Cystic Fibrosis

- Introduction cystic fibrosis(to a fault cal take cformucoviscidosis) is anautosomal recessive finishlyelebrokertic disorderthat touchs most critically thelungs, and alike thepancreas,liver, andintestine. It is characterized by unnatural transport ofchlorideand atomic number 11across anepithelium, hint to dense, viscous secretions. The namerefers to the propertyscarring(fibrosis) andcyst validation within thepancreas that was foremost recognized in the 1930s.Difficulty in breathingis the most serious symptom and results from frequentlung transmittingswhich ar toughened withantibiotics, therapies and any(prenominal)(prenominal) other medicinal doses. Othersymptoms, including fistulous withers infections, paltry drawth, andinfertility affect other parts of the consistence. A breathing intervention for cystic fibrosis, hire a mask nebulizer and a ThAIRapy Vest A breathing trea twainrk forcet for cystic fibrosis, using a mask nebulizer and a ThAIRapy Vest cf.is cause by a funin the elementfor theproteincystic fibrosis trans-tissue layer conductance regulator(CFTR).This protein is required to regulate the comp starnts of electric shaverbed,digestivejuices, and mucous secretion. CFTR regulates the move custodyt ofchlorideandsodium ions across epithelial membranes, much(prenominal)(prenominal) as the alveolar epithelia located in thelungs. Although most peck without CF restrain two working copies of the CFTR comp superstarnt, provided one is ask to oppose cystic fibrosis collectable to the disorders recessive nature. CF splits when neither broker works frequently (as a result of edition) and therefore hasautosomal recessiveinheritance.CF is most earthy among Caucasics one in 25 passel of European descentcarries oneallelefor CF. TheWorld Health plaquestates that In the European Union, 1 in 20003000 invigorated-borns is bring to be bear upon by CF. Individuals with cystic fibrosis merchant ship be diagnosed before assume by transmissible testing or by a soapsuds testin early childhood. Ultimately,lung transplantationis lots ms necessary as CF worsens. - Signs and symptomsThe hallmark symptoms of cystic fibrosis ar salty tasting skin,poor growth and poor weight mictu subscribe to despite a linguistic rule food intake,accumulation of thick, sticky mucus, frequent chest infections, and coughing or shortness of breath. Signs and symptoms often appear in infancy and childhood, much(prenominal) asbowel forepart restraintin new-born babies. As the children grow, they must manipulation to release the mucus set out in the alveoli. Ciliatedepithelial cubicles presentin the patient corroborate a mutated protein that moves to abnormally viscous mucus production.The poor growth in children typically presents as an inability to gain weight or height at the similar rate as their peers and is occasionally non diagnosed until investigation is initiated for poor growth. The causes of growth failure be multi factorial and include de factorrative lung infection, poor absorption of nutrients with the gastro intestinal tract, and enlarged metabolic demand referable to chronic illness. In high-minded cases, cystic fibrosis posterior manifest itself as a clotting disorder. A double recessive allele is needed for cystic fibrosis to be app bent.Young children are especially sensitive to vitaminmalabsorptive disorders because only a very small list of vitamin K crosses the placenta, leaving the child with very confused reserves. Because factors II, VII, IX, and X (clotting factors) are vitamin Kdependent, low levels of vitamin K throne result in coagulation problems. Consequently, when a child presents with unexplained bruising, a coagulation valuation whitethorn be warranted to determine whether there is an underlying illness. Lungs and sinuses Lung disease results from clogging of the airline businesss repayable to mucus build-up, decreasedmucociliary croupenistera nce, and resultinginflammation.Inflammation and infection cause injury and structural changes to the lungs, in the lead to a variety of symptoms. In the early st come alongs, regular incessant coughing along with copiousphlegmproduction, and decreased ability to exercise are harsh. numerous of these symptoms occur when bacterium that normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages, changes in the architecture of the lung, such(prenominal) as pathology in the major airways (bronchiectasis), further aggravate difficulties in breathing.Other symptoms include coughing up split (hemoptysis), high inception pressurein the lung (pulmonary hypertension), heart and soul failure, difficulties getting comelyoxygen to the body (hypoxia), and respiratory failure requiring support with breathing masks, such asbi-level positive degree airway pressuremachines orventilators. Staphylococcus aureus, Haemophilus influenzae, andgenus Pseudomonas aeruginos aare the trio most usual organisms create lung infections in CF patients. In accessory to typical bacterial infections, people with CF more unremarkably develop other types of lung disease.Among these isallergic bronchopulmonary aspergillosis, in which the bodys response to the normalfungusgenus Aspergillus fumigatuscauses worsen of breathing problems. A nonher is infection with Mycobacterium aviumcomplex (MAC), a congregation of bacteria related totuberculosis, which can cause a lot of lung harm and does not respond to common antibiotics. Mucus in thepara impecunious sinusesis every bit thick and whitethorn in addition cause barricadeage of the sinus passages, booster cable to infection. This may cause facial pain, fever, nasal drainage, andheadaches.Individuals with CF may develop oergrowth of the nasal tissue (nasal polyps) due to inflammation from chronic sinus infections. Recurrent sinonasal polyps can occur in as legion(predicate) as 10% to 25% of CF patients. Th ese polyps can interrupt the nasal passages and increase breathing difficulties. Cardiorespiratory complications are the most common cause of demolition (80%) in patients at most CF centers in the united States. Gastrointestinal Prior to prenatal andnewborn sifting, 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 numerous as 10% of children with CF, and it is caused 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 divine service break down food.These secretions block theexocrinemovement of the digestive enzymes into theduodenum and r esult in irreversible ravish to the pancreas, often with painful inflammation (pancreatitis). Thepancreatic ductsare totally blocked in more advanced cases, commonly seen in older children or adolescents. This causes atrophy of the exocrine glands and progressive fibrosis. The deficiency of digestive enzymes leads to difficulty take up nutrients with their subsequent excretion in the feces, a disorder cognize as malabsorption. Malabsorption leads tomalnutritionand poor growth and evelopment because of calorie loss. Resultant hypoproteinemiamay be horrendous enough to cause componentralized edema. Individuals with CF too set out difficulties sorb the fat-soluble vitaminsA,D,E, andK. In addition to the pancreas problems, people with cystic fibrosis experience moreheartburn, intestinal mental block byintussusception, and constipation. Older somebodys with CF may developdistal intestinal obstruction syndromewhen thickened feces cause intestinal blockage. exocrine gland pancr eatic insufficiency occurs in the mass (85% to 90%) of patients with CF.It is in the first place associated with fearful CFTR mutations, where two alleles are completely non junctureal (e. g. ?F508/? F508). It occurs in 10% to 15% of patients with one exacting and one diffused CFTR mutation where there windlessness is a subatomic CFTR activity, or where there are two mild CFTR mutations. In these milder cases, there is still sufficient pancreatic exocrine function so that enzyme supplementation is not required. There are usually no other GI complications in pancreas-sufficient phenotypes, and in constituentral, such individuals usually perplex 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 emotional state-threatening complications. Thickened secretions also may cause liver problems in patients with CF. Bilesecreted by the liv er to aid in digestion may block thebile ducts, tether to liver equipment casualty. Over season, this can lead to scarring and nodularity (cirrhosis). The liver fails to rid the credit line of toxins and does not make importantproteins, such as those responsible for phone line clotting. Liver disease is the third most common cause of oddment associated with cystic fibrosis.Endocrine club 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 devising 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 base intype 1andtype 2diabetics, and is one of the principal non-pulmonary complications of CF.Vitamin D is involved incalciumand orthophosphateregulati on. Poor uptake of vitamin D from the diet because of malabsorption can lead to the turn out diseaseosteoporosisin which weakened bones are more unprotected tofractures. In addition, people with CF often develop clubbingof their fingers and toes due to the effects of chronic illness andlow oxygenin their tissues. asepsis Infertilityaffects both men and women. At least 97% of men with cystic fibrosis are infertile, but not sterile and can charter 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 causingazoo spermatozoonia,teratospermiaandoligoasthenospermia. Many men found to generate congenital absence of the vas deferens during evaluation for infertility live with a mild, previously undiagnosed form of CF. Some women consecrate fertility difficulties due to thic kened cervical mucus or malnutrition. In severe cases, malnutrition disruptsovulationand causesamenorrhea. Cause CF is caused 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 aminic acidphenylalanine(F) at the 508th position on the protein. This mutation accounts for two-thirds (6670%) of CF cases worldwide and 90% of cases in the united States however, there are over 1500 other mutations that can produce CF.Although most people fuddle 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 level pairslong, and creates a protein that is 1,480amino acidslong. More specifically the location is between tail end pair 117,120,016 to 117,308,718 on the long arm of chromosome 7, region 3, band 1 and sub-band 2, represented as 7q31. . Structurally, CFTR is a type of gene cognize 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 useenergyin the form ofATP. It also contains two domains comprising 6alpha helicesapiece, which allow the protein to cross the cell membrane. A regulatorybinding siteon 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 oftenness and severity of the disease. wizard example ismannan-binding lectin, which is involved ininnate ohmic protectionby facilitatingphagocytosisof microorganisms. Polymo rphisms in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a three mickle higher put on the line of end-stage lung disease, as swell up as an increased burden of chronic bacterial infections. Pathophysiology Molecular structure of the CFTR protein Molecular structure of the CFTR protein There are several(prenominal) mutations in theCFTRgene, 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. ?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 prematurely. Other mutations produce proteins that do not use energy normally, do not allowchloride iodideandthiocyanateto cross the membrane app ropriately,or are degraded at a faster rate than normal. Mutations may also lead to hardly a(prenominal)er copies of the CFTR protein universe produced. The protein created by this gene is anchored to theouter membrane ofcellsin thesweat glands, lungs, pancreas, and all other remain exocrine glands in the body.The protein spans this membrane and acts as achannelconnecting the intragroup part of the cell (cytoplasm) to thesurrounding fluid. This channel is primarily responsible for lordly the movement of halogens from inwardly 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 immune defence force system.Because chloride isnegatively charged, this creates a difference in the electrical potential inside and outside the cell causi ngcationsto 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 hind end 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 mist from the bodysimmune system.Another theory is that the CFTR protein failure leads to a parad oxical 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 colonized and infected by bacteria from an early age. These bacteria, which often diffuse 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. embarrassing 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 initi al stage, common bacteria such asStaphylococcus aureusandHemophilus influenzaecolonize and infect the lungs.Eventually,Pseudomonas aeruginosa(and sometimesBurkholderia cepacia) dominates. By 18 days of age, 80% of patients with classic cystic fibrosis cheerPseudomonas 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 special characteristics that allow the formation of large colonies, known as mucoidPseudomonas, which are rarely seen in people that do not have CF. One way infection spreads is by passing between different individuals with CF.In the away, people with CF often participated in summer CF Camps and other recreational gatherings. infirmarys 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 bac teria 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 acquire gowns and gloves when examining patients with CF to lay out 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 consideration of CF.Defective mucociliary clearance characterizing CF is associated with topical anaesthetic immunological disorders. In addition, the protracted therapy with antibiotics and the use of corti make uperoid give-and-takes may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may work to the local inflammatory response, and therefore to the progressive deterioration 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 response 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 toping,sweat testing, and genetic testing. As of 2006 in the United States, 10 percent of cases are diagnosed shortly subsequently birth as part of newborn screening programs.The newborn screen ab initio measures for raised blood concentration of immunoreactive trypsinogen. Infants with an abnormal newborn sc reen 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 genius mutated copy of theCFTRgene (carriers) or, in rare instances, in individuals with two normal copies of theCFTRgene. Due to these irrational 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 subsequently 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 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 give out electrode on the skin.The resultant sweat is then co llected on pervade paper or in a capillary tube and canvas 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 saliva and mucus. CF can also be diagnosed by realisation of mutations in the CFTR gene. People with CF may be listed in adisease registrythat allows searchers and doctors to track health results and signalize 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. interrogatory is typically performed first on one or both parents and, if the risk of CF is high, testing on thefoetusis performed. TheAmerican College of Obstetricians and Gynecologists(ACOG) recommends testing for couples who have a personal or fold family history of CF, and they recommend that carrier te sting be offered to all Caucasian couples and be make 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 gee 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 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 theplacenta(chorionic vill us sampling) or the fluid around the fetus (amniocentesis). However,chorionic villus samplinghas a risk of fetal ending of 1 in 100 and amniocentesis of 1 in 200a youthful study has indicated this may be much lower, approximately 1 in 1,600.Economically, for carrier couples of cystic fibrosis, when comparing pre-implantation genetic diagnosis (PGD) with natural supposition (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net economical benefits up to a maternal age of approximately 40 years, afterwards which NC, prenatal testing and abortion has higher economic benefit. - Management bandage there are no cures for cystic fibrosis there are several care forment methods. The management of cystic fibrosis has improved significantly over the past 70 years.While infants born with cystic fibrosis 70 years ago would have been un probably to live beyond their first year, infants today are promising to live well into adulthood. Recent advances in th e 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 musical note of life.At best, current treatments delay the decline in organ function. Because of the wide edition in disease symptoms treatment typically occurs at specialist multidisciplinary centers, and is accommodate 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 spoken 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 for the patient. One of the most important battles that CF patients face is finding the time to come after with prescribed treatments while balancing a normal life. In addition, therapies such astransplantationandgene therapyaim to cure some of the effects of cystic fibrosis. divisor therapy aims to introduce normal CFTR to airway. Theoretically this process should 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 (adenocomputer virus, 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 i mmune 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 elongate therapy often necessitates hospitalization and get intoion 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 t he inward 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 some(prenominal) 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 pester 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 altered for home use. Aerosolized medications that help loosen secretions includedornase alfaandhypertonicsaline. Dornase is arecombinanthuman deoxyribonuclea se, 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 become 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 strong-arm therapy to improve sputum clearance. During severe illness, atubemay be placed in the throat (a procedure known as atracheostomy) to enable breathing supported by aventilator.For children living with CF, fire 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 andexerc ise 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 quiet 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 endurance 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 alternate of missing digestive enzymes allows the duodenum to aright absorb nutrients and vi tamins 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 inappropriate 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 af eeding 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 reproductiontechnology (ART) with the help of conceptus 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 wo men 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 half-dozen 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 boilers suit 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 challenging 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 insalubrious relationship that chronic illnesses place on the quality of life. Havermans and colleagues (2006) have shown that preadolescent 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 outlook for themselves. shape upmore, 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 perfunctory routine can significantly improve th e quality of life. There is no definitive cure for Cystic Fibrosis. However, there are diverse medications used such as, mucolytics, bronchodilators, steroids and antibiotics that have the purpose of loosening mucus, expanding airways, decreasing inflammation and scrap 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. rough 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 Asians consort at least one abnormal CFTR gene. Ireland has the worlds highest inciden ce 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, near 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 fibrosis is diagnosed in males and females equally. For reasons that remain unclear, data has shown that males tend to have a longerlife 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 dispersion of CF alleles varies among populations. The frequency of ? F508 carriers has been estimated at 1200 in blue 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 lethal mutation has persisted and spread in the human population.Other 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 host CFTR proteins to function properly, it was hypothesized that carr iers 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 essentially for the entry ofSalmonella typhiinto cells,suggesting that carriers of the mutant CFTR genes might be disgusting 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. * looseness of the bowels It has also been hypothesized that the prevalence 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, prior 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, authentic aspects of CF were identified much earlier.Indeed, literaturefrom Germany and Switzerland in the 18th cytosine 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 in brief must die, recognizing the association between the salt loss in CF and illness. Dorothy Hansine Andersen Dorothy Hansine Andersen In the 19th century,Carl von Rokitansky exposit 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 betweenceliac disease, cystic fibrosis of the pan creas, 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 fit 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 developed and improved over the following 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. Bec ause mutations in the CFTR gene are typically small,classical geneticstechniques had been unable to accurately atom 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 explored 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 fib rosis, 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 paid 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 thestop 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 treat 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. biota TEXTBOOK FOR CLASS XII (NCERT) 2. TRUEMANS BIOLOGY FOR CLASS XII 3. SCIENCE REPORTER (September, 2007) 4. THE NEWYORK TIMES (December 22, 2009) 5. www. googl e. 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/