The Hunters: Phantom Chapter 32

Matt watched in horror as the phantom shook Damon like a rag dol . Elena spun around to lock eyes with Matt and Bonnie. â€Å"We have to save him,† she whispered, a fierce determination on her face, and immediately took off running, shoving her way through the piles of ash. Matt figured that if Damon, with al his vampire strength and fighting skil s honed over the centuries, was so completely helpless in the hands of this phantom – and jeez, with the way it was yanking him back and forth now, his head real y was going to pop off – then Matt, Bonnie, and Elena had less than a snowbal ‘s chance in hel of making any difference to this fight. The only real question would be whether the phantom would kil them, too. And the truth was that Matt didn't even like Damon, not one tiny little bit. Sure, Damon had helped save Fel ‘s Church from Katherine and Klaus, and from the kitsune demons, but he was stil a murderous, sarcastic, unrepentant, cocky, arrogant, nasty, usual y unpleasant vampire. Damon had undoubtedly hurt more people than he had helped over his long life, even if you generously credited him with saving every single resident of Fel ‘s Church. And he always cal ed Matt â€Å"Mutt,† pretending that he couldn't remember his actual name, which was completely infuriating. As Damon meant it to be. Stil , Elena loved Damon. For whatever reason. Probably the same inexplicable reason that regular girls loved regular old bad boys, Matt suspected. A dyed-in-the-wool good guy, he'd never seen the appeal himself. But Elena did. And Damon was part of the team, sort of, and you didn't leave your teammates to get decapitated by demon icewomen on ash-blanketed moons in other dimensions without at least doing your best to put up a fight. Not even if you didn't like them at al . Matt ran after Elena, and Bonnie fol owed. When they reached the phantom, Elena was already scrabbling at the icy blue hand clutched around Damon's throat, trying to pry its fingers up enough to slip her own underneath. The phantom barely glanced at her. Matt gave an inward sigh at the hopelessness of it al and swung a powerful roundhouse blow toward the phantom's stomach. Before his fist could connect, his target turned from ice to swirling, intangible mist, and his punch passed right through the phantom. Thrown off balance, Matt staggered and fel into the phantom's now-vaporous torso. It was like fal ing into a freezing-cold river of sewage. A numbing chil and a horrible, sickening smel washed over Matt. He pul ed back out of the mist, nauseous and shivering but upright. He blinked dazedly around. Elena was grappling with the phantom's fingers, scratching and yanking, and the phantom watched her with a kind of distant amusement, not the least bit alarmed or discomforted by the girl's efforts. Then it moved, so quickly Matt saw only a blur of bluish green, sending Elena flying, her arms and legs flailing, into a heap of ash. She scrambled to her feet immediately, blood trickling from her hairline, leaving red tracks through the ash that now coated her skin. Bonnie was trying, too: She'd worked her way around behind the phantom and was hitting and kicking at it. Mostly, her feet and fists swung harmlessly right through the phantom's mist, but occasional y a blow would connect with the more solid ice. These blows seemed like they were total y ineffective, though: Matt couldn't tel whether the phantom had even noticed Bonnie was attacking it. Veins were bulging out of Damon's face and neck, and he hung from the phantom's hand. The flesh of his neck was white around the stretched tendons. Superpowered strong old vampire or not, Damon was hurting. Matt tossed up a prayer in the direction of whatever saint looked after people pursuing hopeless causes, and threw himself back into the fight. There was blackness. And then there was pain, and the darkness reddened, then cleared, and Damon could see once more. The phantom – that bitch of a phantom – was holding him by the neck, and her skin was so cold, so cold it burned everywhere it touched him. He couldn't move. But he could see Elena standing below him. Beautiful Elena, covered in ash, streaked with blood, her teeth bared and her eyes flashing like a warrior goddess. His heart swel ed with love and fear. The brave little redbird and the boy Mutt fought beside her. Please, he wanted to say. Don't try to save me. Run. Elena, you have to run. But he couldn't move, couldn't speak. Then the phantom shifted her stance and, as Damon watched, Elena stopped her attack and clutched at her stomach, grimacing in pain. Matt and Bonnie were holding themselves as wel , their faces pale and strained, their mouths open in screams. With a wail, Bonnie col apsed. Oh no, Damon thought with a bolt of horror. Not Elena. Not the redbird. Not for me. Then suddenly, a gusting wind swirled around him, and he was flung from the phantom's grip. There was a roaring in his ears and a stinging in his eyes. Looking around, he saw Bonnie and Elena, their long hair flying around them wildly; Matt, his arms pinwheeling; and the phantom, its glass-green face for once startled instead of knowing. Tornado, Damon thought vaguely, and then, Gateway, and he realized he was being thrown upward, back into the darkness once more. The wind was howling at a deafening pitch now, and Stefan had to raise his voice to a shout to even hear himself over it. He had to keep both hands clamped down on the book – it was being pul ed out of his hands as if something alive and very strong were consciously trying to yank it away. â€Å"Mihi adi. Te voco. Necesse est tibi parere,† Stefan said. â€Å"Come to me. I summon you. You must obey.† That was the end of the summoning spel in Latin. The next part was the banishing spel , which would be in English. Of course, the phantom would have to actual y be there for that part of the spel to be effective. The wind whipping through the garage grew even stronger. Outside, thunder rumbled. Stefan watched the innermost circle, deep in the shadows of the garage, but there was nothing there. The unnatural wind was beginning to let up. Panic rose in his chest. Had they failed? He glanced anxiously at Alaric and Meredith, then at Mrs. Flowers, but none of them were looking at him, staring transfixed at the circle. Stefan looked back into it, hoping against hope. But there was nothing there. Wait. There was the faintest movement of something, right in the center of the circle, the tiniest flash of blue-green light, and along with it came a chil . Not like the cold wind that had spun through the garage, but more like an icy breath – inhale and exhale, inhale and exhale – slow and steady and freezing cold, right from that one spot. The glimmer widened, deepened, darkened, and suddenly what Stefan was looking at shifted and changed from an amorphous glimmer to a woman. An icy, misty, giant woman tinted in shades of blue and green. Inside her chest was a deep red rose, its stem a solid mass of thorns. Meredith and Celia let out audible gasps. Mrs. Flowers stared calmly, while Alaric's jaw had dropped. This must be the jealousy phantom. Stefan had always thought of jealousy as burning hot. Fiery kisses, fiery anger. But anger, lust, envy, al the things that made up jealousy, could be cold, too, and he had no doubt that they had the right phantom. Stefan noticed al these things about the phantom and forgot them again in a split second, because it wasn't just the ice-woman who materialized at the center of the circle. Confused, weeping, staggering, streaked with ash and mud, three humans had appeared there as wel . His beautiful, elegant Elena, caked in grime, her golden hair tangled and matted, lines of blood running down her face. Delicate little Bonnie, tearstained and pale as milk, but with an expression of fury as she kicked and clawed at the phantom. And al -American, always reliable Matt, dusty and disheveled, turning to peer out at them with a peculiarly blank expression, as if simply wondering what fresh hel he'd landed in now. And then one more person, a fourth figure wobbling and gasping, the last to shimmer into view. For a moment, Stefan didn't recognize him – couldn't recognize him, because this man wasn't supposed to exist anymore. Instead he just felt like a hauntingly familiar stranger. The stranger put his hands to his throat protectively and looked out of the circle, straight at Stefan. Through a bloody, swol en lip and bruised slits of eyes, the ghost of a bril iant smile appeared, and the gears of Stefan's mind slotted into place and began to turn again at last. Damon. Stefan was so flabbergasted he didn't know what to feel at first. Then, deep within him, a slow warmth spread with the realization that his brother was back. The last piece left of al his strange history was here once again. Stefan wasn't alone. Stefan took a step forward toward the edge of the diagram, holding his breath. â€Å"Damon?† he said softly, wonderingly. Jealousy snapped its head toward him, and Stefan was pinned to his spot by its glassy cold gaze. â€Å"He came back before, you know,† it said conversational y, and its voice chil ed Stefan as if ice water had been thrown in his face. â€Å"He just didn't want you to know so he could have Elena al to himself. He's been lurking around, lying low, playing tricks like he always does.† Jealousy was undoubtedly feminine, and its cool observational tone reminded Stefan of the little voice that sometimes spoke from the back of his mind, cal ing out his darkest and most shameful thoughts. Could the others even hear it? Or was it speaking straight into his mind? He risked a glance around. They al – Meredith, Celia, Alaric, Mrs. Flowers – stood stil as statues, staring at Jealousy. Behind them, the makeshift beds lay empty. When the three sleepers' astral forms had entered the circle with the phantom, their bodies must have somehow joined them, making them solid within the inner circle. â€Å"He came to Elena,† the phantom taunted. â€Å"He kept his resurrection a secret from you so that he could pursue her. Damon didn't worry for a moment about how you felt about his death. And while you were busy mourning him, he was busy visiting Elena's bedroom.† Stefan reeled backward. â€Å"He always wants what you have, and you know it,† the phantom continued, its translucent lips curving in a smile. â€Å"It's been true since you were mortals. Remember how he came home from university and stole Katherine away from you? He used al his charms on her, just because he knew you loved her. Even with the smal things: If you had a toy, he'd take it. If you wanted a horse, he'd ride it. If there was a piece of meat on the platter between you, he'd take it even if he wasn't hungry, just so you wouldn't get it.† Stefan shook his head slowly from side to side, again feeling too slow, like he had once again missed the important moment. Damon had been visiting Elena? When he had cried on her shoulder about his fal en brother, had Elena known Damon was alive? â€Å"But you thought you could trust Elena, didn't you, Stefan?† Elena turned to stare at him, her cheeks pale beneath their coating of ash. She looked sick and apprehensive. â€Å"No, Stefan – † Elena started to say, but the phantom went swiftly on, its words soothingly spoken poison. Stefan knew what it was doing. He wasn't a fool. Yet he felt himself nodding, agreeing, a slow red anger rising inside him despite his more rational self's struggle against it. â€Å"Elena kept his secret from you, Stefan. She knew you were in pain and that knowing Damon was alive would have eased that suffering, but stil she kept silent, because Damon asked her to, and what Damon wanted was more important than helping you. Elena's always wanted both of the Salvatore brothers. It's funny, real y, Stefan, how you're never quite enough for the women you love. This isn't the first time Elena's chosen Damon over you, is it?† Elena shook her head, but Stefan could barely see her through the tide of fury and misery rising up inside him. â€Å"Secrets and lies,† the phantom went on merrily, with an icy tinkling laugh, â€Å"and foolish Stefan Salvatore always a few steps behind. You've known al along there was something between Elena and Damon that you weren't part of, Stefan, and yet you would never have suspected she'd betray you for him.† Damon seemed to snap out of his daze, as if suddenly hearing the phantom for the first time. His brows drew into a heavy frown and he slowly turned his head to stare at it. He opened his mouth to speak, but at that moment, something in Stefan broke, and before Damon could issue whatever denial or taunt was on the tip of his tongue, Stefan lunged forward with a shout of rage, plunging straight through the chalked diagram. Faster than the human eye could fol ow, Stefan knocked Damon backward out of the circle and threw him against the far wal of the garage.

Cold War: question and answers Essay

1) The â€Å"iron curtain† was a dividing line because it was dividing Eastern and Western Europe. Western Europe had more of a democratic form of government where as Eastern Europe was ruled by the Soviet Union. 2) The policy President Truman is suggesting in his speech to Congress is the Truman Doctrine. The Truman Doctrine is a policy that stated that the United States would support Greece and Turkey with economic and military aid to prevent them from falling into the Soviet Sphere. This policy gave $400 million in aid to Greece and Turkey. 3) The Secretary of State Marshall suggested this plan(the Marshall Plan) for European recovery so if Europe would come into economic, social, and political damage it would also affect the United States very negatively also. The Secretary of State wanted to avoid those negative affects on the United States. He wanted to avoid the negative effect the European situation would have on the United States economy. 4) The purpose of NATO is to protect North American countries and ten Western European countries from attack by the USSR. The North Atlantic Treaty stated that any and all attacks made against any member of NATO would be considered an attack against them all. Its basic goal waste increase the stability and defense of its member countries. 5) The â€Å"satellites† help provide a buffer for the Soviet Union because they can track which invader is coming toward their border or see if any bombs are heading towards the Soviet Union. The â€Å"satellites† also act as a buffer but protecting the Soviet Union. The Soviet Union won’t care about these other countries that will get caught up in war and social and economic upheaval. 6) Khrushchev’s view of U.S. actions are that moves made by the United States such as the â€Å"anti-communism† movement was used to cover up statements of one power for world domination. The U.S. wanted to have a secure, dominant world power in the capitalist world. In document sic Khrushchev states that the fight for capitalism will lead to another world war. 7) The impact the â€Å"arms race† had on the world was countries racing for nuclear weapons/WMD which led to a â€Å"balance of terror.† A lot feared use of these weapons and saw this as a deterrent to war. 8)The basis for President Kennedy’s demand that the missiles be removed from Cuba was that it threatened the peace and security of the United States, Kennedy wanted to stop any chance the missiles could be used against America for any reason. He saw it as a threat to world peace. 9)Krushchev explains that the missiles were placed in Cuba for defensive reasons and to stop any aggression against Cuba. He now explains the missiles could now be removed because there is no chance that Cuba will be attacked by any country in the Western Hemisphere . Essay: How did the Cold War begin and what â€Å"weapons† were used to fight this war? The Cold War began at the end of World War II. The Cold War was the conflict between the Communist Nations led by the Soviet Union and the Democratic Nations led by the United States. The entire purpose behind the Cold War was to stop the spread of communism which the United States was against. Communism was thought to corrupt and cripple the entire world. They fought by propaganda, economic war, and constant military clashes. The Cold War started September 3rd 1945 and ended in 1989. When the â€Å"Iron Curtain† came down in Eastern Europe, as Winston Churchill stated in his speech on March 5th, 1946 as shown in document one, that was when the Cold War began. The Soviet Union made many countries into â€Å"Soviet satellites†. A satellite nation is a nation that is effectively dominated by another. The Soviet satellite nations were: Albania, Bulgaria, Yugoslavia, Romania, Poland, Hungary, Soviet Union, East Germany, and Czech. The Untied States wanted for all the European countries to have the freedom to pick their own governments. The war between the two nations escalated quickly when the Soviet Union successfully developed their  own atomic bomb. It became a â€Å" war of words†, the words was â€Å"weapons†. No active shooting was done and no actual weapons were used. It was basically Democratic nations against Communist Nations, a war of words on who had atomic bombs to use against other nations. As stated in document two President Truman believed it was the Untied States duty to support those who are resisting attempted domination. He believed if communism was forced on Turkey or Greece by the Soviet Union, it will have effects that are far reaching to the West. The policy President Truman is suggesting in his speech to Congress on March 12th, 1947 is the Truman Doctrine. The Truman Doctrine is a policy that stated that the United States would support Greece and Turkey with economic and military aid to prevent them from falling into the Soviet Sphere. This policy gave $400 million in aid to Greece and Turkey. Secretary of State Marshall gave a speech on June 5th, 1947 explaining his plan for European recovery as expressed in document three. The plan he was suggesting was the Marshall Plan. The Secretary of State Marshall suggested this plan(the Marshall Plan) for European recovery so if Europe would come into economic, social, and political damage it would also affect the United States very negatively too. The Secretary of State wanted to avoid those negative effects on the United States. He wanted to avoid the negative effect the European situation would have on the United States economy. It’s presented in both documents two and three that President Truman and Secretary of State Marshall had the best interest of the United States and other nations against communism at heart with both their policies. As presented on document four NATO is the North Atlantic Treaty. It was signed by the United States, Canada, and ten other nations of Western Europe in 1948. The purpose of NATO was to protect North American countries and those ten Western European countries from attack by the USSR. The North Atlantic Treaty stated that any and all attacks made against any member of NATO would be considered an attack against them all. Its basic goal was to increase the stability and defense of its member countries. NATO was basically an intergovernmental military alliance against the Soviet  Union and what they stood for which was communism. NATO constitutes a system of collective defense whereby its members state to agree to mutual defense in response to an attack by any external party(any communist nation). In conclusion, the Cold War began because fear of the spread of communism that the United States and West Europe had hated. This prevented chances of negotiations and friendly approach in diplomacy and foreign policy. Another reason on how the Cold War began was grouping of world nations in rival alliances such as NATO and the Warsaw Pact members. The Warsaw Pact members were German Democratic Republic, Poland, Czechoslovakia, Hungary, Romania, Bulgaria and the Soviet Union as shown in document five. The piling up of atomic weapons and picking either the democratic side or the communist side generated suspicion in one another.

A Job Experience in story form

I am a Reader in English and earn my livelihood by delivering at least 35 lectures a week to undergraduate major degree students.Apart from my daily schedule, I enjoy writing for a reputed Essaywriters Company of United States and dabbling into creative writing along with that. Whatever the case may be, I am keen on taking my classes regularly with much devotion. My seniors are well-established academics. They love me and adore my dedication to this job.But things began to change as and when I earned my PhD from Wisconsin. I began to take Postgraduate classes, 6 in average per week and surprisingly enough I was offered   supervisor-ship by my immediate boss.As I took to guide a PhD student, I began to draw the ire of a spiteful colleague who thought that taking classes might be my forte but not, of course, guiding a PhD scholar. He began to look for my pitfalls. A month ago, when I was coming back from my class, the Dean of the Faculty sent a message to me asking me to meet him aft er the classes. My heart missed a beat or two.  However, I went to his cubicle after my day’s lecture-schedule. I found him engrossed in a book and as I entered he shot me a glance of nonchalance. A fear of some unknown flashed past my mind. He lifted his face from the book he was reading, and said, â€Å"So, Dr. Wilson, how do you feel to interact with the new students?† I hummed and hawed to answer. At last I said, â€Å"I enjoy really, I do.† He resumed, â€Å"Hmm, but I heard that you are neglecting these classes and devoting much time in guiding two PhD scholars.But your appointment in this college entails a regular class-schedule with the undergraduate students.† I could see ulterior motive of my envious, mischievous colleague behind it. And, of course, it was not totally baseless. However, I rejoined in an instant, â€Å" I know, and I never shirk my duties.† He reminded me again of my primary duties and I left his room mutely, feeling a b it enraged.I came straight to my cubicle where I found an undergraduate bursar was waiting for my return. I took up the matter he was in need of clarifying and as he went out, I fished out a pen and a sheaf of loose sheets from my drawer. I went on scribbling, lighting up a cigar and holding it in between my left fore-and mid-fingers—An individual must be aware of his duties first of all. Maybe he is capable enough of accomplishing too many jobs at one go, i.e. putting too many irons in the fire, he must yet be deterred in doing so. After successful completion of his scheduled works if he yet finds time to do that he is at liberty to do so.I stopped, touched my lips with the pen and continued, If he is honest to his profession, he must not any room for any criticism. Yet, if any sneaky colleague comes to cast a spanner in his way, he must not leave any hole unplugged for him to take an opportunity to commit any mischief. He should resolve that duty is his foremost concern. An d after that, he must enrich himself in accomplishing something of his choice. He must be free to choose a work he likes to be engrossed with.  What on earth was I up to? I put out the light and buried my head in my hands , crushed the last butt of the cigar in the ashtray and went on recounting . No doubt, I was deeply hurt by the Dean’s remonstrating attitude. But I was no less surprised by the jealous, denigrating backbiting of my colleague. However, though it is case in point, I must not attack or inflict any harm on him.If a superfluous suavity is maintained , he may not get any wrong signal. And again, he may change his line of action. However, no loophole in work might be allowed.   Later on, I faced no difficulty in smooth-sailing with my work.

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Global Warming's effects on Tornadoes in the Mid West - Research Proposal Example However, it is quite clear that different locations experiences distinct global warming effects. Indeed, Mid-West and especially Oklahoma is prone to global warming effects in form of tornadoes. Purpose Statement The main aim, of this paper is to research on global warming and provide supporting data on the global warming effect on strength and frequency of tornadoes on the mid-west, specifically Oklahoma and surrounding states. The research will provide evidence that indeed global warming has been leading to adverse weather effects like tornadoes in the mid-west during the recent times. In this study, I will define global warming as an independent variable, which relates to extreme changes in global temperatures due to the increase of greenhouse gases such as Carbon Dioxide (CO2), nitrous oxide, and methane due to anthropogenic (synthetic) causes (Union of Concerned Scientists, 2011). I will also define a combination of atmospheric instability and wind shear as the causes of tornado es (Centre for Climate and Energy Solutions, 2013). I hope that my study will seek to establish the correlation between global warming effects and the changes in the strength and frequency of tornadoes on the mid-west with special focus on Oklahoma and surrounding states. ... Many scientists assert that unless we address the causes and effects of climatic changes from global warming, the world is prone to extreme climatic effects. Various researches establish that carbon dioxide and other global warming pollutants are collecting in the atmosphere thus trapping the sun's heat and causing the planet to warm up (Natural Resources Defense Council, 2011). This has led to fast fluctuation of local temperatures in the last 50 years and scientists claim that this may advance to an increase of 3 to 9 degrees in U.S. temperatures if we do not contain the situation (Natural Resources Defense Council, 2011). Notably, droughts, tornadoes, and hurricanes are some of the adverse effects of global warming across the globe (Kunzig, 2013). Ideally, scientists have been trying to establish the relationship between global warming and tornadoes. As a result, scientists have established that indeed global warming may increase or suppress the intensity or frequency of tornadoes across the globe especially in Oklahoma and surrounding states (Kunzig, 2013). Research Questions This research seeks to address specific questions, which include: 1) Is global warming the direct cause of tornadoes in the mid-west United States? 2) If global warming persist what impact will it have on the frequency and strength of tornadoes in the mid-west United States? 3) What effect will tornadoes have on the environment, economy, agriculture, human life, settlements, aquatic life, transport, and health in Oklahoma and surrounding states? 4) What measures can reduce the incidence of tornadoes in Oklahoma and surrounding states? 6) What are the main causes and influencing

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Environments of organization - Essay Example To create the fruit of this cooperative enterprise, LEJ employs about eleven full time staff and employs approximately fifty paid youth interns each year. Pfeffer & Salancik argue that Organizations are inescapably bound up with the conditions of their environment & they engage in activities which lead them to quicker adjustment in their environment (Pfeffer p.233). The Resource Dependency Theory (RDT) developed by Pfeffer & Salancik highlights that most important task of an organization is to survive & the most influencing factor on the shape of an organization is not how it consumes resources but how it acquires it (Pfeffer p.234). Therefore according to Pfeffer & Salancik, the effective organization is the one which satisfies the demand of those in the environment from whom it requires support for its continued existence (Pfeffer p.242) DiMaggio & Powell similarly argue in their seminal article on institutional isomorphism & collective rationality that organizations tend to look more and more similar the more an organizational field develops (DiMaggio & Powell, P.147). This process which they name Isomorphism in organization not necessarily drives it towards more efficiency but more acceptability. They argue that the major factor which organizations must take into account is other organizations as they not only compete for resources and customers but also political power & institutional legitimacy (DiMaggio & Powell, P.150). They suggest three mechanisms for this change which they term as coercive, mimetic & normative isomorphism. The biggest survival issue for any non-profit organization like LEJ is the constant supply of funding to various projects. With propping up of new non-profit organization with the same domain of work & the temporary down turn in economy post 9/11 caused LEJ to reconsider its funding issues. The leadership decided to stick to its mission principle and reject any funding & project proposals which are outside its scope to create an image of a principled organization which appeals to donors having environment related donations. This required restructuring, introducing processes within the organization which makes channelizing of ideas easily into grants proposals and actively pursuing potential donors for grants and ideas which can quickly be converted to grant proposals. This resulted into creation of a slot for full time grant writer, who can convert ideas into grant proposals. This was a classical attempt to improve their chances of securing their resources which in case of non-profi ts is extremely important. As Pfeffer & Salancik have argues that organizations always attempt to secure their resources without owning it (Pfeffer & Salancik, p. 236) in the environments once continuous availability of a resource is a problematic issue. Coercive Isomorphism always comes into play while dealing with Government & Donors (in case of non-profits). The constant change of government's procedures to ensure check and balances in non-profit organizations, LEJ has to constantly transform how it works through employee orientation and training for the departments which deal with government like taxations and audits etc. Moreover funding by donors also comes with certain compulsions in denial of donations to certain projects and emphasis on certain others, LEJ has to ensure that they constantly satisfy their

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Performance - Essay Example The findings of the study show that the extensive research carried out has not been able to come up with a concrete relationship between the human resource and performance. Brudan (2011) postulated the focus of performance management as a discipline and the proposition of an integrated performance management (Brudan, 2011). The paper’s aim was to track the various developments that performance management has gone through regarding the various levels of the organization. The paper was able to identify various crucial dichotomies that were intertwined in the performance management model. Many firms have taken performance management a notch higher in terms of evaluating their workers output and ensuring that there is an improvement in their daily tasks (Gruman & Saks et al., 2011). Performance management, as a result, should be directed towards engaging the workers to improve their performance and thus increase their output to the benefit of the organization. In addition, the company puts in place various measures that ensure that the employees at each level meet their expected targets as stipulated in the objectives and goals of the company at a certain period. Performance management in such a case does not only look at the rewards that workers should get but also on their performance and hence output to the company. The company, therefore, rewards employees at various levels and ensures that they are up to their tasks. Luong (2012) investigated the factors that drive engagement, engagement, and performance. The study noted that there have been inefficiencies of performance management systems used by companies. Some of the studies have indicated that there needs to be an overhaul of the performance management systems in place to help come up with efficient systems that help organizations, and their employees achieved desired targets and goals. The study was an added development on the Gruman and Sak’s (2011) employee engagement model. The study

Comparison & Contrast Between Two Online Holiday Companies Essay

Comparison & Contrast Between Two Online Holiday Companies - Essay Example This report stresses that lowcostholidays.com is essentially targeting the middle class families who look forward to travelling but have a very limited budget for the same. Kuoni.co.uk, on the other hand, has a different approach and a different feel to the website. The moment we get into the website, it gives a rich appeal and talks about luxury destinations, which clearly implicates their target market. Kouni.co.uk targets the upper class by offering luxury holidays packages with premium pricing which is not affordable by the average middle class families. This paper makes a conclusion that they are still successful with their physical promotion and presence and attract many customers who are looking for relaxations by travelling to some exotic locations. Lowcostholidays.com, on the other hand, is successful in their own way by doing significant online promotions and launching their exclusive application on facebook with the help of Betapond. They have successfully established themselves as low cost solution for travelers worldwide. Sticking to their current market and trying to capitalize on their target customers would help them to continuously be successful in their respective areas. The author of the report approves that since customer feedback is quite essential for the process, there is a rating prompt after every chat to enable the visitor comment on the level of service. This is very important for quality assurance purposes. It is also interesting to note that the company’ website is able to provide online booking and qu ote services. As a result, one does not have to visit Kuoni’s offices to be able to book for his or her preferred destination.

Control Over Prices Essay Example for Free

Control Over Prices Essay The degree of control over prices which the companies may exercise varies widely with the competitive situation in which they operate. Sellers operating under conditions of pure competition do not have any control over the prices they receive. A monopolist, on the other hand, may fix prices according to his discretion. Sellers operating under imperfect competition may have some pricing discretion. The marketer, therefore, needs to know the degree of pricing discretion enjoyed by him. Wal-Mart is selling varieties of items and one of these is Toys. It has got a good percentage of customers in the market but other competitors have also have their own share and Toys R Us is quite close to it. Both the companies have their own approach of pricing the toys in the market. The approach is whether WalMart should use the loss leader pricing policy to stay comfortable in the market. Perfect competition is said to exist when (i) there are a large number of buyers and sellers, (ii) each purchasing and selling such a small quantity that their withdrawal from the market will not affect the total demand and supply, (iii) the products sold by sellers are homogeneous in nature. Prices under perfect competition are determined by the forces of supply and demand. Prices will be fixed at a point where supply and demand are at equilibrium. In pure competition, all that the individual seller can do is to accept the price prevailing in the market, i.e. the company is in the position of a Price Taker. If it wants to charge a higher price, buyers will purchase from other sellers. And it need not charge less since it can sell its supply at the going market price. Under monopoly, a single producer has complete control of the entire supply of a certain product.   The main features of monopoly are (i) there is only one seller of a particular good or service and (ii) rivalry from the producers of substitutes is so remote that it is almost insignificant. As a result, the monopolist is in a position to set the price himself. Thus, it is in the position of a Price Setter. Even in the case of monopoly, there are limits to the extent to which it can increase its prices. Much depends on the elasticity of demand for the product. This, in turn, depends on the extent of availability of substitutes for the product. In most cases, there is rather an infinite series of closely competing substitutes. Bigger organizations must take into account potential competition by alternative services. The closer the substitute and greater the elasticity of the demand for a monopolist’s product, the less it can raise its price without frightening away its customers. Monopolies are constantly tending the break down due to many reasons: (i)shifts in consumer demand, (ii) continuous process of innovations and technological developments leading to development of substitutes, (iii) lack of stimulus to efficiency provided by competition, (iv)entry of new competitors.   Loss leader pricing policy of Wal-Mart It is a type of strategy applied by the company where the item is sold below the cost price in an effort to balance other profit sales. It is just another way of promoting sales of the products which are slow moving or to counterbalance some other competitive firm. It is the market situation characterized by a few sellers each having an appreciable share in the total output of the commodity. In each of these industries, each seller knows his competitors individually in each market. Each company realizes that any change in his price and advertising policy may lead rivals to change their policies. Hence, Wal-Mart may consider the possible reactions of the other firms to its own policies. The smaller the number of firms, the more interdependent are their policies. In such cases, there is a strong tendency towards close collaboration in policy determination both in regard to production and prices. Such type of   industries are usually characterized by what is known as price leadership—a situation where firms fix their prices in a manner dependent upon the price charged by one of the firms in the industry,i.e.,Toys R Us, called the price leader. The price leader has lower costs and adequate financial resources, a substantial share of the market and a reputation for sound pricing decisions. Price leaders with the strongest position in the market may often increase their prices with the hope that competitors will follow suit. Price followers may also delay raising their prices in the hope of snatching a part of the market share away from the leader. Monopolistic competition is a market situation, in which there are many sellers of a particular product, but the product of each seller is in some way differentiated in the minds of consumers from the product of every other seller. None of the sellers is in a position to control a major part of the total supply of the commodity but every seller so differentiates his portion of the supply from the portions sold by others, that buyers hesitate to shift their purchases from his product to that of another in response to price differences. At times, one manufacturer may differentiate his own products. Wal-Mart sells toys of many brands. This differentiation of product by each manufacturer by giving it a brand name gives him some amount of monopoly if he is able to create goodwill for his product and he may be able to charge higher prices thereof to some extent. Still, his product will have to compete with similar products of other manufacturers which puts a limit on his pricing discretion. If he charges too high a price, consumers may shift their loyalty to other competing suppliers. One can find it out by going to the market, as a large number of toys are subject to a large degree of product differentiation as a means of attracting customer. As long as a consumer has an impression that a particular product brand is different and superior to others, he will be willing to pay more for that brand than for any other brand of the same commodity. The differences real or illusory may be built up in his mind by (a)   advertising, and (b) his own experience and observation. The producer gains and retains his customers by (a) competitive advertising and sales promotion, (b) the use of brand names quite as much as by (c) price competition. Product differentiation is more typical of the present day economic system, than either pure competition or monopoly. And, in most cases, a firm has to face monopolistic competition. It tries to maintain its position and promotes its sales by either (i) changing its price and indulging in price competition, or (ii) intensifying the differentiation of its product, and (iii) increasing its advertisement and sales promotion efforts. Instead of the cost, the emphasis here is on the market. The firm adjusts it own price policy to the general pricing structure in the industry. Where costs are particularly difficult to measure, this may seem to be the logical first step in a rational pricing policy. Many cases of this type are situations of price leadership. Where price leadership is well established, charging according to what competitors are charging may be the only safe policy. Normal pricing is not quite the same as accepting a price impersonally set by a near perfect market. Rather it would seem that the firm has some power to set its own price and could be a price maker if it chooses to face all the consequences. It prefers, however, to take the safe course and conform to the policy of others. Prices of certain goods become more or less fixed, not by deliberate action on the sellers’ part but as a result of their having prevailed for a considerable period of time. For such goods, changes in costs are usually reflected in changes in quality or quantity. Only when the costs change significantly the customary prices of these goods are changed. Customary prices may be maintained even when products are changed. For example, the new model of toy may be priced at the same level as the discontinued model. This is usually so even in the face of lower costs. A lower price may cause an adverse reaction on the competitors leading to a price war so also on the consumers who may think that the quality of the new model is inferior. Perhaps, going along with the old price is the easiest thing to do. Whatever be the reasons, the maintenance of existing prices as long as possible is a factor in the pricing of many products. If a change in prices is intended, Wal-Mart must study the pricing policies and practices of competing firms and the behavior and emotional make-up of his opposite number in those firms. References Philip Kotler (2002) Marketing Management, Prentice-Hall, New York Beaumont, P.B.,(1999) Pricing Policies and Procedures, Sage Publications, London, . Flippo Edwin B., (1989) Marketing Management, McGraw-Hill, New York Purecell J.,Boxall P.,(2003) Marketing Development, Plagrave, Macmillan, New York.

The Global Economy Essay Example for Free

The Global Economy Essay The world economy is mostly described by globalization. Globalization is the growth and development of economies all over the world. This is integration and interactions of world’s greatest economies and the development of the emerging market economies. Globalization is not new, since it has existed for thousands of years in terms of the oldest long distance trade across Asia and Europe. Many large corporations have invested in businesses in other counties (multinational businesses) implying that the current characteristics of globalization existed even before the First World War. The recent technological developments (especially ICT-information and communication technology) and economic policies are the major stimulation factors that contributed to increased globalization (Maddison 2001). Current policies aimed at bringing about disinflation have significantly opened up countries’ economies both locally and globally. This is because after the Second World War, most nations were motivated to start developing their economies since they had lost most of the resources in the war. The most effective policy was the adoption of free market systems which significantly improved the rate and volumes of productivity in their regions of origin and opened up numerous international markets as many barriers to free trade and commerce had been reduced. Economic Growth The world economy is the concern of every nation, because every country has some dependence of others. For such a reason most countries comply with economic policies aimed at improving world economy hoping to improve their own. The world market opened up with the opening of free market in the individual states that had split from the former Soviet Union plus other nations of the Eastern Europe (Maddison 2001). The Eastern Europe was very critical player for increased globalization in the 1990s. Most of the nations in the region joined the world trade organization and played a significant role as a supply foundation in to the western countries. China’s role in the cold war was a swift one and by the time the cold war was culminating, it had established itself in Asia as the economic stronghold serving as a market and supplier to Japan and other developed nations in the region (Maddison 2001). Inflation Structural changes in the global financial market have influenced the international, market environment in terms of prices of consumer products. Development and innovative technology plus anti-inflation policies adopted by many nations also played a significant role in the disinflation development. The inflation rates in the Group of eight G-8 countries (United States, Germany, Japan, Italy, Canada, Britain, Russia and France) countries declined by about 3-4%, these countries are the greatest economies in the World (Maddison 2001). In 1990s the world experienced a change in disinflation rates reflected by a notable increase in the supply of products to the world market as a result of the rapid industrialization in the emerging market economies. Poverty Reduction The developing nations have improved considerably and have found a place in the world economy as critical players. These countries have actually increased the value of global economy as they are rapidly developing in terms of industrialization and are being termed as emerging market economies as well. Example of emerging economies are china an India, which have invested in Multinational firms that accommodate information technology and have a greater influence on the world economy, which is also supported by worldwide economic connection Information technology has played a role in facilitating economic growth in most of the countries but it has also come with some negative features which are a threat to economic growth (Maddison 2001). Globalization Condemnation It is argued that the international corporations like international monetary fund, World Bank and world trade organization have become undemocratic assuming power of decision making about economic policies. Environmental preservation is no longer a priority; detrimental labor practices like child labor and prisoner service have become the order of the day As much as the Globalization Phenomenon has been praised for the improved economies of the world, On the other hand, it has been criticized for economic problems and financial crises in other nations could easily be transferred to other countries as a result of these interactions. This was evident with the Asian currency crisis of 1997 that affected the major economies of the Asian region; the Russian financial crisis that saw countries of former Soviet Union suffer an economic depression and the disintegration of the long-term capital management in 1998 (Maddison 2001). Many countries have now undertaken a process of finding a solution to such occurrences in future and the most notable research is that conducted by the Japanese central bank. Globalization has been blamed for unfair trade by the emerging economies who introduce fake products to the international market especially the Chinese companies. It has also been argued that Globalization has brought about in equality in economies and environmental deprivation. Globalization includes interaction of communities, a concept that has been found to have a negative influence on the environment, culture as well as on political administration of some countries discriminately (Maddison 2001). Economic development has been found to be uneven around the world. Opponents of globalization argue that the creation of free markets only benefits the multi-national companies that are already established from the western nations at the expense of the local companies and people in the developing countries. The so called free and far trade is not fair after all; nations compete for international ventures where they offer low environmental standards as well as poor working conditions and low wages. The free and fair trade arrangements usually snatch power from local governance of host nations to the multi-national corporations. As these businesses are seen to control the economy and hence make up financial policies, economic changes and other corporate manipulations (Maddison 2001). Conclusion Globalization has greatly affected business around the globe and many businesses have benefited from it while others have suffered a down fall. Third world companies have been brought to the international market while inflation in several countries has been transferred to other as a result of free market. Major phenomena that stimulated economic development were agriculture and capitalist economy, but the recent and significant of them was the industrialization which has intensely revolutionized economy. In order to understand the effects of globalization, both those who are for plus those against have to come to a consensus of the effects that have been brought about by globalization. All these interactions proof that globalization is a complex subject for discussion. References Maddison A. (2001). The World Economy: A Millennial Perspective. Organization for Economic Co-operation and Development Centre

History of perodua analysis

History of perodua analysis Perusahaan Otomobil Kedua Sdn Bhd (PERODUA), established in 1993. In Malaysia Perodua is second automobile manufacturer which after Proton. It is a joint venture company between Malaysian and Japanese. The shareholders of Perodua are UMW Corporation Sdn Bhd 38%, MBM Resources Berhad 20%, Daihatsu Motor Co. Ltd 20%, PNB Equity Resource Corporation Sdn Berhad 10%, Daihatsu (Malaysia) Sdn Bhd 5%, Mitsui Co. Ltd 4.2% and Mitsui Co, (Asia Pacific) Pte Ltd 2.8% (Corporate Information n.d). Perodua does not contend with Proton for the similar market niche because Perodua mostly produce small-compact cars. Since end of 2009, Perodua has sold some 1.67 million units of vehicle of a variety of models. Perodua also sell overseas their cars to UK, Singapore, Brunei, Fiji, Nepal and Sri Lanka. 1.2 Background of Perodua Perodua is located on a 138-hectare site in Sungai Choh, Rawang, Selangor Darul Ehsan. Besides, in the year of 2001, Perodua Auto Corporation Sdn Bhd (PCSB) was established in the final quarter year. Furthermore, there are also another two joint venture partners of PCBS from Japan which are Daihatsu Motor.Co.Ldt. and Mitsui Co. Ltd. The PCBS are being managed the manufacturing operations of the Perodua Group (Corporate Information, 2010). 1.3 Mission and Vision 1.3.1 Mission Perodua mission is to Professionalism in all our operations Efficiency in utilizing technologies and available resources Resilience in meeting our challenges Optimizing benefits to customers and stakeholders Dedication towards social responsibility to community, the environment and development of competent workforce Uniqueness in our products Aspiration to glorify the name of PERODUA 1.3.2 Vision The vision of Perodua is to be the most preferred automotive brand renowned for products and services of excellent quality which contributes to the development of the nation. 1.4 Product Milestone Below is the list of the vehicle that Perodua produce: The Perodua Kancil-August 1994 The Perodua Rusa March 1996 The Perodua Kembara August 1998 The Perodua Kenari   June 2000 The Perodua Kelisa August 2001 The Perodua Myvi May 2005 The Perodua Viva   May 2007 The Perodua Nautica 4WD May 2008 The Perodua Alza November 2009 (Corporate Information, 2010) 2.0 Analysis of Market Environment Factors that Affect this Company For a company it is very necessary to have updated date and to have a close watch and to assess the ever changing environment around them. There are 2 types of environment and there are Micro Environment and Macro Environment (Pride.et.al, 2007). 2.1 The Micro Environment The close forces to the company that have effect on its capability to get the goods successfully to the customer. While for the micro environment consists of 6 factors (Pride.et.al, 2007). 2.1.1 Customer Customer can be divided into 5 types of markets to get a better idea on them which are: 2.1.1 (a) Consumer Market The person who buys the product for consumption is called the consumer market (Pride.et.al, 2007). Perodua Company comes with varies vehicles that can attract buyers especially these who want an affordable yet efficient vehicle. The company mostly targets on individuals or families who want to buy quality car at a premium as Perodua Company sets up the prices that are reasonable and affordable by most consumers. Perodua Myvi is product on May 2005 by Perodua Company which is one of the examples for individual or family use. 2.1.1 (b) Business Market The companies which buy goods and services are to be used in the production id other goods (Pride.et.al, 2007). For instance, Perodua Company buys the parts from other countries but the assembling is done in Malaysia. 2.1.1(c) Reseller Market The companies that purchases the goods or services and resell the product without making any changes to it (Pride.et.al, 2007). For examples, Perodua dealers get the product from the main company and finally distribute to them without making any changes of the cars. 2.1.1 (d) Government Market For government market they may purchase it to be used it in the production of goods and services (Pride.et.al, 2007). For example, the model of Perodua Myvi, Perodua Kancil, Perodua Viva are provided to the government for the use of National Parade Day. 2.1.1 (e) International Market The products used for the use of the government to carry on with the government duties (Pride.et.al, 2007). For international market, Perodua Myvi purchases for the overseas market such as United Kingdom, Singapore, Brunei, Fiji, Nepal and Sri Lanka. 2.1.2 Company This segment is about the togetherness which should be there among all departments so that the product will be delivered to the customer in the desired time. This process will be an incomplete process if there are disagreements between departments, which will result in a delay of not delivering the product to the customer on time (Pride.et.al, 2007). 2.1.3 Competitors There are two types of competitors that will affect the sales of Perodua Company which are direct and in direct competitors. 2.1.3 (a) Direct Competitors The companies which manufacture the same products within the same industry (Pride.et.al, 2007). For instance, Suzuki, Toyota and Proton are Perodua Companys direct competitors as the companies sell similar types of vehicles within the same industry. 2.1.3(b) Indirect Competitors Indirect competitors mean that when any company which competes for the same customer dollar (Pride.et.al, 2007). The indirect competitors for Perodua will be Toyota, Proton, Naza, Honda, BMW, and Mercedes. This is because they are also produce cars and they are also competing for the consumer dollars (Corporate Information, 2009). 2.1.4 Suppliers Suppliers could be defined as those who supply the necessary parts to build the product. The supplier influences the quality and delivery of the ended product. Suppliers should be from a reliable source and should be consistent at an arms reach (Pride.et.al, 2007). 2.1.5 Marketing Intermediaries Marketing Intermediaries is also known as the middle man. The mediating is usually done by a company in order to distribute or promote goods to the customer (Pride.et.al, 2007). The sales Manager stated that Giga Shipping Company transports all the Perodua Products worldwide. There is also a trailer company which provides trailer service to transport products around Malaysia (Personal Development Leadership, n.d). Besides marketing intermediaries, mediating can also be financially. As an example, EON bank, RHB Bank, Islam Bank act as a mediator in order to promote Peroduas cars. These companies provide a loan system so that the customers could have a minimum payment monthly and enjoy the same benefits of a comfortable car. 2.1.6 Publics Publics could be defined as a crowd of people who have an interest in a company and also who make an impact to an organization to achieve its objectives. Moreover, a company will take this consideration and try building up relationships and also offer helpfulness to these groups. There are the 7 types of publics such as local, media, citizen action, government, general, internal and financial (Pride.et.al, 2007). 2.1.6 (a) Local A community relations officer is appointed by the company to be present at meetings with the local publics (Pride.et.al, 2007). Perodua Myvi customer are eligible to join the club via (http://www.myviclub.com/). There is a public relations officer is appointed from Perodua Company regarding this club. On the other hand, the officer also can meet with the customer and makes interaction with the customer. 2.1.6 (b) Financial The company issues an annual publication which is the annual report which also includes the financial statements in the company. The shareholders were given by the company (Pride.et.al, 2007). All the Perodua Company share holders receive the annual report of the company in order to keep the shareholders informed about the financial status of the company (Corporate Information, 2010). 2.1.6 (c) Media Media can be described as a company would promote their product more with a positively media coverage (Pride.et.al, 2007). For example, Perodua Company promotes Perodua Myvi on television advertisements. The official advertisement is telecasted on television. Also, they also advertise the product on the World Wide Web (Corporate Information, 2010). 2.1.6 (d) General The general publics view in the company is called general (Pride.et.al, 2007). Through our research, most of the customer would like to view on the Perodua Company. Hence, positive or negative, it is basically what the customer thinks about the company. 2.2 Macro Environment The societal forces that influence the organizations ability to provide the customers are called macro environment factors which are 6 factors. 2.2.1 Political Legal The legislation and laws which influences the industry, marketers should be on watch out of the laws which can involve the company in the future (Pride.et.al, 2007). Since Perodua Company is fully owned by the government of Malaysia, the tax is already included in the price of the vehicle. Therefore, the government gets a sum of charges (Corporate Information, 2010). 2.2.2 Economic Environment The Economic environment investigates the disposable income levels. In addition, the economic conditions include the business cycle, inflation, interest rate and inflations rates (Pride.et.at, 2007). 2.2.2(a) Inflation Rate 2.2.3 Technological Environment 2.2.4 Demographic 2.2.5 Cultural 2.3 How the Company faces Threats and how they convert them to Opportunity The SWOT analysis is known as the tool to asses a companys Strength, Weakness, Opportunity and Threats. Strength and Weakness are known as internal factors while Opportunity and Threats are known as the positive conditions which could bring plunder to the company if acted in the necessary way. For Threats, it can be defined as the barriers which prevent the Company from reaching the companys objectives. When a company puts out a new product, there could be threats which come the companys way. Then the company should be ready with a defensive strategy to stand up against the threat and that strategy is known as Opportunity (Pride.et.at, 2007). After the release of Perodua Myvi, the company has faced several threats. So, to get rid of these threats of Perodua Company, Perodua Company came made that threats into opportunity by making up a strategic plan (Corporate Information, 2010). 2.3.1 The Entry to the Domestic Market The entrance of Perodua to the market was in the year of 1993 and it also result a massive change in the industry. Nissan and Toyota were dominating the market which result Perodua getting a small slice in the market. And Perodua got a boost because Indonesia. This is because they tend to sell about 500 Perodua Myvi cars in a month (paultan.org, 2010). 2.3.2 The Support Since Perodua was quite new to the domestic market, as mentioned previously there was also because of Indonesia. As a result of this undertaking of Indonesia, the workforce of Perodua was sent to Japan for a special training to learn more about engineering skills and assembling skills. This opportunity could be known as a Human Resource 2.3.3 The Competitors Perodua is known as the second National Car producer in Malaysia which is after Proton Company. But, the competitors to Perodua are from the domestic Market as well as the International Market. The Domestic competitors are named as Proton and Naza while the competitors from the international market are Toyota, BMW and Mercedes. Through these competitors are threats to the company, Peroduas strategic plan has kept them as the best car in the Malaysia up-to-date. Besides, Perodua Company is always on the watch out of product life cycle. So, if any company comes out with any new model, Perodua will try to modify the existing model or trying to put out a new model. All in all, company will always want to produce products according to customer trends and not company trends. If the company produces according to the company trends then the sales can go down. But, if the company acts according to the customer trends there can be good sales. 3.0 Target Market 3.1 Target Customer Characteristics Target market involves dividing a market into segments and then concentrating on marketing products on one or a few key segments (Pride.et.al, 2007). The target market of Perodua Myvi is segmented by demographic consumer such as the businessman who likes to work and it is convenient to them. Therefore, the comfort of the passenger is the main target. Also, the vehicle price of Perodua Myvi is affordable and reasonable for the customers which fulfill their demands too. Furthermore, the first target market strategy used is differentiated marketing. Differentiated market is the organization selects several market segments and designs different marketing mixes for each segment (Pride.et.al, 2007). The Perodua Company has used different strategy to attract different customers. Therefore, the Perodua Company offered the other vehicles for its different target segments to meet the customer demands. Some of the customers are looking for more convenient cars such as Perodua Viva while customers with big family would like to choose Perodua Alza. Another target market strategy used is undifferentiated marketing. The marketing mix, which are the 4Ps are the organization at the whole market. Besides, the organizations also used to avoid other segments from existing, the organization chooses to mass market (Pride.et.al, 2007). For example, 30 September of 2009, Citibank credit card deals have organized Perodua Myvi 10X rewards points Easy Pay Campaign. This is use to the customer can make a down payment by using the Citibank credit card and enjoy 0% interest on the customer down payment and 10X rewards point (Citibank Perodua Myvi 10X Rewards Points Easy Pay Campaign, 2009). While for the last target market strategy used is concentrated marketing. There are one or two segments will be selected by the company and a marketing mix for these few segments will be proposed (Pride.et.al, 2007). Therefore, the aim of Perodua Company use concentrated marketing strategy is not to maximize sales; it is efficiency, attracting a large portion of once section while controlling costs. 4.0 Product 4.1 Product Lines that are offered A product line is viewed as a unit because of marketing, technical or for end-use considerations, by groups of closely related product items (Pride.et.al, 2007). Perodua have released many models of Myvi to suit the different taste of the customers. Firstly, there is the original Myvi and now comes with another two different versions which is the Myvi SE and the Myvi EE (Exclusive Edition). Each of these models comes with a different pricing and specifications. 4.2 Core, Actual and Augmented When purchasing tangible product, the buyer will not only obtain the product itself, but also all the extra things that come together with the product. This is also known as total product. The total product of the item can be separated into three categories which are the core product, actual product and augmented product. 4.2.1 Core Product Core products are the essential benefits that the buyer want when purchasing the product. The actual benefit that the buyers get when purchasing a Perodua Myvi is transportation. Buying a Perodua Myvi allows the buyer can move around in a vehicle without depending on public transport. This allows the buyer to be able to travel to any destination at any time without relying on the rigid time frame of a public transport. 4.2.2 Actual Product Actual products are the fundamental expectation of the buyer of the product (Pride.et.al, 2007). The consumers most basic expectations from buying a Perodua Myvi are the style and design of the car. In the Perodua official website it is stated that the design of Perodua Myvi is a mix of classy and sporty characteristic (Perodua 2009). Besides that, there are many colours for the buyer to customize the Perodua Myvi to suit the their taste. The engine of Perodua is also manufactured in Japan by Daihatsu. The Perodua Myvi is also known to be more fuel efficient as compared to other cars sold in the market. It is said that Perodua Myvi Auto uses around 13.5 km per litre and the Perodua Myvi manual is clocked at approximately 17.1km per litre of petrol (Tan, P 2009). The Perodua Myvi is readily built with air-conditioner and entertainment system with the latest audio technology like mp3 and a USB reader (Perodua 2009). The consumer can have the option of the transmission of the car to be automatic or manual. To prevent the car from being stolen, Perodua Myvi is equipped with a security system which includes an engine immobiliser. The only way to unlock the immobilizer to start the car is by using the owners car keys. As a result, if somebody breaks into the car, they wont be able start the car by using duplicated keys or by tampering with the wires. 4.2.3 Augmented Product The augmented products are the additional services the consumer will receive when buying the product. The augmented product of buying a Perodua Myvi is that it easier to apply for a loan compared to other imported cars because it is a national car. Besides that, Perodua provide services like parts replacement and repair at their service centre. The spare parts of Perodua Myvi are also easily available compared to imported cars. Other than that, Perodua also provide an extended warranty service for free (Perodua, 2009). 4.3 Branding, Packaging, Labeling, Warranty, Customer Service 4.3.1 Branding (Shenron, 2009) Branding is a blend of a term, sign, name, symbol or design which is used to recognize and distinguish products and companies (Pride.et.al, 2007). Perodua has a small car like Myvi with a big future. Hence, Malaysias leading compact carmaker is always taken by Perodua. Besides, their management team still not really satisfied with their position at the top and their research and development facilities have given the most critical activity, innovation in design and creative engineering methods. Nowadays, Perodua is now able to deliver more stylish, unique, and cars with an attractive price to their consumers. This new brand statement, Building Cars, People First, is Peroduas new visual identity (Interbrand, 2010). Perodua expects to manage all their customers in harmony with their guiding vision. Besides, Perodua was at the position of seventh most valuable Malaysia brand in Interbrands 2007 survey and it looks set to continue get build up and enhance. This shows that Perodua try their very best to respond their customer satisfactory. 4.3.2 Warranties and Customer Services Perodua Company consists of customer service which is known as smart assist. In the even of a breakdown, members can call the toll free number: 1-800-88-5555. The call centre will dispatch a rescue team to the location of the vehicle. This service is available 24 hours a day, 7 days a week. Besides, all the customer service agents practice a friendly, thoughtful, humble and committed routine to give their customers very best service. Furthermore, 1-hour Superservis also provided and this service is a speedy service package that comes with a money-back guarantee once the customers car is not serviced in one hour. While for the warranty period, Perodua Company has given 3-year/100,000km manufacturers warranty. For the extended warranty is plus 3-year/75,000km. ETP is stand for Extended Warranty Programme which is an extension of the Basic Warranty Coverage that comes with your Perodua by giving the customer an additional coverage period (Perodua, 2010). 4.3.3 Product life Cycle Product life cycle can be defined as progression of a product through development, introduction, growth, maturity and decline stage. 4.3.3 (a) Development Product development is the incubation stage of the product life cycle. There are no sales and the firm prepares to introduce the product. 4.3.3 (b) Introduction In introduction stage, the product has just appeared in the market with the company having little profit or the negative profit as there is only little consumer awareness on the product. In this stage, the company increases the awareness of the public about the product through promotion or advertising. The Perodua Myvi is marketed to the public through local mediums such as newspapers, radio and television. 4.3.3 (c) Growth During the growth stage, sales start to increase rapidly but the promotion costs are still high due to increasing consumer awareness thru advertising and etc. The growth stage is critical to a products survival because competitive reactions to the products success during this period will influence the products life expectancy. The profits begin to decline late in this stage as other car competitors enter the market with their own cars to compete with the Perodua Myvi. 4.3.3 (d) Maturity During maturity stage, the sale curve peaks as there are maximum sales and production efficiencies lead to maximum profits occurring in this stage. In this stage, the company will want to maintain the sales on the product. In keeping the maturity stage going for as long as possible, the company reintroduces the Perodua Myvi with versions and will also have a facelift. Example of this is the introduction of the Perodua Myvi SE to the market. 4.3.3 (e) Decline In the final stage, which is the decline stage, the sales will fall rapidly. This is because the sales and profits of the product decline. Therefore, the company needs to determine whether to retain or drop the product. The current Perodua Myvi is in a decline stage but is still doing well in the market as it is ranked the top selling car in the country in the compact segment for the third year running in the assessment conducted by J.D. Power Asia Pacific, therefore leading the Perodua Company to continue the production of the car. The graph above illustrates how the product life cycle of Perodua Myvi has reached the maturity stage where the company is making maximum profit from the sales of its product that is the Perodua Myvi. (Managing Products and Brand, n.d). 5.0 Pricing Price is the value exchanged for product in a marketing transaction but price is not always money (Pride.et.al, 2007). There are some pricing strategies that use in Perodua Myvi product. For example, optional product-pricing, psychological pricing and geographical pricing. The optional product-pricing is the pricing the accessory sold with the main product. For instance, car sells with the air-conditioning. While for the psychological pricing is the price set reflects the psychology of pricing and not just the costs. For example, $45900 instead of $46000. Lastly the Perodua company also use the geographical pricing strategies in the Perodua Myvi product. The geographical pricing is pricing products to customers in different parts of the country such as FOB (free on board) and Zone pricing. FOB means that the customers need to pay the freighter fee from the carrier to the final destination and zone pricing is the company set up one zones, the customer in the more distant zones (Pride. et.al, 2007). 5.1 Optional Product Pricing Type of carsThe Perodua Company uses the optional pricing in the Perodua Myvi product, which is the pricing the accessory sold with the main product. The Perodua Myvi is divided into eight type, Myvi 1.0L SR, Myvi 1.3L SX, Myvi 1.3L EZ, Myvi 1.3L SXi, Myvi 1.3L EZi, Myvi SE GHS, Myvi SE ZHS and Myvi 1.3 ZHL. The different accessory of Myvi contains different prices. The different prices are as shown in the table below: (Based on the price listed given in the catalogue) Colour Solid Metallic SMET Myvi 1.0L SR RM 40,721.80 RM41,240.20 Myvi 1.3L SX RM 45,450.20 RM 45,925.20 RM 46,325.20 Myvi 1.3L EZ RM 48,425.50 RM 48,900.20 RM 49300.20 Myvi 1.3L SXi RM48,225.50 RM48,700.20 RM49,100.20 Myvi 1.3L EZi RM 51,240.30 RM 51,700.20 RM52,100.20 Myvi SE GHS RM 51,926.00 RM52,401.00 RM52818.20 Myvi SE ZHS RM 54,940.00 RM 55,426.00 RM 55,826.00 Myvi 1.3 ZHL RM 51,000.00 RM 53,500.20 5.2 Psychological Pricing The psychological pricing is the price set reflects the psychology of pricing and not just the cost. It is also apply in the Perodua Myvi product. Example: (Based on the price list given the catalogue) Myvi 1.3L EZ (solid) RM 48,425.50 Myvi 1.3L EZ (Metallic) RM 48,900.20 Myvi 1.3L EZ (SMET) RM 49300.20 5.3 Geographical Pricing The geographical pricing is the pricing products to customers in different parts of the country. The Perodua Myvi contains different prices according at the different country or different zone. Example (Based on the price list given in the catalogue) The Perodua Myvis Price in Malaysia (1.3L EZi) The Perodua Myvis price in UK (1.3 EZi) RM 52,240.30  £7,499 In the table above shown that the Perodua price in United Kingdom is cheaper once the price convert to Malaysia dollars. The reason Perodua Myvis price in UK is more expensive than Malaysia is because of the sales tax in under vehicle pricing and special interest rate is included (Perodua-uk.com, n.d) 6.0 Distribution According to Perodua Company, there are many branches in Kuching such as at Satok Parade, Jalan Matang and others. The location of Perodua Company can be easily found in Kuching. On the other hand, the Perodua Company also has branches at the overseas country such as in United Kingdom. The Channel organization that is used by the Perodua Company is shown below: 6.1 Conventional Channels The Conventional channels consist of independent producers, wholesalers and retailers. They are all self business which are trying to maximize own profit (Pride.et.al, 2007). 6.2 Vertical Marketing Channels For the vertical marketing channels, the channel members work in a group rather than individually. It is either one who owns the others or they are in contract with each other or has so much power that they all corporate (Pride.et.al, 2007). 6.3 Horizontal Marketing System It is an arrangement with two or more companies at the same level linked together to follow a marketing chance (Pride.et.al, 2007). 7.0 Promotion 7.1 Promotion Goals Promotion is communication by marketers that informs, persuades and reminds potential buyers of a product in order to influence an opinion or to get a response. While inform is a communication used to increase understanding of new brand, or a new product. The company explain how the products function, and recommend the new application for product. The other goals of promotion, persuade the customer to buy now. Finally, remind is a task of retaining the customer knowledge and to call attention to the customers about the importance of the products for they might be used in the future (Pride.et.al, 2007). The promotion goal of Perodua Company in the Perodua Myvi product is inform. Perodua Myvi is still the good selling product in the market. It is convenient and suitable for businessman but also good for small family. In addition, Perodua Company gave information about the Perodua Myvi to society by using several methods, such as brochures, internet advertising through Perodua official websites, road show and many more (Pride.et.al, 2007). 7.2 Promotion Tools To communicate with individuals, groups and organisations, various promotional tactics have been used by Perodua. When Perodua merges specific plans used to manage the integrated marketing communications for Perodua Myvi, that combinations form the promotion mix for Perodua Myvi. Advertisement, personal selling and sales promotion some of the elements of promotion mix. The elements of the marketing communications mix Sources from: (Dolak,D 2009) The main promotion mix used by Perodua in promoting Perodua Myvi is advertisement. Advertisement is the activity of attracting public attention to a product or business, as by paid announcements in the print, broadcast, or electronic media (advertising, 2010). Advertisements used by Perodua are television, the internet, newspapers and prints. The benefit of using advertisement is that it can cover a wide range of audience but is very costly. Personal selling is defined as oral communication with potential buyers of a product with the intention of making a sale (promotion-personal selling, n.d). The advantage of this that it can influence the customer more compare to advertisement. The disadvantage is that it depends on the attitude and the skilfulness of the salesperson to convince the customer. Perodua Myvi is sold through direct selling which is face-to-face by using a sales person. The sales person who does not directly work for the company mostly can lower the price of Perodua Myvi to attract customers. This is because they can deduct the price using their commission. While buying from salesperson at the showroom is more convenient as everything is handled by them and also the quality of the service is much better. Sales promotion refers to many kinds of incentives and techniques directed towards consumers and traders with the intention to produce immediate or short-term sales effects (Definition of Sales Promotion, 2010). Perodua have created many sales promotions to aid in the sales of Perodua Myvi such as the scrapping programme which was scheduled on 1 April 2009. This promotion allows customers to trade-in their old car for a reduction of RM5000 off any Perodua cars (Perodua 2009). Another sales promotion is customers can buy a Perodua Myvi on loan for RM347 a month for the first 5 years. If they booked and registered a Myvi from 13 June to 31 July 2009, the customer is entitled to join their contest. 7.3 Communication Process The communication process is a process whereby the sender is marketing their product to the receiver who is the public and except some feedback from them. Interference in this process which prevents the message being conveyed to the receiver is called noise. One of the noises that can affect Perodua promotion is competitors message. Other automobile companies will also have their own promotions to attract customers. They will always try to convince the customers in believing that their product is better than the rest. When P

The Deployment of Security Policy in Information Systems Essay

Database auditing is considered as a contemporary article on database due to a vital role on the database security (Abraham, etal .,2002). There are many different of motivations that make one very excited to do this work , Nevertheless there are millions of database transactions that being executed among different of hosts all-round the organization sites. There are many question arise such as How to do some statistical analysis on database, also How to reveal out the crimes that the database is vulnerable to. Surrounding the world that fully of millions of end users part of this huge figure doing malicious activities that may create crises and Misleading ,thus, firms depend on the information that being manipulated on the database and as it has been noticed the information is strategic material on organization. With the many of database crimes it is very difficult to determine the person that is responsible of some malicious activities in the database, therefore, database auditing implementation is generated to stand behind this issues wherever a crimes appears on an organization. On other hand the database auditing implementation assist on the assessment of our organization’s behaviors, attitudes, and rationality in dealing with organizational database. Within the technological competence awareness is important, different security solutions have been presented and the best solution is to audit the database logs, actions on database and any alteration on the objects of database to avoid any data modification. Through revolution of information technology (rapid, vast technology) Database auditing implementation should afford the velocity and power full to monitor the database activities. Moreover, we are in a bottle n... ...erience in analysis and design of distributed information systems, I+D Computation, Vol.1, No.1, July 2002. [8] H.G. Sol, R.L. Crosslin, Dynamic modelling of information systems II, North Holland, Amsterdam,1992. [9] P.I Rivera-Vega, R. Karlapalem, M. Ra, A mixed fragmentation approach for inintial distributed database design, Proceedings of International conference on data engineering, IEEE, 1990. [10] K. Hui, Knowledge Fusion and Constraint Solving in a Distributed Environment, PhD Thesis, University of Aberdeen, Kings College, Aberdeen, 2000. [11] R. Varadarajan, P.I. Rivera-Vega, S.B. Navathe, Data redistribution scheduling in fully connected networks, Proceedings of 27th Annual Alberton conference on communication, Control and Computing, 1989. [12] M.T. Ãâ€"zsu, P. Valduriez, Principles of distributed database systems, Prentice Hall Edt, New Jersey, 1999.

Lorraine Hansberrys A Raisin In The Sun Essay -- essays research pap

Dream’s Recovered   Ã‚  Ã‚  Ã‚  Ã‚  Everyone has dreams; everyone has goals they want to accomplish. Some know what it is instantly and some take time to realize what they want to do. But not everyone will achieve their dreams and some, because of sad circumstances lose their grip on their dream and fall into a state of disappointment. Langston Hughes poem relates to the dreams of Mama, Ruth, and Walter in Lorraine Hansberry’s play A Raisin in the Sun.   Ã‚  Ã‚  Ã‚  Ã‚  Ruth has to listen to Walter’s extravagant dreams of being rich and powerful all the time and know that these dreams will never happen. They are very poor and Travis must sleep on the couch because they only have a two-room apartment. Ruth’s dream of having a baby seems crushed when she finds out that she’s pregnant and realizes they can’t support another in the household. When mama and Walter argue about Ruth getting an abortion Walter says she wouldn’t do anything like that as she walks in, she says â€Å"Yes I would too Walter. I gave her a five-dollar down payment.† (1.2.75). Ruth’s dream of having a baby is dried up when she knows they can’t support another child in the household.   Ã‚  Ã‚  Ã‚  Ã‚  Lena Younger has always dreamed of a garden with beautiful flowers in her own yard next to her own house. But she is devastated when she hears that Walter took the rest of money for the house and Beneatha’s school money and gave it to Willy Harris who literally stole the Young... Lorraine Hansberry's A Raisin In The Sun Essay -- essays research pap Dream’s Recovered   Ã‚  Ã‚  Ã‚  Ã‚  Everyone has dreams; everyone has goals they want to accomplish. Some know what it is instantly and some take time to realize what they want to do. But not everyone will achieve their dreams and some, because of sad circumstances lose their grip on their dream and fall into a state of disappointment. Langston Hughes poem relates to the dreams of Mama, Ruth, and Walter in Lorraine Hansberry’s play A Raisin in the Sun.   Ã‚  Ã‚  Ã‚  Ã‚  Ruth has to listen to Walter’s extravagant dreams of being rich and powerful all the time and know that these dreams will never happen. They are very poor and Travis must sleep on the couch because they only have a two-room apartment. Ruth’s dream of having a baby seems crushed when she finds out that she’s pregnant and realizes they can’t support another in the household. When mama and Walter argue about Ruth getting an abortion Walter says she wouldn’t do anything like that as she walks in, she says â€Å"Yes I would too Walter. I gave her a five-dollar down payment.† (1.2.75). Ruth’s dream of having a baby is dried up when she knows they can’t support another child in the household.   Ã‚  Ã‚  Ã‚  Ã‚  Lena Younger has always dreamed of a garden with beautiful flowers in her own yard next to her own house. But she is devastated when she hears that Walter took the rest of money for the house and Beneatha’s school money and gave it to Willy Harris who literally stole the Young...

Why Did We Drop the Bombs on Hiroshima and Nagasaki? :: Atomic Bombings of Hiroshima and Nagasaki

Why did we drop the bomb on Hiroshima? There are lots of arguments for and against dropping the bomb’s on Hiroshima and Nagasaki. Since the day that that monumental event took place people have debated whether the U.S.A. should have drooped the bombs on Hiroshima and Nagasaki. Opinions on whether it was right or wrong differ, an absolutist might say that you are killing so it is wrong. But and a relativist would say that in the long run you would be saving thousands of lives both civilian and military. Is that not what all military leaders strive for? But was it fair to pick a civilian target? Is war between soldiers of a nation or the nations them selves? How you answer these questions dictates what you opinion on this controversial subject is. Why did president Truman drop the bomb and was he right to drop it where he did? Why should the U.S.A. have dropped the bomb? With the end to the Japanese role in the war it would effectively bring the war to an end. After pearl harbour the Americans had been humiliated. The government and the people wanted to see someone pay for the tremendous loss of life in that fateful attack. The bombs where the perfect way to get their own back for that incident at Pearl Harbour and show the world that they were boss and should not be challenged or the consequences would be devastating. It spelled out America’s start of the new dominant military power over every other nation. No one would ever challenge America after they had seen what they where destructive power they were capable of. It would also bring an end to the U.S.A’s war with Japan. There is also the fact that the Americans had spent millions of dollars to build the bomb. If they did not use it the public would question whether they should pay tax for something like this to be build and never use it. The public unless shown that it was needed would loose faith in their government's choice of spending. But even after The U.S.A. had inflected such a terrible curse On the people of Hiroshima, they droped a second bomb on another Civilians Area with Just as much horror as the first. Inflicting the same death and destruction on thousands more. The second bomb showed that the USA was prepared to continue using such force if the Japanese did not surrender and admit defeat.

Cystic Fibrosis

————————————————- Introduction Cystic fibrosis  (also called  CF  or  mucoviscidosis) is an  autosomal  recessive  genetic disorder  that affects most critically the  lungs, and also the  pancreas,  liver, and  intestine. It is characterized by abnormal transport of  chloride  and  sodium  across an  epithelium, leading to thick, viscous secretions. The name  refers to the characteristic  scarring  (fibrosis) and  cyst  formation within the  pancreas that was first recognized in the 1930s.Difficulty in breathing  is the most serious symptom and results from frequent  lung infections  which are treated with  antibiotics, therapies and several other medications. Other  symptoms, including  sinus infections,  poor growth, and  infertility affect other parts of the body. A breathing treatment for cystic fibrosis, usi ng a mask nebulizer and a ThAIRapy Vest A breathing treatment for cystic fibrosis, using a mask nebulizer and a ThAIRapy Vest CF is caused by a  mutation  in the  gene  for the  protein  cystic fibrosis trans-membrane conductance regulator  (CFTR).This protein is required to regulate the components of sweat,  digestive  juices, and  mucus. CFTR regulates the movement of  chloride  and  sodium ions across epithelial membranes, such as the alveolar epithelia located in the  lungs. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis due to the disorder's recessive nature. CF develops when neither gene works normally (as a result of mutation) and therefore has  autosomal recessive  inheritance.CF is most common among  Caucasians; one in 25 people of European descent  carries one  allele  for CF. The  World Health Organization  states that â€Å"In the European Union, 1 in 200 0–3000 new-borns is found to be affected by CF†. Individuals with cystic fibrosis can be diagnosed before birth by  genetic testing or by a  sweat test  in early childhood. Ultimately,  lung transplantation  is often necessary as CF worsens. ————————————————- Signs and symptomsThe hallmark symptoms of cystic fibrosis are salty tasting skin,  poor growth and poor weight gain despite a normal 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, such as  bowel movement obstruction  in new-born babies. As the children grow, they must exercise to release the mucus present in the alveoli. Ciliated  epithelial cells present  in the patient have a mutated protein that leads to abnormally viscous mucus production.The poor growth in children typically presents as an inability 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 causes of growth failure are multifactorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness. In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. A double recessive allele is needed for cystic fibrosis to be apparent.Young children are especially sensitive to vitamin  malabsorptive 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 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 whet her there is an underlying disease. Lungs and sinuses Lung disease results from clogging of the airways due to mucus build-up, decreased  mucociliary clearance, and resulting  inflammation.Inflammation and infection cause injury and structural changes to the lungs, leading to a variety of symptoms. In the early stages, regular incessant coughing along with copious  phlegm  production, and decreased ability to exercise are common. Many of these symptoms occur when  bacteria 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 exacerbate difficulties in breathing.Other symptoms include coughing up blood (hemoptysis), 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 asà ‚  bi-level 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. In addition to typical bacterial infections, people with CF more commonly develop other types of lung disease.Among these is  allergic bronchopulmonary aspergillosis, in which the body's response to the common  fungus  Aspergillus fumigatus  causes worsening of breathing problems. Another is infection with Mycobacterium avium  complex (MAC), a group of bacteria related to  tuberculosis, which can cause a lot of lung damage and does 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 inflammati on from chronic 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 complications are the most common cause of death (~80%) in patients at most CF centers in the United States. Gastrointestinal Prior to prenatal and  newborn screening, cystic fibrosis was often diagnosed when a newborn infant failed to pass feces (meconium).Meconium may completely block the  intestines  and cause serious illness. This condition, called  meconium ileus, occurs in 5–10%  of newborns with CF. 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  pressure due to coughing. The thick mucus seen in the lungs has a counterpart in thickened secretions from the  pancreas, an organ responsible for provi ding digestive  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. The lack of digestive enzymes leads to difficulty absorbing nutrients with their subsequent excretion in the feces, a disorder known as malabsorption. Malabsorption leads to  malnutrition  and poor growth and evelopment because of calorie loss. Resultant hypoproteinemia  may be severe enough to cause generalized edema. Individuals with CF also have difficulties absorbing the fat-soluble vitamins  A,  D,  E, and  K. In addition to the pancreas problems, people with cystic fibrosis experience more  heartburn, intestinal blockage by  intussusception , and constipation. Older individuals with CF may develop  distal intestinal obstruction syndrome  when thickened feces cause intestinal blockage. Exocrine pancreatic insufficiency occurs in the majority (85% to 90%) of patients with CF.It is mainly associated with â€Å"severe† CFTR mutations, where both alleles are completely nonfunctional (e. g. ?F508/? F508). It occurs in 10% to 15% of patients with one â€Å"severe† and one â€Å"mild† CFTR mutation where there still is a little CFTR activity, or where there are two â€Å"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 general, such individuals usually have excellent growth and development.Despite this, idiopathic  chronic pancreatitis  can occur in a subset of pancreas-sufficient individuals with CF, and is a ssociated 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. 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 cystic fibrosis.Endocrine Clubbing in the fingers of a person with cystic fibrosis Clubbing in the fingers of a person with cystic fibrosis The  pancreas  contains the  islets of Langerhans, which are responsible for making insulin, a hormone that helps regulate blood  glucose. Damage of the pancreas can lead to loss of the islet  cells, 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 in  type 1and  type 2  diabetics, and is one of the principal non-pulmonary 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. In addition, people with CF often develop clubbing  of their fingers and toes due to the effects of chronic illness and  low oxygen  in their tissues. 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 cystic fibrosis 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  azoospermia,  te ratospermia  and  oligoasthenospermia. 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 disrupts  ovulation  and causes  amenorrhea. ———————————————— Cause CF is caused by a  mutation  in the  gene  cystic fibrosis trans-membrane conductance regulator  (CFTR). The most common mutation,  ? F508, is a deletion (? 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, there are over 1500 other mutations that can produce CF.Althou gh 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 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 known as an  ABC gene. The product of this gene (the CFTR) 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 6  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. In addition, there is increasing evidence 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. ———————————————— Pathophysiology Molecular structure of the CFTR protein Molecular structure of the CFTR protein There are several mutations in the  CFTR  gene, 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 not  fold  normally and is degraded by the cell.Other mutations result in proteins that are too short (truncated) because  production  is ended prematurely. Other mutations produce proteins that do not use energy normally, do not allow  chloride iodide  and  thiocyanate  to cross the membrane appropriately,  or are degraded 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.Th e 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 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 thiocyanate  are trapped inside the cells in the airway and outside in the skin. Then  hypothiocyanite, OSCN, cannot be produced by immune defense system.Because chloride is  negatively charged, this creates a difference in the electrical potential inside and outside the cell causing  cations  to cross into the cell. Sodium is the most common cation in the extracellular space 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 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 body's  immune 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 movement  out  of the cell leads to dehydration of mucus, pancreatic secretions, biliary secretions, etc. Chr onic 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. Over time, both the types of bacteria and their individual characteristics change in individuals with CF. In the initial stage, common bacteria such as  Staphylococcus aureus  and  Hemophilus influenzae  colonize and infect the lungs.Eventually,  Pseudomonas aeruginosa  (and sometimes  Burkholderia cepacia) dominates. By 18 years of age, 80% of patients with classic cystic fibrosis harbor  Ps eudomonas aeruginosa, and another 3. 5% harbor Burkholderia 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 â€Å"mucoid†Ã‚  Pseudomonas, 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 past, people with CF often participated in summer â€Å"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 routinely isolated from one another in the healthcare setting and healthcare providers are encouraged to wear gowns and gloves when examining p atients 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 like  Penicillium emersonii  and  Acrophialophora 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 corticosteroid treatments may also facilitate fungal growth. Although the clinical relevance of the fungal airway colonization is still a ma tter 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 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 including  newborn 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. 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.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 of a medication that stimulates sweating (pilocarpine). To deliver the medication through the skin, iontophoresis  is used to, whereby one  electrode  is placed onto the applied medication and an electric current  is passed to a separate electrode on the skin.The resultant sweat is then collected on filter paper or in a capi llary tube and analyzed for abnormal amounts of  sodium  and  chloride. People with CF have increased amounts of sodium and chloride in their sweat. In contrast, people with CF have less thiocyanate and  hypothiocyanite  in their saliva and mucus. CF can also be diagnosed by identification of mutations in the CFTR gene. 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. 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 the  fetus  is performed. The  American College of Obstetricians and Gynecologists  (ACOG) recommends testing for couples who have a personal or close family history of CF, and they recommend that carrie r 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 ? F508—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  pla centa  (chorionic villus sampling) or the fluid around the fetus (amniocentesis). However,  chorionic villus sampling  has a risk of fetal death of 1 in 100 and amniocentesis of 1 in 200;  a recent 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 conception (NC) followed by prenatal testing and abortion of affected pregnancies, PGD provides net economic benefits up to a maternal age of approximately 40 years, 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 management of cystic fibrosis has improved significantly over the past 70 years.While infants born with cystic fibrosis 70 years ag o 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 an individual with cystic fibrosis can live a fuller life less encumbered by their condition. The cornerstones of management are proactive treatment of  airway infection, and encouragement of good nutrition and an active lifestyle. Management of cystic fibrosis continues throughout a patient's 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 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 (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, 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 comply with prescribed treatments while balancing a normal life. In addition, therapies such as  transplantation  and  gene therapy  aim to cure some of the effects of cystic fibrosis. Gene 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 (adenovirus, adeno-associated virus or retro virus) and secondly the use of  lipo some. 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 more  antibiotics  at all times, even when healthy, to  prophylactically  suppress 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 patient's past response. This prolonged therapy often necessitates hospitalization and insertion of a more permanent  IV  such as a  peripherally inserted central catheter  (PICC line) 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. Oral antibiotics such as ciprofloxacin or  azithromycin  are given to hel p prevent infection or to control ongoing infection. The  aminoglycoside  antibiotics (e. g. obramycin) with long-term use can cause  several side effects such as hearing loss, damaging the  balance system  present in the  inner ear  and producing many chronic kidney problems  . To prevent these  side-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 individual's chest with his or her hands several times a day, to loosen up secretions.Devices that recreate this percussive therapy include the  ThAIRapy Vest  and the  intrapulmonary percussive ventilator  (IPV). Newer methods such as  Biphasic Cuirass Ventilation, and associated clearance mode available in such devices, integrate a cough a ssistance phase, as well as a vibration phase for dislodging secretions. These are portable and adapted for home use. 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.Denufosol  is 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 as  bi-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, a  tube  may be placed in the throat (a procedure known as a  tracheostomy) to enable breathing supported by a  ven tilator.For children living 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 transplantation  often becomes necessary for individuals with cystic fibrosis as lung function ceases and  exercise tolerance  declines. 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 c an be used to provide fertility for men with cystic. .fibrosis New-borns 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 faeces. 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 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.Diabetes  is the most common non-pulmonary complication of CF. It mixes features of  type 1and  type 2  diabetes, and is recognized as a distinct entity,  cystic fibrosis-related diabetes (CFRD). While oral  anti-diabetic drugs  are somet imes used, the only 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. Development of  osteoporosis  can be prevented by increased intake of vitamin D and  calcium, and can be treated by  bisphosphonates, although  adverse effects  can be an issue.Poor growth may be avoided by insertion of a  feeding tube  for increasing  calories  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 patient's sense of smell. Sinus surgery is often used to alleviate nasal obstruction and to limit further infections. Nasal steroids such as  fluticasone  are used to decrease nasal inflammation.Female infertility may be overc ome by  assisted reproduction  technology (ART) with the help of embryo transfer  techniques. Male infertility caused by absence of the  vas deferens  may be overcome with  testicular sperm extraction  (TEST), 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. ————————————————- 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 from  high 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 Russia  the 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 â€Å"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 pati ents 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) â€Å"rated some QOL domains higher than did their parents†. Consequently, outpatients with CF have a more positive outlook 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 patient’s daily routine can significantly improve the 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 fighting lung infections. ————————— Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€Ã¢â‚¬â€-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 of  Caucasian heritage. In the United States, approximately 30,000 individuals have CF; most are diagnosed by six months of age. In  Canada, 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 46  Hispanics, 1 in 65  Africans  and 1 in 90 Asians  carry at least one abnormal CFTR gene. Ireland has the world's highest incidence of cystic fibrosis, at 1:1353. Although technically a  rare 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 is  Finland, 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 fibrosis is diagnosed in males and females equally. For reasons that remain unclear, data has shown that males tend to have a longer  life expectancy  than 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 1:200 in northern Sweden, 1:143 in Lithuanians, and 1 :38 in Denmark. No ? F508 carriers were found among 171  Finns  and 151  Saami 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  ? F508  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, a concept known as  heterozygote advantage. Resistances to the following have all been proposed as possible sources of heterozygote advantage: * Cholera: With the finding and 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 required essentially for the entry of  Salmonella typhi  into cells,  suggesting that carriers of the 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: 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. ——————————————à ¢â‚¬â€Ã¢â‚¬â€- 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, literature  from Germany and Switzerland in the 18th century warned  Wehe dem Kind, das beim Ku? auf die Stirn salzig schmekt, er ist verhext und muss bald sterbeor â€Å"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. Dorothy Hansine Andersen Dorothy Hansine Andersen In the 19th century,  Carl von Rokitansky  described a case of fetal death with  meconium peritonitis, a complication of meconium ileus associated with cystic fibrosis.Meconium ileus was first described in 1905 by  Karl Landsteiner. In 1936,  Guido Fanconi  published a paper describing a conn ecting link between  celiac disease, cystic fibrosis of the pancreas, and bronchiectasis. In 1938  Dorothy Hansine Andersen  published an article, â€Å"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 Sant' Agnese 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, indicating that only one locus exists for CF  Hans Eiberg. In 1988 the first mutation for CF,  ? F508  was discovered by  Francis Collins,  Lap-Che e 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  -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.Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of  reverse genetics. ————————————————- Research Gene therapy Gene therapy  has been explored as a potential cure for cystic fibrosis. Ideally, gene therapy places 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 in all target cells, without adverse reactions or an inflammation response.Studies have shown that to prevent the lung manifestations of cystic fibrosis, 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. 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 the  Cystic Fibrosis Trust, which has a league of highly professional gene therapists, both somatic and Adeno -associated viral vector have made advances. The  Adenoviridae, or more commonly known as the cold virus, is genetically altered, allowing the CFTR gene to enter lung cells. Small molecules A number of  small molecules  that 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  stop codon  and 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 mutations  such as G542X, which consists of the amino acid  glycine  in 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 aminoglycoside  gentamicin  has been used to treat lun g cells from CF patients in the laboratory to induce the cells to grow full-length proteins. Another drug targeting nonsense mutations is  ataluren, which is undergoing Phase III clinical trials as of October 2011. BIBLIOGRAPHY 1. BIOLOGY TEXTBOOK FOR CLASS – XII (NCERT) 2. TRUEMAN’S 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/