<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 Hyperkalemia and can you explain it in depth? [/INST] Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0 mmol/L (3.5 and 5.0 mEq/L) with levels above 5.5 mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasionally when severe it can cause palpitations, muscle pain, muscle weakness, or numbness. Hyperkalemia can cause an abnormal heart rhythm which can result in cardiac arrest and death.Common causes of hyperkalemia include kidney failure, hypoaldosteronism, and rhabdomyolysis. A number of medications can also cause high blood potassium including spironolactone, NSAIDs, and angiotensin converting enzyme inhibitors. The severity is divided into mild (5.5–5.9 mmol/L), moderate (6.0–6.4 mmol/L), and severe (>6.5 mmol/L). High levels can be detected on an electrocardiogram (ECG). Pseudohyperkalemia, due to breakdown of cells during or after taking the blood sample, should be ruled out.Initial treatment in those with ECG changes is salts, such as calcium gluconate or calcium chloride. Other medications used to rapidly reduce blood potassium levels include insulin with dextrose, salbutamol, and sodium bicarbonate. Medications that might worsen the condition should be stopped and a low potassium diet should be started. Measures to remove potassium from the body include diuretics such as furosemide, potassium-binders such as polystyrene sulfonate and sodium zirconium cyclosilicate, and hemodialysis. Hemodialysis is the most effective method.Hyperkalemia is rare among those who are otherwise healthy. Among those who are  hospitalized, rates are between 1% and 2.5%. It is associated with an increased mortality, whether due to hyperkalaemia itself or as a marker of severe illness, especially in those without chronic kidney disease. The word hyperkalemia comes from hyper- high + kalium potassium + -emia blood condition.

Signs and symptoms
The symptoms of an elevated potassium level are generally few and nonspecific. Nonspecific symptoms may include feeling tired, numbness  and weakness. Occasionally palpitations and shortness of breath may occur. Hyperventilation may indicate a compensatory response to metabolic acidosis, which is one of the possible causes of hyperkalemia. Often, however, the problem is detected during screening blood tests for a medical disorder, or after hospitalization for complications such as cardiac arrhythmia or sudden cardiac death. High levels of potassium (> 5.5 mmol/L) have been associated with cardiovascular events.

Causes
Ineffective elimination
Decreased kidney function is a major cause of hyperkalemia. This is especially pronounced in acute kidney injury where the glomerular filtration rate and tubular flow are markedly decreased, characterized by reduced urine output. This can lead to a dramatically elevated potassium in conditions of increased cell breakdown as the potassium is released from the cells and cannot be eliminated in the kidney. In chronic kidney disease, hyperkalemia occurs as a result of reduced aldosterone responsiveness and reduced sodium and water delivery in distal tubules.Medications that interfere with urinary excretion by inhibiting the renin–angiotensin system is one of the most common causes of hyperkalemia. Examples of medications that can cause hyperkalemia include ACE inhibitors, angiotensin receptor blockers, non-selective beta blockers, and calcineurin inhibitor immunosuppressants such as ciclosporin and tacrolimus. For potassium-sparing diuretics, such as amiloride and triamterene; both the drugs block epithelial sodium channels in the collecting tubules, thereby preventing potassium excretion into urine. Spironolactone acts by competitively inhibiting the action of aldosterone. NSAIDs such as ibuprofen, naproxen, or celecoxib inhibit prostaglandin synthesis, leading to reduced production of renin and aldosterone, causing potassium retention. The antibiotic trimethoprim and the antiparasitic medication pentamidine inhibits potassium excretion, which is similar to mechanism of action by amiloride and triamterene.Mineralocorticoid (aldosterone) deficiency or resistance can also cause hyperkalemia. Primary adrenal insufficiency are: Addisons disease and congenital adrenal hyperplasia (CAH) (including enzyme deficiencies such as 21α hydroxylase, 17α hydroxylase, 11β hydroxylase, or 3β dehydrogenase).
Type IV renal tubular acidosis (aldosterone resistance of the kidneys tubules)
Gordons syndrome (pseudohypoaldosteronism type II) ("familial hypertension with hyperkalemia"), a rare genetic disorder caused by defective modulators of salt transporters, including the thiazide-sensitive Na-Cl cotransporter.

Excessive release from cells
Metabolic acidosis can cause hyperkalemia as the elevated hydrogen ions in the cells can displace potassium, causing the potassium ions to leave the cell and enter the bloodstream. However, in respiratory acidosis or organic acidosis such as lactic acidosis, the effect on serum potassium are much less significant although the mechanisms are not completely understood.Insulin deficiency can cause hyperkalemia as the hormone insulin increases the uptake of potassium into the cells. Hyperglycemia can also contribute to hyperkalemia by causing hyperosmolality in extracellular fluid, increasing water diffusion out of the cells and causes potassium to move alongside water out of the cells also. The co-existence of insulin deficiency, hyperglycemia, and hyperosmolality is often seen in those affected by diabetic ketoacidosis. Apart from diabetic ketoacidosis, there are other causes that reduce insulin levels such as the use of the medication octreotide, and fasting which can also cause hyperkalemia. Increased tissue breakdown such as rhabdomyolysis, burns, or any cause of rapid tissue necrosis, including tumor lysis syndrome can cause the release of intracellular potassium into blood, causing hyperkalemia.Beta2-adrenergic agonists act on beta-2 receptors to drive potassium into the cells. Therefore, beta blockers can raise potassium levels by blocking beta-2 receptors. However, the rise in potassium levels is not marked unless there are other co-morbidities present. Examples of drugs that can raise the serum potassium are non-selective beta-blockers such as propranolol and labetalol. Beta-1 selective blockers such as metoprolol do not increase serum potassium levels.Exercise can cause a release of potassium into bloodstream by increasing the number of potassium channels in the cell membrane. The degree of potassium elevation varies with the degree of exercise, which range from 0.3 meq/L in light exercise to 2 meq/L in heavy exercise, with or without accompanying ECG changes or lactic acidosis. However, peak potassium levels can be reduced by prior physical conditioning and potassium levels are usually reversed several minutes after exercise. High levels of adrenaline and noradrenaline have a protective effect on the cardiac electrophysiology because they bind to beta 2 adrenergic receptors, which, when activated, extracellularly decrease potassium concentration.Hyperkalemic periodic paralysis is an autosomal dominant clinical condition where there is a mutation in gene located at 17q23 that regulates the production of protein SCN4A. SCN4A is an important component of sodium channels in skeletal muscles. During exercise, sodium channels would open to allow influx of sodium into the muscle cells for depolarization to occur. But in hyperkalemic periodic paralysis, sodium channels are slow to close after exercise, causing excessive influx of sodium and displacement of potassium out of the cells.Rare causes of hyperkalemia are discussed as follows. Acute digitalis overdose such as digoxin toxicity may cause hyperkalemia through the inhibition of sodium-potassium-ATPase pump. Massive blood transfusion can cause hyperkalemia in infants due to leakage of potassium out of the red blood cells during storage. Giving succinylcholine to people with conditions such as burns, trauma, infection, prolonged immobilisation can cause hyperkalemia due to widespread activation of acetylcholine receptors rather than a specific group of muscles. Arginine hydrochloride is used to treat refractory metabolic alkalosis. The arginine ions can enter cells and displace potassium out of the cells, causing hyperkalemia. Calcineurin inhibitors such as cyclosporine, tacrolimus, diazoxide, and minoxidil can cause hyperkalemia. Box jellyfish venom can also cause hyperkalemia.

Excessive intake
Excessive intake of potassium is not a primary cause of hyperkalemia because the human body usually can adapt to the rise in the potassium levels by increasing the excretion of potassium into urine through aldosterone hormone secretion and increasing the number of potassium secreting channels in kidney tubules. Acute hyperkalemia in infants is also rare even though their body volume is small, with accidental ingestion of potassium salts or potassium medications. Hyperkalemia usually develops when there are other co-morbidities such as hypoaldosteronism and chronic kidney disease.

Pseudohyperkalemia
Pseudohyperkalemia occurs when the measured potassium level is falsely elevated. This condition is usually suspected when the patient is clinically well without any ECG changes. Mechanical trauma during blood drawing can cause potassium leakage out of the red blood cells due to haemolysis of the blood sample. Repeated fist clenching during the blood draw can cause a transient rise in potassium levels. Prolonged length of blood storage can also increase serum potassium levels. Hyperkalemia may become apparent when a persons platelet concentration is more than 500,000/microL in a clotted blood sample (serum blood sample). Potassium leaks out of platelets after clotting has occurred. A high white cell count (greater than 120,000/microL) in people with chronic lymphocytic leukemia increases the fragility of red blood cells, thus causing pseudohyperkalemia during blood processing. This problem can be avoided by processing serum samples, because clot formation protects the cells from haemolysis during processing. A familial form of pseudohyperkalemia, a benign condition characterised by increased serum potassium in whole blood stored at cold temperatures, also exists. This is due to increased potassium permeability in red blood cells.

Mechanism
Physiology
Potassium is the most abundant intracellular cation and about 98% of the bodys potassium is found inside cells, with the remainder in the extracellular fluid including the blood. Membrane potential is maintained principally by the concentration gradient and membrane permeability to potassium with some contribution from the Na+/K+ pump. The potassium gradient is critically important for many physiological processes, including maintenance of cellular membrane potential, homeostasis of cell volume, and transmission of action potentials in nerve cells.Potassium is eliminated from the body through the gastrointestinal tract, kidney and sweat glands. In the kidneys, elimination of potassium is passive (through the glomeruli), and reabsorption is active in the proximal tubule and the ascending limb of the loop of Henle. There is active excretion of potassium in the distal tubule and the collecting duct; both are controlled by aldosterone. In sweat glands potassium elimination is quite similar to the kidney, its excretion is also controlled by aldosterone.Regulation of serum potassium is a function of intake, appropriate distribution between intracellular and extracellular compartments, and effective bodily excretion. In healthy individuals, homeostasis is maintained when cellular uptake and kidney excretion naturally counterbalance a patients dietary intake of potassium. When kidney function becomes compromised, the ability of the body to effectively regulate serum potassium via the kidney declines. To compensate for this deficit in function, the colon increases its potassium secretion as part of an adaptive response. However, serum potassium remains elevated as the colonic compensating mechanism reaches its limits.

Elevated potassium
Hyperkalemia develops when there is excess production (oral intake, tissue breakdown) or ineffective elimination of potassium. Ineffective elimination can be hormonal (in aldosterone deficiency) or due to causes in the kidney that impair excretion.Increased extracellular potassium levels result in depolarization of the membrane potentials of cells due to the increase in the equilibrium potential of potassium. This depolarization opens some voltage-gated sodium channels, but also increases the inactivation at the same time. Since depolarization due to concentration change is slow, it never generates an action potential by itself; instead, it results in accommodation. Above a certain level of potassium the depolarization inactivates sodium channels, opens potassium channels, thus the cells become refractory. This leads to the impairment of neuromuscular, cardiac, and gastrointestinal organ systems. Of most concern is the impairment of cardiac conduction, which can cause ventricular fibrillation and/or abnormally slow heart rhythms.

Diagnosis
To gather enough information for diagnosis, the measurement of potassium must be repeated, as the elevation can be due to hemolysis in the first sample. The normal serum level of potassium is 3.5 to 5 mmol/L. Generally, blood tests for kidney function (creatinine, blood urea nitrogen), glucose and occasionally creatine kinase and cortisol are performed. Calculating the trans-tubular potassium gradient can sometimes help in distinguishing the cause of the hyperkalemia.Also, electrocardiography (ECG) may be performed to determine if there is a significant risk of abnormal heart rhythms. Physicians taking a medical history may focus on kidney disease and medication use (e.g. potassium-sparing diuretics), both of which are known causes of hyperkalemia.

Definitions
Normal serum potassium levels are generally considered to be between 3.5 and 5.3 mmol/L. Levels above 5.5 mmol/L generally indicate hyperkalemia, and those below 3.5 mmol/L indicate hypokalemia.

ECG findings
With mild to moderate hyperkalemia, there is prolongation of the PR interval and development of peaked T waves. Severe hyperkalemia results in a widening of the QRS complex, and the ECG complex can evolve to a sinusoidal shape. There appears to be a direct effect of elevated potassium on some of the potassium channels that increases their activity and speeds membrane repolarisation. Also, (as noted above), hyperkalemia causes an overall membrane depolarization that inactivates many sodium channels. The faster repolarisation of the cardiac action potential causes the tenting of the T waves, and the inactivation of sodium channels causes a sluggish conduction of the electrical wave around the heart, which leads to smaller P waves and widening of the QRS complex. Some of potassium currents are sensitive to extracellular potassium levels, for reasons that are not well understood. As the extracellular potassium levels increase, potassium conductance is increased so that more potassium leaves the myocyte in any given time period. To summarize, classic ECG changes associated with hyperkalemia are seen in the following progression: peaked T wave, shortened QT interval, lengthened PR interval, increased QRS duration, and eventually absence of the P wave with the QRS complex becoming a sine wave.  Bradycardia, junctional rhythms and QRS widening are particularly associated with increased risk of adverse outcomesThe serum potassium concentration at which electrocardiographic changes develop is somewhat variable. Although the factors influencing the effect of serum potassium levels on cardiac electrophysiology are not entirely understood, the concentrations of other electrolytes, as well as levels of catecholamines, play a major role.ECG findings are not a reliable finding in hyperkalemia. In a retrospective review, blinded cardiologists documented peaked T-waves in only 3 of 90 ECGs with hyperkalemia. Sensitivity of peaked-Ts for hyperkalemia ranged from 0.18 to 0.52 depending on the criteria for peak-T waves.

Prevention
Preventing recurrence of hyperkalemia typically involves reduction of dietary potassium, removal of an offending medication, and/or the addition of a diuretic (such as furosemide or hydrochlorothiazide). Sodium polystyrene sulfonate and sorbitol (combined as Kayexalate) are occasionally used on an ongoing basis to maintain lower serum levels of potassium though the safety of long-term use of sodium polystyrene sulfonate for this purpose is not well understood.High dietary sources include vegetables such as avocados, tomatoes and potatoes, fruits such as bananas, oranges and nuts.

Treatment
Emergency lowering of potassium levels is needed when new arrhythmias occur at any level of potassium in the blood, or when potassium levels exceed 6.5 mmol/L. Several agents are used to temporarily lower K+ levels. The choice depends on the degree and cause of the hyperkalemia, and other aspects of the persons condition.

Myocardial excitability
Calcium (calcium chloride or calcium gluconate) increases threshold potential through a mechanism that is still unclear, thus restoring normal gradient between threshold potential and resting membrane potential, which is elevated abnormally in hyperkalemia. A standard ampule of 10% calcium chloride is 10 mL and contains 6.8 mmol of calcium. A standard ampule of 10% calcium gluconate is also 10 mL but has only 2.26 mmol of calcium. Clinical practice guidelines recommend giving 6.8 mmol for typical EKG findings of hyperkalemia. This is 10 mL of 10% calcium chloride or 30 mL of 10% calcium gluconate. Though calcium chloride is more concentrated, it is caustic to the veins and should only be given through a central line. Onset of action is less than one to three minutes and lasts about 30–60 minutes. The goal of treatment is to normalise the EKG and doses can be repeated if the EKG does not improve within a few minutes.Some textbooks suggest that calcium should not be given in digoxin toxicity as it has been linked to cardiovascular collapse in humans and increased digoxin toxicity in animal models. Recent literature questions the validity of this concern.

Temporary measures
Several medical treatments shift potassium ions from the bloodstream into the cellular compartment, thereby reducing the risk of complications. The effect of these measures tends to be short-lived, but may temporise the problem until potassium can be removed from the body.
Insulin (e.g. intravenous injection of 10 units of regular insulin along with 50 mL of 50% dextrose to prevent the blood sugar from dropping too low) leads to a shift of potassium ions into cells, secondary to increased activity of the sodium-potassium ATPase. Its effects last a few hours, so it sometimes must be repeated while other measures are taken to suppress potassium levels more permanently. The insulin is usually given with an appropriate amount of glucose to help prevent hypoglycemia following the insulin administration, though hypoglycaemia remains common especially in the context of acute or chronic renal impairment and capillary blood glucose measurements should be taken regularly after administration to identify this.
Salbutamol (albuterol), a β2-selective catecholamine, is administered by nebuliser (e.g. 10–20 mg). This medication also lowers blood levels of K+ by promoting its movement into cells, and will work within 30 minutes. It is recommended to use 20 mg for maximum potassium lowering effect, but to use lower doses if the patient is tachycardic or has ischaemic heart disease.  Note that 12-40% of patients do not respond to salbutamol therapy for reasons unknown, especially if on beta-blockers, so it should not be used as monotherapy
Sodium bicarbonate may be used with the above measures if it is believed the person has metabolic acidosis, though time to effectiveness is longer and its use is controversial.

Elimination
Severe cases require hemodialysis, which are the most rapid methods of removing potassium from the body. These are typically used if the underlying cause cannot be corrected swiftly while temporising measures are instituted or there is no response to these measures.
Loop diuretics (furosemide, bumetanide, torasemide) and thiazide diuretics (e.g., chlortalidone, hydrochlorothiazide, or chlorothiazide) can increase kidney potassium excretion in people with intact kidney function.Potassium can bind to a number of agents in the gastrointestinal tract </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 Hairy cell leukemia and can you explain it in depth? [/INST] Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes.  It is usually classified as a subtype of chronic lymphocytic leukemia (CLL). Hairy cell leukemia makes up about 2% of all leukemias, with fewer than 2,000 new cases diagnosed annually in North America and Western Europe combined.
Hairy cell leukemia (HCL) was originally described as histiocytic leukemia, malignant reticulosis, or lymphoid myelofibrosis in publications dating back to the 1920s. The disease was formally named leukemic reticuloendotheliosis, and its characterization was significantly advanced by Bertha Bouroncle and colleagues at the Ohio State University College of Medicine in 1958.  Its common name, which was coined in 1966, is derived from the "hairy" appearance of the malignant B cells under a microscope.

Signs and symptoms
In HCL, the "hairy cells" (malignant B lymphocytes) accumulate in the bone marrow, interfering with the production of normal white blood cells, red blood cells, and platelets.  Consequently, patients may develop infections related to low white blood cell count, anemia and fatigue due to a lack of red blood cells, or easy bleeding due to a low platelet count. Leukemic cells may gather in the spleen and cause it to swell; this can have the side effect of making the person feel full even when he or she has not eaten much.Hairy cell leukemia is commonly diagnosed after a routine blood count shows unexpectedly low numbers of one or more kinds of normal blood cells, or after unexplained bruises or recurrent infections in an otherwise apparently healthy patient.Platelet function may be somewhat impaired in HCL patients, although this does not appear to have any significant practical effect.  It may result in somewhat more mild bruises than would otherwise be expected for a given platelet count or a mildly increased bleeding time for a minor cut, likely the result of producing slightly abnormal platelets in the overstressed bone marrow tissue.
Patients with a high tumor burden may also have somewhat reduced levels of cholesterol, especially in patients with an enlarged spleen.  Cholesterol levels return to more normal values with successful treatment of HCL.

Cause
As with many cancers, the cause of HCL is unknown. Exposure to tobacco smoke, ionizing radiation, or industrial chemicals (with the possible exception of diesel) does not appear to increase the risk of developing it.  Farming and gardening correlate with an increased risk of HCL development in some studies which does not necessarily imply causation.A 2011 study identified somatic BRAF V600E mutations in all 47 HCL patients studied, and no such mutations in the 193 peripheral B-cell lymphomas/leukemias other than HCL.The U.S. Institute of Medicine (IOM) found a correlation which permits an association between exposure to herbicides and later development of chronic B-cell leukemias and lymphomas in general. The IOM report emphasizes that neither animal nor human studies indicate an association of herbicides with HCL specifically. However, the IOM extrapolated data from chronic lymphocytic leukemia and non-Hodgkin lymphoma to conclude that HCL and other rare B-cell neoplasms may share this risk factor. As a result of the IOM report, the U.S. Department of Veterans Affairs considers HCL an illness presumed to be a service-related disabilityHuman T-lymphotropic virus 2 (HTLV-2) has been isolated in a small number of patients with the variant form of HCL. In the 1980s, HTLV-2 was identified in a patient with a T-cell lymphoproliferative disease; this patient later developed HCL, but HTLV-2 was not found in the hairy cell clones.  There is no evidence that HTLV-II causes any sort of hematological malignancy, including HCL.

Pathophysiology
Pancytopenia in HCL is caused primarily by marrow failure and splenomegaly.  Bone-marrow failure is caused by the accumulation of hairy cells and reticulin fibrosis in the bone marrow, as well as by the detrimental effects of dysregulated cytokine production.  Splenomegaly reduces blood counts through sequestration, marginalization, and destruction of healthy blood cells inside the spleen.Hairy cells are nearly mature B cells, which are activated clonal cells with signs of VH gene differentiation.  They may be related to pre-plasma marginal zone B cells or memory cells.
Cytokine production is disturbed in HCL.  Hairy cells produce and thrive on TNF-alpha.  This cytokine also suppresses normal production of healthy blood cells in the bone marrow.Unlike healthy B cells, hairy cells express and secrete an immune system protein called interleukin-2 receptor (IL-2R).  In HCL-V, only part of this receptor is expressed. As a result, disease status can be monitored by measuring changes in the amount of IL-2R in the blood serum.  The level increases as hairy cells proliferate, and decreases when they are killed.  Although uncommonly used in North America and Northern Europe, this test correlates better with disease status and predicts relapse more accurately than any other test.
Hairy cells respond to normal production of some cytokines by T cells with increased growth.  Treatment with interferon-alpha suppresses the production of this pro-growth cytokine from T cells.  A low level of T cells, which is commonly seen after treatment with cladribine or pentostatin, and the consequent reduction of these cytokines, is also associated with reduced levels of hairy cells.
In June 2011, E Tiacci et al discovered that 100% of HCL samples analysed had the oncogenic BRAF mutation V600E, and proposed that this is the diseases driver mutation. Until this point, only a few genomic imbalances had been found in the hairy cells, such as trisomy 5 had been found. The expression of genes is also dysregulated in a complex and specific pattern.  The cells underexpress 3p24, 3p21, 3q13.3-q22, 4p16, 11q23, 14q22-q24, 15q21-q22, 15q24-q25, and 17q22-q24 and overexpress 13q31 and Xq13.3-q21.  It has not yet been demonstrated that any of these changes have any practical significance to the patient.

Diagnosis
The diagnosis of HCL may be suggested by abnormal results on a complete blood count (CBC), but additional testing is necessary to confirm the diagnosis. A CBC normally shows low counts for white blood cells, red blood cells, and platelets in HCL patients.  However, if large numbers of hairy cells are in the blood stream, then normal or even high lymphocyte counts may be found.
On physical examination, 80–90% of patients have an enlarged spleen, which can be massive.  This is less likely among patients who are diagnosed at an early stage.  Peripheral lymphadenopathy (enlarged lymph nodes) is uncommon (less than 5% of patients), but abdominal lymphadenopathy is a relatively common finding on computed tomography scans.

The most important laboratory finding is the presence of hairy cells in the bloodstream.  Hairy cells are abnormal white blood cells with hair-like projections of cytoplasm; they can be seen by examining a blood smear or bone marrow biopsy specimen.  The blood film examination is done by staining the blood cells with Wrights stain and looking at them under a microscope.  Hairy cells are visible in this test in about 85% of cases.Most patients require a bone-marrow biopsy for final diagnosis.  The bone marrow biopsy is used both to confirm the presence of HCL and also the absence of any additional diseases, such as Splenic marginal zone lymphoma or B-cell prolymphocytic leukemia.  The diagnosis can be confirmed by viewing the cells with a special stain known as TRAP (tartrate resistant acid phosphatase). More recently, DB44 testing assures more accurate results.
Definitively diagnosing HCL is also possible through flow cytometry on blood or bone marrow.  The hairy cells are larger than normal and positive for CD19, CD20, CD22, CD11c, CD25, CD103, and FMC7 antigens. (CD103, CD22, and CD11c are strongly expressed.)Hairy cell leukemia-variant (HCL-V), which shares some characteristics with B cell prolymphocytic leukemia (B-PLL), does not show CD25 (also called the interleukin-2 receptor, alpha).
The differential diagnoses include several kinds of anemia, including myelophthisis and aplastic anemia, and most kinds of blood neoplasms, including hypoplastic myelodysplastic syndrome, atypical chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, or idiopathic myelofibrosis.

Classification
When not further specified, the "classic" form is often implied, but two variants have been described:  Hairy cell leukemia-variant and a Japanese variant. The non-Japanese variant is more difficult to treat than either classic HCL or the Japanese HCL.

HCL-V
Hairy cell leukemia-variant (HCL-V) is usually described as a prolymphocytic variant of HCL.  It was first formally described in 1980 by a paper from the University of Cambridges Hayhoe laboratory.  About 10% of people with HCL have this variant form of the disease, representing about 60-75 new cases of HCL-V each year in the U.S.  While classic HCL primarily affects men, HCL-V is more evenly divided between males and females.  While the disease can appear at any age, the median age at diagnosis is over 70.Similar to B-cell prolymphocytic leukemia (B-PLL) in chronic lymphocytic leukemia, HCL-V is a more aggressive disease.  Historically, it has been considered less likely to be treated successfully than is classic HCL, and remissions have tended to be shorter. The introduction of combination therapy with concurrent rituximab and cladribine therapy, though, has shown excellent results in early follow-up. As of 2016, this therapy is considered the first-line treatment of choice for many people with HCL-V.Many older treatment approaches, such as interferon-alpha, the combination chemotherapy regimen "CHOP", and common alkylating agents such as cyclophosphamide, showed very little benefit. Pentostatin and cladribine administered as monotherapy (without concurrent rituximab) provide some benefit to many people with HCL-V, but typically induce shorter remission periods and lower response rates than when they are used in classic HCL.  More than half of people respond partially to splenectomy.In terms of B-cell development, the prolymphocytes are less developed than are lymphocytes or plasma cells, but are still more mature than their lymphoblastic precursors.
HCL-V differs from classic HCL principally in these respects:

Higher white blood cell counts, sometimes exceeding 100,000 cells per microliter
A more aggressive course of disease requiring more frequent treatment
Hairy cells with an unusually large nucleolus for their size
Production of little excess fibronectin produced by classic hairy cells to interfere with bone marrow biopsies
Low or no cell-surface expression of CD25 (interleukin-2 [IL-2] receptor alpha chain, or p55).Low levels of CD25, a part of the receptor for a key immunoregulating hormone, may explain why HCL-V cases are generally much more resistant to treatment by immune-system hormones.HCL-V, which usually features a high proportion of hairy cells without a functional p53 tumor suppressor gene, is somewhat more likely to transform into a higher-grade malignancy. A typical transformation rate of 5-6% has been postulated in the UK, similar to the Richters transformation rate for splenic lymphoma with villous lymphocytes (SLVL) and CLL.  Among HCL-V patients, the most aggressive cases normally have the least amount of p53 gene activity.  Hairy cells without the p53 gene tend, over time, to displace the less aggressive p53(+) hairy cells.
Some evidence suggests that a rearrangement of the immunoglobulin gene VH4-34, which is found in about 40% of HCL-V patients and 10% of classic HCL patients, may be a more important poor prognostic factor than variant status, with HCL-V patients without the VH4-34 rearrangement responding about as well as classic HCL patients.

Hairy cell leukemia-Japanese variant
The variant called hairy cell leukemia-Japanese variant, or HCL-J, is more easily treated.  Treatment with cladribine has been reported.

Prevention
Because the cause is unknown, no effective preventive measures can be taken, but the U.S. Institute of Medicine permits an association to exposure to herbicides (atrazine).  The U.S. Department of Veterans Affairs also considers it a service disability related to Agent Orange.  Because the disease is rare, routine screening is not cost effective.

Treatment
Several treatments are available, and successful control of the disease is common.

Not everyone needs treatment immediately. Treatment is usually given when the symptoms of the disease interfere with the patients everyday life, or when white blood cell or platelet counts decline to dangerously low levels, such as an absolute neutrophil count below 1000 cells per microliter (1.0 K/μL).  Not all patients need treatment immediately upon diagnosis.
Treatment delays are less important than in solid tumors. Unlike most cancers, treatment success does not depend on treating the disease at an early stage.  Because delays do not affect treatment success, no standards exist for how quickly a patient should receive treatment.  Waiting too long, though, can cause its own problems, such as an infection that might have been avoided by proper treatment to restore immune-system function.  Also, having a higher number of hairy cells at the time of treatment can make certain side effects somewhat worse, as some side effects are primarily caused by the bodys natural response to the dying hairy cells.  This can result in the hospitalization of a patient whose treatment would otherwise be carried out entirely at the hematologists office.
Single-drug treatment is typical. Unlike most cancers, only one drug is normally given to a patient at a time.  While monotherapy is normal, combination therapy—typically using one first-line therapy and one second-line therapy—is being studied in current clinical trials, and is used more frequently for refractory cases.  Combining rituximab with cladribine or pentostatin may or may not produce any practical benefit to the patient. Combination therapy is almost never used with a new patient.  Because the success rates with purine analog monotherapy are already so high, the additional benefit from immediate treatment with a second drug in a treatment-naïve patient is assumed to be very low.  For example, one round of either cladribine or pentostatin gives the median first-time patient a decade-long remission; the addition of rituximab, which gives the median patient only three or four years, might provide no additional value for this easily treated patient.  In a more difficult case, however, the benefit from the first drug may be substantially reduced, so a combination may provide some benefit.

First-line therapy
Cladribine (2CDA) and pentostatin (DCF) are the two most common first-line therapies.  They both belong to a class of medications called purine analogs, which have mild side effects compared to traditional chemotherapy regimens.
Cladribine can be administered by injection under the skin, by infusion over a few hours into a vein (inravenous - IV), or by a pump worn by the patient that provides a slow drip into a vein, 24 hours a day for 7 days.  Most patients receive cladribine by IV infusion once a day for five to seven days, but more patients are being given the option of taking this drug once a week for six weeks.  The different dosing schedules used with cladribine are roughly equally effective and safe. Relatively few patients have significant side effects other than fatigue and a high fever caused by the cancer cells dying, although complications such as infection and acute kidney failure have been seen.  Pentostatin is chemically similar to cladribine, and has a similar success rate and side effect profile, but it is always given over a much longer period of time, usually one dose by IV infusion every two weeks for 3–6 months.
During the weeks following treatment, the patients immune systems are severely weakened, but their bone marrow will begin to produce normal blood cells again.  Treatment often results in long-term remission. About 85% of patients achieve a complete response from treatment with either cladribine or pentostatin, and another 10% receive some benefit from these drugs, although no permanent cure for this disease is known.  If the cancer cells return, the treatment may be repeated and should again result in remission, although the odds of success decline with repeated treatment.  Remission lengths vary significantly, from one year to more than twenty years.  The median patient can expect a treatment-free interval of about ten years.
2-Chlorodeoxyadenosine (Cladribine) induced complete responses in patients with hairy cell leukemia resistant to DCF, suggesting a lack of cross-resistance. Also, 2-CdA is not prohibitively toxic in patients intolerant of DCF (Pentostatin).

Second-line therapy
If a patient is resistant to either cladribine or pentostatin, then second-line therapy is pursued.

Monoclonal antibodies: The most common treatment for cladribine-resistant disease is infusing monoclonal antibodies that destroy cancerous B cells.  Rituximab is by far the most commonly used.  Most patients receive one IV infusion over several hours each week for 4–8 weeks.  Two partial and 10 complete responses resulted fromf 15 patients with relapsed disease, for a total of 80% responding.  The median patient (including nonresponders) did not require further treatment for more than 3 years.  This eight-dose study had a higher response rate than a four-dose study at Scripps, which achieved only 25% response rate.  Rituximab has successfully induced a complete response in Hairy Cell-Variant.Rituximabs major side effect is serum sickness, commonly described as an "allergic reaction", which can be severe, especially on the first infusion.  Serum sickness is primarily caused by the antibodies clumping during infusion and triggering the complement cascade.  Although most patients find that side effects are adequately controlled by antiallergy drugs, some severe, and even fatal, reactions have occurred.  Consequently, the first dose is always given in a hospital setting, although subsequent infusions may be given in a physicians office.  Remissions are usually shorter than with the preferred first-line drugs, but hematologic remissions of several years duration are not uncommon. Other B cell-destroying monoclonal antibodies such as alemtuzumab, ibritumomab tiuxetan and I-131 tositumomab may be considered for refractory cases.

Interferon-alpha is an immune system hormone that is very helpful to a relatively small number of patients, and somewhat helpful to most patients.  In about 65% of patients, the drug helps stabilize the disease or produce a slow, minor improvement for a partial response.The typical dosing schedule injects at least 3 million units of interferon-alpha (not pegylated versions) three times a week, although the original protocol began with 6 months of daily injections.
Some patients tolerate IFN-alpha very well after the first fw weeks, while others find that its characteristic flu-like symptoms persist.  About 10% of patients develop a level of depression.  By maintaining a steadier level of the hormone in the body, daily injections might cause fewer side effects in selected patients.  Drinking at least 2 liters of water each day, while avoiding caffeine and alcohol, can reduce many of the side effects.
A drop in blood counts is usually seen during the first 1–2 months of treatment.  Most patients find that their blood counts get worse for a few weeks immediately after starting treatment, although some patients find their blood counts begin to improve within just 2 weeks.Typically, 6 months are neededto figure out whether this therapy is useful.  Common criteria for treatment success include:

Normalization of hemoglobin levels (above 12.0 g/dL),
A normal or somewhat low platelet count (above 100 K/µL), and
A normal or somewhat low absolute neutrophil count (above 1.5 K/µL).If it is well tolerated, patients usually take the hormone for 12 to 18 months.  An attempt may be made then to end the treatment, but most patients discover that they need to continue taking the drug for it to be successful.  These patients often continue taking this drug indefinitely, until either the disease becomes resistant to this hormone, or the body produces an immune system response that limits the drugs ability to function.  A few patients are able to achieve a sustained clinical remission after taking this drug for six months to one year.  This may be more likely when IFN-alpha has been initiated shortly after another therapy.  IFN-alpha is considered the drug of choice for pregnant women with active HCL, although it carries some risks, such as the potential for decreased blood flow to the placenta.
IFN-alpha works by sensitizing the hairy cells to the killing effect of the immune-system hormone TNF-alpha, whose production it promotes.  IFN-alpha works best on classic hairy cells that are not protectively adhered to vitronectin or fibronectin, which suggests that patients who encounter less fibrous tissue in their bone-marrow biopsies may be more likely to respond to IFN-alpha therapy.  It also explains why unadhered hairy cells, such as those in the bloodstream, disappear during IFN-alpha treatment well before reductions are seen in adhered hairy cells, such as those in the bone marrow and spleen.

Other treatments
Splenectomy can produce long-term remissions in patients whose spleens seem to be heavily involved, but its success rate is noticeably lower than cladribine or pentostatin.  Splenectomies are also performed for patients whose persistently enlarged spleens cause significant discomfort or in patients whose persistently low platelet counts suggest idiopathic thrombocytopenic purpura.
Bone marrow transplants are usually shunned in this highly treatable disease because of the inherent risks in the procedure.  They may be considered for refractory cases in younger, otherwise healthy individuals.  "Minitransplants" are possible.
People with low numbers of red blood cells or platelets may also receive red blood cells and platelets through blood transfusions. Blood transfusions are always irradiated to remove white blood cells and thereby reduce the risk of graft-versus-host disease. Affected people may also receive a hormone to stimulate production of red blood cells. These treatments may be medically necessary, but do not kill the hairy cells.
People with low neutrophil counts may be given filgrastim or a similar hormone to stimulate production of white blood cells.  However, a 1999 study indicates that routine administration of this expensive injected drug has no practical value for HCL patients after cladribine administration.  In this study, patients who received filgrastim were just as likely to experience a high fever and to be admitted to the hospital as those who did not, even though the drug artificially inflated their white blood cell counts.  This study leaves open the possibility that filgrastim may still be appropriate for patients who have symptoms of infection, or at times other than shortly after cladribine treatment.
Although hairy cells are technically long-lived, instead of rapidly dividing, some late-stage patients are treated with broad-spectrum chemotherapy agents such as methotrexate that are effective at killing rapidly dividing cells.  This is not typically attempted unless all other options have been exhausted and it is typically unsuccessful.

Prognosis
Treatment success
More than 95% of new patients are treated well or at least adequately by cladribine or pentostatin.  A majority of new patients can expect a disease-free remission time span of about ten years, or sometimes much longer after taking one of these drugs just once.  If retreatment is necessary in the future, the drugs are normally effective again, although the average length of remission is somewhat shorter in subsequent treatments.  There is also the risk of Shingles, and Peripheral Neuropathy after treatment with cladribine.
As with B-cell chronic lymphocytic leukemia, mutations in the IGHV on hairy cells are associated with better responses to initial treatments and with prolonged survival.How soon after treatment a patient feels "normal" again depends on several factors, including:

how advanced the disease was at the time of treatment;
the patients underlying health status;
whether the patient had a "complete response" or only a partial response to the treatment;
whether the patient experienced any of the rare, but serious side effects such as kidney failure;
how aggressive the individuals disease is;
whether the patient is experiencing unusual psychological trauma from the "cancer" diagnosis; and
how the patient perceived his or her pre-treatment energy level and daily functioning.

Lifespan
With appropriate treatment, the overall projected lifespan for patients is normal or near-normal.  In all patients, the first two years after diagnosis have the highest risk for fatal outcome; generally, surviving five years predicts good control of the disease.  After five years clinical remission, patients in the United States with normal blood counts can often qualify for private life insurance with some US companies.Accurately measuring survival for patients with the variant form of the disease (HCL-V) is complicated by the relatively high median age (70 years old) at diagnosis.  However, HCL-V patients routinely survive for more than 10 years, and younger patients can likely expect a long life.

Follow-up care
Despite decade-long remissions and years of living very normal lives after treatment, hairy cell leukemia is officially considered an incurable disease.  While survivors of solid tumors are commonly declared to be permanently cured after two, three, or five years, people who have hairy cell leukemia are never considered cured.  Relapses of HCL have happened even after more than twenty years of continuous remission.  Patients will require lifelong monitoring and should be aware that the disease can recur even after decades of good health.
While most oncologists consider Hairy Cell Leukemia to be incurable, there is some evidence that some patients are in fact cured after treatments.   Of the original 358-patient cohort treated with cladribine at the Scripps Clinic, 9 of 19 in continuous CR for a median of 16 years were free of HCL MRD by flow cytometry and IHC. This suggests that the disease of at least some patients may be cured.People in remission need regular follow-up examinations after their treatment is over.  Most physicians insist on seeing patients at least once a year for the rest of the patients life, and getting blood counts about twice a year.  Regular follow-up care ensures that patients are carefully monitored, any changes in health are discussed, and new or recurrent cancer can be detected and treated as soon as possible. Between regularly scheduled appointments, people who have hairy cell leukemia should report any health problems, especially viral or bacterial infections, as soon as they appear.
HCL patients are also at a slightly higher than average risk for developing a second kind of cancer,  such as colon cancer or lung cancer, at some point during their lives (including before their HCL diagnosis).  This appears to relate best to the number of hairy cells, and not to different forms of treatment.  On average, patients might reasonably expect to have as much as double the risk of developing another cancer, with a peak about two years after HCL diagnosis and falling steadily after that, assuming that the HCL was successfully treated.  Aggressive surveillance and prevention efforts are generally warranted, although the lifetime odds of developing a second cancer after HCL diagnosis are still less than 50%.
There is also a higher risk of developing an autoimmune disease. Polyarteritis nodosa has been associated with underlying hairy cell leukemia in certain cases. Autoimmune diseases may also go into remission after treatment of HCL.

Epidemiology
This disease is rare, with fewer than 1 in 10,000 people being diagnosed with HCL during their lives.  Men are four to five times more likely to develop hairy cell leukemia than women.  In the United States, the annual incidence is approximately 3 cases per 1,000,000 men each year, and 0.6 cases per 1,000,000 women each year.Most patients are white males over the age of 50, although it has been diagnosed in at least one teenager </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 Flaccid paralysis and can you explain it in depth? [/INST] Flaccid paralysis is a neurological condition characterized by weakness or paralysis and reduced muscle tone without other obvious cause (e.g., trauma). This abnormal condition may be caused by disease or by trauma affecting the nerves associated with the involved muscles.  For example, if the somatic nerves to a skeletal muscle are severed, then the muscle will exhibit flaccid paralysis.  When muscles enter this state, they become limp and cannot contract.  This condition can become fatal if it affects the respiratory muscles, posing the threat of suffocation. It also occurs in spinal shock stage in complete transection of spinal cord occurred in injuries like gunshots injuries.

Causes
Polio and other viruses
The term acute flaccid paralysis (AFP) is often used to describe an instance with a sudden onset, as might be found with polio.AFP is the most common sign of acute polio, and used for surveillance during polio outbreaks. AFP is also associated with a number of other pathogenic agents including enteroviruses other than polio, echoviruses, West Nile virus, and adenoviruses, among others.

Botulism
The Clostridium botulinum bacteria are the cause of botulism.  Vegetative cells of C. botulinum may be ingested. Introduction of the bacteria may also occur via endospores in a wound.  When the bacteria are in vivo, they induce flaccid paralysis.  This happens because C. botulinum produces a toxin that blocks the release of acetylcholine.  Botulism toxin blocks the exocytosis of presynaptic vesicles containing acetylcholine (ACh).  When this occurs, the muscles are unable to contract.  Other symptoms associated with infection from this neurotoxin include double vision, blurred vision, drooping eyelids, slurred speech, difficulty swallowing, dry mouth, and muscle weakness.  Botulism prevents muscle contraction by blocking the release of acetylcholine, thereby halting postsynaptic activity of the neuromuscular junction </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 Prothrombin G20210A and can you explain it in depth? [/INST] Prothrombin G20210A is a genetic condition that increases the risk of blood clots including from deep vein thrombosis, and of pulmonary embolism. One copy of the mutation increases the risk of a blood clot from 1 in 1,000 per year to 2.5 in 1,000. Two copies increases the risk to up to 20 in 1,000 per year. Most people never develop a blood clot in their lifetimes.It is due to a specific gene mutation in which a guanine (G) is changed to an adenine (A) at position 20210 of the DNA of the prothrombin gene. Other blood clotting pathway mutations that increase the risk of clots include factor V Leiden.
Prothrombin G20210A was identified in the 1990s. About 2% of Caucasians carry the variant, while it is less common in other populations. It is estimated to have originated in Caucasians about 20,000 years ago.

Signs and symptoms
The variant causes elevated plasma prothrombin levels (hyperprothrombinemia), possibly due to increased pre-mRNA stability. Prothrombin is the precursor to thrombin, which plays a key role in causing blood to clot (blood coagulation). G20210A can thus contribute to a state of hypercoagulability, but not particularly with arterial thrombosis. A 2006 meta-analysis showed only a 1.3-fold increased risk for coronary disease. Deficiencies in the anticoagulants Protein C and Protein S further increase the risk five- to tenfold. Behind non-O blood type and factor V Leiden, prothrombin G20210A is one of the most common genetic risk factors for venous thromboembolism (VTE). Increased production of prothrombin heightens the risk of blood clotting. Moreover, individuals who carry the mutation can pass it on to their offspring.The mutation increases the risk of developing deep vein thrombosis (DVT), which can cause pain and swelling, and sometimes post-thrombotic syndrome, ulcers, or pulmonary embolism.
Most individuals do not require treatment but do need to be cautious during periods when the possibility of blood clotting are increased; for example, during pregnancy, after surgery, or during long flights. Occasionally, blood-thinning medication may be indicated to reduce the risk of clotting.Heterozygous carriers who take combined birth control pills are at a 15-fold increased risk of VTE, while carriers also heterozygous with factor V Leiden have an approximate 20-fold higher risk. In a recommendation statement on VTE, genetic testing for G20210A in adults that developed unprovoked VTE was disadvised, as was testing in asymptomatic family members related to G20210A carriers who developed VTE. In those who develop VTE, the results of thrombophilia tests (wherein the variant can be detected) rarely play a role in the length of treatment.

Cause
The polymorphism is located in a noncoding region of the prothrombin gene (3 untranslated region nucleotide 20210), replacing guanine with adenine. The position is at or near where the pre-mRNA will have the poly-A tail attached.

Diagnosis
Diagnosis of the prothrombin G20210A mutation is straightforward because the mutation involves a single base change (point mutation) that can be detected by genetic testing, which is unaffected by intercurrent illness or anticoagulant use.Measurement of an elevated plasma prothrombin level cannot be used to screen for the prothrombin G20210A mutation, because there is too great of an overlap between the upper limit of normal and levels in affected patients.

Treatment
Patients with the prothrombin mutation are treated similarly to those with other types of thrombophilia, with anticoagulation for at least three to six months. Continuing anticoagulation beyond three to six months depends on the circumstances surrounding thrombosis, for example, if the patient experiences a thromboembolic event that was unprovoked, continuing anticoagulation would be recommended. The choice of anticoagulant (warfarin versus a direct oral anticoagulant) is based on a number of different factors (the severity of thrombosis, patient preference, adherence to therapy, and potential drug and dietary interactions).Patients with the prothrombin G20210A mutation who have not had a thromboembolic event are generally not treated with routine anticoagulation.
However, counseling the patient is recommended in situations with increased thrombotic risk is recommended (pregnancy, surgery, and acute illness). Oral contraceptives should generally be avoided in women with the mutation as they increase the thrombotic risk.

Terminology
Because prothrombin is also known as factor II, the mutation is also sometimes referred to as the factor II mutation or simply the prothrombin mutation; in either case, the names may appear with or without the accompanying G20210A location specifier (unhelpfully, since prothrombin mutations other than G20210A are known).

Notes
References
External links

Mannucci, P </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 Medical procedure 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 Cardiac catheterization and can you explain it in depth? [/INST] Cardiac catheterization (heart cath) is the insertion of a catheter into a chamber or vessel of the heart. This is done both for diagnostic and interventional purposes.
A common example of cardiac catheterization is coronary catheterization that involves catheterization of the coronary arteries for coronary artery disease and myocardial infarctions ("heart attacks"). Catheterization is most often performed in special laboratories with fluoroscopy and highly maneuverable tables. These "cath labs" are often equipped with cabinets of catheters, stents, balloons, etc. of various sizes to increase efficiency. Monitors show the fluoroscopy imaging, electrocardiogram (ECG), pressure waves, and more.

Uses
Coronary angiography is a diagnostic procedure that allows visualization of the coronary vessels. Fluoroscopy is used to visualize the lumens of the arteries as a 2-D projection. Should these arteries show narrowing or blockage, then techniques exist to open these arteries. Percutaneous coronary intervention is a blanket term that involves the use of mechanical stents, balloons, etc. to increase blood flow to previously blocked (or occluded) vessels.Measuring pressures in the heart is also an important aspect of catheterization. The catheters are fluid filled conduits that can transmit pressures to outside the body to pressure transducers. This allows measuring pressure in any part of the heart that a catheter can be maneuvered into.Measuring blood flow is also possible through several methods. Most commonly, flows are estimated using the Fick principle and thermodilution. These methods have drawbacks, but give invasive estimations of the cardiac output, which can be used to make clinical decisions (e.g., cardiogenic shock, heart failure) to improve the persons condition.Cardiac catheterization can be used as part of a therapeutic regimen to improve outcomes for survivors of out-of-hospital cardiac arrest.Cardiac catheterization often requires the use of fluoroscopy to visualize the path of the catheter as it enters the heart or as it enters the coronary arteries. The coronary arteries are known as "epicardial vessels" as they are located in the epicardium, the outermost layer of the heart. The use of fluoroscopy requires radiopaque contrast, which in rare cases can lead to contrast-induced kidney injury (see Contrast-induced nephropathy). People are constantly exposed to low doses of ionizing radiation during procedures. Ideal table positioning between the x-ray source and receiver, and radiation monitoring via thermoluminescent dosimetry, are two main ways of reducing a persons exposure to radiation. People with certain comorbidities (people who have more than one condition at the same time) have a higher risk of adverse events during the cardiac catheterization procedure. These comorbidity conditions include aortic aneurysm, aortic stenosis, extensive three-vessel coronary artery disease, diabetes, uncontrolled hypertension, obesity, chronic kidney disease, and unstable angina.

Left heart catheterization
Left heart catheterization (LHC) is an ambiguous term and sometime clarification is required:
LHC can mean measuring the pressures of the left side of the heart.
LHC can be synonymous with coronary angiography.technique is also used to assess the amount of occlusion (or blockage) in a coronary artery, often described as a percentage of occlusion. A thin, flexible wire is inserted into either the femoral artery or the radial artery and threaded toward the heart until it is in the ascending aorta. Radial access is not associated with an increased risk of stroke over femoral access. At this point, a catheter is guided over the wire into the ascending aorta, where it can be maneuvered into the coronary arteries through the coronary ostia. In this position, the interventional cardiologist can inject contrast and visualize the flow through the vessel. If necessary, the physician can utilize percutaneous coronary intervention techniques, including the use of a stent (either bare-metal or drug-eluting) to open the blocked vessel and restore appropriate blood flow. In general, occlusions greater than 70% of the width of the vessel lumen are thought to require intervention. However, in cases where multiple vessels are blocked (so-called "three-vessel disease"), the interventional cardiologist may opt instead to refer the patient to a cardiothoracic surgeon for coronary artery bypass graft (CABG; see Coronary artery bypass surgery) surgery.

Right heart catheterization
Right heart catheterization (RHC) allows the physician to determine the pressures within the heart (intracardiac pressures). The heart is most often accessed via the internal jugular or femoral vein; arteries are not used. Values are commonly obtained for the right atrium, right ventricle, pulmonary artery, and pulmonary capillary "wedge" pressures. Right heart catheterizations also allow the physician to estimate the cardiac output, the amount of blood that flows from the heart each minute, and the cardiac index, a hemodynamic parameter that relates the cardiac output to a patients body size. Determination of cardiac output can be done by releasing a small amount of saline solution (either chilled or at room temperature) in one area of the heart and measuring the change in blood temperature over time in another area of the heart.Right heart catheterization is often done for pulmonary hypertension, heart failure, and cardiogenic shock. The pulmonary artery catheter can be placed, used, and removed, or it can be placed and left in place for continuous monitoring. The latter can be done an intensive care unit (ICU) to permit frequent measurement of the hemodynamic parameters in response to interventions.Parameters obtainable from a right heart catheterization:
Right atrial pressure
Right ventricular pressure
Pulmonary artery pressure
Pulmonary capillary wedge pressure
Systemic vascular resistance
Pulmonary vascular resistance
Cardiac output
Blood oxygenationImplantation of a CardioMEMS is done during a right heart catheterization. This device is implanted into the pulmonary artery to permit real-time measurement of the pulmonary artery pressure over time.

Coronary catheterization
Coronary catheterization is an invasive process and comes with risks that include stroke, heart attack, and death. Like any procedure, the benefits should outweigh the risks and so this procedure is reserved for those with symptoms of serious heart diseases and is never used for screening purposes. Other, non-invasive tests are better used when the diagnosis or certainty of the diagnosis is not as clear.Indications for cardiac catheterization include the following:
Acute coronary syndromes: ST elevation MI (STEMI), non-ST Elevation MI (NSTEMI), and unstable angina
Evaluation of coronary artery disease as indicated by
Abnormal stress test
As part of the pre-op evaluation for other cardiac procedures (e.g., valve replacement) as coronary artery bypass grafting may be done at the same time
Risk stratification for high cardiac risk surgeries (e.g., endovascular aneurysm repair)
Persistent chest pain despite medical therapy thought to be cardiac in origin
New-onset unexplained heart failure
Survival of sudden cardiac death or dangerous cardiac arrhythmias
Workup of suspected Prinzmetal angina (coronary vasospasm)Right heart catheterization, along with pulmonary function testing and other testing should be done to confirm pulmonary hypertension prior to having vasoactive pharmacologic treatments approved and initiated.
to measure intracardiac and intravascular blood pressures
to take tissue samples for biopsy
to inject various agents for measuring blood flow in the heart; also to detect and quantify the presence of an intracardiac shunt
to inject contrast agents in order to study the shape of the heart vessels and chambers and how they change as the heart beats

Pacemakers and defibrillators
Placement of internal pacemakers and defibrillators are done through catheterization as well. An exception to this is placement of electrodes on the outer surface of the heart (called epicardial electrodes). Otherwise, electrodes are placed through the venous system into the heart and left there permanently. Typically, these devices are placed in the left upper chest and enter the left subclavian vein and electrodes are placed in the right atrium, right ventricle, and coronary sinus (for the left ventricle stimulation).

Valve assessment
Echocardiography is a non-invasive method to evaluate the heart valves. However, sometimes the valve pressure gradients need to be measured directly because echo is equivocal for the severity of valve disease. Invasive assessment of the valve can be done with catheterization by placing a catheter across the valve and measuring the pressures simultaneously on each side of the valve to obtain the pressure gradient. In conjunction with a right heart catheterization, the valve area can be estimated. For example, in aortic valve area calculation the Gorlin equation can be used to calculate the area if the cardiac output, pressure gradient, systolic period, and heart rate are known.

Pulmonary angiography
Evaluation of the blood flow to the lungs can be done invasively through catheterization. Contrast is injected into the pulmonary trunk, left or right pulmonary artery, or segment of the pulmonary artery.

Shunt evaluation
Cardiac shunts can be evaluated through catheterization. Using oxygen as a marker, the oxygen saturation of blood can be sampled at various locations in and around the heart. For example, a left-to-right atrial septal defect will show a marked increase in oxygen saturation in the right atrium, ventricle, and pulmonary artery as compared to the mixed venous oxygen saturation from the oxygenated blood from the lungs mixing into the venous return to the heart. Utilizing the Fick principle, the ratio of blood flow in the lungs (Qp) and system circulations (Qs) can calculate the Qp:Qs ratio. Elevation of the Qp:Qs ratio above 1.5 to 2.0 suggests that there is a hemodynamically significant left-to-right shunt (such that the blood flow through the lungs is 1.5 to 2.0 times more than the systemic circulation). This ratio can be evaluated non-invasively with echocardiography too, however.A "shunt run" is often done when evaluating for a shunt by taking blood samples from superior vena cava (SVC), inferior vena cava (IVC), right atrium, right ventricle, pulmonary artery, and system arterial. Abrupt increases in oxygen saturation support a left-to-right shunt and lower than normal systemic arterial oxygen saturation supports a right-to-left shunt. Samples from the SVC & IVC are used to calculate mixed venous oxygen saturation.

Ventriculography
By injecting contrast into the left ventricle, the outline of the ventricle can be measured in both systole and diastole to estimate the ejection fraction (a marker of heart function). Due to the high contrast volumes and injection pressures, this is often not performed unless other, non-invasive methods are not acceptable, not possible, or conflicting.

Percutaneous aortic valve replacement
Advancements in cardiac catheterization have permitted replacement of heart valves by means of blood vessels. This method allows valve replacement without open heart surgery and can be performed on people who are high-risk for such a surgery.

Balloon septostomy
Catheterization can also be used to perform balloon septostomy, which is the widening of a foramen ovale, patent foramen ovale (PFO), or atrial septal defect (ASD) using a balloon catheter. This can be done in certain congenital heart diseases in which the mechanical shunting is required to sustain life such as in transposition of the great vessels.

Alcohol septal ablation
Hypertrophic cardiomyopathy is a disease in which the myocardium is thickened and can cause blood flow obstruction. If hemodynamically significant, this excess muscle can be removed to improve blood flow. Surgically, this can be done with septal myectomy. However, it can be done through catheterization and by injecting ethanol to destroy the tissue in an alcohol septal ablation. This is done by selected an appropriate septal artery supplying the intended area and, essentially, causing a localized, controlled myocardial infarction of the area with ethanol.

Complications
Complications of cardiac catheterization and tools used during catheterization include, but not limited to:
Death
Stroke
Heart attack
Ventricular ectopy and ventricular arrhythmias
Pericardial effusion
Bleeding: internal and external
Infection
Radiation burn
Contrast induced nephropathy from contrast useThe likelihood of these risks depends on many factors that include the procedure being performed, the overall health state of the patient, situational (elective vs emergent), medications (e.g., anticoagulation), and more.

Procedure
"Cardiac catheterization" is a general term for a group of procedures. Access to the heart is obtained through a peripheral artery or vein. Commonly, this includes the radial artery, internal jugular vein, and femoral artery/vein. Each blood vessel has its advantages and disadvantages. Once access is obtained, plastic catheters (tiny hollow tubes) and flexible wires are used to navigate to and around the heart. Catheters come in numerous shapes, lengths, diameters, number of lumens, and other special features such as electrodes and balloons. Once in place, they are used to measure or intervene. Imaging is an important aspect to catheterization and commonly includes fluoroscopy but can also include forms of echocardiography (TTE, TEE, ICE) and ultrasound (IVUS).Obtaining access uses the Seldinger technique by puncturing the vessel with a needle, placing a wire through the needle into the lumen of the vessel, and then exchanging the needle for a larger plastic sheath. Finding the vessel with a needle can be challenging and both ultrasound and fluoroscopy can be used to aid in finding and confirming access. Sheaths typically have a side port that can be used to withdraw blood or injection fluids/medications, and they also have an end hole that permits introducing the catheters, wires, etc. coaxially into the blood vessel.Once access is obtained, what is introduced into the vessel depends on the procedure being performed </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 GM2 gangliosidoses and can you explain it in depth? [/INST] The GM2 gangliosidoses are a group of three related genetic disorders that result from a deficiency of the enzyme beta-hexosaminidase. This enzyme catalyzes the biodegradation of fatty acid derivatives known as gangliosides. The diseases are better known by their individual names: Tay–Sachs disease, AB variant, and Sandhoff disease.
Beta-hexosaminidase is a vital hydrolytic enzyme, found in the lysosomes, that breaks down lipids. When beta-hexosaminidase is no longer functioning properly, the lipids accumulate in the nervous tissue of the brain and cause problems. Gangliosides are made and biodegraded rapidly in early life as the brain develops. Except in some rare, late-onset forms, the GM2 gangliosidoses are fatal.All three disorders are rare in the general population. Tay–Sachs disease has become famous as a public health model because an enzyme assay test for TSD was discovered and developed in the late 1960s and early 1970s, providing one of the first "mass screening" tools in medical genetics. It became a research and public health model for understanding and preventing all autosomal genetic disorders.Tay–Sachs disease, AB variant, and Sandhoff disease might easily have been defined together as a single disease, because the three disorders are associated with failure of the same metabolic pathway and have the same outcome. Classification and naming for many genetic disorders reflects history, because most diseases were first observed and classified based on biochemistry and pathophysiology before genetic diagnosis was available. However, the three GM2 gangliosidoses were discovered and named separately. Each represents a distinct molecular point of failure in a subunit that is required for activation of the enzyme.

Tay–Sachs disease
Tay–Sachs disease is a rare autosomal recessive genetic disorder that causes a progressive deterioration of nerve cells and of mental and physical abilities that begins around six months of age and usually results in death by the age of four. It is the most common of the GM2 gangliosidoses. The disease occurs when harmful quantities of cell membrane gangliosides accumulate in the brains nerve cells, eventually leading to the premature death of the cells.

Sandhoff disease
Sandhoff disease is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. The disease results from mutations on chromosome 5 in the HEXB gene, critical for the lysosomal enzymes beta-N-acetylhexosaminidase A and B. Sandhoff disease is clinically indistinguishable from Tay–Sachs disease. The most common form, infantile Sandhoff disease, is usually fatal by early childhood.

AB variant
GM2-gangliosidosis, AB variant is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord </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 Acrophobia and can you explain it in depth? [/INST] Acrophobia is an extreme or irrational fear or phobia of heights, especially when one is not particularly high up. It belongs to a category of specific phobias, called space and motion discomfort, that share both similar causes and options for treatment.
Most people experience a degree of natural fear when exposed to heights, known as the fear of falling. On the other hand, those who have little fear of such exposure are said to have a head for heights. A head for heights is advantageous for those hiking or climbing in mountainous terrain and also in certain jobs such as steeplejacks or wind turbine mechanics.
People with acrophobia can experience a panic attack in high places and become too agitated to get themselves down safely. Approximately 2–5% of the general population has acrophobia, with twice as many women affected as men. The term is from the Greek: ἄκρον, ákron, meaning "peak, summit, edge" and φόβος, phóbos, "fear".

Confusion with vertigo
"Vertigo" is often used to describe a fear of heights, but it is more accurately a spinning sensation that occurs when one is not actually spinning. It can be triggered by looking down from a high place, by looking straight up at a high place or tall object, or even by watching something (i.e. a car or a bird) go past at high speed, but this alone does not describe vertigo. True vertigo can be triggered by almost any type of movement (e.g. standing up, sitting down, walking) or change in visual perspective (e.g. squatting down, walking up or down stairs, looking out of the window of a moving car or train). Vertigo is called height vertigo when the sensation of vertigo is triggered by heights.
Height vertigo is caused by a conflict between vision, vestibular and somatosensory senses. This occurs when vestibular and somatosensory systems sense a body movement that is not detected by the eyes. More research indicate that this conflict leads to both motion sickness and anxiety.

Causes
Traditionally, acrophobia has been attributed, like other phobias, to conditioning or a traumatic experience. Recent studies have cast doubt on this explanation. Individuals with acrophobia are found to be lacking in traumatic experiences. Nevertheless, this may be due to the failure to recall the experiences, as memory fades as time passes. To address the problems of self report and memory, a large cohort study with 1000 participants was conducted from birth; the results showed that participants with less fear of heights had more injuries because of falling. Psychologists Richie Poulton, Simon Davies, Ross G. Menzies, John D. Langley, and Phil A. Silva sampled subjects from the Dunedin Multidisciplinary Health and Development Study who had been injured in a fall between the ages of 5 and 9, compared them to children who had no similar injury, and found that at age 18, acrophobia was present in only 2 percent of the subjects who had an injurious fall but was present among 7 percent of subjects who had no injurious fall (with the same sample finding that typical basophobia was 7 times less common in subjects at age 18 who had injurious falls as children than subjects that did not).More studies have suggested a possible explanation for acrophobia is that it emerges through accumulation of non-traumatic experiences of falling that are not memorable but can influence behaviours in the future. Also, fear of heights may be acquired when infants learn to crawl. If they fell, they would learn the concepts about surfaces, posture, balance, and movement. Cognitive factors may also contribute to the development of acrophobia. People tend to wrongly interpret visuo-vestibular discrepancies as dizziness and nausea and associate them with a forthcoming fall. A traumatic conditional event of falling may not be necessary at this point.
A fear of falling, along with a fear of loud noises, is one of the most commonly suggested inborn or "non-associative" fears. The newer non-association theory is that a fear of heights is an evolved adaptation to a world where falls posed a significant danger. If this fear is inherited, it is possible that people can get rid of it by frequent exposure of heights in habituation. In other words, acrophobia could be attributed to the lack of exposure in early times. The degree of fear varies and the term phobia is reserved for those at the extreme end of the spectrum. Researchers have argued that a fear of heights is an instinct found in many mammals, including domestic animals and humans. Experiments using visual cliffs have shown human infants and toddlers, as well as other animals of various ages, to be reluctant in venturing onto a glass floor with a view of a few meters of apparent fall-space below it. Although human infants initially experienced fear when crawling on the visual cliff, most of them overcame the fear through practice, exposure and mastery and retained a level of healthy cautiousness. While an innate cautiousness around heights is helpful for survival, an extreme fear can interfere with the activities of everyday life, such as standing on a ladder or chair, or even walking up a flight of stairs. Still, it is uncertain if acrophobia is related to the failure to reach a certain developmental stage. Besides associative accounts, a diathetic-stress model is also very appealing for considering both vicarious learning and hereditary factors such as personality traits (i.e., neuroticism).
Another possible contributing factor is a dysfunction in maintaining balance. In this case the anxiety is both well founded and secondary. The human balance system integrates proprioceptive, vestibular and nearby visual cues to reckon position and motion. As height increases, visual cues recede and balance becomes poorer even in normal people. However, most people respond by shifting to more reliance on the proprioceptive and vestibular branches of the equilibrium system.
Some people are known to be more dependent on visual signals than others. People who rely more on visual cues to control body movements are less physically stable. An acrophobic, however, continues to over-rely on visual signals whether because of inadequate vestibular function or incorrect strategy. Locomotion at a high elevation requires more than normal visual processing. The visual cortex becomes overloaded, resulting in confusion. Some proponents of the alternative view of acrophobia warn that it may be ill-advised to encourage acrophobics to expose themselves to height without first resolving the vestibular issues. Research is underway at several clinics. Recent studies found that participants experienced increased anxiety not only during elevation in height, but also when they were required to move sideways in a fixed height.A recombinant model of the development of acrophobia is very possible, in which learning factors, cognitive factors (e.g. interpretations), perceptual factors (e.g. visual dependence), and biological factors (e.g. heredity) interact to provoke fear or habituation.

Assessment
ICD-10 and DSM-5 are used to diagnose acrophobia. Acrophobia Questionnaire (AQ) is a self report that contains 40 items, assessing anxiety level on a 0–6 point scale and degree of avoidance on a 0–2 point scale. The Attitude Towards Heights Questionnaires (ATHQ) and Behavioural Avoidance Tests (BAT) are also used.However, acrophobic individuals tend to have biases in self-reporting. They often overestimate the danger and question their abilities of addressing height relevant issues. A Height Interpretation Questionnaire (HIQ) is a self-report to measure these height relevant judgements and interpretations. The Depression Scale of the Depression Anxiety Stress Scales short form (DASS21-DS) is a self report used to examine validity of the HIQ.

Treatment
Traditional treatment of phobias is still in use today. Its underlying theory states that phobic anxiety is conditioned and triggered by a conditional stimulus. By avoiding phobic situations, anxiety is reduced. However, avoidance behaviour is reinforced through negative reinforcement. Wolpe developed a technique called systematic desensitization to help participants avoid "avoidance". Research results have suggested that even with a decrease in therapeutic contact, densensitization is still very effective. However, other studies have shown that therapists play an essential role in acrophobia treatment. Treatments like reinforced practice and self-efficacy treatments also emerged.There have been a number of studies into using virtual reality therapy for acrophobia. Botella and colleagues and Schneider were the first to use VR in treatment. Specifically, Schneider utilised inverted lenses in binoculars to "alter" the reality. Later in the mid-1990s, VR became computer-based and was widely available for therapists. A cheap VR equipment uses a normal PC with head-mounted display (HMD). In contrast, VRET uses an advanced computer automatic virtual environment (CAVE). VR has several advantages over in vivo treatment: (1) therapist can control the situation better by manipulating the stimuli, in terms of their quality, intensity, duration and frequency; (2) VR can help participants avoid public embarrassment and protect their confidentiality; (3) therapists office can be well-maintained; (4) VR encourages more people to seek treatment; (5) VR saves time and money, as participants do not need to leave the consulting room.Many different types of medications are used in the treatment of phobias like fear of heights, including traditional anti-anxiety drugs such as benzodiazepines, and newer options such as antidepressants and beta-blockers.

Prognosis
Some desensitization treatments produce short-term improvements in symptoms. Long-term treatment success has been elusive.

Epidemiology
Approximately 2–5% of the general population has acrophobia, with twice as many women affected as men.A related, milder form of visually triggered fear or anxiety is called visual height intolerance (vHI). Up to one-third of people may have some level of visual height intolerance </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 Rectocele and can you explain it in depth? [/INST] In gynecology, a rectocele ( REK-tə-seel) or posterior vaginal wall prolapse results when the rectum bulges (herniates) into the vagina. Two common causes of this defect are childbirth and hysterectomy. Rectocele also tends to occur with other forms of pelvic organ prolapse, such as enterocele, sigmoidocele and cystocele.Although the term applies most often to this condition in females, males can also develop it. Rectoceles in men are uncommon, and associated with prostatectomy.

Signs and symptoms
Mild cases may simply produce a sense of pressure or protrusion within the vagina, and the occasional feeling that the rectum has not been completely emptied after a bowel movement. Moderate cases may involve difficulty passing stool (because the attempt to evacuate pushes the stool into the rectocele instead of out through the anus), discomfort or pain during evacuation or intercourse, constipation, and a general sensation that something is "falling down" or "falling out" within the pelvis. Severe cases may cause vaginal bleeding, intermittent fecal incontinence, or even the prolapse of the bulge through the mouth of the vagina, or rectal prolapse through the anus. Digital evacuation, or, manual pushing, on the posterior wall of the vagina helps to aid in bowel movement in a majority of cases of rectocele. Rectocele can be a cause of symptoms of obstructed defecation.

Causes
Rectoceles result from the weakening of the pelvic floor also called pelvic organ prolapse. Weakened pelvic structures occur as a result of an episiotomy during previous births, even decades later. Other causes of pelvic floor prolapse can be advanced age, multiple vaginal deliveries, and birthing trauma. Birthing trauma includes vacuum delivery, forceps delivery, and perineal tear.  In addition, a history of chronic constipation and excessive straining with bowel movements are thought to play a role in rectocele </s>


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