<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 Multiple myeloma and can you explain it in depth? [/INST] Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, kidney dysfunction, and infections may occur. Complications may include amyloidosis.The cause of multiple myeloma is unknown. Risk factors include obesity, radiation exposure, family history, and certain chemicals. Multiple myeloma may develop from monoclonal gammopathy of undetermined significance that progresses to smoldering myeloma. The abnormal plasma cells produce abnormal antibodies, which can cause kidney problems and overly thick blood. The plasma cells can also form a mass in the bone marrow or soft tissue. When one tumor is present, it is called a plasmacytoma; more than one is called multiple myeloma. Multiple myeloma is diagnosed based on blood or urine tests finding abnormal antibodies, bone marrow biopsy finding cancerous plasma cells, and medical imaging finding bone lesions. Another common finding is high blood calcium levels.Multiple myeloma is considered treatable, but generally incurable. Remissions may be brought about with steroids, chemotherapy, targeted therapy, and stem cell transplant. Bisphosphonates and radiation therapy are sometimes used to reduce pain from bone lesions.Globally, multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015. In the United States, it develops in 6.5 per 100,000 people per year and 0.7% of people are affected at some point in their lives. It usually occurs around the age of 60 and is more common in men than women. It is uncommon before the age of 40. Without treatment,  the median survival in the prechemotherapy era was about 7 months. After the introduction of chemotherapy, prognosis improved significantly with a median survival of 24 to 30 months and a 10-year survival rate of 3%. Even further improvements in prognosis have occurred because of the introduction of newer biologic therapies and better salvage options, with median survivals now exceeding 60 to 90 months. With current treatments, survival is usually 4–5 years. The five-year survival rate is about 54%. The word myeloma is from the Greek myelo- meaning "marrow" and -oma meaning "tumor".

Signs and symptoms
Because many organs can be affected by myeloma, the symptoms and signs vary greatly.  Fatigue and bone pain are the most common symptoms at presentation. The CRAB criteria encompass the most common signs of multiple myeloma:: 651
Calcium: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >1.77 mol/L (>2 mg/dL)
Anemia: hemoglobin value of >2g/dL below the lowest limit of normal, or a hemoglobin value <10g/dL
Bone lesions: osteolytic lesions on skeletal radiography, CT, or PET/CT

Bone pain
Bone pain affects almost 70% of people with multiple myeloma and is one of the most common symptoms.: 653   Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent, localized pain may indicate a pathological bone fracture. Involvement of the vertebrae may lead to spinal cord compression or kyphosis. Myeloma bone disease is due to the overexpression of receptor activator for nuclear factor κ B ligand (RANKL) by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. The resultant bone lesions are lytic (cause breakdown) in nature, and are best seen in plain radiographs, which may show "punched-out" resorptive lesions (including the "raindrop" appearance of the skull on radiography). The breakdown of bone also leads to the release of calcium ions into the blood, leading to hypercalcemia and its associated symptoms.

Anemia
The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.

Impaired kidney function
Impaired kidney function may develop, either acutely or chronically, and with any degree of severity.
The most common cause of kidney failure in multiple myeloma is due to proteins secreted by the malignant cells.  Myeloma cells produce monoclonal proteins of varying types, most commonly immunoglobulins (antibodies) and free light chains, resulting in abnormally high levels of these proteins in the blood.  Depending on the size of these proteins, they may be excreted through the kidneys.  Kidneys can be damaged by the effects of proteins or light chains. Increased bone resorption leads to hypercalcemia and causes nephrocalcinosis, thereby contributing to kidney failure. Amyloidosis is a distant third in the causation.  People with amyloidosis have high levels of amyloid protein that can be excreted through the kidneys and cause damage to the kidneys and other organs.Light chains produce myriad effects that can manifest as the Fanconi syndrome (type II kidney tubular acidosis).

Infection
The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S. pneumoniae, S. aureus, and K. pneumoniae, while common pathogens causing pyelonephritis include E. coli and other Gram-negative organisms.  The greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy. The increased risk of infection is due to immune deficiency.  Although the total immunoglobulin level is typically elevated in multiple myeloma, the majority of the antibodies are ineffective monoclonal antibodies from the clonal plasma cell.  A selected group of people with documented hypogammaglobulinemia may benefit from replacement immunoglobulin therapy to reduce the risk of infection.

Neurological symptoms
Some symptoms (e.g., weakness, confusion, and fatigue) may be due to anemia or hypercalcemia. Headache, visual changes, and retinopathy may be the result of hyperviscosity  of the blood depending on the properties of the paraprotein. Finally, radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome, and other neuropathies (due to infiltration of peripheral nerves by amyloid) may occur. It may give rise to paraplegia in late-presenting cases.When the disease is well-controlled, neurological symptoms may result from current treatments, some of which may cause peripheral neuropathy, manifesting itself as numbness or pain in the hands, feet, and lower legs.

Mouth
The initial symptoms may involve pain, numbness, swelling, expansion of the jaw, tooth mobility, and radiolucency. Multiple myeloma in the mouth can mimic common teeth problems like periapical abscess or periodontal abscess, gingivitis, periodontitis, or other gingival enlargement or masses.

Cause
The cause of multiple myeloma is generally unknown.

Risk factors
Monoclonal gammopathy of undetermined significance (MGUS) increases the risk of developing multiple myeloma. MGUS transforms to multiple myeloma at the rate of 1% to 2% per year, and almost all cases of multiple myeloma are preceded by MGUS.
Smoldering multiple myeloma increases the risk of developing multiple myeloma. Individuals diagnosed with this premalignant disorder develop multiple myeloma at a rate of 10% per year for the first 5 years, 3% per year for the next 5 years, and then 1% per year.
Obesity is related to multiple myeloma with each increase of body mass index by five increasing the risk by 11%.Studies have reported a familial predisposition to myeloma. Hyperphosphorylation of a number of proteins—the paratarg proteins—a tendency that is inherited in an autosomal dominant manner, appears a common mechanism in these families. This tendency is more common in African-American with myeloma and may contribute to the higher rates of myeloma in this group.

Epstein–Barr virus
Rarely, Epstein–Barr virus (EBV) is associated with multiple myeloma, particularly in individuals who have an immunodeficiency due to e.g. HIV/AIDS, organ transplantation, or a chronic inflammatory condition such as rheumatoid arthritis. EBV-positive multiple myeloma is classified by the World Health Organization (2016) as one form of the Epstein–Barr virus-associated lymphoproliferative diseases and termed Epstein–Barr virus-associated plasma cell myeloma. EBV-positive disease is more common in the plasmacytoma rather than multiple myeloma form of plasma cell cancer. Tissues involved in EBV+ disease typically show foci of EBV+ cells with the appearance of rapidly proliferating immature or poorly differentiated plasma cells. The cells express products of EBV genes such as EBER1 and EBER2. While the EBV contributes to the development and/or progression of most Epstein–Barr virus-associated lymphoproliferatve diseases, its role in multiple myeloma is not known. However, people who are EBV-positive with localized plasmacytoma(s) are more likely to progress to multiple myeloma compared to people with EBV-negative plasmacytoma(s). This suggest that EBV may have a role in the progression of plasmacytomas to systemic multiple myeloma.

Pathophysiology
B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surfaces. When they are activated to secrete antibodies, they are known as plasma cells.
Multiple myeloma develops in B lymphocytes after they have left the part of the lymph node known as the germinal center. The normal cell type most closely associated with MM cells is generally taken to be either an activated memory B cell or the precursor to plasma cells, the plasmablast.The immune system keeps the proliferation of B cells and the secretion of antibodies under tight control. When chromosomes and genes are damaged, often through rearrangement, this control is lost. Often, a promoter gene moves (or translocates) to a chromosome, where it stimulates an antibody gene to overproduction.
A chromosomal translocation between the immunoglobulin heavy chain gene (on chromosome 14, locus q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11) is frequently observed in people with multiple myeloma.  This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma.  The result is a proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) chromosome 13 is also observed in about 50% of cases.
Production of cytokines (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the generation of new blood vessels) is increased.
The produced antibodies are deposited in various organs, leading to kidney failure, polyneuropathy, and various other myeloma-associated symptoms.

Epigenetics
In a study that investigated the DNA methylation profile of multiple myeloma cells and normal plasma cells, a gradual demethylation from stem cells to plasma cells was observed. The observed methylation pattern of CpG within intronic regions with enhancer-related chromatin marks in multiple myeloma is similar to undifferentiated precursor and stem cells. These results may represent a de novo epigenetic reprogramming in multiple myeloma, leading to the acquisition of a methylation pattern related to stemness. Other studies have identified a multiple myeloma specific gene silencing pattern associated with the polycomb repressive complex 2 (PRC2). Increased expression of the PRC2 subunit, EZH2 have been described to be a common feature in multiple myeloma, resulting in an accumulation and redistribution of histone H3 lysine 27 trimethylation which advances with disease severity.

Genetics
Chromosomal abnormalities commonly found in this disease, like trisomy of multiple odd-numbered chromosomes, t(11;14), and del(13q), are not associated with a worse prognosis. However, about 25% of patients with newly diagnosed disease have abnormalities associated with a worse prognosis, like t(4;14), t(14;16), and del(17p). Other less common abnormalities associated with a worse prognosis include t(14;20) and ≥4 copies of 1q.: 1730–1 Associated genetic mutations include ATM, BRAF, CCND1, DIS3, FAM46C, KRAS, NRAS and TP53.

Development
The genetic and epigenetic changes occur progressively. The initial change, often involving one chromosome 14 translocation, establishes a clone of bone marrow plasma cells that causes the asymptomatic disorder MGUS, which is a premalignant disorder characterized by increased numbers of plasma cells in the bone marrow or the circulation of a myeloma protein immunoglobulin. Further genetic or epigenic changes produce a new clone of bone marrow plasma cells, usually descendant from the original clone, that causes the more serious, but still asymptomatic premalignant disorder smoldering multiple myeloma. This myeloma is characterized by a rise in the number of bone marrow plasma cells or levels of the circulating myeloma protein above that seen in MGUS.
Subsequent genetic and epigenetic changes lead to a new, more aggressive clone of plasma cells, which cause further rises in the level of the circulating myeloma protein, further rises in the number of bone marrow plasma cells, or the development of one or more of a specific set of "CRAB" symptoms, which are the basis for diagnosing malignant multiple myeloma and treating the disease.
In a small percentage of multiple myeloma cases, further genetic and epigenetic changes lead to the development of a plasma cell clone that moves from the bone marrow into the circulatory system, invades distant tissues, and thereby causes the most malignant of all plasma cell dyscrasias, plasma cell leukemia. Thus, a fundamental genetic instability in plasma cells or their precursors leads to the progression:

Monoclonal gammopathy of undetermined significance → smoldering multiple myeloma → multiple myeloma → plasma cell leukemia

Being asymptomatic, monoclonal gammopathy of undetermined significance and smoldering multiple myeloma are typically diagnosed fortuitously by detecting a myeloma protein on serum protein electrophoresis tests done for other purposes. MGUS is a relatively stable condition afflicting 3% of people aged 50 and 5% of people aged 70; it progresses to multiple myeloma at a rate of 0.5–1% cases per year; smoldering multiple myeloma does so at a rate of 10% per year for the first 5 years, but then falls off sharply to 3% per year for the next 5 years and thereafter to 1% per year.Overall, some 2–4% of multiple myeloma cases eventually progress to plasma cell leukemia.

Diagnosis
Blood tests
The globulin level may be normal in established disease. A doctor may request protein electrophoresis of the blood and urine, which might show the presence of a paraprotein (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the Bence Jones protein, which is a urinary paraprotein composed of free light chains.  Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal immunoglobulin produced by the tumor clone.
In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains). People without evidence of a monoclonal protein may have "nonsecretory" myeloma (not producing immunoglobulins); this represents about 3% of all people with multiple myeloma.Additional findings may include a raised calcium level (when osteoclasts are breaking down bone, releasing it into the bloodstream), raised serum creatinine level due to reduced kidney function, which is mainly due to casts of paraprotein deposition in the kidney, although the cast may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin.Other useful laboratory tests include quantitative measurement of IgA, IgG, and IgM to look for immune paresis, and beta-2 microglobulin, which provides prognostic information.  On peripheral blood smear, the rouleaux formation of red blood cells is commonly seen, though this is not specific.
The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from MGUS to multiple myeloma.This assay, the serum free light chain assay, has recently been recommended by the International Myeloma Working Group for the screening, diagnosis, prognosis, and monitoring of plasma cell dyscrasias.

Histopathology
A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells that express immunoglobulin in the cytoplasm and occasionally on the cell surface; myeloma cells are often CD56, CD38, CD138, and CD319 positive and CD19, CD20, and CD45 negative. Flow cytometry is often used to establish the clonal nature of the plasma cells, which will generally express only kappa or lambda light chain. Cytogenetics may also be performed in myeloma for prognostic purposes, including a myeloma-specific fluorescent in situ hybridization and virtual karyotype.
The plasma cells seen in multiple myeloma have several possible morphologies. First, they could have the appearance of a normal plasma cell, a large cell two or three times the size of a peripheral lymphocyte. Because they are actively producing antibodies, the Golgi apparatus typically produces a light-colored area adjacent to the nucleus, called a perinuclear halo. The single nucleus (with inside a single nucleolus with vesicular nuclear chromatin) is eccentric, displaced by an abundant cytoplasm.
Other common morphologies seen, but which are not usual in normal plasma cells, include:

Bizarre cells, which are multinucleated
Mott cells, containing multiple clustered cytoplasmic droplets or other inclusions (sometimes confused with auer rods, commonly seen in myeloid blasts)
Flame cells, having a fiery red cytoplasmHistorically, the CD138 has been used to isolate myeloma cells for diagnostic purposes. However, this antigen disappears rapidly ex vivo. Recently, however,  the surface antigen CD319 (SLAMF7) was discovered to be considerably more stable and allows robust isolation of malignant plasma cells from delayed or even cryopreserved samples.The prognosis varies widely depending upon various risk factors. The Mayo Clinic has developed a risk-stratification model termed Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART), which divides people into high-risk and standard-risk categories. People with deletion of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), t(14;20) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or more) are considered to have high-risk myeloma.

Medical imaging
The diagnostic examination of a person with suspected multiple myeloma typically includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton, and proximal long bones. Myeloma activity sometimes appears as "lytic lesions" (with local disappearance of normal bone due to resorption). And on the skull X-ray as "punched-out lesions" (raindrop skull). Lesions may also be sclerotic, which is seen as radiodense. Overall, the radiodensity of myeloma is between −30 and 120 Hounsfield units (HU). Magnetic resonance imaging is more sensitive than simple X-rays in the detection of lytic lesions, and may supersede a skeletal survey, especially when vertebral disease is suspected.  Occasionally, a CT scan is performed to measure the size of soft-tissue plasmacytomas. Bone scans are typically not of any additional value in the workup of people with myeloma (no new bone formation; lytic lesions not well visualized on bone scan).

Diagnostic criteria
In 2003, the IMG agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma, and MGUS, which was subsequently updated in 2009:
Symptomatic myeloma (all three criteria must be met):
Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
A monoclonal protein (myeloma protein) in either serum or urine and it has to be more than 3g/dL (except in cases of true nonsecretory myeloma)
Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, CRAB):
HyperCalcemia (corrected calcium >2.75 mmol/L, >11 mg/dL)
Renal failure (kidney insufficiency) attributable to myeloma
Anemia (hemoglobin <10 g/dL)
Bone lesions (lytic lesions or osteoporosis with compression fractures)Note: Recurrent infections alone in a person who has none of the CRAB features is not sufficient to make the diagnosis of myeloma. People who lack CRAB features, but have evidence of amyloidosis, should be considered as amyloidosis and not myeloma. CRAB-like abnormalities are common with numerous diseases, and these abnormalities must be felt to be directly attributable to the related plasma cell disorder and every attempt made to rule out other underlying causes of anemia, kidney failure, etc.
In 2014, the IMWG updated their criteria further to include biomarkers of malignancy.  These biomarkers are >60% clonal plasma cells, a serum involved / uninvolved free light chain ratio ≥ 100 (the concentration of the involved free light chain must be ≥ 100 mg/L) and more than one focal lesion ≥ 5 mm by MRI.  Together, these biomarkers and the CRAB criteria are known as myeloma-defining events (MDEs).  A person must have >10 % clonal plasma cells and any MDE to be diagnosed with myeloma.  The biomarker criteria were added so that smouldering people with multiple myeloma at high risk of developing multiple myeloma could be diagnosed before organ damage occurred, so they would therefore have a better prognosis.
Asymptomatic/smoldering myeloma:
Serum M protein >30 g/L (3 g/dL) or
Clonal plasma cells >10% on bone marrow biopsy and
No myeloma-related organ or tissue impairment
Monoclonal gammopathy of undetermined significance (MGUS):
Serum paraprotein <30 g/L (3 g/dL) and
Clonal plasma cells <10% on bone marrow biopsy and
No myeloma-related organ or tissue impairment or a related B-cell lymphoproliferative disorderRelated conditions include solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (where only the antibodies produce symptoms, e.g., AL amyloidosis), and peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes.

Staging
In multiple myeloma, staging helps with prognostication but does not guide treatment decisions. The Durie-Salmon staging system was used historically and was replaced by the International Staging System (ISS), published by the International Myeloma Working Group In 2005. The revised ISS (R-ISS) was published in 2015 and incorporates cytogenetics and lactate dehydrogenase (LDH).: 1730–1 : 732–3
Stage I: β2 microglobulin (β2M) < 3.5 mg/L, albumin ≥ 3.5 g/dL, normal cytogenetics, no elevated LDH
Stage II: Not classified under Stage I or Stage III
Stage III: β2M ≥ 5.5 mg/L and either elevated LDH or high-risk cytogenetics [t(4,14), t(14,16), and/or del(17p)]

Prevention
The risk of multiple myeloma can be reduced slightly by maintaining a normal body weight.

Treatment
Treatment is indicated in myeloma with symptoms. If there are no symptoms, but a paraprotein typical of myeloma and diagnostic bone marrow is present without end-organ damage, treatment is usually deferred or restricted to clinical trials. Treatment for multiple myeloma is focused on decreasing the clonal plasma cell population and consequently decrease the symptoms of disease.

Chemotherapy
Initial
Initial treatment of multiple myeloma depends on the persons age and other illnesses present.
The preferred treatment for those under the age of 65 is high-dose chemotherapy, commonly with bortezomib-based regimens, and lenalidomide–dexamethasone, to be followed by a stem cell transplant. A 2016 study concluded that stem cell transplant is the preferred treatment of multiple myeloma. There are two types of stem cell transplants to treat multiple myeloma. In autologous hematopoietic stem-cell transplantation (ASCT) – the patients own stem cells are collected from the patients own blood. The patient is given high-dose chemotherapy, and the patients stem cells are then transplanted back into the patient. The process is not curative, but does prolong overall survival and complete remission. In allogeneic stem-cell transplantation, a healthy donors stem cells are transplanted into the affected person. Allogenic stem-cell transplantation has the potential for a cure, but is used in a very small percentage of people (and in the relapsed setting, not as part of initial treatment). Furthermore, a 5–10% treatment-associated mortality rate is associated with allogeneic stem-cell transplant.
People over age 65 and people with significant concurrent illnesses often cannot tolerate stem-cell transplantation.  For these people, the standard of care has been chemotherapy with melphalan and prednisone.  Recent studies among this population suggest improved outcomes with new chemotherapy regimens, e.g., with bortezomib. Treatment with bortezomib, melphalan, and prednisone had an estimated overall survival of 83% at 30 months, lenalidomide plus low-dose dexamethasone an 82% survival at 2 years, and melphalan, prednisone, and lenalidomide had a 90% survival at 2 years. Head-to-head studies comparing these regimens have not been performed as of 2008.There is support for continuous therapies with multiple drug combinations of antimyeloma drugs bortezomib, lenalidomide and thalidomide as initial treatment for transplant-ineligible multiple myeloma. Further clinical studies are required to determine the potential harms of these drugs and the effect on the persons quality of life. A 2009 review noted, "Deep venous thrombosis and pulmonary embolism are the major side effects of
thalidomide and lenalidomide. Lenalidomide causes more myelosuppression, and thalidomide causes more sedation. Chemotherapy-induced peripheral neuropathy and thrombocytopenia are major side effects of bortezomib."Treatment of related hyperviscosity syndrome may be required to prevent neurologic symptoms or kidney failure.

Maintenance
Most people, including those treated with ASCT, relapse after initial treatment. Maintenance therapy using a prolonged course of low-toxicity medications is often used to prevent relapse. A 2017 meta-analysis showed that post-ASCT maintenance therapy with lenalidomide improved progression-free survival and overall survival in people at standard risk. A 2012 clinical trial showed that people with intermediate- and high-risk disease benefit from a bortezomib-based maintenance regimen.

Relapse
Reasons for relapse include disease evolution, either from the selective pressure applied by treatment or by de novo mutations and/or if disease was inadequately represented in the initial biopsy. Relapse within the first 18 months of diagnosis is considered as functional high risk multiple myeloma. Depending on the persons condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include retreatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide, or dexamethasone, alone or in combination), and a second ASCT.
Later in the course of the disease, it becomes refractory (resistant) to formerly effective treatment.  This stage is referred to as relapsed/refractory multiple myeloma (RRMM). Treatment modalities that are commonly use to treat RRMM include dexamethasone, proteasome inhibitors (e.g. bortezomib and carfilzomib), immunomodulatory imide drugs (e.g. thalidomide, lenalidomide, and pomalidomide), and certain monoclonal antibodies (e.g. against CD38 and CD319). Survival expectancy has risen in recent years, and new treatments are under development.Kidney failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute kidney failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic kidney failure is dependent on the type of kidney failure and may involve dialysis.
Several newer options are approved for the management of advanced disease:

belantamab mafodotin — a monoclonal antibody against B-cell maturation antigen (BCMA), also known as CD269, indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
carfilzomib—a proteasome inhibitor that is indicated:
as a single agent in people who have received one or more lines of therapy
in combination with dexamethasone or with lenalidomide and dexamethasone in people who have received one to three lines of therapy
daratumumab—a monoclonal antibody against CD38 indicated in people who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent
elotuzumab—an immunostimulatory humanized monoclonal antibody against SLAMF7 (also known as CD319) indicated in combination with lenalidomide and dexamethasone in people who have received one to three prior therapies
isatuximab—a monoclonal antibody against CD38 indicated in combination with pomalidomide and dexamethasone for the treatment of adults with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
ixazomib—an orally available proteasome inhibitor indicated in combination with lenalidomide and dexamethasone in people who have received at least one prior therapy
panobinostat—an orally available histone deacetylase inhibitor used in combination with bortezomib and dexamethasone in people who have received at least two prior chemotherapy regimens, including bortezomib and an immunomodulatory agent
selinexor—an orally available selective inhibitor of nuclear export indicated in combination with dexamethasone in people who have received at least four prior therapies and whose disease does not respond to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody
idecabtagene vicleucel—first cell-based gene therapy was approved by FDA in 2021 for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies

Stem cell transplant
Stem cell transplant can be used to treat multiple myeloma. Stem cell transplants come with a risk of a graft-versus-host-disease. Mesenchymal stromal cells may reduce the all-cause mortality if they are used for a therapeutic reason and the therapeutic use of MSCs may increase the complete response of acute and chronic GvHD, but the evidence is very uncertain. The evidence suggests that MSCs for prophylactic reason result in little to no difference in the all-cause mortality, in the relapse of malignant diseases and in the incidence of acute GvHD. The evidence suggests that MSCs for prophylactic reason reduce the incidence of chronic GvHD.

Gene therapy
idecabtagene vicleucel (Abecma) – first cell-based gene therapy was approved by FDA in 2021 for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies
ciltacabtagene autoleucel (Carvykti) was approved for medical use in the United States in February  2022. Ciltacabtagene autoleucel is indicated for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Other measures
In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g., pamidronate or zoledronic acid) are routinely administered to prevent fractures; they have also been observed to have a direct antitumor effect even in people without known skeletal disease.  If needed, red blood cell transfusions or erythropoietin can be used for management of anemia.

Side effects
Chemotherapies and stem cell transplants can cause unwanted bleedings and may require platelet transfusions. It was seen that platelet transfusions for people undergoing a chemotherapy or a stem cell transplantation for the prevention of bleeding events had different effects on the number of participants with a bleeding event, the number of days on which a bleeding occurred, the mortality secondary to bleeding and the number of platelet transfusions depending on the way they were used (therapeutic, depending on a threshold, different dose schedules or prophylactic).

Supportive treatment
Adding physical exercises to the standard treatment for adult patients with haematological malignancies like multiple myeloma may result in little to no difference in the mortality, in the quality of life and in the 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 and serious adverse events

Palliative care
Multiple national cancer treatment guidelines recommend early palliative care for people with advanced multiple myeloma at the time of diagnosis and for anyone who has significant symptoms.Palliative care is appropriate at any stage of multiple myeloma and can be provided alongside curative treatment.  In addition to addressing symptoms of cancer, palliative care helps manage unwanted side effects, such as pain and nausea related to treatments.

Teeth
Oral prophylaxis, hygiene instruction and elimination of sources of infection within the mouth before beginning cancer treatment, can reduce the risk of infectious complications. Before starting bisphosphonates therapy, the persons dental health should be evaluated to assess the risk factors to prevent the development of medication-related osteonecrosis of the jaw (MRONJ). If there are any symptoms or radiographic appearance of MRONJ like jaw pain, loose tooth, mucosal swelling, early referral to an oral surgeon is recommended. Dental extractions should be avoided during the active period of treatment and treat the tooth with nonsurgical root canal treatment instead.

Prognosis
Overall the 5-year survival rate is around 54% in the United States. With high-dose therapy followed by ASCT, the median survival has been estimated in 2003 to be about 4.5 years, compared to a median around 3.5 years with "standard" therapy.The international staging system can help to predict survival, with a median survival (in 2005) of 62 months for stage-1 disease, 45 months for stage-2 disease, and 29 months for stage-3 disease. The median age at diagnosis is 69 years.

Genetic testing
SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel.

Epidemiology
Globally, multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015. This is up from 49,000 in 1990.

United States
In the United States in 2016, an estimated 30,330 new cases and 12,650 deaths were reported. These numbers are based on assumptions made using data from 2011, which estimated the number of people affected as 83,367 people, the number of new cases as 6.1 per 100,000 people per year, and the mortality as 3.4 per 100,000 people per year.
Multiple myeloma is the second-most prevalent blood cancer (10%) after non-Hodgkins lymphoma. It represents about 1.8% of all new cancers and 2.1% of all cancer deaths.Multiple myeloma affects slightly more men than women. African Americans and native Pacific Islanders have the highest reported number of new cases of this disease in the United States and Asians the lowest. Results of one study found the number of new cases of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top-10 causes of cancer death.

UK
Myeloma is the 17th-most common cancer in the UK: around 4,800 people were diagnosed with the disease in 2011. It is the 16th-most common cause of cancer death: around 2,700 people died of it in 2012.

Other animals
Multiple myeloma has been diagnosed in dogs, cats, and horses.In dogs, multiple myeloma accounts for around 8% of all haemopoietic tumors </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 Myocarditis and can you explain it in depth? [/INST] Myocarditis, also known as inflammatory cardiomyopathy, is an acquired cardiomyopathy due to inflammation of the heart muscle. Symptoms can include shortness of breath, chest pain, decreased ability to exercise, and an irregular heartbeat. The duration of problems can vary from hours to months. Complications may include heart failure due to dilated cardiomyopathy or cardiac arrest.Myocarditis is most often due to a viral infection. Other causes include bacterial infections, certain medications, toxins and autoimmune disorders. A diagnosis may be supported by an electrocardiogram (ECG), increased troponin, heart MRI, and occasionally a heart biopsy. An ultrasound of the heart is important to rule out other potential causes such as heart valve problems.Treatment depends on both the severity and the cause. Medications such as ACE inhibitors, beta blockers, and diuretics are often used. A period of no exercise is typically recommended during recovery. Corticosteroids or intravenous immunoglobulin (IVIG) may be useful in certain cases. In severe cases an implantable cardiac defibrillator or heart transplant may be recommended.In 2013, about 1.5 million cases of acute myocarditis occurred. While people of all ages are affected, the young are most often affected. It is slightly more common in males than females. Most cases are mild. In 2015 cardiomyopathy, including myocarditis, resulted in 354,000 deaths up from 294,000 in 1990. The initial descriptions of the condition are from the mid-1800s.

Signs and symptoms
The signs and symptoms associated with myocarditis are varied, and relate either to the actual inflammation of the myocardium or to the weakness and dysfunction of the heart muscle that is secondary to the inflammation. While myocarditis may develop over periods ranging from hours to months, patients typically present with signs and symptoms that resemble heart failure, including the following:
Since myocarditis is often due to a viral illness, many patients experience symptoms consistent with a recent viral infection including a fever, rash, loss of appetite, abdominal pain, vomiting, diarrhea, joint pains, and easily becoming tired. Additionally, myocarditis is often associated with pericarditis, and many people with myocarditis present with signs and symptoms that suggest myocarditis and pericarditis at the same time.Children primarily present with the aforementioned symptoms associated with a viral infection. Since they overlap with many other illnesses, this can make it more challenging to diagnose myocarditis in younger patients.  Later stages of the illness can involve the respiratory system and lead to increased work of breathing. These are often mistaken for asthma.Myocarditis can be distinguished as either fulminant or acute based on the severity of symptoms on presentation, as well as the time course over which symptoms develop and persist. This categorization can help predict the treatment, outcomes, and complications of myocarditis.
Fulminant myocarditis is defined as sudden and severe myocarditis that is associated with signs and symptoms of heart failure while at rest. More specifically, fulminant myocarditis is characterized by a distinct, rapid onset of severe heart failure symptoms, such as shortness of breath and chest pain, that develop over the course of hours to days. Additionally, treatment requires the use of medications or mechanical devices to improve heart function.Acute non-fulminant myocarditis has a less distinct onset in contrast to fulminant myocarditis, and evolves over days to months. While the symptoms of acute myocarditis overlap with those of fulminant myocarditis, they do not typically occur at rest, and treatment does not require the use of mechanical circulatory support.

Causes
While many causes of myocarditis are known, there are many cases in which a causative agent cannot be identified. In Europe and North America, viruses are common culprits. Worldwide, however, the most common cause is Chagas disease, an illness endemic to Central and South America that results from infection with the protozoan Trypanosoma cruzi. Overall, myocarditis can be caused by infections, immune conditions, toxins, drug reactions, and physical injuries to the heart. These different etiologies are detailed below. Myocarditis is a rare adverse side effect from mRNA COVID-19 vaccines.

Infections
The most common causes of myocarditis are infectious organisms. Viral infections are the most common cause in developed countries, with a majority of cases being caused by those with single-stranded RNA genetic information such as Coxsackie viruses (especially Coxsackie B3 and B5). Globally, Chagas disease is the leading cause of myocarditis, which results from infection with the protozoan Trypanosoma cruzi. Bacteria can also result in myocarditis, although it is rare in patients with normal heart function and without a preexisting immunodeficiency. A list of the most relevant infectious organisms is below.

Viral: adenovirus, parvovirus B19, coxsackie virus, rubella virus, polio virus, Epstein-Barr virus, hepatitis C virus, and severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2, causing COVID-19)
Protozoan: Trypanosoma cruzi and Toxoplasma gondii (causing Chagas disease and toxoplasmosis, respectively)
Bacterial: Brucella, Corynebacterium diphtheriae, Neisseria gonorrhoeae, Haemophilus influenzae, Actinomyces, Tropheryma whipplei, Vibrio cholerae, Borrelia burgdorferi, Leptospira, Rickettsia, Mycoplasma pneumoniae
Fungal: Aspergillus
Parasitic: Ascaris, Echinococcus granulosus, Paragonimus westermani, Schistosoma, Taenia solium, Trichinella spiralis, visceral larva migrans, Wuchereria bancrofti

Immune conditions
Allergic reaction (e.g., to acetazolamide or amitriptyline)
Kawasaki disease
Autoimmunity (scleroderma, lupus, sarcoidosis, and systemic vasculitides)
Toxic shock syndrome

Drug reactions and toxins
Anthracyclines and other forms of chemotherapy
Antipsychotics including clozapine
Alcohol
Stimulants such as mephedrone and cocaine
Arsenic
Carbon monoxide
Snake venom
Heavy metals (copper or iron)

Vaccination
Myocarditis and pericarditis can be a rare side effect of some vaccines like the smallpox vaccine.
Some COVID-19 vaccination doses carry a very small risk (33 per million overall) of causing myocarditis and pericarditis, more so in young men at repeated administration. According to a meta-analysis that does not differentiate between the two mRNA-vaccines BNT162b2 and mRNA-1273, the risk is less than that associated with COVID-19 itself. In adolescent males aged 16 to 17 years the crude reporting rate of myocarditis was 105.9 per million doses of the BNT162b2 vaccine.

Physical injuries
Electric shock
Hyperpyrexia, and radiation

Mechanism
Most forms of myocarditis involve the infiltration of heart tissues by one or two types of pro-inflammatory blood cells, lymphocytes and macrophages plus two respective descendants of these cells, NK cells and macrophages. Eosinophilic myocarditis is a subtype of myocarditis in which cardiac tissue is infiltrated by another type of pro-inflammatory blood cell, the eosinophil. Eosinophilic myocarditis is further distinguished from non-eosinophilic myocarditis by having a different set of causes and recommended treatments. Coxsackie B, specifically B3 and B5, has been found to interact with coxsackievirus-adenovirus receptor (CAR) and decay-accelerating factor (DAF). However, other proteins have also been identified that allow Coxsackieviruses to bind to cardiac cells. The natural function of CAR and mechanism that the Coxsackievirus uses to infect the cardiac muscle is still unknown. The mechanism by which coxsackie B viruses (CBVs) trigger inflammation is believed to be through the recognition of CBV virions by Toll-like receptors.The binding of the SARS-CoV-2 virus through ACE2 receptors present in heart tissue may be responsible for direct viral injury leading to myocarditis. In a study done during the SARS outbreak,  SARS virus RNA  was ascertained in the autopsy of heart specimens in 35% of the patients who died due to SARS. It was also observed that an already diseased heart has increased expression of ACE2 receptor contrasted to healthy individuals. Hyperactive immune responses in COVID-19 Patients may lead to the initiation of the cytokine storm. This excess release of cytokines may lead to myocardial injury.

Diagnosis
Myocarditis refers to an underlying process that causes inflammation and injury of the heart.  It does not refer to inflammation of the heart as a consequence of some other insult.  Many secondary causes, such as a heart attack, can lead to inflammation of the myocardium and therefore the diagnosis of myocarditis cannot be made by evidence of inflammation of the myocardium alone.Myocardial inflammation can be suspected on the basis of electrocardiographic (ECG) results, elevated C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR), and increased IgM (serology) against viruses known to affect the myocardium. Markers of myocardial damage (troponin or creatine kinase cardiac isoenzymes) are elevated.The ECG findings most commonly seen in myocarditis are diffuse T wave inversions; saddle-shaped ST-segment elevations may be present (these are also seen in pericarditis).The gold standard is the biopsy of the myocardium, in general done in the setting of angiography. A small tissue sample of the endocardium and myocardium is taken and investigated. The cause of the myocarditis can be only identified by a biopsy. Endomyocardial biopsy samples are assessed for histopathology (how the tissue looks like under the microscope): myocardial interstitium may show abundant edema and inflammatory infiltrate, rich in lymphocytes and macrophages. Focal destruction of myocytes explains the myocardial pump failure. In addition samples may be assessed with  immunohistochemistry to determine which types of immune cells are involved in the reaction and how they are distributed. Furthermore, PCR and/or RT-PCR may be performed to identify particular viruses. Finally, further diagnostic methods like microRNA assays and gene-expression profile may be performed.Cardiac magnetic resonance imaging (cMRI or CMR) has been shown to be very useful in diagnosing myocarditis by visualizing markers for inflammation of the myocardium. Consensus criteria for the diagnosis of myocarditis by CMR were published in 2009.

Treatment
While myocarditis has many etiologies and a variable constellation of signs and symptoms, there are few causes that are treatable and thus the main focus is on symptom management. In cases with biopsy-proven myocarditis, the causative cell type can indicate potentially beneficial treatments. These treatments typically consist of corticosteroids, or medications with known benefits in certain autoimmune and systemic conditions. In a majority of cases, the main therapies are used to support patients and are dependent on the severity of symptoms and the time course across which myocarditis develops. Supportive therapies can be divided into two broad categories, medications and mechanical support, since there has yet to be any demonstrated benefits from complementary therapies.

Medication
The specific medications that are used to support patients are directly related to the cause of the symptom or sign. Just as the symptoms of myocarditis mirror those of congestive heart failure, so too do the therapies. Additionally, the order in which  therapies are used depends on the degree of heart dysfunction, with stabilization of patient blood pressure and breathing taking highest priority when present. This can involve the use of inotropes, or medications that make the heart contract with greater force, as well as antiarrhythmic drugs such as adenosine or carvedilol. In patients that have stable and adequate heart function, further treatments are based on heart failure guidelines. ACE inhibitors can have a protective benefit to the heart, so they are typically used in any patient with symptomatic myocarditis. Simultaneously, beta blockers are used in patients that can tolerate their heart beating at a slower rate. Shortness of breath at rest and swelling can be relieved with diuretics such as furosemide, and the addition of aldosterone receptor blockers can augment the diuresis while preventing the excess loss of potassium. In patients with symptoms while resting, additional medications can be added such as digoxin.

Mechanical support
Mechanical support is used in cases of myocarditis in which medications alone do not lead to adequate heart function and the body requires additional support to achieve organ perfusion. Myocarditis cases that require mechanical circulatory support are categorized as fulminant by definition. People that require additional support with their heart function can benefit from the use of ventricular assist devices like intra-aortic balloon pumps. In people with myocarditis severe enough to cause cardiac arrest, extracorporeal membrane oxygenation (ECMO) is used to adequately pump blood and provide oxygen if needed. Both ventricular assist devices and ECMO can be used as bridge therapy until heart transplantation in patients that are candidates. Heart transplantation is reserved for those that do not respond to the aforementioned conventional medical therapies.

Prognosis
The prognosis associated with myocarditis is stratified by the severity and time course along which symptoms develop. In addition to symptom severity, there are also several indicators of heart function that can be used to predict patient outcomes, many of which are part of the standard evaluation of patients presenting with cardiovascular dysfunction.
An electrocardiogram is one of the most common screening tools used in cases of suspected cardiac pathology, such as myocarditis. The findings that correlate with poorer outcomes are non-specific and include widened QRS complexes and QT intervals, partial or complete atrial-ventricular heart block, and malignant ventricular arrhythmias like sustained ventricular tachycardia or ventricular fibrillation. Electrocardiogram findings of ST elevations with upward concavity and an early repolarization pattern, however, were associated with a better cardiovascular prognosis in general.In cases of acute myocarditis, cardiac magnetic resonance imaging can reveal several prognostic indicators that, similar to ECGs, are non-specific and reflect poorer cardiac physiology. Late gadolinium enhancement on cardiac MRI demonstrates perturbations in extracellular volume as a result of cell necrosis or edema, and is significantly associated with increases in all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events. The association was strongest with any late gadolinium enhancement, but remained true for findings of anterolateral-specific enhancement. A similar relationship was found between a left ventricular ejection fraction < 50%, increased mortality, and increased major adverse cardiovascular events.Myocarditis has been reported to be a major cause of sudden cardiac death (SCD) in infants, adolescents, and young adults, but the reported rates show wide variation (1 to 14 percent) among young people depending on differences in SCD definition and classification/ definition of myocarditis post-mortem as well as inhomogeneity in the study populations. And one has also to distinguish between studies about myocarditis in general and fulminant myocarditis.

Epidemiology
The exact incidence of myocarditis is unknown since many cases are not associated with any symptoms. However, in series of routine autopsies, 1–9% of all patients had evidence of myocardial inflammation.
The prevalence rate of myocarditis is estimated to be about 22 cases per 100,000 persons annually. Fulminant myocarditis, the most severe subtype, has been shown to occur in up to 2.5% of known myocarditis presentations. When looking at different causes of myocarditis, viral infection is the most prevalent, especially in children; however, the prevalence rate of myocarditis is often underestimated since the condition is easily overlooked. Viral myocarditis being an outcome of viral infection depends heavily on genetic host factors and the pathogenicity unique to the virus. If one tests positive for an acute viral infection, clinical developments have discovered that 1-5% of said population may show some form of myocarditis.In regard to the population affected, myocarditis is more common in pregnant women, children, and those who are immunocompromised </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 Lymphomatoid papulosis 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 Hyperhidrosis and can you explain it in depth? [/INST] Hyperhidrosis is a condition characterized by abnormally increased sweating, in excess of that required for regulation of body temperature. Although primarily a benign physical burden, hyperhidrosis can deteriorate quality of life from a psychological, emotional, and social perspective. This excess of sweat happens even if the person is not engaging in tasks that require muscular effort, and it does not depend on the exposure to heat. Common places to sweat can include underarms, face, neck, back, groin, feet, and hands. It has been called by some researchers the silent handicap.Both diaphoresis and hidrosis can mean either perspiration (in which sense they are synonymous with sweating) or excessive perspiration, in which case they refer to a specific, narrowly defined, clinical disorder.

Classification
Hyperhidrosis can either be generalized, or localized to specific parts of the body. Hands, feet, armpits, groin, and the facial area are among the most active regions of perspiration due to the high number of sweat glands (eccrine glands in particular) in these areas. When excessive sweating is localized (e.g. palms, soles, face, underarms, scalp) it is referred to as primary hyperhidrosis or focal hyperhidrosis. Excessive sweating involving the whole body is termed generalized hyperhidrosis or secondary hyperhidrosis.  It is usually the result of some other, underlying condition.
Primary or focal hyperhidrosis may be further divided by the area affected, for instance, palmoplantar hyperhidrosis (symptomatic sweating of only the hands or feet) or gustatory hyperhidrosis (sweating of the face or chest a few moments after eating certain foods).Hyperhidrosis can also be classified by onset, either congenital (present at birth) or acquired (beginning later in life). Primary or focal hyperhidrosis usually starts during adolescence or even earlier and seems to be inherited as an autosomal dominant genetic trait. It must be distinguished from secondary hyperhidrosis, which can start at any point in life. Secondary hyperhidrosis may be due to a disorder of the thyroid or pituitary glands, diabetes mellitus, tumors, gout, menopause, certain drugs, or mercury poisoning.One classification scheme uses the amount of skin affected. In this scheme, excessive sweating in an area of  100 square centimeters (16 square inches) or more is differentiated from sweating that affects only a small area.Another classification scheme is based on possible causes of hyperhidrosis.

Causes
The cause of primary hyperhidrosis is unknown. Anxiety or excitement can exacerbate the condition. A common complaint of patients is they get nervous because they sweat, then sweat more because they are nervous. Other factors can play a role, including certain foods and drinks, nicotine, caffeine, and smells.
Similarly, secondary (generalized) hyperhidrosis has many causes including certain types of cancer, disturbances of the endocrine system, infections, and medications.

Primary
Primary (focal) hyperhidrosis has many causes.

Idiopathic unilateral circumscribed hyperhidrosis
Reported association with:
Blue rubber bleb nevus
Glomus tumor
POEMS syndrome
Burning feet syndrome (Gopalans)
Trench foot
Causalgia
Pachydermoperiostosis
Pretibial myxedema
Gustatory sweating associated with:
Encephalitis
Syringomyelia
Diabetic neuropathies
Herpes zoster (shingles)
Parotitis
Parotid abscesses
Thoracic sympathectomy
Auriculotemporal or Freys syndrome
Miscellaneous
Lacrimal sweating (due to postganglionic sympathetic deficit, often seen in Raeders syndrome)
Harlequin syndrome
Emotional hyperhidrosis

Cancer
A variety of cancers have been associated with the development of secondary hyperhidrosis including lymphoma, pheochromocytoma, carcinoid tumors (resulting in carcinoid syndrome), and tumors within the thoracic cavity.

Endocrine
Certain endocrine conditions are also known to cause secondary hyperhidrosis including diabetes mellitus (especially when blood sugars are low), acromegaly, hyperpituitarism, pheochromocytoma (tumor of the adrenal glands, present in 71% of patients) and various forms of thyroid disease.

Medications
Use of selective serotonin reuptake inhibitors (e.g., sertraline) is a common cause of medication-induced secondary hyperhidrosis. Other medications associated with secondary hyperhidrosis include tricyclic antidepressants, stimulants, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), glyburide, insulin,  anxiolytic agents, adrenergic agonists, and cholinergic agonists.

Miscellaneous
In people with a history of spinal cord injuries
Autonomic dysreflexia
Orthostatic hypotension
Posttraumatic syringomyelia
Associated with peripheral neuropathies
Familial dysautonomia (Riley-Day syndrome)
Congenital autonomic dysfunction with universal pain loss
Exposure to cold, notably associated with cold-induced sweating syndrome
Associated with probable brain lesions
Episodic with hypothermia (Hines and Bannick syndrome)
Episodic without hypothermia
Olfactory
Associated with systemic medical problems
Parkinsons disease
Fibromyalgia
Congestive heart failure
Anxiety
Obesity
Menopausal state
Night sweats
Compensatory
Infantile acrodynia induced by chronic low-dose mercury exposure, leading to elevated catecholamine accumulation and resulting in a clinical picture resembling pheochromocytoma.
Febrile diseases
Vigorous exercise
A hot, humid environment

Diagnosis
Symmetry of excessive sweating in hyperhidrosis is most consistent with primary hyperhidrosis. To diagnose this condition, a dermatologist gives the patient a physical exam. This includes looking closely at the areas of the body that sweat excessively. A dermatologist also asks very specific questions. This helps the doctor understand why the patient has excessive sweating. Sometimes medical testing is necessary. Some patients require a test called the sweat test. This involves coating some of their skin with a powder that turns purple when the skin gets wet.
Excessive sweating affecting only one side of the body is more suggestive of secondary hyperhidrosis and further investigation for a neurologic cause is recommended.

Treatment
Antihydral cream is one of the solutions prescribed for hyperhidrosis for palms. Topical agents for hyperhidrosis therapy include formaldehyde lotion,  topical anticholinergics etc. These agents reduce perspiration by denaturing keratin, in turn occluding the pores of the sweat glands. They have a short-lasting effect.  Formaldehyde is classified as a probable human carcinogen. Contact sensitization is increased, especially with formalin. Aluminium chlorohydrate is used in regular antiperspirants. However, hyperhidrosis requires solutions or gels with a much higher concentration. These antiperspirant solutions or hyperhidrosis gels are especially effective for treatment of axillary or underarm regions. Normally it takes around three to five days to see improvement. The most common side-effect is skin irritation. For severe cases of plantar and palmar hyperhidrosis, there has been some success with conservative measures such as higher strength aluminium chloride antiperspirants. Treatment algorithms for hyperhidrosis recommend topical antiperspirants as the first line of therapy for hyperhidrosis. Both the International Hyperhidrosis Society and the Canadian Hyperhidrosis Advisory Committee have published treatment guidelines for focal hyperhidrosis that are said to be evidence-based.
Prescription medications called anticholinergics, often taken by mouth, are sometimes used in the treatment of both generalized and focal hyperhidrosis. Anticholinergics used for hyperhidrosis include propantheline, glycopyrronium bromide or glycopyrrolate, oxybutynin, methantheline, and benzatropine. Use of these drugs can be limited, however, by side-effects, including dry mouth, urinary retention, constipation, and visual disturbances such as mydriasis (dilation of the pupils) and cycloplegia. For people who find their hyperhidrosis is made worse by anxiety-provoking situations (public speaking, stage performances, special events such as weddings, etc.), taking an anticholinergic medicine before the event may be helpful.Several anticholinergic drugs can reduce hyperhidrosis. Oxybutynin (brand name Ditropan) is one that has shown promise,  although it can have side-effects, such as drowsiness, visual symptoms and dryness of the mouth and other mucous membranes. Glycopyrrolate is another drug sometimes used. It is said to be nearly as effective as oxybutynin, but has similar side-effects. In 2018, the U.S. Food and Drug Administration (FDA) approved a glycopyrronium bromide-containing disposable cloth (brand name Qbrexza) for the treatment of primary axillary hyperhidrosis.For peripheral hyperhidrosis, some chronic patients have found relief by simply ingesting crushed ice water. Ice water helps to cool excessive body heat during its transport through the blood vessels to the extremities, effectively lowering overall body temperature to normal levels within ten to thirty minutes.

Procedures
Injections of botulinum toxin type A can be used to block neural control of sweat glands. The effect can last from 3–9 months depending on the site of injections.  This use has been approved by the U.S. Food and Drug Administration (FDA). The duration of the beneficial effect in primary palmar hyperhidrosis has been found to increase with repetition of the injections. The Botox injections tend to be painful. Various measures have been tried to minimize the pain, one of which is the application of ice.
This was first demonstrated by Khalaf Bushara and colleagues as the first nonmuscular use of BTX-A in 1993. BTX-A has since been approved for the treatment of severe primary axillary hyperhidrosis (excessive underarm sweating of unknown cause), which cannot be managed by topical agents.A microwave-based device has been tried for excessive underarm perspiration and appears to show promise.Tap water iontophoresis as a treatment for palmoplantar hyperhidrosis was originally described in the 1950s. Studies showed positive results and good safety with tap water iontophoresis. One trial found it decreased sweating by about 80%.

Surgery
Sweat gland removal or destruction is one surgical option available for axillary hyperhidrosis (excessive underarm perspiration). There are multiple methods for sweat gland removal or destruction, such as sweat gland suction, retrodermal curettage, and axillary liposuction, Vaser, or Laser Sweat Ablation. Sweat gland suction is a technique adapted for liposuction.The other main surgical option is endoscopic thoracic sympathectomy (ETS), which cuts, burns, or clamps the thoracic ganglion on the main sympathetic chain that runs alongside the spine. Clamping is intended to permit the reversal of the procedure. ETS is generally considered a "safe, reproducible, and effective procedure and most patients are satisfied with the results of the surgery". Satisfaction rates above 80% have been reported, and are higher for children. The procedure brings relief from excessive hand sweating in about 85–95% of patients. ETS may be helpful in treating axillary hyperhidrosis, facial blushing and facial sweating, but failure rates in patients with facial blushing and/or excessive facial sweating are higher and such patients may be more likely to experience unwanted side effects.ETS side-effects have been described as ranging from trivial to devastating. The most common side-effect of ETS is compensatory sweating (sweating in different areas than prior to the surgery). Major problems with compensatory sweating are seen in 20–80% of patients undergoing the surgery. Most people find the compensatory sweating to be tolerable while 1–51% claim that their quality of life decreased as a result of compensatory sweating." Total body perspiration in response to heat has been reported to increase after sympathectomy. The original sweating problem may recur due to nerve regeneration, sometimes as early as 6 months after the procedure.Other possible side-effects include Horners Syndrome (about 1%), gustatory sweating (less than 25%) and excessive dryness of the palms (sandpaper hands). Some patients have experienced cardiac sympathetic denervation, which can result in a 10% decrease in heart rate both at rest and during exercise, resulting in decreased exercise tolerance.Percutaneous sympathectomy is a minimally invasive procedure similar to the botulinum method, in which nerves are blocked by an injection of phenol. The procedure provides temporary relief in most cases. Some physicians advocate trying this more conservative procedure before resorting to surgical sympathectomy, the effects of which are usually not reversible.

Prognosis
Hyperhidrosis can have physiological consequences such as cold and clammy hands, dehydration, and skin infections secondary to maceration of the skin. Hyperhidrosis can also have devastating emotional effects on ones individual life.Those with hyperhidrosis may have greater stress levels and more frequent depression.Excessive sweating or focal hyperhidrosis of the hands interferes with many routine activities, such as securely grasping objects </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 Entropion and can you explain it in depth? [/INST] Entropion is a medical condition in which the eyelid (usually the lower lid) folds inward. It is very uncomfortable, as the eyelashes continuously rub against the cornea causing irritation. Entropion is usually caused by genetic factors. This is different from when an extra fold of skin on the lower eyelid causes lashes to turn in towards the eye (epiblepharon). In epiblepharons, the eyelid margin itself is in the correct position, but the extra fold of skin causes the lashes to be misdirected. Entropion can also create secondary pain of the eye (leading to self trauma, scarring of the eyelid, or nerve damage).  The upper or lower eyelid can be involved, and one or both eyes may be affected. When entropion occurs in both eyes, this is known as "bilateral entropion". Repeated cases of trachoma infection may cause scarring of the inner eyelid, which may cause entropion. In human cases, this condition is most common to people over 60 years of age.

Symptoms
Symptoms of entropion include:

Redness and pain around the eye
Sensitivity to light and wind
Sagging skin around the eye
Eye watering
Decreased vision, especially if the cornea is damaged

Causes
Congenital
Aging creating loose skin and stretched and loose ligaments and muscles (senile entropion).
Scarring (mechanical entropion)
Spasm
An eye infection called trachoma is still common in North Africa and South Asia and this can cause scarring of the inner eyelid, which may cause friction and entropion.

Treatment
Treatment is a relatively simple surgery in which excess skin of the outer lids is removed or tendons and muscles are shortened with one or two stitches. General anesthesia is sometimes used before local anesthetics are injected into the muscles around the eye.  Prognosis is excellent if surgery is performed before the cornea is damaged.

Entropion in other species
Entropion has been documented in most dog breeds, although there are some breeds (particularly purebreds) that are more commonly affected than others.  These include the Akita, Pug, Chow Chow, Shar Pei, St. Bernard, Cocker Spaniel, Boxer, English Springer Spaniel, Welsh Springer Spaniel, Labrador Retriever, Cavalier King Charles Spaniel, Neapolitan Mastiff, Bull Mastiff, Great Dane, Irish Setter, Shiba Inu, Rottweiler, Poodle and particularly Bloodhound. The condition is usually present by six months of age </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 Canine degenerative myelopathy and can you explain it in depth? [/INST] Canine degenerative myelopathy, also known as chronic degenerative radiculomyelopathy, is an incurable, progressive disease of the canine spinal cord that is similar in many ways to amyotrophic lateral sclerosis (ALS). Onset is typically after the age of 7 years and it is seen most frequently in the German shepherd dog, Pembroke Welsh corgi, and boxer dog, though the disorder is strongly associated with a gene mutation in SOD1 that has been found in 43 breeds as of 2008, including the wire fox terrier, Chesapeake Bay retriever, Rhodesian ridgeback, and Cardigan Welsh corgi. Progressive weakness and incoordination of the rear limbs are often the first signs seen in affected dogs, with progression over time to complete paralysis. Myelin is an insulating sheath around neurons in the spinal cord.  One proposed cause of degenerative myelopathy is that the immune system attacks this sheath, breaking it down.  This results in a loss of communication between nerves in lower body of the animal and the brain.

Testing
The Orthopedic Foundation for Animals has a DNA saliva test to screen for the mutated gene that has been seen in dogs with degenerative myelopathy. Now that a test is available the disease can be bred out of breeds with a high preponderance. The test is only recommended for predisposed breeds, but can be performed on DNA from any dog on samples collected through swabbing the inside of the animals cheek with a sterile cotton swab or through venipuncture.
The test determines whether the mutated copy of SOD1 is present in the DNA sample submitted. It must be interpreted with caution by a veterinary clinician in combination with the animals clinical signs and other lab test results.
The results reported are:

Normal / Normal (N/N, or clear): The dog does not have the mutation and is extremely unlikely to develop degenerative myelopathy. There have been cases, however, in which dogs that tested clear were found to have DM upon necropsy.
Normal / Abnormal (N/A or carrier): The dog has one mutated copy of the gene (is heterozygous) and is a carrier but will not have degenerative myelopathy though there has now been some cases of heterozygous carriers developing DM. It will be possible for it to pass the mutation to offspring. A thorough examination of the dogs pedigree and DNA testing should be undertaken prior to breeding a dog with this result.
Abnormal / Abnormal (A/A or At Risk): The dog has two copies (is homozygous) for the mutation and is at risk for degenerative myelopathy.

Genetics
Breeding risks for degenerative myelopathy can be calculated using the Punnett Square:

If both parents are clear (N/N) then all of the puppies will be clear.
If one parent is a carrier (N/A) and one is clear (N/N) each puppy has a 50% chance of being clear and a 50% chance of being a carrier.
If both parents are carriers (N/A) each puppy has a 25% chance of being clear (N/N), 50% chance of being a carrier (N/A), and 25% chance of being affected and carrier (A/A)
If one parent is clear (N/N) and one parent is affected (A/A) then all puppies will be carriers (N/A)
If one parent is a carrier (N/A) and one is at risk (A/A) each puppy has a 50% chance of being a carrier(N/A) and 50% chance of being affected and carrier (A/A)
If both parents are at risk (A/A) then all puppies will be affected and carrier (A/A)

Symptoms
Degenerative myelopathy initially affects the back legs and causes muscle weakness and loss, and lack of coordination.  These cause a staggering affect that may appear to be arthritis. The dog may drag one or both rear paws when it walks. This dragging can cause the nails of one foot to be worn down.  The condition may lead to extensive paralysis of the back legs. As the disease progresses, the animal may display symptoms such as incontinence and has considerable difficulties with both balance and walking. If allowed to progress, the animal will show front limb involvement and extensive muscle atrophy and paralysis.  Eventually cranial nerve or respiratory muscle involvement necessitates euthanasia or long term palliative care.Progression of the disease is generally slow but highly variable. The animal could be crippled within a few months, or may survive as long as three years or more.

Causes
The etiology of this disease is unknown. Recent research has shown that a mutation in the SOD1 gene is a risk factor for developing degenerative myelopathy in several breeds. Mutations in SOD1 are also associated with familial amyotrophic lateral sclerosis (Lou Gehrigs disease) in people. More than 100 SOD1 gene mutations are involved in human familial amyotrophic lateral sclerosis (ALS), and the pathologic spinal lesions of ALS are similar to those of canine DM, making canine DM a potentially useful animal model of ALS.
Known causes of spinal cord dysfunction should be excluded before accepting the diagnosis of degenerative myelopathy;  disc disease (protrusions) or spinal cord tumors can cause compression of the spinal cord with similar signs to degenerative myelopathy.

Treatment
Degenerative myelopathy is an irreversible, progressive disease that cannot currently be cured. There are no treatments that have been clearly shown to stop or slow progression of DM.

Exercise
Exercise has been recommended to maintain the dogs ability to walk. Physiotherapy may prolong the length of time that the dog remains mobile and increase survival time. Canine hydrotherapy (swimming) may be more useful than walking. Use of a belly sling or hand-held harness allows the handler the ability to support the dogs hind legs for exercising or going up and down stairs. A 2-wheel dog cart, or "dog wheelchair" can allow the dog to remain active and maintain its quality of life once signs of weakness or paralysis of the hind limbs is detected.

Prognosis
The prognosis for the disease is generally poor. Aggressive therapy may be used to combat the disease, but even this puts the life expectancy at only around 14 months. It is recommended to put the dog to sleep at around 12 months, to prevent unnecessary suffering that comes from the disease. Some dogs have lived for many years with the disease, with one female boxer even living for 11 years. Without treatment, survival is around 3 months. The disease progresses rapidly without treatment, but this option arguably comes with less suffering. The dog begins to realize it is ill during the late stages </s>


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<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 Osteochondritis 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 Renal physiology and can you explain it in depth? [/INST] Renal physiology (Latin rēnēs, "kidneys") is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules;  regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.
Much of renal physiology is studied at the level of the nephron, the smallest functional unit of the kidney. Each nephron begins with a filtration component that filters the blood entering the kidney. This filtrate then flows along the length of the nephron, which is a tubular structure lined by a single layer of specialized cells and surrounded by capillaries. The major functions of these lining cells are the reabsorption of water and small molecules from the filtrate into the blood, and the secretion of wastes from the blood into the urine.
Proper function of the kidney requires that it receives and adequately filters blood. This is performed at the microscopic level by many hundreds of thousands of filtration units called renal corpuscles, each of which is composed of a glomerulus and a Bowmans capsule. A global assessment of renal function is often ascertained by estimating the rate of filtration, called the glomerular filtration rate (GFR).

Formation of urine
The kidneys ability to perform many of its functions depends on the three fundamental functions of filtration, reabsorption, and secretion, whose sum is called renal clearance or renal excretion.  That is:

Urinary excretion rate = Filtration rate – Reabsorption rate + Secretion rateAlthough the strictest sense of the word excretion with respect to the urinary system is urination itself, renal clearance is also conventionally called excretion (for example, in the set term fractional excretion of sodium).

Filtration
The blood is filtered by nephrons, the functional units of the kidney. Each nephron begins in a renal corpuscle, which is composed of a glomerulus enclosed in a Bowmans capsule. Cells, proteins, and other large molecules are filtered out of the glomerulus by a process of ultrafiltration, leaving an ultrafiltrate that resembles plasma (except that the ultrafiltrate has negligible plasma proteins) to enter Bowmans space. Filtration is driven by Starling forces.

The ultrafiltrate is passed through, in turn, the proximal convoluted tubule, the loop of Henle, the distal convoluted tubule, and a series of collecting ducts to form urine.

Reabsorption
Tubular reabsorption is the process by which solutes and water are removed from the tubular fluid and transported into the blood. It is called reabsorption (and not absorption) both because these substances have already been absorbed once (particularly in the intestines) and because the body is reclaiming them from a postglomerular fluid stream that is well on its way to becoming urine (that is, they will soon be lost to the urine unless they are reclaimed).
Reabsorption is a two-step process beginning with the active or passive extraction of substances from the tubule fluid into the renal interstitium (the connective tissue that surrounds the nephrons), and then the transport of these substances from the interstitium into the bloodstream. These transport processes are driven by Starling forces, diffusion, and active transport.

Indirect reabsorption
In some cases, reabsorption is indirect. For example, bicarbonate (HCO3−) does not have a transporter, so its reabsorption involves a series of reactions in the tubule lumen and tubular epithelium. It begins with the active secretion of a hydrogen ion (H+) into the tubule fluid via a Na/H exchanger:

In the lumen
The H+ combines with HCO3− to form carbonic acid (H2CO3)
Luminal carbonic anhydrase enzymatically converts H2CO3 into H2O and CO2
CO2 freely diffuses into the cell
In the epithelial cell
Cytoplasmic carbonic anhydrase converts the CO2 and H2O (which is abundant in the cell) into H2CO3
H2CO3 readily dissociates into H+ and HCO3−
HCO3− is facilitated out of the cells basolateral membrane

Influence of hormones
Some key regulatory hormones for reabsorption include:

aldosterone, which stimulates active sodium reabsorption (and water as a result)
antidiuretic hormone, which stimulates passive water reabsorptionBoth hormones exert their effects principally on the collecting ducts.
Tubular secretion occurs simultaneously during reabsorption of filtrate. Substances, generally produced by body or the by-products of cell metabolism that can become toxic in high concentration, and some drugs (if taken). These all are secreted into the lumen of renal tubule. Tubular secretion can be either active or passive or co-transport.
Substances mainly secreted into renal tubule are; H+, K+, NH3, urea, creatinine, histamine and drugs like penicillin.
Tubular secretion occurs at Proximal Convoluted Tubule (PCT) and Distal Convoluted Tubule (DCT); for example, at proximal convoluted tubule, potassium is secreted by means of sodium-potassium pump, hydrogen ion is secreted by means of active transport and co-transport, i.e. antiporter, and ammonia diffuses into renal tubule.

Other functions
Hormone secretion
The kidneys secrete a variety of hormones, including erythropoietin, calcitriol, and renin. Erythropoietin is released in response to hypoxia (low levels of oxygen at tissue level) in the renal circulation. It stimulates erythropoiesis (production of red blood cells) in the bone marrow. Calcitriol, the activated form of vitamin D, promotes intestinal absorption of calcium and the renal reabsorption of phosphate.  Renin is an enzyme which regulates angiotensin and aldosterone levels.

Maintaining homeostasis
The kidney is responsible for maintaining a balance of the following substances:

The body is very sensitive to its pH. Outside the range of pH that is compatible with life, proteins are denatured and digested, enzymes lose their ability to function, and the body is unable to sustain itself. The kidneys maintain acid-base homeostasis by regulating the pH of the blood plasma. Gains and losses of acid and base must be balanced. Acids are divided into "volatile acids" and "nonvolatile acids". See also titratable acid.
The major homeostatic control point for maintaining this stable balance is renal excretion.  The kidney is directed to excrete or retain sodium via the action of aldosterone, antidiuretic hormone (ADH, or vasopressin), atrial natriuretic peptide (ANP), and other hormones. Abnormal ranges of the fractional excretion of sodium can imply acute tubular necrosis or glomerular dysfunction.

Acid-base
Two organ systems, the kidneys and lungs, maintain acid-base homeostasis, which is the maintenance of pH around a relatively stable value. The lungs contribute to acid-base homeostasis by regulating carbon dioxide (CO2) concentration.  The kidneys have two very important roles in maintaining the acid-base balance: to reabsorb and regenerate bicarbonate from urine, and to excrete hydrogen ions and fixed acids (anions of acids) into urine.

Osmolality
The kidneys help maintain the water and salt level of the body. Any significant rise in plasma osmolality is detected by the hypothalamus, which communicates directly with the posterior pituitary gland. An increase in osmolality causes the gland to secrete antidiuretic hormone (ADH), resulting in water reabsorption by the kidney and an increase in urine concentration. The two factors work together to return the plasma osmolality to its normal levels.
ADH binds to principal cells in the collecting duct that translocate aquaporins to the membrane, allowing water to leave the normally impermeable membrane and be reabsorbed into the body by the vasa recta, thus increasing the plasma volume of the body.
There are two systems that create a hyperosmotic medulla and thus increase the body plasma volume: Urea recycling and the single effect.
Urea is usually excreted as a waste product from the kidneys. However, when plasma blood volume is low and ADH is released the aquaporins that are opened are also permeable to urea. This allows urea to leave the collecting duct into the medulla, creating a hyperosmotic solution that "attracts" water. Urea can then re-enter the nephron and be excreted or recycled again depending on whether ADH is still present or not.
The single effect describes the fact that the ascending thick limb of the loop of Henle is not permeable to water but is permeable to sodium chloride. This allows for a countercurrent exchange system whereby the medulla becomes increasingly concentrated, but at the same time setting up an osmotic gradient for water to follow should the aquaporins of the collecting duct be opened by ADH.

Blood pressure
Although the kidney cannot directly sense blood, long-term regulation of blood pressure predominantly depends upon the kidney. This primarily occurs through maintenance of the extracellular fluid compartment, the size of which depends on the plasma sodium concentration </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 Retained placenta and can you explain it in depth? [/INST] Retained placenta is a condition in which all or part of the placenta or membranes remain in the uterus during the third stage of labour. Retained placenta can be broadly divided into:

failed separation of the placenta from the uterine lining
placenta separated from the uterine lining but retained within the uterusA retained placenta is commonly a cause of postpartum haemorrhage, both primary and secondary.Retained placenta is generally defined as a placenta that has not undergone placental expulsion within 30 minutes of the baby’s birth where the third stage of labor has been managed actively.

Signs and symptoms
Risks of retained placenta include hemorrhage and infection </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 Viral pneumonia and can you explain it in depth? [/INST] Viral pneumonia is a pneumonia caused by a virus. Pneumonia is an infection that causes inflammation in one or both of the lungs. The pulmonary alveoli fill with fluid or pus making it difficult to breathe. Pneumonia can be caused by bacteria, viruses, fungi or parasites. Viruses are the most common cause of pneumonia in children, while in adults bacteria are a more common cause.

Signs and symptoms
Symptoms of viral pneumonia include fever, non-productive cough, runny nose, and systemic symptoms (e.g. myalgia, headache). Different viruses cause different symptoms.

Diagnosis
Diagnosis, like with any infection, relies on the detection of the infectious cause. With viral pneumonia, samples are taken from the upper and/or lower respiratory tracts. The samples can then be run through polymerase chain reaction (PCR), allowing for amplification of the virus as that allows better detection if present in the sample. Other ways for a diagnosis to be obtained is by ordering a chest x-ray, blood tests, pulse oximetry, and a medical/family history to see if there are any known risks or previous exposures to a person with viral pneumonia. If the person is in serious condition and in the hospital there are more invasive studies that can be run to diagnosis the person.

Cause
Common causes of viral pneumonia are:

Influenza virus A and B
Respiratory syncytial virus (RSV)
Human parainfluenza viruses (in children)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)Rarer viruses that commonly result in pneumonia include:

Adenoviruses (in military recruits)
Metapneumovirus
Severe acute respiratory syndrome coronavirus (SARS-CoV)
Middle East respiratory syndrome virus (MERS-CoV)
HantavirusesViruses that primarily cause other diseases, but sometimes cause pneumonia include:

Herpes simplex virus (HSV), mainly in newborns or young children
Varicella-zoster virus (VZV)
Measles virus
Rubella virus
Cytomegalovirus (CMV), mainly in people with immune system problems
Smallpox virus
Dengue virusThe most commonly identified agents in children are respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainfluenza viruses.

History
In the pre-antibiotic age, pneumonias had been treated with specific anti-serums of highly variable therapeutic effect and undesirable side-effects (a practice eliminated by the advent of sulfamides in 1936 and the beginning availability of penicillin in the 1940s).
Viral pneumonia was first described by Hobart Reimann in 1938, in an article published by JAMA, An Acute Infection of the Respiratory Tract with Atypical Pneumonia: a disease entity probably caused by a filtrable virus. Reimann, Chairman of the Department of Medicine at Jefferson Medical College, had established the practice of routinely typing the pneumococcal organism in cases where pneumonia presented. Out of this work, the distinction between viral and bacterial strains was noticed.

Pathophysiology
Viruses must invade cells in order to reproduce. Typically, a virus will reach the lungs by traveling in droplets through the mouth and nose with inhalation. There, the virus invades the cells lining the airways and the alveoli. This invasion often leads to cell death either through direct killing by the virus or by self-destruction through apoptosis.
Further damage to the lungs occurs when the immune system responds to the infection. White blood cells, in particular lymphocytes, are responsible for activating a variety of chemicals (cytokines) which cause leaking of fluid into the alveoli. The combination of cellular destruction and fluid-filled alveoli interrupts the transportation of oxygen into the bloodstream.
In addition to the effects on the lungs, many viruses affect other organs and can lead to illness affecting many different bodily functions. Some viruses also make the body more susceptible to bacterial infection; for this reason, bacterial pneumonia often complicates viral pneumonia.

Prevention
The best prevention against viral pneumonia is vaccination against influenza, chickenpox (varicella zoster), herpes zoster, measles, respiratory syncytial virus vaccine (RSV), rubella, and adenovirus vaccine.  Besides vaccination there are no other ways to prevent viral pneumonia besides basic hygiene skills like covering the mouth when coughing or sneezing, staying home when sick, and washing your hands frequently.

Treatment
In cases of viral pneumonia where influenza A or B are thought to be causative agents, patients who are seen within 48 hours of symptom onset may benefit from treatment with oseltamivir, or zanamivir, or peramivir.  Respiratory syncytial virus (RSV) has no direct acting treatments, but ribavirin is indicated for severe cases </s>


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