<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 Recurrent painful ophthalmoplegic neuropathy and can you explain it in depth? [/INST] Recurrent painful ophthalmoplegic neuropathy (RPON), previously known as ophthalmoplegic migraine (OM), is a rare neurological disorder that is characterized by repeated headache attacks and reversible ipsilateral paresis of one or more ocular cranial nerves (CN). Oculomotor nerve (CNIII) is by far the most common cranial nerve involves in RPON, while abducens nerve (CNVI) and trochlear nerve (CNIV) involvements are also reported. Globally, RPON was estimated to have an annual incidence rate of 0.7 per million as of 1990, no further epidemiological studies have been conducted. It occurs more often in children and females.Although the etiology of RPON is unknown owing to the rarity of this disease, various potential theories including migrainous and neuropathic mechanisms have been developed. Diagnosis is based on physical examination, magnetic resonance imaging (MRI), and ruling out other possible causes. Despite the fact that there are currently no evidence-based treatment guidelines for RPON, the most commonly used medications are corticosteroids that have been proven effective in alleviating the symptoms. As for people who are unresponsive to steroids, other treatments, such as anti-migraine drugs, botulinum toxin injection and strabismus surgery, may be utilized. For prevention, several medications including calcium channel blockers may be used. However, none have been proved consistently effective. RPON has a good overall prognosis as a result of the self-limiting nature of the condition, but permanent neurological damage may accumulate over repeated episodes.

Signs and symptoms
The typical symptoms of RPON are recurrent headaches and ipsilateral paralysis of the extraocular muscles (ophthalmoplegia) that are responsible for controlling eye movements. People with RPON experience different severity of pain, duration of symptoms, and frequency of attacks, which are also dependent on the treatment they received. The attacks of RPON usually occur on the same side of the head in subsequent episodes.

Headache
The most common type of headache is migraine-like, usually accompanied by symptoms such as nausea, vomiting, photophobia, or phonophobia.  Less commonly, RPON can occur without migrainous headache nor accompanied by the classical migrainous symptoms. The frequency of headaches can range from several times per month to once in several years, while the duration varies from several days to a week, which lasts longer than that of a typical migraine.

Ophthalmoplegia
Ophthalmoplegia usually occurs either concurrently or within 1 week after the onset of headache, and less commonly up to 2 weeks. The ocular manifestation of RPON depend on which ocular cranial nerve is being affected. CNIII is involved in the vast majority of cases, but the involvement of CNVI and CNIV is also reported in studies. Typical ocular signs involving CNIII include outwards and downwards drifting of eyes (strabismus), difficulty in controlling inward and upward eye movements, drooping of eyelid (ptosis) and double vision. Pupil dilation (mydriasis) and reduction in pupillary light reflexes can also be observed as pupillomotor fibers are also affected by CNIII paralysis.  Rare cases involve abducens nerve paralysis affects lateral eye movement while trochlear nerve paralysis affects vertical eye movement. Similar to headache, ophthalmoplegia usually resolve gradually and completely over time, but recovery may be incomplete after several episodes.

Pathophysiology
The etiology of RPON is still unknown and remains controversial - some scientists believe that RPON is a subtype of migraine, while others believe that it is a neuropathic disorder. As such, different potential etiologic mechanisms have been proposed based on case reports, including migrainous and neuropathic mechanisms. Yet, the renaming of RPON from OM indicates that the neuropathic cause may play a more important role than the migrainous cause in the pathophysiology of RPON.

Migrainous mechanism
RPON was previously thought to be having a migrainous origin since it shares some common characteristics with migraine, and their only differences are the intensity and duration of headaches. Therefore, it was postulated that migraine caused ophthalmoplegia in RPON. However, the major argument against a migrainous origin is the long latency period between the onset of headache and ophthalmoplegia (up to 14 days), which is not consistent with a typical migraine. Nevertheless, several migrainous mechanisms have been proposed.

Nerve compression
Compression mechanism is the first theory postulated regarding the pathophysiology of RPON. It is proposed that headache is caused by direct pressure on CNIII (compression neuropathy) within the cavernous sinus due to edema of the walls of the internal carotid artery (ICA) or posterior cerebral artery (PCA) during migraine episodes.

Ischemia
Cavernous section of the ICA and a perforating vessel from the proximal PCA are responsible for supplying CNIII, CNIV, and CNVI. During migraine attacks, vasoconstriction of the ICA and PCA may lead to a reversible and ischemic breakdown of the blood-brain barrier.  The blood-brain barrier breakdown results in vasogenic edema, which promotes the development of RPON.

Neuropeptides-induced
Alternatively, it is proposed that migraine-related release of neuropeptides from trigeminal nerve fibers terminating on the circle of Willis might be the cause. Some of the neuropeptides released are potentially toxic, and may induce blood-brain barrier breakdown that accounts for ophthalmoplegia.

Neuropathic mechanism
Additional models have been proposed to explain the cause of RPON. The thickened and enhanced symptomatic nerve, as shown in recent MRI findings, might be indicative of the existence of structural nerve damage in RPON. Therefore, neuropathy is suggested as the primary cause of RPON, either induced by recurrent viral infections or immune-mediated inflammation. However, cerebrospinal fluid (CSF) analyses are normal in the vast majority of RPON cases, which is inconsistent with the findings of autoimmune or inflammatory-mediated pathomechanism. Nevertheless, several neuropathic mechanisms have been proposed.

Benign viral infection
The enhancement and thickening of the oculomotor nerve can occur in a variety of infectious inflammatory conditions. However, spontaneous resolution is unlikely to occur in viral infection, except for benign viral infection that usually causes mild or no symptoms in humans. Therefore, benign viral infection could be an explanation for the development of RPON.

Immune-mediated inflammation
Recent MRI findings have led to the current understanding of RPON as an inflammation-induced neuropathy. Recurrent demyelinating neuropathy is proposed as a pathophysiological pathway because similar MRI findings have been observed in both RPON and chronic inflammatory demyelinating neuropathy. Inflammatory demyelination of the ocular cranial nerves would likely lead to the release of neuropeptides, such as calcitonin gene-related peptide, to the trigeminovascular system. This would irritate the trigeminal sensory fibers, and consequently, a headache as manifested in RPON is triggered.

Diagnosis
Diagnostic criteria
To be diagnosed with RPON, a person must have a minimum of 2 unilateral headache attacks with ipsilateral ocular cranial nerve paralysis that cannot be explained by other causes of headache in ICHD-3 after investigation.

Diagnostic tests
RPON is a diagnosis of exclusion, meaning that other conditions with similar clinical presentation, such as vascular, inflammatory, neoplastic, and infectious causes, must be ruled out before the confirmation of RPON diagnosis. Physical examination, neuroimaging, and laboratory tests are routinely conducted in clinical practice to evaluate this disease.

Physical examination
After obtaining the medical history of people with suspected RPON, thorough eye examination and neurological examination are usually performed to assess the extent of neurological impairment, localize the brain regions being affected, and rule out other possible causes for the symptoms. These involve the assessments of visual acuity, eye movements and alignment, pupillary responses, and mental status.

Neuroimaging
Contrast-enhanced magnetic resonance imaging (MRI) is a diagnostic tool that can facilitate the differentiation of RPON from other diseases. The transient, reversible enhancement or thickening of the ocular motor nerve(s), which can be observed in the MRI scans of a small proportion of affected individuals during acute attacks, is a distinguishing feature of RPON. Cranial nerve enhancement resulted from RPON would gradually disappear as the symptoms subside after an episode, but spontaneous resolution of nerve enhancement is very unlikely to be seen in neoplastic (e.g. schwannoma), inflammatory and infectious diseases. Contrast-enhanced MRI results can also reveal the location of nerve inflammation for disease diagnosis. Although Tolosa–Hunt syndrome (THS) and RPON share many clinical features, THS can be identified by the presence of granulomatous inflammation in the cavernous sinus, superior orbital fissure, or orbit in MRI scans.Magnetic resonance angiography (MRA) or CT angiography (CTA) can be used to examine cerebral blood vessels and to rule out vascular abnormalities, such as an aneurysm. In cases where intracranial vascular lesions, for example, subarachnoid hemorrhage cannot be completely ruled out after performing MRA or CTA, physicians may consider using traditional digital subtraction angiography (DSA) for more detailed investigation.

Laboratory tests
Lumbar punctures and blood tests might be performed on those with RPON to identify other possible causes of cranial neuropathy, including diabetes, inflammatory diseases, infections, tumors, and other systemic diseases that involve either the central nervous system or the peripheral nervous system. The detection of abnormalities in these tests suggests that RPON is highly unlikely to be the culprit in cranial neuropathy, and more diagnostic tests should be done to find out the underlying condition.

Treatment
To date, no clinical trials or treatment guidelines for RPON have been published. Since the evaluation of effective treatments is entirely based on evidence from a limited number of case reports, there is some uncertainty surrounding the proposed efficacy of the drugs for treating RPON.
Potential treatments for RPON can be divided into three main categories: preventative therapy, symptomatic treatment, and management of residual symptoms.

Preventative therapy
Migraine preventive medications, including beta-blockers (e.g. propranolol), calcium channel blockers (e.g. flunarizine), anticonvulsants (e.g. valproate), and antidepressants (e.g. amitriptyline), may be given to those with RPON with the intent of preventing RPON recurrence. Although the efficacy of these preventives has been proposed in various published case studies, there is a lack of compelling evidence suggesting that these anti-migraine drugs have long-term prophylactic effect on future RPON attacks. The initiation of migraine preventive therapy in RPON is only recommended for people who have typical migraine with frequent attacks as a concurrent condition.

Symptomatic treatment
Corticosteroids are the most frequently reported drugs for treating acute symptoms of RPON. The rationale behind their use in RPON treatment is to reduce ocular cranial nerve inflammation, which is indicated by the presence of nerve enhancement and is also theorized to be a pathophysiological mechanism of RPON, in affected individuals </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 Malum perforans and can you explain it in depth? [/INST] Malum perforans is a long-lasting, usually painless ulcer that penetrates deep into or through the skin, usually on the sole of the foot (in which case it may be called malum perforans pedis). It is often a complication in diabetes mellitus and other conditions affecting the nerves.

Presentation
These ulcers have punched-out edge and slough in floor, resembling gummatous ulcer. Surrounding area might have loss of sensation.

Cause
This condition results from denervation of areas exposed to day-to-day friction of bony prominences. The denervation may be result of any of the following diseases:
Spinal injuries
Leprosy
Peripheral nerve injury
Diabetic neuropathy
Tabes dorsalis
Transverse myelitis
Meningomyelocele
Syringomyelia

Pathophysiology
Normal pressure and pain sensations are essential for protecting the foot from excessive and prolonged pressures over bony prominences </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 Brittle asthma 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 Cannabis (drug) and can you explain it in depth? [/INST] Cannabis, also known as marijuana among other names, is a psychoactive drug from the Cannabis plant. Native to Central and South Asia, the cannabis plant has been used as a drug for both recreational and entheogenic purposes and in various traditional medicines for centuries. Tetrahydrocannabinol (THC) is the main psychoactive component of cannabis, which is one of the 483 known compounds in the plant, including at least 65 other cannabinoids, including cannabidiol (CBD). Cannabis can be used by smoking, vaporizing, within food, or as an extract.Cannabis has various mental and physical effects, which include euphoria, altered states of mind and sense of time, difficulty concentrating, impaired short-term memory, impaired body movement (balance and fine psychomotor control),: p7  relaxation, and an increase in appetite. Onset of effects is felt within minutes when smoked, but may take up to 90 minutes when eaten. The effects last for two to six hours, depending on the amount used. At high doses, mental effects can include anxiety, delusions (including ideas of reference), hallucinations, panic, paranoia, and psychosis. There is a strong relation between cannabis use and the risk of psychosis, though the direction of causality is debated. Physical effects include increased heart rate, difficulty breathing, nausea, and behavioral problems in children whose mothers used cannabis during pregnancy; short-term side effects may also include dry mouth and red eyes. Long-term adverse effects may include addiction, decreased mental ability in those who started regular use as adolescents, chronic coughing, susceptibility to respiratory infections, and cannabinoid hyperemesis syndrome.
Cannabis is mostly used recreationally or as a medicinal drug, although it may also be used for spiritual purposes. In 2013, between 128 and 232 million people used cannabis (2.7% to 4.9% of the global population between the ages of 15 and 65). It is the most commonly used illegal drug in the world, though it is legal in some jurisdictions, with the highest use among adults (as of 2018) in Zambia, the United States, Canada, and Nigeria.While cannabis plants have been grown since at least the 3rd millennium BCE, evidence suggests that it was being smoked for psychoactive effects at least 2,500 years ago in the Pamir Mountains, Asia. Since the early 20th century, cannabis has been subject to legal restrictions. The possession, use, and cultivation of cannabis is illegal in most countries. In 2013, Uruguay became the first country to legalize recreational use of cannabis. Other countries to do so are Canada, Georgia, Malta, Mexico, and South Africa. In the United States, the recreational use of cannabis is legal in 19 states, two territories, and the District of Columbia, though the drug remains federally illegal.

Uses
Medical
Medical cannabis, or medical marijuana, refers to the use of cannabis to treat disease or improve symptoms; however, there is no single agreed-upon definition (e.g., cannabinoids derived from cannabis and synthetic cannabinoids are also used). The rigorous scientific study of cannabis as a medicine has been hampered by production restrictions and by the fact that it is classified as an illegal drug by many governments. There is limited evidence suggesting cannabis can be used to reduce nausea and vomiting during chemotherapy, to improve appetite in people with HIV/AIDS, or to treat chronic pain and muscle spasms. Its use for other medical applications is insufficient for drawing conclusions about safety or efficacy. There is evidence supporting the use of cannabis or its derivatives in the treatment of chemotherapy-induced nausea and vomiting, neuropathic pain, and multiple sclerosis. Lower levels of evidence support its use for AIDS wasting syndrome, epilepsy, rheumatoid arthritis, and glaucoma.So far, the medical use of cannabis is legal only in a limited number of territories, including Canada, Belgium, Australia, the Netherlands, New Zealand, Spain, and many U.S. states. This usage generally requires a prescription, and distribution is usually done within a framework defined by local laws.

Recreational
According to DEA Chief Administrative Law Judge, Francis Young, "cannabis is one of the safest therapeutically active substances known to man." Being under the effects of cannabis is usually referred to as being "high" or "stoned." Cannabis consumption has both psychoactive and physiological effects. The "stoned" experience can vary widely, based (among other things) on the users prior experience with cannabis, and the type of cannabis consumed.: p647  When smoking cannabis, a euphoriant effect can occur within minutes of smoking.: p104  Aside from a subjective change in perception and mood, the most common short-term physical and neurological effects include increased heart rate, increased appetite, impairment of short-term and working memory, and psychomotor coordination.Additional desired effects from consuming cannabis include relaxation, a general alteration of conscious perception, increased awareness of sensation, increased libido and distortions in the perception of time and space. At higher doses, effects can include altered body image, auditory and/or visual illusions, pseudohallucinations and ataxia from selective impairment of polysynaptic reflexes. In some cases, cannabis can lead to dissociative states such as depersonalization and derealization.

Spiritual
Cannabis has held sacred status in several religions and has served as an entheogen – a chemical substance used in religious, shamanic, or spiritual contexts – in the Indian subcontinent since the Vedic period. The earliest known reports regarding the sacred status of cannabis in the Indian subcontinent come from the Atharva Veda, estimated to have been composed sometime around 1400 BCE.
The Hindu god Shiva is described as a cannabis user, known as the "Lord of bhang.: p19 In modern culture, the spiritual use of cannabis has been spread by the disciples of the Rastafari movement who use cannabis as a sacrament and as an aid to meditation.

Modes of cannabis consumption
Cannabis is consumed in many different ways, all of which involve heating to decarboxylate THCA in the plant into THC. Common available forms are:

Smoking, which typically involves burning and inhaling vaporized cannabinoids ("smoke") from small pipes, bongs (portable versions of hookahs with a water chamber), paper-wrapped joints or tobacco-leaf-wrapped blunts, and other items.
Vaporizer, which heats any form of cannabis to 165–190 °C (329–374 °F), causing the active ingredients to evaporate into vapor without burning the plant material (the boiling point of THC is 157 °C (315 °F) at atmospheric pressure).
Cannabis tea, which contains relatively small concentrations of THC because THC is an oil (lipophilic) and is only slightly water-soluble (with a solubility of 2.8 mg per liter). Cannabis tea is made by first adding a saturated fat to hot water (e.g. cream or any milk except skim) with a small amount of cannabis.
Edibles, where cannabis is added as an ingredient to one of a variety of foods, including butter and baked goods. In India it is commonly made into a beverage, bhang.
Tincture of cannabis, sometimes known as green dragon, is an alcoholic cannabis concentrate.
Capsules, typically containing cannabis oil, and other dietary supplement products, for which some 220 were approved in Canada in 2018.

Adverse effects
Short-term
Acute negative effects may include anxiety and panic, impaired attention and memory, an increased risk of psychotic symptoms, the inability to think clearly, and an increased risk of accidents. Cannabis impairs a persons driving ability, and THC was the illicit drug most frequently found in the blood of drivers who have been involved in vehicle crashes. Those with THC in their system are from three to seven times more likely to be the cause of the accident than those who had not used either cannabis or alcohol, although its role is not necessarily causal because THC stays in the bloodstream for days to weeks after intoxication.Some immediate undesired side effects include a decrease in short-term memory, dry mouth, impaired motor skills, reddening of the eyes, dizziness, feeling tired and vomiting. Some users may experience an episode of acute psychosis, which usually abates after six hours, but in rare instances, heavy users may find the symptoms continuing for many days.Legalization has increased the rates at which children are exposed to cannabis, particularly from edibles. While the toxicity and lethality of THC in children is not known, they are at risk for encephalopathy, hypotension, respiratory depression severe enough to require ventilation, somnolence and coma.

Fatality
Cannabis is suspected of being a potential, and under-reported, contributory factor or direct cause in cases of sudden death, due to the strain it can place on the cardiovascular system. Multiple deaths have been attributed to cannabinoid hyperemesis syndrome.A 16-month survey of Oregon and Alaska emergency departments found a report of the death of an adult who had been admitted for acute cannabis toxicity.

Long-term
Psychological effects
A 2015 meta-analysis found that, although a longer period of abstinence was associated with smaller magnitudes of impairment, both retrospective and prospective memory were impaired in cannabis users. The authors concluded that some, but not all, of the deficits associated with cannabis use were reversible. A 2012 meta-analysis found that deficits in most domains of cognition persisted beyond the acute period of intoxication, but was not evident in studies where subjects were abstinent for more than 25 days. Few high quality studies have been performed on the long-term effects of cannabis on cognition, and the results were generally inconsistent. Furthermore, effect sizes of significant findings were generally small. One review concluded that, although most cognitive faculties were unimpaired by cannabis use, residual deficits occurred in executive functions. Impairments in executive functioning are most consistently found in older populations, which may reflect heavier cannabis exposure, or developmental effects associated with adolescent cannabis use. One review found three prospective cohort studies that examined the relationship between self reported cannabis use and intelligence quotient (IQ). The study following the largest number of heavy cannabis users reported that IQ declined between ages 7–13 and age 38. Poorer school performance and increased incidence of leaving school early were both associated with cannabis use, although a causal relationship was not established. Cannabis users demonstrated increased activity in task-related brain regions, consistent with reduced processing efficiency.A reduced quality of life is associated with heavy cannabis use, although the relationship is inconsistent and weaker than for tobacco and other substances. The direction of cause and effect, however, is unclear.The long-term effects of cannabis are not clear. There are concerns surrounding memory and cognition problems, risk of addiction, and the risk of schizophrenia in young people.

Neuroimaging
Although global abnormalities in white matter and grey matter are not consistently associated with heavy cannabis use, reduced hippocampal volume is consistently found. Amygdala abnormalities are sometimes reported, although findings are inconsistent.Cannabis use is associated with increased recruitment of task-related areas, such as the dorsolateral prefrontal cortex, which is thought to reflect compensatory activity due to reduced processing efficiency. Cannabis use is also associated with downregulation of CB1 receptors. The magnitude of down regulation is associated with cumulative cannabis exposure, and is reversed after one month of abstinence. There is limited evidence that chronic cannabis use can reduce levels of glutamate metabolites in the human brain.

Cannabis dependence
About 9% of those who experiment with marijuana eventually become dependent according to DSM-IV (1994) criteria. A 2013 review estimates daily use is associated with a 10–20% rate of dependence. The highest risk of cannabis dependence is found in those with a history of poor academic achievement, deviant behavior in childhood and adolescence, rebelliousness, poor parental relationships, or a parental history of drug and alcohol problems. Of daily users, about 50% experience withdrawal upon cessation of use (i.e. are dependent), characterized by sleep problems, irritability, dysphoria, and craving. Cannabis withdrawal is less severe than withdrawal from alcohol.According to DSM-V criteria, 9% of those who are exposed to cannabis develop cannabis use disorder, compared to 20% for cocaine, 23% for alcohol and 68% for nicotine. Cannabis use disorder in the DSM-V involves a combination of DSM-IV criteria for cannabis abuse and dependence, plus the addition of craving, without the criterion related to legal troubles.

Psychiatric
At an epidemiological level, a dose–response relationship exists between cannabis use and increased risk of psychosis and earlier onset of psychosis. Although the epidemiological association is robust, evidence to prove a causal relationship is lacking. But a biological causal pathway is plausible, especially if there is a genetic predisposition to mental illness, in which case cannabis may be a trigger.Cannabis may also increase the risk of depression, but insufficient research has been performed to draw a conclusion. Cannabis use is associated with increased risk of anxiety disorders, although causality has not been established.A review in 2019 found that research was insufficient to determine the safety and efficacy of using cannabis to treat schizophrenia, psychosis, or other mental disorders. Another found that cannabis during adolescence was associated with an increased risk of developing depression and suicidal behavior later in life, while finding no effect on anxiety.

Physical
Heavy, long-term exposure to marijuana may have physical, mental, behavioral and social health consequences. It may be "associated with diseases of the liver (particularly with co-existing hepatitis C), lungs, heart, and vasculature". A 2014 review found that while cannabis use may be less harmful than alcohol use, the recommendation to substitute it for problematic drinking was premature without further study. Various surveys conducted between 2015 and 2019 found that many users of cannabis substitute it for prescription drugs (including opioids), alcohol, and tobacco; most of those who used it in place of alcohol or tobacco either reduced or stopped their intake of the latter substances.Cannabinoid hyperemesis syndrome (CHS) is a severe condition seen in some chronic cannabis users where they have repeated bouts of uncontrollable vomiting for 24–48 hours.
Four cases of death have been reported as a result of CHS.A limited number of studies have examined the effects of cannabis smoking on the respiratory system. Chronic heavy marijuana smoking is associated with coughing, production of sputum, wheezing, and other symptoms of chronic bronchitis. The available evidence does not support a causal relationship between cannabis use and chronic obstructive pulmonary disease. Short-term use of cannabis is associated with bronchodilation. Other side effects of cannabis use include cannabinoid hyperemesis syndrome (CHS), a condition which involves recurrent nausea, cramping abdominal pain, and vomiting.Cannabis smoke contains thousands of organic and inorganic chemical compounds. This tar is chemically similar to that found in tobacco smoke, and over fifty known carcinogens have been identified in cannabis smoke, including; nitrosamines, reactive aldehydes, and polycylic hydrocarbons, including benz[a]pyrene. Cannabis smoke is also inhaled more deeply than tobacco smoke. As of 2015, there is no consensus regarding whether cannabis smoking is associated with an increased risk of cancer. Light and moderate use of cannabis is not believed to increase risk of lung or upper airway cancer. Evidence for causing these cancers is mixed concerning heavy, long-term use. In general there are far lower risks of pulmonary complications for regular cannabis smokers when compared with those of tobacco. A 2015 review found an association between cannabis use and the development of testicular germ cell tumors (TGCTs), particularly non-seminoma TGCTs. Another 2015 meta-analysis found no association between lifetime cannabis use and risk of head or neck cancer. Combustion products are not present when using a vaporizer, consuming THC in pill form, or consuming cannabis foods.There is concern that cannabis may contribute to cardiovascular disease, but as of 2018, evidence of this relationship was unclear. Research in these events is complicated because cannabis is often used in conjunction with tobacco, and drugs such as alcohol and cocaine that are known to have cardiovascular risk factors. Smoking cannabis has also been shown to increase the risk of myocardial infarction by 4.8 times for the 60 minutes after consumption.There is preliminary evidence that cannabis interferes with the anticoagulant properties of prescription drugs used for treating blood clots. As of 2019, the mechanisms for the anti-inflammatory and possible pain relieving effects of cannabis were not defined, and there were no governmental regulatory approvals or clinical practices for use of cannabis as a drug.

Emergency Department Visits
Emergency room (ER) admissions associated with cannabis use rose significantly from 2012 to 2016; adolescents from age 12-17 had the highest risk.

At one Colorado medical center following legalization, approximately two percent of ER admissions were classified as cannabis users. The symptoms of one quarter of these users were partially attributed to cannabis (a total of 2567 out of 449,031 patients); other drugs were sometimes involved. Of these cannabis admissions, one quarter were for acute psychiatric effects, primarily suicidal ideation, depression, and anxiety. An additional third of the cases were for gastrointestinal issues including Cannabinoid hyperemesis syndrome.According to the United States Department of Health and Human Services, there were 455,000 emergency room visits associated with cannabis use in 2011. These statistics include visits in which the patient was treated for a condition induced by or related to recent cannabis use. The drug use must be "implicated" in the emergency department visit, but does not need to be the direct cause of the visit. Most of the illicit drug emergency room visits involved multiple drugs. In 129,000 cases, cannabis was the only implicated drug.

Reproductive health
There is sufficient evidence of reproductive health harms from cannabis that its use when trying to conceive, during pregnancy, and while breastfeeding, is not advisable.It has been recommended that cannabis use be stopped before and during pregnancy as it can result in negative outcomes for both the mother and baby. However, maternal use of marijuana during pregnancy does not appear to be associated with low birth weight or early delivery after controlling for tobacco use and other confounding factors.

Pharmacology
Mechanism of action
The high lipid-solubility of cannabinoids results in their persisting in the body for long periods of time. Even after a single administration of THC, detectable levels of THC can be found in the body for weeks or longer (depending on the amount administered and the sensitivity of the assessment method). Investigators have suggested that this is an important factor in marijuanas effects, perhaps because cannabinoids may accumulate in the body, particularly in the lipid membranes of neurons.Researchers confirmed that THC exerts its most prominent effects via its actions on two types of cannabinoid receptors, the CB1 receptor and the CB2 receptor, both of which are G protein-coupled receptors. The CB1 receptor is found primarily in the brain as well as in some peripheral tissues, and the CB2 receptor is found primarily in peripheral tissues, but is also expressed in neuroglial cells. THC appears to alter mood and cognition through its agonist actions on the CB1 receptors, which inhibit a secondary messenger system (adenylate cyclase) in a dose-dependent manner.
Via CB1 receptor activation, THC indirectly increases dopamine release and produces psychotropic effects. CBD also acts as an allosteric modulator of the μ- and δ-opioid receptors. THC also potentiates the effects of the glycine receptors. It is unknown if or how these actions contribute to the effects of cannabis.

Chemistry
Chemical composition
The main psychoactive component of cannabis is THC, which is formed via decarboxylation of THCA from the application of heat. Raw leaf is not psychoactive because the cannabinoids are in the form of carboxylic acids.

Cannabinoids
Detection in body fluids
THC and its major (inactive) metabolite, THC-COOH, can be measured in blood, urine, hair, oral fluid or sweat using chromatographic techniques as part of a drug use testing program or a forensic investigation of a traffic or other criminal offense. The concentrations obtained from such analyses can often be helpful in distinguishing active use from passive exposure, elapsed time since use, and extent or duration of use. These tests cannot, however, distinguish authorized cannabis smoking for medical purposes from unauthorized recreational smoking. Commercial cannabinoid immunoassays, often employed as the initial screening method when testing physiological specimens for marijuana presence, have different degrees of cross-reactivity with THC and its metabolites. Urine contains predominantly THC-COOH, while hair, oral fluid and sweat contain primarily THC. Blood may contain both substances, with the relative amounts dependent on the recency and extent of usage.The Duquenois–Levine test is commonly used as a screening test in the field, but it cannot definitively confirm the presence of cannabis, as a large range of substances have been shown to give false positives. Researchers at John Jay College of Criminal Justice reported that dietary zinc supplements can mask the presence of THC and other drugs in urine. However, a 2013 study conducted by researchers at the University of Utah School of Medicine refute the possibility of self-administered zinc producing false-negative urine drug tests.

Varieties and strains
CBD is a 5-HT1A receptor agonist, which is under laboratory research to determine if it has an anxiolytic effect. It is often claimed that sativa strains provide a more stimulating psychoactive high while indica strains are more sedating with a body high. However, this is disputed by researchers.A 2015 review found that the use of high CBD-to-THC strains of cannabis showed significantly fewer positive symptoms, such as delusions and hallucinations, better cognitive function and both lower risk for developing psychosis, as well as a later age of onset of the illness, compared to cannabis with low CBD-to-THC ratios.

Psychoactive ingredients
According to the United Nations Office on Drugs and Crime (UNODC), "the amount of THC present in a cannabis sample is generally used as a measure of cannabis potency." The three main forms of cannabis products are the flower/fruit, resin (hashish), and oil (hash oil). The UNODC states that cannabis often contains 5% THC content, resin "can contain up to 20% THC content", and that "Cannabis oil may contain more than 60% THC content."A 2012 review found that the THC content in marijuana had increased worldwide from 1970 to 2009. It is unclear, however, whether the increase in THC content has caused people to consume more THC or if users adjust based on the potency of the cannabis. It is likely that the higher THC content allows people to ingest less tar. At the same time, CBD levels in seized samples have lowered, in part because of the desire to produce higher THC levels and because more illegal growers cultivate indoors using artificial lights. This helps avoid detection but reduces the CBD production of the plant.Australias National Cannabis Prevention and Information Centre (NCPIC) states that the buds (infructescences) of the female cannabis plant contain the highest concentration of THC, followed by the leaves. The stalks and seeds have "much lower THC levels". The UN states that the leaves can contain ten times less THC than the buds, and the stalks one hundred times less THC.After revisions to cannabis scheduling in the UK, the government moved cannabis back from a class C to a class B drug. A purported reason was the appearance of high potency cannabis. They believe skunk accounts for between 70 and 80% of samples seized by police (despite the fact that skunk can sometimes be incorrectly mistaken for all types of herbal cannabis). Extracts such as hashish and hash oil typically contain more THC than high potency cannabis infructescences.

Laced cannabis and synthetic cannabinoids
Hemp buds (or low-potency cannabis buds) laced with synthetic cannabinoids started to be sold as cannabis street drug in 2020.The short term effects of cannabis can be altered if it has been laced with opioid drugs such as heroin or fentanyl. The added drugs are meant to enhance the psychoactive properties, add to its weight, and increase profitability, despite the increased danger of overdose.

Preparations
Marijuana
Marijuana or marihuana (herbal cannabis) consists of the dried flowers and fruits and subtending leaves and stems of the female Cannabis plant. This is the most widely consumed form, containing 3% to 20% THC, with reports of up to 33% THC. This is the stock material from which all other preparations are derived. Although herbal cannabis and industrial hemp derive from the same species and contain the psychoactive component (THC), they are distinct strains with unique biochemical compositions and uses. Hemp has lower concentrations of THC and higher concentrations of CBD, which gives lesser psychoactive effects.

Kief
Kief is a powder, rich in trichomes, which can be sifted from the leaves, flowers and fruits of cannabis plants and either consumed in powder form or compressed to produce cakes of hashish. The word "kif" derives from colloquial Arabic كيف kēf/kīf, meaning pleasure.

Hashish
Hashish (also spelled hasheesh, hashisha, or simply hash) is a concentrated resin cake or ball produced from pressed kief, the detached trichomes and fine material that falls off cannabis fruits, flowers and leaves. or from scraping the resin from the surface of the plants and rolling it into balls. It varies in color from black to golden brown depending upon purity and variety of cultivar it was obtained from. It can be consumed orally or smoked, and is also vaporized, or vaped. The term "rosin hash" refers to a high quality solventless product obtained through heat and pressure.

Tincture
Cannabinoids can be extracted from cannabis plant matter using high-proof spirits (often grain alcohol) to create a tincture, often referred to as "green dragon".: p17  Nabiximols is a branded product name from a tincture manufacturing pharmaceutical company.

Hash oil
Hash oil is a resinous matrix of cannabinoids obtained from the Cannabis plant by solvent extraction, formed into a hardened or viscous mass. Hash oil can be the most potent of the main cannabis products because of its high level of psychoactive compound per its volume, which can vary depending on the plants mix of essential oils and psychoactive compounds. Butane and supercritical carbon dioxide hash oil have become popular in recent years.

Infusions
There are many varieties of cannabis infusions owing to the variety of non-volatile solvents used. The plant material is mixed with the solvent and then pressed and filtered to express the oils of the plant into the solvent. Examples of solvents used in this process are cocoa butter, dairy butter, cooking oil, glycerine, and skin moisturizers. Depending on the solvent, these may be used in cannabis foods or applied topically.

Marihuana prensada
Marihuana prensada (pressed marijuana) is a cannabis-derived product widespread among the lower classes of South America, especially from the 90s. Locally it is known as "paraguayo" or "paragua", since its main producer is Paraguay. Marijuana is dried and mixed with binding agents that make it toxic and highly harmful to health. It is cut into the shape of bricks (ladrillos) and sold for a low price in Argentina, Brazil, Chile, Peru, Venezuela, and even the United States.

History
Ancient history
Cannabis is indigenous to Central Asia and the Indian subcontinent, and its uses for fabric and rope dates back to the Neolithic age in China and Japan. It is unclear when cannabis first became known for its psychoactive properties. The oldest archeological evidence for the burning of cannabis was found in Romanian kurgans dated 3,500 BC, and scholars suggest that the drug was first used in ritual ceremonies by Proto-Indo-European tribes living in the Pontic-Caspian steppe during the Chalcolithic period, a custom they eventually spread throughout western Eurasia during the Indo-European migrations. Some research suggests that the ancient Indo-Iranian drug soma, mentioned in the Vedas, sometimes contained cannabis. This is based on the discovery of a basin containing cannabis in a shrine of the second millennium BC in Turkmenistan.Cannabis was known to the ancient Assyrians, who discovered its psychoactive properties through the Iranians. Using it in some religious ceremonies, they called it qunubu (meaning "way to produce smoke"), a probable origin of the modern word "cannabis". The Iranians also introduced cannabis to the Scythians, Thracians and Dacians, whose shamans (the kapnobatai – "those who walk on smoke/clouds") burned cannabis infructescences to induce trance. The plant was used in China before 2800 BC, and found therapeutic use in India by 1000 BC, where it was used in food and drink, including bhang.

Cannabis has an ancient history of ritual use and has been used by religions around the world. The earliest evidence of cannabis smoking has been found in the 2,500-year-old tombs of Jirzankal Cemetery in the Pamir Mountains in Western China, where cannabis residue were found in burners with charred pebbles possibly used during funeral rituals. Hemp seeds discovered by archaeologists at Pazyryk suggest early ceremonial practices like eating by the Scythians occurred during the 5th to 2nd century BC, confirming previous historical reports by Herodotus. It was used by Muslims in various Sufi orders as early as the Mamluk period, for example by the Qalandars. Smoking pipes uncovered in Ethiopia and carbon-dated to around c. AD 1320 were found to have traces of cannabis.

Modern history
Cannabis was introduced to the New World by the Spaniards in 1530–45. Following an 1836–1840 travel in North Africa and the Middle East, French physician Jacques-Joseph Moreau wrote on the psychological effects of cannabis use; he was a member of Paris Club des Hashischins. In 1842, Irish physician William Brooke OShaughnessy, who had studied the drug while working as a medical officer in Bengal with the East India Company, brought a quantity of cannabis with him on his return to Britain, provoking renewed interest in the West. Examples of classic literature of the period featuring cannabis include Les paradis artificiels (1860) by Charles Baudelaire and The Hasheesh Eater (1857) by Fitz Hugh Ludlow.

Cannabis was criminalized in various countries beginning in the 19th century. The colonial government of Mauritius banned cannabis in 1840 over concerns on its effect on Indian indentured workers; the same occurred in Singapore in 1870. In the United States, the first restrictions on sale of cannabis came in 1906 (in the District of Columbia). Canada criminalized cannabis in The Opium and Narcotic Drug Act, 1923, before any reports of the use of the drug in Canada, but eventually legalized its consumption for recreational and medicinal purposes in 2018.In 1925, a compromise was made at an international conference in The Hague about the International Opium Convention that banned exportation of "Indian hemp" to countries that had prohibited its use, and requiring importing countries to issue certificates approving the importation and stating that the shipment was required "exclusively for medical or scientific purposes". It also required parties to "exercise an effective control of such a nature as to prevent the illicit international traffic in Indian hemp and especially in the resin". In the United States in 1937, the Marihuana Tax Act was passed, and prohibited the production of hemp in addition to cannabis.

In 1972, the Dutch government divided drugs into more- and less-dangerous categories, with cannabis being in the lesser category. Accordingly, possession of 30 grams (1.1 oz) or less was made a misdemeanor. Cannabis has been available for recreational use in coffee shops since 1976. Cannabis products are only sold openly in certain local "coffeeshops" and possession of up to 5 grams (0.18 oz) for personal use is decriminalized, however: the police may still confiscate it, which often happens in car checks near the border. Other types of sales and transportation are not permitted, although the general approach toward cannabis was lenient even before official decriminalization.In Uruguay, President Jose Mujica signed legislation to legalize recreational cannabis in December 2013, making Uruguay the first country in the modern era to legalize cannabis. In August 2014, Uruguay legalized growing up to six plants at home, as well as the formation of growing clubs (Cannabis social club), and a state-controlled marijuana dispensary regime.
As of 17 October 2018 when recreational use of cannabis was legalized in Canada, dietary supplements for human use and veterinary health products containing not more than 10 parts per million of THC extract were approved for marketing; Nabiximols (as Sativex) is used as a prescription drug in Canada.The United Nations World Drug Report stated that cannabis "was the worlds most widely produced, trafficked, and consumed drug in the world in 2010", and estimated between 128 million and 238 million users globally in 2015.

Society, culture, legal status, and economics
Society and culture
Cannabis has been one of the most used psychoactive drugs in the world since the late 20th century, following only tobacco and alcohol in popularity. According to Vera Rubin, the use of cannabis has been encompassed by two major cultural complexes over time: a continuous, traditional folk stream, and a more circumscribed, contemporary configuration. The former involves both sacred and secular use, and is usually based on small-scale cultivation: the use of the plant for cordage, clothing, medicine, food, and a "general use as an euphoriant and symbol of fellowship." The second stream of expansion of cannabis use encompasses "the use of hemp for commercial manufacturers utilizing large-scale cultivation primarily as a fiber for mercantile purposes"; but it is also linked to the search for psychedelic experiences (which can be traced back to the formation of the Parisian Club des Hashischins).

Legal status
Since the beginning of the 20th century, most countries have enacted laws against the cultivation, possession or transfer of cannabis. These laws have had an adverse effect on cannabis cultivation for non-recreational purposes, but there are many regions where handling of cannabis is legal or licensed. Many jurisdictions have lessened the penalties for possession of small quantities of cannabis so that it is punished by confiscation and sometimes a fine, rather than imprisonment, focusing more on those who traffic the drug on the black market.
In some areas where cannabis use had been historically tolerated, new restrictions were instituted, such as the closing of cannabis coffee shops near the borders of the Netherlands, and closing of coffee shops near secondary schools in the Netherlands. In Copenhagen, Denmark in 2014, mayor Frank Jensen discussed possibilities for the city to legalize cannabis production and commerce.Some jurisdictions use free voluntary treatment programs and/or mandatory treatment programs for frequent known users. Simple possession can carry long prison terms in some countries, particularly in East Asia, where the sale of cannabis may lead to a sentence of life in prison or even execution. Political parties, non-profit organizations, and causes based on the legalization of medical cannabis and/or legalizing the plant entirely (with some restrictions) have emerged in such countries as China and Thailand.In December 2012, the U.S. state of Washington became the first state to officially legalize cannabis in a state law (Washington Initiative 502) (but still illegal by federal law), with the state of Colorado following close behind (Colorado Amendment 64). On 1 January 2013, the first marijuana "club" for private marijuana smoking (no buying or selling, however) was allowed for the first time in Colorado. The California Supreme Court decided in May 2013 that local governments can ban medical marijuana dispensaries despite a state law in California that permits the use of cannabis for medical purposes. At least 180 cities across California have enacted bans in recent years.In December 2013, Uruguay became the first country to legalize growing, sale and use of cannabis. After a long delay in implementing the retail component of the law, in 2017 sixteen pharmacies were authorized to sell cannabis commercially. On 19 June 2018, the Canadian Senate passed a bill and the Prime Minister announced the effective legalization date as 17 October 2018. Canada is the second country to legalize the drug.In November 2015, Uttarakhand became the first state of India to legalize the cultivation of hemp for industrial purposes. Usage within the Hindu and Buddhist cultures of the Indian subcontinent is common, with many street vendors in India openly selling products infused with cannabis, and traditional medical practitioners in Sri Lanka selling products infused with cannabis for recreational purposes and well as for religious celebrations. Indian laws criminalizing cannabis date back to the colonial period. India and Sri Lanka have allowed cannabis to be taken in the context of traditional culture for recreational/celebratory purposes and also for medicinal purposes.On 17 October 2015, Australian health minister Sussan Ley presented a new law that will allow the cultivation of cannabis for scientific research and medical trials on patients.On 17 October 2018, Canada legalized cannabis for recreational adult use making it the second country in the world to do so after Uruguay and the first G7 nation. The Canadian Licensed Producer system aims to become the Gold Standard in the world for safe and secure cannabis production, including provisions for a robust craft cannabis industry where many expect opportunities for experimenting with different strains. Laws around use vary from province to province including age limits, retail structure, and growing at home.As the drug has increasingly been seen as a health issue instead of criminal behavior, marijuana has also been legalized or decriminalized in: Czech Republic, Colombia, Ecuador, Portugal, South Africa and Canada. Medical marijuana was legalized in Mexico in mid-2017; legislators plan to legalize its recreational use by late 2019.On 28 June 2021, Clarence Thomas, one of the U.S. Supreme Courts most conservative justices, possibly opened the door to federal legalization of cannabis in the United States when he wrote "A prohibition on interstate use or cultivation of marijuana may no longer be necessary or proper to support the federal governments piecemeal approach."

Legality by country
Currently, Uruguay and Canada are the only countries that have fully legalized the cultivation, consumption and bartering of recreational cannabis nationwide. In the United States, 19 states, 2 territories, and the District of Columbia have legalized the recreational use of cannabis – though the drug remains illegal at the federal level. Laws vary from state to state when it comes to the commercial sale. Court rulings in Georgia and South Africa have led to the legalization of cannabis consumption, but not legal sales. A policy of limited enforcement has also been adopted in many countries, in particular Spain and the Netherlands where the sale of cannabis is tolerated at licensed establishments. Contrary to popular belief, cannabis is not legal in the Netherlands but it has been decriminalized since the 1970s. In 2021, Malta was the first European Union member to legalize the use of cannabis for recreational purposes. In Estonia, it is only legal to sell cannabis products with a THC content of less than 0.2%, although products may contain more cannabidiol. Lebanon has recently become the first Arab country to legalize the plantation of cannabis for medical use.Penalties for illegal recreational use ranges from confiscation or small fines to jail time and even death. In some countries citizens can be punished if they have used the drug in another country, including Singapore and South Korea.

Usage
In 2013, between 128 and 232 million people used cannabis (2.7% to 4.9% of the global population between the ages of 15 and 65). Cannabis is by far the most widely used illicit substance.

United States
Between 1973 and 1978, eleven states decriminalized marijuana. In 2001, Nevada reduced marijuana possession to a misdemeanor and since 2012, several other states have decriminalized and even legalized marijuana.In 2018, almost half of the people in the United States had tried marijuana, 16% had used it in the past year, and 11% had used it in the past month. In 2014, daily marijuana use amongst US college students had reached its highest level since records began in 1980, rising from 3.5% in 2007 to 5.9% in 2014 and had surpassed daily cigarette use.In the US, men are over twice as likely to use marijuana as women, and 18–29-year-olds are six times more likely to use as over-65-year-olds. In 2015, a record 44% of the US population has tried marijuana in their lifetime, an increase from 38% in 2013 and 33% in 1985.Marijuana use in the United States is three times above the global average, but in line with other Western democracies. Forty-four percent of American 12th graders have tried the drug at least once, and the typical age of first-use is 16, similar to the typical age of first-use for alcohol but lower than the first-use age for other illicit drugs.

Economics
Production
Sinsemilla (Spanish for "without seed") is the dried, seedless (i.e. parthenocarpic) infructescences of female cannabis plants. Because THC production drops off once pollination occurs, the male plants (which produce little THC themselves) are eliminated before they shed pollen to prevent pollination, thus inducing the development of parthenocarpic fruits gathered in dense infructescences. Advanced cultivation techniques such as hydroponics, cloning, high-intensity artificial lighting, and the sea of green method are frequently employed as a response (in part) to prohibition enforcement efforts that make outdoor cultivation more risky.
"Skunk" refers to several named strains of potent cannabis, grown through selective breeding and sometimes hydroponics. It is a cross-breed of Cannabis sativa and C. indica (although other strains of this mix exist in abundance). Skunk cannabis potency ranges usually from 6% to 15% and rarely as high as 20%. The average THC level in coffee shops in the Netherlands is about 18–19%.The average levels of THC in cannabis sold in the United States rose dramatically between the 1970s and 2000. This is disputed for various reasons, and there is little consensus as to whether this is a fact or an artifact of poor testing methodologies. According to Daniel Forbes writing for slate.com, the relative strength of modern strains are likely skewed because undue weight is given to much more expensive and potent, but less prevalent, samples. Some suggest that results are skewed by older testing methods that included low-THC-content plant material such as leaves in the samples, which are excluded in contemporary tests. Others believe that modern strains actually are significantly more potent than older ones.

Price
The price or street value of cannabis varies widely depending on geographic area and potency. Prices and overall markets have also varied considerably over time.

In 1997, cannabis was estimated to be overall the number four value crop in the US, and number one or two in many states, including California, New York, and Florida. This estimate is based on a value to growers of ~60% of retail value, or $3,000 per pound ($6,600/kg).
In 2006, cannabis was estimated to have been a $36 billion market. This estimate has been challenged as exaggerated. The UN World Drug Report (2008) estimated that 2006 street prices in the US and Canada ranged from about US$8.8 to $25 per gram (approximately $250 to $700 per ounce), depending on quality. Typical U.S. retail prices were $10–15 per gram (approximately $280–420 per ounce).
In 2017, the U.S. was estimated to constitute 90% of the worldwide $9.5 billion legal trade in cannabis.After some U.S. states legalized cannabis, street prices began to drop. In Colorado, the price of smokable buds (infructescences) dropped 40 percent between 2014 and 2019, from $200 per ounce to $120 per ounce ($7 per gram to $4.19 per gram).The European Monitoring Centre for Drugs and Drug Addiction reports that typical retail prices in Europe for cannabis varied from €2 to €20 per gram in 2008, with a majority of European countries reporting prices in the range €4–10.

Cannabis as a gateway drug
The gateway hypothesis states that cannabis use increases the probability of trying "harder" drugs. The hypothesis has been hotly debated as it is regarded by some as the primary rationale for the United States prohibition on cannabis use. A Pew Research Center poll found that political opposition to marijuana use was significantly associated with concerns about the health effects and whether legalization would increase weed use by children.Some studies state that while there is no proof for the gateway hypothesis, young cannabis users should still be considered as a risk group for intervention programs. Other findings indicate that hard drug users are likely to be poly-drug users, and that interventions must address the use of multiple drugs instead of a single hard drug. Almost two-thirds of the poly drug users in the 2009–2010 Scottish Crime and Justice Survey used cannabis.The gateway effect may appear due to social factors involved in using any illegal drug. Because of the illegal status of cannabis, its consumers are likely to find themselves in situations allowing them to acquaint with individuals using or selling other illegal drugs. Studies have shown that alcohol and tobacco may additionally be regarded as gateway drugs; however, a more parsimonious explanation could be that cannabis is simply more readily available (and at an earlier age) than illegal hard drugs. In turn, alcohol and tobacco are typically easier to obtain at an earlier age than is cannabis (though the reverse may be true in some areas), thus leading to the "gateway sequence" in those individuals, since they are most likely to experiment with any drug offered.A related alternative to the gateway hypothesis is the common liability to addiction (CLA) theory. It states that some individuals are, for various reasons, willing to try multiple recreational substances. The "gateway" drugs are merely those that are (usually) available at an earlier age than the harder drugs </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 Fetal trimethadione syndrome 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 Complement receptor and can you explain it in depth? [/INST] A complement receptor is a membrane-bound receptor belonging to the complement system, which is part of the innate immune system. Complement receptors bind effector protein fragments that are produced in response to antigen-antibody complexes or damage-associated molecules. Complement receptor activation contributes to the regulation of inflammation, leukocyte extravasation, and phagocytosis; it also contributes to the adaptive immune response. Different complement receptors can participate in either the classical complement pathway, the alternative complement pathway, or both.

Expression and function
White blood cells, particularly monocytes and macrophages, express complement receptors on their surface. All four complement receptors can bind to fragments of complement component 3 or complement component 4 coated on pathogen surface, but the receptors trigger different downstream activities. Complement receptor (CR) 1, 3, and 4 function as opsonins which stimulate phagocytosis, whereas CR2 is expressed only on B cells as a co-receptor.
Red blood cells (RBCs) also express CR1, which enables RBCs to carry complement-bound antigen-antibody complexes to the liver and spleen for degradation.
a.^ B: B cell </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 Laryngeal paralysis and can you explain it in depth? [/INST] Laryngeal paralysis in animals is a condition in which the nerves and muscles that control the movements of one or both arytenoid cartilages of the larynx cease to function, and instead of opening during aspiration and closing during swallowing, the arytenoids remain stationary in a somewhat neutral position. Specifically, the muscle that causes abduction of the arytenoid cartilage, the cricoarytenoideus dorsalis muscle, ceases to function. This leads to inadequate ventilation during exercise and during thermoregulatory panting as well as incomplete protection of the airway during swallowing.
One of the most common forms of laryngeal paralysis develops in geriatric medium to large breed dogs, in particular the Labrador retriever, but also some other breeds. This had been traditionally known as idiopathic laryngeal  paralysis ("ILP": idiopathic means "of unknown cause"), and was believed to be a result of a condition affecting the nerves of the larynx (bilateral mononeuropathy of the recurrent laryngeal nerves). However investigations into ILP by two groups in Michigan and Tennessee between 2005 - 2013 showed that the condition was not limited to, or specifically a result of, dysfunction of the laryngeal nerves. Instead it was the most visible symptom of a slowly progressing polyneuropathy of old age, which also affected other nerves in the body.  This finding, now generally believed correct following further research, has led to the proposed renaming of this type of laryngeal paralysis from "Idiopathic laryngeal paralysis" ("ILP") to "Geriatric onset laryngeal paralysis polyneuropathy" ("GOLPP").
Animals affected by laryngeal paralysis have reduced tolerance for exercise and heat and an increased risk of aspiration pneumonia. The condition is not generally regarded as causing pain, other than physical distress and anxiety caused by any difficulty in breathing or emotional distress from any difficulty with physical movement.  Where laryngeal paralysis is related to a general progressive polyneuropathy, as in GOLPP, the nervous system will gradually degenerate causing increasing difficulty in management of the limbs (especially rear limbs), swallowing and breathing, and eventually in most cases euthanasia. Laryngeal paralysis is fairly common in large breed and geriatric dogs, particularly in the Labrador retriever, is rarely found in cats, and can also occur in horses where it is referred to as roaring, roarers syndrome, or medically as laryngeal hemiplegia or  recurrent laryngeal neuropathy (RLN). Laryngeal paralysis can be unilateral or bilateral depending upon dysfunction of one or both arytenoid cartilages.

Causes
In most cases, the cause of laryngeal paralysis is unknown or idiopathic.  However, the disorder may arise secondary to general neuropathies, generalized neuromuscular diseases, muscular diseases, neoplasia either in the cervical (neck) region or the cranial mediastinum, or trauma. This acquired form occurs predominantly in middle-aged to old large breed or giant breed dogs such as the Labrador Retriever, golden retriever, Siberian Husky, Newfoundland, and St. Bernard.  Usually these dogs are born with a normal larynx, but over time the nerves and muscles that control the laryngeal cartilages lose function.Laryngeal paralysis may also be congenital in some breeds (e.g. Bouvier des Flandres, Dalmatians, Siberian huskies, and bulldogs), appearing in dogs between two and six months of age. Affected puppies may have difficulty swallowing and breathing, they may gag frequently, and their bark often sounds abnormal.  In Dalmatians it is part of another condition called laryngeal paralysis-polyneuropathy complex.   Affected puppies should not be used for breeding.Choke collars are not thought to be a significant risk factor for this disorder. However, after LP is diagnosed it is usually recommended to stop using a collar or anything else around the dogs neck and to switch to a harness instead.

Signs
Signs of laryngeal paralysis include voice change (the dogs bark becomes hoarse-sounding), gagging or coughing (often during or after eating or drinking), exercise intolerance, inspiratory stridor (noisy breathing on inspiration), difficulty breathing, and in severe cases cyanosis or syncope (fainting).  Secondary problems may also occur, including aspiration or edema in the lungs, though often the problem remains an upper respiratory problem.  Affected dogs are vulnerable to heat stroke and heat exhaustion due to their limited ability to cool themselves down by panting, but the disorder itself can be mistaken for heat stroke.
Signs may occur at any time, but initially owners may only notice that their dogs bark sounds different, that their dog cant run as much as before, or that the dog has trouble in hot weather in unilateral cases because the unaffected side can compensate for the paralysed side.  However most unilateral cases will eventually progress to include both sides of the larynx, a more serious problem with symptoms appearing more often.
Signs are usually worse in hot and humid weather, during exercise, during times of stress or excitement, and in obese pets.  Acute or late-stage symptoms are usually unmistakable and require immediate emergency treatment.

Diagnosis
This condition is usually diagnosed by direct examination of the larynx under light sedation, which also allows checking for benign or malignant tumors.  Tests, such as thoracic radiographs, CT-scans, or echocardiography, are sometimes needed to rule out heart, lung, or mediastinal diseases or other possible causes of the symptoms often seen with LP.  Some vets may also recommend running a thyroid profile since LP can be a symptom or complication of hypothyroidism.

Treatment
Mild cases are managed by limiting activity, keeping a healthy body weight, and avoiding exposure to high ambient temperatures. Mild sedatives can be used to decrease anxiety and panting and therefore improve respiration. Corticosteroids may also be administered in acute cases to decrease inflammation and edema of the larynx.
Severe acute symptoms, such as difficulty breathing, hyperthermia, or aspiration pneumonia, must be stabilized with sedatives and oxygen therapy and may require steroid or antibiotic medications. Sometimes a tracheotomy is required to allow delivery of oxygen. Once the patient is stabilized, surgical treatment may be beneficial especially when paralysis occurs in both arytenoid cartilages (bilateral paralysis). The surgery (aretynoid lateralization, or a "laryngeal tieback") consists of suturing one of the aretynoid cartilages in a maximally abducted (open) position. This reduces the signs associated with inadequate ventilation (such as exercise intolerance or overheating) but may exacerbate the risk of aspiration and consequent pneumonia.  Tying back only one of the arytenoid cartilages instead of both helps reduce the risk of aspiration </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 Bacillary peliosis 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 Erythema multiforme and can you explain it in depth? [/INST] Erythema multiforme (EM) is a skin condition that appears with red patches evolving into target lesions, typically on both hands.It is a type of erythema possibly mediated by deposition of immune complexes (mostly IgM-bound complexes) in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure. It is an uncommon disorder, with peak incidence in the second and third decades of life. The disorder has various forms or presentations, which its name reflects (multiforme, "multiform", from multi- + formis) </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 Cryofibrinogenemic purpura 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 Congenital malaria 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 Alveolar soft part sarcoma and can you explain it in depth? [/INST] Alveolar soft part sarcoma, abbreviated ASPS, is a very rare type of soft-tissue sarcoma, that grows slowly and whose cell of origin is unknown.
ASPS arises mainly in children and young adults and can migrate (metastasize) into other parts of the body, typically the lungs and the brain. Typically, ASPS arises in muscles and deep soft tissue of the thigh or the leg (lower extremities), but can also appear in the upper extremities (hands, neck, and head). While ASPS is a soft tissue sarcoma, it can also spread and grow inside the bones.

Etymology
The term alveolar comes from the microscopic pattern, visible during the analysis of slides of ASPS under the microscope in histopathology. The tumor cells seem to be arranged in the same pattern as the cells of the small air sacks (alveoli) in the lungs. However, this is just a structural similarity. ASPS was first described and characterized in 1952.ASPS is a sarcoma, and that indicates that this cancer initially arises from tissue of embryonic mesenchymal origin.  (The fertilized egg divides and redivides forming a sphere.  Early in embryogenesis, dimples appear in the poles of the sphere and burrow through the sphere forming an inner passage that will ultimately form the gut. Malignancies arising from cells that were originally part of the outer layer of the sphere and those that were part of the embryonic tunnel are termed carcinomas; malignancies arising from the cells between the outer layer and the inner burrow are termed sarcomas.)

Causes
Chromosomal analysis of ASPS shows the breaking and joining of two chromosomes in the tumor cells. A piece of chromosome X breaks and is joined to chromosome 17. This translocation creates a fusion between two genes named ASPL and TFE3, which results in the formation of an aberrant protein (termed fusion protein) that is not found in normal cells. Two sorts of fusions between chromosome X and chromosome 17 are found in different ASPS tumors: type one and type two.
Dr. Marc Ladanyi at Memorial Sloan-Kettering Cancer Center, in New York City, has pioneered this work </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 Undervirilization 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 Venous lake 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 Simyra (moth) 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 Diffuse leprosy of Lucio and Latapí and can you explain it in depth? [/INST] The diffuse leprosy of Lucio and Latapí, also known as diffuse lepromatous leprosy or "pretty leprosy" is a clinical variety of lepromatous leprosy </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 Fat embolism syndrome and can you explain it in depth? [/INST] Fat embolism syndrome occurs when fat enters the blood stream (fat embolism) and results in symptoms. Symptoms generally begin within a day. This may include a petechial rash, decreased level of consciousness, and shortness of breath. Other symptoms may include fever and decreased urine output. The risk of death is about 10%.Fat embolism most commonly occurs as a result of fractures of bones such as the femur or pelvis. Other potential causes include pancreatitis, orthopedic surgery, bone marrow transplant, and liposuction. The underlying mechanism involved widespread inflammation. Diagnosis is based on symptoms.Treatment is mostly supportive care. This may involve oxygen therapy, intravenous fluids, albumin, and mechanical ventilation. While small amounts of fat commonly occur in the blood after a bone fracture, fat embolism syndrome is rare. The condition was first diagnosed in 1862 by Zenker.

Signs and symptoms
Symptoms of fat embolism syndrome (FES) can start from 12 hours to 3 days after diagnosis of the underlying clinical disease. The three most characteristic features are: respiratory distress, neurological features, and skin petechiae. Respiratory distress (present in 75% of the cases) can vary from mild distress which requires supplemental oxygen to severe distress which requires mechanical ventilation. For neurologic features, those who have FES may become lethargic, restless, with a drop in Glasgow Coma Scale (GCS) due to cerebral oedema rather than cerebral ischaemia. Therefore, neurological signs are not lateralised to one side of the body. In the severe form of cerebral odema, a person may become unresponsive. Petechiae rash usually happens in 50% of the patients. Such skin manifestation is temporary and can disappear within one day. The fat embolism syndrome can be divided into three types:
Subclinical FES - It manifests as reduced partial pressure of oxygen (PaO2) on arterial blood gas (ABG) with deranged blood parameters (reduced haemoglobin or thrombocytopenia) associated with fever, pain, discomfort, tachypnoea, tachycardia. However, there is no respiratory distress. However, it is often confused with post-operative symptoms of fever, pain, and discomfort.
Subacute FES (non-fulminant FES) - The three characteristic features of fat embolism are present: respiratory distress, neurological signs, and skin petechiae. Petechiae are seen on the chest, axilla, shoulder, and mouth. Occulsion of dermal capillaries by the fat emboli result in petechial rash. Petechiae rash occurs in 50 to 60% of the cases. Neurologic signs such as confusion, stupor, and coma may be present. These are usually temporary and do not happen on one side of the body. Respiratory distress can be mild and tends to improve on the third day. Retinal changes similar to Purtschers retinopathy may also be present. Retinal changes happens in 50% of the patients with FES. These are the cotton wool exudates and small haemorrhages along the retinal vessels and macula.
Fulminant FES - This type of FES is much rarer than the above two types. It usually happens within the first few hours of the injury. The three characteristics of FES existed in the most severe form. Cause of death is usually due to acute right heart failure.

Causes
Orthopaedic injuries especially fractures of the long bones are the most common cause of fat embolism syndrome (FES). The rates of fat embolism in long bone fractures vary from 1% to 30%. The mortality rate of fat-embolism syndrome is approximately 10–20%. However, fat globules have been detected in 67% of those with orthopaedic trauma and can reach as high as 95% if the blood is sampled near the fracture site. As the early operative fixation of long bone fractures became a common practice, the incidence of FES has been reduced to between 0.9% and 11%.

Other rare causes of fat embolism syndrome are:
Severe burns
Liver injury
Closed chest cardiac massage (during cardiopulmonary resuscitation)
Bone marrow transplantation
Liposuction
Parenteral lipid infusion
Decompression sickness
Extracorporeal circulation
Acute haemorrhagic pancreatitis
Alcoholic liver disease
Prolonged corticosteriod therapy
Sickle cell disease
Carbon tetrachloride poisoning
Osteomyelitis

Pathophysiology
Once fat emboli enter the blood circulation, they can lodge at various sites of the body, most commonly in the lungs (up to 75% of cases). However, it can also enter the brain, skin, eyes, kidneys, liver, and heart circulation, causing capillary damage, and subsequently cause organ damage in these areas. There are two theories that describe the formation of a fat embolus:
Mechanical theory - Following trauma, fat is released directly from the bone marrow into the circulation. This is because after trauma, an elevated pressure in the medullary cavity (central cavity of the bone where the bone marrow are stored) causes the release of fat globules into the venous system supplying the bone. Since venous blood returns to the right heart and is pumped to the lungs for reoxygenation, the fat globules often get lodged in the pulmonary circulation. Fat globules may also pass through lung circulation back into the left ventricle of the heart to be pumped throughout the body in the systemic circulation. They may also reach the systemic circulation through a patent foramen ovale (a hole communicating the right atrium directly to the left atrium of the heart). If fat globules obstruct 80% of the lung capillary network, the resulting back pressure on the right heart increases workload and causes right heart dilatation through cor pulmonale, leading to acute right heart failure.
Biochemical theory - Following trauma, an inflammation causes bone marrow to liberate fatty acids into the venous circulation. This is achieved through the increased activity of lipoprotein lipase which break down triglycerides into free fatty acids. Both the release of fatty acids and the inflammation causes damage to the capillary beds of the lungs and other organs, causing interstitial lung disease, chemical pneumonitis, and acute respiratory distress syndrome (ARDS). This theory can help to explain non-traumatic causes of fat embolism.

Diagnosis
Fat embolism is presence of fat particles in the micro-circulation of the body. Meanwhile, fat embolism syndrome is the clinical manifestation as the result of fat particles lodging in the body micro-circulation. There are three major diagnostic criteria proposed for fat embolism syndrome, however, none of them are validated and accepted universally. However, Gurd and Wilsons criteria for fat embolism become more commonly used when compared to the other two diagnostic criteria.

Gurd and Wilsons criteria
Major criteria
Axillary or subconjunctival petechiae
Hypoxaemia PaO2 <60 mm Hg, FIO2 = 0.4
Central nervous system depression disproportionate to hypoxaemia
Pulmonary oedemaMinor criteria
Tachycardia more than 110 beats per minute
Pyrexia more than 38.5 °C
Fat globules present in urine
Changes in renal function (reduced urine output)
Drop in haemoglobin values (more than 20% of the value upon admission)
Drop in haematocrit values
Drop in platelet values (more than 50% of the value upon admission)
Increasing erythrocyte sedimentation rate (ESR) (greater than 71 mm per hour)
Fat globules present in the sputum
Emboli present in the retina on fundoscopyA least two positive major criteria plus one minor criteria or four positive minor criteria are suggestive of fat embolism syndrome. Fat embolism syndrome is a clinical diagnosis. There are no laboratory tests sensitive or specific enough to diagnose FES. Such laboratory tests are only used to support the clinical diagnosis only. Chest X-ray may show diffuse interstitial infiltrates while chest CT scan will show diffuse vascular congestion and pulmonary oedema. Bronchoalveolar lavage has been proposed to look for fat droplets in alveolar macrophages however it is time-consuming and is not specific to fat embolism syndrome. Looking for fat globules in sputum and urine is also not specific enough to diagnose FES.

Prevention
For those treated conservatively with immobilisation of long bone fractures, the incidence of FES  is 22%. Early operative fixation of long bone fractures can reduce the incidence of FES especially with the usage of internal fixation devices. Patients undergoing urgent fixation of long bone fractures has a rate of 7% of acute respiratory distress syndrome (ARDS) when compared to those undergoing fixation after 24 hours (39% with ARDS). However, movement of the fracture ends of the long bones during the operative fixation can cause transient increase of fat emboli in the blood circulation. Cytokines are persistently elevated if the long bone fractures is treated conservatively using immobilisation. The cytokine levels would return to normal after operative fixation. Although ream nailing increases pressure in the medullary cavity of the long bones, it does not increase the rates of FES. Other methods such as drilling of holes in the bony cortex, lavaging bone marrow prior to fixation, and the use of tourniquets to prevent embolisation have not been shown to reduce the rates of FES.Corticosteroid therapy such as methylprednisolone (6 to 90 mg/kg) has been proposed for the treatment of FES, however, it is controversial. Corticosteroid can be used to limit free fatty acid levels, stabilising membranes, and inhibit leukocyte aggregation. A meta-analysis conducted in 2009 reported prophylactic corticosteroids can reduce the risk of FES by 77%. However, there is no difference in mortality, infection, and avascular necrosis when compared to the control group. However, a randomised trial conducted in 2004 reported no differences in FES incidence when comparing treatment with the control group. Administration of corticosteroids for 2 to 3 days is not associated with increased rates of infection. However, there is insufficient data to support the use of methyprednisolone once FES is established.Heparin has been used in the prevention of venous thrombosis in post-operative patients; however its regular use in those with FES has been contraindicated due to increase risk of bleeding in those with polytrauma. Placement of inferior vena cava filters has been proposed to reduce the amount of emboli going into the lung vascular system, however, this method has not been studied in detail.

Treatment
Once FES develops,  the person should be admitted into intensive care unit (ICU), preferably with central venous pressure (CVP) monitoring. CVP monitoring would be helpful to guide the volume resuscitation. Supportive treatment is the only proven treatment method. Supplemental oxygen can be given if a person has mild respiratory distress. However, if a person has severe respiratory distress, either continuous positive pressure ventilation (CPAP), or mechanical ventilation using positive end-expiratory pressure (PEEP) may be indicated. Fluid replacement is required to prevent shock. Volume resuscitation with human albumin is recommended because it can restore blood volume in the circulatory system while also binds to free fatty acids in order to reduce lung injuries. In severe cases, dobutamine should be used to support the right ventricular failure </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 Atonic seizure and can you explain it in depth? [/INST] An atonic seizure (also called drop seizure, akinetic seizure,  astatic seizure, or drop attack) is a type of seizure that consists of partial or complete loss of muscle tone that is caused by temporary alterations in brain function. These seizures are brief – usually less than fifteen seconds. They usually begin in childhood and may persist into adulthood. The seizure itself causes no physical injury, but the loss of control, predominantly in trunk muscles, can result in direct injury from falling </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 Idiopathic pulmonary haemosiderosis and can you explain it in depth? [/INST] Idiopathic pulmonary haemosiderosis (IPH) is a lung disease of unknown cause that is characterized by alveolar capillary bleeding and accumulation of haemosiderin in the lungs. It is rare, with an incidence between 0.24 and 1.23 cases per million people.

Pathophysiology
Being idiopathic, IPH by definition has an unknown cause. It is thought to be an immune-mediated disease. The lung bleeding causes accumulation of iron, which in itself causes additional lung damage. Meanwhile, there is insufficient iron for inclusion into the haemoglobin molecules inside red blood cells which carry oxygen to body tissues for cellular respiration.Idiopathic pulmonary haemosiderosis can occur either as a primary lung disorder or as the sequela to other pulmonary, cardiovascular or immune system disorder.

PH1 involves PH with circulating anti-GBM antibodies.
PH2 involves PH with immune complex disease such as systemic lupus erythematosus, SLE.
PH3 involves no demonstrable immune system involvement.A distinct subset of patients with pulmonary hemosiderosis has hypersensitivity to cows milk which result in formation of IgG antibodies against basement membrane. This is called Heiner syndrome. Mechanism of haemorrhage is similar to that observed in Goodpasture syndrome.

Related or similar conditions
There are many pulmonary problems that may seem to mimic haemosiderosis but do not necessarily include the deposits of iron into the lung. The deposition of iron in the lungs, occurring in the form of haemosiderin, is the defining characteristic of this illness. These other conditions may occur separately or together with haemosiderosis.
Pulmonary fibrosis
Adult respiratory distress syndrome (ARDS)
Immune complex disease
intra-alveolar bleeding

Diagnosis
Clinically, IPH manifests as a triad of haemoptysis, diffuse parenchymal infiltrates on chest radiographs, and iron deficiency anaemia. It is diagnosed at an average age of 4.5 plus or minus 3.5 years, and it is twice as common in females. The clinical course of IPH is exceedingly variable, and most of the patients continue to have episodes of pulmonary haemorrhage despite therapy. Death may occur suddenly from acute pulmonary haemorrhage or after progressive pulmonary insufficiency resulting in chronic respiratory failure.

Treatment
Corticosteroids are the mainstay of treatment of IPH, though they are controversial and lack clear evidence in their favour </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 Phlegmasia alba dolens and can you explain it in depth? [/INST] Phlegmasia alba dolens (also colloquially known as milk leg or white leg; not to be confused with phlegmasia cerulea dolens) is part of a spectrum of diseases related to deep vein thrombosis. Historically, it was commonly seen during pregnancy and in mothers who have just given birth.  In cases of pregnancy, it is most often seen during the third trimester, resulting from a compression of the left common iliac vein against the pelvic rim by the enlarged uterus.  Today, this disease is most commonly (40% of the time) related to some form of underlying malignancy.  Hypercoagulability (a propensity to clot formation) is a well-known state that occurs in many cancer states. The incidence of this disease is not well reported.

Cause
The disease presumably begins with a deep vein thrombosis that progresses to total occlusion of the deep venous system.  It is at this stage that it is called phlegmasia alba dolens.  It is a sudden (acute) process.  The leg, then, must rely on the superficial venous system for drainage.  The superficial system is not adequate to handle the large volume of blood being delivered to the leg via the arterial system.  The result is edema, pain and a white appearance (alba) of the leg </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 Comedo and can you explain it in depth? [/INST] A comedo is a clogged hair follicle (pore) in the skin. Keratin (skin debris) combines with oil to block the follicle. A comedo can be open (blackhead) or closed by skin (whitehead) and occur with or without acne. The word "comedo" comes from the Latin comedere, meaning "to eat up", and was historically used to describe parasitic worms; in modern medical terminology, it is used to suggest the worm-like appearance of the expressed material.The chronic inflammatory condition that usually includes comedones, inflamed papules, and pustules (pimples) is called acne. Infection causes inflammation and the development of pus. Whether a skin condition classifies as acne depends on the number of comedones and infection. Comedones should not be confused with sebaceous filaments.
Comedo-type ductal carcinoma in situ (DCIS) is not related to the skin conditions discussed here. DCIS is a noninvasive form of breast cancer, but comedo-type DCIS may be more aggressive, so may be more likely to become invasive.

Causes
Oil production in the sebaceous glands increases during puberty, causing comedones and acne to be common in adolescents. Acne is also found premenstrually and in women with polycystic ovarian syndrome. Smoking may worsen acne.Oxidation rather than poor hygiene or dirt causes blackheads to be black. Washing or scrubbing the skin too much could make it worse, by irritating the skin. Touching and picking at comedones might cause irritation and spread infection. What effect shaving has on the development of comedones or acne is unclear.Some skin products might increase comedones by blocking pores, and greasy hair products (such as pomades) can worsen acne. Skin products that claim to not clog pores may be labeled noncomedogenic or nonacnegenic. Make-up and skin products that are oil-free and water-based may be less likely to cause acne. Whether dietary factors or sun exposure make comedones better, worse, or neither is unknown.A hair that does not emerge normally, an ingrown hair, can also block the pore and cause a bulge or lead to infection (causing inflammation and pus).Genes may play a role in the chances of developing acne. Comedones may be more common in some ethnic groups. People of Latino and recent African descent may experience more inflammation in comedones, more comedonal acne, and earlier onset of inflammation.

Pathophysiology
Comedones are associated with the pilosebaceous unit, which includes a hair follicle and sebaceous gland. These units are mostly on the face, neck, upper chest, shoulders, and back. Excess keratin combined with sebum can plug the opening of the follicle. This small plug is called a microcomedo.  Androgens increase sebum (oil) production. If sebum continues to build up behind the plug, it can enlarge and form a visible comedo.A comedone may be open to the air ("blackhead") or closed by skin ("whitehead"). Being open to the air causes oxidation, which turns it black. Cutibacterium acnes is the suspected infectious agent in acne. It can proliferate in sebum and cause inflamed pustules (pimples) characteristic of acne. Nodules are inflamed, painful, deep bumps under the skin.Comedones that are 1 mm or larger are called macrocomedones. They are closed comedones and are more frequent on the face than neck.Solar comedones (sometimes called senile comedones) are related to many years of exposure to the sun, usually on the cheeks, not to acne-related pathophysiology.

Management
Using nonoily cleansers and mild soap may not cause as much irritation to the skin as regular soap. Blackheads can be removed across an area with commercially available pore-cleansing strips (which can still damage the skin by leaving the pores wide open and ripping excess skin) or the more aggressive cyanoacrylate method used by dermatologists.Squeezing blackheads and whiteheads can remove them, but  can also damage the skin. Doing so increases the risk of causing or transmitting infection and scarring, as well as potentially pushing any infection deeper into the skin </s>