injuries, lifelong medical complications, and reduction in life expectancy. It may result in complications in several major organ systems and a significant reduction in mobility or paralysis. Spinal shock causes temporary paralysis and loss of reflexes. Unlike most other injuries, damage to the peripheral nerves is not healed through cellular proliferation. Following nerve injury, the nerves undergo degeneration before regenerating, and other pathways can be strengthened or reprogrammed to make up for lost function. The most common form of peripheral nerve injury is stretching, due to their inherent elasticity. Nerve injuries may also be caused by laceration or compression. Pelvis Injuries to the pelvic area include injuries to the bladder, rectum, colon, and reproductive organs. Traumatic injury to the bladder is rare and often occurs with other injuries to the abdomen and pelvis. The bladder is protected by the peritoneum, and most cases of bladder injury are concurrent with a fracture of the pelvis. Bladder trauma typically causes hematuria, or blood in the urine. Ingestion of alcohol may cause distension of the bladder, increasing the risk of injury. A catheter may be used to extract blood from the bladder in the case of hemorrhaging, though injuries that break the peritoneum typically require surgery. The colon is rarely injured by blunt trauma, with most cases occurring from penetrative trauma through the abdomen. Rectal injury is less common than injury to the colon, though the rectum is more susceptible to injury following blunt force trauma to the pelvis.Injuries to the male reproductive system are rarely fatal and typically treatable through grafts and reconstruction. The elastic nature of the scrotum makes it resistant to injury, accounting for 1% of traumatic injuries. Trauma to the scrotum may cause damage to the testis or the spermatic cord. Trauma to the penis can cause penile fracture, typically as a result of vigorous intercourse. Injuries to the female reproductive system are often a result of pregnancy and childbirth or sexual activity. They are rarely fatal, but they can produce a variety of complications, such as chronic discomfort, dyspareunia, infertility, or the formation of fistulas. Age can greatly affect the nature of genital injuries in women due to changes in hormone composition. Childbirth is the most common cause of genital injury to women of reproductive age. Many cultures practice female genital mutilation, which is estimated to affect over 125 million women and girls worldwide as of 2018. Tears and abrasions to the vagina are common during sexual intercourse, and these may be exacerbated in instances of non-consensual sexual activity. Respiratory tract Injuries to the respiratory tract affect the lungs, diaphragm, trachea, bronchus, pharynx, or larynx. Tracheobronchial injuries are rare and often associated with other injuries. Bronchoscopy is necessary for an accurate diagnosis of tracheobronchial injury. The neck, including the pharynx and larynx, is highly vulnerable to injury due to its complex, compacted anatomy. Injuries to this area can cause airway obstruction. Ingestion of corrosive chemicals can cause chemical burns to the larynx. Inhalation of toxic materials can also cause serious injury to the respiratory tract.Severe trauma to the chest can cause damage to the lungs, including pulmonary contusions, accumulation of blood, or a collapsed lung. The inflammation response to a lung injury can cause acute respiratory distress syndrome. Injuries to the lungs may cause symptoms ranging from shortness of breath to terminal respiratory failure. Injuries to the lungs are often fatal, and survivors often have a reduced quality of life. Injuries to the diaphragm are uncommon and rarely serious, but blunt trauma to the diaphragm can result in the formation of a hernia over time. Injuries to the diaphragm may present in many ways, including abnormal blood pressure, cardiac arrest, gastroinetestinal obstruction, and respiratory insufficiency. Injuries to the diaphragm are often associated with other injuries in the chest or abdomen, and its position between two major cavities of the human body may complicate diagnosis. Skin Most injuries to the skin are minor and do not require specialist treatment. Lacerations of the skin are typically repaired with sutures, staples, or adhesives. The skin is susceptible to burns, and burns to the skin often cause blistering. Abrasive trauma scrapes or rubs off the skin, and severe abrasions require skin grafting to repair. Skin tears involve the removal of the epidermis or dermis through friction or shearing forces, often in vulnerable populations such as the elderly. Skin injuries are potentially complicated by foreign bodies such as glass, metal, or dirt that entered the wound, and skin wounds often require cleaning. Treatment Much of medical practice is dedicated to the treatment of injuries. Traumatology is the study of traumatic injuries and injury repair. Certain injuries may be treated by specialists. Serious injuries sometimes require trauma surgery. Following serious injuries, physical therapy and occupational therapy are sometimes used for rehabilitation. Medication is commonly used to treat injuries. Emergency medicine during major trauma prioritizes the immediate consideration of life-threatening injuries that can be quickly addressed. The airway is evaluated, clearing bodily fluids with suctioning or creating an artificial airway if necessary. Breathing is evaluated by evaluating motion of the chest wall and checking for blood or air in the pleural cavity. Circulation is evaluated to resuscitate the patient, including the application of intravenous therapy. Disability is evaluated by checking for responsiveness and reflexes. Exposure is then used to examine the patient for external injury. Following immediate life-saving procedures, a CT scan is used for a more thorough diagnosis. Further resuscitation may be required, including ongoing blood transfusion, mechanical ventilation and nutritional support.Pain management is another aspect of injury treatment. Pain serves as an indicator to determine the nature and severity of an injury, but it can also worsen an injury, reduce mobility, and affect quality of life. Analgesic drugs are used to reduce the pain associated with injuries, depending on the persons age, the severity of the injury, and previous medical conditions that may affect pain relief. NSAIDs such as aspirin and ibuprofen are commonly used for acute pain. Opioid medications such as fentanyl, methadone, and morphine are used to treat severe pain in major trauma, but their use is limited due to associated long-term risks such as addiction. Complications Complications may arise as a result of certain injuries, increasing the recovery time, further exasperating the symptoms, or potentially causing death. The extent of the injury and the age of the injured person may contribute to the likelihood of complications. Infection of wounds is a common complication in traumatic injury, resulting in diagnoses such as pneumonia or sepsis. Wound infection prevents the healing process from taking place and can cause further damage to the body. A majority of wounds are contaminated with microbes from other parts of the body, and infection takes place when the immune system is unable to address this contamination. The surgical removing of devitalized tissue and the use of topical antimicrobial agents can prevent infection.Hemorrhaging of blood is a common result of injuries, and it can cause several complications. Pooling of blood under the skin can cause a hematoma, particularly after blunt trauma or the suture of a laceration. Hematomas are susceptible to infection and are typically treated compression, though surgery is necessary in severe cases. Excessive blood loss can cause hypovolemic shock in which cellular oxygenation can no longer take place. This can cause tachycardia, hypotension, coma, or organ failure. Fluid replacement is often necessary to treat blood loss. Other complications of injuries include cavitation, development of fistulas, and organ failure. Social and psychological aspects Injuries often cause psychological harm in addition to physical harm. Traumatic injuries are associated with psychological trauma and distress, and some victims of traumatic injuries will display symptoms of post-traumatic stress disorder during and after the recovery of the injury. The specific symptoms and their triggers vary depending on the nature of the injury. Body image and self-esteem can also be affected by injury. Injuries that cause permanent disabilities, such as spinal cord injuries, can have severe effects on self-esteem. Disfiguring injuries can negatively affect body image, leading to a lower quality of life. Burn injuries in particular can cause dramatic changes in a persons appearance that may negatively affect body image.Severe injury can also cause social harm. Disfiguring injuries may also result in stigma due to scarring or other changes in appearance. Certain injuries may necessitate a change in occupation or prevent employment entirely. Leisure activities are similarly limited, and athletic activities in particular may be impossible following severe injury. In some cases, the effects of injury may strain personal relationships, such as marriages. Psychological and social variables have been found to affect the likelihood of injuries among athletes. Increased life stress can cause an increase in the likelihood of athletic injury, while social support can decrease the likelihood of injury. Social support also assists in the recovery process after athletic injuries occur. See also Injury prevention List of causes of death by rate First aid Medical emergency References External links International Trauma Conferences (registered trauma charity providing trauma education for medical professionals worldwide) Trauma.org (trauma resources for medical professionals) Emergency Medicine Research and Perspectives (emergency medicine procedure videos) American Trauma Society Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine
Cutaneous leishmaniasis	Cutaneous leishmaniasis is the most common form of leishmaniasis affecting humans. It is a skin infection caused by a single-celled parasite that is transmitted by the bite of a phlebotomine sand fly. There are about thirty species of Leishmania that may cause cutaneous leishmaniasis. This disease is considered to be a zoonosis (an infectious disease that is naturally transmissible from animals to humans), with the exception of Leishmania tropica — which is often an anthroponotic disease (an infectious disease that is naturally transmissible from humans to vertebrate animals). Signs and symptoms Post kala-azar dermal leishmaniasis Post-kala-azar dermal leishmaniasis (PKDL) is a recurrence of kala-azar that may appear on the skin of affected individuals months and up to 20 years after being partially treated, untreated or even in those considered adequately treated. In Sudan, they can be demonstrated in up to 60% of treated cases. They manifest as hypopigmented skin lesions (such as macules, papules, nodules), or facial redness. Though any organism causing kala-azar can lead to PKDL, it is commonly associated with Leishmania donovani which gives different disease patterns in India and Sudan. In the Indian variant, nodules enlarge with time and form plaques but rarely ulcerate, but nodules from the African variety often ulcerate as they progress. Nerve involvement is common in African variety but rare in Indian subcontinent. Histology demonstrates a mixture of chronic inflammatory cells; there can be macrophage or epitheloid granuloma. Parasite concentration is not consistent among studies, perhaps reflecting low sensitivity of diagnostic methods used in earlier entries.Current approach to diagnosis involves demonstration of parasite by microscopy, in vitro culture or animal inoculation; immunodiagnosis of parasite antigen; detection of parasite DNA in tissue.Newer polymerase chain reaction (PCR) based tools have higher sensitivity and specificity. Emergence of PKDL has been reported in HIV affected individuals and may become a problem in the future. Sodium stibogluconate alone or in combination with rifampicin is used for the treatment of PKDL for a long course of up to 4 months. Compliance can be an issue for such a long course. Mucocutaneous leishmaniasis Mucocutaneous leishmaniasis is an especially disturbing form of cutaneous leishmaniasis, because it produces destructive and disfiguring lesions of the face. It is most often caused by Leishmania braziliensis, but cases caused by L. aethiopica have also been described.Mucocutaneous leishmaniasis is very difficult to treat. Treatment involves the use of pentavalent antimonial compounds, which are highly toxic (common side effects include thrombophlebitis, pancreatitis, cardiotoxicity and hepatotoxicity) and not very effective. For example, in one study, despite treatment with high doses of sodium stibogluconate for 28 days, only 30% of patients remained disease-free at 12 months follow-up. Even in those patients who achieve an apparent cure, as many as 19% will relapse. Several drug combinations with immunomodulators have been tested, for example, a combination of pentoxifylline (inhibitor of TNF-α) and a pentavalent antimonial at a high dose for 30 days in a small-scale (23 patients) randomised placebo-controlled study from Brazil achieved cure rates of 90% and reduced time to cure, a result that should be interpreted cautiously in light of inherent limitations of small-scale studies. In an earlier small-scale (12 patients) study, addition of imiquimod showed promising results which need yet to be confirmed in larger trials. Pathophysiology Promastigotes of Leishmania are transmitted to human skin by the bite of a sandfly. Leishmania then invades human macrophages and replicates intracellularly. A raised, red lesion develops at the site of the bite (often weeks or sometimes years afterwards). The lesion then ulcerates and may become secondarily infected with bacteria. In many species (for example, L. major) the lesion often spontaneously heals with atrophic scarring. In some species (for example, L. braziliensis) the lesion may spontaneously heal with scarring, but then reappear elsewhere (especially as destructive mucocutaneous lesions). Lesions of other Leishmania species may spontaneously heal and then reappear as satellite lesions around the site of the original lesion, or along the route of lymphatic drainage.Some species tend to cause cutaneous leishmaniasis (e.g., L. major and L.tropica), whereas some species tend to cause visceral leishmaniasis (e.g., L. infantum and L. donovani), though emerging research (due to high deployment rates of western countries to indigenous areas) is showing these species specific presentation lines are blurring. Diagnosis Diagnosis is based on the characteristic appearance of non-healing raised, scaling lesions that may ulcerate and become secondarily infected with organisms such as Staphylococcus aureus, in someone who has returned from an endemic area.In resource limited settings, fine-needle aspiration of the lesion is confirmatory with identification of amastigote form of Leishmania. The gold standard for diagnosis is a PCR test. Treatment American cutaneous and mucocutaneous leishmaniasis The best treatment for American cutaneous and mucocutaneous leishmaniasis (ACML) is not known. Pentavalent antimonial drugs (sodium stibogluconate (SSG) and meglumine antimonate (Glucantime, MA)) have been used since the 1940s, but they are expensive, toxic, and painful. Treatments that work for one species of Leishmania may not work for another; therefore, it is recommended that the exact species be identified prior to initiating treatment. Unfortunately, leishmaniasis is an orphan disease in developed nations, and almost all the current treatment options are toxic with significant side effects.The best-studied treatments for ACML caused by two Leishmania species are listed below. However, one should note that most of the studies examining treatments of ACML were poorly designed. Therefore, no definitive treatment guidelines or recommendations are currently available, as large-scale and well-conducted studies are necessary to evaluate the long-term effects of current treatments. Leishmania braziliensis and Leishmania panamensis: There is good evidence that oral allopurinol plus intramuscular MA is superior to either medication alone. In addition, a 20-day course of intravenous MA was better than a 7-day course as well as a 3- or 7-day course of intravenous MA with paromomycin + 12% methylbenzethonium chloride. For L. braziliensis, oral pentoxifylline plus intravenous SSG seems to be more efficacious than intravenous SSG alone, and intravenous MA was superior to intramuscular paromomycin sulfate and IV pentamidine. Likewise, intramuscular MA was shown to be better than the Bacillus Calmette-Guerin vaccine. For L. panamensis, oral ketoconazole, oral miltefosine, and topical paromomycin + 12% methylbenzethonium chloride were shown to be superior to placebo.There is no strong evidence for the efficacy of surgery, oral itraconazole and fluconazole, oral antibiotics (rifampicin, metronidazole, cotrimoxazole), intravenous or topical amphotericin B, oral dapsone, photodynamic therapy, promoting healing therapies, laser, or cryotherapy treatments. Old World cutaneous leishmaniasis Similar to ACML, the treatment recommendations for Old World cutaneous leishmaniasis (OWCL) are uncertain due to the variability of and inconsistencies within the research.Most studies done to assess treatments of OWCL included two species of parasites, Leishmania major and Leishmania tropica. The most well-studied treatments for OWCL are oral itraconazole and topical paromomycin.Patients treated with oral itraconazole for an average of 2.5 months had a higher cure rate compared to placebo, but they also had a higher rate of side effects, including gastrointestinal complaints, abnormal liver function, headaches, and dizziness.Patients treated with topical paromomycin showed no difference in cure rate compared to placebo, but patients treated with paromomycin had a higher rate of adverse skin reactions.The treatments for other Leishmania species responsible for OWCL, such as L. infantum, L. aethiopica, and L. donovani, have not been thoroughly studied. In addition, the effects of leishmaniasis treatment in children, women of childbearing age, patients with comorbidities, and immunocompromised patients have not been well established. Epidemiology Cutaneous leishmaniasis is endemic in all tropical and subtropical areas of the world. The distribution of this disease is very tightly linked to geography, and villages even 15 miles apart can have very different rates of cutaneous leishmaniasis.Most species of Leishmania are capable of infecting humans and causing cutaneous leishmaniasis. In the New World, these organisms include L. amazonensis, L. braziliensis, L. guyanensis, L. lainsoni, L. lindenbergi, L. mexicana, L. naiffi, L. panamensis, L. peruviana, L. shawi, and L. venezuelensis. Old World species that cause cutaneous leishmaniasis include L. aethiopica, L. infantum, L. major, and L. tropica. With the exception of L. tropica — which is commonly associated with human settlements and therefore considered to be an anthroponotic species — all of these organisms are zoonotic. As demographic changes occur in developing nations, some species that have traditionally been considered to be zoonotic (e.g., L. panamensis) are becoming primarily human pathogens.Dogs and rodents serve as the primary animal reservoir hosts in the sylvatic cycle, but people with chronic PKDL can also serve as important reservoir hosts for cutaneous leishmaniasis. The most common vectors for cutaneous leishmaniasis in the Old World are sandflies of the genus Phlebotomus, while Lutzomyia and those within the family Psychodidae (especially the genus Psychodopygus) are the most common vectors in the New World. There are more than 600 species of phlebotomine sandflies, and only 30 of these are known vectors. Cutaneous leishmaniasis has been seen in American and Canadian troops coming back from Afghanistan. Means of Prevention The sand fly stings mainly at night, and it usually occurs about half a meter above the ground (so sleeping on high beds can prevent infection). To avoid stinging, apply mosquito repellent, and cover the body.Studies conducted in recent years show that the plant Bougainvillea glabra may protect against the sand fly. The plant was found to be toxic to sand flies and that the life span of flies that ate from this plant was significantly shortened and sometimes led to their premature death before they could spread the disease.Hebrew University study found that some plants attract sand flies. These plants often attract sand flies up to 14 times more than Bougainvillea glabra, but unlike Bougainvillea glabra, are not toxic to the sand flies. Based on this information, the dispersion of sand flies can be controlled by limiting the growth of these plants near populated areas. Alternatively, these plants may serve to capture and control sand flies by using their odor compounds or the plants themselves alongside simple glue traps, or by spraying them with deadly pesticides for sand flies which are safe for humans and mammals (e.g., boric acid or spinosad) thereby stopping the spread of the disease. Of the dozens of plants examined, the three plants that attracted especially sand flies are the Ochradenus baccatus, Prosopis farcta, and Tamarix nilotica. Outbreak in 2016 The Middle East, in 2016, seems to be experiencing an increase in the cutaneous leishmaniasis disease due to migrants fleeing the Islamic State of Iraq and the Levant. Reports of the increase in the disease have surfaced in Turkey, Lebanon, and elsewhere.The huge increase in the spread of the disease is attributed to the refugee crises in the Middle East and North Africa over the past five years, particularly due to the displacement of millions of Syrian refugees. The outbreak among Syrian refugees was documented by the World Health Organization (WHO) in 2012 and recognized as ongoing. Nepal A recent study with large series of cases from Mid-western region of Nepal have demonstrated that cutaneous leishmaniasis is an under recognized medical condition posing health challenges mandating new guidelines for its elimination/ eradication. Other animals Besides humans, cutaneous leishmaniasis often affects other animals, notably in dogs as canine leishmaniasis. References == External links ==
Nicotine dependence	Nicotine dependence is a state of dependence upon nicotine. Nicotine dependence is a chronic, relapsing disease defined as a compulsive craving to use the drug, despite social consequences, loss of control over drug intake, and emergence of withdrawal symptoms. Tolerance is another component of drug dependence. Nicotine dependence develops over time as a person continues to use nicotine. The most commonly used tobacco product is cigarettes, but all forms of tobacco use and e-cigarette use can cause dependence. Nicotine dependence is a serious public health problem because it leads to continued tobacco use, which is one of the leading preventable causes of death worldwide, causing more than 8 million deaths per year.According to the World Health Organization, "Greater nicotine dependence has been shown to be associated with lower motivation to quit, difficulty in trying to quit, and failure to quit, as well as with smoking the first cigarette earlier in the day and smoking more cigarettes per day." The WHO estimates that there are 1.1 billion smokers globally. Of the 34 million smokers in the US in 2018, 74.6% smoked every day, indicating the potential for some level of nicotine dependence. There is an increased frequency of nicotine dependence in people with anxiety disorders.There are different ways of measuring nicotine dependence. Common dependence assessment scales for cigarette smokers are the Fagerström Test for Nicotine Dependence, the Diagnostic and Statistical Manual of Mental Disorders, the Cigarette Dependence Scale, the Nicotine Dependence Syndrome Scale, and the Wisconsin Inventory of Smoking Dependence Motives (WISDM).Nicotine is a parasympathomimetic stimulant that attaches to nicotinic acetylcholine receptors in the brain. Neuroplasticity within the brains reward system, including an increase in the number of nicotine receptors, occurs as a result of long-term nicotine use, leading to nicotine dependence. There are genetic risk factors for developing dependence. For instance, genetic markers for a specific type of nicotinic receptor (the α5-α3-β4 nicotine receptors) have been linked to increased risk for dependence. Evidence-based treatments, including medications (nicotine replacement therapy, bupropion, varenicline, or cytisine) and behavioral counseling, can double or triple a smokers chances of quitting successfully. Definition Nicotine dependence is defined as a neurobiological adaptation to repeated drug exposure that is manifested by highly controlled or compulsive use, the development of tolerance, experiencing withdrawal symptoms upon cessation including cravings, and an inability to quit despite harmful effects. Nicotine dependence has also been conceptualized as a chronic, relapsing disease. A 1988 Surgeon General report states, "Tolerance" is another aspect of drug addiction [dependence] whereby a given dose of a drug produces less effect or increasing doses are required to achieve a specified intensity of response. Physical dependence on the drug can also occur, and is characterized by a withdrawal syndrome that usually accompanies drug abstinence. After cessation of drug use, there is a strong tendency to relapse."Nicotine dependence leads to heavy smoking and causes severe withdrawal symptoms and relapse back to smoking. Nicotine dependence develops over time as a person continues to use nicotine. Teenagers do not have to be daily or long-term smokers to show withdrawal symptoms. Relapse should not frustrate the nicotine user from trying to quit again. A 2015 review found "Avoiding withdrawal symptoms is one of the causes of continued smoking or relapses during attempts at cessation, and the severity and duration of nicotine withdrawal symptoms predict relapse." Symptoms of nicotine dependence include irritability, anger, impatience, and problems in concentrating. Diagnosis There are different ways of measuring nicotine dependence. The five common dependence assessment scales are the Fagerström Test for Nicotine Dependence, the Diagnostic and Statistical Manual of Mental Disorders, the Cigarette Dependence Scale, the Nicotine Dependence Syndrome Scale, and the Wisconsin Inventory of Smoking Dependence Motives.The Fagerström Test for Nicotine Dependence focuses on measuring physical dependence which is defined "as a state produced by chronic drug administration, which is revealed by the occurrence of signs of physiological dysfunction when the drug is withdrawn; further, this dysfunction can be reversed by the administration of drug". The long use of Fagerström Test for Nicotine Dependence is supported by the existence of significant preexisting research, and its conciseness.The 4th edition of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) had a nicotine dependence diagnosis which was defines as "...a cluster of cognitive, behavioral, and physiological symptoms..." In the updated DSM-5 there is no nicotine dependence diagnosis, but rather Tobacco Use Disorder, which is defined as, "A problematic pattern of tobacco use leading to clinically significant impairment or distress, as manifested by at least 2 of the following [11 symptoms], occurring within a 12-month period."The Cigarette Dependence Scale was developed "to index dependence outcomes and not dependence mechanisms". The Nicotine Dependence Syndrome Scale, "a 19-item self-report measure, was developed as a multidimensional scale to assess nicotine dependence". The Wisconsin Inventory of Smoking Dependence Motives "is a 68-item measure developed to assess dependence as a motivational state". Mechanisms Traditional cigarettes are the most common delivery device for nicotine. However, electronic cigarettes are becoming more popular. Nicotine can also be delivered via other tobacco products such as chewing tobacco, snus, pipe tobacco, hookah, all of which can produce nicotine dependence. Biomolecular Pre-existing cognitive and mood disorders may influence the development and maintenance of nicotine dependence. Nicotine is a parasympathomimetic stimulant that binds to and activates nicotinic acetylcholine receptors in the brain, which subsequently causes the release of dopamine and other neurotransmitters, such as norepinephrine, acetylcholine, serotonin, gamma-aminobutyric acid, glutamate, endorphins, and several neuropeptides. Repeated exposure to nicotine can cause an increase in the number of nicotinic receptors, which is believed to be a result of receptor desensitization and subsequent receptor upregulation. This upregulation or increase in the number of nicotinic receptors significantly alters the functioning of the brain reward system. With constant use of nicotine, tolerance occurs at least partially as a result of the development of new nicotinic acetylcholine receptors in the brain. After several months of nicotine abstinence, the number of receptors go back to normal. Nicotine also stimulates nicotinic acetylcholine receptors in the adrenal medulla, resulting in increased levels of adrenaline and beta-endorphin. Its physiological effects stem from the stimulation of nicotinic acetylcholine receptors, which are located throughout the central and peripheral nervous systems. Chronic nicotinic acetylcholine receptor activation from repeated nicotine exposure can induce strong effects on the brain, including changes in the brains physiology, that result from the stimulation of regions of the brain associated with reward, pleasure, and anxiety. These complex effects of nicotine on the brain are still not well understood.When these receptors are not occupied by nicotine, they are believed to produce withdrawal symptoms. These symptoms can include cravings for nicotine, anger, irritability, anxiety, depression, impatience, trouble sleeping, restlessness, hunger, weight gain, and difficulty concentrating.Neuroplasticity within the brains reward system occurs as a result of long-term nicotine use, leading to nicotine dependence. There are genetic risk factors for developing dependence. For instance, genetic markers for a specific type of nicotinic receptor (the α5-α3-β4 nicotine receptors) have been linked to increased risk for dependence. The most well-known hereditary influence related to nicotine dependence is a mutation at rs16969968 in the nicotinic acetylcholine receptor CHRNA5, resulting in an amino acid alteration from aspartic acid to asparagine. The single-nucleotide polymorphisms (SNPs) rs6474413 and rs10958726 in CHRNB3 are highly correlated with nicotine dependence. Many other known variants within the CHRNB3–CHRNA6 nicotinic acetylcholine receptors are also correlated with nicotine dependence in certain ethnic groups. There is a relationship between CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptors and complete smoking cessation. Increasing evidence indicates that the genetic variant CHRNA5 predicts the response to smoking cessation medicine. Psychosocial In addition to the specific neurological changes in nicotinic receptors, there are other changes that occur as dependence develops. Through various conditioning mechanisms (operant and cue/classical), smoking comes to be associated with different mood and cognitive states as well as external contexts and cues. Treatment There are treatments for nicotine dependence, although the majority of the evidence focuses on treatments for cigarette smokers rather than people who use other forms of tobacco (e.g., chew, snus, pipes, hookah, e-cigarettes). Evidence-based medicine can double or triple a smokers chances of quitting successfully. Medication There are eight major evidence-based medications for treating nicotine dependence: bupropion, cytisine (not approved for use in some countries, including the US), nicotine gum, nicotine inhaler, nicotine lozenge/mini-lozenge, nicotine nasal spray, nicotine patch, and varenicline. These medications have been shown to significantly improve long-term (i.e., 6-months post-quit day) abstinence rates, especially when used in combination with psychosocial treatment. The nicotine replacement treatments (i.e., patch, lozenge, gum) are dosed based on how dependent a smoker is—people who smoke more cigarettes or who smoke earlier in the morning use higher doses of nicotine replacement treatments. There is no consensus for remedies for tobacco use disorder among pregnant smokers who also use alcohol and stimulants. Vaccine TA-NIC is a proprietary vaccine in development similar to TA-CD but being used to create human anti-nicotine antibodies in a person to destroy nicotine in the human body so that it is no longer effective. Psychosocial Psychosocial interventions delivered in-person (individually or in a group) or over the phone (including mobile phone interventions) have been shown to effectively treat nicotine dependence. These interventions focus on providing support for quitting and helping with smokers with problem-solving and developing healthy responses for coping with cravings, negative moods, and other situations that typically lead to relapse. The combination of pharmacotherapy and psychosocial interventions has been shown to be especially effective. Epidemiology First-time nicotine users develop a dependence about 32% of the time. There are approximately 976 million smokers in the world. Estimates are that half of smokers (and one-third of former smokers) are dependent based on DSM criteria, regardless of age, gender or country of origin, but this could be higher if different definitions of dependence were used. Recent data suggest that, in the United States, the rates of daily smoking and the number of cigarettes smoked per day are declining, suggesting a reduction in population-wide dependence among current smokers. However, there are different groups of people who are more likely to smoke than the average population, such as those with low education or low socio-economic status and those with mental illness. There is also evidence that among smokers, some subgroups may be more dependent than other groups. Men smoke at higher rates than do women and score higher on dependence indices; however, women may be less likely to be successful in quitting, suggesting that women may be more dependent by that criterion. There is an increased frequency of nicotine dependence in people with anxiety disorders. 6% of smokers who want to quit smoking each year are successful at quitting. Nicotine withdrawal is the main factor hindering smoking cessation. A 2010 World Health Organization report states, "Greater nicotine dependence has been shown to be associated with lower motivation to quit, difficulty in trying to quit, and failure to quit, as well as with smoking the first cigarette earlier in the day and smoking more cigarettes per day." E-cigarettes may result in starting nicotine dependence again. Greater nicotine dependence may result from dual use of traditional cigarettes and e-cigarettes. Like tobacco companies did in the last century, there is a possibility that e-cigarettes could result in a new form of dependency on nicotine across the world. Concerns Nicotine dependence results in substantial mortality, morbidity, and socio-economic impacts. Nicotine dependence is a serious public health concern due to it being one of the leading causes of avoidable deaths worldwide. The medical community is concerned that e-cigarettes may escalate global nicotine dependence, particularly among adolescents who are attracted to many of the flavored e-cigarettes. There is strong evidence that vaping induces symptoms of dependence in users. Many organizations such the World Health Organization, American Lung Association, and Australian Medical Association do not approve of vaping for quitting smoking in youth, making reference to concerns about their safety and the potential that experimenting with vaping may result in nicotine dependence and later tobacco use. Notes See also Nicotine poisoning Nicotine withdrawal Bibliography Stratton, Kathleen; Kwan, Leslie Y.; Eaton, David L. (January 2018). Public Health Consequences of E-Cigarettes (PDF). National Academies of Sciences, Engineering, and Medicine. National Academies Press. pp. 1–774. doi:10.17226/24952. ISBN 978-0-309-46834-3. PMID 29894118. References External links Fagerstrom Test of Nicotine Dependence (Heatherton et al., 1991) Heaviness of Smoking Index (Heatherton et al., 1989) Diagnostic and Statistical Manual of Mental Disorders V (DSM-V) Tobacco Dependence Screener (Kawakami et al., 1999) Nicotine Dependence Syndrome Scale (NDSS; Shiffman, Waters & Hickcox, 2004) Cigarette Dependence Scale (Etter et al., 2003) Wisconsin Inventory of Smoking Dependence Motives (Piper et al., 2004)
Cat anatomy	The anatomy of the domestic cat is similar to that of other members of the genus Felis. Mouth Permanent dentition teeth Cats are carnivores that have highly specialized teeth. There are four types of permanent dentition teeth that structure the mouth: twelve incisors, four canines, ten premolars and four molars. The premolar and first molar are located on each side of the mouth that together are called the carnassial pair. The carnassial pair specialize in cutting food and are parallel to the jaw. The incisors located in the front section of the lower and upper mouth are small, narrow, and have a single root. They are used for grasping and biting food. Deciduous dentition teeth A cat also has a deciduous dentition prior to the formation of the permanent one. This dentition emerges seven days after birth and it is composed of 26 teeth with slight differences. The mouth will have smaller incisors, slender and strongly curved upper canines, vertical lower canines, and even smaller upper and lower molars. Although the upper and lower molars are smaller than the ones that arise during permanent dentition, the similarities are striking. Tongue The cats tongue is covered in a mucous membrane and the dorsal aspect has 5 types of sharp spines, or papillae. The 5 papillae are filiform, fungiform, foliate, vallate, and conical. A cats sense of smell and taste work closely together, having a vomeronasal organ that allows them to use their tongue as scent tasters, while its longitudinal, transverse, and vertical intrinsic muscles aid in movement. Ears Similar to dogs, cats have sensitive ears that allow them to move each ear independently of one another. Because of this mobility, a cat can move its body in one direction and point its ears in another direction. The rostral, caudal, dorsal, and ventral auricular muscle groups of each ear comprise fifteen muscles that are responsible for this ability. Most cats have straight ears pointing upward. Unlike with dogs, flap-eared breeds are extremely rare (Scottish Folds have one such exceptional mutation). When angry or frightened, a cat will lay back its ears to accompany the growling or hissing sounds it makes. Cats also turn their ears back when they are playing or to listen to a sound coming from behind them. The fold of skin forming a pouch on the lower posterior part of the ear, known as Henrys pocket, is usually prominent in a cats ear. Its function is unknown, though it may assist in filtering sounds. Nose Cats are highly territorial, and secretion of odors plays a major role in cat communication. The nose helps cats to identify territories, other cats and mates, to locate food, and has various other uses. A cats sense of smell is believed to be about fourteen times more sensitive than that of humans. The rhinarium (the leathery part of the nose we see) is quite tough, to allow it to absorb rather rough treatment sometimes. The color varies according to the genotype (genetic makeup) of the cat. A cats skin has the same color as the fur, but the color of the nose leather is probably dictated by a dedicated gene. Cats with white fur have skin susceptible to damage by ultraviolet light, which may cause cancer. Extra care is required when outside in the hot sun. Legs Cats are digitigrades, which means that they walk on their toes just like dogs. The advantage of this is that cats (including other digitigrades) are more agile than other animals. This is because all animals usually have ground reaction forces (GRFs) at around two to three times their body weight per limb. Digitigrades have a higher GRF compared to other animals due to the increased weight on a smaller surface area, which would be about six times their body weight per limb.Toe tufts are commonly found on cats with medium to long coats. Clumps of fur that stick out at least 1–2 cm (0.39–0.79 in) beyond the paw pad can be considered tufts. In addition to soft paw pads, toe tufts help a cat to silently stalk its prey by muffling excess noise. However, outdoor cats tend to lose their toe tufts due to excessive abrasion on the rougher outdoor surfaces. This is in distinct contrast to indoor cats who spend most of their time walking on carpet or smooth floors. Cats are also able to walk very precisely. Adult cats walk with a "four-beat gait" meaning that each foot does not step on the same spot as each other. Whether they walk fast or slow, a cats walk is considered symmetric because the right limbs imitate the position of the left limbs as they walk. This type of locomotion provides sense of touch on all four paws that are necessary for precise coordination.The Cats vertebrae are held by muscles rather than ligaments like humans. This contributes to the cats elasticity and ability to elongate and contract their back by curving it upwards or oscillating it along their vertebral line. Cats are also able to jump from larger heights without serious injury due to the efficient performance in their limbs and ability to control impact forces. In this case, hindlimbs are able to absorb more shock and energy in comparison to the forelimbs, when jumping from surface to surface, as well as steer the cat for weight bearing and breaking. Claws Like nearly all members of the family Felidae, cats have protractable claws. In their normal, relaxed position, the claws are sheathed with the skin and fur around the toe pads. This keeps the claws sharp by preventing wear from contact with the ground and allows the silent stalking of prey. The claws on the forefeet are typically sharper than those on the hind feet. Cats can voluntarily extend their claws on one or more paws. They may extend their claws in hunting or self-defense, climbing, "kneading", or for extra traction on soft surfaces (bedspreads, thick rugs, skin, etc.). It is also possible to make a cooperative cat extend its claws by carefully pressing both the top and bottom of the paw. The curved claws can become entangled in carpet or thick fabric, which can cause injury if the cat is unable to free itself. Most cats have a total of 18 digits and claws. 5 on each forefoot, the 5th digit being the dewclaw; and 4 on each hind foot. The dewclaw is located high on the foreleg, is not in contact with the ground and is non-weight bearing.Some cats can have more than 18 digits, due to a common mutation called polydactyly or polydactylism, which can result in five to seven toes per paw. Temperature and heart rate The normal body temperature of a cat is between 38.3 and 39.0 °C (100.9 and 102.2 °F). A cat is considered febrile (hyperthermic) if it has a temperature of 39.5 °C (103.1 °F) or greater, or hypothermic if less than 37.5 °C (99.5 °F). For comparison, humans have an average body temperature of about 37.0 °C (98.6 °F). A domestic cats normal heart rate ranges from 140 to 220 beats per minute (bpm), and is largely dependent on how excited the cat is. For a cat at rest, the average heart rate usually is between 150 and 180 bpm, more than twice that of a human, which averages 70 bpm. Skin Cats possess rather loose skin, which allows them to turn and confront a predator or another cat in a fight, even when it has a grip on them. This is also an advantage for veterinary purposes, as it simplifies injections. In fact, the lives of cats with chronic kidney disease can sometimes be extended for years by the regular injection of large volumes of fluid subcutaneously. Scruff The particularly loose skin at the back of the neck is known as the scruff, and is the area by which a mother cat grips her kittens to carry them. As a result, cats tend to become quiet and passive when gripped there. This behavior also extends into adulthood, when a male will grab the female by the scruff to immobilize her while he mounts, and to prevent her from running away as the mating process takes place.This technique can be useful when attempting to treat or move an uncooperative cat; however, since an adult cat is heavier than a kitten, a pet cat should never be carried by the scruff, but should instead have its weight supported at the rump and hind legs, and at the chest and front paws. Primordial pouches Some cats share common traits due to heredity. One of those is the primordial pouch, sometimes referred to as "spay sway" by owners who notice it once the cat has been spayed or neutered. It is located on a cats belly. Its appearance is similar to a loose flap of skin that might occur if the cat had been overweight and had then lost weight. It provides a little extra protection against kicks, which are common during cat fights as a cat will try to rake with its rear claws. In wild cats, the ancestors of domesticated felines, this pouch appears to be present to provide extra room in case the animal has the opportunity to eat a large meal and the stomach needs to expand. This stomach pouch also allows the cat to bend and expand, allowing for faster running and higher jumping. Skeleton Cats have seven cervical vertebrae like almost all mammals, thirteen thoracic vertebrae (humans have twelve), seven lumbar vertebrae (humans have five), three sacral vertebrae (humans have five because of their bipedal posture), and, except for Manx cats and other shorter tailed cats, twenty-two or twenty-three caudal vertebrae (humans have three to five, fused into an internal coccyx). The extra lumbar and thoracic vertebrae account for the cats enhanced spinal mobility and flexibility, compared to humans. The caudal vertebrae form the tail, used by the cat as a counterbalance to the body during quick movements. Between their vertebrae, they have elastic discs, useful for cushioning the jump landings. Unlike human arms, cat forelimbs are attached to the shoulder by free-floating clavicle bones, which allows them to pass their body through any space into which they can fit their heads. Skull The cat skull is unusual among mammals in having very large eye sockets and a powerful and specialized jaw.: 35 Compared to other felines, domestic cats have narrowly spaced canine teeth, adapted to their preferred prey of small rodents. Muscles Internal abdominal oblique This muscles origin is the lumbodorsal fascia and ribs. Its insertion is at the pubis and linea alba (via aponeurosis), and its action is the compression of abdominal contents. It also laterally flexes and rotates the vertebral column. Transversus abdominis This muscle is the innermost abdominal muscle. Its origin is the second sheet of the lumbodorsal fascia and the pelvic girdle and its insertion is the linea alba. Its action is the compression of the abdomen. Rectus abdominis This muscle is under the extensive aponeurosis situated on the ventral surface of the cat. Its fibers are extremely longitudinal, on each side of the linea alba. It is also traversed by the inscriptiones tendinae, or what others called myosepta. Deltoid The deltoid muscles lie just lateral to the trapezius muscles, originating from several fibers spanning the clavicle and scapula, converging to insert at the humerus. Anatomically, there are only two deltoids in the cat, the acromiodeltoid and the spinodeltoid. However, to conform to human anatomy standards, the clavobrachialis is now also considered a deltoid and is commonly referred to as the clavodeltoid. Acromiodeltoid The acromiodeltoid is the shortest of the deltoid muscles. It lies lateral to (to the side of) the clavodeltoid, and in a more husky cat it can only be seen by lifting or reflecting the clavodeltoid. It originates at the acromion process and inserts at the deltoid ridge. When contracted, it raises and rotates the humerus outward. Spinodeltoid A stout and short muscle lying posterior to the acromiodeltoid. It lies along the lower border of the scapula, and it passes through the upper forelimb, across the upper end of muscles of the upper forelimb. It originates at the spine of the scapula and inserts at the deltoid ridge. Its action is to raise and rotate the humerus outward. Head Masseter The Masseter is a great, powerful, and very thick muscle covered by a tough, shining fascia lying ventral to the zygomatic arch, which is its origin. It inserts into the posterior half of the lateral surface of the mandible. Its action is the elevation of the mandible (closing of the jaw). Temporalis The temporalis is a great mass of mandibular muscle, and is also covered by a tough and shiny fascia. It lies dorsal to the zygomatic arch and fills the temporal fossa of the skull. It arises from the side of the skull and inserts into the coronoid process of the mandible. It too, elevates the jaw. Ocular Cats have three eyelids. The cats third eyelid is known as the nictitating membrane. It is located in the inner corner of the eye, which is also covered by conjunctiva. In healthy cats, the conjunctiva of the eyelids is not readily visible and has a pale, pink color. Integumental The two main integumental muscles of a cat are the platysma and the cutaneous maximus. The cutaneous maximus covers the dorsal region of the cat and allows it to shake its skin. The platysma covers the neck and allows the cat to stretch the skin over the pectoralis major and deltoid muscles. Neck and back Rhomboideus The rhomboideus is a thick, large muscle below the trapezius muscles. It extends from the vertebral border of the scapula to the mid-dorsal line. Its origin is from the neural spines of the first four thoracic vertebrae, and its insertion is at the vertebral border of the scapula. Its action is to draw the scapula to the dorsal. Rhomboideus capitis The Rhomboideus capitis is the most cranial of the deeper muscles. It is underneath the clavotrapezius. Its origin is the superior nuchal line, and its insertion is at the scapula. Action draws scapula cranially. Splenius The Splenius is the most superficial of all the deep muscles. It is a thin, broad sheet of muscle underneath the clavotrapezius and deflecting it. It is crossed also by the rhomboideus capitis. Its origin is the mid-dorsal line of the neck and fascia. The insertion is the superior nuchal line and atlas. It raises or turns the head. Serratus ventralis The serratus ventralis is exposed by cutting the wing-like latissimus dorsi. The said muscle is covered entirely by adipose tissue. The origin is from the first nine or ten ribs and from part of the cervical vertebrae. Serratus Dorsalis The serratus dorsalis is medial to both the scapula and the serratus ventralis. Its origin is via apoeurosis following the length of the mid-dorsal line, and its insertion is the dorsal portion of the last ribs. Its action is to depress and retracts the ribs during breathing. Intercostals The intercostals are a set of muscles sandwiched among the ribs. They interconnect ribs, and are therefore the primary respiratory skeletal muscles. They are divided into the external and the internal subscapularis. The origin and insertion are in the ribs. The intercostals pull the ribs backwards or forwards. Caudofemoralis The caudofemoralis is a muscle found in the pelvic limb. The Caudofemoralis acts to flex the tail laterally to its respective side when the pelvic limb is bearing weight. When the pelvic limb is lifted off the ground, contraction of the caudofemoralis causes the limb to abduct and the shank to extend by extending the hip joint. Pectoral Pectoantebrachialis Pectoantebrachialis muscle is just one-half-inch wide and is the most superficial in the pectoral muscles. Its origin is the manubrium of the sternum, and its insertion is in a flat tendon on the fascia of the proximal end of the ulna. Its action is to draw the forelimb towards the chest. There is no human equivalent. Pectoralis major The pectoralis major, also called pectoralis superficialis, is a broad triangular portion of the pectoralis muscle which is immediately below the pectoantebrachialis. It is smaller than the pectoralis minor muscle. Its origin is the sternum and median ventral raphe, and its insertion is at the humerus. Its action is to draw the forelimb towards the chest. Pectoralis minor The pectoralis minor muscle is larger than the pectoralis major. However, most of its anterior border is covered by the pectoralis major. Its origins are ribs three–five, and its insertion is the coracoid process of the scapula. Its actions are the tipping of the scapula and the elevation of ribs three–five. Xiphihumeralis The most posterior, flat, thin, and long strip of pectoral muscle is the xiphihumeralis. It is a band of parallel fibers that is found in felines but not in humans. Its origin is the xiphoid process of the sternum. The insertion is the humerus. Trapezius In the cat there are three thin flat muscles that cover the back, and to a lesser extent, the neck. They pull the scapula toward the mid-dorsal line, anteriorly, and posteriorly. Clavotrapezius The most anterior of the trapezius muscles, it is also the largest. Its fibers run obliquely to the ventral surface. Its origin is the superior nuchal line and median dorsal line and its insertion is the clavicle. Its action is to draw the clavicle dorsally and towards the head. Acromiotrapezius Acromiotrapezius is the middle trapezius muscle. It covers the dorsal and lateral surfaces of the scapula. Its origin is the neural spines of the cervical vertebrae and its insertion is in the metacromion process and fascia of the clavotrapezius. Its action is to draw the scapula to the dorsal, and hold the two scapula together. Spinotrapezius Spinotrapezius, also called thoracic trapezius, is the most posterior of the three. It is triangular shaped. Posterior to the acromiotrapezius and overlaps latissimus dorsi on the front. Its origin is the neural spines of the thoracic vertebrae and its insertion is the scapular fascia. Its action is to draw the scapula to the dorsal and caudal region. Digestive system The digestion system of cats begins with their sharp teeth and abrasive tongue papillae, which help them tear meat, which is most, if not all, of their diet. Cats naturally do not have a diet high in carbohydrates, and therefore, their saliva doesnt contain the enzyme amylase. Food moves from the mouth through the esophagus and into the stomach. The gastrointestinal tract of domestic cats contains a small cecum and unsacculated colon. The cecum while similar to dogs, doesnt have a coiled cecum. The stomach of the cat can be divided into distinct regions of motor activity. The proximal end of the stomach relaxes when food is digested. While food is being digested this portion of the stomach either has rapid stationary contractions or a sustained tonic contraction of muscle. These different actions result in either the food being moved around or the food moving towards the distal portion of the stomach. The distal portion of the stomach undergoes rhythmic cycles of partial depolarization. This depolarization sensitizes muscle cells so they are more likely to contract. The stomach is not only a muscular structure, it also serves a chemical function by releasing hydrochloric acid and other digestive enzymes to break down food. Food moves from the stomach into the small intestine. The first part of the small intestine is the duodenum. As food moves through the duodenum, it mixes with bile, a fluid that neutralizes stomach acid and emulsifies fat. The pancreas releases enzymes that aid in digestion so that nutrients can be broken down and pass through the intestinal mucosa into the blood and travel to the rest of the body. The pancreas doesnt produce starch processing enzymes because cats dont eat a diet high in carbohydrates. Since the cat digests low amounts of glucose, the pancreas uses amino acids to trigger insulin release instead. Food then moves on to the jejunum. This is the most nutrient absorptive section of the small intestine. The liver regulates the level of nutrients absorbed into the blood system from the small intestine. From the jejunum, whatever food that has not been absorbed is sent to the ileum which connects to the large intestine. The first part of the large intestine is the cecum and the second portion is the colon. The large intestine reabsorbs water and forms fecal matter. There are some things that the cats are not able to digest. For example, cats clean themselves by licking their fur with their tongue, which causes them to swallow a lot of fur. This causes a build-up of fur in a cats stomach and creates a mass of fur. This is often thrown up and is better known as a hairball.The short length of the digestive tract of the cat causes cats digestive system to weigh less than other species of animals, which allows cats to be active predators. While cats are well adapted to be predators they have a limited ability to regulate catabolic enzymes of amino acids meaning amino acids are constantly being destroyed and not absorbed. Therefore, cats require a higher protein proportion in their diet than many other species. Cats are not adapted to synthesize niacin from tryptophan and, because they are carnivores, cant convert carotene to vitamin A, so eating plants while not harmful does not provide them nutrients. Genitalia Female genitalia In the female cat, the genitalia includes the uterus, the vagina, the genital passages and teats. Together with the vulva, the vagina of the cat is involved in mating and provides a channel for newborns during parturition, or birth. The vagina is long and wide. Genital passages are the oviducts of the cat. They are short, narrow, and not very sinuous. Male genitalia In the male cat, the genitalia includes two gonads and the penis, which is covered with small spines. Physiology Cats are familiar and easily kept animals, and their physiology has been particularly well studied; it generally resembles those of other carnivorous mammals, but displays several unusual features probably attributable to cats descent from desert-dwelling species. Heat tolerance Cats are able to tolerate quite high temperatures: Humans generally start to feel uncomfortable when their skin temperature passes about 38 °C (100 °F), but cats show no discomfort until their skin reaches around 52 °C (126 °F),: 46 and can tolerate temperatures of up to 56 °C (133 °F) if they have access to water. Temperature regulation Cats conserve heat by reducing the flow of blood to their skin and lose heat by evaporation through their mouths. Cats have minimal ability to sweat, with glands located primarily in their paw pads, and pant for heat relief only at very high temperatures (but may also pant when stressed). A cats body temperature does not vary throughout the day; this is part of cats general lack of circadian rhythms and may reflect their tendency to be active both during the day and at night.: 1 Water conservation Cats feces are comparatively dry and their urine is highly concentrated, both of which are adaptations to allow cats to retain as much water as possible. Their kidneys are so efficient, they can survive on a diet consisting only of meat, with no additional water. They can tolerate high levels of salt only in combination with freshwater to prevent dehydration. Ability to swim While domestic cats are able to swim, they are generally reluctant to enter water as it quickly leads to exhaustion. See also Cat senses Natural bobtail References External links The cat; an introduction to the study of backboned animals, especially mammals (1881) A laboratory guide for the dissection of the cat: An introduction to the study of anatomy (1895) Anatomy of the cat (1902)
Oculopharyngeal muscular dystrophy	Oculopharyngeal muscular dystrophy (OPMD) is a rare form of muscular dystrophy with symptoms generally starting when an individual is 40 to 50 years old. It can be autosomal dominant neuromuscular disease or autosomal recessive. The most common inheritance of OPMD is autosomal dominant, which means only one copy of the mutated gene needs to be present in each cell. Children of an affected parent have a 50% chance of inheriting the mutant gene.Autosomal dominant inheritance is the most common form of inheritance. Less commonly, OPMD can be inherited in an autosomal recessive pattern, which means that two copies of the mutated gene need to be present in each cell, both parents need to be carriers of the mutated gene, and usually show no signs or symptoms. The PABPN1 mutation contains a GCG trinucleotide repeat at the 5 end of the coding region, and expansion of this repeat which then leads to autosomal dominant oculopharyngeal muscular dystrophy (OPMD) disease. Signs and symptoms In terms of the signs (and symptoms) of oculopharyngeal muscular dystrophy would be consistent with the following: PtosisWeakness of the extraocular musclesDysphagiaAspiration pneumonia (complication)Proximal limb weaknessThough the aforementioned signs/symptoms are the most common, there have been cases though rare, where the peripheral nervous system has had involvement with significant reduction of myelinated fibers In homozygous cases, this muscular dystrophy is severe and starts earlier in the affected individuals life. Genetics The genetics of this type of muscular dystrophy revolve around the PABPN1 gene. This gene suffers mutations that cause the PABPN1 protein to have extra alanine (amino acids), this manifests itself physically in the symptoms of this MD.The expansion caused by the mutations on the PABPN1 gene ultimately interrupts the cellular mechanics of poly(A) RNA. In most cases oculopharyngeal muscular dystrophy is inherited via autosomal dominance.The alleles, which are a variant form of a gene involved in this form of MD are: PABPN1, (GCG)n EXPANSION, (GCG)8-13, PABPN1, (GCG)n EXPANSION, (GCG)7 and PABPN1, GLY12ALA. Diagnosis The diagnosis of oculopharyngeal muscular dystrophy can be done via two methods, a muscle biopsy or a blood draw with genetic testing for GCG trinucleotide expansions in the PABPN1 gene. The genetic blood testing is more common. Additionally, a distinction between OPMD and myasthenia gravis or mitochondrial myopathy must be made, in regards to the differential diagnosis of this condition. Treatment Currently no cure or specific treatment exists to eliminate the symptoms or stop the disease progression. A consistent diet planned with the help of a dietitian along with exercises taught by a speech therapist can assist with mild symptoms of dysphagia. Surgical intervention can also help temporarily manage symptoms related to the ptosis and dysphagia. Cutting one of the throat muscles internally, an operation called cricopharyngeal myotomy, can be one way to ease symptoms in more severe cases. However, for a majority of people, the benefits from such treatments are only temporary. There is currently no treatment available to address the proximal limb weakness. Many of those affected with the proximal limb weakness will eventually require assistive devices such as canes, braces or a wheelchair. As with all surgical procedures, they come with many risk factors. As the dysphagia becomes more severe, patients become malnourished, lose significant weight, become dehydrated and suffer from repeated incidents of aspiration pneumonia. These last two are often the cause of death. Epidemiology The disease is found across 5 continents (30 countries) and is frequently seen in French Canadians, with a prevalence 1:1000. OPMD affects males and females equally, and affected individuals have been found in Europe (France), Jewish Ashkenazi, and Spanish Americans. See also Muscular dystrophy PABPN1 References Further reading Raz, Yotam; Raz, Vered (2014-01-01). "Oculopharyngeal muscular dystrophy as a paradigm for muscle aging". Frontiers in Aging Neuroscience. 6: 317. doi:10.3389/fnagi.2014.00317. PMC 4226162. PMID 25426070. Hill, M. E.; Creed, G. A.; McMullan, T. F. W.; Tyers, A. G.; Hilton-Jones, D.; Robinson, D. O.; Hammans, S. R. (1 March 2001). "Oculopharyngeal muscular dystrophy". Brain. 124 (3): 522–526. doi:10.1093/brain/124.3.522. ISSN 0006-8950. PMID 11222452. Gómez-Torres, Antonio; Abrante Jiménez, Antonio; Rivas Infante, Eloy; Menoyo Bueno, Alicia; Tirado Zamora, Isabel; Esteban Ortega, Francisco (November 2012). "Cricopharyngeal Myotomy in the Treatment of Oculopharyngeal Muscular Dystrophy". Acta Otorrinolaringologica (English Edition). 63 (6): 465–469. doi:10.1016/j.otoeng.2012.11.009. ISSN 2173-5735. PMID 22898142. Oculopharyngeal muscular dystrophy at NIHs Office of Rare Diseases == External links ==
Spondylolisthesis	Spondylolisthesis is the displacement of one spinal vertebra compared to another. While some medical dictionaries define spondylolisthesis specifically as the forward or anterior displacement of a vertebra over the vertebra inferior to it (or the sacrum), it is often defined in medical textbooks as displacement in any direction. Spondylolisthesis is graded based upon the degree of slippage of one vertebral body relative to the subsequent adjacent vertebral body. Spondylolisthesis is classified as one of the six major etiologies: degenerative, traumatic, dysplastic, isthmic, pathologic, or post-surgical. Spondylolisthesis most commonly occurs in the lumbar spine, primarily at the L5-S1 level with the L5 vertebral body anteriorly translating over the S1 vertebral body. Types Olisthesis (synonym olisthy) is a term that more explicitly denotes displacement in any direction. Forward or anterior displacement can specifically be called anterolisthesis. Anterolisthesis commonly involves the fifth lumbar vertebra. Backward displacement is called retrolisthesis. Lateral displacement is called lateral listhesis or laterolisthesis.A hangmans fracture is a specific type of spondylolisthesis where the second cervical vertebra (C2) is displaced anteriorly relative to the C3 vertebra due to fractures of the C2 vertebras pedicles. Anterolisthesis Classification Anterolisthesis can be categorized by cause, location and severity. By causes Degenerative anterolisthesis (a.k.a. type 3) is a disease of the older adult that develops as a result of facet arthritis and joint remodeling. Joint arthritis, and ligamentum flavum weakness, may result in slippage of a vertebra. Degenerative forms are more likely to occur in women, persons older than fifty, and African Americans. Traumatic anterolisthesis is rare and results from acute fractures in the neural arch, other than the pars. Dysplastic anterolisthesis (a.k.a. type 1) results from congenital abnormalities of the upper sacral facets or inferior facets of the fifth lumbar vertebra, and accounts for 14% to 21% of all anterolisthesis. Isthmic anterolisthesis (a.k.a. type 2) is caused by a defect in the pars interarticularis but it can also be seen with an elongated pars. Pathologic anterolisthesis (a.k.a. type 5) is caused by either infection or a malignancy. Post-surgical/iatrogenic anterolisthesis (a.k.a. type 6) is caused by complications after surgery. By location Anterolisthesis location includes which vertebrae are involved, and may also specify which parts of the vertebrae are affected. Isthmic anterolisthesis is where there is a defect in the pars interarticularis. It is the most common form of spondylolisthesis; also called spondylolytic spondylolisthesis, it occurs with a reported prevalence of 5–7 percent in the US population. A slip or fracture of the intravertebral joint is usually acquired between the ages of 6 and 16 years, but remains unnoticed until adulthood. Roughly 90 percent of these isthmic slips are low-grade (less than 50 percent slip) and 10 percent are high-grade (greater than 50 percent slip). It is divided into three subtypes: A: pars fatigue fracture B: pars elongation due to multiple healed stress effects C: pars acute fracture Severity Classification by degree of the slippage, as measured as percentage of the width of the vertebral body: Grade I spondylolisthesis accounts for approximately 75% of all cases. Grade I: 0–25% Grade II: 25- 50% Grade III: 50–75% Grade IV: 75–100% Grade V: greater than 100% Signs and symptoms Symptoms of lumbar anterolisthesis include: A general stiffening of the back and a tightening of the hamstrings, with a resulting change in both posture and gait. A leaning-forward or semi-kyphotic posture may be seen, due to compensatory changes. A "waddle" may be seen in more advanced causes, due to compensatory pelvic rotation due to decreased lumbar spine rotation. A result of the change in gait is often a noticeable atrophy in the gluteal muscles due to lack of use. Generalized lower-back pain may also be seen, with intermittent shooting pain from the buttocks to the posterior thigh, and/or lower leg via the sciatic nerve.Other symptoms may include tingling and numbness. Coughing and sneezing can intensify the pain. An individual may also note a "slipping sensation" when moving into an upright position. Sitting and trying to stand up may be painful and difficult. Physical Exam The major components of the physical exam for spondylolisthesis consists of observation, palpation, and maneuvers. The most common finding is pain with lumbar extension. The following physical involves specific assessment for spondylolisthesis. However, a general examination, most importantly neurological examination, must be done to rule out alternative causes for signs and symptoms. Neurological examination is often normal in patients with spondylolisthesis, but lumbosacral radiculopathy is commonly seen in patients with degenerate spondylolisthesis. Observation The patient should be observed walking and standing. Most patients present with a normal gait. An abnormal gait is often the sign of a high grade case. A patient with high grade spondylolisthesis may present with a posterior pelvic tilt causing a loss in the normal contour of the buttocks. An antalgic gait, rounded back and decreased hip extension, can result from severe pain. While standing, the patient should be observed from the front, back, and sides. Increased and decreased lumbar lordosis, inward curvature of the lower spine, has been seen. Palpation Detection of spondylolisthesis by palpation is most often done by palpating for the spinous process. Each level of the lumbar spine should be palpated. Spinous process palpation by itself is not a definitive method for the detection of spondylolisthesis. Maneuvers Spinal range of motion testing – Range of motion limitations may be seen. Lumbar hyperextension – Extension often elicits pain. This can be assessed by having the patient hyperextend the lumbar spine, provide resistance against back extensions, or undergo repeated lumbar extensions. Sport-specific motion – Patient can be asked to repeat aggravating movements that they experience during their activity. During the movement, ask patient to point to any places with focal pain. Straight leg raise – Maneuver used to assess for hamstring tightness. The straight leg raise has been found to be positive in only 10% of patients with spondylolisthesis. Muscle strength exercises – Lower abdominal, gluteal, and lumbar extensors should be assessed for weakness. Weakness in these muscles can increase lordosis and contribute to sacroiliac instability. Abdominal flexor strength can be assessed with the abdominal flexor endurance test. The test involves the patient lying supine while holding a 45 degree flexed trunk and 90 degree flexed knees for 30 seconds. Gluteal strength can be assessed with a single-leg squat. Lastly, lumbar extension can be assessed with a single-leg bridge. Diagnostic Imaging In adults with non-specific low back pain, strong evidence suggests medical imaging should not be done within the first six weeks. It is also suggested to avoid advanced imaging, such as CT or MRI, for adults without neurological symptoms or "red flags" in the patients history. General recommendations for initial low back pain treatment is remaining active, avoiding twisting and bending, avoiding activities that worsen pain, avoiding bed rest, and possibly initiating a trial of non-steroidal anti-inflammatory drugs after consulting a physician. Children and adolescents with persistent low back pain may require earlier imaging and should be seen by physician. Once imaging is deemed necessary, a combination of plain radiography, computed tomography, and magnetic resonance imaging may be used. Images are most often taken of the lumbar spine due to spondylolisthesis most commonly involving the lumbar region. Images of the thoracic spine can be taken if a patients history and physical suggest thoracic involvement. Plain Radiography (X-Ray) Plain radiography is often the first step in medical imaging. Anteroposterior (front-back) and lateral (side) images are used to allow the physician to view the spine at multiple angles. Oblique view are no longer recommended. In evaluating for spondylolithesis, plain radiographs provide information on the positioning and structural integrity of the spine. Therefore, if further detail is needed a physician may request advanced imaging. Magnetic Resonance Imaging (MRI) Magnetic resonance imaging is the preferred advanced imaging technique for evaluation of spondylolisthesis. Preference is due to effectiveness, lack of radiation exposure, and ability to evaluate for soft tissue abnormalities and spinal canal involvement. MRI is limited in its ability to evaluate fractures in great detail, compared to other advanced imaging modalities. Computed Tomography (CT) Computed tomography can be helpful in evaluating bony vertebral abnormalities, such as fractures. This can be helpful in determining if the fracture is a new, old, and/or progressing fracture. CT use in spondylolisthesis evaluation is controversial due to high radiation exposure. Treatment Spondylolisthesis patients without symptoms do not need to be treated. Conservative Non-operative management, also referred to as conservative treatment, is the recommended treatment for spondylolisthesis in most cases with or without neurological symptoms. Most patients with spondylolisthesis respond to conservative treatment. Conservative treatment consists primarily of physical therapy, intermittent bracing, aerobic exercise, pharmacological intervention, and epidural steroid injections. The majority of patients with degenerative spondylolisthesis do not require surgical intervention. Physical therapy can evaluate and address postural and compensatory movement abnormalities. Physical therapy primarily includes spinal flexion and extension exercises with a focus on core stabilization and muscle strengthening. In particular, lumbar spondylolisthesis may benefit from core stabilization exercises focusing on lower abdominal, lumbar muscles, hamstrings, and hip flexors, which may temporarily or permanently improve symptoms and improve general function. Some patients may benefit from bracing in combination with physical therapy. Additionally, bracing was found to be beneficial when performed immediately following the onset of symptoms, in particular patients with lumbar pars interarticular defects. Exercises such as cycling, elliptical training, swimming, and walking are considered low-impact aerobic exercises and are recommended for pain relief. Anti-inflammatory medications (NSAIDS) in combination with paracetamol can be tried initially. If a severe radicular component is present, a short course of oral steroids such as prednisone or methylprednisolone can be considered. Epidural steroid injections, either interlaminal or transforaminal, performed under fluoroscopic guidance can help with severe radicular (leg) pain, but lacks conclusive benefit in relieving back pain in lumbar spondylolisthesis. Chiropractic Specific spinal manipulation identifies the joints that are restricted or those that show abnormal motion. A gentle thrusting technique that helps to return motion to the joint by stretching the soft tissues and stimulating the nervous system. The purpose is to facilitate movement above and below the anterior slipped vertebrae. Other techniques are non thrusting flexion distraction or instrument assisted adjusting. Surgical There are no clear radiological or medical guidelines or indications for surgical interventions in degenerative spondylolisthesis. A minimum of three months of conservative management should be completed prior to considering surgical intervention. Three indications for potential surgical treatment are as follows: persistent or recurrent back pain or neurologic pain with a persistent reduction of quality of life despite a reasonable trial of conservative (non-operative) management, new or worsening bladder or bowel symptoms, or a new or worsening neurological deficit. Both minimally invasive and open surgical techniques are used to treat anterolisthesis. Retrolisthesis A retrolisthesis is a posterior displacement of one vertebral body with respect to the subjacent vertebra to a degree less than a luxation (dislocation). Retrolistheses are most easily diagnosed on lateral x-ray views of the spine. Views, where care has been taken to expose for a true lateral view without any rotation, offer the best diagnostic quality. Retrolistheses are found most prominently in the cervical and lumbar region, but can also be seen in the thoracic area. History Spondylolisthesis was first described in 1782 by Belgian obstetrician Herbinaux. He reported a bony prominence anterior to the sacrum that obstructed the vagina of a small number of patients. The term “spondylolisthesis” was coined in 1854 from the Greek σπονδυλος, "spondylos" = "vertebra" and ὀλίσθησης "olisthesis" = "slipping, sliding," See also Spondylosis Spondylolysis Failed back syndrome Joint dislocation References == External links ==
Prurigo nodularis	Prurigo nodularis (PN), also known as nodular prurigo, is a skin disease characterised by pruritic (itchy) nodules which usually appear on the arms or legs. Patients often present with multiple excoriated lesions caused by scratching. PN is also known as Hyde prurigo nodularis, Pickers nodules, atypical nodular form of neurodermatitis circumscripta, lichen corneus obtusus. Lichen simplex chronicus is a distinct clinical entity. Signs and symptoms Nodules are discrete, generally symmetric, hyperpigmented or purpuric, and firm. They are greater than 0.5 cm in both width and depth (as opposed to papules which are less than 0.5 cm). They can appear on any part of the body, but generally begin on the arms and legs. Excoriated lesions are often flat, umbilicated, or have a crusted top. Nodules may appear to begin in the hair follicles. Nodule pattern may be follicular. In true prurigo nodularis, a nodule forms before itching begins. Typically, these nodules are extremely pruritic and are alleviated only by steroids. Causes The cause of prurigo nodularis is unknown, although other conditions may induce PN. PN has been linked to Beckers nevus, linear IgA disease, an autoimmune condition, liver disease and T cells. Systemic pruritus has been linked to cholestasis, thyroid disease, polycythaemia rubra vera, uraemia, Hodgkins disease, HIV and other immunodeficiency diseases. Internal malignancies, liver failure, kidney failure, and psychiatric illnesses have been considered to induce PN, although more recent research has refuted a psychiatric cause for PN. Patients report an ongoing battle to distinguish themselves from those with psychiatric disorders, such as delusions of parasitosis and other psychiatric conditions. Pathophysiology Chronic and repetitive scratching, picking, or rubbing of the nodules may result in permanent changes to the skin, including nodular lichenification, hyperkeratosis, hyperpigmentation, and skin thickening. Unhealed, excoriated lesions are often scaly, crusted or scabbed. Many patients report a lack of wound healing even when medications relieve the itching and subsequent scratching.Patients often: seek treatment during middle-age, although PN can occur at any age. have a history of chronic severe pruritus. have a significant medical history for unrelated conditions. develop liver or kidney dysfunctions. develop secondary skin infections. have a personal or family history of atopic dermatitis. have other autoimmune disorders. have low vitamin D levels. Diagnosis Diagnosis is based on visual examination and the presence of itching. A skin biopsy is often performed to exclude other diseases. Lesion biopsies usually show light inflammation, sometimes with increased numbers of eosinophils. A culture of at least one lesion will rule out staphylococcus infection, which has been significantly linked to atopic dermatitis. Treatment Prurigo nodularis is very hard to treat, but current therapies include steroids, vitamins, cryosurgery, thalidomide and UVB light. In the event that staphylococcus or other infection is present, antibiotics have proven effective, but tend to cause more harm than good for this particular disease. A physician may administer a strong dose of prednisone, which will almost immediately stop the itch/scratch cycle. However, cessation of steroids allows relapse to occur, usually within a few weeks. Horiuchi et al recently reported significant improvement in PN with antibiotic therapy.Another drug a physician may administer is Apo-Azathioprine. Azathioprine, also known by its brand name Imuran, is an immunosuppressive drug used in organ transplantation and autoimmune diseases and belongs to the chemical class of purine analogues. History Prurigo nodularis was first described by Hyde and Montgomery in 1909. See also Pruritus Skin lesion Notes External links DermNet NZ: Prurigo nodularis DermAtlas -2016053621
Erythema multiforme minor	Erythema multiforme is usually a reaction of the skin and mucous membranes that occurs suddenly. It appears as a symmetrical rash and may include the mucous membrane lesions. This means that the body is sensitive to something that causes the skin and mucous membranes to react. The more common mild form is refer to as EM minor. It consists of a skin rash that involve no more than one mucosal surface. The sudden onset will progress rapidly as symmetrical lesions with circular color changes in some or all of the lesions. Rash will spread towards center or trunk of the body. Evenly distributed bumps on the skin become classic iris or target lesions. They have bright red borders and small white bumps in the center. The cause of EM appears to be a highly sensitive reaction that can be triggered by a variety of causes. The causes can include bacterial, viral or chemical products, such as antibiotics – specifically penicillins or cephalosporins. This reaction is an allergic reaction and is in no way contagious. : 140 Erythema multiforme minor is sometimes divided into papular and vesiculobullous forms. See also Erythema Diascopy Erythema multiforme List of cutaneous conditions References == External links ==
Localized lipodystrophy	Localized lipodystrophy is a skin condition characterized by the loss of subcutaneous fat localized to sites of insulin injection.: 497 See also Lipodystrophy List of cutaneous conditions Skin lesion References == External links ==
Glutaric acidemia type 2	Glutaric acidemia type 2 is an autosomal recessive metabolic disorder that is characterised by defects in the ability of the body to use proteins and fats for energy. Incompletely processed proteins and fats can build up, leading to a dangerous chemical imbalance called acidosis. Genetics Mutations in the ETFA, ETFB, and ETFDH genes cause glutaric acidemia type II. Mutations in these genes result in a deficiency in one of two enzymes that normally work together in the mitochondria, which are the energy-producing centers of cells. The ETFA and ETFB genes encode two subunits of the enzyme electron transfer flavoprotein, while the ETFDH gene encodes the enzyme electron-transferring-flavoprotein dehydrogenase. When one of these enzymes is defective or missing, the mitochondria cannot function normally, partially broken-down proteins and fats accumulate in the cells and damage them; this damage leads to the signs and symptoms of glutaric acidemia type II.This condition is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the gene – one from each parent – are needed to inherit the disorder. The parents of an individual with an autosomal recessive disorder are carriers of one copy of the defective gene, but do not show signs and symptoms of the disorder themselves. Diagnosis Glutaric acidemia type 2 often appears in infancy as a sudden metabolic crisis, in which acidosis and low blood sugar (hypoglycemia) cause weakness, behavior changes, and vomiting. There may also be enlargement of the liver, heart failure, and a characteristic odor resembling that of sweaty feet. Some infants with glutaric acidemia type 2 have birth defects, including multiple fluid-filled growths in the kidneys (polycystic kidneys). Glutaric acidemia type 2 is a very rare disorder. Its precise incidence is unknown. It has been reported in several different ethnic groups. Treatment It is important for patients with MADD to strictly avoid fasting to prevent hypoglycemia and crises of metabolic acidosis; for this reason, infants and small children should eat frequent meals. Patients with MADD can experience life-threatening metabolic crises precipitated by common childhood illnesses or other stresses on the body, so avoidance of such stresses is critical. Patients may be advised to follow a diet low in fat and protein and high in carbohydrates, particularly in severe cases. Depending on the subtype, riboflavin (100-400 mg/day), coenzyme Q10 (CoQ10), L-carnitine, or glycine supplements may be used to help restore energy production. Some small, uncontrolled studies have reported that racemic salts of beta-hydroxybutyrate were helpful in patients with moderately severe disease; further research is needed. See also Glutaric acidemia type 1 Riboflavin-responsive exercise intolerance - similar in biochemical features, also responsive to riboflavin References This article incorporates public domain text from The U.S. National Library of Medicine == External links ==
Noma neonatorum	Noma neonatorum is a cutaneous condition, a manifestation of infection, usually Pseudomonas aeruginosa sepsis, and has been reported almost exclusively in developing countries. Despite the similarity of facial lesions, noma neonatorum is not related to noma. See also Green nail syndrome List of cutaneous conditions == References ==
Carnivore protoparvovirus 1	Carnivore protoparvovirus 1 (CPPV 1) is a species of parvovirus that infects carnivorans. It causes a highly contagious disease in both dogs and cats. The disease is generally divided into two major genogroups: CPV-1 containing the classical feline panleukopenia virus (FPLV), and CPV-2 containing the canine parvovirus (CPV) which appeared in the 1970s.FPLV is known to infect all wild and domestic members of the felid (cat) family worldwide. It is a highly contagious, severe infection that causes gastrointestinal, immune system, and nervous system disease. Its primary effect is to decrease the number of white blood cells, causing the disease known as feline panleukopenia. It was once thought that only CPV-1 or FPLV infects cats. However, it has been confirmed that a feline panleukopenia illness can be caused by CPV 2a, 2b, and 2c.FPLV is commonly referred to as: feline infectious enteritis virus (FIE) feline parvovirus (FPV or FP or "feline parvo") feline parvoviral enteritisIt is sometimes confusingly referred to as "cat plague" and "feline distemper".In addition to members of the felid family, it can also affect other carnivorans (e.g. raccoon, mink). Etymology Formed within English using elements derived from Greek: pan- a combining form meaning "universal" or "worldwide", -leuco- a combining form meaning (in biologic sciences) "white blood cell", and -penia a combining form meaning "loss of" or "decrease of". Thus the word means universal loss of white blood cells. The universal part refers to both its worldwide distribution and to the fact that all species of cats are infected. Transmission The feline panleukopenia virus is considered ubiquitous, meaning it is in virtually every place that is not regularly disinfected. The infection is highly contagious among unvaccinated cats.Antibodies against FPLV, produced by the adaptive immune system, play an important role in the feline response to the virus. Maternally-derived antibodies (MDA) efficiently protect kittens from fatal infection. This passively acquired immunity is later replaced by an active immune response obtained by vaccination or as a consequence of a natural infection. In kittens, the period of greatest susceptibility to infection is when maternal antibodies are absent, or waning, and vaccine-induced immunity has not yet fully developed.Free-roaming cats are thought to be exposed to the virus during their first year of life. Those that develop a subclinical infection or survive acute illness mount a robust, long-lasting, protective immune response.An infected cat sheds large amounts of virus in all body secretions including feces, vomit, urine, saliva, and mucus during the acute phase of illness. It can continue to shed the virus for as long as 6 weeks after recovery. Subclinically ill cats can also shed the virus in body secretions. The virus can be carried or transferred on an infected object (such as bedding, food dishes, fur) or by other animals, fleas, and humans (see: fomites). It persists long after evidence of the original body secretion has faded away, and can be transported long distances. Like all parvoviruses, FPLV is extremely resistant to inactivation and can survive for longer than one year in a suitable environment. Kitten deaths have been reported in households of fully vaccinated cats, possibly because of exposure to large amounts of virus in the environment.Infection occurs when the virus enters the body through the mouth or nose. Whether illness results or not depends on the immunity in the victim vs. the number of individual virus particles (i.e. the amount of virus) entering the body. Clinical signs The clinical manifestations of FPLV are variable based on the dose of the virus, the age of the cat, potential breed predispositions, and prior immunity from maternal antibodies, previous exposure, or vaccination. Most infections are subclinical, as evidenced by the high seroprevalence of anti-FPV antibodies among some populations of unvaccinated, healthy cats. The cats that become clinically ill are usually less than one year old, but older cats are also at risk. There is high mortality in clinically affected kittens and sudden death can occur.Clinical signs usually develop in 4–6 days after exposure, but can show in 2–14 days. The virus infects and destroys actively dividing cells in bone marrow, lymphoid tissues, intestinal epithelium, and—in very young animals—in the cerebellum and retina. The virus primarily attacks the lining of the gastrointestinal tract, causing internal ulceration and, ultimately, total sloughing of the intestinal epithelium. Primary signs include: anorexia lethargy profuse watery to bloody diarrhea (bloody diarrhea is more common in dogs with parvovirus than cats) vomiting (most common in cats)Clinical laboratory findings include (but are not limited to): electrolyte and total protein concentrations that reflect dehydration, vomiting, and diarrhea. leukopenia lymphopenia neutropenia thrombocytopeniaOther signs include: fever, loss of skin elasticity due to dehydration, abdominal pain, sternal recumbency with splayed legs and head droop, nasal discharge and conjunctivitis. Cats may sit at a water bowl, but not drink. Terminal cases are hypothermic and may develop septic shock and disseminated intravascular coagulation.Infection in pregnant cats can result in fetal resorption, mummification, abortion, or stillbirth of neonates. Fetuses infected in utero that survive and kittens less than a few weeks of age that become infected can have cerebellar hypoplasia, retinal dysplasia, and optic neuropathy. Diagnosis A presumptive clinical diagnosis of FPLV can be made for kittens with appropriate signalment, history, clinical findings and the history of no prior vaccination.The clinical diagnosis is usually supported by documenting parvovirus antigen in feces by ELISA (enzyme-linked immunosorbent assay) and PCR (polymerase chain reaction) assays. The availability of validated assays varies by country but is becoming more common. PCR assays are so sensitive that FPV DNA can be amplified from feces of cats vaccinated with modified live strains of the virus. At least one of the ELISA antigen tests for dogs (SNAP®Parvo; IDEXX Laboratories) detects FPV in feline feces and has a cut point for a positive test result that excludes most vaccinated cats. Thus, this ELISA is superior to PCR for screening cats for FPV infection and can also be performed in the veterinary clinic. (These are only approved and licensed for detecting canine parvovirus, but it is generally known that they also detect FPL viral antigen in feline feces. These tests are used extra-label because they allow rapid, inexpensive, in-house detection of the virus.) Some cats will have completed the shedding period by the time the test is run, leading to false-negative results. Electron microscopy, virus isolation and seroconversion can also be used to document active or recent infection. Leukopenia on a complete blood count (nadir 50–3,000 WBC/μL) supports a diagnosis of FPLV. In an unvaccinated cat, the presence of antibodies against FPV indicates that the cat either has the disease or has had the disease in the past. Elevated IgM titers (1:10 or greater) indicate active infection and if clinical signs are obvious (diarrhea, panleukopenia) the prognosis is poor. Elevated IgG titers (1:100 or greater) in a cat with clinical signs indicates a better prognosis.Differential diagnoses include salmonellosis, enteric toxins, feline immunodeficiency virus (FIV), feline leukemia virus (FeLV), cryptosporidiosis, pancreatitis, septicaemia with acute endotoxemia, toxoplasmosis, peritonitis, and lymphoma. Treatment To contain the virus, cats with suspected or diagnosed FPLV should be kept in isolation.It requires immediate, aggressive treatment if the cat is to survive, as it can be fatal in less than 24 hours. Several articles and publications provide guidance for rescuers and veterinarians for optimizing outcomes.Treatment involves: anti-emetics IV antibiotics intravenous fluids with electrolytes injections of vitamin B plasma or whole blood transfusionFeeding should be continued as long as possible. A highly digestible diet is preferred, but the individual animals preferences may dictate giving whatever it will eat. In anorexic, hypoproteinemic, vomiting and diarrheic cats parenteral nutrition is required.In a disease outbreak, unvaccinated kittens or adults can be given anti-FPV serum containing FPV antibodies injected subcutaneously or intraperitoneal. This may provide protection for 2–4 weeks. Therapeutic efficacy of anti-FPV serum has been demonstrated in dogs, and similar beneficial effects may be expected in cats.Several studies have shown recombinant feline interferon omega is effective in the treatment of parvoviral enteritis in dogs and also inhibits replication of FPV in cell culture. So far no data are available on its efficacy in FPV-infected cats. Complications Cats typically die due to complications associated with sepsis, dehydration, and disseminated intravascular coagulopathy (DIC). Leukocytopenia predisposes patients to secondary infections, especially bacterial and fungal, though secondary viral infections also occur. It has been stated that cats with FPLV may be at risk for endocarditis or cardiomyopathy (since CPV-2 is a well-known cause of viral myocarditis in young puppies), but a 2017 retrospective study concluded that "Feline Panleukopenia Virus Is Not Associated With Myocarditis or Endomyocardial Restrictive Cardiomyopathy in Cats". Prognosis Mortality in affected felid litters varies between 20 and 100%. Mortality of FPLV is 25–90% in domestic cats with the acute form of the disease and up to 100% in cats with peracute disease.In 2010, a retrospective study of 244 infected cats showed that "leukocyte and thrombocyte counts as well as serum albumin and potassium concentrations at presentation are prognostic indicators in cats with panleukopenia, whereas vaccination status, age, clinical signs, and housing conditions are not."A survival rate of about 50% has been reported with supportive therapies. Cats with FPLV that survive the first 5 days of treatment usually recover, however the decrease in the cats white blood cells compromises its immune system, leaving it vulnerable to secondary infection.Lifelong immunity is thought to follow recovery from disease, and a carrier state of the disease has never been identified. Preventing transmission from infected cats Quarantine/isolation Cats with suspected or diagnosed FPLV should be kept in isolation. This non-enveloped virus is very resistant to environmental conditions and many disinfectants, is highly contagious, and rapidly accumulates in the environment due to high shedding of virus from affected animals. Strict protocols for containment – with isolation, minimal handling, and disinfection of all potential sources of fomites – is warranted. Recovered cats can still shed the virus for up to 6 weeks and can carry it on their body for prolonged periods. Vaccination The practice of recommending and giving vaccines on a fixed schedule with annual boosters has been widely discarded. Current recommendations are based on the philosophy of vaccinating each cat no more frequently than necessary. These recommendations take into account considerations for the efficacy and longevity of each specific vaccine; the exposure, risk, and need of different cat populations; and socioeconomic limitations.Recommendations vary for: animal shelters boarding facilities (or animals going into them) breeders community cats (free-roaming and/or feral) or TNR (Trap Neuter Return) programs owned pets (and based on "inside only" or "in and out")The FPLV vaccination is considered a "core" (essential for health) vaccine and is recommended for all domestic cats. Even cats kept indoors can be infected from fomite transmission.Several types and brands of commercial FPLV vaccines are available to induce acquired immunity. These include: killed virus ("non-infectious") adjuvanted killed virus non adjuvanted modified-live virus (MLV or "infectious") adjuvanted modified-live virus non adjuvantedCombination vaccines that protect against several common viruses, including FPLV, are also available. Selection or use of a specific type/brand of a vaccine may vary depending on the overall risk of viral infection to the specific animal in its environment, along with considerations for the time it takes to confer protection, its overall efficacy, the animals health, and the potential risks associated with MLV vs killed, adjuvanted vs nonadjuvanted, intranasal/ocular vs injection. Modified-live FPLV vaccines are not recommended in pregnant queens, very young kittens, or cats with FIV or FeLV.Kittens without maternally derived antibodies are especially vulnerable. FPLV vaccination can start as early as 4 weeks of age for kittens at high risk but are usually started at 6 weeks, then given every 3 – 4 weeks until 16 weeks of age. For cats older than 16 weeks, 2 doses, 3 to 4 weeks apart is generally recommended, followed by a 6-month to 1-year booster. Thereafter, a booster vaccination every 3 years is usually recommended; a blood titer test can be done to determine individual antibody levels for catering the timing of boosters. References External links Feline Distemper (Panleukopenia) from The Pet Health Library How to Limit Parvo in Shelters, Rescues and Transfer Animals
Polysubstance dependence	Polysubstance dependence refers to a type of substance use disorder in which an individual uses at least three different classes of substances indiscriminately and does not have a favorite substance that qualifies for dependence on its own. Although any combination of three substances can be used, studies have shown that alcohol is commonly used with another substance. This is supported by one study on polysubstance use that separated participants who used multiple substances into groups based on their preferred substance. The results of a longitudinal study on substance use led the researchers to observe that excessively using or relying on one substance increased the probability of excessively using or relying on another substance. Common combinations The three substances were cocaine, alcohol, and heroin, which implies that those three are very popular. Other studies have found that opiates, cannabis, amphetamines, hallucinogens, inhalants and benzodiazepines are often used in combination as well. Presentation Associated cognitive impairments Cognition refers to what happens in the mind, such as mental functions like "perception, attention, memory, language, problem solving, reasoning, and decision making." Although many studies have looked at cognitive impairments of individuals who are dependent on one substance, there are few researchers who have tried to determine the problems with cognitive functioning that are caused by dependence on multiple substances. Therefore, what is known about the effects of polysubstance dependence on mental abilities is based on the results of a few studies. Learning ability The effect of polysubstance dependence on learning ability is one area of interest to researchers. A study involving 63 polysubstance dependent women and 46 controls (participants who were not using substances) used the Benton Visual Retention Test (BVRT) and the California Verbal Learning Test (CVLT) to look at visual memory and verbal ability. This study showed that in polysubstance dependent women, verbal learning ability was significantly decreased, though visual memory was not affected. In addition, alcohol and cocaine use led to more severe issues with verbal learning, recall, and recognition. Memory, reasoning and decision making Sometimes studies about specific groups in the general population can be informative. One study decided to test the cognitive abilities of participants in rave parties who used multiple substances. To do this, they compared 25 rave party attenders with 27 control participants who were not using substances. The results of this study indicated that in general, the rave attender group did not perform as well on tasks that tested speed of information processing, working memory, knowledge of similarities between words, ability to attend to a task with interference in the background, and decision making. Certain substances were associated with particular mental functions, but the researchers suggested that the impairments for working memory and reasoning were caused by the misuse of multiple substances.Another study that tried to find differences between the effects of particular substances focused on people with polysubstance use who were seeking treatment for addictions to cannabis, cocaine, and heroin. They studied a group of people with polysubstance use and a group that was not dependent on any substances. Because alcohol was a common co-substance for nearly all of the people in the polysubstance use group, it was difficult to tell exactly which substances were affecting certain cognitive functions. The researchers found that the difference in the two groups performance levels on executive function, or higher-level cognitive processing tasks were consistently showing that the polysubstance group scored lower than the control group. In general, this meant that multiple substances negatively affected the polysubstance groups cognitive functioning. More specifically, the researchers found that the amount of cannabis and cocaine affected the verbal part of working memory, the reasoning task, and decision making, while cocaine and heroin had a similar negative effect on visual and spatial tasks, but cannabis particularly affected visual and spatial working memory. These results suggest that the combined use of cannabis, cocaine, and heroin impair more cognitive functions more severely than if used separately.Alcohols negative effects on learning, spatial abilities and memory has been shown in many studies. This raises a question: does using alcohol in combination with other substances impair cognitive functioning even more? One study decided to try to determine if people with polysubstance use who also recreationally use alcohol would display poorer performance on a verbal learning and memory test in comparison to those who consumed excessive amounts of alcohol specifically. The California Verbal Learning Test (CVLT) was used due to its ability to "quantify small changes in verbal learning and memory" by evaluating errors made during the test and the strategies used to make those errors. The results of this study showed that the group of people with polysubstance and alcohol use performed poorly on the CVLT recall and recognition tests compared to the group of people who exclusively consumed excessive alcohol only, which implies that polysubstance use impaired the memory and learning in a different way than the effects of alcohol alone can explain. Length of abstinence matter To examine whether abstinence for long periods of time helps people with polysubstance use recover their cognitive function, a group of researchers tested 207 polysubstance dependent men, of whom 73.4% were dependent on three or more substances. The researchers were interested in six areas of cognitive functioning, which included visual memory, verbal memory, knowledge of words, abstract reasoning, inhibition (interference), and attention. The study used the Benton Visual Retention Test (BVRT) for testing visual memory, the California Verbal Learning Test (CVLT) for verbal memory, the Wechsler Adult Intelligence Scale vocabulary portion for knowledge of words, the Booklet Category Test for abstract reasoning, the Stroop Neuropsychological Screening task for inhibition, and the Trail Making Test for attention. The results showed that neuropsychological ability did not improve with increases in the length of time abstinent. This suggests that polysubstance dependence leads to serious impairment which cannot be recovered much over the span of a year. Causes Biological There is data to support that some genes contribute to substance dependence. Some studies have focused on finding genes that predispose the person to be dependent on marijuana, cocaine, or heroin by studying genes that control a persons dopamine and opioid receptors, but no conclusive findings were reported. Other researchers found a connection between dopamine receptor genes and dependency on a substance. A potential problem with this study was that alcohol is commonly used with another substance, so the results of the study may not have been caused by dependency on a single substance. This means that multiple substances may have been contributing to the results, but the researchers suggested that further research should be done.However, there are studies that have found evidence of the influence of genes on vulnerability to substance dependence. These studies often use genotype, or the genetic information found on a persons chromosomes, and phenotype, which consists of the visible features of a person, to look at genetic patterns. One study examined the phenotype and genotype of 1,858 participants from 893 families to look at differences in three nicotinic acetylcholine receptor genes found within these individuals. The experimenters found significant connections between receptor genes for nicotine and polysubstance dependence, which indicated that differences in these genes can create the risk of being dependent on multiple substances. Psychological A 1989 study conducted by Khantzian and Treece found that nearly 60% of their opioid-dependent sample met criteria for an Axis II diagnosis. In the same study, 93% of the sample had a comorbid disorder, implying that the comorbid disorder plays some role in the addiction. It has also been shown that depression and polysubstance dependence are often both present at the same time. If a person is genetically predisposed to be depressed then they are at a higher risk of having polysubstance dependence.Possibly the most widely accepted cause of addictions is the self-medication hypothesis, that views substance addiction as a form of coping with stress through negative reinforcement, by temporarily alleviating awareness of or concerns over the stressor. People who use substances learn that the effects of each type of substance works to relieve or better painful states. They use substances as a form of self-medication to deal with difficulties of self-esteem, relationships, and self-care. Individuals with substance use disorders often are overwhelmed with emotions and painful situations and turn to substances as a coping method. Sociocultural The sociocultural causes are areas in a persons life that might have influenced their decision to start and continue using multiple substances. Sociocultural causes can be divided into social causes and cultural causes. Social Causes: Some studies have shown that adolescents have one of the highest rates of polysubstance dependence. According to one study this population, ages 12–25, represents about half of the nations population that uses illicit substances. Of these individuals, half of them have started using substances by the end of 12th grade. This could be attributed to social expectations of peers, peer pressure to fit it, or a way of numbing their emotions. Some of these young kids start trying different substances initially to fit in, but then after a while they start to develop a tolerance for these substances and experience withdrawal if they dont have enough substances in their system and eventually become dependent on having the effects of substance dependence. With tolerance comes the craving for additional substances to get high, this constant need for that feeling is polysubstance dependence.In the older generations, polysubstance dependence had been linked to additional considerations such as personality disorder, homelessness, bipolar disorder, major depressive disorder and so on. Medical care being so expensive and difficult to get long term has been linked to polysubstance dependence. Those who need psychological help sometimes use multiple substances as a type of self medication to help manage their mental illnesses. Comorbidity of mental disorders For most of these disorders, in relation to polysubstance dependence, there is a vicious cycle that those with a dependence go through. First, Ingesting the substance creates a need for more, which creates a dopamine surge, which then creates pleasure. As the dopamine subsides, the pleasure adds to the emotional and physical pain and triggers stress transmitters, which in turn creates a craving, which must then be medicated, and thus the cycle begins again. However, the next time they use, more of the substance will need to be used to get to the same degree of intoxication . Depression Scientists have hypothesized that the use of a substance either causes a mood disorder such as depression or at least attributes to a pre-existing one. Additionally, the substances that people with depression use can be a misguided method of self-medication in order to manage their depression. This is the classic chicken or egg hypothesis, does the pre-existing condition cause dependence or does dependence cause the condition? The underlying mental illness needs to be identified and treated in conjunction with treating the polysubstance dependence in order to increase the success rate of treatment and decrease the probability of relapse. One specific study focused on alcohol and depression, because they are so commonly inter-related. Researchers have discovered that depression continues for several weeks after a patient had been rehabilitated and those who relapsed developed depression again. This means that the onset of depression happens after alcohol dependence occurs, which means that alcohol is a major contributor to depression. Eating disorders One study showed that patients who are recovering from an addiction, who have had an eating disorder in the past, often use food to try to replace the substance that they are no longer getting. Or they obsess over controlling their weight and appearance. Some rehabilitation centers have licensed nutritionists to help patients develop healthy eating habits to help them cope while recovering from their addictions. It is important that those who have a former eating disorder be taught how to eat healthfully, so they dont continuously switch from one addiction back to another. Diagnosis According to the DSM-IV, a diagnosis of polysubstance dependence must include a person who has used at least three different substances (not including caffeine or nicotine) indiscriminately, but does not have a preference to any specific one. In addition they must show a minimum of three of the following symptoms listed below, all within the past twelve months. There is a distinct difference between a person having three separate dependence issues and having Polysubstance dependence the main difference is polysubstance dependence means that they are not specifically addicted to one particular substance. This is often confused with multiple specific dependences present at the same time. To elaborate, if a person is addicted to three separate substance such as cocaine, methamphetamines and alcohol and is dependent on all three then they would be diagnosed with three separate dependence disorders existing together (cocaine dependence, methamphetamine dependence and alcohol dependence,) not polysubstance dependence. In addition to using three different substances without a preference to one, there has to be a certain level of dysfunction in a persons life to qualify for a diagnosis of polysubstance dependence. One of the bigger challenges that often occurs when trying to diagnose is the fact that people dont always report what they are taking because they are afraid of getting into legal trouble. When coding polysubstance Dependence in a DSM-IV it would be a multiaxial diagnosis 304.80- Polysubstance Dependence", next to the classification, it is accompanied by a list of other types of Substance dependence (e.g. "305.00 Alcohol Abuse" or "305.60 Cocaine Abuse").The DSM-IV requires at least three of the following symptoms present during a 12-month period for a diagnoses of polysubstance dependence. Tolerance: Use of increasingly high amounts of a substance or they find the same amount less and less effective ( the amount has to be at least 50% more of the original amount needed.) Withdrawal: Either withdrawal symptoms when the substance stops being used or the substance is used to prevent withdrawal symptoms. Loss of control: Repeated use of more substance than was initially planned or use of the substances over longer periods of time than was planned. Inability to stop using: Either unsuccessfully attempted to cut down or stop using the substances or a persistent desire to stop using. Time: Spending a lot of time studying substances, obtaining substances, using substances, being under the influence of substances, and recovering from the effects of substances. Interference with activities: Give up or reduce the amount of time involved in recreational activities, social activities, and/or occupational activities because of the use of substances. Harm to self: Continuous use of substances despite having a physical or psychological problem caused by or made worse by the use of substances.DSM-5 eliminated polysubstance disorder; there the substances must be specified, among other related changes. Treatment Treatment for polysubstance dependence has many critical aspects. Substance rehabilitation is a lengthy and difficult process. Treatment must be individualized and last a sufficient amount of time to ensure the patient has kicked the addictions and to ensure the prevention of relapse. The most common forms of treatment for polysubstance dependence include: inpatient and outpatient treatment centers, counseling and behavioral treatments, and medications. It is important that treatments be carried on throughout the patients life in order to prevent relapse. It is a good idea that recovering addicts continue to attend social support groups or meet with counselors to ensure they do not relapse. Inpatient treatment center Inpatient treatment centers are treatment centers where addicts move to the facility while they are undergoing treatment. Inpatient treatment centers offer a safe environment where patients will not be exposed to potentially harmful situations during their treatments as they would on the outside. Inpatients usually undergo the process of detoxification. Detox involves withdrawing the user (usually medically) from all substances of concern. During their stay in the treatment facility, patients often are learning to manage and identify their substance addictions and to find alternate ways to cope with whatever is the cause of their addiction. Outpatient treatments Outpatient treatments include many of the same activities offered in an inpatient treatment facility, but the patient is not protected by the secure and safe environment of an inpatient treatment center. For this reason, they are significantly less effective. The patient usually continues to hold a job and goes to treatment nightly. Twelve-step programs Both in-patient and out-patient treatments can offer introductions to 12-step programs. Suggested 12-step programs are Alcoholics Anonymous (AA) and Narcotics Anonymous (NA). They offer regular meetings where members can discuss their experiences in a non-judgmental and supportive place. Cognitive behavioral therapy Also offered to patients are one-on-one counseling sessions and cognitive behavioral therapy(CBT). When looked at through a cognitive-behavioral perspective, addictions are the result of learned behaviors developed through positive experiences. In other words, when an individual uses a substance and receives desired results (happiness, reduced stress, etc.) it may become the preferred way of attaining those results, leading to addictions. The goal of CBT is to identify the needs that the addictions are being used to meet and to develop skills and alternative ways of meeting those needs. The therapist will work with the patient to educate them on their addictions and give them the skills they need to change their cognitions and behaviors.Addicts will learn to identify and correct problematic behavior. They will be taught how to identify harmful thoughts and substance cravings. CBT is an effective treatment for addictions. Medications Medications can be very helpful in the long-term treatment of polysubstance dependence. Medications are a useful aid in helping to prevent or reducing substance cravings. Another benefit of medications is helping to preventing relapse. Since substance use disorders affect brain functioning, medications assist in returning to normal brain functioning. People who use multiple substances require medications for each substance they use, as the current medications do not treat all substance use disorders simultaneously. Medications are a useful aid in treatments, but are not effective when they are the sole treatment method. Substance use Disorder Medications Methadone treatment for heroin addiction. Naltrexone: Reduces opiates and alcohol cravings. Disulfiram: induces intense nausea after drinking alcohol. Acamprosate: normalizes brain chemistry disrupted by alcohol withdrawal and aids alcohol abstinence. Buprenorphine/naloxone: The two medications together reduce cravings and block the pleasure from opiates. Epidemiology There are not very many studies that have examined how often polysubstance dependence occurs or how many people are dependent on multiple substances. However, according to a study that analyzed the results from the National Epidemiological Survey on Alcohol and Related Conditions, approximately 215.5 out of a total of 43,093 individuals in the United States (0.5%) met the requirements for polysubstance use disorder. Another study suggested that the number of new cases of polysubstance dependence has been going up. This idea was supported by a study that took place in Munich, Germany. A group of researchers chose to look at responses to a survey using the M-Composite International Diagnostic Interview (M-CIDI). The M-CIDI is a version of the Composite International Diagnostic Interview (CIDI). The researchers collected data from 3,021 participants, all between the ages of 14 and 24, to estimate the prevalence, or total number of cases, of substance use and of polysubstance use/dependence. The results of this study indicated that of the 17.3% who said that they regularly used substances, 40% said that they used more than one substance, but 3.9% specifically reported using three or more substances, indicating that there is a lot of overlap in the use of different substances. The researchers compared their results to earlier German studies and found that substance dependence seems to be increasing, at least in Germany. Gender differences Women and men differ in various ways when it comes to addictions. Research has shown that women are more likely to be polysubstance dependent. It has been noted that a larger percentage of women use licit (legal) substances such as tranquilizers, sedatives, and stimulants. On the other hand, men are more likely to use illicit (illegal) substances such as cocaine, methamphetamine, and other illicit substances. Research suggests that women addicts more frequently have a family history of substance use. When asked to describe their onset of addictions, women more frequently describe their addiction as sudden where as men describe them as gradual. Females have a higher percentage of fatty tissues and a lower percentage of body water than men. Therefore, women absorb substances more slowly. This means these substances are at a higher concentration in a womans bloodstream. Female addicts are known to be at greater risk for fatty liver disease, hypertension, anemia, and other disorders. See also Self-medication References External links A great resource for more information: http://www.nida.nih.gov/nidahome.html
Vascular malformation	A vascular malformation is a blood vessel or lymph vessel abnormality. Vascular malformations are one of the classifications of vascular anomalies, the other grouping is vascular tumors. They may cause aesthetic problems as they have a growth cycle, and can continue to grow throughout life. Vascular malformations of the brain (VMBs) include those involving capillaries, and those involving the veins and arteries. Capillary malformations in the brain are known as cerebral cavernous malformations or capillary cavernous malformations (CCMs). Those involving the mix of vessels are known as cerebral arteriovenous malformations (AVMs or cAVMs). The arteriovenous type is the most common in the brain. Types A simple division of the vascular malformations is made into low-flow and high-flow types. Low-flow malformations involve a single type of blood or lymph vessel, and are known as simple vascular malformations; high-flow malformations involve an artery. There are also malformations that are of mixed-flow involving more than one type of vessel, such as an arteriovenous malformation.Low-flow vascular malformations include capillary malformations, venous malformations, and lymphatic malformations. Capillary malformation Capillary malformations involve the capillaries, and are the most common type. They used to refer only to port-wine stains but now include others. Capillary malformations are limited to the superficial layers of the skin but they can thicken, become nodular, and sometimes become disfiguring. It has been proposed that the category of capillary malformations, also called vascular stains, be classified into seven major clinical types including nevus flammeus nuchae also known as nevus simplex, commonly known as stork bite or salmon patch.A capillary malformation is also a feature of the disorder macrocephaly-capillary malformation. Venous malformation Venous malformations are typically ill-defined masses, coloured from pale to dark blue. They can affect any tissue in the body. The mass is soft, and easily compressed, and their blue colouring is due to the dilated anomalous involved veins. They are most commonly found in the head and neck. Venous malformations can often extend deeper from their surface appearance, reaching underlying muscle or bone. In the neck they may extend into the lining of the mouth cavity or into the salivary glands.A severe venous malformation can involve the lymph vessels as a lymphaticovenous malformation. Lymphatic malformation Lymphatic malformations are congenital, developing from badly-formed lymphatic vessels in early embryonic development. Abnormal development of the lymph vessels results in their failure to connect and drain into the venous system.These lymph vessels can become blocked due to the collection of lymph which forms a cyst as a mass, and are known as lymphangiomas. They can be macrocystic, microcystic, or a combination of the two. Macrocystic have cysts greater than 2 cubic centimetres (0.12 cu in), and microcystic lymphangiomas have cysts that are smaller than 2 cubic centimetres (0.12 cu in). A macrocystic lymphangioma is also known as a cystic hygroma. Cystic hygromas most often occur in the neck where they are known as nuchal hygromas.A severe venous malformation is known as a lymphaticovenous malformation that also involves the lymph vessels. Arteriovenous malformation Arteriovenous malformations occur between an artery and a vein. In the brain a cerebral arteriovenous malformation causes arterial blood to be directly shunted into the veins as there is an absence of a capillary bed. This carries a high risk of an intracranial hemorrhage. See also Arteriovenous fistula Lymphohemangioma Telangiectasia Vascular disease == References ==
Perichondritis	Perichondritis is inflammation of the perichondrium, a layer of connective tissue which surrounds cartilage. A common form, auricular perichondritis (perichondritis auriculae) involves infection of the pinna due to infection of traumatic or surgical wound or the spread of inflammation into depth (e.g. Infected transcartilaginous ear piercings). It may lead to severe deformation of the pinna if not treated vigorously with IV antibiotics. The causative organism is usually Pseudomonas aeruginosa. A rare form is laryngeal perichondritis (perichondritis laryngis). It develops suddenly due to an injury, virulent organisms or compromised immune status of the host, and also affects cartilage of the larynx. This may result in deformations and stenoses. Signs and symptoms Signs of perichondritis or chondritis in patients with an embedded earring are similar (these include pain, swelling and erythema of the overlying skin) and fluctuant swelling indicate an abscess that we should drain (typically associated with chondritis). Clinically, perichondritis can be differentiated from cellulitis of the pinna, in that the first usually does not involve the earlobe.In serious cases pus appears between the perichondrium and cartilage. Purulent melting of auricular cartilage takes place. Dead tissue tears away, as a result, auricle deforms strongly and becomes shrunken. See also Chondritis References == External links ==
Neuronal ceroid lipofuscinosis	Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the bodys tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys. Signs and symptoms The classic characterization of the group of neurodegenerative, lysosomal storage disorders called the neuronal ceroid lipofuscinoses (NCLs) is through the progressive, permanent loss of motor and psychological ability with a severe intracellular accumulation of lipofuscins, with the United States and Northern European populations having slightly higher frequency with an occurrence of one in 10,000. Four classic diagnoses have received the most attention from researchers and the medical field, differentiated from one another by age of symptomatic onset, duration, early-onset manifestations such as blindness or seizures, and the forms which lipofuscin accumulation takes.In the early infantile variant of NCL (also called INCL or Santavuori-Haltia), probands appear normal at birth, but early visual loss leading to complete retinal blindness by the age of 2 years is the first indicator of the disease; by 3 years of age, a vegetative state is reached, and by 4 years, isoelectric encephalograms confirm brain death. Late infantile variant usually manifests between 2 and 4 years of age with seizures and deterioration of vision. The maximum age before death for late infantile variant is 10–12 years. Juvenile NCL (JNCL, Batten disease, or Spielmeyer-Vogt), with a prevalence of one in 100,000, usually arises between 4 and 10 years of age; the first symptoms include considerable vision loss due to retinal dystrophy, with seizures, psychological degeneration, and eventual death in the mid- to late 20s or 30s ensuing. Adult variant NCL (ANCL or Kufs disease) is less understood and generally manifests milder symptoms; however, while symptoms typically appear around 30 years of age, death usually occurs 10 years later.All the mutations that have been associated with this disease have been linked to genes involved with the neural synapses metabolism – most commonly with the reuse of vesicle proteins. Genetics Childhood NCLs are generally autosomal recessive disorders; that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry one defective gene, each of their children faces a one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children. The most commonly identified mutations are in the CLN3 gene, which is located on the short arm of chromosome 16 (16p12.1). The normal function of the gene is not presently known, but results in a transmembrane protein.Adult NCL may be inherited as an autosomal recessive (Kufs), or less often, as an autosomal dominant (Parrys) disorder. In autosomal dominant inheritance, all people who inherit a single copy of the disease gene develop the disease. As a result, no carriers of the gene are unaffected.Many authorities refer to the NCLs collectively as Batten disease. Diagnosis Because vision loss is often an early sign, NCL may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often, an eye specialist or other physician who suspects NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. To diagnose NCL, the neurologist needs the patients medical history and information from various laboratory tests.Diagnostic tests used for NCLs include: Skin or tissue sampling: The doctor can examine a small piece of tissue under a microscope to spot typical NCL deposits. These deposits are found in many different tissues, including skin, muscle, conjunctiva, rectal and others. Blood can also be used. These deposits take on characteristic shapes, depending on the variant under which they are said to occur: granular osmophilic deposits (GRODs) are generally characteristic of INCL, while curvilinear profiles, fingerprint profiles, and mixed-type inclusions are typically found in LINCL, JNCL, and ANCL, respectively. Electroencephalogram or EEG: An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brains electrical activity that suggest a patient has seizures. Electrical studies of the eyes: These tests, which include visual-evoked responses and electroretinograms, can detect various eye problems common in childhood NCLs. Brain scans: Imaging can help doctors look for changes in the brains appearance. The most commonly used imaging technique is computed tomography (CT), which uses x-rays and a computer to create a sophisticated picture of the brains tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. An increasingly common tool is magnetic resonance imaging, which uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain. Enzyme assay: A recent development in diagnosis of NCL is the use of enzyme assays that look for specific missing lysosomal enzymes for infantile and late infantile versions only. This is a quick and easy diagnostic test. Types The older classification of NCL divided the condition into four types (CLN1, CLN2, CLN3, and CLN4) based upon age of onset, while newer classifications divide it by the associated gene.CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene. Mutations Infantile form Nonsense and frameshift mutations in the CLN1 gene (located at 1p32) always induce classical INCL, while some missense mutations have been associated with ANCL in addition to the infantile and juvenile forms. The mutation typically results in a deficient form of a lysosomal enzyme called palmitoyl protein thioesterase 1 (PPT1).The wild-type PPT1 is a 306-amino acid polypeptide that is typically targeted for transport into lysosomes by the mannose 6-phosphate (M6P) receptor-mediated pathway. Here, the protein appears to function in removing palmitate residues by cleaving thioester linkages in s-acylated (or palmitoylated) proteins, encouraging their breakdown. Defective polypeptides, however, are unable to exit the endoplasmic reticulum (ER), most likely due to misfolding; further analyses of this pathway could serve to categorize INCL among lysosomal enzyme deficiencies. The human PPT gene shows 91% similarity to bovine PPT and 85% similarity to rat PPT; these data indicate that the PPT gene is highly conserved and likely plays a vital role in cell metabolism. In addition, buildup of defective PPT1 in the ER has been shown to cause the increased release of Ca2+. This homeostasis-altering event leads to increased mitochondrial membrane permeability and subsequent activation of caspase-9, eventually leading to an accumulation of cleft and uncleft poly(ADP-ribose) polymerase and eventual apoptosis. Late infantile form The CLN2 gene encodes a 46kDa protein called lysosomal tripeptidyl peptidase I (TPP1), which cleaves tripeptides from terminal amine groups of partially unfolded proteins. Mutations of this gene typically result in a LINCL phenotype.On April 27, 2017, the U.S. Food and Drug Administration approved cerliponase alfa (Brineura) as the first specific treatment for NCL. It is enzyme replacement therapy manufactured through recombinant DNA technology. The active ingredient in Brineura, cerliponase alfa, is intended to slow loss of walking ability in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as TPP1 deficiency. Brineura is administered into the cerebrospinal fluid by infusion via a surgically implanted reservoir and catheter in the head (intraventricular access device). Juvenile form All mutations resulting in the juvenile variant of NCL have been shown to occur at the CLN3 gene on 16p12; of the mutations known to cause JNCL, 85% result from a 1.02-kb deletion, with a loss of amino acids 154–438, while the remaining 15% appear to result from either point or frameshift mutations. The wild-type CLN3 gene codes for a protein with no known function, but studies of the yeast CLN3 ortholog, the product of which is called battenin (after its apparent connections to Battens disease, or JNCL), have suggested that the protein may play a role in lysosomal pH homeostasis. Furthermore, recent studies have also implied the proteins role in cathepsin D deficiency; the overexpression of the defective protein appears to have significant effects on cathepsin D processing, with implications suggesting that accumulation of ATP synthase subunit C would result. Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D. Adult dominant form Between 1.3 and 10% of cases are of the adult form. The age at onset is variable (6–62 yr). Two main clinical subtypes have been described: progressive myoclonus epilepsy (type A) and dementia with motor disturbances, such as cerebellar, extrapyramidal signs and dyskinesia (type B). Unlike the other NCLs, retinal degeneration is absent. Pathologically, the ceroid-lipofuscin accumulates mainly in neurons and contains subunit C of the mitochondrial ATP synthase.Two independent families have been shown to have mutations in the DNAJC5 gene – one with a transversion and the other with a deletion mutation. The mutations occur in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of the encoded protein cysteine-string protein alpha (CSPα). The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene. Treatment Currently, no widely accepted treatment can cure, slow down, or halt the symptoms in the great majority of patients with NCL, but seizures may be controlled or reduced with use of antiepileptic drugs. Additionally, physical, speech, and occupational therapies may help affected patients retain functioning for as long as possible. Several experimental treatments are under investigation. Cystagon In 2001, a drug used to treat cystinosis, a rare genetic disease that can cause kidney failure if not treated, was reported to be useful in treating the infantile form of NCL. Preliminary results report the drug has completely cleared away storage material from the white blood cells of the first six patients, as well as slowing down the rapid neurodegeneration of infantile NCL.Currently, two drug trials are underway for infantile NCL, both using Cystagon. Gene therapy A gene therapy trial using an adenoassociated virus vector called AAV2CUhCLN2 began in June 2004 in an attempt to treat the manifestations of late infantile NCL. The trial was conducted by Weill Medical College of Cornell University and sponsored by the Nathans Battle Foundation. In May 2008, the gene therapy given to the recipients reportedly was "safe, and that, on average, it significantly slowed the diseases progression during the 18-month follow-up period" and "suggested that higher doses and a better delivery system may provide greater benefit".A second gene therapy trial for late infantile NCL using an adenoassociated virus derived from the rhesus macaque (a species of Old World monkey) called AAVrh.10 began in August 2010, and is once again being conducted by Weill Medical College of Cornell University. Animal models of late infantile NCL showed that the AAVrh.10 delivery system "was much more effective, giving better spread of the gene product and improving survival greatly".A third gene therapy trial, using the same AAVrh.10 delivery system, began in 2011 and has been expanded to include late infantile NCL patients with moderate tosevere impairment or uncommon genotypes, and uses a novel administration method that reduces general anesthesia time by 50% to minimize potential adverse side effects. Flupirtine A painkiller available in several European countries, flupirtine, has been suggested to possibly slow down the progress of NCL, particularly in the juvenile and late infantile forms. No trial has been officially supported in this venue, however. Currently, the drug is available to NCL families either from Germany, Duke University Medical Center in Durham, North Carolina, or the Hospital for Sick Children in Toronto. Stem cells On October 20, 2005, the Food and Drug Administration approved a phase-I clinical trial of neural stem cells to treat infantile and late infantile Batten disease. Subsequent approval from an independent review board also approved the stem cell therapy in early March 2006. This treatment will be the first transplant of fetal stem cells performed on humans. The therapy is being developed by Stem Cells Inc and is estimated to have six patients. The treatment was to be carried out in Oregon.Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone-marrow or stem-cell transplants for this condition. A bone-marrow transplant has been attempted in the late infantile form of NCL with disappointing results; while the transplant may have slowed the onset of the disease, the child eventually developed the disease and died in 1998.Trials testing the effectiveness of bone-marrow transplants for infantile NCL in Finland have also been disappointing, with only a slight slowing of disease reported. Immunosuppressants In late 2007, Dr. David Pearce et al. reported that Cellcept, an immunosuppressant medication commonly used in bone-marrow transplants, may be useful in slowing down the progress of juvenile NCL. Enzyme replacement therapy On April 27, 2017, the U.S. FDA approved cerliponase alfa as the first specific treatment for NCL. Epidemiology Incidence can vary greatly from type-to-type, and from country-to-country.In Germany, one study reported an incidence of 1.28 per 100,000.A study in Italy reported an incidence of 0.56 per 100,000.A study in Norway reported an incidence of 3.9 per 100,000 using the years from 1978 to 1999, with a lower rate in earlier decades. History 19th century The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel, who described 4 affected siblings in a small mining community in Norway. Although no pathological studies were performed on these children the clinical descriptions are so succinct that the diagnosis of the Spielmeyer-Sjogren (juvenile) type is fully justified. 1900 to 1950 More fundamental observations were reported by F. E. Batten in 1903, and by Heinrich Vogt in 1905, who performed extensive clinicopathological studies on several families. Retrospectively, these papers disclose that the authors grouped together different types of the syndrome. Furthermore, Batten, at least for some time, insisted that the condition that he described was distinctly different from Tay–Sachs disease, the prototype of a neuronal lysosomal disorder now identified as GM2 gangliosidosis type A. Around the same time, Walther Spielmeyer reported detailed studies on three siblings, who have the Spielmeyer-Sjogren (juvenile) type, which led him to the very firm statement that this malady is not related to Tay–Sachs disease. Subsequently, however, the pathomorphological studies of Károly Schaffer made these authors change their minds to the extent that they reclassified their respective observations as variants of Tay–Sachs disease, which caused confusion lasting about 50 years.In 1913–14, Max Bielschowsky delineated the late infantile form of NCL. However, all forms were still thought to belong in the group of "familial amaurotic idiocies", of which Tay–Sachs was the prototype. In 1931, Torsten Sjögren, a Swedish psychiatrist and geneticist, presented 115 cases with extensive clinical and genetic documentation and came to the conclusion that the disease now called the Spielmeyer-Sjogren (juvenile) type is genetically separate from Tay–Sachs. 1950 to today Departing from the careful morphological observations of Spielmeyer, Hurst, and Sjovall and Ericsson, Zeman and Alpert made a determined effort to document the previously suggested pigmentary nature of the neuronal deposits in certain types of storage disorders. Simultaneously, Terry and Korey and Svennerholm demonstrated a specific ultrastructure and biochemistry for Tay–Sachs disease, and these developments led to the distinct identification and also separation of the NCLs from Tay–Sachs disease by Zeman and Donahue. At that time, it was proposed that the late-infantile (Jansky–Bielschowsky), the juvenile (Spielmeyer–Vogt), and the adult form (Kufs) were quite different from Tay–Sachs disease with respect to chemical pathology and ultrastructure and also different from other forms of sphingolipidoses.Subsequently, Santavuori and Haltia showed that an infantile form of NCL exists, which Zeman and Dyken had included with the Jansky Bielschowsky type. References External links GeneReviews/NCBI/NIH/UW entry on Neuronal ceroid-Lipofuscinosis
Gender dysphoria	Gender dysphoria (GD) is the distress a person experiences due to a mismatch between their gender identity—their personal sense of their own gender—and their sex assigned at birth. The diagnostic label gender identity disorder (GID) was used until 2013 with the release of the diagnostic manual DSM-5. The condition was renamed to remove the stigma associated with the term disorder.People with gender dysphoria commonly identify as transgender. Gender nonconformity is not the same thing as gender dysphoria and does not always lead to dysphoria or distress. According to the American Psychiatric Association, not all transgender people experience dysphoria; the critical element of gender dysphoria is "clinically significant distress".The causes of gender dysphoria are unknown but a gender identity likely reflects genetic, biological, environmental, and cultural factors. Treatment for gender dysphoria may include supporting the individuals gender expression or their desire for hormone therapy or surgery. Treatment may also include counseling or psychotherapy.Some researchers and transgender people support declassification of the condition because they say the diagnosis pathologizes gender variance and reinforces the binary model of gender. Without the classification of gender dysphoria as a medical disorder, HRT and gender affirming surgery may be viewed as cosmetic treatments by health insurance, as opposed to medically necessary treatment, and may not be covered. Signs and symptoms Distress arising from an incongruence between a persons felt gender and assigned sex/gender (usually at birth) is the cardinal symptom of gender dysphoria.Gender dysphoria in those assigned male at birth (AMAB) tends to follow one of two broad trajectories: early-onset or late-onset. Early-onset gender dysphoria is behaviorally visible in childhood. Sometimes gender dysphoria will stop for a while in this group and they will identify as gay or homosexual for a period of time, followed by recurrence of gender dysphoria. This group is usually sexually attracted to members of their natal sex in adulthood, commonly identifying as heterosexual. Late-onset gender dysphoria does not include visible signs in early childhood, but some report having had wishes to be the opposite sex in childhood that they did not report to others. Transgender people assigned male at birth who experience late-onset gender dysphoria will usually be attracted to women and may identify as lesbians or bisexual, while those with early-onset will usually be attracted to men. A similar pattern occurs in those assigned female at birth (AFAB), with those experiencing early-onset GD being most likely to be attracted to women and those with late-onset being most likely to be attracted to men and identify as gay.Symptoms of GD in children include preferences for opposite sex-typical toys, games, or activities; great dislike of their own genitalia; and a strong preference for playmates of the opposite sex. Some children may also experience social isolation from their peers, anxiety, loneliness, and depression. In adolescents and adults, symptoms include the desire to be and to be treated as a different gender. Adults with GD are at increased risk for stress, isolation, anxiety, depression, poor self-esteem, and suicide. Transgender people are also at heightened risk for eating disorders and substance abuse. Causes The specific causes of gender dysphoria remain unknown, and treatments targeting the etiology or pathogenesis of gender dysphoria do not exist. Evidence from studies of twins suggests that genetic factors play a role in the development of gender dysphoria. Gender identity is thought to likely reflect a complex interplay of biological, environmental, and cultural factors. Diagnosis The American Psychiatric Association permits a diagnosis of gender dysphoria in adolescents or adults if two or more of the following criteria are experienced for at least six months duration: A strong desire to be of a gender other than ones assigned gender A strong desire to be treated as a gender other than ones assigned gender A significant incongruence between ones experienced or expressed gender and ones sexual characteristics A strong desire for the sexual characteristics of a gender other than ones assigned gender A strong desire to be rid of ones sexual characteristics due to incongruence with ones experienced or expressed gender A strong conviction that one has the typical reactions and feelings of a gender other than ones assigned genderIn addition, the condition must be associated with clinically significant distress or impairment.The DSM-5 moved this diagnosis out of the sexual disorders category and into a category of its own. The diagnosis was renamed from gender identity disorder to gender dysphoria, after criticisms that the former term was stigmatizing. Subtyping by sexual orientation was deleted. The diagnosis for children was separated from that for adults, as "gender dysphoria in children". The creation of a specific diagnosis for children reflects the lesser ability of children to have insight into what they are experiencing, or ability to express it if they have insight. Other specified gender dysphoria or unspecified gender dysphoria can be diagnosed if a person does not meet the criteria for gender dysphoria but still has clinically significant distress or impairment. Intersex people are now included in the diagnosis of GD.The International Classification of Diseases (ICD-10) lists several disorders related to gender identity: Transsexualism (F64.0): Desire to live and be accepted as a member of the opposite sex, usually accompanied by a desire for surgery and hormonal treatment Gender identity disorder of childhood (F64.2): Persistent and intense distress about ones assigned gender, manifested prior to puberty Other gender identity disorders (F64.8) Gender identity disorder, unspecified (F64.9) Sexual maturation disorder (F66.0): Uncertainty about ones gender identity or sexual orientation, causing anxiety or distressThe ICD-11, which came into effect on 1 January 2022, significantly revised classification of gender identity-related conditions. Under "conditions related to sexual health", the ICD-11 lists "gender incongruence", which is coded into three conditions: Gender incongruence of adolescence or adulthood (HA60): replaces F64.0 Gender incongruence of childhood (HA61): replaces F64.2 Gender incongruence, unspecified (HA6Z): replaces F64.9In addition, sexual maturation disorder has been removed, along with dual-role transvestism. ICD-11 defines gender incongruence as "a marked and persistent incongruence between an individuals experienced gender and the assigned sex", with no requirement for significant distress or impairment. Treatment Treatment for a person diagnosed with GD may include psychological counseling, supporting the individuals gender expression, or hormone therapy or surgery. This may involve physical transition resulting from medical interventions such as hormonal treatment, genital surgery, electrolysis or laser hair removal, chest/breast surgery, or other reconstructive surgeries. The goal of treatment may simply be to reduce problems resulting from the persons transgender status, for example, counseling the patient in order to reduce guilt associated with cross-dressing.Guidelines have been established to aid clinicians. The World Professional Association for Transgender Health (WPATH) Standards of Care are used by some clinicians as treatment guidelines. Others use guidelines outlined in Gianna Israel and Donald Tarvers Transgender Care. Guidelines for treatment generally follow a "harm reduction" model. Children Medical, scientific, and governmental organizations have opposed conversion therapy, defined as treatment viewing gender nonconformity as pathological and something to be changed, instead supporting approaches that affirm childrens diverse gender identities. People are more likely to keep having gender dysphoria the more intense their gender dysphoria, cross-gendered behavior, and verbal identification with the desired/experienced gender are (i.e. stating that they are a different gender rather than wish to be a different gender).Professionals who treat gender dysphoria in children sometimes prescribe puberty blockers to delay the onset of puberty until a child is believed to be old enough to make an informed decision on whether hormonal or surgical gender reassignment is in their best interest.A review published in Child and Adolescent Mental Health found that puberty blockers are fully reversible, and that they are associated with such positive outcomes as decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life.A review commissioned by the UK Department of Health found that there was very low certainty of quality of evidence about puberty blocker outcomes in terms of mental health, quality of life and impact on gender dysphoria. The Finnish government commissioned a review of the research evidence for treatment of minors and the Finnish Ministry of Health concluded that there are no research-based health care methods for minors with gender dysphoria. Nevertheless, they recommend the use of puberty blockers for minors on a case-by-case basis, and the American Academy of Pediatrics state that "pubertal suppression in children who identify as TGD [transgender and gender diverse] generally leads to improved psychological functioning in adolescence and young adulthood.".In the United States, several states have introduced or are considering legislation that would prohibit the use of puberty blockers in the treatment of transgender children. The American Medical Association, the Endocrine Society, the American Psychological Association, the American Academy of Child and Adolescent Psychiatry and the American Academy of Pediatrics oppose bans on puberty blockers for transgender children. In the UK, in the case of Bell v Tavistock, an appeal court, overturning the original decision, ruled that children under 16 could give consent to receiving puberty blockers. Psychological treatments Until the 1970s, psychotherapy was the primary treatment for gender dysphoria and generally was directed to helping the person adjust to their assigned sex. Psychotherapy is any therapeutic interaction that aims to treat a psychological problem. Psychotherapy may be used in addition to biological interventions, although some clinicians use only psychotherapy to treat gender dysphoria. Psychotherapeutic treatment of GD involves helping the patient to adapt to their gender incongruence or to explorative investigation of confounding co-occurring mental health issues. Attempts to alleviate GD by changing the patients gender identity to reflect assigned sex have been ineffective and are regarded as conversion therapy by most health organizations.: 1741 Biological treatments Biological treatments physically alter primary and secondary sex characteristics to reduce the discrepancy between an individuals physical body and gender identity. Biological treatments for GD are typically undertaken in conjunction with psychotherapy; however, the WPATH Standards of Care state that psychotherapy should not be an absolute requirement for biological treatments.Hormonal treatments have been shown to reduce a number of symptoms of psychiatric distress associated with gender dysphoria. A WPATH commissioned systematic review of the outcomes of hormone therapy "found evidence that gender-affirming hormone therapy may be associated with improvements in [quality of life] scores and decreases in depression and anxiety symptoms among transgender people." The strength of the evidence was low due to methodological limitations of the studies undertaken. Some literature suggests that gender-affirming surgery is associated with improvements in quality of life and decreased incidence of depression. Those who choose to undergo sex reassignment surgery report high satisfaction rates with the outcome, though these studies have limitations including risk of bias (lack of randomization, lack of controlled studies, self-reported outcomes) and high loss to follow up.For adolescents, much is unknown, including persistence. Disagreement among practitioners regarding treatment of adolescents is in part due to the lack of long-term data. Young people qualifying for biomedical treatment according to the Dutch model (including having GD from early childhood on which intensifies at puberty and absence of psychiatric comorbidities that could challenge diagnosis or treatment) found reduction in gender dysphoria, although limitations to these outcome studies have been noted, such as lack of controls or considering alternatives like psychotherapy.In its position statement published December 2020, the Endocrine Society stated that there is durable evidence for a biological underpinning to gender identity and that pubertal suppression, hormone therapy, and medically indicated surgery are effective and relatively safe when monitored appropriately and have been established as the standard of care. They noted a decrease in suicidal ideation among youth who have access to gender-affirming care and comparable levels of depression to cisgender peers among socially transitioned pre-pubertal youth. In its 2017 guideline on treating those with gender dysphoria, it recommends puberty blockers be started when the child has started puberty (Tanner Stage 2 for breast or genital development) and cross-sex hormones be started at 16, though they note "there may be compelling reasons to initiate sex hormone treatment prior to the age of 16 years in some adolescents with GD/gender incongruence". They recommend a multidisciplinary team of medical and mental health professionals manage the treatment for those under 18. They also recommend "monitoring clinical pubertal development every 3 to 6 months and laboratory parameters every 6 to 12 months during sex hormone treatment".A review published in Child and Adolescent Mental Health found that puberty blockers are fully reversible, and that they are associated with such positive outcomes as decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life.More rigorous studies are needed to assess the effectiveness, safety, and long-term benefits and risks of hormonal and surgical treatments. For instance, a 2020 Cochrane review found insufficient evidence to determine whether feminizing hormones were safe or effective. Several studies have found significant long-term psychological and psychiatric pathology after surgical treatments.In 2021, a review published in Plastic And Reconstructive Surgery found that less than 1% of people who undergo gender-affirming surgery regret the decision. Comorbidities Among youth, around 20% to 30% of individuals attending gender clinics meet the DSM criteria for an anxiety disorder. Gender dysphoria is also associated with an increased risk of eating disorders in transgender youth.A widely held view among clinicians is that there is an over-representation of neurodevelopmental conditions amongst individuals with GD, although this view has been questioned due to the low quality of evidence. Studies on children and adolescents with gender dysphoria have found a high prevalence of autism spectrum disorder (ASD) traits or a confirmed diagnosis of ASD. Adults with gender dysphoria attending specialist gender clinics have also been shown to have high rates of ASD traits or an autism diagnosis as well. It has been estimated that children with ASD were over four times as likely to be diagnosed with GD, with ASD being reported from 6% to over 20% of teens referring to gender identity services. Epidemiology Different studies have arrived at different conclusions about the prevalence of gender dysphoria. The DSM-5 estimates that about 0.005% to 0.014% of people assigned male at birth and 0.002% to 0.003% of people assigned female at birth are diagnosable with gender dysphoria.According to Blacks Medical Dictionary, gender dysphoria "occurs in one in 30,000 male births and one in 100,000 female births." Studies in European countries in the early 2000s found that about 1 in 12,000 natal male adults and 1 in 30,000 natal female adults seek out sex reassignment surgery. Studies of hormonal treatment or legal name change find higher prevalence than sex reassignment, with, for example a 2010 Swedish study finding that 1 in 7,750 adult natal males and 1 in 13,120 adult natal females requested a legal name change to a name of the opposite gender.Studies that measure transgender status by self-identification find even higher rates of gender identity different from sex assigned at birth (although some of those who identify as transgender or gender nonconforming may not experience clinically significant distress and so do not have gender dysphoria). A study in New Zealand found that 1 in 3,630 natal males and 1 in 22,714 natal females have changed their legal gender markers. A survey of Massachusetts adults found that 0.5% identify as transgender. A national survey in New Zealand of 8,500 randomly selected secondary school students from 91 randomly selected high schools found 1.2% of students responded "yes" to the question "Do you think you are transgender?". Outside of a clinical setting, the stability of transgender or non-binary identities is unknown.Research indicates people who transition in adulthood are up to three times more likely to be male assigned at birth, but that among people transitioning in childhood the sex ratio is close to 1:1. The prevalence of gender dysphoria in children is unknown due to the absence of formal prevalence studies. History Neither the DSM-I (1952) nor the DSM-II (1968) contained a diagnosis analogous to gender dysphoria. Gender identity disorder first appeared as a diagnosis in the DSM-III (1980), where it appeared under "psychosexual disorders" but was used only for the childhood diagnosis. Adolescents and adults received a diagnosis of transsexualism (homosexual, heterosexual, or asexual type). The DSM-III-R (1987) added "Gender Identity Disorder of Adolescence and Adulthood, Non-Transsexual Type" (GIDAANT). DSM-V (2013) replaced gender identity disorder (GID) with gender dysphoria (GD) to avoid the stigma of the term disorder. Society and culture Researchers disagree about the nature of distress and impairment in people with GD. Some authors have suggested that people with GD suffer because they are stigmatized and victimized; and that, if society had less strict gender divisions, transgender people would suffer less.Some controversy surrounds the creation of the GD diagnosis, with Davy et al. stating that although the creators of the diagnosis state that it has rigorous scientific support, "it is impossible to scrutinize such claims, since the discussions, methodological processes, and promised field trials of the diagnosis have not been published."Some cultures have three or more defined genders. The existence of accepted social categories other than man or woman may alleviate the distress associated with cross-gender identity. For example, in Samoa, the faafafine, a group of feminine males, are mostly socially accepted. The faafafine appear similar to transgender women in terms of their lifelong identities and gendered behavior, but experience far less distress than do transgender women in Western cultures. This suggests that the distress of gender dysphoria is mostly not caused by the cross-gender identity itself, but by difficulties encountered from social disapproval by ones culture. Overall, it is unclear whether or not gender dysphoria persists in cultures with third gender categories. Classification as a disorder The psychiatric diagnosis of gender identity disorder (now gender dysphoria) was introduced in DSM-III in 1980. Arlene Istar Lev and Deborah Rudacille have characterized the addition as a political maneuver to re-stigmatize homosexuality. (Homosexuality was declassified as a mental disorder in the DSM-II in 1974.) By contrast, Kenneth Zucker and Robert Spitzer argue that gender identity disorder was included in DSM-III because it "met the generally accepted criteria used by the framers of DSM-III for inclusion." Some researchers, including Spitzer and Paul J. Fink, contend that the behaviors and experiences seen in transsexualism are abnormal and constitute a dysfunction. The American Psychiatric Association stated that gender nonconformity is not the same thing as gender dysphoria, and that "gender nonconformity is not in itself a mental disorder. The critical element of gender dysphoria is the presence of clinically significant distress associated with the condition."Individuals with gender dysphoria may or may not regard their own cross-gender feelings and behaviors as a disorder. Advantages and disadvantages exist to classifying gender dysphoria as a disorder. Because gender dysphoria had been classified as a disorder in medical texts (such as the previous DSM manual, the DSM-IV-TR, under the name "gender identity disorder"), many insurance companies are willing to cover some of the expenses of sex reassignment therapy. Without the classification of gender dysphoria as a medical disorder, sex reassignment therapy may be viewed as a cosmetic treatment, rather than medically necessary treatment, and may not be covered. In the United States, transgender people are less likely than others to have health insurance, and often face hostility and insensitivity from healthcare providers. Gender dysphoria being a disorder also means it is covered by the Americans with Disabilities Act, which may aid transgender people in accessing legal protections they otherwise may be unable to. Some researchers and transgender people support declassification of the condition because they say the diagnosis pathologizes gender variance and reinforces the binary model of gender.An analysis of the Samoan third gender faafafine suggests that the DSM-IV-TR diagnostic component of distress is not inherent in the cross-gender identity; rather, it is related to social rejection and discrimination suffered by the individual. Psychology professor Darryl Hill insists that gender dysphoria is not a mental disorder, but rather that the diagnostic criteria reflect psychological distress in children that occurs when parents and others have trouble relating to their childs gender variance. Transgender people have often been harassed, socially excluded, and subjected to discrimination, abuse and violence, including murder.In December 2002, the British Lord Chancellors office published a Government Policy Concerning Transsexual People document that categorically states, "What transsexualism is not ... It is not a mental illness." In May 2009, the government of France declared that a transsexual gender identity will no longer be classified as a psychiatric condition, but according to French trans rights organizations, beyond the impact of the announcement itself, nothing changed. Denmark made a similar statement in 2016.In the ICD-11, GID is reclassified as "gender incongruence", a condition related to sexual health. The working group responsible for this recategorization recommended keeping such a diagnosis in ICD-11 to preserve access to health services. Gender euphoria Gender euphoria (GE) is a proposed term for the opposite of gender dysphoria. It is the satisfaction, enjoyment, or relief felt by trans people when they feel their body matches their personal gender identity. Healthline defines it as "feelings of alignment or joy about [ones] gender identity or expression," while Psych Centrals definition is "deep joy when your internal gender identity matches your gender expression."In 1986, the term was first published in a trans context, as part of an interview with a trans person: "gender dysphoria, and a term of which he seems inordinately proud, gender euphoria." Similar uses were published in 1988. (The same term had been used as early as 1979, but to describe male privilege present in Black men.)In a 1988 interview with a trans man, the subject states, "I think that day [Dr. Charles Ilhenfeld] administered my first shot of the wonder-drug must have been one of the peak-experiences of my life -- talk about gender euphoria!" The interview indicates he is referring to testosterone.In 1989, Mariette Pathy Allen published an unnamed transgender persons quote in her photography book Transformations: "The shrinks may call it gender dysphoria, but for some of us, its gender euphoria, and were not going to apologize anymore!"In 1990, Virginia Prince used the phrase in trans magazine Femme Mirror, ending an article with, "...from here on you can enjoy GENDER EUPHORIA - HAVE A GOOD LIFE!"Starting in 1991, a monthly newsletter named Gender Euphoria was released, featuring articles about transgender topics; Leslie Feinberg read the newsletter to better understand the transgender community. In 1993, the blurb of Nan Goldins The Other Side read, "The pictures in this book are not of people suffering dysphoria but rather expressing gender euphoria."In 1994, Scottish "TV/TS" periodical The Tartan Skirt wrote, "Lets accentuate the positive, discard the negative, and promote the new condition of Gender Euphoria."In 1997, Patrick Califia described transgender activists picketing using signs that read "Gender Euphoria NOT Gender Dysphoria" and handing out "thousands of leaflets" at protests. The following year, in 1998, Second Skins: The Body Narratives of Transsexuality reported:The transactivist group Transexual Menace is campaigning to have the diagnosis "Gender Identity Disorder" removed entirely from the Diagnostic and Statistical Manual of Mental Disorders. "Gender Euphoria NOT Gender Dysphoria"; its slogans invert the pathologizing of transgender, offering pride in queer difference as an alternative to the psychiatric story.Transgender congruence is also used to ascribe transgender individuals feeling genuine, authentic, and comfortable with their gender identity and external appearance.In 2019, the Midsumma festival in Australia hosted "Gender Euphoria," a cabaret focusing on "bliss" in transgender experiences, including musical, ballet, and burlesque performances. A reviewer described it as "triumphant – honest, unpretentious, touching, and a vital celebration." See also List of transgender-related topics Transmedicalism Gender transitioning Detransition Rapid-onset gender dysphoria controversy ICD-11 § Gender incongruence References Further reading Conway, Lynn (June 26, 2014). "Successful TransMen: Links and Photos". ai.eecs.umich.edu. Retrieved December 2, 2014. Conway, Lynn (February 5, 2011). "Transsexual Womens Successes: Links and Photos". ai.eecs.umich.edu. Retrieved December 2, 2014. Jacques, Juliet. "A Transgender Journey". The Guardian. Retrieved December 2, 2014. Sharp, Victoria Madeleine; Lewis, Clive Buckland; Lieven, Natalie Marie Daniella. "Bell v Tavistock" (PDF). In the High Court of Justice Administrative Court Divisional Court ([2020] EWHC 3274 (Admin)): CO/60/2020. World Professional Association for Transgender Health (2012). Standards of Care for Gender Identity Disorders (PDF). Harry Benjamin International Gender Dysphoria Association. Archived from the original (PDF) on September 24, 2014. Includes a description of ICD-10 criteria. External links Health Law Standards of Care for Transsexualism – An alternative to the Benjamin Standards of Care proposed by the International Conference on Transgender Law and Employment Policy. The Lord Chancellors Department Government Policy concerning Transsexual People
Barraquer–Simons syndrome	Barraquer–Simons syndrome is a rare form of lipodystrophy, which usually first affects the head, and then spreads to the thorax. It is named for Luis Barraquer Roviralta (1855–1928), a Spanish physician, and Arthur Simons (1879–1942), a German physician. Some evidence links it to LMNB2. Causes The etiology of this condition has not been fully elucidated. Lipodystrophy is often associated with glomerulonephritis, low C3 serum complement levels, and the presence of a C3 nephritic factor. C3 nephritic factor is a serum immunoglobulin G that interacts with the C3bBb alternative pathway convertase to activate C3. C3 nephritic factor induces the lysis of adipocytes that secrete adipsin, a product identical to complement factor D. The distribution of the lipoatrophy is postulated to be dictated by the variable amounts of adipsin secreted by the adipocytes at different locations.Human PTRF mutations may cause secondary deficiency of caveolins, resulting in generalized lipodystrophy in association with in muscular dystrophy. Complement dysfunction may predispose some patients to bacterial infections. Diagnosis The diagnosis of the disease is mainly clinical (see diagnostic criteria). A laboratory workup is needed primarily to investigate for the presence of associated disorders (metabolic, autoimmune, and renal diseases). Every patient should have a fasting blood glucose and lipid profile, creatinine evaluation, and urinalysis for protein content at the first visit, after which he/she should have these tests on a regular basis. Although uncommon, lipid abnormalities can occur in the form of raised triglyceride levels and low high-density lipoprotein cholesterol levels. Patients usually have decreased serum C3 levels, normal levels of C1 and C4, and high levels of C3NeF (autoantibody), which may indicate the presence of renal involvement. Antinuclear antibodies (ANA) and antidouble-stranded deoxyribonucleic acid (DNA) antibodies have reportedly been observed in some patients with acquired partial lipodystrophy. A genetic workup should be performed if the familial form of lipodystrophy is suggested.Laboratory work for associated diseases includes: Metabolic disease - fasting glucose, glucose tolerance test, lipid profile, and fasting insulin to characterize the insulin resistance state; free testosterone (in women) to look for polycystic ovary syndrome. Autoimmune disease - ANA, antidouble-stranded DNA, rheumatoid factor, thyroid antibodies, C3, and C3NeF.As a confirmatory test, whole-body MRI usually clearly demonstrates the extent of lipodystrophy. MRI is not recommended on a routine basis. Diagnostic criteria A review published in 2004, which was based on 35 patients seen by the respective authors over 8 years and also a literature review of 220 cases of acquired partial lipodystrophy (APL), proposed an essential diagnostic criterion. Based on the review and the authors experience, they proposed that APL presents as a gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the "cephalocaudal" sequence, sparing the lower extremities. The median age of the onset of lipodystrophy was seven years. Several autoimmune diseases, in particular systemic lupus erythematosus and dermatomyositis, were associated with APL. The prevalence rates of diabetes mellitus and impaired glucose tolerance were 6.7% and 8.9%, respectively. Around 83% of APL patients had low complement 3 (C3) levels and the presence of polyclonal immunoglobulin C3 nephritic factor. About 22% of patients developed membranoproliferative glomerulonephritis (MPGN) after a median of about 8 years following the onset of lipodystrophy. Compared with patients without renal disease, those with MPGN had earlier age of onset of lipodystrophy (12.6 ± 10.3 yr vs 7.7 ± 4.4 yr, respectively; p < 0.001) and a higher prevalence of C3 hypocomplementemia (78% vs 95%, respectively; p = 0.02).The adipose stores of the gluteal regions and lower extremities (including soles) tend to be either preserved or increased, particularly among women. Variable fat loss of the palms, but no loss of intramarrow or retro-orbital fat, has been demonstrated. Treatment In general, treatment for acquired partial lipodystrophy is limited to cosmetic, dietary, or medical options. Currently, no effective treatment exists to halt its progression. Diet therapy has been shown to be of some value in the control of metabolic problems. The use of small, frequent feedings and partial substitution of medium-chain triglycerides for polyunsaturated fats appears to be beneficial.Plastic surgery with implants of monolithic silicon rubber for correction of the deficient soft tissue of the face has been shown to be effective. False teeth may be useful in some cases for cosmetic reasons. Long-term treatment usually involves therapy for kidney and endocrine dysfunction.Data on medications for APL are very limited. Thiazolidinediones have been used in the management of various types of lipodystrophies. They bind to peroxisome proliferator-activator receptor gamma (PPAR-gamma), which stimulates the transcription of genes responsible for growth and differentiation of adipocytes. A single report has suggested a beneficial effect from treatment with rosiglitazone on fat distribution in acquired partial lipodystrophy; however, preferential fat gain was in the lower body.Direct drug therapy is administered according to the associated condition. Membranoproliferative glomerulonephritis and the presence of renal dysfunction largely determine the prognosis of acquired partial lipodystrophy. Standard guidelines for the management of renal disease should be followed. The course of membranoproliferative glomerulonephritis in acquired partial lipodystrophy has not been significantly altered by treatment with corticosteroids or cytotoxic medications. Recurrent bacterial infections, if severe, might be managed with prophylactic antibiotics. Prognosis Estimating the mortality rate based on the available literature is difficult. Several case reports have revealed an association between acquired partial lipodystrophy and other diseases.Nephropathy, in the form of membranoproliferative glomerulonephritis, occurs in about 20% of patients. Usually, patients do not have clinically evident renal disease or abnormalities in renal function until they have had the disease for 8 or more years. Membranoproliferative glomerulonephritis usually presents with asymptomatic proteinuria or hematuria.The disease may gradually progress. About 40-50% of patients develop end-stage renal disease over the course of 10 years. This condition is responsible for most recurrent hospital admissions in patients with acquired partial lipodystrophy. Rapid progression of renal disease in a pregnant patient was reported. Recurrent disease in transplanted kidneys is common, although there have been reports of successful transplantations.Associated autoimmune diseases (e.g., systemic lupus erythematosus, thyroiditis) contribute significantly to increased morbidity in these patients compared with the general population. Although uncommon, insulin resistance increases cardiovascular risk. Susceptibility to bacterial infections probably results from a C3 deficiency (due to complement activation and consumption of C3). Low C3 levels may impair complement-mediated phagocytosis and bacterial killing. Epidemiology Around 250 cases have been reported since the recognition of this syndrome. It is a rare syndrome with no known prevalence, although it is more common than the generalized form of acquired lipodystrophy (Lawrence syndrome). Race: No clear relationship exists between incidence and race in this syndrome; however, most reported patients have been of European descent. Age: The median age of onset of lipodystrophy has been reported to be around seven years; however, onset occurring as late as the fourth or fifth decade of life also has been reported. The median age at presentation has been about 25 years, and women have been found to present later than men (age 28 for women, age 18 for men). Sex: Analysis of the pooled data revealed female patients were affected about four times more often than males. See also Lipodystrophy Laminopathy List of cutaneous conditions References == External links ==
Nager acrofacial dysostosis	Nager acrofacial dysostosis, also known as Nager syndrome, is a genetic disorder which displays several or all of the following characteristics: underdevelopment of the cheek and jaw area, down-sloping of the opening of the eyes, lack or absence of the lower eyelashes, kidney or stomach reflux, hammer toes, shortened soft palate, lack of development of the internal and external ear, possible cleft palate, underdevelopment or absence of the thumb, hearing loss (see hearing loss with craniofacial syndromes) and shortened forearms, as well as poor movement in the elbow, and may be characterized by accessory tragi. Occasionally, affected individuals develop vertebral anomalies such as scoliosis. The inheritance pattern is autosomal, but there are arguments as to whether it is autosomal dominant or autosomal recessive. Most cases tend to be sporadic. Nager syndrome shares many characteristics with five other craniofacial syndromes: Miller, Treacher Collins, Pierre Robin, Genee–Wiedemann and Franceschetti–Zwahlen–Klein. Genetics While Nager syndrome is thought to be most often caused by haploinsufficiency of the spliceosomal factor SF3B4, in over one third of patients tested, the SF3B4 mutation is not found. Genetic sequencing shows that the syndrome can be caused by either autosomal recessive or autosomal dominant inheritance. Treatment Due to craniofacial development, it is recommended that families work closely with craniofacial specialists as soon as Nager is recognized or suspected. Children born with Nager may need intubation immediately after birth, requiring tube feeding and a tracheotomy tube to help with breathing. Surgical intervention is commonly necessary to increase mandibular mobility. As the child grows and develops, further surgery is usually required on the lower jaw and is often done in tandem with orthodontic treatments. Further treatment depends upon the symptoms of the individual patient and may include oral surgery, plastic surgery, audiological intervention to manage hearing loss, speech therapy, and surgery on the limbs to aid with mobility limitations. See also Dermoid cyst References == External links ==
Nontuberculous mycobacteria	Nontuberculous mycobacteria (NTM), also known as environmental mycobacteria, atypical mycobacteria and mycobacteria other than tuberculosis (MOTT), are mycobacteria which do not cause tuberculosis or leprosy (also known as Hansens disease). NTM do cause pulmonary diseases that resemble tuberculosis. Mycobacteriosis is any of these illnesses, usually meant to exclude tuberculosis. They occur in many animals, including humans and are commonly found in soil and water. Introduction Mycobacteria are a family of small, rod-shaped bacilli that can be classified into three main groups for the purpose of diagnosis and treatment: Mycobacterium tuberculosis complex, which can cause tuberculosis: M. tuberculosis, M. bovis, M. africanum, M. microti and M. canetti M. leprae and M. lepromatosis, which cause Hansens disease, also called leprosy Nontuberculous mycobacteria (NTM) are all the other mycobacteria that can cause pulmonary disease resembling tuberculosis, lymphadenitis, skin disease, or disseminated disease. Although over 150 different species of NTM have been described, pulmonary infections are most commonly due to Mycobacterium avium complex (MAC), Mycobacterium kansasii, and Mycobacterium abscessus (see image). Taxonomy In 1959, botanist Ernest Runyon put these human disease-associated bacteria into four groups (Runyon classification): Photochromogens develop pigments in or after being exposed to light. Examples include M. kansasii, M. simiae, and M. marinum. Scotochromogens become pigmented in darkness. Examples include M. scrofulaceum and M. szulgai. Nonchromogens include a group of prevalent opportunistic pathogens called M. avium complex (MAC). Other examples are M. ulcerans, M. xenopi, M. malmoense, M. terrae, M. haemophilum, and M. genavense. Rapid growers include four well-recognized, pathogenic, rapidly growing, nonchromogenic species: M. chelonae, M. abscessus, M. fortuitum, and M. peregrinum. Other examples cause disease rarely, such as M. smegmatis and M. flavescens.The number of identified and cataloged NTM species has been increasing rapidly, from about 50 in 1997 to over 125 by January 2007. The surge is mainly due to improved isolation and identification techniques.Even with these new techniques, though, the Runyon classification is still sometimes used to organize the mycobacteria into categories. Epidemiology NTM are widely distributed in the environment, particularly in wet soil, marshland, streams, rivers and estuaries. Different species of NTM prefer different types of environment. Human disease is believed to be acquired from environmental exposures. Unlike tuberculosis and leprosy, animal-to-human or human-to-human transmission of NTM rarely occurs.NTM diseases have been seen in most industrialized countries, where incidence rates vary from 1.0 to 1.8 cases per 100,000 persons. Recent studies, including one done in Ontario, Canada, suggest that incidence is much higher. Pulmonary NTM is estimated by some experts in the field to be at least ten times more common than TB in the U.S., with at least 150,000 cases per year. Most NTM disease cases involve the species known as Mycobacterium avium complex or MAC for short, M. abscessus, M. fortuitum and M. kansasii. M. abscessus is being seen with increasing frequency and is particularly difficult to treat.Mayo Clinic researchers found a three-fold increased incidence of cutaneous NTM infection between 1980 and 2009 in a population-based study of residents of Olmsted County, Minnesota. The most common species were M. marinum, accounting for 45% of cases and M. chelonae and M. abscessus, together accounting for 32% of patients. M. chelonae infection outbreaks, as a consequence of tattooing with infected ink, have been reported in the United Kingdom and the United States.Rapidly growing NTMs are implicated in catheter infections, post-LASIK, skin and soft tissue (especially post-cosmetic surgery) and pulmonary infections. Pathogenesis The most common clinical manifestation of NTM disease is lung disease, but lymphatic, skin/soft tissue, and disseminated diseases are also important.Pulmonary disease caused by NTM is most often seen in postmenopausal women and patients with underlying lung disease such as cystic fibrosis, bronchiectasis, and prior tuberculosis. It is not uncommon for alpha 1-antitrypsin deficiency, Marfan syndrome, and primary ciliary dyskinesia patients to have pulmonary NTM colonization and/or infection. Pulmonary NTM can also be found in individuals with AIDS and malignant disease. It can be caused by many NTM species, which depends on region, but most frequently MAC and M. kansasii.Clinical symptoms vary in scope and intensity, but commonly include chronic cough, often with purulent sputum. Hemoptysis may also be present. Systemic symptoms include malaise, fatigue, and weight loss in advanced disease. The diagnosis of M. abscessus pulmonary infection requires the presence of symptoms, radiologic abnormalities, and microbiologic cultures. Lymphadenitis can be caused by various species that differ from one place to another, but again, MAC is the main cause worldwide. Most patients are aged less than 5 years, but the incidence is rare for children having BCG vaccine. The disease has a high curability.Soft-tissue disease due to NTM infection include post-traumatic abscesses (caused by rapid growers), swimming pool granuloma (caused by M. marinum) and Buruli ulcer (caused by M. ulcerans or M. shinshuense). Post-traumatic abscesses most commonly occur after injection.Disseminated mycobacterial disease was common in US and European AIDS patients in the 1980s and early 1990s, though the incidence has declined in developed nations since the introduction of highly active antiretroviral therapy. It can also occur in individuals after having renal transplantation. Diagnosis Diagnosis of opportunistic mycobacteria is made by repeated isolation and identification of the pathogen with compatible clinical and radiological features. Similar to M. tuberculosis, most nontuberculous mycobacteria can be detected microscopically and grow on Löwenstein-Jensen medium. Many reference centres now use a nucleic acid-based method such as sequence differences detection in the gene coding for 16S ribosomal RNA to identify the species.Pulmonary NTM disease diagnosis requires both identification of the mycobacterium in the patients lung(s), as well as a high-resolution CT scan of the lungs. Research French researchers finalized the genome sequence of M. abscessus in March 2008. The genome is available at https://www.ncbi.nlm.nih.gov/sites/entrez?db=genome&cmd=search&term=abscessus. References Further reading Griffith David E.; Aksamit Timothy; Brown-Elliott Barbara; et al. (2007). "American Thoracic Society Guidelines: Diagnosis, Treatment and Prevention of Nontuberculous Mycobacterial Diseases". American Journal of Respiratory and Critical Care Medicine. 175 (4): 367–417. doi:10.1164/rccm.200604-571st. PMID 17277290. New BTS Guideline has been published in 2017, https://www.brit-thoracic.org.uk/standards-of-care/guidelines/bts-guidelines-for-non-tuberculous-mycobacteria/ Grange, J. M. (2007). "Environmental mycobacteria". In Greenwood, David; Slack, Richard; Peitherer, John; & Barer, Mike (Eds.), Medical Microbiology (17th ed.), pp. 221–227. Elsevier. ISBN 978-0-443-10209-7. Deppisch C et al. (2016). Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study. Infection. 44(4):513-20. pmid= 26861246. Meng-Rui Lee et al., (2015). Mycobacterium abscessus Complex Infections in Humans. Emerg Infect Dis.; 21(9): 1638–1646. PMC 4550155. External links The NTM Handbook: A Guide for Patients with Nontuberculous Mycobacterial Infections Including MAC NTM Info & Research, a nonprofit research and patient support organization NTMinfo produced this 21-page PDF entitled "Insight -- A Patients Perspective" and vetted by experts in 2014 Stop NTM Now National Jewish Medical and Research Center University of Texas, Tyler Health Center Lung, Nontuberculous Mycobacterial Infections from eMedicine Radiology A guide for patients and clinicians - AIT Therapeutics
Fetal hydantoin syndrome	Fetal hydantoin syndrome, also called fetal dilantin syndrome, is a group of defects caused to the developing fetus by exposure to teratogenic effects of phenytoin. Dilantin is the brand name of the drug phenytoin sodium in the United States, commonly used in the treatment of epilepsy. It may also be called congenital hydantoin syndrome, fetal hydantoin syndrome, dilantin embryopathy, or phenytoin embryopathy. Association with EPHX1 has been suggested. Signs and symptoms About one third of children whose mothers are taking this drug during pregnancy typically have intrauterine growth restriction with a small head and develop minor dysmorphic craniofacial features (microcephaly and intellectual disability) and limb defects including hypoplastic nails and distal phalanges (birth defects). Heart defects including ventricular septal defect, atrial septal defect, patent ductus arteriosus and coarctation of the aorta may occur in these children. A smaller population will have growth problems and developmental delay, or intellectual disability. Heart defects and cleft lip may also be featured. Diagnosis There is no diagnostic testing that can identify fetal hydantoin syndrome. A diagnosis is made clinically based upon identification of characteristic symptoms in an affected infant in conjunction with a history of phenytoin exposure during gestation. It is important to note that the majority of infants born to women who take phenytoin during pregnancy will not develop fetal hydantoin syndrome. Treatment The treatment of fetal hydantoin syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, oral surgeons, plastic surgeons, neurologists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affected childs treatment. Infants with fetal hydantoin syndrome can benefit from early developmental intervention to ensure that affected children reach their potential. Affected children may benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services may be necessary. Psychosocial support for the entire family is essential as well.When cleft lip and/or palate are present, the coordinated efforts of a team of specialists may be used to plan an affected childs treatment and rehabilitation. Cleft lip may be surgically corrected. Generally surgeons repair the lip when the child is still an infant. A second surgery is sometimes necessary for cosmetic purposes when the child is older. Cleft palate may be repaired by surgery or covered by an artificial device (prosthesis) that closes or blocks the opening. Surgical repair can be carried out in stages or in a single operation, according to the nature and severity of the defect. The first palate surgery is usually scheduled during the toddler period. References == External links ==
Thyroid storm	Thyroid storm is a rare but severe and potentially life-threatening complication of hyperthyroidism (overactivity of the thyroid gland). It is characterized by a high fever (temperatures often above 40 °C/104 °F), fast and often irregular heart beat, elevated blood pressure, vomiting, diarrhea, and agitation. Hypertension with a wide pulse pressure occurs in early to mid crisis, with hypotension accompanying shock occurring in the late stage. Heart failure and heart attack may occur. Death may occur despite treatment. Most episodes occur either in those with known hyperthyroidism whose treatment has been stopped or become ineffective, or in those with untreated mild hyperthyroidism who have developed an intercurrent illness (such as an infection).The primary treatment of thyroid storm is with inorganic iodine and antithyroid drugs (propylthiouracil or methimazole) to reduce synthesis and release of thyroid hormone. Temperature control and intravenous fluids are also mainstays of management. Beta blockers are often used to reduce the effects of thyroid hormone. Patients often require admission to the intensive care unit. Signs and symptoms Thyroid storm is characterized by an acute onset of symptoms of hyperthyroidism (fast heart rate, restlessness, agitation) accompanied by other features such as fever (temperatures often above 40 °C/104 °F), hypertension, mental status changes, diarrhea, and vomiting.Individuals can exhibit varying signs of organ dysfunction. Patients may experience liver dysfunction, and jaundice (yellowing of the skin), which is considered a poor prognostic sign. Cardiac (heart) symptoms include abnormal heart rhythms, myocardial infarction (heart attack), and congestive heart failure, which may lead to cardiovascular collapse. Mortality can be as high as 20-30%.In some situations, individuals may not experience the classic signs of restlessness and agitation, but instead present with apathetic signs of weakness and confusion. Causes The transition from hyperthyroidism to thyroid storm is typically triggered by a non-thyroidal insult including, but not limited to fever, sepsis, dehydration, myocardial infarction, and psychiatric diseases. Individuals are at higher risk of thyroid storm if their hyperthyroidism is incompletely treated or if their anti-thyroid drugs are discontinued. Many of these individuals have underlying primary causes of hyperthyroidism (Graves disease, toxic multi-nodular goiter, solitary toxic adenoma, amiodarone). However, thyroid storm can occur in individuals with unrecognized thyrotoxicosis experiencing non-thyroid surgery, labor, infection, or exposure to certain medications and radiocontrast dyes. Pathophysiology The precise mechanism for the development of thyroid storm is poorly understood. In the human body, thyroid hormone may be free (biologically active T3/T4) or bound to thyroid binding hormone (biologically inactive) to be transported. The release of thyroid hormone is tightly regulated by a feedback system involving the hypothalamus, pituitary gland, and thyroid gland. Hyperthyroidism results from a dysregulation of this system that eventually leads to increases in levels of free T3/T4. The transition from simple hyperthyroidism to the medical emergency of thyroid storm may be triggered by conditions (see Causes) that lead to the following: Increases in free thyroid hormone Individuals with thyroid storm tend to have increased levels of free thyroid hormone, although total thyroid hormone levels may not be much higher than in uncomplicated hyperthyroidism. The rise in the availability of free thyroid hormone may be the result of manipulating the thyroid gland. In the setting of an individual receiving radioactive iodine therapy, free thyroid hormone levels may acutely increase due to the release of hormone from ablated thyroid tissue. Decrease in thyroid hormone binding protein A decrease in thyroid hormone binding protein in the setting of various stressors or medications may also cause a rise in free thyroid hormone. Increased sensitivity to thyroid hormone Along with increases in thyroid hormone availability, it is also suggested that thyroid storm is characterized by the bodys heightened sensitivity to thyroid hormone, which may be related to sympathetic activation (see below). Sympathetic activation Sympathetic nervous system activation during times of stress may also play a significant role in thyroid storm. Sympathetic activation increases production of thyroid hormone by the thyroid gland. In the setting of elevated thyroid hormone, the density of thyroid hormone receptors (esp. beta-receptors) also increases, which enhances the response to catecholamines. This is likely responsible for several of the cardiovascular symptoms (increased cardiac output, heart rate, stroke volume) seen in thyroid storm. Thyroid storm as allostatic failure According to newer theories, thyroid storm results from allostatic failure in a situation where thyrotoxicosis hampers the development of non-thyroidal illness syndrome, which would help to save energy in critical illness and other situations of high metabolic demand.Usually, in critical illness (e.g. sepsis, myocardial infarction and other causes of shock) thyroid function is tuned down to result in low-T3 syndrome and, occasionally, also low TSH concentrations, low-T4 syndrome and impaired plasma protein binding of thyroid hormones. This endocrine pattern is referred to as euthyroid sick syndrome (ESS), non-thyroidal illness syndrome (NTIS) or thyroid allostasis in critical illness, tumours, uraemia and starvation (TACITUS). Although NTIS is associated with significantly worse prognosis, it is also assumed to represent a beneficial adaptation (type 1 allostasis). In cases, where critical illness is accompanied by thyrotoxicosis, this comorbidity prevents the down-regulation of thyroid function. Therefore, the consumption of energy, oxygen and glutathione remains high, which leads to further increased mortality.These new theories imply that thyroid storm results from an interaction of thyrotoxicosis with the specific response of the organism to an oversupply of thyroid hormones. Diagnosis The diagnosis of thyroid storm is based on the presence of signs and symptoms consistent with severe hyperthyroidism. Multiple approaches have been proposed to calculate the probability of thyroid storm based on clinical criteria, however, none have been universally adopted by clinicians. For instance, Burch and Wartofsky published the Burch-Wartofsky point scale (BWPS) in 1993, assigning a numerical value based on the presence of specific signs and symptoms organized within the following categories: temperature, cardiovascular dysfunction (including heart rate and presence of atrial fibrillation or congestive heart failure), central nervous system (CNS) dysfunction, gastrointestinal or liver dysfunction and presence of a precipitating event. A Burch-Wartofsky score below 25 is not suggestive of thyroid storm whereas 25 to 45 suggests impending thyroid storm and greater than 45 suggests current thyroid storm. Alternatively, the Japanese Thyroid Association (JTA) criteria, derived from a large cohort of patients with thyroid storm in Japan and published in 2012, provide a qualitative method to determine the probability of thyroid storm. The JTA criteria separate the diagnosis of thyroid storm into definite versus suspected based on the specific combination of signs and symptoms a patient exhibits and require elevated free triiodothyronine (T3) or free thyroxine (T4) for definite thyroid storm. Laboratory findings As with hyperthyroidism, TSH is suppressed. Both free and serum (or total) T3 and T4 are elevated. An elevation in thyroid hormone levels is suggestive of thyroid storm when accompanied by signs of severe hyperthyroidism but is not diagnostic as it may also correlate with uncomplicated hyperthyroidism. Moreover, serum T3 may be normal in critically ill patients due to decreased conversion of T4 to T3. Other potential abnormalities include the following: Hyperglycemia likely due to catecholamine-mediated effects on insulin release and metabolism as well as increased glycogenolysis, evolving into hypoglycemia when glycogen stores are depleted Elevated aspartate aminotransferase (AST), bilirubin and lactate dehydrogenase (LDH) Hypercalcemia and elevated alkaline phosphatase due to increased bone resorption Elevated white blood cell count Management The main strategies for the management of thyroid storm are reducing production and release of thyroid hormone, reducing the effects of thyroid hormone on tissues, replacing fluid losses, and controlling temperature. Thyroid storm requires prompt treatment and hospitalization. Often, admission to the intensive care unit is needed.In high fever, temperature control is achieved with fever reducers such as paracetamol/acetaminophen and external cooling measures (cool blankets, ice packs). Dehydration, which occurs due to fluid loss from sweating, diarrhea, and vomiting, is treated with frequent fluid replacement. In severe cases, mechanical ventilation may be necessary. Any suspected underlying cause is also addressed. Iodine Guidelines recommend the administration of inorganic iodide (potassium iodide or Lugols iodine) to reduce the synthesis and release of thyroid hormone. In high dosage, iodine may reduce the synthesis of thyroid hormone via the Wolff-Chaikoff effect and its release via the Plummer effect. Some guidelines recommend that iodine be administered after antithyroid medications are started, because iodine is also a substrate for the synthesis of thyroid hormone, and may worsen hyperthyroidism if administered without antithyroid medications. Antithyroid medications Antithyroid drugs (propylthiouracil or methimazole) are used to reduce the synthesis and release of thyroid hormone. Propylthiouracil is preferred over methimazole due to its additional effects on reducing peripheral conversion of T4 to T3, however both are commonly used. Beta blockers The administration of beta-1-selective beta blockers (e.g. metoprolol) is recommended to reduce the effect of circulating thyroid hormone on end organs. In addition, propranolol at high doses also reduces peripheral conversion of T4 to T3, which is the more active form of thyroid hormone. Although previously non-selective beta blockers (e.g., propranolol) have been suggested to be beneficial due to their inhibitory effects on peripheral deiodinases, recent research suggests them to be associated with increased mortality. Therefore, cardioselective beta blockers may be favourable. Corticosteroids High levels of thyroid hormone result in a hypermetabolic state, which can result in increased breakdown of cortisol, a hormone produced by the adrenal gland. This results in a state of relative adrenal insufficiency, in which the amount of cortisol is not sufficient. Guidelines recommend that corticosteroids (hydrocortisone and dexamethasone are preferred over prednisolone or methylprednisolone) be administered to all patients with thyroid storm. However, doses should be altered for each individual patient to ensure that the relative adrenal insufficiency is adequately treated while minimizing the risk of side effects. Plasmapheresis Plasmapheresis removes cytokines, antibodies, and thyroid hormones from the plasma. It is usually reserved for severe refractory cases of thyroid storm as a bridge to surgery. See also Myxedema coma Euthyroid sick syndrome References == External links ==
Rhinosporidiosis	Rhinosporidiosis is an infection caused by Rhinosporidium seeberi. Classification This organism was previously considered to be a fungus, and rhinosporidiosis is classified as a fungal disease under ICD-10. It is now considered to be a protist classified under Mesomycetozoea.Authors of detailed studies have revealed superficial similarities between Dermocystidium and Rhinosporidium when using light microscopy, but substantial morphological differences between the groups exist.There is some evidence that DNA extracted from purified uncontaminated round bodies (Rhinosporidium seeberi) is of cyanobacterial origin. Pathophysiology Rhinosporidiosis is a granulomatous disease affecting the mucous membrane of nasopharynx, oropharynx, conjunctiva, rectum and external genitalia. Though the floor of the nose and inferior turbinate are the most common sites, the lesions may appear elsewhere too. Traumatic inoculation from one site to others is common. Laryngeal rhinosporidiosis, too, has been described and may be due to inoculation from the nose during endotracheal intubation. After inoculation, the organism replicates locally, resulting in hyperplasia of host tissue and localised immune response. infection of nose and nasopharynx - 70% infection of palpebral conjunctiva - 15% Diagnosis History Unilateral nasal obstruction Epistaxis Local pruritus Rhinorrhea Coryza (rhinitis) with sneezing Post nasal discharge with cough Foreign body sensation History of exposure to contaminated water Increased tearing and photo phobia in cases of infection of palpebral conjunctiva On examination Pink to deep red polyps Strawberry like appearance Bleeds easily upon manipulation Diagnosis confirmed by biopsy and histopathology - several round or oval sporangia and spores which may be seen bursting through its chitinous wall Treatment Surgical excision - wide excision with wide area electro-coagulation of the lesion base Medical treatment is not so effective but treatment with a year-long course of dapsone has been reported Recurrence is common Epidemiology Disease endemic in Chhattisgarh South India, Sri Lanka, South America and Africa. It is presumed to be transmitted by exposure to the pathogen when taking a bath in stagnant water pools where animals also bathe. References == External links ==
Sudden acquired retinal degeneration syndrome	Sudden acquired retinal degeneration syndrome (SARDS) is a disease in dogs causing sudden blindness. It can occur in any breed, but female dogs may be predisposed. Approximately 4000 cases are seen in the United States annually. Characteristics Symptoms include sudden permanent blindness, but may occur more slowly over several days, weeks or months, dilated pupils. Pupillary light reflexes are usually reduced but present; the slow phase mediated by melanopsin in retinal ganglion cells is retained. Other symptoms commonly seen are similar to those seen with Cushings disease and include increased water consumption and urination, weight gain, confusion, restlessness, behavioral changes and lethargy. These symptoms may develop over a few months preceding the onset of SARDS. Clinical signs and disease progression vary markedly among individual animals, depending on the number and type of hormones that are increased, the degree of hormone elevation, and the age of the dog.Some owners notice a more obvious "eye shine" in photographs due to the dilated pupils and retinal atrophy creating what is described as a "hyper-reflective tapetum". Causes The cause of SARDS is considered to be idiopathic and the veterinary community is divided as to its cause, but the most common hypotheses on the causes of the disease possibly include autoimmune disease, or exposure to toxins. Autoimmune disease as a cause is controversial because some studies have supported the presence of antiretinal autoantibodies in dogs with SARDS, but others have failed to show a link. Despite similar symptoms and blood test results to Cushings disease, evaluation of dogs with SARDS did not reveal any tumors in the pituitary or adrenal glands, and recent work has indicated significant differences in the clinical and laboratory test parameters between the two diseases. Diagnosis Examination with an ophthalmoscope will initially show no changes, but in a few months atrophy of the retina will resemble the appearance of progressive retinal atrophy. Pathologically, there is a loss of the rod and cone cells followed by degeneration of other layers of the retina. The retinal degeneration appears to be related to apoptosis of these cells. SARDS must be distinguished from other causes of sudden blindness that have no visible pathology, including retrobulbar optic neuritis, a tumor at the optic chiasm, or other central nervous system diseases. Electroretinography is useful to definitively diagnose SARDS. Treatment While there is no unilateral treatment for SARDS researchers at the Iowa State University led by Dr. Siniša Grozdanić, ISU Veterinary Ophthalmologist have successfully restored vision in two dogs who have been in 2007 successfully treated through an experimental treatment by intravenous immunoglobin (IVIg). "Although the dogs wont be catching any Frisbees, they can navigate and not bump into objects,", Dr. Grozdanić notes.Various immunosuppressive treatment regimens have been tried, but are not consistently effective. Treatment regimens with adrenal steroids and thyroid hormones have been proposed, but as of 2016 no controlled, peer reviewed studies had investigated the effectiveness of such treatments. == References ==
Adenylosuccinate lyase deficiency	Adenylosuccinate lyase deficiency is a rare autosomal recessive metabolic disorder characterized by the appearance of succinylaminoimidazolecarboxamide riboside (SAICA riboside) and succinyladenosine (S-Ado) in cerebrospinal fluid, urine. These two succinylpurines are the dephosphorylated derivatives of SAICA ribotide (SAICAR) and adenylosuccinate (S-AMP), the two substrates of adenylosuccinate lyase (ADSL), which catalyzes an important reaction in the de novo pathway of purine biosynthesis. ADSL catalyzes two distinct reactions in the synthesis of purine nucleotides, both of which involve the β-elimination of fumarate to produce aminoimidazole carboxamide ribotide (AICAR) from SAICAR or adenosine monophosphate (AMP) from S-AMP. Types ASLD is divided into three categories based on the severity of symptoms: the fatal neonatal form, type I and type II. However, as symptoms occur along a spectrum there are no set criteria to determine which category a patient should be ascribed to. Fatal neonatal form Patients with this form of ASLD present with fatal neonatal encephalopathy, respiratory failure, a lack of spontaneous movement and intractable seizures. Possible prenatal symptoms such as microcephaly, intrauterine growth restriction, loss of fetal heart rate variability and hypokinesia have been reported. Death occurs within the first few weeks of life. Type I This is the most common form of ASLD. Symptoms become apparent in the first months of life and include seizures, microcephaly and severe psychomotor retardation are purely neurological. Some patients display axial hypotonia, peripheral hypertonia and normal tendon reflexes. Autistic-like behaviour including poor eye contact, stereotypies, agitation, tantrums and self injurious behaviour may occur. Type II This is considered to be a mild to moderate form of ASLD. They may demonstrate a milder degree of psychomotor retardation and transient visual and auditory contact disturbances Seizures, if they occur, begin later than in Type I, typically between 2 and 4 years old but sometimes as late as 9 years old. Speech is impaired with receptive language skills and nonverbal communication skills being better than expressive language skills. Ataxia may occur and cause increasingly severe gait disturbances. Signs and symptoms Among the signs and symptoms of adenylosuccinate lyase deficiency are the following: Aggressive behavior Microcephaly Autism Brachycephaly Mild Cerebellar hypoplasia Seizures Pathophysiology Adenylosuccinate lyase deficiency is responsible for a range of symptoms that involve psychomotor retardation, often accompanied by epileptic seizures, and autistic features. Two common theories were proposed to account for these effects, the first is that they result from decreased concentrations of purine nucleotides needed for purine biosynthesis. Decreased concentrations, however, could not be found in various tissues taken from ADSL-deficient people, probably because purines are furnished via the purine salvage pathway. The second is the buildup of accumulating succinylpurines causes neurotoxic effects. In the severely affected individuals, the concentration levels of SAICA riboside and S-Ado are comparable, whereas in people with milder forms of the disease, the ratio of S-Ado is more than double that of those more severely affected, while SAICA riboside concentration levels remain comparable. Biochemical studies of the enzyme have focused on proteins of ADSL from nonhuman species, the ADSL structure from the crystallized protein of Thermotoga maritime has been used, along with DNA sequencing data, to construct homology models for a variety of other organisms, including human ADSL. A variety of studies have been done using the equivalent enzyme from Bacillus subtilis, which shares a significant percentage of identity along with about some percentage of similarity in amino acid sequence with the human enzyme. Homology models overlaid on each other show a high degree of overlap between the enzymes.The family of enzymes to which ADSL belongs and that catalyze β-eliminations in which fumarate is one of the products are homotetramers with four active sites composed of amino acid residues from three distinct subunits. Much is known about the active site of human ADSL due to studies of the active site in the B. subtilis ADSL through affinity labeling and site-directed mutagenesis. While there is some variability among species in the sequencing of ADSL, the active site of the enzyme contains many residues that are conserved across species and have been shown to be critical to the enzymes function. His68 and His141 seem to serve as the general acid and base catalysts, and are critical to the catalyzing reaction of the substrate. His89 seems to enhance the binding of the substrates phosphoryl group and orient adenylosuccinate for catalysis. All three histidines are conserved throughout the 28 species for which the structure of ADSL is known. Glu275 and Lys268 have also been shown to contribute to the active site, indicating there are four active sites, each of which is formed from regions of three subunits. ADSL deficiency in different people is often caused by different mutations to the enzyme, more than 50 different mutations in the ADSL gene have been discovered Diagnosis In terms of the diagnosis of adenylosuccinate lyase deficiency one should look for (or exam/method): MRI Demonstration of succinylpurines in extracellular fluids like plasma, cerebrospinal fluid and/or urine using high-pressure liquid chromatography, with or without mass spectroscopy Genetic testing - genomic cDNA sequencing of the ADSL gene and characterization of mutant proteins. Treatment Treatment of adenylosuccinate lyase deficiency can be done via epilepsy management with anticonvulsive drugs. Additionally the following options include: D-ribose and uridine administration Ketogenic diet S-adenosyl-l-methionine Prognosis The prognosis of this condition in childhood usually has a stable outcome, whereas in neonatal is almost always fatal, according to Jurecka, et al. See also Adenylosuccinate Adenylosuccinate lyase List of genetic disorders References Further reading Saudubray, Jean-Marie; Berghe, Georges van den; Walter, John H. (2011-11-16). Inborn Metabolic Diseases: Diagnosis and Treatment. Springer Science & Business Media. ISBN 9783642157202. Blau, Nenad; Hoffmann, Georg F.; Leonard, J. V.; Clarke, Joe T. R. (2006-01-16). Physicians Guide to the Treatment and Follow-Up of Metabolic Diseases. Springer Science & Business Media. ISBN 9783540289623. == External links ==
Noise-induced hearing loss	Noise-induced hearing loss (NIHL) is a hearing impairment resulting from exposure to loud sound. People may have a loss of perception of a narrow range of frequencies or impaired perception of sound including sensitivity to sound or ringing in the ears. When exposure to hazards such as noise occur at work and is associated with hearing loss, it is referred to as occupational hearing loss.Hearing may deteriorate gradually from chronic and repeated noise exposure (such as to loud music or background noise) or suddenly from exposure to impulse noise, which is a short high intensity noise (such as a gunshot or airhorn). In both types, loud sound overstimulates delicate hearing cells, leading to the permanent injury or death of the cells. Once lost this way, hearing cannot be restored in humans.There are a variety of prevention strategies available to avoid or reduce hearing loss. Lowering the volume of sound at its source, limiting the time of exposure and physical protection can reduce the impact of excessive noise. If not prevented, hearing loss can be managed through assistive devices and communication strategies. The largest burden of NIHL has been through occupational exposures; however, noise-induced hearing loss can also be due to unsafe recreational, residential, social and military service-related noise exposures. It is estimated that 15% of young people are exposed to sufficient leisure noises (i.e. concerts, sporting events, daily activities, personal listening devices, etc.) to cause NIHL. There is not a limited list of noise sources that can cause hearing loss; rather, exposure to excessively high levels from any sound source over time can cause hearing loss. Signs and symptoms The first symptom of NIHL may be difficulty hearing a conversation against a noisy background. The effect of hearing loss on speech perception has two components. The first component is the loss of audibility, which may be perceived as an overall decrease in volume. Modern hearing aids compensate this loss with amplification. The second component is known as "distortion" or "clarity loss" due to selective frequency loss. Consonants, due to their higher frequency, are typically affected first. For example, the sounds "s" and "t" are often difficult to hear for those with hearing loss, affecting clarity of speech. NIHL can affect either one or both ears. Unilateral hearing loss causes problems with directional hearing, affecting the ability to localize sound. Temporary and permanent hearing changes PTS (Permanent Threshold Shift) is a permanent change of the hearing threshold (the intensity necessary for one to detect a sound) following an event, which will never recover. PTS is measured in decibels. TTS (Temporary Threshold Shift) is a temporary change of the hearing threshold the hearing loss that will be recovered after a few hours to couple of days. Also called auditory fatigue. TTS is also measured in decibels.In addition to hearing loss, other external symptoms of an acoustic trauma can be: Tinnitus Otalgia Hyperacusis Dizziness or vertigo; in the case of vestibular damages, in the inner-ear Tinnitus Tinnitus is described as hearing a sound when an external sound is not present. Noise-induced hearing loss can cause high-pitched tinnitus. An estimated 50 million Americans have some degree of tinnitus in one or both ears; 16 million of them have symptoms serious enough for them to see a doctor or hearing specialist. As many as 2 million become so debilitated by the unrelenting ringing, hissing, chirping, clicking, whooshing or screeching, that they cannot carry out normal daily activities.Tinnitus is the largest single category for disability claims in the military, with hearing loss a close second. The third largest category is post-traumatic stress disorder, which itself may be accompanied by tinnitus and may exacerbate it. Quality of life NIHL has implications on quality of life that extend beyond related symptoms and the ability to hear. The annual disability-adjusted life years (DALYs) were estimated for noise-exposed U.S. workers.[20] DALYs represent the number of healthy years lost due to a disease or other health condition. They were defined by the 2013 Global Burden of Disease (GBD) Study. The DALYs calculation accounts for life limitations experienced because of hearing loss as a lost portion of a healthy year of life. So the results indicate the number of healthy years lost by a group of people over a specific time period. NIOSH used DALYs to estimate the impact of hearing loss on quality of life in the CDC Morbidity and Mortality Weekly Report article "Hearing Impairment Among Noise-Exposed Workers in the United States, 2003-2012." It reported that 2.5 healthy years were lost each year for every 1,000 noise-exposed U.S. workers because of hearing impairment (hearing loss that impacts day-to-day activities). These lost years were shared among the 13% of workers with hearing impairment (about 130 workers out of each 1,000 workers). Mining, Construction and Manufacturing workers lost more healthy years than workers in other industry sectors; specifically and respectively in those sectors, 3.5, 3.1 and 2.7 healthy years were lost each year for every 1,000 workers. Negative impacts The negative impacts of NIHL on ones ability to reciprocate communication, socialize and interact with society are largely invisible. Hearing loss, in general, is not just an issue of volume; individuals may experience difficulty in understanding what is said over the phone, when several people are talking at once, in a large space, or when the speakers face cannot be seen. Subsequently, challenging social interactions can negatively lead to decreased self-esteem, shame, and fear. This can be more acutely felt by those who experience hearing impairment or loss earlier in life, rather than later when it is more socially accepted. Such psychosocial states, regardless of age, can lead to social isolation, which is known to negatively impact ones overall health and well-being. The compounding impacts can also lead to depression, especially if hearing impairment leads to tinnitus. Research suggests that those with hearing impairment or loss may be at a greater risk for deterioration of quality of life, as captured by a quote from Helen Keller: "Blindness cuts us off from things, but deafness cuts us off from people." Hearing impairment and loss of hearing, regardless of source or age, also limits experiencing the many benefits of sound on quality of life. In addition to the interpersonal social benefits, new studies suggest the effects of nature sounds, such as birds chirping and water, can positively affect an individuals capacity to recover after being stressed or to increase cognitive focus. Quality of life questionnaire Hearing loss is typically quantified by results from an audiogram; however, the degree of loss of hearing does not predict the impact on ones quality of life. The impact that NIHL can have on daily life and psychosocial function can be assessed and quantified using a validated questionnaire tool, such as the Hearing Handicap Inventory for the Elderly (HHIE). The HHIE is considered a "useful tool for quantifying the perceived emotional and social/situational consequences of hearing loss." The original tool was designed to test adults 65 years of age and older; however, modified versions exist. For adults the Hearing Handicap Inventory for Adults (HHIA) can be used and for adolescents the modified 28-item Hearing Environments And Reflection on Quality of Life (HEAR-QL-28) can be used. The HHIA, for example, is a 25-item questionnaire that asks both social and emotional-specific questions such as: Does a hearing problem cause you to avoid groups of people?" (social) and "Does a hearing problem cause you to feel frustrated when talking to members of your family?" (emotional). Response options are yes, no and sometimes. A greater score indicates greater perceived handicap. Cause The ear can be exposed to short periods of sound in excess of 120 dB without permanent harm — albeit with discomfort and possibly pain; but long term exposure to sound levels over 85 dB(A) can cause permanent hearing loss.There are two basic types of NIHL: NIHL caused by acoustic trauma and gradually developing NIHL. Acute acoustic trauma NIHL caused by acute acoustic trauma refers to permanent cochlear damage from a one-time exposure to excessive sound pressure. This form of NIHL commonly results from exposure to high-intensity sounds such as explosions, gunfire, a large drum hit loudly, and firecrackers. According to one US study, excessive noise levels in cinemas are sufficiently brief that movie-goers do not experience hearing loss. Perceived harmfulness vs. actual harmfulness The discomfort threshold is the loudness level from which a sound starts to be felt as too loud and thus painful by an individual. Industry workers tend to have a higher discomfort threshold (i.e. the sounds must be louder to feel painful than for non-industry workers), but the sound is just as harmful to their ears. Industry workers often have NIHL because the discomfort threshold is not a relevant indicator of the harmfulness of a sound. Gradually developing Gradually developing NIHL refers to permanent cochlear damage from repeated exposure to loud sounds over a period of time. Unlike acoustic trauma, this form of NIHL does not occur from a single exposure to a high-intensity sound pressure level. Gradually developing NIHL can be caused by multiple exposures to excessive noise in the workplace or any source of repetitive, frequent exposures to sounds of excessive volume, such as home and vehicle stereos, concerts, nightclubs, and personal media players. Earplugs have been recommended for those people who regularly attend live music concerts. A range of earplugs are now available ranging from inexpensive disposable sets to custom fit, attenuated earplugs which provide true fidelity at reduced audio levels. Personal listening devices Although research is limited, it suggests that increased exposure to loud noise through personal listening devices is a risk factor for noise induced hearing loss. More than half of people are exposed to sound through music exposure on personal devices greater than recommended levels. Research suggests stronger correlations between extended duration or elevated usage of personal listening devices and hearing loss. Workplace About 22 million workers are exposed to hazardous noise, with additional millions exposed to solvents and metals that could put them at increased risk for hearing loss. Occupational hearing loss is one of the most common occupational diseases. 49% of male miners have hearing loss by the age of 50. By the age of 60, this number goes up to 70%. Construction workers also have an elevated risk. A screening program focused on construction workers employed at US Department of Energy facilities found 58% with significant abnormal hearing loss due to noise exposures at work. Occupational hearing loss is present in up to 33% of workers overall. Occupational exposure to noise causes 16% of adult disabling hearing loss worldwide.The following is a list of occupations that are most susceptible to hearing loss: Agriculture Mining Police Construction Manufacturing Utilities Transportation Military Musicians Orchestra conductors Among musicians Musicians, from classical orchestras to rock groups, are exposed to high decibel ranges. Some rock musicians experience noise-induced hearing loss from their music, and some studies have found that "symphonic musicians suffer from hearing impairment and that the impairment might be ascribed to symphonic music."In terms of the population of musicians, usually the rates of hearing disorders is lower than other occupational groups. However, many exposure scenarios can be considered a risk of hearing disorders, and many individuals are negatively impacted by tinnitus and other hearing problems. While some population studies have shown that the risk for hearing loss increases as music exposure increases, other studies found little to no correlation between the two. Experts at the 2006 "Noise-Induced Hearing Loss in Children at Work and Play" Conference agreed that further research into this field was still required before making a broad generalization about music-induced hearing loss.Given the extensive research suggesting that industrial noise exposure can cause sensorineural hearing loss, a link between hearing loss and music exposures of similar level and duration (to industrial noise) seems highly plausible. Determining which individuals or groups are at risk for such exposures may be a difficult task. Despite concerns about the proliferation of personal music players, there is only scarce evidence supporting their impact on hearing loss, and some small-sample studies suggest that only a fraction of users are affected. People from ages to 6–19 have an approximately 15% rate of hearing loss. Recommendations for musicians to protect their hearing were released in 2015 by NIOSH. The recommendations emphasized education of musicians and those who work in or around the music industry. Annual hearing assessments were also recommended to monitor thresholds as were sound level assessments to help determine the amount of time musicians and related professionals should spend in that environment. Hearing protection was also recommended, and the authors of the NIOSH recommendations even suggested that musicians consider custom earplugs as a way to combat NIHL.In 2016, the National Association of Schools of Music (NASM), a music school accreditation body in the US, published a hearing health advisory to help with efforts directed at informing faculty and music students about potential risks associated with school activities, during rehearsal and performance.[1] Specific resources are available for administrators, faculty and staff, and students. The use of the documents is voluntary and are not to be used as standards or as part of accreditation procedures. Despite these recommendations, musicians continue to face unique challenges in protecting their hearing when compared to individuals in industrial settings. Typically environmental controls are the first line of defense in a hearing conservation program, and depending on the type of musicians some recommendations have been proposed. These recommendations can include adjusting risers or level of the speakers and adjusting the layout of a band or orchestra. These changes in the environment can be beneficial to musicians, but the ability to accomplish them is not always possible. In the cases where these changes cannot be made, hearing protection is recommended. Hearing protection in musicians offers its own sets of benefits and complications. When used properly, hearing protection can limit the exposure of noise in individuals. Musicians have the ability to pick from several different types of hearing protection from conventional ear plugs to custom or high fidelity hearing protection. Despite this, use of hearing protection among musicians is low for several different reasons. Musicians often feel that hearing protective devices can distort how music sounds or makes it too quiet for them to hear important cues which makes them less likely to wear hearing protection even when aware of the risks. Research suggests that educations programs can be beneficial to musicians as well as working with hearing care professionals to help address the specific issues that musicians face.[2] In 2018, a musician named Chris Goldscheider won a case against Royal Opera House for damaging his hearing in a rehearsal of Wagners thunderous opera Die Walkure. Workplace standards In the United States, the Occupational Safety and Health Administration (OSHA) describes standards for occupational noise exposure in articles 1910.95 and 1926.52. OSHA states that an employer must implement hearing conservation programs for employees if the noise level of the workplace is equal to or above 85 dB(A) for an averaged eight-hour time period. OSHA also states that "exposure to impulsive or impact noise should not exceed 140 dB peak sound pressure level". The National Institute for Occupational Safety and Health (NIOSH) recommends that all worker exposures to noise should be controlled below a level equivalent to 85 dBA for eight hours to minimize occupational noise induced hearing loss. NIOSH also recommends a 3 dBA exchange rate so that every increase by 3 dBA doubles the amount of the noise and halves the recommended amount of exposure time. The United States Department of Defense (DoD) instruction 605512 has some differences from OSHA 1910.95 standard, for example, OSHA 1910.95 uses a 5 dB exchange rate and DoD instruction 605512 uses a 3 dB exchange rate. There are programs that seek to increase compliance and therefore effectiveness of hearing protection rules; the programs include the use of hearing tests and educating people that loud sound is dangerousEmployees are required to wear hearing protection when it is identified that their eight-hour time weighted average (TWA) is above the exposure action value of 90 dB. If subsequent monitoring shows that 85 dB is not surpassed for an eight-hour TWA, the employee is no longer required to wear hearing protection.In the European Union, directive 2003/10/EC mandates that employers shall provide hearing protection at noise levels exceeding 80 dB(A), and that hearing protection is mandatory for noise levels exceeding 85 dB(A). Both values are based on 8 hours per day, with a 3 dB exchange rate. A 2017 Cochrane review found low-quality evidence that legislation to reduce noise in the workplace was successful in reducing exposure both immediately and long-term. Sporting events Several sports stadiums pride themselves in having louder stadiums than their opponents because it may create a more difficult environment for opposing teams to play in. Currently, there are few studies on noise in sports stadiums, but some preliminary measurements show noise levels reaching 120 dB, and informal studies suggest that people may receive up to a 117% noise dose in one game. There are many challenges that face hearing conservationists such as sports culture. Sports fans will create noise in an attempt to distract other teams, and some sports teams have been known to create artificial noise in an attempt to make the stadium louder. In doing that, workers, teams, and fans may be at potential risk for damage to the auditory system. NIOSH conducted a health hazard evaluation and studies at Monster Trucking and Stock Car racing events, spectators average noise levels ranged from 95 to 100 dBA at the Monster Truck event and over 100 dBA at the stock car racing event. NIOSH researchers also published noise exposure levels for drivers, crew members, and staff. Noise levels at the Bristol Motor Speedway ranged from 96 dBA in the stands to 114 dBA for a driver inside a car during practice. Peak noise levels in the Pit area reached or exceeded 130 dB SPL, a level often associated with human hearing threshold for pain. Several prominent NASCAR drivers have complete or partial hearing loss and other symptoms from their many years of exposure.During the FIFA World Cup in 2010, noise levels created by fans blowing Vuvuzela averaged 131 dBA at the horn opening and 113 dBA at 2 meter distance. Peak levels reached 144 dB SPL, louder than a jet engine at takeoff.A study of occupational and recreational noise exposure at indoor hockey arenas found noise levels from 81 dBA to 97 dBA, with peak sound pressure levels ranging from 105 dB SPLto 124 dB SPL. Another study examined the hearing threshold of hockey officials and found mean noise exposures of 93 dBA. Hearing threshold shifts were observed in 86% of the officials (25/29).In a study of noise levels at 10 intercollegiate basketball games showed noise levels in 6 of the 10 basketball games to exceed the national workplace noise exposure standards, with participants showing temporary threshold levels at one of the games.While there is no agency that currently monitors sports stadium noise exposure, organizations such as NIOSH or OSHA use occupational standards for industrial settings that some experts feel could be applied for those working at sporting events. Workers often will not exceed OSHA standards of 90 dBA, but NIOSH, whose focus is on best practice, has stricter standards which say that when exposed to noise at or exceeding 85 dBA workers need to be put on a hearing conservation program. Workers may also be at risk for overexposure because of impact noises that can cause instant damage. Experts are suggesting that sports complexes create hearing conservation programs for workers and warn fans of the potential damage that may occur with their hearing.Studies are still being done on fan exposure, but some preliminary findings show that there are often noises that can be at or exceed 120 dB which, unprotected, can cause damage to the ears in seconds. Mechanisms NIHL occurs when too much sound intensity is transmitted into and through the auditory system. An acoustic signal from a sound source, such as a radio, enters into the external auditory canal (ear canal), and is funneled through to the tympanic membrane (eardrum), causing it to vibrate. The vibration of the tympanic membrane drives the middle ear ossicles, the malleus, incus, and stapes to vibrate in sync with the eardrum. The middle ear ossicles transfer mechanical energy to the cochlea by way of the stapes footplate hammering against the oval window of the cochlea, effectively amplifying the sound signal. This hammering causes the fluid within the cochlea (perilymph and endolymph) to be displaced. Displacement of the fluid causes movement of the hair cells (sensory cells in the cochlea) and an electrochemical signal to be sent from the auditory nerve (CN VIII) to the central auditory system within the brain. This is where sound is perceived. Different groups of hair cells are responsive to different frequencies. Hair cells at or near the base of the cochlea are most sensitive to higher frequency sounds while those at the apex are most sensitive to lower frequency sounds. There are two known biological mechanisms of NIHL from excessive sound intensity: damage to the structures called stereocilia that sit atop hair cells and respond to sound, and damage to the synapses that the auditory nerve makes with hair cells, also termed "hidden hearing loss". Physiological response The symptoms mentioned above are the external signs of the physiological response to cochlear overstimulation. Here are some elements of this response: Damaged sensory hairs (stereocilia) of the hair cells; damaged hair cells degenerate and die. In humans and other mammals, dead hair-cells are never replaced; the resulting hearing loss is permanent. Inflammation of the exposed areas. This inflammation causes poor blood flow in the exposed blood vessels (vascular stasis), and poor oxygen supply for the liquid inside the cochlea (endolymphatic hypoxia) Those noxious conditions worsen the damaged hair cell degeneration. Synaptic damages, by excitotoxicity. Noise overstimulation causes an excessive release of glutamate, causing the postsynaptic bouton to swell and burst. However the neuron connection can be repaired, and the hearing loss only caused by the "wiring" (i.e. excitotoxicity) can thus be recovered within 2–3 days. Hair cell damage or death When the ear is exposed to excessive sound levels or loud sounds over time, the overstimulation of the hair cells leads to heavy production of reactive oxygen species, leading to oxidative cell death. In animal experiments, antioxidant vitamins have been found to reduce hearing loss even when administered the day after noise exposure. They were not able to fully prevent it. Antioxidants however do not seem to be effective in protecting the human ear. Damage ranges from exhaustion of the hair (hearing) cells in the ear to loss of those cells. NIHL is, therefore, the consequence of overstimulation of the hair cells and supporting structures. Structural damage to hair cells (primarily the outer hair cells) will result in hearing loss that can be characterized by an attenuation and distortion of incoming auditory stimuli. During hair cell death scars develop, which prevent potassium rich fluid of the endolymph from mixing with the fluid on the basal domain. The potassium rich fluid is toxic to the neuronal endings and can damage hearing of the entire ear. If the endolymph fluid mixes with the fluid on the basal domain the neurons become depolarized, causing complete hearing loss. In addition to complete hearing loss, if the area is not sealed and leakage continues further tissue damage will occur. The scars that form to replace the damaged hair cell are caused by supporting hair cells undergoing apoptosis and sealing the reticular lamina, which prevents fluid leakage. The cell death of two supporting hair cells rapidly expands their apical domain, which compresses the hair cell beneath its apical domain. Nerve damage Recent studies have investigated additional mechanisms of NIHL involving delayed or disabled electrochemical transmission of nerve impulses from the hair cell to and along the auditory nerve. In cases of extreme acute acoustic trauma, a portion of the postsynaptic dendrite (where the hair cell transfers electrochemical signals to the auditory nerve) can rupture from overstimulation, temporarily stopping all transmission of auditory input to the auditory nerve. This is known as excitotoxicity. Usually, this sort of rupture heals within about five days, resulting in functional recovery of that synapse. While healing, an over-expression of glutamate receptors can result in temporary tinnitus, or ringing in the ears. Repeated ruptures at the same synapse may eventually fail to heal, leading to permanent hearing loss.Prolonged exposure to high intensity noise has also been linked to the disruption of ribbon synapses located in the synaptic cleft between inner hair cells and spiral ganglion nerve fibers, leading to a disorder referred to as cochlear synaptopathy or hidden hearing loss. This disorder is cumulative and over time, leads to degeneration of the spiral ganglion cells of the inner ear and overall dysfunction in the neural transmission between auditory nerve fibers and the central auditory pathway. The most common symptom of cochlear synaptopathy is difficulty understanding speech, especially in the presence of competing noise. However, this type of hearing impairment is often undetectable by conventional pure tone audiometry, thus the name "hidden" hearing loss. Acoustic over-exposure can also result in decreased myelination at specific points on the auditory nerve. Myelin, an insulating sheath surrounding nerve axons, expedites electrical impulses along nerves throughout the nervous system. Thinning of the myelin sheath on the auditory nerve significantly slows the transmission of electrical signals from hair cell to auditory cortex, reducing comprehension of auditory stimuli by delaying auditory perception, particularly in noisy environments. Individual susceptibility towards noise There appear to be large differences in individual susceptibility to NIHL. The following factors have been implicated: missing acoustic reflex previous sensorineural hearing loss a bad general health state: bad cardiovascular function, insufficient intake of oxygen, a high platelet aggregation rate; and most importantly, a high viscosity of the blood cigarette smoking exposure to ototoxic chemicals (medication or environmental chemicals that can damage the ear), including certain solvents and heavy metals type 2 diabetes Diagnosis Both NIHL caused by acoustic trauma and gradually-developed-NIHL can often be characterized by a specific pattern presented in audiological findings. NIHL is generally observed to decrease hearing sensitivity in the higher frequencies, also called an audiometric notch, especially at 4000 Hz, but sometimes at 3000 or 6000 Hz. The symptoms of NIHL are usually presented equally in both ears.This typical 4000 Hz notch is due to the transfer function of the ear. As does any object facing a sound, the ear acts as a passive filter, although the inner ear is not an absolute passive filter because the outer hair cells provide active mechanisms. A passive filter is a low pass: the high frequencies are more absorbed by the object because high frequencies impose a higher pace of compression-decompression to the object. The high frequency harmonics of a sound are more harmful to the inner-ear.However, not all audiological results from people with NIHL match this typical notch. Often a decline in hearing sensitivity will occur at frequencies other than at the typical 3000–6000 Hz range. Variations arise from differences in peoples ear canal resonance, the frequency of the harmful acoustic signal, and the length of exposure. As harmful noise exposure continues, the commonly affected frequencies will broaden to lower frequencies and worsen in severity. Prevention NIHL can be prevented through the use of simple, widely available, and economical tools. This includes but is not limited to personal noise reduction through the use of ear protection (i.e. earplugs and earmuffs), education, and hearing conservation programs. For the average person, there are three basic things that one can do to prevent NIHL: turn down the volume on devices, move away from the source of noise, and wear hearing protectors in loud environments.Non-occupational noise exposure is not regulated or governed in the same manner as occupational noise exposure; therefore prevention efforts rely heavily on education awareness campaigns and public policy. The WHO cites that nearly half of those affected by hearing loss could have been prevented through primary prevention efforts such as: "reducing exposure (both occupational and recreational) to loud sounds by raising awareness about the risks; developing and enforcing relevant legislation; and encouraging individuals to use personal protective devices such as earplugs and noise-cancelling earphones and headphones." Personal noise reduction devices Personal noise reduction devices can be passive, active or a combination. Passive ear protection includes earplugs or earmuffs which can block noise up to a specific frequency. Earplugs and earmuffs can provide the wearer with 10 dB to 40 dB of attenuation. However
Noise-induced hearing loss	, use of earplugs is only effective if the users have been educated and use them properly; without proper use, protection falls far below manufacturer ratings. A Cochrane review found that training of earplug insertion can reduce noise exposure at short term follow-up compared to workers wearing earplugs without training. Higher consistency of performance has been found with custom-molded earplugs. Because of their ease of use without education, and ease of application or removal, earmuffs have more consistency with both compliance and noise attenuation. Active ear protection (electronic pass-through hearing protection devices or EPHPs) electronically filter out noises of specific frequencies or decibels while allowing the remaining noise to pass through. A personal attenuation rating can be objectively and subjectively measured by using a hearing protection fit testing system. Education Education is key to prevention. Before hearing protective actions will take place, a person must understand they are at risk for NIHL and know their options for prevention. Hearing protection programs have been hindered by people not wearing the protection for various reasons, including the desire to converse, uncomfortable devices, lack of concern about the need for protection, and social pressure against wearing protection. Although youth are at risk for hearing loss, one study found that 96.3% of parents did not believe their adolescents were at risk, and only 69% had talked to their children about hearing protection; those aware of NIHL risks were more likely to talk to their teens.A systematic review of the effectiveness of interventions to promote the use of hearing protection devices such as earplugs and earmuffs among workers found that tailored interventions improve the average use of such devices when compared with no intervention. Tailored interventions involve the use of communication or other types of interventions that are specific to an individual or a group and aim to change behavior. Mixed interventions such as mailings, distribution of hearing protection devices, noise assessments, and hearing testing are also more effective in improving the use of hearing protection devices compared with hearing testing alone. Programs that increased the proportion of workers wearing hearing protection equipment did reduce overall hearing loss. Hearing conservation programs Workers in general industry who are exposed to noise levels above 85 dBA are required by the Occupational Safety and Health Administration (OSHA) to be in a hearing conservation program (HCP), which includes noise measurement, noise control, periodic audiometric testing, hearing protection, worker education, and record keeping. Twenty-four states, Puerto Rico, and the U.S. Virgin Islands have OSHA-approved state plans and have adopted their own standards and enforcement policies. Most of these state standards are identical to those of federal OSHA. However, some states have adopted different standards or may have different enforcement policies. Most health and safety regulations are designed to keep damage risk within "acceptable limits" — that is, some people are likely to incur a hearing loss even when exposed to less than the maximum daily amount of noise specified in a regulation. Hearing conservation programs in other arenas (schools, military) have become more common, and it has been established that unsafe listening behaviors, such as listening to loud noise for extended periods of time without protection, persist despite knowledge of potential hearing loss effects.However, it is understood that HCPs are designed to change behavior, which is known to be a complex issue that requires a multi-faceted approach. According to Keppler et al. in their 2015 study of such programming, they cite the necessary attitude change towards the susceptibility of risk and degree of severity of hearing loss. Among young adults, the concept of severity is most crucial because it has been found that behavior change may not occur unless an individual experiences NIHL or similarly related NIHL tinnitus, furthering warranting a multi-pronged approach based on hearing conservation programming and education. Interventions to prevent noise-induced hearing loss often have many components. A 2017 Cochrane review found that hearing loss prevention programs suggest that stricter legislation might reduce noise levels. Giving workers information on their noise exposure levels by itself was not shown to decrease exposure to noise. Ear protection, if used correctly, has the potential to reduce noise to safer levels, but does not necessarily prevent hearing loss. External solutions such as proper maintenance of equipment can lead to noise reduction, but further study of this issue under real-life conditions is needed. Other possible solutions include improved enforcement of existing legislation and better implementation of well-designed prevention programmes, which have not yet been proven conclusively to be effective. The implications is that further research could affect conclusions reached. Several hearing conservation programs have been developed to educate a variety of audiences about the dangers of NIHL and how to prevent it. Dangerous Decibels aims to significantly reduce the prevalence of noise induced hearing loss and tinnitus through exhibits, education and research. Were hEAR for You is a small non-profit that distributes information and ear plugs at concert and music festival venues. The Buy Quiet program was created to combat occupational noise exposures by promoting the purchase of quieter tools and equipment and encourage manufacturers to design quieter equipment. The National Institute on Deafness and Other Communication Disorders developed the Its a Noisy Planet. Protect their Hearing educational campaign to inform preteens, parents, and educators about the causes and prevention of NIHL. The National Institute for Occupational Safety and Health partnered with the National Hearing Conservation Association in 2007 to establish the Safe-in-Sound Excellence and Innovation in Hearing Loss Prevention Awards to recognize organizations that are successfully implementing hearing loss prevention concepts into their daily routines. Medication Medications are still being researched to determine if they can prevent NIHL. No medication has been proven to prevent or repair NIHL in humans. There is evidence that hearing loss can be minimized by taking high doses of magnesium for a few days, starting as soon as possible after exposure to the loud noise. A magnesium-high diet also seems to be helpful as an NIHL-preventative if taken in advance of exposure to loud noises. Along the same line of research, higher dietary or supplemental intakes of magnesium combined with antioxidant vitamins, specifically β-carotene and vitamin C, appear to be associated with a lower risk of hearing loss. Consuming excessive amounts of magnesium can be potentially harmful, so any treatments should be followed with caution.Tentative research in a mouse model suggests that blocking the GluA2-lacking, calcium-permeable forms of the AMPA receptor protects against hearing damage. Sound or stress training Despite different people having different thresholds for what noises are painful, this pain threshold has no correlation with which noises cause hearing damage. The ear can not get more resistant to noise harmfulness by training it to noise. The cochlea is partially protected by the acoustic reflex, but being frequently exposed to noise does not lower the reflex threshold. It had been observed that noise conditioning (i.e. exposure to loud non-traumatizing noise) several hours prior to the exposure to traumatizing sound level, significantly reduced the damages inflicted to the hair-cells. The same "protective effect" was also observed with other stressors such as heat-shock conditioning and stress (by restraint) conditioning. This "protective effect" only happens if the traumatizing noise is presented within an optimum interval of time after the sound-conditioning session (-24 hours for a 15 min. sound-conditioning; no more protection after 48 hours). This "protective effect" had long been thought to involve the active mechanisms of the outer hair cells and the efferent system commanding them. The contractile effect of the outer hair cells, activated by the efferent nervous system has been proven to provide a protective effect against acoustic trauma. However, a 2006 study revealed a different protective mechanism for stress conditioning. The study revealed that the stressor (sound, heat, or stress) conditioning increases the receptibility to glucocorticoid, a kind of anti-inflammatory hormone. The effects of glucocorticoid thus mitigate the inflammation from an acoustic trauma that can lead to hearing loss. In fact, high doses of corticoids are often prescribed by physicians after an acoustic-trauma in order to mitigate the inflammatory response. Summarized, sound (or other stressor) conditioning is a pre-emptive medication against cochlea inflammation. It does not make the ear more resistant to noise. It reduces the inflammation caused by the acoustic trauma, which would cause subsequent damages to hair cells. While an anti-inflammatory medication would increase the quantity of anti-inflammatory hormone in the whole body, noise conditioning increases the number of receptors for the anti-inflammatory hormone, and only in the areas where it is much needed (i.e. cochlea). Physiological response stressor (noise, heat shock or stress) conditioning activates hormonal glands: the HPA axis. Note that the HPA axis is associated to the immune system this HPA axis activation results in the up regulation of glucocorticoid receptors (GR) in the cochlea and the paraventricular nucleus (PVN) of the hypothalamus. Note that the glucocorticoid hormone is a kind of immune-reaction-inhibitor, including the inflammation reaction. This up regulation of GR thus prevents GR down regulation induced by acoustic trauma The protective effect of noise-conditioning is blocked by adrenalectomy or pharmacological treatment with RU486 + metyrapone (a glucocorticoid receptor antagonist). Treatment Treatment options that offer "cures" for NIHL are under research and development. Currently there are no commonly used cures, but rather assistive devices and therapies to try and manage the symptoms of NIHL. Acute acoustic trauma Several clinical trials have been conducted to treat temporary NIHL occurring after a traumatic noise event, such as a gunshot or firework. In 2007, individuals with acute acoustic trauma after firecracker exposure were injected intratympanically with a cell permeable ligand, AM-111. The trial found AM-111 to have a therapeutic effect on at least two cases of those with acute trauma. Treatment with a combination of prednisolone and piracetam appeared to rescue patients with acute trauma after exposure to gunshots. However, those who received the treatment within an hour of exposure had higher rates of recovery and significantly lower threshold shifts compared to those who received treatment after one hour.Additionally, clinical trials using antioxidants after a traumatic noise event to reduce reactive oxygen species have displayed promising results. Injections with allopurinol, lazaroids, α-D-tocopherol, and mannitol were found to reduce the threshold shift after noise exposure. Another antioxidant, Ebselen, has been shown to have promising results for both TTS and PTS. Ebselen mimics gluthathione peroxide, an enzyme that has many functions, including scavenging hydrogen peroxide and reactive oxygen species. After noise exposure, gluthathione peroxide decreases in the ear. An oral administration of ebselen in both preclinical tests on guinea pigs and human trials indicate that noise induced TTS and PTS was reduced.Recently, combination therapy with hyperbaric oxygen therapy (HBO) and corticosteroids has been found to be effective for acute acoustic trauma. Acute noise exposure causes inflammation and lower oxygen supply in the inner ear. Corticosteroids hinder the inflammatory reaction and HBO provides an adequate oxygen supply. This therapy has been shown to be effective when initiated within three days after acoustic trauma. Therefore, this condition is considered an ENT emergency. Gradually occurring NIHL At the present time, no established clinical treatments exist to reverse the effects of permanent NIHL. However, current research for the possible use of drug and genetic therapies look hopeful. In addition, management options such as hearing aids and counseling exist. Many studies have been conducted looking at regeneration of hair cells in the inner ear. While hair cells are generally not replaced through cell regeneration, mechanisms are being studied to induce replacement of these important cells. One study involves the replacement of damaged hair cells with regenerated cells, via the mechanism of gene transfer of atonal gene Math1 to pluripotent stem cells within the inner ear. Other atonal genes are being studied to induce regeneration of hair cells in the inner ear. Management For people living with NIHL, there are several management options that can improve the ability to communicate. These options include counseling, amplification, and other assisted listening devices, such as frequency modulation (FM) systems. FM systems can enhance the use of hearing aids and overcome the effects of poor listening conditions because the signal is sent from the microphone worn by the speaker directly to the listener. The prognosis has improved with the recent advancements in digital hearing aid technology, such as directional microphones, open-fit hearing aids, and more advanced algorithms. Hearing aids can mask or cover up the tinnitus, and many with hearing loss and tinnitus find relief by using hearing aids. Though there is no cure or agreed-upon treatment for tinnitus, some drugs have been shown to provide temporary reduction of tinnitus. Other treatments for tinnitus include cognitive-behavioral therapy, biofeedback, and electrical stimulation. Annual audiological evaluations are recommended to monitor any changes in a patients hearing and to modify hearing-aid prescriptions. A systematic-review conducted by the American Academy of Audiology Task Force On the Health-Related Quality of Life Benefits of Amplification in Adults found the use of hearing aids to increase quality of life. The review pertained to adults who experienced sensorineural hearing loss, which can be caused by excessive, loud noise. Epidemiology The World Health Organization estimates that nearly 360 million people have moderate to profound hearing loss from all causes. Rates of hearing loss has traditionally been attributed to occupational or firearm-related exposure, as well as recreational exposure. The World Health Organization estimated in 2015 that 1.1 billion young people are at risk for hearing loss caused by unsafe listening practices. The over-exposure to excessive loud noise is partially attributed to recreational exposure, such as the use of personal audio devices with music at high volumes for long durations, or social settings such as bars, entertainment and sporting events.The International Organization for Standardization (ISO) developed the ISO 1999 standards for the estimation of hearing thresholds and noise-induced hearing impairment. They used data from two noise and hearing study databases, one presented by Burns and Robinson (Hearing and Noise in Industry, Her Majestys Stationery Office, London, 1970) and by Passchier-Vermeer (1968). As race and ethnicity are some of the factors that can affect the expected distribution of pure-tone hearing thresholds several other national or regional datasets exist, from Sweden, Norway, South Korea, the United States and Spain. In the United States hearing is one of the health outcomes measure by the National Health and Nutrition Examination Survey (NHANES), a survey research program conducted by the National Center for Health Statistics. It examines health and nutritional status of adults and children in the United States. While there is no perfect way to pinpoint hearing loss from excessive noise, researchers look for audiometric notches in a hearing test—dips in the ability to hear certain frequencies—as signs of possible NIHL. As of 2011 data, approximately 24% adults age 20–69 in the United States has an audiometric notch. This data identified differences in NIHL based on age, gender, race/ethnicity, and whether or not a person is exposed to noise at work. Among people aged 20–29, 19.2% had an audiometric notch, compared to 27.3% of people aged 50–59. Males in general had a notch more often than females, regardless of occupational noise exposure, for both unilateral and bilateral audiometric notches. An epidemiological study of 6557 automotive manufacturing workers in China (median age 28 years old) reported that in 62% of the settings where noise exposures were evaluated, levels exceeded the recommended level of 85 dBA. The prevalence of hearing loss was 41% among auto part manufacturing workers, followed by 31% of power train workers and 24% in automotive manufacturing. Across job categories, the highest prevalence rate was observed among welders, of 53%. The prevalence rates were associated with noise levels and the workers cumulative noise exposure. Occupational noise exposure is the main risk factor for work-related hearing loss. One study examined hearing test results obtained between 2000 and 2008 for workers ages 18–65 who had a higher occupational noise exposure than the average worker. Of the sample taken, 18% of the workers had hearing loss. Of the occupations considered, the Mining industry had the highest prevalence and risk of hearing loss, at approximately 27%. Other industries with a higher prevalence and risk included Construction (23.48%) and Manufacturing, especially Wood Product and Non-metallic Mineral Product (19.89%), Apparel (20.18%), and Machinery (21.51%). Estimates of rates of hearing loss have been reported for workers in the Agriculture, Forestry, Fishing, and Hunting (AFFH) sector. The overall prevalence of hearing loss (defined as a pure‐tone average threshold across frequencies 1000, 2000, 3000, and 4000 Hz of 25 dB or more in either ear) was 15% but that rate was exceeded in several of the subsectors of those industries. Prevalences were highest among workers in Forest Nurseries and Gathering of Forest Products at 36% and Timber Tract Operations at 22%. The Aquaculture sub‐sector had the highest adjusted risk (adjusted probability ratio of 1.7) of all sub‐sectors of the Agriculture, Forestry, Fishing, and Hunting industries. The same methodology was used to estimate the prevalence of hearing loss for noise-exposed U.S. workers within the Health Care and Social Assistance sector. The prevalence of hearing loss in the Medical Laboratories subsector was 31% and in the Offices of All Other Miscellaneous Health Practitioners subsector was 24%. The Child Day Care Services subsector had a 52% higher risk than the reference industry.While the overall HSA sector prevalence for hearing loss was 19%, the prevalence in the Medical Laboratories subsector and the Offices of All Other Miscellaneous Health Practitioners subsector were 31% and 24%, respectively. The Child Day Care Services subsector had a 52% higher risk than the reference industry of workers who are not exposed to noise at work (Couriers and Messengers). Overall, audiometric records show that about 33% of working-age adults with a history of occupational noise exposure have evidence of noise-induced hearing damage, and 16% of noise-exposed workers have material hearing impairment. See also Medical Acoustic trauma Auditory fatigue Health effects from noise Hearing aid Hearing loss Hearing protection fit testing Occupational hearing loss Ototoxicity Presbycusis Sensorineural hearing loss TinnitusGeneral Noise Noise pollution Noise regulation Noise control Environmental noiseOrganizations and awareness-raising initiatives Dont Lose The Music H.E.A.R. Safe-In-Sound Award Youth hearing conservation programs Hearing conservation program Safe listening World Hearing Day, by the World Health Organization World Report on Hearing, World Health Organization, 2021. National Association of Schools of Music (NASM) and the Performing Arts Medicine Association (PAMA) Advisories on Hearing Health.[3]Noise from power sources NIOSH Power Tools Database Buy Quiet References External links Noise-Induced Hearing Loss from the National Institutes of Health Dangerous Decibels Includes general information and a "virtual exhibit" as well as resources for teachers. NIOSH Noise and Hearing Loss Prevention Topic Page NIOSH Power Tools Sound Pressure and Vibrations Database New York City construction noise control products and vendor guidance sheet Online Audiometric Test Calibrated test, up to 80 dBHL. Confirm your hearing status loss and track if it changes over time. An online audiometric test featuring equal loudness curves NIOSH Buy Quiet Topic Page www.cochlea.org/en/noise - animation of damage of hairs, harmful intensities graph www.cochlea.eu/en/hair-cells - illustrations and images of hair cells
Sleep inertia	Sleep inertia is a physiological state of impaired cognitive and sensory-motor performance that is present immediately after awakening. It persists during the transition of sleep to wakefulness, where an individual will experience feelings of drowsiness, disorientation and a decline in motor dexterity. Impairment from sleep inertia may take several hours to dissipate. In the majority of cases, morning sleep inertia is experienced for 15 to 30 minutes after waking.Sleep inertia is of concern with decision-making abilities, safety-critical tasks and the ability to operate efficiently soon after awakening. In these situations, it poses an occupational hazard due to the cognitive and motor deficits that may be present. Symptoms "Grogginess", as defined by a drowsy or disoriented state in which there is a dampening of sensory acuity and mental processing. Impaired motor dexterity and decrease in cognitive ability. These gross impairments may be responsible for the associated increase in reaction time and drop in attentiveness. Deficits in spatial memory Reports of heightened subjective fatigueThese symptoms are expressed with the greatest intensity immediately after waking, and dissipate following a period of extended wakefulness. The duration of symptoms varies on a conditional basis, with primary expression during the first 15–60 minutes after waking and potentially extending for several hours. Tasks that require more complex cognitive operations will feature greater deficits as compared to a simple motor task; the accuracy of sensory and motor functioning is more impaired by sleep inertia as compared to sheer speed. In order to measure the cognitive and motor deficiencies associated with sleep inertia, a battery of tests may be utilized including psychomotor vigilance task, descending subtraction task (DST), auditory reaction time task, and the finger tapping task. Causes Studies have shown that abrupt awakening during stage 3 sleep, slow-wave sleep (SWS), produces more sleep inertia than awakening during sleep stages 1, 2 or REM sleep. Prior sleep deprivation increases the percentage of time spent in slow-wave sleep (SWS). Therefore, an individual who was previously sleep deprived will have a greater chance of experiencing sleep inertia. Adenosine levels in the brain progressively increase with sleep deprivation, and return to normal during sleep. Upon awakening with sleep deprivation, high amounts of adenosine will be bound to receptors in the brain, neural activity slows down, and a feeling of tiredness will result. Studies show that individuals express a lack of blood flow to the brain upon awakening. Levels of cerebral blood flow (CBF) and cerebral blood flow velocities (CBFV) will take up to 30 minutes to increase and reach daytime levels. Studies using advanced imaging have shown that cerebral blood flow will return to waking levels in the brainstem and thalamus first. Then, after 15 minutes, the brains anterior cortical regions receive normal daytime blood flow. This 15 minute time period corresponds to the sleep inertia period. Studies show that drinking alcoholic beverages in the evening causes physiological distress upon wake up. This phenomenon is known colloquially as a hangover. Treatments / countermeasures There has been a great deal of research into potential methods to relieve the effects of sleep inertia. The demand for remedies is driven by the occupational hazards of sleep inertia for employees who work extended shifts such as medical professionals, emergency responders, or military personnel. The motor functioning and cognitive ability of these professionals who must immediately respond to a call can pose a safety hazard in the workplace. Below are some of the various methods that have been suggested to combat sleep inertia. Napping When a person is sleep deprived, re-entering sleep may provide a viable route to reduce mental and physical fatigue but it can also induce sleep inertia. In order to limit sleep inertia, one should avoid waking from the deeper stages of slow-wave sleep. The onset of slow-wave sleep occurs approximately 30 minutes after falling asleep, therefore a nap should be limited to under 30 minutes to prevent waking during slow-wave sleep and enhancing sleep inertia. Furthermore, self-awakening from a short nap was shown to relieve disorientation of sleep inertia as opposed to a forced awakening, but these results may warrant more research into the nature of arousal after sleep periods. Caffeine Caffeine is a xanthine derivative that can cross the blood-brain barrier. The caffeine present in coffee or tea exerts its stimulating action by blocking adenosine receptors in the brain. By antagonizing the adenosine receptors caffeine limits the effects of adenosine buildup in the brain and increases alertness and attentiveness. Previous research has shown that coupled with a short nap, consuming caffeine prior to the nap can alleviate the effects of sleep inertia. Nonetheless, individual degree of consumption and tolerance to caffeine may be responsible for variation in its efficacy to reduce sleep inertia symptoms. Light The natural light provided by the sunrise may contribute to a reduction in sleep inertia effects. Research simulating increase of light at dawn was shown to potentiate the cortisol awakening response (CAR). The CAR is a spike in blood cortisol levels following awakening, and is associated with the return to an alert cognitive state. Other Some other interventions that could potentially minimize the effects of sleep inertia are sound and temperature. There is moderate evidence that the presence of mild sounds and a sharp decrease in the temperature of the extremities may independently reverse sleep inertia symptoms. Noise, especially music, is thought to increase attentiveness and decrease ones subjective feeling of sleepiness upon awakening. A drop in temperature of the extremities may prevent heat loss upon awakening, facilitating the return of core body temperature to homeostatic daytime levels. See also Circadian rhythm sleep disorder Delayed sleep phase syndrome Shift work Sleep deprivation References External links Flying Safely Article on Napping
Cradle cap	Cradle cap or cradle hat causes crusty or oily scaly patches on a babys scalp. The condition is not painful or itchy, but it can cause thick white or yellow scales that are not easy to remove. Cradle cap most commonly begins sometime in the first three months but can occur in later years. Similar symptoms in older children are more likely to be dandruff than cradle cap. The rash is often prominent around the ear, the eyebrows or the eyelids. It may appear in other locations as well, where it is called infantile seborrhoeic dermatitis. Cradle cap is just a special - and more benign - case of this condition. The exact cause of cradle cap is not known. Cradle cap is not spread from person to person (contagious). It is also not caused by poor hygiene. It is not an allergy, and it is not dangerous. Cradle cap often lasts a few months. In some children, the condition can last until age 2 or 3. Signs and symptoms Cradle cap is seborrheic dermatitis that affects infants. It presents on the scalp as greasy patches of scaling, which appear thick, crusty, yellow, white or brown. The affected regions are not usually itchy and do not bother the child. Other affected areas can include the eyelids, ear, around the nose, and in the groin. Hair loss can also occur. Causes Cradle cap is not caused by bacterial infection, allergy or poor hygiene. Cradle cap is also not contagious. Doctors do not agree on what causes cradle cap, but the two most common hypotheses are fungal infection and overactive sebaceous glands. Cradle cap is an inflammatory condition.Possibly it has to do with overactive sebaceous glands in the skin of newborn babies, due to the mothers hormones still in the babys circulation. The glands release a greasy substance that makes old skin cells attach to the scalp instead of falling off as they dry. There is a relationship with skin yeasts (Pityrosporum ovale, newly renamed Malassezia furfur). Warning signs If the condition thickens, turns red and irritated, starts spreading, appears on other body parts, or if the baby develops thrush (fungal mouth infection), fungal ear infection (an ear infection that does not respond to antibiotics) or a persistent diaper rash, medical intervention is recommended. Severe cases of cradle cap, especially with cracked or bleeding skin, can provide a place for bacteria to grow. If the cradle cap is caused by a fungal infection which has worsened significantly over days or weeks to allow bacterial growth (impetigo, most commonly), a combination treatment of antibiotics and antifungals may be necessary. Since it is difficult for a layperson to distinguish the difference between sebaceous gland cradle cap, fungal cradle cap, or either of these combined with a bacterial infection, medical advice should be sought if the condition appears to worsen. Cradle cap is occasionally linked to immune disorders. If the baby is not thriving and has other problems (e.g. diarrhea), a doctor should be consulted. Treatment To help with cradle cap, parents can gently massage their babys scalp with their fingers or a soft brush to loosen the scales. They may want to shampoo the babys hair more frequently (no more than once a day), and after shampooing gently brush the babys scalp with a soft brush or a terrycloth towel. Oil remedies can be used by rubbing a small amount of pure, plant-derived oil (coconut oil, pure olive oil, almond oil) on the babys scalp and leaving it on for 15 minutes. After 15 minutes, gently comb out the flakes with a fine tooth comb or brush. Be sure to wash out all of the oil to avoid making the cradle cap worse.In cases that are related to fungal infection, such as Tinea capitis, doctors may recommend a treatment application of clotrimazole (commonly prescribed for jock itch or athletes foot) or miconazole (commonly prescribed for vaginal candidiasis). Doctors may recommend a treatment with a mild dandruff shampoo such as Selsun Blue even though the treatment may cause initial additional scalp irritation. A doctor may instead prescribe an antifungal soap such as ketoconazole (2%) shampoo, which can work in a single treatment and shows significantly less irritation than over-the-counter shampoos such as selenium disulfide shampoos.There are only a limited number of studies regarding the efficacy and safety of treatments for cradle cap and infantile seborrheic dermatitis. Several treatments including Promiseb, lactamide MEA gel, hydrocortisone 1% lotion, licochalcone 0.025%, flumethasone pivalate 0.02% ointment, and eosin 2% aqueous solution have been studied, however there is uncertainty regarding the efficacy and safety of these treatments.For adults: see the article on seborrheic dermatitis (the adult version of cradle cap). Scalp, behind ears, eyebrows If the cradle cap is not severe, it could simply be combed out gently after bathing. The softened scales can then be brushed away with a soft brush, comb or cloth, but if not done very gently, this could worsen the condition and bring about temporary hair loss. Applying petroleum jelly (e.g., Vaseline) liberally overnight is another popular treatment. The softened scales either fall off during the night, or can be brushed off in the morning.There is broad disagreement regarding the role of shampoos. Some sources warn against frequent shampooing, others recommend it. Mild baby shampoo is often recommended, but the exact denotation of the label "mild" in this context is not quite clear. Baby shampoos often contain detergent surfactants, perfumes, quaternium-15 and other eczemagenic irritants. No studies have been performed on non-prescription shampoos.In stubborn cases some doctors may recommend keratolytic (dandruff) shampoos (e.g. with sulfur, selenium, zinc pyrithione, or salicylic acid) while others warn against the use of medicated shampoos in newborns due to systemic absorption. Dandruff shampoos often contain sodium dodecyl sulfate, a noted skin irritant.Steroid and tar preparations have also been used but may have drawbacks. The immunomodulators tacrolimus/Protopic and pimecrolimus/Elidel have not been approved for children under two years. Ketoconazole shampoos and creams are currently shown to be the most effective medical treatment of moderate to serious cradle cap. There appears to be little to no absorption of topical ketoconazole into the bloodstream. Eyelids Typical medical advice is to use baby shampoo, diluted with warm water, on a cotton swab to cleanse the eyelid. There is no agreement on the dilution, which ranges from as high as a 1:1 mix to as low as a few drops of shampoo per half-cup of water. Prognosis/differential diagnosis Assurances that this condition will clear as the baby matures are very common. However, the condition occasionally persists into the toddler years, and less commonly into later childhood. It tends to recur in adolescence and persists into adulthood. In an Australian study, about 15 percent of previously diagnosed children still had eczema 10 years later. It is common that people mistake cradle cap for atopic dermatitis due to the similar symptoms. Unlike some signs and symptoms of cradle cap, atopic dermatitis affect infants sleep and feeding habits with moderate to severe itching. In addition, one of the physical diagnosis of atopic dermatitis is poor crusted lesions on certain surfaces of the baby, such as scalp and cheek. Rarely, it turns out to be misdiagnosed psoriasis. References External links DermNet dermatitis/cradle-cap
Serositis	Serositis refers to inflammation of the serous tissues of the body, the tissues lining the lungs (pleura), heart (pericardium), and the inner lining of the abdomen (peritoneum) and organs within. It is commonly found with fat wrapping or creeping fat. Causes Serositis is seen in numerous conditions: Lupus erythematosus (SLE), for which it is one of the criteria, Rheumatoid arthritis Familial Mediterranean fever (FMF) Chronic kidney failure / Uremia Juvenile idiopathic arthritis Inflammatory bowel disease (especially Crohns disease) Acute appendicitis Diffuse cutaneous systemic sclerosis See also Hyaloserositis References == External links ==
Speech disfluency	A speech disfluency, also spelled speech dysfluency, is any of various breaks, irregularities, or non-lexical vocables which occur within the flow of otherwise fluent speech. These include "false starts", i.e. words and sentences that are cut off mid-utterance; phrases that are restarted or repeated and repeated syllables; "fillers", i.e. grunts or non-lexical utterances such as "huh", "uh", "erm", "um", "well", "so", "like", and "hmm"; and "repaired" utterances, i.e. instances of speakers correcting their own slips of the tongue or mispronunciations (before anyone else gets a chance to). "Huh" is claimed to be a universal syllable. Fillers Fillers are parts of speech which are not generally recognized as purposeful or containing formal meaning, usually expressed as pauses such as "uh", "like" and "er", but also extending to repairs ("He was wearing a black—uh, I mean a blue, a blue shirt"), and articulation problems such as stuttering. Use is normally frowned upon in mass media such as news reports or films, but they occur regularly in everyday conversation, sometimes representing upwards of 20% of "words" in conversation. Fillers can also be used as a pause for thought ("I arrived at, um—3 oclock"), and when used in this function are called hesitation markers or planners. Language-dependence Research in computational linguistics has revealed a correlation between native language and patterns of disfluencies in spontaneously uttered speech. Besides that research, there are other subjective accounts reported by individuals. According to one commentator, Americans use pauses such as "um" or "em", the Irish commonly use the pause "em", the British say "uh" or "eh", the French use "euh", the Germans say "äh" (pronounced eh or er), the Dutch use "eh", Japanese use "ā", "anō" or "ēto", the Spanish say "ehhh" (also used in Hebrew) and "como" (normally meaning like), and Latin Americans but not the Spanish use "este" (normally meaning this). Besides "er" and "uh", the Portuguese use "hã" or "é". In Mandarin, "那个(nà gè)" and "这个(zhè ge)" are used, meaning "that" or "this", respectively. Arabic speakers say "يعني", the pronunciation of which is close to "yaani", [jæʕni] or [jaʕni], (literally he means, there is no grammatical gender-neutral third person) and Turkish say "şey" in addition to "yani" (without the [ʕ] found in Arabic) and "ııı".Despite the differences between languages, pause fillers in different languages often sound similar because they tend to be the easiest and most neutral vowel sounds to make (such as the schwa), i.e the sounds that can be pronounced with a relaxed tongue or jaw. Research Recent linguistic research has suggested that non-pathological disfluencies may contain a variety of meaning; the frequency of "uh" and "um" in English is often reflective of a speakers alertness or emotional state. Some have hypothesized that the time of an "uh" or "um" is used for the planning of future words; other researchers have suggested that they are actually to be understood as full-fledged function words rather than accidents, indicating a delay of variable time in which the speaker wishes to pause without voluntarily yielding control of the dialogue. There is some debate as to whether to consider them a form of noise or as a meaning-filled part of language. Speech disfluencies have also become important in recent years with the advent of speech-to-text programs and other attempts at enabling computers to make sense of human speech. "Hmm" Hmm is an exclamation (an emphatic interjection) typically used to express reflection, uncertainty, thoughtful absorption, or hesitation. Hmm is technically categorized as an interjection, like um, huh, ouch, erm, and wow. The first h-sound is a mimic for breathing out, and the second m-sound, since the mouth is closed, is representing that the person is not currently sure what to say ("erm" and "um" are used similarly). The pause filler indicates that the person is temporarily speechless, but still engaged in thought. The variety of tones, pitches, and lengths used add nuances in meaning. Etymology The expression is used in many different languages, however the origin of "hmm" is difficult to find, mainly because "the word is so natural that it may have arisen at any time," as highlighted by linguist at the University of Minnesota and an expert on word origins, Anatoly Liberman. It is possible Neanderthals might have used "hmm". Nicholas Christenfeld, a psychologist at the University of California, San Diego, and an expert on filled pauses, attests "hmm" is popular largely since its such a neutral sound and that "its easier to say than anything else". The earliest attestations of "hmm" are from Shakespeare, "I cried hum... But markt him not a word" (1598 Shakespeare Henry IV, Pt. 1 iii. i. 154). It may be a vocable that grew out of lexicalized throat-clearing. Use as a filler word "Hmm" is a "filler" word, such as "um" and "er". Use of "hmm" for "filled pauses" has been considered by many as stupidity and showing a lack of skill or competence, but many linguists attest this judgement is unjustified. Typically, "hmm" is uttered when the person is being especially conscious about whom they are talking with, and as a result are thinking deeply about what to say. Moreover, the use of "hmm" is often interactional and cognitive. The interactional function is to do with politeness: if someone is invited to a party and responded "no" without a filled pause, they might appear rude, but a reply of "Hmm, sorry, no" might appear much more polite, as it seems the speaker is giving the offer some thought, rather than abruptly declining. Thoughtful absorption The use of "hmm" is typically used during "thoughtful absorption", which is when one is engrossed in their flow of ideas and associations, that lead to a reality-oriented conclusion. The utterance of "hmm" is key for listeners to understand that the speaker is currently engaged in thought; if the speaker thought silently instead, listeners may be unsure if the speaker had finished their utterance. "Um" and "er" are also used during thoughtful absorption; however, typically the extent of the absorption of thought is more limited since "um" and "er" are usually spoken mid-sentence and for shorter periods of time than "hmm". For this reason, thoughtful absorption is typically associated with the utterance of "hmm". "Huh" – the universal syllable Research has shown that the word/syllable "huh" is perhaps the most recognized syllable throughout the world. It is an interrogative. This crosses geography, language, cultures and nationalities. See also References Further reading Clark, HH.; Fox Tree, JE. (May 2002). "Using uh and um in spontaneous speaking" (PDF). Cognition. 84 (1): 73–111. CiteSeerX 10.1.1.5.7958. doi:10.1016/S0010-0277(02)00017-3. PMID 12062148. S2CID 37642332. Archived from the original (PDF) on 2013-11-10. Corley, Martin; Stewart, Oliver W. (2008). "Hesitation Disfluencies in Spontaneous Speech: The Meaning of Um" (PDF). Language and Linguistics Compass. 2 (4): 589–602. doi:10.1111/j.1749-818X.2008.00068.x. hdl:20.500.11820/0e5f2f2f-7383-42c5-a7ba-63f2587ad877. ISSN 1749-818X. Daniel, Ari (5 Feb 2015). "Are we witnessing the death of uh? Um, maybe—and not just in English". Eklund, Robert (2004). Disfluency in Swedish human-human and human-machine travel booking dialogues (PDF) (Thesis). Linköping Studies in Science and Technology Dissertation No. 882 (Corrected ed.). Department of Computer and Information Science, Linköping University. ISBN 91-7373-966-9. ISSN 0345-7524. OCLC 940753621. Retrieved 11 August 2021. Erard, Michael (2008). Um...: Slips, Stumbles, and Verbal Blunders, and What They Mean. Anchor. ISBN 978-1-4000-9543-8. Erard, Michael (January 3, 2004). "Just Like, Er, Words, Not, Um, Throwaways". The New York Times. Retrieved November 10, 2013. Ing, John (September 26, 2019). "Pause Fillers for Speaking". Retrieved May 3, 2020. Schuessler, Jennifer (November 9, 2013). "The Syllable That Everyone Understands". The New York Times. Retrieved November 9, 2013.
Pica	Pica or PICA may refer to: Biology Pica (disorder), an abnormal appetite for earth and other non-foods Posterior inferior cerebellar artery, a major artery supplying blood to the cerebellum Organisms Aechmea Pica, a hybrid cultivar in the Bromeliad family of flowering plants Pica (genus), a genus of magpie Pika, a small mammal (archaic spelling "pica") Organizations OCLC PICA, a library automation company Palestine Jewish Colonization Association, known by its Yiddish acronym as PICA Pennsylvania Intergovernmental Cooperation Authority, a governmental agency in Philadelphia, Pennsylvania Perth Institute of Contemporary Arts, Western Australia Pica Press, a publishing imprint Pittsburgh Intergovernmental Cooperation Authority, a governmental agency in Pittsburgh, Pennsylvania Portland Institute for Contemporary Art, Oregon People Antonio Pica (1923–2014), Spanish actor Joe Pica (1923–1973), American pianist Pierre Pica (born 1951), French linguist Teresa P. Pica (1945–2011), American educator Tina Pica (1884–1968), Italian actress Yamantaka Eye (born 1964), Japanese artist known as DJ Pica Pica Pica (DJ 光光光) Places Pica, Chile, an oasis town in the Atacama Desert of Chile Limón de Pica, a lime variety from Pica Pica, Cumbria, a village in northwest England Pica, Jayuya, Puerto Rico, a barrio Technology Acer PICA, a system logic chipset introduced in 1993 Phenolic-impregnated carbon ablator, a spacecraft heat shield material Pre-integrated COF APM, part of the International Space Stations Columbus module systems Other uses Pica, an alternative name for the grape Merille Pica, a lance used by a picador in bullfighting Pica (typography), a unit of length used in typesetting and document layout píča, a rude expression for a vagina in the Czech Republic and Slovakia See also Pico (disambiguation) Piga (disambiguation) Pika (disambiguation)
Dejerine–Roussy syndrome	Dejerine–Roussy syndrome or thalamic pain syndrome is a condition developed after a thalamic stroke, a stroke causing damage to the thalamus. Ischemic strokes and hemorrhagic strokes can cause lesioning in the thalamus. As initial stroke symptoms (numbness and tingling) dissipate, an imbalance in sensation causes these later syndromes, characterizing Dejerine–Roussy syndrome. Although some treatments exist, they are often expensive, chemically based, invasive, and only treat patients for some time before they need more treatment, called "refractory treatment". Symptoms and signs Dejerine–Roussy syndrome is most commonly preceded by numbness in the affected side. In these cases, numbness is replaced by burning and tingling sensations, widely varying in degree of severity across all cases. The majority of those reported are cases in which the symptoms are severe and debilitating. Burning and tingling can also be accompanied by hypersensitivity, usually in the form of dysaesthesia or allodynia. Less commonly, some patients develop severe ongoing pain with little or no stimuli.Allodynia is pain from a stimulus that would normally not cause pain. For example, there is a patient who experiences unrelenting pain when a breeze touches his skin. Most patients experiencing allodynia, experience pain with touch and pressure, however some can be hypersensitive to temperature.Dysaesthesia is defined as an unpleasant, abnormal sense of touch. It often presents as pain. In this condition it is due to thalamic lesioning. This form of neuropathic pain can be any combination of itching, tingling, burning, or searing experienced spontaneously or from stimuli.Allodynia and dysaesthesia replace numbness between one week and a few months after a thalamic stroke. In general, once the development of pain has stopped, the type and severity of pain will be unchanging and if untreated, persist throughout life. Consequentially, many will undergo some form of pain treatment and adjust to their new lives as best they can.Pain associated with Dejerine–Roussy syndrome is sometimes coupled with anosognosia or somatoparaphrenia which causes a patient having undergone a right-parietal, or right-sided stroke to deny any paralysis of the left side when indeed there is, or deny the paralyzed limb(s) belong to them. Although debatable, these symptoms are rare and considered part of a "thalamic phenomenon", and are not normally considered a characteristic of Dejerine–Roussy syndrome. Mechanism Although there are many contributing factors and risks associated with strokes, there are very few associated with Dejerine–Roussy syndrome and thalamic lesions specifically. In general, strokes damage one hemisphere of the brain, which can include the thalamus. The thalamus is generally believed to relay sensory information between a variety of subcortical areas and the cerebral cortex. It is known that sensory information from environmental stimuli travels to the thalamus for processing and then to the somatosensory cortex for interpretation. The final product of this communication is the ability to see, hear or feel something as interpreted by the brain. Dejerine–Roussy syndrome most often compromises tactile sensation. Therefore, the damage in the thalamus causes miscommunication between the afferent pathway and the cortex of the brain, changing what or how one feels. The change could be an incorrect sensation experienced, or inappropriate amplification or dulling of a sensation. Because the brain is considered plastic and each individuals brain is different, it is almost impossible to know how a sensation will be changed without brain mapping and individual consultation.Recently, magnetic resonance imaging has been utilized to correlate lesion size and location with area affected and severity of condition. Although preliminary, these findings hold promise for an objective way to understand and treat patients with Dejerine–Roussy syndrome. Diagnosis Dejerine-Roussy is a rare pain syndrome. Individuals with emerging Dejerine–Roussy syndrome usually report they are experiencing unusual pain or sensitivity that can be allodynic in nature or triggered by seemingly unrelated stimuli (sounds, tastes). Symptoms are typically lateralized and may include vision loss or loss of balance (position sense). Workup should be performed by a neurologist and brain imaging to look for evidence of infarction or tumor should be obtained. Treatments Many chemical medications have been used for a broad range of neuropathic pain including Dejerine–Roussy syndrome. Symptoms are generally not treatable with ordinary analgesics. Traditional chemicals include opiates and anti-depressants. Newer pharmaceuticals include anti-convulsants and Kampo medicine. As there is no scientific basis in the analgesic efficacy of Kampo medicine beyond placebo, mainstream methods are preferred. Pain treatments are most commonly administered via oral medication or periodic injections. Topical In addition, physical therapy has traditionally been used alongside a medication regimen. More recently, electrical stimulation of the brain and spinal cord and caloric stimulation have been explored as treatments.The most common treatment plans involve a schedule of physical therapy with a medication regimen. Because the pain is mostly unchanging after development, many patients test different medications and eventually choose the regimen that best adapts to their lifestyle, the most common of which are orally and intravenously administered. Pharmaceutical treatment Opiates contain the narcotics morphine, codeine, and papaverine which provide pain relief. Opiates activate μ-opioid receptors in the brain which alter the brains perception of sensory input, alleviating pain and sometimes inducing pleasure for a short time period. When intravenously administered, opiates can relieve neuropathic pain but only for a time between 4 and 24 hours. After this time window, the pain returns and the patient must be treated again. Although this method of treatment has been proven to reduce pain, the repetitive use of opiates has also been linked to the activation of the brains reward system and therefore poses a threat of addiction. Heavy doses of opiates can also cause constipation, and respiratory depression. More common side effects include light-headedness, dizziness, sedation, itching, nausea, vomiting, and sweating. Anti-depressants are traditionally administered for treatment of mood disorders, also linked to the thalamus, and can be used to treat Dejerine–Roussy symptoms. Specifically, tricyclic anti-depressants such as amitriptyline and selective serotonin reuptake inhibitors have been used to treat this symptom and they are effective to some degree within a short time window. Anti-convulsants reduce neuronal hyperexcitability, effectively targeting Dejerine–Roussy syndrome. Gabapentin and pregabalin are the most common anti-convulsants. They have significant efficacy in treatment of peripheral and central neuropathic pain. Treatments last 4–12 hours and in general are well tolerated, and the occurrence of adverse events does not differ significantly across patients. Commonly reported side-effects are dizziness, decreased intellectual performance, somnolence, and nausea. Topical treatment such as lidocaine patches can be used to treat pain locally. The chemical is released to the skin to act as a numbing agent that feels cool, then feels warm, much like IcyHot. Stimulation treatments Electrode stimulation from surgically implanted electrodes has been studied in the past decade in hopes of a permanent pain treatment without refraction. Electric stimulation utilizing implants deliver specific voltages to a specific part of the brain for specific durations. More recently, research is being done in radiation therapy as long-term treatment of Dejerine–Roussy syndrome. In general, these studies have concluded initial efficacy in such implants, but pain often re-appears after a year or so. Long-term efficacy of stimulation treatments must be further tested and evaluated.Expensive and invasive, the above treatments are not guaranteed to work, and are not meeting the needs of patients. There is a need for a new, less expensive, less invasive form of treatment, two of which are postulated below. Spinal cord stimulation has been studied in the last couple of years. In a long case study, 8 patients were given spinal cord stimulation via insertion of a percutaneous lead at the appropriate level of the cervical or thoracic spine. Between 36 and 149 months after the stimulations, the patients were interviewed. 6 of the 8 had received initial pain relief, and three experienced long-term pain relief. Spinal cord stimulation is cheaper than brain stimulation and less invasive, and is thus a more promising option for pain treatment. Epidemiology 8% of all stroke patients will experience central pain syndrome, with 5% experiencing moderate to severe pain. The risk of developing Dejerine–Roussy syndrome is higher in older stroke patients, about 11% of stroke patients over the age of 80. History In 1906, Joseph Jules Dejerine and Gustave Roussy provided descriptions of central post-stroke pain (CPSP) in their paper entitled: "Le syndrome thalamique". The name Dejerine–Roussy syndrome was coined after their deaths. The syndrome included "…severe, persistent, paroxysmal, often intolerable, pains on the hemiplegic side, not yielding to any analgesic treatment".In 1911, it was found that the patients often developed pain and hypersensitivity to stimuli during recovery of function. And thus it was thought that the pain associated after stroke was part of the stroke and lesion repair process occurring in the brain. It is now accepted that Dejerine–Roussy syndrome is a condition developed due to lesions interfering with the sensory process, which triggered the start of pharmaceutical and stimulation treatment research. The last 50 years have been filled with refractory treatment research. As of the early 2000s, longer treatments lasting months to years have been explored in the continued search for permanent removal of abnormal pain. Eponym Dejerine–Roussy syndrome has also been referred to as: "Posterior Thalamic Syndrome", "Retrolenticular Syndrome", "Thalamic Hyperesthetic Anesthesia", "Thalamic Pain Syndrome", "Thalamic Syndrome", "Central Pain Syndrome", and "Central Post-Stroke Syndrome". This condition is not associated with Roussy–Lévy syndrome or Dejerine–Sottas disease, both of which are genetic disorders. See also Central pain syndrome References == External links ==
Hydropneumothorax	Hydropneumothorax is defined as the presence of both air and fluid within the pleural space. An upright chest x-ray will show air fluid levels. The horizontal fluid level is usually well defined and extends across the whole length of one of the hemithorax. Signs and symptoms This can be remembered by the 4 S: straight line dullness, shifting dullness, splash, sound of coin. Causes Iatrogenic: Introduction of air during pleural fluid aspiration in effusion Presence of a gas-forming organism Thoracic trauma Diagnosis Diagnosis can be via CXR. CT is better to outline borders of air fluid levels, however, CT has a greater radiation exposure. Treatment Treatment includes ICD (intercostal drainage) of fluid and air and treatment of underlying conditions. References == External links ==
Cryoglobulinemic vasculitis	Cryoglobulinemic vasculitis is a form of inflammation affecting the blood vessels caused by the deposition of abnormal proteins called cryoglobulins in the blood vessels, in patients affected by mixed cryoglobulinemia (type 2 and 3), since simple or type 1 cryoglobulinemia does not cause complement activation (but a hyperviscosity syndrome only). Cryoglobulinemic vasculitis affects the skin and causes a rash in roughly 15% of people with detectable circulating cryoglobulin proteins.: 835 Additionally, the kidneys may be affected by this form of vasculitis resulting in membranoproliferative glomerulonephritis. Fevers, painful muscles and joints, and peripheral nerve damage are other common manifestations of cryoglobulinemic vasculitis. Due to deposition of complement (in particular, C4), low levels of circulating complement factors may be seen. See also Cryoglobulinemia Cutaneous small-vessel vasculitis Skin lesion References == External links ==
Carbuncle	A carbuncle is a cluster of boils caused by bacterial infection, most commonly with Staphylococcus aureus or Streptococcus pyogenes. The presence of a carbuncle is a sign that the immune system is active and fighting the infection. The infection is contagious and may spread to other areas of the body, or other people; those living in the same residence may develop carbuncles at the same time. In the early 21st century, infection involving methicillin-resistant Staphylococcus aureus (MRSA) has become more common. Signs and symptoms A carbuncle is a cluster of several boils, which is typically filled with purulent exudate (dead neutrophils, phagocytized bacteria, and other cellular components). Fluid may drain freely from the carbuncle, or intervention involving an incision and drainage procedure may be needed. Carbuncles may develop anywhere, but they are most common on the back and the nape of the neck.A carbuncle is palpable and can range in size to be as small as a pea or as large as a golf ball. The surrounding area is indurated. Later, skin on the centre of the carbuncle softens and peripheral satellite vesicles appear, which rupture discharging pus and give rise to cribriform appearance. As the impending infection develops, itching may occur. There may be localized erythema, skin irritation, and the area may be painful when touched. Sometimes more severe symptoms may occur, such as fatigue, fever, chills, and general malaise as the body fights the infection. Cause The initial cause of a carbuncle can often not be determined. Triggers that make carbuncle infections more likely include recent incidence of folliculitis; friction from clothing or shaving; having hair pulled out, such as sites where clothing or furniture grab at hairs; generally poor hygiene; poor nutrition; or weakened immunity. Poor health may be a predisposing factor – for example, persons with diabetes and immune system diseases are more likely to develop infections (especially bacterial infections of the leg or foot). Society and culture Etymology The word is believed to have originated from the Latin: carbunculus, originally a small coal; diminutive of carbon-, carbo: charcoal or ember, but also a carbuncle stone, "precious stones of a red or fiery colour", usually garnets. Metaphor: the "monstrous carbuncle" In 1984 Charles III, then Prince of Wales, described the proposed Sainsbury Wing extension to the National Gallery in London as a "monstrous carbuncle on the face of a much-loved and elegant friend", a term he has used since to describe other pieces of architecture. == References ==
Pituitary adenoma	Pituitary adenomas are benign tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. Pituitary adenomas represent from 10% to 25% of all intracranial neoplasms and the estimated prevalence rate in the general population is approximately 17%.Non-invasive and non-secreting pituitary adenomas are considered to be benign in the literal as well as the clinical sense; however a recent meta-analysis (Fernández-Balsells, et al. 2011) of available research has shown there are to date scant studies – of poor quality – to either support or refute this assumption. Adenomas exceeding 10 mm (0.39 in) in size are defined as macroadenomas, with those smaller than 10 mm (0.39 in) referred to as microadenomas. Most pituitary adenomas are microadenomas and have an estimated prevalence of 16.7% (14.4% in autopsy studies and 22.5% in radiologic studies). A majority of pituitary microadenomas often remain undiagnosed, and those that are diagnosed are often found as an incidental finding and are referred to as incidentalomas. Pituitary macroadenomas are the most common cause of hypopituitarism.While pituitary adenomas are common, affecting approximately one in 6 of the general population, clinically active pituitary adenomas that require surgical treatment are more rare, affecting approximately one in 1,000 of the general population. Signs and symptoms Physical Hormone secreting pituitary adenomas cause one of several forms of hyperpituitarism. The specifics depend on the type of hormone. Some tumors secrete more than one hormone, the most common combination being GH and prolactin, which present as unexpected bone growth and unexpected lactation (in both men and women).A patient with pituitary adenoma may present with visual field defects, classically bitemporal hemianopsia. It arises from the compression of the optic nerve by the tumor. The specific area of the visual pathway at which compression by these tumours occurs is at the optic chiasma. The anatomy of this structure causes pressure on it to produce a defect in the temporal visual field on both sides, a condition called bitemporal hemianopsia. If originating superior to the optic chiasm, more commonly in a craniopharyngioma of the pituitary stalk, the visual field defect will first appear as bitemporal inferior quadrantanopia, if originating inferior to the optic chiasm the visual field defect will first appear as bitemporal superior quadrantanopia. Lateral expansion of a pituitary adenoma can also compress the abducens nerve, causing a lateral rectus palsy.Also, a pituitary adenoma can cause symptoms of increased intracranial pressure. Prolactinomas often start to give symptoms especially during pregnancy, when the increased hormone level estrogen can increase the tumors growth rate.Various types of headaches are common in patients with pituitary adenomas. The adenoma may be the prime causative factor behind the headache or may serve to exacerbate a headache caused by other factors. Amongst the types of headaches experienced are both chronic and episodic migraine, and more uncommonly various unilateral headaches; primary stabbing headache, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) - another type of stabbing headache characterized by short stabs of pain -, cluster headache, and hemicrania continua (HS).Compressive symptoms of pituitary adenomas (visual field deficits, decreased visual acuity, headaches) are more commonly seen with macroadenomas (which are greater than 10 mm in diameter) than with microadenomas (which are less than 10 mm in diameter).Non-secreting adenomas can go undetected for an extended time because no obvious abnormalities are seen; the gradual reduction in normal activities due to decreased production of hormones is rather less evident. For example, insufficient adrenocorticotropic hormone means that the adrenal glands will not produce sufficient cortisol, resulting in slow recovery from illness, inflammation, and chronic fatigue; insufficient growth hormone in children and adolescents leads to diminished stature but which can have many other explanations. Psychiatric Various psychiatric manifestations have been associated with pituitary disorders including pituitary adenomas. Psychiatric symptoms such as depression, anxiety apathy, emotional instability, easy irritability and hostility have been noted. Complications Acromegaly is a syndrome that results when the anterior pituitary gland produces excess growth hormone (GH). Approximately 90–95% of acromegaly cases are caused by a pituitary adenoma and it most commonly affects middle aged adults, Acromegly can result in severe disfigurement, serious complicating conditions, and premature death if unchecked. The disease which is often also associated with gigantism, is difficult to diagnose in the early stages and is frequently missed for many years, until changes in external features, especially of the face, become noticeable with the median time from the development of initial symptoms to diagnosis being twelve years. Cushings syndrome is a hormonal disorder that causes hypercortisolism, which is elevated levels of cortisol in the blood. Cushings disease (CD) is the most frequent cause of Cushings syndrome, responsible for approximately 70% of cases. CD results when a pituitary adenoma causes excessive secretion of adrenocorticotropic hormone (ACTH) that stimulates the adrenal glands to produce excessive amounts of cortisol.Cushings disease may cause fatigue, weight gain, fatty deposits around the abdomen and lower back (truncal obesity) and face ("moon face"), stretch marks (striae) on the skin of the abdomen, thighs, breasts, and arms, hypertension, glucose intolerance, and various infections. In women, it may cause excessive growth of facial hair (hirsutism) and in men erectile dysfunction. Psychiatric manifestations may include depression, anxiety, easy irritability, and emotional instability. It may also result in various cognitive difficulties.Hyperpituitarism is a disease of the anterior lobe of the pituitary gland which is usually caused by a functional pituitary adenoma and results in hypersecretion of adenohypophyseal hormones such as growth hormone; prolactin; thyrotropin; luteinizing hormone; follicle-stimulating hormone; and adrenocorticotropic hormone. Pituitary apoplexy is a condition that occurs when pituitary adenomas suddenly hemorrhage internally, causing a rapid increase in size or when the tumor outgrows its blood supply which causes tissue necrosis and subsequent swelling of the dead tissue. Pituitary apoplexy often presents with visual loss and sudden onset headache and requires timely treatment often with corticosteroids and if necessary surgical intervention. Central diabetes insipidus is caused by diminished production of the antidiuretic hormone vasopressin that causes severe thirst and excessive production of very dilute urine (polyuria) which can lead to dehydration. Vasopressin is produced in the hypothalamus and is then transported down the pituitary stalk and stored in the posterior lobe of the pituitary gland which then secretes it into the bloodstream.As the pituitary gland is in close proximity to the brain, invasive adenomas may invade the dura mater, cranial bone, or sphenoid bone. Risk factors Multiple endocrine neoplasia Adenomas of the anterior pituitary gland are a major clinical feature of multiple endocrine neoplasia type 1 (MEN1), a rare inherited endocrine syndrome that affects 1 person in every 30,000. MEN causes various combinations of benign or malignant tumors in various glands in the endocrine system or may cause the glands to become enlarged without forming tumors. It often affects the parathyroid glands, pancreatic islet cells, and anterior lobe of the pituitary gland. MEN1 may also cause non-endocrine tumors such as facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas. Approximately 25 percent of patients with MEN1 develop pituitary adenomas. Carney complex Carney complex (CNC), also known as LAMB syndrome and NAME syndrome is an autosomal dominant condition comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity and is distinct from Carneys triad. Approximately 7% of all cardiac myxomas are associated with Carney complex. Patients with CNC develop growth hormone (GH)-producing pituitary tumors and in some instances these same tumors also secrete prolactin. There are however no isolated prolactinomas or any other type of pituitary tumor. In some patients with CNC, the pituitary gland is characterized by hyperplastic areas with the hyperplasia most likely preceding the formation of GH-producing adenomas. Familial isolated pituitary adenoma Familial isolated pituitary adenoma (FIPA) is a term that is used to identify a condition that displays an autosomal dominant inheritance and is characterised by the presence of two or more related patients affected by adenomas of the pituitary gland only, with no other associated symptoms that occur in multiple endocrine neoplasia type 1 (MEN-1), Carney complex and with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. FIPA was first described in a limited cohort of families by Albert Beckers group in Liège, Belgium; later FIPA was fully characterized in a multicenter international study of 64 families. FIPA families are divided into those that are homogenous and have the same type of pituitary adenoma in all the affected family members (e.g. only acromegaly, only prolactinoma, etc.), while heterogeneous FIPA families can have different pituitary adenomas in affected family members. Genetics of FIPA FIPA has two known genetic causes, mutations in the AH receptor-interacting protein (AIP) gene and duplications in chromosome Xq26.3 that include the GPR101 gene that also causes X-linked acrogigantism (X-LAG) syndrome. About 15-20% of FIPA families carry a germline AIP gene mutation or deletion, and the disease occurs as autosomal dominant with incomplete penetrance, meaning that about 20% of AIP mutation carriers will develop a pituitary adenoma. AIP mutation associated pituitary adenomas (either presenting as FIPA or as individual, non familial cases) are usually growth hormone-secreting (acromegaly) or prolactin-secreting (prolactinoma) adenomas that are large (macroadenomas) and often occur in children, adolescents and young adults. Daly and colleagues showed that acromegaly cases with AIP mutations occurred about 20 years before acromegaly cases without AIP mutations and these tumors are large and relatively treatment-resistant. Due to their young age at onset, AIP mutations are the most frequent genetic cause of pituitary gigantism (29% of cases).X-LAG is a rare syndrome of very early childhood onset pituitary tumors/hyperplasia that leads to growth hormone excess and severe overgrowth and pituitary gigantism. Three FIPA families with X-LAG have been reported to date all of which had transmission of a chromosome Xq26.3 duplication from affected mother to affected son. The disease characteristics of very young onset pituitary gigantism leads to severe overgrowth if not treated adequately; many of the tallest humans in history (e.g. Robert Pershing Wadlow; Sandy Allen, André Rousimoff (Andre the Giant), Zeng Jinlian) had a similar clinical history to patients with X-LAG syndrome. The tallest historical individual with a known genetic cause was Julius Koch (Geant Constantin) who was found to have X-LAG on genetic study of his skeleton. X-LAG has 100% penetrance so far (all affected with the Xq26.3 duplication have the disease and it affects predominantly females. Isolated non familial cases of X-LAG can either have a constitutional duplication of a chromosome Xq26.3 including GPR101, or mosaicism for the duplication (present in a minority of cells) in the case of isolated male patients. X-LAG causes about 10% of cases of pituitary gigantism. Mechanism The pituitary gland or hypophysis is often referred to as the "master gland" of the human body. Part of the hypothalamic-pituitary axis, it controls most of the bodys endocrine functions via the secretion of various hormones into the circulatory system. The pituitary gland is located below the brain in a depression (fossa) of the sphenoid bone known as the sella turcica. Although anatomically and functionally connected to the brain, the pituitary gland sits outside the blood–brain barrier. It is separated from the subarachnoid space by the diaphragma sella, therefore the arachnoid mater and thus cerebral spinal fluid cannot enter the sella turcica.The pituitary gland is divided into two lobes, the anterior lobe (which accounts for two thirds of the volume of the gland), and the posterior lobe (one third of the volume) separated by the pars intermedia.The posterior lobe (the neural lobe or neurohypophysis) of the pituitary gland is not, despite its name, a true gland. The posterior lobe contains axons of neurons that extend from the hypothalamus to which it is connected via the pituitary stalk. The hormones vasopressin and oxytocin, produced by the neurons of the supraoptic and paraventricular nuclei of the hypothalamus, are stored in the posterior lobe and released from axon endings (dendrites) within the lobe.The pituitary glands anterior lobe (adenohypophysis) is a true gland which produces and secretes six different hormones: thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and prolactin (PRL). Diagnosis Diagnosis of pituitary adenoma can be made, or at least suspected, by a constellation of related symptoms presented above.The differential diagnosis includes pituitary tuberculoma, especially in developing countries and in immumocompromised patients. The diagnosis is confirmed by testing hormone levels, and by radiographic imaging of the pituitary (for example, by CT scan or MRI). Classification Unlike tumors of the posterior Pituitary, Pituitary adenomas are classified as endocrine tumors (not brain tumors). Pituitary adenomas are classified based upon anatomical, histological and functional criteria. Anatomically pituitary tumors are classified by their size based on radiological findings; either microadenomas (less than <10 mm) or macroadenomas (equal or greater than ≥10 mm).Classification based on radioanatomical findings places adenomas into 1 of 4 grades (I–IV):Stage I: microadenomas (<1 cm) without sella expansion.Stage II: macroadenomas (≥1 cm) and may extend above the sella.Stage III: macroadenomas with enlargement and invasion of the floor or suprasellar extension.Stage IV: destruction of the sella.Histological classification utilizes an immunohistological characterization of the tumors in terms of their hormone production. Historically they were classed as either basophilic, acidophilic, or chromophobic on the basis of whether or not they took up the tinctorial stains hematoxylin and eosin. This classification has fallen into disuse, in favor of a classification based on what type of hormone is secreted by the tumor. Approximately 20–25% of adenomas do not secrete any readily identifiable active hormones (non-functioning tumors) yet they are still sometimes referred to as chromophobic. Functional classification is based upon the tumors endocrine activity as determined by serum hormone levels and pituitary tissue cellular hormone secretion detected via immunohistochemical staining. The "Percentage of hormone production cases" values are the fractions of adenomas producing each related hormone of each tumor type as compared to all cases of pituitary tumors, and does not directly correlate to the percentages of each tumor type because of smaller or greater incidences of absence of secretion of the expected hormone. Thus, non secretive adenomas may be either null cell adenomas or a more specific adenoma that, however, remains non-secretive. Any type of pituitary adenocarcinoma listed in the table below may cause compressive symptoms due to local expansion in addition to the systemic effects of secreted hormones listed in the pathology column. Null cell adenomas by definition do not secrete hormones, but they commonly cause compressive effects on the pituitary stalk (stalk effect). This leads to decreased levels of dopamine from the hypothalamus reaching the anterior pituitary gland. Dopamine exerts an inhibitory effect on prolactin secretion. With the absence of this inhibitory effect, prolactin levels increase and are often increased in null cell adenomas. This leads to symptoms of hypogonadism. Pituitary incidentalomas Pituitary incidentalomas are pituitary tumors that are characterized as an incidental finding. They are often discovered by computed tomography (CT) or magnetic resonance imaging (MRI), performed in the evaluation of unrelated medical conditions such as suspected head trauma, in cancer staging or in the evaluation of nonspecific symptoms such as dizziness and headache. It is not uncommon for them to be discovered at autopsy. In a meta-analysis, adenomas were found in an average of 16.7% in postmortem studies, with most being microadenomas (<10mm); macrodenomas accounted for only 0.16% to 0.2% of the decedents. While non-secreting, noninvasive pituitary microadenomas are generally considered to be literally as well as clinically benign, there are to date scant studies of low quality to support this assertion.It has been recommended in the current Clinical Practice Guidelines (2011) by the Endocrine Society - a professional, international medical organization in the field of endocrinology and metabolism – that all patients with pituitary incidentalomas undergo a complete medical history and physical examination, laboratory evaluations to screen for hormone hypersecretion and for hypopituitarism. If the lesion is in close proximity to the optic nerves or optic chiasm, a visual field examination should be performed. For those with incidentalomas which do not require surgical removal, follow up clinical assessments and neuroimaging should be performed as well follow-up visual field examinations for incidentalomas that abut or compress the optic nerve and chiasm and follow-up endocrine testing for macroincidentalomas. Ectopic pituitary adenoma An ectopic (occurring in an abnormal place) pituitary adenoma is a rare type of tumor which occurs outside of the sella turcica, most often in the sphenoid sinus, suprasellar region, nasopharynx and the cavernous sinuses. Metastases to the pituitary gland Carcinomas that metastasize into the pituitary gland are uncommon and typically seen in the elderly, with lung and breast cancers being the most prevalent, In breast cancer patients, metastases to the pituitary gland occur in approximately 6-8% of cases.Symptomatic pituitary metastases account for only 7% of reported cases. In those who are symptomatic Diabetes insipidus often occurs with rates approximately 29–71%. Other commonly reported symptoms include anterior pituitary dysfunction, visual field defects, headache/pain, and ophthalmoplegia. Treatment Treatment options depend on the type of tumor and on its size: Prolactinomas are most often treated with cabergoline or bromocriptine (both dopamine agonists), which decrease tumor size as well as alleviates symptoms, followed by serial imaging to detect any increase in size. Treatment, where the tumor is large, can be with radiation therapy, proton therapy or surgery, and patients generally respond well. Unlike prolactinomas, thyrotrophic adenomas characteristically respond poorly to dopamine agonist treatment. Somatotrophic adenomas respond to octreotide or lanreotide, which are long-acting somatostatin analogs. These somatostatin receptor analogs inhibit secretion of growth hormone. They were found to be about 50–55% effective in reducing tumor mass and reducing growth hormone and insulin like growth factor 1 (IGF-1) levels in studies. The growth hormone receptor antagonist pegvisomant is also used in the treatment of somatotrophic adenomas. Pegvisomant blocks the action of growth hormone. It can either be used as monotherapy or combined with a somatostatin analog. Surgery is a common treatment for pituitary tumors. The normal approach is trans-sphenoidal adenectomy, which usually can remove the tumor without affecting the brain or optic nerves. Radiation is also used to treat pituitary adenomas. Examples include external beam or proton beam radiation therapy or stereotactic radiosurgery. External radiation of pituitary adenomas can arrest tumor growth for several years but pituitary failure develops within 10 years in most patients necessitating lifelong hormone replacement. Radiation therapy for pituitary adenomas is associated with a 4 fold increase in mortality due to cerebrovascular disease. See also Pituitary disease References External links Cancer.gov: pituitary tumors
Persistent vegetative state	A persistent vegetative state (PVS) or post-coma unresponsiveness (PCU) is a disorder of consciousness in which patients with severe brain damage are in a state of partial arousal rather than true awareness. After four weeks in a vegetative state (VS), the patient is classified as being in a persistent vegetative state. This diagnosis is classified as a permanent vegetative state some months (three in the US and six in the UK) after a non-traumatic brain injury or one year after a traumatic injury. The term unresponsive wakefulness syndrome may be alternatively used, as "vegetative state" has some negative connotations among the public. Definition There are several definitions that vary by technical versus laymans usage. There are different legal implications in different countries. Medical definition Per the British Royal College of Physicians of London, a persistent vegetative state is "a wakeful unconscious state that lasts longer than a few weeks is referred to as a persistent (or continuing) vegetative state". "Vegetative state" The vegetative state is a chronic or long-term condition. This condition differs from a coma: a coma is a state that lacks both awareness and wakefulness. Patients in a vegetative state may have awoken from a coma, but still have not regained awareness. In the vegetative state patients can open their eyelids occasionally and demonstrate sleep-wake cycles, but completely lack cognitive function. The vegetative state is also called a "coma vigil". The chances of regaining awareness diminish considerably as the time spent in the vegetative state increases. "Persistent vegetative state" Persistent vegetative state is the standard usage (except in the UK) for a medical diagnosis, made after numerous neurological and other tests, that due to extensive and irreversible brain damage a patient is highly unlikely ever to achieve higher functions above a vegetative state. This diagnosis does not mean that a doctor has diagnosed improvement as impossible, but does open the possibility, in the US, for a judicial request to end life support. Informal guidelines hold that this diagnosis can be made after four weeks in a vegetative state. US caselaw has shown that successful petitions for termination have been made after a diagnosis of a persistent vegetative state, although in some cases, such as that of Terri Schiavo, such rulings have generated widespread controversy. In the UK, the term is discouraged in favor of two more precisely defined terms that have been strongly recommended by the Royal College of Physicians (RCP). These guidelines recommend using a continuous vegetative state for patients in a vegetative state for more than four weeks. A medical determination of a permanent vegetative state can be made if, after exhaustive testing and a customary 12 months of observation, a medical diagnosis is made that it is impossible by any informed medical expectations that the mental condition will ever improve. Hence, a "continuous vegetative state" in the UK may remain the diagnosis in cases that would be called "persistent" in the US or elsewhere. While the actual testing criteria for a diagnosis of "permanent" in the UK are quite similar to the criteria for a diagnosis of "persistent" in the US, the semantic difference imparts in the UK a legal presumption that is commonly used in court applications for ending life support. The UK diagnosis is generally only made after 12 months of observing a static vegetative state. A diagnosis of a persistent vegetative state in the US usually still requires a petitioner to prove in court that recovery is impossible by informed medical opinion, while in the UK the "permanent" diagnosis already gives the petitioner this presumption and may make the legal process less time-consuming.In common usage, the "permanent" and "persistent" definitions are sometimes conflated and used interchangeably. However, the acronym "PVS" is intended to define a "persistent vegetative state", without necessarily the connotations of permanence, and is used as such throughout this article. Bryan Jennett, who originally coined the term "persistent vegetative state", has now recommended using the UK division between continuous and permanent in his book The Vegetative State, arguing that "the persistent component of this term ... may seem to suggest irreversibility".The Australian National Health and Medical Research Council has suggested "post coma unresponsiveness" as an alternative term for "vegetative state" in general. Lack of legal clarity Unlike brain death, permanent vegetative state (PVS) is recognized by statute law as death in only a very few legal systems. In the US, courts have required petitions before termination of life support that demonstrate that any recovery of cognitive functions above a vegetative state is assessed as impossible by authoritative medical opinion. In England, Wales and Scotland, the legal precedent for withdrawal of clinically assisted nutrition and hydration in cases of patients in a PVS was set in 1993 in the case of Tony Bland, who sustained catastrophic anoxic brain injury in the 1989 Hillsborough disaster. An application to the Court of Protection is no longer required before nutrition and hydration can be withdrawn or withheld from PVS (or minimally conscious – MCS) patients.This legal grey area has led to vocal advocates that those in PVS should be allowed to die. Others are equally determined that, if recovery is at all possible, care should continue. The existence of a small number of diagnosed PVS cases that have eventually resulted in improvement makes defining recovery as "impossible" particularly difficult in a legal sense. This legal and ethical issue raises questions about autonomy, quality of life, appropriate use of resources, the wishes of family members, and professional responsibilities. Signs and symptoms Most PVS patients are unresponsive to external stimuli and their conditions are associated with different levels of consciousness. Some level of consciousness means a person can still respond, in varying degrees, to stimulation. A person in a coma, however, cannot. In addition, PVS patients often open their eyes in response to feeding, which has to be done by others; they are capable of swallowing, whereas patients in a coma subsist with their eyes closed.Cerebral cortical function (e.g. communication, thinking, purposeful movement, etc.) is lost while brainstem functions (e.g. breathing, maintaining circulation and hemodynamic stability, etc.) are preserved. Non-cognitive upper brainstem functions such as eye-opening, occasional vocalizations (e.g. crying, laughing), maintaining normal sleep patterns, and spontaneous non-purposeful movements often remain intact. PVS patients eyes might be in a relatively fixed position, or track moving objects, or move in a disconjugate (i.e., completely unsynchronized) manner. They may experience sleep-wake cycles, or be in a state of chronic wakefulness. They may exhibit some behaviors that can be construed as arising from partial consciousness, such as grinding their teeth, swallowing, smiling, shedding tears, grunting, moaning, or screaming without any apparent external stimulus. Individuals in PVS are seldom on any life-sustaining equipment other than a feeding tube because the brainstem, the center of vegetative functions (such as heart rate and rhythm, respiration, and gastrointestinal activity) is relatively intact. Recovery Many people emerge spontaneously from a vegetative state within a few weeks. The chances of recovery depend on the extent of injury to the brain and the patients age – younger patients having a better chance of recovery than older patients. A 1994 report found that of those who were in a vegetative state a month after a trauma, 54% had regained consciousness by a year after the trauma, whereas 28% had died and 18% were still in the vegetative state. For non-traumatic injuries such as strokes, only 14% had recovered consciousness at one year, 47% had died, and 39% were still vegetative. Patients who were vegetative six months after the initial event were much less likely to have recovered consciousness a year after the event than in the case of those who were simply reported vegetative at one month. A New Scientist article from 2000 gives a pair of graphs showing changes of patient status during the first 12 months after head injury and after incidents depriving the brain of oxygen. After a year, the chances that a PVS patient will regain consciousness are very low and most patients who do recover consciousness experience significant disability. The longer a patient is in a PVS, the more severe the resulting disabilities are likely to be. Rehabilitation can contribute to recovery, but many patients never progress to the point of being able to take care of themselves. The medical literature also includes case reports of the recovery of a small number of patients following the removal of assisted respiration with cold oxygen. The researchers found that in many nursing homes and hospitals unheated oxygen is given to non-responsive patients via tracheal intubation. This bypasses the warming of the upper respiratory tract and causes a chilling of aortic blood and chilling of the brain which the authors believe may contribute to the persons nonresponsive state. The researchers describe a small number of cases in which removal of the chilled oxygen was followed by recovery from the PVS and recommend either warming of oxygen with a heated nebulizer or removal of the assisted oxygen if it is no longer needed. The authors further recommend additional research to determine if this chilling effect may either delay recovery or even may contribute to brain damage. There are two dimensions of recovery from a persistent vegetative state: recovery of consciousness and recovery of function. Recovery of consciousness can be verified by reliable evidence of awareness of self and the environment, consistent voluntary behavioral responses to visual and auditory stimuli, and interaction with others. Recovery of function is characterized by communication, the ability to learn and to perform adaptive tasks, mobility, self-care, and participation in recreational or vocational activities. Recovery of consciousness may occur without functional recovery, but functional recovery cannot occur without recovery of consciousness. Causes There are three main causes of PVS (persistent vegetative state): Acute traumatic brain injury Non-traumatic: neurodegenerative disorder or metabolic disorder of the brain Severe congenital abnormality of the central nervous systemPotential causes of PVS are: Bacterial, viral, or fungal infection, including meningitis Increased intracranial pressure, such as a tumor or abscess Vascular pressure which causes intracranial hemorrhaging or stroke Hypoxic ischemic injury (hypotension, cardiac arrest, arrhythmia, near-drowning) Toxins such as uremia, ethanol, atropine, opiates, lead, dimethylmercury, endrin, parathion, and colloidal silver Physical trauma: Concussion, contusion, etc. Seizure, both nonconvulsive status epilepticus and postconvulsive state (postictal state) Electrolyte imbalance, which involves hyponatremia, hypernatremia, hypomagnesemia, hypoglycemia, hyperglycemia, hypercalcemia, and hypocalcemia Postinfectious: Acute disseminated encephalomyelitis (ADEM) Endocrine disorders such as adrenal insufficiency and thyroid disorders Degenerative and metabolic diseases including urea cycle disorders, Reye syndrome, and mitochondrial disease Systemic infection and sepsis Hepatic encephalopathyIn addition, these authors claim that doctors sometimes use the mnemonic device AEIOU-TIPS to recall portions of the differential diagnosis: Alcohol ingestion and acidosis, Epilepsy and encephalopathy, Infection, Opiates, Uremia, Trauma, Insulin overdose or inflammatory disorders, Poisoning and psychogenic causes, and Shock. Diagnosis Despite converging agreement about the definition of persistent vegetative state, recent reports have raised concerns about the accuracy of diagnosis in some patients, and the extent to which, in a selection of cases, residual cognitive functions may remain undetected and patients are diagnosed as being in a persistent vegetative state. Objective assessment of residual cognitive function can be extremely difficult as motor responses may be minimal, inconsistent, and difficult to document in many patients, or may be undetectable in others because no cognitive output is possible. In recent years, a number of studies have demonstrated an important role for functional neuroimaging in the identification of residual cognitive function in persistent vegetative state; this technology is providing new insights into cerebral activity in patients with severe brain damage. Such studies, when successful, may be particularly useful where there is concern about the accuracy of the diagnosis and the possibility that residual cognitive function has remained undetected. Diagnostic experiments Researchers have begun to use functional neuroimaging studies to study implicit cognitive processing in patients with a clinical diagnosis of persistent vegetative state. Activations in response to sensory stimuli with positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and electrophysiological methods can provide information on the presence, degree, and location of any residual brain function. However, use of these techniques in people with severe brain damage is methodologically, clinically, and theoretically complex and needs careful quantitative analysis and interpretation. For example, PET studies have shown the identification of residual cognitive function in persistent vegetative state. That is, an external stimulation, such as a painful stimulus, still activates "primary" sensory cortices in these patients but these areas are functionally disconnected from "higher order" associative areas needed for awareness. These results show that parts of the cortex are indeed still functioning in "vegetative" patients.In addition, other PET studies have revealed preserved and consistent responses in predicted regions of auditory cortex in response to intelligible speech stimuli. Moreover, a preliminary fMRI examination revealed partially intact responses to semantically ambiguous stimuli, which are known to tap higher aspects of speech comprehension.Furthermore, several studies have used PET to assess the central processing of noxious somatosensory stimuli in patients in PVS. Noxious somatosensory stimulation activated midbrain, contralateral thalamus, and primary somatosensory cortex in each and every PVS patient, even in the absence of detectable cortical evoked potentials. In conclusion, somatosensory stimulation of PVS patients, at intensities that elicited pain in controls, resulted in increased neuronal activity in primary somatosensory cortex, even if resting brain metabolism was severely impaired. However, this activation of primary cortex seems to be isolated and dissociated from higher-order associative cortices.Also, there is evidence of partially functional cerebral regions in catastrophically injured brains. To study five patients in PVS with different behavioral features, researchers employed PET, MRI and magnetoencephalographic (MEG) responses to sensory stimulation. In three of the five patients, co-registered PET/MRI correlate areas of relatively preserved brain metabolism with isolated fragments of behavior. Two patients had had anoxic injuries and demonstrated marked decreases in overall cerebral metabolism to 30–40% of normal. Two other patients with non-anoxic, multifocal brain injuries demonstrated several isolated brain regions with higher metabolic rates, that ranged up to 50–80% of normal. Nevertheless, their global metabolic rates remained <50% of normal. MEG recordings from three PVS patients provide clear evidence for the absence, abnormality or reduction of evoked responses. Despite major abnormalities, however, these data also provide evidence for localized residual activity at the cortical level. Each patient partially preserved restricted sensory representations, as evidenced by slow evoked magnetic fields and gamma band activity. In two patients, these activations correlate with isolated behavioral patterns and metabolic activity. Remaining active regions identified in the three PVS patients with behavioral fragments appear to consist of segregated corticothalamic networks that retain connectivity and partial functional integrity. A single patient who sustained severe injury to the tegmental mesencephalon and paramedian thalamus showed widely preserved cortical metabolism, and a global average metabolic rate of 65% of normal. The relatively high preservation of cortical metabolism in this patient defines the first functional correlate of clinical–pathological reports associating permanent unconsciousness with structural damage to these regions. The specific patterns of preserved metabolic activity identified in these patients reflect novel evidence of the modular nature of individual functional networks that underlie conscious brain function. The variations in cerebral metabolism in chronic PVS patients indicate that some cerebral regions can retain partial function in catastrophically injured brains. Misdiagnoses Statistical PVS misdiagnosis is common. An example study with 40 patients in the United Kingdom reported 43% of their patients classified as PVS were believed so and another 33% had recovered whilst the study was underway. Some PVS cases may actually be a misdiagnosis of patients being in an undiagnosed minimally conscious state. Since the exact diagnostic criteria of the minimally conscious state were only formulated in 2002, there may be chronic patients diagnosed as PVS before the secondary notion of the minimally conscious state became known. Whether or not there is any conscious awareness with a patients vegetative state is a prominent issue. Three completely different aspects of this should be distinguished. First, some patients can be conscious simply because they are misdiagnosed (see above). In fact, they are not in vegetative states. Second, sometimes a patient was correctly diagnosed but is then examined during the early stages of recovery. Third, perhaps some day the notion itself of vegetative states will change so to include elements of conscious awareness. Inability to disentangle these three example cases causes confusion. An example of such confusion is the response to an experiment using functional magnetic resonance imaging which revealed that a woman diagnosed with PVS was able to activate predictable portions of her brain in response to the testers requests that she imagine herself playing tennis or moving from room to room in her house. The brain activity in response to these instructions was indistinguishable from those of healthy patients.In 2010, Martin Monti and fellow researchers, working at the MRC Cognition and Brain Sciences Unit at the University of Cambridge, reported in an article in the New England Journal of Medicine that some patients in persistent vegetative states responded to verbal instructions by displaying different patterns of brain activity on fMRI scans. Five out of a total of 54 diagnosed patients were apparently able to respond when instructed to think about one of two different physical activities. One of these five was also able to "answer" yes or no questions, again by imagining one of these two activities. It is unclear, however, whether the fact that portions of the patients brains light up on fMRI could help these patients assume their own medical decision making.In November 2011, a publication in The Lancet presented bedside EEG apparatus and indicated that its signal could be used to detect awareness in three of 16 patients diagnosed in the vegetative state. Treatment Currently no treatment for vegetative state exists that would satisfy the efficacy criteria of evidence-based medicine. Several methods have been proposed which can roughly be subdivided into four categories: pharmacological methods, surgery, physical therapy, and various stimulation techniques. Pharmacological therapy mainly uses activating substances such as tricyclic antidepressants or methylphenidate. Mixed results have been reported using dopaminergic drugs such as amantadine and bromocriptine and stimulants such as dextroamphetamine. Surgical methods such as deep brain stimulation are used less frequently due to the invasiveness of the procedures. Stimulation techniques include sensory stimulation, sensory regulation, music and musicokinetic therapy, social-tactile interaction, and cortical stimulation. Zolpidem There is limited evidence that the hypnotic drug zolpidem has an effect. The results of the few scientific studies that have been published so far on the effectiveness of zolpidem have been contradictory. Epidemiology In the United States, it is estimated that there may be between 15,000 and 40,000 patients who are in a persistent vegetative state, but due to poor nursing home records exact figures are hard to determine. History The syndrome was first described in 1940 by Ernst Kretschmer who called it apallic syndrome. The term persistent vegetative state was coined in 1972 by Scottish spinal surgeon Bryan Jennett and American neurologist Fred Plum to describe a syndrome that seemed to have been made possible by medicines increased capacities to keep patients bodies alive. Society and culture Ethics and policy An ongoing debate exists as to how much care, if any, patients in a persistent vegetative state should receive in health systems plagued by limited resources. In a case before the New Jersey Superior Court, Betancourt v. Trinitas Hospital, a community hospital sought a ruling that dialysis and CPR for such a patient constitutes futile care. An American bioethicist, Jacob M. Appel, argued that any money spent treating PVS patients would be better spent on other patients with a higher likelihood of recovery. The patient died naturally prior to a decision in the case, resulting in the court finding the issue moot. In 2010, British and Belgian researchers reported in an article in the New England Journal of Medicine that some patients in persistent vegetative states actually had enough consciousness to "answer" yes or no questions on fMRI scans. However, it is unclear whether the fact that portions of the patients brains light up on fMRI will help these patient assume their own medical decision making. Professor Geraint Rees, Director of the Institute of Cognitive Neuroscience at University College London, responded to the study by observing that, "As a clinician, it would be important to satisfy oneself that the individual that you are communicating with is competent to make those decisions. At the moment it is premature to conclude that the individual able to answer 5 out of 6 yes/no questions is fully conscious like you or I." In contrast, Jacob M. Appel of the Mount Sinai Hospital told the Telegraph that this development could be a welcome step toward clarifying the wishes of such patients. Appel stated: "I see no reason why, if we are truly convinced such patients are communicating, society should not honour their wishes. In fact, as a physician, I think a compelling case can be made that doctors have an ethical obligation to assist such patients by removing treatment. I suspect that, if such individuals are indeed trapped in their bodies, they may be living in great torment and will request to have their care terminated or even active euthanasia." Notable cases Tony Bland – first patient in English legal history to be allowed to die Paul Brophy – first American to die after court-authorization Sunny von Bülow – lived almost 28 years in a persistent vegetative state until her death Gustavo Cerati – Argentine singer-songwriter, composer and producer who died after four years in a coma Prichard Colón – Puerto Rican former professional boxer and gold medal winner who spent years in a vegetative state after a bout Nancy Cruzan – American woman involved in a landmark United States Supreme Court case Gary Dockery – American police officer who entered, emerged and later reentered a persistent vegetative state Eluana Englaro – Italian woman from Lecco whose life was ended after a legal case after spending 17 years in a vegetative state Elaine Esposito – American woman who was a previous record holder for having spent 37 years in a coma Lia Lee – Hmong person who spent 26 years in a vegetative state and was the subject of a 1997 book by Anne Fadiman Martin Pistorius South African man who is a rare example of a survivor as his state progressed to minimally conscious after 3 years, locked in syndrome after another 4 more years, and fully came out of a coma after another 5 years. He is now a web designer, developer, and author. In 2011, he wrote a book called Ghost Boy, in which he describes his many years of being comatose. Annie Shapiro Canadian woman who is also another rare example of a survivor as it is known she couldnt think for her first 2 years of her 29 years total of being comatose. In 1992 she awakened fully recovered and lived her last 10 years peacefully. She is the longest a person has been in a coma and woken up apart from the catatonic stupor patients in Awakenings. Haleigh Poutre Karen Ann Quinlan Terri Schiavo Rita Greene Aruna Shanbaug – Indian woman in persistent vegetative state for 42 years until her death. Owing to her case, the Supreme Court of India allowed passive euthanasia in the country. Ariel Sharon Chayito Valdez Vice Vukov Helga Wanglie Otto Warmbier See also Anencephaly Brain death Botulism Catatonia Karolina Olsson Locked-in syndrome Process Oriented Coma Work, for an approach to working with residual consciousness in patients in comatose and persistent vegetative states References This article contains text from the NINDS public domain pages on TBI. [1] Archived 2005-10-19 at the Wayback Machine and [2]. == Further reading ==
Roths spot	Roths spots, also known as Litten spots or the Litten sign, are non-specific red spots with white or pale centres, seen on the retina and although traditionally associated with infective endocarditis, can occur in a number of other conditions including hypertension, diabetes, collagen vascular disease, extreme hypoxia, leukemia and HIV.Red and white retinal spots were first observed in 1872 by Swiss physician Moritz Roth, and named "Roth spots" six years later by Moritz Litten. They are typically observed via fundoscopy (using an ophthalmoscope to view inside the eye) or slit lamp exam.The original retinal spots identified in 1872 were attributed to nerve-fibres that had burst. Present-day analysis shows that they can be composed of coagulated fibrin including platelets, focal ischaemia, inflammatory infiltrate, infectious organisms, or neoplastic cells. Cause Roths spots occur in conditions that predispose to endothelial damage of retinal capillaries, that is when there is dysfunction and disruption of the endothelium of retinal capillaries. Looking through the microscope reveals lesions with white centers made mainly of fibrin, depicting a fibrin-platelet plug at the site of vessel damage. Associated conditions Conditions associated with Roths spots include: Infective endocarditis Anaemia/thrombocytopenia Collagen vascular disease Leukemia Hypertensive retinopathy Diabetic retinopathy Pre-eclampsia Human Immunodeficiency Virus (HIV) Extreme hypoxia Shaken-baby syndromeand also: Candida albicans infection vascular diseases kala azar Prevalence Roths spots occur in only 5% of people with infective endocarditis. Litten, however reported a figure of 80%. See also Oslers nodes Janeway lesion Splinter haemorrhage References External links Image from the New England Journal of Medicine: Endocarditis Image from the New England Journal of Medicine: CML
Hormone receptor positive breast tumor	A hormone-receptor-positive (HR+) tumor is a tumor which consists of cells that express receptors for certain hormones. The term most commonly refers to estrogen receptor positive tumors (i.e. tumors that contain estrogen receptor positive cells), but can also include progesterone receptor positive tumors. Estrogen-receptor-positive tumors depend on the presence of estrogen for ongoing proliferation. Classification ER-positive is one of the Receptor statuses identified in the classification of breast cancer. Receptor status was traditionally considered by reviewing each individual receptor (ER, PR, her2) in turn, but newer approaches look at these together, along with the tumor grade, to categorize breast cancer into several conceptual molecular classes that have different prognoses and may have different responses to specific therapies. DNA microarrays have assisted this approach. Diagnosis Treatment Endocrine treatment may be beneficial for patients with hormone receptor positive breast tumors.There are two ways for treating these kind of tumors: Lowering systemic levels of estrogen, achieved by the use of drugs from the aromatase inhibitor category. These drugs target one of the enzymes that takes part in the biosynthesis of estrogen. Blockage of the estrogen receptors on the cancerous cells, thus preventing estrogen binding, leading to decreased proliferation. Drugs in this category are also referred to as SERMs (Selective estrogen receptor modulator) since they are able to block estrogen receptors in a selective manner. See also Tamoxifen Raloxifene Triple-negative breast cancer References Further reading http://www.breastcancer.org/treatment/hormonal/what_is_it/hormone_role.jsp
Gunther disease	Gunther disease is a congenital form of erythropoietic porphyria. The word porphyria originated from the Greek word porphura. Porphura actually means "purple pigment", which, in suggestion, the color that the body fluid changes when a person has Gunthers disease. It is a rare, autosomal recessive metabolic disorder affecting heme, caused by deficiency of the enzyme uroporphyrinogen cosynthetase. It is extremely rare, with a prevalence estimated at 1 in 1,000,000 or less. There have been times that prior to birth of a fetus, Gunthers disease has been shown to lead to anemia. In milder cases patients have not presented any symptoms until they have reached adulthood. In Gunthers disease, porphyrins are accumulated in the teeth and bones and an increased amount are seen in the plasma, bone marrow, feces, red blood cells, and urine. Symptoms and signs Though expressivity is varied depending on the mutation responsible for decrease in enzyme function, severe cutaneous sensitivity is present in most cases of this Porphyria. An estimated 30–40% of cases are due to the C73R mutation, which decreases stability of the enzyme and results in <1% of its activity. Exposure to long-wave ultraviolet light causes the affected skin to thicken and produce vesicles that are prone to rupture and infection; these secondary infections, along with bone resorption, can lead to disfigurement of the sun-exposed face and extremities. Enzyme dysfunction prevents the normal production of heme and hemolytic anemia is another common symptom, though a lack of hemolysis in this disease is possible. Porphyrins additionally accumulate in the bone and teeth, resulting in erythrodontia. When unexpected attacks occur, abdominal pain, as well as vomiting and constipation commonly follow the attacks. Exposure to the sunlight can cause discomfort and result in blistering, consciousness of heat, and swelling and redness of the skin. Complications Photomutilation and transfusion-dependent anemia are common complications. Liver disease is also observed in some cases. It has been reported that early childhood-onset haematological manifestations is a poor prognosis factor. Causes Gunther disease is caused by mutations in the gene that encodes the enzyme uroporphyrinogen III synthase (UROS), located at human chromosome 10q25.2-q26.3. The disorder is inherited in an autosomal recessive manner. This means the defective gene is responsible for the disorder and is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. When there is a homozygous mutation it causes a uroporphyrinogen III synthase and uroporphyrinogen cosynthase defect. When the enzyme uroporphyrinogen III synthase is reacting normally it results in the making of isomer III porphyrinogen, which is what is used to form heme. When isomer III porphyrinogen is not produced because of a poor production of uroporphyrinogen III synthase then isomer I porphyrinogen is made which will oxidize and give a reddish tint skin. Diagnosis When diagnosing Congenital Erythroipoetic Porphyria (Gunther Disease) one must exclude other forms of porphyria. These include Hepatoerythropoietic Porphyria and rare homozygous variants of Variegate Porphyria, Hereditary Coproporphyria, and STING-associated vasculopathy with onset in Infancy (SAVI). Mild variants may be present similarly to Porphyria Cutanea Tarda.There are four steps in establishing the diagnosis of any porphyria. First, a thorough history (particularly family history) and physical exam are performed with special attention paid to sun-exposed skin. Biochemical measurements of porphyrins and precursors in the urine, feces, and blood are necessary. Specialized labs are helpful in measuring activity of specific enzymes of the heme synthesis pathway and/or DNA and mutational analyses. In CEP, activity of uroporphyrinogen III synthase (the fourth enzyme in the heme biosynthetic pathway) will be markedly decreased.In congenital erythropoietic porphyria, urine aminolavulanic acid and porphobilinogen are typically normal. However, uroporphyrin and coproporphyrin tend to be markedly elevated and moderately elevated, respectively, in the urine more than in the feces. Additionally, fecal protoporphyrin is typically mildly elevated.In the red blood cells, uroporphyrin, coproporphyrin and protoporphyrin are all elevated, distinguishing this form of porphyria from the others. Finally, plasma analysis will demonstrate elevated uroporphyrin and coproporphyrin.Other nonspecific but helpful diagnostic clues are history of cutaneous photosensitivity, blistering, erosions, crusts and ulcerations leading to extensive scarring and deformation of the hands, loss of eyebrows, eyelashes with severe mutilation of cartilaginous structures like the nose, erythrodontia, and variable degree of hematologic involvement ranging from mild hemolytic anemia to intrauterine hydrops fetalis. Other early clues are red or violet staining of diapers. Treatment There are a multiple ways to treat Gunthers diseases, but one of the most crucial things that a person with this disease can do is limit themselves from sun exposure or eliminate sun exposure altogether. There are some sunscreens that have undesirable effects such as tropical sunscreens, but other sunscreens containing zinc oxide and titanium dioxide are shown to provide protection due to those light-reflective agents. To block the ultraviolet and visible light wavelengths and get the protection that patients with Gunthers disease require, physical barriers are needed. It is also advised that patients wear protective clothing to block the sun from their skin. Plastic films can be attached to car windows and homes to filter out some of the wavelengths that could cause harm to someones skin with this disease. Incandescent bulbs replace the normal fluorescent lamps. These bulbs release less light, which prevents the "porphyrin-exciting" wavelengths that fluorescent lights emit.Other less beneficial treatments have been used to help treat Gunthers disease. These include oral beta-carotene and other treatments such as activated charcoal and cholestyramine, which are used to interrupt and stop the porphyrins from being reabsorbed in the body. The reason that these oral treatments are unreasonable is because they require an extremely large dose of medicine and therefore are not beneficial.Erythrocyte transfusions have been shown to be a successful measure in decreasing the appearance of the disease by trying to lower the erythropoiesis and circulating porphyrin levels. Unfortunately, having chronic erythrocyte transfusions, it can be extremely harmful to the body and can cause severe complications.To help with dry eye symptoms and visual function, topical lubrication can be used. A more invasive way to help treat Gunthers disease would be to have surgery. There have been numerous studies that have stated that bone marrow transplantation is successful. This is a recently new development for Gunthers disease so the long-term effects are still unresourced. If a patient has a life-threatening infectious complication then bone marrow transplantation is no longer relevant for them. There are also reports that stem cell transplantation is successful in a limited number of participants Eponym The disorder is named after the German physician who discovered it, Hans Günther (1884-1956). See also Porphyria cutanea tarda List of cutaneous conditions List of dental abnormalities associated with cutaneous conditions References External links Porphyria, congenital erythropoietic at NIHs Office of Rare Diseases
Nocardiosis	Nocardiosis is an infectious disease affecting either the lungs (pulmonary nocardiosis) or the whole body (systemic nocardiosis). It is due to infection by a bacterium of the genus Nocardia, most commonly Nocardia asteroides or Nocardia brasiliensis. It is most common in adult males, especially those with a weakened immune system. In patients with brain nocardia infection, mortality exceeds 80%; in other forms, mortality is 50%, even with appropriate therapy.It is one of several conditions that have been called "the great imitator". Cutaneous nocardiosis commonly occurs in immunocompetent hosts and is caused in 80% of cases by Nocardia brasiliensis. Signs and symptoms Pulmonary infection Produces a virulent form of pneumonia (progressive) Night sweats, fever, cough, chest pain Pulmonary nocardiosis is subacute in onset and refractory to treatment with standard antibiotics Symptoms are more severe in immunocompromised individuals Radiologic studies show multiple pulmonary infiltrates, with a tendency to central necrosisNeurological infection Headache, lethargy, confusion, seizures, sudden onset of neurological deficit CT scan shows cerebral abscess Nocardial meningitis is difficult to diagnoseCardiac conditions Nocardia has been highly linked to endocarditis as a main manifestation In recorded cases, it has caused damage to heart valves whether natural or prostheticLymphocutaneous disease Nocardial cellulitis is akin to erysipelas but is less acute Nodular lymphangeitis mimics sporotrichosis with multiple nodules alongside a lymphatic pathway Chronic subcutaneous infection is a rare complication and osteitis may ensue May be misidentified and treated as a staph infection, specifically superficial skin infections Cultures must incubate more than 48 hours to guarantee an accurate testOcular disease Very rarely, nocardiae cause keratitis Generally there is a history of ocular traumaDisseminated nocardiosis Dissemination occurs through the spreading enzymes possessed by the bacteria Disseminated infection can occur in very immunocompromised patients It generally involves both lungs and brain Fever, moderate or very high can be seen Multiple cavitating pulmonary infiltrates develop Cerebral abscesses arise later Cutaneous lesions are very rarely seen If untreated, the prognosis is poor for this form of disease Causes Normally found in soil, these organisms cause occasional sporadic disease in humans and animals throughout the world. Another well publicized find is that of Nocardia as part of the oral microflora. Nocardia spp. have been reported in the normal gingivae and periodontal pockets along with other species such as Actinomyces, Arthromyces and Streptomyces spp.The usual mode of transmission is inhalation of organisms suspended in dust. Another very common method is by traumatic introduction, especially in the jaw. This leads to the entrance of Nocardia into the blood stream and the propagation of its pathogenic effects. Transmission by direct inoculation through puncture wounds or abrasions is less common. Generally, nocardial infection requires some degree of immune suppression.A weakened immune system is a general indicator of a person who is more susceptible to nocardiosis, such as someone who already has a disease that weakens their immune system. Additionally, those with low T-cell counts or other complications involving T-cells can expect to have a higher chance of becoming infected. Besides those with weak immune systems, a local traumatic inoculation can cause nocardiosis, specifically the cutaneous, lymphocutaneous, and subcutaneous forms of the disease. There is no racial pattern in the risk of becoming infected with Nocardiosis. Diagnosis Diagnosis of nocardiosis can be made by a doctor using various techniques. These techniques include, but are not limited to: a chest x-ray to analyze the lungs, a bronchoscopy, a brain/lung/skin biopsy, or a sputum culture. However, diagnosis may be difficult. Nocardiae are gram positive, weakly acid-fast, branching rod-shaped bacteria and can be visualized by a modified Ziehl–Neelsen stain such as the Fite-Faraco method. In the clinical laboratory, routine cultures may be held for insufficient time to grow nocardiae, and referral to a reference laboratory may be needed for species identification. Pulmonary infiltration and pleural effusion are usually detected via x-ray. Treatment Nocardiosis requires at least 6 months of treatment, preferably with trimethoprim/sulfamethoxazole or high doses of sulfonamides. In patients who do not respond to sulfonamide treatment, other drugs, such as ampicillin, erythromycin, or minocycline, may be added.Treatment also includes surgical drainage of abscesses and excision of necrotic tissue. The acute phase requires complete bed rest; as the patient improves, activity can increase.A new combination drug therapy (sulfonamide, ceftriaxone, and amikacin) has also shown promise. Prognosis The prognosis of nocardiosis is highly variable. The state of the hosts health, site, duration, and severity of the infection all play parts in determining the prognosis. Currently, skin and soft tissue infections have a 100% cure rate, and pleuropulmonary infections have a 90% cure rate with appropriate therapy. The cure rate falls to 63% with those infected with disseminated nocardiosis, with only half of patients surviving infections that cause brain abscess. Additionally, 44% of people who are infected in the central nervous system (CNS) die, increasing to 85% if that person has an already weakened immune system. There are no preventative treatments for nocardiosis. The only recommendation is to protect open wounds to limit entrance of the bacterium. Epidemiology Although there are no international data available on worldwide infection rates per year, there are roughly 500–1000 documented cases of nocardiosis per year in the US. Most of these cases occur in men, as there is a 3:1 ratio of male of female cases annually; however, this difference may be due to exposure frequency rather than susceptibility differences. From an age perspective, it is not highly more prevalent in one age group than another. Cutaneous nocardiosis is slightly more common in middle aged men, but as a whole, all age groups are susceptible. There is no racial pattern in the risk of becoming infected with nocardiosis. References External links Webmd article on Nocardiosis
Limb body wall complex	Limb body wall complex (LBWC) is a rare fetal malformation of unknown origins. Traditionally diagnosis has been based on the Van Allen et al., criteria, i.e. the presence of two out of three of the following anomalies: Exencephaly or encephalocele with facial clefts Thoraco and or abdominoschisis and Limb defects.LBWC occurs in approximately 0.32 in 100,000 births.At this time, there is no known cause of Limb Body Wall Complex. However, there have been tentative links made between a diagnosis of LBWC and cocaine use. In addition, current research has shown that there may be a genetic cause for a small limited number of LBWC cases.Limb Body Wall Complex is a lethal birth defect. There are only anecdotal stories of survivors. == References ==
Tremor	A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the hands. In some people, a tremor is a symptom of another neurological disorder. A very common tremor is the teeth chattering, usually induced by cold temperatures or by fear. Types Tremor is most commonly classified by clinical features and cause or origin. Some of the better-known forms of tremor, with their symptoms, include the following: Cerebellar tremor (also known as intention tremor) is a slow, broad tremor of the extremities that occurs at the end of a purposeful movement, such as trying to press a button or touching a finger to the tip of ones nose. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from stroke, tumor, or disease such as multiple sclerosis or some inherited degenerative disorder. It can also result from chronic alcoholism or overuse of some medicines. In classic cerebellar tremor, a lesion on one side of the brain produces a tremor in that same side of the body that worsens with directed movement. Cerebellar damage can also produce a "wing-beating" type of tremor called rubral or Holmes tremor — a combination of rest, action, and postural tremors. The tremor is often most prominent when the affected person is active or is maintaining a particular posture. Cerebellar tremor may be accompanied by other manifestations of ataxia, including dysarthria (speech problems), nystagmus (rapid, involuntary rolling of the eyes), gait problems and postural tremor of the trunk and neck. Titubation is tremor of the head and is of cerebellar origin. Dystonic tremor occurs in individuals of all ages who are affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body and is seen most often when the patient is in a certain position or moves a certain way. The pattern of dystonic tremor may differ from essential tremor. Dystonic tremors occur irregularly and can often be relieved by complete rest. Touching the affected body part or muscle may reduce tremor severity (a geste antagoniste). The tremor may be the initial sign of dystonia localized to a particular part of the body. The dystonic tremor has usually a frequency of about 7 Hz. Essential tremor (sometimes inaccurately called benign essential tremor) is the most common of the more than 20 types of tremor. Although the tremor may be mild and nonprogressive in some people, in others, the tremor is slowly progressive, starting on one side of the body but affecting both sides within 3 years. The hands are most often affected but the head, voice, tongue, legs, and trunk may also be involved. Head tremor may be seen as a vertical or horizontal motion. Essential tremor may be accompanied by mild gait disturbance. Tremor frequency may decrease as the person ages, but the severity may increase, affecting the persons ability to perform certain tasks or activities of daily living. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors or increase their severity. Onset is most common after age 40, although symptoms can appear at any age. It may occur in more than one family member. Children of a parent who has essential tremor have a 50 percent chance of inheriting the condition. Essential tremor is not associated with any known pathology. Its frequency is between 4 and 8 Hz. Orthostatic tremor is characterized by fast (>12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing up. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. No other clinical signs or symptoms are present and the shaking ceases when the patient sits or is lifted off the ground. The high frequency of the tremor often makes the tremor look like rippling of leg muscles while standing. Orthostatic tremor may also occur in patients who have essential tremor, and there might be an overlap between these categories of tremor. Parkinsonian tremor is caused by damage to structures within the brain that control movement. This resting tremor, which can occur as an isolated symptom or be seen in other disorders, is often a precursor to Parkinsons disease (more than 25 percent of patients with Parkinsons disease have an associated action tremor). The tremor, which is classically seen as a "pill-rolling" action of the hands that may also affect the chin, lips, legs, and trunk, can be markedly increased by stress or emotion. Onset is generally after age 60. Movement starts in one limb or on one side of the body and usually progresses to include the other side. The tremors frequency is between 4 and 6 Hz. Physiological tremor occurs in every normal individual and has no clinical significance. It is rarely visible and may be heightened by strong emotion (such as anxiety or fear), physical exhaustion, hypoglycemia, hyperthyroidism, heavy metal poisoning, stimulants, alcohol withdrawal or fever. It can be seen in all voluntary muscle groups and can be detected by extending the arms and placing a piece of paper on top of the hands. Enhanced physiological tremor is a strengthening of physiological tremor to more visible levels. It is generally not caused by a neurological disease but by reaction to certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. It is usually reversible once the cause is corrected. This tremor classically has a frequency of about 10 Hz. Psychogenic tremor (also called hysterical tremor and functional tremor) can occur at rest or during postural or kinetic movement. The characteristics of this kind of tremor may vary but generally include sudden onset and remission, increased incidence with stress, change in tremor direction or body part affected, and greatly decreased or disappearing tremor activity when the patient is distracted. Many patients with psychogenic tremor have a conversion disorder (see Posttraumatic stress disorder) or another psychiatric disease. Rubral tremor is characterized by coarse slow tremor which is present at rest, at posture and with intention. This tremor is associated with conditions which affect the red nucleus in the midbrain, classically unusual strokes. Neuropathic tremor may occur in patients with peripheral neuropathies, when the nerves that supply the bodys muscles are traumatized by injury, disease, abnormality in the central nervous system, or as the result of systemic illnesses. It is most commonly observed in patients with an immunoglobulin M paraproteinaemic neuropathy (IgMNP), but also in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The tremor is predominantely exhibited as an action or postural tremor with a frequency of 3 to 10 Hz. Peripheral neuropathy can affect the whole body or certain areas, such as the hands, and may be progressive. Resulting sensory loss may be seen as a tremor or ataxia (inability to coordinate voluntary muscle movement) of the affected limbs and problems with gait and balance. Clinical characteristics may be similar to those seen in patients with essential tremor.Tremor can result from other conditions as well Alcoholism, excessive alcohol consumption, or alcohol withdrawal can kill certain nerve cells, resulting in a tremor known as asterixis. Conversely, small amounts of alcohol may help to decrease familial and essential tremor, but the mechanism behind it is unknown. Alcohol potentiates GABAergic transmission and might act at the level of the inferior olive. Tobacco withdrawal symptoms include tremor. Most of the symptoms can also occur randomly when panicked. Causes Tremor can be a symptom associated with disorders in those parts of the brain that control muscles throughout the body or in particular areas, such as the hands. Neurological disorders or conditions that can produce tremor include multiple sclerosis, stroke, traumatic brain injury, chronic kidney disease and a number of neurodegenerative diseases that damage or destroy parts of the brainstem or the cerebellum, Parkinsons disease being the one most often associated with tremor. Lesions of the Guillain-Mollaret triangle (also called myoclonic triangle or dentato-rubro-olivary pathway) impair the predictions performed by the cerebellum, causing repetitive muscle discharges by triggering oscillatory activity in the central nervous system. Other causes include the use of drugs (such as amphetamines, cocaine, caffeine, corticosteroids, SSRIs) or alcohol, mercury poisoning, or the withdrawal of drugs such as alcohol or benzodiazepine. Tremors can also be seen in infants with phenylketonuria (PKU), overactive thyroid or liver failure. Tremors can be an indication of hypoglycemia, along with palpitations, sweating and anxiety. Tremor can also be caused by lack of sleep, lack of vitamins, or increased stress. Deficiencies of magnesium and thiamine have also been known to cause tremor or shaking, which resolves when the deficiency is corrected. Tremors in animals can also be caused by some spider bites, e.g. the redback spider of Australia. Diagnosis During a physical exam, a doctor can determine whether the tremor occurs primarily during action or at rest. The doctor will also check for tremor symmetry, any sensory loss, weakness or muscle atrophy, or decreased reflexes. A detailed family history may indicate if the tremor is inherited. Blood or urine tests can detect thyroid malfunction, other metabolic causes, and abnormal levels of certain chemicals that can cause tremor. These tests may also help to identify contributing causes, such as drug interaction, chronic alcoholism, or another condition or disease. Diagnostic imaging using CT or MRI imaging may help determine if the tremor is the result of a structural defect or degeneration of the brain.The doctor will perform a neurological examination to assess nerve function and motor and sensory skills. The tests are designed to determine any functional limitations, such as difficulty with handwriting or the ability to hold a utensil or cup. The patient may be asked to place a finger on the tip of her or his nose, draw a spiral, or perform other tasks or exercises.The doctor may order an electromyogram to diagnose muscle or nerve problems. This test measures involuntary muscle activity and muscle response to nerve stimulation. The selection of the sensors used is important. In addition to studies of muscle activity, tremor can be assessed with accuracy using accelerometers . Categories The degree of tremor should be assessed in four positions. The tremor can then be classified by which position most accentuates the tremor: Treatment There is no cure for most tremors. The appropriate treatment depends on accurate diagnosis of the cause. Some tremors respond to treatment of the underlying condition. For example, in some cases of psychogenic tremor, treating the patients underlying psychological problem may cause the tremor to disappear. A few medications can help relieve symptoms temporarily. Medications Medications remain the basis of therapy in many cases. Symptomatic drug therapy is available for several forms of tremor: Parkinsonian tremor drug treatment involves L-DOPA or dopamine-like drugs such as pergolide, bromocriptine and ropinirole; They can be dangerous, however, as they may cause symptoms such as tardive dyskinesia, akathisia, clonus, and in rare instances tardive (late developing) psychosis. Other drugs used to lessen parkinsonian tremor include amantadine and anticholinergic drugs like benztropine Essential tremor may be treated with beta blockers (such as propranolol and nadolol) or primidone, an anticonvulsant Cerebellar tremor symptoms may decrease with the application of alcohol (ethanol) or benzodiazepine medications, both of which carry some risk of dependence or addiction Rubral tremor patients may receive some relief using L-DOPA or anticholinergic drugs. Surgery may be helpful Dystonic tremor may respond to diazepam, anticholinergic drugs, and intramuscular injections of botulinum toxin. Botulinum toxin is also prescribed to treat voice and head tremors and several movement disorders Primary orthostatic tremor sometimes is treated with a combination of diazepam and primidone. Gabapentin provides relief in some cases Enhanced physiological tremor is usually reversible once the cause is corrected. If symptomatic treatment is needed, beta blockers can be used Lifestyle Eliminating tremor "triggers" such as caffeine and other stimulants from the diet is often recommended. Essential tremor may benefit from slight doses of ethanol, but the potential negative consequences of regular ethanol intake need to be taken into account. Beta blockers have been used as an alternative to alcohol in sports such as competitive dart playing and carry less potential for addiction.Physical therapy and occupational therapy may help to reduce tremor and improve coordination and muscle control for some patients. A physical therapist or occupational therapist will evaluate the patient for tremor positioning, muscle control, muscle strength, and functional skills. Teaching the patient to brace the affected limb during the tremor or to hold an affected arm close to the body is sometimes useful in gaining motion control. Coordination and balancing exercises may help some patients. Some occupational therapists recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating. Surgery Surgical intervention such as thalamotomy and deep brain stimulation may ease certain tremors. These surgeries are usually performed only when the tremor is severe and does not respond to drugs. Response can be excellent.Thalamotomy, involving the creation of lesions in the brain region called the thalamus, is quite effective in treating patients with essential, cerebellar, or Parkinsonian tremor. This in-hospital procedure is performed under local anesthesia, with the patient awake. After the patients head is secured in a metal frame, the surgeon maps the patients brain to locate the thalamus. A small hole is drilled through the skull and a temperature-controlled electrode is inserted into the thalamus. A low-frequency current is passed through the electrode to activate the tremor and to confirm proper placement. Once the site has been confirmed, the electrode is heated to create a temporary lesion. Testing is done to examine speech, language, coordination, and tremor activation, if any. If no problems occur, the probe is again heated to create a 3-mm permanent lesion. The probe, when cooled to body temperature, is withdrawn and the skull hole is covered. The lesion causes the tremor to permanently disappear without disrupting sensory or motor control. Deep brain stimulation (DBS) uses implantable electrodes to send high-frequency electrical signals to the thalamus. The electrodes are implanted as described above. The patient uses a hand-held magnet to turn on and turn off a pulse generator that is surgically implanted under the skin. The electrical stimulation temporarily disables the tremor and can be "reversed", if necessary, by turning off the implanted electrode. Batteries in the generator last about 5 years and can be replaced surgically. DBS is currently used to treat parkinsonian tremor and essential tremor. It is also applied successfully for other rare causes of tremor. The most common side effects of tremor surgery include dysarthria (problems with motor control of speech), temporary or permanent cognitive impairment (including visual and learning difficulties), and problems with balance. Biomechanical loading As well as medication, rehabilitation programmes and surgical interventions, the application of biomechanical loading on tremor movement has been shown to be a technique that is able to suppress the effects of tremor on the human body. It has been established in the literature that most of the different types of tremor respond to biomechanical loading. In particular, it has been clinically tested that the increase of damping or inertia in the upper limb leads to a reduction of the tremorous motion. Biomechanical loading relies on an external device that either passively or actively acts mechanically in parallel to the upper limb to counteract tremor movement. This phenomenon gives rise to the possibility of an orthotic management of tremor.Starting from this principle, the development of upper-limb non-invasive ambulatory robotic exoskeletons is presented as a promising solution for patients who cannot benefit from medication to suppress the tremor. In this area robotic exoskeletons have emerged, in the form of orthoses, to provide motor assistance and functional compensation to disabled people. An orthosis is a wearable device that acts in parallel to the affected limb. In the case of tremor management, the orthosis must apply a damping or inertial load to a selected set of limb articulations.Recently, some studies demonstrated that exoskeletons could achieve a consistent 40% of tremor power reduction for all users, being able to attain a reduction ratio in the order of 80% tremor power in specific joints of users with severe tremor. In addition, the users reported that the exoskeleton did not affect their voluntary motion. These results indicate the feasibility of tremor suppression through biomechanical loading. The main drawbacks of this mechanical management of tremor are (1) the resulting bulky solutions, (2) the inefficiency in transmitting loads from the exoskeleton to the human musculo-skeletal system and (3) technological limitations in terms of actuator technologies. In this regard, current trends in this field are focused on the evaluation of the concept of biomechanical loading of tremor through selective Functional Electrical Stimulation (FES) based on a (Brain-to-Computer Interaction) BCI-driven detection of involuntary (tremor) motor activity. See also Cerebral Palsy Fasciculation ("at rest" muscle twitches; usually benign). Fibrillation Restless Leg Syndrome Shivering Chronic solvent-induced encephalopathy Neurology References External links "NINDS Tremor Information Page". National Institute of Neurological Disorders and Stroke. July 20, 2007. Archived from the original on October 6, 2007. Retrieved 2007-10-08. Some text copied with permission and thanks. Sigvardt, Karen A.; Wheelock, Vicki L.; Kuznetsov, Alexey S.; Rubchinsky, Leonid L. (4 October 2007). "Leonid L. Rubchinsky et al. (2007) Tremor". Scholarpedia. 2 (10): 1379. doi:10.4249/scholarpedia.1379. orthostatictremor.org
Zellweger syndrome	Zellweger syndrome is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called Zellweger spectrum disorders which are leukodystrophies. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician, a professor of pediatrics and genetics at the University of Iowa who researched this disorder. Signs and symptoms Zellweger syndrome is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). The other two disorders are neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). Although all have a similar molecular basis for disease, Zellweger syndrome is the most severe of these three disorders.Zellweger syndrome is associated with impaired neuronal migration, neuronal positioning, and brain development. In addition, individuals with Zellweger syndrome can show a reduction in central nervous system (CNS) myelin (particularly cerebral), which is referred to as hypomyelination. Myelin is critical for normal CNS functions, and in this regard, serves to insulate nerve fibers in the brain. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision.Zellweger syndrome can also affect the function of many other organ systems. Patients can show craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel), hepatomegaly (enlarged liver), chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body), eye abnormalities, and renal cysts. Newborns may present with profound hypotonia (low muscle tone), seizures, apnea, and an inability to eat. Cause Zellweger syndrome is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for the normal assembly of peroxisomes. Most commonly, patients have mutations in the PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, or PEX26 genes. In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these aforementioned PEX genes.As a result of impaired peroxisome function, an individuals tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems, as discussed above. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain and lung function. Diagnosis In addition to genetic tests involving the sequencing of PEX genes, biochemical tests have proven highly effective for the diagnosis of Zellweger syndrome and other peroxisomal disorders. Typically, Zellweger syndrome patients show elevated very long chain fatty acids in their blood plasma. Cultured primarily skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired very long chain fatty acid beta-oxidation, phytanic acid alpha-oxidation, pristanic acid alpha-oxidation, and plasmalogen biosynthesis. Treatment The malabsorption resulting from lack of bile acid has resulted in elemental formula being suggested, which are low in fat with < 3% of calories derived from long chain triglycerides (LCT). However, reduced very long chain fatty acids (VLCFA) has not been shown to reduce blood VLCFA levels, likely because humans can endogenously produce most VLCFA. Plasma VLCFA levels are decreased when dietary VLCFA is reduced in conjunction with supplementation of Lorenzos oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) in X-ALD patients. Since docosahexaenoic acid (DHA) synthesis is impaired [59], DHA supplementation was recommended, but a placebo-controlled study has since showed no clinical efficacy. Due to the defective bile acid synthesis, fat soluble supplements of vitamins A, D, E, and K are recommended. Prognosis Currently, no cure for Zellweger syndrome is known, nor is there a standard course of treatment. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive. Patients usually do not survive beyond one year of age. References External links Zellweger-Syndrome at NINDS Zellweger syndrome at NIHs Office of Rare Diseases
Carnitine-acylcarnitine translocase deficiency	Carnitine-acylcarnitine translocase deficiency is a rare, autosomal recessive metabolic disorder that prevents the body from converting long-chain fatty acids into energy, particularly during periods without food. Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. People with this disorder have a faulty enzyme that prevents long-chain fatty acids from being transported into the innermost part of the mitochondria for processing. Presentation The signs of carnitine-acylcarnitine translocase deficiency usually begin within the first few hours of life. Seizures, an irregular heartbeat, and breathing problems are often the first signs of this disorder. This disorder may also cause extremely low levels of ketones (products of fat breakdown that are used for energy) and low blood sugar (hypoglycemia). Together, these two signs are called hypoketotic hypoglycemia. Other signs that are often present include ammonia in the blood (hyperammonemia), an enlarged liver (hepatomegaly), heart abnormalities (cardiomyopathy), and muscle weakness. This disorder can cause sudden infant death. Pathophysiology Mutations in the SLC25A20 gene lead to the production of a defective version of an enzyme called carnitine-acylcarnitine translocase. Without this enzyme, long-chain fatty acids from food and fats stored in the body cannot be broken down and processed. As a result, these fatty acids are not converted into energy, which can lead to characteristic signs and symptoms of this disorder, such as weakness, hypoglycemia, and an irregular heartbeat. Free long-chain fatty acids or those that are joined with carnitine can affect the electrical properties of cardiac cells causing an irregular heart beat (arrhythmia, which can lead to cardiac arrest). Fatty acids may also build up in tissues and can damage the heart, liver, and muscles, and cause more serious complications.This condition has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene - one from each parent - must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder. Diagnosis Treatment See also Primary carnitine deficiency Carnitine palmitoyltransferase I deficiency Carnitine palmitoyltransferase II deficiency References This article incorporates public domain text from The U.S. National Library of Medicine == External links ==
Hearing loss	Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken language, and in adults it can create difficulties with social interaction and at work. Hearing loss can be temporary or permanent. Hearing loss related to age usually affects both ears and is due to cochlear hair cell loss. In some people, particularly older people, hearing loss can result in loneliness. Deaf people usually have little to no hearing.Hearing loss may be caused by a number of factors, including: genetics, ageing, exposure to noise, some infections, birth complications, trauma to the ear, and certain medications or toxins. A common condition that results in hearing loss is chronic ear infections. Certain infections during pregnancy, such as cytomegalovirus, syphilis and rubella, may also cause hearing loss in the child. Hearing loss is diagnosed when hearing testing finds that a person is unable to hear 25 decibels in at least one ear. Testing for poor hearing is recommended for all newborns. Hearing loss can be categorized as mild (25 to 40 dB), moderate (41 to 55 dB), moderate-severe (56 to 70 dB), severe (71 to 90 dB), or profound (greater than 90 dB). There are three main types of hearing loss: conductive hearing loss, sensorineural hearing loss, and mixed hearing loss.About half of hearing loss globally is preventable through public health measures. Such practices include immunization, proper care around pregnancy, avoiding loud noise, and avoiding certain medications. The World Health Organization recommends that young people limit exposure to loud sounds and the use of personal audio players to an hour a day in an effort to limit exposure to noise. Early identification and support are particularly important in children. For many, hearing aids, sign language, cochlear implants and subtitles are useful. Lip reading is another useful skill some develop. Access to hearing aids, however, is limited in many areas of the world.As of 2013 hearing loss affects about 1.1 billion people to some degree. It causes disability in about 466 million people (5% of the global population), and moderate to severe disability in 124 million people. Of those with moderate to severe disability 108 million live in low and middle income countries. Of those with hearing loss, it began during childhood for 65 million. Those who use sign language and are members of Deaf culture may see themselves as having a difference rather than a disability. Many members of Deaf culture oppose attempts to cure deafness and some within this community view cochlear implants with concern as they have the potential to eliminate their culture. The terms hearing impairment or hearing loss are often viewed negatively as emphasizing what people cannot do, although the terms are still regularly used when referring to deafness in medical contexts. Definition Hearing loss is defined as diminished acuity to sounds which would otherwise be heard normally. The terms hearing impaired or hard of hearing are usually reserved for people who have relative inability to hear sound in the speech frequencies. The severity of hearing loss is categorized according to the increase in intensity of sound above the usual level required for the listener to detect it. Deafness is defined as a degree of loss such that a person is unable to understand speech, even in the presence of amplification. In profound deafness, even the highest intensity sounds produced by an audiometer (an instrument used to measure hearing by producing pure tone sounds through a range of frequencies) may not be detected. In total deafness, no sounds at all, regardless of amplification or method of production, can be heard. Speech perception is another aspect of hearing which involves the perceived clarity of a word rather than the intensity of sound made by the word. In humans, this is usually measured with speech discrimination tests, which measure not only the ability to detect sound, but also the ability to understand speech. There are very rare types of hearing loss that affect speech discrimination alone. One example is auditory neuropathy, a variety of hearing loss in which the outer hair cells of the cochlea are intact and functioning, but sound information is not faithfully transmitted by the auditory nerve to the brain.Use of the terms "hearing impaired", "deaf-mute", or "deaf and dumb" to describe deaf and hard of hearing people is discouraged by many in the deaf community as well as advocacy organizations, as they are offensive to many deaf and hard of hearing people. Hearing standards Human hearing extends in frequency from 20 to 20,000 Hz, and in intensity from 0 dB to 120 dB HL or more. 0 dB does not represent absence of sound, but rather the softest sound an average unimpaired human ear can hear; some people can hear down to −5 or even −10 dB. Sound is generally uncomfortably loud above 90 dB and 115 dB represents the threshold of pain. The ear does not hear all frequencies equally well: hearing sensitivity peaks around 3,000 Hz. There are many qualities of human hearing besides frequency range and intensity that cannot easily be measured quantitatively. However, for many practical purposes, normal hearing is defined by a frequency versus intensity graph, or audiogram, charting sensitivity thresholds of hearing at defined frequencies. Because of the cumulative impact of age and exposure to noise and other acoustic insults, typical hearing may not be normal. Signs and symptoms difficulty using the telephone loss of sound localization difficulty understanding speech, especially of children and women whose voices are of a higher frequency. difficulty understanding speech in the presence of background noise (cocktail party effect) sounds or speech sounding dull, muffled or attenuated need for increased volume on television, radio, music and other audio sourcesHearing loss is sensory, but may have accompanying symptoms: pain or pressure in the ears a blocked feelingThere may also be accompanying secondary symptoms: hyperacusis, heightened sensitivity with accompanying auditory pain to certain intensities and frequencies of sound, sometimes defined as "auditory recruitment" tinnitus, ringing, buzzing, hissing or other sounds in the ear when no external sound is present vertigo and disequilibrium tympanophonia, also known as autophonia, abnormal hearing of ones own voice and respiratory sounds, usually as a result of a patulous (a constantly open) eustachian tube or dehiscent superior semicircular canals disturbances of facial movement (indicating a possible tumour or stroke) or in persons with Bells palsy Complications Hearing loss is associated with Alzheimers disease and dementia. The risk increases with the hearing loss degree. There are several hypotheses including cognitive resources being redistributed to hearing and social isolation from hearing loss having a negative effect. According to preliminary data, hearing aid usage can slow down the decline in cognitive functions.Hearing loss is responsible for causing thalamocortical dysrthymia in the brain which is a cause for several neurological disorders including tinnitus and visual snow syndrome. Cognitive decline Hearing loss is an increasing concern especially in aging populations. The prevalence of hearing loss increases about two-fold for each decade increase in age after age 40. While the secular trend might decrease individual level risk of developing hearing loss, the prevalence of hearing loss is expected to rise due to the aging population in the US. Another concern about aging process is cognitive decline, which may progress to mild cognitive impairment and eventually dementia. The association between hearing loss and cognitive decline has been studied in various research settings. Despite the variability in study design and protocols, the majority of these studies have found consistent association between age-related hearing loss and cognitive decline, cognitive impairment, and dementia. The association between age-related hearing loss and Alzheimers disease was found to be nonsignificant, and this finding supports the hypothesis that hearing loss is associated with dementia independent of Alzheimer pathology. There are several hypothesis about the underlying causal mechanism for age-related hearing loss and cognitive decline. One hypothesis is that this association can be explained by common etiology or shared neurobiological pathology with decline in other physiological system. Another possible cognitive mechanism emphasize on individuals cognitive load. As people developing hearing loss in the process of aging, the cognitive load demanded by auditory perception increases, which may lead to change in brain structure and eventually to dementia. One other hypothesis suggests that the association between hearing loss and cognitive decline is mediated through various psychosocial factors, such as decrease in social contact and increase in social isolation. Findings on the association between hearing loss and dementia have significant public health implication, since about 9% of dementia cases are associated with hearing loss. Falls Falls have important health implications, especially for an aging population where they can lead to significant morbidity and mortality. Elderly people are particularly vulnerable to the consequences of injuries caused by falls, since older individuals typically have greater bone fragility and poorer protective reflexes. Fall-related injury can also lead to burdens on the financial and health care systems. In literature, age-related hearing loss is found to be significantly associated with incident falls. There is also a potential dose-response relationship between hearing loss and falls—greater severity of hearing loss is associated with increased difficulties in postural control and increased prevalence of falls. The underlying causal link between the association of hearing loss and falls is yet to be elucidated. There are several hypotheses that indicate that there may be a common process between decline in auditory system and increase in incident falls, driven by physiological, cognitive, and behavioral factors. This evidence suggests that treating hearing loss has potential to increase health-related quality of life in older adults. Depression Depression is one of the leading causes of morbidity and mortality worldwide. In older adults, the suicide rate is higher than it is for younger adults, and more suicide cases are attributable to depression. Different studies have been done to investigate potential risk factors that can give rise to depression in later life. Some chronic diseases are found to be significantly associated with risk of developing depression, such as coronary heart disease, pulmonary disease, vision loss and hearing loss. Hearing loss can attribute to decrease in health-related quality of life, increase in social isolation and decline in social engagement, which are all risk factors for increased risk of developing depression symptoms. Spoken language ability Post-lingual deafness is hearing loss that is sustained after the acquisition of language, which can occur due to disease, trauma, or as a side-effect of a medicine. Typically, hearing loss is gradual and often detected by family and friends of affected individuals long before the patients themselves will acknowledge the disability. Post-lingual deafness is far more common than pre-lingual deafness. Those who lose their hearing later in life, such as in late adolescence or adulthood, face their own challenges, living with the adaptations that allow them to live independently. Prelingual deafness is profound hearing loss that is sustained before the acquisition of language, which can occur due to a congenital condition or through hearing loss before birth or in early infancy. Prelingual deafness impairs an individuals ability to acquire a spoken language in children, but deaf children can acquire spoken language through support from cochlear implants (sometimes combined with hearing aids). Non-signing (hearing) parents of deaf babies (90–95% of cases) usually go with oral approach without the support of sign language, as these families lack previous experience with sign language and cannot competently provide it to their children without learning it themselves. Unfortunately, this may in some cases (late implantation or not sufficient benefit from cochlear implants) bring the risk of language deprivation for the deaf baby because the deaf baby would not have a sign language if the child is unable to acquire spoken language successfully. The 5–10% of cases of deaf babies born into signing families have the potential of age-appropriate development of language due to early exposure to a sign language by sign-competent parents, thus they have the potential to meet language milestones, in sign language in lieu of spoken language. Causes Hearing loss has multiple causes, including ageing, genetics, perinatal problems and acquired causes like noise and disease. For some kinds of hearing loss the cause may be classified as of unknown cause. There is a progressive loss of ability to hear high frequencies with aging known as presbycusis. For men, this can start as early as 25 and women at 30. Although genetically variable, it is a normal concomitant of ageing and is distinct from hearing losses caused by noise exposure, toxins or disease agents. Common conditions that can increase the risk of hearing loss in elderly people are high blood pressure, diabetes, or the use of certain medications harmful to the ear. While everyone loses hearing with age, the amount and type of hearing loss is variable.Noise-induced hearing loss (NIHL), also known as acoustic trauma, typically manifests as elevated hearing thresholds (i.e. less sensitivity or muting). Noise exposure is the cause of approximately half of all cases of hearing loss, causing some degree of problems in 5% of the population globally. The majority of hearing loss is not due to age, but due to noise exposure. Various governmental, industry and standards organizations set noise standards. Many people are unaware of the presence of environmental sound at damaging levels, or of the level at which sound becomes harmful. Common sources of damaging noise levels include car stereos, childrens toys, motor vehicles, crowds, lawn and maintenance equipment, power tools, gun use, musical instruments, and even hair dryers. Noise damage is cumulative; all sources of damage must be considered to assess risk. In the US, 12.5% of children aged 6–19 years have permanent hearing damage from excessive noise exposure. The World Health Organization estimates that half of those between 12 and 35 are at risk from using personal audio devices that are too loud. Hearing loss in adolescents may be caused by loud noise from toys, music by headphones, and concerts or events.Hearing loss can be inherited. Around 75–80% of all these cases are inherited by recessive genes, 20–25% are inherited by dominant genes, 1–2% are inherited by X-linked patterns, and fewer than 1% are inherited by mitochondrial inheritance. Syndromic deafness occurs when there are other signs or medical problems aside from deafness in an individual, such as Usher syndrome, Stickler syndrome, Waardenburg syndrome, Alports syndrome, and neurofibromatosis type 2. Nonsyndromic deafness occurs when there are no other signs or medical problems associated with the deafness in an individual.Fetal alcohol spectrum disorders are reported to cause hearing loss in up to 64% of infants born to alcoholic mothers, from the ototoxic effect on the developing fetus plus malnutrition during pregnancy from the excess alcohol intake. Premature birth can be associated with sensorineural hearing loss because of an increased risk of hypoxia, hyperbilirubinaemia, ototoxic medication and infection as well as noise exposure in the neonatal units. Also, hearing loss in premature babies is often discovered far later than a similar hearing loss would be in a full-term baby because normally babies are given a hearing test within 48 hours of birth, but doctors must wait until the premature baby is medically stable before testing hearing, which can be months after birth. The risk of hearing loss is greatest for those weighing less than 1500 g at birth. Disorders responsible for hearing loss include auditory neuropathy, Down syndrome, Charcot–Marie–Tooth disease variant 1E, autoimmune disease, multiple sclerosis, meningitis, cholesteatoma, otosclerosis, perilymph fistula, Ménières disease, recurring ear infections, strokes, superior semicircular canal dehiscence, Pierre Robin, Treacher-Collins, Usher Syndrome, Pendred Syndrome, and Turner syndrome, syphilis, vestibular schwannoma, and viral infections such as measles, mumps, congenital rubella (also called German measles) syndrome, several varieties of herpes viruses, HIV/AIDS, and West Nile virus. Some medications may reversibly affect hearing. These medications are considered ototoxic. This includes loop diuretics such as furosemide and bumetanide, non-steroidal anti-inflammatory drugs (NSAIDs) both over-the-counter (aspirin, ibuprofen, naproxen) as well as prescription (celecoxib, diclofenac, etc.), paracetamol, quinine, and macrolide antibiotics. Others may cause permanent hearing loss. The most important group is the aminoglycosides (main member gentamicin) and platinum based chemotherapeutics such as cisplatin and carboplatin.In addition to medications, hearing loss can also result from specific chemicals in the environment: metals, such as lead; solvents, such as toluene (found in crude oil, gasoline and automobile exhaust, for example); and asphyxiants. Combined with noise, these ototoxic chemicals have an additive effect on a persons hearing loss. Hearing loss due to chemicals starts in the high frequency range and is irreversible. It damages the cochlea with lesions and degrades central portions of the auditory system. For some ototoxic chemical exposures, particularly styrene, the risk of hearing loss can be higher than being exposed to noise alone. The effects is greatest when the combined exposure include impulse noise. A 2018 informational bulletin by the US Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) introduces the issue, provides examples of ototoxic chemicals, lists the industries and occupations at risk and provides prevention information.There can be damage either to the ear, whether the external or middle ear, to the cochlea, or to the brain centers that process the aural information conveyed by the ears. Damage to the middle ear may include fracture and discontinuity of the ossicular chain. Damage to the inner ear (cochlea) may be caused by temporal bone fracture. People who sustain head injury are especially vulnerable to hearing loss or tinnitus, either temporary or permanent. Pathophysiology Sound waves reach the outer ear and are conducted down the ear canal to the eardrum, causing it to vibrate. The vibrations are transferred by the 3 tiny ear bones of the middle ear to the fluid in the inner ear. The fluid moves hair cells (stereocilia), and their movement generates nerve impulses which are then taken to the brain by the cochlear nerve. The auditory nerve takes the impulses to the brainstem, which sends the impulses to the midbrain. Finally, the signal goes to the auditory cortex of the temporal lobe to be interpreted as sound.Hearing loss is most commonly caused by long-term exposure to loud noises, from recreation or from work, that damage the hair cells, which do not grow back on their own.Older people may lose their hearing from long exposure to noise, changes in the inner ear, changes in the middle ear, or from changes along the nerves from the ear to the brain. Diagnosis Identification of a hearing loss is usually conducted by a general practitioner medical doctor, otolaryngologist, certified and licensed audiologist, school or industrial audiometrist, or other audiometric technician. Diagnosis of the cause of a hearing loss is carried out by a specialist physician (audiovestibular physician) or otorhinolaryngologist. Hearing loss is generally measured by playing generated or recorded sounds, and determining whether the person can hear them. Hearing sensitivity varies according to the frequency of sounds. To take this into account, hearing sensitivity can be measured for a range of frequencies and plotted on an audiogram. Other method for quantifying hearing loss is a hearing test using a mobile application or hearing aid application, which includes a hearing test. Hearing diagnosis using mobile application is similar to the audiometry procedure. Audiograms, obtained using mobile applications, can be used to adjust hearing aid applications. Another method for quantifying hearing loss is a speech-in-noise test. which gives an indication of how well one can understand speech in a noisy environment. Otoacoustic emissions test is an objective hearing test that may be administered to toddlers and children too young to cooperate in a conventional hearing test. Auditory brainstem response testing is an electrophysiological test used to test for hearing deficits caused by pathology within the ear, the cochlear nerve and also within the brainstem. A case history (usually a written form, with questionnaire) can provide valuable information about the context of the hearing loss, and indicate what kind of diagnostic procedures to employ. Examinations include otoscopy, tympanometry, and differential testing with the Weber, Rinne, Bing and Schwabach tests. In case of infection or inflammation, blood or other body fluids may be submitted for laboratory analysis. MRI and CT scans can be useful to identify the pathology of many causes of hearing loss. Hearing loss is categorized by severity, type, and configuration. Furthermore, a hearing loss may exist in only one ear (unilateral) or in both ears (bilateral). Hearing loss can be temporary or permanent, sudden or progressive. The severity of a hearing loss is ranked according to ranges of nominal thresholds in which a sound must be so it can be detected by an individual. It is measured in decibels of hearing loss, or dB HL. There are three main types of hearing loss: conductive hearing loss, sensorineural hearing loss, and mixed hearing loss. An additional problem which is increasingly recognised is auditory processing disorder which is not a hearing loss as such but a difficulty perceiving sound. The shape of an audiogram shows the relative configuration of the hearing loss, such as a Carhart notch for otosclerosis, noise notch for noise-induced damage, high frequency rolloff for presbycusis, or a flat audiogram for conductive hearing loss. In conjunction with speech audiometry, it may indicate central auditory processing disorder, or the presence of a schwannoma or other tumor. People with unilateral hearing loss or single-sided deafness (SSD) have difficulty in hearing conversation on their impaired side, localizing sound, and understanding speech in the presence of background noise. One reason for the hearing problems these patients often experience is due to the head shadow effect. Prevention It is estimated that half of cases of hearing loss are preventable. About 60% of hearing loss in children under the age of 15 can be avoided. There are a number of effective preventative strategies, including: immunization against rubella to prevent congenital rubella syndrome, immunization against H. influenza and S. pneumoniae to reduce cases of meningitis, and avoiding or protecting against excessive noise exposure. The World Health Organization also recommends immunization against measles, mumps, and meningitis, efforts to prevent premature birth, and avoidance of certain medication as prevention. World Hearing Day is a yearly event to promote actions to prevent hearing damage. Noise exposure is the most significant risk factor for noise-induced hearing loss that can be prevented. Different programs exist for specific populations such as school-age children, adolescents and workers. Education regarding noise exposure increases the use of hearing protectors. The use of antioxidants is being studied for the prevention of noise-induced hearing loss, particularly for scenarios in which noise exposure cannot be reduced, such as during military operations. Workplace noise regulation Noise is widely recognized as an occupational hazard. In the United States, the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) work together to provide standards and enforcement on workplace noise levels. The hierarchy of hazard controls demonstrates the different levels of controls to reduce or eliminate exposure to noise and prevent hearing loss, including engineering controls and personal protective equipment (PPE). Other programs and initiative have been created to prevent hearing loss in the workplace. For example, the Safe-in-Sound Award was created to recognize organizations that can demonstrate results of successful noise control and other interventions. Additionally, the Buy Quiet program was created to encourage employers to purchase quieter machinery and tools. By purchasing less noisy power tools like those found on the NIOSH Power Tools Database and limiting exposure to ototoxic chemicals, great strides can be made in preventing hearing loss.Companies can also provide personal hearing protector devices tailored to both the worker and type of employment. Some hearing protectors universally block out all noise, and some allow for certain noises to be heard. Workers are more likely to wear hearing protector devices when they are properly fitted.Often interventions to prevent noise-induced hearing loss have many components. A 2017 Cochrane review found that stricter legislation might reduce noise levels. Providing workers with information on their sound exposure levels was not shown to decrease exposure to noise. Ear protection, if used correctly, can reduce noise to safer levels, but often, providing them is not sufficient to prevent hearing loss. Engineering noise out and other solutions such as proper maintenance of equipment can lead to noise reduction, but further field studies on resulting noise exposures following such interventions are needed. Other possible solutions include improved enforcement of existing legislation and better implementation of well-designed prevention programmes, which have not yet been proven conclusively to be effective. The conclusion of the Cochrane Review was that further research could modify what is now regarding the effectiveness of the evaluated interventions.The Institute for Occupational Safety and Health of the German Social Accident Insurance has created a hearing impairment calculator based on the ISO 1999 model for studying threshold shift in relatively homogeneous groups of people, such as workers with the same type of job. The ISO 1999 model estimates how much hearing impairment in a group can be ascribed to age and noise exposure. The result is calculated via an algebraic equation that uses the A-weighted sound exposure level, how many years the people were exposed to this noise, how old the people are, and their sex. The models estimations are only useful for people without hearing loss due to non-job related exposure and can be used for prevention activities. Screening The United States Preventive Services Task Force recommends neonatal hearing screening for all newborns.The American Academy of Pediatrics advises that children should have their hearing tested several times throughout their schooling: When they enter school At ages 6, 8, and 10 At least once during middle school At least once during high schoolWhile the American College of Physicians indicated that there is not enough evidence to determine the utility of screening in adults over 50 years old who do not have any symptoms, the American Language, Speech Pathology and Hearing Association recommends that adults should be screened at least every decade through age 50 and at three-year intervals thereafter, to minimize the detrimental effects of the untreated condition on quality of life. For the same reason, the US Office of Disease Prevention and Health Promotion included as one of Healthy People 2020 objectives: to increase the proportion of persons who have had a hearing examination. Management Management depends on the specific cause if known as well as the extent, type and configuration of the hearing loss. Sudden hearing loss due to an underlying nerve problem may be treated with corticosteroids.Most hearing loss, that resulting from age and noise, is progressive and irreversible, and there are currently no approved or recommended treatments. A few specific kinds of hearing loss are amenable to surgical treatment. In other cases, treatment is addressed to underlying pathologies, but any hearing loss incurred may be permanent. Some management options include hearing aids, cochlear implants, middle ear implants, assistive technology, and closed captioning. This choice depends on the level of hearing loss, type of hearing loss, and personal preference. Hearing aid applications are one of the options for hearing loss management. For people with bilateral hearing loss, it is not clear if bilateral hearing aids (hearing aids in both ears) are better than a unilateral hearing aid (hearing aid in one ear). Epidemiology Globally, hearing loss affects about 10% of the population to some degree. It caused moderate to severe disability in 124.2 million people as of 2004 (107.9 million of whom are in low and middle income countries). Of these 65 million acquired the condition during childhood. At birth ~3 per 1000 in developed countries and more than 6 per 1000 in developing countries have hearing problems.Hearing loss increases with age. In those between 20 and 35 rates of hearing loss are 3% while in those 44 to 55 it is 11% and in those 65 to 85 it is 43%.A 2017 report by the World Health Organization estimated the costs of unaddressed hearing loss and the cost-effectiveness of interventions, for the health-care sector, for the education sector and as broad societal costs. Globally, the annual cost of unaddressed hearing loss was estimated to be in the range of $750–790 billion international dollars. The International Organization for Standardization (ISO) developed the ISO 1999 standards for the estimation of hearing thresholds and noise-induced hearing impairment. They used data from two noise and hearing study databases, one presented by Burns and Robinson (Hearing and Noise in Industry, Her Majestys
Hearing loss	Stationery Office, London, 1970) and by Passchier-Vermeer (1968). As race are some of the factors that can affect the expected distribution of pure-tone hearing thresholds several other national or regional datasets exist, from Sweden, Norway, South Korea, the United States and Spain.In the United States hearing is one of the health outcomes measure by the National Health and Nutrition Examination Survey (NHANES), a survey research program conducted by the National Center for Health Statistics. It examines health and nutritional status of adults and children in the United States. Data from the United States in 2011-2012 found that rates of hearing loss has declined among adults aged 20 to 69 years, when compared with the results from an earlier time period (1999-2004). It also found that adult hearing loss is associated with increasing age, sex, ethnicity, educational level, and noise exposure. Nearly one in four adults had audiometric results suggesting noise-induced hearing loss. Almost one in four adults who reported excellent or good hearing had a similar pattern (5.5% on both sides and 18% on one side). Among people who reported exposure to loud noise at work, almost one third had such changes. Social and cultural aspects People with extreme hearing loss may communicate through sign languages. Sign languages convey meaning through manual communication and body language instead of acoustically conveyed sound patterns. This involves the simultaneous combination of hand shapes, orientation and movement of the hands, arms or body, and facial expressions to express a speakers thoughts. "Sign languages are based on the idea that vision is the most useful tool a deaf person has to communicate and receive information".Deaf culture refers to a tight-knit cultural group of people whose primary language is signed, and who practice social and cultural norms which are distinct from those of the surrounding hearing community. This community does not automatically include all those who are clinically or legally deaf, nor does it exclude every hearing person. According to Baker and Padden, it includes any person or persons who "identifies him/herself as a member of the Deaf community, and other members accept that person as a part of the community," an example being children of deaf adults with normal hearing ability. It includes the set of social beliefs, behaviors, art, literary traditions, history, values, and shared institutions of communities that are influenced by deafness and which use sign languages as the main means of communication. Members of the Deaf community tend to view deafness as a difference in human experience rather than a disability or disease. When used as a cultural label especially within the culture, the word deaf is often written with a capital D and referred to as "big D Deaf" in speech and sign. When used as a label for the audiological condition, it is written with a lower case d.There also multiple educational institutions for both deaf and Deaf people, that usually use sign language as the main language of instruction. Famous institutions include Gallaudet University and the National Technical Institute for the Deaf in the US, and the National University Corporation of Tsukuba University of Technology in Japan. Research Stem cell transplant and gene therapy A 2005 study achieved successful regrowth of cochlea cells in guinea pigs. However, the regrowth of cochlear hair cells does not imply the restoration of hearing sensitivity, as the sensory cells may or may not make connections with neurons that carry the signals from hair cells to the brain. A 2008 study has shown that gene therapy targeting Atoh1 can cause hair cell growth and attract neuronal processes in embryonic mice. Some hope that a similar treatment will one day ameliorate hearing loss in humans.Recent research, reported in 2012 achieved growth of cochlear nerve cells resulting in hearing improvements in gerbils, using stem cells. Also reported in 2013 was regrowth of hair cells in deaf adult mice using a drug intervention resulting in hearing improvement. The Hearing Health Foundation in the US has embarked on a project called the Hearing Restoration Project. Also Action on Hearing Loss in the UK is also aiming to restore hearing.Researchers reported in 2015 that genetically deaf mice which were treated with TMC1 gene therapy recovered some of their hearing. In 2017, additional studies were performed to treat Usher syndrome and here, a recombinant adeno-associated virus seemed to outperform the older vectors. Audition Besides research studies seeking to improve hearing, such as the ones listed above, research studies on the deaf have also been carried out in order to understand more about audition. Pijil and Shwarz (2005) conducted their study on the deaf who lost their hearing later in life and, hence, used cochlear implants to hear. They discovered further evidence for rate coding of pitch, a system that codes for information for frequencies by the rate that neurons fire in the auditory system, especially for lower frequencies as they are coded by the frequencies that neurons fire from the basilar membrane in a synchronous manner. Their results showed that the subjects could identify different pitches that were proportional to the frequency stimulated by a single electrode. The lower frequencies were detected when the basilar membrane was stimulated, providing even further evidence for rate coding. See also Deaf hearing H.870 Otologics Safe listening World Hearing Day References External links Hearing loss at Curlie National Institute for the Prevention of Deafness and other Communication Disorders Global Costs of unaddressed hearing loss and cost-effectiveness of interventions World Health Organization. 2017. Internet archive on 12 May 2020. Deafness and Hearing Loss. World Health Organization. 2022. Internet archive on 9 June 2022 ISBN 978-92-4-151204-6. Occupational Noise and Hearing Loss Prevention U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. (6 February 2018). Preventing Hearing Loss Caused by Chemical (Ototoxicity) and Noise Exposure Safety and Health Information Bulletin (SHIB). U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. doi:10.26616/NIOSHPUB2018124 (8 March 2018). Publication No. 2018-124. Themann, Christa L.; Morata, Thais; Afanuh, Susan (27 September 2019). "Using Total Worker Health® concepts to address hearing health". U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. Cincinnati, OH. doi:10.26616/NIOSHPUB2019155. S2CID 242864449. Retrieved 4 March 2020. Publication No. 2019-155 World Report on Hearing. World Health Organization. 3 March 2021. World report archived on 10 June 2022.
Language delay	A language delay is a language disorder in which a child fails to develop language abilities at the usual age-appropriate period in their developmental timetable. It particularly affects deaf children who are denied sign language. It is most commonly seen in children ages two to seven years-old and can continue into adulthood. The reported prevalence of language delay ranges from 2.3 to 19 percent.Language is a uniquely human form of communication that entails the use of words in a standard and structured way. Language is distinct from communication. Communication is a two-stage process. The first stage is the process of encoding the message into a set of words (or signs in the case of Sign Languages) and sentence structures that convey the required meaning, i.e. into language. In the second stage, language is translated into motor commands that control the articulators (hands, face, body, lungs, vocal cords, mouth, tongue, teeth, etc.), thereby creating speech. Language delays are distinct from speech delays, in which the development of the mechanical and motor aspects of speech production are delayed. Many tend to confuse language delay with speech delay or even just late talker. All of these have different telltale signs and determining factors. Speech delay seems to be more similar to late talker compared to language delay. Speech is the verbal motor production of language, while language is a means of communication. Because language and speech are independent, they may be individually delayed. For example, a child may be delayed in speech (i.e., unable to produce intelligible speech sounds), but not delayed in language because they use a Sign Language. Additionally, language delay encompasses the entirety of language developmental progress being slowed and not just the speech aspects. Language delays are recognized by comparing language development of children to recognized developmental milestones. They are presented in a variety of ways, as every individual child has a unique set of language skills and deficiencies that are identifiable through many different screenings and tools. There are different causes leading to language delay; it is often a result of another developmental disorder and treatment requires analysis of the unique individual causes. The condition is frequently observed early on, among two- and three-year-olds. Early language delays are only considered risk-factors in leading to more severe language disorders. Language Development The anatomical language centers of the brain are the Brocas and Wernickes area. These two areas include all aspects of the development of language. The Brocas area is the motor portion of language at the left posterior inferior frontal gyrus and involves speech production. The Wernickes area is the sensory portion of language at the posterior part of the left superior temporal gyrus and involves auditory verbal comprehension.There are recognizable speech and language developmental milestones in children. For children with language delays, milestones in their language development may be different or slowed. Recent studies have shown the different milestones for children with language delay compared to children with normal language development. Language delays are often identified when a child strays from the expected developments in the timeline of typical speech and language developmental milestones that researchers agree on. Children can stray slightly from the confines of the expected timeline; however, if a child is observed to be largely straying from the expected timeline, the childs caretaker should consult with a medical specialist. Timeline of typical speech and language developmental milestones This timeline only provides a very general and brief outline of expected developments from birth to age five, individual children can still exhibit varying development patterns as this timeline only serves as a general guideline. This timeline is only one model, other models regarding language development exist. The development of language remains a theoretical mystery. Around 2 months, babies can make "cooing" sounds.Around 4 months, babies can respond to voices.Around 6 months, babies begin to babble and respond to names.Around 9 months, babies begin to produce mama/dada - appropriate terms and are able to imitate one word at a time.Around 12 months, toddlers can typically speak one or more words. They can produce two words with meaning.Around 15 months, toddlers begin to produce jargon, which is defined as "pre-linguistic vocalizations in which infants use adult-like stress and intonation".Around 18 months, toddlers can produce 10 words and follow simple commands.Around 24 months, toddlers begin to produce 2-3 words and phases that use "I", "Me", and "you", indicating possession. They are about 25% intelligible.Around 3 years, toddlers are able to use language in numerical terms. Based on the milestones set for typical toddlers, if the child tends to have a lot of or very long delays, they may be deemed as having language delay. However, proper testing by a professional like a speech therapist or a doctors confirmation will be required to determine if a child has language delay. Although these milestones are the typical milestones for a child, they should not be followed strictly as they are mere guidelines. Language development in language delay Early developmental language delay is characterized by slow language development in preschoolers. Language development for children with language delay takes longer than the general timeline provided above. It is not only slower, but also presents itself in different forms. For example, a child with a language delay could have weaker language skills such as the ability to produce phrases at 24 months-old. They may find themselves producing language that is different from language norms in developing children. Types of Language Delay A language delay is commonly divided into receptive and expressive categories. Both categories are essential in developing effective communication. Receptive language refers to the process of understanding language, both verbal (spoken) and nonverbal (written, gestural). This may involve gaining information from sounds and words, visual information from surrounding environment, written information and grammar.Expressive language refers to the use of sentences (made of words or signs) to communicate messages to others. It enables children to express their needs and wants to the people around them, interact with others and develop their language skills in speech and writing. Some expressive language skills include putting words together into sentences, being able to label objects in an environment and describing events and actions. Receptive Language Delay Children that are diagnosed with receptive language delay have difficulties understanding language. They may have trouble with receptive language skills such as identifying vocabulary and basic concepts, understanding gestures, following directions and answering questions. The number of language skills that children have difficulties with can differ greatly, with some having trouble with only a single skill and others having trouble with multiple. Expressive Language Delay A child diagnosed with expressive language delay (ELD) has trouble with language usage in some way. As this diagnosis is very broad, each child diagnosed with ELD can be very different in terms of the language skills they have problems with. Some may have difficulty with using the correct words and vocabulary, some have trouble forming sentences and others are unable to sequence information together coherently. Expressive language symptoms come in many forms and each one is treated with different methods. Presentation and Diagnosis A language delay is most commonly identified around 18 months of age with an enhanced well-baby visit. It presents itself in many forms and can be comorbid or develop as a result of other developmental delays. It is important to remember that language delays act and develop differently individually. Language delay is different than individual variation in language development, and is defined by children falling behind on the timeline for recognized milestones. Screening Regular appointments with a pediatrician in infancy can help identify signs of language delay. According to the American Academy of Pediatrics (AAP), formal screening for language delay is recommended at three ages: 9, 18, and 24–30 months. Screening is a two-part process: first, a general developmental screening using tools such as the Parents Evaluation of Developmental Status or Ages and Stages Questionnaire (ASQ-3); and second, specific screening for autism spectrum disorder using tools like the Modified Checklist for Autism in Toddlers. Not all patients with language delay have autism spectrum disorder, so the AAP recommends both screens to assess for delays in developmental milestones.However, the US Preventive Services Task Force (last updated in 2015) has determined that there is insufficient evidence to recommend screening for language delay in children under the age of 5. Other national panels, including the UK National Screening Committee and Canadian Task Force for Preventive Health Care, have also concluded that there is limited evidence on the benefits of screening all infants for language delay. Early signs and symptoms (red flags) There are several red flags in early infancy and childhood that may indicate a need for evaluation by a pediatrician. For example, language delay can present as a lack of communicative gestures or sounds. Language delay in children is associated with increased difficulty with reading, writing, attention, and/or socialization. In addition, an inability to engage in social exchanges is a sign of language delay at all ages.Communicative deficits at specific ages and milestones might indicate language delay, including: Not smiling at 3 months Not turning the head toward sounds at 4 months Not laughing or responding to sounds at 6 months Not babbling at 9 months Not pointing and using gestures at 12 months Not producing more than 5 words at 18 months Not producing more than 50 words at 24 months Losing language and/or social skills after 36 monthsLater in life, important signs include: A lack of speech An inability to comprehend, process, or understand language presented to the child Consequences of Language Delay Language delay is a risk factor for other types of developmental delay, including social, emotional, and cognitive delay. Language delay can impact behavior, reading and spelling ability, and overall IQ scores. Some children may outgrow deficits in reading and writing while others do not. Other conditions associated with language delay include attention-deficit/hyperactivity disorder, autism spectrum disorder, and social communication disorder. Causes Language delays are the most frequent developmental delays, and can occur for many reasons. A delay can be due to being a "late bloomer", "late talker", or a more serious problem. Such delays can occur in conjunction with a lack of mirroring of facial responses, unresponsiveness or unawareness of certain noises, a lack of interest in playing with other children or toys, or no pain response to stimuli. Socio-economic factors Socio-economic status Children from families of low educational level are more likely to have delays and difficulties in expressive language. While language development is not directly affected by the socioeconomic level of a family, the conditions that are associated with the socioeconomic level affects the process of language development to a certain extent. A childs early vocabulary development can be influenced by socioeconomic status via maternal speech, which varies according to the socioeconomic status of the family. Mothers with higher education levels are more likely to use rich vocabulary and speak in longer utterances when interacting with their children, which helps them develop their productive vocabulary more than children from a lower socioeconomic status.Poverty is also a high risk factor for language delay as it results in a lack of access appropriate therapies and services. The likelihood of those requiring early intervention for language delays actually receiving help is extremely low compared to those that dont actually need it. Natural/medical factors Hearing loss The process of children acquiring language skills involves hearing sounds and words from their caregivers and surroundings. Hearing loss causes that lack of these sound inputs, causing these children to have difficulties learning to use and understand language, which will eventually lead to delayed speech and language skills. For example, they may struggle with putting sentences together, understanding speech from other people or using the correct grammar, which are some language skills that typically developing children possess. Autism There is strong evidence that autism is commonly associated with language delay. Children with autism may have difficulties in developing language skills and understanding what is being said to them. They may also have troubles communicating non-verbally by using hand gestures, eye contact and facial expressions. The extent of their language usage is heavily influenced by their intellectual and social developments. The range of their skills can be very different and on opposite ends of a spectrum. Many children with autism develop some speech and language skills, but not like typically developing children, and with uneven progress.Asperger syndrome, which is classified under the broad umbrella term of autistic spectrum disorder, however, is not associated with language delay. Children diagnosed with Asperger syndrome have decent language skills but use language in different ways from others. They may not be able to understand the use of language devices, such as irony and humor, or conversation reciprocity between involved parties.Heritability Genes have a very big influence in the presence of language impairments. Neurobiological and genetic mechanisms have a strong influence on late language emergence. A child with a family history of language impairments is more likely to have delayed language emergence and persistent language impairments. They are also 2 times more likely to be late talkers as compared to those with no such family history.Genetic abnormalities may also be a cause of language delays. In 2005, researchers found a connection between expressive language delay and a genetic abnormality: a duplicate set of the same genes that are missing in individuals with Williams-Beuren syndrome. Also so called XYY syndrome can often cause speech delay.Twins Being a twin increases the chance of speech and language delays. Reasons for this are thought to include less one-on-one time with parents, the premature birth of twins, and the companionship of their twin sibling reducing their motivation to talk to others. A twin study has also shown that genetic factors have an important role in language delay. Monozygotic twin pairs (identical twins) recorded a higher consistency than dizygotic twin (fraternal twins) pairs, revealing monozygotic twins experiencing early vocabulary delay is attributed to genetic etiology. The environmental factors that influences both twins also play a big role in causing early language delay, but only when it is transient.Gender Research has shown that boys are at greater risk for delayed language development than girls. Almost all developmental disorders that affect communication, speech and language skills are more common in males than in females. British scientists have found that the male sex hormone (testosterone) levels were related to the development of both autism and language disorders, which explains why boys are at a greater risk of developmental disorders biologically.Perinatal conditions There is a high prevalence of early language delay among toddlers with neonatal brachial plexus palsy. Hand usage and gestures are part of the motor system and have been proven correlate to comprehension and production aspects in language development. An interruption in the hand/arm usage caused by this condition during stages of language development could possibly cause these children to experience language delays.Stress during pregnancy is associated with language delay. High levels of prenatal stress can result in poorer general intellectual and language outcomes. Chemical exposure during pregnancy may also be a factor that causes language delays. Environmental factors Interactive communication and parental inputs Psychosocial deprivation can cause language delays in children. An example of this is when a child does not spend enough time communicating with adults through ways such as babbling and joint attention. Research on early brain development shows that babies and toddlers have a critical need for direct interactions with parents and other significant care givers for healthy brain growth and the development of appropriate social, emotional, and cognitive skills.A study examining the role of interactive communication between parents and children has shown that parents language towards toddlers with language delay differ from parents language towards typically developing toddlers in terms of the quality of interaction. While late talkers and children with typical language development both receive similar quantitative parental input in terms of the number of utterances and words, parents of late talkers are found to respond less often to their children than parents of children with typical language development. Parents of late talkers tend to change or introduce topics more often than other parents in order to engage their children in more talk rather than responding to their childs speech. They also seem to not provide an environment that is suitable for child engagement, nor do they establish routines that serve as a platform for communicative acts with their children. This, together with the fact that they respond less often to their children, shows that parents of late talkers do not follow their childs lead. Instead, these parents are more likely to adapt to the childs communication, which results in an "idiosyncratic feedback cycle" that worsens the childs language difficulties rather than help with their language acquisition.Birth Order First-born children grow up in an environment that provides more possibilities of communicative interaction with adults, which differs from what is experienced by their younger siblings. Younger siblings are likely to have less one-on-one time with their parents or guardians. Older siblings also tend to talk for their younger siblings, giving them less opportunities to grow their language skills.Television viewing Excessive television viewing is associated with delayed language development. Children who watched television alone were 8.47 times more likely to have language delay when compared to children who interacted with their caregivers during television viewing. Some educational television shows, such as Blues Clues, have been found to enhance a childs language development. But, as recommended by the American Academy of Pediatrics, children under the age of 2 should watch no television at all, and after age 2 watch no more than one to two hours of quality programming a day. Therefore, exposing such young children to television programs should be discouraged, especially television shows with no educational value. Parents should engage children in more conversational activities to avoid television-related delays to their children language development, which could impair their intellectual performance. However, in a study conducted by Dr. Birken of the Hospital for Sick Children, it was found that watching television while interacting with a parent of caregiver is actually beneficial for children who are bilingual. The study spanned four years, from 2011 to 2015, and was based on parent report and clinician observation. Over the four years it was found that if a bilingual child had interaction with an adult while watching television they did not experience language delay and it in fact helped them develop English, their second language. Treatment Studies have failed to find clear evidence that a language delay can be prevented by training or educating health care professionals in the subject. Overall, some of the reviews show positive results regarding interventions in language delay, but are not curative. To treat an already existing language delay a child would need Speech and Language Therapy to correct any deficits. These therapists can be found in schools, clinics, through home care agencies, and also colleges where Communication Sciences and Disorders are studied. Most young children with language delay recover to a normal range by five years of age.Aside from these, it is still encouraged for the childs parent to get involved. A few ways that a parent could get involved with helping to improve a childs language and speech skills includes speaking to their child with enthusiasm, engaging in conversations revolving what the child is focusing on, and reading to their child frequently.Social and play skills appear to be more difficult for children with language delays due to their decreased experience in conversation. Speech Pathologists utilize methods such as prompting to improve a childs social skills through play intervention. While recent studies have consistently found play intervention to be helpful, further research is required in order to determine the effectiveness of this form of therapy.Unfortunately, there is still not a lot of methods and cures that help children with language delay. However, there have been some recent therapy methods that have caused improvement in children with language delay. Certain types of therapy have been seen to show more or better improvement for the children compared to regular speech therapy. One such example is in the form of therapeutic horseback riding. It is also mentioned in a study that animals are a good source of therapy for children with special needs in areas including communication skills.In regards to demographic factors causing language delay, specifically poverty, system-level changes improve access to treatment and therapy for children with language delay. Intervention The parent and child relationship is bi-directional, which means that parents have an influence over their childs language development, while the child has an influence over the parents communication styles. Parents have the ability to maintain language delay by offering the child a non-verbal environment or one where their communication may not be challenged. Intervention programs and strategies are found to be beneficial to children with a specific language impairments. Research has found that the management strategies put to use are influenced by the child and the important participation of the parents. Parents are likely to follow the lead of the childs language development. One approach for intervening is naturalistic intervention. The child is in a natural environment where the communication is more responsive, rather than being more direct. See also References Further reading External links Speech Therapy for Down Syndrome Different Issues in Speech and Language Development - American Speech-Language-Hearing Association (ASHA) Delay in Speech and Language - KidsHealth Early Identification of Speech -Language Delays and Disorders Speech and Language Delays and Disorders - University of Michigan Health System CHAPTER III - Assessment Methods for Young Children With Communications Disorders Statistics on Voice, Speech, and Language - National Institute of Deafness and Other Communication Disorders
Pili multigemini	Pili multigemini, also known as "compound hairs," is a malformation characterized by the presence of bifurcated or multiple divided hair matrices and papillae, giving rise to the formation of multiple hair shafts within the individual follicles. Description The name describes a condition where several separate hair fibers bunch together and emerge from the skin through a single hair canal. Pathology shows that deep in the skin several dermal papilla are closely situated with each producing a fiber, but these separate hair follicle bulbs combine into one hair canal towards the skin surface. Folliculitis can sometimes be associated with this condition. Treatment Electrolysis will permanently remove pili multigemini. Depilating laser treatment has been suggested to improve symptomatic pili multigemini. See also Pili bifurcati List of cutaneous conditions References == External links ==
Inborn errors of metabolism	Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic disorders. To this concept its possible to include the new term of Enzymopathy. This term was created following the study of Biodynamic Enzymology, a science based on the study of the enzymes and their derivated products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923. Classification and symptoms of metabolic diseases Traditionally the inherited metabolic diseases were classified as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Because of the enormous number of these diseases the wide range of systems affected badly, nearly every "presenting complaint" to a healthcare provider may have a congenital metabolic disease as a possible cause, especially in childhood and adolescence. The following are examples of potential manifestations affecting each of the major organ systems. Diagnostic Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially expanded testing using mass spectrometry. gas chromatography–mass spectrometry-based technology with an integrated analytics system, which has now made it possible to test a newborn for over 100 mm genetic metabolic disorders. Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis. Common screening tests used in the last sixty years: Ferric chloride test (detects abnormal metabolites in urine) Ninhydrin paper chromatography (detects abnormal amino acid patterns) Guthrie test (detects excessive amounts of specific amino acids in blood) The dried blood spot can be used for multianalyte testing using Tandem Mass Spectrometry (MS/MS). This given an indication for a disorder. The same has to be further confirmed by enzyme assays, IEX-Ninhydrin, GC/MS or DNA Testing. Quantitative measurement of amino acids in plasma and urine IEX-Ninhydrin post-column derivitization liquid ion chromatography (detects abnormal amino acid patterns and quantitative analysis) Urine organic acid analysis by gas chromatography–mass spectrometry Plasma acylcarnitine analysis by mass spectrometry Urine purine and pyrimidine analysis by gas chromatography-mass spectrometrySpecific diagnostic tests (or focused screening for a small set of disorders): Tissue biopsy: liver, muscle, brain, bone marrow Skin biopsy and fibroblast cultivation for specific enzyme testing Specific DNA testingA 2015 review reported that even with all these diagnostic tests, there are cases when "biochemical testing, gene sequencing, and enzymatic testing can neither confirm nor rule out an IEM, resulting in the need to rely on the patients clinical course". A 2021 review showed that several neurometabolic disorders converge on common neurochemical mechanisms that interfere with biological mechanisms also considered central in ADHD pathophysiology and treatment. This highlights the importance of close collaboration between health services to avoid clinical overshadowing. Treatment In the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications. In the past twenty years, new medications, enzyme replacement, gene therapy, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising therapies are listed: Epidemiology In a study in British Columbia, the overall incidence of the inborn errors of metabolism were estimated to be 40 per 100,000 live births or 1 in 2,500 births, overall representing more than approximately 15% of single gene disorders in the population. While a Mexican study established an overall incidence of 3.4: 1000 live newborns and a carrier detection of 6.8:1000 NBS. References Further reading Price, Nicholas C; Stevens, Lewis (1996). Principi di enzimologia [Principles of enzymology] (in Italian). A. Delfino. ISBN 978-88-7287-100-3. OCLC 879866185. Mazzucato, Fernando; Giovagnoni, Andrea (2019). Manuale di tecnica, metodologia e anatomia radiografica tradizionali [Manual of traditional radiographic technique, methodology and anatomy] (in Italian). Piccin. ISBN 978-88-299-2959-7. OCLC 1141547603. Torricelli, P; Antonelli, F; Ferorelli, P; Borromeo, I; Shevchenko, A; Lenzi, S; De Martino, A (March 2020). "Oral nutritional supplement prevents weight loss and reduces side effects in patients in advanced lung cancer chemotherapy". Amino Acids. 52 (3): 445–451. doi:10.1007/s00726-020-02822-7. PMID 32034492. S2CID 211053578. External links Portal of Chemistry (Italian)
Congenital dyserythropoietic anemia type IV	Congenital dyserythropoietic anemia type IV (CDA IV) has been described with typical morphologic features of CDA II but a negative acidified-serum test. Presentation CDA type IV is characterized by mild to moderate splenomegaly. Hemoglobin is very low and patients are transfusion dependent. MCV is normal or mildly elevated. Erythropoiesis is normoblastic or mildly to moderately megaloblastic. Nonspecific erythroblast dysplasia is present. Genetics Congenital dyserythropoietic anemia type IV is an autosomal dominant inherited red blood cell disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals with CDAN4 also have increased levels of fetal hemoglobin. Diagnosis Treatment Treatment consists of frequent blood transfusions and chelation therapy. Potential cures include bone marrow transplantation and gene therapy. See also Congenital dyserythropoietic anemia Thalassemia Hemoglobinopathy List of hematologic conditions References Further reading Congenital dyserythropoietic anemia at the US National Institutes of Health Home Genetic Reference] == External links ==
Folliculitis decalvans	Folliculitis decalvans is an inflammation of the hair follicle that leads to bogginess or induration of involved parts of the scalp along with pustules, erosions, crusts, ulcers, and scale.: 649 : 760–1 It begins at a central point and spreads outward, leaving scarring, sores, and, due to the inflammation, hair loss in its wake. No permanent cure has been found for this condition, but there is promise in a regimen of dual therapy with rifampin 300 mg twice daily and clindamycin 300 mg twice daily. This new treatment can be used to control the condition, and tests have indicated that after 3 to 5 months long uninterrupted courses of treatment, many patients have seen limited to no recurrence. Causes There is no certainty about the cause of this disorder, but the bacterial species Staphylococcus aureus has a central role and can be detected in the lesions of most patients. It is unclear if another primarily sterile process with secondary colonization by Staphylococcus aureus is present, or if Staphylococcus aureus starts the process by causing a strong immune reaction. Another possibility is that Staphylococcus aureus produces toxins that act as superantigens which directly activate the T-cells over the variable domain of T-cell receptors. Nonetheless Staphylococcus aureus can by found in almost all patients affected by this disorder, while it is detected in only 20–30% of non-affected people. As Staphylococcus aureus is not always found in people with folliculitis decalvans, other factors must be present. Through examinations in families it was found that there is a family connection to the occurrences, which leads to the conclusion that there is a genetic predisposition for it; for example, patients with folliculitis decalvans could have a hereditary different opening of the hair follicle that could facilitate the lodging of the bacteria. Immunologically, another possibility is that especially strong intercellular fixation protein ICAM-1 contributes to inflammation with its strong effect of attracting white blood cells such as granulocytes and lymphocytes. Diagnosis Management Some sufferers have found that a daily intake of MSM helps relieve the inflammation and scarring that comes with chronic Folliculitis decalvans. Epidemiology This disorder was first described by Charles-Eugène Quinquaud in 1888. He isolated bacteria from the hair follicles of affected patients and introduced them in rats, mice and rabbits, with no result. In 1905 it was then differentiated from other scarring alopecias and the name Folliculitis decalvans, that remains current, was introduced. About 11% of the occurrences of scarring alopecias are of this type. Men are more commonly affected than women and its appearance is usually between the late teens and middle adult years. According to studies in the United States, African Americans are more frequently affected than White Americans. See also Cicatricial alopecia References == External links ==
Wrinkly skin syndrome	Wrinkly skin syndrome (WSS) is a rare genetic condition characterized by sagging, wrinkled skin, low skin elasticity, and delayed fontanel (soft spot) closure along with a range of other symptoms. The disorder exhibits an autosomal recessive inheritance pattern with mutations in the ATP6V0A2 gene, leading to abnormal glycosylation events. There are only about 30 known cases of WSS as of 2010. Given its rarity and symptom overlap to other dermatological conditions, reaching an accurate diagnosis is difficult and requires specialized dermatological testing. Limited treatment options are available but long-term prognosis is variable from patient-to-patient, on the basis of individual case studies. Some skin symptoms recede with increasing age while progressive neurological advancement of the disorder causes seizures and mental deterioration later in life for some patients. Symptoms and signs The predominant clinical symptoms of wrinkly skin syndrome are wrinkled and inelastic skin over the face, backs of hands/fingers, tops of feet, and abdomen, delayed closure of the fontanel (babys soft spot), and increased palmar and plantar creases in the hands and feet, respectively.Patients may experience a wide variety of symptoms (see table). The assortment of symptoms displayed and symptom severity (particularly growth and developmental delays) vary from patient to patient. Microscopic analysis of epidermal samples of a four-month year old with WSS revealed an irregular pattern of elastic fiber distribution. Fewer elastic fibers are present in the papillary dermis and fragmented elastic fibers in the reticular dermis are observed. Epidermal samples from the same patient subjected to electron microscopy revealed that elastin fibers display abnormally high levels of fragmentation and clumping of microfibrils, with little amorphous elastin. Within collagen bundles, collagen fibrils are of irregular shape and thickness. These disruptions of the patients connective tissue play a role in the inelasticity of the skin and wrinkling. Mechanism Importance of the ATP6V0A2 pump Vacuolar ATPases (V-ATPase) regulate the pH of the subcellular compartments found within the endosomal membrane system. V-ATPases are multiprotein complexes composed of two functional domains, a V0 domain, and a V1 domain. The V1 domain catalyzes the hydrolysis of ATP in order to power the pumping of protons through the V0 channel, which spans the lipid bilayer of endosomal compartments. Vacuolar ATPases are also localized within the plasma membrane of both renal cells and osteoclasts. In osteoclasts, V-ATPases are required for pumping protons onto the bone surface. The protons are then used for bone resorption. In renal cells, V-ATPases are used to pump protons into the urine. This facilitates bicarbonate reabsorption into the blood. The ATP6V0A2 gene encodes the a2 isoform of the a-subunit (present in the V0 domain). The a2 subunit anchors the V-ATPase to the membrane, and it is also directly involved with proton transport. ATP6V0A2 is encoded by the ATP6V0A2 gene. The ATP6V0A2 pump is found in virtually all cells and is thought to play an important role in the process of vesicular fusion in the secretory pathway, including the secretion of extracellular matrix components. Function of the Golgi apparatus in protein maturation The most important subcellular structure in the context of wrinkly skin syndrome (WSS), is the Golgi apparatus. The Golgi apparatus is an important part of the endomembrane system because it processes proteins and lipids prior to their delivery to the plasma membrane and/or secretion into the extracellular environment. The Golgi is organized into a polarized series of membrane-bound stacks, called cisternae, through which proteins are trafficked in sequence once they leave the endoplasmic reticulum (ER), where the proteins and lipids are synthesized. Proteins destined for secretion or delivery to the plasma membrane arrive first at the cis-Golgi, before being trafficked through the medial and trans-Golgi. In the Golgi, proteins undergo extensive post-translational modifications (PTMs). In the context of WSS, the most significant PTM events are the glycosylation of proteins comprising the extracellular matrix (ECM) of epidermal cells. The two types of glycosylation events in the Golgi are N-linked glycosylation and O-linked glycosylation. Glycosylation of proteins destined for secretion occurs through the forward movement of proteins throughout the Golgi apparatus. The proteins destined for secretion are then trafficked to the plasma membrane in secretory vesicles. Retrograde (backward) transport in the Golgi apparatus is also important. In order to retain the enzymes responsible for protein glycosylation in the correct regions of the Golgi, there must be retrograde transport of these enzymes back into the Golgi apparatus. In addition, retrograde transport serves a quality control function, by shuttling misfolded proteins back into the ER or retaining them within the Golgi itself until proper protein folding and maturation is completed. The activity of protein-modifying enzymes, like glycosyltransferases and glycosidases, relies on the lumenal pH of the Golgi apparatus. Cisternal pH becomes increasingly acidic (lower pH) with progression from cis- to trans- regions of the Golgi. Disruption of decreasing pH can impart significant effects on the efficiency and sequence of glycosylation events. Maintenance of the pH gradient across the Golgi is instrumental for proper post-translational modification of proteins prior to secretion. Retrograde transport and pH regulation are therefore vital to the proper functioning of the Golgi apparatus. Genetic causes of WSS Patients with both missense and/or nonsense mutations of the ATP6V0A2 gene have been shown to phenotypically express wrinkly skin syndrome (WSS) or autosomal recessive cutis laxa type II (ARCL II) (another cutis laxa disorder). Some consider WSS to be a milder variant of ARCL II, but the genetic causes of WSS are not yet known. A large number of patients with WSS and ARCL II show a loss-of-function in the a2-subunit. These mutations in ATP6V0A2 are associated with defective glycan biosynthesis and defective Golgi apparatus structure. However, the exact mechanism of how mutations in the ATP6V0A2 gene lead to these effects is unclear. Aberrant Golgi functioning and clinical symptoms of WSS WSS is characterized by defects in the elastic fiber system that comprises the extracellular matrix of epidermal cells. The skins elastic fiber system consists of elastin (which is normally non-glycosylated) and glycosylated proteins (fibulin, fibronectin, and collagen). It is speculated that either abnormal glycosylation and/or impaired secretion of proteins caused by ATP6V0A2 dysfunction lead to WSS. The ATP6V0A2 pump is highly expressed within the Golgi apparatus. ATP6V0A2 is primarily found within the medial-Golgi and the trans-Golgi. ATP6V0A2 acidifies the medial- and trans-Golgi so that their resident enzymes (e.g. glycosidases and glycosyltransferases) function properly. Therefore, mutations in the ATP6V0A2 gene reduce the ability of ATP6V0A2 to produce the necessary pH gradient for these glycosylation enzymes, which results in abnormal N- and O-linked glycosylation. Because the physical properties of skin rely heavily on the structural proteins of the elastic fiber system of epidermal cells, abnormal glycosylation can lead to structural defects in the elastic fibers, and therefore lead to the inelastic skin seen in WSS. WSS patients may also have defective secretion of another ECM component of the skin called tropoelastin. The process of secreting tropoelastin from the cell is dependent on the acidic pH of vesicles. It is thought that increased pH levels (lower acidity) lead to the premature aggregation (coacervation) of tropoelastin inside the vesicle. The process of coacervation is thought to be essential for proper elastin assembly in the ECM. Coacervation must occur outside of the cell within the ECM ( the ECM has a more alkaline environment than the vesicle) for proper elastic fiber assembly. However, defective ATP6V0A2 pumps in the vesicle increase the lumenal pH of the vesicle, leading to premature coacervation and defective elastic fiber assembly. The abnormal assembly and glycosylation of proteins used to make elastic fibers explains the connective tissue phenotypes associated with ARCL2 and WSS but does not explain the neurodevelopmental disorders or growth defects of these patients (18). Elastin is not required for brain or bone growth. However, it is believed that abnormal/impaired secretion of the brain and bone-specific ECM proteins caused by dysregulation of Golgi acidification is what leads to the neural and skeletal defects in ARCL2. Diagnosis Accurate diagnosis of wrinkly skin syndrome generally requires specialized dermatological assessment. In addition to assessment of clinical physical symptoms, diagnosis may be aided by: x-rays to identify joint abnormalities ophthalmologic evaluation of hypertelorism, downslanting eyes, and myopia brain MRI scans to evaluate the degree of microcephaly genetic screening for congenital disorders of glycosylation (CDG) skin biopsy and histological analysis genetic screening for mutations in the ATP6VOA2 geneThe pigmentation patterns observed in skin biopsies reveal a characteristic lack of elastic fibers in the papillary dermis and clumping of elastic fibers in the reticular dermis. Despite assessment of each of these diagnostic factors, a definitive diagnosis differentiating WSS from cutis laxa requires genetic testing. Differential diagnosis Several symptoms are shared with cutis laxa type II (CLT2) including wrinkling of skin, microcephaly, and developmental delay which has made proper diagnosis difficult in several cases. However, the severity of skin abnormalities and facial dysmorphia is greater in cutis laxa type II. Management While there is no corrective cure for the disease, some symptoms can be managed therapeutically and/or monitored. Therapeutic treatment options include physical therapy to improve muscular development while patient growth and osteoporosis can be monitored via developmental assessments and bone density scans, respectively. Prognosis Long-term progression of this disorder varies between patients. Due to therapeutic interventions for developmental symptoms, long-term outcomes are improved by diagnosis of the disorder during childhood. In some cases, dermatological symptoms subside while associated neurological symptoms may worsen with age, including frequency of seizures and mental deterioration. Epidemiology As of January 2020, only ~ 30 cases of wrinkly skin syndrome have been reported. The majority of reported cases have come from Middle Eastern regions such as Iraq, Saudi Arabia, and Oman. Both males and females of Middle Eastern descent have been reported to be affected. Consanguineous (marriage of first-cousins) relationships are a prevalent feature of parents with children diagnosed with WSS. Such marriages and relationships are more common in Middle Eastern regions. Multiple children of the same parents have also been reported to be affected by WSS. There is currently insufficient epidemiological data to provide frequency of WSS occurrence in other ethnic groups. History Wrinkly skin syndrome is a very rare disease that was amenable to molecular diagnosis only recently. Consequently, the history of this disease has been minimally documented. However, in 1973, "wrinkly skin syndrome" received its name because of its characterized features of exceedingly wrinkled skin in the hands and feet in Iraqui-Jewish first-cousins. In the same year, WSS was established as a new heritable disorder of connective tissue that appeared to be transmitted as an . In 1993, WSS was diagnosed in a mother and her son. Both patients displayed decreased elastic recoil of the skin and an increase in the number of palmar creases. In 1999, there were up to nine reported cases of WSS. In 2008, Kornak et al. investigated glycosylation of serum proteins with individuals with WSS and found that they had defects in N-glycosylation at the level of the Golgi apparatus. References NIH GARD (Genetic and Rare Diseases Information Center) Monarch Initiative Online Mendelian Inheritance in Man Database See also Ehlers–Danlos syndrome Cutis Laxa Type II List of cutaneous conditions References == External links ==
Neonatal stroke	Neonatal stroke, similar to a stroke which occurs in adults, is defined as a disturbance to the blood supply of the developing brain in the first 28 days of life. This description includes both ischemic events, which results from a blockage of vessels, and hypoxic events, which results from a lack of oxygen to the brain tissue, as well as some combination of the two. One treatment with some proven benefits is hypothermia, but may be most beneficial in conjunction with pharmacological agents. Well-designed clinical trials for stroke treatment in neonates are lacking, but some current studies involve the transplantation of neural stem cells and umbilical cord stem cells; it is not yet known if this therapy is likely to be successful.Neonatal strokes may lead to cerebral palsy, learning difficulties, or other disabilities. A neonatal stroke occurs in approximately 1 in 4000 births, but is likely much higher due to the lack of noticeable symptoms. Presentation A neonatal stroke is one that occurs in the first 28 days of life, though a late presentation is not uncommon (as contrasted with perinatal stroke, which occurs from 28 weeks gestation through the first 7 days of life). 80% of neonatal strokes are ischemic, and their presentation is varied, making diagnosis very difficult. The most common manifestation of neonatal strokes are seizures, but other manifestations include lethargy, hypotonia, apnoea, and hemiparesis. Seizures can be focal or generalized in nature. Stroke accounts for about 10% of seizures in term neonates. Risk factors Many different risk factors play a role in causing a neonatal stroke. Some maternal disorders that may contribute to neonatal strokes include: autoimmune disorders, coagulation disorders, prenatal cocaine exposure, infection, congenital heart disease, diabetes, and trauma. Placental disorders that increase the risk of stroke include placental thrombosis, placental abruption, placental infection, and chorioamnionitis. Other disorders that may increase the risk of a neonatal stroke are blood, homocysteine and lipid disorders, such as polycythemia, disseminated intravascular coagulopathy, prothrombin mutation, lipoprotein (a) deficiency, factor VIII deficiency (hemophilia A), and factor V Leiden mutation. Infectious disorders such as central nervous system (CNS) infection or systemic infection may also contribute.Many infants who have a neonatal stroke also follow an uncomplicated pregnancy and delivery without identifiable risk factors, which exemplifies the necessity for further research on this subject. Mechanism A neonatal stroke in the developing brain involves excitotoxicity, oxidative stress, and inflammation, which accelerate cell death through necrosis or apoptosis, depending on the region of the brain and severity of stroke. The pathophysiology of neonatal stroke may include thrombosis and thrombolysis, and vascular reactivity. Apoptosis mechanisms may have a more prominent role in developing an ischemic brain injury in neonatal humans than in adult brain ischemia, as a majority of cells die in the environment where edema developed after a neonatal stroke. There is an increased inflammatory response after hypoxia-ischemia, which corresponds to extensive neuronal apoptosis. Apoptosis involves the mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF), which activate caspase-dependent and –independent execution pathways, respectively. Injury may also occur due to O2 accumulation via the production of O2 by microglia, a type of glial cell that are responsible for immune response in the CNS, but their role in injury after neonatal stroke is still relatively unknown. As observed by Alberi, et al., progressive atrophy in the ipsilateral hemisphere over three weeks after the stroke occurred, suggesting that a neonatal stroke has long-lasting effects on neuronal viability and the potential for a prolonged therapeutic window for alleviating the progression of cell death. Diagnosis Neonatal strokes occur in approximately 1 in 4000 births, but this number is likely much higher due to lack of noticeable symptoms at time of birth. They generally present with seizures, but only half to three quarters of cases have identifiable causes. Diagnosis often occurs around 36 hours after onset of neonatal stroke due to the interval between stroke and clinical presentation, if any occurs at all. Neonatal strokes can be confirmed with neuroimaging or neuropathalogical studies, and other various imaging techniques can be used to diagnose neonatal strokes, such as ultrasound, Doppler sonography, computerized tomography (CT) scan, CT angiography, and multimodal MR. Prevention Some evidence suggests that magnesium sulfate administered to mothers prior to early preterm birth reduces the risk of cerebral palsy in surviving neonates. Due to the risk of adverse effects treatments may have, it is unlikely that treatments to prevent neonatal strokes or other hypoxic events would be given routinely to pregnant women without evidence that their fetus was at extreme risk or has already sustained an injury or stroke. This approach might be more acceptable if the pharmacologic agents were endogenously occurring substances (those that occur naturally in an organism), such as creatine or melatonin, with no adverse side-effects. Because of the period of high neuronal plasticity in the months after birth, it may be possible to improve the neuronal environment immediately after birth in neonates considered to be at risk of neonatal stroke. This may be done by enhancing the growth of axons and dendrites, synaptogenesis and myelination of axons with systemic injections of neurotrophins or growth factors which can cross the blood–brain barrier. Treatment Treatment remains controversial with regards to the risk/benefit ratio, which differs significantly from treatment of stroke in adults. Presence or possibility of organ or limb impairment and bleeding risks are possible with treatments using antithrombotic agents. Therapeutic Hypothermia Hypothermia treatment induced by head cooling or systemic cooling administered within 6 hours of birth for 72 hours has proven beneficial in reducing death and neurological impairments at 18 months of age. This treatment does not completely protect the injured brain and may not improve the risk of death in the most severely hypoxic-ischemic neonates and has also not been proven beneficial in preterm infants. Combined therapies of hypothermia and pharmacological agents or growth factors to improve neurological outcomes are most likely the next direction for damaged neonatal brains, such as after a stroke. Other Treatments A successful use of urokinase in a newborn with an aortic clot has been reported, but the bleeding risks associated with thrombolytic agents are still unclear.Heparin, an anticoagulant, treatments have been used in cases of cerebro-venous sinus thrombosis (CVST) in order to stop thrombosis extension and recurrence, to induce thrombosis resolution, and to prevent further brain damage. In the case of extremely high intracranial pressure, surgical removal of hematoma may be beneficial. Prognosis Of the infants that survive, there may be as many as 1 million a year that develop cerebral palsy, learning difficulties or other disabilities. Cerebral palsy is the most common physical disability in childhood, and it is characterized by a lack of control of movement. Other neurological defects that can occur after a neonatal stroke include hemiparesis and hemi-sensory impairments Some studies suggest that when tested as toddlers and preschoolers, children who previously had neonatal strokes fall within normal ranges of cognitive development. Less is known about longer-term cognitive outcome, but there has been evidence that cognitive deficits may emerge later in childhood when more complex cognitive processes are expected to develop. Research Direction Well-designed clinical trials for stroke treatment in neonates are lacking Recent clinical trials show that therapeutic intervention by brain cooling beginning up to 6 hours after perinatal asphyxia reduces cerebral injury and may improve outcome in term infants, indicating cell death is both delayed and preventable Pancaspase inhibition and Casp3-selective inhibition have been found to be neuroprotective in neonatal rodents with models of neonatal brain injury, which may lead to pharmacological intervention In a study done by Chauvier, et al., it is suggested that a Caspase inhibitor, TRP601, is a candidate for neuroprotective strategy in prenatal brain injury conditions. They found a lack of detectable side effects in newborn rodents and dogs. This may be a useful treatment in combination with hypothermia.MRI has proven valuable for defining brain injury in the neonate, but animal models are still needed to identify causative mechanisms and to develop neuroprotective therapies. In order to model human fetal or neonatal brain injury, one needs a species in which a similar proportion of brain development occurs in utero, the volume of white to grey matter is similar to the human brain, an insult can be delivered at an equivalent stage of development, the physiological outcome of the insult can be monitored, and neurobehavioral parameters can be tested. Some animals that meet these criteria are sheep, non-human primates, rabbits, spiny mice, and guinea pigs.Transplantation of neural stem cells and umbilical cord stem cells is currently being trialed in neonatal brain injury, but it is not yet known if this therapy is likely to be successful. References Further reading Nelson, KB; Lynch, JK (March 2004). "Stroke in newborn infants". Lancet Neurology. 3 (3): 150–8. doi:10.1016/s1474-4422(04)00679-9. PMID 14980530. S2CID 11194017. Nelson, K. B. (29 January 2007). "Perinatal Ischemic Stroke". Stroke. 38 (2): 742–745. doi:10.1161/01.STR.0000247921.97794.5e. PMID 17261729. Rutherford, MA; Ramenghi, LA; Cowan, FM (September 2012). "Neonatal stroke". Archives of Disease in Childhood: Fetal and Neonatal Edition. 97 (5): F377-84. doi:10.1136/fetalneonatal-2010-196451. PMID 22933099. S2CID 32645328. Perinatal Stroke-Classification Unique Approach to Neonatal Stroke Treatment
Subclinical infection	A subclinical infection — sometimes called a preinfection or inapparent infection — is an infection that, being subclinical, is nearly or completely asymptomatic (no signs or symptoms). A subclinically infected person is thus a paucisymptomatic or asymptomatic carrier of a microbe, intestinal parasite, or virus that usually is a pathogen causing illness, at least in some individuals. Many pathogens spread by being silently carried in this way by some of their host population. Such infections occur both in humans and animals.An example of an asymptomatic infection is a mild common cold that is not noticed by the infected individual. Since subclinical infections often occur without eventual overt sign, their existence is only identified by microbiological culture or DNA techniques such as polymerase chain reaction. Infection transmission/signs An individual may only develop signs of an infection after a period of subclinical infection, a duration that is called the incubation period. This is the case, for example, for subclinical sexually transmitted diseases such as AIDS and genital warts. It is thought that individuals with such subclinical infections, and those that never develop overt illness, creates a reserve of individuals that can transmit an infectious agent to infect other individuals. Because such cases of infections do not come to clinical attention, health statistics can often fail to measure the true prevalence of an infection in a population, and this prevents the accurate modeling of its infectious transmission. Types of subclinical infections The following pathogens (together with their symptomatic illnesses) are known to be carried asymptomatically, often in a large percentage of the potential host population: Host tolerance Fever and sickness behavior and other signs of infection are often taken to be due to them. However, they are evolved physiological and behavioral responses of the host to clear itself of the infection. Instead of incurring the costs of deploying these evolved responses to infections, the body opts to tolerate an infection as an alternative to seeking to control or remove the infecting pathogen.Subclinical infections are important since they allow infections to spread from a reserve of carriers. They also can cause clinical problems unrelated to the direct issue of infection. For example, in the case of urinary tract infections in women, this infection may cause preterm delivery if the person becomes pregnant without proper treatment. See also References Further reading Endara, Pablo; Trueba, Gabriel; Solberg, Owen D.; Bates, Sarah J.; Ponce, Karina; Cevallos, William; Matthijnssens, Jelle; Eisenberg, Joseph N.S. (April 2007). "Symptomatic and Subclinical Infection with Rotavirus P[8]G9, Rural Ecuador". Emerging Infectious Diseases. 13 (4): 574–580. doi:10.3201/eid1304.061285. PMC 2391297. PMID 17553272.
Pineoblastoma	Pineoblastoma is a malignant tumor of the pineal gland. A pineoblastoma is a supratentorial midline primitive neuroectodermal tumor.Pineoblastoma may occur in patients with hereditary uni- or bilateral retinoblastoma. When retinoblastoma patients present with pineoblastoma this is characterized as "trilateral retinoblastoma". Up to 5% of patients with hereditary retinoblastoma are at risk of developing trilateral retinoblastoma. Prognosis of patients with trilateral retinoblastoma is dismal, only a few patients have survived more than 5 years after diagnosis; all survivors were diagnosed with small tumors in a subclinical stage. Recent advances in (high-dose) chemotherapy treatment regimens and early detection have improved survival of patients with trilateral retinoblastoma to up to 50%. References == External links ==
Insomnia	Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, irritability, and a depressed mood. It may result in an increased risk of motor vehicle collisions, as well as problems focusing and learning. Insomnia can be short term, lasting for days or weeks, or long term, lasting more than a month. The concept of the word insomnia has two possibilities: insomnia disorder and insomnia symptoms, and many abstracts of randomized controlled trials and systematic reviews often underreport on which of these two possibilities the word insomnia refers to.Insomnia can occur independently or as a result of another problem. Conditions that can result in insomnia include psychological stress, chronic pain, heart failure, hyperthyroidism, heartburn, restless leg syndrome, menopause, certain medications, and drugs such as caffeine, nicotine, and alcohol. Other risk factors include working night shifts and sleep apnea. Diagnosis is based on sleep habits and an examination to look for underlying causes. A sleep study may be done to look for underlying sleep disorders. Screening may be done with two questions: "do you experience difficulty sleeping?" and "do you have difficulty falling or staying asleep?"Although their efficacy as first line treatments is not unequivocally established, sleep hygiene and lifestyle changes are typically the first treatment for insomnia. Sleep hygiene includes a consistent bedtime, a quiet and dark room, exposure to sunlight during the day and regular exercise. Cognitive behavioral therapy may be added to this. While sleeping pills may help, they are sometimes associated with injuries, dementia, and addiction. These medications are not recommended for more than four or five weeks. The effectiveness and safety of alternative medicine is unclear.Between 10% and 30% of adults have insomnia at any given point in time and up to half of people have insomnia in a given year. About 6% of people have insomnia that is not due to another problem and lasts for more than a month. People over the age of 65 are affected more often than younger people. Females are more often affected than males. Descriptions of insomnia occur at least as far back as ancient Greece. Signs and symptoms Symptoms of insomnia: Difficulty falling asleep, including difficulty finding a comfortable sleeping position Waking during the night, being unable to return to sleep and waking up early Not able to focus on daily tasks, difficulty in remembering Daytime sleepiness, irritability, depression or anxiety Feeling tired or having low energy during the day Trouble concentrating Being irritable, acting aggressive or impulsiveSleep onset insomnia is difficulty falling asleep at the beginning of the night, often a symptom of anxiety disorders. Delayed sleep phase disorder can be misdiagnosed as insomnia, as sleep onset is delayed to much later than normal while awakening spills over into daylight hours.It is common for patients who have difficulty falling asleep to also have nocturnal awakenings with difficulty returning to sleep. Two-thirds of these patients wake up in the middle of the night, with more than half having trouble falling back to sleep after a middle-of-the-night awakening.Early morning awakening is an awakening occurring earlier (more than 30 minutes) than desired with an inability to go back to sleep, and before total sleep time reaches 6.5 hours. Early morning awakening is often a characteristic of depression. Anxiety symptoms may well lead to insomnia. Some of these symptoms include tension, compulsive worrying about the future, feeling overstimulated, and overanalyzing past events. Poor sleep quality Poor sleep quality can occur as a result of, for example, restless legs, sleep apnea or major depression. Poor sleep quality is defined as the individual not reaching stage 3 or delta sleep which has restorative properties.Major depression leads to alterations in the function of the hypothalamic–pituitary–adrenal axis, causing excessive release of cortisol which can lead to poor sleep quality. Nocturnal polyuria, excessive nighttime urination, can also result in a poor quality of sleep. Subjectivity Some cases of insomnia are not really insomnia in the traditional sense, because people experiencing sleep state misperception often sleep for a normal amount of time. The problem is that, despite sleeping for multiple hours each night and typically not experiencing significant daytime sleepiness or other symptoms of sleep loss, they do not feel like they have slept very much, if at all. Because their perception of their sleep is incomplete, they incorrectly believe it takes them an abnormally long time to fall asleep, and they underestimate how long they remain asleep. Causes Symptoms of insomnia can be caused by or be associated with: Sleep breathing disorders, such as sleep apnea or upper airway resistance syndrome Use of psychoactive drugs (such as stimulants), including certain medications, herbs, caffeine, nicotine, cocaine, amphetamines, methylphenidate, aripiprazole, MDMA, modafinil, or excessive alcohol intake Use of or withdrawal from alcohol and other sedatives, such as anti-anxiety and sleep drugs like benzodiazepines Use of or withdrawal from pain-relievers such as opioids Heart disease Restless legs syndrome, which can cause sleep onset insomnia due to the discomforting sensations felt and the need to move the legs or other body parts to relieve these sensations Periodic limb movement disorder (PLMD), which occurs during sleep and can cause arousals of which the sleeper is unaware Pain: an injury or condition that causes pain can preclude an individual from finding a comfortable position in which to fall asleep, and can also cause awakening. Hormone shifts such as those that precede menstruation and those during menopause Life events such as fear, stress, anxiety, emotional or mental tension, work problems, financial stress, birth of a child, and bereavement Gastrointestinal issues such as heartburn or constipation Mental, neurobehavioral, or neurodevelopmental disorders such as bipolar disorder, clinical depression, generalized anxiety disorder, post traumatic stress disorder, schizophrenia, obsessive compulsive disorder, autism, dementia,: 326 ADHD, Asperger syndrome, and FASD Disturbances of the circadian rhythm, such as shift work and jet lag, can cause an inability to sleep at some times of the day and excessive sleepiness at other times of the day. Chronic circadian rhythm disorders are characterized by similar symptoms. Certain neurological disorders such as brain lesions, or a history of traumatic brain injury Medical conditions such as hyperthyroidism Abuse of over-the-counter or prescription sleep aids (sedative or depressant drugs) can produce rebound insomnia Poor sleep hygiene, e.g., noise or over-consumption of caffeine A rare genetic condition can cause a prion-based, permanent and eventually fatal form of insomnia called fatal familial insomnia Physical exercise: exercise-induced insomnia is common in athletes in the form of prolonged sleep onset latency Increased exposure to the blue light from artificial sources, such as phones or computers Chronic pain Lower back pain AsthmaSleep studies using polysomnography have suggested that people who have sleep disruption have elevated nighttime levels of circulating cortisol and adrenocorticotropic hormone. They also have an elevated metabolic rate, which does not occur in people who do not have insomnia but whose sleep is intentionally disrupted during a sleep study. Studies of brain metabolism using positron emission tomography (PET) scans indicate that people with insomnia have higher metabolic rates by night and by day. The question remains whether these changes are the causes or consequences of long-term insomnia. Genetics Heritability estimates of insomnia vary between 38% in males to 59% in females. A genome-wide association study (GWAS) identified 3 genomic loci and 7 genes that influence the risk of insomnia, and showed that insomnia is highly polygenic. In particular, a strong positive association was observed for the MEIS1 gene in both males and females. This study showed that the genetic architecture of insomnia strongly overlaps with psychiatric disorders and metabolic traits. It has been hypothesised that the epigenetics might also influence insomnia through a controlling process of both sleep regulation and brain-stress response having an impact as well on the brain plasticity. Substance-induced Alcohol-induced Alcohol is often used as a form of self-treatment of insomnia to induce sleep. However, alcohol use to induce sleep can be a cause of insomnia. Long-term use of alcohol is associated with a decrease in NREM stage 3 and 4 sleep as well as suppression of REM sleep and REM sleep fragmentation. Frequent moving between sleep stages occurs, with awakenings due to headaches, the need to urinate, dehydration, and excessive sweating. Glutamine rebound also plays a role as when someone is drinking; alcohol inhibits glutamine, one of the bodys natural stimulants. When the person stops drinking, the body tries to make up for lost time by producing more glutamine than it needs. The increase in glutamine levels stimulates the brain while the drinker is trying to sleep, keeping him/her from reaching the deepest levels of sleep. Stopping chronic alcohol use can also lead to severe insomnia with vivid dreams. During withdrawal REM sleep is typically exaggerated as part of a rebound effect. Benzodiazepine-induced Like alcohol, benzodiazepines, such as alprazolam, clonazepam, lorazepam, and diazepam, are commonly used to treat insomnia in the short-term (both prescribed and self-medicated), but worsen sleep in the long-term. While benzodiazepines can put people to sleep (i.e., inhibit NREM stage 1 and 2 sleep), while asleep, the drugs disrupt sleep architecture: decreasing sleep time, delaying time to REM sleep, and decreasing deep slow-wave sleep (the most restorative part of sleep for both energy and mood). Opioid-induced Opioid medications such as hydrocodone, oxycodone, and morphine are used for insomnia that is associated with pain due to their analgesic properties and hypnotic effects. Opioids can fragment sleep and decrease REM and stage 2 sleep. By producing analgesia and sedation, opioids may be appropriate in carefully selected patients with pain-associated insomnia. However, dependence on opioids can lead to long-term sleep disturbances. Risk factors Insomnia affects people of all age groups but people in the following groups have a higher chance of acquiring insomnia: Individuals older than 60 History of mental health disorder including depression, etc. Emotional stress Working late night shifts Traveling through different time zones Having chronic diseases such as diabetes, kidney disease, lung disease, Alzheimers, or heart disease Alcohol or drug use disorders Gastrointestinal reflux disease Heavy smoking Work stress Mechanism Two main models exists as to the mechanism of insomnia, cognitive and physiological. The cognitive model suggests rumination and hyperarousal contribute to preventing a person from falling asleep and might lead to an episode of insomnia. The physiological model is based upon three major findings in people with insomnia; firstly, increased urinary cortisol and catecholamines have been found suggesting increased activity of the HPA axis and arousal; second, increased global cerebral glucose utilization during wakefulness and NREM sleep in people with insomnia; and lastly, increased full body metabolism and heart rate in those with insomnia. All these findings taken together suggest a dysregulation of the arousal system, cognitive system, and HPA axis all contributing to insomnia. However, it is unknown if the hyperarousal is a result of, or cause of insomnia. Altered levels of the inhibitory neurotransmitter GABA have been found, but the results have been inconsistent, and the implications of altered levels of such a ubiquitous neurotransmitter are unknown. Studies on whether insomnia is driven by circadian control over sleep or a wake dependent process have shown inconsistent results, but some literature suggests a dysregulation of the circadian rhythm based on core temperature. Increased beta activity and decreased delta wave activity has been observed on electroencephalograms; however, the implication of this is unknown.Around half of post-menopausal women experience sleep disturbances, and generally sleep disturbance is about twice as common in women as men; this appears to be due in part, but not completely, to changes in hormone levels, especially in and post-menopause.Changes in sex hormones in both men and women as they age may account in part for increased prevalence of sleep disorders in older people. Diagnosis In medicine, insomnia is widely measured using the Athens insomnia scale. It is measured using eight different parameters related to sleep, finally represented as an overall scale which assesses an individuals sleep pattern. A qualified sleep specialist should be consulted for the diagnosis of any sleep disorder so the appropriate measures can be taken. Past medical history and a physical examination need to be done to eliminate other conditions that could be the cause of insomnia. After all other conditions are ruled out a comprehensive sleep history should be taken. The sleep history should include sleep habits, medications (prescription and non-prescription), alcohol consumption, nicotine and caffeine intake, co-morbid illnesses, and sleep environment. A sleep diary can be used to keep track of the individuals sleep patterns. The diary should include time to bed, total sleep time, time to sleep onset, number of awakenings, use of medications, time of awakening, and subjective feelings in the morning. The sleep diary can be replaced or validated by the use of out-patient actigraphy for a week or more, using a non-invasive device that measures movement.Workers who complain of insomnia should not routinely have polysomnography to screen for sleep disorders. This test may be indicated for patients with symptoms in addition to insomnia, including sleep apnea, obesity, a thick neck diameter, or high-risk fullness of the flesh in the oropharynx. Usually, the test is not needed to make a diagnosis, and insomnia especially for working people can often be treated by changing a job schedule to make time for sufficient sleep and by improving sleep hygiene.Some patients may need to do an overnight sleep study to determine if insomnia is present. Such a study will commonly involve assessment tools including a polysomnogram and the multiple sleep latency test. Specialists in sleep medicine are qualified to diagnose disorders within the, according to the ICSD, 81 major sleep disorder diagnostic categories. Patients with some disorders, including delayed sleep phase disorder, are often mis-diagnosed with primary insomnia; when a person has trouble getting to sleep and awakening at desired times, but has a normal sleep pattern once asleep, a circadian rhythm disorder is a likely cause. In many cases, insomnia is co-morbid with another disease, side-effects from medications, or a psychological problem. Approximately half of all diagnosed insomnia is related to psychiatric disorders. For those who have depression, "insomnia should be regarded as a co-morbid condition, rather than as a secondary one;" insomnia typically predates psychiatric symptoms. "In fact, it is possible that insomnia represents a significant risk for the development of a subsequent psychiatric disorder." Insomnia occurs in between 60% and 80% of people with depression. This may partly be due to treatment used for depression.Determination of causation is not necessary for a diagnosis. DSM-5 criteria The DSM-5 criteria for insomnia include the following:Predominant complaint of dissatisfaction with sleep quantity or quality, associated with one (or more) of the following symptoms: Difficulty initiating sleep. (In children, this may manifest as difficulty initiating sleep without caregiver intervention.) Difficulty maintaining sleep, characterized by frequent awakenings or problems returning to sleep after awakenings. (In children, this may manifest as difficulty returning to sleep without caregiver intervention.) Early-morning awakening with inability to return to sleep.In addition: The sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning. The sleep difficulty occurs at least 3 nights per week. The sleep difficulty is present for at least 3 months. The sleep difficulty occurs despite adequate opportunity for sleep. The insomnia is not better explained by and does not occur exclusively during the course of another sleep-wake disorder (e.g., narcolepsy, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a parasomnia). The insomnia is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication). Coexisting mental disorders and medical conditions do not adequately explain the predominant complaint of insomnia. Types Insomnia can be classified as transient, acute, or chronic. Transient insomnia lasts for less than a week. It can be caused by another disorder, by changes in the sleep environment, by the timing of sleep, severe depression, or by stress. Its consequences – sleepiness and impaired psychomotor performance – are similar to those of sleep deprivation. Acute insomnia is the inability to consistently sleep well for a period of less than a month. Insomnia is present when there is difficulty initiating or maintaining sleep or when the sleep that is obtained is non-refreshing or of poor quality. These problems occur despite adequate opportunity and circumstances for sleep and they must result in problems with daytime function. Acute insomnia is also known as short term insomnia or stress related insomnia. Chronic insomnia lasts for longer than a month. It can be caused by another disorder, or it can be a primary disorder. Common causes of chronic insomnia include persistent stress, trauma, work schedules, poor sleep habits, medications, and other mental health disorders. People with high levels of stress hormones or shifts in the levels of cytokines are more likely than others to have chronic insomnia. Its effects can vary according to its causes. They might include muscular weariness, hallucinations, and/or mental fatigue. Prevention Prevention and treatment of insomnia may require a combination of cognitive behavioral therapy, medications, and lifestyle changes.Among lifestyle practices, going to sleep and waking up at the same time each day can create a steady pattern which may help to prevent insomnia. Avoidance of vigorous exercise and caffeinated drinks a few hours before going to sleep is recommended, while exercise earlier in the day may be beneficial. Other practices to improve sleep hygiene may include: Avoiding or limiting naps Treating pain at bedtime Avoiding large meals, beverages, alcohol, and nicotine before bedtime Finding soothing ways to relax into sleep, including use of white noise Making the bedroom suitable for sleep by keeping it dark, cool, and free of devices, such as clocks, cell phones, or televisions Maintain regular exercise Try relaxing activities before sleeping Management It is recommended to rule out medical and psychological causes before deciding on the treatment for insomnia. Cognitive behavioral therapy is generally the first line treatment once this has been done. It has been found to be effective for chronic insomnia. The beneficial effects, in contrast to those produced by medications, may last well beyond the stopping of therapy.Medications have been used mainly to reduce symptoms in insomnia of short duration; their role in the management of chronic insomnia remains unclear. Several different types of medications may be used. Many doctors do not recommend relying on prescription sleeping pills for long-term use. It is also important to identify and treat other medical conditions that may be contributing to insomnia, such as depression, breathing problems, and chronic pain. As of 2022, many people with insomnia were reported as not receiving overall sufficient sleep or treatment for insomnia. Non-medication based Non-medication based strategies have comparable efficacy to hypnotic medication for insomnia and they may have longer lasting effects. Hypnotic medication is only recommended for short-term use because dependence with rebound withdrawal effects upon discontinuation or tolerance can develop.Non medication based strategies provide long lasting improvements to insomnia and are recommended as a first line and long-term strategy of management. Behavioral sleep medicine (BSM) tries to address insomnia with non-pharmacological treatments. The BSM strategies used to address chronic insomnia include attention to sleep hygiene, stimulus control, behavioral interventions, sleep-restriction therapy, paradoxical intention, patient education, and relaxation therapy. Some examples are keeping a journal, restricting the time spent awake in bed, practicing relaxation techniques, and maintaining a regular sleep schedule and a wake-up time. Behavioral therapy can assist a patient in developing new sleep behaviors to improve sleep quality and consolidation. Behavioral therapy may include, learning healthy sleep habits to promote sleep relaxation, undergoing light therapy to help with worry-reduction strategies and regulating the circadian clock.Music may improve insomnia in adults (see music and sleep). EEG biofeedback has demonstrated effectiveness in the treatment of insomnia with improvements in duration as well as quality of sleep. Self-help therapy (defined as a psychological therapy that can be worked through on ones own) may improve sleep quality for adults with insomnia to a small or moderate degree.Stimulus control therapy is a treatment for patients who have conditioned themselves to associate the bed, or sleep in general, with a negative response. As stimulus control therapy involves taking steps to control the sleep environment, it is sometimes referred interchangeably with the concept of sleep hygiene. Examples of such environmental modifications include using the bed for sleep and sex only, not for activities such as reading or watching television; waking up at the same time every morning, including on weekends; going to bed only when sleepy and when there is a high likelihood that sleep will occur; leaving the bed and beginning an activity in another location if sleep does not occur in a reasonably brief period of time after getting into bed (commonly ~20 min); reducing the subjective effort and energy expended trying to fall asleep; avoiding exposure to bright light during nighttime hours, and eliminating daytime naps.A component of stimulus control therapy is sleep restriction, a technique that aims to match the time spent in bed with actual time spent asleep. This technique involves maintaining a strict sleep-wake schedule, sleeping only at certain times of the day and for specific amounts of time to induce mild sleep deprivation. Complete treatment usually lasts up to 3 weeks and involves making oneself sleep for only a minimum amount of time that they are actually capable of on average, and then, if capable (i.e. when sleep efficiency improves), slowly increasing this amount (~15 min) by going to bed earlier as the body attempts to reset its internal sleep clock. Bright light therapy may be effective for insomnia.Paradoxical intention is a cognitive reframing technique where the insomniac, instead of attempting to fall asleep at night, makes every effort to stay awake (i.e. essentially stops trying to fall asleep). One theory that may explain the effectiveness of this method is that by not voluntarily making oneself go to sleep, it relieves the performance anxiety that arises from the need or requirement to fall asleep, which is meant to be a passive act. This technique has been shown to reduce sleep effort and performance anxiety and also lower subjective assessment of sleep-onset latency and overestimation of the sleep deficit (a quality found in many insomniacs). Sleep hygiene Sleep hygiene is a common term for all of the behaviors which relate to the promotion of good sleep. They include habits which provide a good foundation for sleep and help to prevent insomnia. However, sleep hygiene alone may not be adequate to address chronic insomnia. Sleep hygiene recommendations are typically included as one component of cognitive behavioral therapy for insomnia (CBT-I). Recommendations include reducing caffeine, nicotine, and alcohol consumption, maximizing the regularity and efficiency of sleep episodes, minimizing medication usage and daytime napping, the promotion of regular exercise, and the facilitation of a positive sleep environment. The creation of a positive sleep environment may also be helpful in reducing the symptoms of insomnia. Cognitive behavioral therapy There is some evidence that cognitive behavioral therapy for insomnia (CBT-I) is superior in the long-term to benzodiazepines and the nonbenzodiazepines in the treatment and management of insomnia. In this therapy, patients are taught improved sleep habits and relieved of counter-productive assumptions about sleep. Common misconceptions and expectations that can be modified include Unrealistic sleep expectations Misconceptions about insomnia causes Amplifying the consequences of insomnia Performance anxiety after trying for so long to have a good nights sleep by controlling the sleep processNumerous studies have reported positive outcomes of combining cognitive behavioral therapy for insomnia treatment with treatments such as stimulus control and the relaxation therapies. Hypnotic medications are equally effective in the short-term treatment of insomnia, but their effects wear off over time due to tolerance. The effects of CBT-I have sustained and lasting effects on treating insomnia long after therapy has been discontinued. The addition of hypnotic medications with CBT-I adds no benefit in insomnia. The long lasting benefits of a course of CBT-I shows superiority over pharmacological hypnotic drugs. Even in the short term when compared to short-term hypnotic medication such as zolpidem, CBT-I still shows significant superiority. Thus CBT-I is recommended as a first line treatment for insomnia.Common forms of CBT-I treatments include stimulus control therapy, sleep restriction, sleep hygiene, improved sleeping environments, relaxation training, paradoxical intention, and biofeedback. CBT is the well-accepted form of therapy for insomnia since it has no known adverse effects, whereas taking medications to alleviate insomnia symptoms have been shown to have adverse side effects. Nevertheless, the downside of CBT is that it may take a lot of time and motivation.Metacognition is a recent trend in approach to behaviour therapy of insomnia. Internet interventions Despite the therapeutic effectiveness and proven success of CBT, treatment availability is significantly limited by a lack of trained clinicians, poor geographical distribution of knowledgeable professionals, and expense. One way to potentially overcome these barriers is to use the Internet to deliver treatment, making this effective intervention more accessible and less costly. The Internet has already become a critical source of health-care and medical information. Although the vast majority of health websites provide general information, there is growing research literature on the development and evaluation of Internet interventions.These online programs are typically behaviorally-based treatments that have been operationalized and transformed for delivery via the Internet. They are usually highly structured; automated or human supported; based on effective face-to-face treatment; personalized to the user; interactive; enhanced by graphics, animations, audio, and possibly video; and tailored to provide follow-up and feedback.There is good evidence for the use of computer based CBT for insomnia. Medications Many people with insomnia use sleeping tablets and other sedatives. In some places medications are prescribed in over 95% of cases. They, however, are a second line treatment. In 2019, the US Food and Drug Administration stated it is going to require warnings for eszopiclone, zaleplon, and zolpidem, due to concerns about serious injuries resulting from abnormal sleep behaviors, including sleepwalking or driving a vehicle while asleep.The percentage of adults using a prescription sleep aid increases with age. During 2005–2010, about 4% of U.S. adults aged 20 and over reported that they took prescription sleep aids in the past 30 days. Rates of use were lowest among the youngest age group (those aged 20–39) at about 2%, increased to 6% among those aged 50–59, and reached 7% among those aged 80 and over. More adult women (5%) reported using prescription sleep aids than adult men (3%). Non-Hispanic white adults reported higher use of sleep aids (5%) than non-Hispanic black (3%) and Mexican-American (2%) adults. No difference was shown between non-Hispanic black adults and Mexican-American adults in use of prescription sleep aids. Antihistamines As an alternative to taking prescription drugs, some evidence shows that an average person seeking short-term help may find relief by taking over-the-counter antihistamines such as diphenhydramine or doxylamine. Diphenhydramine and doxylamine are widely used in nonprescription sleep aids. They are the most effective over-the-counter sedatives currently available, at least in much of Europe, Canada, Australia, and the United States, and are more sedating than some prescription hypnotics. Antihistamine effectiveness for sleep may decrease over time, and anticholinergic side-effects (such as dry mouth) may also be a drawback with these particular drugs. While addiction does not seem to be an issue with this class of drugs, they can induce dependence and rebound effects upon abrupt cessation of use. However, people whose insomnia is caused by restless legs syndrome may have worsened symptoms with antihistamines. Antidepressants While insomnia is a common symptom of depression, antidepressants are effective for treating sleep problems whether or not they are associated with depression. While all antidepressants help regulate sleep, some antidepressants, such as amitriptyline, doxepin, mirtazapine, trazodone, and trimipramine, can have an immediate sedative effect, and are prescribed to treat insomnia. Amitriptyline, doxepin, and trimipramine all have antihistaminergic, anticholinergic, antiadrenergic, and antiser
Insomnia	otonergic properties, which contribute to both their therapeutic effects and side effect profiles, while mirtazapines actions are primarily antihistaminergic and antiserotonergic and trazodones effects are primarily antiadrenergic and antiserotonergic. Mirtazapine is known to decrease sleep latency (i.e., the time it takes to fall asleep), promoting sleep efficiency and increasing the total amount of sleeping time in people with both depression and insomnia.Agomelatine, a melatonergic antidepressant with claimed sleep-improving qualities that does not cause daytime drowsiness, is approved for the treatment of depression though not sleep conditions in the European Union and Australia. After trials in the United States, its development for use there was discontinued in October 2011 by Novartis, who had bought the rights to market it there from the European pharmaceutical company Servier.A 2018 Cochrane review found the safety of taking antidepressants for insomnia to be uncertain with no evidence supporting long term use. Melatonin agonists Melatonin receptor agonists such as melatonin and ramelteon are used in the treatment of insomnia. The evidence for melatonin in treating insomnia is generally poor. There is low-quality evidence that it may speed the onset of sleep by 6 minutes. Ramelteon does not appear to speed the onset of sleep or the amount of sleep a person gets.Usage of melatonin as a treatment for insomnia in adults has increased from 0.4% between 1999 and 2000 to nearly 2.1% between 2017 and 2018. Most melatonin agonists have not been tested for longitudinal side effects. Prolonged-release melatonin may improve quality of sleep in older people with minimal side effects.Studies have also shown that children who are on the autism spectrum or have learning disabilities, attention-deficit hyperactivity disorder (ADHD) or related neurological diseases can benefit from the use of melatonin. This is because they often have trouble sleeping due to their disorders. For example, children with ADHD tend to have trouble falling asleep because of their hyperactivity and, as a result, tend to be tired during most of the day. Another cause of insomnia in children with ADHD is the use of stimulants used to treat their disorder. Children who have ADHD then, as well as the other disorders mentioned, may be given melatonin before bedtime in order to help them sleep. Benzodiazepines The most commonly used class of hypnotics for insomnia are the benzodiazepines.: 363 Benzodiazepines are not significantly better for insomnia than antidepressants. Chronic users of hypnotic medications for insomnia do not have better sleep than chronic insomniacs not taking medications. In fact, chronic users of hypnotic medications have more regular nighttime awakenings than insomniacs not taking hypnotic medications. Many have concluded that these drugs cause an unjustifiable risk to the individual and to public health and lack evidence of long-term effectiveness. It is preferred that hypnotics be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible, especially in the elderly. Between 1993 and 2010, the prescribing of benzodiazepines to individuals with sleep disorders has decreased from 24% to 11% in the US, coinciding with the first release of nonbenzodiazepines.The benzodiazepine and nonbenzodiazepine hypnotic medications also have a number of side-effects such as day time fatigue, motor vehicle crashes and other accidents, cognitive impairments, and falls and fractures. Elderly people are more sensitive to these side-effects. Some benzodiazepines have demonstrated effectiveness in sleep maintenance in the short term but in the longer term benzodiazepines can lead to tolerance, physical dependence, benzodiazepine withdrawal syndrome upon discontinuation, and long-term worsening of sleep, especially after consistent usage over long periods of time. Benzodiazepines, while inducing unconsciousness, actually worsen sleep as – like alcohol – they promote light sleep while decreasing time spent in deep sleep. A further problem is, with regular use of short-acting sleep aids for insomnia, daytime rebound anxiety can emerge. Although there is little evidence for benefit of benzodiazepines in insomnia compared to other treatments and evidence of major harm, prescriptions have continued to increase. This is likely due to their addictive nature, both due to misuse and because – through their rapid action, tolerance and withdrawal they can "trick" insomniacs into thinking they are helping with sleep. There is a general awareness that long-term use of benzodiazepines for insomnia in most people is inappropriate and that a gradual withdrawal is usually beneficial due to the adverse effects associated with the long-term use of benzodiazepines and is recommended whenever possible.Benzodiazepines all bind unselectively to the GABAA receptor. Some theorize that certain benzodiazepines (hypnotic benzodiazepines) have significantly higher activity at the α1 subunit of the GABAA receptor compared to other benzodiazepines (for example, triazolam and temazepam have significantly higher activity at the α1 subunit compared to alprazolam and diazepam, making them superior sedative-hypnotics – alprazolam and diazepam, in turn, have higher activity at the α2 subunit compared to triazolam and temazepam, making them superior anxiolytic agents). Modulation of the α1 subunit is associated with sedation, motor impairment, respiratory depression, amnesia, ataxia, and reinforcing behavior (drug-seeking behavior). Modulation of the α2 subunit is associated with anxiolytic activity and disinhibition. For this reason, certain benzodiazepines may be better suited to treat insomnia than others. Z-Drugs Nonbenzodiazepine or Z-drug sedative–hypnotic drugs, such as zolpidem, zaleplon, zopiclone, and eszopiclone, are a class of hypnotic medications that are similar to benzodiazepines in their mechanism of action, and indicated for mild to moderate insomnia. Their effectiveness at improving time to sleeping is slight, and they have similar—though potentially less severe—side effect profiles compared to benzodiazepines. Prescribing of nonbenzodiazepines has seen a general increase since their initial release on the US market in 1992, from 2.3% in 1993 among individuals with sleep disorders to 13.7% in 2010. Orexin antagonists Orexin receptor antagonists are a more recently introduced class of sleep medications and include suvorexant, lemborexant, and daridorexant, all of which are FDA-approved for treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Antipsychotics Certain atypical antipsychotics, particularly quetiapine, olanzapine, and risperidone, are used in the treatment of insomnia. However, while common, use of antipsychotics for this indication is not recommended as the evidence does not demonstrate a benefit, and the risk of adverse effects are significant. A major 2022 systematic review and network meta-analysis of medications for insomnia in adults found that quetiapine did not demonstrate any short-term benefits for insomnia. Some of the more serious adverse effects may also occur at the low doses used, such as dyslipidemia and neutropenia. Concerns regarding side effects are greater in the elderly. Other sedatives Gabapentinoids like gabapentin and pregabalin have sleep-promoting effects but are not commonly used for treatment of insomnia.Barbiturates, while once used, are no longer recommended for insomnia due to the risk of addiction and other side effects. Comparative effectiveness A major systematic review and network meta-analysis of medications for the treatment of insomnia was published in 2022. It found a wide range of effect sizes (standardized mean difference (SMD)) in terms of efficacy for insomnia. The assessed medications included benzodiazepines (SMDs 0.58 to 0.83), Z-drugs (SMDs 0.03 to 0.63), sedative antidepressants and antihistamines (SMDs 0.30 to 0.55), quetiapine (SMD 0.07), orexin receptor antagonists (SMDs 0.23 to 0.44), and melatonin receptor agonists (SMDs 0.00 to 0.13). The certainty of evidence varied and ranged from high to very low depending on the medication. The meta-analysis concluded that the orexin antagonist lemborexant and the Z-drug eszopiclone had the best profiles overall in terms of efficacy, tolerability, and acceptability. Alternative medicine Herbal products, such as valerian, kava, chamomile, and lavender, have been used to treat insomnia. However, there is no quality evidence that they are effective and safe. The same is true for cannabis and cannabinoids. It is likewise unclear if acupuncture is useful in the treatment of insomnia. Prognosis A survey of 1.1 million residents in the United States found that those that reported sleeping about 7 hours per night had the lowest rates of mortality, whereas those that slept for fewer than 6 hours or more than 8 hours had higher mortality rates. Getting 8.5 or more hours of sleep per night was associated with a 15% higher mortality rate. Severe insomnia – sleeping less than 3.5 hours in women and 4.5 hours in men – is associated with a 15% increase in mortality.With this technique, it is difficult to distinguish lack of sleep caused by a disorder which is also a cause of premature death, versus a disorder which causes a lack of sleep, and the lack of sleep causing premature death. Most of the increase in mortality from severe insomnia was discounted after controlling for associated disorders. After controlling for sleep duration and insomnia, use of sleeping pills was also found to be associated with an increased mortality rate.The lowest mortality was seen in individuals who slept between six and a half and seven and a half hours per night. Even sleeping only 4.5 hours per night is associated with very little increase in mortality. Thus, mild to moderate insomnia for most people is associated with increased longevity and severe insomnia is associated only with a very small effect on mortality. It is unclear why sleeping longer than 7.5 hours is associated with excess mortality. Epidemiology Between 10% and 30% of adults have insomnia at any given point in time and up to half of people have insomnia in a given year, making it the most common sleep disorder. About 6% of people have insomnia that is not due to another problem and lasts for more than a month. People over the age of 65 are affected more often than younger people. Females are more often affected than males. Insomnia is 40% more common in women than in men.There are higher rates of insomnia reported among university students compared to the general population. Society and culture The word insomnia is from Latin: in + somnus "without sleep" and -ia as a nominalizing suffix. The popular press have published stories about people who supposedly never sleep, such as that of Thái Ngọc and Al Herpin. Horne writes "everybody sleeps and needs to do so," and generally this appears true. However, he also relates from contemporary accounts the case of Paul Kern, who was shot in wartime and then "never slept again" until his death in 1943. Kern appears to be a completely isolated, unique case. References == External links ==
Radiologically isolated syndrome	Radiologically isolated syndrome (RIS) is a clinical situation in which a person has white matter lesions suggestive of multiple sclerosis (MS), as shown on an MRI scan that was done for reasons unrelated to MS symptoms. The nerve lesions in these people show dissemination in space with an otherwise normal neurological examination and without historical accounts of typical MS symptoms.MRI findings that are consistent with multiple sclerosis have been observed in healthy people who underwent MRI scanning, and 50% go on to develop symptomatic MS, sometimes with a primary progressive course. This condition was first characterized in 2009. Diagnosis The criteria for an RIS diagnosis are as follows: The presence of incidental MRI findings in the CNS white matter: Ovoid and well-circumscribed homogeneous foci, with or without involvement of the corpus callosum T2 hyperintensities larger than 3 mm in diameter, which fulfill at least 3 of the 4 Barkhof MRI criteria for DIS The CNS abnormalities are not consistent with a vascular condition No historical accounts of clinical symptoms consistent with neurological dysfunction. MRI anomalies do not account for apparent impairment in social, occupational, or generalized areas of functioning. MRI anomalies are not due to substance abuse, such as recreational drug use, toxic exposure, or a prior known medical condition. Exclusion of a differential diagnosis of leukoaraiosis, or extensive white matter pathology excluding the corpus callosum. MRI anomalies of the CNS are not accounted for by another disease. Discovery RIS is discovered when an MRI scan is performed for other reasons. The most common symptom that led to the incidental discovery of RIS is headache. Other common reasons are trauma, psychiatric disorders, and endocrinological disorders. Management Currently, routine clinical follow-up and MRI neuroimaging surveillance is the standard by which patients are observed. While treatment of MS disease modifying therapies have been given to some individuals with RIS, the majority opt for active surveillance and the appearance of clinical symptoms before commencing treatment, as treatment is considered controversial. Prognosis In a 5 year study, clinical events, which refers to the first symptoms of exacerbations, clinical attacks, flare ups, or severe symptoms, indicative of MS, appeared in 34% of individuals. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive multiple sclerosis (PPMS). Epidemiology Due to the incidental nature of RIS, exact figures on prevalence is unknown, though it has been suggested that RIS is the most common type of asymptomatic MS. The prevalence may be higher in relatives of patients with MS. One study, at a university hospital that is located in a high region of MS disease incidence, put the disease prevalence at approximately 1 in 2000. An earlier study in 1961 of 15,644 autopsies found 12 cases (0.08%) of unexpected MS findings without a previous history of MS symptoms. The mean age of first indication of RIS from 451 patients is 37.2 years. RIS in children Though rare, some children that have had MRI scans for reasons unrelated to MS have shown signs of RIS. The most common reason for an initial MRI in these children was a headache. The first occurrence of a clinical event characteristic of MS in nearly half of the children examined was 2 years, though in a majority of cases, radiologic evolution, i.e. the increase in the number of size of lesions as detected in subsequent MRI, developed after one year. The presence of oligoclonal bands in the CSF and spinal cord lesions were associated with an increased risk of a first clinical event characteristic of MS. It was found that children with RIS had a substantial risk of subsequent clinical symptoms and/or radiologic evolution. Research directions Calls have been made for longer prospective studies, tracking the development of potential disease progression over a longer period of time are warranted. This would ensure criteria in RIS is satisfactory and whether consideration should be given to treating individuals with RIS on current MS medication.RIS has been linked to prodromal multiple sclerosis. Etymology The acronym RIS was coined in 2009 by Okuda and colleagues. Siva and colleagues suggested an alternate name, radiologically uncovered asymptomatic possible inflammatory-demyelinating disease (RAPIDD). == References ==
Pseudoxanthoma elasticum	Pseudoxanthoma elasticum (PXE) is a genetic disease that causes mineralization of elastic fibers in some tissues. The most common problems arise in the skin and eyes, and later in blood vessels in the form of premature atherosclerosis. PXE is caused by autosomal recessive mutations in the ABCC6 gene on the short arm of chromosome 16 (16p13.1). Signs and symptoms Usually, pseudoxanthoma elasticum affects the skin first, often in childhood or early adolescence. Small, yellowish papular lesions form and cutaneous laxity mainly affect the neck, axillae (armpits), groin, and flexural creases (the inside parts of the elbows and knees). Skin may become lax and redundant. Many individuals have "oblique mental creases" (horizontal grooves of the chin)PXE first affects the retina through a dimpling of the Bruch membrane (a thin membrane separating the blood vessel-rich layer from the pigmented layer of the retina), that is only visible during ophthalmologic examinations. This is called peau dorange (a French term meaning "skin of the orange"). Eventually the mineralization of the elastic fibers in the Bruch membrane create cracks called angioid streaks that radiate out from the optic nerve. Angioid streaks themselves do not cause distortion of vision, even if they cross into the foveal area. This symptom is present in almost all PXE patients and is usually noticed a few years after the onset of cutaneous lesions. These cracks may allow small blood vessels that were originally held back by Bruchs membrane to penetrate the retina. These blood vessels sometimes leak, and these retinal hemorrhages may lead to the loss of central vision. Vision loss is a major issue in many PXE patients.PXE may affect the gastrointestinal and cardiovascular systems. Gastrointestinal bleeding is a rare symptom and usually involved bleeding from the stomach. In the circulatory system, intermittent claudication, a condition in which cramping pain in the leg is induced by exercise, is a prominent feature. At later stages, coronary artery disease may develop, leading to angina and myocardial infarction (heart attack). Cerebral ischemia in PXE is caused by small vessel occlusive disease. Other rare neurological complications may include intracranial aneurysms, subarachnoid and intracerebral hemorrhages. Genetics 80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene. Mutations in almost all parts of the gene have been described, of all types (missense, nonsense, splice alteration, insertion, small deletion or large deletion). Although there have been reports of autosomal dominant inheritance, the inheritance is typically autosomal recessive (both parents need to be carriers, and there is a 25% chance that a child will inherit both abnormal copies of the gene and therefore develop the condition).Strong genetic linkage was found with mutations in the ABCC6 gene, which codes for the ABCC6 protein, which is a membrane transporter from the large ATP-binding cassette transporter family. The protein is expressed in most organs, but mainly in the liver and kidney. ABCC6 mediates ATP release in the liver. This is the main source of circulating pyrophosphate (PPi), and individuals affected by PXE have strongly reduced plasma PPi levels, explaining their mineralization disorder. One study suggested that mutations causing total absence of an ABCC6 protein caused a more severe disease, but this could not be confirmed in a subsequent case series. Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic, environmental, and lifestyle) may be involved.Premature atherosclerosis is also associated with mutations in the ABCC6 gene, even in those without PXE. A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies (sickle-cell disease and thalassemia) through a poorly understood mechanism. In addition, there appears to be another PXE-like syndrome with a similar phenotype but as a result of problems with another gene, gamma-glutamyl carboxylase. Mutations in ABCC6 can also cause generalized arterial calcification of infancy. In some cases of PXE, mutations in ABCC6 cannot be found, and other genes such as ENPP1 may be implicated Pathophysiology In PXE, there is mineralization (accumulation of calcium and other minerals) and fragmentation of the elastin-containing fibers in connective tissue, but primarily in the midlaminar layer of the dermis, Bruchs membrane and the midsized arteries. Recent studies have confirmed that PXE is a metabolic disease, and that its features arise because metabolites of vitamin K cannot reach peripheral tissues. Low levels of PPi cause mineralization in peripheral tissues. Diagnosis The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaks in the retina. Criteria were established by consensus of clinicians and researchers at the 2010 biennial research meeting of the PXE Research Consortium. and confirmed at the 2014 meeting These consensus criteria state that definitive PXE is characterized by two pathogenic mutations in the ABCC6 or ocular findings – angioid streaks > 1 DD or peau d’orange in an individual <20 years of age together with skin findings: Characteristic pseudoxanthomatous papules and plaques on the neck or flexural creases. Diagnostic histopathological changes in lesional skin: Calcified elastic fibers in the mid and lower dermis, confirmed by positive calcium stain Differential diagnosis Treatment There is no confirmed treatment that directly interferes with the disease process.Cosmetic surgery to remove excessive skin has been used to improve aesthetic appearance in PXE patients but because of the non-life-threatening nature of these symptoms, should be used with caution.One of the most critical symptom of PXE is choroidal neovascularization which can lead to deterioration of central vision. Photodynamic therapy has been used as a treatment, but this has been replaced with endothelial growth factor (VEGF) inhibitors (such as bevacizumab, ranibizumab, and aflibercept) with efficacy similar to their use in treatment of age-related macular degeneration.To limit cardiovascular symptoms, reduction of cardiovascular risk factors through lifestyle changes is recommended. Generally clinicians recommend avoidance of non-steroidal anti-inflammatory drugs (NSAIDS) that increase bleeding risk, such as aspirin, and ibuprofen to prevent eye and gastrointestinal bleeding.Formerly, dietary restriction of calcium was tried with no benefit, and in fact accelerated mineralization in mice. There are a number of potential treatments that are currently being tested or have just undergone testing including magnesium, etidronate, PPi, and tissue-nonspecific alkaline phosphatase inhibitors.Given that ABCC6 heterozygous mutations result in few symptoms of PXE, this disease is a candidate for gene therapy. Some initial proof-of-principle experiments have been done in mice that have relieved some of symptoms of PXE, but as with all gene therapy treatments, there are many hurdles that must be over come including insuring that the treatment will be long-lasting and reducing the risk of insertional mutagenesis and severe immune reactions. Epidemiology The reported prevalence of pseudoxanthoma elasticum is about 1:25,000. Females are twice as likely to be affected as males. The disease occurs in all ethnicities, but Afrikaners are more likely to have PXE as a result of a founder effect (i.e., higher prevalence in the small group of people from whom Afrikaners descend). History The first description of PXE that distinguished it from other xanthoma conditions was by Dr Ferdinand-Jean Darrier in 1896. The eponym "Grönblad-Strandberg syndrome" is used in older literature, after two physicians who made further discoveries in the disease manifestations.PXE has the distinction of being the only disease for which a layperson is the discover of the mutated gene. The ABCC6 gene mutation was discovered simultaneously by four research teams, all of which published at the same time. The principal investigators were (in order of the date of publication): Jouni Uitto, Arthur Bergen, Charles Boyd, and Klaus Lindpainter. The gene was patented by Charles D. Boyd, Katalin Csiszar, Olivier LeSaux, Zsolt Urban, Sharon Terry, and assigned to PXE International by these co-inventors. Between the filing and 2013, when the Supreme Court of the United States declared that genes may not be patented. PXE International freely licensed the gene to any lab for clinical testing and research. PXE International continues to hold and maintain other patents (diagnosis and treatment patents).PXE International, a support organization, was founded in 1995, by Patrick and Sharon Terry, following the diagnosis of their two children. It has a registry of 4,600 affected individuals. Images See also List of cutaneous conditions References External links PXE international pxe at NIH/UW GeneTests Pseudoxanthoma elasticum at NLM Genetics Home Reference
Ring chromosome 14 syndrome	Ring chromosome 14 syndrome is a very rare human chromosome abnormality. It occurs when one or both of the telomeres that mark the ends of chromosome 14 are lost allowing the now uncapped ends to fuse together forming a ring chromosome. It causes a number of serious health issues. Symptoms and signs The most common symptoms are intellectual disability and recurrent seizures developing in infancy or early childhood. Typically the seizures are resistant to treatment with anti-epileptic drugs. Other symptoms may include: Microcephaly Lymphedema Facial abnormalities Immune deficiencies Abnormalities of retina Slow growth Short stature Cause The syndrome is caused by the loss of genetic material near the end of the long arm (q) of chromosome 14 . The break that causes the telomere(s) to be lost occurs near the end of the chromosome, and is called a constitutional ring. These rings arise spontaneously ( it is rarely inherited).The genetic abnormality occurs randomly in sperm or egg cells or it may occur in early embryonic growth, if it occurs during embryonic growth the ring chromosome may be present in only some of a persons cells. Diagnosis Diagnosis is achieved by examining the structure of the chromosomes through karyotyping; while once born, one can do the following to ascertain a diagnosis of the condition: MRI EEG Management In terms of the management of ring chromosome 14 syndrome, anticonvulsive medication for seizures, as well as, proper therapy to help prevent respiratory infections in the affected individual are management measures that can be taken. Epidemiology Ring chromosome 14 syndrome is extremely rare, the true rate of occurrence is unknown (as it is less than 1 per 1,000,000), but there are at least 50 documented cases in the literature. See also Ring chromosome 18 syndrome Ring chromosome 20 syndrome References Further reading Disorders, National Organization for Rare (2003-01-01). NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. ISBN 9780781730631. Zollino M.; Seminara L.; Orteschi D.; Gobbi G.; Giovannini S.; Della Giustina E.; Frattini D.; Scarano A.; Neri G. (2009). "The Ring14 Syndrome: Clinical and Molecular Definition" (PDF). American Journal of Medical Genetics. 149A (6): 1116–1124. doi:10.1002/ajmg.a.32831. PMID 19441122. S2CID 22919033. == External links ==

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