Cystic Fibrosis

- Introduction Cystic fibrosis( as well as c each(prenominal)edCFormucoviscidosis) is anautosomal recessionaryfamilial disorderthat affects most critically thelungs, and also thepancreas,liver, andintestine. It is characterized by deviant transport ofchlorideandsodiumacross anepithelium, jumper breaking wind to recondite, viscous secretions. The namerefers to the characteristicscarring(fibrosis) and cystformation within thepancreas that was starting line recognised in the 1930s.Difficulty in breathingis the most solid symptom and results from frequentlung infectionswhich atomic number 18 treated withantibiotics, therapies and several other(a) medications. former(a)symptoms, includingsinus infections,poor promoteth, andin cornucopia affect other parts of the body. A breathing discourse for cystic fibrosis, using a mask nebulizer and a ThAIRapy Vest A breathing treatment for cystic fibrosis, using a mask nebulizer and a ThAIRapy Vest CF is lay subdued by a transitionin the factorfor theproteincystic fibrosis trans-membrane conductance regulator(CFTR).This protein is required to regulate the comp iodinnts of diaphoresis,digestivejuices, andmucus. CFTR regulates the execution ofchlorideandsodium ions across epithelial membranes, such(prenominal) as the alveolar epithelia located in thelungs. Although most people without CF kick in devil working copies of the CFTR factor, only one is needed to prevent cystic fibrosis due to the disorders recessive nature. CF fixs when incomplete ingredient works roughhewnly (as a result of mutation) and at that office stafffore hasautosomal recessiveinheritance.CF is most vernacular amongCaucasians one in 25 people of European descentcarries oneallelefor CF. TheWorld Health Organizationstates that In the European Union, 1 in 20003000 new-innate(p)s is found to be affected by CF. Individuals with cystic fibrosis can be diagnosed before birth by agenttic testing or by asweat testin early childhood. Ultimate ly,lung transplantationis frequently necessary as CF worsens. - Signs and symptomsThe hallmark symptoms of cystic fibrosis ar salty tasting skin,poor growth and poor exercising weight gain despite a normal food intake,accumulation of thick, sticky mucus, frequent chest infections, and coughing or shortness of breath. Signs and symptoms very much appear in infancy and childhood, such asbowel movement obstructionin new-born babies. As the children grow, they mustiness exercise to release the mucus present in the alveoli. roughepithelial cells presentin the patient of progress to a mutated protein that leads to abnormally viscous mucus production.The poor growth in children typically presents as an softness to gain weight or height at the same rate as their peers and is occasionally not diagnosed until investigation is initiated for poor growth. The arrests of growth failure be multifactorial and intromit continuing lung infection, poor absorption of nutrients through the gastrointestinal tract, and profitd metabolic demand due to inveterate sickness. In rargon cases, cystic fibrosis can manifest itself as a coagulation disorder. A double recessive allele is needed for cystic fibrosis to be app arent.Young children are especially tender to vitaminmalabsorptive disorders because only a very small amount of vitamin K crosses the placenta, leaving the child with very low reserves. Because factors II, VII, IX, and X (clotting factors) are vitamin Kdependent, low takes of vitamin K can result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation evaluation may be warranted to g everywheren whether in that respect is an profound disease. Lungs and sinuses Lung disease results from clogging of the airways due to mucus build-up, decreasedmucociliary clearance, and resulting ardor.Inflammation and infection cause injury and structural dislodges to the lungs, jumper cable to a variety of symptoms. In th e early stages, continual incessant coughing along with copiousphlegmproduction, and decreased ability to exercise are common. Many of these symptoms occur whenbacteria that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages, changes in the architecture of the lung, such as pathology in the major airways (bronchiectasis), further alter difficulties in breathing. otherwise symptoms include coughing up blood (hemoptysis), highblood drawin the lung (pulmonary hypertension), shopping center failure, difficulties getting affluentoxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks, such asbi-level positive airway pressuremachines orventilators. Staphylococcus aureus, Haemophilus influenzae, andPseudomonas aeruginosaare the three most common electronic organisms cause lung infections in CF patients. In addition to typical bacterial infections, people with CF more than commonly develop other qualitys of lung disease.Among these isallergic bronchopulmonary aspergillosis, in which the bodys response to the commonfungusAspergillus fumigatuscauses worsening of breathing problems. Another is infection with Mycobacterium aviumcomplex (MAC), a group of bacteria related to resistancerculosis, which can cause a lot of lung prostitute and does not respond to common antibiotics. Mucus in theparanasal sinusesis equally thick and may also cause obstacle of the sinus passages, leading to infection. This may cause facial pain, fever, nasal drainage, andheadaches.Individuals with CF may develop overgrowth of the nasal tissue (nasal polyps) due to inflammation from degenerative sinus infections. Recurrent sinonasal polyps can occur in as many as 10% to 25% of CF patients. These polyps can block the nasal passages and increase breathing difficulties. Cardiorespiratory ramifications are the most common cause of last (80%) in patients at most CF centers in the unify States. gastrointestinal Prio r to prenatal andnewborn screening, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (meconium).Meconium may completely block theintestinesand cause serious illness. This condition, calledmeconium ileus, occurs in 510%of newborns with CF. In addition, protrusion of internalrectalmembranes (rectal prolapse) is more common, occurring in as many as 10% of children with CF, and it is ca employ by increased fecal volume, malnutrition, andpressure due to coughing. The thick mucus seen in the lungs has a counterpart in inspissate secretions from thepancreas, an organ responsible for providing digestivethat armed service break down food.These secretions block theexocrinemovement of the digestive enzymes into theduodenum and result in irreversible damage to the pancreas, often with painful inflammation (pancreatitis). Thepancreatic ductsare totally plugged in more advanced cases, commonly seen in older children or adolescents. This causes atrophy of the exocr ine glands and progressive fibrosis. The lack of digestive enzymes leads to obstruction absorbing nutrients with their subsequent excretion in the feces, a disorder known as malabsorption. Malabsorption leads tomalnutritionand poor growth and evelopment because of calorie loss. Resultant hypoproteinemiamay be loathsome enough to cause generalized edema. Individuals with CF also soak up difficulties absorbing the fat-soluble vitaminsA,D,E, andK. In addition to the pancreas problems, people with cystic fibrosis experience moreheartburn, intestinal obstructor byintussusception, and constipation. Older individuals with CF may developdistal intestinal obstruction syndromewhen thickened feces cause intestinal blockage. Exocrine pancreatic inadequacy occurs in the majority (85% to 90%) of patients with CF.It is mainly associated with puckish CFTR mutations, where twain alleles are completely non affaireal (e. g. ?F508/? F508). It occurs in 10% to 15% of patients with one severe and one mild CFTR mutation where there still is a little CFTR activity, or where there are two mild CFTR mutations. In these milder cases, there is still able pancreatic exocrine function so that enzyme supplementation is not required. There are usually no other GI complications in pancreas-sufficient phenotypes, and in general, such individuals usually have excellent growth and development.Despite this, idiopathicchronic pancreatitiscan occur in a subset of pancreas-sufficient individuals with CF, and is associated with recurrent abdominal pain and life-threatening complications. alter secretions also may cause liver problems in patients with CF. Bilesecreted by the liver to aid in digestion may block thebile ducts, leading to liver damage. Over time, this can lead to scarring and nodularity (cirrhosis). The liver fails to rid the blood of toxins and does not make importantproteins, such as those responsible forblood clotting. liver-colored disease is the third most common cause of d eath associated with cystic fibrosis.Endocrine Clubbing in the fingers of a person with cystic fibrosis Clubbing in the fingers of a person with cystic fibrosis Thepancreascontains theislets of Langerhans, which are responsible for making insulin, a hormone that helps regulate bloodglucose. Damage of the pancreas can lead to loss of the isletcells, leading to a type of diabetes that is unique to those with the disease. This cystic fibrosis-related diabetes(CFRD) shares characteristics that can be found intype 1andtype 2diabetics, and is one of the principal non-pulmonary complications of CF.Vitamin D is twisting incalciumandphosphateregulation. Poor uptake of vitamin D from the diet because of malabsorption can lead to the bone diseaseosteoporosisin which weakened bones are more susceptible tofractures. In addition, people with CF often develop clubbingof their fingers and toes due to the effects of chronic illness andlow oxygenin their tissues. Infertility Infertilityaffects twai n 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 cystic fibrosis is congenital absence of the vas deferens(which normally connects thetestesto theejaculatory ductsof thepenis), but potentially also by other mechanisms such as causingazoospermia,teratospermiaandoligoasthenospermia. Many men found to have congenital absence of the vas deferens during evaluation for infertility have a mild, previously undiagnosed form of CF. Some women have fertility difficulties due to thickened cervical mucus or malnutrition. In severe cases, malnutrition disruptsovulationand causesamenorrhea. Cause CF is ca apply by amutationin thegenecystic fibrosis trans-membrane conductance regulator(CFTR). The most common mutation,? F508, is a deletion (? signifying deletion) of three nucleotidesthat results in a loss of the amino acidphenylalanine(F) at the 508th positio n on the protein. This mutation accounts for two-thirds (6670%) of CF cases worldwide and 90% of cases in theUnited States however, there are over 1500 other mutations that 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 anautosomal recessive disease. TheCFTR gene, found at the q31. 2locusofchromosome 7, is 230,000 habitation pairslong, and creates a protein that is 1,480amino acidslong. More specifically the location is between base pair 117,120,016 to 117,308,718 on the long arm of chromosome 7, region 3, band 1 and sub-band 2, stand for as 7q31. . Structurally, CFTR is a type of gene known as anABC gene. The product of this gene (the CFTR) is a chloride ion channel important in creating sweat,digestivejuices andmucus. This protein possesses twoATP-hydrolyzingdomains, which allows the protein to use zi pin the form ofATP. It also contains two domains comprising 6alpha helicesapiece, which allow the protein to cross the cell membrane. A regulatorybinding aimon the protein allows activation byphosphorylation, mainly bycAMP-dependent protein kinase.Thecarboxyl terminalof the protein is anchored to thecytoskeletonby aPDZdomain interaction. In addition, there is increasing evidence thatgenetic modifiersbesides CFTR modulate the frequency and severity of the disease. One example ismannan-binding lectin, which is involved ininnate immunityby facilitatingphagocytosisof 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. Pathophysiology Molecular structure of the CFTR protein Molecular structure of the CFTR protein There are several mutations in theCFTRgene, and polar mutations cause different flees 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. ?F508-CFTR, which occurs in 90% of patients in the U. S. , creates a protein that does notfoldnormally and is degraded by the cell.Other mutations result in proteins that are too short (truncated) becauseproductionis ended previous(p)ly. Other mutations produce proteins that do not use energy normally, do not allowchloride iodideandthiocyanateto cross the membrane appropriately,or are degraded at a faster rate than normal. Mutations may also lead to someer copies of the CFTR protein being produced. The protein created by this gene is anchored to theouter membrane ofcellsin thesweat glands, lungs, pancreas, and all other retaining exocrine glands in the body.The protein spans this membrane and acts as achannelconnecting the inner part of the cell (cytoplasm) to thesurrounding fluid. This channel is primarily responsible for controlling the movement of halogens from inside to outside of the cell however, in the sweat ducts it facilitates the movement of chloride from the sweat into the cytoplasm. When the CFTR protein does not work, chloride and thiocyanateare trapped inside the cells in the airway and outside in the skin. Thenhypothiocyanite, OSCN, cannot be produced by resistive defense establishment.Because chloride isnegatively charged, this creates a difference in the electrical potential inside and outside the cell causingcationsto cross into the cell. Sodium is the most common cation in the extracellular space and the combination of sodium and chloride creates thesalt, 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 faeces, etc. There are several theories on how the defects in the protein and cellular function cause the clinical effects. One theory is that the lack of halogen and pseudohalogen (mainly, chloride, iodide and thiocyanate) exiting through the CFTR protein leads to the accumulation of more viscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the bodysimmune system.Another theory is that the CFTR protein failure leads to a paradoxical increase in sodium and chloride uptake, which, by leading to increased water reabsorption, creates dehydrated and thick mucus. Yet another theory is that abnormal chloride movementoutof the cell leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc. Chronic infections The lungs of individuals with cystic fibrosis are annex and infected by bacteria from an early age. These bacteria, which often spread among individuals with C F, 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. gluey secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate. Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such asStaphylococcus aureusandHemophilus influenzaecolonize and infect the lungs.Eventually,Pseudomonas aeruginosa(and sometimesBurkholderia cepacia) dominates. By 18 years of age, 80% of patients with classic cystic fibrosis harborPseudomonas aeruginosa, and another 3. 5% harbor Burkholderia cepacia. Once within the lungs, these bacteria adapt to the environment and developresistanceto commonly used antibiotics. Pseudomonascan develop specia l characteristics that allow the formation of large colonies, known as mucoidPseudomonas, which are seldom seen in people that do not have CF. One way infection spreads is 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 asnebulizers)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 routinely isolated from one another in the health care 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 asAspergillus fumigatus,Scedosporium apiospermum,Aspergillus terreus) and/or yeasts (such asCandida albicans ) other filamentous fungi less commonly isolated include Aspergillus flavusandAspergillus nidulans(occur transiently in CF respiratory secretions), andExophiala dermatitidisand Scedosporium prolificans(chronic airway-colonizers) some filamentous fungi likePenicillium emersoniiandAcrophialophora fusisporaare 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 corti saluteeroid 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 constipation of the lung function, as often happens with allergic broncho-pulmonary aspergillosis (ABPA) the ost common fungal disease in the context of CF, involving a Th2-driven immune respons e to Aspergillus. - Diagnosis and monitoring CFTR gene on chromosome 7 CFTR gene on chromosome 7 Cystic fibrosis may be diagnosed by many different methods includingnewborn screening,sweat testing, and genetic testing. As of 2006 in the United States, 10 percent of cases are diagnosed shortly after birth as part of newborn screening programs.The newborn screen initially measures for raised blood concentration of immunoreactive trypsinogen. Infants with an abnormal newborn screen need a sweat test to confirm the CF diagnosis. In many cases, a parent makes the diagnosis because the infant tastes salty. Trypsinogenlevels can be increased in individuals who have a single mutated copy of theCFTRgene (carriers) or, in rare instances, in individuals with two normal copies of theCFTRgene. Due to thesefalse positives, CF screening in newborns can be controversial.Most states and countries do not screen for CF routinely at birth. Therefore, most individuals are diagnosed after symptoms (e. g. sinopulmonary disease and GI manifestations) prompt an evaluation for cystic fibrosis. The most commonly used form of testing is the sweat test. Sweat-testing involves application program of a medication that stimulates sweating (pilocarpine). To deliver the medication through the skin, iontophoresisis used to, whereby oneelectrodeis placed onto the applied medication and an electric currentis passed to a separate electrode on the skin.The resultant sweat is then collected on filter paper or in a capillary tube and analyse for abnormal amounts ofsodiumandchloride. People with CF have increased amounts of sodium and chloride in their sweat. In contrast, people with CF have less thiocyanate andhypothiocyanitein their spittle and mucus. CF can also be diagnosed by identification of mutations in the CFTR gene. People with CF may be listed in adisease cash registerthat allows researchers and doctors to track health results and identify candidates forclinical trials. PrenatalCouples who are pregnant or planning a pregnancy can have themselves tested for the CFTR gene mutations to determine the risk that their child will be born with cystic fibrosis. Testing is typically performed first on one or both parents and, if the risk of CF is high, testing on thefetusis performed. TheAmerican College of Obstetricians and Gynecologists(ACOG) recommends testing for couples who have a personal or close family history of CF, and they recommend that carrier testing be offered to all Caucasian couples and be made available to couples of other ethnic backgrounds.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, and as of 2006 it is not possible to test for each one. Testing analyzes the blood for the most common mutations such as ? F508most commercially available tests attend 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 theplacenta(chorionic villus sampling) or the fluid around the fetus (amniocentesis). except,chorionic villus samplinghas a risk of fetal death of 1 in 100 and amniocentesis of 1 in 200a recent study has indicated this may be much lower, virtually 1 in 1,600.Economically, for carrier couples of cystic fibrosis, when comparing pre-implantation genetic diagnosis (PGD) with natural conception (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net sparing benefits up to a maternal age of approximately 40 y ears, after which NC, prenatal testing and abortion has higher economic benefit. - Management While there are no cures for cystic fibrosis there are several treatment methods. The charge of cystic fibrosis has ameliorate significantly over the past 70 years.While infants born with cystic fibrosis 70 years ago would have been unlikely to live beyond their first year, infants today are likely to live well into adulthood. new-made advances in the treatment of cystic fibrosis have meant that an individual with cystic fibrosis can live a fuller life less encumbered by their condition. The cornerstones of management are proactive treatment ofairway infection, and encouragement of good nutrition and an active lifestyle. Management of cystic fibrosis continues throughout a patients life, and is aimed at maximizing organ function, and therefore quality of life.At best, current treatments delay the decline in organ function. Because of the wide variation in disease symptoms treatment typica lly occurs at specialiser multidisciplinary centers, and is tailored to the individual. Targets for therapy are thelungs,gastrointestinal tract(including pancreatic enzyme supplements), thereproductive organs(including (ART) and psychological support. The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection. 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, art object effective, can be extremely time-consuming for the patient. One of the most important battles that CF patients face is finding the time to comply with prescribed treatments while balancing a normal life. In addition, therapies such astransplantationandgene therapyaim to cure some of the effects of cystic fibrosis. Gene therapy aims to produce normal CFTR to airway. Theoretically this process s hould be simple as the airway is easily accessible and there is only a single gene defect to correct.There are two CFTR gene introduction mechanisms involved, the first use of a viral vector (adenovirus, adeno-associated virus or retro virus) and secondly the use ofliposome. However there are some problems associated with these methods involving efficiency (liposomes insufficient protein) and delivery (virus provokes an immune response). Antibiotics Many CF patients are on one or moreantibioticsat all times, even when healthy, toprophylacticallysuppress infection. Antibiotics are absolutely necessary whenever pneumonia is suspected or there has been a noticeable decline in lung function, and are usually chosen based on the results of a putum analysis and the patients past response. This prolonged therapy often necessitates hospitalization and insertion of a more permanentIVsuch as aperipherally inserted central catheter(PICC line) orPort-a-Cath. Inhaled therapy with antibiotics such as tobramycin,colistin, andaztreonamis often given for months at a time to improve lung function by impeding the growth of colonized bacteria. Oral antibiotics such as ciprofloxacin orazithromycinare given to help prevent infection or to control ongoing infection. Theaminoglycosideantibiotics (e. g. obramycin) with long-term use can causeseveral side effects such as hearing loss, damaging thebalance systempresent in theinner earand producing many chronic kidney problems. To prevent theseside-effects, the amount of antibiotics in the blood are routinely measured and adjusted accordingly. Other treatments for lung disease Several mechanical techniques are used to dislodge sputum and encourage its expectoration. In the hospital setting, chest physiotherapy (CPT) is utilized a respiratory therapist percusses an individuals chest with his or her hands several times a day, to loosen up secretions.Devices that recreate this percussive therapy include theThAIRapy Vestand theintrapulmonary percussive ventilator(IPV). Newer methods such asBiphasic 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. Aerosolized medications that help loosen secretions includedornase alfaandhypertonicsaline. Dornase is arecombinanthuman deoxyribonuclease, which breaks down DNA in thesputum, thus decreasing itsviscosity.Denufosolis an investigational drug that opens an alternative chloride channel, helping to liquefy mucus. As lung disease worsens, mechanical breathing support may go necessary. Individuals with CF may need to wear special masks at night that help push air into their lungs. These machines, known asbi-level positive airway pressure(BiPAP) ventilators, help prevent low blood oxygen levels during sleep. BiPAP may also be used during physical therapy to improve sputum clearance. During severe illness, atubemay be pla ced in the throat (a procedure known as atracheostomy) to enable breathing supported by aventilator.For children financial support with CF, preliminary studies show pediatric massage therapy may improve patients and their families quality of life, though more rigorous studies must be done. Transplantation Lung transplantationoften becomes necessary for individuals with cystic fibrosis as lung function ceases andexercise tolerancedeclines. 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 in order 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 patient survival is threatened. Other aspects Intracytoplasmic sperm injection can be used to provide fertility for men with cystic. .fibrosis Intracytoplasmic sperm injection can be used to provide fertility for men with cystic. .fibrosis New-borns with intestinal obstruction typically require surgery, whereas adults withdistal intestinal obstruction syndrome typically do not.Treatment of pancreatic insufficiency by replacement of lacking(p) digestive enzymes allows the duodenum to properly absorb nutrients and vitamins that would otherwise be lost in the faeces. So far, no large-scale research involving the incidence ofatherosclerosisandcoronary heart diseasein adults with cystic fibrosis has been conducted. This is likely due to the fact that the vast majority of people with cystic fibrosis do not live long enough to develop clinically significant atherosclerosis or coronary heart disease.Diabetesis the most common non-pulmonary complication of CF. It mixes features oftype 1andtype 2diabetes, and is recognized as a distinct entity,cystic fibrosis-related diabetes (CFRD) . While oralanti-diabetic drugsare sometimes used, the only recommended treatment is the use ofinsulininjections or aninsulin pump,and unlike in type 1 and 2 diabetes, dietary restrictions are not recommended. Development ofosteoporosiscan be prevented by increased intake of vitamin D andcalcium, and can be treated bybisphosphonates, althoughadverse effectscan be an issue.Poor growth may be avoided by insertion of afeeding tubefor increasingcaloriesthrough supplemental feeds or by administration of injectedgrowth 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 patients sense of smell. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such asfluticasoneare used to decrease nasal inflammation.Female infertility may be overcome byassisted reproductionte chnology (ART) with the help of embryo transfertechniques. Male infertility caused by absence of thevas deferensmay be overcome withtesticular sperm extraction(TEST), collecting sperm cells directly from the testicles. If the collected sample contains too few sperm cells to likely have a spontaneousfertilization,intracytoplasmic sperm injectioncan be performed. Third party reproductionis also a possibility for women with CF. - PrognosisThe prognosis for cystic fibrosis has improved due to earlier diagnosis through screening, better treatment and access to health care. In 1959, the median age of survival of children with cystic fibrosis in the United States was six months. In 2008, survival averaged 37. 4 years. In Canada, median survival increased from 24 years in 1982 to 47. 7 in 2007. Of those with cystic fibrosis who are more than 18 years old as of 2009 92% had graduated fromhigh school, 67% had at least some college education, 15% were disabled and 9% were unemployed, 56% were single and 39% were married or living with a partner.In Russiathe overall median age of patients is 25, which is caused by the absence or high cost of medication and the fact that lung transplantation is not performed. Quality of life Chronic illnesses can be very difficult to manage. Cystic fibrosis (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. Therefore, mucus makes it dispute to breathe.If it is compromised, it affects the quality of life of someone with CF, and their ability to complete such tasks as everyday chores. It is important for CF patients to understand the detrimental relationship that chronic illnesses place on the quality of life. Havermans and colleagues (2006) have shown that young outpatients with CF that have participated in the CFQ-R (Cystic Fibrosis Questionnaire-Revised) rated some QOL domains higher than did their parents. Consequently, outpatients with CF have a more positive brainpower for themselves.Furthermore, there are many ways to improve the QOL in CF patients. Exercise is promoted to increase lung function. The fact of integrating an exercise regimen into the CF patients daily routine can significantly improve the quality of life. There is no definitive cure for Cystic Fibrosis. However, there are respective(a) medications used such as, mucolytics, bronchodilators, steroids and antibiotics that have the purpose of loosening mucus, expanding airways, decreasing inflammation and fighting lung infections. -Epidemiology Mutation Frequency worldwide ?F508 66%70% G542X 2. 4% G551D 1. 6% N1303K 1. 3% W1282X 1. 2% All others 27. 5% Cystic fibrosis is the most common life-limiting autosomal recessive disease among people ofCaucasian heritage. In the United States, approximately 30,000 individuals have CF most are diagnosed by six months of age. InCanada, there are approximately 3,500 people with CF. Approximately 1 in 25 people of European descent, and one in 30 of Caucasian Americans, is a carrier of a cystic fibrosis mutation.Although CF is less common in these groups, approximately 1 in 46Hispanics, 1 in 65Africansand 1 in 90 Asianscarry at least one abnormal CFTR gene. Ireland has the worlds highest incidence of cystic fibrosis, at 11353. Although technically arare disease, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception isFinland, where only one in 80 people carry a CF mutation. In the United States, 1 in 4,000 children are born with CF. In 1997, about 1 in 3,300 Caucasian children in the United States was born with cystic fibrosis.In contrast, only 1 in 15,000 African American children suffered from cystic fibrosis, and in Asian Americans the rate was even lower at 1 in 32,000. Cystic fi brosis is diagnosed in males and womanishs equally. For reasons that remain unclear, data has shown that males tend to have a lengthylife expectancythan females,however recent studies suggest this gender gap may no longer exist perhaps due to improvements in health care facilities,while 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 ? F508 carriers has been estimated at 1200 in northern Sweden, 1143 in Lithuanians, and 138 in Denmark. No ? F508 carriers were found among 171Finnsand 151Saami people. ?F508 does occur in Finland, but it is a minority allele there. Cystic fibrosis is known to occur in only 20 families (pedigrees) in Finland. Hypotheses about prevalence The? F508mutation is estimated to be up to 52,000 years old. Numerous hypotheses have been advanced as to why such a deadly mutation has persisted and spread in the human population.Othe r common autosomal recessive diseases such assickle-cell anemia have been found to protect carriers from other diseases, a concept known asheterozygote advantage. Resistances to the following have all been proposed as possible sources of heterozygote advantage * Cholera With the finding and discovery thatcholera toxinrequires normal soldiers 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 required basically for the entry ofSalmonella typhiinto cells,suggesting that carriers of the mutant CFTR genes might be resistant totyphoid fever. Noin vivostudy has yet confirmed this. In both cases, the low level of cystic fibrosis outside of Europe, in places where both cholera and typhoid fever areendemic, is not immediately explicable. * Diarrhea It has also been hypothesized that the prevalenc e of CF in Europe might be connected with the development of cattle domestication. In this hypothesis, carriers of a ingle mutant CFTR chromosome had some protection from diarrhea caused by lactose intolerance, preceding to the appearance of the mutations that created lactose tolerance. * Tuberculosis Another explanation is that carriers of the gene could have some resistance to TB. - History It is supposed that CF 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, literaturefrom Germany and Switzerland in the 18th century warnedWehe dem Kind, das beim Ku? auf die Stirn salzig schmekt, er ist verhext und muss bald sterbeor 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. Doro thy Hansine Andersen Dorothy Hansine Andersen In the 19th century,Carl von Rokitansky give awayd a case of fetal death withmeconium peritonitis, a complication of meconium ileus associated with cystic fibrosis.Meconium ileus was first described in 1905 byKarl Landsteiner. In 1936,Guido Fanconipublished a paper describing a connecting link between celiac disease, cystic fibrosis of the pancreas, and bronchiectasis. In 1938Dorothy Hansine Andersenpublished an article, Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease a Clinical and Pathological Study, in theAmerican 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 Sant Agnese discovered abnormalities insweatelectrolytes asweat testwas d eveloped and improved over the next decade. The first linkage between CF and another marker (Paroxonase) was found in 1985, indicating that only one locus exists for CFHans Eiberg. In 1988 the first mutation for CF,? F508was discovered byFrancis Collins,Lap-Chee TsuiandJohn R. Riordanon 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 geneticstechniques had been unable to accurately pinpoint the mutated gene. Using protein markers,gene-linkagestudies were able to map the mutation to chromosome 7. Chromosome-walking and-jumpingtechniques were then used to identify andsequencethe gene. In 1989 Lap-Chee Tsui led a team of researchers at the Hospital for Sick ChildreninTorontothat discovered the gene responsible for CF.Cystic fibrosis represents the first genetic disorder elucidated strictly by the process ofreverse genetics. - Research Gene therapy Gene therapyhas been exp lored as a potential cure for cystic fibrosis. Ideally, gene therapy places a normal copy of theCFTR gene into affected cells. Transferring the normal CFTR gene into the affected epithelium cells would result in the production of functional CFTR in all target cells, without adverse reactions or an inflammation response.Studies have shown that to prevent the lung manifestations of cystic fibrosis, only 510% the normal amount of CFTRgene expressionis 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. The main reason is that 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.With the help of theCystic Fibrosis Trust, which has a league of highly profess ional gene therapists, both somatic and Adeno-associated viral vector have made advances. TheAdenoviridae, or more commonly known as the cold virus, is genetically altered, allowing the CFTR gene to enter lung cells. Small molecules A number ofsmall moleculesthat aim at compensating various mutations of the CFTR gene are under development. One approach is to develop drugs that get the ribosome to overcome the tarry codonand synthesize 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 mutationssuch as G542X, which consists of the amino acidglycinein position 542 being replaced by a stop codon. Aminoglycoside antibiotics interfere with DNA synthesis and error-correction. In some cases, they can cause the cell to overcome the stop codon, insert a random amino acid, and express a full-length protein.The aminoglycosidegentamicinhas been used to tr eat lung cells from CF patients in the laboratory to induce the cells to grow full-length proteins. Another drug targeting nonsense mutations isataluren, which is undergoing Phase III clinical trials as of October 2011. BIBLIOGRAPHY 1. BIOLOGY TEXTBOOK FOR crystallise XII (NCERT) 2. TRUEMANS BIOLOGY FOR CLASS XII 3. SCIENCE REPORTER (September, 2007) 4. THE NEWYORK TIMES (December 22, 2009) 5. www. google. co. in/cysticfibrosis 6. en. wikipedia. org/wiki/Cystic_fibrosis 7. www. ncbi. nlm. nih. gov 8. www. cff. org/ 9. www. cysticfibrosis. com/ 10. www. cftrust. org. uk/