<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 Bronchiolitis obliterans and can you explain it in depth? [/INST] Bronchiolitis obliterans (BO), also known as obliterative bronchiolitis, constrictive bronchiolitis and popcorn lung, is a disease that results in obstruction of the smallest airways of the lungs (bronchioles) due to inflammation. Symptoms include a dry cough, shortness of breath, wheezing and feeling tired. These symptoms generally get worse over weeks to months. It is not related to cryptogenic organizing pneumonia, previously known as bronchiolitis obliterans organizing pneumonia.Causes include breathing in toxic fumes, respiratory infections, connective tissue disorder or complications following a bone marrow or heart-lung transplant. Symptoms may not occur until two to eight weeks following toxic exposure or infection. The underlying mechanism involves inflammation that results in scar tissue formation. Diagnosis is by CT scan, pulmonary function tests or lung biopsy. A chest X-ray is often normal.While the disease is not reversible, treatments can slow further worsening. This may include the use of corticosteroids or immunosuppressive medication. A lung transplant may be offered. Outcomes are often poor, with most people dying in months to years.Bronchiolitis obliterans is rare in the general population. It, however, affects about 75% of people by ten years following a lung transplant and up to 10% of people who have received a bone marrow transplant from someone else. The condition was first clearly described in 1981. Prior descriptions occurred as early as 1956, with the term "bronchiolitis obliterans" used first by Reynaud in 1835.

Signs and symptoms
Bronchiolitis obliterans results in worsening shortness of breath, wheezing, and a dry cough. The symptoms can start gradually, or severe symptoms can occur suddenly. These symptoms represent an obstructive pattern that is non-reversible with bronchodilator therapy, and need to be related to various lung insults. These insults include inhalation damage, post transplant auto-immune injury, post-infectious disease, drug reactions, and several auto-immune diseases.

Cause
Bronchiolitis obliterans has many possible causes, including collagen vascular disease, transplant rejection in organ transplant patients, viral infection (adenovirus, respiratory syncytial virus, influenza, HIV, cytomegalovirus), Stevens–Johnson syndrome, Pneumocystis pneumonia, drug reaction, aspiration and complications of prematurity (bronchopulmonary dysplasia), and exposure to toxic fumes. Toxins implicated in the condition include diacetyl, sulfur dioxide, nitrogen dioxide, ammonia, chlorine, thionyl chloride, methyl isocyanate, hydrogen fluoride, hydrogen bromide, hydrogen chloride, hydrogen sulfide, phosgene, polyamide-amine dyes, mustard gas and ozone. It can also be present in patients with IBD, systemic lupus erythematosus, juvenile idiopathic arthritis, rheumatoid arthritis, GERD, IgA nephropathy, and ataxia telangiectasia. Activated charcoal has been known to cause it when aspirated. The ingestion of large doses of papaverine in the vegetable Sauropus androgynus has caused it. Additionally, the disorder may be idiopathic (without known cause).

Lung transplant
Bronchiolitis obliterans is a common complication in lung transplants because transplanted lungs are at greater risk of alloimmunization as compared to healthy lungs. The disease is often termed bronchiolitis obliterans syndrome (BOS) in the setting of post lung transplantation and hematopoietic stem cell transplant (HSCT). Patients who develop BOS post lung transplant vary in disease latency and severity. Patients often initially have normal lung function on pulmonary function testing and have normal chest radiographs. As the disease progresses they begin to have symptoms of shortness of breath, cough, and wheezing as their lung function declines. The Journal of Heart and Lung Transplantation published updated guidelines in 2001 for grading the severity of BOS. The original guidelines and classification system were published in 1993 by the International Society for Heart and Lung Transplantation.  Their scoring system is based on the changes in FEV1 in patients from their baseline. When patients are first diagnosed with BOS they have their baseline lung function established by doing pulmonary function testing at the time of diagnosis. The BOS scoring system is as follows:
BOS 0: FEV1 > 90% of baseline and FEF25-75 > 75% of baseline
BOS 0-p: FEV1 81-89% of baseline and/or FEF25-75 <= 75% of baseline
BOS 1: FEV1 66-80% of baseline
BOS 2: FEV1 51-65% of baseline
BOS 3: FEV1 50% or less of baseline
The scoring system shows an increased severity of the disease as the BOS number increases.

Hematopoietic stem cell transplant
Bronchiolitis obliterans affects up to 5.5% of people who have received HSCT. One of the biggest risk factors after HSCT is the development of GVHD with a 14% risk. Other risk factors post transplant including tobacco use, age of donor, age of recipient, lower baseline FEV1/FVC ratio, non-caucasian race, peripheral and lower circulating IgG levels. Studies have, however, shown mixed results regarding these other risk factors. There has been an association shown between the increased use of peripheral stem cells and the risk of developing bronchiolitis obliterans. Also, research has shown an increased risk for developing the disease within the first year of transplant if the person is infected with respiratory syncytial virus or parainfluenza virus within the first 100 days post transplant.

Inhalants
There are many industrial inhalants that are known to cause various types of bronchiolitis, including bronchiolitis obliterans.Industrial workers who have presented with bronchiolitis:

nylon-flock workers
workers who spray prints onto textiles with polyamide-amine dyes
battery workers who are exposed to thionyl chloride fumes
workers at plants that use or manufacture flavorings such as diacetylDiacetyl is a chemical used to produce the artificial butter flavoring in many foods such as candy and microwave popcorn and occurring naturally in wines. This first came to public attention when eight former employees of the Gilster-Mary Lee popcorn plant in Jasper, Missouri developed bronchiolitis obliterans. Due to this event, bronchiolitis obliterans began to be referred to in the popular media as "popcorn lung" or "popcorn workers lung". It is also referred to as "flavorings-related lung disease".

Post-infectious
Typically found in young children and is the most common cause at this age. Generally occurs after a viral infection of adenovirus (types 3, 7, and 21), measles (rubeola), mycoplasma, CMV, influenza, and parainfluenza. Swyer-James syndrome is a rare complication of bronchiolitis obliterans caused by measles or adenovirus. Post-infectious bronchiolitis obliterans is most common in the southern hemisphere particularly in countries such as Brazil, Argentina, Australia, Chile and New Zealand. There was a large prevalence of the disease in these areas during the 1990s and early 2000s. In one hospital in Buenos Aires, the Ricardo Gutiérrez Childrens hospital, the disease accounted for 14% of their inpatient respiratory population from 1993 to 2002. As such, much of the information about post-infectious bronchiolitis obliterans has come from research out of South America. The most significant risk factors for the disease are infection with adenovirus and the need for ventilator support. In contrast with another cause of bronchiolitis obliterans in children, Stevens Johnsons syndrome, post-infectious bronchiolitis obliterans tends to be a chronic but non-progressive disease. The disease can have varying impact on children and their quality of life, which has been studied by lung function tests, as well as their exercise tolerance. Children with lower lung function based on their pulmonary function testing, have lower exercise tolerance, which compounds the impact of the disease on cardiovascular function as they are not able to maintain age appropriate aerobic fitness. This ultimately affects their activities of daily living (ADLs) and their quality of life going forward.

Burn pits
A form of constrictive bronchiolitis is starting to present in Iraq and Afghanistan veterans. It has been attributed to veterans being exposed to trash burn pits. Veterans present with shortness of breath and other asthma-like symptoms. The only way to diagnose this condition is by doing a lung biopsy as chest X-rays and CT scans come back as normal. The government still denies that there is any correlation between burn pits and health problems but the government has started an "Airborne Hazards and Open Burn Pit Registry" to begin tracking the health of veterans who were exposed to burn pits to see if there is a connection.

E-cigarettes
The American Lung Association lists flavored e-cigarettes as a risk in 2016. Health Canada has, however seen no cases as of 2019. Public Health England writes that the association has come about as "some flavourings used in e-liquids to provide a buttery flavour contain the chemical diacetyl... however, diacetyl is banned as an ingredient from e-cigarettes and e-liquids in the UK."

Mechanism
The underlying mechanism involves injury and inflammation of epithelial and sub-epithelial cells. These cells then lose the ability to repair the tissue, in particular they lose the ability to regenerate the epithelial or outermost layer, leading to the excess growth of cells that cause scarring. There are multiple pathways of the disease including fibrotic, lymphocytic, and antibody-mediated that have been described. However, while each pathway has a more unique starting point and cause, the result is still injury and inflammation leading to scarring of the lung tissue. The scarred tissue then makes the expiration phase of respiration more difficult, leading to air not being expelled from the lungs. This is termed "air-trapping", which can be seen on medical imaging. Since the scarring is non-reversible, the disease generally does not improve over time, and depending on the inciting can progress to death.

Diagnosis
Bronchiolitis obliterans is often diagnosed based on the symptoms of obstructive lung disease following lung injury. The definitive diagnosis is through biopsy, but due to the variable distribution of lesions, leading to falsely negative tests, and invasive nature of this procedure it is often not performed. Several tests are often needed to diagnose bronchiolitis obliterans, including spirometry, diffusing capacity of the lung tests (DLCO), lung volume tests, chest X-rays,  high-resolution CT (HRCT), and lung biopsy.

Pulmonary function testing
Spirometry tests usually show an obstructive pattern and is the most common presentation. A slightly reduced to normal forced vital capacity (FVC), and a reduced FEV1 to FVC ratio and forced expiratory volume (FEV) with little to no correction with the use of bronchodialators are common findings. Lung volume tests may show hyperinflation (excessive air in lungs caused by air trapping). Diffusing capacity of the lung (DLCO) tests are usually normal; people with early-stage OB are more likely to have normal DLCO.FEV1 (forced expiratory volume in 1 second) should be above 80% of predicted values to be considered normal. Bronchiolitis obliterans reduces this to between 16% and 21%.

Medical imaging
Early in the disease chest radiography is typically normal but may show hyperinflation. As the disease progresses a reticular pattern with thickening of airway walls may be present. HRCT can also show air trapping when the person being scanned breathes out completely; it can also show thickening in the airway and haziness in the lungs. A common finding on HRCT is patchy areas of decreased lung density, signifying reduced vascular caliber and air trapping. This pattern is often described as a "mosaic pattern", and may indicate bronchiolitis obliterans.

Lung biopsy
Transthoracic lung biopsies are preferable for diagnosis of constrictive BO compared to transbronchial biopsies; regardless of the type of biopsy, a diagnosis may only be achieved by examination of multiple samples. Transthoracic biopsies are preferred over transbronchial due to the heterogeneity and distribution of the lesions. OB can be further classified into two categories: constrictive or proliferative. The constrictive pattern is demonstrated by peribronchiolar cellular infiltrates which eventually causes small airway damage and leads to subepithelial fibrosis. The bronchial muscle can eventually become fibrosed which can be identified with trichrome staining. In regards to proliferative disease, intraluminal buds called "Masson bodies" fill the lumen, which results in bronchiolar plugging. Often people with proliferative disease will show butterfly wing-like appearance under microscopy. One key determinate that can be seen on biopsy to differentiate constrictive from proliferative disease is the extent of lesions </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 Hypohidrosis and can you explain it in depth? [/INST] Hypohidrosis is a disorder in which a person exhibits diminished sweating in response to appropriate stimuli. In contrast with hyperhidrosis, which is a socially troubling yet often benign condition, the consequences of untreated hypohidrosis include hyperthermia, heat stroke and death. An extreme case of hypohidrosis in which there is a complete absence of sweating and the skin is dry is termed anhidrosis.

Causes
Diagnosis
Sweat is readily visualized by a topical indicator such as iodinated starch (Minor test) or sodium alizarin sulphonate, both of which undergo a dramatic colour change when moistened by sweat. A thermoregulatory sweat test can evaluate the body’s response to a thermal stimulus by inducing sweating through a hot box ⁄ room, thermal blanket or exercise. Failure of the topical indicator to undergo a colour change during thermoregulatory sweat testing indicates hypohidrosis, and further tests may be required to localize the lesion.
Magnetic resonance imaging of the brain and ⁄ or spinal cord is the best modality for evaluation when the lesion is suspected to be localized to the central nervous system.
Skin biopsies are useful when anhidrosis occurs as part of a dermatological disorder </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 Miliaria and can you explain it in depth? [/INST] Miliaria, also called heat rash, sweat rash, or prickly heat, is a skin disease marked by small, itchy rashes due to sweat trapped under the skin by clogged sweat-gland ducts. Miliaria is a common ailment in hot and humid conditions, such as in the tropics and during the summer. Although it affects people of all ages, it is especially common in children and infants due to their underdeveloped sweat glands.

Signs and symptoms
Symptoms of miliaria include small, red rashes, called papules, which are irritated and itchy. These may simultaneously occur at a number of areas on a patients body, the most common including the upper chest, neck, elbow creases, under the breasts, and under the scrotum. Other areas include skin folds and areas of the body that may rub against clothing, such as the back, chest, and stomach. A related and sometimes simultaneous condition is folliculitis, where hair follicles become plugged with foreign matter, resulting in inflammation.
The symptoms relating to miliaria should not be confused with shingles, as they can be very similar. Shingles is limited to one side of the body, but also has a rash-like appearance. It is also accompanied by a prickly sensation and pain throughout the region. Those who suspect they have shingles and not miliaria should seek medical advice immediately as the sooner antivirals are taken, the better.

Types
Miliaria can be classified according to the top level at which obstruction occurs in the sweat glands.

Miliaria crystalline
The most superficial obstruction (with the most mild clinical presentation), is known as miliaria crystalline; instead of a rash, the patient presents with multiple, tiny, blister-like lesions that look like beads of perspiration and essentially cause no symptoms.: 23  Miliaria crystalline is also known as miliaria crystallina, and sudamina.  The superficial vesicles are not associated with an inflammatory reaction.: 23

Miliaria rubra
The most commonly encountered form of the illness is miliaria rubra, in which obstruction causes leakage of sweat into the deeper layers of the epidermis, provoking a local inflammatory reaction and giving rise to the typical appearance of redness (hence rubra) and larger (but still only a few millimetres), blister-like lesions. This form of the illness is often accompanied by the typical symptoms—intense itching or "pins and needles" with a lack of sweating (anhidrosis) to affected areas.: 23  A small risk of heat exhaustion exists due to inability to sweat if the rash affects a large proportion of the bodys surface area or the patient continues to engage in heat-producing activity. Miliaria rubra is also known as prickly heat and heat rash. Differential diagnosis should be used to rule out polycythemia vera, which is a rare hematological disorder and appears more often in males than females, generally not before the age of 40. Both disorders share a common trait of appearing after taking a hot shower.

Miliaria profunda
The most severe form of miliaria, miliaria profunda, sometimes referred to as "wildfire" due to the rapid spread and severe burning sensations, generally occurs as a complication of repeated episodes of miliaria rubra. The obstruction is deep in the structure of the sweat gland, causing the glands secretions to leak between the superficial and deep layers of the skin. The rash and associated symptoms tend to appear within hours of an activity provoking sweating, but similarly fade within hours when the stimulus for the sweating is removed. Miliaria profunda is characterised by nonpruritic, flesh-coloured, deep-seated, whitish papules.: 24  The rash tends to be flesh-coloured as opposed to the prominent redness of miliaria rubra, and the risk of heat exhaustion is larger. Miliaria profunda is also less commonly known as "mammillaria": chapter 40

Miliaria pustulosa
Miliaria pustulosa describes pustules due to inflammation and bacterial infection.  Miliaria pustulosa is preceded by another dermatitis that has produced injury, destruction, or blocking of the sweat ducts.: 23

Postmiliarial hypohidrosis
Postmiliarial hypohidrosis is a skin condition that results from occlusion of sweat ducts and pores, and may be severe enough to impair an individuals ability to perform sustained work in a hot environment.: 24

Tropical anhidrotic asthenia
Tropical anhidrotic asthenia is a skin condition, a rare form of miliaria, with long-lasting poral occlusion, which produces anhidrosis and heat retention.: 24

Occlusion miliaria
Occlusion miliaria is a skin condition that is accompanied by anhidrosis and increased heat-stress susceptibility, all after the application of extensive polyethylene film occlusion for 48 hours or longer.: 24

Colloid milium
Colloid milium is a skin condition characterized by a translucent, flesh-colored, or slightly yellow, 1 to 5 mm papules.: 31

Pathophysiology
Miliaria occurs when the sweat gland ducts get clogged due to dead skin cells or bacteria such as Staphylococcus epidermidis, a common bacterium that occurs on the skin, which is also associated with acne.
The trapped sweat leads to irritation (prickling), itching, and a rash of very small blisters, usually in a localized area of the skin.

Prevention
Prickly heat can be prevented by avoiding activities that induce sweating, using air conditioning to cool the environment, wearing light clothing, and in general, avoiding hot and humid weather.  Frequent cool showers or cool baths with mild soap can help to prevent heat rash.

Treatment
The primary remedy for prickly heat or rash is to wear lighter clothing, or otherwise avoid overheating ones body.  The immediate treatment of the involved skin areas involves the use of a soothing ointment such as calamine lotion. Talcum powder may be used in some cases.
Medical assistance should be sought for the first episode of a rash with the appearance of miliaria. The differential diagnosis includes several conditions that an experienced practitioner should be able to recognise and may require treatment distinct from the usual measures taken for miliaria </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 Acute liver failure and can you explain it in depth? [/INST] Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complications are hepatic encephalopathy and impaired protein synthesis (as measured by the levels of serum albumin and the prothrombin time in the blood). The 1993 classification defines hyperacute as within 1 week, acute as 8–28 days, and subacute as 4–12 weeks; both the speed with which the disease develops and the underlying cause strongly affect outcomes.

Signs and symptoms
The main features of acute liver failure are rapid-onset jaundice, weakness, and eventually, changes in mental status that can begin as mild confusion but progress to coma.

Encephalopathy and cerebral edema
In ALF, hepatic encephalopathy leads to cerebral edema, coma, brain herniation, and eventually death.  Detection of encephalopathy is central to the diagnosis of ALF.  It may vary from subtle deficit in higher brain function (e.g. mood, concentration in grade I) to deep coma (grade IV).  Patients presenting as acute and hyperacute liver failure are at greater risk of developing cerebral edema and grade IV encephalopathy. The pathogenesis remains unclear, but is likely to be a consequence of several phenomena.  There is a buildup of toxic substances like ammonia, mercaptan, serotonin and tryptophan in the brain.  This affects neurotransmitter level and neuroreceptor activation.  Autoregulation of cerebral blood flow is impaired, and is associated with anaerobic glycolysis and oxidative stress.  Neuronal cell astrocytes are susceptible to these changes, and they swell up, resulting in increased intracranial pressure.  Inflammatory mediators also play important role.Unfortunately, signs of elevated intracranial pressure, such as papilledema and loss of pupillary reflexes, are not reliable, and occur late in the disease process.  CT imaging of the brain is also unhelpful in detecting early cerebral oedema, but is often performed to rule out intra-cerebral bleeding.  Invasive intracranial pressure monitoring via subdural route is often recommended; however, the risk of complications must be weighed against the possible benefit (1% fatal haemorrhage).  The aim is to maintain intracranial pressures below 25 mm Hg, and cerebral perfusion pressures above 50 mm Hg.

Coagulopathy
Coagulopathy is another cardinal feature of ALF. The liver has the central role in the synthesis of almost all coagulation factors and some inhibitors of coagulation and fibrinolysis. Hepatocellular necrosis leads to impaired synthesis of many coagulation factors and their inhibitors. The former produces a prolongation in prothrombin time which is widely used to monitor the severity of hepatic injury. There is significant platelet dysfunction (with both quantitative and qualitative platelet defects). Progressive thrombocytopenia with the loss of larger and more active platelets is almost universal. Thrombocytopenia with or without DIC increases risk of intracerebral bleeding.

Kidney failure
Kidney failure is common, present in more than 50% of ALF patients, either due to original insult such as paracetamol resulting in acute tubular necrosis or from hyperdynamic circulation leading to hepatorenal syndrome or functional kidney failure. Because of impaired production of urea, blood urea does not represent the degree of kidney impairment.

Inflammation and infection
About 60% of all ALF patients fulfil the criteria for systemic inflammatory syndrome irrespective of presence or absence of infection. This often contributes towards multi organ failure. Impaired host defence mechanism, due to impaired opsonization, chemotaxis and intracellular killing, substantially increases risk of sepsis. Bacterial sepsis mostly due to gram positive organisms and fungal sepsis are observed in up to 80% and 30% patients, respectively.

Metabolic derangements
Hyponatraemia is an almost universal finding due to water retention and a shift in intracellular sodium transport from inhibition of Na/K ATPase. Hypoglycaemia (due to depleted hepatic glycogen store and hyperinsulinaemia), hypokalaemia, hypophosphataemia and metabolic alkalosis are often present, independent of renal function. Lactic acidosis occurs predominantly in paracetamol (also known as acetaminophen) overdose.

Haemodynamic and cardio-respiratory compromise
Hyperdynamic circulation, with peripheral vasodilatation from low systemic vascular resistance, leads to hypotension. There is a compensatory increase in cardiac output. Adrenal insufficiency has been documented in 60% of ALF cases, and is likely to contribute in haemodynamic compromise. There is also abnormal oxygen transport and utilization. Although delivery of oxygen to the tissues is adequate, there is a decrease in tissue oxygen uptake, resulting in tissue hypoxia and lactic acidosis.Pulmonary complications occur in up to 50% of patients. Severe lung injury and hypoxemia result in high mortality. Most cases of severe lung injury are due to ARDS, with or without sepsis. Pulmonary haemorrhage, pleural effusions, atelectasis, and intrapulmonary shunts also contribute to respiratory difficulty.

Late pregnancy
In late pregnancy liver function decreases significantly, which can be easily monitored by blood tests. Early clinical manifestations of ALF in late pregnancy include hypodynamia, decrease in appetite, dark amber urine, deep jaundice, nausea, vomiting, and abdominal distention. Among patients whose deaths were attributed to ALF in late pregnancy, the majority had experienced vaginal deliveries.

Causes
Common causes for acute liver failure are paracetamol (acetaminophen) overdose, idiosyncratic reaction to medication (e.g. tetracycline, troglitazone), excessive alcohol consumption (severe alcoholic hepatitis), viral hepatitis (hepatitis A or B—it is extremely uncommon in hepatitis C), acute fatty liver of pregnancy, and idiopathic (without an obvious cause). Reye syndrome is acute liver failure in a child with a viral infection (e.g. chickenpox); it appears that aspirin use may play a significant role. Wilsons disease (hereditary copper accumulation) may infrequently present with acute liver failure. Acute liver failure also results from poisoning by the death cap mushroom (Amanita phalloides) as well as other amatoxin-producing fungus species. Certain strains of Bacillus cereus—a common species of bacterium implicated as a frequent cause of food poisoning—can cause fulminant liver failure through the production of cereulide, a toxin which destroys the mitochondria in affected hepatocytes, resulting in cell death. While most instances of B. cereus infection are resolved by the bodys immune system and do not affect the liver, severe cases resulting in liver damage can be fatal without immediate treatment or liver transplantation.

Pathophysiology
In the majority of acute liver failure (ALF) there is widespread hepatocellular necrosis beginning in the centrizonal distribution and progressing towards portal tracts. The degree of parenchymal inflammation is variable and  is proportional to duration of disease.Zone 1 (periportal) occurs in phosphorus poisoning or eclampsia.
Zone 2 (mid-zonal), although rare, is seen in yellow fever.
Zone 3 (centrilobular) occurs with ischemic injury, toxic effects, carbon tetrachloride exposure, or chloroform ingestion.  In acute acetaminophen overdose, toxification occurs, mostly in Zone III which has the highest level of P450 micro-enzymes.  That fact along with Zone IIIs decreased oxygen level helps to explain why it is preferentially one of the initial sites of damage.

Diagnosis
All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have an immediate measurement of prothrombin time and careful evaluation of mental status. If the prothrombin time is prolonged by ≈ 4–6 seconds or more (INR ≥ 1.5),
and there is any evidence of altered sensorium, the diagnosis of ALF should be strongly suspected, and hospital admission is mandatory. Initial laboratory examination must be extensive in order to evaluate both the etiology and severity.

Initial laboratory analysisProthrombin time/INR
Complete blood count
Chemistries
Liver function test: AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin
Creatinine, urea/blood urea nitrogen, sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate
Glucose
Amylase and lipase
Arterial blood gas, lactate
Blood type and screen
Paracetamol (acetaminophen) level, toxicology screen
Viral hepatitis serologies: anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HCV
Autoimmune markers: ANA, ASMA, LKMA, immunoglobulin levels
Ceruloplasmin level (when Wilsons disease suspected)
Pregnancy test (females)
Ammonia (arterial if possible)
HIV status (has implication for transplantation)History taking should include a careful review of possible exposures to viral infection and drugs or other toxins. From history and clinical examination, the possibility of underlying chronic disease should be ruled out as it may require different management.
A liver biopsy done via the transjugular route because of coagulopathy is not usually necessary, other than in occasional malignancies. As the evaluation continues, several important decisions have to be made; such as whether to admit the patient to an ICU, or whether to transfer the patient to a transplant facility. Consultation with the transplant center as early as possible is critical due to the possibility of rapid progression of ALF.

Definition
Acute liver failure is defined as "the rapid development of hepatocellular dysfunction, specifically coagulopathy and mental status changes (encephalopathy) in a patient without known prior liver disease".page 1557The diagnosis of acute liver failure is based on physical exam, laboratory findings, patient history, and past medical history to establish mental status changes, coagulopathy, rapidity of onset, and absence of known prior liver disease respectively.page 1557The exact definition of "rapid" is somewhat questionable, and different sub-divisions exist which are based on the time from onset of first hepatic symptoms to onset of encephalopathy. One scheme defines "acute hepatic failure" as the development of encephalopathy within 26 weeks of the onset of any hepatic symptoms. This is sub-divided into "fulminant hepatic failure", which requires onset of encephalopathy within 8 weeks, and "subfulminant", which describes onset of encephalopathy after 8 weeks but before 26 weeks. Another scheme defines "hyperacute" as onset within 7 days, "acute" as onset between 7 and 28 days, and "subacute" as onset between 28 days and 24 weeks.page 1557

Treatment
General concerns
Because ALF often involves the rapid deterioration of mental status and the potential for multiorgan failure, patients should be managed in the intensive care unit. For patients not at a transplant center, the possibility of rapid progression of ALF makes early consultation with a transplant facility critical. Accordingly, plans for transfer to a transplant center should begin in patients with any abnormal mentation. Early institution of antidotes or specific therapy may prevent the need for liver transplantation and reduce the likelihood of poor outcome. Measures appropriate for specific causes of ALF are described in detail later in this chapter.

Neurologic complications
Patients with grade I–II encephalopathy should be transferred to a liver transplant facility and listed for transplantation. Consider a brain computed tomography (CT) scan to rule out other causes of altered or impaired mental status. Stimulation and overhydration can cause elevations in intracranial pressure (ICP) and should be avoided. Unmanageable agitation may be treated with short-acting benzodiazepines in small doses. Lactulose can be considered at this stage. A preliminary report from the ALFSG on 117 patients suggests that use of lactulose in the first 7 days after diagnosis is associated with a small increase in survival time, but with no difference in severity of encephalopathy or in the overall outcome. For patients who progress to grade III–IV encephalopathy, intubation for airway protection is generally required. Many centers use propofol for sedation because it may reduce cerebral blood. The head of the bed should be elevated to 30 degrees, and electrolytes, blood gasses, glucose, and neurologic status monitored frequently.

Cardiovascular complications
Increased cardiac output and low systemic vascular resistance are characteristic of ALF. Pulmonary artery catheterization should be considered. Hypotension should be treated preferentially with fluids, but systemic vasopressor support with agents such as epinephrine, norepinephrine, or dopamine should be used if fluid replacement fails to maintain mean arterial pressure of 50–60 mm Hg. Vasoconstrictive agents (especially vasopressin) should be avoided.

Pulmonary complications
Pulmonary edema and pulmonary infections are commonly seen in patients with ALF. Mechanical ventilation may be required. However, positive end-expiratory pressure can worsen cerebral edema.

Coagulopathy and gastrointestinal bleeding
Impaired liver synthesis of clotting factors, low-grade fibrinolysis, and intravascular coagulation are typical of ALF. Thrombocytopenia is common and may also be dysfunctional. Replacement therapy is recommended only in the setting of bleeding or prior to an invasive procedure. Vitamin K can be given to treat an abnormal prothrombin time, regardless of whether there is poor nutritional status. Administration of recombinant factor VIIa has shown promise; however, this treatment approach requires further study. The use of gastrointestinal hemorrhage prophylaxis with a histamine-2 (H2) blocker, proton pump inhibitor, or sucralfate is recommended.

Nutrition, electrolytes, and metabolic derangements
In patients with grade I or II encephalopathy, enteral feeding should be initiated early. Parenteral nutrition should be used only if enteral feeding is contraindicated as it increases the risk of infection. Severe restriction of protein is not beneficial; 60 g/day of protein is generally reasonable. Fluid replacement with colloid (e.g. albumin) is preferred rather than crystalloid (e.g. saline); all solutions should contain dextrose to maintain euglycemia. Multiple electrolyte abnormalities are common in ALF. Correction of hypokalemia is essential as hypokalemia increases the kidneys ammonia production, potentially exacerbating encephalopathy. Hypophosphatemia is especially common in patients with acetaminophen-induced ALF and in those with intact renal function. Hypoglycemia occurs in many patients with ALF and is often due to depletion of hepatic glycogen stores and impaired gluconeogenesis. Plasma glucose concentration should be monitored and hypertonic glucose administered as needed.

Infection
Bacterial and fungal infections are common in ALF, with one study demonstrating culture-proven infection in 80% of ALF patients. Defective cellular and humoral immunity as well as presence of indwelling catheters, coma, broad-spectrum antibiotics, and medications that suppress immunity all predispose to infection. Localizing symptoms of infection such as fever and sputum production are frequently absent and the only clues to an underlying infectious process may be worsening of encephalopathy or renal function. There must be a low threshold for obtaining frequent cultures (blood, urine, and sputum), chest radiographs, and paracentesis. Bacteria that enter through the skin, such as streptococci and staphylococci, tend to predominate. Aggressive surveillance is essential as prophylactic antibiotics have shown little benefit. Fungal infections, particularly in the setting of broad-spectrum antibiotics, are also common, and disseminated fungemia is a poor prognostic sign.

Liver transplantation
The advent of transplantation has changed survival from as low as 15% in the pretransplant era to more than 60% today. Liver transplantation is indicated for many patients with ALF, and survival rates of 56–90% can be achieved. In addition to transplantation, better critical care and the trend toward more benign causes, such as acetaminophen, all contribute to improved survival rates. Spontaneous survival is now around 40%. The application of transplantation among patients with ALF remains low, suggesting that the full potential of this modality may not be realized. Timely availability of an allograft is one of the major factors determining transplant outcomes. In the largest U.S. study, only 29% of patients received a liver graft, while 10% of the overall group (one fourth of patients listed for transplantation) died on the waiting list. Other series have reported death rates of those listed for transplant as high as 40%.
In the ALFSG, the transplantation rate was higher in the groups with lower short-term spontaneous survival, making overall survival similar in all groups: acetaminophen, 73%; drug induced, 70%; indeterminate group, 64%; and other causes, 61%. Causes of death for the 101 patients who died within the 3-week period included cerebral edema, multiorgan failure, sepsis, cardiac arrhythmia or arrest and respiratory 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 Perioral dermatitis and can you explain it in depth? [/INST] Perioral dermatitis, also known as periorificial dermatitis, is a common type of skin rash. Symptoms include multiple small (1–2 mm) bumps and blisters sometimes with background redness and scale, localized to the skin around the mouth and nostrils. Less commonly the eyes and genitalia may be involved. It can be persistent or recurring and resembles particularly rosacea and to some extent acne and allergic dermatitis. The term "dermatitis" is a misnomer because this is not an eczematous process.The cause is unclear. Topical steroids are associated with the condition and moisturizers and cosmetics may contribute. The underlying mechanism may involve blockage of the skin surface followed by subsequent excessive growth of skin flora. Fluoridated toothpaste and some micro-organisms including Candida may also worsen the condition, but their roles in this condition is unclear. It is considered a disease of the hair follicle with biopsy samples showing microscopic changes around the hair follicle. Diagnosis is based on symptoms.Treatment is typically by stopping topical steroids, changing cosmetics, and in more severe cases, taking tetracyclines by mouth. Stopping steroids may initially worsen the rash. The condition is estimated to affect 0.5-1% of people a year in the developed world. Up to 90% of those affected are women between the ages of 16 and 45 years, though it also affects children and the elderly, and has an increasing incidence in men.

History
The disorder appears to have made a sudden appearance with a case of light sensitive seborrhoeid in 1957, which  is said to be the first nearest description of the condition. By 1964, the condition in adults became popularly known as perioral dermatitis, but without clear clinical criteria. In 1970, the condition was recognised in children. That all rashes around the mouth are perioral dermatitis has since been frequently debated. That this condition should be renamed periorificial dermatitis has been proposed. Darrell Wilkinson, 1919–2009, was a British dermatologist who gave one of the earliest definitive descriptions of perioral dermatitis and noted that the condition was not always associated with the use of fluoridated steroid creams.

Signs and symptoms
A stinging and burning sensation with rash is often felt and noticed, but itching is less common. Often the rash is steroid responsive, initially improving with application of topical steroid. The redness caused by perioral dermatitis has been associated with variable level of depression and anxiety.Initially, there may be small pinpoint papules either side of the nostrils. Multiple small (1-2mm) papules and pustules then occur around the mouth, nose and sometimes cheeks. The area of skin directly adjacent to the lips, also called the vermillion border, is spared and looks normal. There may be some mild background redness and occasional scale. These areas of skin are felt to be drier and therefore there is a tendency to moisturise them more frequently. Hence, they do not tolerate drying agents well and the rash can be worsened by them.Perioral dermatitis is also known by other names including rosacea-like dermatoses, periorofacial dermatitis and periorificial dermatitis.
Unlike rosacea which involves mainly the nose and cheeks, there is no telangiectasia in perioral dermatitis. Rosacea also has a tendency to be present in older people. Acne can be distinguished by the presence of comedones and by its wider distribution on the face and chest. There are no comedones in perioral dermatitis.

Causes
The cause of perioral dermatitis is unclear. The use of topical steroids and cosmetics have the most important role. Although light exposure has been discounted as a causal factor, some reports of perioral dermatitis have been made by some patients receiving Psoralen and ultraviolet A therapy.

Corticosteroids
Perioral dermatitis often happens after the use of topical steroids on the face, and is more likely to occur the greater the strength of topical steroid used. Discontinuing the steroids often initially worsens the dermatitis, and dependency on the steroids can occur as people believe the steroids were initially controlling the condition. Inhaled corticosteroids may also trigger perioral dermatitis. Perioral dermatitis has a tendency to occur on the drier parts of the face and can be aggravated by drying agents including topical benzoyl peroxide, tretinoin and lotions with an alcohol base.

Immunosuppressants
Reports of perioral dermatitis in renal transplant recipients treated with oral corticosteroids and azathioprine have been documented.

Cosmetics
Cosmetics play an important role as causal factors for perioral dermatitis.  Regular generous applications of moisturising creams cause persistent hydration of the layer causing impairment and occlusion of the barrier function, irritation of the hair follicle, and proliferation of skin flora. Combining this with night cream and foundation significantly increases risk of perioral dermatitis 13-fold.

Micro-organisms
Topical corticosteroids may lead to increase micro-organism density in the hair follicle. The role of infectious agents such as Candida species, Demodex folliculorum, and fusiform bacteria has not been confirmed.

Psychosocial
As a cosmetic impairment, perioral dermatitis is increasingly documented to have psychosocial aspects to its cause and clinical findings. Specific personality structures, professions and social habits have been implicated in the type of person the condition occurs in.

Other potential causes
The condition may be potentially worsened by fluoridated toothpaste and inhaled corticosteroids. A high prevalence of atopy has been found in those with perioral dermatitis. The possibility of an association with the wearing of the veil in Arab women has been documented.

Pathophysiology
The pathophysiology of perioral dermatitis is related to disease of the hair follicle as is now included in the ICD-11 due to be finalised in 2018. Lip lickers dermatitis or perioral irritant contact dermatitis due to lip-licking is considered a separate disease categorised under irritant contact dermatitis due to saliva.Perioral dermatitis is frequently histologically similar to rosacea with the two conditions overlapping considerably. There is a lymphohistiocytic infiltrate with perifollicular localization and marked granulomatous inflammation. Occasionally, perifollicular abscesses may be present when pustules and papules are the dominant clinical findings.

Diagnosis
A diagnosis of perioral dermatitis is typically made based on the characteristics of the rash. A skin biopsy is usually not required to make the diagnosis but can be helpful to rule out other skin diseases which may resemble perioral dermatitis. Extended patch testing may be useful to also rule out allergic contact causes.Other skin diseases that may resemble perioral dermatitis include:

Rosacea
Acne vulgaris
Seborrheic dermatitis
Allergic contact dermatitis
Irritant contact dermatitis
Angular cheilitis

Treatment
Multiple treatment regimes are available and treatment algorithms have been proposed.Perioral dermatitis will usually resolve within a few months without medication, by limiting the use of irritants, including products with fragrance, cosmetics, benzoyl peroxide, occlusive sunscreens, and various acne products. This is called zero treatment </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 Hemolytic anemia and can you explain it in depth? [/INST] Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly occurs within the spleen, but also can occur in the reticuloendothelial system or mechanically (prosthetic valve damage). Hemolytic anemia accounts for 5% of all existing anemias. It has numerous possible consequences, ranging from general symptoms to life-threatening systemic effects. The general classification of hemolytic anemia is either intrinsic or extrinsic. Treatment depends on the type and cause of the hemolytic anemia.Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition, the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications, such as gallstones and pulmonary hypertension.

Signs and symptoms
Symptoms of hemolytic anemia are similar to the general signs of anemia. General signs and symptoms include: fatigue, pallor, shortness of breath, and tachycardia. In small children, failure to thrive may occur in any form of anemia. In addition, symptoms related to hemolysis may be present such as chills, jaundice, dark urine, and an enlarged spleen. Certain aspects of the medical history can suggest a cause for hemolysis, such as drugs, medication side effects, autoimmune disorders, blood transfusion reactions, the presence of prosthetic heart valve, or other medical illness.Chronic hemolysis leads to an increased excretion of bilirubin into the biliary tract, which in turn may lead to gallstones. The continuous release of free hemoglobin has been linked with the development of pulmonary hypertension (increased pressure over the pulmonary artery); this, in turn, leads to episodes of syncope (fainting), chest pain, and progressive breathlessness. Pulmonary hypertension eventually causes right ventricular heart failure, the symptoms of which are peripheral edema (fluid accumulation in the skin of the legs) and ascites (fluid accumulation in the abdominal cavity).

Causes
They may be classified according to the means of hemolysis, being either intrinsic in cases where the cause is related to the red blood cell (RBC) itself, or extrinsic in cases where factors external to the RBC dominate. Intrinsic effects may include problems with RBC proteins or oxidative stress handling, whereas external factors include immune attack and microvascular angiopathies (RBCs are mechanically damaged in circulation).

Intrinsic causes
Hereditary (inherited) hemolytic anemia can be due to :

Defects of red blood cell membrane production (as in hereditary spherocytosis and hereditary elliptocytosis).
Defects in hemoglobin production (as in thalassemia, sickle-cell disease and congenital dyserythropoietic anemia).
Defective red cell metabolism (as in glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency).
Wilsons disease may infrequently present with hemolytic anemia without due to excessive inorganic copper in blood circulation, which destroys red blood cells (though the mechanism of hemolysis is still unclear).

Extrinsic causes
Acquired hemolytic anemia may be caused by immune-mediated causes, drugs, and other miscellaneous causes.
Immune-mediated causes could include transient factors as in Mycoplasma pneumoniae infection (cold agglutinin disease) or permanent factors as in autoimmune diseases like autoimmune hemolytic anemia (itself more common in diseases such as systemic lupus erythematosus, rheumatoid arthritis, Hodgkins lymphoma, and chronic lymphocytic leukemia).
Spur cell hemolytic anemia
Any of the causes of hypersplenism (increased activity of the spleen), such as portal hypertension.
Acquired hemolytic anemia is also encountered in burns and as a result of certain infections (e.g. malaria).
Paroxysmal nocturnal hemoglobinuria (PNH), sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterized by complement-induced intravascular hemolytic anemia.
Lead poisoning resulting from the environment causes non-immune hemolytic anemia.
Similarly, poisoning by arsine or stibine also causes hemolytic anemia.
Runners can develop hemolytic anemia due to "footstrike hemolysis", owing to the destruction of red blood cells in feet at foot impact.
Low-grade hemolytic anemia occurs in 70% of prosthetic heart valve recipients, and severe hemolytic anemia occurs in 3%.

Mechanism
In hemolytic anemia, there are two principal mechanisms of hemolysis; intravascular and extravascular.

Intravascular hemolysis
Intravascular hemolysis describes hemolysis that happens mainly inside the vasculature. As a result, the contents of the red blood cell are released into the general circulation, leading to hemoglobinemia and increasing the risk of ensuing hyperbilirubinemia.Intravascular hemolysis may occur when red blood cells are targeted by autoantibodies, leading to complement fixation, or by damage by parasites such as Babesia.

Extravascular hemolysis
Extravascular hemolysis refers to hemolysis taking place in the liver, spleen, bone marrow, and lymph nodes. In this case little hemoglobin escapes into blood plasma. The macrophages of the reticuloendothelial system in these organs engulf and destroy structurally-defective red blood cells, or those with antibodies attached, and release unconjugated bilirubin into the blood plasma circulation. Typically, the spleen destroys mildly abnormal red blood cells or those coated with IgG-type antibodies, while severely abnormal red blood cells or those coated with IgM-type antibodies are destroyed in the circulation or in the liver.If extravascular hemolysis is extensive, hemosiderin can be deposited in the spleen, bone marrow, kidney, liver, and other organs, resulting in hemosiderosis.In a healthy person, a red blood cell survives 90 to 120 days in the circulation, so about 1% of human red blood cells break down each day. The spleen (part of the reticulo-endothelial system) is the main organ that removes old and damaged RBCs from the circulation. In healthy individuals, the breakdown and removal of RBCs from the circulation is matched by the production of new RBCs in the bone marrow.In conditions where the rate of RBC breakdown is increased, the body initially compensates by producing more RBCs; however, breakdown of RBCs can exceed the rate that the body can make RBCs, and so anemia can develop. Bilirubin, a breakdown product of hemoglobin, can accumulate in the blood, causing jaundice.In general, hemolytic anemia occurs as a modification of the RBC life cycle. That is, instead of being collected at the end of its useful life and disposed of normally, the RBC disintegrates in a manner allowing free iron-containing molecules to reach the blood. With their complete lack of mitochondria, RBCs rely on pentose phosphate pathway (PPP) for the materials needed to reduce oxidative damage. Any limitations of PPP can result in more susceptibility to oxidative damage and a short or abnormal lifecycle. If the cell is unable to signal to the reticuloendothelial phagocytes by externalizing phosphatidylserine, it is likely to lyse through uncontrolled means.The distinguishing feature of intravascular hemolysis is the release of RBC contents into the blood stream. The metabolism and elimination of these products, largely iron-containing compounds capable of doing damage through Fenton reactions,  is an important part of the condition. Several reference texts exist on the elimination pathways, for example.
Free hemoglobin can bind to haptoglobin, and the complex is cleared from the circulation; thus, a decrease in haptoglobin can support a diagnosis of hemolytic anemia. Alternatively, hemoglobin may oxidize and release the heme group that is able to bind to either albumin or hemopexin. The heme is ultimately converted to bilirubin and removed in stool and urine. Hemoglobin may be cleared directly by the kidneys resulting in fast clearance of free hemoglobin but causing the continued loss of hemosiderin loaded renal tubular cells for many days.
Additional effects of free hemoglobin seem to be due to specific reactions with NO.

Diagnosis
The diagnosis of hemolytic anemia can be suspected on the basis of a constellation of symptoms and is largely based on the presence of anemia, an increased proportion of immature red cells (reticulocytes) and a decrease in the level of haptoglobin, a protein that binds free hemoglobin. Examination of a peripheral blood smear and some other laboratory studies can contribute to the diagnosis. Symptoms of hemolytic anemia include those that can occur in all anemias as well as the specific consequences of hemolysis. All anemias can cause fatigue, shortness of breath, decreased ability to exercise when severe </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cardiac fibrosis and can you explain it in depth? [/INST] Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. Fibrotic cardiac muscle is stiffer and less compliant and is seen in the progression to heart failure. The description below focuses on a specific mechanism of valvular pathology but there are other causes of valve pathology and fibrosis of the cardiac muscle.
Fibrocyte cells normally secrete collagen, and function to provide structural support for the heart. When over-activated this process causes thickening and fibrosis of the valve, with white tissue building up primarily on the tricuspid valve, but also occurring on the pulmonary valve. The thickening and loss of flexibility eventually may lead to valvular dysfunction and right-sided heart failure.

Types
Following are types of myocardial fibrosis:

Interstitial fibrosis, which is unspecific, and has been described in congestive heart failure, hypertension, and normal aging.
Subepicardial fibrosis, also unspecific, and is associated with non-infarction diagnoses such as myocarditis and non-ischemic cardiomyopathy.
Replacement fibrosis, which indicates an older infarction.

Connection with excess blood serotonin (5-HT)
Certain diseases such as neuroendocrine tumor of the small intestine (also known by the obsolete term carcinoid), which sometimes release large amounts of 5-hydroxytryptamine, commonly known as 5-HT or serotonin into the blood, may produce a characteristic pattern of mostly right-sided cardiac fibrosis which can be identified with echocardiography. Cardiac fibrosis is a significant source of morbidity and mortality in patients with functional neuroendocrine tumors. This pathology has also been seen in certain East-African tribes who eat foods (Matoke —a green banana) containing excess amounts of serotonin.

Connection with direct serotonergic agonist drugs
Elevated prevalence of cardiac fibrosis and related valvopathies was found to be associated with use of a number of unrelated drugs following long-term statistical analysis once the drugs had been on the market for some time. The cause of this was unknown at the time, but eventually it was realised that all the implicated drugs acted as agonists at 5-HT2B receptors in the heart in addition to their intended sites of action elsewhere in the body.The precise mechanisms involved remain elusive however, as while the cardiotoxicity shows some dose–response relationship, it does not always develop, and consistent daily use over an extended period tends to be most strongly predictive of development of valvopathy.The drugs most classically associated with the condition are weight loss drugs such as fenfluramine and chlorphentermine, and antiparkinson drugs such as pergolide and cabergoline, which are prescribed for chronic use.The heart valve changes seen with moderate and intermittent use can result in permanent damage and life-threatening heart problems if use of the causative drug is increased or continued, however longitudinal studies of former patients suggest that the damage will heal over time to some extent at least.

Anorectics
Some appetite suppressant drugs such as fenfluramine (which in combination with phentermine was marketed as Pondimin and commonly referred to as fen-phen), chlorphentermine, and aminorex (along with its analogue 4-Methylaminorex which has seen sporadic use as a recreational drug) induce a similar pattern of cardiac fibrosis (and pulmonary hypertension), apparently by overstimulating 5HT2B receptors on the cardiac fibroblast cells.These drugs consequently tend to cause increased risk of heart valve damage and subsequent heart failure, which eventually led to them being withdrawn from the market.

Antimigraine drugs
Certain antimigraine drugs which are targeted at serotonin receptors as vasoconstrictive agents, have long been known to be associated with pulmonary hypertension and Raynauds phenomenon (both vasoconstrictive effects), as well as retroperitoneal fibrosis (a fibrotic cell/fibrocyte proliferation effect, thought to be similar to cardiac valve fibrosis).These drugs include ergotamine and methysergide and both drugs can also cause cardiac fibrosis.

Antiparkinson drugs
Certain antiparkinson drugs, although targeted at dopaminergic receptors, cross-react with serotoninergic 5-HT2B receptors as well, and have been reported to cause cardiac fibrosis.
These drugs include pergolide and cabergoline.

Antihypertensive drugs
Guanfacine may be a 5-HT2B agonist, based on the results of theoretical modeling and high-throughput screening.

Pergolide
Pergolide was an antiparkinson medications that was in decreasing use since reported in 2003 to be associated with cardiac fibrosis. In March 2007, pergolide was withdrawn from the U.S. market due to serious valvular damage that was shown in two independent studies.

Cabergoline
Like pergolide, cabergoline has been linked to cardiac damage </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 Retroperitoneal fibrosis and can you explain it in depth? [/INST] Retroperitoneal fibrosis or Ormonds disease is a disease featuring the proliferation of fibrous tissue in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract, and various other structures </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 Rhabdomyolysis and can you explain it in depth? [/INST] Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of the muscle breakdown products, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure.The muscle damage is most often the result of a crush injury, strenuous exercise, medications, or a substance use disorder. Other causes include infections, electrical injury, heat stroke, prolonged immobilization, lack of blood flow to a limb, or snake bites. Statins (prescription drugs to lower cholesterol) are considered a small risk. Some people have inherited muscle conditions that increase the risk of rhabdomyolysis. The diagnosis is supported by a urine test strip which is positive for "blood" but the urine contains no red blood cells when examined with a microscope. Blood tests show a creatine kinase activity greater than 1,000 U/L, with severe disease being above 5,000-15,000 U/L.The mainstay of treatment is large quantities of intravenous fluids. Other treatments may include dialysis or hemofiltration in more severe cases. Once urine output is established, sodium bicarbonate and mannitol are commonly used but they are poorly supported by the evidence. Outcomes are generally good if treated early. Complications may include high blood potassium, low blood calcium, disseminated intravascular coagulation, and compartment syndrome.Rhabdomyolysis occurs in about 26,000 people a year in the United States. While the condition has been commented on throughout history, the first modern description was following an earthquake in 1908. Important discoveries as to its mechanism were made during the Blitz of London in 1941. It is a significant problem for those injured in earthquakes, and relief efforts for such disasters often include medical teams equipped to treat survivors with rhabdomyolysis.

Signs and symptoms
The symptoms of rhabdomyolysis depend on its severity and whether kidney failure develops. Milder forms may not cause any muscle symptoms, and the diagnosis is based on abnormal blood tests in the context of other problems. More severe rhabdomyolysis is characterized by muscle pain, tenderness, weakness and swelling of the affected muscles. If the swelling is very rapid, as may happen with a crush injury after someone is released from under heavy collapsed debris, the movement of fluid from the bloodstream into damaged muscle may cause low blood pressure and shock. Other symptoms are nonspecific and result either from the consequences of muscle tissue breakdown or from the condition that originally led to the muscle breakdown. Release of the components of muscle tissue into the bloodstream causes electrolyte disturbances, which can lead to nausea, vomiting, confusion, coma or abnormal heart rate and rhythm. The urine may be dark, often described as "tea-colored", due to the presence of myoglobin. Damage to the kidneys may give rise to decreased or absent urine production, usually 12 to 24 hours after the initial muscle damage.Swelling of damaged muscle occasionally leads to compartment syndrome—compression of surrounding tissues, such as nerves and blood vessels, in the same fascial compartment—leading to the loss of blood supply and damage or loss of function in the part(s) of the body supplied by these structures. Symptoms of this complication include pain or reduced sensation in the affected limb. A second recognized complication is disseminated intravascular coagulation (DIC), a severe disruption in blood clotting that may lead to uncontrollable bleeding.

Causes
Any form of muscle damage of sufficient severity can cause rhabdomyolysis. Multiple causes can be present simultaneously in one person. Some have an underlying muscle condition, usually hereditary in nature, that makes them more prone to rhabdomyolysis.

Genetic predisposition
Recurrent rhabdomyolysis may result from intrinsic muscle enzyme deficiencies, which are usually inherited and often appear during childhood. Many structural muscle diseases feature episodes of rhabdomyolysis that are triggered by exercise, general anesthesia or any of the other causes of rhabdomyolysis listed above. Inherited muscle disorders and infections together cause the majority of rhabdomyolysis in children.The following hereditary disorders of the muscle energy supply may cause recurrent and usually exertional rhabdomyolysis:
Glycolysis and glycogenolysis defects: McArdles disease, phosphofructokinase deficiency, glycogen storage diseases VIII, IX, X and XI
Lipid metabolism defects: carnitine palmitoyltransferase I and II deficiency, deficiency of subtypes of acyl CoA dehydrogenase (LCAD, SCAD, MCAD, VLCAD, 3-hydroxyacyl-coenzyme A dehydrogenase deficiency), thiolase deficiency
Mitochondrial myopathies: deficiency of succinate dehydrogenase, cytochrome c oxidase and coenzyme Q10
Others: glucose-6-phosphate dehydrogenase deficiency, myoadenylate deaminase deficiency and muscular dystrophies

Mechanism
Damage to skeletal muscle may take various forms. Crush and other physical injuries cause damage to muscle cells directly or interfere with blood supply, while non-physical causes interfere with muscle cell metabolism. When damaged, muscle tissue rapidly fills with fluid from the bloodstream, including sodium ions. The swelling itself may lead to destruction of muscle cells, but those cells that survive are subject to various disruptions that lead to rise in intracellular calcium ions; the accumulation of calcium outside the sarcoplasmic reticulum leads to continuous muscle contraction and depletion of ATP, the main carrier of energy in the cell. ATP depletion can itself lead to uncontrolled calcium influx. The persistent contraction of the muscle cell leads to breakdown of intracellular proteins and disintegration of the cell.Neutrophil granulocytes—the most abundant type of white blood cell—enter the muscle tissue, producing an inflammatory reaction and releasing reactive oxygen species, particularly after crush injury. Crush syndrome may also cause reperfusion injury when blood flow to decompressed muscle is suddenly restored.The swollen, inflamed muscle may directly compress structures in the same fascial compartment, causing compartment syndrome. The swelling may also further compromise blood supply into the area. Finally, destroyed muscle cells release potassium ions, phosphate ions, the heme-containing protein myoglobin, the enzyme creatine kinase and uric acid (a breakdown product of purines from DNA) into the blood. Activation of the coagulation system may precipitate disseminated intravascular coagulation. High potassium levels may lead to potentially fatal disruptions in heart rhythm. Phosphate binds to calcium from the circulation, leading to low calcium levels in the blood.Rhabdomyolysis may cause kidney failure by several mechanisms. The most important is the accumulation of myoglobin in the kidney tubules. Normally, the blood protein haptoglobin binds circulating myoglobin and other heme-containing substances, but in rhabdomyolysis the quantity of myoglobin exceeds the binding capacity of haptoglobin. Myoglobinuria, the presence of myoglobin in the urine, occurs when the level in plasma exceeds 0.5–1.5 mg/dL; once plasma levels reach 100 mg/dL, the concentration in the urine becomes sufficient for it to be visibly discolored and corresponds with the destruction of about 200 grams of muscle. As the kidneys reabsorb more water from the filtrate, myoglobin interacts with Tamm–Horsfall protein in the nephron to form casts (solid aggregates) that obstruct the normal flow of fluid; the condition is worsened further by high levels of uric acid and acidification of the filtrate, which increase cast formation. Iron released from the heme generates reactive oxygen species, damaging the kidney cells. In addition to the myoglobinuria, two other mechanisms contribute to kidney impairment: low blood pressure leads to constriction of the blood vessels and therefore a relative lack of blood flow to the kidney, and finally uric acid may form crystals in the tubules of the kidneys, causing obstruction. Together, these processes lead to acute tubular necrosis, the destruction of the cells of tubules. Glomerular filtration rate falls and the kidney is unable to perform its normal excretory functions. This causes disruption of electrolyte regulation, leading to a further rise in potassium levels, and interferes with vitamin D processing, further worsening the low calcium levels.

Diagnosis
A diagnosis of rhabdomyolysis may be suspected in anyone who has sustained trauma, crush injury or prolonged immobilization, but it may also be identified at a later stage due to deteriorating kidney function (abnormally raised or increasing creatinine and urea levels, falling urine output) or reddish-brown discoloration of the urine.

General investigations
The most reliable test in the diagnosis of rhabdomyolysis is the level of creatine kinase (CK) in the blood. This enzyme is released by damaged muscle, and levels above 1000 U/L (5 times the upper limit of normal (ULN)) indicate rhabdomyolysis. More than 5,000 U/L indicates severe disease but depending on the extent of the rhabdomyolysis, concentrations up to 100,000 U/l are not unusual. CK concentrations rise steadily for 12 hours after the original muscle injury, remain elevated for 1–3 days and then fall gradually. Initial and peak CK levels have a linear relationship with the risk of acute kidney failure: the higher the CK, the more likely it is that kidney damage will occur. There is no specific concentration of CK above which kidney impairment definitely occurs; concentrations below 20,000 U/L are unlikely to be associated with a risk of kidney impairment, unless there are other contributing risk factors. Mild rises without kidney impairment are referred to as "hyperCKemia". Myoglobin has a short half-life, and is therefore less useful as a diagnostic test in the later stages. Its detection in blood or urine is associated with a higher risk of kidney impairment. Despite this, use of urine myoglobin measurement is not supported by evidence as it lacks specificity and the research studying its utility is of poor quality.Elevated concentrations of the enzyme lactate dehydrogenase (LDH) may be detected. Other markers of muscle damage, such as aldolase, troponin, carbonic anhydrase type 3 and fatty acid-binding protein (FABP), are mainly used in chronic muscle diseases. The transaminases, enzymes abundant in both liver and muscle tissue, are also usually increased; this can lead to the condition being confused with acute liver injury, at least in the early stages. The incidence of actual acute liver injury is 25% in people with non-traumatic rhabdomyolysis; the mechanism for this is uncertain.High potassium levels tend to be a feature of severe rhabdomyolysis. Electrocardiography (ECG) may show whether the elevated potassium levels are affecting the conduction system of the heart, as suggested by the presence of T wave changes or broadening of the QRS complex. Low calcium levels may be present in the initial stage due to binding of free calcium to damaged muscle cells.As detectable levels of myoglobinemia and myoglobinuria occur, blood tests and urine tests may show elevated levels of myoglobin. For example, a urine test strip may reveal a positive result for "blood", even though no red blood cells can be identified on microscopy of the urine; this occurs because the reagent on the test strip reacts with myoglobin. The same phenomenon may happen in conditions that lead to hemolysis, the destruction of red blood cells; in hemolysis the blood serum is also visibly discolored, while in rhabdomyolysis it is normal. If kidney damage has occurred, microscopy of the urine also reveals urinary casts that appear pigmented and granular.

Complications
Compartment syndrome is a clinical diagnosis, i.e., no diagnostic test conclusively proves its presence or absence, but direct measurement of the pressure in a fascial compartment, and the difference between this pressure and the blood pressure, may be used to assess its severity. High pressures in the compartment and a small difference between compartment pressure and blood pressure indicate that the blood supply is likely to be insufficient, and that surgical intervention may be needed.Disseminated intravascular coagulation, another complication of rhabdomyolysis and other forms of critical illness, may be suspected on the basis of unexpected bleeding or abnormalities in hematological tests, such as a decreasing platelet count or prolongation of the prothrombin time. The diagnosis can be confirmed with standard blood tests for DIC, such as D-dimer.

Underlying disorders
If an underlying muscle disease is suspected, for instance, if there is no obvious explanation or there have been multiple episodes, it may be necessary to perform further investigations. During an attack, low levels of carnitine in the blood and high levels of acylcarnitine in blood and urine may indicate a lipid metabolism defect, but these abnormalities revert to normal during convalescence. Other tests may be used at that stage to demonstrate these disorders. Disorders of glycolysis can be detected by various means, including the measurement of lactate after exercise; a failure of the lactate to rise may be indicative of a disorder in glycolysis, while an exaggerated response is typical of mitochondrial diseases. Electromyography (EMG) may show particular patterns in specific muscle diseases; for instance, McArdles disease and phosphofructokinase deficiency show a phenomenon called cramp-like contracture. There are genetic tests available for many of the hereditary muscle conditions that predispose to myoglobinuria and rhabdomyolysis.Muscle biopsy can be useful if an episode of rhabdomyolysis is thought to be the result of an underlying muscle disorder. A biopsy sample taken during an episode is often uninformative, as it will show only evidence of cell death or may appear normal. Taking the sample is therefore delayed for several weeks or months. The histopathological appearance on the biopsy indicates the nature of the underlying disorder. For instance, mitochondrial diseases are characterized by ragged red fibers. Biopsy sites may be identified by medical imaging, such as magnetic resonance imaging, as the muscles may not be uniformly affected.

Treatment
The main goal of treatment is to treat shock and preserve kidney function. Initially this is done through the administration of generous amounts of intravenous fluids, usually isotonic saline (0.9% weight per volume sodium chloride solution). In victims of crush syndrome, it is recommended to administer intravenous fluids even before they are extracted from collapsed structures. This will ensure sufficient circulating volume to deal with the muscle cell swelling (which typically commences when blood supply is restored), and to prevent the deposition of myoglobin in the kidneys. Amounts of 6 to 12 liters over 24 hours are recommended. The rate of fluid administration may be altered to achieve a high urine output (200–300 mL/h in adults), unless there are other reasons why this might lead to complications, such as a history of heart failure.While many sources recommend additional intravenous agents to reduce damage to the kidney, most of the evidence supporting this practice comes from animal studies, and is inconsistent and conflicting. Mannitol acts by osmosis to enhance urine production and is thought to prevent myoglobin deposition in the kidney, but its efficacy has not been shown in studies and there is a risk of worsening kidney function. The addition of bicarbonate to the intravenous fluids may alleviate acidosis (high acid level of the blood) and make the urine more alkaline to prevent cast formation in the kidneys; evidence suggesting that bicarbonate has benefits above saline alone is limited, and it can worsen hypocalcemia by enhancing calcium and phosphate deposition in the tissues. If urine alkalinization is used, the pH of the urine is kept at 6.5 or above. Furosemide, a loop diuretic, is often used to ensure sufficient urine production, but evidence that this prevents kidney failure is lacking.

Electrolytes
In the initial stages, electrolyte levels are often abnormal and require correction. High potassium levels can be life-threatening, and respond to increased urine production and renal replacement therapy (see below). Temporary measures include the administration of calcium to protect against cardiac complications, insulin or salbutamol to redistribute potassium into cells, and infusions of bicarbonate solution.Calcium levels initially tend to be low, but as the situation improves calcium is released from where it has precipitated with phosphate, and vitamin D production resumes, leading to hypercalcemia (abnormally high calcium levels). This "overshoot" occurs in 20–30% of those people who have developed kidney failure.

Acute kidney impairment
Kidney dysfunction typically develops 1–2 days after the initial muscle damage. If supportive treatment is inadequate to manage this, renal replacement therapy (RRT) may be required. RRT removes excess potassium, acid and phosphate that accumulate when the kidneys are unable to function normally and is required until kidney function is regained.Three main modalities of RRT are available: hemodialysis, continuous hemofiltration and peritoneal dialysis. The former two require access to the bloodstream (a dialysis catheter) and peritoneal dialysis is achieved by instilling fluid into the abdominal cavity and later draining it. Hemodialysis, which is normally done several times a week in chronic kidney disease, is often required on a daily basis in rhabdomyolysis. Its advantage over continuous hemofiltration is that one machine can be used multiple times a day, and that continuous administration of anticoagulant drugs is not necessary. Hemofiltration is more effective at removing large molecules from the bloodstream, such as myoglobin, but this does not seem to confer any particular benefit. Peritoneal dialysis may be difficult to administer in someone with severe abdominal injury, and it may be less effective than the other modalities.

Other complications
Compartment syndrome is treated with surgery to relieve the pressure inside the muscle compartment and reduce the risk of compression on blood vessels and nerves in that area. Fasciotomy is the incision of the affected compartment. Often, multiple incisions are made and left open until the swelling has reduced. At that point, the incisions are closed, often requiring debridement (removal of non-viable tissue) and skin grafting in the process. The need for fasciotomy may be decreased if mannitol is used, as it can relieve muscle swelling directly.Disseminated intravascular coagulation generally resolves when the underlying causes are treated, but supportive measures are often required. For instance, if the platelet count drops significantly and there is resultant bleeding, platelets may be administered.

Prognosis
The prognosis depends on the underlying cause and whether any complications occur. Rhabdomyolysis complicated by acute kidney impairment in patients with traumatic injury may have a mortality rate of 20%. Admission to the intensive care unit is associated with a mortality of 22% in the absence of acute kidney injury, and 59% if kidney impairment occurs. Most people who have sustained kidney impairment due to rhabdomyolysis fully recover their kidney function.

Epidemiology
The exact number of cases of rhabdomyolysis is difficult to establish because different definitions have been used. In 1995, hospitals in the U.S. reported 26,000 cases of rhabdomyolysis. Up to 85% of people with major traumatic injuries will experience some degree of rhabdomyolysis. Of those with rhabdomyolysis, 10–50% develop acute kidney injury. The risk is higher in people with a history of illicit drug use, alcohol misuse or trauma when compared to muscle diseases, and it is particularly high if multiple contributing factors occur together. Rhabdomyolysis accounts for 7–10% of all cases of acute kidney injury in the U.S.Crush injuries are common in major disasters, especially in earthquakes. The aftermath of the 1988 Spitak earthquake prompted the establishment, in 1995, of the Renal Disaster Relief Task Force, a working group of the International Society of Nephrology (a worldwide body of kidney experts). Its volunteer doctors and nurses assisted for the first time in the 1999 İzmit earthquake in Turkey, where 17,480 people died, 5392 were hospitalized and 477 received dialysis, with positive results. Treatment units are generally established outside the immediate disaster area, as aftershocks could potentially injure or kill staff and make equipment unusable.Acute exertional rhabdomyolysis happens in 2% to 40% of people going through basic training for the United States military. In 2012, the United States military reported 402 cases. Another group at increased risk is firefighters.

History
The Bible may contain an early account of rhabdomyolysis. In Numbers 11:4–6,31–33, the Pentateuch says that the Jews demanded meat while traveling in the desert; God sent quail in response to the complaints, and people ate large quantities of quail meat. A plague then broke out, killing numerous people. Rhabdomyolysis after consuming quail was described in more recent times and called coturnism (after Coturnix, the main quail genus). Migrating quail consume large amounts of hemlock, a known cause of rhabdomyolysis.In modern times, early reports from the 1908 Messina earthquake and World War I on kidney failure after injury were followed by studies by London physicians Eric Bywaters and Desmond Beall, working at the Royal Postgraduate Medical School and the National Institute for Medical Research, on four victims of The Blitz in 1941 </s>


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