<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Glutathione synthetase deficiency and can you explain it in depth? [/INST] Glutathione synthetase deficiency (GSD) is a rare autosomal recessive metabolic disorder that prevents the production of glutathione. Glutathione helps prevent damage to cells by neutralizing harmful molecules generated during energy production. Glutathione also plays a role in processing medications and cancer-causing compounds (carcinogens), and building DNA, proteins, and other important cellular components.

Genetics
Mutations in the GSS gene cause glutathione synthetase deficiency. This gene provides instructions for making the enzyme glutathione synthetase. This enzyme is involved in a process called the gamma-glutamyl cycle, which takes place in most of the bodys cells. This cycle is necessary for producing a molecule called glutathione. Glutathione protects cells from damage caused by unstable oxygen-containing molecules, which are byproducts of energy production. Glutathione is called an antioxidant because of its role in protecting cells from the damaging effects of these unstable molecules which are byproducts of energy production. Mutations in the GSS gene prevent cells from making adequate levels of glutathione, leading to the signs and symptoms of glutathione synthetase deficiency.
This disorder 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 required to be born with the disorder. The parents of an individual with an autosomal recessive disorder each carry one copy of the defective gene, but usually are not affected by the disorder.

Diagnosis
Glutathione synthetase deficiency can be classified into three types: mild, moderate and severe.
Mild glutathione synthetase deficiency usually results in the destruction of red blood cells (hemolytic anemia). Rarely, affected people also excrete large amounts of a compound called 5-oxoproline (also called pyroglutamic acid, or pyroglutamate) in their urine (5-oxoprolinuria) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Choledochal cysts and can you explain it in depth? [/INST] Choledochal cysts (a.k.a. bile duct cyst) are congenital conditions involving cystic dilatation of bile ducts. They are uncommon in western countries but not as rare in East Asian nations like Japan and China.

Signs and symptoms
Most patients have symptoms in the first year of life.  It is rare for symptoms to be undetected until adulthood, and usually adults have associated complications.  The classic triad of intermittent abdominal pain, jaundice, and a right upper quadrant abdominal mass is found only in minority of patients.In infants, choledochal cysts usually lead to obstruction of the bile ducts and retention of bile. This leads to jaundice and an enlarged liver. If the obstruction is not relieved, permanent damage may occur to the liver - scarring and cirrhosis - with the signs of portal hypertension  (obstruction to the flow of blood through the liver) and ascites (fluid accumulation in the abdomen). There is an increased risk of cancer in the wall of the cyst.In older individuals, choledochal cysts are more likely to cause abdominal pain and intermittent episodes of jaundice and occasionally cholangitis (inflammation within the bile ducts caused by the spread of bacteria from the intestine into the bile ducts) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Glandular odontogenic cyst and can you explain it in depth? [/INST] A glandular odontogenic cyst (GOC) is a rare and usually benign odontogenic cyst developed at the odontogenic epithelium of the mandible or maxilla. Originally, the cyst was labeled as "sialo-odontogenic cyst" in 1987. However, the World Health Organization (WHO) decided to adopt the medical expression "glandular odontogenic cyst". Following the initial classification, only 60 medically documented cases were present in the population by 2003. GOC was established as its own biological growth after differentiation from other jaw cysts such as the "central mucoepidermoid carcinoma (MEC)", a popular type of neoplasm at the salivary glands. GOC is usually misdiagnosed with other lesions developed at the glandular and salivary gland due to the shared clinical signs. The presence of osteodentin supports the concept of an odontogenic pathway. This odontogenic cyst is commonly described to be a slow and aggressive development. The inclination of GOC to be large and multilocular is associated with a greater chance of remission. GOC is an infrequent manifestation with a 0.2% diagnosis in jaw lesion cases. Reported cases show that GOC mainly impacts the mandible and male individuals. The presentation of GOC at the maxilla has a very low rate of incidence. The GOC development is more common in adults in their fifth and sixth decades.GOC has signs and symptoms of varying sensitivities, and dysfunction. In some cases, the GOC will present no classic abnormalities and remains undiagnosed until secondary complications arise. The proliferation of GOC requires insight into the foundations of its unique histochemistry and biology. The comparable characteristics of GOC with other jaw lesions require the close examination of its histology, morphology, and immunocytochemistry for a differential diagnosis. Treatment modes of the GOC follow a case-by-case approach due to the variable nature of the cyst. The selected treatment must be accompanied with an appropriate pre and post-operative plan.

Signs and Symptoms
The appearance of a protrusive growth will be present at their mandible or maxilla. The expansive nature of this cyst may destruct the quality of symmetry at the facial region and would be a clear physical sign of abnormality. The area of impact may likely be at the anterior region of mandible as described in a significant number of reported cases. At this region, GOC would eventually mediate expansion at the molars. A painful and swollen sensation at the jaw region caused by GOC may be reported. Detailing of a painless feeling or facial paraesthesia can be experienced. Alongside GOC, "root resorption, cortical bone thinning and perforation, and tooth displacement may occur". Experience of swelling at the buccal and lingual zones can occur. Usually, the smaller sized GOCs present no classical signs or symptoms to the case (i.e. "asymptomatic"). GOC is filled with cystic a fluid that differs in viscosity and may appear as transparent, brownish-red, or creamy in colour.

Causes
The GOC can arise through a number of causes:The origin of the GOC can be understood through its biological and histochemistry foundations. It has been suggested that GOC can be a result of a traumatic event. The occurrence of GOC may be from a mutated cell from "the oral mucosa and the dental follicle" origin. Another probable cause is from pre-existing cysts or cancerous constituents. A potential biological origin of GOC is a cyst developed at a salivary gland or simple epithelium, which undergoes maturation at the glandular. Another origin is a primordial cyst that infiltrates the glandular epithelial tissue through a highly organised cellular differentiation. Pathologists discovered a BCL-2 protein, commonly present in neoplasms, to exist in the tissue layers of the GOC. The protein is capable of disrupting normal cell death function at the odontogenic region. The analysis of PTCH, a gene that specialises in neoplasm inhibition, was carried out to determine if any existing mutations played a role in the initiation of the GOC. It is confirmed that the gene had no assistance in triggering cystic advancement.

Diagnosis
Radiology
The performance of radiographic imaging i.e. computed tomography, at the affected area is considered essential. Radiographic imaging of the GOC can display a defined unilocular or multilocular appearance that may be "rounded or oval" shaped upon clinical observation. Scans may present a distribution of the GOC at the upper jaw as it presents a 71.8% prevalence in cases. The margin surrounding the GOC is usually occupied with a scalloped definition. A bilateral presentation of the GOC is possible but is not common at either the maxilla or mandible sites. The GOC has an average size of 4.9 cm that can develop over the midline when positioned at the mandible or maxilla region. Analysis of scans allow for the differentiation of GOC from other parallel lesions, i.e. "ameloblastoma, odontogenic myxoma, or dentigerous cyst" in order to minimise the chance of a misdiagnosis. These scans can display the severity of cortical plate, root, and tooth complications, which is observed to determine the necessary action for reconstruction.

Histology
Histological features related to the GOC differ in each scenario; however, there is a general criterion to identify the cyst. The GOC usually features a "stratified squamous epithelium" attached to connective tissue that is filled with active immune cells. The lining of the epithelium features a very small diameter that is usually non-keratinised. In contrast, the lining of the GOC has rather an inconsistent diameter. The basal cells of the GOC usually has no association to a cancerous origin. Tissue cells can be faced with an abnormal increase in the concentration of calcium, which can cause the region to calcify. The transformation of the epithelium is associated with a focal luminal development. Eosinophilic organelles such as columnar and cuboidal cells can be observed during microscopy. Intra-epithelial crypts may be identified in the internal framework of the epithelium or at the external space where it presents itself as papillae protrusions. Mucin is observable after the application of "alcian blue dye" on the tissue specimen. The histological observation of goblet cells is a common feature with the "odontogenic dentigerous cyst". In some circumstances, the epithelium can have variable plaque structures that appear as swirls in the tissue layers. Interestingly, histologists were able to identify hyaline bodies within the tissue framework of the GOC. It is encouraged that the histological identification of at least seven of these biological characteristics is required to accurately distinguish the presence of the GOC.

Intraepithelial Hemosiderin
Pathologists have identified hemosiderin pigments that are considered unique to the GOC. The discovery of this pigment can be pivotal to the differentiation of the GOC from other lesions. The staining at the epithelium is due to the haemorrhaging of the lining. The cause of the haemorrhaging can be triggered by the type of treatment, cellular degradation, or structural deformation inflicted during GOC expansion. Examination of the GOC tissue section indicated that red blood cells from the intraluminal space had combined with the extracellular constituents. This process is carried out through transepithelial elimination. This clinical procedure is beneficial to confirm the benign or malignant nature of the GOC.

Immunocytochemistry
The examination of cytokeratin profiles is deemed useful when observing the differences between the GOC and the central MEC. These two lesions show individualised expression for cytokeratin 18 and 19.  Past studies observed Ki-67, p53, and PCNA expression in common jaw cysts that shared similar characteristics. There was a lack of p53 expression found in radicular cysts. Similarly, Ki-67 was seen less in the central MEC compared to the other lesions, though this discovery is not essential to the process of differential diagnosis. Proliferating cell nuclear antigen readings were established to have no role in the differentiation process. The TGF-beta marker is present in the GOC and can explain the limited concentration of normal functioning cells.

MAML2 rearrangement
The observation of a MAML2 rearrangement is described as a procedure useful in the differential diagnosis of the GOC and its closely related lesion, the central MEC. A second cystic development displayed the presence of CRTC3-MAML2 fusion after an in-vitro application. The MAML2 rearrangement represents the developmental growth of the central MEC from the GOC. The use of fusion-gene transcript may be helpful towards the differentiation of the GOC from the central MEC of the jaw and salivary glands.

Treatment
Pre-treatment protocols
A computed tomography and panoramic x-ray must be undertaken in order to observe the severity of internal complications. These scans allow for the observation of the GOC size, radiolucency, cortical bone, dentition, root, and vestibular zone. In some cases, the dentition may be embedded into the cavity walls of the lesion, depending on the position of expansion at the odontogenic tissue. The diagnosis of a smaller sized GOC is related to the attachment of only two teeth. While, a greater sized GOC develops over two teeth. Presentation of a greater sized lesion usually requires a biopsy for a differential diagnosis and a precise treatment plan.

Treatment process
The unilocular and multilocular nature is imperative to the determination of treatment style. Local anesthesia is regularly provided as the GOC is embedded within the tissue structure of the jaw and requires an invasive procedure for a safe and accurate extraction. For unilocular GOCs with minimal tissue deterioration, "enucleation, curettage, and marsupialization" is a suitable treatment plan. Notably, the performance of enucleation or curettage as the primary action is linked to an incomplete extraction of the GOC and is only recommended to the less invasive lesions. Multilocular GOCs require a more invasive procedure such as "peripheral ostectomy, marginal resection, or partial jaw resection". GOCs associated with a more severe structural damage are encouraged to undergo marsupialization as either an initial or supplementary surgery. The frequency of reappearance is likely due to the lingering cystic tissue structures that remain after the performance of curettage. The incorporation of a "dredging method i.e. repetition of enucleation and curettage" is also suggested until the remnants of the GOC diminishes for certain. The treatment ensures scar tissue is removed to promote the successful reconstruction of osseous material for jaw preservation. Alongside the main treatments, bone allograft application, cryosurgery, and apicoectomy are available but have not been consistently recommended. Though Carnoys solution, the chloroform-free version, is recommended with the treatment as it degenerates the majority of the damaged dental lamina. The most effective type of treatment remains unknown due to the lack of detailed data from reported cases.

Post-treatment protocols
Follow-up appointments are necessary after the removal of the GOC as there is a high chance of remission, which may be exacerbated in cases dealing with "cortical plate perforation". The GOC has a significant remission rate of 21 to 55% that can potentially develop during the period of 0.5 to 7 years post-surgery. Cases occupied with a lower risk lesion are expected to continue appointments with physicians for up to 3 years post-surgery. A higher risk lesion is encouraged to consistently consult with physicians during a 7-year period after treatment. Remission events require immediate attention and appropriate procedures such as enucleation or curettage. In more damaging cases of remission, tissue resection, and marsupialization may have to be performed.

Epidemiology
The clinical presentation of the GOC is very low in the population as noted by the 0.12 to 0.13% occurrence rate, extrapolated from a sample size of the 181 individuals. The GOC mainly affects older individuals in the population, especially those that are in their 40 to 60s. However, the GOC can affect younger individuals i.e. 11, and more older individuals i.e. 82 in the population. The age distribution starts at a much lower number for people living in Asia and Africa. Those in their first 10 years of life have not been diagnosed with the GOC. The GOC does present a tendency to proliferate in more males than females. There is no definitive conclusion towards the relevance of gender and its influence on the rate of incidence.

References
Bibliography
AbdullGaffar, Badr; Koilelat, Mohamed (May 2017). "Glandular Odontogenic Cyst: The Value of Intraepithelial Hemosiderin". International Journal of Surgical Pathology. 25 (3): 250–252. doi:10.1177/1066896916672333. PMID 27829208. S2CID 46588216.
Akkaş, İsmail; Toptaş, Orçun; Özan, Fatih; Yılmaz, Fahri (1 March 2015). "Bilateral Glandular Odontogenic Cyst of Mandible: A Rare Occurrence". Journal of Maxillofacial and Oral Surgery. 14 (1): 443–447. doi:10.1007/s12663-014-0668-y. PMC 4379287. PMID 25848155.
Alaeddini, Mojgan; Eshghyar, Nosratollah; Etemad‐Moghadam, Shahroo (2017). "Expression of podoplanin and TGF-beta in glandular odontogenic cyst and its comparison with developmental and inflammatory odontogenic cystic lesions". Journal of Oral Pathology & Medicine. 46 (1): 76–80. doi:10.1111/jop.12475. PMID 27391558. S2CID 40879254.
Borges, Leandro Bezerra; Fechine, Francisco Vagnaldo; Mota, Mário Rogério Lima; Sousa, Fabrício Bitu; Alves, Ana Paula Negreiros Nunes (March 2012). "Odontogenic lesions of the jaw: a clinical-pathological study of 461 cases". Revista Gaúcha de Odontologia. 60 (1): 71–78. S2CID 46982083.
Cano, Jorge; Benito, Dulce María; Montáns, José; Rodríguez-Vázquez, José Francisco; Campo, Julián; Colmenero, César (1 July 2012). "Glandular odontogenic cyst: Two high-risk cases treated with conservative approaches". Journal of Cranio-Maxillofacial Surgery. 40 (5): e131–e136. doi:10.1016/j.jcms.2011.07.005. PMID 21865053.
Faisal, Mohammad; Ahmad, Syed Ansar; Ansari, Uzma (September 2015). "Glandular odontogenic cyst – Literature review and report of a paediatric case". Journal of Oral Biology and Craniofacial Research. 5 (3): 219–225. doi:10.1016/j.jobcr.2015.06.011. PMC 4623883. PMID 26587384.
Kaplan, Ilana; Gal, Gavriel; Anavi, Yakir; Manor, Ronen; Calderon, Shlomo (April 2005). "Glandular odontogenic cyst: Treatment and recurrence". Journal of Oral and Maxillofacial Surgery. 63 (4): 435–441. doi:10.1016/j.joms.2004.08.007. PMID 15789313.
Motooka, Naomi; Ohba, Seigo; Uehara, Masataka; Fujita, Syuichi; Asahina, Izumi (1 January 2015). "A case of glandular odontogenic cyst in the mandible treated with the dredging method". Odontology. 103 (1): 112–115. doi:10.1007/s10266-013-0143-0. PMID 24374982. S2CID 21059170.
Nagasaki, Atsuhiro; Ogawa, Ikuko; Sato, Yukiko; Takeuchi, Kengo; Kitagawa, Masae; Ando, Toshinori; Sakamoto, Shinnichi; Shrestha, Madhu; Uchisako, Kaori; Koizumi, Koichi; Toratani, Shigeaki; Konishi, Masaru; Takata, Takashi (January 2018). "Central mucoepidermoid carcinoma arising from glandular odontogenic cyst confirmed by analysis of MAML2 rearrangement: A case report: Central MEC arising from GOC". Pathology International. 68 (1): 31–35. doi:10.1111/pin.12609. PMID 29131467. S2CID 8932602.
Neville, Brad W. (2016). "Cyst, Glandular Odontogenic".  In Slootweg, Pieter (ed.). Dental and Oral Pathology. Encyclopedia of Pathology. Springer International Publishing. pp. 89–93. doi:10.1007/978-3-319-28085-1_677. ISBN 978-3-319-28084-4.
Prabhu, Sudeendra; Rekha, K; Kumar, GS (2010). "Glandular odontogenic cyst mimicking central mucoepidermoid carcinoma". Journal of Oral and Maxillofacial Pathology. 14 (1): 12–5. doi:10.4103/0973-029X.64303. PMC 2996005. PMID 21180452.
Momeni Roochi, Mehrnoush; Tavakoli, Iman; Ghazi, Fatemeh Mojgan; Tavakoli, Ali (1 July 2015). "Case series and review of glandular odontogenic cyst with emphasis on treatment modalities". Journal of Cranio-Maxillofacial Surgery. 43 (6): 746–750. doi:10.1016/j.jcms.2015.03.030. PMID 25971944.
Patel, Govind; Shah, Monali; Kale, Hemant; Ranginwala, Amena (2014). "Glandular odontogenic cyst: A rare entity". Journal of Oral and Maxillofacial Pathology. 18 (1): 89–92. doi:10.4103/0973-029X.131922. PMC 4065455. PMID 24959044.
Shah, AmishaA; Sangle, Amit; Bussari, Smita; Koshy, AjitV (2016). "Glandular odontogenic cyst: A diagnostic dilemma". Indian Journal of Dentistry. 7 (1): 38–43 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tropical acne and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Corticobasal degeneration and can you explain it in depth? [/INST] Corticobasal degeneration (CBD)  is a rare neurodegenerative disease involving the cerebral cortex and the basal ganglia. CBD symptoms typically begin in people from 50 to 70 years of age, and the average disease duration is six years. It is characterized by marked disorders in movement and cognition, and is classified as one of the Parkinson plus syndromes. Diagnosis is difficult, as symptoms are often similar to those of other disorders, such as Parkinsons disease, progressive supranuclear palsy, and dementia with Lewy bodies, and a definitive diagnosis of CBD can only be made upon neuropathologic examination.

Signs and symptoms
Because CBD is progressive, a standard set of diagnostic criteria can be used, which is centered on the diseases evolution.  Included in these fundamental features are problems with cortical processing, dysfunction of the basal ganglia, and a sudden and detrimental onset.  Psychiatric and cognitive dysfunctions, although present in CBD, are much less prevalent and lack establishment as common indicators of the presence of the disease.Although corticobasal degeneration has a plethora of symptoms, some are more prevalent than others. In a study of 147 patients with CBD, it was found that all of them had at least one Parkinsonian sign, 95% having two and 93% had some higher order dysfunction (cognitive impairments like acalculia, sensory loss, dementia, neglect, etc.). In a separate study of 14 patients recorded 3 years after the onset of symptoms, many patients had high numbers of motor symptoms. 71% had bradykinesia (slow movements), 64% showed apraxia, 43% reported limb dystonia, and although more cognitive 36% had dementia. In another study of 36, over half had a useless/alien arm and 27% had a gait impediment[21]. From this, we can see why CBD is hard to diagnose. Even if it can be distinguished as different from one of the other similar diseases, the varying combinations of symptoms create a difficult path to diagnosis.

Motor and associated cortical dysfunctions
Some of the most prevalent symptom types in people exhibiting CBD pertain to identifiable movement disorders and problems with cortical processing.  These symptoms are initial indicators of the presence of the disease.  Each of the associated movement complications typically appears asymmetrically and the symptoms are not observed uniformly throughout the body.  For example, a person exhibiting an alien hand syndrome (explained later) in one hand, will not correspondingly display the same symptom in the other hand.  Predominant movement disorders and cortical dysfunctions associated with CBD include:
Parkinsonism
Alien hand syndrome
Apraxia (ideomotor apraxia and limb-kinetic apraxia)
Aphasia

Parkinsonism
The presence of parkinsonism as a clinical symptom of CBD is largely responsible for complications in developing unique diagnostic criteria for the disease.  Other such diseases in which parkinsonism forms an integral diagnostic characteristic are Parkinsons disease (PD) and progressive supranuclear palsy (PSP).  Parkinsonism in CBD is largely present in an extremity such as the arm, and is always asymmetric. It has been suggested that non-dominant arm is involved more often. Common associated movement dysfunctions that comprise parkinsonism are rigidity, bradykinesia, and gait disorder, with limb rigidity forming the most typical manifestation of parkinsonism in CBD.  Despite being relatively indistinct, this rigidity can lead to disturbances in gait and correlated movements.  Bradykinesia in CBD occurs when there is notable slowing in the completion of certain movements in the limbs.  In an associated study, it was determined that, three years following first diagnosis, 71% of persons with CBD demonstrate the presence of bradykinesia.

Alien hand syndrome
Alien hand syndrome has been shown to be prevalent in roughly 60% of those people diagnosed with CBD.  This disorder involves the failure of an individual to control the movements of their hand, which results from the sensation that the limb is "foreign".  The movements of the alien limb are a reaction to external stimuli and do not occur sporadically or without stimulation.  The presence of an alien limb has a distinct appearance in CBD, in which the diagnosed individual may have a "tactile mitgehen". This mitgehen (German, meaning "to go with") is relatively specific to CBD, and involves the active following of an experimenters hand by the subjects hand when both hands are in direct contact.  Another, rarer form of alien hand syndrome has been noted in CBD, in which an individuals hand displays an avoidance response to external stimuli.  Additionally, sensory impairment, revealed through limb numbness or the sensation of prickling, may also concurrently arise with alien hand syndrome, as both symptoms are indicative of cortical dysfunction.  Like most of the movement disorders, alien hand syndrome also presents asymmetrically in those diagnosed with CBD.

Apraxia
Ideomotor apraxia (IMA), although clearly present in CBD, often manifests atypically due to the additional presence of bradykinesia and rigidity in those individuals exhibiting the disorders.  The IMA symptom in CBD is characterized by the inability to repeat or mimic particular movements (whether significant or random) both with or without the implementation of objects.  This form of IMA is present in the hands and arms, while IMA in the lower extremities may cause problems with walking.  Those with CBD that exhibit IMA may appear to have trouble initiating walking, as the foot may appear to be fixed to floor.  This can cause stumbling and difficulties in maintaining balance.  IMA is associated with deterioration in the premotor cortex, parietal association areas, connecting white matter tracts, thalamus, and basal ganglia.  Some individuals with CBD exhibit limb-kinetic apraxia, which involves dysfunction of more fine motor movements often performed by the hands and fingers.

Aphasia
Aphasia in CBD is revealed through the inability to speak or a difficulty in initiating spoken dialogue and falls under the non-fluent (as opposed to fluent or flowing) subtype of the disorder. This may be related to speech impairment such as dysarthria, and thus is not a true aphasia, as aphasia is related to a change in language function, such as difficulty retrieving words or putting words together to form meaningful sentences.   The speech and/or language impairments in CBD result in disconnected speech patterns and the omission of words.  Individuals with this symptom of CBD often lose the ability to speak as the disease progresses.

Psychiatric and cognitive disorders
Psychiatric problems associated with CBD often present as a result of the debilitating symptoms of the disease.  Prominent psychiatric and cognitive conditions cited in individuals with CBD include dementia, depression, and irritability, with dementia forming a key feature that sometimes leads to the misdiagnosis of CBD as another cognitive disorder such as Alzheimers disease (AD). Frontotemporal dementia can be an early feature.

Molecular features
Neuropathological findings associated with CBD include the presence of astrocytic abnormalities within the brain and improper accumulation of the protein tau (referred to as tauopathy).

Astroglial inclusions
Postmortem histological examination of the brains of individuals diagnosed with CBD reveal unique characteristics involving the astrocytes in localized regions.  The typical procedure used in the identification of these astroglial inclusions is the Gallyas-Braak staining method.  This process involves exposing tissue samples to a silver staining material which marks for abnormalities in the tau protein and astroglial inclusions.  Astroglial inclusions in CBD are identified as astrocytic plaques, which present as annularly displays of blurry outgrowths from the astrocyte.  A recent study indicated that  produces a high density of astrocytic plaques in the anterior portion of the frontal lobe and in the premotor area of the cerebral cortex.

Tauopathy
The protein tau is an important microtubule-associated protein (MAP), and is typically found in neuronal axons.  However, malfunctioning of the development of the protein can result in unnatural, high-level expression in astrocytes and glial cells.  As a consequence, this is often responsible for the astrocytic plaques prominently noted in histological CBD examinations.  Although they are understood to play a significant role in neurodegenerative diseases such as CBD, their precise effect remains a mystery.In recent years Corticobasal Degeneration is seen to be a tauopathy[22]. This is believed due to the most common indicator of CBD being a faulty tau protein. Tau proteins are integral in keeping microtubules stable and these defective cells create 4 microtubule-binding repeats[23]. These 4 binding repeats have increased affinity in binding with microtubules[25]. Because of this increased affinity, they form insoluble fibers (also called "paired helical filaments). Microtubules themselves keep the cell and cytoskeletal structure stable[24]. Thus, when Tau proteins create unnatural configurations, microtubules become unstable, and eventually leads to cell death.

Diagnosis
New diagnostic criteria known as the Armstrong criteria were proposed in 2013, although the accuracy of these is limited and further research is needed.

Criteria
Insidious onset and gradual progression
Lasts 1 year or more
Meets one of the four subtypes:
Possible CBS
FBS or NAV
PSPS plus at least one CBS feature other than limb rigidity or akinesia
No exclusion criteria present
More likely if onset is after age 50
More likely if no family history (2 or more relatives)
More likely if no genetic mutation affecting T (e.g., MAPT)

Possible corticobasal syndrome subtype
Symptoms may be symmetric or asymmetric.
One or more of:
limb rigidity or akinesia
limb dystonia
limb myoclonus, plus one of:
orobuccal or limb apraxia
cortical sensory deficit
alien limb phenomena (more than simple levitation)More likely (probable sporadic CBS) if:
Asymmetric presentation
Onset after age 50
No family history (2 or more relatives)
No genetic mutation affecting T (e.g. MAPT)
plus two of:limb rigidity or akinesia
limb dystonia
limb myoclonusplus two of:orobuccal or limb apraxia,
cortical sensory deficit
alien limb phenomena (more than simple levitation)

Frontal behavioural-spatial syndrome subtype
Two of:
executive dysfunction
behavioural or personality changes
visuospatial deficits

NAV of primary progressive aphasia subtype
Effortful, agrammatic speech plus at least one of:
impaired grammar/sentence comprehension with relatively preserved single word comprehension or
groping, distorted speech production (apraxia of speech)

Progressive supranuclear palsy syndrome subtype
Three of:
axial or symmetric limb rigidity or akinesia
postural instability or falls
urinary incontinence
behavioural changes
supranuclear vertical gaze palsy or decreased vertical saccade velocity

Exclusion criteria
These apply to all types of CBD.

Evidence of Lewy body disease
multiple system atrophy
Alzheimers disease
ALS
semantic or logopenic variant primary progressive aphasia
structural lesion suggestive of focal cause
granulin mutation or reduced plasma progranulin levels
TDP-43 or fused in sarcoma (FUS) mutationsThe diagnostic criteria for clinical use may result in a misdiagnosis of other tau-based diseases.The probable criteria are proposed for clinical research.

Clinical vs. postmortem
One of the most significant problems associated with CBD is the inability to perform a definitive diagnosis while an individual exhibiting the symptoms associated with CBD is still alive.  A clinical diagnosis of CBD is performed based upon the specified diagnostic criteria, which focus mainly on the symptoms correlated with the disease.  However, this often results in complications as these symptoms often overlap with numerous other neurodegenerative diseases.  Frequently, a differential diagnosis for CBD is performed, in which other diseases are eliminated based on specific symptoms that do not overlap.  However, some of the symptoms of CBD used in this process are rare to the disease, and thus the differential diagnosis cannot always be used.Postmortem diagnosis provides the only true indication of the presence of CBD.  Most of these diagnoses utilize the Gallyas-Braak staining method, which is effective in identifying the presence of astroglial inclusions and coincidental tauopathy.

Overlap with other diseases
Progressive supranuclear palsy (PSP) is frequently the disease most often confused with CBD.  Both PSP and CBD result in similar symptoms, and both display tauopathies upon histological inspection.  However, it has been noted that tauopathy in PSP results in tuft-shaped astrocytes in contrast with the ring-shaped astrocytic plaques found as a result of CBD.Individuals diagnosed with PD often exhibit similar movement dysfunction as those diagnosed with CBD, which adds complexity to its diagnosis.  Some other neurodegenerative diseases including Alzheimers disease (AD), dementia with Lewy bodies (DLB), chronic traumatic encephalopathy (CTE) and frontotemporal dementia (FTD) also show commonalities with CBD.

Neuroimaging
The types of imaging techniques that are most prominently utilized when studying and/or diagnosing CBD are:
magnetic resonance imaging (MRI)
single-photon emission computed tomography (SPECT)
fluorodopa positron emission tomography (FDOPA PET)Developments or improvements in imaging techniques provide the future possibility for definitive clinical diagnosis prior to death.  However, despite their benefits, information learned from MRI and SPECT during the beginning of CBD progression tend to show no irregularities that would indicate the presence of such a neurodegenerative disease.  FDOPA PET is used to study the efficacy of the dopamine pathway.Despite the undoubted presence of cortical atrophy (as determined through MRI and SPECT) in individuals experiencing the symptoms of CBD, this is not an exclusive indicator for the disease.  Thus, the utilization of this factor in the diagnosis of CBD should be used only in combination with other clinically present dysfunctions.

MRI
MRI images are useful in displaying atrophied portions of neuroanatomical positions within the brain.  As a result, it is especially effective in identifying regions within different areas of the brain that have been negatively affected due to the complications associated with CBD.  To be specific, MRI of CBD typically shows posterior parietal and frontal cortical atrophy with unequal representation in corresponding sides.  In addition, atrophy has been noted in the corpus callosum.Functional MRI (fMRI) has been used to evaluate the activation patterns in various regions of the brain of individuals affected with CBD.  Upon the performance of simple finger motor tasks, subjects with CBD experienced lower levels of activity in the parietal cortex, sensorimotor cortex, and supplementary motor cortex than those individuals tested in a control group.

SPECT
SPECT is currently being used to try to detect CBD. With many patients of CBD, there are areas in the basal ganglia which have difficulties receiving dopamine, typically asymmetrically. Specifically affected, are dopamine transporters which are presynaptic on the nigrostriatal cells. SPECT is used to detect these abnormalities in Dopamine transporters. Given that many patients have asymmetrical loss of function and metabolism this can help differentiate patients with CBD and those with Alzheimers.SPECT studies of individuals diagnosed with CBD involve perfusion analysis throughout the parts of the brain.  SPECT evaluation through perfusion observation consists of monitoring blood release into different locations in tissue or organ regions, which, in the case of CBD, pertains to localized areas within the brain.  Tissue can be characterized as experiencing overperfusion, underperfusion, hypoperfusion, or hyperperfusion.  Overperfusion and underperfusion relate to a comparison with the overall perfusion levels within the entire body, whereas hypoperfusion and hyperperfusion are calculated in comparison to the blood flow requirements of the tissue in question.  In general, the measurements taken for CBD using SPECT are referred to as regional cerebral blood flow (rCBF).In general, SPECT reveals hypoperfusion within both the posterior regions of the frontal and parietal lobes.  As in images gathered through MRI, SPECT images indicated asymmetry in the presentation of abnormalities throughout the brain.  Additional studies have revealed the presence of perfusion anomalies in the thalamus, temporal cortex, basal ganglia, and pontocerebellar (from the pons to the cerebellum) locations within subjects brains.

FDOPA PET
Research has suggested that the integrity of the dopamine system in the striatum has been damaged as an effect of CBD.  Current studies employing the use of FDOPA PET scanning (FDOPA PET) as a possible method for identifying CBD have focused on analyzing the efficiency of neurons in the striatum that utilize the neurotransmitter dopamine.  These studies have concluded that, in general, dopamine uptake was diminished in the caudate and the putamen.  This characteristic also has the potential to be useful in distinguishing CBD from the similar PD, as individuals having been diagnosed with PD were more likely to have a lower uptake of dopamine than in individuals with CBD.Other clinical tests or procedures that monitor the presence of dopamine within the brain (β-CIT SPECT and IBZM SPECT) have shown similar findings.  β-CIT serves as an indicator for presynaptic dopaminergic neurons, whereas IBZM is a tracer that shows an affinity for the postsynaptic neurons of the same type.  Despite agreement with other imaging studies, these two SPECT methods suffer some scrutiny due to better accuracy in other imaging methods.  However, β-CIT SPECT has proven to be helpful in distinguishing CBD from PSP and multiple system atrophy (MSA).

Corticobasal syndrome
All of the disorders and dysfunctions associated with CBD can often be categorized into a class of symptoms that present with the disease of CBD.  These symptoms that aid in clinical diagnosis are collectively referred to as corticobasal syndrome (CBS) or corticobasal degeneration syndrome (CBDS). Alzheimers disease, Picks disease, FTDP-17 and progressive supranuclear palsy can display a corticobasal syndrome. It has been suggested that the nomenclature of corticobasal degeneration only be used for naming the disease after it has received verification through postmortem analysis of the neuropathology.  CBS patients with greater temporoparietal degeneration are more likely to have AD pathology as opposed to frontotemporal lobar degeneration.

Treatment
Because the exact cause of CBD is unknown, there exists no formal treatment for the disease.  Instead, treatments focus on minimizing the appearance or effect of the symptoms resulting from CBD.  The most easily treatable symptom of CBD is parkinsonism, and the most common form of treatment for this symptom is the application of dopaminergic drugs.  However, in general only moderate improvement is seen and the relief from the symptom is not long-lasting.  In addition, palliative therapies, including the implementation of wheelchairs, speech therapy, and feeding techniques, are often used to alleviate many of the symptoms that show no improvement with drug administration.There is no consensus on what causes CBD and so most of the treatment goes in helping symptoms. Many treatments have low success rates or have not been tested thoroughly or produced frequently. For example, in relation to the motor aspect of disability, CBD has a high resistance against treatments to help the dopamine intake like levodopa. A number of studies have reported no real levels of improvement based with the use of similar drugs/dopaminergic agonists. Because of the brains levels of inhibition, some medications have focused on creating an inhibition that would negate the effect. Many of these relaxants and anticonvulsants have some success but also have unwanted side effects[21]. Cognitive and associative effects of CBD are also hard to treat as we are still unsure of many of the treatments for the symptomatic diseases that ensue like dementia, aphasia, neglect, apraxia and others.

Epidemiology
Clinical presentation of CBD usually does not occur until age 60, with the earliest recorded diagnosis and subsequent postmortem verification being age 28.  Although men and women present with the disease, some analysis has shown a predominant appearance of CBD in women.  Current calculations suggest that the prevalence of CBD is approximately 4.9 to 7.3 per 100,000 people.  The prognosis for an individual diagnosed with CBD is death within approximately eight years, although some patients have been diagnosed over 17 years ago (2017) and are still in relatively good standing, but with serious debilitation such as dysphagia, and overall limb rigidity. The partial (or total) use of a feeding tube may be necessary and will help prevent aspiration pneumonia, primary cause of death in CBD. Incontinence is common, as  patients often cant express their need to go, due to eventual loss of speech. Therefore, proper hygiene is mandatory to prevent urinary tract infections.CBD research has been limited by the rarity of the disease and the lack of research criteria. It is estimated to affect 0.6-0.9 per 100,000 per year.Progressive supranuclear palsy (PSP) without CBD is estimated to be ten times more common. CBD represents roughly 4–6% of patients with Parkinsonism. Average age at disease onset is about 64, with the youngest confirmed onset being at age 43. There may be a slight female predominance.

History
Corticobasal syndrome was first recognized in 1967 when Rebeiz, Kolodny, and Richardson Jr described three people with a progressive asymmetric akinetic-rigid syndrome combined with apraxia, which they named corticodentatonigral degeneration with neuronal achromasia. The condition was "mostly forgotten" until 1989, when Marsden et al. used the name corticobasal degeneration. In 1989 Gibb and colleagues provided detailed clinical and pathological descriptions in a further three cases adopting the name corticobasal degeneration, after which various other names included "corticonigral degeneration with nuclear achromasia" and "cortical basal ganglionic degeneration".  Although the underlying cause of CBD is unknown, the disease occurs as a result of damage to the basal ganglia, specifically marked by neuronal degeneration or depigmentation (loss of melanin in a neuron) in the substantia nigra.  Additional distinguishing neurological features of those diagnosed with CBD consist of asymmetric atrophy of the frontal and parietal cortical regions of the brain.  Postmortem studies of patients diagnosed with CBD indicate that histological attributes often involve ballooning of neurons, gliosis, and tauopathy.  Much of the pioneering advancements and research performed on CBD has been completed within the past decade or so, due to the relatively recent formal recognition of the disease.The Office of Rare Diseases in the United States created the first criteria in 2002, and the Armstrong clinical diagnostic criteria were created in 2013.

Society and culture
The Salt Path by Raynor Winn is an inspiring account of walking Englands 630 mile South West Coast Path with her husband who had corticobasal degeneration.

See also
Frontotemporal lobar degeneration

References

Boeve BF (2011). "The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: Implications for further study". Journal of Molecular Neuroscience. 45 (3): 350–3. doi:10.1007/s12031-011-9624-1. PMID 21853287. S2CID 30307394.
Hassan A, Whitwell JL, Josephs KA (2011). "The corticobasal syndrome-alzheimers disease conundrum". Expert Review of Neurotherapeutics. 11 (11): 1569–78. doi:10.1586/ern.11.153. PMC 3232678. PMID 22014136.{{cite journal}}:  CS1 maint: multiple names: authors list (link)
Goode BL, Chau M, Denis PE, Feinstein SC (2000). "Structural and Functional Differences between 3-Repeat and 4-Repeat Tau Isoforms". Journal of Biological Chemistry. 275 (49): 38182–38189. doi:10.1074/jbc.m007489200. PMID 10984497. S2CID 30896096.{{cite journal}}:  CS1 maint: multiple names: authors list (link)
Mahapatra RK, Edwards MJ, Schott JM, Bhatia KP (2004). "Corticobasal degeneration". The Lancet Neurology </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Balanitis circinata and can you explain it in depth? [/INST] Balanitis circinata (also known as circinate balanitis) is a skin condition of reactive arthritis comprising a serpiginous ring-shaped dermatitis of the glans penis. Circinate balanitis is one of the most common cutaneous manifestation of reactive arthritis. However, balanitis circinata can also occur independently. Topical corticosteroid therapy is the most commonly used treatment, and topical calcineurin inhibitors have also been used successfully.

Signs and symptoms
At the beginning, people show pin-sized dots with white plaque on them which constantly grow into flat, red areas hardly surrounded by white plaque. Despite the visible symptoms, patients in nearly all cases do not suffer from burning or itching, nor does it smell strange. Due to its analogy to a fungal skin infection, balanitis circinata is often misdiagnosed as mycosis – especially in cases where patients have no other symptoms of reactive arthritis.

Cause
Reactive arthritis is characterized by nongonococcal urethritis, conjunctivitis, and arthritis. Reactive arthritis belongs to the group of arthritides known as the spondyloarthritides. There are two main types of reactive arthritis: post-venereal and post-enteric </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Acne mechanica and can you explain it in depth? [/INST] Acne mechanica is an acneiform eruption that has been observed after repetitive physical trauma to the skin such as rubbing, occurring from clothing (belts and straps) or sports equipment (football helmets and shoulder pads).: 499   In addition to those mechanisms, the skin not getting enough exposure to air also contributes to the formation of acne mechanica. It is often mistaken as a rash that forms on sweaty skin that is constantly being rubbed, but in reality, it is a breakout of acne mechanica. The term "acne" itself describes the occurrence in which hair follicles (also known as pores) in the skin get clogged by oil, dead skin cells, dirt and bacteria, or cosmetic products and create a pimple. Pimples can vary in type, size, and shape, but the sole basis of them occurring is the same - the oil gland in the pore becomes clogged and sometimes infected, which creates pus in order to fight the infection and subsequently causes the development of swollen, red lesions on the skin.

Signs and symptoms
The signs and symptoms at an early stage are harder to be seen. At first look, acne mechanica seems very similar to any other type of acne. However, it differs in how it is caused. A lot of acne has to do with hormones, the amount of oil production in the skin, and genetic predispositions. Acne mechanica specifically refers to the skin irritation that is formed by excess pressure, heat, and rubbing against the skin.
When the skin is constantly rubbed, it initially becomes rough and then starts to develop acne-like bumps with continuing irritation like sweating or more friction. If the skin continues to be irritated for a longer period of time, a more serious acne lesion develops that grows in size and redness. They appear as small, red tender bumps called papules. There may be a combination of whiteheads and blackheads that also appear around the area affected, the difference being that whiteheads are closed and clogged pores whereas blackheads are also clogged but open pores. The symptoms may vary also depending on a persons skin type; overly oily or dry skin can cause a number of symptoms that heighten the possibility for acne mechanica to develop.

Cause
Repetitive rubbing of the skin, in instances such as backpack strings rubbing on your shoulders or helmet straps rubbing on your chin are actions that can irritate the skin and cause acne mechanica.
Acne mechanica is a specific type of acne that is caused by friction, heat, and/or pressure on the skin. Especially occurs when the skin is not exposed to air. It is commonly found in athletes because sweaty, constantly rubbed skin by a tight uniform, for example, can result in a rash. What may look like a rash is actually acne mechanica. Another common area for acne mechanica to show up is on the sides of your face where you hold your cell phone, especially with the added bacteria it carries on it.
There are some people who are more prone to develop acne mechanica. The biggest group of people affected by this type of acne are teenagers and young adults in their twenties who already experience issues with acne on their back, shoulders, and buttocks.
Other people who have a type of acne commonly described as "sandpaper acne," which is characterized as small but rough acne lesions that are not very visible but feel like sandpaper to the touch, also are more prone to developing acne mechanica.

Mechanism
Acne mechanica specifically is triggered by both mechanical and heat stress on the skin working together to cause this irritation. The skin that is exposed to these stressors initially develops a harder surface to protect itself, but if the skin is continually dealing with this pressure, it gets irritated and forms a rash. At this point, it gets qualified as acne mechanica.
When you are in a hot climate or are working out and your body temperature rises, the heat causes the pores in your skin to open up. The dilation of the pores makes it easier for bacteria, oil, and dead skin cells to collect in the pores and clog them. Every pore in your body has a tiny hair follicle, and the blockage causes the hair follicle to become irritated and inflamed, which ends up forming pimples; specifically acne mechanica. White blood cells flood the area of inflammation, and once they die, they accumulate on the surface of the pore, causing what is known as a "whitehead". When people pop pimples, pus comes out, which has the dead white blood cells in it that originally came to diffuse the inflammation.
Depending on the continuation of the stressors, the inflammatory pimples (also known as papules and pustules) can develop into nodules and cysts, which are more severe forms of acne that are rooted deeper within the skin.

Diagnosis
Acne mechanica can be diagnosed by a dermatologist via a physical examination. In more extreme cases, a skin biopsy is performed to examine the pathology.
Family and medical history are also looked at to see if the patient has a hereditary tendency to certain conditions that cause different types of acne, which may play a role in acne mechanica development. For example, if a patients parents had acne, there is a very strong probability they will also have similar issues. The issues can range from things like overproducing dead skin cells or the pores having a higher tendency to clog.

Treatment
Acne mechanica has no direct cure, however, there are preventive measures that can be taken to minimize its breakouts. The most obvious solution to prevent extra rubbing or heat entrapment on the surface of the skin is to wear either loose-fitting clothes or wearing clothes made out of more breathable fabrics, especially during exercising, playing sports, or when performing physical activities such as hiking. Loose clothes will not rub as much and create the mechanical stress on the skin. Instead of wearing clothes made out of polyester and rayon, choosing cotton materials will help relieve the heat stress on the skin and not trap sweat in the pores. Taking showers immediately after any form of physical exercise will also help keep the skin as clean as possible. Keeping up with a skin care regimen so the skin is moisturized helps as well </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Rheumatoid vasculitis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Rett syndrome and can you explain it in depth? [/INST] Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age in females. Symptoms include impairments in language, coordination, and repetitive movements. Those affected often have slower growth, difficulty walking, and a smaller head size. Complications of Rett syndrome can include seizures, scoliosis, and sleeping problems. The severity of the condition is variable.Rett syndrome is due to a genetic mutation in the MECP2 gene, on the X chromosome. It almost always occurs as a new mutation, with less than one percent of cases being inherited from a persons parents. It occurs almost exclusively in girls; boys who have a similar mutation typically die shortly after birth. Diagnosis is based on the symptoms and can be confirmed with genetic testing.There is no known cure for Rett syndrome. Treatment is directed at improving symptoms. Anticonvulsants may be used to help with seizures. Special education, physiotherapy, and braces may also be useful. Many of those with the condition live into middle age.The condition affects about 1 in 8,500 females.  In 1999, Lebanese-American physician Huda Zoghbi discovered the mutation that causes the condition.

Signs and symptoms
Stage I
Stage I, called early-onset, typically begins between 6 and 18 months of age. This stage is often overlooked because symptoms of the disorder may be somewhat vague, and parents and doctors may not notice the subtle slowing of development at first. The infant may begin to show less eye contact and have reduced interest in toys. There may be delays in gross motor skills such as sitting or crawling. Hand-wringing and decreasing head growth may occur, but not enough to draw attention. This stage usually lasts for a few months but can continue for more than a year.

Stage II
Stage II, or the rapid destructive stage, usually begins between ages 1 and 4 and may last for weeks or months. Its onset may be rapid or gradual as the child loses purposeful hand skills and spoken language. Characteristic hand movements such as wringing, washing, clapping, or tapping, as well as repeatedly moving the hands to the mouth often begin during this stage which is called mouthing. The child may hold the hands clasped behind the back or held at the sides, with random touching, grasping, and releasing. The movements continue while the child is awake but disappear during sleep. Breathing irregularities such as episodes of apnea and hyperventilation may occur, although breathing usually improves during sleep. Some girls also display autistic-like symptoms such as loss of social interaction and communication. Walking may be unsteady and initiating motor movements can be difficult. Slowed head growth is usually noticed during this stage.

Stage III
Stage III, or the plateau or pseudo-stationary stage, usually begins between ages 2 and 10 and can last for years. Apraxia, motor problems, and seizures are prominent during this stage. However, there may be improvement in behavior, with less irritability, crying, and autistic-like features. In stage III there may be more interest in the surroundings and alertness, attention span, and communication skills may improve. Many girls remain in this stage for most of their lives.

Stage IV
Stage IV, or the late motor deterioration stage, can last for years or decades. Prominent features include reduced mobility, curvature of the spine, and muscle weakness, rigidity, spasticity, and increased muscle tone with abnormal posturing of an arm or leg. Girls who were previously able to walk may stop walking. Cognition, communication, or hand skills generally do not decline in stage IV. Repetitive hand movements may decrease and eye gaze usually improves.

Variants
The signs and symptoms of the typical form of the Rett syndrome are well described.
In addition to the classical form of Rett syndrome, several atypical forms have been described over the years; the main groups are:

Congenital variant (Rolando variant): in this severe subtype of Rett syndrome, the development of the patients and their head circumference are abnormal from birth. The typical gaze of Rett syndrome patients is usually absent;
Zappella variant of Rett Syndrome or preserved speech variant: in this subtype of Rett syndrome the patients acquire some manual skills and language is partially recovered around the age of 5 years (that is after the regression phase). Height, weight and head circumference are often in the normal range, and a good gross motor function can be observed. The Zappella variant is a milder form of Rett syndrome;
Hanefeld variant or early epilepsy variant. In this form of Rett syndrome, the patients have epilepsy before 5 months of age.The definition itself of the Rett syndrome has been refined over the years: as the atypical forms subsist near to the classical form (Hagberg & Gillgerg, 1993), the "Rett Complex" terminology has been introduced.

Cause
Genetically, Rett syndrome (RTT) is caused by mutations in the gene MECP2 located on the X chromosome (which is involved in transcriptional silencing and epigenetic regulation of methylated DNA), and can arise sporadically or from germline mutations. In less than 10% of RTT cases, mutations in the genes CDKL5 or FOXG1 have also been found to resemble it. Rett syndrome is initially diagnosed by clinical observation, but the diagnosis is definitive when there is a genetic defect in the MECP2 gene.
It has been argued that Rett syndrome is in fact a neurodevelopmental condition as opposed to a neurodegenerative condition. One piece of evidence for this is that mice with induced Rett Syndrome show no neuronal death, and some studies have suggested that their phenotypes can be partially rescued by adding functional MECP2 gene back when they are adults. This information has also helped lead to further studies aiming to treat the disorder.

Sporadic mutations
In at least 95% of Rett syndrome cases, the cause is a de novo mutation in the child. That is, it is not inherited from either parent. Parents are generally genotypically normal, without a MECP2 mutation.In cases of the sporadic form of RTT, the mutated MECP2 is thought to derive almost exclusively from a de novo mutation on the male copy of the X chromosome. It is not yet known what causes the sperm to mutate, and such mutations are rare.

Germline mutations
It can also be inherited from phenotypically normal mothers who have a germline mutation in the gene encoding methyl-CpG-binding protein-2, MeCP2. In these cases, inheritance follows an X-linked dominant pattern and is seen almost exclusively in females, as most males die in utero or shortly after birth. MECP2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of RTT, characterized by infantile spasms or early onset epilepsy, can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). As stated by Aine Merwick, Margaret OBrien, and Norman Delanty in an article on gene disorders titled Complex single gene disorders and epilepsy, "Rett syndrome affects one in every 12,500 female live births by age 12 years."

Mechanism
Pontine noradrenergic deficits
Brain levels of norepinephrine are lower in people with Rett syndrome (reviewed in). The genetic loss of MECP2 changes the properties of cells in the locus coeruleus, the exclusive source of noradrenergic innervation to the cerebral cortex and hippocampus. These changes include hyperexcitability and decreased functioning of its noradrenergic innervation. Moreover, a reduction of the tyrosine hydroxylase (Th) mRNA level, the rate-limiting enzyme in catecholamine synthesis, was detected in the whole pons of MECP2-null male as well as in adult heterozygous (MECP2+/-) female mice. Using immunoquantitative techniques, a decrease of Th protein staining level, number of locus coeruleus TH-expressing neurons and density of dendritic arborization surrounding the structure was shown in symptomatic MeCP2-deficient mice. However, locus coeruleus cells are not dying, but are more likely losing their fully mature phenotype, since no apoptotic neurons in the pons were detected.Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus coeruleus is a critical site at which loss of MECP2 results in CNS dysfunction." The restoration of normal locus coeruleus function may therefore be of potential therapeutic value in the treatment of Rett syndrome.

Midbrain dopaminergic disturbances
The majority of dopamine in the mammalian brain is synthesized by nuclei located in the mesencephalon. The substantia nigra pars compacta (SNpc), the ventral tegmental area (VTA) and the retrorubral field (RRF) contains dopaminergic neurons expressing tyrosine hydroxylase (Th, i.e. the rate-limiting enzyme in catecholamine synthesis).The nigro-striatal pathway originates from SNpc and irradiate its principal rostral target, the Caudate-Putamen (CPu) through the median forebrain bundle (MFB). This connection is involved in the tight modulation of motor strategies computed by a cortico-basal ganglia- thalamo-cortical loop.Indeed, based on the canonical anatomofunctional model of basal ganglia, nigrostriatal dopamine is able to modulate the motor loop by acting on dopaminergic receptors located on striatal GABAergic medium spiny neurons.Dysregulation of the nigrostriatal pathway is causative from Parkinson disease (PD) in humans. Toxic and/or genetic ablation of SNpc neurons produces experimental parkinsonism in mice and primates. The common features of PD and PD animal models are motor impairments (hypotonia, bradykinesia, hypokinesia).
RTT pathology, in some aspects, overlaps the motor phenotype observed in PD patients. Several neuropathological studies on postmortem brain samples argued for an SNpc alteration evidenced by neuromelanin hypopigmentation, reduction in the structure area, and even controversial, signs of apoptosis. In parallel, an hypometabolism was underlined by a reduction of several catecholamines (dopamine, noradrenaline, adrenaline) and their principal metabolic by-products. Mouse models of RTT are available and the most studied are constitutively deleted Mecp2 mice developed by Adrian Bird or Katelyn McCormick laboratories.In accordance with the motor spectrum of the RTT phenotype, Mecp2-null mice show motor abnormalities from postnatal day 30 that worsen until death. These models offer a crucial substrate to elucidate the molecular and neuroanatomical correlates of an MeCP2-deficiency. Recently (2008), it was shown that the conditional deletion of Mecp2 in catecholaminergic neurons (by crossing of Th-Cre mice with loxP-flanked Mecp2 ones) recapitulates a motor symptomatology, it was further documented that brain levels of Th in mice lacking MeCP2 in catecholaminergic neurons only are reduced, participating to the motor phenotype.However, the most studied model for the evaluation of therapeutics is the Mecp2-null mouse (totally devoid of MeCP2). In this context, a reduction in the number and soma size of Th-expressing neurons is present from 5 weeks of age and is accompanied by a decrease of Th immunoreactivity in the caudate-putamen, the principal target of dopaminergic neurons arising from the SNpc. Moreover, a neurochemical analysis of dopaminergic contents in microdissected midbrain and striatal areas revealed a reduction of dopamine at five and nine weeks of age. It is noteworthy that later on (at nine weeks), the morphological parameters remain altered but not worsen, whereas the phenotype progresses and behavioral deficits are more severe. The amount of fully activated Th (Serine40-phosphorylated isoform) in neurons that remain in the SNpc is mildly affected at 5 weeks but severely impaired by 9 weeks. Finally, using a chronic and oral L-Dopa treatment on MeCP2-deficient mice authors reported an amelioration of some of the motor deficits previously identified. Altogether, these results argue for an alteration of the nigrostriatal dopaminergic pathway in MeCP2-deficient animals as a contributor of the neuromotor deficits.There is an association of the disease with brain-derived neurotrophic factor (BDNF).

Molecular Functions of MECP2 in Rett Syndrome Pathology
As reviewed by Sharifi and Yasui, MECP2 protein, encoded by the MECP2 gene binds to DNA with a high affinity for CpG methylated DNA sites and affects transcription. MECP2 can bind to 5mc (5-methylcytosine) and 5hmc (5-hydroxymethylcytosine) with similar affinity, and these dinucleotides account for the majority of MECP2 binding sites in the mammalian genome.  MECP2 is involved in higher order chromatin organization and appears necessary for compacting chromosomes.  MECP2 binding to DNA influences mRNA splicing events.  MECP2 also appears to function in DNA repair processes.  MECP2-/+ deficient female mice have elevated rates of cell death when exposed to DNA damaging agents and are prone to early senescence.

Interactive pathway map
An interactive pathway map of Rett syndrome has been published.

Diagnosis
Prior to the discovery of a genetic cause, Rett syndrome had been designated as a pervasive developmental disorder by the Diagnostic and Statistical Manual of Mental Disorders (DSM), together with the autism spectrum disorders. Some argued against this conclusive assignment because RTT resembles non-autistic disorders such as fragile X syndrome, tuberous sclerosis, or Down syndrome that also exhibit autistic features.
After research proved the molecular mechanism, in 2013 the DSM-5 removed the syndrome altogether from classification as a mental disorder.Rett syndrome diagnosis involves close observation of the childs growth and development to observe any abnormalities in regards to developmental milestones. A diagnosis is considered when decreased head growth is observed. Conditions with similar symptoms must first be ruled out.There is a certain criteria that must be met for the diagnosis. A blood test can rule in or rule out the presence of the MECP2 mutation, however, this mutation is present in other conditions as well.For a classic diagnosis, all four criteria for ruling in a diagnosis must be met, as well as the two criteria for ruling out a diagnosis. Supportive criteria may also be present, but are not required for diagnosis. For an atypical or variant diagnosis, at least two of the four criteria for ruling in the diagnosis must be met, as well as five of the eleven supportive criteria. A period of symptom regression followed by recovery or symptom stabilization must also occur. Children are often misdiagnosed as having autism, cerebral palsy, or another form of developmental delay. A positive test for the MECP2 mutation is not enough to make a diagnosis.Ruling in
Decreased or loss of use of fine motor skills
Decreased or loss of verbal speech
Abnormalities during gait
Repetitive hand movements such as wringing/squeezing or clapping/tappingRuling out
Traumatic or anoxic/hypoxic brain injury, neurometabolic disease, or severe infection that may better explain symptoms
Abnormal psychomotor development during the first six months of lifeSupportive criteria
Breathing disturbances when awake
Bruxism while awake
Impaired sleep pattern
Abnormal muscle tone
Peripheral vasomotor disturbances
Scoliosis/kyphosis
Growth retardation
Small cold hands and feet
Inappropriate laughing/screaming spells
Diminished response to pain
Intense eye communication (eye pointing)

Differential diagnosis
Signs of Rett syndrome that are similar to autism:

Signs of Rett syndrome that are also present in cerebral palsy (regression of the type seen in Rett syndrome would be unusual in cerebral palsy; this confusion could rarely be made):

Treatment
Currently there is no cure for Rett syndrome. Treatment is directed towards improving function and addressing symptoms. A multi-disciplinary team approach is typically used to treat the person throughout life. This team may include primary care physician, physical therapist, occupational therapist, speech-language pathologist, nutritionist, and support services in academic and occupational settings. Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight.Because of the increased risk of sudden cardiac death, when long QT syndrome is found on an annual screening EKG it is treated with an anti-arrhythmic such as a beta-blocker. There is some evidence that phenytoin may be more effective than a beta-blocker.While medicinal interventions to mitigate breathing challenges in children with Rett Syndrome (RTT) are still being developed, children with RTT may be prescribed rebreathing techniques (e.g., rebreathing masks), oxygen delivery, or non-invasive ventilation as preventative or rescue breathing treatments. High oxidative stress levels in individuals with RTT have exacerbated effects on their cardiorespiratory health and functionality, dramatically increasing the risk for sudden cardiac death—an anomaly that has an associated 300x increased occurrence risk in children with Rett Syndrome. Due to this, it is vital to closely monitor atypical breathing behaviors in children with RTT, making sure to effectively use lifesaving respiratory improvement devices and strategies as prescribed.
Prescribed treatment methods may vary depending on the breathing characteristic phenotype expressed by the child. Physicians have identified three major RTT breathing phenotypes; forceful breathers, feeble breathers, and apneustic breathers. For forceful breathers, for example, rebreathing masks may be used while the child is awake.

Prognosis
Males with pathogenic MECP2 mutations usually die within the first 2 years from severe encephalopathy, unless they have one or more extra X chromosomes, or have somatic mosaicism.
Male fetuses with the disorder rarely survive to term. Because the disease-causing gene is located on the X chromosome, a female born with an MECP2 mutation on her X chromosome has another X chromosome with an ostensibly normal copy of the same gene, while a male with the mutation on his X chromosome has no other X chromosome, only a Y chromosome; thus, he has no normal gene </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Degenerative disc disease and can you explain it in depth? [/INST] Degenerative disc disease (DDD) is a medical condition typically brought on by the normal aging process in which there are anatomic changes and possibly a loss of function of one or more intervertebral discs of the spine. DDD can take place with or without symptoms, but is typically identified once symptoms arise. The root cause is thought to be loss of soluble proteins within the fluid contained in the disc with resultant reduction of the oncotic pressure, which in turn causes loss of fluid volume. Normal downward forces cause the affected disc to lose height, and the distance between vertebrae is reduced. The anulus fibrosus, the tough outer layers of a disc, also weakens. This loss of height causes laxity of the longitudinal ligaments, which may allow anterior, posterior, or lateral shifting of the vertebral bodies, causing facet joint malalignment and arthritis; scoliosis; cervical hyperlordosis; thoracic hyperkyphosis; lumbar hyperlordosis; narrowing of the space available for the spinal tract within the vertebra (spinal stenosis); or narrowing of the space through which a spinal nerve exits (vertebral foramen stenosis) with resultant inflammation and impingement of a spinal nerve, causing a radiculopathy.
DDD can cause mild to severe pain, either acute or chronic, near the involved disc, as well as neuropathic pain if an adjacent spinal nerve root is involved. Diagnosis is suspected when typical symptoms and physical findings are present; and confirmed by x-rays of the vertebral column. Occasionally the radiologic diagnosis of disc degeneration is made incidentally when a cervical x-ray, chest x-ray, or abdominal x-ray is taken for other reasons, and the abnormalities of the vertebral column are recognized. The diagnosis of DDD is not a radiologic diagnosis, since the interpreting radiologist is not aware whether there are symptoms present or not. Typical radiographic findings include disc space narrowing, displacement of vertebral bodies, fusion of adjacent vertebral bodies, and development of bone in adjacent soft tissue (osteophyte formation). An MRI is typically reserved for those with symptoms, signs, and x-ray findings suggesting the need for surgical intervention.
Treatment may include chiropractic to reduce pain and increase any reduced range of motion (ROM) of the spine; Physical Therapy for pain relief, ROM, and appropriate muscle/strength training with emphasis on correcting abnormal posture, assisting the paravertebral (paraspinous) muscles in stabilizing the spine, and core muscle strengthening; stretching exercises; massage therapy; oral analgesia with non-steroidal anti-inflammatory agents (NSAIDS); and topical analgesia with lidocaine, ice and heat. Immediate surgery may be indicated if the symptoms are severe or sudden in onset, or there is a sudden worsening of symptoms. Elective surgery may be indicated after six months of conservative therapy with unsatisfactory relief of symptoms.

Signs and symptoms
Degenerative disc disease can result in lower back or upper neck pain. The amount of degeneration does not correlate well with the amount of pain patients experience. Many people experience no pain while others, with the same amount of damage have severe, chronic pain. Whether a patient experiences pain or not largely depends on the location of the affected disc and the amount of pressure that is being put on the spinal column and surrounding nerve roots.
Nevertheless, degenerative disc disease is one of the most common sources of back pain and affects approximately 30 million people every year. With symptomatic degenerative disc disease, the pain can vary depending on the location of the affected disc. A degenerated disc in the lower back can result in lower back pain, sometimes radiating to the hips, as well as pain in the buttocks, thighs or legs. If pressure is being placed on the nerves by exposed nucleus pulposus, sporadic tingling or weakness through the knees and legs can also occur.
A degenerated disc in the upper neck will often result in pain to the neck, arm, shoulders and hands; tingling in the fingers may also be evident if nerve impingement is occurring.
Pain is most commonly felt or worsened by movements such as sitting, bending, lifting and twisting.
After an injury, some discs become painful because of inflammation and the pain comes and goes. Some people have nerve endings that penetrate more deeply into the anulus fibrosus (outer layer of the disc) than others, making discs more likely to generate pain. In the alternative, the healing of trauma to the outer anulus fibrosus may result in the innervation of the scar tissue and pain impulses from the disc, as these nerves become inflamed by nucleus pulposus material. Degenerative disc disease can lead to a chronic debilitating condition and can have a serious negative impact on a persons quality of life. When pain from degenerative disc disease is severe, traditional nonoperative treatment may be ineffective.

Cause
There is a disc between each of the vertebrae in the spine. A healthy, well-hydrated disc will contain a great deal of water in its center, known as the nucleus pulposus, which provides cushioning and flexibility for the spine. Much of the mechanical stress that is caused by everyday movements is transferred to the discs within the spine and the water content within them allows them to effectively absorb the shock. At birth, a typical human nucleus pulposus will contain about 80% water. However natural daily stresses and minor injuries can cause these discs to gradually lose water as the annulus fibrosus, or the tough outer fibrous material of a disc, weakens. Because degenerative disc disease is largely due to natural daily stresses, the American Academy of Orthopaedic Manual Physical Therapists have suggested it is not truly a "disease" process.This water loss makes the discs more flexible and results in the gradual collapse and narrowing of the gap in the spinal column. As the space between vertebrae gets smaller, extra pressure can be placed on the discs causing tiny cracks or tears to appear in the annulus. If enough pressure is exerted, it is possible for the nucleus pulposus material to seep out through the tears in the annulus and can cause what is known as a herniated disc.
As the two vertebrae above and below the affected disc begin to collapse upon each other, the facet joints at the back of the spine are forced to shift which can affect their function.Additionally, the body can react to the closing gap between vertebrae by creating bone spurs around the disc space in an attempt to stop excess motion. This can cause issues if the bone spurs start to grow into the spinal canal and put pressure on the spinal cord and surrounding nerve roots as it can cause pain and affect nerve function. This condition is called spinal stenosis.
For women, there is evidence that menopause and related estrogen-loss are associated with lumbar disc degeneration, usually occurring during the first 15 years of the climacteric. The potential role of sex hormones in the etiology of degenerative skeletal disorders is being discussed for both genders.Mutations in several genes have been implicated in intervertebral disc degeneration. Probable candidate genes include type I collagen (sp1 site), type IX collagen, vitamin D receptor, aggrecan, asporin, MMP3, interleukin-1, and interleukin-6 polymorphisms. Mutation in genes – such as MMP2 and THBS2 – that encode for proteins and enzymes involved in the regulation of the extracellular matrix has been shown to contribute to lumbar disc herniation.

Mechanisms
Degenerative discs typically show degenerative fibrocartilage and clusters of chondrocytes, suggestive of repair. Inflammation may or may not be present. Histologic examination of disc fragments resected for presumed DDD is routine to exclude malignancy.
Fibrocartilage replaces the gelatinous mucoid material of the nucleus pulposus as the disc changes with age. There may be splits in the anulus fibrosus, permitting herniation of elements of nucleus pulposus. There may also be shrinkage of the nucleus pulposus that produces prolapse or folding of the anulus fibrosus with secondary osteophyte formation at the margins of the adjacent vertebral body. The pathologic findings in DDD include protrusion, spondylolysis, and subluxation of vertebrae (spondylolisthesis) and spinal stenosis. It has been hypothesized that Cutibacterium acnes may play a role.

Diagnosis
Diagnosis of degenerative disc disease will usually consist of an analysis of a patients individual medical history, a physical exam designed to reveal muscle weakness, tenderness or poor range of motion, and an x-ray to confirm the diagnosis and rule out other causes.

Treatment
Often, the symptoms of degenerative disc disease can be successfully treated without surgery. One or a combination of treatments such as physical therapy, anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs, traction, or epidural steroid injection can provide adequate relief of troubling symptoms.
Surgery may be recommended if the conservative treatment options do not provide relief within two to three months for cervical or 6 months for lumbar symptoms. If leg or back pain limits normal activity, if there is weakness or numbness in the legs, if it is difficult to walk or stand, or if medication or physical therapy are ineffective, surgery may be necessary, most often spinal fusion </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Trigonitis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Chronic mucocutaneous candidiasis and can you explain it in depth? [/INST] Chronic mucocutaneous candidiasis is an immune disorder of T cells. It is characterized by chronic infections with Candida that are limited to mucosal surfaces, skin, and nails.: 310  It can also be associated with other types of infections, such as human papilloma virus. An association with chromosome 2 has been identified.

Signs and symptoms
The signs and symptoms of this condition are thickened skin, skin ulcer, dyspareunia, endocardium abnormality, vision problems, hepatitis, seizures, bloody urine, and meningitis.

Associated Diseases or Conditions
There are a number of disorders associated with chronic mucocutaneous candidiasis including endocrine dysfunctions, vitiligo, malabsorption syndromes, neoplasms, and others. In most patients, chronic mucocutaneous candidiasis is correlated to abnormalities in cell-mediated immunity (T-lymphocyte mediated response). The T-lymphocytes fail to produce the necessary cytokines that are required for immunity against Candida. Current effective treatments include anti-fungal drugs and, for long-term remissions, restoration of cellular immunity.Patients with autosomal-dominant mucocutaneous candidiasis may be at risk for epidermoid esophageal cancer due to the nitrosamine compounds produced by chronic candida infections.

Cause
Chronic mucocutaneous candidiasis can be inherited either autosomal dominant or autosomal recessive. There are 9 types of this condition with the first CANDF1 being located at 2p22.3-p21 (cytogenetically).

Mechanism
The mechanism the human immune system has is normally to fight an infection (like Candida). Initially, Th17 cells are made by the immune system, which in turn produces interleukin-17 (IL-17). This induces inflammation and white blood cells confront infection.Chronic mucocutaneous candidiasis mutations affect IL-17 by inhibiting its pathway. This in turn affects the human immune systems ability to fight infection, in total there are 9 possible types of this condition.

Diagnosis
Chronic mucocutaneous candidiasis can be diagnosed in an affected individual via the following methods/tests:

Types
Treatment
Management for an individual with chronic mucocutaneous candidiasis consists of the following (relapse occurs once treatment is ceased, in many cases):
Systemic anti-fungal therapy (e.g., Fluconazole)
Transfer factor
Combination therapy
Screening (annually)

See also
Candidiasis
List of cutaneous conditions

Notes
^  Indicates 9 references to specific, numbered pages in the Online Mendelian Inheritance in Man database.

References
Further reading
Kauffman, Carol A.; Pappas, Peter G.; Sobel, Jack D.; Dismukes, William E </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Harlequin-type ichthyosis and can you explain it in depth? [/INST] Harlequin-type ichthyosis is a genetic disorder that results in thickened skin over nearly the entire body at birth. The skin forms large, diamond/trapezoid/rectangle-shaped plates that are separated by deep cracks. These affect the shape of the eyelids, nose, mouth, and ears and limit movement of the arms and legs. Restricted movement of the chest can lead to breathing difficulties. These plates fall off over several weeks. Other complications can include premature birth, infection, problems with body temperature, and dehydration. The condition is the most severe form of ichthyosis, a group of genetic disorders characterised by scaly skin.Harlequin-type ichthyosis is caused by mutations in the ABCA12 gene. This gene codes for a protein necessary for transporting lipids out of cells in the outermost layer of skin. The disorder is autosomal recessive and inherited from parents who are carriers. Diagnosis is often based on appearance at birth and confirmed by genetic testing. Before birth, amniocentesis or ultrasound may support the diagnosis.There is no cure for the condition. Early in life, constant supportive care is typically required. Treatments may include moisturizing cream, antibiotics, etretinate or retinoids. Around half of those affected die within the first few months; however, retinoid treatment can increase chances of survival. Children who survive the first year of life often have long-term problems such as red skin, joint contractures and delayed growth. The condition affects around 1 in 300,000 births. It was first documented in a diary entry by Reverend Oliver Hart in America in 1750.

Signs and symptoms
Newborns with harlequin-type ichthyosis present with thick, fissured armor-plate hyperkeratosis. Sufferers feature severe cranial and facial deformities. The ears may be very poorly developed or absent entirely, as may the nose. The eyelids may be everted (ectropion), which leaves the eyes and the area around them very susceptible to infection. Babies with this condition often bleed during birth. The lips are pulled back by the dry skin (eclabium).Joints are sometimes lacking in movement, and may be below the normal size. Hypoplasia is sometimes found in the fingers. Polydactyly has also been found on occasion. In addition, the fish mouth appearance, mouth breathing, and xerostomia place affected individuals at extremely high risk for developing rampant dental decay.Patients with this condition are extremely sensitive to changes in temperature due to their hard, cracked skin, which prevents normal heat loss. The skin also restricts respiration, which impedes the chest wall from expanding and drawing in enough air. This can lead to hypoventilation and respiratory failure. Patients are often dehydrated, as their plated skin is not well suited to retaining water.

Cause
Harlequin-type ichthyosis is caused by a loss-of-function mutation in the ABCA12 gene. This gene is important in the regulation of protein synthesis for the development of the skin layer. Mutations in the gene cause impaired transport of lipids in the skin layer and may also lead to shrunken versions of the proteins responsible for skin development. Less severe mutations result in a collodion membrane and congenital ichthyosiform erythroderma-like presentation.ABCA12 is an ATP-binding cassette transporter (ABC transporter), which are members of a large family of proteins that hydrolyze ATP to transport cargo across cell membranes. ABCA12 is thought to be a lipid transporter in keratinocytes necessary for lipid transport into lamellar granules during the formation of the lipid barrier in the skin.

Diagnosis
The diagnosis of harlequin-type ichthyosis relies on both physical examination and laboratory tests. Physical assessment at birth is vital for the initial diagnosis of harlequin ichthyosis. Physical examination reveals characteristic symptoms of the condition especially the abnormalities in the skin surface of newborns. Abnormal findings in physical assessments usually result in employing other diagnostic tests to ascertain the diagnosis.Genetic testing is the most specific diagnostic test for harlequin ichthyosis. This test reveals a loss of function mutation on the ABCA12 gene. Biopsy of skin may be done to assess the histologic characteristics of the cells. Histological findings usually reveal hyperkeratotic skin cells, which leads to a thick, white and hard skin layer.

Treatment
Constant care is required to moisturize and protect the skin. The hard outer layer eventually peels off, leaving the vulnerable inner layers of the dermis exposed. Early complications result from infection due to fissuring of the hyperkeratotic plates and respiratory distress due to physical restriction of chest wall expansion.Management includes supportive care and treatment of hyperkeratosis and skin barrier dysfunction. A humidified incubator is generally used. Intubation is often required until nares are present. Nutritional support with tube feeds is essential until eclabium resolves and infants can begin nursing. Ophthalmology consultation is useful for the early management of ectropion, which is initially pronounced and resolves as scales are shed. Liberal application of petrolatum is needed multiple times a day. In addition, careful debridement of constrictive bands of hyperkeratosis should be performed to avoid digital ischemia.Cases of digital autoamputation or necrosis have been reported due to cutaneous constriction bands. Relaxation incisions have been used to prevent this morbid complication.

Prognosis
In the past, the disorder was nearly always fatal, whether due to dehydration, infection (sepsis), restricted breathing due to the plating, or other related causes. The most common cause of death was systemic infection, and sufferers rarely survived for more than a few days. However, improved neonatal intensive care and early treatment with oral retinoids, such as the drug Isotretinoin, may improve survival. Early oral retinoid therapy has been shown to soften scales and encourage desquamation. After as little as two weeks of daily oral isotretinoin, fissures in the skin can heal, and plate-like scales can nearly resolve. Improvement in the eclabium and ectropion can also be seen in a matter of weeks.
Children who survive the neonatal period usually evolve to a less severe phenotype, resembling a severe congenital ichthyosiform erythroderma. Patients continue to suffer from temperature dysregulation and may have heat and cold intolerance. Patients can also have generalized poor hair growth, scarring alopecia, contractures of digits, arthralgias, failure to thrive, hypothyroidism, and short stature. Some patients develop a rheumatoid factor-positive polyarthritis. Survivors can also develop fish-like scales and retention of a waxy, yellowish material in seborrheic areas, with ear adhered to the scalp.The oldest known survivor is Nusrit "Nelly" Shaheen, who was born in 1984 and is in relatively good health as of June 2021. The maximum lifespan of patients with this disease has not yet been determined with the new treatments.A study published in 2011 in the Archives of Dermatology concluded: "Harlequin ichthyosis should be regarded as a severe chronic disease that is not invariably fatal. With improved neonatal care and probably the early introduction of oral retinoids, the number of survivors is increasing."

Epidemiology
The condition occurs in roughly 1 in 300,000 people. As an autosomal recessive condition, rates are higher among certain ethnic populations with a higher likelihood of consanguinity.

History
The disease has been known since 1750, and was first described in the diary of Rev. Oliver Hart from Charleston, South Carolina:

"On Thursday, April the 5th, 1750, I went to see a most deplorable object of a child, born the night before of one Mary Evans in Chastown. It was surprising to all who beheld it, and I scarcely know how to describe it. The skin was dry and hard and seemed to be cracked in many places, somewhat resembling the scales of a fish. The mouth was large and round and open. It had no external nose, but two holes where the nose should have been. The eyes appeared to be lumps of coagulated blood, turned out, about the bigness of a plum, ghastly to behold. It had no external ears, but holes where the ears should be. The hands and feet appeared to be swollen, were cramped up and felt quite hard </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Klismaphilia and can you explain it in depth? [/INST] Klismaphilia (or klysmaphilia), from the Greek words κλύσμα ("enema", from κατακλυσμός, "deluge, flood") and φιλία ("love"), is a paraphilia involving enjoyment of, and sexual arousal from, enemas.

History
The term klismaphilia was coined in 1973 by Dr. Joanne Denko, an early investigator in this field, in her article "Klismaphilia: Enema as a Sexual Preference[:] Report of Two Cases," to describe the activities of some of her patients, whom she referred to as klismaphiliacs. Klismaphile has come into use as a synonym for klismaphiliac.

Manifestation
Klismaphiles might gain pleasure from a large, water distended belly or the feeling of internal pressure. An enema fetish may include the sexual attraction to the equipment, processes, environments, situations, or scenarios, and some may be sexually aroused by the preparations, such as by the feel and smell of a latex rubber or plastic syringe, by the smell of soapsuds enema solution, or by preparing the recipient. Often, klismaphiles report discovering these desires after a chance administration of an enema sometime in their childhood, but some do report discovering these feelings later on. Klismaphiles can gain satisfaction of enemas through fantasies, by actually receiving or giving one, or through the process of eliminating steps to being administered one (e.g., under the pretense of being constipated). Usually, klismaphiles carry out normal lives and successfully engage in this behavior secretly.
An enema can be an auxiliary to, or a substitute for, genital sexual activity.That some women use enemas while masturbating was documented by Alfred Kinsey in "Sexual Behavior in the Human Female." He stated, "There still other masturbatory techniques which were regularly or occasionally employed by some 11 percent of the females in the sample ... enemas, and other anal insertions, ... were employed.Sadomasochistic activities may incorporate enemas for erotic humiliation or for physical discomfort. BDSM punishment scenes can involve administering an enema in a manner that is humiliating and painful and for producing pain and cramps an extra-large volumes or highly irritating substances can be injected. Among the attractions to enema play in BDSM are erotic humiliation, dominance and submission, discipline, psychodrama, power exchange, and so on. An erotic enema allows acting out vulnerability in a primal form.

Classification
The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) classifies klismaphilia under the diagnosis of "Paraphilias, Not Otherwise Specified". The diagnostic code is 302.9. Proactive treatment for klismaphilics is not generally recommended, due to the lack of any significant desire to be "cured". Health treatment for klismaphilia thus is typically only focused on ensuring the techniques employed and chemicals used are not harmful to the practitioner </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Radiation retinopathy and can you explain it in depth? [/INST] Radiation retinopathy is damage to retina due to exposure to ionizing radiation. Radiation retinopathy has a delayed onset, typically after months or years of radiation, and is slowly progressive. In general, radiation retinopathy is seen around 18 months after treatment with external-beam radiation and with brachytherapy </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is African histoplasmosis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Carcinosis and can you explain it in depth? [/INST]  </s>