<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Palpitations and explain in detail? [/INST] Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart.Symptoms include a rapid pulsation, an abnormally rapid or irregular beating of the heart. Palpitations are a sensory symptom and are often described as a skipped beat, rapid fluttering in the chest, pounding sensation in the chest or neck, or a flip-flopping in the chest.Palpitation can be associated with anxiety and does not necessarily indicate a structural or functional abnormality of the heart, but it can be a symptom arising from an objectively rapid or irregular heartbeat. Palpitation can be intermittent and of variable frequency and duration, or continuous. Associated symptoms include dizziness, shortness of breath, sweating, headaches and chest pain.
Palpitation may be associated with coronary heart disease, hyperthyroidism, diseases affecting cardiac muscle such as hypertrophic cardiomyopathy, diseases causing low blood oxygen such as asthma and emphysema; previous chest surgery; kidney disease; blood loss and pain; anemia; drugs such as antidepressants, statins, alcohol, nicotine, caffeine, cocaine and amphetamines; electrolyte imbalances of magnesium, potassium and calcium; and deficiencies of nutrients such as taurine, arginine, iron, vitamin B12.

Signs and symptoms
Three common descriptions of palpitation are  "flip-flopping" (or "stop and start"), often caused by premature contraction of the atrium or ventricle, with the perceived "stop" from the pause following the contraction, and the "start" from the subsequent forceful contraction;  rapid "fluttering in the chest", with regular "fluttering" suggesting supraventricular or ventricular arrhythmias (including sinus tachycardia) and irregular "fluttering" suggesting atrial fibrillation, atrial flutter, or tachycardia with variable block; and  "pounding in the neck" or neck pulsations, often due to cannon A waves in the jugular venous, pulsations that occur when the right atrium contracts against a closed tricuspid valve.Palpitation associated with chest pain suggests coronary artery disease, or if the chest pain is relieved by leaning forward, pericardial disease is suspected. Palpitation associated with light-headedness, fainting or near fainting suggest low blood pressure and may signify a life-threatening abnormal heart rhythm. Palpitation that occurs regularly with exertion suggests a rate-dependent bypass tract or hypertrophic cardiomyopathy. If a benign cause for these concerning symptoms cannot be found at the initial visit, then ambulatory monitoring or prolonged heart monitoring in the hospital might be warranted. Noncardiac symptoms should also be elicited since the palpitations may be caused by a normal heart responding to a metabolic or inflammatory condition. Weight loss suggests hyperthyroidism. Palpitation can be precipitated by vomiting or diarrhea that leads to electrolyte disorders and hypovolemia. Hyperventilation, hand tingling, and nervousness are common when anxiety or panic disorder is the cause of the palpitations.

Causes
The current knowledge of the neural pathways responsible for the perception of the heartbeat is not clearly elucidated. It has been hypothesized that these pathways include different structures located both at the intra-cardiac and extra-cardiac level. Palpitations are a widely diffused complaint and particularly in subjects affected by structural heart disease. The list of etiologies of palpitations is long, and in some cases, the etiology is unable to be determined. In one study reporting the etiology of palpitations, 43% were found to be of cardiac etiology, 31% of psychiatric etiology and approximately 10% were classified as miscellaneous (medication induced, thyrotoxicosis, caffeine, cocaine, anemia, amphetamine, mastocytosis).The cardiac etiologies of palpitations are the most life-threatening and include ventricular sources (premature ventricular contractions (PVC), ventricular tachycardia and ventricular fibrillation), atrial sources (atrial fibrillation, atrial flutter) high output states (anemia, AV fistula, Pagets disease of bone or pregnancy), structural abnormalities (congenital heart disease, cardiomegaly, aortic aneurysm, or acute left ventricular failure), and miscellaneous sources (postural orthostatic tachycardia syndrome abbreviated as POTS, Brugada syndrome, and sinus tachycardia).Palpitation can be attributed to one of four main causes:

Extra-cardiac stimulation of the sympathetic nervous system (inappropriate stimulation of the sympathetic and parasympathetic, particularly the vagus nerve, (which innervates the heart), can be caused by anxiety and stress due to acute or chronic elevations in glucocorticoids and catecholamines. Gastrointestinal distress such as bloating or indigestion, along with muscular imbalances and poor posture, can also irritate the vagus nerve causing palpitations)
Sympathetic overdrive (panic disorder, low blood sugar, hypoxia, antihistamines (levocetirizine), low red blood cell count, heart failure, mitral valve prolapse).
Hyperdynamic circulation (valvular incompetence, thyrotoxicosis, hypercapnia, high body temperature, low red blood cell count, pregnancy).
Abnormal heart rhythms (ectopic beat, premature atrial contraction, junctional escape beat, premature ventricular contraction, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, heart block).Palpitations can occur during times of catecholamine excess, such as during exercise or at times of stress.  The cause of the palpitations during these conditions is often a sustained supraventricular tachycardia or ventricular tachyarrhythmia.  Supraventricular tachycardias can also be induced at the termination of exercise when the withdrawal of catecholamines is coupled with a surge in the vagal tone.  Palpitations secondary to catecholamine excess may also occur during emotionally startling experiences, especially in patients with a long QT syndrome.

Psychiatric problems
Anxiety and stress elevate the bodys level of cortisol and adrenaline, which in turn can interfere with the normal functioning of the parasympathetic nervous system resulting in overstimulation of the vagus nerve. Vagus nerve induced palpitation is felt as a thud, a hollow fluttery sensation, or a skipped beat, depending on at what point during the hearts normal rhythm the vagus nerve fires. In many cases, the anxiety and panic of experiencing palpitations cause a patient to experience further anxiety and increased vagus nerve stimulation. The link between anxiety and palpitation may also explain why many panic attacks involve an impending sense of cardiac arrest. Similarly, physical and mental stress may contribute to the occurrence of palpitation, possibly due to the depletion of certain micronutrients involved in maintaining healthy psychological and physiological function. Gastrointestinal bloating, indigestion and hiccups have also been associated with overstimulation of the vagus nerve causing palpitations, due to branches of the vagus nerve innervating the GI tract, diaphragm, and lungs.Many psychiatric conditions can result in palpitations including depression, generalized anxiety disorder, panic attacks, and somatization. However one study noted that up to 67% of patients diagnosed with a mental health condition had an underlying arrhythmia. There are many metabolic conditions that can result in palpitations including, hyperthyroidism, hypoglycemia, hypocalcemia, hyperkalemia, hypokalemia, hypermagnesemia, hypomagnesemia, and pheochromocytoma.

Medication
The medications most likely to result in palpitations include sympathomimetic agents, anticholinergic drugs, vasodilators and withdrawal from beta blockers.Common etiologies also include excess caffeine, or marijuana. Cocaine, amphetamines,  3-4 methylenedioxymethamphetamine (Ecstasy or MDMA) can also cause palpitations.

Pathophysiology
The sensation of palpitations can arise from extra-systoles or tachyarrhythmia. It is very rarely noted due to bradycardia. Palpitations can be described in many ways. The most common descriptions include a flip-flopping in the chest, a rapid fluttering in the chest, or pounding in the neck. The description of the symptoms may provide a clue regarding the etiology of the palpitations, and the pathophysiology of each of these descriptions is thought to be different.  In patients who describe the palpitations as a brief flip-flopping in the chest, the palpitations are thought to be caused by extra- systoles such as supraventricular or ventricular premature contractions. The flip-flop sensation is thought to result from the forceful contraction following the pause, and the sensation that the heart is stopped results from the pause. The sensation of rapid fluttering in the chest is thought to result from a sustained ventricular or supraventricular arrhythmia. Furthermore, the sudden cessation of this arrythmia can suggest paroxysmal supraventricular tachycardia.  This is further supported if the patient can stop the palpitations by using Valsalva maneuvers. The rhythm of the palpitations may indicate the etiology of the palpitations (irregular palpitations indicate atrial fibrillation as a source of the palpitations). An irregular pounding sensation in the neck can be caused by the dissociation of mitral valve and tricuspid valve, and the subsequent atria are contracting against a closed tricuspid and mitral valves, thereby producing cannon A waves. Palpitations induced by exercise could be suggestive of cardiomyopathy, ischemia or channelopathies.

Diagnosis
The most important initial clue to the diagnosis is ones description of palpitation. The approximate age of the person when first noticed and the circumstances under which they occur are important, as is information about caffeine intake (tea or coffee drinking), and whether continual palpitations can be stopped by deep breathing or changing body positions. It is also very helpful to know how they start and stop (abruptly or not), whether or not they are regular, and approximately how fast the pulse rate is during an attack. If the person has discovered a way of stopping the palpitations, that is also helpful information.A complete and detailed history and physical examination are two essential elements of the evaluation of a patient with palpitations. The key components of a detailed history include age of onset, description of the symptoms including rhythm, situations that commonly result in the symptoms, mode of onset (rapid or gradual), duration of symptoms, factors that relieve symptoms (rest, Valsalva), positions and other associated symptoms such as chest pain, lightheadedness or syncope. A patient can tap out the rhythm to help demonstrate if they are not currently experiencing the symptoms. The patient should be questioned regarding all medications, including over-the-counter medications. Social history, including exercise habits, caffeine consumption, alcohol and illicit drug use, should also be determined. Also, past medical history and family history may provide indications to the etiology of the palpitations.Palpitations that have been a condition since childhood are most likely caused by a supraventricular tachycardia, whereas palpitations that first occur later in life are more likely to be secondary to structural heart disease. A rapid regular rhythm is more likely to be secondary to paroxysmal supraventricular tachycardia or ventricular tachycardia, and a rapid and irregular rhythm is more likely to be an indication of atrial fibrillation, atrial flutter, or tachycardia with variable block.  Supraventricular and ventricular tachycardia is thought to result in palpitations with abrupt onset and abrupt termination.  In patients who can terminate their palpitations with a Valsalva maneuver, this is thought to indicate possibly a supraventricular tachycardia.  Palpitations associated with chest pain may suggest myocardial ischemia. Lastly, when lightheadedness or syncope accompanies the palpitations, ventricular tachycardia, supraventricular tachycardia, or other arrhythmias should be considered.The diagnosis is usually not made by a routine medical examination and scheduled electrical tracing of the hearts activity (ECG) because most people cannot arrange to have their symptoms be present while visiting the hospital. Nevertheless, findings such as a heart murmur or an abnormality of the ECG might be indicative of probable diagnosis. In particular, ECG changes that are associated with specific disturbances of the heart rhythm may be noticed; thus physical examination and ECG remain important in the assessment of palpitation. Moreover, a complete physical exam should be performed including vital signs (with orthostatic vital signs), cardiac auscultation, lung auscultation, and examination of extremities.  A patient can tap out the rhythm to help demonstrate what they felt previously, if they are not currently experiencing the symptoms.Positive orthostatic vital signs may indicate dehydration or an electrolyte abnormality. A mid-systolic click and heart murmur may indicate mitral valve prolapse.  A harsh holo-systolic murmur best heard at the left sternal border which increases with Valsalva may indicate hypertrophic obstructive cardiomyopathy. An irregular rhythm indicates atrial fibrillation or atrial flutter. Evidence of cardiomegaly and peripheral edema may indicate heart failure and ischemia or a valvular abnormality.Blood tests, particularly tests of thyroid gland function, are also important baseline investigations (an overactive thyroid gland is a potential cause for palpitations; the treatment, in that case, is to treat the thyroid gland over-activity).The next level of diagnostic testing is usually 24-hour (or longer) ECG monitoring, using a recorder called a Holter monitor, which can record the ECG continuously during a 24-hour or 48-hour period. If symptoms occur during monitoring it is a simple matter to examine the ECG recording and see what the cardiac rhythm was at the time. For this type of monitoring to be helpful, the symptoms must be occurring at least once a day. If they are less frequent, the chances of detecting anything with continuous 24- or even 48-hour monitoring are substantially lowered. More recent technology such as the Zio Patch allows continuous recording for up to 14 days; the patient indicates when symptoms occur by pushing a button on the device and keeps a log of the events.Other forms of monitoring are available, and these can be useful when symptoms are infrequent. A continuous-loop event recorder monitors the ECG continuously, but only saves the data when the wearer activates it. Once activated, it will save the ECG data for a period of time before the activation and for a period of time afterwards – the cardiologist who is investigating the palpitations can program the length of these periods. An implantable loop recorder may be helpful in people with very infrequent but disabling symptoms. This recorder is implanted under the skin on the front of the chest, like a pacemaker. It can be programmed and the data examined using an external device that communicates with it by means of a radio signal.Investigation of heart structure can also be important. The heart in most people with palpitation is completely normal in its physical structure, but occasionally abnormalities such as valve problems may be present. Usually, but not always, the cardiologist will be able to detect a murmur in such cases, and an ultrasound scan of the heart (echocardiogram) will often be performed to document the hearts structure. This is a painless test performed using sound waves and is virtually identical to the scanning done in pregnancy to look at the fetus.

Evaluation
A 12-lead electrocardiogram must be performed on every patient complaining of palpitations.  The presence of a short PR interval and a delta wave (Wolff-Parkinson-White syndrome) is an indication of the existence of ventricular pre-excitation.  Significant left ventricular hypertrophy with deep septal Q waves in I, L, and V4 through V6 may indicate hypertrophic obstructive cardiomyopathy.  The presence of Q waves may indicate a prior myocardial infarction as the etiology of the palpitations, and a prolonged QT interval may indicate the presence of the long QT syndrome.Laboratory studies should be limited initially.  Complete blood count can assess for anemia and infection.  Serum urea, creatinine and electrolytes to assess for electrolyte imbalances and renal dysfunction.  Thyroid function tests may demonstrate a hyperthyroid state.Most patients have benign conditions as the etiology for their palpitations. The goal of further evaluation is to identify those patients who are at high risk for an arrhythmia.  Recommended laboratory studies include an investigation for anemia, hyperthyroidism and electrolyte abnormalities.  Echocardiograms are indicated for patients in whom structural heart disease is a concern.Further diagnostic testing is recommended for those in whom the initial diagnostic evaluation (history, physical examination, and EKG) suggest an arrhythmia, those who are at high risk for an arrhythmia, and those who remain anxious to have a specific explanation of their symptoms.  People considered to be at high risk for an arrhythmia include those with organic heart disease or any myocardial abnormality that may lead to serious arrhythmias.  These conditions include a scar from myocardial infarction, idiopathic dilated cardiomyopathy, clinically significant valvular regurgitant, or stenotic lesions and hypertrophic cardiomyopathies.An aggressive diagnostic approach is recommended for those at high risk and can include ambulatory monitoring or electrophysiologic studies. There are three types of ambulatory EKG monitoring devices: Holter monitor, continuous-loop event recorder, and an implantable loop recorder.People who are going to have these devices checked should be made aware of the properties of the devices and the accompanying course of the examination for each device. The Holter monitor is a 24-hour monitoring system that is worn by exam takers themselves and records and continuously saves data.  Holter monitors are typically worn for a few days.  The continuous-loop event recorders are also worn by the exam taker and continuously record data, but the data is saved only when someone manually activates the monitor.  The continuous-loop recorders can be long worn for longer periods of time than the Holter monitors and therefore have been proven to be more cost-effective and efficacious than Holter monitors.  Also, because the person triggers the device when he/she feel the symptoms, they are more likely to record data during palpitations.  An implantable loop recorder is a device that is placed subcutaneously and continuously monitors for cardiac arrhythmias.  These are most often used in those with unexplained syncope and can be used for longer periods of time than the continuous loop event recorders. An implantable loop recorder is a device that is placed subcutaneously and continuously monitors for the detection of cardiac arrhythmias.  These are most often used in those with unexplained syncope and are a used for longer periods of time than the continuous loop event recorders.  Electrophysiology testing enables a detailed analysis of the underlying mechanism of the cardiac arrhythmia as well as the site of origin.  EPS studies are usually indicated in those with a high pretest likelihood of a serious arrhythmia. The level of evidence for evaluation techniques is based upon consensus expert opinion.

Treatment
Treating palpitation will depend on the severity and cause of the condition. Radiofrequency ablation can cure most types of supraventricular and many types of ventricular tachycardias. While catheter ablation is currently a common treatment approach, there have been advances in stereotactic radioablation for certain arrythmias.  This technique is commonly used for solid tumors and has been applied with success in management of difficult to treat Ventricular Tachycardia and Atrial Fibrillation.The most challenging cases involve palpitations that are secondary to supraventricular or ventricular ectopy or associated with normal sinus rhythm. These conditions are thought to be benign, and the management involves reassurance of the patient that these arrhythmias are not life-threatening. In these situations when the symptoms are unbearable or incapacitating, treatment with beta-blocking medications could be considered, and may provide a protective effect for otherwise healthy individuals.People who present to the emergency department who are asymptomatic, with unremarkable physical exams, have non-diagnostic EKGs and normal laboratory studies, can safely be sent home and instructed to follow up with their primary care provider or cardiologist. Patients whose palpitations are associated with syncope, uncontrolled arrhythmias, hemodynamic compromise, or angina should be admitted for further evaluation.Palpitation that is caused by heart muscle defects will require specialist examination and assessment. Palpitation that is caused by vagus nerve stimulation rarely involves physical defects of the heart. Such palpitations are extra-cardiac in nature, that is, palpitation originating from outside the heart itself. Accordingly, vagus nerve induced palpitation is not evidence of an unhealthy heart muscle.Treatment of vagus nerve induced palpitation will need to address the cause of irritation to the vagus nerve or the parasympathetic nervous system generally. It is of significance that anxiety and stress are strongly associated with increased frequency and severity of vagus nerve induced palpitation. Anxiety and stress reduction techniques such as meditation and massage may prove extremely beneficial to reduce or eliminate symptoms temporarily </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is ABO blood group system and explain in detail? [/INST] The ABO blood group system is used to denote the presence of one, both, or neither of the A and B antigens on erythrocytes. For human blood transfusions, it is the most important of the 43 different blood type (or group) classification systems currently recognized by the International Society of Blood Transfusions (ISBT) as of June 2021. A mismatch (very rare in modern medicine) in this, or any other serotype, can cause a potentially fatal adverse reaction after a transfusion, or an unwanted immune response to an organ transplant. The associated anti-A and anti-B antibodies are usually IgM antibodies, produced in the first years of life by sensitization to environmental substances such as food, bacteria, and viruses.
The ABO blood types were discovered by Karl Landsteiner in 1901; he received the Nobel Prize in Physiology or Medicine in 1930 for this discovery. ABO blood types are also present in other primates such as apes and Old World monkeys.

History
Discovery
The ABO blood types were first discovered by an Austrian physician, Karl Landsteiner, working at the Pathological-Anatomical Institute of the University of Vienna (now Medical University of Vienna). In 1900, he found that red blood cells would clump together (agglutinate) when mixed in test tubes with sera from different persons, and that some human blood also agglutinated with animal blood. He wrote a two-sentence footnote:

The serum of healthy human beings not only agglutinates animal red cells, but also often those of human origin, from other individuals. It remains to be seen whether this appearance is related to inborn differences between individuals or it is the result of some damage of bacterial kind.
This was the first evidence that blood variations exist in humans – it was believed that all humans have similar blood. The next year, in 1901, he made a definitive observation that blood serum of an individual would agglutinate with only those of certain individuals. Based on this he classified human blood into three groups, namely group A, group B, and group C. He defined that group A blood agglutinates with group B, but never with its own type. Similarly, group B blood agglutinates with group A. Group C blood is different in that it agglutinates with both A and B.This was the discovery of blood groups for which Landsteiner was awarded the Nobel Prize in Physiology or Medicine in 1930. In his paper, he referred to the specific blood group interactions as isoagglutination, and also introduced the concept of agglutinins (antibodies), which is the actual basis of antigen-antibody reaction in the ABO system. He asserted:

[It] may be said that there exist at least two different types of agglutinins, one in A, another one in B, and both together in C. The red blood cells are inert to the agglutinins which are present in the same serum.
Thus, he discovered two antigens (agglutinogens A and B) and two antibodies (agglutinins – anti-A and anti-B). His third group (C) indicated absence of both A and B antigens, but contains anti-A and anti-B. The following year, his students Adriano Sturli and Alfred von Decastello discovered the fourth type (but not naming it, and simply referred to it as "no particular type").

In 1910, Ludwik Hirszfeld and Emil Freiherr von Dungern introduced the term O (null) for the group Landsteiner designated as C, and AB for the type discovered by Sturli and von Decastello. They were also the first to explain the genetic inheritance of the blood groups.

Classification systems
Czech serologist Jan Janský independently introduced blood type classification in 1907 in a local journal. He used the Roman numerical I, II, III, and IV (corresponding to modern O, A, B, and AB). Unknown to Janský, an American physician William L. Moss devised a slightly different classification using the same numerical; his I, II, III, and IV corresponding to modern AB, A, B, and O.These two systems created confusion and potential danger in medical practice. Mosss system was adopted in Britain, France, and US, while Janskýs was preferred in most European countries and some parts of US. To resolve the chaos, the American Association of Immunologists, the Society of American Bacteriologists, and the Association of Pathologists and Bacteriologists made a joint recommendation in 1921 that the Jansky classification be adopted based on priority. But it was not followed particularly where Mosss system had been used.In 1927, Landsteiner had moved to the Rockefeller Institute for Medical Research in New York. As a member of a committee of the National Research Council concerned with blood grouping, he suggested to substitute Janskýs and Mosss systems with the letters O, A, B, and AB. (There was another confusion on the use of figure 0 for German null as introduced by Hirszfeld and von Dungern, because others used the letter O for ohne, meaning without or zero; Landsteiner chose the latter.) This classification was adopted by the National Research Council and became variously known as the National Research Council classification, the International classification, and most popularly the "new" Landsteiner classification. The new system was gradually accepted and by the early 1950s, it was universally followed.

Other developments
The first practical use of blood typing in transfusion was by an American physician Reuben Ottenberg in 1907. Large-scale application began during the First World War (1914–1915) when citric acid began to be used for blood clot prevention. Felix Bernstein demonstrated the correct blood group inheritance pattern of multiple alleles at one locus in 1924. Watkins and Morgan, in England, discovered that the ABO epitopes were conferred by sugars, to be specific, N-acetylgalactosamine for the A-type and galactose for the B-type. After much published literature claiming that the ABH substances were all attached to glycosphingolipids, Finne et al. (1978) found that the human erythrocyte glycoproteins contain polylactosamine chains that contains ABH substances attached and represent the majority of the antigens. The main glycoproteins carrying the ABH antigens were identified to be the Band 3 and Band 4.5 proteins and glycophorin. Later, Yamamotos group showed the precise glycosyl transferase set that confers the A, B and O epitopes.

Genetics
Blood groups are inherited from both parents. The ABO blood type is controlled by a single gene (the ABO gene) with three types of alleles inferred from classical genetics: i, IA, and IB. The I designation stands for isoagglutinogen, another term for antigen. The gene encodes a glycosyltransferase—that is, an enzyme that modifies the carbohydrate content of the red blood cell antigens. The gene is located on the long arm of the ninth chromosome (9q34).The IA allele gives type A, IB gives type B, and i gives type O. As both IA and IB are dominant over i, only ii people have type O blood. Individuals with IAIA or IAi have type A blood, and individuals with IBIB or IBi have type B. IAIB people have both phenotypes, because A and B express a special dominance relationship: codominance, which means that type A and B parents can have an AB child. A couple with type A and type B can also have a type O child if they are both heterozygous (IBi,IAi). The cis-AB phenotype has a single enzyme that creates both A and B antigens. The resulting red blood cells do not usually express A or B antigen at the same level that would be expected on common group A1 or B red blood cells, which can help solve the problem of an apparently genetically impossible blood group.

The table above summarizes the various blood groups that children may inherit from their parents. Genotypes are shown in the second column and in small print for the offspring: AO and AA both test as type A; BO and BB test as type B. The four possibilities represent the combinations obtained when one allele is taken from each parent; each has a 25% chance, but some occur more than once. The text above them summarizes the outcomes.

Historically, ABO blood tests were used in paternity testing, but in 1957 only 50% of American men falsely accused were able to use them as evidence against paternity. Occasionally, the blood types of children are not consistent with expectations—for example, a type O child can be born to an AB parent—due to rare situations, such as Bombay phenotype and cis AB.

Subgroups
The A blood type contains about 20 subgroups, of which A1 and A2 are the most common (over 99%). A1 makes up about 80% of all A-type blood, with A2 making up almost all of the rest. These two subgroups are not always interchangeable as far as transfusion is concerned, as some A2 individuals produce antibodies against the A1 antigen. Complications can sometimes arise in rare cases when typing the blood.With the development of DNA sequencing, it has been possible to identify a much larger number of alleles at the ABO locus, each of which can be categorized as A, B, or O in terms of the reaction to transfusion, but which can be distinguished by variations in the DNA sequence. There are six common alleles in white individuals of the ABO gene that produce ones blood type:
The same study also identified 18 rare alleles, which generally have a weaker glycosylation activity. People with weak alleles of A can sometimes express anti-A antibodies, though these are usually not clinically significant as they do not stably interact with the antigen at body temperature.Cis AB is another rare variant, in which A and B genes are transmitted together from a single parent.

Distribution and evolutionary history
The distribution of the blood groups A, B, O and AB varies across the world according to the population. There are also variations in blood type distribution within human subpopulations.In the UK, the distribution of blood type frequencies through the population still shows some correlation to the distribution of placenames and to the successive invasions and migrations including Celts, Norsemen, Danes, Anglo-Saxons, and Normans who contributed the morphemes to the placenames and the genes to the population. The native Celts tended to have more type O blood, while the other populations tended to have more type A.The two common O alleles, O01 and O02, share their first 261 nucleotides with the group A allele A01. However, unlike the group A allele, a guanosine base is subsequently deleted. A premature stop codon results from this frame-shift mutation. This variant is found worldwide, and likely predates human migration from Africa. The O01 allele is considered to predate the O02 allele.Some evolutionary biologists theorize that there are four main lineages of the ABO gene and that mutations creating type O have occurred at least three times in humans. From oldest to youngest, these lineages comprise the following alleles: A101/A201/O09, B101, O02 and O01. The continued presence of the O alleles is hypothesized to be the result of balancing selection. Both theories contradict the previously held theory that type O blood evolved first.

Origin theories
It is possible that food and environmental antigens (bacterial, viral, or plant antigens) have epitopes similar enough to A and B glycoprotein antigens. The antibodies created against these environmental antigens in the first years of life can cross-react with ABO-incompatible red blood cells that it comes in contact with during blood transfusion later in life. Anti-A antibodies are hypothesized to originate from immune response towards influenza virus, whose epitopes are similar enough to the α-D-N-galactosamine on the A glycoprotein to be able to elicit a cross-reaction. Anti-B antibodies are hypothesized to originate from antibodies produced against Gram-negative bacteria, such as E. coli, cross-reacting with the α-D-galactose on the B glycoprotein.However, it is more likely that the force driving evolution of allele diversity is simply negative frequency-dependent selection; cells with rare variants of membrane antigens are more easily distinguished by the immune system from pathogens carrying antigens from other hosts. Thus, individuals possessing rare types are better equipped to detect pathogens. The high within-population diversity observed in human populations would, then, be a consequence of natural selection on individuals.

Clinical relevance
The carbohydrate molecules on the surfaces of red blood cells have roles in cell membrane integrity, cell adhesion, membrane transportation of molecules, and acting as receptors for extracellular ligands, and enzymes. ABO antigens are found having similar roles on epithelial cells as well as red blood cells.

Bleeding and thrombosis (von Willebrand factor)
The ABO antigen is also expressed on the von Willebrand factor (vWF) glycoprotein, which participates in hemostasis (control of bleeding). In fact, having type O blood predisposes to bleeding, as 30% of the total genetic variation observed in plasma vWF is explained by the effect of the ABO blood group, and individuals with group O blood normally have significantly lower plasma levels of vWF (and Factor VIII) than do non-O individuals. In addition, vWF is degraded more rapidly due to the higher prevalence of blood group O with the Cys1584 variant of vWF (an amino acid polymorphism in VWF): the gene for ADAMTS13 (vWF-cleaving protease) maps to human chromosome 9 band q34.2, the same locus as ABO blood type. Higher levels of vWF are more common amongst people who have had ischemic stroke (from blood clotting) for the first time. The results of this study found that the occurrence was not affected by ADAMTS13 polymorphism, and the only significant genetic factor was the persons blood group.

ABO hemolytic disease of the newborn
ABO blood group incompatibilities between the mother and child do not usually cause hemolytic disease of the newborn (HDN) because antibodies to the ABO blood groups are usually of the IgM type, which do not cross the placenta. However, in an O-type mother, IgG ABO antibodies are produced and the baby can potentially develop ABO hemolytic disease of the newborn.

Clinical applications
In human cells, the ABO alleles and their encoded glycosyltransferases have been described in several oncologic conditions. Using anti-GTA/GTB monoclonal antibodies, it was demonstrated that a loss of these enzymes was correlated to malignant bladder and oral epithelia. Furthermore, the expression of ABO blood group antigens in normal human tissues is dependent the type of differentiation of the epithelium. In most human carcinomas, including oral carcinoma, a significant event as part of the underlying mechanism is decreased expression of the A and B antigens. Several studies have observed that a relative down-regulation of GTA and GTB occurs in oral carcinomas in association with tumor development. More recently, a genome wide association study (GWAS) has identified variants in the ABO locus associated with susceptibility to pancreatic cancer.
In addition, another large GWAS study has associated ABO-histo blood groups as well as FUT2 secretor status with the presence in the intestinal microbiome of specific bacterial species. In this case the association was with Bacteroides and Faecalibacterium spp.  Bacteroides of the same OTU (operational taxonomic unit) have been shown to be associated with inflammatory bowel disease, thus the study suggests an important role for the ABO histo-blood group antigens as candidates for direct modulation of the human microbiome in health and disease.

Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the ABO gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).

Alteration of ABO antigens for transfusion
In April 2007, an international team of researchers announced in the journal Nature Biotechnology an inexpensive and efficient way to convert types A, B, and AB blood into type O. This is done by using glycosidase enzymes from specific bacteria to strip the blood group antigens from red blood cells. The removal of A and B antigens still does not address the problem of the Rh blood group antigen on the blood cells of Rh positive individuals, and so blood from Rh negative donors must be used. The sort of blood is named "enzyme converted to O" (ECO) blood. Patient trials will be conducted before the method can be relied on in live situations. One such Phase II trial was done on B-to-O blood in 2002.Another approach to the blood antigen problem is the manufacture of artificial blood, which could act as a substitute in emergencies.

Pseudoscience
During the 1930s, connecting blood groups to personality types became popular in Japan and other areas of the world. Studies of this association have yet to confirm its existence definitively.Other popular but unsupported ideas include the use of a blood type diet, claims that group A causes severe hangovers, group O is associated with perfect teeth, and those with blood group A2 have the highest IQs </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Herpesviridae and explain in detail? [/INST] Herpesviridae is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ἕρπειν (herpein to creep), referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster (shingles). In 1971, the International Committee on the Taxonomy of Viruses (ICTV) established Herpesvirus as a genus with 23 viruses among four groups. As of 2020, 115 species are recognized, all but one of which are in one of the three subfamilies. Herpesviruses can cause both latent and lytic infections.
Nine herpesvirus types are known to primarily infect humans, at least five of which – herpes simplex viruses 1 and 2 (HSV-1 and HSV-2, also known as HHV-1 and HHV-2; both of which can cause orolabial herpes and genital herpes), varicella zoster virus (or HHV-3; the cause of chickenpox and shingles), Epstein–Barr virus (EBV or HHV-4; implicated in several diseases, including mononucleosis and some cancers), and human cytomegalovirus (HCMV or HHV-5) – are extremely common among humans. More than 90% of adults have been infected with at least one of these, and a latent form of the virus remains in almost all humans who have been infected. Other human herpesviruses are human herpesvirus 6A and 6B (HHV-6A and HHV-6B), human herpesvirus 7 (HHV-7), and Kaposis sarcoma-associated herpesvirus (KSHV, also known as HHV-8).In total,  more than 130 herpesviruses are known, some of them from mammals, birds, fish, reptiles, amphibians, and molluscs. Among the animal herpesviruses are pseudorabies virus, the causative agent of Aujeszkys disease in pigs, and bovine herpesvirus 1, the causative agent of bovine infectious rhinotracheitis and pustular vulvovaginitis.

Taxonomy
Subfamily Alphaherpesvirinae
Iltovirus
Mardivirus
Scutavirus
Simplexvirus
Varicellovirus
Subfamily Betaherpesvirinae
Cytomegalovirus
Muromegalovirus
Proboscivirus
Quwivirus
Roseolovirus
Subfamily Gammaherpesvirinae
Bossavirus
Lymphocryptovirus
Macavirus
Manticavirus
Patagivirus
Percavirus
RhadinovirusAdditionally, the species Iguanid herpesvirus 2 is currently unassigned to a genus and subfamily.See Herpesvirales#Taxonomy for information on taxonomic history, phylogenetic research, and the nomenclatural system.

Structure
All members of the Herpesviridae share a common structure; a relatively large, monopartite, double-stranded, linear DNA genome encoding 100-200 genes encased within an icosahedral protein cage (with T=16 symmetry) called the capsid, which is itself wrapped in a protein layer called the tegument containing both viral proteins and viral mRNAs and a lipid bilayer membrane called the envelope. This whole particle is known as a virion.
The structural components of a typical HSV virion are the Lipid bilayer envelope, Tegument, DNA, Glycoprotein spikes and Nucleocapsid. The four-component Herpes simplex virion encompasses the double-stranded DNA genome into an icosahedral nucleocapsid. There is tegument around. Tegument contains filaments, each 7 nm wide. It is an amorphous layer with some structured regions. Finally, it is covered with a lipoprotein envelope. There are spikes made of glycoprotein protruding from each virion. These can expand the diameter of the virus to 225 nm. The diameters of virions without spikes are around 186 nm. There are at least two unglycosylated membrane proteins in the outer envelope of the virion. There are also 11 glycoproteins. These are gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL and gM. Tegument contains 26 proteins. They have duties such as capsid transport to the nucleus and other organelles, activation of early gene transcription, and mRNA degradation. The icosahedral nucleocapsid is similar to that of tailed bacteriophage in the order Caudovirales. This capsid has 161 capsomers consisting of 150 hexons and 11 pentons, as well as a portal complex that allows entry and exit of DNA into the capsid.

Life cycle
All herpesviruses are nuclear-replicating—the viral DNA is transcribed to mRNA within the infected cells nucleus.Infection is initiated when a viral particle contacts a cell with specific types of receptor molecules on the cell surface.  Following binding of viral envelope glycoproteins to cell membrane receptors, the virion is internalized and dismantled, allowing viral DNA to migrate to the cell nucleus. Within the nucleus, replication of viral DNA and transcription of viral genes occurs.During symptomatic infection, infected cells transcribe lytic viral genes. In some host cells, a small number of viral genes termed latency-associated transcript (LAT) accumulate, instead. In this fashion, the virus can persist in the cell (and thus the host) indefinitely. While primary infection is often accompanied by a self-limited period of clinical illness, long-term latency is symptom-free.Chromatin dynamics regulate the transcription competency of entire herpes virus genomes. When the virus enters a cell, the cellular immune response is to protect the cell. The cell does so by wrapping the viral DNA around histones and condensing it into chromatin, causing the virus to become dormant, or latent. If cells are unsuccessful and the chromatin is loosely bundled, the viral DNA is still accessible. The viral particles can turn on their genes and replicate using cellular machinery to reactivate, starting a lytic infection.Reactivation of latent viruses has been implicated in a number of diseases (e.g. shingles, pityriasis rosea).  Following activation, transcription of viral genes transitions from LAT to multiple lytic genes; these lead to enhanced replication and virus production. Often, lytic activation leads to cell death. Clinically, lytic activation is often accompanied by emergence of nonspecific symptoms, such as low-grade fever, headache, sore throat, malaise, and rash, as well as clinical signs such as swollen or tender lymph nodes and immunological findings such as reduced levels of natural killer cells.In animal models, local trauma and system stress have been found to induce reactivation of latent herpesvirus infection. Cellular stressors like transient interruption of protein synthesis and hypoxia are also sufficient to induce viral reactivation.

Evolution
The three mammalian subfamilies – Alpha-, Beta- and Gamma-herpesviridae – arose approximately 180 to 220 mya. The major sublineages within these subfamilies were probably generated before the mammalian radiation of 80 to 60 mya. Speciations within sublineages took place in the last 80 million years probably with a major component of cospeciation with host lineages.All the currently known bird and reptile species are alphaherpesviruses. Although the branching order of the herpes viruses has not yet been resolved, because herpes viruses and their hosts tend to coevolve this is suggestive that the alphaherpesviruses may have been the earliest branch.The time of origin of the genus Iltovirus has been estimated to be 200 mya while those of the mardivirus and simplex genera have been estimated to be between 150 and 100 mya.

Immune system evasions
Herpesviruses are known for their ability to establish lifelong infections. One way this is possible is through immune evasion. Herpesviruses have many different ways of evading the immune system. One such way is by encoding a protein mimicking human interleukin 10 (hIL-10) and another is by downregulation of the major histocompatibility complex II (MHC II) in infected cells.

cmvIL-10
Research conducted on cytomegalovirus (CMV) indicates that the viral human IL-10 homolog, cmvIL-10, is important in inhibiting pro-inflammatory cytokine synthesis. The cmvIL-10 protein has 27% identity with hIL-10 and only one conserved residue out of the nine amino acids that make up the functional site for cytokine synthesis inhibition on hIL-10. There is, however, much similarity in the functions of hIL-10 and cmvIL-10. Both have been shown to down regulate IFN-γ, IL-1α, GM-CSF, IL-6 and TNF-α, which are all pro-inflammatory cytokines. They have also been shown to play a role in downregulating MHC I and MHC II and up regulating HLA-G (non-classical MHC I). These two events allow for immune evasion by suppressing the cell-mediated immune response and natural killer cell response, respectively. The similarities between hIL-10 and cmvIL-10 may be explained by the fact that hIL-10 and cmvIL-10 both use the same cell surface receptor, the hIL-10 receptor.  One difference in the function of hIL-10 and cmvIL-10 is that hIL-10 causes human peripheral blood mononuclear cells (PBMC) to both increase and decrease in proliferation whereas cmvIL-10 only causes a decrease in proliferation of PBMCs. This indicates that cmvIL-10 may lack the stimulatory effects that hIL-10 has on these cells.It was found that cmvIL-10 functions through phosphorylation of the Stat3 protein. It was originally thought that this phosphorylation was a result of the JAK-STAT pathway. However, despite evidence that JAK does indeed phosphorylate Stat3, its inhibition has no significant influence on cytokine synthesis inhibition. Another protein, PI3K, was also found to phosphorylate Stat3. PI3K inhibition, unlike JAK inhibition, did have a significant impact on cytokine synthesis. The difference between PI3K and JAK in Stat3 phosphorylation is that PI3K phosphorylates Stat3 on the S727 residue whereas JAK phosphorylates Stat3 on the Y705 residue. This difference in phosphorylation positions seems to be the key factor in Stat3 activation leading to inhibition of pro-inflammatory cytokine synthesis. In fact, when a PI3K inhibitor is added to cells, the cytokine synthesis levels are significantly restored. The fact that cytokine levels are not completely restored indicates there is another pathway activated by cmvIL-10 that is inhibiting cytokine system synthesis. The proposed mechanism is that cmvIL-10 activates PI3K which in turn activates PKB (Akt). PKB may then activate mTOR, which may target Stat3 for phosphorylation on the S727 residue.

MHC downregulation
Another one of the many ways in which herpes viruses evade the immune system is by down regulation of MHC I and MHC II. This is observed in almost every human herpesvirus. Down regulation of MHC I and MHC II can come about by many different mechanisms, most causing the MHC to be absent from the cell surface. As discussed above, one way is by a viral chemokine homolog such as IL-10. Another mechanism to down regulate MHCs is to encode viral proteins that detain the newly formed MHC in the endoplasmic reticulum (ER) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Plague and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Coital incontinence and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Trichostrongylus and explain in detail? [/INST] Trichostrongylus species are nematodes (round worms), which are ubiquitous among herbivores worldwide, including cattle, sheep, donkeys, goats, deer, and rabbits.
At least 10 Trichostrongylus species have been associated with human infections. Infections occur via ingestion of infective larvae from contaminated vegetables or water. Epidemiological studies indicate a worldwide distribution of Trichostrongylus infections in humans, with the highest prevalence rates observed in individuals from regions with poor sanitary conditions, in rural areas, or who are farmers / herders. Human infections are most prevalent in the Middle East and Asia, with a worldwide estimated prevalence of 5.5 million people.

Life cycle
Eggs are passed through the feces of an infected definitive host, usually a mammalian herbivore including rabbits, sheep, cattle, and rodents. Under certain environmental conditions, which include optimal temperature and humidity, larvae hatch from eggs after several days. Hatched rhabditiform larvae grow on vegetation or within soil. After 5 to 10 days, two molts (L1 & L2) have occurred and the parasite becomes a filariform (L3) larvae that is infectious. Infection in mammals occurs upon ingestion of infective filariform (L3) larvae. The larvae reaches the small intestine to reside and mature into adult worms within their definitive hosts. Infections in humans may occur as incidental infections. Trichostrongylus consists of multiple species that relate to each of its host, when it comes to parasitic survival and infection. For example, Trichostrongylus affinis primarily infects cottontail rats, Trichostrongylus sigmodontis affects hispid cotton rat, and marsh rice rat, and Trichostrongylus retortaeformis primarily affects European rabbits (Oryctolagus cuniculus).

Clinical presentation
The majority of human infections are asymptomatic or associated with mild symptoms. Symptomatic individuals may experience abdominal pain, nausea, diarrhea, flatulence, dizziness, generalized fatigue, and malaise. Eosinophilia is frequently observed. Infections with a heavy worm burden can lead to anemia, cholecystitis, and emaciation </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Vaginal septum and explain in detail? [/INST] A vaginal septum is a vaginal anomaly that is partition within the vagina; such a septum could be either longitudinal or transverse </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Military vehicle and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Megavitamin-B6 syndrome and explain in detail? [/INST] Megavitamin-B6 syndrome is a collection of symptoms that can result from chronic supplementation, or acute overdose, of vitamin B6. While it is also known as hypervitaminosis B6, vitamin B6 toxicity and vitamin B6 excess, megavitamin-b6 syndrome is the name used in the ICD-10.

Signs and symptoms
The predominant symptom is peripheral sensory neuropathy that is experienced as numbness, pins-and-needles and burning sensations (paresthesia) in a patients limbs on both sides of their body. Patients may experience unsteadiness of gait, incoordination (ataxia), involuntary muscle movements (choreoathetosis) the sensation of an electric zap in their bodies (Lhermittes sign), a heightened sensitivity to sense stimuli including photosensitivity (hyperesthesia), impaired skin sensation (hypoesthesia), numbness around the mouth, and gastrointestinal symptoms such as nausea and heartburn. The ability to sense vibrations and to sense ones position are diminished to a greater degree than pain or temperature. Skin lesions have also been reported. Megavitamin-B6 syndrome may also contribute to burning mouth syndrome. Potential psychiatric symptoms range from anxiety, depression, agitation, and cognitive deficits to psychosis.Symptom severity appears to be dose-dependent (higher doses cause more severe symptoms) and the duration of supplementation with vitamin B6 before onset of systems appears to be inversely proportional to the amount taken daily (the smaller the daily dosage, the longer it will take for symptoms to develop). It is also possible that some individuals are more susceptible to the toxic effects of vitamin B6 than others. Megavitamin-B6 syndrome has been reported in doses as low as 24 mg/day.Symptoms may also be dependent on the form of vitamin B6 taken in supplements. It has been proposed that vitamin B6 in supplements should be in pyridoxal or pyridoxal phosphate form rather than pyridoxine as these are thought to reduce the likelihood of toxicity. A tissue culture study, however, showed that all B6 vitamers that could be converted into active coenzymes (pyridoxal, pyridoxine and pyridoxamine) were neurotoxic at similar concentrations. It has been shown, in vivo, that supplementing with pyridoxal or pyridoxal phosphate increases pyridoxine concentrations in humans, meaning there are metabolic pathways from each vitamer of B6 to the all other forms. Consuming high amounts of vitamin B6 from food has not been reported to cause adverse effects.Early diagnosis and cessation of vitamin B6 supplementation can reduce the morbidity of the syndrome.

Cause
While vitamin B6 is water-soluble, it has a half-life of 25–33 days and accumulates in the body where it is stored in muscle, plasma, the liver, red blood cells and bound to proteins in tissues.

Potential mechanisms
The common supplemental form of vitamin B6, pyridoxine, is similar to pyridine which can be neurotoxic. Pyridoxine has limited transport across the blood–brain barrier explaining why the central nervous system is spared. Cell bodies of motor fibers are located within the spinal cord that is also restricted by the blood-brain barrier explaining why motor impairment is rare. The dorsal root ganglia, however, are located outside of the blood-brain barrier making them more susceptible.Pyridoxine is converted to pyridoxal phosphate via two enzymes, pyridoxal kinase and pyridoxine 5′-phosphate oxidase. High levels of pyridoxine can inhibit these enzymes. As pyridoxal phosphate is the active form of vitamin B6, this saturation of pyridoxine could mimic a deficiency of vitamin B6.

Tolerable upper limits
Several government agencies have reviewed the data on vitamin B6 supplementation and produced consumption upper limits with the desired goal to prevent sensory neuropathy from excessive amounts. Each agency developed its own criteria for usable studies in relation to tolerable upper limits, and as such the recommendations vary by agency. Between agencies, current tolerable upper limit guidelines vary from 10 mg per day to 100 mg per day.
Reviews of vitamin B6 related neuropathy cautioned that supplementation at doses greater than 50 mg per day for extended periods of time may be harmful and should be discouraged. In 2008, the Australian Complementary Medicines Evaluation Committee recommended warning statements appear on products containing daily doses of 50 mg or more vitamin B6 to avoid toxicity.The relationship between the amount of vitamin B6 consumed, and serum the levels of those who consume it, varies between individuals. Some people may have high serum concentrations without symptoms of neuropathy. It is not known if inhalation of vitamin B6 while, for example, working with animal feed containing vitamin B6 is safe.

Exceptions
High parenteral doses of vitamin B6 are used to treat isoniazid overdose with no adverse effects found, although a preservative in parenteral vitamin B6 may cause transient worsening of metabolic acidosis. High doses of vitamin B6 are used to treat gyromitra mushroom (false morel) poisoning, hydrazine exposure and homocystinuria Doses of 50 mg to 100 mg per day may also be used to treat pyridoxine deficient seizures and when patients are taking other medications that reduce vitamin B6. Daily doses of 10 mg to 50 mg are recommended for patients undergoing hemodialysis.Outside of rare medical conditions, placebo-controlled studies have generally failed to show benefits of high doses of vitamin B6. Reviews of supplementing with vitamin B6 have not found it to be effective at reducing swelling, reducing stress, producing energy, preventing neurotoxicity, or treating asthma. A

Diagnosis
The clinical hallmark of megavitamin-B6 syndrome is ataxia due to sensory polyneuropathy. Blood tests are performed to rule out other causes and to confirm an elevated level of vitamin B6 with an absence of hypophosphatasia. Examination does not typically show signs of a motor deficit, dysfunction of the autonomic nervous system or impairment of the central nervous system, although in severe cases motor and autonomic imparement can occur. When examined, patients typically have diminished reflexes (hyporeflexia), such as a diminished response when performing an ankle jerk reflex test. Nerve conduction studies typically show normal motor conduction but decrease in large sensory wave amplitude in the arms and legs. Needle electromyography studies generally reveal no signs of denervation.

Classification
Megavitamin-B6 syndrome is characterized mainly by degeneration of dorsal root ganglion axons and cell bodies, although it also affects the trigeminal ganglia. It is classified as a sensory ganglionopathy due to involvement of these ganglia. In electrodiagnostic testing,
it has characteristic non-length-dependent abnormalities of sensory action potentials that occur globally, rather than distally decreasing of sensory nerve action potential amplitudes. Megavitamin-B6 syndrome is predominately a large fiber neuropathy characterized by sensory loss of joint position, vibration and ataxia. Although it has characteristics of small fiber neuropathy in severe cases where there is impairment of pain, temperature, and autonomic functions.

Treatment
The primary treatment for megavitamin-B6 syndrome is to stop taking supplemental vitamin B6. Physical therapy, including vestibular rehabilitation, has been used in attempts to improve recovery following cessation of vitamin B6 supplementation. Medications such as amitriptyline have been used to help with neuropathic pain.In experimental tests using animal subjects, neurotrophic factors, specifically neurotrophin-3, were shown to potentially reverse the neuropathy caused from the vitamin B6 toxicity. With rats and mice, improvement has also been seen with 4-methylcatechol, a specific chicory extract, coffee and trigonelline.

Prognosis
Other than with extremely high doses of vitamin B6, neurologic dysfunction improves following cessation of vitamin B6 supplementation and usually, but not always, resolves within six months. In cases of acute high doses, for example in people receiving daily doses of 2 grams of vitamin B6 per kilogram of body weight, symptoms may be irreversible and may additionally cause pseudoathetosis.In the immediate 2–6 weeks following discontinuation of vitamin B6, patients may experience a symptom progression before gradual improvement begins. This is known as coasting and is encountered in other toxic neuropathies. A vitamin B6 substance dependency may exist in daily dosages of 200 mg or more, making a drug withdrawal effect possible when discontinued.

See also
Notes
References
Further reading
A chapter with a story about a woman experiencing a severe case of Megavitamin-B6 syndrome titled "The Disembodied Lady" appears in Chapter 3 of The Man Who Mistook His Wife for a Hat: Oliver Sacks; Oliver W. Sacks (1998). "Chapter 3: The Disembodied Lady". The Man Who Mistook His Wife For A Hat: And Other Clinical Tales. Simon and Schuster. pp </s>