<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 Thalassemia and can you explain it in depth? [/INST] Thalassemias are inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result in feeling tired and pale skin. There may also be bone problems, an enlarged spleen, yellowish skin, and dark urine. Slow growth may occur in children.Thalassemias are genetic disorders inherited from a persons parents. There are two main types, alpha thalassemia and beta thalassemia. The severity of alpha and beta thalassemia depends on how many of the four genes for alpha globin or two genes for beta globin are missing. Diagnosis is typically by blood tests including a complete blood count, special hemoglobin tests, and genetic tests. Diagnosis may occur before birth through prenatal testing.Treatment depends on the type and severity. Treatment for those with more severe disease often includes regular blood transfusions, iron chelation, and folic acid. Iron chelation may be done with deferoxamine, deferasirox or deferiprone. Occasionally, a bone marrow transplant may be an option. Complications may include iron overload from the transfusions with resulting heart or liver disease, infections, and osteoporosis. If the spleen becomes overly enlarged, surgical removal may be required. Thalassemia patients who do not respond well to blood transfusions can take hydroxyurea or thalidomide, and sometimes a combination of both. Hydroxyurea is the only FDA approved drug for thalassemia. Patients who took 10 mg/kg of hydroxyurea every day for a year had significantly higher hemoglobin levels, and it was a well-tolerated treatment for patients who did not respond well to blood transfusions. Another hemoglobin-inducer includes thalidomide, although it has not been tested in a clinical setting. The combination of thalidomide and hydroxyurea resulted in hemoglobin levels increasing significantly in transfusion-dependent and non-transfusion dependent patients As of 2015, thalassemia occurs in about 280 million people, with about 439,000 having severe disease. It is most common among people of Greek, Italian, Middle Eastern, South Asian, and African descent. Males and females have similar rates of disease. It resulted in 16,800 deaths in 2015, down from 36,000 deaths in 1990. Those who have minor degrees of thalassemia, similar to those with sickle-cell trait, have some protection against malaria, explaining why they are more common in regions of the world where malaria exists.

Signs and symptoms
Iron overload: People with thalassemia can get an overload of iron in their bodies, either from the disease itself or from frequent blood transfusions. Too much iron can result in damage to the heart, liver, and endocrine system, which includes glands that produce hormones that regulate processes throughout the body. The damage is characterized by excessive deposits of iron. Without adequate iron chelation therapy, almost all patients with beta-thalassemia accumulate potentially fatal iron levels.
Infection: People with thalassemia have an increased risk of infection. This is especially true if the spleen has been removed.
Bone deformities: Thalassemia can make the bone marrow expand, which causes bones to widen. This can result in abnormal bone structure, especially in the face and skull. Bone marrow expansion also makes bones thin and brittle, increasing the risk of broken bones.
Enlarged spleen: The spleen aids in fighting infection and filters unwanted material, such as old or damaged blood cells. Thalassemia is often accompanied by the destruction of a large number of red blood cells and the task of removing these cells causes the spleen to enlarge. Splenomegaly can make anemia worse, and it can reduce the life of transfused red blood cells. Severe enlargement of the spleen may necessitate its removal.
Slowed growth rates: anemia can cause the growth of a child to slow down. Puberty may also be delayed in children with thalassemia.
Heart problems: Diseases, such as congestive heart failure and abnormal heart rhythms, may be associated with severe thalassemia.

Hemoglobin structural biology
Normal human hemoglobins are tetrameric proteins composed of two pairs of globin chains, each of which contains one alpha-like (α-like) chain and one beta-like (β-like) chain. Each globin chain is associated with an iron-containing heme moiety. Throughout life, the synthesis of the alpha-like and the beta-like (also called non-alpha-like) chains is balanced so that their ratio is relatively constant and there is no excess of either type.The specific alpha and beta-like chains that are incorporated into Hb are highly regulated during development:

Embryonic Hbs are expressed as early as four to six weeks of embryogenesis and disappear around the eighth week of gestation as they are replaced by fetal Hb. Embryonic Hbs include:
Hb Gower-1, composed of two ζ globins (zeta globins) and two ε globins (epsilon globins) (ζ2ε2)
Hb Gower-2, composed of two alpha globins and two epsilon globins (α2ε2)
Hb Portland, composed of two zeta globins and two gamma globins (ζ2γ2)
Fetal Hb (Hb F) is produced from approximately eight weeks of gestation through birth and constitutes approximately 80 percent of Hb in the full-term neonate. It declines during the first few months of life and, in the normal state, constitutes <1 percent of total Hb by early childhood. Hb F is composed of two alpha globins and two gamma globins (α2γ2).
Adult Hb (Hb A) is the predominant Hb in children by six months of age and onward; it constitutes 96-97% of total Hb in individuals without a hemoglobinopathy. It is composed of two alpha globins and two beta globins (α2β2).
Hb A2 is a minor adult Hb that normally accounts for approximately 2.5-3.5% of total Hb from six months of age onward. It is composed of two alpha globins and two delta globins (α2δ2).

Cause
Both α- and β-thalassemias are often inherited in an autosomal recessive manner. Cases of dominantly inherited α- and β-thalassemias have been reported, the first of which was in an Irish family with two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β-globin gene. For the autosomal recessive forms of the disease, both parents must be carriers for a child to be affected. If both parents carry a hemoglobinopathy trait, the risk is 25% for each pregnancy for an affected child.The genes involved in thalassemia control the production of healthy hemoglobin. Hemoglobin binds oxygen in the lungs and releases it when the red cells reach peripheral tissues, such as the liver. The binding and release of oxygen by hemoglobin are essential for survival.

Evolution
Having a single genetic variant for thalassemia may protect against malaria and thus can be an advantage.People diagnosed with heterozygous (carrier) β-thalassemia have some protection against coronary heart disease.

Pathophysiology
Normally, the majority of adult hemoglobin (HbA) is composed of four protein chains, two α and two β-globin chains arranged into a heterotetramer. In thalassemia, patients have defects in either the α or β-globin chain, causing production of abnormal red blood cells.The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α-thalassemias, production of the α-globin chain is affected, while in β-thalassemia, production of the β-globin chain is affected.The β-globin chains are encoded by a single gene on chromosome 11; α-globin chains are encoded by two closely linked genes on chromosome 16. Thus, in a normal person with two copies of each chromosome, two loci encode the β chain, and four loci encode the α chain. Deletion of one of the α loci has a high prevalence in people of African or Asian descent, making them more likely to develop α-thalassemia. β-Thalassemias are not only common in Africans, but also in Greeks and Turks.

Alpha-thalassemias
The α-thalassemias involve the genes HBA1 and HBA2, inherited in a Mendelian recessive fashion. Two gene loci and so four alleles exist. Two genetic loci exist for α-globin, thus four alleles are in diploid cells. Two alleles are maternal and two alleles are paternal in origin. The severity of the α-thalassemias is correlated with the number of affected α-globin; alleles: the greater, the more severe will be the manifestations of the disease. Alpha-thalassemias result in decreased alpha-globin production; therefore, fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called hemoglobin H or HbH of 4 beta chains), which have abnormal oxygen dissociation curves. Alpha thalassemias often are found in people from Southeast Asia, the Middle East, China, and in those of African descent.

Beta-thalassemia
Beta thalassemias are due to mutations in the HBB gene on chromosome 11, also inherited in an autosomal, recessive fashion. The severity of the disease depends on the nature of the mutation and on the presence of mutations in one or both alleles.
Mutated alleles are called β+ when partial function is conserved (either the protein has a reduced function, or it functions normally but is produced in reduced quantity) or βo, when no functioning protein is produced.
The situation of both alleles determines the clinical picture:

β thalassemia major (Mediterranean anemia or Cooley anemia) is caused by a βo/βo genotype. No functional β chains are produced, and thus no hemoglobin A can be assembled. This is the most severe form of β-thalassemia;
β thalassemia intermedia is caused by a β+/βo or β+/β+ genotype. In this form, some hemoglobin A is produced;
β thalassemia minor is caused by a β/βo or β/β+ genotype. Only one of the two β globin alleles contains a mutation, so β chain production is not terribly compromised and patients may be relatively asymptomatic.Beta thalassemia most often occurs in people of Mediterranean origin. To a lesser extent, Chinese, other Asians, and African Americans can be affected.

Delta-thalassemia
As well as alpha and beta chains present in hemoglobin, about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations that affect the ability of this gene to produce delta chains can occur.

Combination hemoglobinopathies
Thalassemia can coexist with other hemoglobinopathies. The most common of these are:

Hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India, it is clinically similar to β thalassemia major or thalassemia intermedia.
Hemoglobin S/thalassemia: common in African and Mediterranean populations, it is clinically similar to sickle-cell anemia, with the additional feature of splenomegaly.
Hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β+ thalassemia produces a milder disease.
Hemoglobin D/thalassemia: common in the northwestern parts of India and Pakistan (Punjab region).

Diagnosis
Thalassemia can be diagnosed via a complete blood count, hemoglobin electrophoresis or high-performance liquid chromatography, and DNA testing. Hemoglobin electrophoresis is not widely available in developing countries, but the Mentzer index can also be used for diagnosis of thalassemia; it is not a definitive test but it can suggest the possibility of thalassemia. The Mentzer index can be calculated from a complete blood count report.

Prevention
The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant be tested to see if they have thalassemia. Genetic counseling and genetic testing are recommended for families who carry a thalassemia trait.A screening policy exists in Cyprus to reduce the rate of thalassemia, which, since the programs implementation in the 1970s (also including prenatal screening and abortion), has reduced the number of children born with the disease from one of every 158 births to almost zero. Greece also has a screening program to identify people who are carriers.In Iran as a premarital screening, the mans red cell indices are checked first. If he has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic, their hemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassemia trait) they are referred to the local designated health post for genetic counseling.Large-scale awareness campaigns are being organized in India both by government and non-government organizations to promote voluntary premarital screening, with marriage between carriers strongly discouraged.

Management
Mild thalassemia: people with thalassemia traits do not require medical or follow-up care after the initial diagnosis is made. People with β-thalassemia trait should be warned that their condition can be misdiagnosed as the more common iron-deficiency anemia. They should avoid routine use of iron supplements, but iron deficiency may develop during pregnancy or from chronic bleeding. Counseling is indicated for all persons with genetic disorders, especially when the family is at risk of a severe form of disease that may be prevented.

Anemia
People with severe thalassemia require medical treatment. A blood transfusion regimen is the first effective measure in prolonging life.

Growth hormone therapy
There is some evidence that growth hormone replacement therapy may help to increase the rate at which children with thalassemia grow taller.

Iron overload
Multiple blood transfusions may result in iron overload. The iron overload related to thalassemia may be treated by chelation therapy with the medications deferoxamine, deferiprone, or deferasirox. These treatments have resulted in longer life expectancy for those with thalassemia major.Deferoxamine is only effective as a daily injection, complicating its long-term use. However, it is inexpensive and safe. Adverse effects include primary skin reactions around the injection site and hearing loss.Deferasirox and deferiprone are both oral medications, whose common side effects include nausea, vomiting and diarrhea. Deferasirox is not effective for all patients and may not be suitable for those with significant cardiac issues related to iron overload, while deferiprone appears to be the most effective agent when the heart is involved. Furthermore, the cost of deferasirox is also significant.There is no evidence from randomized controlled trial to support zinc supplementation for those with thalassemia.

Bone-marrow transplantation
Bone-marrow transplantation may offer the possibility of a cure in young people who have an HLA-matched donor. Success rates have reached the 80–90% range. Mortality from the procedure is about 3%. There are no randomized controlled trials that have tested the safety and efficacy of non-identical donor bone-marrow transplantation in persons with β- thalassemia who are dependent on blood transfusion.Graft-versus-host diseases (GvHD) are one relevant side effect of bone-marrow transplantation. Further research is necessary to evaluate whether mesenchymal stromal cells can be used as prophylaxis or treatment for GvHD.If the patient does not have an HLA-matched compatible donor, bone-marrow transplantation from haploidentical mother to child (mismatched donor) may be attempted. In a study of 31 people, the thalassemia-free survival rate was 70%, rejection 23% and mortality 7%. The most positive results tend to occur with very young people.

Epidemiology
The beta form of thalassemia is particularly prevalent among Mediterranean peoples, and this geographical association is responsible for its original name. Thalassemia resulted in 25,000 deaths in 2013 down from 36,000 deaths in 1990.In Europe, the highest concentrations of the disease are found in Greece, coastal regions in Turkey (particularly the Aegean Region such as İzmir, Balıkesir, Aydın, Muğla, and Mediterranean Region such as Antalya, Adana, Mersin), in southern Spain, in parts of Italy, particularly southern Italy. With the exception of the Balearics, the major Mediterranean Islands, such as Sicily, Sardinia, Malta, Corsica, Cyprus, and Crete are heavily affected. Other Mediterranean peoples, as well as those in the vicinity of the Mediterranean, also have high rates of thalassemia, including people from North Africa and West Asia. Far from the Mediterranean, South Asians are also affected, with the worlds highest concentration of carriers (16–18% of the population) in the Maldives.The disease is also found in populations living in Africa, the Americas, and in Tharu people in the Terai region of Nepal and India. It is believed to account for much lower rates of malaria illnesses and deaths, accounting for the historic ability of Tharus to survive in areas with heavy malaria infestation while others could not. Thalassemias are particularly associated with people of Mediterranean origin, Arabs (especially Palestinians and people of Palestinian descent), and Asians. The estimated prevalence is 16% in people from Cyprus, 1% in Thailand, and 3–8% in populations from Bangladesh, China, India, Malaysia and Pakistan.
Estimates suggest that approximately 1.5% of the global population (80 – 90 million people) are β-thalassemia carriers. However, exact data on carrier rates in many populations are lacking, particularly in developing areas of the world known or expected to be heavily affected. Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult. While there are some diagnostic and treatment facilities in developing countries, in most cases these are not provided by government services and are available only to patients who can afford them. In general, poorer populations only have access to limited diagnostic facilities and blood transfusions. In some developing countries, there are virtually no facilities for diagnosis or management of thalassemia.

Etymology and synonym
The word thalassemia () derives from the Greek  thalassa (θάλασσα), "sea", and New Latin -emia (from the Greek compound stem -aimia (-αιμία), from haima (αἷμα), "blood"). It was coined because the condition called "Mediterranean anemia" was first described in people of Mediterranean ethnicities. "Mediterranean anemia" was renamed thalassemia major once the genetics were better understood </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 Orthostatic albuminuria 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 Mast cell leukemia and can you explain it in depth? [/INST] Mast cell leukemia is an extremely aggressive subtype of acute myeloid leukemia that usually occurs de novo but can, rarely, evolve from transformation of chronic myeloid leukemia into the more aggressive acute myeloid leukemia. In a small proportion of cases, acute mast cell leukemia may evolve from a more progressive form of systemic mastocytosis. The diagnosis of acute mast cell leukemia by the WHO criteria includes the requirement for a prevalence of 20% neoplastic mast cells in marrow and 10% in blood. If the mast cells represent less than 10% of blood cells, the tumor is called "aleukemic" mast cell leukemia.

Signs and symptoms
Acute mast cell leukemia is a rapidly progressive disorder with leukemic mast cells in blood and in large numbers in marrow. The common signs and symptoms include fever, headache, flushing of face and trunk. The typical cutaneous mast cell infiltrates of urticaria pigmentosa are usually not present before, during, or after diagnosis in patients who have mast cell leukemia. Symptoms include abdominal pain, bone pain, and peptic ulcer which are more prevalent than in other subtypes of acute myeloid leukemia. These former symptoms are due to release of a substance called histamine from neoplastic mast cells. Enlargement of the liver and spleen, or hepatosplenomegaly is characteristic. The mast cells release also many anticoagulants like heparin which can lead to serious bleeding. Liver and splenic dysfunction also contributes to hemorrhage. Involvement of the bone can lead to osteoporosis. Abdominal ultrasound or computerized tomography (CT) scanning is used to look for hepatosplenomegaly and lymphadenopathy. Plain radiography and bone densitometry can be used to assess bone involvement and the presence of osteoporosis. Endoscopy and biopsy can be useful if gut involvement is suspected.

Diagnosis
Cytochemistry
Cytochemical properties of the leukemic cells must be typical of mast cell derivation (presence of metachromatic granules staining with alpha-naphthyl chloroacetate esterase, but not with peroxidase). Mast cell tryptase is an enzyme contained in mast cell granules. Mast cell numbers are best estimated by tryptase immunostaining because very poorly granulated cells may stain very weakly if at all for alpha-naphthol chloroacetate esterase.

Tumor markers
The leukemic cells usually are strongly positive for CD13, CD33, CD68, and CD117. Characteristically, basophil (e.g. CD11b, CD123) and monocyte markers (CD14, CD15) are absent. The cells usually express CD2 and CD25. Malignant mast cells overexpress the anti-apoptosis gene, bcl-2. A mutation called KIT mutation is detected in most patients.

Biochemistry
Total serum tryptase is elevated in mast cell leukemia. Normal total (alpha + beta) serum tryptase is approximately 6 micro g/L (range 0 to 11 micro g/L) </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 Anterior compartment syndrome and can you explain it in depth? [/INST] A compartment syndrome is an increased pressure within a muscular compartment that compromises the circulation to the muscles.

Symptoms and  signs
Diffuse tightness and tenderness over the entire belly of the tibialis anterior muscle that does not respond to elevation or pain medication can be early warning signs and suggestive of Anterior Compartment 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 External cause 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 Acute myelomonocytic leukemia and can you explain it in depth? [/INST] Acute myelomonocytic leukemia (AMML) is a form of acute myeloid leukemia that involves a proliferation of CFU-GM myeloblasts and monoblasts. AMML occurs with a rapid increase amount in white blood cell count and is defined by more than 20% of myeloblast in the bone marrow. It is classified under "M4" in the French-American-British classification (FAB). It is classified under "AML, not otherwise classified" in the WHO classification.Translocations have been observed. Progression from myelodysplastic syndrome has been reported.

Signs and symptoms
Some patients may experience:
Fatigue
Easy Bruising
Abnormal Bleeding
Anemia
Thrombocytopenia
DyspneaIf the blast count gets too high and clog up blood vessels, some patients may experience:
Slurred Speech
Headache
Confusion
Weakness on one side of the body
Sleepiness

Cause
The cause has not yet been determined. It has been said that acute myeloid leukemia can occur from a progression of chronic myelomonocytic leukemia type 1 and 2. Normal red blood cells decrease and a rapid proliferation of the abnormal myeloblasts occur. Apoptosis functional ability decreases which causes a back up of myeloblasts in the bone marrow and blood. AML with a translocation or inversion is seen in different chromosomes. Specifically, AML with inversion in chromosome 16 also known as inv(16) is commonly seen in children.

Mechanism
AMML does not have an exact mechanism. The underlying pathophysiology of acute myeloid leukemia consist of maturational arrest of the bone marrow cell during the early stages of development. A myeloblast is an immature precursor cell that will change into a monocyte, healthy white blood cell. In AML, Myeloblast do not mature but grow and multiply with regulation. The abnormal cells build up in the bone marrow and prevent the development of other healthy cells. This type of arrest is still under study but in most cases, a gene inactivation or activation has occurred due to chromosome translocations or inversion. AML-M4 with an inversion of chromosome 16 is caused by breakage and rearrangement within itself.

Diagnosis
Criteria for AMML is confirmed if the myeloblasts and promonocytes in the bone marrow are greater than 20 percent. It can also be confirmed if the blood monocytes is 5x109/L or higher. Testing available to diagnosis AML includes a complete blood count which is characterized by blood that is taken from the vein in the arm to test for leukemia, a peripheral blood smear and a bone marrow test. During a peripheral blood smear, a sample of blood is checked for blast cells, white blood cell count and changes in shape of blood cells. During a bone marrow test, bone marrow is taken from the hip bone in a search for leukemia cells. Aspiration and biopsy are two types of testing that can be done in order to obtain bone marrow. Further classification can be done for the type of AML by examining the cells shape and size. Generally youll find immature cells which lack normal features of a cell.

Treatment
AMML can be treated depending on the degree of disease, age of patient, and current patients health status. Treatment consists of a multi-drug chemotherapy regimen. Chemotherapy drugs often used to treat AML are cytarabine and an anthracycline drug. Chemotherapy is broken down into 2 phases:

Induction therapy: first short and invasive phase of treatment with the goal to the blood of blasts and reduce the number of blasts in the bone marrow back to normal.
Consolidation therapy: second phase given in cycles that occur after the patient has recovered from induction therapy </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 Acute bronchitis and can you explain it in depth? [/INST] Acute bronchitis, also known as a chest cold, is short-term bronchitis – inflammation of the bronchi (large and medium-sized airways) of the lungs. The most common symptom is a cough. Other symptoms include coughing up mucus, wheezing, shortness of breath, fever, and chest discomfort. The infection may last from a few to ten days. The cough may persist for several weeks afterward with the total duration of symptoms usually around three weeks. Some have symptoms for up to six weeks.In more than 90% of cases, the cause is a viral infection. These viruses may be spread through the air when people cough or by direct contact. Risk factors include exposure to tobacco smoke, dust, and other air pollution. A small number of cases are due to high levels of air pollution or bacteria such as Mycoplasma pneumoniae or Bordetella pertussis. Diagnosis is typically based on a persons signs and symptom. The color of the sputum does not indicate if the infection is viral or bacterial. Determining the underlying organism is typically not needed. Other causes of similar symptoms include asthma, pneumonia, bronchiolitis, bronchiectasis, and COPD. A chest X-ray may be useful to detect pneumonia.Prevention is by not smoking and avoiding other lung irritants. Frequent hand washing and flu vaccination may also be protective. Treatment of acute bronchitis typically involves rest, paracetamol (acetaminophen), and NSAIDs to help with the fever. Cough medicine has little support for its use and is not recommended in children less than six years of age. Antibiotics should generally not be used. An exception is when acute bronchitis is due to pertussis. Tentative evidence supports honey and pelargonium to help with symptoms.Acute bronchitis is one of the most common diseases. About 5% of adults are affected and about 6% of children have at least one episode a year. It occurs more often in the winter. More than 10 million people in the United States visit a doctor each year for this condition with approximately 70% receiving antibiotics, most of which are not needed. There are efforts to decrease the use of antibiotics in acute bronchitis.

Signs and symptoms
The primary symptom is cough with sputum that may be purulent. The illness may also cause shortness of breath or wheezing. Upper respiratory tract infections often precede acute bronchitis, with overlapping symptoms including headache, nasal congestion, sore throat. Fever and other systemic symptoms are rare in acute bronchitis; their presence raises suspicion for influenza or pneumonia.

Cause
Acute bronchitis can be caused by contagious pathogens, most commonly viruses. Typical viruses include respiratory syncytial virus, rhinovirus, influenza, and others. Bacteria are uncommon pathogens but may include Mycoplasma pneumoniae, Chlamydophila pneumoniae, Bordetella pertussis, Streptococcus pneumoniae, and Haemophilus influenzae.
Damage caused by irritation of the airways leads to inflammation and leads to neutrophils infiltrating the lung tissue.
Mucosal hypersecretion is promoted by a substance released by neutrophils.
Further obstruction to the airways is caused by more goblet cells in the small airways. This is typical of chronic bronchitis.
Although infection is not the reason or cause of chronic bronchitis, it is seen to aid in sustaining the bronchitis.

Diagnosis
A physical examination will often reveal decreased intensity of breath sounds, wheezing, rhonchi, and prolonged expiration. During examination for physicians rely on history and the presence of persistent or acute onset of cough, followed by a URTI with no traces of pneumonia. Acute bronchitis is typically a clinical diagnosis that relies on patients history and exam, and should be suspected in patients with an acute onset of cough, which often follows a URTI without traces of pneumonia.Although there is no universally-accepted clinical definition for acute bronchitis, there is a proposed set of practical criteria (Macfarlane, 2001) that include:

An acute illness of less than three weeks.
Cough as the predominant symptom.
At least one other lower respiratory tract symptom, such as sputum production, wheezing, chest pain.
No alternative explanation for the symptoms.A variety of tests may be performed in people presenting with cough and shortness of breath:
A chest X-ray is useful to exclude pneumonia which is more common in those with a fever, fast heart rate, fast respiratory rate, or who are old.
A sputum sample showing neutrophil granulocytes (inflammatory white blood cells) and culture showing that has pathogenic microorganisms such as Streptococcus species.
A blood test would indicate inflammation (as indicated by a raised white blood cell count and elevated C-reactive protein).Decreased breath sounds, crackles, wheezing, and rhonchi that clears with coughs may be heard in the chest. Dullness to percussion and pleural rub suggest disease extension beyond the bronchi such as seen with pneumonia. Paroxysms of cough followed by inspiratory whoop and vomiting suggests pertussis.

Prevention
Prevention is by not smoking and avoiding other lung irritants. Frequent hand washing may also be protective. Furthermore, an oral whole cell nontypeable Haemophilus influenzae vaccine given in the fall has demonstrated short term effectiveness in reducing the frequency and severity of the disease during the winter.

Treatment
Most cases are self-limited and resolve themselves in a few weeks.
Pain medications may help with symptoms. Other recommendations may include rest and keeping well hydrated.

Antibiotics
Evidence does not support the general use of antibiotics in acute bronchitis. A systematic review found antibiotics reduced cough by an average of 12 hours (out of a total average of about 14–28 days). Antibiotics caused more side effects such as nausea and diarrhoea, and also may promote antibiotic-resistant bacteria. It is possible they are useful in susceptible groups such as the frail and elderly but there was not enough research information to determine this.Calling acute bronchitis with benign-sounding labels such as chest cold or viral infections may reduce antibiotic usage by improving patients satisfaction when antibiotics are not prescribed.

Smoking cessation
To help the bronchial tree heal faster and not make bronchitis worse, smokers should quit smoking completely.

Alternative therapeutic approaches
Salbutamol is not effective in children with an acute cough who do not have restricted airways </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 Tract 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 Osteolysis and can you explain it in depth? [/INST] Osteolysis is an active resorption of bone matrix by osteoclasts and can be interpreted as the reverse of ossification. Although osteoclasts are active during the natural formation of healthy bone the term "osteolysis" specifically refers to a pathological process </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 Caught and can you explain it in depth? [/INST] Caught is a method of dismissing a batsman in cricket. A batsman is out caught if the batsman hits the ball, from a legitimate delivery, with the bat, and the ball is caught by the bowler or a fielder before it hits the ground.
If the ball hits the stumps after hitting the wicket-keeper, If the wicket-keeper fails to do this, the delivery is a "no ball", and the batsman cannot be stumped (nor run out, unless he attempts to run to the other wicket.)
If the catch taken by the wicket-keeper,then informally it is known as caught behind or caught at the wicket. A catch by the bowler is known as caught and bowled. This has nothing to do with the dismissal bowled but is rather a shorthand for saying the catcher and bowler are the same player. (The scorecard annotation is usually c. and b. or c&b followed by the bowlers name.)
Caught is the most common method of dismissal at higher levels of competition, accounting for 36,190 Test match dismissals between 1877 and 2012, which is 56.9% of all Test match dismissals in this period.South African wicket-keeper Mark Boucher holds the record for the most Test match catches, with 532, while Rahul Dravid holds the record for the most Test match catches by non-wicket-keepers, with 210.

Laws
This method of dismissal is covered by Law 33 of the Laws of cricket which reads:
The striker is out Caught if a ball delivered by the bowler, not being a No ball, touches his/her bat without having previously been in contact with any fielder, and is subsequently held by a fielder as a fair catch,..., before it touches the wicket and ground.This means that the batsman cannot be out caught if:
The ball is called a no-ball or dead ball.
The batsman does not hit the ball with his bat or a gloved hand holding the bat.
The ball, having been hit, makes contact with the field before a fielder catches the ball.
The ball does not remain under the control of the fielder.
The ball is hit and lands beyond or on the boundary; (six runs).
A fielder taking the catch makes contact with the boundary rope or the area outside the boundary, with any part of his body, equipment, when touching the ball.
An airborne fielder taking the catch, having not previously legally touched the ball, had his last contact with the ground not entirely within the boundary.Note that if a batsman could be given out both caught and by another method, caught takes precedence, unless the other method is bowled.If a batsman is out caught, any runs scored off that delivery are voided.
If a batsman is caught, the bowler is credited with the batsmans wicket and the catching fielder is credited for the dismissal, there is no catch assists for a saving boundaries before catch, or deflecting the ball to a different fielder in the slips cordon. If the two batsmen cross each other, in attempting to take a run, before the catch was taken, the non-striking batsman at the time remains at the opposite end of the pitch as the new incoming batsman comes to the crease at his former end. This means, unless it is now a new over, he is now on strike and the incoming batsman is not.

Adjudication
If the catch taken is pronounced or obvious, the players need not appeal to the umpire; the batsman normally chooses to acknowledge the dismissal himself </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 Coma scale 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 Tuberous sclerosis and can you explain it in depth? [/INST] Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease.TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively, with TSC2 mutations accounting for the majority and tending to cause more severe symptoms. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.Prognosis is highly variable and depends on the symptoms, but life expectancy is normal for many.The prevalence of the disease is estimated to be 7 to 12 in 100,000. The disease is often abbreviated to tuberous sclerosis, which refers to the hard swellings in the brains of patients, first described by French neurologist Désiré-Magloire Bourneville in 1880.

Signs and symptoms
The physical manifestations of TSC are due to the formation of hamartia (malformed tissue such as the cortical tubers), hamartomas (benign growths such as facial angiofibroma and subependymal nodules), and very rarely, cancerous hamartoblastomas. The effect of these on the brain leads to neurological symptoms such as seizures, intellectual disability, developmental delay, and behavioral problems.

Neurological
Three types of brain tumours are associated with TSC:

Giant cell astrocytoma: (grows and blocks the cerebrospinal fluid  flow, leading to dilatation of ventricles causing headache and vomiting)
Cortical tubers: after which the disease is named
Subependymal nodules: form in the walls of ventriclesClassic intracranial manifestations of TSC include subependymal nodules and cortical/subcortical tubers.The tubers are typically triangular in configuration, with the apex pointed towards the ventricles, and are thought to represent foci of abnormal neuronal migration. The T2 signal abnormalities may subside in adulthood, but will still be visible on histopathological analysis. On magnetic resonance imaging (MRI), TSC patients can exhibit other signs consistent with abnormal neuron migration such as radial white matter tracts hyperintense on T2WI and heterotopic grey matter.Subependymal nodules are composed of abnormal, swollen glial cells and bizarre multinucleated cells which are indeterminate for glial or neuronal origin. Interposed neural tissue is not present. These nodules have a tendency to calcify as the patient ages. A nodule that markedly enhances and enlarges over time should be considered suspicious for transformation into a subependymal giant cell astrocytoma, which typically develops in the region of the foramen of Monro, in which case it is at risk of developing an obstructive hydrocephalus.A variable degree of ventricular enlargement is seen, either obstructive (e.g. by a subependymal nodule in the region of the foramen of Monro) or idiopathic in nature.

Neuropsychiatric
About 90% of people with TSC develop a range of neurodevelopmental, behavioural, psychiatric, and psychosocial difficulties. The "TSC‐associated neuropsychiatric disorders" are abbreviated TAND. These difficulties are less frequently identified and thus undertreated when compared with the neurological symptoms. Most problems are associated with more severe intellectual delay or associated with childhood and adolescence, and some (for example depressed mood) may be unreported if the person is unable to communicate. TAND can be investigated and considered at six levels: behavioural, psychiatric, intellectual, academic, neuropsychological, and psychosocial.Behavioural problems most commonly seen include overactivity, impulsivity and sleeping difficulties. Also common are anxiety, mood swings, and severe aggression. Less common are depressed mood, self-injury, and compulsive behaviours.People with TSC are frequently also diagnosed with psychiatric disorders: autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorder and depressive disorder. TSC is one of the most common genetic causes of autism spectrum disorder, which affects nearly half of people with TSC. ASD is more common in TSC2 than TSC1 and more common with earlier and more severe epilepsy, and with lower intellectual ability. ADHD is nearly as frequently seen in TSC as ASD (up to half of all people with TSC). Anxiety and depressive disorders, when they occur, are typically diagnosed in early adulthood and among those intellectually able to express their moods. Schizophrenia (and symptoms like hallucinations or psychosis) is no more common in TSC than the general population.The intellectual ability of people with TSC varies enormously. About 40–50% have a normal IQ. A normal IQ is much more commonly seen in TSC1 than TSC2, and profound intellectual disability seen in 34% of TSC2 compared with 10% of TSC1 in one study. Many studies have examined whether early onset, type and severity of epilepsy associates with intellectual ability. Academic issues occur even in people with TSC who have normal intellectual ability. These are often specific learning disorders such as dyscalculia (understanding mathematics), but also include other aspects affecting school life such as anxiety, lack of social skills or low self-esteem.About half of people with TSC, when assessed for neuropsychological skills, are in the bottom 5th percentile in some areas, which indicates a severe impairment. These include problems with attention (for example, being able to concentrate on two separate things like looking and listening), memory (particularly recall, verbal and spatial working memory) and executive function (for example, planning, self-monitoring, cognitive flexibility).The psychosocial impacts of TSC include low self-esteem and self-efficacy in the individual, and a burden on the family coping with a complex and unpredictable disorder.

Kidneys
Between 60 and 80% of TSC patients have benign tumors (once thought hamartomatous, but now considered true neoplasms) of the kidneys called angiomyolipomas frequently causing hematuria. These tumors are composed of vascular (angio–), smooth muscle (–myo–), and fat (–lip-) tissue. Although benign, an angiomyolipoma larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma. Angiomyolipomas are found in about one in 300 people without TSC. However, those are usually solitary, whereas in TSC they are commonly multiple and bilateral.About 20-30% of people with TSC have renal cysts, causing few problems. However, 2% may also have autosomal dominant polycystic kidney disease.Very rare (< 1%) problems include renal cell carcinoma and oncocytomas (benign adenomatous hamartoma).

Lungs
Patients with TSC can develop progressive replacement of the lung parenchyma with multiple cysts, known as lymphangioleiomyomatosis (LAM). Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in TSC-related lymphangioleiomyomatosis is monoclonal metastasis from a coexisting renal angiomyolipoma. Cases of TSC-related lymphangioleiomyomatosis recurring following lung transplant have been reported.

Heart
Small tumours of the heart muscle, called cardiac rhabdomyomas, are rare in the general population (perhaps 0.2% of children) but very common in people with TSC. Around 80% of children under two-years-old with TSC have at least one rhabdomyoma, and about 90% of those will have several. The vast majority of children with at least one rhabdomyoma, and nearly all children with multiple rhabdomyomas will be found to have TSC. Prenatal ultrasound, performed by an obstetric sonographer specializing in cardiology, can detect a rhabdomyoma after 20 weeks. Rhabdomyoma vary in size from a few millimetres to several centimetres, and are usually found in the lower chambers (ventricles) and less often in the upper chambers (atria). They grow in size during the second half of pregnancy, but regress after birth, and are seen in only around 20% of children over two years old.Most rhabdomyomas cause no problems but some may cause heart failure in the foetus or first year of life. Rhabdomyomas are believed to be responsible for the development of heart arrhythmia later in life, which is relatively common in TSC. Arrhythmia can be hard to spot in people with TSC, other than by performing routine ECG. For example, arrhythmia may cause fainting that is confused with drop seizures, and symptoms of arrhythmia such as palpitations may not be reported in an individual with developmental delay.

Skin
Some form of dermatological sign is present in 96% of individuals with TSC. Most cause no problems, but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

Hypomelanic macules ("ash leaf spots") are present in about 90% of people with TSC. These small white or lighter patches of skin may appear anywhere on the body, and are caused by a lack of melanin. They are usually the only visible sign of TSC at birth. In fair-skinned individuals, a Woods lamp (ultraviolet light) may be required to see them. On the scalp, the effect may be a white patch of hair (poliosis). Patches smaller than 3mm are known as "confetti" skin lesions.
Facial angiofibromas are present in about 75% of people with TSC. These are a rash of reddish spots or bumps on the nose and cheeks in a butterfly distribution, which consist of blood vessels and fibrous tissue. This potentially socially embarrassing rash starts to appear during childhood.
Ungual fibromas: Also known as Koenens tumors, these are small fleshy tumors that grow around and under the toenails or fingernails. These are rare in childhood, but common by middle age. They are generally more common on toes than on fingers, develop at 15–29 years, and are more common in women than in men.
Fibrous cephalic plaques are present in about 25% of people with TSC. These are raised, discoloured areas usually found on the forehead, but sometimes on the face or elsewhere on the scalp.
Shagreen patches are present in about half of people with TSC, appearing in childhood. They are areas of thick leathery skin that are dimpled like an orange peel, and pigmented, they are usually found on the lower back or nape of the neck, or scattered across the trunk or thighs. The frequency of these lesions rises with age.
Dental enamel pits are found in almost all adults with TSC.
Intraoral fibromas are small surface-tumours found in the gums, inside the cheeks or tongue. Gum (gingival) fibromas are found in about 20-50% of people with TSC, more commonly in adults.

Eyes
Retinal lesions, called astrocytic hamartomas (or "phakomas"), which appear as a greyish or yellowish-white lesion in the back of the globe on the ophthalmic examination. Astrocytic hamartomas can calcify, and they are in the differential diagnosis of a calcified globe mass on a CT scan.Nonretinal lesions associated with TSC include:

Coloboma
Angiofibromas of the eyelids
Papilledema (related to hydrocephalus)

Pancreas
Pancreatic neuroendocrine tumours have been described in rare cases of TSC.

Variability
Individuals with TSC may experience none or all of the clinical signs discussed above. The following table shows the prevalence of some of the clinical signs in individuals diagnosed with TSC.

Genetics
TSC is a genetic disorder with an autosomal dominant pattern of inheritance, variable expressivity, and incomplete penetrance. Two-thirds of TSC cases result from sporadic genetic mutations, not inheritance, but their offspring may inherit it from them. Current genetic tests have difficulty locating the mutation in roughly 20% of individuals diagnosed with the disease. So far, it has been mapped to two genetic loci, TSC1 and TSC2.TSC1 encodes for the protein hamartin, is located on chromosome 9 q34, and was discovered in 1997. TSC2 encodes for the protein tuberin, is located on chromosome 16 p13.3, and was discovered in 1993. TSC2 is contiguous with PKD1, the gene involved in one form of polycystic kidney disease (PKD). Gross deletions affecting both genes may account for the 2% of individuals with TSC who also develop polycystic kidney disease in childhood. TSC2 has been associated with a more severe form of TSC. However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 range from 55% to 90%.TSC1 and TSC2 are both tumor suppressor genes that function according to Knudsons "two hit" hypothesis. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its high penetrance, TSC has wide expressivity.

Pathophysiology
Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. The complex appears to interact with RHEB GTPase, thus sequestering it from activating mTOR signalling, part of the growth factor (insulin) signalling pathway. Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors. TSC affects tissues from different germ layers. Cutaneous and visceral lesions may occur, including angiofibroma, cardiac rhabdomyomas, and renal angiomyolipomas. The central nervous system  lesions seen in this disorder include hamartomas of the cortex, hamartomas of the ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of the foramina of Monro.Molecular genetic studies have defined at least two loci for TSC. In TSC1, the abnormality is localized on chromosome 9q34, but the nature of the gene protein, called hamartin, remains unclear. No missense mutations occur in TSC1. In TSC2, the gene abnormalities are on chromosome 16p13. This gene encodes tuberin, a guanosine triphosphatase–activating protein. The specific function of this protein is unknown. In TSC2, all types of mutations have been reported; new mutations occur frequently. Few differences have yet been observed in the clinical phenotypes of patients with mutation of one gene or the other.Cells from individuals with pathogenic mutations in the TSC2 gene display abnormal accumulation of glycogen that is associated with depletion of lysosomes and autophagic impairment. The defective degradation of glycogen by the autophagy-lysosome pathway is, at least in part, independent of impaired regulation of mTORC1 and is restored, in cultured cells, by the combined use of PKB/Akt and mTORC1 pharmacological inhibitors.

Diagnosis
Tuberous sclerosis complex is diagnosed with clinical and genetic tests. There are many different mutations in the TSC1 and TSC2 genes that have been identified in individuals with TSC. A pathogenic mutation in the gene prevents the proteins from being made or inactivates the proteins. If such a pathogenic mutation is found then this alone is sufficient to diagnose TSC. However, some mutations are less clear in their effect, and so not sufficient alone for diagnosis. Between 1 in 10 and 1 in 4 of individuals with TSC have no mutation that can be identified. Once a particular mutation is identified in someone with TSC, this mutation can be used to make confident diagnoses in other family members.For clinical diagnosis, there isnt one sign that is unique (pathognomonic) to TSC, nor are all signs seen in all individuals. Therefore, several signs are considered together, classed as either major or minor features. An individual with two major features, or one major feature and at least two minor features can be given a definite diagnosis of TSC. If only one major feature or at least two minor features are present, the diagnosis is only regarded as possibly TSC.
TSC can be first diagnosed at any stage of life. Prenatal diagnosis is possible by chance if heart tumours are discovered during routine ultrasound. In infancy, epilepsy, particularly infantile spasms, or developmental delay may lead to neurological tests. The white patches on the skin may also first become noticed. In childhood, behavioural problems and autism spectrum disorder may provoke a diagnosis. During adolescence, the skin problems appear. In adulthood, kidney and lung problems may develop. An individual may also be diagnosed at any time as a result of genetic testing of family members of another affected person.

Management
Tuberous sclerosis complex affects multiple organ systems so a multidisciplinary team of medical professionals is required.In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.
Take a personal and family history covering three generations. Genetic counselling and tests determine if other individuals are at risk.
A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).
Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.
Assess children for behavioural issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.
Scan the abdomen for tumours in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.
In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.
Examine the skin under a Woods lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).
In infants under three, perform an echocardiogram to spot rhabdomyomas, and electrocardiogram (ECG) for any arrhythmia.
Use a fundoscope to spot retinal hamartomas or achromic patches.The various symptoms and complications from TSC may appear throughout life, requiring continued surveillance and adjustment to treatments. The following ongoing tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.
In children and adults younger than 25 years, a magnetic resonance imaging (MRI) of the brain is performed every one to three years to monitor for subependymal giant cell astrocytoma (SEGA). If a SEGA is large, growing or interfering with ventricles, the MRI is performed more frequently. After 25 years, if there are no SEGAs then periodic scans may no longer be required. A SEGA causing acute symptoms are removed with surgery, otherwise either surgery or drug treatment with an mTOR inhibitor may be indicated.
Repeat screening for TSC-associated neuropsychiatric disorders (TAND) at least annually. Sudden behavioural changes may indicate a new physical problem (for example with the kidneys, epilepsy or a SEGA).
Routine EEG determined by clinical need.
Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).
Repeat MRI of abdomen every one to three years throughout life. Check renal (kidney) function annually. Should angiomyolipoma bleed, this is best treated with embolisation and then corticosteroids. Removal of the kidney (nephrectomy) is strongly to be avoided. An asymptomatic angiomyolipoma that is growing larger than 3 cm is best treated with an mTOR inhibitor drug. Other renal complications spotted by imaging include polycystic kidney disease and renal cell carcinoma.
Repeat chest HRCT in adult women every five to 10 years. Evidence of lymphangioleiomyomatosis (LAM) indicates more frequent testing. An mTOR inhibitor drug can help, though a lung transplant may be required.
A 12-lead ECG should be performed every three to five years.The mTOR inhibitor everolimus was approved in the US for treatment of TSC-related tumors in the brain (subependymal giant cell astrocytoma) in 2010 and in the kidneys (renal angiomyolipoma) in 2012.  Oral everolimus (rapalog) reduces tumour size, is effective in terms of response to skin lesions and does not increase the risk of adverse events. Everolimus also showed evidence of effectiveness at treating epilepsy in some people with TSC. In 2017, the European Commission approved everolimus for treatment of refractory partial-onset seizures associated with TSC.Neurosurgical intervention may reduce the severity and frequency of seizures in TSC patients. Embolization and other surgical interventions can be used to treat renal angiomyolipoma with acute hemorrhage. Surgical treatments for symptoms of lymphangioleiomyomatosis (LAM) in adult TSC patients include pleurodesis to prevent pneumothorax and lung transplantation in the case of irreversible lung failure.Other treatments that have been used to treat TSC manifestations and symptoms include a ketogenic diet for intractable epilepsy and pulmonary rehabilitation for LAM. Facial angiofibromas can be reduced with laser treatment and the effectiveness of mTOR inhibitor topical treatment is being investigated. Laser therapy is painful, requires anaesthesia, and has risks of scarring and dyspigmentation.

Prognosis
The prognosis for individuals with TSC depends on the severity of symptoms, which range from mild skin abnormalities to varying degrees of learning disabilities and epilepsy to severe intellectual disability, uncontrollable seizures, and kidney failure. Those individuals with mild symptoms generally do well and live long, productive lives, while individuals with the more severe form may have serious disabilities. However, with appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.A study of 30 TSC patients in Egypt found, "...earlier age of seizures commencement (<6 months) is associated with poor seizure outcome and poor intellectual capabilities. Infantile spasms and severely epileptogenic EEG patterns are related to the poor seizure outcome, poor intellectual capabilities and autistic behavior. Higher tubers numbers is associated with poor seizure outcome and autistic behavior. Left-sided tuber burden is associated with poor intellect, while frontal location is more encountered in ASD [autism spectrum disorders]. So, close follow up for the mental development and early control of seizures are recommended in a trial to reduce the risk factors of poor outcome. Also early diagnosis of autism will allow for earlier treatment and the potential for better outcome for children with TSC."Leading causes of death include renal disease, brain tumour, lymphangioleiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe intellectual disability. Cardiac failure due to rhabdomyomas is a risk in the fetus or neonate but is rarely a problem subsequently. Kidney complications such as angiomyolipoma and cysts are common and more frequent in females than males and in TSC2 than TSC1. Renal cell carcinoma is uncommon. Lymphangioleiomyomatosis  is only a risk for females with angiomyolipomas. In the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas. These may block the circulation of cerebrospinal fluid around the brain, leading to hydrocephalus.Detection of the disease should be followed by genetic counselling. It is also important to realise that though the disease does not have a cure, symptoms can be treated symptomatically. Hence, awareness regarding different organ manifestations of TSC is important.

Epidemiology
TSC occurs in all races and ethnic groups, and in both genders </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 Agnosia and can you explain it in depth? [/INST] Agnosia is the inability to process sensory information. Often there is a loss of ability to recognize objects, persons, sounds, shapes, or smells while the specific sense is not defective nor is there any significant memory loss. It is usually associated with brain injury or neurological illness, particularly after damage to the occipitotemporal border, which is part of the ventral stream.  Agnosia only affects a single modality, such as vision or hearing. More recently, a top-down interruption is considered to cause the disturbance of handling perceptual information.

Types
Visual agnosia
Visual agnosia is a broad category that refers to a deficiency in the ability to recognize visual objects. Visual agnosia can be further subdivided into two different subtypes: apperceptive visual agnosia and associative visual agnosia.Individuals with apperceptive visual agnosia display the ability to see contours and outlines when shown an object, but they experience difficulty if asked to categorize objects. Apperceptive visual agnosia is associated with damage to one hemisphere, specifically damage to the posterior sections of the right hemisphere.In contrast, individuals with associative visual agnosia experience difficulty when asked to name objects. Associative agnosia is associated with damage to both the right and left hemispheres at the occipitotemporal border.  A specific form of associative visual agnosia is known as prosopagnosia.  Prosopagnosia is the inability to recognize faces.  For example, these individuals have difficulty recognizing friends, family and coworkers. However, individuals with prosopagnosia can recognize all other types of visual stimuli.

Speech agnosia
Speech agnosia, or auditory verbal agnosia, refers to "an inability to comprehend spoken words despite intact hearing, speech production and reading ability". Patients report that they hear sounds being produced, but that the sounds are fundamentally unrecognizable or untranslatable.
EXAMINER: What did you eat for breakfast?
PATIENT: Breakfast, breakfast, it sounds familiar but it doesnt speak to me. (Obler & Gjerlow 1999:45)Despite an inability to process what the speaker is saying, some patients have been reported to recognize certain characteristic information about the speakers voice (such as being a man or woman).

Causes
Agnosia can result from strokes, dementia, or other neurological disorders. It may also be trauma-induced by a head injury, brain infection, or hereditary.  Additionally, some forms of agnosia may be the result of developmental disorders. Damage causing agnosia usually occurs in either the occipital or parietal lobes of the brain.  Although one modality may be affected, cognitive abilities in other areas are preserved.Patients who experience dramatic recovery from blindness experience significant to total agnosia.The effect of damage to the superior temporal sulcus is consistent with several types of neurolinguistic deficiencies, and some contend that agnosia is one of them. The superior temporal sulcus is vital for speech comprehension because the region is highly involved with the lexical interface. According to the 1985 TRACE II Model, the lexical interface associates sound waves (phonemes) with morphological features to produce meaningful words. This association process is accomplished by lateral inhibition/excitement of certain words within an individuals lexicon (vocabulary). For instance, if an experimenter were to say DOG aloud, the utterance would activate and inhibit various words within the subjects lexical interface:

DOG activates 3, and inhibits 0 letters in DOG. – +3
DOG activates 2, and inhibits 1 letters in FOG. – +2
DOG activates 1, and inhibits 2 letters in DAN. – +1The consistency of this model to agnosia is shown by evidence that bilateral lesions to the superior temporal sulcus produces pure word deafness (Kussmaul, 1877), or as it is understood today, speech agnosia. Patients with pure word deafness demonstrate the inability to recognize and process speech sounds with normal auditory processing for non-speech sounds below the level of the cortex.

Diagnosis
In order to assess an individual for agnosia, it must be verified that the individual does not have a loss of sensation, and that both their language abilities and intelligence are intact.  In order for an individual to be diagnosed with agnosia, they must only be experiencing a sensory deficit in a single modality.  To make a diagnosis, the distinction between apperceptive and associative agnosia must be made.  This distinction can be made by having the individual complete copying and matching tasks.  If the individual has a form of apperceptive agnosia they will not be able to match two stimuli that are identical in appearance.  In contrast, if an individual has a form of associative agnosia, they will not be able to match different examples of a stimulus.  For example, an individual who has been diagnosed with associative agnosia in the visual modality would not be able to match pictures of a laptop that is open with a laptop that is closed.

Pure alexia
Individuals with pure alexia usually have difficulty reading words as well as difficulty with identifying letters.  In order to assess whether an individual has pure alexia, tests of copying and recognition must be performed. An individual with pure alexia should be able to copy a set of words, and should be able to recognize letters.

Prosopagnosia
Individuals are usually shown pictures of human faces that may be familiar to them such as famous actors, singers, politicians or family members.  The pictures shown to the patient are selected to be age and culture appropriate.  The task involves the examiner asking the individual to name each face.  If the individual cannot name whose face appears in the picture, the examiner may ask a question that would help to recognize the face in the picture.

Treatment
For all practical purposes, there is no direct cure. Patients may improve if information is presented in other modalities than the damaged one. Different types of therapies can help to reverse the effects of agnosia. In some cases, occupational therapy or speech therapy can improve agnosia, depending on its cause.Initially many individuals with a form of agnosia are unaware of the extent to which they have either a perceptual or recognition deficit.  This may be caused by anosognosia which is the lack of awareness of a deficit.  This lack of awareness usually leads to a form of denial and resistance to any form of help or treatment.  There are various methods that can be used which can help the individual recognize the impairment in perception or recognition that they may have.  A patient can be presented with a stimulus to the impaired modality only to help increase their awareness of their deficit.  Alternatively, a task can be broken down into its component parts so that the individual can see each part of the problem caused by the deficit.  Once the individual acknowledges their perceptual or recognition deficit, a form of treatment may be recommended.  There are various forms of treatment such as compensatory strategies with alternate modalities, verbal strategies, alternate cues and organizational strategies.

Verbal strategies
Using verbal descriptions may be helpful for individuals with certain types of agnosia.  Individuals such as prosopagnosics may find it useful to listen to a description of their friend or family member and recognize them based on this description more easily than through visual cues.

Alternate cues
Alternate cues may be particularly useful to an individual with environmental agnosia or prosopagnosia.  Alternate cues for an individual with environmental agnosia may include color cues or tactile markers to symbolize a new room or to remember an area by.  Prosopagnosics may use alternate cues such as a scar on an individuals face or crooked teeth in order to recognize the individual. Hair color and length can be helpful cues as well.

Organizational strategies
Organizational strategies may be extremely helpful for an individual with visual agnosia.  For example, organizing clothes according to different hangers provides tactile cues for the individual, making it easier to identify certain forms of clothing as opposed to relying solely on visual cues.

Alternative medicine
These strategies elicit the use of an unaffected modality.  For example, visual agnosics can use tactile information in replacement of visual information.  Alternatively, an individual with prosopagnosia can use auditory information in order to replace visual information.  For example, an individual with prosopagnosia can wait for someone to speak, and will usually recognize the individual from their speech.

Current research
There are clinical trials being done to further research for treatments. At the National Institute of Neurological Disorders and Stroke (NINDS) they support research for rare diseases like agnosia. Some organizations that are recruiting for trials are using clincaltrials.gov and give status updates on the trials.

History
The term agnosia  comes from the Ancient Greek ἀγνωσία (agnosia), "ignorance", "absence of knowledge". It was introduced by Sigmund Freud in 1891: "For disturbances in the recognition of objects, which Finkelnburg classes as asymbolia, I should like to propose the term agnosia." Prior to Freuds introduction of the term, some of the first ideas about agnosia came from Carl Wernicke, who created theories about receptive aphasia in 1874.  He noted that individuals with receptive aphasia did not possess the ability to understand speech or repeat words </s>