<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 Endocarditis and can you explain it in depth? [/INST] Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves. Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or the surfaces of intracardiac devices. Endocarditis is characterized by lesions, known as vegetations, which is a mass of platelets, fibrin, microcolonies of microorganisms, and scant inflammatory cells. In the subacute form of infective endocarditis, the vegetation may also include a center of granulomatous tissue, which may fibrose or calcify.There are several ways to classify endocarditis. The simplest classification is based on cause: either infective or non-infective, depending on whether a microorganism is the source of the inflammation or not. Regardless, the diagnosis of endocarditis is based on clinical features, investigations such as an echocardiogram, and blood cultures demonstrating the presence of endocarditis-causing microorganisms.
Signs and symptoms include fever, chills, sweating, malaise, weakness, anorexia, weight loss, splenomegaly, flu-like feeling, cardiac murmur, heart failure, petechia (red spots on the skin), Oslers nodes (subcutaneous nodules found on hands and feet), Janeway lesions (nodular lesions on palms and soles), and Roths spots (retinal hemorrhages).

Infective endocarditis
Infective endocarditis is an infection of the inner surface of the heart, usually the valves. Symptoms may include fever, small areas of bleeding into the skin, heart murmur, feeling tired, and low red blood cells. Complications may include valvular insufficiency, heart failure, stroke, and kidney failure.The cause is typically a bacterial infection and less commonly a fungal infection. Risk factors include valvular heart disease including rheumatic disease, congenital heart disease, artificial valves, hemodialysis, intravenous drug use, and electronic pacemakers. The bacterial most commonly involved are streptococci or staphylococci.The diagnosis of infective endocarditis relies on the Duke criteria, which were originally described in 1994 and modified in 2000. Clinical features and microbiological examinations are the first steps to diagnose an infective endocarditis. The imaging is also crucial. Echocardiography is the cornerstone of imaging modality in the diagnosis of infective endocarditis. Alternative imaging modalities as computer tomography, magnetic resonance imaging, and positron emission tomography/computer tomography (PET/CT) with 2-[18F]fluorodeoxyglucose (FDG) are playing an increasing role in the diagnosis and management of infective endocarditis.The usefulness of antibiotics following dental procedures for prevention is unclear. Some recommend them in those at high risk. Treatment is generally with intravenous antibiotics. The choice of antibiotics is based on the blood cultures. Occasionally heart surgery is required.The number of people affected is about 5 per 100,000 per year. Rates, however, vary between regions of the world. Males are affected more often than females. The risk of death among those infected is about 25%. Without treatment it is almost universally fatal.

Non-infective endocarditis
Nonbacterial thrombotic endocarditis (NBTE) is most commonly found on previously undamaged valves.  As opposed to infective endocarditis, the vegetations in NBTE are small, sterile, and tend to aggregate along the edges of the valve or the cusps.  Also unlike infective endocarditis, NBTE does not cause an inflammation response from the body.  NBTE usually occurs during a hypercoagulable state such as system-wide bacterial infection, or pregnancy, though it is also sometimes seen in patients with venous catheters.  NBTE may also occur in patients with cancers, particularly mucinous adenocarcinoma where Trousseau syndrome can be encountered. Typically NBTE does not cause many problems on its own, but parts of the vegetations may break off and embolize to the heart or brain, or they may serve as a focus where bacteria can lodge, thus causing infective endocarditis.Another form of sterile endocarditis is termed Libman–Sacks endocarditis; this form occurs more often in patients with lupus erythematosus and is thought to be due to the deposition of immune complexes.  Like NBTE, Libman-Sacks endocarditis involves small vegetations, while infective endocarditis is composed of large vegetations.  These immune complexes precipitate an inflammation reaction, which helps to differentiate it from NBTE.  Also unlike NBTE, Libman-Sacks endocarditis does not seem to have a preferred location of deposition and may form on the undersurfaces of the valves or even on the endocardium.

References
Further reading
Meine TJ, Nettles RE, Anderson DJ, Cabell CH, Corey GR, Sexton DJ, Wang A (2001) </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 Renal hypoplasia 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 Aluminosis 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 Mansonelliasis and can you explain it in depth? [/INST] Mansonelliasis  is the condition of infection by the nematode Mansonella.
The disease exists in Africa and tropical Americas, spread by biting midges or blackflies. It is usually asymptomatic.

Symptoms and signs
Infections by Mansonella perstans, while often asymptomatic, can be associated with angioedema, pruritus, fever, headaches, arthralgias, and neurologic manifestations. Mansonella streptocerca can manifest on the skin via pruritus, papular eruptions and pigmentation changes. Mansonella ozzardi can cause symptoms that include arthralgias, headaches, fever, pulmonary symptoms, adenopathy, hepatomegaly, and pruritus. Eosinophilia is often prominent but do not occur in all cases of Mansonelliasis. M. perstans can also present with Calabar-like swellings, hives, and a condition known as Kampala, or Ugandan eye worm. This occurs when adult M. perstans invades the conjunctiva or periorbital connective tissues in the eye. M. perstans can also present with hydrocele in South America. However, it is often hard to distinguish between the symptoms of Mansonelliasis and other nematode infections endemic to the same areas.

Causes
Mansonelliasis is caused by nematodes (roundworms) in the Mansonella genus that reside in the skin or certain body cavities. The specific species are M. perstans, M. streptocerca and M. ozzardi.

Vectors and life cycle
During a blood meal, an infected midge (genus Culicoides) or blackfly (genus Simulium) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound. They develop into adults that reside in body cavities, most commonly the peritoneal cavity or pleural cavity, but also occasionally in the pericardium (M. perstans), subcutaneous tissue (M. ozzardi) or dermis (M. steptocerca).In M. perstans, size range for female worms is 70 to 80 mm long and 120 μm in diameter, and the males measure approximately 45 mm by 60 μm. In M. steptocerca, the females measure approximately 27 mm long. Their diameter is 50 μm at the level of the vulva (anteriorly) and ovaries (near the posterior end), and up to 85 μm at the mid-body. Males measure 50 μm in diameter. In M. ozzardi, adult worms are rarely found in humans. The size range for females worms is 65 to 81 mm long and 0.21 to 0.25 mm in diameter but unknown for males. Adult worms recovered from experimentally infected Patas monkeys measured 24 to 28 mm long and 70 to 80 μm in diameter (males) and 32 to 62 mm long and .130 to .160 mm in diameter (females).Adults produce unsheathed and non-periodic (sub-periodic in M. perstans) microfilariae that reach the blood stream. A midge or black fly ingests microfilariae during a blood meal. After ingestion, the microfilariae migrate from the midgut through the hemocoel to the thoracic muscles of the arthropod. There the microfilariae develop into first-stage larvae and later into third-stage infective larvae. The third-stage infective larvae migrate to the arthropod’s proboscis where they can then infect another human when the midge or blackfly takes a blood meal. Asymptomatic humans serve as a significant reservoir for the disease. Little is known about other reservoirs of the disease.

Pathogenesis
Mansonelliasis infection has been considered a minor filariasis, remaining asymptomatic in most infected subjects. Larvae develop in the subject and migrate to their respective regions in the skin or body cavities. It is likely that aside from being caused by the worm itself, some of the pathological changes observed are induced by the immune response to the infection leading to some of the various symptoms mentioned above. However, Mansonelliasis is little studied compared to other forms of filariasis so there is not as much information known regarding its specific pathogenesis.

Diagnosis
Examination of blood samples will allow identification of microfilariae of M. perstans, and M. ozzardi based. This diagnosis can be made on the basis of the morphology of the nuclei distribution in the tails of the microfilariae. The blood sample can be a thick smear, stained with Giemsa or hematoxylin and eosin. For increased sensitivity, concentration techniques can be used. These include centrifugation of the blood sample lyzed in 2% formalin (Knotts technique), or filtration through a Nucleopore membrane.Examination of skin snips will identify microfilariae of Onchocerca volvulus and M. streptocerca. Skin snips can be obtained using a corneal-scleral punch, or more simply a scalpel and needle. It is important that the sample be allowed to incubate for 30 minutes to 2 hours in saline or culture medium and then examined. This allows for the microfilariae that would have been in the tissue to migrate to the liquid phase of the specimen. Additionally, to differentiate the skin-dwelling filariae M. streptocerca and Onchocerca volvulus, a nested polymerase chain reaction (PCR) assay was developed using small amounts of parasite material present in skin biopsies.

Prevention
Prevention can be partially achieved through limiting contact with vectors through the use of DEET and other repellents, but due to the predominantly relatively mild symptoms and the infection being generally asymptomatic, little has formally been done to control the disease.

Treatment
There is no consensus on optimal therapeutic approach. The most commonly used drug is diethylcarbamazine (DEC), but it is, however, often ineffective. Although other drugs have been tried such as praziquantel, ivermectin, and albendozole, none has proven to be reliably and rapidly effective. Mebendazole appeared more active than DEC in eliminating the infection, and had comparable overall responses. Thiabendazole evidenced a small, but significant activity against the infection. A combination of treatments, DEC plus mebendazole, was much more effective than single drug doses.

Epidemiology
Mansonelliasis is found in Latin America from the Yucatán peninsula to northern Argentina, in the Caribbean, and in Africa from Senegal to Kenya and south to Angola and Zimbabwe. M. ozzardi is found only in the New World, M. steptocerca is found only in the Congo Basin, and M. perstans is found in both the previously described areas of Africa and Latin America. Prevalence rates vary from a few percent to as much as 90% in areas like Trinidad, Guyana and Colombia.Infection is more common and has a higher microfilarial dose with age, though studies have found microfilarial dose not to be correlated with symptoms. In parts of rural South America, men have been found more susceptible than women, possibly due to more outdoors work by males as children, and possibly due to cooking fires serving as deterrents to vectors for women who perform more domestic duties. One study in central Africa found M. perstans to be a much more common cause of filariasis symptoms compared to Loa loa and Wuchereria bancrofti.Since most Mansonelliasis is asymptomatic, it has been considered a relatively minor filarial disease, and has a very low, if any, mortality, though there is little data on which to base estimates.

History
Mansonelliasis, in the form of M. ozzardi, was first documented in 1897.

See also
Filariasis
Mansonella

References
Further reading
Marinkelle CJ, German E (March 1970). "Mansonelliasis in the Comisaría del Vaupes of Colombia". Tropical and Geographical Medicine. 22 (1): 101–11. PMID 5435931.
Cohen JM, Ribeiro JA, Martins M (2008) </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 fibrosis and can you explain it in depth? [/INST] Idiopathic pulmonary fibrosis (IPF), or (formerly) fibrosing alveolitis, is a rare, progressive illness of the respiratory system, characterized by the thickening and stiffening of lung tissue, associated with the formation of scar tissue. It is a type of chronic scarring lung disease characterized by a progressive and irreversible decline in lung function. The tissue in the lungs becomes thick and stiff, which affects the tissue that surrounds the air sacs in the lungs. Symptoms typically include gradual onset of shortness of breath and a dry cough. Other changes may include feeling tired, and abnormally large and dome shaped finger and toenails (nail clubbing). Complications may include pulmonary hypertension, heart failure, pneumonia or pulmonary embolism.The cause is unknown, hence the term idiopathic. Risk factors include cigarette smoking, acid reflux disease (GERD),  certain viral infections, and genetic predisposition. The underlying mechanism involves scarring of the lungs. Diagnosis requires ruling out other potential causes. It may be supported by a HRCT scan or lung biopsy which show usual interstitial pneumonia (UIP). It is a type of interstitial lung disease (ILD).People often benefit from pulmonary rehabilitation and supplemental oxygen. Certain medications like pirfenidone (Esbriet) or nintedanib (Ofev) may slow the progression of the disease. Lung transplantation may also be an option.About 5 million people are affected globally. The disease newly occurs in about 12 per 100,000 people per year. Those in their 60s and 70s are most commonly affected. Males are affected more often than females. Average life expectancy following diagnosis is about four years. Updated international guidelines were published in 2022, which some simplification in diagnosis and the removal of antacids as a possible adjunct therapy.

Signs and symptoms
In many people, symptoms are present for a considerable time before diagnosis. The most common clinical features of IPF include the following:
Age over 50 years
Dry, non-productive cough on exertion
Progressive exertional dyspnea (shortness of breath with exercise)
Dry, inspiratory bibasilar "velcro-like" crackles on auscultation (a crackling sound in the lungs during inhalation similar to Velcro being torn apart slowly, heard with a stethoscope).
Clubbing of the digits, a disfigurement of the finger tips or toes (see image)
Abnormal pulmonary function test results, with evidence of restriction and impaired gas exchange.Some of these features are due to chronic hypoxemia (oxygen deficiency in the blood), are not specific for IPF, and can occur in other pulmonary disorders. IPF should be considered in all patients with unexplained chronic exertional dyspnea who present with cough, inspiratory bibasilar crackles, or finger clubbing.Assessment of "velcro" crackles on lung auscultation is a practical way to improve the earlier diagnosis of IPF. Fine crackles are easily recognized by clinicians and are characteristic of IPF.If bilateral fine crackles are present throughout the inspiratory time and are persisting after several deep breaths, and if remaining present on several occasions several weeks apart in a subject aged ≥60 years, this should raise the suspicion of IPF and lead to consideration of an HRCT scan of the chest which is more sensitive than a chest X-ray. As crackles are not specific for IPF, they must prompt a thorough diagnostic process.

Causes
The cause of IPF is unknown but certain environmental factors and exposures have been shown to increase the risk of getting IPF. Cigarette smoking is the best recognized and most accepted risk factor for IPF, and increases the risk of IPF by about twofold. Other environmental and occupation exposures such as exposure to metal dust, wood dust, coal dust, silica, stone dust, biologic dusts coming from hay dust or mold spores or other agricultural products, and occupations related to farming/livestock have also been shown to increase the risk for IPF. There is some evidence that viral infections may be associated with idiopathic pulmonary fibrosis and other fibrotic lung diseases.

Pathogenesis
Despite extensive investigation, the cause of IPF remains unknown. The fibrosis in IPF has been linked to cigarette smoking, environmental factors (e.g. occupational exposure to gases, smoke, chemicals or dusts), other medical conditions including gastroesophageal reflux disease (GERD), or to genetic predisposition (familial IPF). However, none of these is present in all people with IPF and therefore do not provide a completely satisfactory explanation for the disease.IPF is believed to be the result of an aberrant wound healing process including/involving abnormal and excessive deposition of collagen (fibrosis) in the pulmonary interstitium with minimal associated inflammation. Cellular senescence is suspected to be a central contributing cause, a belief which is supported by benefits seen in patients given senolytic therapy.It is hypothesized that the initial or repetitive injury in IPF occurs to the lung cells, called alveolar epithelial cells (AECs, pneumocytes), which line the majority of the alveolar surface. When type I AECs are damaged or lost, it is thought that type II AECs undergo proliferation to cover the exposed basement membranes. In normal repair, the hyperplastic type II AECs die and the remaining cells spread and undergo a differentiation process to become type I AECs. Under pathologic conditions and in the presence of transforming growth factor beta (TGF-β), fibroblasts accumulate in these areas of damage and differentiate into myofibroblasts that secrete collagen and other proteins. In the current classification of the pathogenesis of IPF, it is believed that it occurs by way of the formation of a UIP (usual interstitial pneumonia) lesion, which then undergoes the aforementioned pathological condition characteristic of IPF. Other proposed repeated injury mechanisms indicate that IPF may result not just from a UIP lesion, but also from NSIP and DAD (nonspecific interstitial pneumonia and diffuse alveolar damage) lesions, or a combination of several.
In the past, it was thought that inflammation was the first event in initiating lung tissue scarring. Later findings showed that the development of fibroblastic foci precedes the accumulation of inflammatory cells and the consequent deposition of collagen. This pathogenetic model is indirectly supported by the clinical features of IPF, including an insidious onset over several years, relatively infrequent acute exacerbations, and failure to respond to immunosuppressive therapy. However, it is the belief of some researchers that the disease is a multi-mechanistic one, wherein the trigger for the disease may stem from abnormalities in any number of wound healing pathways, including the inflammatory response. Such abnormalities could occur in any number of the nine implicated pathways (clotting cascade, antioxidant pathways, apoptosis, inflammatory cytokines, angiogenesis and vascular remodelling, growth factors, surfactant and matrix regulatory factors), and that through further investigation into all nine, novel therapies and approaches could be proposed on a unique or case-by-case basis should attempts at treating or circumventing complications in any one pathway prove unsuccessful. A number of therapies that target fibroblast activation or the synthesis of extracellular matrix are currently in early testing or are being considered for development.Familial IPF accounts for less than 5% of the total of patients with IPF and is clinically and histologically indistinguishable from sporadic IPF. Genetic associations include mutations in pulmonary surfactant proteins A1, A2, C (SFTPA1, SFTPA2B) and mucin (MUC5B).
A remarkable aspect of the MUC5B variant is its high frequency of detection, as it is found in approximately 20% of individuals with Northern and Western European ancestry and in 19% of the Framingham Heart Study population.
Mutations in human telomerase genes are also associated with familial pulmonary fibrosis and in some patients with sporadic IPF (e.g. the TERT, TERC genes). Recently an X-linked mutation in a third telomerase-associated gene, dyskerin (DKC1), has been described in a family with IPF.

Diagnosis
An earlier diagnosis of IPF is a prerequisite for earlier treatment and, potentially, improvement of the long-term clinical outcome of this progressive and ultimately fatal disease. If IPF is suspected, diagnosis can be challenging but a multidisciplinary approach involving a pulmonologist, radiologist and pathologist expert in interstitial lung disease has been shown to improve the accuracy of IPF diagnosis.A Multidisciplinary Consensus Statement on the Idiopathic Interstitial Pneumonias published by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) in 2000 proposed specific major and minor criteria for establishing the diagnosis of IPF. However, in 2011, new simplified and updated criteria for the diagnosis and management of IPF were published by the ATS, ERS, together with the Japanese Respiratory Society (JRS) and Latin American Thoracic Association (ALAT). Currently, a diagnosis of IPF requires:

Exclusion of known causes of ILD, e.g., domestic and occupational environmental exposures, connective tissue disorders, or drug exposure/toxicity
The presence of a typical radiological pattern of usual interstitial pneumonia (UIP) on high-resolution computed tomography (HRCT).In the right clinical setting, it is possible to make the diagnosis of IPF by HRCT alone, obviating the need for surgical lung biopsy.Various technologies using Artificial Intelligence have been developed to help with diagnosis. A deep learning algorithm for categorizing high-resolution CT images reported high accuracy  and a research project led by Nagoya University Graduate School of Medicine and Riken used a combination of Deep learning and Machine learning algorithm to accurately diagnose the disease.

Differential diagnosis
Recognizing IPF in clinical practice can be challenging as symptoms often appear similar to those of more common diseases, such as asthma, chronic obstructive pulmonary disease (COPD) and congestive heart failure (www.diagnoseipf.com). The key issue facing clinicians is whether the presenting history, symptoms (or signs), radiology, and pulmonary function testing are collectively in keeping with the diagnosis of IPF or whether the findings are due to another process. It has long been recognized that patients with ILD related to asbestos exposure, drugs (such as chemotherapeutic agents or nitrofurantoin), rheumatoid arthritis and scleroderma/systemic sclerosis may be difficult to distinguish from IPF. Other differential diagnostic considerations include interstitial lung disease related to mixed connective tissue disease, advanced sarcoidosis, chronic hypersensitivity pneumonitis, pulmonary Langerhans cell histiocytosis and radiation-induced lung injury.

Classification
Idiopathic pulmonary fibrosis (IPF) belongs to a large group of more than 200 lung diseases known as interstitial lung diseases (ILDs), which are characterized by the involvement of the lung interstitium, the tissue between the air sacs of the lung. IPF is one specific presentation of idiopathic interstitial pneumonia (IIP), which is in turn a type of ILD, also known as diffuse parenchymal lung disease (DPLD).The 2002 American Thoracic Society/European Respiratory Society (ATS/ERS) classification of IIPs was updated in 2013. In this new classification there are three main categories of idiopathic interstitial pneumonias (IIPs): major IIPs, rare IIPs, and unclassifiable IIPs. The major IIPs are grouped into chronic fibrosing IPs (this includes IPF and non-specific interstitial pneumonia [NSIP]); smoking-related IPs (i.e. respiratory bronchiolitis–interstitial lung disease [RB-ILD] and desquamative interstitial pneumonia [DIP]); and acute/subacute IPs (i.e. cryptogenic organizing pneumonia [COP] and acute interstitial pneumonia [AIP]).The diagnosis of IIPs requires exclusion of known causes of ILD. Examples of ILD of known cause include hypersensitivity pneumonitis, pulmonary Langerhans cell histiocytosis, asbestosis, and collagen vascular disease. However, these disorders frequently affect not only the interstitium, but also the airspaces, peripheral airways, and blood vessels.

Radiology
Chest X-rays are useful in the follow up routine of IPF patients. Plain chest X-rays are unfortunately not diagnostic but may reveal decreased lung volumes, typically with prominent reticular interstitial markings near the lung bases. The radiological evaluation through HRCT is an essential point in the diagnostic pathway in IPF. HRCT is performed using a conventional computed axial tomographic scanner without injection of contrast agents. Evaluation slices are very thin, 1–2 mm.
Typical HRCT of the chest of IPF demonstrates fibrotic changes in both lungs, with a predilection for the bases and the periphery. According to the joint ATS/ERS/JRS/ALAT 2011 guidelines, HRCT is an essential component of the diagnostic pathway in IPF which can identify UIP by the presence of:
Reticular opacities, often associated with traction bronchiectasis
Honeycombing manifested as cluster cystic airspaces, typically of comparable diameters (3–10 mm) but occasionally large. Usually sub-pleural and characterized by well-defined walls and disposed in at least two lines. Generally one line of cysts is not sufficient to define honeycombing
Ground-glass opacities are common but less extensive than the reticulation
Distribution characteristically basal and peripheral though often patchy.

Histology
According to the updated 2011 guidelines, in the absence of a typical UIP pattern on HRCT, a surgical lung biopsy is required for confident diagnosis.Histologic specimens for the diagnosis of IPF must be taken at least in three different places and be large enough that the pathologist can comment on the underlying lung architecture. Small biopsies, such as those obtained via transbronchial lung biopsy (performed during bronchoscopy) are usually not sufficient for this purpose. Hence, larger biopsies obtained surgically via a thoracotomy or thoracoscopy are usually necessary.Lung tissue from people with IPF usually show a characteristic histopathologic UIP pattern and is therefore the pathologic counterpart of IPF. Although a pathologic diagnosis of UIP often corresponds to a clinical diagnosis of IPF, a UIP histologic pattern can be seen in other diseases as well, and fibrosis of known origin (rheumatic diseases for example). There are four key features of UIP including interstitial fibrosis in a patchwork pattern, interstitial scarring, honeycomb changes and fibroblast foci.Fibroblastic foci are dense collections of myofibroblasts and scar tissue and, together with honeycombing, are the main pathological findings that allow a diagnosis of UIP.

Bronchoalveolar lavage
Bronchoalveolar lavage (BAL) is a well-tolerated diagnostic procedure in ILD. BAL cytology analyses (differential cell counts) should be considered in the evaluation of patients with IPF at the discretion of the treating physician based on availability and experience at their institution. BAL may reveal alternative specific diagnoses: malignancy, infections, eosinophilic pneumonia, histiocytosis X, or alveolar proteinosis. In the evaluation of patients with suspected IPF, the most important application of BAL is in the exclusion of other diagnoses. Prominent lymphocytosis (>30%) generally allows excluding a diagnosis of IPF.

Pulmonary function tests
Spirometry classically reveals a reduction in the vital capacity (VC) with either a proportionate reduction in airflows, or increased airflows for the observed vital capacity. The latter finding reflects the increased lung stiffness (reduced lung compliance) associated with pulmonary fibrosis, which leads to increased lung elastic recoil.Measurement of static lung volumes using body plethysmography or other techniques typically reveals reduced lung volumes (restriction). This reflects the difficulty encountered in inflating the fibrotic lungs.
The diffusing capacity for carbon monoxide (DLCO) is invariably reduced in IPF and may be the only abnormality in mild or early disease. Its impairment underlies the propensity of patients with IPF to exhibit oxygen desaturation with exercise which can also be evaluated using the 6-minute walk test (6MWT).Terms such as mild, moderate, and severe are sometimes used for staging disease and are commonly based on resting pulmonary function test measurements. However, there is no clear consensus regarding the staging of IPF patients and what are the best criteria and values to use. Mild-to-moderate IPF has been characterized by the following functional criteria:
Forced vital capacity (FVC) of ≥50%
DLCO of ≥30%
6MWT distance ≥150 meters.

Treatment
The goals of treatment in IPF are essentially to reduce the symptoms, stop disease progression, prevent acute exacerbations, and prolong survival. Preventive care (e.g. vaccinations) and symptom-based treatment should be started early in every patient.

Oxygen therapy
In the 2011 IPF guidelines, oxygen therapy, or supplementary oxygen for home use, became a strong recommendation for use in those patients with significantly low oxygen levels at rest. Although oxygen therapy has not been shown to improve survival in IPF, some data indicate an improvement in exercise capacity.

Pulmonary rehabilitation
Fatigue and loss of muscular mass are common and disabling problems for patients with IPF. Pulmonary rehabilitation may alleviate the overt symptoms of IPF and improve functional status by stabilizing and/or reversing the extrapulmonary features of the disease. The number of published studies on the role of pulmonary rehabilitation in idiopathic pulmonary fibrosis is small, but most of these studies have found significant short-term improvements in functional exercise tolerance, quality of life, and dyspnea on exertion. Typical programs of rehabilitation include exercise training, nutritional modulation, occupational therapy, education and psychosocial counseling. In the late phase of disease, IPF patients tend to discontinue physical activity due to increasing dyspnea. Whenever possible, this should be discouraged.

Medications
A number of treatments have been investigated in the past for IPF, including interferon gamma-1β, bosentan, ambrisentan, and anticoagulants, but these are no longer considered effective treatment options. Many of these earlier studies were based on the hypothesis that IPF is an inflammatory disorder.

Pirfenidone
A Cochrane review comparing pirfenidone with placebo, found a reduced risk of disease progression by 30%. FVC or VC was also improved, even if a mild slowing in FVC decline could be demonstrated only in one of the two CAPACITY trials. A third study, which was completed in 2014 found reduced decline in lung function and IPF disease progression. The data from the ASCEND study were also pooled with data from the two CAPACITY studies in a pre-specified analysis which showed that pirfenidone reduced the risk of death by almost 50% over one year of treatment.

N-acetylcysteine and triple therapy
N-Acetylcysteine (NAC) is a precursor to glutathione, an antioxidant. It has been hypothesized that treatment with high doses of NAC may repair an oxidant–antioxidant imbalance that occurs in the lung tissue of patients with IPF. In the first clinical trial of 180 patients (IFIGENIA), NAC was shown in previous study to reduce the decline in VC and DLCO over 12 months of follow-up when used in combination with prednisone and azathioprine (triple therapy).More recently, a large randomized, controlled trial (PANTHER-IPF) was undertaken by the National Institutes of Health (NIH) in the US to evaluate triple therapy and NAC monotherapy in IPF patients. This study found that the combination of prednisone, azathioprine, and NAC increased the risk of death and hospitalizations and the NIH announced in 2012 that the triple-therapy arm of the PANTHER-IPF study had been terminated early.This study also evaluated NAC alone and the results for this arm of the study were published in May 2014 in the New England Journal of Medicine, concluding that "as compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function".

Nintedanib
Nintedanib is a triple angiokinase inhibitor that targets receptor tyrosine kinases involved in the regulation of angiogenesis: fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR), which have also been implicated in the pathogenesis of fibrosis and IPF. In both phase III trials, nintedanib reduced the decline in lung function by approximately 50% over one year. It was approved by the US FDA in October 2014 and authorised in Europe in January 2015.

Lung transplantation
Lung transplantation may be suitable for those patients physically eligible to undergo a major transplant operation. In IPF patients, lung transplant has been shown to reduce the risk of death by 75% as compared with patients who remain on the waiting list. Since the introduction of the lung allocation score (LAS), which prioritizes transplant candidates based on survival probability, IPF has become the most common indication for lung transplantation in the USA.Symptomatic patients with IPF younger than 65 years of age and with a body mass index (BMI) ≤26 kg/m2 should be referred for lung transplantation, but there are no clear data to guide the precise timing for LTx. Although controversial, the most recent data suggest that bilateral lung transplantation is superior to single lung transplantation in patients with IPF. Five-year survival rates after lung transplantation in IPF are estimated at between 50 and 56%.

Palliative care
Palliative care focuses on reducing symptoms and improving the comfort of patients rather than treating the disease. This may include treatment of worsening symptoms with the use of chronic opioids for severe dyspnea and cough. Further, oxygen therapy may be useful for palliation of dyspnea in hypoxemic patients.
Palliative care also includes relief of physical and emotional suffering and psychosocial support for patients and caregivers. With disease progression, patients may experience fear, anxiety and depression and psychological counseling should therefore be considered. In a recent study of outpatients with ILDs, including IPF, depression score, functional status (as assessed by walk test), as well as pulmonary function, all contributed to the severity of dyspnea.In selected cases of particularly severe dyspnea morphine could be considered. It can reduce dyspnea, anxiety and cough without significant decrease in oxygen saturation.

Follow-up
IPF is often misdiagnosed, at least until physiological and/or imaging data suggest the presence of an ILD leading to delay in accessing appropriate care. Considering that IPF is a disease with a median survival of three years after diagnosis, early referral to a center with specific expertise should therefore be considered for any patient with suspected or known ILD. On the basis of the complex differential diagnostic, multidisciplinary discussion between pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD is of the utmost importance to an accurate diagnosis.Those with IPF have higher chances of getting lung cancer, at a rate of 13.5% where the most common cancer type is Squamous-cell carcinoma of the lung. a routine evaluation every 3 to 6 months, including spirometry (body plethysmography), diffusion capacity testing, chest X-rays, 6MWT, assessment of dyspnea, quality of life, oxygen requirement is mandatory.In addition, the increasing awareness of complications and common concomitant conditions frequently associated with IPF requires a routinely evaluation of comorbidities, most of them simply reflecting concurrent diseases of aging, and medications with their interaction and side effects.

Acute exacerbations
Acute exacerbations of IPF (AE-IPF) are defined as an unexplained worsening or development of dyspnea within 30 days with new radiological infiltrates at HRCT abnormality often superimposed on a background consistent with UIP pattern. The yearly incidence of AE-IPF is between 10 and 15% of all patients. The prognosis of AE-IPF is poor, with mortality ranging from 78% to 96%. Other causes of AE-IPF such as pulmonary embolism, congestive heart failure, pneumothorax, or infection need to be excluded. Pulmonary infection have to be ruled out by endotracheal aspirate or BAL.
Many patients experiencing acute deterioration require intensive care treatment, particularly when respiratory failure is associated with hemodynamic instability, significant comorbidities or severe hypoxemia. However, mortality during hospitalization is high. Mechanical ventilation should be introduced only after carefully weighing the persons long-term prognosis and, whenever possible, the persons wishes. However, current guidelines discourage the use of mechanical ventilation in patients with respiratory failure secondary to IPF.

Prognosis
The clinical course of IPF can be unpredictable. IPF progression is associated with an estimated median survival time of 2 to 5 years following diagnosis.
The 5-year survival for IPF ranges between 20 and 40%, a mortality rate higher than that of a number of malignancies, including colon cancer, multiple myeloma and bladder cancer.Recently a multidimensional index and staging system has been proposed to predict mortality in IPF. The name of the index is GAP and is based on gender [G], age [A], and two lung physiology variables [P] (FVC and DLCO that are commonly measured in clinical practice to predict mortality in IPF. The highest stage of GAP (stage III) has been found to be associated with a 39% risk of mortality at 1 year. This model has also been evaluated in IPF and other ILDs and shown  good performance in predicting mortality in all main ILD subtypes. A modified ILD-GAP Index has been developed for application across ILD subtypes to provide disease-specific survival estimates. In IPF patients, the overall mortality at 5 years rate is high but the annual rate of all-cause mortality in patients with mild to moderate lung impairment is relatively low. This is the reason  why change in lung function (FVC) is usually measured in 1-year clinical trials of IPF treatments rather than survival.In addition to clinical and physiological parameters to predict how rapidly patients with IPF might progress, genetic and molecular features are also associated with IPF mortality. For example, it has been shown that IPF patients who have a specific genotype in the mucin MUC5B gene polymorphism (see above) experience slower decline in FVC and significantly improved survival. Even if such data are interesting from a scientific point of view, the application in the clinical routine of a prognostic model based on specific genotypes is still not possible.

Epidemiology
Although rare, IPF is the most common form of IIP.  The prevalence of IPF has been estimated between 14.0 and 42.7 per 100,000 persons based on a USA analysis of healthcare claims data, with variation depending on the case definitions used in this analyses. IPF is more common in men than in women and is usually diagnosed in people over 50 years of age.The incidence of IPF is difficult to determine as uniform diagnostic criteria have not been applied consistently. A recent study from the USA estimated the incidence of IPF to be between 6.8 and 16.3 per 100,000 persons </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 Hypokalemia and can you explain it in depth? [/INST] Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abnormal heart rhythm, which is often too slow and can cause cardiac arrest.Causes of hypokalemia include vomiting, diarrhea, medications like furosemide and steroids, dialysis, diabetes insipidus, hyperaldosteronism, hypomagnesemia, and not enough intake in the diet. Normal potassium levels are between 3.5 and 5.0 mmol/L (3.5 and 5.0 mEq/L) with levels below 3.5 mmol/L defined as hypokalemia. It is classified as severe when levels are less than 2.5 mmol/L. Low levels may also be suspected based on an electrocardiogram (ECG). Hyperkalemia is a high level of potassium in the blood serum.The speed at which potassium should be replaced depends on whether or not there are symptoms or abnormalities on an electrocardiogram. Potassium levels that are only slightly below the normal range can be managed with changes in the diet. Lower levels of potassium require replacement with supplements either taken by mouth or given intravenously. If given intravenously, potassium is generally replaced at rates of less than 20 mmol/hour. Solutions containing high concentrations of potassium (>40 mmol/L) should generally be given using a central venous catheter. Magnesium replacement may also be required.Hypokalemia is one of the most common water–electrolyte imbalances. It affects about 20% of people admitted to hospital. The word hypokalemia comes from hypo- under +  kalium potassium + -emia blood condition.

Signs and symptoms
Mild hypokalemia is often without symptoms, although it may cause elevation of blood pressure, and can provoke the development of an abnormal heart rhythm. Severe hypokalemia, with serum potassium concentrations of 2.5–3 meq/L (Nl: 3.5–5.0 meq/L), may cause muscle weakness, myalgia, tremor, and muscle cramps (owing to disturbed function of skeletal muscle), and constipation (from disturbed function of smooth muscle). With more severe hypokalemia, flaccid paralysis and hyporeflexia may result. Reports exist of rhabdomyolysis occurring with profound hypokalemia with serum potassium levels less than 2 meq/L. Respiratory depression from severe impairment of skeletal muscle function is found in some people.It can also cause psychotic as well as other mental symptoms, including hypokalemic sensory overstimulation.

Causes
Hypokalemia can result from one or more of these medical conditions:

Inadequate potassium intake
Not eating a diet with enough potassium-containing foods or fasting can cause the gradual onset of hypokalemia. This is a rare cause and may occur in those with anorexia nervosa or those on a ketogenic diet.

Gastrointestinal or skin loss
A more common cause is excessive loss of potassium, often associated with heavy fluid losses that flush potassium out of the body. Typically, this is a consequence of diarrhea, excessive perspiration, or losses associated with muscle-crush injury, or surgical procedures. Vomiting can also cause hypokalemia, although not much potassium is lost from the vomitus. Rather, heavy urinary losses of K+ in the setting of post-emetic bicarbonaturia force urinary potassium excretion. (See discussion of alkalosis below.) Other gastrointestinal causes include pancreatic fistulae and the presence of adenoma.

Urinary loss
Certain medications can cause excess potassium loss in the urine. Blood pressure medications such as loop diuretics (e.g. furosemide) and thiazide diuretics (e.g. hydrochlorothiazide) commonly cause hypokalemia. Other medications such as the antifungal amphotericin B or the cancer drug cisplatin can also cause long-term hypokalemia. Diuretic abuse among athletes and people with eating disorders may present with hypokalemia due to urinary potassium loss.
A special case of potassium loss occurs with diabetic ketoacidosis. Hypokalemia is observed with low total body potassium and a low intracellular concentration of potassium. In addition to urinary losses from polyuria and volume contraction, also an obligate loss of potassium from kidney tubules occurs as a cationic partner to the negatively charged ketone, β-hydroxybutyrate.
A low level of magnesium in the blood can also cause hypokalemia. Magnesium is required for adequate processing of potassium. This may become evident when hypokalemia persists despite potassium supplementation. Other electrolyte abnormalities may also be present.

An increase in the pH of the blood (alkalosis) can cause temporary hypokalemia by causing a shift of potassium out of the plasma and interstitial fluids into the urine via a number of interrelated mechanisms.1) Type B intercalated cells in the collecting duct reabsorb H+ and secrete HCO3, while in type A intercalated cells protons are secreted via both H+-K+ATPases and H+ ATP-ases on the apical/luminal surface of the cell. By definition, the H+-K+ATPase reabsorbs one potassium ion into the cell for every proton it secretes into the lumen of the collecting duct of a nephron. In addition, when H+ is expelled from the cell (by H+ATP-ase), cations—in this case potassium—are taken up by the cell in order to maintain electroneutrality (but not through direct exchange as with the H+-K+ATPase).  In order to correct the pH during alkalosis, these cells will use these mechanisms to reabsorb great amounts of H+, which will concomitantly increase their intracellular concentrations of potassium. This concentration gradient drives potassium to be secreted across the apical surface of the cell into the tubular lumen through potassium channels (this facilitated diffusion occurs in both Type B intercalated cells and Principal cells in the collecting duct).2) Metabolic alkalosis is often present in states of volume depletion, such as vomiting, so potassium is also lost via aldosterone-mediated mechanisms.3) During metabolic alkalosis, the acute rise of plasma HCO3− concentration (caused by vomiting, for example) will exceed the capacity of the renal proximal tubule to reabsorb this anion, and potassium will be excreted as an obligate cation partner to the bicarbonate.
Disease states that lead to abnormally high aldosterone levels can cause hypertension and excessive urinary losses of potassium. These include renal artery stenosis and tumors (generally nonmalignant) of the adrenal glands, e.g., Conns syndrome (primary hyperaldosteronism). Cushings syndrome can also lead to hypokalemia due to excess cortisol binding the Na+/K+ pump and acting like aldosterone. Hypertension and hypokalemia can also be seen with a deficiency of the 11-beta-hydroxysteroid dehydrogenase type 2 enzyme which allows cortisols to stimulate aldosterone receptors. This deficiency—known as apparent mineralocorticoid excess syndrome—can either be congenital or caused by consumption of glycyrrhizin, which is contained in extract of licorice, sometimes found in herbal supplements, candies, and chewing tobacco.
Rare hereditary defects of renal salt transporters, such as Bartter syndrome or Gitelman syndrome, can cause hypokalemia, in a manner similar to that of diuretics. As opposed to disease states of primary excesses of aldosterone, blood pressure is either normal or low in Bartters or Gitelmans.

Distribution away from extracellular fluid
In addition to alkalosis, other factors can cause transient shifting of potassium into cells, presumably by stimulation of the Na+/K+ pump. These hormones and medications include insulin, epinephrine, and other beta agonists (e.g. salbutamol or salmeterol), and xanthines (e.g. theophylline). Stimulants (amphetamines, methylphenidate, cocaine) can also cause hypokalemia by stimulating beta-2 receptors.
Rare hereditary defects of muscular ion channels and transporters that cause hypokalemic periodic paralysis can precipitate occasional attacks of severe hypokalemia and muscle weakness. These defects cause a heightened sensitivity to the normal changes in potassium produced by catecholamines and/or insulin and/or thyroid hormone, which lead to movement of potassium from the extracellular fluid into the muscle cells.

Other
A handful of published reports describe individuals with severe hypokalemia related to chronic extreme consumption (4–10 L/day) of colas. The hypokalemia is thought to be from the combination of the diuretic effect of caffeine and copious fluid intake, although it may also be related to diarrhea caused by heavy fructose ingestion.

Pseudohypokalemia
Pseudohypokalemia is a decrease in the amount of potassium that occurs due to excessive uptake of potassium by metabolically active cells in a blood sample after it has been drawn. It is a laboratory artifact that may occur when blood samples remain in warm conditions for several hours before processing.

Pathophysiology
About 98% of the bodys potassium is found inside cells, with the remainder in the extracellular fluid including the blood. This concentration gradient is maintained principally by the Na+/K+ pump.
Potassium is essential for many body functions, including muscle and nerve activity. The electrochemical gradient of potassium between the intracellular and extracellular space is essential for nerve function; in particular, potassium is needed to repolarize the cell membrane to a resting state after an action potential has passed. Lower potassium levels in the extracellular space cause hyperpolarization of the resting membrane potential. This hyperpolarization is caused by the effect of the altered potassium gradient on resting membrane potential as defined by the Goldman equation. As a result, a greater-than-normal stimulus is required for depolarization of the membrane to initiate an action potential.
In the heart, hypokalemia causes arrhythmias because of less-than-complete recovery from sodium-channel inactivation, making the triggering of an action potential less likely. In addition, the reduced extracellular potassium (paradoxically) inhibits the activity of the IKr potassium current and delays ventricular repolarization. This delayed repolarization may promote reentrant arrhythmias.

Diagnosis
Blood
Normal potassium levels are between 3.5 and 5.0 mmol/L with levels below 3.5 mmol/L (less than 3.5 mEq/L) defined as hypokalemia.

Electrocardiogram
Hypokalemia leads to characteristic ECG changes (PR prolongation, ST-segment and T-wave depression, U-wave formation).The earliest electrocardiographic (ECG) findings, associated with hypokalemia, are decreased T wave height. Then, ST depressions and T inversions appear as serum potassium levels reduce further. Due to prolonged repolarization of ventricular Purkinje fibers, prominent U waves occur (usually seen at V2 and V3 leads), frequently superimposed upon T waves, therefore producing the appearance of prolonged QT intervals, when serum potassium levels fall below 3 mEq/L.

Amount
The amount of potassium deficit can be calculated using the following formula:Kdeficit (in mmol) = (Knormal lower limit − Kmeasured) × body weight (kg) × 0.4
Meanwhile, the daily body requirement of potassium is calculated by multiplying 1 mmol to body weight in kilograms. Adding potassium deficit and daily potassium requirement would give the total amount of potassium need to be corrected in mmol. Dividing mmol by 13.4 will give the potassium in grams.

Treatment
Treatment includes addressing the cause, such as improving the diet, treating diarrhea, or stopping an offending medication. People without a significant source of potassium loss and who show no symptoms of hypokalemia may not require treatment. Acutely, repletion with 10 mEq of potassium is typically expected to raise serum potassium by 0.1 mEq/L immediately after administration. However, for those with chronic hypokalemia, repletion takes time due to tissue redistribution. For example, correction by 1 mEq/L can take more than 1000 mEq of potassium over many days.

Oral potassium supplementation
Mild hypokalemia (>3.0 mEq/L) may be treated by eating potassium-containing foods or by taking potassium chloride supplements in a tablet or syrup form (by mouth supplements). Foods rich in potassium include dried fruits (particularly dried figs), nuts, bran cereals and wheat germ, lima beans, molasses, leafy green vegetables, broccoli, winter squash, beets, carrots, cauliflower, potatoes, avocados, tomatoes, coconut water, citrus fruits (particularly oranges), cantaloupe, kiwis, mangoes, bananas, and red meats.Eating potassium-rich foods may not be sufficient for correcting low potassium; potassium supplements may be recommended. Potassium contained in foods is almost entirely coupled with phosphate and is thus ineffective in correcting hypokalemia associated with hypochloremia that may occur due to vomiting, diuretic therapy, or nasogastric drainage. Additionally, replacing potassium solely through diet may be costly and result in weight gain due to potentially large amounts of food needed. An effort should also be made to limit dietary sodium intake due to an inverse relationship with serum potassium. Increasing magnesium intake may also be beneficial for similar physiological reasons.Potassium chloride supplements by mouth have the advantage of containing precise quantities of potassium, but the disadvantages of a taste which may be unpleasant, and the potential for side-effects including nausea and abdominal discomfort. Potassium bicarbonate is preferred when correcting hypokalemia associated with metabolic acidosis.

Intravenous potassium replacement
Severe hypokalemia (<3.0 mEq/L) may require intravenous supplementation. Typically, a saline solution is used, with 20–40 meq/L KCl per liter over 3–4 hours. Giving IV potassium at faster rates (20–25 meq/hr) may inadvertently expose the heart to a sudden increase in potassium, potentially causing dangerous abnormal heart rhythms such as heart block or asystole. Faster infusion rates are therefore generally only performed in locations in which the heart rhythm can be continuously monitored such as a critical care unit. When replacing potassium intravenously, particularly when higher concentrations of potassium are used, infusion by a central line is encouraged to avoid the occurrence of a burning sensation at the site of infusion, or the rare occurrence of damage to the vein. When peripheral infusions are necessary, the burning can be reduced by diluting the potassium in larger amounts of fluid, or adding a small dose of lidocaine to the intravenous fluid, although adding lidocaine may increase the likelihood of medical errors. Even in severe hypokalemia, oral supplementation is preferred given its safety profile. Sustained-release formulations should be avoided in acute settings.

Potassium-sparing diuretics
Hypokalemia which is recurrent or resistant to treatment may be amenable to a potassium-sparing diuretic, such as amiloride, triamterene, spironolactone, or eplerenone. Concomitant hypomagnesemia will inhibit potassium replacement, as magnesium is a cofactor for potassium uptake.

Popular culture
The plot of the science fiction novel Destinys Road by Larry Niven centers around the settings scarcity of available potassium, and the resulting deficiency and its effects on the worlds colonists and their society.In the video game Deltarune, Queen expresses concern about one of the characters (Noelle) clipping into a wall and dying slowly from Hypokalemia.

See also
Bartter syndrome
Gitelman syndrome
Hypokalemic acidosis
Potassium deficiency (plant disorder)
Superior mesenteric artery syndrome

References
Further reading
Firth, J (2010). "Disorders of potassium homeostasis".  In David A. Warrell; Timothy M. Cox; John D. Firth; Graham S. Ogg (eds.). Oxford Textbook of Medicine. Vol. 1 (5th ed.). Oxford: Oxford University Press. pp. 3831–3845. doi:10.1093/med/9780199204854.003.210202_update_001 </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 Toxic megacolon and can you explain it in depth? [/INST] Toxic megacolon is an acute form of colonic distension. It is characterized by a very dilated colon (megacolon), accompanied by abdominal distension (bloating), and sometimes fever, abdominal pain, or shock.
Toxic megacolon is usually a complication of inflammatory bowel disease, such as ulcerative colitis and, more rarely, Crohns disease, and of some infections of the colon, including Clostridium difficile infections, which have led to pseudomembranous colitis. Other forms of megacolon exist and can be congenital (present since birth, such as Hirschsprungs disease). It can also be caused by Entamoeba histolytica and Shigella. It may also be caused by the use of loperamide.

Signs and symptoms
Abdominal pain
Abdominal bloating
Abdominal tenderness
Fever
Tachycardia (rapid heart rate)
DehydrationThere may be signs of septic shock. A physical examination reveals abdominal tenderness and possible loss of bowel sounds. An abdominal radiography shows colonic dilation. White blood cell count is usually elevated. Severe sepsis may present with hypothermia or leukopenia.

Complications
Perforation of the colon
Sepsis
ShockEmergency action may be required if severe abdominal pain develops, particularly if it is accompanied by fever, rapid heart rate, tenderness when the abdomen is pressed, bloody diarrhea, frequent diarrhea, or painful bowel movements.
Colonoscopy is contraindicated, as it may rupture the dilated colon resulting in peritonitis and septic shock.

Pathophysiology
The pathological process involves inflammation and damage to the colonic wall with unknown toxins breaking down the protective mucosal barrier and exposing the muscularis propria. There is relative destruction of the ganglion cells and swelling of the nerve fibers in the myenteric plexus, with concomitant damage to the colonic musculature. This results  in almost complete paralysis of the diseased segment of the colon with loss of smooth muscle substance, tone and motility. This can lead to further complications as pressure builds up in the colon due to relative fecal stasis including sepsis, intestinal hemorrhage or free perforation and spontaneous decompression.

Diagnosis
"Abdominal X-ray with the features of Air-fluid level can be shown or CT Scan with Contrast can be done if the patient is stable."

Treatment
The objective of treatment is to decompress the bowel and to prevent swallowed air from further distending the bowel. If decompression is not achieved or the patient does not improve within 24 hours, a colectomy (surgical removal of all or part of the colon) is indicated. When surgery is required the recommended procedure is a subtotal colectomy with end ileostomy </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 Methylenetetrahydrofolate reductase deficiency and can you explain it in depth? [/INST] Methylenetetrahydrofolate reductase deficiency is the most common genetic cause of elevated serum levels of homocysteine (hyperhomocysteinemia). It is caused by genetic defects in MTHFR, which is an important enzyme in the methyl cycle.Common variants of MTHFR deficiency are asymptomatic and have only minor effects on disease risk. Severe variants (from nonsense mutations) are vanishingly rare.

Symptoms
The common MTHFR deficiencies are usually asymptomatic, although the 677T variant can cause a mildly increased risk of some diseases.
For individuals homozygous in the 677T variant, there is a mildly elevated risk of thromboembolism (odds ratio 1.2), and stroke (odds ratio 1.26). There is also an elevated risk of neural tube defects among children of individuals with the C677T polymorphism (odds ratio 1.38).For cardiovascular risk, common MTHFR deficiencies were once thought to be associated but meta-analyses indicate that correlation this was an artifact of publication bias.

Causes
MTHFR is the rate-limiting enzyme in the methyl cycle, which includes the conversion of homocysteine into methionine. Defects in variants of MTHFR can therefore lead to hyperhomocysteinemia.There are two common variants of MTHFR deficiency. In the more significant of the two, the individual is homozygous for the 677T polymorphism. This variant in particular is the most common genetic cause of hyperhomocysteinemia. The resulting enzyme is thermolabile and in homozygotes, enzymatic activity is depressed to 35% of its usual level. The second variant is a milder one, caused by a homologous 1298C polymorphism </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 Catheter and can you explain it in depth? [/INST] In medicine, a catheter (/ˈkæθətər/) is a thin tube made from medical grade materials serving a broad range of functions. Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgical procedure. Catheters are manufactured for specific applications, such as cardiovascular, urological, gastrointestinal, neurovascular and ophthalmic procedures. The process of inserting a catheter is catheterization.
In most uses, a catheter is a thin, flexible tube (soft catheter) though catheters are available in varying levels of stiffness depending on the application. A catheter left inside the body, either temporarily or permanently, may be referred to as an "indwelling catheter" (for example, a peripherally inserted central catheter). A permanently inserted catheter may be referred to as a "permcath" (originally a trademark).
Catheters can be inserted into a body cavity, duct, or vessel, brain, skin or adipose tissue. Functionally, they allow drainage, administration of fluids or gases, access by surgical instruments, and also perform a wide variety of other tasks depending on the type of catheter. Special types of catheters, also called probes, are used in preclinical or clinical research for sampling of lipophilic and hydrophilic compounds, protein-bound and unbound drugs, neurotransmitters, peptides and proteins, antibodies, nanoparticles and nanocarriers, enzymes and vesicles.

Etymology
"Catheter" (from Greek καθετήρ kathetḗr) comes from the Greek verb καθίεμαι kathíemai, meaning "to thrust into" or "to send down" because the catheter allowed fluid to be "sent down" from the body.

Uses
Placement of a catheter into a particular part of the body may allow:

Draining urine from the urinary bladder as in urinary catheterization, using intermittent catheters or Foley catheter inserted through urethra. When the urethra is damaged, suprapubic catheterisation is used instead. The suprapubic catheter is inserted through the lower part of the abdomen directly into the urinary bladder.
drainage of urine from the kidney by percutaneous (through the skin) nephrostomy
drainage of fluid collections, e.g. an abdominal abscess
pigtail catheter: used to drain air from around the lung (pneumothorax)
administration of intravenous fluids, medication or parenteral nutrition with a peripheral venous catheter or central venous catheter
angioplasty, angiography, balloon septostomy, balloon sinuplasty, cardiac electrophysiology testing, catheter ablation. Often the Seldinger technique is used.
direct measurement of blood pressure in an artery or vein
direct measurement of intracranial pressure
administration of anaesthetic medication into the epidural space, the subarachnoid space, or around a major nerve bundle such as the brachial plexus
transfer of fertilized embryos, from in vitro fertilization, or sperm, during artificial insemination, into the uterus
administration of oxygen, volatile anesthetic agents, and other breathing gases into the lungs using a tracheal tube
subcutaneous administration of insulin or other medications, with the use of an infusion set and insulin pump

History
Ancient inventors
Ancient Chinese used onion stalks, the Romans, Hindus, and Greeks used tubes of wood or precious metals.The ancient Syrians created catheters from reeds.

Modern
The earliest invention of the flexible catheter was during the 18th century. Extending his inventiveness to his familys medical problems, Benjamin Franklin invented the flexible catheter in 1752 when his brother John suffered from bladder stones. Franklins catheter was made of metal with segments hinged together with a wire enclosed to provide rigidity during insertion.According to a footnote in his letter in Volume 4 of the Papers of Benjamin Franklin (1959), Franklin credits Francesco Roncelli-Pardino from 1720 as the inventor of a flexible catheter. In fact, Franklin claims the flexible catheter may have been designed even earlier.An early modern application of the catheter was employed by Claude Bernard for the purpose of cardiac catheterization in 1844. The procedure involved entering a horses ventricles via the jugular vein and carotid artery. This appears to be an earlier and modern application of the catheter because this catheter approach technique is still performed by neurosurgeons, cardiologists, and cardiothoracic surgeons.David S. Sheridan invented the modern disposable catheter in the 1940s.  Prior to this, some reusable catheters consisted of braided cotton tubes, which were varnished, heat-treated and polished. As these were primarily produced in France, the advent of World War II threatened the supply chain.In 1959, Teschan first described central venous catheter as means of blood vessel access for haemodialysis.Other reusable catheters consisted of red rubber tubes. Although sterilized prior to reuse, they still posed a high risk of infection and often led to the spread of disease.: 142 In 1982, Quinton together with Dr Sakharam Mahurkar, a nephrologist at County Cook Hospital in Chicago, developed dual-lumen catheter which became the standard for haemodialysis and apheresis.Sheridan was dubbed the "Catheter King" by Forbes magazine in 1988. He also invented the modern "disposable" plastic endotracheal tube now used routinely in surgery.

Materials
Urinary catheters
A range of polymers are used for the construction of catheters, including silicone rubber, nylon, polyurethane, polyethylene terephthalate (PET), latex, and thermoplastic elastomers. Silicone is one of the most common implantable choice because it is inert and unreactive to body fluids and a range of medical fluids with which it might come into contact. On the other hand, the polymer is weak mechanically, and a number of serious fractures have occurred in catheters. For example, silicone is used in Foley catheters where fractures have been reported, often requiring surgery to remove the tip left in the bladder.
There are many different types of catheters for bladder problems. A typical modern intermittent catheter is made from polyurethane and comes in different lengths and sizes for men, women and children.Some catheters are packed in a sterile saline solution.

Catheters used in interventional procedures
Polyimides are used to manufacture vascular catheters for insertion into small vessels in the neck, head and brain.Guiding catheters (catheters that guides angioplasty balloons and stents) is made up of polytetrafluoroethylene (PTFE) innermost layer which is lubricant, followed by stainless steel braid wire outer layer which helps to provide support for the catheter and prevent kinking while travelling through blood vessels, and Nylon elastomer outermost layer which provides extra support for the catheter and preserve the curvature of the catheter while passing through tortuous vessels.Some catheters have a thin hydrophilic surface coating.  When immersed in water this coating swells to a smooth, slippery film making the catheter safer and more comfortable to insert. Since this wire is too slippery to handle,  torque devices are used to control the direction and spin the wire. It is useful in subintimal angioplasty. However, care should be taken as it can easily cause dissection of vascular wall.

Interventional procedures
Diagnostic catheters
There are various catheters used in angiography procedures. Diagnostic catheters direct wires through blood vessels. Radiocontrast agent is then injected through the catheter to visualise the vessels via various imaging methods such as computed tomography (CT), projectional radiography, and fluoroscopy. Pigtail catheter is a non-selective catheter with multiple side holes that can deliver large volumes of contrast into a blood vessel for imaging purposes. Cobra catheter is a selective catheter used to catheterise downgoing vessels in the abdomen. Cobra catheters move forward by pushing and are removed by pulling. Sidewinder catheter is a selective catheter is used to navigate the aorta. Headhunter, Newton, Simmons, Bentson, and Berenstein catheters are used to navigate the into one of the three branches of the arch of aorta </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 Merkel-cell carcinoma and can you explain it in depth? [/INST] Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer occurring in about 3 people per 1,000,000 members of the population. It is also known as cutaneous APUDoma, primary neuroendocrine carcinoma of the skin, primary small cell carcinoma of the skin, and trabecular carcinoma of the skin. Factors involved in the development of MCC include the Merkel cell polyomavirus (MCPyV or MCV), a weakened immune system, and exposure to ultraviolet radiation. Merkel-cell carcinoma usually arises on the head, neck, and extremities, as well as in the perianal region and on the eyelid. It is more common in people over 60 years old, Caucasian people, and males. MCC is less common in children.

Signs and symptoms
Merkel cell carcinoma (MCC) usually presents as a firm nodule (up to 2 cm diameter) or mass (>2 cm diameter). These flesh-colored, red, or blue tumors typically vary in size from 0.5 cm (less than one-quarter of an inch) to more than 5 cm (2 inches) in diameter and may enlarge rapidly. Tumors can present as painless, tender or itchy, and other MCC manifestations as papules or plaques have also been reported. Although MCC may arise almost anywhere on the body, it is most commonly found in sun-exposed areas such as the head, neck or extremities. Five key attributes of MCC were summarized in 2008 in the acronym AEIOU (Asymptomatic/lack of tenderness, Expanding rapidly, Immune suppression, Older than 50 years, and Ultraviolet-exposed site on a person with fair skin). Ninety percent of MCCs have three or more of those features.
MCC is sometimes mistaken for other histological types of cancer, including basal cell carcinoma, squamous cell carcinoma, malignant melanoma, lymphoma, and small cell carcinoma, or as a benign cyst.  Merkel cell carcinomas have been described in children, however pediatric cases are very rare.Merkel-cell cancers tend to invade locally, infiltrating the underlying subcutaneous fat, fascia, and muscle, and typically metastasize early in their natural history, most often to the regional lymph nodes. MCCs also spread aggressively through the blood vessels to many organs, particularly to liver, lung, brain, and bone.

Pathophysiology
Cell of origin
Although MCC was initially named for the Merkel cell due to histologic and physiologic similarities between MCC and Merkel cells, the cellular progenitor of MCC has been a heavily debated question. Merkel cells are highly specialized cells that act as pressure receptors in the epidermis. The origin of Merkel cells themselves is debated and proposed to be derived from neural crest cells or epidermal progenitors. MCC is similar to Merkel cells in its histological appearance (see below: Diagnosis) and shares many immunohistochemical markers with Merkel cells, including epidermal marker cytokeratin 20 and neuroendocrine markers synaptophysin and chromogranin A. Furthermore, the ion channel Piezo2 and transcription factor Atoh1, both specific to Merkel cells, are also expressed by MCC. However, Merkel cells are post-mitotic cells with a low probability of cancerous transformation. Additionally, they have not been shown to support Merkel-cell polyoma virus infection, which is believed to drive oncogenesis in approximately 80% of MCC.Instead, it has been proposed the MCC may originate from a Merkel cell precursor, at which point it gains features similar to those of Merkel cells. One such precursor is the human fibroblast. Evidence for a fibroblast precursor includes its location in the dermis, which is thought to be the primary site of origin for MCC. Additionally, in vitro experiments have demonstrated that fibroblasts not only support Merkel cell polyomavirus (MCV) infection but can be induced into having a MCC phenotype by the expression of viral proteins.However, others have argued that MCC likely derives from an epithelial precursor cell due to its frequent presence in mixed tumors including epithelial neoplasms such as squamous cell carcinoma. While epithelial cells are not typically found in the dermis, hair follicles include epithelial cells that have been shown to have oncogenic potential, and have therefore been proposed as a possible site for a MCC precursor.Finally, the presence of B-cell surface markers on MCC in addition to the high correlation between MCC and B-cell lymphomatous cancers have also led to suggestions that MCC may share a progenitor with B-cells. Because of the differences in physiology and prognosis between MCV+ and MCV- MCC (see below), however, some have suggested that these two subtypes of MCC may actually derive from different progenitor cells.Several factors are involved in the pathophysiology of MCC, including MCV, ultraviolet radiation (UV) exposure, and weakened immune function.

Merkel cell polyomavirus
The MCV is a small double-stranded DNA virus that is believed to contribute to the development of the majority of MCC. About 80% of MCC tumors are infected with MCV, with the virus integrated into the host genome in a monoclonal pattern. However, the majority of people with MCV infection do not develop MCC: MCV is a ubiquitous virus and infection commonly occurs during childhood but remains asymptomatic throughout an individuals lifetime.MCC was first believed to be associated with MCV when it was observed to occur at a much higher rate in HIV patients during the 1980s. Since then, studies have demonstrated integration of the MCV genome into the genome of MCC tumor cells. Central to the our understanding of the pathogenicity of MCV are two viral proteins expressed in infected cells known as the large tumor antigen (LT) and small tumor antigen (sT). Normally, patients infected with MCV show low levels of antibodies to the LT protein, perhaps due to a nuclear localization domain in its C-terminal that limits its cellular dispersion. However, integration of the viral genome into the host genome can result in truncation of the LT protein proximal to this domain. This serves two oncogenic purposes: first, it prevents successful viral replication that would culminate in lysis of the infected cell. Second, it redistributes the LT protein to the cytoplasm, where it can interact with cytoplasmic signaling. The N-terminal LXCXE motif of the LT protein has been shown to interact with known oncogene Rb and is conserved in other cancer-causing viruses. Studies suggest that LT may also preserve cell proliferation signals such as c-Myc and cyclin E and cause DNA injury to the p53 tumor suppressor.Meanwhile, sT has been shown to induce cell proliferation through hyper-phosphorylation of the translation initiator 4EBP1 as well as inhibition of a ubiquitin ligase complex responsible for degradation of cellular proliferation signals. sT also contains a region known as the LT stabilization domain (LSD), which potentiates the LT proteins oncogenic function. Unlike LT, MCC samples have been identified that express sT alone, and sT expression in fibroblasts has been shown to cause MCC phenotype development.

UV light
About 20% of MCC tumors are MCV negative. In contrast to MCV-induced MCC, these tumors tend to have much higher mutational burdens with mutational signatures characteristic of UV damage. Genes frequently mutated in MCV-negative MCC include p53 and Rb, among others. The link between MCC and UV exposure has been demonstrated through various epidemiological studies indicating a higher incidence of MCC in fair-skinned people in areas of high UV exposure, as well as among those receiving UV phototherapy. The typical distribution of MCC in sun-exposed regions and its co-occurrence with other skin cancers also indicate that UV exposure is a contributing factor to MCC development. It is unclear whether this is through direct mutational impact, immune down-regulation, or some combination of the two.

Immunosuppression
The incidence of MCC is increased in conditions with defective immune functions such as malignancy, HIV infection, and organ transplant patients, etc. Conversely, patients with brisk immune response have been shown to have improved prognoses. This is suspected to be due to the inability of the body to defend itself from infection by or reactivation of MVC. The body of data indicating the importance of immune function in MCC pathogenesis has been exploited for the development of immunotherapies discussed below.

Diagnosis
Diagnosis of MCC begins with a clinical examination of the skin and lymph nodes. Following clinical exam, definitive diagnosis of Merkel cell carcinoma (MCC) requires examination of biopsy tissue to identify its histopathologic features. An ideal biopsy specimen is either a punch biopsy or a full-thickness incisional biopsy of the skin including full-thickness dermis and subcutaneous fat. On light microscopy, MCC shows basaloid tumor nests with neuroendocrine features ("salt and pepper" chromatin, scarce cytoplasm, and brisk mitotic activity). In addition to standard examination under light microscopy, immunohistochemistry (IHC) is also generally required to differentiate MCC from other morphologically similar tumors such as small cell lung cancer, the small cell variant of melanoma, various cutaneous leukemic/lymphoid neoplasms, and Ewings sarcoma. Neuroendocrine molecular markers such as synaptophysin or chromogranin A are characteristic of MCC and other neuroendocrine tumors, while other markers such as PAX5 or cytokeratin 20 can distinguish MCC from these tumors. Longitudinal imaging may also help in ruling out a diagnosis of metastatic small cell lung cancer. Once an MCC diagnosis is made, a sentinel lymph node biopsy as well as other imaging is recommended as a part of the staging work-up needed to determine prognosis and subsequent treatment options.

Prevention
Sunlight exposure is thought to be one of the causes of Merkel cell carcinoma (MCC). The World Health Organization, American Academy of Dermatology, and Skin Cancer Foundation recommend the following measures to prevent excessive UV exposure and skin cancer:
Limiting sun exposure between the hours of 10am and 4pm, when UV rays are the strongest
Seeking shade when UV rays are most intense
Wearing sun-protective clothing including a wide brim hat, sunglasses, and tightly woven, loose-fitting clothing
Using sunscreen
Avoiding tanning beds and artificial UV exposure

Treatment
MCC is rare and expedient referral to radiation oncology is critical. MCC will quickly relapse following any attempted excisional biopsy.

Surgery
The first step and primary goal of surgical treatment is to obtain negative histologic margins with 1-cm to 2-cm margins. Retrospective analyses of data from the National Comprehensive Database (NCDB) suggest no difference in the overall and relative survival of patients with stage I to II MCC who were treated with wide local excision versus MMS.

Radiation
Radiation therapy is the primary management of Merkel cell carcinoma (MCC). The largest series we have are from Australia and have demonstrated that radiotherapy alone achieves equal outcomes with upfront or neoadjuvant surgery followed by radiation therapy. The role of surgery is largely historical and relegated to biopsy. There have been no head-to-head trials comparing the two treatment strategies, and in the absence of this, surgeons tend to most commonly perform excisional biopsy prior to referring for radiation therapy to eradicate MCC. MCC is exquisitely radiosensitive. The conclusion amongst published studies in the Radiation Oncology community is that MCC should be managed ideally with radiation therapy alone.

Chemotherapy
Because of its significant adverse effects, traditional chemotherapy has been saved for late-stage highly metastasized cases of MCC. While some chemotherapeutic regiments have been shown to have transient effects, studies have not found any significant long-term effect on recurrence rate or life expectancy. As of 2015, there were no FDA-approved standard chemotherapy regimens for MCC treatment. The most recent American guidelines do not recommend adjuvant chemotherapy, citing a lack of evidence to suggest improved outcomes. Instead, consideration of the need for chemotherapy on a case-by-case basis is recommended.

Drug therapy
Immunotherapies, namely inhibitors of the PD1-PDL1 checkpoint signaling pathway, are novel anticancer agents that have shown benefit in advanced-stage MCC or chemotherapy-resistant MCC. The PD-1 pathway is responsible for regulating the balance between T-cell activation and over-activation leading to T-cell exhaustion or autoimmunity. However, over-expression of PD-1 ligands (PDL1) have been observed in tumors as a method of evading immune attack. PD-1 inhibition therefore enhances the bodys immune response, enabling it to target cancer cells for destruction. Due to their side effects, however, National Comprehensive Cancer Network guidelines recommend PD-1 inhibitors for people with disseminated rather than early-stage MCC.PD1/PDL1 pathway inhibitors approved or in clinical trials for use in MCC treatment include:

In March 2017, the U.S. Food and Drug Administration granted accelerated approval to avelumab, a PDL1 inhibitor, to treat adults and children above 12 years with metastatic MCC.
In December 2018, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co. Inc.) for all ages (adults and pediatrics) with recurrent locally advanced or metastatic Merkel cell carcinoma
Nivolumab (brand name Opdivo, Bristol-Myers Squibb) is in phase III/IV clinical trials
Ipilimumab (brand name Yervoy, Bristol-Myers Squibb) is in phase II clinical trials for use in adults with metastatic MCC.Studies to date have shown a clinical response rate between 50 and 65% for MCC treated with PD-1 pathway inhibitors. Suggestions for further immunotherapy research areas have included therapeutic vaccines or epigenetic modification of HLA-receptors.

Prognosis
According to the American Joint Committee on Cancer (AJCC), the natural course of MCC is "variable and depends heavily on the stage at diagnosis". Staging of MCC is classified according to the TNM staging system, a notation system that describes the stage of cancer according to the size of the primary tumor (T), the degree of spread to regional lymph nodes (N), and the presence of distant metastasis (M). A combination of T, N, and M stages dictate the final clinical stage group (0, I, IIA, IIB, IIIA, IIIB, IV). Advanced stage (i.e. increased size of the tumor, spreading of the tumor into surrounding and/or distant tissue, and involvement of lymph nodes) is associated with lower survival rates.The National Cancer Data Base has survival rates collected from nearly 3000 MCC patients from year 1996–2000 with 5-year survival rates listed as follows:Stage IA: 80%.   Stage IB: 60%.
Stage IIA: 60%.    Stage IIB: 50%.   Stage IIC: 50%.
Stage IIIA: 45%.     Stage IIIB: 25%.
Stage IV:  20%.
5 yr survival may be 51% among people with localized disease, 35% for those with nodal disease, and 14% with metastases to a distant site.Several other features may also affect prognosis, independent of tumor stage. They include MCV viral status, histological features, and immune status. In viral status, MCV large tumor antigen (LT antigen) and retinoblastoma protein (RB protein) expression correlates with more favorable prognosis, while p63 expression correlates with a poorer prognosis. Histological features such as intratumoral CD8+ T lymphocyte infiltration may be associated with a favorable prognosis, while lymphovascular infiltrative pattern may be associated with a poorer prognosis. Immune status, especially T cell immunosuppression (e.g., organ transplant, HIV infection, certain malignancy) predicts poorer prognosis and higher mortality.The antibody titer in the blood to the Merkel cell polyomavirus oncoprotein can be used as a treatment response biomarker in people that have detectable antibodies at the time of diagnosis.

Epidemiology
Merkel cell carcinoma occurs most often in Caucasians between 60 and 80 years of age. Its incidence is about twice as high in males as in females. It is a rare type of skin cancer, with a 2013 incidence of only 0.7 per 100,000 persons in the U.S. As of 2005, roughly 2,500 new cases of MCC are diagnosed each year in the United States, as compared to around 60,000 new cases of malignant melanoma and over 1 million new cases of nonmelanoma skin cancer. Similar to melanoma, the incidence of MCC in the US is increasing rapidly </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 Portal hypertension and can you explain it in depth? [/INST] Portal hypertension is abnormally increased portal venous pressure – blood pressure in the portal vein and its branches, that drain from most of the intestine to the liver. Portal hypertension is defined as a hepatic venous pressure gradient greater than 5 mmHg. Cirrhosis (a form of chronic liver failure) is the most common cause of portal hypertension; other, less frequent causes are therefore grouped as non-cirrhotic portal hypertension. When it becomes severe enough to cause symptoms or complications, treatment may be given to decrease portal hypertension itself or to manage its complications.

Signs and symptoms
Signs and symptoms of portal hypertension include:

Ascites (free fluid in the peritoneal cavity),Abdominal pain or tenderness  (when bacteria infect the ascites, as in spontaneous bacterial peritonitis).
Increased spleen size (splenomegaly), which may lead to lower platelet counts (thrombocytopenia)
Anorectal varices
Swollen veins on the anterior abdominal wall (sometimes referred to as caput medusae) In addition, a widened (dilated) portal vein as seen on a CT scan or MRI may raise the suspicion about portal hypertension. A cutoff value of 13 mm is widely used in this regard, but the diameter is often larger than this is in normal individuals as well.

Causes
The causes for portal hypertension are classified as originating in the portal venous system before it reaches the liver (prehepatic causes), within the liver (intrahepatic) or between the liver and the heart (post-hepatic). The most common cause is cirrhosis (chronic liver failure). Other causes include:Prehepatic causes

Portal vein thrombosis
Splenic vein thrombosis
Arteriovenous fistula (increased portal blood flow)
Splenomegaly and/or hypersplenism (increased portal blood flow)Hepatic causes

Cirrhosis of any cause.
alcohol use disorder
chronic viral hepatitis
biliary atresia
Primary biliary cirrhosis
Primary sclerosing cholangitis
Chronic pancreatitis
Hereditary haemorrhagic telangiectasia
Schistosomiasis
Congenital hepatic fibrosis
Nodular regenerative hyperplasia
Fibrosis of space of Disse
Granulomatous or infiltrative liver diseases (Gaucher disease, mucopolysaccharidosis, sarcoidosis, lymphoproliferative malignancies, amyloidosis, etc.)
Toxicity (from arsenic, copper, vinyl chloride monomers, mineral oil, vitamin A, azathioprine, dacarbazine, methotrexate, amiodarone, etc.)
Viral hepatitis
Fatty liver disease
Veno-occlusive diseasePosthepatic causes

Inferior vena cava obstruction
Right-sided heart failure, e.g. from constrictive pericarditis
Budd–Chiari syndrome also known as hepatic vein thrombosis

Pathophysiology
The pathophysiology of portal hypertension is indicated by increased vascular resistance via different causes; additionally, hepatic stellate cells and myofibroblasts are activated. Increased endogenous vasodilators in turn promote more blood flow in the portal veins.Nitric oxide is an endogenous vasodilator and it regulates intrahepatic vascular tone (it is produced from L-arginine). Nitric oxide inhibition has been shown in some studies to increase portal hypertension and hepatic response to norepinephrine.

Diagnosis
Ultrasonography (US) is the first-line imaging technique for the diagnosis and follow-up of portal hypertension because it is non-invasive, low-cost and can be performed on-site.A dilated portal vein (diameter of greater than 13 or 15 mm) is a sign of portal hypertension, with a sensitivity estimated at 12.5% or 40%. On Doppler ultrasonography, a slow velocity of <16 cm/s in addition to dilatation in the main portal vein are diagnostic of portal hypertension. Other signs of portal hypertension on ultrasound include a portal flow mean velocity of less than 12 cm/s, porto–systemic collateral veins (patent paraumbilical vein, spleno–renal collaterals and dilated left and short gastric veins), splenomegaly and signs of cirrhosis (including nodularity of the liver surface).The hepatic venous pressure gradient (HVPG) measurement has been accepted as the gold standard for assessing the severity of portal hypertension </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 Polymyalgia rheumatica and can you explain it in depth? [/INST] Polymyalgia rheumatica (PMR) is a syndrome experienced as pain or stiffness, usually in the neck, shoulders, upper arms, and hips, but which may occur all over the body. The pain can be sudden, or can occur gradually over a period. Most people with PMR wake up in the morning with pain in their muscles; however, cases have occurred in which the person has developed the pain during the evenings or has pain and stiffness all day long.People who have polymyalgia rheumatica may also have temporal arteritis (giant cell arteritis), an inflammation of blood vessels in the face which can cause blindness if not treated quickly. The pain and stiffness can result in a lowered quality of life, and can lead to depression. It is thought to be brought on by a viral or bacterial illness or trauma of some kind, but genetics play a role as well. Persons of Northern European descent are at greater risk. There is no definitive laboratory test, but C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can be useful.
PMR is usually treated with corticosteroids taken by mouth. Most people need to continue the corticosteroid treatment for two to three years. PMR sometimes goes away on its own in a year or two, but medications and self-care measures can improve the rate of recovery.PMR was first established as a distinct disease in 1966 by a case report on 11 patients at Mount Sinai Hospital in New York, NY. It takes its name from the Greek word Πολυμυαλγία polymyalgia, which means "pain in many muscles".

Signs and symptoms
A wide range of symptoms can indicate if a person has polymyalgia rheumatica. The classic symptoms include:
Pain and stiffness (moderate to severe) in the neck, shoulders, upper arms, thighs, and hips, which inhibits activity, especially in the morning/after sleeping. Pain can also occur in the groin area and in the buttocks. The pain can be limited to one of these areas as well.  It is a disease of the "girdles" meaning shoulder girdle or pelvic girdle.
Fatigue and lack of appetite (possibly leading to weight loss)
Anemia
An overall feeling of illness or flu-like symptoms.
Low-grade (mild) fever or abnormal temperature is sometimes present.
In most people, it is characterized by constant fatigue, weakness and sometimes exhaustion.About 15% of people who are diagnosed with polymyalgia rheumatica also have temporal arteritis, and about 50% of people with temporal arteritis have polymyalgia rheumatica. Some symptoms of temporal arteritis include headaches, scalp tenderness, jaw or facial soreness, distorted vision, or aching in the limbs caused by decreased blood flow, and fatigue.

Causes
The cause of PMR is not well understood. The pain and stiffness result from the activity of inflammatory cells and proteins that are normally a part of the bodys disease-fighting immune system, and the inflammatory activity seems to be concentrated in tissues surrounding the affected joints. During this disorder, the white blood cells in the body attack the lining of the joints, causing inflammation. Inherited factors also play a role in the probability that an individual will develop PMR. Several theories have included viral stimulation of the immune system in genetically susceptible individuals.Infectious diseases may be a contributing factor. This would be expected with sudden onset of symptoms, for example. In addition, new cases often appear in cycles in the general population, implying a viral connection. Studies are inconclusive, but several somewhat common viruses were identified as possible triggers for PMR. The viruses thought to be involved include the adenovirus, which causes respiratory infections; the human parvovirus B19, an infection that affects children; and the human parainfluenza virus. Some patients attribute the onset of PMR to stress.Persons having the HLA-DR4 type of human leucocyte antigen appear to have a higher risk of PMR.

Diagnosis
No specific test exists to diagnose polymyalgia rheumatica; many other diseases can cause inflammation and pain in muscles, but a few tests can help narrow down the cause of the pain. Limitation in shoulder motion, or swelling of the joints in the wrists or hands, are noted by the doctor. A patients answers to questions, a general physical exam, and the results of tests can help a doctor determine the cause of pain and stiffness.One blood test usually performed is the erythrocyte sedimentation rate (ESR) which measures how fast the patients red blood cells settle in a test tube </s>