<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 Endometrial cancer and can you explain it in depth? [/INST] Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most often vaginal bleeding not associated with a menstrual period. Other symptoms include pain with urination, pain during sexual intercourse, or pelvic pain. Endometrial cancer occurs most commonly after menopause.Approximately 40% of cases are related to obesity. Endometrial cancer is also associated with excessive estrogen exposure, high blood pressure and diabetes. Whereas taking estrogen alone increases the risk of endometrial cancer, taking both estrogen and a progestogen in combination, as in most birth control pills, decreases the risk. Between two and five percent of cases are related to genes inherited from the parents. Endometrial cancer is sometimes loosely referred to as "uterine cancer", although it is distinct from other forms of uterine cancer such as cervical cancer, uterine sarcoma, and trophoblastic disease. The most frequent type of endometrial cancer is endometrioid carcinoma, which accounts for more than 80% of cases. Endometrial cancer is commonly diagnosed by endometrial biopsy or by taking samples during a procedure known as dilation and curettage. A pap smear is not typically sufficient to show endometrial cancer. Regular screening in those at normal risk is not called for.The leading treatment option for endometrial cancer is abdominal hysterectomy (the total removal by surgery of the uterus), together with removal of the Fallopian tubes and ovaries on both sides, called a bilateral salpingo-oophorectomy. In more advanced cases, radiation therapy, chemotherapy or hormone therapy may also be recommended. If the disease is diagnosed at an early stage, the outcome is favorable, and the overall five-year survival rate in the United States is greater than 80%.In 2012, endometrial cancers newly occurred in 320,000 women and caused 76,000 deaths. This makes it the third most common cause of death in cancers which only affect women, behind ovarian and cervical cancer. It is more common in the developed world and is the most common cancer of the female reproductive tract in developed countries. Rates of endometrial cancer have risen in a number of countries between the 1980s and 2010. This is believed to be due to the increasing number of elderly people and increasing rates of obesity.

Signs and symptoms
Vaginal bleeding or spotting in women after menopause occurs in 90% of endometrial cancer. Bleeding is especially common with adenocarcinoma, occurring in two-thirds of all cases. Abnormal menstrual cycles or extremely long, heavy, or frequent episodes of bleeding in women before menopause may also be a sign of endometrial cancer.Symptoms other than bleeding are not common. Other symptoms include thin white or clear vaginal discharge in postmenopausal women.  More advanced disease shows more obvious symptoms or signs that can be detected on a physical examination. The uterus may become enlarged or the cancer may spread, causing lower abdominal pain or pelvic cramping. Painful sexual intercourse or painful or difficult urination are less common signs of endometrial cancer. The uterus may also fill with pus (pyometrea). Of women with these less common symptoms (vaginal discharge, pelvic pain, and pus), 10–15% have cancer.

Risk factors
Risk factors for endometrial cancer include obesity, insulin resistance and diabetes mellitus, breast cancer, use of tamoxifen, never having had a child, late menopause, high levels of estrogen, and increasing age. Immigration studies (migration studies), which examine the change in cancer risk in populations moving between countries with different rates of cancer, show that there is some environmental component to endometrial cancer. These environmental risk factors are not well characterized.

Hormones
Most of the risk factors for endometrial cancer involve high levels of estrogens. An estimated 40% of cases are thought to be related to obesity. In obesity, the excess of adipose tissue increases conversion of androstenedione into estrone, an estrogen. Higher levels of estrone in the blood causes less or no ovulation, and exposes the endometrium continuously to high levels of estrogens. Obesity also causes less estrogen to be removed from the blood. Polycystic ovary syndrome (PCOS), which also causes irregular or no ovulation, is associated with higher rates of endometrial cancer for the same reasons as obesity. Specifically, obesity, type II diabetes, and insulin resistance are risk factors for Type I endometrial cancer. Obesity increases the risk for endometrial cancer by 300–400%.Estrogen replacement therapy during menopause when not balanced (or "opposed") with progestin is another risk factor. Higher doses or longer periods of estrogen therapy have higher risks of endometrial cancer. Women of lower weight are at greater risk from unopposed estrogen. A longer period of fertility—either from an early first menstrual period or late menopause—is also a risk factor. Unopposed estrogen raises an individuals risk of endometrial cancer by 2–10 fold, depending on weight and length of therapy. In trans men who take testosterone and have not had a hysterectomy, the conversion of testosterone into estrogen via androstenedione may lead to a higher risk of endometrial cancer.

Genetics
Genetic disorders can also cause endometrial cancer. Overall, hereditary causes contribute to 2–10% of endometrial cancer cases. Lynch syndrome, an autosomal dominant genetic disorder that mainly causes colorectal cancer, also causes endometrial cancer, especially before menopause. Women with Lynch syndrome have a 40–60% risk of developing endometrial cancer, higher than their risk of developing colorectal (bowel) or ovarian cancer. Ovarian and endometrial cancer develop simultaneously in 20% of people. Endometrial cancer nearly always develops before colon cancer, on average, 11 years before. Carcinogenesis in Lynch syndrome comes from a mutation in MLH1 or MLH2: genes that participate in the process of mismatch repair, which allows a cell to correct mistakes in the DNA. Other genes mutated in Lynch syndrome include MSH2, MSH6, and PMS2, which are also mismatch repair genes. Women with Lynch syndrome represent 2–3% of endometrial cancer cases; some sources place this as high as 5%. Depending on the gene mutation, women with Lynch syndrome have different risks of endometrial cancer. With MLH1 mutations, the risk is 54%; with MSH2, 21%; and with MSH6, 16%.Women with a family history of endometrial cancer are at higher risk. Two genes most commonly associated with some other womens cancers, BRCA1 and BRCA2, do not cause endometrial cancer. There is an apparent link with these genes but it is attributable to the use of tamoxifen, a drug that itself can cause endometrial cancer, in breast and ovarian cancers. The inherited genetic condition Cowden syndrome can also cause endometrial cancer. Women with this disorder have a 5–10% lifetime risk of developing endometrial cancer, compared to the 2–3% risk for unaffected women.Common genetic variation has also been found to affect endometrial cancer risk in large-scale genome-wide association studies. Sixteen genomic regions have been associated with endometrial cancer and the common variants explain up to 7% of the familial relative risk.

Other health problems
Some therapies for other forms of cancer increase the lifetime risk of endometrial cancer, which is a baseline 2–3%. Tamoxifen, a drug used to treat estrogen-positive breast cancers, has been associated with endometrial cancer in approximately 0.1% of users, particularly older women, but the benefits for survival from tamoxifen generally outweigh the risk of endometrial cancer. A one to two-year course of tamoxifen approximately doubles the risk of endometrial cancer, and a five-year course of therapy quadruples that risk. Raloxifene, a similar drug, did not raise the risk of endometrial cancer. Previously having ovarian cancer is a risk factor for endometrial cancer, as is having had previous radiotherapy to the pelvis. Specifically, ovarian granulosa cell tumors and thecomas are tumors associated with endometrial cancer.
Low immune function has also been implicated in endometrial cancer. High blood pressure is also a risk factor, but this may be because of its association with obesity. Sitting regularly for prolonged periods is associated with higher mortality from endometrial cancer. The risk is not negated by regular exercise, though it is lowered.

Protective factors
Smoking and the use of progestin are both protective against endometrial cancer. Smoking provides protection by altering the metabolism of estrogen and promoting weight loss and early menopause. This protective effect lasts long after smoking is stopped. Progestin is present in the combined oral contraceptive pill and the hormonal intrauterine device (IUD). Combined oral contraceptives reduce risk more the longer they are taken: by 56% after four years, 67% after eight years, and 72% after twelve years. This risk reduction continues for at least fifteen years after contraceptive use has been stopped. Obese women may need higher doses of progestin to be protected. Having had more than five infants (grand multiparity) is also a protective factor, and having at least one child reduces the risk by 35%. Breastfeeding for more than 18 months reduces risk by 23%. Increased physical activity reduces an individuals risk by 38–46%. There is preliminary evidence that consumption of soy is protective.

Pathophysiology
Endometrial cancer forms when there are errors in normal endometrial cell growth. Usually, when cells grow old or get damaged, they die, and new cells take their place. Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should. The buildup of extra cells often forms a mass of tissue called a growth or tumor. These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.In 10–20% of endometrial cancers, mostly Grade 3 (the highest histologic grade), mutations are found in a tumor suppressor gene, commonly p53 or PTEN. In 20% of endometrial hyperplasias and 50% of endometrioid cancers, PTEN has a loss-of-function mutation or a null mutation, making it less effective or completely ineffective. Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth. The p53 pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of p53 is overexpressed, the cancer tends to be particularly aggressive. P53 mutations and chromosome instability are associated with serous carcinomas, which tend to resemble ovarian and Fallopian carcinomas. Serous carcinomas are thought to develop from endometrial intraepithelial carcinoma.

PTEN and p27 loss of function mutations are associated with a good prognosis, particularly in obese women. The Her2/neu oncogene, which indicates a poor prognosis, is expressed in 20% of endometrioid and serous carcinomas. CTNNB1 (beta-catenin; a transcription gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear. Beta-catenin mutations are commonly found in endometrial cancers with squamous cells. FGFR2 mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear. SPOP is another tumor suppressor gene found to be mutated in some cases of endometrial cancer: 9% of clear cell endometrial carcinomas and 8% of serous endometrial carcinomas have mutations in this gene.Type I and Type II cancers (explained below) tend to have different mutations involved. ARID1A, which often carries a point mutation in Type I endometrial cancer, is also mutated in 26% of clear cell carcinomas of the endometrium, and 18% of serous carcinomas. Epigenetic silencing and point mutations of several genes are commonly found in Type I endometrial cancer.  Mutations in tumor suppressor genes are common in Type II endometrial cancer. PIK3CA is commonly mutated in both Type I and Type II cancers. In women with Lynch syndrome-associated endometrial cancer, microsatellite instability is common.Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasias can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia. Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so. An atypical hyperplasia is one with visible abnormalities in the nuclei. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia. Mutations in the KRAS gene can cause endometrial hyperplasia and therefore Type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of p53, and develops into a serous carcinoma.

Diagnosis
Diagnosis of endometrial cancer is made first by a physical examination, endometrial biopsy, or dilation and curettage (removal of endometrial tissue; D&C). This tissue is then examined histologically for characteristics of cancer. If cancer is found, medical imaging may be done to see whether the cancer has spread or invaded tissue.

Examination
Routine screening of asymptomatic people is not indicated since the disease is highly curable in its early, symptomatic stages. Instead, women, particularly menopausal women, should be aware of the symptoms and risk factors of endometrial cancer. A cervical screening test, such as a Pap smear, is not a useful diagnostic tool for endometrial cancer because the smear will be normal 50% of the time. A Pap smear can detect disease that has spread to the cervix. Results from a pelvic examination are frequently normal, especially in the early stages of disease. Changes in the size, shape or consistency of the uterus or its surrounding, supporting structures may exist when the disease is more advanced. Cervical stenosis, the narrowing of the cervical opening, is a sign of endometrial cancer when pus or blood is found collected in the uterus (pyometra or hematometra).Women with Lynch syndrome should begin to have annual biopsy screening at the age of 35. Some women with Lynch syndrome elect to have a prophylactic hysterectomy and salpingo-oophorectomy to greatly reduce the risk of endometrial and ovarian cancer.Transvaginal ultrasound to examine the endometrial thickness in women with postmenopausal bleeding is increasingly being used to aid in the diagnosis of endometrial cancer in the United States. In the United Kingdom, both an endometrial biopsy and a transvaginal ultrasound used in conjunction are the standard of care for diagnosing endometrial cancer. The homogeneity of the tissue visible on transvaginal ultrasound can help to indicate whether the thickness is cancerous. Ultrasound findings alone are not conclusive in cases of endometrial cancer, so another screening method (for example endometrial biopsy) must be used in conjunction. Other imaging studies are of limited use. CT scans are used for preoperative imaging of tumors that appear advanced on physical exam or have a high-risk subtype (at high risk of metastasis). They can also be used to investigate extrapelvic disease. An MRI can be of some use in determining if the cancer has spread to the cervix or if it is an endocervical adenocarcinoma. MRI is also useful for examining the nearby lymph nodes.Dilation and curettage or an endometrial biopsy are used to obtain a tissue sample for histological examination. Endometrial biopsy is the less invasive option, but it may not give conclusive results every time. Hysteroscopy only shows the gross anatomy of the endometrium, which is often not indicative of cancer, and is therefore not used, unless in conjunction with a biopsy. Hysteroscopy can be used to confirm a diagnosis of cancer. New evidence shows that D&C has a higher false negative rate than endometrial biopsy.Before treatment is begun, several other investigations are recommended. These include a chest x-ray, liver function tests, kidney function tests, and a test for levels of CA-125, a tumor marker that can be elevated in endometrial cancer.

Classification
Endometrial cancers may be tumors derived from epithelial cells (carcinomas), mixed epithelial and mesenchymal tumors (carcinosarcomas), or mesenchymal tumors.

Traditional classification of endometrial carcinomas is based either on clinical and endocrine features (Type I and Type II), or histopathological characteristics (endometrioid, serous, and clear-cell). Some tumors are difficult to classify and have features overlapping more than one category. High grade endometrioid tumors, in particular, tend to have both type I and type II features.

Carcinoma
The vast majority of endometrial cancers are carcinomas (usually adenocarcinomas), meaning that they originate from the single layer of epithelial cells that line the endometrium and form the endometrial glands. There are many microscopic subtypes of endometrial carcinoma, but they are broadly organized into two categories, Type I and Type II, based on clinical features and pathogenesis. The two subtypes are genetically distinct.Type I endometrial carcinomas occur most commonly before and around the time of menopause. In the United States, they are more common in white women, particularly those with a history of endometrial hyperplasia. Type I endometrial cancers are often low-grade, minimally invasive into the underlying uterine wall (myometrium), estrogen-dependent, and have a good outcome with treatment. Type I carcinomas represent 75–90% of endometrial cancer.Type II endometrial carcinomas usually occur in older, post-menopausal people, in the United States are more common in black women, and are not associated with increased exposure to estrogen or a history of endometrial hyperplasia. Type II endometrial cancers are often high-grade, with deep invasion into the underlying uterine wall (myometrium), are of the serous or clear cell type, and carry a poorer prognosis. They can appear to be epithelial ovarian cancer on evaluation of symptoms. They tend to present later than Type I tumors and are more aggressive, with a greater risk of relapse and/or metastasis.

Endometrioid adenocarcinoma
In endometrioid adenocarcinoma, the cancer cells grow in patterns reminiscent of normal endometrium, with many new glands formed from columnar epithelium with some abnormal nuclei. Low-grade endometrioid adenocarcinomas have well differentiated cells, have not invaded the myometrium, and are seen alongside endometrial hyperplasia. The tumors glands form very close together, without the stromal tissue that normally separates them. Higher-grade endometrioid adenocarcinomas have less well-differentiated cells, have more solid sheets of tumor cells no longer organized into glands, and are associated with an atrophied endometrium. There are several subtypes of endometrioid adenocarcinoma with similar prognoses, including villoglandular, secretory, and ciliated cell variants. There is also a subtype characterized by squamous differentiation. Some endometrioid adenocarcinomas have foci of mucinous carcinoma.The genetic mutations most commonly associated with endometrioid adenocarcinoma are in the genes PTEN, a tumor suppressor; PIK3CA, a kinase; KRAS, a GTPase that functions in signal transduction; and CTNNB1, involved in adhesion and cell signaling. The CTNNB1 (beta-catenin) gene is most commonly mutated in the squamous subtype of endometrioid adenocarcinoma.

Serous carcinoma
Serous carcinoma is a Type II endometrial tumor that makes up 5–10% of diagnosed endometrial cancer and is common in postmenopausal women with atrophied endometrium and black women. Serous endometrial carcinoma is aggressive and often invades the myometrium and metastasizes within the peritoneum (seen as omental caking) or the lymphatic system. Histologically, it appears with many atypical nuclei, papillary structures, and, in contrast to endometrioid adenocarcinomas, rounded cells instead of columnar cells. Roughly 30% of endometrial serous carcinomas also have psammoma bodies. Serous carcinomas spread differently than most other endometrial cancers; they can spread outside the uterus without invading the myometrium.The genetic mutations seen in serous carcinoma are chromosomal instability and mutations in TP53, an important tumor suppressor gene.

Clear cell carcinoma
Clear cell carcinoma is a Type II endometrial tumor that makes up less than 5% of diagnosed endometrial cancer. Like serous cell carcinoma, it is usually aggressive and carries a poor prognosis. Histologically, it is characterized by the features common to all clear cells: the eponymous clear cytoplasm when H&E stained and visible, distinct cell membranes. The p53 cell signaling system is not active in endometrial clear cell carcinoma. This form of endometrial cancer is more common in postmenopausal women.

Mucinous carcinoma
Mucinous carcinomas are a rare form of endometrial cancer, making up less than 1–2% of all diagnosed endometrial cancer. Mucinous endometrial carcinomas are most often stage I and grade I, giving them a good prognosis. They typically have well-differentiated columnar cells organized into glands with the characteristic mucin in the cytoplasm. Mucinous carcinomas must be differentiated from cervical adenocarcinoma.

Mixed or undifferentiated carcinoma
Mixed carcinomas are those that have both Type I and Type II cells, with one making up at least 10% of the tumor. These include the malignant mixed Müllerian tumor, which derives from endometrial epithelium and has a poor prognosis.Undifferentiated endometrial carcinomas make up less than 1–2% of diagnosed endometrial cancers. They have a worse prognosis than grade III tumors. Histologically, these tumors show sheets of identical epithelial cells with no identifiable pattern.

Other carcinomas
Non-metastatic squamous cell carcinoma and transitional cell carcinoma are very rare in the endometrium. Squamous cell carcinoma of the endometrium has a poor prognosis. It has been reported fewer than 100 times in the medical literature since its characterization in 1892. For primary squamous cell carcinoma of the endometrium (PSCCE) to be diagnosed, there must be no other primary cancer in the endometrium or cervix and it must not be connected to the cervical epithelium. Because of the rarity of this cancer, there are no guidelines for how it should be treated, nor any typical treatment. The common genetic causes remain uncharacterized. Primary transitional cell carcinomas of the endometrium are even more rare; 16 cases had been reported as of 2008. Its pathophysiology and treatments have not been characterized. Histologically, TCCE resembles endometrioid carcinoma and is distinct from other transitional cell carcinomas.

Sarcoma
In contrast to endometrial carcinomas, the uncommon endometrial stromal sarcomas are cancers that originate in the non-glandular connective tissue of the endometrium. They are generally non-aggressive and, if they recur, can take decades. Metastases to the lungs and pelvic or peritoneal cavities are the most frequent. They typically have estrogen and/or progesterone receptors. The prognosis for low-grade endometrial stromal sarcoma is good, with 60–90% five-year survival. High-grade undifferentiated endometrial sarcoma (HGUS) has a worse prognosis, with high rates of recurrence and 25% five-year survival. HGUS prognosis is dictated by whether or not the cancer has invaded the arteries and veins. Without vascular invasion, the five-year survival is 83%; it drops to 17% when vascular invasion is observed. Stage I ESS has the best prognosis, with five-year survival of 98% and ten-year survival of 89%. ESS makes up 0.2% of uterine cancers.

Metastasis
Endometrial cancer frequently metastasizes to the ovaries and Fallopian tubes when the cancer is located in the upper part of the uterus, and the cervix when the cancer is in the lower part of the uterus. The cancer usually first spreads into the myometrium and the serosa, then into other reproductive and pelvic structures. When the lymphatic system is involved, the pelvic and para-aortic nodes are usually first to become involved, but in no specific pattern, unlike cervical cancer. More distant metastases are spread by the blood and often occur in the lungs, as well as the liver, brain, and bone. Endometrial cancer metastasizes to the lungs 20–25% of the time, more than any other gynecologic cancer.

Histopathology
There is a three-tiered system for histologically classifying endometrial cancers, ranging from cancers with well-differentiated cells (grade I), to very poorly-differentiated cells (grade III). Grade I cancers are the least aggressive and have the best prognosis, while grade III tumors are the most aggressive and likely to recur. Grade II cancers are intermediate between grades I and III in terms of cell differentiation and aggressiveness of disease.The histopathology of endometrial cancers is highly diverse. The most common finding is a well-differentiated endometrioid adenocarcinoma, which is composed of numerous, small, crowded glands with varying degrees of nuclear atypia, mitotic activity, and stratification. This often appears on a background of endometrial hyperplasia. Frank adenocarcinoma may be distinguished from atypical hyperplasia by the finding of clear stromal invasion, or "back-to-back" glands which represent nondestructive replacement of the endometrial stroma by the cancer. With progression of the disease, the myometrium is infiltrated.

Staging
Endometrial carcinoma is surgically staged using the FIGO cancer staging system.  The 2009 FIGO staging system is as follows:
Myometrial invasion and involvement of the pelvic and para-aortic lymph nodes are the most commonly seen patterns of spread. A Stage 0 is sometimes included, in this case it is referred to as "carcinoma in situ". In 26% of presumably early-stage cancers, intraoperative staging revealed pelvic and distant metastases, making comprehensive surgical staging necessary.

Management
Surgery
The initial treatment for endometrial cancer is surgery; 90% of women with endometrial cancer are treated with some form of surgery. Surgical treatment typically consists of hysterectomy including a bilateral salpingo-oophorectomy, which is the removal of the uterus, and both ovaries and Fallopian tubes. Lymphadenectomy, or removal of pelvic and para-aortic lymph nodes, is performed for tumors of histologic grade II or above. Lymphadenectomy is routinely performed for all stages of endometrial cancer in the United States, but in the United Kingdom, the lymph nodes are typically only removed with disease of stage II or greater. The topic of lymphadenectomy and what survival benefit it offers in stage I disease is still being debated. In women with presumed stage I disease, a 2017 systematic review found no evidence that lymphadenectomy reduces the risk of death or relapse of cancer when compared with no lymphadenectomy. Women who undergo lymphadenectomy are more likely to experience systemic morbidity related to surgery or lymphoedema/lymphocyst formation. In stage III and IV cancers, cytoreductive surgery is the norm, and a biopsy of the omentum may also be included. In stage IV disease, where there are distant metastases, surgery can be used as part of palliative therapy. Laparotomy, an open-abdomen procedure, is the traditional surgical procedure; however, in those with presumed early stage primary endometrial cancer, laparoscopy (keyhole surgery) is associated with reduced operative morbidity and similar overall and disease free survival. Removal of the uterus via the abdomen is recommended over removal of the uterus via the vagina because it gives the opportunity to examine and obtain washings of the abdominal cavity to detect any further evidence of cancer. Staging of the cancer is done during the surgery.The few contraindications to surgery include inoperable tumor, massive obesity, a particularly high-risk operation, or a desire to preserve fertility. These contraindications happen in about 5–10% of cases. Women who wish to preserve their fertility and have low-grade stage I cancer can be treated with progestins, with or without concurrent tamoxifen therapy. This therapy can be continued until the cancer does not respond to treatment or until childbearing is done. Uterine perforation may occur during a D&C or an endometrial biopsy. Side effects of surgery to remove endometrial cancer can specifically include sexual dysfunction, temporary incontinence, and lymphedema, along with more common side effects of any surgery, including constipation.

Add-on therapy
There are a number of possible additional therapies. Surgery can be followed by radiation therapy and/or chemotherapy in cases of high-risk or high-grade cancers. This is called adjuvant therapy.

Chemotherapy
Adjuvant chemotherapy is a recent innovation, consisting of some combination of paclitaxel (or other taxanes like docetaxel), doxorubicin (and other anthracyclines), and platins (particularly cisplatin and carboplatin). Adjuvant chemotherapy has been found to increase survival in stage III and IV cancer more than added radiotherapy. Mutations in mismatch repair genes, like those found in Lynch syndrome, can lead to resistance against platins, meaning that chemotherapy with platins is ineffective in people with these mutations. Side effects of chemotherapy are common. These include hair loss, low neutrophil levels in the blood, and gastrointestinal problems.In cases where surgery is not indicated, palliative chemotherapy is an option; higher-dose chemotherapy is associated with longer survival. Palliative chemotherapy, particularly using capecitabine and gemcitabine, is also often used to treat recurrent endometrial cancer.Low certainty evidence suggests that in women with recurrent endometrial cancer who have had chemotherapy, receiving drugs that inhibit the mTOR pathway may reduce the risk of disease worsening compared to having more chemotherapy or hormonal therapy. Though, mTOR inhibitors may increase the chance of experiencing digestive tract ulcers.

Radiotherapy
Adjuvant radiotherapy is commonly used in early-stage (stage I or II) endometrial cancer. It can be delivered through vaginal brachytherapy (VBT), which is becoming the preferred route due to its reduced toxicity, or external beam radiotherapy (EBRT). Brachytherapy involves placing a radiation source in the organ affected; in the case of endometrial cancer a radiation source is placed directly in the vagina. External beam radiotherapy involves a beam of radiation aimed at the affected area from outside the body. VBT is used to treat any remaining cancer solely in the vagina, whereas EBRT can be used to treat remaining cancer elsewhere in the pelvis following surgery. However, the benefits of adjuvant radiotherapy are controversial. Though EBRT significantly reduces the rate of relapse in the pelvis, overall survival and metastasis rates are not improved. VBT provides a better quality of life than EBRT.Radiotherapy can also be used before surgery in certain cases. When pre-operative imaging or clinical evaluation shows tumor invading the cervix, radiation can be given before a total hysterectomy is performed. Brachytherapy and EBRT can also be used, singly or in combination, when there is a contraindication for hysterectomy. Both delivery methods of radiotherapy are associated with side effects, particularly in the gastrointestinal tract.

Hormonal therapy
Hormonal therapy is only beneficial in certain types of endometrial cancer. It was once thought to be beneficial in most cases. If a tumor is well-differentiated and known to have progesterone and estrogen receptors, progestins may be used in treatment. There is no evidence to support the use of progestagen in addition to surgery for newly diagnosed endometrial cancer. About 25% of metastatic endometrioid cancers show a response to progestins. Also, endometrial stromal sarcomas can be treated with hormonal agents, including tamoxifen, hydroxyprogesterone caproate, letrozole, megestrol acetate, and medroxyprogesterone. This treatment is effective in endometrial stromal sarcomas because they typically have estrogen and/or progestin receptors. Progestin receptors function as tumor suppressors in endometrial cancer cells. Preliminary research and clinical trials have shown these treatments to have a high rate of response even in metastatic disease.In 2010 hormonal therapy is of unclear effect in those with advanced or recurrent endometrial cancer. There is insufficient evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer.

Targeted therapy
Dostarlimab has been approved by the FDA for therapy of endometrial cancer with specific biomarker

Monitoring
The tumor marker CA-125 is frequently elevated in endometrial cancer and can be used to monitor response to treatment, particularly in serous cell cancer or advanced disease. Periodic MRIs or CT scans may be recommended in advanced disease and women with a history of endometrial cancer should receive more frequent pelvic examinations for the five years following treatment. Examinations conducted every three to four months are recommended for the first two years following treatment, and every six months for the next three years.Women with endometrial cancer should not have routine surveillance imaging to monitor the cancer unless new symptoms appear or tumor markers begin rising. Imaging without these indications is discouraged because it is unlikely to detect a recurrence or improve survival, and because it has its own costs and side effects. If a recurrence is suspected, PET/CT scanning is recommended.

Prognosis
Survival rates
The five-year survival rate for endometrial adenocarcinoma following appropriate treatment is 80%. Most women, over 70%, have FIGO stage I cancer, which has the best prognosis. Stage III and especially Stage IV cancers has a worse prognosis, but these are relatively rare, occurring in only 13% of cases. The median survival time for stage III–IV endometrial cancer is nine to ten months. Older age indicates a worse prognosis. In the United States, white women have a higher survival rate than black women, who tend to develop more aggressive forms of the disease by the time of their diagnosis. Tumors with high progesterone receptor expression have a good prognosis compared to tumors with low progesterone receptor expression; 93% of women with high progesterone receptor disease survived to three years, compared with 36% of women with low progesterone receptor disease. Heart disease is the most common cause of death among those who survive endometrial cancer, with other obesity-related health problems also being common. Following diagnosis, quality of life is also positively associated with a healthy lifestyle (no obesity, high-quality diet, physical activity).

Recurrence rates
Recurrence of early stage endometrial cancer ranges from 3 to 17%, depending on primary and adjuvant treatment. Most recurrences (75–80%) occur outside of the pelvis, and most occur within two to three years of treatment—64% within two years and 87% within three years.Higher-staged cancers are more likely to recur, as are those that have invaded the myometrium or cervix, or that have metastasized into the lymphatic system. Papillary serous carcinoma, clear cell carcinoma, and endometrioid carcinoma are the subtypes at the highest risk of recurrence. High-grade histological subtypes are also at elevated risk for recurrence.The most common site of recurrence is in the vagina; vaginal relapses of endometrial cancer have the best prognosis. If relapse occurs from a cancer that has not been treated with radiation, EBRT is the first-line treatment and is often successful. If a cancer treated with radiation recurs, pelvic exenteration is the only option for curative treatment. Palliative chemotherapy, cytoreductive surgery, and radiation are also performed. Radiation therapy (VBT and EBRT) for a local vaginal recurrence has a 50% five-year survival rate. Pelvic recurrences are treated with surgery and radiation, and abdominal recurrences are treated with radiation and, if possible, chemotherapy. Other common recurrence sites are the pelvic lymph nodes, para-aortic lymph nodes, peritoneum (28% of recurrences), and lungs, though recurrences can also occur in the brain (<1%), liver (7%), adrenal glands (1%), bones (4–7%; typically the axial skeleton), lymph nodes outside the abdomen (0.4–1%), spleen, and muscle/soft tissue (2–6%).

Epidemiology
As of 2014, approximately 320,000 women are diagnosed with endometrial cancer worldwide each year and 76,000 die, making it the sixth most common cancer in women. It is more common in developed countries, where the lifetime risk of endometrial cancer in women is 1.6%, compared to 0.6% in developing countries. It occurs in 12.9 out of 100,000 women annually in developed countries.In the United States, endometrial cancer is the most frequently diagnosed gynecologic cancer and, in women, the fourth most common cancer overall, representing 6% of all cancer cases in women. In that country, as of 2014 it was estimated that 52,630 women were diagnosed yearly and 8,590 would die from the disease. Northern Europe, Eastern Europe, and North America have the highest rates of endometrial cancer, whereas Africa and West Asia have the lowest rates. Asia saw 41% of the worlds endometrial cancer diagnoses in 2012, whereas Northern Europe, Eastern Europe, and North America together comprised 48% of diagnoses. Unlike most cancers, the number of new cases has risen in recent years, including an increase of over 40% in the United Kingdom between 1993 and 2013. Some of this rise may be due to the increase in obesity rates in developed countries, increasing life expectancies, and lower birth rates. The average lifetime risk for endometrial cancer is approximately 2–3% in people with uteruses. In the UK, approximately 7,400 cases are diagnosed annually, and in the EU, approximately 88,000.Endometrial cancer appears most frequently during perimenopause (the period just before, just after, and during menopause), between the ages of 50 and 65; overall, 75% of endometrial cancer occurs after menopause. Women younger than 40 make up 5% of endometrial cancer cases and 10–15% of cases occur in women under 50 years of age. This age group is at risk for developing ovarian cancer at the same time. The worldwide median age of diagnosis is 63 years of age; in the United States, the average age of diagnosis is 60 years of age. White American women are at higher risk for endometrial cancer than black American women, with a 2.88% and 1.69% lifetime risk respectively. Japanese-American women and American Latina women have a lower rates and Native Hawaiian women have higher rates.

Research
There are several experimental therapies for endometrial cancer under research, including immunologic, hormonal, and chemotherapeutic treatments. Trastuzumab (Herceptin), an antibody against the Her2 protein, has been used in cancers known to be positive for the Her2/neu oncogene, but research is still underway. Immunologic therapies are also under investigation, particularly in uterine papillary serous carcinoma.Cancers can be analyzed using genetic techniques (including DNA sequencing and immunohistochemistry) to determine if certain therapies specific to mutated genes can be used to treat it. PARP inhibitors are used to treat endometrial cancer with PTEN mutations, specifically, mutations that lower the expression of PTEN. The PARP inhibitor shown to be active against endometrial cancer is olaparib. Research is ongoing in this area as of the 2010s.Research is ongoing on the use of metformin, a diabetes medication, in obese women with endometrial cancer before surgery. Early research has shown it to be effective in slowing the rate of cancer cell proliferation. Preliminary research has shown that preoperative metformin administration can reduce expression of tumor markers. Long-term use of metformin has not been shown to have a preventative effect against developing cancer, but may improve overall survival.Temsirolimus, an mTOR inhibitor, is under investigation as a potential treatment. Research shows that mTOR inhibitors may be particularly effective for cancers with mutations in PTEN. Ridaforolimus (deforolimus) is also being researched as a treatment for people who have previously had chemotherapy. Preliminary research has been promising, and a stage II trial for ridaforolimus was completed by 2013. There has also been research on combined ridaforolimus/progestin treatments for recurrent endometrial cancer. Bevacizumab and tyrosine kinase inhibitors, which inhibit angiogenesis, are being researched as potential treatments for endometrial cancers with high levels of vascular endothelial growth factor. Ixabepilone is being researched as a possible chemotherapy for advanced or recurrent endometrial cancer. Treatments for rare high-grade undifferentiated endometrial sarcoma are being researched, as there is no established standard of care yet for this disease. Chemotherapies being researched include doxorubicin and ifosfamide.There is also research in progress on more genes and biomarkers that may be linked to endometrial cancer. The protective effect of combined oral contraceptives and the IUD is being investigated. Preliminary research has shown that the levonorgestrel IUD placed for a year, combined with six monthly injections of gonadotropin-releasing hormone, can stop or reverse the progress of endometrial cancer in young women; specifically complex atypical hyperplasia however the results have been inconclusive. An experimental drug that combines a hormone with doxorubicin is also under investigation for greater efficacy in cancers with hormone receptors.  Hormone therapy that is effective in treating breast cancer, including use of aromatase inhibitors, is also being investigated for use in endometrial cancer. One such drug is anastrozole, which is currently being researched in hormone-positive recurrences after chemotherapy. Research into hormonal treatments for endometrial stromal sarcomas is ongoing as well. It includes trials of drugs like mifepristone, a progestin antagonist, and aminoglutethimide and letrozole, two aromatase inhibitors.Research continues into the best imaging method for detecting and staging endometrial cancer </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 Neu–Laxova syndrome and can you explain it in depth? [/INST] Neu–Laxova syndrome (also known as Neu syndrome or Neu-Povysilová syndrome, abbreviated as NLS) is a rare autosomal recessive disorder characterized by severe intrauterine growth restriction and multiple congenital malformations. Neu–Laxova syndrome is a very severe disorder, leading to stillbirth or death shortly after birth. It was first described by Dr. Richard Neu in 1971 and Dr </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 Haber syndrome 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 Pressure urticaria 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 Leigh syndrome and can you explain it in depth? [/INST] Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after  Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily.

Signs and symptoms
The symptoms of Leigh syndrome are classically described as beginning in infancy and leading to death within a span of several years; however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis. Symptoms are often first seen after a triggering event that taxes the bodys energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.Infants with the syndrome have symptoms that include diarrhea, vomiting, and dysphagia (trouble swallowing or sucking), leading to a failure to thrive. Children with early Leigh disease also may appear irritable and cry much more than healthy babies. Seizures are often seen. Excess lactate may be seen in the urine, cerebrospinal fluid, and blood of a person with Leigh syndrome.As the disease progresses, the muscular system is debilitated throughout the body, as the brain cannot control the contraction of muscles. Hypotonia (low muscle tone and strength), dystonia (involuntary, sustained muscle contraction), and ataxia (lack of control over movement) are often seen in people with Leigh disease. The eyes are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called ophthalmoparesis (weakness or paralysis) and nystagmus (involuntary eye movements). Slow saccades are also sometimes seen. The heart and lungs can also fail as a result of Leigh disease. Hypertrophic cardiomyopathy (thickening of part of the heart muscle) is also sometimes found and can cause death; asymmetric septal hypertrophy has also been associated with Leigh syndrome. In children with Leigh-syndrome associated ventricular septal defects, caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.However, respiratory failure is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include peripheral neuropathy, loss of sensation in extremities caused by damage to the peripheral nervous system.Hypertrichosis is seen in Leigh syndrome caused by mutations in the nuclear gene SURF1.

Genomics
Mutations in mitochondrial DNA (mtDNA) and over 30 genes in nuclear DNA (gene SURF1 and some COX assembly factors) have been implicated in Leigh disease.Disorders of oxidative phosphorylation, the process by which cells produce their main energy source of adenosine triphosphate (ATP), may be caused by mutations in either mtDNA or in nuclear encoded genes. The latter account for the majority of Leigh disease, although it is not always possible to identify the specific mutation responsible for the condition in a particular individual. Four out of the five protein complexes involved in oxidative phosphorylation are most commonly disrupted in Leigh syndrome, either because of malformed protein or because of an error in the assembly of these complexes. Regardless of the genetic basis, it results in an inability of the complexes affected by the mutation to perform their role in oxidative phosphorylation. In the case of Leigh disease, crucial cells in the brain stem and basal ganglia are affected. This causes a chronic lack of energy in the cells, which leads to cell death and in turn, affects the central nervous system and inhibits motor functions. The heart and other muscles also require a lot of energy and are affected by cell death caused by chronic energy deficiencies in Leigh syndrome.

Mitochondrial DNA mutations
Mitochondria are essential organelles in eukaryotic cells. Their function is to convert the potential energy of glucose, amino acids, and fatty acids into adenosine triphosphate (ATP) in a process called oxidative phosphorylation. Mitochondria carry their own DNA, called mitochondrial DNA (mtDNA). The information stored in the mtDNA is used to produce several of the enzymes essential to the production of ATP.Between 20 and 25 percent of Leigh syndrome cases are caused by mutations in mitochondrial DNA. The most common of these mutations is found in 10 to 20 percent of Leigh syndrome and occurs in MT-ATP6, a gene that codes for a protein in the last complex of the oxidative phosphorylation chain, ATP synthase, an enzyme that directly generates ATP. Without ATP synthase, the electron transport chain will not produce any ATP. The most common MT-ATP6 mutation found with Leigh syndrome is a point mutation at nucleotide 8993 that changes a thymine to a guanine. This and other point mutations associated with Leigh syndrome destabilize or malform the protein complex and keep energy production down in affected cells. Several mitochondrial genes involved in creating the first complex of the oxidative phosphorylation chain can be implicated in a case of Leigh syndrome, including genes MT-ND2, MT-ND3, MT-ND5, MT-ND6 and MT-CO1.Mitochondrial DNA is passed down matrilineally in a pattern called maternal inheritance — a mother can transmit the genes for Leigh syndrome to both male and female children, but fathers cannot pass down mitochondrial genes.

Nuclear DNA mutations
Nuclear DNA comprises most of the genome of an organism and in sexually reproducing organisms is inherited from both parents, in contrast to mitochondrial DNAs maternal pattern of inheritance. Leigh syndrome caused by nuclear DNA mutations is inherited in an autosomal recessive pattern. This means that two copies of the mutated gene are required to cause the disease, so two unaffected parents, each of whom carries one mutant allele, can have an affected child if that child inherits the mutant allele from both parents.75 to 80 percent of Leigh syndrome is caused by mutations in nuclear DNA; mutations affecting the function or assembly of the fourth complex involved in oxidative phosphorylation, cytochrome c oxidase (COX), cause most cases of Leigh disease. Mutations in a gene called SURF1 (surfeit1) are the most common cause of this subtype of Leigh syndrome. The protein that SURF1 codes for is terminated early and therefore cannot perform its function, shepherding the subunits of COX together into a functional protein complex. This results in a deficit of COX protein, reducing the amount of energy produced by mitochondria. SURF1 is located on the long arm of chromosome 9. Another nuclear DNA mutation that causes Leigh syndrome affects another protein complex in the mitochondria, pyruvate dehydrogenase, which is an enzyme in the Link reaction pathway. Some types of SURF1 mutations cause a subtype of Leigh syndrome that has a particularly late onset but similarly variable clinical course.Other nuclear genes associated with Leigh syndrome are located on chromosome 2 (BCS1L and NDUFA10); chromosome 5 (SDHA, NDUFS4, NDUFAF2, and NDUFA2); chromosome 8 (NDUFAF6), chromosome 10 (COX15); chromosome 11 (NDUFS3, NDUFS8, and FOXRED1); chromosome 12 (NDUFA9 and NDUFA12); and chromosome 19 (NDUFS7). Many of these genes affect the first oxidative phosphorylation complex.

X-linked Leigh syndrome
Leigh syndrome can also be caused by deficiency of the pyruvate dehydrogenase complex (PDHC), most commonly involving a PDHC subunit which is encoded by an X-linked gene (OMIM 308930). The neurological features of Leigh syndrome caused by PDHC deficiency are indistinguishable from other forms. However, non-neurological features (other than lactic acidosis) are not seen in PDHC deficiency.X-linked recessive Leigh syndrome affects male children far more often than female children because they only have one copy of the X chromosome. Female children would need two copies of the faulty gene to be affected by X-linked Leigh syndrome.

French Canadian Leigh syndrome
The type of Leigh syndrome found at a much higher rate in the Saguenay-Lac-Saint-Jean region of Quebec is caused by a mutation in the LRPPRC gene, located on the small (p) arm of chromosome 2. Both compound heterozygosity and homozygous mutations have been observed in French Canadian Leigh syndrome. This subtype of the disease was first described in 1993 in 34 children from the region, all of whom had a severe deficiency in cytochrome c oxidase (COX), the fourth complex in the mitochondrial electron transport chain. Though the subunits of the protein found in affected cells were functional, they were not properly assembled. The deficiency was found to be almost complete in brain and liver tissues and substantial (approximately 50% of normal enzyme activity) in fibroblasts (connective tissue cells) and skeletal muscle. Kidney and heart tissues were found to not have a COX deficiency.French Canadian Leigh syndrome has similar symptoms to other types of Leigh syndrome. The age of onset is, on average, 5 months and the median age of death is 1 year and 7 months. Children with the disease are developmentally delayed, have mildly dysmorphic facial features, including hypoplasia of the midface and wide nasal bridge, chronic metabolic acidosis, and hypotonia (decreased muscular strength). Other symptoms include tachypnea (unusually quick breathing rate), poor sucking ability, hypoglycemia (low blood sugar), and tremors. Severe, sudden metabolic acidosis is a common cause of mortality.Estimates of the rate of genetic carriers in the Saguenay-Lac-Saint-Jean region range from 1 in 23 to 1 in 28; the number of children born with the disease has been estimated at 1 in 2063 to 1 in 2473 live births. Genealogic studies suggest that the responsible mutation was introduced to the region by early European settlers.

Pathophysiology
The characteristic symptoms of Leigh syndrome are at least partially caused by bilateral, focal lesions in the brainstem, basal ganglia, cerebellum, and other regions of the brain. The lesions take on different forms, including areas of demyelination, spongiosis, gliosis, necrosis, and capillary proliferation. Demyelination is the loss of the myelin sheath around the axons of neurons, inhibiting their ability to communicate with other neurons. The brain stem is involved in maintaining basic life functions such as breathing, swallowing, and circulation; the basal ganglia and cerebellum control movement and balance. Damage to these areas therefore results in the major symptoms of Leigh syndrome—loss of control over functions controlled by these areas.The lactic acidosis sometimes associated with Leigh syndrome is caused by the buildup of pyruvate, which is unable to be processed in individuals with certain types of oxidative phosphorylation deficiencies. The pyruvate is either converted into alanine via alanine aminotransferase or converted into lactic acid by lactate dehydrogenase; both of these substances can then build up in the body.

Diagnosis
Leigh syndrome is suggested by clinical findings and confirmed with laboratory and genetic testing.

Clinical findings
Dystonia, nystagmus, and problems with the autonomic nervous system suggest damage to the basal ganglia and brain stem potentially caused by Leigh syndrome. Other symptoms are also indicative of brain damage, such as hypertrichosis and neurologically caused deafness. Laboratory findings of lactic acidosis or acidemia and hyperalaninemia (elevated levels of alanine in the blood) can also suggest Leigh syndrome. Assessing the level of organic acids in urine can also indicate a dysfunction in the metabolic pathway.

Differential diagnosis
Other diseases can have a similar clinical presentation to Leigh syndrome; excluding other causes of similar clinical symptoms is often a first step to diagnosing Leigh syndrome. Conditions that can appear similar to Leigh disease include perinatal asphyxia, kernicterus, carbon monoxide poisoning, methanol toxicity, thiamine deficiency, Wilsons disease, biotin-responsive basal ganglia disease, and some forms of encephalitis. Perinatal asphyxia can cause bilateral ganglial lesions and damage to the thalamus, which are similar to the signs seen with Leigh syndrome. When hyperbilirubinemia is not treated with phototherapy, the bilirubin can accumulate in the basal ganglia and cause lesions similar to those seen in Leigh syndrome. This is not common since the advent of phototherapy.

Treatment
Succinic acid has been studied, and shown effective for both Leigh syndrome, and MELAS syndrome. A high-fat, low-carbohydrate diet may be followed if a gene on the X chromosome is implicated in an individuals Leigh syndrome </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 Fourth nerve palsy 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 Cotard delusion and can you explain it in depth? [/INST] Cotards delusion, also known as walking corpse syndrome or Cotards syndrome, is a rare mental disorder in which the affected person holds the delusional belief that they are dead, do not exist, are putrefying, or have lost their blood or internal organs. Statistical analysis of a hundred-patient cohort indicated that denial of self-existence is present in 45% of the cases of Cotards syndrome; the other 55% of the patients presented with delusions of immortality.In 1880, the neurologist Jules Cotard described the condition as le délire des négations ("the delirium of negation"), a psychiatric syndrome of varied severity. A mild case is characterized by despair and self-loathing, while a severe case is characterized by intense delusions of negation, and chronic psychiatric depression.The case of "Mademoiselle X" describes a woman who denied the existence of parts of her body (somatoparaphrenia) and of her need to eat. She claimed that she was condemned to eternal damnation, and therefore could not die a natural death. In the course of experiencing "the delirium of negation", Mademoiselle X died of starvation.Cotards delusion is not mentioned in either the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) of the World Health Organization.

Signs and symptoms
Delusions of negation are the central symptom in Cotards syndrome. The patient usually denies their own existence, the existence of a certain body part, or the existence of a portion of their body. Cotards syndrome exists in three stages:

Germination stage: symptoms of psychotic depression and of hypochondria appear;
Blooming stage: full development of the syndrome and delusions of negation; and;
Chronic stage: continued severe delusions along with chronic psychiatric depression.Cotards syndrome withdraws the person with the condition from other people due to neglect of their personal hygiene and physical health. Delusions of negation of self prevent the patient from making sense of external reality, which then produces a distorted view of the external world. Such delusions of negation are usually found in schizophrenia. Although a diagnosis of Cotards syndrome does not require the patient to have had hallucinations, the strong delusions of negation are comparable to those found in schizophrenic patients.

Distorted reality
The article Betwixt Life and Death: Case Studies of the Cotard Delusion (1996) describes a contemporary case of Cotards delusion which occurred in a Scotsman whose brain was damaged in a motorcycle accident:

[The patients] symptoms occurred in the context of more general feelings of unreality and [of] being dead. In January 1990, after his discharge from hospital in Edinburgh, his mother took him to South Africa. He was convinced that he had been taken to Hell (which was confirmed by the heat) and that he had died of sepsis (which had been a risk early in his recovery), or perhaps from AIDS (he had read a story in The Scotsman about someone with AIDS who died from sepsis), or from an overdose of a yellow fever injection. He thought he had "borrowed [his] mothers spirit to show [him] around Hell" and that she was asleep in Scotland.
The article Recurrent Postictal Depression with Cotard Delusion (2005) describes the case of a 14-year-old epileptic boy who experienced Cotards syndrome after seizures. His mental health history showed themes of death, chronic sadness, decreased physical activity in leisure time, social withdrawal, and disturbed biological functions.
About twice a year, the boy had episodes that lasted between three weeks and three months. In the course of each episode, he said that everyone and everything was dead (including trees), described himself as a dead body, and warned that the world would be destroyed within hours. Throughout the episode, the boy showed no response to pleasurable stimuli, and had no interest in social activities.

Pathophysiology
The underlying neurophysiology and psychopathology of Cotards syndrome might be related to problems of delusional misidentification. Neurologically, Cotards delusion (negation of the self) is thought to be related to Capgras delusion (people replaced by impostors); each type of delusion is thought to result from neural misfiring in the fusiform face area of the brain, which recognizes faces, and in the amygdalae, which associate emotions to a recognized face.The neural disconnection creates in the patient a sense that the face they are observing is not the face of the person to whom it belongs; therefore, that face lacks the familiarity (recognition) normally associated with it. This results in derealization or a disconnection from the environment. If the observed face is that of a person known to the patient, they experience that face as the face of an impostor (Capgras delusion). If the patient sees their own face, they might perceive no association between the face and their own sense of self—which results in the patient believing that they do not exist (Cotards syndrome).
Cotards syndrome is usually encountered in people with psychosis, as in schizophrenia. It is also found in clinical depression, derealization, brain tumor, and migraine headaches. The medical literature indicate that the occurrence of Cotards delusion is associated with lesions in the parietal lobe. As such, the Cotards delusion patient presents a greater incidence of brain atrophy—especially of the median frontal lobe—than do people in control groups.Cotards delusion also has resulted from a patients adverse physiological response to a drug (e.g., acyclovir) and to its prodrug precursor (e.g., valaciclovir). The occurrence of Cotards delusion symptoms was associated with a high serum-concentration of 9-carboxymethoxymethylguanine (CMMG), the principal metabolite of acyclovir.As such, the patient with weak kidneys (impaired renal function) continued risking the occurrence of delusional symptoms despite the reduction of the dose of acyclovir. Hemodialysis resolved the patients delusions (of negating the self) within hours of treatment, which suggests that the occurrence of Cotards delusion symptoms might not always be cause for psychiatric hospitalization of the patient.

Treatment
Pharmacological treatments, both mono-therapeutic and multi-therapeutic, using antidepressants, antipsychotics, and mood stabilizers have been successful. Likewise, with the depressed patient, electroconvulsive therapy (ECT) is more effective than pharmacotherapy.Cotards syndrome resulting from an adverse drug reaction to valacyclovir is attributed to elevated serum concentration of one of valacyclovirs metabolites, 9-carboxymethoxymethylguanine (CMMG). Successful treatment warrants cessation of valacyclovir </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 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency and can you explain it in depth? [/INST] 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is an uncommon inherited disorder in which the body cannot properly process the amino acid leucine. Additionally, the disorder prevents the body from making ketones, which are used for energy during fasting.

Presentation
This disorder usually appears within the first year of life. The signs and symptoms of HMG-CoA lyase deficiency include vomiting, dehydration, lethargy, convulsions, and coma. When episodes occur in an infant or child, blood sugar becomes extremely low (hypoglycemia), and harmful compounds can build up and cause the blood to become too acidic (metabolic acidosis). These episodes are often triggered by an infection, fasting, strenuous exercise, or sometimes other types of stress.

Cause
Mutations in the HMGCL gene cause 3-hydroxy-3-methylglutaryl-CoA lyase deficiency </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 Intravenous leiomyomatosis 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 Gangliosidosis 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 Uveitis–glaucoma–hyphema syndrome and can you explain it in depth? [/INST] Uveitis–glaucoma–hyphaema (UGH) syndrome, also known as Ellingson syndrome, is a complication of cataract surgery, caused by intraocular lens subluxation or dislocation. The chafing of mispositioned intraocular lens over iris, ciliary body or iridocorneal angle cause elevated intraocular pressure (IOP) anterior uveitis and hyphema. It is most commonly caused by anterior chamber IOLs and sulcus IOLs but, the condition can be seen with any type of IOL, including posterior chamber lenses and cosmetic iris implants.

Pathophysiology
The mechanical irritation of mispositioned intraocular lens over iris, ciliary body or iridocorneal angle cause spectrum of iris transillumination defects including anterior uveitis, hyphema and elevated intraocular pressure (IOP). Uveitis results from mechanical breakdown of the blood–aqueous barrier and resultant intraocular inflammation. A hyphema results from damage to vascular tissue of the iris, ciliary body, or angle by mispositioned IOL </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 Ventricular escape beat and can you explain it in depth? [/INST] In cardiology, a ventricular escape beat is a self-generated electrical discharge initiated by, and causing contraction of the ventricles of the heart; normally the heart rhythm is begun in the atria of the heart and is subsequently transmitted to the ventricles. The ventricular escape beat follows a long pause in ventricular rhythm and acts to prevent cardiac arrest. It indicates a failure of the electrical conduction system of the heart to stimulate the ventricles (which would lead to the absence of heartbeats, unless ventricular escape beats occur).

Causes
Ventricular escape beats occur when the rate of electrical discharge reaching the ventricles (normally initiated by the hearts sinoatrial node (SA node), transmitted to the atrioventricular node (AV node), and then further transmitted to the ventricles) falls below the base rate determined by the rate of Phase 4 spontaneous depolarisation of ventricular pacemaker cells.
An escape beat usually occurs 2–3 seconds after an electrical impulse has failed to reach the ventricles.This phenomenon can be caused by the sinoatrial node (SA node) failing to initiate a beat, by a failure of the conductivity from the SA node to the atrioventricular node (AV node), or by atrioventricular block (especially third degree AV block). Normally, the pacemaker cells of the sinoatrial node discharge at the highest frequency and are thus dominant over other cells with pacemaker activity. The AV node normally has the second fastest discharge rate. When the sinus rate falls below the discharge rate of the AV node, this becomes the dominant pacemaker, and the result is called a junctional escape beat </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 Dopamine transporter deficiency syndrome and can you explain it in depth? [/INST] Dopamine transporter deficiency syndrome (DTDS), also known as infantile parkinsonism-dystonia, is a rare movement disorder that causes progressively worsening dystonia and parkinsonism. It is the first known inherited dopamine transportophathy.
DTDS is an extremely rare disease; only about 20 affected individuals have been described in the medical literature. Researchers believe this condition is likely underdiagnosed because its signs and symptoms overlap with other movement disorders, including cerebral palsy.The onset of DTDS is a continuum that ranges from early-onset DTDS (in the first 6 months) to atypical later-onset DTDS (in childhood, adolescence, or adulthood).

Signs and symptoms
The main symptom of DTDS, presenting in 80-99% of DTDS patients, is Parkinsonism. This is a neurological anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, and is characterized by shaking and tremors, rigidity, slowness of movement, and difficulty with walking and gait.Various other symptoms present less commonly (30-79%), including bradykinesia (slowness of movement), acid reflux, muscular hypertonia, and chorea.

Causes
DTDS is caused by mutations in the SLC6A3 gene, which codes for the dopamine transporter protein DAT. In contrast to various mutations that up-regulate DAT activity, which is implicated in clinical depression, this mutation results in DAT down-regulation and, consequently, DTDS. Known DTDS-related SLC6A3 mutations include:

R85L
A314V
G386R
R445C
Y470SIn vitro replication of SLC6A3 mutations like those present in DTDS demonstrate multifaceted loss of dopamine transporter functions. Dopamine intake is universally impaired. These mutants also demonstrated diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation, and failure of amphetamine-mediated dopamine efflux.The age at which signs and symptoms appear seems to be related to the severity of DAT dysfunction. Early-onset DTDS movement problems in infancy most often have transporter activity that is less than 5 percent of normal. Those whose movement problems appear in childhood or later tend to have somewhat higher levels of transporter activity, although they are still lower than normal. Researchers speculate that higher levels of transporter activity may delay the onset of the disease in these individuals.
DTDS is inherited in an autosomal recessive pattern, which means, for affected individuals, both copies of the gene in each cell have SLC6A3 mutations. As such, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and 25% chance of being unaffected and not a carrier. Once a SLC6A3 pathogenic variant is identified within an affected family member, carrier testing for at-risk relatives and prenatal testing or preimplantation genetic diagnosis for pregnancies can be options considered for genetic counseling.

Diagnosis
Diagnosis of SLC6A3-negative DTDS is established in a proband via molecular genetic testing, looking for biallelic (i.e. homozygous or compound heterozygous) pathogenic SLC6A3 variants. DTDS-positive patients are further identified by matching their genetic testing results with known characteristic clinical, laboratory, and imaging findings.To date, another potential diagnostic tool is neurotransmitter analysis of patient cerebrospinal fluid. All individuals tested with classical early-onset, SLC6A3-related DTDS display raised homovanillic acid (HVA) levels with normal 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite) levels. DTDS patients demonstrate a HVA:5-HIAA ratio of 5.0-13.0, above the normal range of 1.0-4.0 </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 Branchial cleft cyst and can you explain it in depth? [/INST] A branchial cleft cyst is a cyst as a swelling in the upper part of neck anterior to sternocleidomastoid. It can, but does not necessarily, have an opening to the skin surface, called a fistula. The cause is usually a developmental abnormality arising in the early prenatal period, typically failure of obliteration of the second, third, and fourth branchial cleft, i.e. failure of fusion of the second branchial arches and epicardial ridge in lower part of the neck. Branchial cleft cysts account for almost 20% of neck masses in children. Less commonly, the cysts can develop from the first, third, or fourth clefts, and their location and the location of associated fistulas differs accordingly.

Symptoms and signs
Most branchial cleft cysts present in late childhood or early adulthood as a solitary, painless mass, which went previously unnoticed, that has now become infected (typically after an upper respiratory tract infection). Fistulas, if present, are asymptomatic until infection arises.

Pathophysiology
Branchial cleft cysts are remnants of embryonic development and result from a failure of obliteration of one of the branchial clefts, which are homologous to the structures in fish that develop into gills.

Pathology
The cyst wall is composed of squamous epithelium (90%), columnar cells with or without cilia, or a mixture of both, with lymphoid infiltrate, often with prominent germinal centers and few subcapsular lymph sinuses. The cyst is typically surrounded by lymphoid tissue that has attenuated or absent overlying epithelium due to inflammatory changes. The cyst may or may not contain granular and keratinaceous cellular debris. Cholesterol crystals may be found in the fluid extracted from a branchial cyst.

Diagnosis
The diagnosis of branchial cleft cysts is typically done clinically due to their relatively consistent location in the neck, typically anterior to the sternocleidomastoid muscle. For masses presenting in adulthood, the presumption should be a malignancy until proven otherwise, since carcinomas of the tonsil, tongue base and thyroid may all present as cystic masses of the neck. Unlike a thyroglossal duct cyst, when swallowing, the mass should not move up or down.

Types
Four branchial clefts (also called "grooves") form during the development of a human embryo. The first cleft normally develops into the external auditory canal, but the remaining three arches are obliterated and have no persistent structures in normal development. Persistence or abnormal formation of these four clefts can all result in branchial cleft cysts which may or may not drain via sinus tracts.
First branchial cleft cysts account for 8% of the sinuses and cysts of the neck </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 Chemical burn and can you explain it in depth? [/INST] A chemical burn occurs when living tissue is exposed to a corrosive substance (such as a strong acid, base or oxidizer) or a cytotoxic agent (such as mustard gas, lewisite or arsine). Chemical burns follow standard burn classification and may cause extensive tissue damage. The main types of irritant and/or corrosive products are: acids, bases, oxidizers / reducing agents, solvents, and alkylants </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 Immunoproliferative disorder 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 Spider angioma and can you explain it in depth? [/INST] A spider angioma or spider naevus (plural: spider naevi), also nevus araneus, is a type of telangiectasis (swollen, spider-like blood vessels on the skin) found slightly beneath the skins surface, often containing a central red spot and deep reddish extensions (see Blood color) which radiate outwards like a spiders web or a spiders legs. They are common and often benign, presenting in around 10–15% of healthy adults and young children. However, having more than three spider angiomas is likely to be abnormal and may be a sign of liver disease and/or hepatitis C (HCV virus); it also suggests the probability of esophageal varices.

Signs and symptoms
Spider angiomas are found only in the distribution of the superior vena cava, and are thus commonly found on the face, neck, upper part of the torso, and arms.

Cause
Spider angiomas form due to failure of the sphincteric muscle surrounding a cutaneous arteriole. The central red dot is the dilated arteriole and the red "spider legs" are small capillaries carrying away the freely flowing blood. If momentary pressure is applied, it is possible to see the emptied capillaries refilling from the center. No other angiomas show this phenomenon.The dilation, in turn, is caused by increased estrogen levels in the blood. Many pregnant women and women using hormonal contraception have spider angiomas, which is due to high estrogen levels in their blood. Individuals with significant liver disease also show many spider angiomas, as their liver cannot metabolize circulating estrogens, specifically estrone, which derives from the androgen androstenedione. About 33% of patients with cirrhosis have spider angiomas.Hepatitis C is an infection that can lead to irreversible liver damage. The hepatitis C virus (HCV) spreads through contaminated blood, and people are often infected by sharing drug paraphernalia or unsanitized tattoo guns and needles, piercing equipment, or manicure tools. To make matters worse, symptoms of the HCV virus can take years to appear, and this is likely why most of those infected with hepatitis C do not even realize that they are infected, and can continue to spread the virus unknowingly.Unfortunately, many symptoms do not start to appear until some damage to the liver has been done. Unlike in the past when hepatitis C was not curable and continued to worsen as years passed, today most positive hepatitis C (HCV virus) cases (95-98%) are now curable by taking a fairly newer treatment in the form of a prescribed daily oral medication for the full duration of 12 weeks. This treatment is usually well tolerated, with little to no side effects whatsoever.
Spider angiomas (spider-like blood vessels on the skin) are one of the main symptoms caused by a hepatitis C (HCV virus) infection. Discovering an infected patient with hepatitis C early on in the infection phase increases the chances of the virus being successfully treated and cured by oral medication. Some patients can be infected with hepatitis C for decades without knowing, and without experiencing any signs or symptoms of the virus </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 Farber disease and can you explain it in depth? [/INST] Farber disease (also known as Farbers lipogranulomatosis, acid ceramidase deficiency, "Lipogranulomatosis", and ASAH1-related disorders) is an extremely rare, progressive, autosomal recessive lysosomal storage disease caused by a deficiency of the acid ceramidase enzyme. Acid ceramidase is responsible for breaking down ceramide into sphingosine and fatty acid. When the enzyme is deficient, this leads to an accumulation of fatty material (called ceramide) in the lysosomes of the cells, leading to the signs and symptoms of this disorder.

Signs and Symptoms
The symptoms of Farber disease develop over time. The onset of symptoms and how quickly they progress vary from person to person.The most common symptoms include:
Bumps under the skin located at pressure points and joints, also called subcutaneous nodules, lipogranulomas, or granulomas
Swollen, painful joints with progressive limitation of range of motion resulting in contracture
Hoarse voice/cryOther symptoms observed in some individuals with Farber disease include:
Respiratory disease, e.g. lung infections, labored breathing, respiratory distress
Central nervous system disease, e.g. developmental delay, muscle weakness, seizures
Systemic inflammation
Failure to thrive
Bone disease, e.g. erosion of bone near joints, osteoporosis, peripheral osteolysis
Enlarged liver (hepatomegaly)
Eye disease, e.g. cherry-red spot, corneal opacities

Genetics
Farber disease is caused by variants in the ASAH1 gene. This gene codes for the acid ceramidase enzyme. Individuals with Farber disease have two copies of this gene that are not functioning properly leading to the enzyme deficiency. Over 73 different gene variants have been reported to cause Farber disease. No definitive genotype-phenotype correlations are known.Farber disease is inherited in an autosomal recessive manner. Affected individuals inherit one copy of the gene that is not functioning properly from each parent. Each parent is a called a carrier and has one copy of the gene that is functioning properly and one that is not. Siblings of individuals with Farber disease have a 25% chance to also have Farber disease, a 50% chance to be a carrier like the parents, and a 25% chance of being unaffected and not a carrier.The ASAH1 gene is also known to cause a condition called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Farber disease and SMA-PME have been classified as separate disorders, however more recent case reports have identified some individuals with overlapping symptoms of both disorders. Some individuals with SMA symptoms without seizures have also been described.

Diagnosis
Disease onset is typically in early infancy but may occur later in life. Children who have the classic form of Farber disease develop symptoms within the first few weeks to months of life </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 MOMO syndrome and can you explain it in depth? [/INST] MOMO syndrome is an extremely rare genetic disorder which belongs to the overgrowth syndromes and has been diagnosed in only seven cases around the world, and occurs in 1 in 100 million births. The name is an acronym of the four primary aspects of the disorder: Macrosomia (excessive birth weight), Obesity, Macrocephaly (excessive head size) and Ocular abnormalities.  It is unknown if it is a life-limiting condition </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 Accessory spleen and can you explain it in depth? [/INST] An accessory spleen is a small nodule of splenic tissue found apart from the main body of the spleen. Accessory spleens are found in approximately 10 percent of the population and are typically around 1 centimetre in diameter. They may resemble a lymph node or a small spleen </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 Crutch paralysis 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 Craniopagus parasiticus and can you explain it in depth? [/INST] Craniopagus parasiticus is an extremely rare type of parasitic twinning occurring in about 2 to 3 of 5,000,000 births. In craniopagus parasiticus, a parasitic twin head with an undeveloped body is attached to the head of a developed twin. Fewer than a dozen cases of this type of conjoined twin have been documented in literature.

Development
The exact development of craniopagus parasiticus is not well known. However, it is known that the underdeveloped twin is a parasitic twin. Parasitic twins are known to occur in utero when monozygotic twins start to develop as an embryo, but the embryo fails to completely split. When this happens, one embryo will dominate development, while the others development is severely altered. The key difference between a parasitic twin and conjoined twins is that in parasitic twins, one twin, the parasite, stops development during gestation, whereas the other twin, the autosite, develops completely.In normal monozygotic twin development, one egg is fertilized by a single sperm. The egg will then completely split into two, normally at the two-cell stage. If the egg splits in the early blastocyst stage, two inner cell masses will be present, eventually leading to the twins sharing the same chorion and placenta, but with separate amnions. However, the egg can split into two, but still have one blastocyst. This will lead to one inner cell mass and one blastocyst. Then, as the twins develop, they will share the same placenta, chorion, and amnion. This is thought to be the most likely reason why conjoined twins occur, and could possibly play a role in the development of craniopagus parasiticus.One hypothesis is that craniopagus parasiticus starts with the development of two fetuses from a single zygote that fail to separate at the head region around the second week of gestation. Some believe, however, that it occurs later in development, around the fourth week of gestation, at which time the two embryos fuse together near the anterior open neuropore.Another hypothesis is that there is joining of the somatic and placental vascular system of the twins, as well as a degeneration of the umbilical cord of the parasitic twin. This suggests that craniopagus parasiticus develops due to the lack of blood supply to one of the twins.

Diagnosis
Related conditions
In addition to craniopagus parasiticus, a few other conditions involve a childs, or animals, birth with two heads or faces.

Dicephalic parapagus
Dicephalic parapagus is a condition where two heads are side by side on a single torso, with varying degrees of twinning of organs and structures within the torso.

Diprosopus
Diprosopus occurs when a single body and neck are present, but there is a duplication of the structures of the face. This is different from craniopagus parasiticus in that there is only one head, although there is a duplication of the craniofacial features. Diprosopus can range from having two fully formed faces to just a duplication of the nose or eyes. Cats with the condition are referred to as Janus cats. A cat named Frankenlouie was a famous example noted by the Guinness Book of World Records in 2012 for being the longest surviving Janus cat.

Treatment
Few individuals survive until birth. For those who do, the only treatment available is to surgically remove the parasitic twin. Of the two documented attempts, however, one child died within hours and neither reached their second birthday. The problem with surgical intervention is that the arterial supplies of the head are so intertwined that it is very hard to control the bleeding, but it has been suggested that cutting off the parasitic twins arterial supply might improve the odds of the developed twins survival.

Prevalence
Only ten cases of craniopagus parasiticus have been documented, out of a total of at least eighty known cases of craniopagus in general.Only four cases have been documented by modern medicine to have survived birth:

An earlier case was the so-called "Two-Headed Boy of Bengal", who was born in 1783 and died of a cobra bite in 1787. His skull remains in the collection of the Hunterian Museum of the Royal College of Surgeons of London.
On December 10, 2003, Rebeca Martínez was born in the Dominican Republic with this rare condition. She was the first baby born with the condition to undergo an operation to remove the second head. She died on February 7, 2004, after an 11-hour operation.
On March 30, 2004, Manar Maged was born with the rare condition. On February 19, 2005, 10-month-old Manar underwent a successful 13-hour surgery in Egypt </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 atrophic rhinitis and can you explain it in depth? [/INST] Chronic atrophic rhinitis, or simply atrophic rhinitis, is a chronic inflammation of the nose characterised by atrophy of nasal mucosa, including the glands, turbinate bones and the nerve elements supplying the nose. Chronic atrophic rhinitis may be primary and secondary. Special forms of chronic atrophic rhinitis are rhinitis sicca anterior and ozaena. It can also be described as the empty nose syndrome.

Signs and symptoms
It is most commonly seen in females.
It is reported among patients from lower socioeconomic groups.
The nasal cavities become roomy and are filled with foul smelling crusts which are black or dark green and dry, making expiration painful and difficult.
Microorganisms are known to multiply and produce a foul smell from the nose, though the patients may not be aware of this, because the nerve endings (responsible for the perception of smell) have become atrophied. This is called merciful anosmia.
Patients usually complain of nasal obstruction despite the roomy nasal cavity, which can be caused either by the obstruction produced by the discharge in the nose, or as a result of sensory loss due to atrophy of nerves in the nose, so the patient is unaware of the air flow </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 Motor neuron disease and can you explain it in depth? [/INST] Motor neuron diseases or motor neurone diseases (MNDs) are a group of rare neurodegenerative disorders that selectively affect motor neurons, the cells which control voluntary muscles of the body. They include amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), pseudobulbar palsy, progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), spinal muscular atrophy (SMA) and monomelic amyotrophy (MMA), as well as some rarer variants resembling ALS.
Motor neuron diseases affect both children and adults. While each motor neuron disease affects patients differently, they all cause movement-related symptoms, mainly muscle weakness. Most of these diseases seem to occur randomly without known causes, but some forms are inherited. Studies into these inherited forms have led to discoveries of various genes (e.g. SOD1) that are thought to be important in understanding how the disease occurs.Symptoms of motor neuron diseases can be first seen at birth or can come on slowly later in life. Most of these diseases worsen over time; while some, such as ALS, shorten ones life expectancy, others do not. Currently, there are no approved treatments for the majority of motor neuron disorders, and care is mostly symptomatic.

Signs and symptoms
Signs and symptoms depend on the specific disease, but motor neuron diseases typically manifest as a group of movement-related symptoms. They come on slowly, and worsen over the course of more than three months. Various patterns of muscle weakness are seen, and muscle cramps and spasms may occur. One can have difficulty breathing with climbing stairs (exertion), difficulty breathing when lying down (orthopnea), or even respiratory failure if breathing muscles become involved. Bulbar symptoms, including difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and excessive saliva production (sialorrhea), can also occur. Sensation, or the ability to feel, is typically not affected. Emotional disturbance (e.g. pseudobulbar affect) and cognitive and behavioural changes (e.g. problems in word fluency, decision-making, and memory) are also seen. There can be lower motor neuron findings (e.g. muscle wasting, muscle twitching), upper motor neuron findings (e.g. brisk reflexes, Babinski reflex, Hoffmans reflex, increased muscle tone), or both.Motor neuron diseases are seen both in children and adults. Those that affect children tend to be inherited or familial, and their symptoms are either present at birth or appear before learning to walk. Those that affect adults tend to appear after age 40. The clinical course depends on the specific disease, but most progress or worsen over the course of months. Some are fatal (e.g. ALS), while others are not (e.g. PLS).

Patterns of weakness
Various patterns of muscle weakness occur in different motor neuron diseases. Weakness can be symmetric or asymmetric, and it can occur in body parts that are distal, proximal, or both. According to Statland et al., there are three main weakness patterns that are seen in motor neuron diseases, which are:
Asymmetric distal weakness without sensory loss (e.g. ALS, PLS, PMA, MMA)
Symmetric weakness without sensory loss (e.g. PMA, PLS)
Symmetric focal midline proximal weakness (neck, trunk, bulbar involvement; e.g. ALS, PBP, PLS)

Lower and upper motor neuron findings
Motor neuron diseases are on a spectrum in terms of upper and lower motor neuron involvement. Some have just lower or upper motor neuron findings, while others have a mix of both. Lower motor neuron (LMN) findings include muscle atrophy and fasciculations, and upper motor neuron (UMN) findings include hyperreflexia, spasticity, muscle spasm, and abnormal reflexes.Pure upper motor neuron diseases, or those with just UMN findings, include PLS.Pure lower motor neuron diseases, or those with just LMN findings, include PMA.Motor neuron diseases with both UMN and LMN findings include both familial and sporadic ALS.

Causes
Most cases are sporadic and their causes are usually not known. It is thought that environmental, toxic, viral, or genetic factors may be involved.

DNA damage
TARDBP (TAR DNA-binding protein 43), also referred to as TDP-43, is a critical component of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNA double-strand breaks in pluripotent stem cell-derived motor neurons. TDP-43 is rapidly recruited to double-strand breaks where it acts as a scaffold for the recruitment of the XRCC4-DNA ligase protein complex that then acts to repair double-strand breaks. About 95% of ALS patients have abnormalities in the nucleus-cytoplasmic localization in spinal motor neurons of TDP43. In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic ALS patients’ spinal cord specimens there is significant double-strand break accumulation and reduced levels of NHEJ.

Associated risk factors
In adults, men are more commonly affected than women.

Diagnosis
Differential diagnosis can be challenging due to the number of overlapping symptoms, shared between several motor neuron diseases. Frequently, the diagnosis is based on clinical findings (i.e. LMN vs. UMN signs and symptoms, patterns of weakness), family history of MND, and a variation of tests, many of which are used to rule out disease mimics, which can manifest with identical symptoms.

Classification
Motor neuron disease describes a collection of clinical disorders, characterized by progressive muscle weakness and the degeneration of the motor neuron on electrophysiological testing. The term "motor neuron disease" has varying meanings in different countries </s>