<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 lymphoblastic leukemia and can you explain it in depth? [/INST] Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.In most cases, the cause is unknown. Genetic risk factors may include Down syndrome, Li-Fraumeni syndrome, or neurofibromatosis type 1. Environmental risk factors may include significant radiation exposure or prior chemotherapy. Evidence regarding electromagnetic fields or pesticides is unclear. Some hypothesize that an abnormal immune response to a common infection may be a trigger. The underlying mechanism involves multiple genetic mutations that results in rapid cell division. The excessive immature lymphocytes in the bone marrow interfere with the production of new red blood cells, white blood cells, and platelets. Diagnosis is typically based on blood tests and bone marrow examination.ALL is typically treated initially with chemotherapy aimed at bringing about remission. This is then followed by further chemotherapy typically over a number of years. Treatment usually also includes intrathecal chemotherapy since systemic chemotherapy can have limited penetration into the central nervous system and the central nervous system is a common site for relapse of acute lymphoblastic leukemia.Treatment can also include radiation therapy if spread to the brain has occurred. Stem cell transplantation may be used if the disease recurs following standard treatment. Additional treatments such as Chimeric antigen receptor T cell immunotherapy are being used and further studied.ALL affected about 876,000 people globally in 2015 and resulted in about 111,000 deaths. It occurs most commonly in children, particularly those between the ages of two and five. In the United States it is the most common cause of cancer and death from cancer among children. ALL is notable for being the first disseminated cancer to be cured. Survival for children increased from under 10% in the 1960s to 90% in 2015. Survival rates remain lower for babies (50%) and adults (35%). According to the National Cancer Intelligence Network (NCIN), generally for people with ALL: around 70 out of 100 people (70%) will survive their leukemia for 5 years or more after they are diagnosed.

Signs and symptoms
Initial symptoms can be nonspecific, particularly in children. Over 50% of children with leukemia had one or more of five features: a liver one can feel (64%), a spleen one can feel (61%), pale complexion (54%), fever (53%), and bruising (52%). Additionally, recurrent infections, feeling tired, arm or leg pain, and enlarged lymph nodes can be prominent features. The B symptoms, such as fever, night sweats, and weight loss, are often present as well.Central nervous system (CNS) symptoms such as cranial neuropathies due to meningeal infiltration are identified in less than 10% of adults and less than 5% of children, particularly mature B-cell ALL (Burkitt leukemia) at presentation.The signs and symptoms of ALL are variable and include:
Generalized weakness and feeling tired
Anemia
Dizziness
Headache, vomiting, lethargy, neck stiffness, or cranial nerve palsies (CNS involvement)
Frequent or unexplained fever and infection
Weight loss and/or loss of appetite
Excessive and unexplained bruising
Bone pain, joint pain (caused by the spread of "blast" cells to the surface of the bone or into the joint from the marrow cavity)
Breathlessness
Enlarged lymph nodes, liver, and/or spleen
Pitting edema (swelling) in the lower limbs and/or abdomen
Petechiae, which are tiny red spots or lines in the skin due to low platelet levels
Testicular enlargement
Mediastinal mass

Cause
The cancerous cell in ALL is the lymphoblast. Normal lymphoblasts develop into mature, infection-fighting B-cells or T-cells, also called lymphocytes. Signals in the body control the number of lymphocytes so neither too few nor too many are made. In ALL, both the normal development of some lymphocytes and the control over the number of lymphoid cells become defective.ALL emerges when a single lymphoblast gains many mutations to genes that affect blood cell development and proliferation. In childhood ALL, this process begins at conception with the inheritance of some of these genes. These genes, in turn, increase the risk that more mutations will occur in developing lymphoid cells. Certain genetic syndromes, like Down Syndrome, have the same effect. Environmental risk factors are also needed to help create enough genetic mutations to cause disease. Evidence for the role of the environment is seen in childhood ALL among twins, where only 10–15% of both genetically identical twins get ALL. Since they have the same genes, different environmental exposures explain why one twin gets ALL and the other does not.Infant ALL is a rare variant that occurs in babies less than one-year-old. KMT2A (formerly MLL) gene rearrangements are most common and occur in the embryo or fetus before birth. These rearrangements result in increased expression of blood cell development genes by promoting gene transcription and through epigenetic changes. In contrast to childhood ALL, environmental factors are not thought to play a significant role. Aside from the KMT2A rearrangement, only one extra mutation is typically found. Environmental exposures are not needed to help create more mutations.

Risk factors
Genetics
Common inherited risk factors include mutations in ARID5B, CDKN2A/2B, CEBPE, IKZF1, GATA3, PIP4K2A and, more rarely, TP53. These genes play important roles in cellular development, proliferation, and differentiation. Individually, most of these mutations are low risk for ALL. Significant risk of disease occurs when a person inherits several of these mutations together.The uneven distribution of genetic risk factors may help explain differences in disease rates among ethnic groups. For instance, the ARID5B mutation is less common in ethnic African populations.Several genetic syndrome also carry increased risk of ALL. These include: Down syndrome, Fanconi anemia, Bloom syndrome, X-linked agammaglobulinemia, severe combined immunodeficiency, Shwachman-Diamond syndrome, Kostmann syndrome, neurofibromatosis type 1, ataxia-telangiectasia, paroxysmal nocturnal hemoglobinuria, and Li-Fraumeni syndrome. Fewer than 5% of cases are associated with a known genetic syndrome.Rare mutations in ETV6 and PAX5 are associated with a familial form of ALL with autosomal dominant patterns of inheritance.

Environmental
The environmental exposures that contribute to emergence of ALL is contentious and a subject of ongoing debate.High levels of radiation exposure from nuclear fallout is a known risk factor for developing leukemia. Evidence whether lesser radiation, as from x-ray imaging during pregnancy, increases risk of disease remains inconclusive. Studies that have identified an association between x-ray imaging during pregnancy and ALL found only a slightly increased risk. Exposure to strong electromagnetic radiation from power lines has also been associated with a slightly increased risk of ALL. This result is questioned as no causal mechanism linking electromagnetic radiation with cancer is known.High birth weight (greater than 4000g or 8.8lbs) is also associated with a small increased risk. The mechanism connecting high birth weight to ALL is also not known.Evidence suggests that secondary leukemia can develop in individuals treated with certain types of chemotherapy, such as epipodophyllotoxins and cyclophosphamide.

Infections
There is some evidence that a common infection, such as influenza, may indirectly promote the emergence of ALL. The delayed-infection hypothesis states that ALL results from an abnormal immune response to infection in a person with genetic risk factors. Delayed development of the immune system due to limited disease exposure may result in excessive production of lymphocytes and increased mutation rate during an illness.  Several studies have identified lower rates of ALL among children with greater exposure to illness early in life. Very young children who attend daycare have lower rates of ALL. Evidence from many other studies looking at disease exposure and ALL is inconclusive. Some researchers have linked the hygiene hypothesis.

Mechanism
Several characteristic genetic changes lead to the creation of a leukemic lymphoblast. These changes include chromosomal translocations, intrachromosomal rearrangements, changes in the number of chromosomes in leukemic cells, and additional mutations in individual genes. Chromosomal translocations involve moving a large region of DNA from one chromosome to another. This move can result in placing a gene from one chromosome that promotes cell division to a more actively transcribed area on another chromosome. The result is a cell that divides more often. An example of this includes the translocation of C-MYC, a gene that encodes a transcription factor that leads to increased cell division, next to the immunoglobulin heavy- or light-chain gene enhancers, leading to increased C-MYC expression and increased cell division. Other large changes in chromosomal structure can result in the placement of two genes directly next to each other. The result is the combination of two usually separate proteins into a new fusion protein. This protein can have a new function that promotes the development of cancer. Examples of this include the ETV6–RUNX1 fusion gene that combines two factors that promote blood cell development and the BCR-ABL1 fusion gene of the Philadelphia chromosome. BCR–ABL1 encodes an always-activated tyrosine kinase that causes frequent cell division. These mutations produce a cell that divides more often, even in the absence of growth factors.Other genetic changes in B-cell ALL include changes to the number of chromosomes within the leukemic cells. Gaining at least five additional chromosomes, called high hyperdiploidy, occurs more commonly. Less often, chromosomes are lost, called hypodiploidy, which is associated with a poorer prognosis. Additional common genetic changes in B-cell ALL involve non-inherited mutations to PAX5 and IKZF1. In T-cell ALL, LYL1, TAL1, TLX1, and TLX3 rearrangements can occur.ALL results when enough of these genetic changes are present in a single lymphoblast. In childhood ALL, for example, one fusion gene translocation is often found along with six to eight other ALL-related genetic changes. The initial leukemic lymphoblast copies itself into an excessive number of new lymphoblasts, none of which can develop into functioning lymphocytes. These lymphoblasts build up in the bone marrow and may spread to other sites in the body, such as lymph nodes, the mediastinum, the spleen, the testicles, and the brain, leading to the common symptoms of the disease.

Diagnosis
Diagnosing ALL begins with a thorough medical history, physical examination, complete blood count, and blood smears. While many symptoms of ALL can be found in common illnesses, persistent or unexplained symptoms raise suspicion of cancer. Because many features on the medical history and exam are not specific to ALL, further testing is often needed. A large number of white blood cells and lymphoblasts in the circulating blood can be suspicious for ALL because they indicate a rapid production of lymphoid cells in the marrow. The higher these numbers typically point to a worse prognosis. While white blood cell counts at initial presentation can vary significantly, circulating lymphoblast cells are seen on peripheral blood smears in the majority of cases.A bone marrow biopsy provides conclusive proof of ALL, typically with >20% of all cells being leukemic lymphoblasts. A lumbar puncture (also known as a spinal tap) can determine whether the spinal column and brain have been invaded. Brain and spinal column involvement can be diagnosed either through confirmation of leukemic cells in the lumbar puncture or through clinical signs of CNS leukemia as described above. Laboratory tests that might show abnormalities include blood count, kidney function, electrolyte, and liver enzyme tests.Pathological examination, cytogenetics (in particular the presence of Philadelphia chromosome), and immunophenotyping establish whether the leukemic cells are myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic (B lymphocytes or T lymphocytes). Cytogenetic testing on the marrow samples can help classify disease and predict how aggressive the disease course will be. Different mutations have been associated with shorter or longer survival. Immunohistochemical testing may reveal TdT or CALLA antigens on the surface of leukemic cells. TdT is a protein expressed early in the development of pre-T and pre-B cells, whereas CALLA is an antigen found in 80% of ALL cases and also in the "blast crisis" of CML.
Medical imaging (such as ultrasound or CT scanning) can find invasion of other organs commonly the lung, liver, spleen, lymph nodes, brain, kidneys, and reproductive organs.

Immunophenotyping
In addition to cell morphology and cytogenetics, immunophenotyping, a laboratory technique used to identify proteins that are expressed on their cell surface, is a key component in the diagnosis of ALL. The preferred method of immunophenotyping is through flow cytometry. In the malignant lymphoblasts of ALL, expression of terminal deoxynucleotidyl transferase (TdT) on the cell surface can help differentiate malignant lymphocyte cells from reactive lymphocytes, white blood cells that are reacting normally to an infection in the body. On the other hand, myeloperoxidase (MPO), a marker for the myeloid lineage, is typically not expressed. Because precursor B cell and precursor T cells look the same, immunophenotyping can help differentiate the subtype of ALL and the level of maturity of the malignant white blood cells. The subtypes of ALL as determined by immunophenotype and according to the stages of maturation.
An extensive panel of monoclonal antibodies to cell surface markers, particularly CD or cluster of differentiation markers, are used to classify cells by lineage. Below are immunological markers associated with B cell and T cell ALL.

Cytogenetics
Cytogenetic analysis has shown different proportions and frequencies of genetic abnormalities in cases of ALL from different age groups. This information is particularly valuable for classification and can in part explain the different prognoses of these groups. In regards to genetic analysis, cases can be stratified according to ploidy, a number of sets of chromosomes in the cell, and specific genetic abnormalities, such as translocations. Hyperdiploid cells are defined as cells with more than 50 chromosomes, while hypodiploid are defined as cells with less than 44 chromosomes. Hyperdiploid cases tend to carry a good prognosis while hypodiploid cases do not. For example, the most common specific abnormality in childhood B-ALL is the t(12;21) ETV6–RUNX1 translocation, in which the RUNX1 gene, encoding a protein involved in transcriptional control of hemopoiesis, has been translocated and repressed by the ETV6–RUNX1 fusion protein.Below is a table with the frequencies of some cytogenetic translocations and molecular genetic abnormalities in ALL.

Classification
French-American-British
Historically, prior to 2008, ALL was classified morphologically using the French-American-British (FAB) system that heavily relied on morphological assessment. The FAB system takes into account information on size, cytoplasm, nucleoli, basophilia (color of cytoplasm), and vacuolation (bubble-like properties).
While some clinicians still use the FAB scheme to describe tumor cell appearance, much of this classification has been abandoned because of its limited impact on treatment choice and prognostic value.: 491 World Health Organization
In 2008, the World Health Organization classification of acute lymphoblastic leukemia was developed in an attempt to create a classification system that was more clinically relevant and could produce meaningful prognostic and treatment decisions. This system recognized differences in genetic, immunophenotype, molecular, and morphological features found through cytogenetic and molecular diagnostics tests.: 1531–1535  This subtyping helps determine the prognosis and the most appropriate treatment for each specific case of ALL.
The WHO subtypes related to ALL are:
B-lymphoblastic leukemia/lymphoma
Not otherwise specified (NOS)
with recurrent genetic abnormalities
with t(9;22)(q34.1;q11.2);BCR-ABL1
with t(v;11q23.3);KMT2A rearranged
with t(12;21)(p13.2;q22.1); ETV6-RUNX1
with t(5;14)(q31.1;q32.3) IL3-IGH
with t(1;19)(q23;p13.3);TCF3-PBX1
with hyperdiploidy
with hypodiploidy
T-lymphoblastic leukemia/lymphoma
Acute leukemias of ambiguous lineage
Acute undifferentiated leukemia
Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR–ABL1
MPAL with t(v;11q23.3); KMT2A rearranged
MPAL, B/myeloid, NOS
MPAL, T/myeloid, NOS

MicroRNA signature
A systematic review of miRNA levels in pediatric B-ALL compared with controls revealed that miR-155 is the most frequently reported upregulated miRNA (followed by miR-146a, miR-181b, miR-222 and miR-708; two citations for miR-16, miR-21, miR-34a, miR-100, miR-128-1, miR-181a, miR-181c, miR-195, miR-210, miR-320a and miR-660), whereas the most frequently reported downregulated miRNA is miR-374a (two citations for miR-27a, miR-30c, miR-196b, miR-223 and miR-494). To date, there is no consensus miRNA signature and this is mainly attributed to different miRNA signatures across ALL subtypes and methodology of conducted studies.

Treatment
The aim of treatment is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells in the bone marrow).
Over the past several decades, there have been strides to increase the efficacy of treatment regimens, resulting in increased survival rates. Possible treatments for acute leukemia include chemotherapy, steroids, radiation therapy, intensive combined treatments (including bone marrow or stem cell transplants), targeted therapy, and/or growth factors.

Chemotherapy
Chemotherapy is the initial treatment of choice, and most people with ALL  receive a combination of medications. There are no surgical options because of the body-wide distribution of the malignant cells. In general, cytotoxic chemotherapy for ALL combines multiple antileukemic drugs tailored to each person. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy.

Due to the presence of CNS involvement in 10–40% of adults with ALL at diagnosis, most providers start Central nervous system (CNS) prophylaxis and treatment during the induction phase, and continue it during the consolidation/intensification period.
Adult chemotherapy regimens mimic those of childhood ALL; however, are linked with a higher risk of disease relapse with chemotherapy alone. It should be known that 2 subtypes of ALL (B-cell ALL and T-cell ALL) require special considerations when it comes to selecting an appropriate treatment regimen in adults with ALL. B-cell ALL is often associated with cytogenetic abnormalities (specifically, t(8;14), t (2;8), and t(8;22)), which require aggressive therapy consisting of brief, high-intensity regimens. T-cell ALL responds to cyclophosphamide-containing agents the most.As the chemotherapy regimens can be intensive and protracted, many people have an intravenous catheter inserted into a large vein (termed a central venous catheter or a Hickman line), or a Portacath, usually placed near the collar bone, for lower infection risks and the long-term viability of the device. Males usually endure a longer course of treatment than females as the testicles can act as a reservoir for cancer.

Radiation therapy
Radiation therapy (or radiotherapy) is used on painful bony areas, in high disease burdens, or as part of the preparations for a bone marrow transplant (total body irradiation). In the past, physicians commonly utilized radiation in the form of whole-brain radiation for central nervous system prophylaxis, to prevent the occurrence and/or recurrence of leukemia in the brain. Recent studies showed that CNS chemotherapy provided results as favorable but with fewer developmental side effects. As a result, the use of whole-brain radiation has been more limited. Most specialists in adult leukemia have abandoned the use of radiation therapy for CNS prophylaxis, instead using intrathecal chemotherapy.

Biological therapy
Selection of biological targets on the basis of their combinatorial effects on the leukemic lymphoblasts can lead to clinical trials for improvement in the effects of ALL treatment. Tyrosine-kinase inhibitors (TKIs), such as imatinib, are often incorporated into the treatment plan for people with Bcr-Abl1+ (Ph+) ALL. However, this subtype of ALL is frequently resistant to the combination of chemotherapy and TKIs and allogeneic stem cell transplantation is often recommended upon relapse.

Immunotherapy
Chimeric antigen receptors (CARs) have been developed as a promising immunotherapy for ALL. This technology uses a single chain variable fragment (scFv) designed to recognize the cell surface marker CD19 as a method of treating ALL.
CD19 is a molecule found on all B-cells and can be used as a means of distinguishing the potentially malignant B-cell population. In this therapy, mice are immunized with the CD19 antigen and produce anti-CD19 antibodies. Hybridomas developed from mouse spleen cells fused to a myeloma cell line can be developed as a source for the cDNA encoding the CD19 specific antibody. The cDNA is sequenced and the sequence encoding the variable heavy and variable light chains of these antibodies are cloned together using a small peptide linker. This resulting sequence encodes the scFv. This can be cloned into a transgene, encoding what will become the endodomain of the CAR. Varying arrangements of subunits serve as the endodomain, but they generally consist of the hinge region that attaches to the scFv, a transmembrane region, the intracellular region of a costimulatory molecule such as CD28, and the intracellular domain of CD3-zeta containing ITAM repeats. Other sequences frequently included are: 4-1bb and OX40. The final transgene sequence, containing the scFv and endodomain sequences is then inserted into immune effector cells that are obtained from the person and expanded in vitro. In trials these have been a type of T-cell capable of cytotoxicity.Inserting the DNA into the effector cell can be accomplished by several methods. Most commonly, this is done using a lentivirus that  encodes the transgene. Pseudotyped, self-inactivating lentiviruses are an effective method for the stable insertion of a desired transgene into the target cell. Other methods include electroporation and transfection, but these are limited in their efficacy as transgene expression diminishes over  time.
The gene-modified effector cells are then transplanted back into the person. Typically this process is done in conjunction with a conditioning regimen such as cyclophosphamide, which has been shown to potentiate the effects of infused T-cells. This effect has been attributed to making an immunologic space within which the cells populate. The process as a whole result in an effector cell, typically a T-cell, that can recognize a tumor cell antigen in a manner that is independent of the major histocompatibility complex and which can initiate a cytotoxic response.
In 2017, tisagenlecleucel was approved by the FDA as a CAR-T therapy for people with acute B-cell lymphoblastic leukaemia  who did not respond adequately to other treatments or have relapsed. In a 22-day process, the "drug" is customized for each person. T cells purified from each person are modified by a virus that inserts genes that encode a chimaeric antigen receptor into their DNA, one that recognizes leukemia cells.

Relapsed ALL
Typically, people who experience a relapse in their ALL after initial treatment have a poorer prognosis than those who remain in complete remission after induction therapy. It is unlikely that recurrent leukemia will respond favorably to the standard chemotherapy regimen that was initially implemented, and instead, these people should be trialed on reinduction chemotherapy followed by allogeneic bone marrow transplantation. These people in relapse may also receive blinatumomab, as it has shown to increase remission rates and overall survival rates, without increased toxic effects.Low dose palliative radiation may also help reduce the burden of tumor inside or outside the central nervous system and alleviate some symptoms.
Recently, there has also been evidence and approval of use for dasatinib, a tyrosine kinase inhibitor. It has shown efficacy in cases of people with Ph1-positive and imatinib-resistant ALL, but more research needs to be done on long-term survival and time to relapse.

Side effects
Chemotherapies or stem cell transplantations may require a platelet transfusion to prevent bleeding. Moreover, patients undergoing a stem cell transplantation can develop a graft-versus-host disease (GvHD). It was evaluated whether mesenchymal stromal cells can be used to prevent a GvHD. The evidence is very uncertain about the therapeutic effect of mesenchymal stromal cells to treat graft-versus-host diseases after a stem cell transplantation on the all-cause mortality and complete disappear of chronic acute graft-versus-host diseases. Mesenchymal stromal cells may results in little to no difference in the all-cause mortality, relapse of malignant disease and incidence of acute and chronic graft-versus-host diseases if they are used for prophylactic reason.

Supportive therapy
Adding physical exercises to the standard treatment for adult patients with haematological malignancies like ALL may result in little to no difference in mortality, the quality of life, and physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect on anxiety and serious adverse events.

Gene therapy
Brexucabtagene autoleucel (Tecartus) was approved for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia in October 2021.Each dose of brexucabtagene autoleucel is a customized treatment created using the recipients own immune system to help fight the lymphoma. The recipients T cells, a type of white blood cell, are collected and genetically modified to include a new gene that facilitates the targeting and killing of the lymphoma cells. These modified T cells are then infused back into the recipient.

Prognosis
Prior to the development of chemotherapy regimens and hematopoietic stem cell transplant, children were surviving a median length of 3 months, largely due to either infection or bleeding. Since the advent of chemotherapy, the prognosis for childhood leukemia has improved greatly and children with ALL are estimated to have a 95% probability of achieving a successful remission after 4 weeks of initiating treatment. People in pediatric care with ALL in developed countries have a greater than 80% five-year survival rate. It is estimated that 60–80% of adults undergoing induction chemotherapy achieve complete remission after 4 weeks, and those over the age of 70 have a cure rate of 5%.

However, there are differing prognoses for ALL among individuals depending on a variety of factors:

Gender: Females tend to fare better than males.
Ethnicity: Caucasians are more likely to develop acute leukemia than African-Americans, Asians, or Hispanics. However, they also tend to have a better prognosis than non-Caucasians.
Age at diagnosis: children 1–10 years of age are most likely to develop ALL and to be cured of it. Cases in older people are more likely to result from chromosomal abnormalities (e.g., the Philadelphia chromosome) that make treatment more difficult and prognoses poorer. Older people are also likely to have co-morbid medical conditions that make it even more difficult to tolerate ALL treatment.
White blood cell count at diagnosis of greater than 30,000 (B-ALL) or 100,000 (T-ALL) is associated with worse outcomes
Cancer spreading into the Central nervous system (brain or spinal cord) has worse outcomes.
Morphological, immunological, and genetic subtypes
Persons response to initial treatment and longer length of time required (greater than 4 weeks) to reach complete remission
Early relapse of ALL
Minimal residual disease
Genetic disorders, such as Down syndrome, and other chromosomal abnormalities (aneuploidy and translocations)Cytogenetics, the study of characteristic large changes in the chromosomes of cancer cells, is an important predictor of outcome. Some cytogenetic subtypes have a worse prognosis than others </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 Bed bug and can you explain it in depth? [/INST] Bed bugs are insects from the genus Cimex that feed on blood, usually at night. Their bites can result in a number of health impacts including skin rashes, psychological effects, and allergic symptoms. Bed bug bites may lead to skin changes ranging from small areas of redness to prominent blisters. Symptoms may take between minutes to days to appear and itchiness is generally present. Some individuals may feel tired or have a fever. Typically, uncovered areas of the body are affected. Their bites are not known to transmit any infectious disease. Complications may rarely include areas of dead skin or vasculitis.Bed bug bites are caused primarily by two species of insects: Cimex lectularius (the common bed bug) and Cimex hemipterus, found primarily in the tropics. Their size ranges between 1 and 7 mm. They spread by crawling between nearby locations or by being carried within personal items. Infestation is rarely due to a lack of hygiene but is more common in high-density areas. Diagnosis involves both finding the bugs and the occurrence of compatible symptoms. Bed bugs spend much of their time in dark, hidden locations like mattress seams, or cracks in a wall.Treatment is directed towards the symptoms. Eliminating bed bugs from the home is often difficult, partly because bed bugs can survive up to 70 days without feeding. Repeated treatments of a home may be required. These treatments may include heating the room to 50 °C (122 °F) for more than 90 minutes, frequent vacuuming, washing clothing at high temperatures, and the use of various pesticides.Bed bugs occur in all regions of the globe. Infestations are relatively common, following an increase since the 1990s. The exact causes of this increase are unclear; theories including increased human travel, more frequent exchange of second-hand furnishings, a greater focus on control of other pests, and increasing resistance to pesticides. Bed bugs have been known human parasites for thousands of years.

Signs and symptoms
Skin
The most common skin findings associated with bed bugs are pruritic, maculopapular, erythematous lesions. Each lesion is about 2–5 mm but may be as large as 2 cm in diameter and there may or may not be the presence of a central punctum. Bites are usually present on areas of exposed skin, especially exposed areas not covered by sheets or blankets, such as arms, legs, feet, face or neck. Individual responses to bites vary, ranging from no visible effect (in about 20–70%), to small flat (macular) spots, to the formation of prominent blisters (wheals and bullae) along with intense itching that may last several days. Vesicles and nodules may also form. The lesions due to bites may become secondarily infected due to scratching but systemic effects from bed bug bites are very rare. A central spot of bleeding may also occur due to the release of blood thinning substances in the bugs saliva.Symptoms may not appear until some days after the bites have occurred. Reactions often become brisker after multiple bites due to possible sensitization to the salivary proteins of the bed bug. Numerous bites may lead to a red rash or hives.

Psychological
Serious infestations and chronic attacks can cause anxiety, stress, and sleep difficulties. Development of refractory delusional parasitosis is possible, as a person develops an overwhelming obsession with bed bugs.

Other
A number of other symptoms may occur from either the bite of the bed bugs or from their exposure. Serious allergic reactions including anaphylaxis from the injection of serum and other nonspecific proteins have been rarely documented. Due to each bite taking a tiny amount of blood, the chronic or severe infestation may lead to anemia. Bacterial skin infection may occur due to skin breakdown from scratching.
Systemic poisoning may occur if the bites are numerous. Exposure to bed bugs may trigger an asthma attack via the effects of airborne allergens although evidence of this association is limited. There is no evidence that bed bugs transmit infectious diseases even though they appear physically capable of carrying pathogens and this possibility has been investigated. The bite itself may be painful thus resulting in poor sleep and worse work performance.Bed bugs can feed on warm-blooded animals other than humans, such as pets. The signs left by the bites are the same as in the case of people and cause identical symptoms (skin irritation, scratching etc.). Bed bugs can infest poultry sheds and cause anemia and a decrease in egg production in hens.

Insect
Bed bug infestations are primarily the result of two species of insects from genus Cimex: Cimex lectularius (the common bed bug) and Cimex hemipterus (the tropical bed bug). These insects feed exclusively on blood and, at any stage of development, may survive up to 70 days without feeding. Adult Cimex are light brown to reddish-brown, flat, oval, and have no hind wings. The front wings are vestigial and reduced to pad-like structures. Adults grow to 4–5 mm (0.16–0.20 in) long and 1.5–3 mm (0.059–0.118 in) wide. Female common bed bugs can lay 1–10 eggs per day and 200–500 eggs in their lifetime, whereas female tropical bed bugs can lay about 50 eggs in their lifetime .Bed bugs have five immature nymph life stages and a final sexually mature adult stage. Bed bugs need at least one blood meal in order to advance to the next stage of development. They shed their skins through ecdysis at each stage, discarding their outer exoskeleton. Newly hatched nymphs are translucent, lighter in color, and become browner as they moult and reach maturity. Bed bugs may be mistaken for other insects, such as booklice, small cockroaches, or carpet beetles; however, when warm and active, their movements are more ant-like, and like most other true bugs, they emit a characteristic disagreeable odor when crushed.
Bed bugs are obligatory bloodsuckers. They have mouth parts that saw through the skin and inject saliva with anticoagulants and painkillers. Sensitivity of humans varies from extreme allergic reaction to no reaction at all (about 20%). The bite usually produces a swelling with no red spot, but when many bugs feed on a small area, reddish spots may appear after the swelling subsides. Bedbugs prefer exposed skin, preferably the face, neck, and arms of a sleeping person.
Bed bugs are attracted to their hosts primarily by carbon dioxide, secondarily by warmth, and also by certain chemicals.  There is strong evidence that bed bugs can respond and orient towards human odors, independently of all other host cues. Cimex lectularius feeds only every five to seven days, which suggests that it does not spend the majority of its life searching for a host. When a bed bug is starved, it leaves its shelter and searches for a host. It returns to its shelter after successful feeding or if it encounters exposure to light.  Cimex lectularius aggregate under all life stages and mating conditions. Bed bugs may choose to aggregate because of predation, resistance to desiccation, and more opportunities to find a mate. Airborne pheromones are responsible for aggregations.

Spread
Infestation is rarely caused by a lack of hygiene. Transfer to new places is usually in the personal items of the human they feed upon. Dwellings can become infested with bed bugs in a variety of ways, such as:

Bugs and eggs inadvertently brought in from other infested dwellings on a visiting persons clothing or luggage;
Infested items (such as furniture especially beds or couches, clothing, or backpacks) brought into a home or business;
Proximity of infested dwellings or items, if easy routes are available for travel, e.g. through ducts or false ceilings;
Wild animals (such as bats or birds) that may also harbour bed bugs or related species such as the bat bug;
People visiting an infested area (e.g. dwelling, means of transport, entertainment venue, or lodging) and carrying the bugs to another area on their clothing, luggage, or bodies. Bedbugs are increasingly found in air travel.Though bed bugs will opportunistically feed on pets, they do not live or travel on the skin of their hosts, and pets are not believed to be a factor in their spread.

Diagnosis
A definitive diagnosis of health effects due to bed bugs requires a search for and finding of the insect in the sleeping environment as symptoms are not sufficiently specific. It is difficult to distinguish bed bug bites from other arthropod bites and the linear pattern of bites (known colloquially as "breakfast, lunch and dinner" bites) is not specific for bed bugs. If the number in a house is large a pungent sweet odour may be described. There are specially trained dogs that can detect this smell.

Detection
Bed bugs can exist singly but tend to congregate once established. Although strictly parasitic, they spend only a tiny fraction of their lives physically attached to hosts. Once a bed bug finishes feeding, it follows a chemical trail to return to a nearby harborage, commonly in or near beds or couches, where they live in clusters of adults, juveniles, and eggs. These places may include luggage, vehicles interiors, furniture, bedside clutter—even inside electrical sockets or laptop computers. Bed bugs may also lodge near animals that have nested within a dwelling, such as bats, birds, or rodents. They are also capable of surviving on domestic cats and dogs, though humans are the preferred host of C. lectularius.
Bed bugs can also be detected by their characteristic smell of rotting raspberries. Bed bug detection dogs are trained to pinpoint infestations, with a possible accuracy rate between 11% and 83%.Homemade detectors have been developed. Bedbug detectors, often referred to as "monitors" or "traps", use attractant based methods such as lactic acid or carbon dioxide (associated with the presence of a human body) or pheromones to trap bugs in a container. Bedbug detectors can confirm a bedbug infestation but they are not effective for eradication.

Differential diagnosis
Other possible conditions with which these conditions can be confused include scabies, gamasoidosis, allergic reactions, mosquito bites, spider bites, chicken pox and bacterial skin infections.

Prevention
To prevent bringing home bed bugs, travelers are advised to take precautions after visiting an infested site: generally, these include checking shoes on leaving the site, changing clothes outside the house before entering, and putting the used clothes in a clothes dryer outside the house. When visiting a new lodging, it is advised to check the bed before taking suitcases into the sleeping area, and putting the suitcase on a raised stand to make bedbugs less likely to crawl in. An extreme measure would be putting the suitcase in the tub. Clothes should be hung up or left in the suitcase, and never left on the floor. Additional preventative measures include sealing cracks and crevices (which are often the sites of bed bug harborages), inspecting furniture, and for exposed travelers to decontaminate clothes and luggage upon returning home. The founder of a company dedicated to bedbug extermination said that 5% of hotel rooms he books into were infested. He advised people never to sit down on public transport; check office chairs, plane seats, and hotel mattresses; and monitor and vacuum home beds once a month. Close all wall openings or gaps; bed bugs tend to hide in dark places and cracked walls are a perfect spot for them to infest.

Management
Treatment of bed bug bites requires keeping the person from being repeatedly bitten, and possible symptomatic use of antihistamines and corticosteroids (either topically or systemically). There however is no evidence that medications improve outcomes, and symptoms usually resolve without treatment in 1–2 weeks.Avoiding repeated bites can be difficult since it usually requires eradicating bed bugs from a home or workplace; eradication is most effective using non-chemical control methods. Non-chemical control methods include vacuuming carpet and furniture (often with scraping) into a disposable bag which is then sealed into a plastic bag to prevent re-infestation. Other methods include removing textile materials from an area and washing them in hot water (at least 60 degrees Celsius) or freezing them at −20 °C (−4 °F). Most consumer grade freezers are inadequate to kill bedbugs due to not having low enough temperatures. Unremovable textiles such as mattresses can be steamed at least 60 °C (140 °F) and this method can penetrate deep into the textile to effectively kill bed bugs quickly (under 1 minute). Heating tents or chambers can be used for infested materials or entire rooms can be heated to at least 55 °C (131 °F) to effectively eradicate infestation.There is no evidence to indicate that a combination of non-chemical methods plus insecticides is more effective than non-chemical methods alone with regards to eradication of bed bug infestations.Insecticides are mostly ineffective for the eradication of bedbug infestations as most bedbugs are resistant to insecticides, including pyrethroids which are found in approximately 90% of commercial grade insecticides. Furthermore, insect foggers (known as "bug bombs") are ineffective in the eradication of bed bug infestation as they are unable to penetrate bed bug harborages. Resistance to pesticides has increased significantly over time, and there are concerns about harm to health from their use.Once established, bed bugs are extremely difficult to get rid of. Bed bugs are particularly difficult to eradicate in apartment complexes as harbors can exist in other areas of the building when single units are treated.Mechanical approaches, such as vacuuming up the insects and heat-treating or wrapping mattresses, are effective. An hour at a temperature of 45 °C (113 °F) or over, or two hours at less than −17 °C (1 °F) kills them. This may include a domestic clothes drier for fabric or a commercial steamer. Bed bugs and their eggs will die on contact when exposed to surface temperatures above 180 °F (82 °C) and a steamer can reach well above 230 °F (110 °C). A study found 100% mortality rates for bed bugs exposed to temperatures greater than 50 °C (122 °F) for more than 2 minutes. The study recommended maintaining temperatures of above 48 °C (118 °F) for more than 20 min to effectively kill all life stages of bed bugs, and because in practice treatment times of 6 to 8 hours are used to account for cracks and indoor clutter. This method is expensive and has caused fires. Starving bedbugs is not effective, as they can survive without eating for 100 to 300 days, depending on temperature.It was stated in 2012 that no truly effective insecticides were available. Insecticides that have historically been found effective include pyrethroids, dichlorvos, and malathion. Resistance to pesticides has increased significantly in recent decades. The carbamate insecticide propoxur is highly toxic to bed bugs, but it has potential toxicity to children exposed to it, and the US Environmental Protection Agency has been reluctant to approve it for indoor use. Boric acid, occasionally applied as a safe indoor insecticide, is not effective against bed bugs because they do not groom.

Epidemiology
Bed bugs occur around the world. Before the 1950s about 30% of houses in the United States had bedbugs. This percentage has since fallen, which is believed to be partly due to the use of DDT to kill cockroaches. The invention of the vacuum cleaner and simplification of furniture design may have also played a role in the decrease. Others believe it might simply be the cyclical nature of the organism.However, rates of infestation in developed countries have increased dramatically since the 1980s. This is thought to be due to greater foreign travel, increased immigration from the developing world to the developed world, more frequent exchange of second-hand furnishings among homes, a greater focus on control of other pests, resulting in neglect of bed bug countermeasures, and increasing bedbug resistance to pesticides. Lower cockroach populations due to insecticide use may have aided bed bugs resurgence, since cockroaches are known to sometimes predate them. Steadily-rising resistance to DDT and other potent pesticides may have also contributed; bans on DDT may have contributed as well, though studies have shown resistance continued to rise in countries where they continued to be used.The U.S. National Pest Management Association reported a 71% increase in bed bug calls between 2000 and 2005. The number of reported incidents in New York City alone rose from 500 in 2004 to 10,000 in 2009. In 2013, Chicago was listed as the number one city in the United States for bedbug infestations. As a result, the Chicago City Council passed a bed bug control ordinance to limit their spread. Additionally, bed bugs are reaching places in which they never established before, such as southern South America.The rise in infestations has been hard to track because bed bugs are not an easily identifiable problem and is one that people prefer not to discuss. Most of the reports are collected from pest-control companies, local authorities, and hotel chains. Therefore, the problem may be more severe than is currently believed.

Species
The common bed bug (Cimex lectularius) is the species best adapted to human environments but is also known from birds, Chiroptera, Gallus (chickens and relatives), Myotis myotis, and sheep (Ovis aries). It is found in temperate climates throughout the world. Other species include C. hemipterus, found in tropical regions,  which also infests poultry (including Gallus)  and bats, and Leptocimex boueti, a relative of C. lectularius adapted for the tropics of West Africa and South America, which infests bats and humans. C. pilosellus and C. pipistrella primarily infest bats, while Haematosiphon inodora, a species of North America, primarily infests poultry.

Evolution
Cimicidae, the ancestor of modern bed bugs, first emerged approximately 115 million years ago, more than 30 million years before bats—their previously presumed initial host—first appeared. From unknown ancestral hosts, a variety of different lineages evolved which specialized in either bats or birds. The common (C. lectularius) and tropical bed bug (C. hemipterus), split 40 million years before Homo evolution. Humans became hosts to bed bugs through host specialist extension (rather than switching) on three separate occasions.

History
Bed bugs were first mentioned in ancient Greece as early as 400 BC, and later by Aristotle. Plinys Natural History, first published circa AD 77 in Rome, claimed bed bugs had medicinal value in treating ailments such as snake bites and ear infections. Belief in the medicinal use of bed bugs persisted until at least the 18th century, when Guettard recommended their use in the treatment of hysteria.Bed bugs were also mentioned in Germany in the 11th century, in France in the 13th century, and in England in 1583, though they remained rare in England until 1670. Some in the 18th century believed bed bugs had been brought to London with supplies of wood to rebuild the city after the Great Fire of London (1666). Giovanni Antonio Scopoli noted their presence in Carniola (roughly equivalent to present-day Slovenia) in the 18th century.Traditional methods of repelling and/or killing bed bugs include the use of plants, fungi, and insects (or their extracts), such as black pepper; black cohosh (Actaea racemosa); Pseudarthria hookeri; Laggera alata (Chinese yángmáo cǎo | 羊毛草); Eucalyptus saligna oil; henna (Lawsonia inermis or camphire); "infused oil of Melolontha vulgaris" (presumably cockchafer); fly agaric (Amanita muscaria); tobacco; "heated oil of Terebinthina" (i.e. true turpentine); wild mint (Mentha arvensis); narrow-leaved pepperwort (Lepidium ruderale); Myrica spp. (e.g. bayberry); Robert geranium (Geranium robertianum); bugbane (Cimicifuga spp.); "herb and seeds of Cannabis"; "opulus" berries (possibly maple or European cranberrybush); masked hunter bugs (Reduvius personatus), "and many others".In the mid-19th century, smoke from peat fires was recommended as an indoor domestic fumigant against bed bugs.Dusts have been used to ward off insects from grain storage for centuries, including plant ash, lime, dolomite, certain types of soil, and diatomaceous earth or Kieselguhr. Of these, diatomaceous earth in particular has seen a revival as a nontoxic (when in amorphous form) residual pesticide for bed bug abatement. While diatomaceous earth often performs poorly, silica gel may be effective.Basket-work panels were put around beds and shaken out in the morning in the UK and in France in the 19th century. Scattering leaves of plants with microscopic hooked hairs around a bed at night, then sweeping them up in the morning and burning them, was a technique reportedly used in Southern Rhodesia and in the Balkans.Bean leaves have been used historically to trap bedbugs in houses in Eastern Europe. The trichomes on the bean leaves capture the insects by impaling the feet (tarsi) of the insects. The leaves are then destroyed.

20th century
Before the mid-20th century, bed bugs were very common. According to a report by the UK Ministry of Health, in 1933, all the houses in many areas had some degree of bed bug infestation. The increase in bed bug populations in the early 20th century has been attributed to the advent of electric heating, which allowed bed bugs to thrive year-round instead of only in warm weather.Bed bugs were a serious problem at US military bases during World War II </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 DiGeorge syndrome and can you explain it in depth? [/INST] DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent infections, developmental delay, learning problems and cleft palate. Associated conditions include kidney problems, schizophrenia, hearing loss and autoimmune disorders such as rheumatoid arthritis or Graves disease.DiGeorge syndrome is typically due to the deletion of 30 to 40 genes in the middle of chromosome 22 at a location known as 22q11.2. About 90% of cases occur due to a new mutation during early development, while 10% are inherited from a persons parents. It is autosomal dominant, meaning that only one affected chromosome is needed for the condition to occur. Diagnosis is suspected based on the symptoms and confirmed by genetic testing.Although there is no cure, treatment can improve symptoms. This often includes a multidisciplinary approach with efforts to improve the function of the potentially many organ systems involved. Long-term outcomes depend on the symptoms present and the severity of the heart and immune system problems. With treatment, life expectancy may be normal.DiGeorge syndrome occurs in about 1 in 4,000 people. The syndrome was first described in 1968 by American physician Angelo DiGeorge. In late 1981, the underlying genetics were determined.

Signs and symptoms
The features of this syndrome vary widely, even among members of the same family, and affect many parts of the body. Characteristic signs and symptoms may include birth defects such as congenital heart disease, defects in the palate, most commonly related to neuromuscular problems with closure (velopharyngeal insufficiency), learning disabilities, mild differences in facial features, and recurrent infections.  Infections are common in children due to problems with the immune systems T cell-mediated response that in some patients is due to an absent or hypoplastic thymus. DiGeorge syndrome may be first spotted when an affected newborn has heart defects or convulsions from hypocalcemia due to malfunctioning parathyroid glands and low levels of parathyroid hormone (parathormone).Affected individuals may also have other kinds of birth defects including kidney abnormalities and significant feeding difficulties as babies. Gastrointestinal issues are also very common in this patient population. Digestive motility issues may result in constipation. Disorders such as hypothyroidism and hypoparathyroidism or thrombocytopenia (low platelet levels), and psychiatric illnesses are common late-occurring features.Microdeletions in chromosomal region 22q11.2 are associated with a 20 to 30-fold increased risk of schizophrenia. Studies provide various rates of 22q11.2DS in schizophrenia, ranging from 0.5 to 2.0% and averaging about 1.0%, compared with the overall estimated 0.025% risk of the 22q11.2DS in the general population.Salient features can be summarized using the mnemonic CATCH-22 to describe 22q11.2DS, with the 22 signifying the chromosomal abnormality is found on the 22nd chromosome, as below:
Cardiac abnormality (commonly interrupted aortic arch, truncus arteriosus and tetralogy of Fallot)
Abnormal facies
Thymic aplasia or hypoplasia
Cleft palate
Hypocalcemia/hypoparathyroidism early in lifeIndividuals can have many possible features, ranging in number of associated features and from the mild to the very serious. Symptoms shown to be common include:

This syndrome is characterized by incomplete penetrance. Therefore, there is a marked variability in clinical expression between the different patients. This often makes early diagnosis difficult.

Cognitive impairments
Children with DiGeorge syndrome have a specific profile in neuropsychological tests. They usually have a below-borderline normal IQ, with most individuals having higher scores in the verbal than the nonverbal domains. Some are able to attend main-stream  schools, while others are home-schooled or in special classes. The severity of hypocalcemia early in childhood is associated with autism-like behavioral difficulties.Adults with DiGeorge syndrome are a specifically high-risk group for developing schizophrenia. About 30% have at least one episode of psychosis and about a quarter develop schizophrenia by adulthood.Individuals with DiGeorge syndrome also have a higher risk of developing early onset Parkinsons disease (PD). Diagnosis of Parkinsons can be delayed by up to 10 years due to the use of antipsychotics, which can cause parkinsonian symptoms.

Speech and language
Current research demonstrates a unique profile of speech and language impairments is associated with 22q11.2DS. Children often perform lower on speech and language evaluations in comparison to their nonverbal IQ scores. Common problems include hypernasality, language delays, and speech sound errors.Hypernasality occurs when air escapes through the nose during the production of oral speech sounds, resulting in reduced intelligibility. This is a common characteristic in the speech and language profile because 69% of children have palatal abnormalities. If the structure of the soft palate velum is such that it does not stop the flow of air from going up to the nasal cavity, it will cause hypernasal speech. This phenomenon is referred as velopharyngeal inadequacy (VPI). Hearing loss can also contribute to increased hypernasality because children with hearing impairments can have difficulty self monitoring their oral speech output. The treatment options available for VPI include prosthesis and surgery.Difficulties acquiring vocabulary and formulating spoken language (expressive language deficits) at the onset of language development are also part of the speech and language profile associated with the 22q11.2 deletion. Vocabulary acquisition is often severely delayed for preschool-age children. In some recent studies, children had a severely limited vocabulary or were still not verbal at 2–3 years of age. School-age children do make progress with expressive language as they mature, but many continue to have delays and demonstrate difficulty when presented with language tasks such as verbally recalling narratives and producing longer and more complex sentences. Receptive language, which is the ability to comprehend, retain, or process spoken language, can also be impaired, although not usually with the same severity as expressive language impairments.Articulation errors are commonly present in children with DiGeorge syndrome. These errors include a limited phonemic (speech sound) inventory and the use of compensatory articulation strategies resulting in reduced intelligibility. The phonemic inventory typically produced consists of sounds made in the front or back of the oral cavity such as: /p/, /w/, /m/, /n/, and glottal stops. Sound made in the middle of the mouth are completely absent. Compensatory articulation errors made by this population of children include: glottal stops, nasal substitutions, pharyngeal fricatives, linguapalatal sibilants, reduced pressure on consonant sounds, or a combination of these symptoms. Of these errors, glottal stops have the highest frequency of occurrence. It is reasoned that a limited phonemic inventory and the use of compensatory articulation strategies is present due to the structural abnormalities of the palate. The speech impairments exhibited by this population are more severe during the younger ages and show a trend of gradual improvement as the child matures.

Genetics
DiGeorge syndrome is caused by a heterozygous deletion of part of the long arm (q) of chromosome 22, region 1, band 1, sub-band 2 (22q11.2). Approximately 80-90% of patients have a deletion of 3 Mb and 8% have a deletion of 1.5Mb. The number of genes affected by the deletion has been cited as approximately 30 to 50. Very rarely, patients with somewhat similar clinical features may have deletions on the short arm of chromosome 10. The disorder has an autosomal dominant inheritance pattern.
A French study of 749 people diagnosed between 1995 and 2013 found that the mutation was inherited in 15% of patients, of which 85.5% was from the mother. Other studies have found inheritance rates of 6-10%. The majority cases are a result of a de novo (new to the family) deletion. This is because the 22q11 region has a structure that makes it highly prone to rearrangements during sperm or egg formation.The exact mechanism that causes all of the associated features of the syndrome is unknown. Of the 30–50 genes in the deleted region, a number have been identified as possibly playing a role in the development of some of the signs and symptoms.

TBX1
Haploinsufficiency of the TBX1 gene (T-box transcription factor TBX1) is thought to be the cause of some of the symptoms observed. Point mutations in this gene have also been observed in individuals with DiGeorge syndrome. TBX1 is part of the T-box family of genes which have an important role in tissue and organ formation during embryonic development and it may have a role in the regulation of differentiation of post migration neural crest cells. The neural crest forms many of the structures affected in DiGeorge syndrome, including  the skull bones, mesenchyme of the face and palate, the outflow tract of the heart, and the thymus and parathyroid stroma. When there is a loss of expression of FGF18 during the development of the pharyngeal arches, neural crest cell death is seen. Although neither FGF18 or TBX1 are expressed in the neural crest cells, TBX1 might have a role in the regulation of FGF18 expression, ensuring that the differentiation of these cells in the pharyngeal region is correct.  Therefore, dysfunction of TBX1 may be responsible for some of the symptoms in DiGeorge syndrome.Research in mouse models has shown that deletion of Tbx1 leads to several defects similar to those seen in humans, mainly affecting development of the great arteries and the thymus.The abnormalities seen in the great arteries of mice deficient of Tbx1 are a consequence of abnormal formation and remodelling of the aortic arches during early development. The role of Tbx1 for correct formation and remodelling of the aortic arches has been extensively studied in various mouse models suggesting the key role of Tbx1 for cardiovascular development and the phenotypes seen in DiGeorge syndrome.

DGCR8
In mice, haploinsufficiency of the DGCR8 gene has been linked to improper regulation of the microRNA miR-338 and 22q11.2 deletion phenotypes.

TANGO2
Transport and golgi organization 2 homolog (TANGO2) also known as chromosome 22 open reading frame 25 (C22orf25) is a protein that in humans is encoded by the TANGO2 gene.The gene coding for C22orf25 is located on chromosome 22 and the location q11.21, so it is often associated with 22q11.2 deletion syndrome. But with TANGO2 disorder being autosomal recessive, will not occur in all cases.
Mutations in the TANGO2 gene may cause defects in mitochondrial β-oxidation and increased endoplasmic reticulum stress and a reduction in Golgi volume density.  These mutations results in early onset hypoglycemia, hyperammonemia, rhabdomyolysis, cardiac arrhythmias, and encephalopathy that later develops into cognitive impairment.

Parkinsons disease genes
22q11.2DS has been associated with a higher risk of early onset Parkinsons disease (PD). The neuropathology seen is similar to LRRK2-associated PD. None of the genes affected in individuals with 22q11.2DS have previously been linked to PD but there are a number that are likely candidates. These include DGCR8 which is important for biogenesis of brain microDNA, SRPT5 which encodes a protein that interacts with the PARK2 protein, COMT which is involved in regulating dopamine levels, and microRNA miR-185 which is thought to target known PD loci LRRK2.

Diagnosis
Diagnosis of DiGeorge syndrome can be difficult due to the number of potential symptoms and the variation in phenotypes between individuals. It is suspected in patients with one or more signs of the deletion. In these cases a diagnosis of 22q11.2DS is confirmed by observation of a deletion of part of the long arm (q) of chromosome 22, region 1, band 1, sub-band 2. Genetic analysis is normally performed using fluorescence in situ hybridization  (FISH), which is able to detect microdeletions that standard karyotyping (e.g. G-banding) miss. Newer methods of analysis include multiplex ligation-dependent probe amplification assay (MLPA) and quantitative polymerase chain reaction (qPCR), both of which can detect atypical deletions in 22q11.2 that are not detected by FISH. qPCR analysis is also quicker than FISH, which can have a turn around of 3 to 14 days.A 2008 study of a new high-definition MLPA probe developed to detect copy number variation at 37 points on chromosome 22q found it to be as reliable as FISH in detecting normal 22q11.2 deletions. It was also able to detect smaller atypical deletions that are easily missed using FISH. These factors, along with the lower expense and easier testing mean that this MLPA probe could replace FISH in clinical testing.Genetic testing using BACs-on-Beads has been successful in detecting deletions consistent with 22q11.2DS during prenatal testing. Array-comparative genomic hybridization (array-CGH) uses a large number of probes embossed in a chip to screen the entire genome for deletions or duplications. It can be used in post and pre-natal diagnosis of 22q11.2.Fewer than 5% of individuals with symptoms of DiGeorge syndrome have normal routine cytogenetic studies and negative FISH testing. In these cases, atypical deletions are the cause. Some cases of 22q11.2 deletion syndrome have defects in other chromosomes, notably a deletion in chromosome region 10p14.

Treatment
No cure is known for DiGeorge syndrome. Certain individual features are treatable using standard treatments. The key is to identify each of the associated features and manage each using the best available treatments.For example, in children, it is important that the immune problems are identified early, as special precautions are required regarding blood transfusion and immunization with live vaccines.  Thymus transplantation can be used to address absence of the thymus in the rare, so-called "complete" DiGeorge syndrome.  Bacterial infections are treated with antibiotics. Cardiac surgery is often required for congenital heart abnormalities. Hypoparathyroidism causing hypocalcaemia often requires lifelong vitamin D and calcium supplements. Specialty clinics that provide multi-system care allow for individuals with DiGeorge syndrome to be evaluated for all of their health needs and allow for careful monitoring of the patients. An example of this type of system is the 22q Deletion Clinic at SickKids Hospital in Toronto, Canada, which provides children with 22q11 deletion syndrome ongoing support, medical care and information from a team of health care workers.Metirosine (methyltyrosine) is used as an off-label treatment for DiGeorge syndrome.

Epidemiology
DiGeorge syndrome is estimated to affect between one in 2000 and one in 4000 live births. This estimate is based on major birth defects and may be an underestimate, because some individuals with the deletion have few symptoms and may not have been formally diagnosed.  It is one of the most common causes of intellectual disability due to a genetic deletion syndrome.The number of people affected has been expected to rise because of multiple reasons: (1) surgical and medical advances, an increasing number of people are surviving heart defects associated with the syndrome. These individuals are in turn having children. The chances of a person with DiGeorge syndrome having an affected child is 50% for each pregnancy; (2) Parents who have affected children, but who were unaware of their own genetic conditions, are now being diagnosed as genetic testing become available; (3) Molecular genetics techniques such as FISH (fluorescence in situ hybridization) have limitations and have not been able to detect all 22q11.2 deletions.  Newer technologies have been able to detect these atypical deletions.

Etymology
The signs and symptoms of DiGeorge syndrome are so varied that different groupings of its features were once regarded as separate conditions. These original classifications included velocardiofacial syndrome, Shprintzen syndrome, DiGeorge sequence/syndrome, Sedlackova syndrome, and conotruncal anomaly face syndrome. All are now understood to be presentations of a single syndrome.
ICD-10 2015 version mentions DiGeorge syndrome using two codes:  D82.1 (Di George syndrome) and Q93.81 (Velo-cardio-facial syndrome). The ICD-11 Beta Draft discusses the syndrome under “LD50.P1 CATCH 22 phenotype". However, since this syndrome is caused by the deletion of a small piece of chromosome 22, some recommend that the name "22q11.2 deletion syndrome (22q11.2DS)" be used. Some experts support changing the name of both DiGeorge and velocardiofacial syndromes to CATCH-22. The International 22q11.2 Foundation, through its "Same Name Campaign", advocates for the name 22q11.2 deletion syndrome.

See also
References
This article incorporates public domain text from The U.S. National Library of Medicine

External links

DiGeorge syndrome at Curlie
McDonald-McGinn DM, Emanuel BS, Zackai EH (December 16, 2005). "22q11.2 Deletion Syndrome".  In Pagon RA, Bird TD, Dolan CR, Stephens K (eds.) </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 Patellofemoral pain syndrome and can you explain it in depth? [/INST] Patellofemoral pain syndrome (PFPS; not to be confused with jumpers knee) is knee pain as a result of problems between the kneecap and the femur. The pain is generally in the front of the knee and comes on gradually. Pain may worsen with sitting, excessive use, or climbing and descending stairs.While the exact cause is unclear, it is believed to be due to overuse. Risk factors include trauma, increased training, and a weak quadriceps muscle. It is particularly common among runners. The diagnosis is generally based on the symptoms and examination. If pushing the kneecap into the femur increases the pain, the diagnosis is more likely.Treatment typically involves rest and rehabilitation with a Physical Therapist. Runners may need to switch to activities such as cycling or swimming. Insoles may help some people. Symptoms may last for years despite treatment. Patellofemoral pain syndrome is the most common cause of knee pain, affecting more than 20% of young adults. It occurs about 2.5 times more often in females than males.

Signs and symptoms
The onset of the condition is usually gradual, although some cases may appear suddenly following trauma. The most common symptom is diffuse vague pain around the kneecap (peripatellar) and localized pain focused behind the kneecap (retropatellar). Affected individuals typically have difficulty describing the location of the pain. They may place their hands over the anterior patella or describe a circle around the patella. This is often called the "circle sign". Pain is usually initiated when weight is put on the knee extensor mechanism, such as when ascending or descending stairs or slopes, squatting, kneeling, cycling, or running. Pain during prolonged sitting is sometimes termed the "movie sign" or "theatre sign" because individuals might experience pain while sitting to watch a film or similar activity. The pain is typically aching and occasionally sharp. Pain may be exacerbated by activities. The knee joint may exhibit noises such as clicking. However, this has no relation to pain and function. Giving-way of the knee may be reported. Reduced knee flexion may be experienced during activities.

Causes
In most patients with PFPS an examination of their history will highlight a precipitating event that caused the injury. Changes in activity patterns such as excessive increases in running mileage, repetitions such as running up steps and the addition of strength exercises that affect the patellofemoral joint are commonly associated with symptom onset. Excessively worn or poorly fitted footwear may be a contributing factor. To prevent recurrence the causal behaviour should be identified and managed correctly.The medical cause of PFPS is thought to be increased pressure on the patellofemoral joint. There are several theorized mechanisms relating to how this increased pressure occurs:

Increased levels of physical activity
Malalignment of the patella as it moves through the femoral groove
Quadriceps muscle imbalance
Tight anatomical structures, e.g. retinaculum or iliotibial band.Causes can also be a result of excessive genu valgum and the above-mentioned repetitive motions leading to abnormal lateral patellar tracking. Individuals with genu valgum have larger than normal Q-angles causing the weight-bearing line to fall lateral to the centre of the knee causing overstretching of the MCL and stressing the lateral meniscus and cartilages.The cause of pain and dysfunction often results from either abnormal forces (e.g. increased pull of the lateral quadriceps retinaculum with acute or chronic lateral PF subluxation/dislocation) or prolonged repetitive compressive or shearing forces (running or jumping) on the PF joint. The result is synovial irritation and inflammation and subchondral bony changes in the distal femur or patella known as "bone bruises". Secondary causes of PF Syndrome are fractures, internal knee derangement, osteoarthritis of the knee and bony tumors in or around the knee.

Diagnosis
Examination
People can be observed standing and walking to determine patellar alignment. The Q-angle, lateral hypermobility, and J-sign are commonly used determined to determine patellar maltracking. The patellofemoral glide, tilt, and grind tests (Clarkes sign), when performed, can provide strong evidence for PFPS. Lastly, lateral instability can be assessed via the patellar apprehension test, which is deemed positive when there is pain or discomfort associated with lateral translation of the patella. Various clinical tests have been investigated for diagnostic accuracy. The Active Instability Test, knee pain during stair climbing, Clarkes test, pain with prolonged sitting, patellar inferior pole tilt, and pain during squatting have demonstrated the best accuracy. However, careful consideration is still needed when using these tests to make a differential diagnosis of PFPS.
Individuals with PFP may be exhibit higher pain level and lower function.Magnetic resonance imaging rarely can give useful information for managing patellofemoral pain syndrome and treatment should focus on an appropriate rehabilitation program including correcting strength and flexibility concerns. In the uncommon cases where a patient has mechanical symptoms like a locked knee, knee effusion, or failure to improve following physical therapy, then an MRI may give more insight into diagnosis and treatment.

Classification
PFPS is one of a handful of conditions sometimes referred to as runners knee; the other conditions being chondromalacia patellae, iliotibial band syndrome, and plica syndrome.
Chondromalacia patellae is a term sometimes used synonymously with PFPS. However, there is general consensus that PFPS applies only to individuals without cartilage damage, thereby distinguishing it from chondromalacia patellae, a condition with softening of the patellar articular cartilage. Despite this distinction, the diagnosis of PFPS is typically made based only on the history and physical examination rather than on the results of any medical imaging. Therefore, it is unknown whether most persons with a diagnosis of PFPS have cartilage damage or not, making the difference between PFPS and chondromalacia theoretical rather than practical. It is thought that only some individuals with anterior knee pain will have true chondromalacia patellae.

Differential diagnosis
The diagnosis of patellofemoral pain syndrome is made by ruling out patellar tendinitis, prepatellar bursitis, plica syndrome, Sinding-Larsen and Johansson syndrome, and Osgood–Schlatter disease. Currently, there is not a gold standard assessment to diagnose PFPS.

Treatment
A variety of treatments for patellofemoral pain syndrome are available. Most people respond well to conservative therapy.

Exercises
Patellofemoral pain syndrome may also result from overuse or overload of the PF joint.  For this reason, knee activity should be reduced until the pain is resolved.There is consistent but low quality evidence that exercise therapy for PFPS reduces pain, improves function and aids long-term recovery. However, there is insufficient evidence to compare the effectiveness of different types of exercises with each other, and exercises with other forms of treatment.Exercise therapy is the recommended first line treatment of PFPS. Various exercises have been studied and recommended. Exercises are described according to 3 parameters:
Type of muscle activity (concentric, eccentric or isometric)
Type of joint movement (dynamic, isometric or static)
Reaction forces (closed or open kinetic chain)The majority of exercise programs intended to treat PFPS are designed to strengthen the quadriceps muscles. Quadriceps strengthening is considered to be the "gold" standard treatment for PFPS. Quadriceps strengthening is commonly suggested because the quadriceps muscles help to stabilize the patella. Quadriceps weakness and muscle imbalance may contribute to abnormal patellar tracking.If the strength of the vastus medialis muscle is inadequate, the usually larger and stronger vastus lateralis muscle will pull sideways (laterally) on the kneecap. Strengthening the vastus medialis to prevent or counter the lateral force of the vastus lateralis is one way of relieving PFPS. However, there is growing evidence that shows proximal factors play a much larger role than vastus medialis (VMO) strength deficits or quadriceps imbalance. Hip abductor, extensor, and external rotator strengthening may help.Emphasis during exercise may be placed on coordinated contraction of the medial and lateral parts of the quadriceps as well as of the hip adductor, hip abductor and gluteal muscles. Many exercise programs include stretches designed to improve lower limb flexibility. Electromyographic biofeedback allows visualization of specific muscle contractions and may help individuals performing the exercises to target the intended muscles during the exercise. Neuromuscular electrical stimulation to strengthen quadracep muscles is sometimes suggested, however the effectiveness of this treatment is not certain.Inflexibility has often been cited as a source of patellofemoral pain syndrome.  Stretching of the lateral knee has been suggested to help.Knee and lumbar joint mobilization are not recommended as primary interventions for PFPS. It can be used as combination intervention, but as we continue to promote use of active and physical interventions for PFPS, passive interventions such as joint mobilizations are not recommended.

Manual Therapy
Manual therapy in addition to exercises helps in reducing pain, improving function, and knee range of motion in patients with PFPS. Manual therapy such as patellar joint mobilization, manipulation and soft tissue mobilization along with Physical therapy exercises is found to be effective in treating PFPS. However, there is no enough evidence that supports lumbopelvic spine manipulation has any effect on the quadriceps muscle activation to improve function & reduce pain.

Medication
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat PFPS; however, there is only very limited evidence that they are effective. NSAIDs may reduce pain in the short term; overall, however, after three months pain is not improved. There is no evidence that one type of NSAID is superior to another in PFPS, and therefore some authors have recommended that the NSAID with fewest side effects and which is cheapest should be used.Glycosaminoglycan polysulfate (GAGPS) inhibits proteolytic enzymes and increases synthesis and degree of polymerization of hyaluronic acid in synovial fluid. There is contradictory evidence that it is effective in PFPS.

Braces and taping
There is no difference in pain symptoms between taping and non-taping in individuals with PFPS.  Although taping alone is not shown to reduce pain, studies show that taping in conjunction with therapeutic exercise can have a significant effect on pain reduction.Knee braces are ineffective in treating PFPS. The technique of McConnell taping involves pulling the patella medially with tape (medial glide). Findings from some studies suggest that there is limited benefit with patella taping or bracing when compared to quadriceps exercises alone. There is a lack of evidence to show that knee braces, sleeves, or straps are effective.

Insoles
Low arches can cause overpronation or the feet to roll inward too much increasing load on the patellofemoral joint.  Poor lower extremity biomechanics may cause stress on the knees and can be related to the development of patellofemoral pain syndrome, although the exact mechanism linking joint loading to the development of the condition is not clear. Foot orthoses can help to improve lower extremity biomechanics and may be used as a component of overall treatment. Foot orthoses may be useful for reducing knee pain in the short term, and may be combined with exercise programs or physical therapy. However, there is no evidence supporting use of combined exercise with foot orthoses as intervention beyond 12 months for adults </s>