<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 Alternating hemiplegia of childhood and can you explain it in depth? [/INST] Alternating hemiplegia of childhood is an ultra-rare neurological disorder named for the transient episodes, often referred to as "attacks", of hemiplegia (weakness or paralysis) from which those with the disorder suffer. It typically presents before the age of 18 months. These hemiplegic attacks can cause anything from mild weakness to complete paralysis on one or both sides of the body, and they can vary greatly in duration. Attacks may also alternate from one side of the body to the other, or alternate between affecting one or both sides during a single attack. Besides hemiplegia, symptoms of the disorder include an extremely broad range of neurological and developmental impairments which are not well understood. Normally, hemiplegia and other associated symptoms cease completely with sleep, but they may recur upon waking.Most frequently AHC is caused by a spontaneous mutation in the ATP1A3 gene. It is an extremely rare disorder – approximately 1 in 1,000,000 people have AHC. It was only recently discovered, having first been characterized in 1971.

Signs and symptoms
AHC patients exhibit a wide range of symptoms in addition to hemiplegic attacks. These can be further characterized as paroxysmal and non-paroxysmal symptoms. Paroxysmal symptoms are generally associated with hemiplegic attacks and may occur suddenly with hemiplegia or on their own. Paroxysmal symptoms may last for variable amounts of time. Non-paroxysmal symptoms tend to be side effects of AHC which are present at all times, not just during episodes or attacks. Epilepsy, which is also considered a paroxysmal symptom, plays an important role in the progression and diagnosis of AHC.

Hemiplegic attacks
Chronologically, hemiplegic attacks are not always the first symptom of AHC, but they are the most prominent symptom, as well as the symptom for which the disorder is named. Hemiplegic attacks may affect one or both sides of the body, and attacks which affect both sides of the body may be referred to as either bilateral or quadriplegic attacks. One of the unique characteristics of AHC is that hemiplegic attacks, as well as other symptoms which may co-occur with hemiplegia, cease immediately upon sleep. During strong attacks, the symptoms may reoccur upon waking. Hemiplegic attacks can occur suddenly or gradually, and the severity of an attack can vary over its duration. The attacks may alternate from one side of the body to another, though this is rare. The length of attacks may also vary from minutes to weeks, though length of attacks varies more greatly between people than between attacks for one person. Both bilateral and hemiplegic attacks are associated with pseudobulbar features such as dysphagia, dysarthria, and respiratory difficulty. Paralysis is also often accompanied by changes in skin color and temperature, sweating, restlessness, tremor, screaming, and the appearance of pain. Hemiplegic attacks happen irregularly and can occur with speech, eating, and swallowing impairment. Patients with AHC are frequently underweight due to these side effects. The average age of onset for hemiplegic episodes has been found to be 6–7 months of age. This early onset gives the name of this disorder the slightly misleading ending "of childhood". AHC is not exclusively limited to childhood – attacks in some cases become milder after the first ten years of life, but they never completely disappear.

Paroxysmal symptoms
AHC patients have exhibited various paroxysmal symptoms which manifest to different degrees in each person. Paroxysmal symptoms include tonic, tonic-clonic, or myoclonic limb movements, dystonic posturing, choreoathetosis, ocular nystagmus, and various other ocular motor abnormalities. Almost half of all people have dystonic symptoms prior to experiencing hemiplegia. These symptoms generally begin before 8 months of age. Ocular motor abnormalities occur early, and these are the most frequent early symptoms of AHC, particularly nystagmus. Almost 1/3 of people with this disorder had episodic ocular motor features within 1–2 days of birth. Many also experienced hemiplegia and dystonia before 3 months of age. A final symptom that may be considered paroxysmal is a temporary change in behavior - some patients will become unreasonable, demanding, and aggressive either before or after an attackNot all patients have all of these symptoms, and it is not known whether they are caused by AHC. Symptoms usually manifest in the first 3 months of the childs life, with an average onset of 2.5 months. Frequently, some of these symptoms will manifest in the neonatal period. These paroxysmal symptoms are often used to help diagnose AHC, since there is no simple test for it.In some cases, EEGs taken during these paroxysmal events were characterized by a generalized background slowing. Overall however, EEG during episodes and other investigative methods such as brain MRI, TACs, angiographic MRIs and CFS have normal results.

Non-paroxysmal symptoms
In the long term, many paroxysmal symptoms occur along with AHC, and while these symptoms vary in strength depending on the person, they are consistent features of AHC. It is thought that some of these symptoms are brought on or worsened by hemiplegic attacks, though it is not known for certain. Patients suffer persistent motor, movement (ataxia), and cognitive deficits. These deficits become more apparent over time and include developmental delays, social problems, and retardation. It is rare for someone with AHC not to have cognitive deficits, but a study in Japan did find two patients who met all of the diagnostic criteria for AHC but who were not mentally impaired. It is not known whether AHC is a progressive disease, but severe attacks are suspected to cause damage which result in permanent loss of function. 100% of children studied in the USA have had some form of mental impairment, which is usually described as mild to moderate, but varies greatly among individuals.

Epilepsy
At least 50% of AHC sufferers also suffer from epilepsy, and AHC is often misdiagnosed as epilepsy because of this. These epileptic events are distinguished from other episodes by an alteration of consciousness, as well as frequent tonic or tonic-clonic activity. Epileptic episodes are generally rare, though they do increase with age. Due to the rarity of epileptic episodes, there are few EEG confirmations of them.

Cause
Recent research suggests that AHC is caused by a de novo (spontaneous) genetic mutation in the ATP1A3 gene on chromosome 19 (locus 19q13.31) which encodes enzyme ATP1A3. A small number of cases seem to be caused by a mutation in the ATP1A2 gene. Where the mutation is inherited, it has the autosomal dominant pattern of inheritance.Previously AHC was thought to be a form of complicated migraine because of strong family histories of migraine reported in AHC cases. AHC has also been considered to be a movement disorder or a form of epilepsy. Suggested causes have included channelopathy, mitochondrial dysfunction, and cerebrovascular dysfunction. The disorder most closely related to AHC is familial hemiplegic migraine which is caused by a mutation in a gene for calcium channel receptors. It was thus thought that AHC may be caused by a similar channelopathy.

Diagnosis
As of 1993 only approximately 30 people with AHC had been described in scientific literature. Due to the rarity and complexity of AHC, it is not unusual for the initial diagnosis to be incorrect, or for diagnosis to be delayed for several months after the initial symptoms become apparent. The average age of diagnosis is just over 36 months. Diagnosis of AHC is not only difficult because of its rarity, but because there is no diagnostic test, making this a diagnosis of exclusion.  There are several generally accepted criteria which define this disorder, however other conditions with a similar presentation, such as HSV encephalitis, must first be ruled out.  Due to these diagnostic difficulties, it is possible that the commonness of the disease is underestimated.The following descriptions are commonly used in the diagnosis of AHC. The initial four criteria for classifying AHC were that it begins before 18 months of age, includes attacks of both hemiplegia on either side of the body, as well as other autonomic problems such as involuntary eye movement (episodic monocular nystagmus), improper eye alignment, choreoathetosis, and sustained muscle contractions (dystonia). Finally, patients suffer from intellectual disabilities, delayed development, and other neurological abnormalities. These diagnostic criteria were updated in 1993 to include the fact that all of these symptoms dissipate immediately upon sleeping. Diagnostic criteria were also expanded to include episodes of bilateral hemiplegia which shifted from one side of the body to the other.Recent criteria have been proposed for screening for AHC early, in order to improve the diagnostic timeline. These screening criteria include focal or unilateral paroxysmal dystonia in the first 6 months of life, as well as the possibility of flaccid hemiplegia either with or separate from these symptoms. Paroxysmal ocular movements should also be considered, and these should include both binocular and monocular symptoms which show in the first 3 months of life.

Treatments
Overall outcomes for AHC are generally poor, which is contributed to by AHCs various diagnostic and management challenges. In the long term, AHC is debilitating due to both the hemiplegic attacks and permanent damage associated with AHC. This damage can include cognitive impairment, behavioral and psychiatric disorders, and various motor impairments. There is, however, not yet any conclusive evidence that AHC is fatal or that it shortens life expectancy, but the relatively recent discovery of the disorder makes large data for this type of information unavailable. Treatment for AHC has not been extremely successful, and there is no cure. There are several drugs available for treatment, as well as management strategies for preventing and dealing with hemiplegic attacks.

Management strategies
Hemiplegic attacks can be brought on by particular triggers, and management of AHC often centers around avoiding common or known triggers. While triggers vary greatly from person to person, there are also some common ones which are prevalent in many patients. Common triggers include temperature changes, water exposure, bright lights, certain foods, emotional stress, and physical activity. While avoiding triggers may help, it cannot prevent all hemiplegic episodes because many occur without being triggered. Because attacks and other associated symptoms end with sleep, various sedatives can be used to help patients sleep.

Flunarizine
The most common drug used to treat AHC is flunarizine. Flunarizine functions by acting as a calcium channel blocker. Other drugs, in order of frequency of use are benzodiazepines, carbamazapine, barbiturates, and valproic acid </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 Aortic dissection and can you explain it in depth? [/INST] Aortic dissection (AD) occurs when an injury to the innermost layer of the aorta allows blood to flow between the layers of the aortic wall, forcing the layers apart. In most cases, this is associated with a sudden onset of severe chest or back pain, often described as "tearing" in character. Also, vomiting, sweating, and lightheadedness may occur. Other symptoms may result from decreased blood supply to other organs, such as stroke, lower extremity ischemia, or mesenteric ischemia. Aortic dissection can quickly lead to death from insufficient blood flow to the heart or complete rupture of the aorta.AD is more common in those with a history of high blood pressure; a number of connective tissue diseases that affect blood vessel wall strength including Marfan syndrome and Ehlers–Danlos syndrome; a bicuspid aortic valve; and previous heart surgery. Major trauma, smoking, cocaine use, pregnancy, a thoracic aortic aneurysm, inflammation of arteries, and abnormal lipid levels are also associated with an increased risk. The diagnosis is suspected based on symptoms with medical imaging, such as computed tomography, magnetic resonance imaging, or ultrasound used to confirm and further evaluate the dissection. The two main types are Stanford type A, which involves the first part of the aorta, and type B, which does not.Prevention is by blood pressure control and smoking cessation. Management of AD depends on the part of the aorta involved. Dissections that involve the first part of the aorta (adjacent to the heart) usually require surgery. Surgery may be done either by an opening in the chest or from inside the blood vessel. Dissections that involve the second part of the aorta can typically be treated with medications that lower blood pressure and heart rate, unless there are complications which then require surgical correction.AD is relatively rare, occurring at an estimated rate of three per 100,000 people per year. It is more common in men than women. The typical age at diagnosis is 63, with about 10% of cases occurring before the age of 40. Without treatment, about half of people with Stanford type A dissections die within three days and about 10% of people with Stanford type B dissections die within one month. The first case of AD was described in the examination of King George II of Great Britain following his death in 1760. Surgery for AD was introduced in the 1950s by Michael E. DeBakey.

Signs and symptoms
About 96% of individuals with AD present with severe pain that had a sudden onset. The pain may be described as a tearing, stabbing, or sharp sensation in the chest, back, or abdomen. About 17% of individuals feel the pain migrate as the dissection extends down the aorta. The location of pain is associated with the location of the dissection. Anterior chest pain is associated with dissections involving the ascending aorta, while interscapular back pain is associated with descending aortic dissections. If the pain is pleuritic in nature, it may suggest acute pericarditis caused by bleeding into the sac surrounding the heart. This is a particularly dangerous eventuality, suggesting that acute pericardial tamponade may be imminent. Pericardial tamponade is the most common cause of death from AD.While the pain may be confused with that of a heart attack, AD is usually not associated with the other suggestive signs, such as heart failure and ECG changes. Less common symptoms that may be seen in the setting of AD include congestive heart failure (7%), fainting (9%), stroke (6%), ischemic peripheral neuropathy, paraplegia, and cardiac arrest. If the individual fainted, about half the time it is due to bleeding into the pericardium, leading to pericardial tamponade. Neurological complications of aortic dissection, such as stroke and paralysis, are due to the involvement of one or more arteries supplying portions of the central nervous system.If the AD involves the abdominal aorta, compromise of one or both renal arteries occurs in 5–8% of cases, while ischemia of the intestines occurs about 3% of the time.

Blood pressure
People with AD often have a history of high blood pressure. The blood pressure is quite variable at presentation with acute AD. It tends to be higher in individuals with a distal dissection. In individuals with a proximal AD, 36% present with hypertension, while 25% present with hypotension. Proximal AD tends to be associated with weakening of the vascular wall due to cystic medial degeneration. In those who present with distal (Stanford type B) AD, 60–70% present with high blood pressure, while 2–3% present with low blood pressure.Severe hypotension at presentation is a grave prognostic indicator. It is usually associated with pericardial tamponade, severe aortic insufficiency, or rupture of the aorta. Accurate measurement of blood pressure is important. Pseudohypotension (falsely low blood-pressure measurement) may occur due to involvement of the brachiocephalic artery (supplying the right arm) or the left subclavian artery (supplying the left arm).

Aortic insufficiency
Aortic insufficiency (AI) occurs in half to two-thirds of ascending AD, and the diastolic heart murmur of aortic insufficiency is audible in about 32% of proximal dissections. The intensity (loudness) of the murmur depends on the blood pressure and may be inaudible in the event of low blood pressure.Multiple causes exist for AI in the setting of ascending AD. The dissection may dilate the annulus of the aortic valve, preventing the leaflets of the valve from coapting. The dissection may extend into the aortic root and detach the aortic valve leaflets. Alternatively, following an extensive intimal tear, the intimal flap may prolapse into the left ventricular outflow tract, causing intimal intussusception into the aortic valve, thereby preventing proper valve closure.

Myocardial infarction
Heart attack occurs in 1–2% of aortic dissections. Infarction is caused by the involvement of the coronary arteries, which supply the heart with oxygenated blood, in the dissection. The right coronary artery is involved more commonly than the left coronary artery. If the myocardial infarction is treated with thrombolytic therapy, the mortality increases to over 70%, mostly due to bleeding into the pericardial sac, causing cardiac tamponade.

Pleural effusion
A pleural effusion (fluid collection in the space between the lungs and the chest wall or diaphragm) can be due to either blood from a transient rupture of the aorta or fluid due to an inflammatory reaction around the aorta. If a pleural effusion were to develop due to AD, it is more common in the left hemithorax rather than the right hemithorax.

Causes
Aortic dissection is associated with hypertension (high blood pressure) and many connective tissue disorders. Vasculitis (inflammation of an artery) is rarely associated with aortic dissection. It can also be the result of chest trauma. About 72 to 80% of individuals who present with an aortic dissection have a previous history of hypertension. Illicit drug use with stimulants such as cocaine and methamphetamine is also a modifiable risk factor for AD. It can also be caused by smoking.
A bicuspid aortic valve (a type of congenital heart disease involving the aortic valve) is found in 7–14% of individuals who have an aortic dissection. These individuals are prone to dissection in the ascending aorta. The risk of dissection in individuals with bicuspid aortic valves is not associated with the degree of stenosis of the valve.Connective tissue disorders such as Marfan syndrome, Ehlers–Danlos syndrome, and Loeys–Dietz syndrome increase the risk of aortic dissection. Similarly, vasculitides such as Takayasus arteritis, giant cell arteritis, polyarteritis nodosa, and Behçets disease have been associated with a subsequent aortic dissection.  Marfan Syndrome is found in 5–9% of individuals who had an aortic dissection. In this subset, the incidence in young individuals is increased. Individuals with Marfan syndrome tend to have aneurysms of the aorta and are more prone to proximal dissections of the aorta.Turner syndrome also increases the risk of aortic dissection, by aortic root dilatation.Chest trauma leading to aortic dissection can be divided into two groups based on cause: blunt chest trauma (commonly seen in car accidents) and iatrogenic. Iatrogenic causes include trauma during cardiac catheterization or due to an intra-aortic balloon pump.Aortic dissection may be a late sequela of heart surgery. About 18% of individuals who present with an acute aortic dissection have a history of open-heart surgery. Individuals who have undergone aortic valve replacement for aortic insufficiency are at particularly high risk because aortic regurgitation causes increased blood flow in the ascending aorta. This can cause dilatation and weakening of the walls of the ascending aorta.Syphilis only potentially causes aortic dissection in its tertiary stage.

Pathophysiology
As with all other arteries, the aorta is made up of three layers, the intima, the media, and the adventitia. The intima is in direct contact with the blood inside the vessel, and mainly consists of a layer of endothelial cells on a basement membrane; the media contains connective and muscle tissue, and the vessel is protected on the outside by the adventitia, comprising connective tissue.In an aortic dissection, blood penetrates the intima and enters the media layer. The high pressure rips the tissue of the media apart along the laminated plane splitting the inner two-thirds and the outer one-third of the media apart. This can propagate along the length of the aorta for a variable distance forward or backward. Dissections that propagate towards the iliac bifurcation (with the flow of blood) are called anterograde dissections and those that propagate towards the aortic root (opposite of the flow of blood) are called retrograde dissections. The initial tear is usually within 100 mm of the aortic valve, so a retrograde dissection can easily compromise the pericardium leading to a hemopericardium. Anterograde dissections may propagate all the way to the iliac bifurcation of the aorta, rupture the aortic wall, or recanalize into the intravascular lumen leading to a double-barrel aorta. The double-barrel aorta relieves the pressure of blood flow and reduces the risk of rupture. Rupture leads to hemorrhaging into a body cavity, and prognosis depends on the area of rupture. Retroperitoneal and pericardial ruptures are both possible.

The initiating event in aortic dissection is a tear in the intimal lining of the aorta. Due to the high pressures in the aorta, blood enters the media at the point of the tear.  The force of the blood entering the media causes the tear to extend. It may extend proximally (closer to the heart) or distally (away from the heart) or both. The blood travels through the media, creating a false lumen (the true lumen is the normal conduit of blood in the aorta). Separating the false lumen from the true lumen is a layer of intimal tissue known as the intimal flap.The vast majority of aortic dissections originate with an intimal tear in either the ascending aorta (65%), the aortic arch (10%), or just distal to the ligamentum arteriosum in the descending thoracic aorta (20%).As blood flows down the false lumen, it may cause secondary tears in the intima. Through these secondary tears, the blood can re-enter the true lumen.While it is not always clear why an intimal tear may occur, quite often it involves degeneration of the collagen and elastin that make up the media. This is known as cystic medial necrosis and is most commonly associated with Marfan syndrome and is also associated with Ehlers-Danlos syndrome.In about 13% of aortic dissections, no evidence of an intimal tear is found. In these cases, the inciting event is thought to be an intramural hematoma (caused by bleeding within the media). Since no direct connection exists between the true lumen and the false lumen in these cases, diagnosing an aortic dissection by aortography is difficult if the cause is an intramural hematoma. An aortic dissection secondary to an intramural hematoma should be treated the same as one caused by an intimal tear.

Diagnosis
Because of the varying symptoms of aortic dissection, the diagnosis is sometimes difficult to make. Concern should be increased in those with low blood pressure, neurological problems, and an unequal pulses.While taking a good history from the individual may be strongly suggestive of an aortic dissection, the diagnosis cannot always be made by history and physical signs alone.  Often, the diagnosis is made by visualization of the intimal flap on a diagnostic imaging test. Common tests used to diagnose an aortic dissection include a CT scan of the chest with iodinated contrast material and a transesophageal echocardiogram. The proximity of the aorta to the esophagus allows the use of higher-frequency ultrasound for better anatomical images. Other tests that may be used include an aortogram or magnetic resonance angiogram of the aorta.  Each of these tests has pros and cons, and they do not have equal sensitivities and specificities in the diagnosis of aortic dissection.In general, the imaging technique chosen is based on the pretest likelihood of the diagnosis, availability of the testing modality, patient stability, and the sensitivity and specificity of the test.

D-dimer
A measurement of blood D-dimer level may be useful in diagnostic evaluation. A level less than 500 ng/ml may be considered evidence against a diagnosis of aortic dissection, although this guideline is only applicable in cases deemed "low risk" and within 24 hours of symptom onset. The American Heart Association does not advise using this test in making the diagnosis, as evidence is still tentative.

Chest X-ray
Chest radiography may although demonstrate a change in the morphology of the thoracic aorta which can be seen in aortic dissection. Classically, new widening of the mediastinum on radiograph is of moderate sensitivity for detecting an ascending aortic dissection; however, this finding is of low specificity, as many other conditions can cause apparent widening of the mediastinum.There are several other associated radiographic findings:
The "calcium sign" describes an apparent separation of the intimal calcification from the outer aortic margin by greater than 10 mm.
Pleural effusions, more commonly in descending aortic dissections, and typically left-sided.
Other: the obliteration of the aortic knob, depression of the left mainstem bronchus, loss of the paratracheal stripe, and tracheal deviation.Importantly, about 12 to 20% of aortic dissections are not detectable by chest radiograph; therefore, a "normal" chest radiograph does not rule out aortic dissection. If there is high clinical suspicion, a more sensitive imaging test (CT angiogram, MR angiography, or transesophageal echo) may be warranted.

Computed tomography
Computed tomography angiography is a fast, non-invasive test that gives an accurate three-dimensional view of the aorta. These images are produced by taking rapid, thin-cut slices of the chest and abdomen, and combining them in the computer to create cross-sectional slices. To delineate the aorta to the accuracy necessary to make the proper diagnosis, an iodinated contrast material is injected into a peripheral vein. Contrast is injected and the scan performed using a bolus tracking method. This type of scan is timed to injection to capture the contrast as it enters the aorta. The scan then follows the contrast as it flows through the vessel. It has a sensitivity of 96 to 100% and a specificity of 96 to 100%. Disadvantages include the need for iodinated contrast material and the inability to diagnose the site of the intimal tear.

MRI
Magnetic resonance imaging (MRI) is also used for the detection and assessment of aortic dissection, with a sensitivity of 98% and a specificity of 98%. An MRI examination of the aorta produces a three-dimensional reconstruction of the aorta, allowing the physician to determine the location of the intimal tear and the involvement of branch vessels, and to locate any secondary tears. It is a noninvasive test, does not require the use of iodinated contrast material, and can detect and quantitate the degree of aortic insufficiency.The disadvantage of the MRI scan in the face of aortic dissection is that it may be available only in larger hospitals, and the scan is relatively time-consuming, which could be dangerous in people who are already very unwell. Due to the high-intensity magnetic fields used during MRI, it cannot be used on individuals with metallic implants. In addition, some individuals experience claustrophobia while surrounded by the MRI magnet.

Ultrasound
The transesophageal echocardiogram (TEE) is a good test in the diagnosis of aortic dissection, with a sensitivity up to 98% and a specificity up to 97%. It has become the preferred imaging modality for suspected aortic dissection. It is a relatively noninvasive test, requiring the individual to swallow the echocardiography probe. It is especially good in the evaluation of AI in the setting of ascending aortic dissection and to determine whether the ostia (origins) of the coronary arteries are involved. While many institutions give sedation during transesophageal echocardiography for added patient comfort, it can be performed in cooperative individuals without the use of sedation. Disadvantages of TEE include the inability to visualize the distal ascending aorta (the beginning of the aortic arch), and the descending abdominal aorta that lies below the stomach. A TEE may be technically difficult to perform in individuals with esophageal strictures or varices.

Aortogram
An aortogram involves the placement of a catheter in the aorta and injection of contrast material while taking X-rays of the aorta. The procedure is known as aortography. Previously thought to be the diagnostic gold standard, it has been supplanted by other, less-invasive imaging modalities.

Classification
Several different classification systems have been used to describe aortic dissections. One such classification is based on chronicity and labels aortic dissections as hyperacute (<24 hours duration), acute (2–7 days), subacute (8–30 days), and chronic (>30 days). The systems commonly in use are based on either the anatomy of the dissection or the duration of onset of symptoms before the presentation. The Stanford system is used more commonly now, as it is more attuned to the management of the patient.

DeBakey
The DeBakey system, named after cardiothoracic surgeon Michael E. DeBakey, is an anatomical description of the aortic dissection. It categorizes the dissection based on where the original intimal tear is located and the extent of the dissection (localized to either the ascending aorta or descending aorta or involving both the ascending and descending aorta).
Type I – originates in ascending aorta, and propagates at least to the aortic arch and often beyond it distally. It is most often seen in patients less than 65 years of age and is the most lethal form of the disease.
Type II – originates in the ascending aorta and is confined to it.
Type III – originates in the descending aorta and rarely extends proximally, but will extend distally. It most often occurs in elderly patients with atherosclerosis and hypertension.

Stanford
The Stanford classification is divided into two groups, A and B, depending on whether the ascending aorta is involved.
A – involves the ascending aorta and/or aortic arch, and possibly the descending aorta. The tear can originate in the ascending aorta, the aortic arch, or more rarely, in the descending aorta. It includes DeBakey types I and II.
B – involves the descending aorta or the arch (distal to the left subclavian artery), without the involvement of the ascending aorta. It includes DeBakey type III.The Stanford classification is useful as it follows clinical practice, as type A ascending aortic dissections generally require primary surgical treatment, whereas type B dissections generally are treated medically as initial treatment with surgery reserved for any complications.The main indication for surgical repair of type A dissections is the prevention of acute hemorrhagic pericardial tamponade due to leakage of blood through the dissected layers of the intrapericardial proximal aorta. A secondary indication is acute aortic valve insufficiency (regurgitation): ascending aortic dissections often involve the aortic valve, which, having lost its suspensory support, telescopes down into the aortic root, resulting in aortic incompetence. The valve must be resuspended to be reseated, as well as to repair or prevent coronary artery injury. Also, the area of dissection is removed and replaced with a Dacron graft to prevent further dissection from occurring. However, type B dissections are not improved, from a mortality point of view, by the operation, unless leaking, rupture, or compromise to other organs, e.g. kidneys, occurs.

Prevention
Among the recognized risk factors for aortic dissection, hypertension, abnormally high levels of lipids (such as cholesterol) in the blood, and smoking tobacco are considered preventable risk factors.Repair of an enlargement of the ascending aorta from an aneurysm or previously unrecognized and untreated aortic dissections is recommended when greater than 5.5 cm (2.2 in) in size to decrease the risk of dissection. Repair may be recommended when greater than 4.5 cm (1.8 in) in size if the person has one of the several connective-tissue disorders or a family history of a ruptured aorta.

Management
In an acute dissection, treatment choice depends on its location. For Stanford type A (ascending aortic) dissection, surgical management is superior to medical management. For uncomplicated Stanford type B (distal aortic) dissections (including abdominal aortic dissections), medical management is preferred over surgery. Complicated Stanford type B aortic dissections require surgical intervention after initiation of medical therapy.The risk of death due to aortic dissection is highest in the first few hours after the dissection begins, and decreases afterward. Because of this, the therapeutic strategies differ for the treatment of an acute dissection compared to a chronic dissection. An acute dissection is one in which the individual presents within the first two weeks. If the individual has managed to survive this window period, their prognosis is improved. About 66% of all dissections present in the acute phase. Individuals who present two weeks after the onset of the dissection are said to have chronic aortic dissections.  These individuals have been self-selected as survivors of the acute episode and can be treated with medical therapy as long as they are stable.

Medication
Aortic dissection generally presents as a hypertensive emergency, and the prime consideration of medical management is to decrease the shear stress in the aortic wall (dP/dt (force of ejection of blood from the left ventricle)) by decreasing blood pressure and the heart rate. The target blood pressure should be a mean arterial pressure (MAP) of 60 to 75 mmHg, or the lowest blood pressure tolerated. Initial decreases should be by about 20%. The target heart rate is less than 65 beats per minute. Long-term blood pressure control is required for every person who has experienced aortic dissection.Beta blockers are the first-line treatment for patients with acute and chronic aortic dissection. In acute dissection, fast-acting agents can be given intravenously and have doses that are easier to adjust (such as esmolol, propranolol, or labetalol) is preferred. Vasodilators such as sodium nitroprusside can be considered for people with ongoing high blood pressure, but they should never be used alone, as they often stimulate a reflexive increase in the heart rate.Calcium channel blockers can be used in the treatment of aortic dissection, particularly if a contraindication to the use of beta-blockers exists.  The calcium channel blockers typically used are verapamil and diltiazem, because of their combined vasodilator and negative inotropic effects.If the individual has refractory hypertension (persistent hypertension on the maximum doses of three different classes of antihypertensive agents), involvement of the renal arteries in the aortic dissection plane should be considered.

Surgical
Indications for the surgical treatment of aortic dissection include an acute proximal aortic dissection and an acute distal aortic dissection with one or more complications.  Complications include compromise of a vital organ, rupture or impending rupture of the aorta, retrograde dissection into the ascending aorta. These are more common with a history of Marfan syndrome or Ehlers-Danlos syndrome.The objective in the surgical management of aortic dissection is to resect (remove) the most severely damaged segments of the aorta and to obliterate the entry of blood into the false lumen (both at the initial intimal tear and any secondary tears along the vessel). While excision of the intimal tear may be performed, it does not significantly change mortality.The particular treatment used depends on the segment or segments of the aorta involved. Some treatments are:
Open aortic surgery with replacement of the damaged section of the aorta with a tube graft (often made of Dacron) when no damage to the aortic valve is seen
Bentall procedure – replacement of the damaged section of the aorta and replacement of the aortic valve
David procedure – replacement of the damaged section of the aorta and reimplantation of the aortic valve
Thoracic endovascular aortic repair, a minimally invasive surgical procedure usually combined with ongoing medical management
Replacement of the damaged section of the aorta with a sutureless vascular ring connector-reinforced Dacron graft: The vascular ring connector is a titanic ring used as a stent in the vascular graft to achieve a quick, blood-sealed, and sutureless anastomosis. Two furrows on the surface of the ring are for fixation of the vascular graft and the aorta. The tapes used to tie against the ring provide a larger contact surface area than the traditional stitches, thus it provides stronger anastomosis and better surgical results.A number of comorbid conditions increase the surgical risk of repair of an aortic dissection.  These conditions include the following:
Prolonged preoperative evaluation (increased length of time prior to surgery)
Advanced age
Comorbid disease states (e.g.: coronary artery disease)
Aneurysm leakage
Cardiac tamponade
Shock - obstructive shock
Past history of myocardial infarction
History of kidney failure (either acute or chronic kidney failure)

Follow-up
The long-term follow-up in individuals who survive aortic dissection involves strict blood pressure control.  The relative risk of late rupture of an aortic aneurysm is 10 times higher in individuals who have uncontrolled hypertension, compared to individuals with a systolic pressure below 130 mmHg.The risk of death is highest in the first two years after the acute event, and individuals should be followed closely during this time period. About 29% of late deaths following surgery are due to rupture of either a dissecting aneurysm or another aneurysm. In addition, a 17% to 25% incidence exists of new aneurysm formation, typically due to dilatation of the residual false lumen. These new aneurysms are more likely to rupture, due to their thinner walls.Serial imaging of the aorta is suggested, with MRI being the preferred imaging technique.

Prognosis
Of all people with aortic dissection, 40% die immediately and do not reach a hospital in time. Of the remainder, 1% die every hour, making prompt diagnosis and treatment a priority. Even after diagnosis, 5–20% die during surgery or in the immediate postoperative period. In ascending aortic dissection, if surgery is decided to be not appropriate, 75% die within 2 weeks. With aggressive treatment, 30-day survival for thoracic dissections may be as high as 90%.

Epidemiology
Establishing the incidence of aortic dissection has been difficult because many cases are only diagnosed after death (which may have been attributed to another cause), and is often initially misdiagnosed. Aortic dissection affects an estimated 2.0–3.5 people per every 100,000 every year. Studies from Sweden suggest that the incidence of aortic dissection may be rising. Men are more commonly affected than women: 65% of all people with aortic dissection are male. The mean age at diagnosis is 63 years. In females before the age of 40, half of all aortic dissections occur during pregnancy (typically in the third trimester or early postpartum period). Dissection occurs in about 0.6% of pregnancies.

History
The earliest fully documented case of aortic dissection is attributed to Frank Nicholls in his autopsy report of King George II of Great Britain, who had been found dead on 25 October 1760; the report describes a dissection of the aortic arch and into the pericardium. The term "aortic dissection" was introduced by the French physician J. P. Maunoir in 1802, and René Laennec labeled the condition "dissecting aneurysm" </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 Hypomagnesemia with secondary hypocalcemia and can you explain it in depth? [/INST] Hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive genetic disorder affecting intestinal magnesium absorption. Decreased intestinal magnesium reabsorption and the resulting decrease in serum magnesium levels is believed to cause lowered parathyroid hormone (PTH) output by the parathyroid gland. This results in decreased PTH and decreased serum calcium levels (hypocalcemia). This manifests in convulsions and spasms in early infancy which, if left untreated, can lead to mental retardation or death. HSH is caused by mutations in the TRPM6 gene.

Pathophysiology
HSH is caused by decreased intestinal magnesium reabsorption through TRPM6 channels. When expressed in cells, TRPM6 produces outwardly rectifying currents with the outward portion composed of Na+ ions and the inward portion of divalent cations (particularly magnesium and calcium). Inward flow of sodium ions is blocked by extracellular divalent cations. Increased intracellular magnesium concentrations also decrease current through TRPM6 channels. There are currently more than 30 known mutations in TRPM6 that are associated with HSH and these mutations are spreading throughout the gene (table 1). Of the eight HSH mutations that have been tested, none have shown to produce whole-cell current. The S141L mutation, one of the few missense mutations, has been of particular interest to researchers. They have found that it prevents coassembly with TRPM7 (and presumably other TRPM6 subunits) and lacks the ability to traffic to the membrane. Whether other mutants are able to traffic properly to the surface or coassemble has not yet been further studied.While the hypomagnesemia in patients with HSH is a direct result of TRPM6 mutations, hypocalcemia is an indirect, secondary result. Parathyroid gland secretion of PTH can be altered by changes in serum magnesium levels. The decreased serum magnesium levels seen in HSH result in decreased PTH secretion. PTH, in turn, controls the availability of serum calcium. Decreasing PTH levels cause a decrease in calcium availability in serum and, thus, the neurological symptoms of HSH.

Diagnosis
Diagnosis typically occurs during the first 6 months of life due to characteristic neurological symptoms. These symptoms include muscle spasms, tetany, and seizures. Laboratory testing indicates hypomagnesemia (decreased serum magnesium levels), hypocalcemia (decreased serum calcium levels), and little to no measurable parathyroid hormone levels. Diagnosis is confirmed with these symptoms and can be further solidified with genetic sequencing of the TRPM6 gene.

Treatment
Treatment of HSH involves administration of high doses of magnesium salts. These salts may be taken orally or otherwise (e.g </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 Neurosis and can you explain it in depth? [/INST] Neurosis is a class of functional mental disorders involving chronic distress, but neither delusions nor hallucinations. The term is no longer used by the professional psychiatric community in the United States, having been eliminated from the Diagnostic and Statistical Manual of Mental Disorders (DSM) in 1980 with the publication of DSM III. However, it is still used in the ICD-10 Chapter V F40–48.
Neurosis should not be mistaken for psychosis, which refers to a loss of touch with reality. Nor should it be mistaken for neuroticism, a fundamental personality trait proposed in the Big Five personality traits theory.

Etymology
The term is derived from the Greek word neuron (νεῦρον, nerve) and the suffix -osis (-ωσις, diseased or abnormal condition).
The term neurosis was coined by Scottish doctor William Cullen in 1769 to refer to "disorders of sense and motion" caused by a "general affection of the nervous system." Cullen used the term to describe various nervous disorders and symptoms that could not be explained physiologically. Physical features, however, were almost inevitably present, and physical diagnostic tests, such as exaggerated knee-jerks, loss of the gag reflex and dermatographia, were used into the 20th century.  The meaning of the term was redefined by Carl Jung and Sigmund Freud over the early and middle 20th century, and has continued to be used in psychology and philosophy.The Diagnostic and Statistical Manual of Mental Disorders (DSM) eliminated the neurosis category in 1980, because of a decision by its editors to provide descriptions of behavior rather than descriptions of hidden psychological mechanisms. This change has been controversial. Likewise, according to the American Heritage Medical Dictionary, neurosis is "no longer used in psychiatric diagnosis."

Symptoms and causes
Neurosis may be defined simply as a "poor ability to adapt to ones environment, an inability to change ones life patterns, and the inability to develop a richer, more complex, more satisfying personality." There are many different neuroses, including:

obsessive–compulsive disorder
obsessive–compulsive personality disorder
impulse control disorder
anxiety disorder
histrionic personality disorder
dissociative disorder
a great variety of phobiasAccording to C. George Boeree, professor emeritus at Shippensburg University, the symptoms of neurosis may involve:
... anxiety, sadness or depression, anger, irritability, mental confusion, low sense of self-worth, etc., behavioral symptoms such as phobic avoidance, vigilance, impulsive and compulsive acts, lethargy, etc., cognitive problems such as unpleasant or disturbing thoughts, repetition of thoughts and obsession, habitual fantasizing, negativity and cynicism, etc. Interpersonally, neurosis involves dependency, aggressiveness, perfectionism, schizoid isolation, socio-culturally inappropriate behaviors, etc.

Jungian theory
Carl Jung found his approach particularly effective for patients who are well adjusted by social standards but are troubled by existential questions. Jung claims to have "frequently seen people become neurotic when they content themselves with inadequate or wrong answers to the questions of life".: 140  Accordingly, the majority of his patients "consisted not of believers but of those who had lost their faith".: 140  A contemporary person, according to Jung, …is blind to the fact that, with all his rationality and efficiency, he is possessed by powers that are beyond his control. His gods and demons have not disappeared at all; they have merely got new names. They keep him on the run with restlessness, vague apprehensions, psychological complications, an insatiable need for pills, alcohol, tobacco, food — and, above all, a large array of neuroses.: 82 Jung found that the unconscious finds expression primarily through an individuals inferior psychological function, whether it is thinking, feeling, sensation, or intuition. The characteristic effects of a neurosis on the dominant and inferior functions are discussed in his Psychological Types. Jung also found collective neuroses in politics: "Our world is, so to speak, dissociated like a neurotic.": 85

Psychoanalytic theory
According to psychoanalytic theory, neuroses may be rooted in ego defense mechanisms, though the two concepts are not synonymous. Defense mechanisms are a normal way of developing and maintaining a consistent sense of self (i.e., an ego). However, only those thoughts and behaviors that produce difficulties in ones life should be called neuroses.
A neurotic person experiences emotional distress and unconscious conflict, which are manifested in various physical or mental illnesses; the definitive symptom being anxiety. Neurotic tendencies are common and may manifest themselves as acute or chronic anxiety, depression, an obsessive–compulsive disorder, a phobia, or a personality disorder.

Horneys theory
In her final book, Neurosis and Human Growth, Karen Horney lays out a complete theory of the origin and dynamics of neurosis. In her theory, neurosis is a distorted way of looking at the world and at oneself, which is determined by compulsive needs rather than by a genuine interest in the world as it is. Horney proposes that neurosis is transmitted to a child from their early environment and that there are many ways in which this can occur:: 18
When summarized, they all boil down to the fact that the people in the environment are too wrapped up in their own neuroses to be able to love the child, or even to conceive of him as the particular individual he is; their attitudes toward him are determined by their own neurotic needs and responses.
The childs initial reality is then distorted by their parents needs and pretenses. Growing up with neurotic caretakers, the child quickly becomes insecure and develops basic anxiety. To deal with this anxiety, the childs imagination creates an idealized self-image:: 22
Each person builds up his personal idealized image from the materials of his own special experiences, his earlier fantasies, his particular needs, and also his given faculties. If it were not for the personal character of the image, he would not attain a feeling of identity and unity. He idealizes, to begin with, his particular "solution" of his basic conflict: compliance becomes goodness, love, saintliness; aggressiveness becomes strength, leadership, heroism, omnipotence; aloofness becomes wisdom, self-sufficiency, independence. What—according to his particular solution—appear as shortcomings or flaws are always dimmed out or retouched.
Once they identify themselves with their idealized image, a number of effects follow. They will make claims on others and on life based on the prestige they feel entitled to because of their idealized self-image. They will impose a rigorous set of standards upon themselves in order to try to measure up to that image. They will cultivate pride, and with that will come the vulnerabilities associated with pride that lacks any foundation. Finally, they will despise themselves for all their limitations. Vicious circles will operate to strengthen all of these effects.
Eventually, as they grow to adulthood, a particular "solution" to all the inner conflicts and vulnerabilities will solidify. They will be either

expansive, displaying symptoms of narcissism, perfectionism, or vindictiveness
self-effacing and compulsively compliant, displaying symptoms of neediness or codependence
resigned, displaying schizoid tendenciesIn Horneys view, mild anxiety disorders and full-blown personality disorders all fall under her basic scheme of neurosis as variations in the degree of severity and in the individual dynamics. The opposite of neurosis is a condition Horney calls self-realization, a state of being in which the person responds to the world with the full depth of their spontaneous feelings, rather than with anxiety-driven compulsion. Thus the person grows to actualize their inborn potentialities. Horney compares this process to an acorn that grows and becomes a tree: the acorn has had the potential for a tree inside it all along.

See also
Individuation
Neurotics Anonymous
Positive disintegration

References
Bibliography
Angyal, Andras. 1965. Neurosis and Treatment: A Holistic Theory, edited by E. Hanfmann and R. M. Jones.
Fenichel, Otto. 1945. The Psychoanalytic Theory of Neurosis. New York: Norton.
Freud, Sigmund. 1953–1974. The Standard Edition of the Complete Psychological Works of Sigmund Freud. (24 vols.), translated by J. Strachey. London: Hogarth.
Horney, Karen. 1937. The Collected Works. (2 vols.). Norton.
—— 1945. Our Inner Conflicts. Norton.
1950. Neurosis and Human Growth. Norton.
Horwitz, A. V. and J. C. Wakefield. 2007. The Loss of Sadness: How Psychiatry Transformed Normal Sorrow into Depressive Disorder. Oxford University Press. ISBN 978-0-19-531304-8.
Jung, Carl G. [1921] 1971. Psychological Types, (The Collected Works of C. G. Jung 6). Princeton University Press. ISBN 0-691-01813-8.
—— 1966. Two Essays on Analytical Psychology, (The Collected Works of C. G. Jung 7). Princeton University Press. ISBN 0-691-01782-4.
Jung, Carl G., and Aniela Jaffé. [1961] 1989. Memories, Dreams, Reflections. New York: Vantage Books. ISBN 0-679-72395-1
Jung, Carl G., et al. 1964. Man and His Symbols. New York: Anchor Books / Doubleday. ISBN 0-385-05221-9.
Ladell, R. M., and T. H. Hargreaves. 1947. "The Extent of Neurosis." British Medical Journal 2(4526):548–49. doi:10.1136/bmj.2.4526.548. PMC 2055884. PMID 20267012.
López-Piñero J.M. (1983) Historical Origins of the Concept of Neurosis (Translated by D. Berrios) Cambridge, Cambridge University Press
McWilliams, Nancy. 2011. Psychoanalytic Diagnosis: Understanding Personality Structure in the Clinical Process (2nd ed.). Guilford Press </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 Brachioradial pruritus and can you explain it in depth? [/INST] Brachioradial pruritus (sometimes abbreviated BRP) is an intense itching sensation of the arm usually between the wrist and elbow of either or both arms.: 36   The itch can be so intense that affected individuals will scratch their own skin to a bleeding condition.
The condition is becoming increasingly common, presenting in patients who are usually fair skinned and middle aged and indulge in golf, tennis, outdoor table tennis, sailing,  or other leisure outdoor activities in sunny climates.: 64 : 402 The cause is not known, although there are a few lines of thought on what causes it.  No cure has been found, but depending on severity, good control with treatment can be achieved. For milder cases, the intense itch/scratch cycle can be broken by applying a topical skin coolant gel containing menthol, camphor, or other topical coolant to affected itchy areas, and then consistently applying 100+SPF sunscreen to affected skin of arms, shoulders, neck, etc., whenever they are expected to be exposed to the sun. A unique prescription topical combination of ketamine .5% and amitriptyline hydrochloride 1% has shown immediate and long term relief with no serious adverse events in at least one severe case.[1]
Many different medications and types of topical creams have been experimented with, but few seem to make any difference, except for the above. The application of ice packs to the affected area can also diminish the itch short-term.

Causes
Brachioradial pruritus (BRP) is a localized pruritus of the dorsolateral aspect of the arm. BRP is an enigmatic condition with a controversial cause; some authors consider BRP to be a photodermatosis, whereas other authors attribute BRP to compression of cervical nerve roots.
BRP may be attributed to a neuropathy, such as chronic cervical radiculopathy. The possibility of an underlying neuropathy should be considered in the evaluation and treatment of all patients with BRP.The main cause of BRP is not known, but there is evidence to suggest that BRP may arise in the nervous system. Cervical spine disease may also be an important contributing factor.
Patients with BRP may have underlying cervical spine pathology. Whether this association is causal or coincidental remains to be determined.
There is controversy regarding the cause of brachioradial pruritus: is it caused by a nerve compression in the cervical spine or is it caused by a prolonged exposure to sunlight?In many patients, itching of the arms or shoulders is seasonal. Some patients reported neck pain.BRP can be linked to the thyroid.

Diagnosis
Treatments
Symptom management may include the application of a unique prescription topical combination of ketamine .5% and amitriptyline hydrochloride 1%.[2]
Milder cases may use lidocaine or capsaicin, and/or cervical traction.
Treatment with lamotrigine has been reported. Treatment by acupuncture has been reported.Treatment with Gabapentin has been reported.

See also
List of cutaneous conditions

References
Further reading
Walcyk, Patricia J.; Elpern, D.J. (1986). "Brachioradial pruritus: a tropical dermopathy". British Journal of Dermatology. 115 (2): 177–80. doi:10.1111/j.1365-2133.1986.tb05714.x. PMID 3741783. S2CID 39609751.
Orton, D.I.; Wakelin, S.H.; George, S.A. (1996). "Brachioradial photopruritus - a rare chronic photodermatosis in Europe". British Journal of Dermatology. 135 (3): 486–7. doi:10.1046/j.1365-2133.1996.d01-1030.x. PMID 8949453. S2CID 41887835.
Dermatology 1977;195:414-5.
Brachioradial Pruritus at eMedicine
Veien, Niels K.; Hattel, Thais; Laurberg, Grete; Spaun, Eva (2001). "Brachioradial pruritus". Journal of the American Academy of Dermatology. 44 (4): 704–5. doi:10.1067/mjd.2001.112912. PMID 11260554.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackermans Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lippincott Williams & Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press </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 Intestinal pseudo-obstruction and can you explain it in depth? [/INST] Intestinal pseudo-obstruction (IPO) is a clinical syndrome caused by severe impairment in the ability of the intestines to push food through. It is characterized by the signs and symptoms of intestinal obstruction without any lesion in the intestinal lumen. Clinical features mimic those seen with mechanical intestinal obstructions and can include abdominal pain, nausea, abdominal distension, vomiting, dysphagia and constipation depending upon the part of the gastrointestinal tract involved.
It is a difficult condition to diagnose, requiring exclusion of any other mechanical cause of obstruction. Many patients are diagnosed late in the course of disease after additional symptoms are seen. Mortality is also difficult to accurately determine. One retrospective study estimated mortality to be between 10 and 25% for chronic intestinal pseudo-obstruction (CIPO) and to vary greatly depending on the etiology of the condition. When present for less than six months, it is diagnosed as acute IPO or Ogilvies Syndrome. Longer than this is considered chronic. Owing to the difficulty of diagnosis, few studies are available which have attempted to estimate its prevalence.The condition can begin at any age. Most studies describing CIPO are in pediatric populations. It can be a primary condition (idiopathic or inherited) or caused by another disease (secondary). It can be a result of myriad of etiologies including infectious, parasitic, autoimmune, genetic, congenital, neurologic, toxic, endocrinological, or anatomical pathology.
Treatment targets nutritional support, improving intestinal motility, and minimizing surgical intervention. Bacterial overgrowth of the small intestine can occur in chronic cases - presenting as malabsorption, diarrhea, and nutrient deficiencies - which may require the use of antibiotics.

Presentation
Clinical features of IPO can include abdominal pain, nausea, abdominal distension, vomiting, dysphagia, and constipation. Symptoms depend on the portion of the gastrointestinal tract involved and the duration of symptoms. Symptoms may occur intermittently and over a prolonged period of time. It is not unusual for patients to present several times owing to the nonspecific nature of the symptoms. Conditions and onset will vary if the disease is primary vs secondary and the underlying disease (if a secondary manifestation) and its management.
Symptoms indicative of advanced disease and possible intestinal failure include diarrhea, loss of appetite, sepsis, bloating, fatigue, signs of low volume status, and malabsorption including nutritional deficiencies and foul-smelling stools.

Causes
In primary CIPO (the majority of chronic cases) the condition results from disruption of the intestines ability to move food. These can be broadly classified as myopathic (affecting the smooth muscle), mesenchymopathic (affecting the interstitial cells of Cajal), or neuropathic (of the nervous system) of the gastrointestinal tract.In some cases there appears to be a genetic association. One form has been associated with DXYS154.Secondary chronic intestinal pseudo-obstruction can occur as a consequence of a number of other conditions including:

Hirschsprungs disease - the absence of colonic nerve cells
Chagas disease - a chronic parasitic infection of the colon leading to loss of nerve endings
Kawasaki disease - a rare presentation for this particular autoimmune disorder of the vasculature
Parkinsons disease - related to the neurodegeneration of gastrointestinal tract
Autoimmune conditions - conditions including systemic lupus erythematosus and scleroderma lead to collagen vascular deposition and gastrointestinal motility disruption
Mitochondrial disease - IPO is a known presentation for mitochondrial disease
Endocrine disorders
Certain medications.The term may be used synonymously with enteric neuropathy if a neurological cause is suspected.

Diagnosis
The symptoms of IPO are nonspecific. It is not unusual for patients to present repeatedly and to undergo numerous tests. Mechanical causes of intestinal obstruction must be excluded to reach a diagnosis of pseudo-obstruction. Attempts must also be made to determine whether the IPO is the result of a primary or secondary condition. A diagnostic work-up may include:
Gastric motility studies
Imaging studies:
 X-rays - may show intestinal air fluid levels (seen with true mechanical intestinal obstruction)
CT scans
Barium enema
Blood tests
Upper and lower endoscopies
Manometry - used to measure pressure of esophagus and stomach

Treatment
Treatment for IPO (acute or chronic) is aimed at removing the disease process and/or managing the complications present. Focus is placed on management of pain, gastrointestinal symptoms, nutritional deficiencies, fluid status, infection control, and improving quality of life. When CIPO is secondary to another disease, treatment is addressed towards the underlying condition. Surgery is sometimes required in severe cases of CIPO.

Medical treatment
Prucalopride, pyridostigmine, metoclopramide, cisapride, erythromycin and octreotide are medications that aim to enhance intestinal motility.
Intestinal stasis, which may lead to bacterial overgrowth and subsequently, diarrhea or malabsorption, is treated with antibiotics.
Nutritional deficiencies are treated by encouraging patients to avoid foods that increase distention and are difficult to digest (e.g. those high in fat and fibre), consuming small frequent meals (5–6 per day), focusing on liquids and soft food. Reducing intake of poorly absorbed sugar alcohols may be of benefit. Referral to an accredited dietitian is recommended. If dietary changes are unsuccessful in meeting nutritional requirements and energy needs, enteral nutrition is used. Many patients eventually require parenteral nutrition.Total parenteral nutrition (TPN) is a form of long-term nutritional treatment reserved for patients that have severe pseudo-obstruction. TPN dependent patients require frequent checkups to monitor catheter function, check liver enzyme levels, and evaluate for signs of blood infections. TPN format is typically changed depending on loss/gain of weight and bloodwork results, and is specially formulated to meet each individual patients needs.

Procedures
Intestinal decompression by tube placement in a small stoma can also be used to reduce distension and pressure within the gut. The stoma may be a gastrostomy, jejunostomy, ileostomy or cecostomy. These may be used for feed (e.g </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 Nevus spilus 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 Pemphigus erythematosus 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 Dysfibrinogenemia and can you explain it in depth? [/INST] The dysfibrinogenemias consist of three types of fibrinogen disorders in which a critical blood clotting factor, fibrinogen, circulates at normal levels but is dysfunctional. Congenital dysfibrinogenemia is an inherited disorder in which one of the parental genes produces an abnormal fibrinogen. This fibrinogen interferes with normal blood clotting and/or lysis of blood clots. The condition therefore may cause pathological bleeding and/or thrombosis. Acquired dysfibrinogenemia is a non-hereditary disorder in which fibrinogen is dysfunctional due to the presence of liver disease, autoimmune disease, a plasma cell dyscrasias, or certain cancers. It is associated primarily with pathological bleeding. Hereditary fibrinogen Aα-Chain amyloidosis is a sub-category of congenital dysfibrinogenemia in which the dysfunctional fibrinogen does not cause bleeding or thrombosis but rather gradually accumulates in, and disrupts the function of, the kidney.Congenital dysfibrinogenemia is the commonest of these three disorders. Some 100 different genetic mutations occurring in more than 400 families have been found to cause it. All of these mutations as well as those causing hereditary fibrinogen Aα-Chain amyloidosis exhibit partial penetrance, i.e. only some family members with one of these mutant genes develop dysfibrinogenemia-related symptoms. While both of these congenital disorders as well as acquired dysfibrinogenemia are considered very rare, it is estimated that ~0.8% of individuals with venous thrombosis have either a congenital or acquired dysfibrinogenemia. Hence, the dysfibrinogenemia disorders may be highly under-diagnosed conditions due to isolated thrombotic events that are not appreciated as reflecting an underlying fibrinogen disorder.Congenital dysfibrinogenemia is distinguished from a similar inherited disorder, congenital hypodysfibrinogenemia. Both disorders involve the circulation of dysfunctional fibrinogen but in congenital hypodysfibrinogenemia plasma fibrinogen levels are low while in congenital dysfibrinogenemia they are normal. Furthermore, the two disorders involve different gene mutations and inheritance patterns as well as somewhat different symptoms.

Fibrinogen
Fibrinogen is a glycoprotein made and secreted into the blood primarily by liver hepatocyte cells. Endothelium cells also make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood platelets and their precursors, bone marrow megakaryocytes, although once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein. The final secreted, hepatocyte-derived glycoprotein is made of two trimers each of which is composed of three polypeptide chains, Aα (also termed α) encoded by the FGA gene, Bβ (also termed β) encoded by the FGB gene, and γ encoded by the FGG gene. All three genes are located on the long (i.e. "p") arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively) and may contain mutations that are the cause of congenital dysfibrinogenemia. The heximer is assembled as a protein in the endoplasmic reticulum of hepatocytes and then transferred to the Golgi where Polysaccharides (i.e. complex sugars) and sialic acid are added by respective glycosylation and sialylation enzyme pathways thereby converting the heximer to a functional fibrinogen glycoprotein. The final circulating glycoprotein (notated as (AαBβγ)2, (αβγ)2, Aα2Bβ2γ2, or α2β2γ2) is arranged as a long flexible rod with nodules at both ends termed D domains and central nodule termed the E domain.The normal process of blood clot formation involves the coordinated operation of two separate pathways that feed into a final common pathway: 1) primary hemostasis, i.e. the adhesion, activation, and aggregation of circulating blood platelets at sites of vascular injury and 2) secondary hemostasis, i.e. cleavage of the Aα and Bβ chains of fibrinogen by thrombin to form individual fibrin strands plus the respective fibrinopeptides A and B formed from this cleavage. In the final common pathway fibrin is cross-linked by activated clotting factor XIII (termed factor XIIIa) to form mature gel-like fibrin clots. Subsequent fibrinolysis pathways act to limit clot formation and dissolve clots no longer needed. Fibrinogen and its Aα fibrin chain have several functions in this process:
Blood clotting: fibrinogen concentration is the rate-limiting factor in blood clot formation and along with blood platelets is critical to this formation (see Coagulation).
Platelet aggregation: fibrinogen promotes platelet aggregation by cross-linking platelet Glycoprotein IIb/IIIa receptors and thereby promotes blood clot formation through the primary hemostasis pathway.
Blood clot lysis: The Aα fibrin chain formed from fibrinogen binds tissue plasminogen activator, an agent that breaks down blood clots to participate thereby in promoting fibrinolysis.Based on these fibrinogen functions, a fibrinogen mutation may act either to inhibit or promote blood clot formation and/or lysis to thereby produce in individuals a diathesis to develop pathological bleeding, thrombosis, or both conditions.

Congenital dysfibrinogenemia
Presentation
Many cases of congenital dysfibrinogenemia are asymptomatic. Since manifestations of the disorder generally occur in early adulthood or middle-age, younger individuals with a gene mutation causing it may not have had time to develop symptoms while previously asymptomatic individuals of advanced age with such a mutation are unlikely to develop symptoms. Bleeding episodes in most cases of this disorder are mild and commonly involve easy bruising and menorrhagia. Less common manifestations of bleeding may be severe or even life-threatening; these include excessive bleeding after tooth extraction, surgery, vaginal birth, and miscarriage. Rarely, these individuals may suffer hemarthrosis or cerebral hemorrhage. In one study of 37 individuals >50 years old afflicted with this disorder, 19% had a history of thrombosis. Thrombotic complications occur in both arteries and veins and include transient ischemic attack, ischemic stroke, myocardial infarction, retinal artery thrombosis, peripheral artery thrombosis, and deep vein thrombosis. In one series of 33 individuals with a history of thrombosis due to congenital dysfibrinogenemia, five developed chronic pulmonary hypertension due to ongoing pulmonary embolism probably stemming form deep vein thrombosis. About 26% of individuals with the disorder suffer both bleeding and thrombosis complications.

Pathophysiology
Congenital dysfibrinogenemia is most often caused by a single autosomal dominant missense mutation in the Aα, Bβ, or γ gene; rarely, it is caused by a homozygous or compound heterozygous missense mutation, a deletion, frameshift mutation, insert mutation, or splice site mutation in one of these genes. The most frequent sites for these mutations code for the N-terminus of the Aα chain or the C-terminus of the γ chain that lead to defective assembly of fibrin in early clot formation and thereby a bleeding predisposition. Two particular missense mutations represent the majority (74% in one study of 101 individuals) of all mutations associated with dysfibrinogenemia and therefore represent prime sites to examine in the initial testing of individuals having a congenital dysfibrinogenmia bleeding disorder. These mutations alter the codon coded for the amino acid arginine at either the 35th position of FGA (termed Arg35; see fibrinogen Metz1 and fibrinogen Bicetre in the Table below) and or the 301st position of FGG (termed Arg301; see fibrinogen Baltimore IV in the Table below).The following Table lists examples of mutations causing congenital dysfibrinogenemias. It gives: a) the mutated proteins trivial name; b) the gene mutated (i.e. FGA, FGB, or FGG), its mutation site (i.e. numbered nucleotide in the cloned gene), and the names of the nucleotides (i.e. C, T, A, G) at these sites before>after the mutation; c) the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using standard abbreviations) found in the normal-mutated circulating fibrinogen; d) the cause of the mutated fibrinogens misfunction(s); e) the clinical consequence(s) of the mutation; and f) comments. Unless noted as a deletion (del), frame shift (fs), or homozygous mutation, all mutations are heterozygous, missense mutations.

Diagnosis
The diagnosis of congenital dysfibrinogenmia is made by clinical laboratory studies that find normal levels of plasma fibrinogen but significant excess in the amount of immunologically detected compared to functionally detected (i.e. able to be clotted) fibrinogen. The ratio of functionally-detected to immunologically detected fibrinogen masses in these cases is <0.7. Partial thromboplastin time, activated partial thromboplastin time, thrombin time, and reptilase time tests are usually prolonged regardless of history of bleeding or thrombosis. Where available, laboratory analyses of the fibrinogen genes and peptide chains solidify the diagnosis. Initial examination of these genes or protein chains should search specifically for "hot spot" mutations, i.e. the most common mutations (see Pathophysiology section) that comprise the large bulk of mutations in the disorder. In cases of dysfibrinogenemia in which acquired disease is suspected, diagnosis requires a proper diagnosis of the presence of a causable disease.Congenital dysfibrinogenmia is initially distinguished form congenital hypodysfibrinogenemia by the finding of normal immunologically-detected levels of fibrinogen in congenital dysfibrinogenemia and sub-normal levels of immunologically-detected fibrinogen in congenital hypodysfibrinogenemia. Both disorders exhibit mass ratios of functionally-detected to immunologically-detected fibrinogen that are below <0.7. Genetic and protein analyses can definitively differentiate the two disorders.

Treatment
In a study of 189 individuals diagnosed with congenital dysfibrinogenemia, ~33% were asymptomatic, ~47% experienced episodic bleeding, and ~20% experienced episodic thromboses. Due to the rareness of this disorder, treatment of individuals with these presentations are based primarily on case reports, guidelines set by the United Kingdom, and expert opinions rather than controlled clinical studies.

Asymptomatic individuals
Treatment of asymptomatic congenital dysfibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as estimated based on the history of family members with the disorder and, where available, determination of the exact mutation causing the disorder plus the propensity of the particular mutation type to develop these complications. In general, individuals with this disorder require regular follow-up and multidiscipline management prior to surgery, pregnancy, and giving childbirth. Women with the disorder appear to have an increased rate of miscarriages and all individuals with fibrinogen activity in clotting tests below 0.5 grams/liter are prone to bleeding and spontaneous abortions. Women with multiple miscarriages and individuals with excessively low fibrinogen activity levels should be considered for prophylaxis therapy with fibrinogen replacement during pregnancy, delivery, and/or surgery.

Symptomatic individuals
Individuals experiencing episodic bleeding as a result of congenital dysfibrinogenemia should be treated at a center specialized in treating hemophilia. They should avoid all medications that interfere with normal platelet function. During bleeding episodes, treatment with fibrinogen concentrates or in emergencies or when these concentrates are unavailable, infusions of fresh frozen plasma and/or cryoprecipitate (a fibrinogen-rich plasma fraction) to maintain fibrinogen activity levels >1 gram/liter. Tranexamic acid or fibrinogen concentrates are recommended for prophylactic treatment prior to minor surgery while fibrinogen concentrates are recommended prior to major surgery with fibrinogen concentrates usage seeking to maintain fibrinogen activity levels at >1 gram/liter. Women undergoing vaginal or Cesarean child birth should be treated at a hemophilia center with fibrinogen concentrates to maintain fibrinogen activity levels at 1.5 gram/liter. The latter individuals require careful observation for bleeding during their post-partum periods.Individuals experiencing episodic thrombosis as a result of congenital dysfibrinogenemia should also be treated at a center specialized in treating hemophilia using antithrombotic agents. They should be instructed on antithrombotic behavioral methods fur use in high risk situations such as long car rides and air flights. Venous thrombosis should be treated with low molecular weight heparin for a period that depends on personal and family history of thrombosis events. Prophylactic treatment prior to minor surgery should avoid fibrinogen supplementation and use prophylactic anticoagulation measures; prior to major surgery, fibrinogen supplementation should be used only if serious bleeding occurs; otherwise, prophylactic anticoagulation measures are recommended.

Hereditary fibrinogen Aα-Chain amyloidosis
Presentation
Individuals with hereditary fibrinogen Aα-chain amyloidosis present with evidence ranging from asymptomatic proteinuria to progressive renal impairment and end-stage kidney disease. They do not evidence pathological bleeding or thrombosis and their amyloidosis is non-systemic in that it is restricted to the kidney. In a report on 474 patients with renal amyloidosis, hereditary fibrinogen Aα chain disease represented only 1.3% of all cases whereas aberrant immunoglobulin-induced renal amyloidosis (e.g. AL amyloidosis) represented 86% of the cases). Hereditary fibrinogen Aα-Chain amyloidosis is, however, the most common form of familial renal amyloidosis.

Pathophysiology
Certain mutations in the fibrinogen Aα-chain gene cause a form of familial renal amyloidosis termed hereditary fibrinogen Aα-Chain amyloidosis. The disorder is due to autosomal dominant inheritance of Aα chain mutations the most common of which is hemoglobin Indianopolis, a heterzyogus missense (c.1718G>T: Arg554Leu) mutation. Other missense mutations causing this disorder are unnamed; they include 1634A>T: Glu526Val; c.1670C>A: Thr538lys; c.1676A.T:Glu540Val; and c1712C>A:Pro552His. A deletion mutation causing a frameshift viz., c.1622delT: Thr525Leu, is also a cause of the disorder. The fibrinogen bearing these mutant Aα-chains is secreted into the circulation and gradually accumulates in, and causes significant injury to, the kidney. The mutant fibrinogen does not appear to accumulate in, or injure, extra-renal tissues.

Diagnosis
The diagnosis of this disorder depends on demonstrating: 1) a dysfunctional plasma fibrinogen, i.e. significantly less functionally-detected compared to immunologically-detected fibrinogen; b) presence of signs and/or symptoms of kidney disease; and c) histological evidence of often massive obliteration of renal glomeruli by amyloid as detected by Congo red staining. There also should be no evidence for systemic amyloidosis </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 Ureterocele and can you explain it in depth? [/INST] A ureterocele is a congenital abnormality found in the ureter. In this condition the distal ureter balloons at its opening into the bladder, forming a sac-like pouch. It is most often associated with a duplicated collection system, where two ureters drain their respective kidney instead of one. Simple ureterocele, where the condition involves only a single ureter, represents only twenty percent of cases.
Since the advent of the ultrasound, most ureteroceles are diagnosed prenatally. The pediatric and adult conditions are often found incidentally, i.e. through diagnostic imaging performed for unrelated reasons.

Classification
Intravesical
Confined within the bladder
Ectopic
Some part extends to the bladder neck or urethra
Stenotic
Intravesical ureterocele with a narrow opening
Sphincteric
Ectopic ureterocele with an orifice distal to the bladder neck
Sphincterostenotic
Orifice is both stenotic and distal to the bladder neck
Cecoureterocele
Ectopic ureterocele that extends into the urethra, but the orifice is in the bladder

Signs and symptoms
The signs and symptoms of ureterocele in the latter two forms can easily be confused with other medical conditions. Symptoms can include:
Frequent urinary tract infections
Pyelonephritis
Obstructive voiding symptoms
Urinary retention
Failure to thrive
Hematuria
Cyclic abdominal pain
Urolithiasis
Cobra head sign is seen in radiography
In females: salpingitis, hydrosalpinx with sepsis or torsion </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 Glutaric aciduria type 1 and can you explain it in depth? [/INST] Glutaric acidemia type 1 (GA1) is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products (glutaric acid, glutaryl-CoA, 3-hydroxyglutaric acid, glutaconic acid) can accumulate and cause damage to the brain (and also other organs), but particularly the basal ganglia, which are regions that help regulate movement. GA1 causes secondary carnitine deficiency, as glutaric acid, like other organic acids, is detoxified by carnitine. Mental retardation may occur.
GA1 is an autosomal recessive disorder caused by deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH), encoded by the GCDH gene.

Signs and symptoms
The severity of glutaric acidemia type 1 varies widely; some individuals are only mildly affected, while others suffer severe problems. GA1 can be defined as two clinical entities: GA-1 diagnosed at birth or pre-birth and managed through dietary restrictions, and GA-1 diagnosed after an encephalopathic crisis. A crisis may occur under both headings, but the care of individuals diagnosed before a crisis can be managed to avoid most or all injury.

GA1 without encephalopathic crisis
Macrocephaly
Babies with glutaric acidemia type 1 often are born with unusually large heads (macrocephaly). Macrocephaly is amongst the earliest signs of GA1. It is thus important to investigate all cases of macrocephaly of unknown origins for GCDH deficiency, given the importance of the early diagnosis of GA1.
Macrocephaly is a pivotal clinical sign of many neurological diseases. Physicians and parents should be aware of the benefits of investigating for an underlying neurological disorder, particularly a neurometabolic one, in children with head circumferences in the highest percentiles.

GA1 after an encephalopathic crisis
Neuromotor aspects
Affected individuals may have difficulty moving and may experience spasms, jerking, rigidity or decreased muscle tone and muscle weakness (which may be the result of secondary carnitine deficiency). GA, in patients who have suffered a crisis, can be defined as a cerebral palsy of genetic origins.

Occupational therapy
A common way to manage striatal necrosis is to provide special seating. These special wheelchairs are designed to limit abnormal movements. However, spasticity can be worsened by constraint. Parents and caregivers can provide a more interactive occupational therapy by enabling the child to use his or her own excessive postural muscle tone to his or her own advantage (see picture; note the care with which minimal pressure is applied while ensuring safety).The excessive tone can also be managed with "jolly jumpers" and other aids to the upright stance that do not constrain the child but help him or her gradually tone down the rigidity.

Bleeding abnormalities
Some individuals with glutaric acidemia have developed bleeding in the brain or eyes that could be mistaken for the effects of child abuse.

Genetics
The condition is inherited in an autosomal recessive pattern: mutated copies of the gene GCDH must be provided by both parents to cause GA1. The GCDH gene encodes the enzyme glutaryl-CoA dehydrogenase. This enzyme is involved in degrading the amino acids lysine, hydroxylysine and tryptophan. Mutations in the GCDH gene prevent production of the enzyme or result in the production of a defective enzyme with very low residual activity, or an enzyme with relatively high residual activity but still phenotypic consequences. This enzyme deficiency allows glutaric acid, 3-hydroxyglutaric acid and to a lesser extent glutaconic acid to build up to abnormal levels, especially at times when the body is under stress. These intermediate breakdown products are particularly prone to affect the basal ganglia, causing many of the signs and symptoms of GA1.
GA1 occurs in approximately 1 of every 30,000 to 40,000 births. As a result of founder effect, it is much more common in the Amish community and in the Ojibway population of Canada, where up to 1 in 300 newborns may be affected.
Relatives of children with GA1 can have low GCDH activity: in an early study of GA1, GCDH activity was found to be 38%, 42%, and 42% in three of the four unaffected relatives tested, a pattern consistent with the 50% level that would be expected in heterozygous carriers. Those levels are close to those found in some heavily symptomatic GA1-affected children.

Diagnosis
Normally, magnetic resonance imaging shows the Sylvian fissure to be operculated, but in GA1-associated encephalopathy, operculation is absent.  In many jurisdictions, GA1 is included in newborn screening panels.  Elevated glutarylcarnitine can be detected by mass spectrometry in a dried blood spot collected shortly after birth.  After a positive screening result, confirmatory testing is performed.  This includes urine organic acid analysis, looking for glutaric acid and 3-hydroxyglutaric acid.  Plasma and urine acylcarnitine analysis can also be informative.  Molecular analysis, including gene sequencing and copy number analysis of GCDH, can be performed to confirm the diagnosis.  Molecular testing can also provide information for family planning and prenatal testing, if desired.

Treatment
Correction of secondary carnitine depletion
Like many other organic acidemias, GA1 causes carnitine depletion. Whole-blood carnitine can be raised by oral supplementation. However, this does not significantly change blood concentrations of glutarylcarnitine or esterified carnitine, suggesting that oral supplementation is suboptimal in raising tissue levels of carnitine. Clinical nutrition researchers have likewise concluded that oral carnitine raises plasma levels but does not affect those in muscles, where most of it is stored and used.In contrast, regular intravenous infusions of carnitine cause distinct clinical improvements: "decreased frequency of decompensations, improved growth, improved muscle strength and decreased reliance on medical foods with liberalization of protein intake."Choline increases carnitine uptake and retention. Choline supplements are inexpensive, are safe (probably even in children requiring anticholinergics) and can increase exercise tolerance, truncal tone and general well-being, providing evidence of the suboptimal efficiency of carnitine supplementation alone.

Selective precursor restriction
Dietary control may help limit progression of the neurological damage.

Lysine
Lysine restriction, as well as carnitine supplementation, are considered the best predictors of a good prognosis for GA1. This excludes, however, patients who already suffered an encephalopathic crisis, for whom the prognosis is more related to the treatment of their acquired disorder (striatal necrosis, frontotemporal atrophy).

Protein restriction
Vegetarian diets and, for younger children, breastfeeding are common ways to limit protein intake without endangering tryptophan transport to the brain.

Tryptophan
Formulas such as XLys, XTrp Analog, XLys, XTrp Maxamaid, XLys, XTrp Maxamum or Glutarex 1 are designed to provide amino acids other than lysine and tryptophan, to help prevent protein malnutrition.
The entry of tryptophan into the brain is crucial in the proper synthesis of the neurotransmitter serotonin in the brain. One way to acutely cause depression, bulimia or anxiety in humans, in order to assess an individuals vulnerability to those disorders, is to supplement with a formula with all or most amino acids except tryptophan. Acute tryptophan depletion is a diagnostic procedure, not a treatment for GA1. The protein synthesis elicited by the amino acids leads circulating amino acids, including tryptophan, to be incorporated into proteins. Tryptophan is thus lowered in the brain as a result of the protein synthesis enhancement, causing circulating tryptophan to drop more than other amino acids. A relative excess of other large neutral amino acids may also compete with tryptophan for transport across the blood–brain barrier through the large neutral amino acid transporter 1. The consequence is acute tryptophan depletion in the brain and a consequent decrease in serotonin synthesis.
5-Hydroxytryptophan, a precursor of serotonin that is not metabolized to glutaryl-CoA, glutaric acid and secondary metabolites, could be used as an adjunct to selective tryptophan restriction, although it has risks. However, the evidence in favour of selective tryptophan restriction remains insufficient and the consensus is evolving towards the restriction of lysine only. In the Amish community, where GA1 is overrepresented, patients with GA1 typically do not receive tryptophan-free formulas, either as the sole source of amino acids or as a supplement to protein restriction.

Enhancement of precursor anabolic pathways
Lysine and hydroxylysine anabolic pathway enhancement
A possible way to prevent the build-up of metabolites is to limit lysine and hydroxylysine degradation, as lysine is one of the most abundant amino acids and tryptophan is one of the least abundant amino acids.

Interaction of GCDH deficiency with vitamin C levels
Humans lack the enzyme L-gulonolactone oxidase, which is necessary for the synthesis of ascorbic acid (vitamin C), leaving them dependent on dietary sources of this vitamin. Vitamin C is a necessary cofactor for the utilization of lysine in collagen synthesis. Collagen, the most abundant protein in the human body, requires great amounts of lysine, the most abundant amino acid in proteins. Ascorbic acid, the main hydroxyl radical quencher, works as the cofactor providing the hydroxyl radical required for collagen cross-linking; lysine thus becomes hydroxylysine.
GA1 worsens during stresses and catabolic episodes, such as fasts and infections. Endogenous catabolism of proteins could be an important route for glutaric acid production. It follows that collagen breakdown (and protein breakdown in general) should be prevented by all possible means.
Ascorbic acid is used to prevent multiple organ failure and to lessen mortality and morbidity in intensive care units. It thus appears reasonable to add sufficient doses of ascorbic acid to the treatment protocol during stresses and other challenges to growth in order to stimulate collagen synthesis and thus prevent lysine breakdown.

Tryptophan anabolic pathway enhancement
The conversion of tryptophan to serotonin and other metabolites depends on vitamin B6. If tryptophan catabolism has any impact on brain glutaric acid and other catabolite levels, vitamin B6 levels should be routinely assayed and normalized in the course of the treatment of GA1.

Management of intercurrent illnesses
Stress caused by infection, fever or other demands on the body may lead to worsening of the signs and symptoms, with only partial recovery.

Prognosis
A 2006 study of 279 patients found that of those with symptoms (185, 66%), 95% had suffered an encephalopathic crises, usually with following brain damage. Of the participants in the study, 49 children died and the median age of death was 6.6 years. A Kaplan–Meier analysis of the data estimated that about 50% of symptomatic people would die by the age of 25.
More recent studies provide an updated prognosis whereby individuals affected can, through proper dietary management and carnitine supplementation, manage the disease with a much improved prognosis.  Newborn screening has allowed affected patients to avoid crises and live full lives without any injury to the brain. It is essential that patients with the disease be diagnosed at or before birth and that all variables be strictly managed in order to maintain quality of life.  When suspected and in the absence of confirmed diagnosis (through genetic sequencing), it is critical that the individual maintain a diet restrictive of all proteins and that blood sugars be monitored rigorously.  The WHO now considers this disease entirely manageable.

Epidemiology
GA1 can be described as a metabolic disorder, a neurometabolic disease, a cerebral palsy or a basal ganglia disorder (it may also be misdiagnosed as shaken baby syndrome).
Depending on the paradigm adopted, GA1 will mostly be managed with precursor restriction or with neurorehabilitation.
So-called "orphan diseases", such as GA1, can be adopted into wider groups of diseases (such as carnitine deficiency diseases, cerebral palsies of diverse origins, basal ganglia disorders, and others); Morton at al. (2003b) emphasize that acute striatal necrosis is a distinctive pathologic feature of at least 20 other disorders of very different etiologies, including, HIV encephalopathy–AIDS dementia complex, pneumococcal meningitis, hypoadrenal crisis, methylmalonic acidemia, propionic acidemia, middle cerebral artery occlusion, hypertensive vasculopathy, acute Mycoplasma pneumoniae infection, 3-nitropropionic acid intoxication, late-onset familial dystonia, cerebrovascular abrupt and severe neonatal asphyxia ("selective neuronal necrosis").
In a cohort of 279 patients who had been reported to have GA1, 185 were symptomatic (two-thirds); being symptomatic was seen as an indication of low treatment efficacy. Screening of those known to be at high risk, neonatal population screening and a diagnosis of macrocephaly are the ways to identify bearers of the GCDH mutation who are not frankly symptomatic. Macrocephaly remains the main sign of GA1 for those who have no relatives with GA1 and have not been included in a population screening program. GA1 is considered a treatable disease.
Two-thirds of the patients who have GA1 encephalopathy will receive little benefit from the treatment for GA1 but can benefit from treatments given to victims of middle cerebral artery occlusion, AIDS dementia and other basal ganglia disorders: brain implants, stem cell neurorestoration, growth factors, monoaminergic agents, and many other neurorehabilitation strategies.

References
Further reading
Mahfoud Hawilou, Antonieta; Domínguez Méndez, Carmen Luisa; Rizzo, Cristiano; Ribes Rubio, Antonia (2004). "Macrocefalia in utero como manifestación clínica de aciduria glutárica tipo I. Informe de una nueva mutación" [In utero macrocephaly as clinical manifestation of glutaric aciduria type I. Report of a novel mutation]. Revista de Neurología (in Spanish). 39 (10): 939–942. doi:10.33588/rn.3910.2004258. PMID 15573311.
Martínez Granero MA, Garcia Pérez A, Martínez-Pardo M, Parra E (2005). "[Macrocephaly the first manifestation of glutaric aciduria type I: the importance of early diagnosis.]". Neurologia (in Spanish) </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 Marburg acute multiple sclerosis 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 Myopericytoma 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 Pinch mark and can you explain it in depth? [/INST]  </s>