<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pruritic urticarial papules and plaques of pregnancy and explain in detail? [/INST] Pruritic urticarial papules and plaques of pregnancy (PUPPP), known in United Kingdom as polymorphic eruption of pregnancy (PEP), is a chronic hives-like rash that strikes some women during pregnancy. Some skin changes are known to occur in people who are pregnant while other skin conditions, or dermatoses, that people have prior to getting pregnant will become altered or symptoms will increase. Pruritic urticarial papules and plaques of pregnancy (PUPPP) is one of many skin conditions that is specific to pregnancy and occurs in about 1 in every 160 (0.625%) of pregnancies.It presents no long-term risk for either the woman or fetus as there is no statistical increase of risk of premature labor or fetal loss, despite frequently severe pruritus.PUPPP usually first appears on the abdomen and often spreads to the legs, feet, arms, chest, and neck. The face is usually not affected. Skin distension (stretching) is thought to be a possible trigger for PUPPP as it most commonly affects primigravida (women in their first pregnancy), those with large fundal measurements (distance from the pubic bone to the top of the uterus) and/or those who are carrying large babies or multiples. The papules and plaques often first appear within stretch marks before changing appearance and spreading to other areas of the body.
It is important that those who are pregnant heavily consider the recommendations of their full healthcare team. For those who may be experiencing signs and symptoms of PUPPP, it is strongly recommended they speak with their primary care physician and receive a consult from a dermatologist regarding skin changes during pregnancy.

Signs and Symptoms
PUPPP most commonly presents as a rash that starts within the stretch marks. This rash may then move to other areas of the body, including, but not limited to the trunk of the body, arms, legs, feet, chest, and neck. Very few people experiencing PUPPP have reported the rash spreading to the face, palms of hands, or soles of feet.This rash usually begins with the skin looking abnormally red and feeling itchy, accompanied by notable swelling of skin tissue that appears raised and within the stretch marks. Over time, individual segments of this rash can join to form one whole, larger rash with the same characteristics. As this happens, people report noticing the skin surrounding the rash to appear white in color (blanched) and in the shape of "halos". Multiple features of the disease can continue with time and have been reported as widespread erythema (a red skin rash due to damage of underlying capillaries) and patches of inflamed, itchy, rough, and cracked patches of skin that appear similarly to eczema. Other features have been reported in some cases of those experiencing PUPPP, such as tiny vesicles, however these are not as common and develop after more time.
Certain reports have shown there is a positive correlation between PUPPP and excessive maternal weight gain along with increased newborn birth weight. Additionally, a study from Ghazeeri and al. showed that 89% of people who underwent conception through in vitro fertilization were Rh-positive.The timeline of onset for these symptoms has been reported with some variability. However, most people report experiencing symptoms during the third trimester (last few weeks of pregnancy) where 15% of the women who have PUPPP reported that symptoms actually began immediately after delivery of the baby. As mentioned above, the papules and plaques usually first appear on the abdomen (although not on the umbilicus/belly button) and often spread to the legs, chest, underarms, etc. However, lesions on or above the breasts are rare. Thats why the face is usually spared and does not become affected. As a result of these papules and plaques from PUPPP, it causes the skin to be very itchy (pruritic) and immensely affects the patients sleep quality throughout the night.

Cause
PUPPP is the most common dermatosis of pregnancy and is the most frequent in pregnant women habitating a male fetus, women who had quick and conspicuous weight gain during a short period, and women who ultimately deliver by a c-section. Although the exact cause of the condition is not known and varying amongst individuals, there have been theories linking the cause of PUPPP to hormonal alterations, damage to the connective tissue during pregnancy, and autoimmune disorder where the evidence for these theories is currently low.This skin condition occurs mostly in first pregnancies (primigravida), in the third trimester and is more likely with multiple pregnancies (more so with triplets than twins or singletons). Estimated 75% of people with typical PUPPP people have never given birth. Occasionally, this condition may also occur postpartum, but rarely does this ever occur in the first and second trimester.Other than additional associations with hypertension and induction of labour, there are no observed difference in the outcome of the pregnancy for mothers or babies.

Dermatological Causes
During pregnancy as the abdominal wall rapid stretching, it is hypothesized that there is an inflammatory reaction that occurs due to the exposure of collagen. This reaction has been seen more frequently in those who are having twins or triplets compared to those with single births. This is hypothesized to be due to increased stretching of the abdominal wall while carrying twins or triplets, causing an earlier onset of PUPPP when compared to those undergoing single births.

Hormonal Causes
Throughout pregnancy, there are hormonal changes that occur where it has been hypothesized that these changes may contribute to the onset of PUPPP. Although current research is low on this hypothesis, it has been seen that those who have had multiple gestations can exhibit an increased level of progesterone. With this increase in progesterone, it causes there to be an increased level of progesterone receptors present eliciting an immune reaction seen by skin lesions in PUPPP. With multiple gestations, there is an increase in sex hormones that has been seen those with the condition such as an increase in progesterone as previously discussed but also higher levels of estradiol. Currently evidence is weak in the role that sex hormones play when contributing to PUPPP where further research is needed.

Immunological Causes
Inflammatory Mediated
From those with PUPPP, it has been seen from an immunohistology profile which is used to determine the of tissue components present within an individual via the use of antibodies, that there are certain immune cells that are in greater amount compared to that of those without PUPPP. Immunohistology profile have shown cells consistent with a delayed hypersensitivity with T helper cell infiltrates, dendritic cells and epidermal Langerhans cells.It has been hypothesized that PUPPP appears in response to fetal antigens that circulate throughout the body. For example, a study showed that fetal male DNA was found within the lesions of the mothers skin which was thought to be caused by the fetal cells seen in the mothers blood throughout pregnancy.

Autoimmune
Although this condition has not been determined as an autoimmune condition, from a single study it has been seen that Immunoglobulin M (IgM) deposition at the dermal-epidermal membrane has been associated with a variety of dermatosis including PUPPP. The problem with the hypothesis that has been proposed is that this condition does not reoccur and it does not progressively worsen. Currently there has been no evidence of detecting circulating antibodies that are associated with the onset on PUPPP in an individual.

Diagnosis
PUPPP is often a diagnosis of exclusion and may need laboratory testing to rule out other dermatoses. Lab tests may include complete blood count, comprehensive metabolic panel, liver function tests, serum human choriogonadotropin and serum cortisol. Additional specialized tests may include serum for indirect immunofluorescence or biopsy of the lesions for direct immunofluorescence to rule out pemphigoid gestationis.A common misdiagnosis is urticarial pemphigoid gestationis, hence it is needed to exclude it while diagnosing PUPPP as clinical features can overlap. Therefore, histological and immunological studies are necessary to ensure there is no mis-diagnosis. During the case of pemphigoid gestationis, lesions usually occur during the earlier periods of gestation and often involve the umbilicus; as well as, having a positive immunofluorescence of perilesional skin. If there is eczema, people generally have a history of atopy, be it personal or through family. The eruption is identified by pruritic erythematous lesions on flexural areas. Furthermore, other clinical differential diagnosis could be from drug eruptions, urticaria, or viral exanthems.Sometimes, people may require a 3- or 4-mm punch biopsy to exclude herpes gestationis, which is a variant of bullous pemphigoid occurring during or immediately after pregnancy. Usually the biopsy has features that are consistent with PUPPP but there are no pathognomonic symptoms of the particular disorder. Additionally, a biopsy of unaffected perilesional skin could be used for direct immunofluorescence studies to have a more precise exclusion of herpes gestationis.

Treatment
It is important to note that diagnosis should be conducted by a trusted medical professional. In the case that a woman is experiencing symptoms of PUPPP, it is recommended that they contact their primary care physician for referral to a dermatologist for treatment guidance and should not self-treat.In the majority of cases, PUPPP resolves within a few days or weeks upon initial onset or spontaneously within a week of delivery. However, a few women continue to experience symptoms long into the postpartum period.
One of the most recent forms of treatment suggested is the intramuscular injection of autologous whole blood as an alternative treatment option for people affected by PUPPP right after childbirth, as it seems to have both subjective and objective improvements of the symptoms. This is a very good option for the people who are worried about taking medications during pregnancy or breastfeedingAntihistamine tablets may be prescribed to provide relief from the itch, although they are generally considered much less effective than corticosteroid treatments, and may decrease itching through blocking histamine release as well as improving sleep quality.
Furthermore, first-generation antihistamines, such as chlorpheniramine, have proven to be safe in pregnancy and can be a supplement treatment for pruritus </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Sphincter of Oddi dysfunction and explain in detail? [/INST] Sphincter of Oddi dysfunction refers to a group of functional disorders leading to abdominal pain due to dysfunction of the Sphincter of Oddi: functional biliary sphincter of Oddi and functional pancreatic sphincter of Oddi disorder. The sphincter of Oddi is a sphincter muscle, a circular band of muscle at the bottom of the biliary tree which controls the flow of pancreatic juices and bile into the second part of the duodenum. The pathogenesis of this condition is recognized to encompass stenosis or dyskinesia of the sphincter of Oddi (especially after cholecystectomy); consequently the terms biliary dyskinesia, papillary stenosis, and postcholecystectomy syndrome have all been used to describe this condition.  Both stenosis and dyskinesia can obstruct flow through the sphincter of Oddi and can therefore cause retention of bile in the biliary tree and pancreatic juice in the pancreatic duct.
Individuals with sphincter of Oddi dysfunction present with abdominal pain resembling that of structural or inflammatory disorders of the gallbladder, biliary tree or pancreas. Among other characteristics, the pain is typically in the upper part of the abdomen or in the right upper quadrant of the abdomen, lasts 30 minutes or longer, and is not associated with a structural abnormality that could lead to these symptoms. The disorder is classified into two subtypes: functional biliary sphincter of Oddi disorder, where there is no disturbance in pancreatic enzyme measurements, such as amylase and lipase; and, functional pancreatic sphincter of Oddi disorder, where pancreatic enzyme measurements are elevated.
Attacks can be precipitated by opioid analgesics, particularly in patients having undergone a cholecystectomy or bariatric surgery.

Classification
Functional disorders of the gallbladder, bile duct and pancreas have been defined and classified by the Rome criteria for functional gastrointestinal disorders. The criteria outline three variants of functional disorders of the gallbladder, bile duct and pancreas, termed functional gallbladder disorder, functional biliary sphincter of Oddi disorder and functional pancreatic sphincter of Oddi disorder. All of the following criteria need to be met for as part of the definition of a functional disorder of the gallbladder:
the pain must be located in the upper part of the abdomen and/or the right upper quadrant of the abdomen
episodes of pain must last at least 30 minutes
the symptoms must be recurrent, and occur at differing intervals
the pain must incrementally increase to a "steady level"
the pain must be severe enough the patients daily activities are affected, or that the patient must attend the emergency department
the pain must not be relieved by any of bowel movements, change in posture, or antacids; and,
other structural disorders that could explain the symptoms must be excluded.

Functional gallbladder disorder
Individuals are classified as having a functional gallbladder disorder if the above criteria are met, if the gallbladder is present, and if the testing of liver enzymes, conjugated bilirubin, and pancreatic enzymes (amylase and lipase) are normal.

Functional biliary sphincter of Oddi disorder
If all of the above criteria are met, individuals are classified as having a functional biliary sphincter of Oddi disorder, if the testing of pancreatic enzymes (amylase and lipase) is normal.The old Milwaukee classification of biliary sphincter of Oddi dysfunction (SOD) used to divide the condition into three subtypes: but it is no longer in use. Type I included patients with biliary-type abdominal pain, with all of altered liver enzymes on blood testing, dilated biliary ducts on ultrasound or ERCP, and delayed bile clearance on HIDA scan. Type II included patients with biliary-type abdominal pain associated with at least one of the following: altered liver enzymes on blood testing, dilated biliary ducts on imaging tests, and delayed bile clearance on HIDA scan. Biliary-type pain in the absence of any sign of biliary or pancreatic alteration was the so-called Type III biliary SOD. The hypothesis that this pain could be linked to SOD has been studied in a large trial published in JAMA (2014)  where patients were randomized to sphincterotomy or sham surgery. Contrary to expectations, patients who were not subjected to sphincterotomy fared better </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Subconjunctival bleeding and explain in detail? [/INST] Subconjunctival bleeding, also known as subconjunctival hemorrhage or subconjunctival haemorrhage, is bleeding from a small blood vessel over the whites of the eye. It results in a red spot in the white of the eye. There is generally little to no pain and vision is not affected. Generally only one eye is affected.Natural causes can include coughing, vomiting, heavy lifting, straining to pass hard stools during acute constipation or the act of "pushing" or "bearing down" during labour/childbirth as these activities can increase the blood pressure in the vascular systems supplying the retina. There are up to four vascular retinal plexuses that are supplied by tiny, delicate capillaries whose walls if encountered with a sudden amount of force from blood will rupture. External causes can include direct impact/injury from an accidental bump or a physical altercation resulting in blunt force trauma. Risk factors include hypertension, diabetes, old age, and blood thinners. They occur in about 2% of newborns following a vaginal delivery. The blood occurs between the conjunctiva and the episclera </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Grisels syndrome and explain in detail? [/INST] Grisels syndrome is a non-traumatic subluxation of the atlanto-axial joint caused by inflammation of the adjacent tissues. This is a rare disease that usually affects children. Progressive throat and neck pain and neck stiffness can be followed by neurologic symptoms such as pain or numbness radiating to arms (radiculopathies). In extreme cases, the condition can lead to quadriplegia and even death from acute respiratory failure.  The condition often follows soft tissue inflammation in the neck such as in cases of upper respiratory tract infections, peritonsillar or retropharyngeal abscesses </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pelvic congestion syndrome and explain in detail? [/INST] Pelvic congestion syndrome, also known as pelvic vein incompetence, is a long term condition believed to be due to enlarged veins in the lower abdomen. The condition may cause chronic pain, such as a constant dull ache, which can be worsened by standing or sex. Pain in the legs or lower back may also occur.While the condition is believed to be due to blood flowing back into pelvic veins as a result of faulty valves in the veins, this hypothesis is not certain. The condition may occur or worsen during pregnancy. The presence of estrogen is believed to be involved in the mechanism. Diagnosis may be supported by ultrasound, CT scan, MRI, or laparoscopy.Early treatment options include medroxyprogesterone or nonsteroidal anti-inflammatory drugs (NSAIDs). Surgery to block the varicose veins may also be done. About 30% of women of reproductive age are affected. It is believed to be the cause of about a third of chronic pelvic pain cases </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Diaphragmatic rupture and explain in detail? [/INST] Diaphragmatic rupture (also called diaphragmatic injury or tear) is a tear of the diaphragm, the muscle across the bottom of the ribcage that plays a crucial role in breathing. Most commonly, acquired diaphragmatic tears result from physical trauma. Diaphragmatic rupture can result from blunt or penetrating trauma and occurs in about 0.5% of all people with trauma.Diagnostic techniques include X-ray, computed tomography, and surgical techniques such as an explorative surgery. Diagnosis is often difficult because signs may not show up on X-ray, or signs that do show up appear similar to other conditions. Signs and symptoms include chest and abdominal pain, difficulty breathing, and decreased lung sounds. When a tear is discovered, surgery is needed to repair it.
Injuries to the diaphragm are usually accompanied by other injuries, and they indicate that more severe injury may have occurred. The outcome often depends more on associated injuries than on the diaphragmatic injury itself. Since the pressure is higher in the abdominal cavity than the chest cavity, rupture of the diaphragm is almost always associated with herniation of abdominal organs into the chest cavity, which is called a diaphragmatic hernia. This herniation can interfere with breathing.

Signs and symptoms
Symptoms may include pain, orthopnea, (shortness of breath when lying flat), and coughing. In people with herniation of abdominal organs, signs of intestinal blockage or sepsis in the abdomen may be present. Bowel sounds may be heard in the chest, and shoulder or epigastric pain may be present. When the injury is not noticed right away, the main symptoms are those that indicate bowel obstruction.

Causes
Diaphragmatic rupture may be caused by blunt trauma, penetrating trauma, and by iatrogenic causes (as a result of medical intervention), for example during surgery to the abdomen or chest. It has also occurred spontaneously at the time of pregnancy or for no discernible reason. Injury to the diaphragm is reported to be present in 8% of cases of blunt chest trauma. In cases of blunt trauma, vehicle accidents and falls are the most common causes. Penetrating trauma has been reported to cause 12.3–20% of cases, but it has also been proposed as a more common cause than blunt trauma; discrepancies could be due to varying regional, social, and economic factors in the areas studied. Stab and gunshot wounds can cause diaphragmatic injuries. Clinicians are trained to suspect diaphragmatic rupture particularly if penetrating trauma has occurred to the lower chest or upper abdomen. With penetrating trauma, the contents of the abdomen may not herniate into the chest cavity right away, but they may do so later, causing the presentation to be delayed. Since the diaphragm moves up and down during breathing, penetrating trauma to various parts of the torso may injure the diaphragm; penetrating injuries as high as the third rib and as low as the twelfth have been found to injure the diaphragm. Iatrogenic cases have occurred as a complication of medical procedures involving the thorax or abdomen. It has occurred as a complication of thoracentesis and radiofrequency ablation.

Mechanism
Although the mechanism is unknown, it is proposed that a blow to the abdomen may raise the pressure within the abdomen so high that the diaphragm ruptures. Blunt trauma creates a large pressure gradient between the abdominal and thoracic cavities; this gradient, in addition to causing the rupture, can also cause abdominal contents to herniate into the thoracic cavity. Abdominal contents in the pleural space interfere with heart function and lung function. High intrathoracic pressure results in an increase in right atrial pressure, disrupting the filling of the heart and venous return of blood. As venous return determines cardiac output, this results in a reduction of cardiac output. If ventilation of the lung on the side of the tear is severely inhibited, hypoxemia (low blood oxygen) results. Usually, the rupture is on the same side as an impact. A blow to the side is three times more likely to cause diaphragmatic rupture than a blow to the front.

Diagnosis
Physical examinations are not accurate, as there is usually no specific physical sign that can be used to diagnose this condition. Thoracoscopic and laparoscopic methods can be accurate. Chest X-ray is known to be unreliable in diagnosing diaphragmatic rupture; it has low sensitivity and specificity for the injury. Often another injury such as pulmonary contusion masks the injury on the X-ray film. Half the time, initial X-rays are normal; in most of those that are not, hemothorax or pneumothorax is present. A nasogastric tube from the stomach may appear on the film in the chest cavity; this sign is pathognomonic for diaphragmatic rupture, but it is rare. The X-ray is better able to detect the injury when taken from the back with the person upright, but this is not usually possible because the person is usually not stable enough; thus it is usually taken from the front with the person lying supine. Positive pressure ventilation helps keep the abdominal organs from herniating into the chest cavity, but this also can prevent the injury from being discovered on an X-ray.A CT scan has an increased accuracy of diagnosis over X-ray, but no specific findings on a CT scan exist to establish a diagnosis. The free edge of a ruptured diaphragm may curl and become perpendicular to the chest wall, a sign known as a dangling diaphragm. A herniated organ may constrict at the location of a rupture, a sign known as the collar sign. If the liver herniates through a rupture on the right side, it may produce two signs known as the hump and band signs. The hump sign is a form of the collar sign on the right. The band sign is a bright line that intersects the liver.  it is believed to result due to the ruptured diaphragm compressing.  Although CT scanning increases chances that diaphragmatic rupture will be diagnosed before surgery, the rate of diagnosis before surgery is still only 31–43.5%. Another diagnostic method is laparotomy, but this misses diaphragmatic ruptures up to 15% of the time. Often diaphragmatic injury is discovered during a laparotomy that was undertaken because of another abdominal injury. Because laparotomies are more common in those with penetrating trauma than compared to those who experienced a blunt force injury, diaphragmatic rupture is found more often in these people. Thoracoscopy is more reliable in detecting diaphragmatic tears than laparotomy and is especially useful when chronic diaphragmatic hernia is suspected.

Location
Between 50 and 80% of diaphragmatic ruptures occur on the left side. It is possible that the liver, which is situated in the right upper quadrant of the abdomen, cushions the diaphragm. However, injuries occurring on the left side are also easier to detect in X-ray films. Half of diaphragmatic ruptures that occur on the right side are associated with liver injury. Injuries occurring on the right are associated with a higher rate of death and more numerous and serious accompanying injuries. Bilateral diaphragmatic rupture, which occurs in 1–2% of ruptures, is associated with a much higher death rate (mortality) than injuries that occur on just one side.

Treatment
Since the diaphragm is in constant motion with respiration, and because it is under tension, lacerations will not heal on their own. The injury usually becomes larger with time if not repaired. The main goals of surgery are to repair any injuries to the diaphragm and to move any herniated abdominal organs back to their original place. This is done be debriding nonviable tissue and closing the rupture. Most of the time, the injury is repaired during laparotomy. Early surgery is important, as diaphragmatic atrophy and adhesions occur over time. Sutures are used in the repair. Other injuries, such as hemothorax, may present a more immediate threat and may need to be treated first if they accompany diaphragmatic rupture. Video-assisted thoracoscopy may be used.

Prognosis
In most cases, isolated diaphragmatic rupture is associated with good outcome if it is surgically repaired. The death rate (mortality) for diaphragmatic rupture after blunt and penetrating trauma is estimated to be 15–40% and 10–30% respectively, but other injuries play a large role in determining outcome. Herniation of abdominal organs is present in 3–4% of people with abdominal trauma who present to a trauma center.

Epidemiology
Diaphragmatic injuries are present in 1–7% of people with significant blunt trauma and an average of 3% of abdominal injuries. A high body mass index may be associated with a higher risk of diaphragmatic rupture in people involved in vehicle accidents. Over 90% occur due to trauma from vehicle accidents. Due to the great force needed to rupture the diaphragm, it is rare for the diaphragm alone to be injured, especially in blunt trauma; other injuries are associated in as many as 80–100% of cases. In fact, if the diaphragm is injured, it is an indication that more severe injuries to organs may have occurred. Thus, the mortality after a diagnosis of diaphragmatic rupture is 17%, with most deaths due to lung complications. Common associated injuries include head injury, injuries to the aorta, fractures of the pelvis and long bones, and lacerations of the liver and spleen. Associated injuries occur in over three quarters of cases.

History
In 1579, Ambroise Paré made the first description of diaphragmatic rupture in a French artillery captain who had been shot eight months before his death.  He died from complications of the rupture. Using autopsies, Paré also described diaphragmatic rupture in people who had suffered blunt and penetrating trauma </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Drug withdrawal and explain in detail? [/INST] Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs.
In order for the symptoms of withdrawal to occur, one must have first developed a form of drug dependence. This may occur as physical dependence, psychological dependence or both. Drug dependence develops from consuming one or more substances over a period of time.
Dependence arises in a dose-dependent manner and produces withdrawal symptoms that vary with the type of drug that is consumed. For example, prolonged use of an antidepressant medication is likely to cause a rather different reaction when discontinued compared to discontinuation of an opioid, such as heroin. Withdrawal symptoms from opiates include anxiety, sweating, vomiting, and diarrhea. Alcohol withdrawal symptoms include irritability, fatigue, shaking, sweating, and nausea. Withdrawal from nicotine can cause irritability, fatigue, insomnia, headache, and difficulty concentrating. Many prescription and legal nonprescription substances can also cause withdrawal symptoms when individuals stop consuming them, even if they were taken as directed by a physician.
The route of administration, whether intravenous, intramuscular, oral or otherwise, can also play a role in determining the severity of withdrawal symptoms. There are different stages of withdrawal as well; generally, a person will start to feel bad (crash or come down), progress to feeling worse, hit a plateau, and then the symptoms begin to dissipate. However, withdrawal from certain drugs (barbiturates, benzodiazepines, alcohol, glucocorticoids) can be fatal. While it is seldom fatal to the user, withdrawal from opiates (and some other drugs) can cause miscarriage, due to fetal withdrawal. The term "cold turkey" is used to describe the sudden cessation use of a substance and the ensuing physiologic manifestations.
The symptoms from withdrawal may be even more dramatic when the drug has masked prolonged malnutrition, disease, chronic pain, infections (common in intravenous drug use), or sleep deprivation, conditions that drug abusers often develop as a secondary consequence of the drug. When the drug is removed, these conditions may resurface and be confused with withdrawal symptoms </s>


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


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Luteal phase and explain in detail? [/INST] The menstrual cycle is on average 28 days in length. It begins with menses (day 1–7) during the follicular phase (day 1–14) and followed by ovulation (day 14) and ending with the luteal phase (day 14–28). Unlike the follicular phase which can vary in length among individuals, the luteal phase is typically fixed at approximately 14 days (i.e. days 14–28) and is characterized by changes to hormone levels, such as an increase in progesterone and estrogen levels, decrease in gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), changes to the endometrial lining to promote implantation of the fertilized egg, and development of the corpus luteum. In the absence of fertilization by sperm, the corpus luteum atrophies leading to a decrease in progesterone and estrogen, an increase in FSH and LH, and shedding of the endometrial lining (menses) to begin the menstrual cycle again.

Hormonal events
After ovulation and release of the oocyte, the anterior pituitary hormones–follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are released and cause the remaining parts of the dominant follicle to transform into the corpus luteum. It continues to grow during the luteal phase after ovulation and produces significant amounts of hormones, particularly progesterone, and, to a lesser extent, estrogen and inhibin. Progesterone plays a vital role in making the endometrium receptive to implantation of the embryo and supportive of early pregnancy. High levels of progesterone inhibit the follicular growth. The increase in estrogen and progesterone also lead to increased basal body temperature during the luteal phase.The LH surge that occurs during ovulation triggers the release of the oocyte and its cumulus oophorus from the ovary and into the fallopian tube and triggers the oocyte to divide and enter metaphase of meiosis II (46 or 2n chromosome) and extrude its first polar body. The oocyte will only continue through meiosis and extrude its second polar body once it is fertilized. Ovulation occurs ~35 hours after the beginning of the LH surge or ~10 hours following the LH surge. Several days after ovulation, the increasing amount of estrogen produced by the corpus luteum may cause one or two days of fertile cervical mucus, lower basal body temperatures, or both. This is known as a "secondary estrogen surge".The hormones released by the corpus luteum suppress production of the FSH and LH from the anterior pituitary gland. The corpus luteum relies on LH activation on its receptors in order to survive. The loss of the corpus luteum can be prevented by implantation of an embryo: after implantation, human embryos produce human chorionic gonadotropin (hCG), which is structurally similar to LH and can preserve the corpus luteum </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Brunner syndrome and explain in detail? [/INST] Brunner syndrome is a rare genetic disorder associated with a mutation in the MAOA gene. It is characterized by lower than average IQ (typically about 85), problematic impulsive behavior (such as pyromania, hypersexuality and violence), sleep disorders and mood swings. It was identified in fourteen males from one family in 1993.  It has since been discovered in  additional families.

Signs and symptoms
Causes
Brunner syndrome is caused by a monoamine oxidase A (MAOA) deficiency, which leads to an excess of monoamines in the brain, such as serotonin, dopamine, and norepinephrine (noradrenaline) </s>


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

Signs and symptoms
The most common signs/symptoms of DAVFs are:
Pulsatile tinnitus
Occipital bruit
Headache
Visual impairment
PapilledemaPulsatile tinnitus is the most common symptom in patients, and it is associated with transverse-sigmoid sinus DAVFs. Carotid-cavernous DAVFs, on the other hand, are more closely associated with pulsatile exophthalmos. DAVFs may also be asymptomatic (e.g. cavernous sinus DAVFs).

Location
Most commonly found adjacent to dural sinuses in the following locations:
Transverse (lateral) sinus, left-sided slightly more common than right
Intratentorial
From the posterior cavernous sinus, usually draining to the transverse or sigmoid sinuses
Vertebral artery (posterior meningeal branch)

Causes
It is still unclear whether DAVFs are congenital or acquired. Current evidence supports transverse-sigmoid sinus junction dural malformations are acquired defects, occurring in response to thrombosis and collateral revascularization of a venous sinus.

Diagnosis
Cerebral angiography is the diagnostic standard. MRIs are typically normal but can identify venous hypertension as a result of arterial-venous shunting.

Classification
Borden Classification
The Borden Classification of dural arteriovenous malformations or fistulas, groups into three types based upon their venous drainage:
Type I: dural arterial supply drains anterograde into venous sinus.
Type II: dural arterial supply drains into venous sinus. High pressure in sinus results in both anterograde drainage and retrograde drainage via subarachnoid veins.
Type III: dural arterial supply drains retrograde into subarachnoid veins.

Type I
Type I dural arteriovenous fistulas are supplied by meningeal arteries and drain into a meningeal vein or dural venous sinus. The flow within the draining vein or venous sinus is anterograde.

Type Ia – simple dural arteriovenous fistulas have a single meningeal arterial supply
Type Ib – more complex arteriovenous fistulas are supplied by multiple meningeal arteriesThe distinction between Types Ia and Ib is somewhat specious as there is a rich system of meningeal arterial collaterals. Type I dural fistulas are often asymptomatic, do not have a high risk of bleeding and do not necessarily need to be treated.

Type II
The high pressure within a Type II dural AV fistula causes blood to flow in a retrograde fashion into subarachnoid veins which normally drain into the sinus. Typically this is because the sinus has outflow obstruction. Such draining veins form venous varices or aneurysms which can bleed. Type II fistulas need to be treated to prevent hemorrhage. The treatment may involve embolization of the draining sinus as well as clipping or embolization of the draining veins.

Type III
Type III dural AV fistulas drain directly into subarachnoid veins. These veins can form aneurysms and bleed. Type III dural fistulas need to be treated to prevent hemorrhage. Treatment can be as simple as clipping the draining vein at the site of the dural sinus </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Testicular dysgenesis syndrome and explain in detail? [/INST] Testicular dysgenesis syndrome is a male reproduction-related condition characterized by the presence of symptoms and disorders such as hypospadias, cryptorchidism, poor semen quality, and testicular cancer. The concept was first introduced by N.E. Skakkaebaek in a research paper along with the department of Growth and Reproduction in Copenhagen University. The paper suggests the origin and underlying cause of TDS can be detected as early as in fetal life, where environmental and genomic factors could affect the development of the male reproductive system.

Causes
Central to the cause of irreversible TDS are disruptions to early fetal testes development. This has genetic, environmental, and lifestyle components, however the rapid increase in the incidence of the disorders associated with TDS in the last decades indicates that it is under a powerful environmental influence. The fetal origins of TDS are reinforced by the high incidence of TDS disorders found occurring together in one individual.
Associated with mutation of Insulin like Factor 3 (INSL3)

Genetic
Many genes have been implicated in the disorders of TDS, with genome wide association studies (GWAS) regularly identifying new gene variants that play a role in abnormal testes development. Some of these are specific to certain disorders, and some are part of a risk factor network that connect TGCC, hypospadias, cryptorchidism, poor semen quality. The majority of these genes are involved in fetal gonad development. Mutations in androgen receptor genes are highly implicated, as these are involved in penile development, testes descent, and testes development. Testicular germ cell cancer (TGCC) shows a strong genetic disposition, with the most significant gene variants being those linked to gonad formation and germ cell function.

Environmental
Exposure of a male fetus to substances that disrupt hormone systems, particularly chemicals that inhibit the action of androgens (male sex hormones) during the development of the reproductive system, has been shown to cause many of the characteristic TDS disorders. These include environmental estrogens and anti-androgens found in food and water sources that have been contaminated with synthetic hormones and pesticides used in agriculture. In historical cases, medicines given to pregnant women, like diethylstilbestrol (DES), have caused many of the features of TDS in fetuses exposed to this chemical during gestation. The impact of environmental chemicals is well documented in animal models. If a substance affects Sertoli and Leydig cell differentiation (a common feature of TDS disorders) at an early developmental stage, germ cell growth and testosterone production will be impaired. These processes are essential for testes descent and genitalia development, meaning that genital abnormalities like cryptorchidism or hypospadias may be present from birth, and fertility problems and TGCC become apparent during adult life. Severity or number of disorders may therefore be dependent on the timing of the environmental exposure. Environmental factors can act directly, or via epigenetic mechanisms, and it is likely that a genetic susceptibility augmented by environmental factors is the primary cause of TDS.

Lifestyle
Links between maternal smoking and TDS are tenuous, but there are stronger associations between maternal alcohol consumption and incidences of cryptorchidism in sons. Smoking does however affect the growth of a fetus, and low birth weight is shown to increase the likelihood of all the disorders encompassed by TDS. Maternal obesity, resulting in gestational diabetes, has also been shown to be a risk factor for impaired testes development and TDS symptoms in sons.

Pathogenesis
The TDS hypothesis proposes that testicular dysgenesis, which has various primary causes, can lead to abnormalities in Sertoli and/or Leydig cell function. This leads to both impaired germ cell development and hormonal changes during male sexual differentiation. For instance, insufficient production of testosterone can result in incomplete masculinisation, whilst reduced expression of insulin-like factor 3 can lead to incomplete testes descent.  The downstream disorders of such abnormalities can include both genital malformations (e.g. hypospadias and cryptorchidism) and delayed reproductive disorders (e.g. testicular cancer and poor semen quality) which comprise TDS.

Diagnosis
Hypospadias
Hypospadias presents as an abnormal location for the end of the urethra which is typically found on the distal end of the penis. It is generally diagnosed at birth from visual confirmation of the hallmark features. As well as an unusual location of the urethra, the prepuce (foreskin) is typically incomplete as well. The abnormal ‘hooded’ prepuce is what often draws attention to the condition but can occur separately to hypospadias.

Cryptorchidism
In Cryptorchidism a diagnosis is made from a physical examination which is performed when the baby is lacking one or both testes in the dependant portion of the scrotal sac. 70% of cryptorchid testes can be felt and are unable to be pulled into the scrotum or retreats quickly after being pulled into a higher position </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Keshan disease and explain in detail? [/INST] Keshan disease is a congestive cardiomyopathy caused by a combination of dietary deficiency of selenium and the presence of a mutated strain of Coxsackievirus, named after Keshan County of Heilongjiang province, Northeast China, where symptoms were first noted. These symptoms were later found prevalent in a wide belt extending from northeast to southwest China, all due to selenium-deficient soil. The disease peaked in 1960–1970, killing thousands of people.Often fatal, the disease affects children and women of child-bearing age, characterized by heart failure and pulmonary edema. Over decades, supplementation with selenium reduced this condition.It had been linked to the coxsackie B virus. Current research suggests that the lack of selenium results in a more virulent strain of the coxsackievirus becoming the dominant viral species present in the population of virus, but the mechanism of this selection event is unclear.Keshan disease can also lead to higher rates of cancer, cardiovascular disease, hypertension, and strokes. In addition, an individual can experience eczema, psoriasis, arthritis, cataracts, alcoholism, and infections.

Signs and symptoms
Cardiac arrythmias,dizziness,fast breathing,shortness of breath(PULMONARY EDEMA)

Diagnosis
Prevention
It is hard to consider Keshan disease extremely preventable because the only way to ensure that the individual is getting enough selenium would be to test the soil in the area. However, one way that selenium intake can be improved is to increase intake of foods that are rich with selenium. Examples include Brazil nuts, onions, canned tuna, beef, cod, turkey, chicken breast, enriched pasta, egg, cottage cheese, oatmeal, white or brown rice, and garlic. If the individual lives in an area that does not have selenium enriched soil, dietary supplementation should be considered. To determine whether or not an individual is selenium deficient, blood testing is performed.

Treatments
The treatment for Keshan disease is selenium supplementation </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Adverse drug reaction and explain in detail? [/INST] An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term differs from the term "side effect" because side effects can be beneficial as well as detrimental. The study of ADRs is the concern of the field known as pharmacovigilance. An adverse drug event (ADE) refers to any unexpected and inappropriate occurrence at the time a drug is used, whether or not associated with the administration of the drug. An ADR is a special type of ADE in which a causative relationship can be shown.  ADRs are only one type of medication-related harm, as harm can also be caused by omitting to take indicated medications.

Classification
ADRs may be classified by e.g. cause and severity.

Cause
Type A: Augmented pharmacologic effects - dose dependent and predictableType A reactions, which constitute approximately 80% of adverse drug reactions, are usually a consequence of the drugs primary pharmacological effect (e.g. bleeding when using the anticoagulant warfarin) or a low therapeutic index of the drug (e.g. nausea from digoxin), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term side effects is often applied to minor type A reactions.Type B: IdiosyncraticTypes A and B were proposed in the 1970s, and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.

Seriousness
The U.S Food and Drug Administration defines a serious adverse event as one when the patient outcome is one of the following:
Death
Life-threatening
Hospitalization (initial or prolonged)
Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patients body function/structure, physical activities or quality of life.
Congenital abnormality
Requires intervention to prevent permanent impairment or damageSeverity is a point on an arbitrary scale of intensity of the adverse event in question.  The terms "severe" and "serious", when applied to adverse events, are technically very different. They are easily confused but can not be used interchangeably, requiring care in usage.
A headache is severe if it causes intense pain. There are scales like "visual analog scale" that help clinicians assess the severity. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migraine may temporally fit criteria), unless it also satisfies the criteria for seriousness listed above.

Location
Adverse effects may be local, i.e. limited to a certain location, or systemic, where medication has caused adverse effects throughout the systemic circulation.
For instance, some ocular antihypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation.

Mechanisms
As research better explains the biochemistry of drug use, fewer ADRs are Type B and more are Type A. Common mechanisms are:

Abnormal pharmacokinetics due to
genetic factors
comorbid disease states
Synergistic effects between either
a drug and a disease
two drugs
Antagonism effects between either
a drug and a disease
two drugs

Abnormal pharmacokinetics
Comorbid disease states
Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drugs metabolism due to disease states.The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) criteria warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms.

Genetic factors
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.

Phase I reactions
Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine

Phase II reactions
Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.

Interactions with other drugs
The risk of drug interactions is increased with polypharmacy.

Protein binding
These interactions are usually transient and mild until a new steady state is achieved. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are:
albumin
α1-acid glycoprotein
lipoproteinsSome drug interactions with warfarin are due to changes in protein binding.

Cytochrome P450
Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions.

Synergistic effects
An example of synergism is two drugs that both prolong the QT interval.

Assessing causality
Causality assessment is used to determine the likelihood that a drug caused a suspected ADR. There are a number of different methods used to judge causation, including the Naranjo algorithm, the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply.
An ADR should not be labeled as certain unless the ADR abates with a challenge-dechallenge-rechallenge protocol (stopping and starting the agent in question). The chronology of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying psychiatric conditions may be factors in the ADR.Assigning causality to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies some ADRs may be missed as large numbers of test individuals are required to find that adverse drug reaction. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population.

Monitoring bodies
Many countries have official bodies that monitor drug safety and reactions. On an international level, the WHO runs the Uppsala Monitoring Centre, and the European Union runs the European Medicines Agency (EMA). In the United States, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies.
In Canada, the Marketed Health Products Directorate of Health Canada is responsible for the surveillance of marketed health products. In Australia, the Therapeutic Goods Administration (TGA) conducts postmarket monitoring of therapeutic products </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Narcolepsy and explain in detail? [/INST] Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affected also experience episodes of sudden loss of muscle strength, known as cataplexy. Narcolepsy paired with cataplexy is evidenced to be an autoimmune disorder. These experiences of cataplexy can be brought on by strong emotions. Less commonly, there may be vivid hallucinations or an inability to move (sleep paralysis) while falling asleep or waking up. People with narcolepsy tend to sleep about the same number of hours per day as people without, but the quality of sleep tends to be lessened.Narcolepsy is a clinical syndrome of hypothalamic disorder, however, the exact cause of narcolepsy is unknown, with potentially several causes. In up to 10% of cases, there is a family history of the disorder. Often, those affected have low levels of the neuropeptide orexin, which may be due to an autoimmune disorder triggered in genetically susceptible individuals by infection with H1N1 influenza. In rare cases, narcolepsy can be caused by traumatic brain injury, tumors, or other diseases affecting the parts of the brain that regulate wakefulness or REM sleep. Diagnosis is typically based on the symptoms and sleep studies, after ruling out other potential causes. Excessive daytime sleepiness can also be caused by other sleep disorders such as sleep apnea, major depressive disorder, anemia, heart failure, drinking alcohol and not getting enough sleep. Cataplexy may be mistaken for seizures.While there is no cure, a number of lifestyle changes and medications may help. Lifestyle changes include taking regular short naps and sleep hygiene. Medications used include modafinil, sodium oxybate and methylphenidate. While initially effective, tolerance to the benefits may develop over time. Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) may improve cataplexy.Estimates of frequency range from 0.2 to 600 per 100,000 people in various countries. The condition often begins in childhood, with males and females being affected equally. Untreated narcolepsy increases the risk of motor vehicle collisions and falls.Narcolepsy can occur anytime between early childhood and 50 years typically, however, there is no upper age limit to getting it, 15 and 36 years of age being the peak time periods of when it occurs.

Signs and symptoms
There are two main characteristics of narcolepsy: excessive daytime sleepiness and abnormal REM sleep. Excessive daytime sleepiness occurs even after adequate night time sleep. A person with narcolepsy is likely to become drowsy or fall asleep, often at inappropriate or undesired times and places, or just be very tired throughout the day. Narcoleptics may not be able to experience the amount of restorative deep sleep that healthy people experience due to abnormal REM regulation – they are not "over-sleeping". Narcoleptics typically have higher REM sleep density than non-narcoleptics, but also experience more REM sleep without atonia. Many narcoleptics have sufficient REM sleep, but do not feel refreshed or alert throughout the day. This can feel like living their entire lives in a constant state of sleep deprivation.Excessive sleepiness can vary in severity, and it appears most commonly during monotonous situations that dont require much interaction. Daytime naps may occur with little warning and may be physically irresistible. These naps can occur several times a day. They are typically refreshing, but only for a few hours or less. Vivid dreams may be experienced on a regular basis, even during very brief naps. Drowsiness may persist for prolonged periods or remain constant. In addition, night-time sleep may be fragmented, with frequent awakenings. A second prominent symptom of narcolepsy is abnormal REM sleep. Narcoleptics are unique in that they enter into the REM phase of sleep in the beginnings of sleep, even when sleeping during the day.The classic symptoms of the disorder, often referred to as the "tetrad of narcolepsy," are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness. Other symptoms may include automatic behaviors and night-time wakefulness. These symptoms may not occur in all people with narcolepsy.

Cataplexy is an episodic loss of muscle function, ranging from slight weakness such as limpness at the neck or knees, sagging facial muscles, weakness at the knees often referred to as "knee buckling", or inability to speak clearly, to a complete body collapse. Episodes may be triggered by sudden emotional reactions such as laughter, anger, surprise, or fear. The person remains conscious throughout the episode. In some cases, cataplexy may resemble epileptic seizures. Usually speech is slurred and vision is impaired (double vision, inability to focus), but hearing and awareness remain normal. Cataplexy also has a severe emotional impact on narcoleptics, as it can cause extreme anxiety, fear, and avoidance of people or situations that might elicit an attack. Cataplexy is generally considered to be unique to narcolepsy and is analogous to sleep paralysis in that the usually protective paralysis mechanism occurring during sleep is inappropriately activated. The opposite of this situation (failure to activate this protective paralysis) occurs in rapid eye movement behavior disorder.
Periods of wakefulness at night
Sleep paralysis is the temporary inability to talk or move when waking (or less often, when falling asleep). It may last a few seconds to minutes. This is often frightening but is not dangerous.
Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing or falling asleep. Hypnopompic hallucinations refer to the same sensations while awakening from sleep. These hallucinations may manifest in the form of visual or auditory sensations.In most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. The other symptoms may begin alone or in combination months or years after the onset of the daytime naps. There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms. The excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not.
Many people with narcolepsy also have insomnia for extended periods of time. The excessive daytime sleepiness and cataplexy often become severe enough to cause serious problems in a persons social, personal, and professional life. Normally, when an individual is awake, brain waves show a regular rhythm. When a person first falls asleep, the brain waves become slower and less regular, which is called non-rapid eye movement (NREM) sleep. After about an hour and a half of NREM sleep, the brain waves begin to show a more active pattern again, called REM sleep (rapid eye movement sleep), when most remembered dreaming occurs. Associated with the EEG-observed waves during REM sleep, muscle atonia is present called REM atonia.In narcolepsy, the order and length of NREM and REM sleep periods are disturbed, with REM sleep occurring at sleep onset instead of after a period of NREM sleep. Also, some aspects of REM sleep that normally occur only during sleep, like lack of muscular control, sleep paralysis, and vivid dreams, occur at other times in people with narcolepsy. For example, the lack of muscular control can occur during wakefulness in a cataplexy episode; it is said that there is an intrusion of REM atonia during wakefulness. Sleep paralysis and vivid dreams can occur while falling asleep or waking up. Simply put, the brain does not pass through the normal stages of dozing and deep sleep but goes directly into (and out of) rapid eye movement (REM) sleep.As a consequence night time sleep does not include as much deep sleep, so the brain tries to "catch up" during the day, hence excessive daytime sleepiness. People with narcolepsy may visibly fall asleep at unpredicted moments (such motions as head bobbing are common). People with narcolepsy fall quickly into what appears to be very deep sleep, and they wake up suddenly and can be disoriented when they do (dizziness is a common occurrence). They have very vivid dreams, which they often remember in great detail. People with narcolepsy may dream even when they only fall asleep for a few seconds. Along with vivid dreaming, people with narcolepsy are known to have audio or visual hallucinations prior to falling asleep.Narcoleptics can gain excess weight; children can gain 20 to 40 lb (9 to 18 kg) when they first develop narcolepsy; in adults the body-mass index is about 15% above average.

Causes
The exact cause of narcolepsy is unknown, and it may be caused by several distinct factors. The mechanism involves the loss of orexin-releasing neurons within the lateral hypothalamus (about 70,000 neurons).Some researches indicated that people with type 1 narcolepsy (narcolepsy with cataplexy) have a lower level of orexin (hypocretin), which is a chemical contributing to the regulation of wakefulness and REM Sleep. It also acts as a neurotransmitter to enable nerve cells to communicate.In up to 10% of cases there is a family history of the disorder. Family history is more common in narcolepsy with cataplexy. There is a strong link with certain genetic variants, which may make T-cells susceptible to react to the orexin-releasing neurons (autoimmunity) after being stimulated by infection with H1N1 influenza.  In addition to genetic factors, low levels of orexin peptides have been correlated with a history of infection, diet, contact with toxins such as pesticides, and brain injuries due to head trauma, brain tumors or strokes.

Genetics
The primary genetic factor that has been strongly implicated in the development of narcolepsy involves an area of chromosome 6 known as the human leukocyte antigen (HLA) complex. Specific variations in HLA genes are strongly correlated with the presence of narcolepsy (HLA DQB1*06:02, frequently in combination with HLA DRB1*15:01); however, these variations are not required for the condition to occur and sometimes occur in individuals without narcolepsy. These genetic variations in the HLA complex are thought to increase the risk of an auto-immune response to orexin-releasing neurons in the lateral hypothalamus.The allele HLA-DQB1*06:02 of the human gene HLA-DQB1 was reported in more than 90% of people with narcolepsy, and alleles of other HLA genes such as HLA-DQA1*01:02 have been linked. A 2009 study found a strong association with polymorphisms in the TRAC gene locus (dbSNP IDs rs1154155, rs12587781, and rs1263646). A 2013 review article reported additional but weaker links to the loci of the genes TNFSF4 (rs7553711), Cathepsin H (rs34593439), and P2RY11-DNMT1 (rs2305795). Another gene locus that has been associated with narcolepsy is EIF3G (rs3826784).

H1N1 Influenza
Type 1 narcolepsy is caused by hypocretin/orexin neuronal loss. T-cells have been demonstrated to be cross-reactive to both a particular piece of the hemagglutinin flu protein of the pandemic 2009 H1N1 and the amidated terminal ends of the secreted hypocretin peptides.Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality.A link between GlaxoSmithKlines H1N1 flu vaccine Pandemrix and narcolepsy has been found in both children and adults. In 2010, Finlands National Institute of Health and Welfare recommended that Pandemrix vaccinations be suspended pending further investigation into narcolepsy. In 2018, it was demonstrated that T-cells stimulated by Pandemrix were cross-reactive by molecular mimicry with part of the hypocretin peptide, the loss of which is associated with type I narcolepsy.

Pathophysiology
Loss of neurons
Orexin, otherwise known as hypocretin, is a neuropeptide that acts within the brain to regulate appetite and wakefulness as well as a number of other cognitive and physiological processes. Loss of these orexin-producing neurons causes narcolepsy and most individuals with narcolepsy have a reduced number of these neurons in their brains. Selective destruction of the HCRT/OX neurons with preservation of proximate structures suggests a highly specific autoimmune pathophysiology. Cerebrospinal fluid HCRT-1/OX-A is undetectable in up to 95% of patients with type 1 narcolepsy.The system which regulates sleep, arousal, and transitions between these states in humans is composed of three interconnected subsystems: the orexin projections from the lateral hypothalamus, the reticular activating system, and the ventrolateral preoptic nucleus. In narcoleptic individuals, these systems are all associated with impairments due to a greatly reduced number of hypothalamic orexin projection neurons and significantly fewer orexin neuropeptides in cerebrospinal fluid and neural tissue, compared to non-narcoleptic individuals. Those with narcolepsy generally experience the REM stage of sleep within five minutes of falling asleep, while people who do not have narcolepsy (unless they are significantly sleep deprived) do not experience REM until after a period of slow-wave sleep, which lasts for about the first hour or so of a sleep cycle.

Disturbed sleep states
The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to REM sleep with little or no intervening non-REM sleep. The changes in the motor and proprioceptive systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem alpha motor neuron hyperpolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. Acetylcholine may be one of the neurotransmitters involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy has features normally seen only in normal REM sleep.

Diagnosis
The third edition of the International Classification of Sleep Disorders (ICSD-3) differentiates between narcolepsy with cataplexy (type 1) and narcolepsy without cataplexy (type 2), while the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the diagnosis of narcolepsy to refer to type 1 narcolepsy only. The DSM-5 refers to narcolepsy without cataplexy as hypersomnolence disorder. The most recent edition of the International Classification of Diseases, ICD-11, currently identifies three types of narcolepsy: type 1 narcolepsy, type 2 narcolepsy, and unspecified narcolepsy.ICSD-3 diagnostic criteria posits that the individual must experience "daily periods of irrepressible need to sleep or daytime lapses into sleep" for both subtypes of narcolepsy. This symptom must last for at least three months. For a diagnosis of type 1 narcolepsy, the person must present with either cataplexy, a mean sleep latency of less than 8 minutes, and two or more sleep-onset REM periods (SOREMPs), or they must present with a hypocretin-1 concentration of less than 110 pg/mL. A diagnosis of type 2 narcolepsy requires a mean sleep latency of less than 8 minutes, two or more SOREMPs, and a hypocretin-1 concentration of more than 110 pg/mL. In addition, the hypersomnolence and sleep latency findings cannot be better explained by other causes.DSM-5 narcolepsy criteria requires that the person to display recurrent periods of "an irrepressible need to sleep, lapsing into sleep, or napping" for at least three times a week over a period of three months. The individual must also display one of the following: cataplexy, hypocretin-1 concentration of less than 110 pg/mL, REM sleep latency of less than 15 minutes, or a multiple sleep latency test (MSLT) showing sleep latency of less than 8 minutes and two or more SOREMPs. For a diagnosis of hypersomnolence disorder, the individual must present with excessive sleepiness despite at least 7 hours of sleep as well as either recurrent lapses into daytime sleep, nonrestorative sleep episodes of 9 or more hours, or difficulty staying awake after awakening. In addition, the hypersomnolence must occur at least three times a week for a period of three months, and must be accompanied by significant distress or impairment. It also cannot be explained by another sleep disorder, coexisting mental or medical disorders, or medication.

Tests
Diagnosis is relatively easy when all the symptoms of narcolepsy are present, but if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult. Three tests that are commonly used in diagnosing narcolepsy are polysomnography (PSG), the multiple sleep latency test (MSLT), and the Epworth Sleepiness Scale (ESS). These tests are usually performed by a sleep specialist.Polysomnography involves the continuous recording of sleep brain waves and a number of nerve and muscle functions during night time sleep. When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may often awaken during the night. The polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness.The Epworth Sleepiness Scale is a brief questionnaire that is administered to determine the likelihood of the presence of a sleep disorder, including narcolepsy.The multiple sleep latency test is performed after the person undergoes an overnight sleep study. The person will be asked to sleep once every 2 hours, and the time it takes for them to do so is recorded. Most individuals will fall asleep within 5 to 8 minutes, as well as display REM sleep faster than non-narcoleptic people.Measuring orexin levels in a persons cerebrospinal fluid sampled in a spinal tap may help in diagnosing narcolepsy, with abnormally low levels serving as an indicator of the disorder. This test can be useful when MSLT results are inconclusive or difficult to interpret.

Treatment
Orexin replacement
People with narcolepsy can be substantially helped, but not cured. However, the technology exists in early form such as experiments in using the prepro-orexin transgene via gene editing restored normal function in mice models by making other neurons produce orexin after the original set have been destroyed, or replacing the missing orexinergic neurons with hypocretin stem cell transplantation, are both steps in that direction for fixing the biology effectively permanently once applied in humans. Additionally effective ideal non-gene editing and chemical-drug methods involve hypocretin treatments methods such as future drugs like hypocretin agonists (such as danavorexton) or hypocretin replacement, in the form of hypocretin 1 given intravenous (injected into the veins), intracisternal (direct injection into the brain), and intranasal (sprayed through the nose), the latter being low in efficacy, at the low amount used in current experiments but may be effective at very high doses in the future.

Behavioral
General strategies like people and family education, sleep hygiene and medication compliance, and discussion of safety issues for example driving license can be useful. Potential side effects of medication can also be addressed. Regular follow-up is useful to be able to monitor the response to treatment, to assess the presence of other sleep disorders like obstructive sleep apnea, and to discuss psychosocial issues.In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS, but only improve symptoms for a short duration. A 120-minute nap provided benefit for 3 hours in the persons alertness whereas a 15-minute nap provided no benefit. Daytime naps are not a replacement for night time sleep. Ongoing communication between the health care provider, person, and their family members is important for optimal management of narcolepsy.

Medications
The main treatment of excessive daytime sleepiness in narcolepsy is central nervous system stimulants such as methylphenidate, amphetamine, dextroamphetamine, modafinil, and armodafinil. In late 2007 an alert for severe adverse skin reactions to modafinil was issued by the FDA. Pemoline was previously used but was withdrawn due to toxicity.Another drug that is used is atomoxetine, a non-stimulant and a norepinephrine reuptake inhibitor (NRI), which has no addiction liability or recreational effects. Other NRIs like viloxazine and reboxetine have also been used in the treatment of narcolepsy. Additional related medications include mazindol and selegiline.Another FDA-approved treatment option for narcolepsy is sodium oxybate, also known as sodium gamma-hydroxybutyrate (GHB). It can be used for cataplexy associated with narcolepsy and excessive daytime sleepiness associated with narcolepsy. Several studies also showed that sodium oxybate is effective to treat cataplexy.Solriamfetol is a new molecule indicated for narcolepsy of type 1 and 2. Solriamfetol works by inhibiting the reuptake of the monoamines via the interaction with both the dopamine transporter and the norepinephrine transporter. This mechanism differs from that of the wake-promoting agents modafinil and armodafinil. These are thought to bind primarily at the dopamine transporter to inhibit the reuptake of dopamine. Solriamfetol also differs from amphetamines as it does not promote the release of norepinephrine in the brain.Narcolepsy has sometimes been treated with selective serotonin reuptake inhibitors and tricyclic antidepressants, such as clomipramine, imipramine, or protriptyline, as well as other drugs that suppress REM sleep. Venlafaxine, an antidepressant which blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy, however, it has notable side-effects including sleep disruption. The antidepressant class is used mainly for the treatment of cataplexy, for people with narcolepsy without cataplexy these are usually not used.

Children
Common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise.Many medications are used in treating adults and may be used to treat children. These medications include central nervous system stimulants such as methylphenidate, modafinil, amphetamine, and dextroamphetamine. Other medications, such as sodium oxybate or atomoxetine may also be used to counteract sleepiness. Medications such as sodium oxybate, venlafaxine, fluoxetine, and clomipramine may be prescribed if the child presents with cataplexy.

Epidemiology
Estimates of frequency range from 0.2 per 100,000 in Israel to 600 per 100,000 in Japan. These differences may be due to how the studies were conducted or the populations themselves.In the United States, narcolepsy is estimated to affect as many as 200,000 Americans, but fewer than 50,000 are diagnosed. The prevalence of narcolepsy is about 1 per 2,000 persons. Narcolepsy is often mistaken for depression, epilepsy, the side effects of medications, poor sleeping habits or recreational drug use, making misdiagnosis likely. While narcolepsy symptoms are often confused with depression, there is a link between the two disorders. Research studies have mixed results on co-occurrence of depression in people with narcolepsy, as the numbers quoted by different studies are anywhere between 6% and 50%.Narcolepsy can occur in both men and women at any age, although typical symptom onset occurs in adolescence and young adulthood. There is about a ten-year delay in diagnosing narcolepsy in adults. Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. For these to occur in the crucial teen years when education, development of self-image, and development of occupational choice are taking place is especially devastating. While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence.

Society and culture
In 2015, it was reported that the British Department of Health was paying for sodium oxybate medication at a cost of £12,000 a year for 80 people who are taking legal action over problems linked to the use of the Pandemrix swine flu vaccine. Sodium oxybate is not available to people with narcolepsy through the National Health Service.

Name
The term "narcolepsy" is from the French narcolepsie. The French term was first used in 1880 by Jean-Baptiste-Édouard Gélineau, who used the Greek νάρκη (narkē), meaning "numbness", and λῆψις (lepsis) meaning "attack".

Research
Histamine-directed medications
It remains to be seen whether H3 antagonists (i.e., compounds such as pitolisant that promote the release of the wakefulness-promoting molecule amine histamine) will be particularly useful as wake-promoting agents. However, usage now does exist in various nations such as in France, United Kingdoms (NHS as of September 2016) after being given marketing authorisation by European Commission on the advice of the European Medicines Agency and in the United States by the approval of the Food and Drug Administration (FDA) as of August 2019.

GABA-directed medications
Given the possible role of hyper-active GABAA receptors in the primary hypersomnias (narcolepsy and idiopathic hypersomnia), medications that could counteract this activity are being studied to test their potential to improve sleepiness. These currently include clarithromycin and flumazenil.

Flumazenil
Flumazenil is the only GABAA receptor antagonist on the market as of Jan 2013, and it is currently manufactured only as an intravenous formulation. Given its pharmacology, researchers consider it to be a promising medication in the treatment of primary hypersomnias. Results of a small, double-blind, randomized, controlled clinical trial were published in November 2012. This research showed that flumazenil provides relief for most people whose CSF contains the unknown "somnogen" that enhances the function of GABAA receptors, making them more susceptible to the sleep-inducing effect of GABA. For one person, daily administration of flumazenil by sublingual lozenge and topical cream has proven effective for several years. A 2014 case report also showed improvement in primary hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion. The supply of generic flumazenil was initially thought to be too low to meet the potential demand for treatment of primary hypersomnias. However, this scarcity has eased, and dozens of people are now being treated with flumazenil off-label.

Clarithromycin
In a test tube model, clarithromycin (an antibiotic approved by the FDA for the treatment of infections) was found to return the function of the GABA system to normal in people with primary hypersomnias. Investigators therefore treated a few people with narcolepsy with off-label clarithromycin, and most felt their symptoms improved with this treatment. In order to help further determine whether clarithromycin is truly beneficial for the treatment of narcolepsy and idiopathic hypersomnia, a small, double-blind, randomized, controlled clinical trial was completed in 2012. "In this pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia. Larger trials of longer duration are warranted." In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of people with GABA-related hypersomnia. "It is important to note that the positive effect of clarithromycin is secondary to a benzodiazepine antagonist-like effect, not its antibiotic effects, and treatment must be maintained."

Orexin receptor agonists
Orexin-A (a.k.a. hypocretin-1) has been shown to be strongly wake-promoting in animal models, but it does not cross the blood–brain barrier. The first line treatment for narcolepsy, modafinil, has been found to interact indirectly with the orexin system. It is also likely that an orexin receptor agonist will be found and developed for the treatment of hypersomnia. One such agent which is currently in clinical trials is danavorexton.

L-carnitine
Abnormally low levels of acylcarnitine have been observed in people with narcolepsy. These same low levels have been associated with primary hypersomnia in general in mouse studies. “Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity.” Administration of acetyl-L-carnitine was shown to improve these symptoms in mice. A subsequent human trial found that people with narcolepsy given L-carnitine spent less total time in daytime sleep than people who were given a placebo.

Animal models
Animal studies try to mimic the disorder in humans by either modifying the Hypocretin/Orexin receptors or by eliminating this peptide. An orexin deficit caused by the degeneration of hypothalamic neurons is suggested to be one of the causes of narcolepsy. More recent clinical studies on both animals and humans have also revealed that hypocretin is involved in other functions beside regulation of wakefulness and sleep. These functions include autonomic regulation, emotional processing, reward learning behaviour or energy homeostasis. In studies where the concentration of the hypocretin was measured under different circumstances, it was observed that the hypocretin levels increased with the positive emotion, anger or social interaction but stayed low during sleep or during pain experience.The most reliable and valid animal models developed are the canine (narcoleptic dogs) and the rodent (orexin-deficient mice) ones which helped investigating the narcolepsy and set the focus on the role of orexin in this disorder.

Dog models
Dogs, as well as other species like cats or horses, can also exhibit spontaneous narcolepsy with similar symptoms as the ones reported in humans </s>