<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 Cystic fibrosis and can you explain it in depth? [/INST] Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males. Different people may have different degrees of symptoms.Cystic fibrosis is inherited in an autosomal recessive manner. It is caused by the presence of mutations in both copies of the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Those with a single working copy are carriers and otherwise mostly healthy. CFTR is involved in the production of sweat, digestive fluids, and mucus. When the CFTR is not functional, secretions which are usually thin instead become thick. The condition is diagnosed by a sweat test and genetic testing. Screening of infants at birth takes place in some areas of the world.There is no known cure for cystic fibrosis. Lung infections are treated with antibiotics which may be given intravenously, inhaled, or by mouth. Sometimes, the antibiotic azithromycin is used long term. Inhaled hypertonic saline and salbutamol may also be useful. Lung transplantation may be an option if lung function continues to worsen. Pancreatic enzyme replacement and fat-soluble vitamin supplementation are important, especially in the young. Airway clearance techniques such as chest physiotherapy have some short-term benefit, but long-term effects are unclear. The average life expectancy is between 42 and 50 years in the developed world. Lung problems are responsible for death in 80% of people with cystic fibrosis.CF is most common among people of Northern European ancestry and affects about one out of every 3,000 newborns. About one in 25 people is a carrier. It is least common in Africans and Asians. It was first recognized as a specific disease by Dorothy Andersen in 1938, with descriptions that fit the condition occurring at least as far back as 1595. The name "cystic fibrosis" refers to the characteristic fibrosis and cysts that form within the pancreas.

Signs and symptoms
Cystic fibrosis typically manifests early in life. Newborns and infants with cystic fibrosis tend to have frequent, large, greasy stools (a result of malabsorption) and are underweight for their age. 15–20% of newborns have their small intestine blocked by meconium, often requiring surgery to correct. Newborns occasionally have neonatal jaundice due to blockage of the bile ducts. Children with cystic fibrosis lose excessive salt in their sweat, and parents often notice salt crystallizing on the skin, or a salty taste when they kiss their child.The primary cause of morbidity and death in people with cystic fibrosis is progressive lung disease, which eventually leads to respiratory failure. This typically begins as a prolonged respiratory infection that continues until treated with antibiotics. Chronic infection of the respiratory tract is nearly universal in people with cystic fibrosis, with Pseudomonas aeruginosa, fungi, and mycobacteria all increasingly common over time. Inflammation of the upper airway results in frequent runny nose and nasal obstruction. Nasal polyps are common, particularly in children and teenagers. As the disease progresses, people tend to have shortness of breath, and a chronic cough that produces sputum. Breathing problems make it increasingly challenging to exercise, and prolonged illness causes those affected to be underweight for their age. In late adolescence or adulthood, people begin to develop severe signs of lung disease: wheezing, digital clubbing, cyanosis, coughing up blood, pulmonary heart disease, and collapsed lung (atelectasis or pneumothorax).In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. Vitamin K is normally absorbed from breast milk, formula, and later, solid foods. This absorption is impaired in some CF patients. Young children are especially sensitive to vitamin K malabsorptive disorders because only a very small amount of vitamin K crosses the placenta, leaving the child with very low reserves and limited ability to absorb vitamin K from dietary sources after birth. Because clotting factors II, VII, IX, and X are vitamin K–dependent, low levels of vitamin K can result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation evaluation may be warranted to determine whether an underlying disease is present.

Lungs and sinuses
Lung disease results from clogging of the airways due to mucus build-up, decreased mucociliary clearance, and resulting inflammation. In later stages, changes in the architecture of the lung, such as pathology in the major airways (bronchiectasis), further exacerbate difficulties in breathing. Other signs include high blood pressure in the lung (pulmonary hypertension), heart failure, difficulties getting enough oxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks, such as bilevel positive airway pressure machines or ventilators. Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the three most common organisms causing lung infections in CF patients.: 1254  In addition, opportunistic infection due to Burkholderia cepacia complex can occur, especially through transmission from patient to patient.In addition to typical bacterial infections, people with CF more commonly develop other types of lung diseases. Among these is allergic bronchopulmonary aspergillosis, in which the bodys response to the common fungus Aspergillus fumigatus causes worsening of breathing problems. Another is infection with Mycobacterium avium complex, a group of bacteria related to tuberculosis, which can cause lung damage and do not respond to common antibiotics.Mucus in the paranasal sinuses is equally thick and may also cause blockage of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, and headaches. Individuals with CF may develop overgrowth of the nasal tissue (nasal polyps) due to inflammation from chronic sinus infections. Recurrent sinonasal polyps can occur in 10% to 25% of CF patients.: 1254  These polyps can block the nasal passages and increase breathing difficulties.Cardiorespiratory complications are the most common causes of death (about 80%) in patients at most CF centers in the United States.: 1254

Gastrointestinal
In addition, protrusion of internal rectal membranes (rectal prolapse) is more common, occurring in as many as 10% of children with CF, and it is caused by increased fecal volume, malnutrition, and increased intra–abdominal pressure due to coughing.The thick mucus seen in the lungs has a counterpart in thickened secretions from the pancreas, an organ responsible for providing digestive juices that help break down food. These secretions block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis). The pancreatic ducts are totally plugged in more advanced cases, usually seen in older children or adolescents. This causes atrophy of the exocrine glands and progressive fibrosis.Individuals with CF also have difficulties absorbing the fat-soluble vitamins A, D, E, and K.In addition to the pancreas problems, people with CF experience more heartburn, intestinal blockage by intussusception, and constipation. Older individuals with CF may develop distal intestinal obstruction syndrome, which occurs when feces becomes thick with mucus (inspissated) and can cause bloating, pain, and incomplete or complete bowel obstruction.Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF.: 1253  It is mainly associated with "severe" CFTR mutations, where both alleles are completely nonfunctional (e.g. ΔF508/ΔF508).: 1253  It occurs in 10% to 15% of patients with one "severe" and one "mild" CFTR mutation where little CFTR activity still occurs, or where two "mild" CFTR mutations exist.: 1253  In these milder cases, sufficient pancreatic exocrine function is still present so that enzyme supplementation is not required.: 1253  Usually, no other GI complications occur in pancreas-sufficient phenotypes, and in general, such individuals usually have excellent growth and development.: 1254  Despite this, idiopathic chronic pancreatitis can occur in a subset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominal pain and life-threatening complications.Thickened secretions also may cause liver problems in patients with CF. Bile secreted by the liver to aid in digestion may block the bile ducts, leading to liver damage. Impaired digestion or absorption of lipids can result in steatorrhea. Over time, this can lead to scarring and nodularity (cirrhosis). The liver fails to rid the blood of toxins and does not make important proteins, such as those responsible for blood clotting. Liver disease is the third-most common cause of death associated with CF.Around 5–7% of people experience liver damage severe enough to cause symptoms: typically gallstones causing biliary colic.

Endocrine
The pancreas contains the islets of Langerhans, which are responsible for making insulin, a hormone that helps regulate blood glucose. Damage to the pancreas can lead to loss of the islet cells, leading to a type of diabetes unique to those with the disease. This cystic fibrosis-related diabetes shares characteristics of type 1 and type 2 diabetes, and is one of the principal nonpulmonary complications of CF.Vitamin D is involved in calcium and phosphate regulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone disease osteoporosis in which weakened bones are more susceptible to fractures.

Infertility
Infertility affects both men and women. At least 97% of men with cystic fibrosis are infertile, but not sterile, and can have children with assisted reproductive techniques. The main cause of infertility in men with CF is congenital absence of the vas deferens (which normally connects the testes to the ejaculatory ducts of the penis), but potentially also by other mechanisms such as causing no sperm, abnormally shaped sperm, and few sperm with poor motility. Many men found to have congenital absence of the vas deferens during evaluation for infertility have a mild, previously undiagnosed form of CF. Around 20% of women with CF have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disrupts ovulation and causes a lack of menstruation.

Causes
CF is caused by a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, is a deletion (Δ signifying deletion) of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein. This mutation accounts for two-thirds (66–70%) of CF cases worldwide and 90% of cases in the United States; however, over 1500 other mutations can produce CF. Although most people have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF is considered an autosomal recessive disease.The CFTR gene, found at the q31.2 locus of chromosome 7, is 230,000 base pairs long, and creates a protein that is 1,480 amino acids long. More specifically, the location is between base pair 117,120,016 and 117,308,718 on the long arm of chromosome 7, region 3, band 1, subband 2, represented as 7q31.2. Structurally, the CFTR is a type of gene known as an ABC gene. The product of this gene (the CFTR protein) is a chloride ion channel important in creating sweat, digestive juices, and mucus. This protein possesses two ATP-hydrolyzing domains, which allows the protein to use energy in the form of ATP. It also contains two domains comprising six alpha helices apiece, which allow the protein to cross the cell membrane. A regulatory binding site on the protein allows activation by phosphorylation, mainly by cAMP-dependent protein kinase. The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction. The majority of CFTR in the lungs passages is produced by rare ion-transporting cells that regulate mucus properties.In addition, the evidence is increasing that genetic modifiers besides CFTR modulate the frequency and severity of the disease. One example is mannan-binding lectin, which is involved in innate immunity by facilitating phagocytosis of microorganisms. Polymorphisms in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a threefold higher risk of end-stage lung disease, as well as an increased burden of chronic bacterial infections.

Carriers
Up to one in 25 individuals of Northern European ancestry is considered a genetic carrier. The disease appears only when two of these carriers have children, as each pregnancy between them has a 25% chance of producing a child with the disease. Although only about one of every 3,000 newborns of the affected ancestry has CF, more than 900 mutations of the gene that causes CF are known. Current tests look for the most common mutations.The mutations screened by the test vary according to a persons ethnic group or by the occurrence of CF already in the family. More than 10 million Americans, including one in 25 white Americans, are carriers of one mutation of the CF gene. CF is present in other races, though not as frequently as in white individuals. About one in 46 Hispanic Americans, one in 65 African Americans, and one in 90 Asian Americans carry a mutation of the CF gene.

Pathophysiology
Several mutations in the CFTR gene can occur, and different mutations cause different defects in the CFTR protein, sometimes causing a milder or more severe disease. These protein defects are also targets for drugs which can sometimes restore their function. ΔF508-CFTR gene mutation, which occurs in >90% of patients in the U.S., creates a protein that does not fold normally and is not appropriately transported to the cell membrane, resulting in its degradation.Other mutations result in proteins that are too short (truncated) because production is ended prematurely. Other mutations produce proteins that do not use energy (in the form of ATP) normally, do not allow chloride, iodide, and thiocyanate to cross the membrane appropriately, and degrade at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced.The protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body.
The protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid. This channel is primarily responsible for controlling the movement of halide anions from inside to outside of the cell; however, in the sweat ducts, it facilitates the movement of chloride from the sweat duct into the cytoplasm. When the CFTR protein does not resorb ions in sweat ducts, chloride and thiocyanate released from sweat glands are trapped inside the ducts and pumped to the skin.
Additionally hypothiocyanite, OSCN, cannot be produced by the immune defense system. Because chloride is negatively charged, this modifies the electrical potential inside and outside the cell that normally causes cations to cross into the cell. Sodium is the most common cation in the extracellular space. The excess chloride within sweat ducts prevents sodium resorption by epithelial sodium channels and the combination of sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals with CF. This lost salt forms the basis for the sweat test.Most of the damage in CF is due to blockage of the narrow passages of affected organs with thickened secretions. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick feces, etc. Several theories have been posited on how the defects in the protein and cellular function cause the clinical effects. The most current theory suggests that defective ion transport leads to dehydration in the airway epithelia, thickening mucus. In airway epithelial cells, the cilia exist in between the cells apical surface and mucus in a layer known as airway surface liquid (ASL). The flow of ions from the cell and into this layer is determined by ion channels such as CFTR. CFTR not only allows chloride ions to be drawn from the cell and into the ASL, but it also regulates another channel called ENac, which allows sodium ions to leave the ASL and enter the respiratory epithelium. CFTR normally inhibits this channel, but if the CFTR is defective, then sodium flows freely from the ASL and into the cell.As water follows sodium, the depth of ASL will be depleted and the cilia will be left in the mucous layer. As cilia cannot effectively move in a thick, viscous environment, mucociliary clearance is deficient and a buildup of mucus occurs, clogging small airways. The accumulation of more viscous, nutrient-rich mucus in the lungs allows bacteria to hide from the bodys immune system, causing repeated respiratory infections. The presence of the same CFTR proteins in the pancreatic duct and sweat glands in the skin also cause symptoms in these systems.

Chronic infections
The lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. These bacteria, which often spread among individuals with CF, thrive in the altered mucus, which collects in the small airways of the lungs. This mucus leads to the formation of bacterial microenvironments known as biofilms that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate. The natural history of CF lung infections and airway remodeling is poorly understood, largely due to the immense spatial and temporal heterogeneity both within and between the microbiomes of CF patients.Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such as S. aureus and H. influenzae colonize and infect the lungs. Eventually, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates. By 18 years of age, 80% of patients with classic CF harbor P. aeruginosa, and 3.5% harbor B. cepacia. Once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. Pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" Pseudomonas, which are rarely seen in people who do not have CF. Scientific evidence suggests the interleukin 17 pathway plays a key role in resistance and modulation of the inflammatory response during P. aeruginosa infection in CF. In particular, interleukin 17-mediated immunity plays a double-edged activity during chronic airways infection; on one side, it contributes to the control of P. aeruginosa burden, while on the other, it propagates exacerbated pulmonary neutrophilia and tissue remodeling.Infection can spread by passing between different individuals with CF. In the past, people with CF often participated in summer "CF camps" and other recreational gatherings. Hospitals grouped patients with CF into common areas and routine equipment (such as nebulizers) was not sterilized between individual patients. This led to transmission of more dangerous strains of bacteria among groups of patients. As a result, individuals with CF are now routinely isolated from one another in the healthcare setting, and healthcare providers are encouraged to wear gowns and gloves when examining patients with CF to limit the spread of virulent bacterial strains.CF patients may also have their airways chronically colonized by filamentous fungi (such as Aspergillus fumigatus, Scedosporium apiospermum, Aspergillus terreus) and/or yeasts (such as Candida albicans); other filamentous fungi less commonly isolated include Aspergillus flavus and Aspergillus nidulans (occur transiently in CF respiratory secretions) and Exophiala dermatitidis and Scedosporium prolificans (chronic airway-colonizers); some filamentous fungi such as Penicillium emersonii and Acrophialophora fusispora are encountered in patients almost exclusively in the context of CF. Defective mucociliary clearance characterizing CF is associated with local immunological disorders. In addition, the prolonged therapy with antibiotics and the use of corticosteroid treatments may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may contribute to the local inflammatory response and therefore to the progressive deterioration of the lung function, as often happens with allergic bronchopulmonary aspergillosis – the most common fungal disease in the context of CF, involving a Th2-driven immune response to Aspergillus species.

Diagnosis
In many localities all newborns are screened for cystic fibrosis within the first few days of life, typically by blood test for high levels of immunoreactive trypsinogen. Newborns with positive tests or those who are otherwise suspected of having cystic fibrosis based on symptoms or family history, then undergo a sweat test. An electric current is used to drive pilocarpine into the skin, stimulating sweating. The sweat is collected and analyzed for salt levels. Having unusually high levels of chloride in the sweat suggests CFTR is dysfunctional; the person is then diagnosed with cystic fibrosis. Genetic testing is also available to identify the CFTR mutations typically associated with cystic fibrosis. Many laboratories can test for the 30–96 most common CFTR mutations, which can identify over 90% of people with cystic fibrosis.People with CF have less thiocyanate and hypothiocyanite in their saliva and mucus (Banfi et al.). In the case of milder forms of CF, transepithelial potential difference measurements can be helpful. CF can also be diagnosed by identification of mutations in the CFTR gene.In many cases, a parent makes the diagnosis because the infant tastes salty. Immunoreactive trypsinogen levels can be increased in individuals who have a single mutated copy of the CFTR gene (carriers) or, in rare instances, in individuals with two normal copies of the CFTR gene. Due to these false positives, CF screening in newborns can be controversial.By 2010 every US state had instituted newborn screening programs   and as of 2016, 21 European countries had programs in at least some regions.

Prenatal
Women who are pregnant or couples planning a pregnancy can have themselves tested for the CFTR gene mutations to determine the risk that their child will be born with CF. Testing is typically performed first on one or both parents and, if the risk of CF is high, testing on the fetus is performed. The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant be tested to see if they are a carrier.Because development of CF in the fetus requires each parent to pass on a mutated copy of the CFTR gene and because CF testing is expensive, testing is often performed initially on one parent. If testing shows that parent is a CFTR gene mutation carrier, the other parent is tested to calculate the risk that their children will have CF. CF can result from more than a thousand different mutations. As of 2016, typically only the most common mutations are tested for, such as ΔF508 Most commercially available tests look for 32 or fewer different mutations. If a family has a known uncommon mutation, specific screening for that mutation can be performed. Because not all known mutations are found on current tests, a negative screen does not guarantee that a child will not have CF.During pregnancy, testing can be performed on the placenta (chorionic villus sampling) or the fluid around the fetus (amniocentesis). However, chorionic villus sampling has a risk of fetal death of one in 100 and amniocentesis of one in 200; a recent study has indicated this may be much lower, about one in 1,600.Economically, for carrier couples of cystic fibrosis, when comparing preimplantation genetic diagnosis (PGD) with natural conception (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net economic benefits up to a maternal age around 40 years, after which NC, prenatal testing, and abortion have higher economic benefit.

Management
While no cures for CF are known, several treatment methods are used. The management of CF has improved significantly over the past 70 years. While infants born with it 70 years ago would have been unlikely to live beyond their first year, infants today are likely to live well into adulthood. Recent advances in the treatment of cystic fibrosis have meant that individuals with cystic fibrosis can live a fuller life less encumbered by their condition. The cornerstones of management are the proactive treatment of airway infection, and encouragement of good nutrition and an active lifestyle. Pulmonary rehabilitation as a management of CF continues throughout a persons life, and is aimed at maximizing organ function, and therefore the quality of life. Occupational therapists use energy conservation techniques (ECT) in the rehabilitation process for patients with Cystic Fibrosis. Examples of energy conservation techniques are ergonomic principles, pursed lip breathing, and diaphragmatic breathing. Patients with CF tend to have fatigue and dyspnoea due to chronic pulmonary infections, so reducing the amount of energy spent during activities can help patients feel better and gain more independence. At best, current treatments delay the decline in organ function. Because of the wide variation in disease symptoms, treatment typically occurs at specialist multidisciplinary centers and is tailored to the individual. Targets for therapy are the lungs, gastrointestinal tract (including pancreatic enzyme supplements), the reproductive organs (including assisted reproductive technology), and psychological support.The most consistent aspect of therapy in CF is limiting and treating the lung damage caused by thick mucus and infection, with the goal of maintaining quality of life. Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time-consuming. Oxygen therapy at home is recommended in those with significant low oxygen levels. Many people with CF use probiotics, which are thought to be able to correct intestinal dysbiosis and inflammation, but the clinical trial evidence regarding the effectiveness of probiotics for reducing pulmonary exacerbations in people with CF is uncertain.

Antibiotics
Many people with CF are on one or more antibiotics at all times, even when healthy, to prophylactically suppress infection. Antibiotics are absolutely necessary whenever pneumonia is suspected or a noticeable decline in lung function is seen, and are usually chosen based on the results of a sputum analysis and the persons past response. This prolonged therapy often necessitates hospitalization and insertion of a more permanent IV such as a peripherally inserted central catheter or Port-a-Cath. Inhaled therapy with antibiotics such as tobramycin, colistin, and aztreonam is often given for months at a time to improve lung function by impeding the growth of colonized bacteria. Inhaled antibiotic therapy helps lung function by fighting infection, but also has significant drawbacks such as development of antibiotic resistance, tinnitus, and changes in the voice. Inhaled levofloxacin may be used to treat Pseudomonas aeruginosa in people with cystic fibrosis who are infected. The early management of Pseudomonas aeruginosa infection is easier and better, using nebulised antibiotics with or without oral antibiotics may sustain its eradication up to two years. When choosing antibiotics to treat CF patients with lung infections caused by Pseudomonas aeruginosa in people with cystic fibrosis, it is still unclear whether the choice of antibiotics should be based on the results of testing antibiotics separately (one at a time) or in combination with each other.Antibiotics by mouth such as ciprofloxacin or azithromycin are given to help prevent infection or to control ongoing infection. The aminoglycoside antibiotics (e.g. tobramycin) used can cause hearing loss, damage to the balance system in the inner ear or kidney failure with long-term use. To prevent these side-effects, the amount of antibiotics in the blood is routinely measured and adjusted accordingly.All these factors related to the antibiotics use, the chronicity of the disease, and the emergence of resistant bacteria demand more exploration for different strategies such as antibiotic adjuvant therapy. Currently, no reliable clinical trial evidence shows the effectiveness of antibiotics for pulmonary exacerbations in people with cystic fibrosis and Burkholderia cepacia complex or for the use of antibiotics to treat nontuberculous mycobacteria in people with CF.

Other medication
Aerosolized medications that help loosen secretions include dornase alfa and hypertonic saline. Dornase is a recombinant human deoxyribonuclease, which breaks down DNA in the sputum, thus decreasing its viscosity. Dornase alpha improves lung function and probably decreases the risk of exacerbations but there is insufficient evidence to know if it is more or less effective than other similar medications. Dornase alpha may improve lung function, however there is no strong evidence that it is better than other hyperosmolar therapies.Denufosol, an investigational drug, opens an alternative chloride channel, helping to liquefy mucus. Whether inhaled corticosteroids are useful is unclear, but stopping inhaled corticosteroid therapy is safe. There is weak evidence that corticosteroid treatment may cause harm by interfering with growth. Pneumococcal vaccination has not been studied as of 2014. As of 2014, there is no clear evidence from randomized controlled trials that the influenza vaccine is beneficial for people with cystic fibrosis.Ivacaftor is a medication taken by mouth for the treatment of CF due to a number of specific mutations responsive to ivacaftor-induced CFTR protein enhancement. It improves lung function by about 10%; however, as of 2014 it is expensive. The first year it was on the market, the list price was over $300,000 per year in the United States. In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor. In 2018, the FDA approved the combination ivacaftor/tezacaftor; the manufacturer announced a list price of $292,000 per year. Tezacaftor helps move the CFTR protein to the correct position on the cell surface, and is designed to treat people with the F508del mutation.In 2019, the combination drug elexacaftor/ivacaftor/tezacaftor marketed as Trikafta in the United States, was approved for CF patients over the age of 12. In 2021, this was extended to include patients over the age of 6. In Europe this drug was approved in 2020 and marketed as Kaftrio.   It is used in those that have a f508del mutation, which occurs in about 90% of patients with cystic fibrosis. According to the Cystic Fibrosis Foundation, "this medicine represents the single greatest therapeutic advancement in the history of CF, offering a treatment for the underlying cause of the disease that could eventually bring modulator therapy to 90 percent of people with CF." In a clinical trial, participants who were administered the combination drug experienced a subsequent 63% decrease in pulmonary exacerbations and a 41.8 mmol/L decrease in sweat chloride concentration. By mitigating a repertoire of symptoms associated with cystic fibrosis, the combination drug significantly improved quality-of-life metrics among patients with the disease as well. The combination drug is also known to interact with CYP3A inducers, such as carbamazepine used in the treatment of bipolar disorder, causing elexafaftor/ivacaftor/tezacaftor to circulate in the body at decreased concentrations. As such, concomitant use is not recommended. The list price in the US is going to be $311,000 per year; however, insurance may cover much of the cost of the drug.Ursodeoxycholic acid, a bile salt, has been used, however there is insufficient data to show if it is effective.

Nutrient supplementation
It is uncertain whether vitamin A or beta-carotene supplementation have any effect on eye and skin problems caused by vitamin A deficiency.There is no strong evidence that people with cystic fibrosis can prevent osteoporosis by increasing their intake of vitamin D.For people with vitamin E deficiency and cystic fibrosis, there is evidence that vitamin E supplementation may improve vitamin E levels, although it is still uncertain what effect supplementation has on vitamin E‐specific deficiency disorders or on lung function.Robust evidence regarding the effects of vitamin K supplementation in people with cystic fibrosis is lacking as of 2020.Various studies have examined the effects of omega-3 fatty acid supplementation for people with cystic fibrosis but the evidence is uncertain whether it has any benefits or adverse effects.

Procedures
Several mechanical techniques are used to dislodge sputum and encourage its expectoration. One technique good for short-term airway clearance is chest physiotherapy where a respiratory therapist percusses an individuals chest by hand several times a day, to loosen up secretions. This "percussive effect" can be administered also through specific devices that use chest wall oscillation or intrapulmonary percussive ventilator. Other methods such as biphasic cuirass ventilation, and associated clearance mode available in such devices, integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. These are portable and adapted for home use.Another technique is positive expiratory pressure physiotherapy that consists of providing a back pressure to the airways during expiration. This effect is provided by devices that consists of a mask or a mouthpiece in which a resistance is applied only on the expiration phase. Operating principles of this technique seems to be the increase of gas pressure behind mucus through collateral ventilation along with a temporary increase in functional residual capacity preventing the early collapse of small airways during exhalation.As lung disease worsens, mechanical breathing support may become necessary. Individuals with CF may need to wear special masks at night to help push air into their lungs. These machines, known as bilevel positive airway pressure (BiPAP) ventilators, help prevent low blood oxygen levels during sleep. Non-invasive ventilators may be used during physical therapy to improve sputum clearance. It is not known if this type of therapy has an impact on pulmonary exacerbations or disease progression. It is not known what role non-invasive ventilation therapy has for improving exercise capacity in people with cystic fibrosis. However, the authors noted that "non‐invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with cystic fibrosis who have difficulty expectorating sputum." During severe illness, a tube may be placed in the throat (a procedure known as a tracheostomy) to enable breathing supported by a ventilator.For children, preliminary studies show massage therapy may help people and their families quality of life.Some lung infections require surgical removal of the infected part of the lung. If this is necessary many times, lung function is severely reduced. The most effective treatment options for people with CF who have spontaneous or recurrent pneumothoraces is not clear.

Transplantation
Lung transplantation may become necessary for individuals with CF as lung function and exercise tolerance decline. Although single lung transplantation is possible in other diseases, individuals with CF must have both lungs replaced because the remaining lung might contain bacteria that could infect the transplanted lung. A pancreatic or liver transplant may be performed at the same time to alleviate liver disease and/or diabetes. Lung transplantation is considered when lung function declines to the point where assistance from mechanical devices is required or someones survival is threatened. According to Merck Manual, "bilateral lung transplantation for severe lung disease is becoming more routine and more successful with experience and improved techniques. Among adults with CF, median survival posttransplant is about 9 years."

Other aspects
Newborns with intestinal obstruction typically require surgery, whereas adults with distal intestinal obstruction syndrome typically do not. Treatment of pancreatic insufficiency by replacement of missing digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the feces. However, the best dosage and form of pancreatic enzyme replacement is unclear, as are the risks and long-term effectiveness of this treatment.So far, no large-scale research involving the incidence of atherosclerosis and coronary heart disease in adults with cystic fibrosis has been conducted. This is likely because the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.Diabetes is the most common nonpulmonary complication of CF. It mixes features of type 1 and type 2 diabetes, and is recognized as a distinct entity, cystic fibrosis-related diabetes. While oral antidiabetic drugs are sometimes used, the recommended treatment is the use of insulin injections or an insulin pump, and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended. While Stenotrophomonas maltophilia is relatively common in people with cystic fibrosis, the evidence about the effectiveness of antibiotics for S. maltophilia is uncertain.Bisphosphonates taken by mouth or intravenously can be used to improve the bone mineral density in people with cystic fibrosis. When taking bisphosphates intravenously, adverse effects such as pain and flu-like symptoms can be an issue. The adverse effects of bisphosphates taken by mouth on the gastrointestinal tract are not known.Poor growth may be avoided by insertion of a feeding tube for increasing food energy through supplemental feeds or by administration of injected growth hormone.Sinus infections are treated by prolonged courses of antibiotics. The development of nasal polyps or other chronic changes within the nasal passages may severely limit airflow through the nose, and over time reduce the persons sense of smell. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as fluticasone propionate are used to decrease nasal inflammation.Female infertility may be overcome by assisted reproduction technology, particularly embryo transfer techniques. Male infertility caused by absence of the vas deferens may be overcome with testicular sperm extraction, collecting sperm cells directly from the testicles. If the collected sample contains too few sperm cells to likely have a spontaneous fertilization, intracytoplasmic sperm injection can be performed. Third party reproduction is also a possibility for women with CF. Whether taking antioxidants affects outcomes is unclear.Physical exercise is usually part of outpatient care for people with cystic fibrosis. Aerobic exercise seems to be beneficial for aerobic exercise capacity, lung function and health-related quality of life; however, the quality of the evidence was poor.Due to the use of aminoglycoside antibiotics, ototoxicity is common. Symptoms may include "tinnitus, hearing loss, hyperacusis, aural fullness, dizziness, and vertigo".

Gastrointestinal
Problems with the gastrointestinal system including constipation and obstruction of the gastrointestinal tract including distal intestinal obstruction syndrome are frequent complications for people with cystic fibrosis. Treatment of gastrointestinal problems is required in order to prevent a complete obstruction, reduce other CF symptoms, and improve the quality of life. While stool softeners, laxatives, and prokinetics (GI-focused treatments) are often suggested, there is no clear consensus from experts at to which approach is the best and comes with the least risks. Mucolytics or systemic treatments aimed at dysfunctional CFTR are also sometimes suggested to improve symptoms.

Prognosis
The prognosis for cystic fibrosis has improved due to earlier diagnosis through screening and better treatment and access to health care. In 1959, the median age of survival of children with CF in the United States was six months.
In 2010, survival is estimated to be 37 years for women and 40 for men. In Canada, median survival increased from 24 years in 1982 to 47.7 in 2007. In the United States those born with CF in 2016 have an predicted life expectancy of 47.7 when cared for in specialty clinics.In the US, of those with CF who are more than 18 years old as of 2009, 92% had graduated from high school, 67% had at least some college education, 15% were disabled, 9% were unemployed, 56% were single, and 39% were married or living with a partner.

Quality of life
Chronic illnesses can be difficult to manage. CF is a chronic illness that affects the "digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections". The thick secretions clog the airways in the lungs, which often cause inflammation and severe lung infections. If it is compromised, it affects the quality of life of someone with CF and their ability to complete such tasks as everyday chores.According to Schmitz and Goldbeck (2006), CF significantly increases emotional stress on both the individual and the family, "and the necessary time-consuming daily treatment routine may have further negative effects on quality of life". However, Havermans and colleagues (2006) have established that young outpatients with CF who have participated in the Cystic Fibrosis Questionnaire-Revised "rated some quality of life domains higher than did their parents". Consequently, outpatients with CF have a more positive outlook for themselves. As Merck Manual notes, "with appropriate support, most patients can make an age-appropriate adjustment at home and school. Despite myriad problems, the educational, occupational, and marital successes of patients are impressive."Furthermore, there are many ways to enhance the quality of life in CF patients. Exercise is promoted to increase lung function. Integrating an exercise regimen into the CF patients daily routine can significantly improve quality of life. No definitive cure for CF is known, but diverse medications are used, such as mucolytics, bronchodilators, steroids, and antibiotics, that have the purpose of loosening mucus, expanding airways, decreasing inflammation, and fighting lung infections, respectively.

Epidemiology
Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of European heritage. In the United States, about 30,000 individuals have CF; most are diagnosed by six months of age. In Canada, about 4,000 people have CF. Around 1 in 25 people of European descent, and one in 30 of white Americans, is a carrier of a CF mutation. Although CF is less common in these groups, roughly one in 46 Hispanics, one in 65 Africans, and one in 90 Asians carry at least one abnormal CFTR gene. Ireland has the worlds highest prevalence of CF, at one in 1353.Although technically a rare disease, CF is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception is Finland, where only one in 80 people carries a CF mutation. The World Health Organization states, "In the European Union, one in 2000–3000 newborns is found to be affected by CF". In the United States, one in 3,500 children is born with CF. In 1997, about one in 3,300 white children in the United States was born with CF. In contrast, only one in 15,000 African American children have it, and in Asian Americans, the rate was even lower at one in 32,000.Cystic fibrosis is diagnosed equally in males and females. For reasons that remain unclear, data have shown that males tend to have a longer life expectancy than females, though recent studies suggest this gender gap may no longer exist, perhaps due to improvements in health care facilities. A recent study from Ireland identified a link between the female hormone estrogen and worse outcomes in CF.The distribution of CF alleles varies among populations. The frequency of ΔF508 carriers has been estimated at one in 200 in northern Sweden, one in 143 in Lithuanians, and one in 38 in Denmark. No ΔF508 carriers were found among 171 Finns and 151 Saami people. ΔF508 does occur in Finland, but it is a minority allele there. CF is known to occur in only 20 families (pedigrees) in Finland.

Evolution
The ΔF508 mutation is estimated to be up to 52,000 years old. Numerous hypotheses have been advanced as to why such a lethal mutation has persisted and spread in the human population. Other common autosomal recessive diseases such as sickle-cell anemia have been found to protect carriers from other diseases, an evolutionary trade-off known as heterozygote advantage. Resistance to the following have all been proposed as possible sources of heterozygote advantage:

Cholera: With the discovery that cholera toxin requires normal host CFTR proteins to function properly, it was hypothesized that carriers of mutant CFTR genes benefited from resistance to cholera and other causes of diarrhea. Further studies have not confirmed this hypothesis.
Typhoid: Normal CFTR proteins are also essential for the entry of Salmonella Typhi into cells, suggesting that carriers of mutant CFTR genes might be resistant to typhoid fever. No in vivo study has yet confirmed this. In both cases, the low level of cystic fibrosis outside of Europe, in places where both cholera and typhoid fever are endemic, is not immediately explicable.
Diarrhea: The prevalence of CF in Europe might be connected with the development of cattle domestication. In this hypothesis, carriers of a single mutant CFTR had some protection from diarrhea caused by lactose intolerance, before the mutations that created lactose tolerance appeared.
Tuberculosis: Another possible explanation is that carriers of the gene could have some resistance to tuberculosis. This hypothesis is based on the thesis that CFTR gene mutation carriers have insufficient action in one of their enzymes – arylsulphatase - which is necessary for Mycobacterium tuberculosis virulence. As M. tuberculosis would use its hosts sources to affect the individual, and due to the lack of enzyme it could not presents its virulence, being a carrier of CFTR mutation could provide resistance against tuberculosis.

History
CF is supposed to have appeared about 3,000 BC because of migration of peoples, gene mutations, and new conditions in nourishment. Although the entire clinical spectrum of CF was not recognized until the 1930s, certain aspects of CF were identified much earlier. Indeed, literature from Germany and Switzerland in the 18th century warned "Wehe dem Kind, das beim Kuß auf die Stirn salzig schmeckt, es ist verhext und muss bald sterben" ("Woe to the child who tastes salty from a kiss on the brow, for he is cursed and soon must die"), recognizing the association between the salt loss in CF and illness.In the 19th century, Carl von Rokitansky described a case of fetal death with meconium peritonitis, a complication of meconium ileus associated with CF. Meconium ileus was first described in 1905 by Karl Landsteiner. In 1936, Guido Fanconi described a connection between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis.In 1938, Dorothy Hansine Andersen published an article, "Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological Study", in the American Journal of Diseases of Children. She was the first to describe the characteristic cystic fibrosis of the pancreas and to correlate it with the lung and intestinal disease prominent in CF. She also first hypothesized that CF was a recessive disease and first used pancreatic enzyme replacement to treat affected children. In 1952, Paul di SantAgnese discovered abnormalities in sweat electrolytes; a sweat test was developed and improved over the next decade.The first linkage between CF and another marker (Paroxonase) was found in 1985 by Hans Eiberg, indicating that only one locus exists for CF. In 1988, the first mutation for CF, ΔF508 was discovered by Francis Collins, Lap-Chee Tsui, and John R. Riordan on the seventh chromosome. Subsequent research has found over 1,000 different mutations that cause CF.Because mutations in the CFTR gene are typically small, classical genetics techniques had been unable to accurately pinpoint the mutated gene. Using protein markers, gene-linkage studies were able to map the mutation to chromosome 7. Chromosome walking and chromosome jumping techniques were then used to identify and sequence the gene. In 1989, Lap-Chee Tsui led a team of researchers at the Hospital for Sick Children in Toronto that discovered the gene responsible for CF. CF represents a classic example of how a human genetic disorder was elucidated strictly by the process of forward genetics.

Research
People with CF may be listed in a disease registry that allows researchers and doctors to track health results and identify candidates for clinical trials.

Gene therapy
Gene therapy has been explored as a potential cure for CF. Results from clinical trials have shown limited success as of 2016, and using gene therapy as routine therapy is not suggested. A small study published in 2015 found a small benefit.The focus of much CF gene therapy research is aimed at trying to place a normal copy of the CFTR gene into affected cells. Transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR protein in all target cells, without adverse reactions or an inflammation response. To prevent the lung manifestations of CF, only 5–10% the normal amount of CFTR gene expression is needed. Multiple approaches have been tested for gene transfer, such as liposomes and viral vectors in animal models and clinical trials. However, both methods were found to be relatively inefficient treatment options, mainly because very few cells take up the vector and express the gene, so the treatment has little effect. Additionally, problems have been noted in cDNA recombination, such that the gene introduced by the treatment is rendered unusable. There has been a functional repair in culture of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.

Phage therapy
Phage therapy is being studied for multidrug resistant bacteria in people with CF.

Gene modulators
A number of small molecules that aim at compensating various mutations of the CFTR gene are under development. CFTR modulator therapies have been used in place of other types of genetic therapies. These therapies focus on the expression of a genetic mutation instead of the mutated gene itself. Modulators are split into two classes: potentiators and correctors. Potentiators act on the CFTR ion channels that are embedded in the cell membrane, and these types of drugs help open up the channel to allow transmembrane flow. Correctors are meant to assist in the transportation of nascent proteins, a protein that is formed by ribosomes before it is morphed into a specific shape, to the cell surface to be implemented into the cell membrane.Most target the transcription stage of genetic expression. One approach has been to try and develop medication that get the ribosome to overcome the stop codon and produce a full-length CFTR protein. About 10% of CF results from a premature stop codon in the DNA, leading to early termination of protein synthesis and truncated proteins. These drugs target nonsense mutations such as G542X, which consists of the amino acid glycine in position 542 being replaced by a stop codon. Aminoglycoside antibiotics interfere with protein synthesis and error-correction </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 Cysticercosis and can you explain it in depth? [/INST] Cysticercosis is a tissue infection caused by the young form of the pork tapeworm. People may have few or no symptoms for years. In some cases, particularly in Asia, solid lumps of between one and two centimetres may develop under the skin. After months or years these lumps can become painful and swollen and then resolve. A specific form called neurocysticercosis, which affects the brain, can cause neurological symptoms. In developing countries this is one of the most common causes of seizures.Cysticercosis is usually acquired by eating food or drinking water contaminated by tapeworms eggs from human feces. Among foods egg-contaminated vegetables are a major source. The tapeworm eggs are present in the feces of a person infected with the adult worms, a condition known as taeniasis. Taeniasis, in the strict sense, is a different disease and is due to eating cysts in poorly cooked pork. People who live with someone with the pork tapeworm have a greater risk of getting cysticercosis. The diagnosis can be made by aspiration of a cyst. Taking pictures of the brain with computer tomography (CT) or magnetic resonance imaging (MRI) are most useful for the diagnosis of disease in the brain. An increased number of a type of white blood cell, called eosinophils, in the cerebral spinal fluid and blood is also an indicator.Infection can be effectively prevented by personal hygiene and sanitation: this includes cooking pork well, proper toilets and sanitary practices, and improved access to clean water. Treating those with taeniasis is important to prevent spread. Treating the disease when it does not involve the nervous system may not be required. Treatment of those with neurocysticercosis may be with the medications praziquantel or albendazole. These may be required for long periods. Steroids, for anti-inflammation during treatment, and anti-seizure medications may also be required. Surgery is sometimes done to remove the cysts.The pork tapeworm is particularly common in Asia, Sub-Saharan Africa, and Latin America. In some areas it is believed that up to 25% of people are affected. In the developed world it is very uncommon. Worldwide in 2015 it caused about 400 deaths. Cysticercosis also affects pigs and cows but rarely causes symptoms as most are slaughtered before symptoms arise. The disease has occurred in humans throughout history. It is one of the neglected tropical diseases.

Signs and symptoms
Muscles
Cysticerci can develop in any voluntary muscle. Invasion of muscle can cause inflammation of the muscle, with fever, eosinophilia, and increased size, which initiates with muscle swelling and later progress to atrophy and scarring. In most cases, it is asymptomatic since the cysticerci die and become calcified.

Nervous system
The term neurocysticercosis is generally accepted to refer to cysts in the parenchyma of the brain. It presents with seizures and, less commonly, headaches. Cysticerca in brain parenchyma are usually 5–20 mm in diameter. In subarachnoid space and fissures, lesions may be as large as 6 cm in diameter and lobulated. They may be numerous and life-threatening.Cysts located within the ventricles of the brain can block the outflow of cerebrospinal fluid and present with symptoms of increased intracranial pressure.Racemose neurocysticercosis refers to cysts in the subarachnoid space. These can occasionally grow into large lobulated masses causing pressure on surrounding structures.Spinal cord neurocysticercosis most commonly presents symptoms such as back pain and radiculopathy.

Eyes
In some cases, cysticerci may be found in the eyeball, extraocular muscles, and under the conjunctiva (subconjunctiva). Depending on the location, they may cause visual difficulties that fluctuate with eye position, retinal edema, hemorrhage, a decreased vision or even a visual loss.

Skin
Subcutaneous cysts are in the form of firm, mobile nodules, occurring mainly on the trunk and extremities. Subcutaneous nodules are sometimes painful.

Cause
The cause of human cysticercosis is the egg form of Taenia solium (often abbreviated as T. solium and also called pork tapeworm), which is transmitted through the oral-fecal route. The eggs enter the intestine where they develop into larvae. The larvae enter the bloodstream and invade host tissues, where they further develop into larvae called cysticerci. The cysticercus larva completes development in about 2 months. It is semitransparent, opalescent white, and elongate oval in shape and may reach a length of 0.6 to 1.8 cm.

Diagnosis
The traditional method of demonstrating either tapeworm eggs or proglottids in stool samples diagnoses only taeniasis, carriage of the tapeworm stage of the life cycle. Only a small minority of patients with cysticercosis will harbor a tapeworm, rendering stool studies ineffective for diagnosis. Ophthalmic cysticercosis can be diagnosed by visualizing parasite in eye by fundoscopy.In cases of human cysticercosis, diagnosis is a sensitive problem and requires biopsy of the infected tissue or sophisticated instruments. Taenia solium eggs and proglottids found in feces, ELISA, or polyacrylamide gel electrophoresis diagnose only taeniasis and not cysticercosis. Radiological tests, such as X-ray, CT scans which demonstrate "ring-enhancing brain lesions", and MRIs, can also be used to detect diseases. X-rays are used to identify calcified larvae in the subcutaneous and muscle tissues, and CT scans and MRIs are used to find lesions in the brain.

Serological
Antibodies to cysticerci can be demonstrated in serum by enzyme linked immunoelectrotransfer blot (EITB) assay and in CSF by ELISA. An immunoblot assay using lentil-lectin (agglutinin from Lens culinaris) is highly sensitive and specific. However, individuals with intracranial lesions and calcifications may be seronegative. In the CDCs immunoblot assay, cysticercosis-specific antibodies can react with structural glycoprotein antigens from the larval cysts of Taenia solium. However, this is mainly a research tool not widely available in clinical practice and nearly unobtainable in resource limited settings.

Neurocysticercosis
The diagnosis of neurocysticercosis is mainly clinical, based on a compatible presentation of symptoms and findings of imaging studies.

Imaging
Neuroimaging with CT or MRI is the most useful method of diagnosis. CT scan shows both calcified and uncalcified cysts, as well as distinguishing active and inactive cysts. Cystic lesions can show ring enhancement and focal enhancing lesions. Some cystic lesions, especially the ones in ventricles and subarachnoid space may not be visible on CT scan, since the cyst fluid is isodense with cerebrospinal fluid (CSF). Thus diagnosis of extraparenchymal cysts usually relies on signs like hydrocephalus or enhanced basilar meninges. In such cases CT scan with intraventricular contrast or MRI can be used. MRI is more sensitive in detection of intraventricular cysts.

CSF
CSF findings include pleocytosis, elevated protein levels and depressed glucose levels; but these may not be always present.

Prevention
Cysticercosis is considered as “tools-ready disease” according to WHO. International Task Force for Disease Eradication in 1992 reported that cysticercosis is potentially eradicable. It is feasible because there are no animal reservoirs besides humans and pigs. The only source of Taenia solium infection for pigs is from humans, a definite host. Theoretically, breaking the life cycle seems easy by doing intervention strategies from various stages in the life cycle.For example,

Massive chemotherapy of infected individuals, improving sanitation, and educating people are all major ways to discontinue the cycle, in which eggs from human feces are transmitted to other humans and/or pigs.
Cooking of pork or freezing it and inspecting meat are effective means to cease the life cycle
The management of pigs by treating them or vaccinating them is another possibility to intervene
The separation of pigs from human faeces by confining them in enclosed piggeries. In Western European countries post World War 2 the pig industry developed rapidly and most pigs were housed. This was the main reason for pig cysticercosis largely being eliminated from the region. This of course is not a quick answer to the problem in developing countries.

Pigs
The intervention strategies to eradicate cysticercosis includes surveillance of pigs in foci of transmission and massive chemotherapy treatment of humans. In reality, control of T. solium by a single intervention, for instance, by treating only human population will not work because the existing infected pigs can still carry on the cycle. The proposed strategy for eradication is to do multilateral intervention by treating both human and porcine populations. It is feasible because treating pigs with oxfendazole has been shown to be effective and once treated, pigs are protected from further infections for at least 3 months.

Limitations
Even with the concurrent treatment of humans and pigs, complete elimination is hard to achieve. In one study conducted in 12 villages in Peru, both humans and pigs were treated with praziquantel and oxfendazole, with the coverage of more than 75% in humans and 90% in pigs The result shows a decrease in prevalence and incidence in the intervention area; however the effect did not eliminate T. solium. The possible reason includes the incomplete coverage and re-infection. Even though T. solium could be eliminated through mass treatment of human and porcine population, it is not sustainable. Moreover, both tapeworm carriers of humans and pigs tend to spread the disease from endemic to non-endemic areas resulting in periodic outbreaks of cysticercosis or outbreaks in new areas.

Vaccines
Given the fact that pigs are part of a life cycle, vaccination of pigs is another feasible intervention to eliminate cysticercosis. Research studies have been focusing on vaccine against cestode parasites, since many immune cell types are found to be capable of destroying cysticercus. Many vaccine candidates are extracted from antigens of different cestodes such as Taenia solium, T. crassiceps, T. saginata, T. ovis and target oncospheres and/or cysticerci. In 1983, Molinari et al. reported the first vaccine candidate against porcine cysticercosis using antigen from cysticercus cellulosae drawn out from naturally infected. Recently, vaccines extracted from genetically engineered 45W-4B antigens have been successfully tested to pigs in an experimental condition. This type of vaccine can protect against cysticercosis in both Chinese and Mexican type of T. solium. However, it has not been tested in endemic field conditions, which is important because the realistic condition in the field differ greatly from experimental condition, and this can result in a great difference in the chances of infection and immune reaction.Even though vaccines have been successfully generated, the feasibility of its production and usage in rural free ranging pigs still remains a challenge. If a vaccine is to be injected, the burden of work and the cost of vaccine administration to pigs will remain high and unrealistic. The incentives of using vaccines by pig owners will decrease if the vaccine administration to pigs takes time by injecting every single pig in their livestock. A hypothetical oral vaccine is proposed to be more effective in this case as it can be easily delivered to the pigs by food.

S3PVAC vaccine
The vaccine constituted by 3 peptide synthetically produced (S3Pvac) has proven its efficacy in natural conditions of transmission. The S3PVAC vaccine so far, can be considered as the best vaccine candidate to be used in endemic areas such as Mexico (20). S3Pvac consists of three protective peptides: KETc12, KETc1 and GK1, whose sequences belong to native antigens that are present in the different developmental stages of T. solium and other cestode parasites.Non-infected pigs from rural villages in Mexico were vaccinated with S3Pvac and the vaccine reduced 98% the number of cysticerci and 50% the number of prevalence. The diagnostic method involves necropsy and tongue inspection of pigs. The natural challenge conditions used in the study proved the efficacy of the S3Pvac vaccine in transmission control of T. solium in Mexico. The S3Pvac vaccine is owned by the National Autonomous University of Mexico and the method of high scale production of the vaccine has already been developed. The validation of the vaccine in agreement with the Secretary of Animal Health in Mexico is currently in the process of completion. It is also hoped that the vaccine will be well-accepted by pig owners because they also lose their income if pigs are infected cysticercosis. Vaccination of pigs against cysticercosis, if successful, can potentially have a great impact on transmission control since there is no chance of re-infection once pigs receive vaccination.

Other
Cysticercosis can also be prevented by routine inspection of meat and condemnation of measly meat by the local government and by avoiding partially cooked meat products. However, in areas where food is scarce, cyst-infected meat might be considered as wasted since pork can provide high quality protein. At times, infected pigs are consumed within the locality or sold at low prices to traffickers who take the uninspected pigs at urban areas for sale.

Management
Neurocysticercosis
Asymptomatic cysts, such as those discovered incidentally on neuroimaging done for another reason, may never lead to symptomatic disease and in many cases do not require therapy. Calcified cysts have already died and involuted. Seizures can also occur in individuals with only calcified cysts.Neurocysticercosis may present as hydrocephalus and acute onset seizures, thus the immediate therapy is emergent reduction of intracranial pressure and anticonvulsant medications. Once the seizures have been brought under control, antihelminthic treatments may be undertaken. The decision to treat with antiparasitic therapy is complex and based on the stage and number of cysts present, their location, and the persons specific symptoms.Adult Taenia solium are easily treated with niclosamide, and is most commonly used in taeniasis. However cysticercosis is a complex disease and requires careful medication. Praziquantel (PZQ) is the drug of choice. In neurocysticercosis praziquantel is widely used. Albendazole appears to be more effective and a safe drug for neurocysticercosis.  In complicated situation a combination of praziquantel, albendazole and steroid (such as corticosteroids to reduce the inflammation) is recommended. In the brain the cysts can be usually found on the surface. Most cases of brain cysts are found by accident, during diagnosis for other ailments. Surgical removals are the only option of complete removal even if treated successfully with medications.Antiparasitic treatment should be given in combination with corticosteroids and anticonvulsants to reduce inflammation surrounding the cysts and lower the risk of seizures. When corticosteroids are given in combination with praziquantel, cimetidine is also given, as corticosteroids decrease action of praziquantel by enhancing its first pass metabolism. Albendazole is generally preferable over praziquantel due to its lower cost and fewer drug interactions.Surgical intervention is much more likely to be needed in cases of intraventricular, racemose, or spinal neurocysticercosis. Treatments includes direct excision of ventricular cysts, shunting procedures, and removal of cysts via endoscopy.

Eyes
In eye disease, surgical removal is necessary for cysts within the eye itself as treating intraocular lesions with anthelmintics will elicit an inflammatory reaction causing irreversible damage to structural components. Cysts outside the globe can be treated with anthelmintics and steroids. Treatment recommendations for subcutaneous cysticercosis includes surgery, praziquantel and albendazole.

Skin
In general, subcutaneous disease does not need specific therapy. Painful or bothersome cysts can be surgically removed.

Epidemiology
Regions
Taenia solium is found worldwide, but is more common where pork is part of the diet. Cysticercosis is most prevalent where humans live in close contact with pigs. Therefore, high prevalences are reported in Mexico, Latin America, West Africa, Russia, India, Pakistan, North-East China, and Southeast Asia. In Europe it is most widespread among Slavic people. However, reviews of the epidemiological in Western and Eastern Europe shows there are still considerable gaps in our understanding of the disease also in these regions.The frequency has decreased in developed countries owing to stricter meat inspection, better hygiene and better sanitation of facilities.

Infection estimates
In Latin America, an estimated 75 million persons live in endemic areas and 400,000 people have symptomatic disease. Some studies suggest that the prevalence of cysticercosis in Mexico is between 3.1 and 3.9 percent. Other studies have found the seroprevalence in areas of Guatemala, Bolivia, and Peru as high as 20 percent in humans, and 37 percent in pigs. In Ethiopia, Kenya and the Democratic Republic of Congo around 10% of the population is infected, in Madagascar 16%. The distribution of cysticercosis coincides with the distribution of T. solium. Cysticercosis is the most common cause of symptomatic epilepsy worldwide.Prevalence rates in the United States have shown immigrants from Mexico, Central and South America, and Southeast Asia account for most of the domestic cases of cysticercosis.In 1990 and 1991, four unrelated members of an Orthodox Jewish community in New York City developed recurrent seizures and brain lesions, which were found to have been caused by T. solium. Researchers who interviewed the families suspect the infection was acquired from domestic workers who were carriers of the tapeworm.

Deaths
Worldwide as of 2010 it caused about 1,200 deaths, up from 700 in 1990. Estimates from 2010 were that it contributed to at least 50,000 deaths annually.In US during 1990–2002, 221 cysticercosis deaths were identified. Mortality rates were highest for Latinos and men. The mean age at death was 40.5 years (range 2–88). Most patients, 84.6%, were foreign born, and 62% had emigrated from Mexico. The 33 US-born persons who died of cysticercosis represented 15% of all cysticercosis-related deaths </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 Cystinosis and can you explain it in depth? [/INST] Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosomal recessive disorder resulting from accumulation of free cystine in lysosomes, eventually leading to intracellular crystal formation throughout the body. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules is impaired, leading to abnormal amounts of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.
Cystinosis was the first documented genetic disease belonging to the group of lysosomal storage disease disorders. Cystinosis is caused by mutations in the CTNS gene that codes for cystinosin, the lysosomal membrane-specific transporter for cystine. Intracellular metabolism of cystine, as it happens with all amino acids, requires its transport across the cell membrane. After degradation of endocytosed protein to cystine within lysosomes, it is normally transported to the cytosol. But if there is a defect in the carrier protein, cystine is accumulated in lysosomes. As cystine is highly insoluble, when its concentration in tissue lysosomes increases, its solubility is immediately exceeded and crystalline precipitates are formed in almost all organs and tissues.However, the progression of the disease is not related to the presence of crystals in target tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are not fully understood. Increased intracellular cystine profoundly disturbs cellular oxidative metabolism and glutathione status, leading to altered mitochondrial energy metabolism, autophagy, and apoptosis.Cystinosis is usually treated with cysteamine, which is prescribed to decrease intralysosomal cystine accumulation. However, the discovery of new pathogenic mechanisms and the development of an animal model of the disease may open possibilities for the development of new treatment modalities to improve long-term prognosis.

Symptoms
There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems (sometimes called renal Fanconi syndrome). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis).

By about age two, cystine crystals may also be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia). Without treatment, children with cystinosis are likely to experience complete kidney failure by about age ten. With treatment this may be delayed into the patients teens or 20s. Other signs and symptoms that may occur in patients include muscle deterioration, blindness, inability to swallow, impaired sweating, decreased hair and skin pigmentation, diabetes, and thyroid and nervous system problems.
The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.
People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.

Crystal morphology and identification
Cystine crystals are hexagonal in shape and are colorless. They are not found often in alkaline urine due to their high solubility. The colorless crystals can be difficult to distinguish from uric acid crystals which are also hexagonal </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 Cystinuria and can you explain it in depth? [/INST] Cystinuria is an inherited autosomal recessive disease characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureters, and bladder. It is a type of aminoaciduria. "Cystine", not "cysteine," is implicated in this disease; the former is a dimer of the latter.

Presentation
Cystinuria is a cause of recurrent kidney stones.  It is a disease involving the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine, and is one of many causes of kidney stones. If not treated properly, the disease could cause serious damage to the kidneys and surrounding organs, and in some rare cases death.  The stones may be identified by a positive nitroprusside cyanide test. The crystals are usually hexagonal, translucent, white. Upon removal, the stones may be pink or yellow in color, but later they turn to greenish due to exposure to air. Cystinuria is usually asymptomatic when no stone is formed. However, once a stone is formed, signs and symptoms can occur:
Nausea
Flank pain
Hematuria
Urinary tract infections
Rarely, acute or chronic kidney diseasePeople with cystinuria pass stones monthly, weekly, or daily, and need ongoing care. Cystinurics have an increased risk for chronic kidney disease and since kidney damage or poor function is often present in cystinurics, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or over the counter (OTC) medications should be used with caution.
Cystine stones are often difficult to detect using plain x-rays. Computed tomography or ultrasound may be used instead for imaging.Urine odor in cystinuria has a smell of rotten eggs due to the increase in cystine.

Genetics
Cystinuria is an autosomal recessive disease, which means that the defective gene responsible for the disease is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disease. The parents of an individual with an autosomal recessive disease both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disease. Although signs and symptoms are rare, there are some directly and indirectly associated with cystinuria. These sign and symptoms consist of 1) hematuria- blood in the urine, 2) flank pain – pain in the side due to kidney pain, 3) renal colic – intense, cramping pain due to stones in the urinary tract, 4) obstructive uropathy- urinary tract disease due to obstruction, and 5) urinary tract infections.

Cause
Cystinuria is caused by mutations in the SLC3A1 and SLC7A9 genes.  These defects prevent proper reabsorption of basic, or positively charged, amino acids: cystine,  lysine, ornithine, arginine. Under normal circumstances, this protein allows certain amino acids, including cystine, to be reabsorbed into the blood from the filtered fluid that will become urine. Mutations in either of these genes disrupt the ability of this transporter protein to reabsorb these amino acids, allowing them to become concentrated in the urine. As the levels of cystine in the urine increase, it forms cystine crystals, resulting in kidney stones.  Cystine crystals form hexagonal-shaped crystals that can be viewed upon microscopic analysis of the urine.  The other amino acids that are not reabsorbed do not create crystals in urine.The overall prevalence of cystinuria is approximately 1 in 7,000 neonates (from 1 in 2,500 neonates in Libyan Jews to 1 in 100,000 among Swedes).

Pathophysiology
Cystinuria is characterized by the inadequate reabsorption of cystine in the proximal convoluted tubules after the filtering of the amino acids by the kidneys glomeruli, thus resulting in an excessive concentration of this amino acid in the urine.  Cystine may precipitate out of the urine, if the urine is neutral or acidic, and form crystals or stones in the kidneys, ureters, or bladder. It is one of several inborn errors of metabolism included in the Garrods tetrad. The disease is attributed to deficiency in transport and metabolism of amino acids.

Diagnosis
Blood: Routine hemogram along with blood sugar, urea, and creatinine.
Urine: For cystine crystals, and casts. The most specific test is the cyanide–nitroprusside test
Ultrasound/CT scan to reveal if a stone is present.
Genetic analysis to determine which mutation associated with the disease may be present. Currently genotyping is not available in the United States but might be available in Spain, Italy, UK, Germany and Russia (by private companies in Germany and Russia).Regular X-rays often fail to show the cystine stones, however they can be visualized in the diagnostic procedure  that is called intravenous pyelogram (IVP). Stones may show up on XR with a fuzzy gray appearance.  They are radioopaque due to sulfur content, though more difficult to visualize than calcium oxalate stones.

Treatment
Initial treatment is with adequate hydration, alkalization of the urine with citrate supplementation or acetazolamide, and dietary modification to reduce salt and protein intake (especially methionine). If this fails then patients are usually started on chelation therapy with an agent such as penicillamine. Tiopronin is another agent.
Once renal stones have formed, however, the first-line treatment is endoscopic laser lithotripsy. ESWL (Extracorporeal shock wave lithotripsy) is often not effective because of the hardness of the stones that do not fragment easily. Conventional open-abdominal surgery is rarely used but has proven to be effective treatment modalities for patients with more advanced disease. Adequate hydration is the foremost aim of treatment to prevent cystine stones. The goal is to increase the urine volume because the concentration of cystine in the urine is reduced which prevents cystine from precipitating from the urine and forming stones </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 Isosporiasis and can you explain it in depth? [/INST] Isosporiasis, also known as cystoisosporiasis, is a human intestinal disease caused by the parasite Cystoisospora belli (previously known as Isospora belli). It is found worldwide, especially in tropical and subtropical areas. Infection often occurs in immuno-compromised individuals, notably AIDS patients, and outbreaks have been reported in institutionalized groups in the United States. The first documented case was in 1915. It is usually spread indirectly, normally through contaminated food or water (CDC.gov).

Signs and symptoms
Infection causes acute, non-bloody diarrhea with crampy abdominal pain, which can last for weeks and result in malabsorption and weight loss. In immunodepressed patients, and in infants and children, the diarrhea can be severe. Eosinophilia may be present (differently from other protozoan infections).

Cause
The coccidian parasite Cystoisospora belli infects the epithelial cells of the small intestine, and is the least common of the three intestinal coccidia that infect humans (Toxoplasma, Cryptosporidium, and Cystoisospora).

Transmission
People become infected by swallowing the mature parasite; this normally occurs through the ingestion of contaminated food or water. The infected host then produces an immature form  of the parasite in their feces, and when the parasite matures, it is capable of infecting its next host, via food or water containing the parasite.

Life cycle
At time of excretion, the immature oocyst contains usually one sporoblast (more rarely two). In further maturation after excretion, the sporoblast divides in two, so the oocyst now contains two sporoblasts. The sporoblasts secrete a cyst wall, thus becoming sporocysts; and the sporocysts divide twice to produce four sporozoites each. Infection occurs by ingestion of sporocyst-containing oocysts: the sporocysts excyst in the small intestine and release their sporozoites, which invade the epithelial cells and initiate schizogony. Upon rupture of the schizonts, the merozoites are released, invade new epithelial cells, and continue the cycle of asexual multiplication. Trophozoites develop into schizonts which contain multiple merozoites. After a minimum of one week, the sexual stage begins with the development of male and female gametocytes </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 Gastroparesis and can you explain it in depth? [/INST] Gastroparesis (gastro- from Ancient Greek γαστήρ - gaster, "stomach"; and -paresis, πάρεσις - "partial paralysis"), also called delayed gastric emptying, is a medical disorder consisting of weak muscular contractions (peristalsis) of the stomach, resulting in food and liquid remaining in the stomach for a prolonged period of time. Stomach contents thus exit more slowly into the duodenum of the digestive tract.  This can result in irregular absorption of nutrients, inadequate nutrition, and poor glycemic control.Symptoms include nausea, vomiting, abdominal pain, feeling full soon after beginning to eat (early satiety), abdominal bloating, and heartburn. The most common known mechanism is autonomic neuropathy of the nerve which innervates the stomach: the vagus nerve. Uncontrolled diabetes mellitus is a major cause of this nerve damage; other causes include post-infectious and trauma to the vagus nerve.
Diagnosis is via one or more of the following: barium swallow X-ray, barium beefsteak meal, radioisotope gastric-emptying scan, gastric manometry, and esophagogastroduodenoscopy (EGD). Complications include malnutrition, fatigue, weight loss, vitamin deficiencies, intestinal obstruction due to bezoars, and  small intestine bacterial overgrowth.
Treatment includes dietary modifications, medications to stimulate gastric emptying, medications to reduce vomiting, and surgical approaches.

Signs and symptoms
The most common symptoms of gastroparesis are the following:
Chronic nausea
Vomiting (especially of undigested food)
Abdominal pain
A feeling of fullness after eating just a few bitesOther symptoms include the following:

Abdominal bloating
Body aches (myalgia)
Erratic blood glucose levels
Acid reflux (GERD)
Heartburn
Lack of appetite
Morning nausea
Muscle weakness
Night sweats
Palpitations
Spasms of the stomach wall
Constipation or infrequent bowel movements
Weight loss, malnutrition
Difficulty swallowingVomiting may not occur in all cases, as those affected may adjust their diets to include only small amounts of food.

Causes
Transient gastroparesis may arise in acute illness of any kind, as a consequence of certain cancer treatments or other drugs which affect digestive action, or due to abnormal eating patterns. The symptoms are almost identical to those of low stomach acid, therefore most doctors will usually recommend trying out supplemental hydrochloric acid before moving on to the invasive procedures required to confirm a damaged nerve. Patients with cancer may develop gastroparesis because of chemotherapy-induced neuropathy, immunosuppression followed by viral infections involving the GI tract, procedures such as celiac blocks, paraneoplastic neuropathy or myopathy, or after an allogeneic bone marrow transplant via graft-versus-host disease.Gastroparesis present similar symptoms to slow gastric emptying caused by certain opioid medications, antidepressants, and allergy medications, along with high blood pressure. For patients already with gastroparesis, these can make the condition worse. More than 50% of all gastroparesis cases are idiopathic in nature, with unknown causes. It is, however, frequently caused by autonomic neuropathy. This may occur in people with type 1 or type 2 diabetes, about 30–50% among long-standing diabetics. In fact, diabetes mellitus has been named as the most common cause of gastroparesis, as high levels of blood glucose may effect chemical changes in the nerves. The vagus nerve becomes damaged by years of high blood glucose or insufficient transport of glucose into cells resulting in gastroparesis. Adrenal and thyroid gland problems could also be a cause.Gastroparesis has also been associated with connective tissue diseases such as scleroderma and Ehlers–Danlos syndrome, and neurological conditions such as Parkinsons disease and multiple system atrophy. It may occur as part of a mitochondrial disease. Opioids and anticholinergic medications can cause medication-induced gastroparesis. Chronic gastroparesis can be caused by other types of damage to the vagus nerve, such as abdominal surgery. Heavy cigarette smoking is also a plausible cause since smoking causes damage to the stomach lining. Idiopathic gastroparesis (gastroparesis with no known cause) accounts for a third of all chronic cases; it is thought that many of these cases are due to an autoimmune response triggered by an acute viral infection. Gastroenteritis, mononucleosis, and other ailments have been anecdotally linked to the onset of the condition, but no systematic study has proven a link.People with gastroparesis are disproportionately female. One possible explanation for this finding is that women have an inherently slower stomach emptying time than men. A hormonal link has been suggested, as gastroparesis symptoms tend to worsen the week before menstruation when progesterone levels are highest. Neither theory has been proven definitively.

Mechanism
On the molecular level, it is thought that gastroparesis can be caused by the loss of neuronal nitric oxide expression since the cells in the GI tract secrete nitric oxide. This important signaling molecule has various responsibilities in the GI tract and in muscles throughout the body. When nitric oxide levels are low, the smooth muscle and other organs may not be able to function properly. Other important components of the stomach are the interstitial cells of Cajal (ICC) which act as a pacemaker since they transduce signals from motor neurons to produce an electrical rhythm in the smooth muscle cells. Lower nitric oxide levels also correlate with loss of ICC cells, which can ultimately lead to the loss of function in the smooth muscle in the stomach, as well as in other areas of the gastrointestinal tract.Pathogenesis of symptoms in diabetic gastroparesis include:

Loss of gastric neurons containing nitric oxide synthase (NOS) is responsible for defective accommodation reflex, which leads to early satiety and postprandial fullness.
Impaired electromechanical activity in the myenteric plexus is responsible for delayed gastric emptying, resulting in nausea and vomiting.
Sensory neuropathy in the gastric wall may be responsible for epigastric pain.
Abnormal pacemaker activity (tachybradyarrhythmia) may generate a noxious signal transmitted to the CNS to evoke nausea and vomiting.

Diagnosis
Gastroparesis can be diagnosed with tests such as barium swallow X-rays, manometry, and gastric emptying scans. For the X-ray, the patient drinks a liquid containing barium after fasting which will show up in the X-ray and the physician is able to see if there is still food in the stomach as well. This can be an easy way to identify whether the patient has delayed emptying of the stomach. The clinical definition for gastroparesis is based solely on the emptying time of the stomach (and not on other symptoms), and severity of symptoms does not necessarily correlate with the severity of gastroparesis. Therefore, some patients may have marked gastroparesis with few, if any, serious complications.In other cases or if the X-ray is inconclusive, the physician may have the patient eat a meal of toast, water, and eggs containing a radioactive isotope so they can watch as it is digested and see how slowly the digestive tract is moving. This can be helpful for diagnosing patients who are able to digest liquids but not solid foods.

Complications
Complications of gastroparesis include:

Fluctuations in blood glucose due to unpredictable digestion times due to changes in rate and amount of food passing into the small bowel. This makes diabetes worse, but does not cause diabetes. Lack of control of blood sugar levels will make the gastroparesis worsen.
General malnutrition due to the symptoms of the disease (which frequently include vomiting and reduced appetite) as well as the dietary changes necessary to manage it. This is especially true for vitamin deficiencies such as scurvy because of inability to tolerate fresh fruits.
Severe fatigue and weight loss due to calorie deficit
Intestinal obstruction due to the formation of bezoars (solid masses of undigested food). This can cause nausea and vomiting, which can in turn be life-threatening if they prevent food from passing the small intestine.
Small intestine bacterial overgrowth is commonly found in patients with gastroparesis.
Bacterial infection due to overgrowth in undigested food
A decrease in quality of life, since it can make keeping up with work and other responsibilities more difficult.

Treatment
Treatment includes dietary modifications, medications to stimulate gastric emptying, medications to reduce vomiting, and surgical approaches.Dietary treatment involves low fiber diets and, in some cases, restrictions on fat or solids. Eating smaller meals, spaced two to three hours apart has proved helpful. Avoiding foods like rice or beef that cause the individual problems such as pain in the abdomen or constipation will help avoid symptoms.Metoclopramide, a dopamine D2 receptor antagonist, increases contractility and resting tone within the GI tract to improve gastric emptying. In addition, dopamine antagonist action in the central nervous system prevents nausea and vomiting. Similarly, the dopamine receptor antagonist domperidone is used to treat gastroparesis. Erythromycin is known to improve emptying of the stomach but its effects are temporary due to tachyphylaxis and wane after a few weeks of consistent use. Sildenafil citrate, which increases blood flow to the genital area in men, is being used by some practitioners to stimulate the gastrointestinal tract in cases of diabetic gastroparesis. The antidepressant mirtazapine has proven effective in the treatment of gastroparesis unresponsive to conventional treatment. This is due to its antiemetic and appetite stimulant properties. Mirtazapine acts on the same serotonin receptor (5-HT3) as does the popular anti-emetic ondansetron. Camicinal is a motilin agonist for the treatment of gastroparesis.
In specific cases where treatment of chronic nausea and vomiting proves resistant to drugs, implantable gastric stimulation may be utilized. A medical device is implanted that applies neurostimulation to the muscles of the lower stomach to reduce the symptoms. This is only done in refractory cases that have failed all medical management (usually at least two years of treatment). Medically refractory gastroparesis may also be treated with a pyloromyotomy, which widens the gastric outlet by cutting the circular pylorus muscle. This can be done laparoscopically or endoscopically.  Vertical sleeve gastrectomy, a procedure in which a part or all of the affected portion of the stomach is removed, has been shown to have some success in the treatment of gastroparesis in obese patients, even curing it in some instances. Further studies have been recommended due to the limited sample size of previous studies.In cases of postinfectious gastroparesis, patients have symptoms and go undiagnosed for an average of 3 weeks to 6 months before their illness is identified correctly and treatment begins.

Prognosis
Post-infectious
Cases of post-infectious gastroparesis are self‐limiting, with recovery within 12 months of initial symptoms, although some cases last well over 2 years. In children, the duration tends to be shorter and the disease course milder than in adolescent and adults.

Diabetic gastropathy
Diabetic gastropathy is usually slowly progressive, and can become severe and lethal.

Prevalence
Post-infectious gastroparesis, which constitutes the majority of idiopathic gastroparesis cases, affects up to 4% of the American population. Women in their 20s and 30s seem to be susceptible. One study of 146 American gastroparesis patients found the mean age of patients was 34 years with 82% affected being women, while another study found the patients were young or middle aged and up to 90% were women.There has only been one true epidemiological study of idiopathic gastroparesis which was completed by the Rochester Epidemiology Project. They looked at patients from 1996 to 2006 who were seeking medical attention instead of a random population sample and found that the prevalence of delayed gastric emptying was fourfold higher in women. It is difficult for medical professionals and researchers to collect enough data and provide accurate numbers since studying gastroparesis requires specialized laboratories and equipment.

References
Further reading
Overview from NIDDK National Institute of Diabetes, Digestive, and Kidney Diseases at NIH
Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L (January 2013). "Clinical guideline: management of gastroparesis" </s>