Genius Defined Essay - 904 Words

The word genius can be used to describe a person, an idea or an invention. As a person, a genius is one that stands out from a crowd and tackles the most difficult of problems in the simplest of ways. A genius is not only very clever, but instinct allows them to think outside the box. The term genius is often associated with names such as Albert Einstein, Leonardo Da Vinci, JS Bach, William Blake, and Socrates. These are just a few of history’s greatest thinkers who helped shape society with their innovative ideas. The universal definition of a â€Å"genius† is â€Å"one who has an exceptional natural capacity of intellect, especially as shown in creative and original work in science, art, music, etc.’ Genius is also defined as ‘a person having†¦show more content†¦Each kind of genius is worlds apart. How a genius is molded from birth to until his death makes him distinct from others. Values, ideals, and beliefs vary from one mastermind to the next, but the genius in them is prominent. Albert Einstein once exclaimed I have no special talents. I am only passionately curious. The world’s greatest geniuses are famous for a profound, open minded sense of curiosity. Curiosity is a personality trait often found in geniuses. This curiosity is usually the key element behind the motivation of a genius. â€Å"This proclivity towards curiosity or inquisitiveness may explain the breadth of interests and preference for complexity displayed by creative individuals† (Simonton 49). The focus of a true genius, whether in sciences, arts, or businesses, is finding new, creative and effective ways to do things. Curiosity sparks inspiration and creativity. A genius has the ability to do more than just memorize and recite existing information and ideas. They can discover, create, or invent new ideas within their particular area of interest. â€Å"The word creativity is closely linked to the word genius, since both words have the root meaning to give birth†. Essentially, creativity designates the capacity to give birth to new ways of looking at things, the ability to make novel connections between disparate things, and the knack for seeing things that might be missed by the typicalShow MoreRelatedThe Social and Personal Impediments Against Which Genius Has to Battle.quot;1455 Words   |  6 Pagescan be no question of Mozarts genius, however, what is genius defined as? The main definition is that genius is a very great and rare innate ability or skill- it is a creative power. It is therefore clear that Mozart was in fact a genius in his music; it does no state anywhere, however, that a genius also has to have a divine personality and behaviour and this is clear as Mozart is shown in Amadeus as a silly, scatological, childish and infantile man. To be a genius in one aspect of the mind, suchRead MoreDivergent Thinking Vs. Creative Thinking Essay1061 Words   |  5 Pagesenvironment, these early surroundings that children are exposed to shape their creativity. As students, parents, and even teachers we dont realize the effects that the education system can have on ones creativity. The public education system is defined by two main ideas, what are the most useful subjects for work and ones academic ability. So, where does this leave creativity? Due to the ideals of the education system, creativity can be seen as unvalued or even stigmatized. Understanding the correlationRead MoreThe Levels Of Intelligence As A Woman And Man1652 Words   |  7 Pagesto even demonstrate their intelligence. Today, in the world of feminism, scientist battle to discover the truth behind intellectual abilities. They present questions like: Is intelligence an innate concept in which women will not be able to meet â€Å"genius† levels like men, or is it based on the norms of society imposing gender roles? This essay explores the levels of intelligence in a woman and man. Moreover, I will analyze enculturation factors, as well as so cial determination to ultimately determineRead MoreApple Strategic Analysis10312 Words   |  42 Pagesviable brand. Finally the threat of substitutes is credible in some usecases, but will not completely usurp personal computers in the foreseeable future. See Appendix A1 for accompanying template. Rivalry Between Competitors While once an industry defined by few large companies and extremely expensive products, pursuing a niche audience, the advent of the personal computer (PC) has caused an industry explosion which now includes dozens of manufacturers pursuing many millions of customers in the UnitedRead MoreThe True Meaning of Intelligence Essays948 Words   |  4 PagesWhen a person utters the word â€Å"intelligence,† people tend to think of a genius like Albert Einstein developing some obscure equation that the great majority of the population will never understand. The problem with the definition of intelligence is that people relate intelligence to words like †Å"genius† which require intelligence but do not have the same definition as intelligence. Often, people try to use related words to define intelligence, but these words are unable to define intelligence sinceRead MoreA Comparison Of Alexander Hamilton And Aaron Burr1156 Words   |  5 Pagesraised. What is genius? Is genius born or can it be learned? Scholars have gone back and forth and there is plenty of evidence and countless examples supporting either side. However, there appears to be a compromise between the two sides in how a genius comes about. To begin, it is common for many people to laud a skilled person as a â€Å"genius†. In reality, a genius is defined as, â€Å"extraordinary intellectual power especially as manifested in creative activity† (Meriam). Clearly, a genius who possessesRead MoreA Brilliant Madness about John Forbes Nash Essay1458 Words   |  6 Pagescreative genius. Indeed, research has proven that the two conditions of psychology display similar characteristics, both behaviourally and genetically. Unfortunately, this subject remains quite ambiguous, and science may never fully grasp the concept (Griffith 626; Ludwig 5; Simonton; Neihart). Although it lacks in hard facts, many compelling theories arise from this field of study: a little madness may bolster creative genius, but too much madness can overpower the creativity and kill the genius. TheRead MoreAesthetics Reflection On Art And The Philosophy Of Beauty1201 Words   |  5 Pagesupside to this repetitive tug of war. On this rock we call home, we are surrounded by the most gorgeous creations, structures, and landscapes that add a touch of serenity to our miserable existences called aesthetics. Aesthetics as an adjective is defined as concern with beauty of the appreciation of beauty. As a noun it means a set of principles underlying and guiding the work of a particular artist or artistic movement. The surrounding beauty that we take for continuous granted is significant towardsRead MoreBaron dHolbach and William James on Free Will and Determinism1192 Words   |  5 Pages So according to this statement freewill is the ability for humans to make decisions without influences or outside restrictions. The other issue that is being discussed between the two philosophers is determinism. Also determinism must be defined before interpreting their views. Determinism according to the Encarta encyclopedia is A philosophical doctrine holding that every event, mental as well as physical, has a cause, and that, the cause being given, the event follows invariably. ThisRead MoreEssay about The Assyrian Winged Protective Deity and Gilgamesh657 Words   |  3 Pagesthan Gilgamesh and the Assyrian Winged Protective Deity both being from Mesopotamia, they have numerous similarities. The Assyrian Winged Protective Deity is a very imposing figure. It measures around seven and a half feet tall (Relief of a Winged Genius). This shows the figures importance, even if the viewer did not know it protected the king from harm. Originally, it was placed next to the throne, which also makes it an important image. The muscles are extremely striking on the figures arms and

Student Name Ira R. Roach - 1423 Words

Student Name: Ira R. Roach Setting/Your Role: Terros is located in Mesa, Arizona which provides individual and group counseling for clients seeking substance use, mental health services and those individuals with co-occurring symptoms. Clients may be mandated to comply with adult probation will complete twelve weeks of intensive group therapy (IOP) four days a week for two hours a day. By the end of the group counseling, clients will have learned new coping skills by utilizing new healthy alternative mechanisms to address substance use utilizing Cognitive Behavioral Therapy (CBT) and Motivational Interviewing (MI). The role of the social worker in this setting is to perform duties as an informed clinician based on evidence based practice to provide individualized case management to all clients. The social worker will complete a comprehensive intake assessment which includes demographics of the client, address presenting problem, and a risk assessment. Client’s also receive mental health screenings an d individual and group counseling to gain new coping skills and address any triggers to prevent relapse utilizing interventions as CBT and Motivational Interviewing. The social worker will discuss limits of confidentiality and a signed informed consent from the client to receive services. Provide a brief discussion of the agency/setting in which services are being provided. Presenting Problems and Strengths: Client presents with a history of substance use in which sheShow MoreRelatedManagement Course: Mba−10 General Management215330 Words   |  862 PagesCulture 5. Managing Across Cultures iv Feigenbaum−Feigenbaum: The Power of Management Capitol 1. New Management for Business Growth in a Demanding Economy Text  © The McGraw−Hill Companies, 2004 1 C H A 1 P T E R NEW MANAGEMENT FOR BUSINESS GROWTH IN A DEMANDING ECONOMY 2 Feigenbaum−Feigenbaum: The Power of Management Capitol 1. New Management for Business Growth in a Demanding Economy Text  © The McGraw−Hill Companies, 2004 Feigenbaum−Feigenbaum:Read MoreDesigning a Customer Driven Statergy23698 Words   |  95 Pagesto sit on a couch, I stay at home.† William Rosenberg opened the first Dunkin’ Donuts in Quincy, Massachusetts, in 1950. Residents flocked to his store each morning for the coffee and fresh doughnuts. Rosenberg started franchising the Dunkin’ Donuts name, and the chain grew rapidly throughout the Midwest and Southeast. By the early 1990s, however, Dunkin’ was losing breakfast sales to morning sandwiches at McDonald’s and Burger King. Starbucks and other high-end cafes began sprouting up, bringing more

Professional Project on Selection and Recruitment for Indeed

Question: Discuss about theProfessional Project on Selection and Recruitment for Indeed. Answer: Introduction and Relevance of the Topic Recruitment and selection is regarding getting the best sources, hiring of best talents, and ensuring that an organization is kept competitive on the contemporary job markets and also ensuring that best employees are retained by an organization (Almeida Fernando, 2017). As an essential Human resource function, recruitment and selection is indeed one of the major activities that have a significant impact on the performance of any firm based on the terms of attainment of the ultimate goals. This topic is quite important in the profession because not only will it help in the identification of the current selection and recruitment methods that have been adopted by organizations but it also helps in the identification of the numerous challenges that are encountered and how they can be resolved (Collings, Mellahi, Cascio, 2017). Literature Review The research proposal will make use of various sources of literature which will include among others secondary sources such as websites. One of the major sources of secondary data that is linked with the issue of Recruitment and selection in organizations is: https://issuu.com/sanjaykumarguptaa/docs/project-report-recruitment-and-selection-process Research Questions What can organization do to ensure that best employees are recruited into the organization? What should be done to ensure that best employees are retained in an organization? What selection and recruitment practices can be used in ensuring that well qualified employees are recruited into the organization? What are some of the barriers to effective recruitment and selection processes in an organization? The Key search Terms Selection recruitment Three Reviewed Scholarly Articles from the search Ployhart, R.E., Schmitt, N. and Tippins, N.T., 2017. Solving the Supreme Problem: 100 years of selection and recruitment at the Journal of Applied Psychology. Journal of Applied Psychology, 102(3), p.291. Rees, G. and Smith, P. eds., 2017. Strategic human resource management: An international perspective. Sage. Lacey, R.J., Wilkie, R., Wynne-Jones, G., Jordan, J.L., Wersocki, E. and McBeth, J., 2017. Evidence for strategies that improve recruitment and retention of adults aged 65 years and over in randomised trials and observational studies: a systematic review. Age and ageing, 46(6), pp.895-903. Two sentences combining the three articles Recruitment and retention are vital human resource processes that should be embraced by all organizations. Effective selection and recruitment practices will thus ensure that numerous problems in the personnel department are resolved. References Almeida, S., Fernando, M. (2017). Making the cut: occupation-specific factors influencing employers in their recruitment and selection of immigrant professionals in the information technology and accounting occupations in regional Australia. The International Journal of Human Resource Management, 28(6), 880-912. Collings, D. G., Mellahi, K., Cascio, W. F. (Eds.). (2017). The Oxford Handbook of Talent Management. Oxford University Press.

Things They Carried By O`Brien Essays - Tim OBrien

Things They Carried By O`Brien The Things They Carried is written from the perspective of the author, Tim O'Brien. The book is a compilation of his stories and experiences relating to the Vietnam War. It encompasses the events and lives of himself, the other members of his company, and the war as a whole. Tim O'Brien, of no important rank, is a solider in the Alpha Company that heads out most operations of Nam. They are the first troop to stake out land, the first to raid the villages, the trailblazers through the minefields. They are the best of the best. As the story is told, First Lieutenant Jimmy Cross heads his troops across the marshes and paddies of Vietnam. It is in him the men must trust. As war for me goes, I had no foundation for what to expect. Being that I have never seen any war movies or read anything like this before, this, in essence, was my first realistic exposure to war. In my choosing this book, what I did expect was to have a book that I could relate to, as well as one that was written about someone's personal experience. And that is exactly what I got. Many stories, written as second-hand experience of O'Brien, take place before many soldiers are placed in or called to Alpha. They also reflect on how O'Brien interprets them. No war story is told without a twist or turn of the truth. Details are imagined, and dreamed up to how the teller finds most appropriate. "Vietnam was full of strange stories, some improbable, some well beyond that, but the stories that will last forever are those that swirl back and forth across the border between trivia and bedlam, the mad and the mundane." (O'Brien, pg. 89) This bias is the basis to a war story. Stories come from speculation, some from absolute fact, others from pure lies. From their origin on, truth relies on the eye of the beholder. "In many cases a true war story cannot be believed. If you believe it, be skeptical. It's a question of credibility. Often the crazy stuff is true, and the normal stuff isn't, because the normal stuff is necessary to make you believe the truly incredible craziness." (O'Brien, pg. 71) For troops, there is no other purpose than to hump their stuff, follow orders and carry their hearts, which they shove, to the bottom of the bag. Many of the troops are burdened with emotion, others with true weight or harsh responsibility. What they hold, they hold dear. If the object had no value, or they just got tired, they'd leave things for waste by the side of their trail. "They would often discard things along the route of march. Purely for comfort, they would throw away rations, blow their Claymores and grenades, no matter, because by nightfall the resupply choppers would arrive with more of the same... and for all the ambiguities of Vietnam, all the mysteries and unknowns, there was at least a single abiding certainty that they would never be at a loss for things to carry." (O'Brien, pg. 15,16) O'Brien has such a power for words relating to the true emotion of the war. Feelings have such contrast, going from no regard, to the only care in the world. Though this story calls itself fiction, you'll have a hard time believing it. The realism, the captivity of emotions, tore at my heart, then turned around and angered me where I considered not reading any more. For example, here's a small story: "Later, higher in the mountains, we came across a baby VC water buffalo. What it was doing there, I don't know-but we chased it down and got a rope around it, and led it along to a deserted village where we set up for the night. After supper, Rat Kiley went over and stroked its nose. He opened up a can of C rations, pork and beans, but the baby buffalo wasn't interested. Rat shrugged. He stepped back and shot it through the right front knee. The animal did not make a sound. It went down hard, then got up again, and Rat took careful aim and shot off an ear. He shot it in the hindquarters and in the little hump at its back. He shot it twice in the flanks. It wasn't to kill; it was to hurt." (O'Brien, pg. 78-79) How could such a thing be done? I was so moved, so shocked. I wanted to

Post Civil War Times essays

Post Civil War Times essays After the Civil War, many settlers from the East moved west, the new frontier during the 1860-1890 period. Among those settlers were farmers, miners, railroad builders, and cattlemen who all wanted the rich, vast lands of the West. The movement west occurred because of the following reasons: the railroad companies wanted land to establish railways from the East to the West, farmers felt that the Western land would make them rich, miners wanted the land for the rich silver, gold, and other minerals, and cattlemen wanted to establish the profitable "cattle business" by using the long drive method. The Whites wanted this land no matter what, and they refused to let anything stand in the way of their goals. This led to Indians facing drastic consequences which impacted their way of life, Indian Wars, and the policy of Americanization. The Whites wanted to drive the Indians out of their own lands, and they accomplished this through several ways. One was the destruction of the buffalo, the staff of life for the Indians. The Whites' purposes for exterminating the buffalo were to stall railroad construction, kill for their hides, certain body parts, and/or just for the pure enjoyment of killing these beasts. The Indians needed the buffalo since it provided food, shelter, clothing, weapons, and religious rituals. With most of the buffalo dead, the Indians lacked the necessities of life. Therefore there was a decline of the Indian population. Another way was the diseases of the White man. Indians weren't resistant to these diseases like small pox; therefore, it also contributed to the decline of the Indian's population. Another brutal way was by form of violence. The Whites used Calvary or the ARMY to control the Indians. They also used the revolver, the "six-shooter," something that the Indians didn't have in order t o defend themselves. The factor of violence led to the Indian Wars, which took place during the 1860s-1890s. The first ba...

How to Select a Science Fair Project Topic

How to Select a Science Fair Project Topic Great science fair projects dont need to be expensive or difficult. Even so, science fair projects can be very stressful and frustrating for students, parents, and teachers! Here are some tips for coming up with science fair project ideas, deciding how to turn an idea into a clever project, performing the science fair project, writing a meaningful report about it, and presenting a great-looking, sturdy display. The key to getting the most out of your science fair project is to start working on it as soon as possible! If you wait until the last minute you will feel rushed, which leads to feelings of frustration and anxiety, which makes good science harder than it needs to be. These steps for developing a science project work, even if you procrastinate until the last possible minute, but your experience wont be as much fun! Science Fair Project Ideas Some people are brimming with great science project ideas. If you are one of those lucky students, feel free to skip to the next section. If, on the other hand, the brainstorming part of the project is your first hurdle, read on! Coming up with ideas isnt a matter of brilliance. Its a matter of practice! Dont try to come up with only one idea and make it work. Come up with lots of ideas. First: think about what interests you. If your science project is restricted to a subject, then think about your interests within those limits. This is a chemistry site, so Ill use chemistry as an example. Chemistry is a huge, broad category. Are you interested in foods? properties of materials? toxins? drugs? chemical reactions? salt? tasting colas? Go through everything you can think of that relates to your broad topic and write down anything that sounds interesting to you. Dont be timid. Give yourself a brainstorming time limit (like 15 minutes), enlist the help of friends, and dont stop thinking or writing until the time is up. If you cant think of anything that interests you about your subject (hey, some classes are required, but not everyones cup of tea, right?), then force yourself to think up and write down every topic under that subject until your time is up. Write down broad topics, write down specific topics. Write anything that comes to mind - have fun! See, there are LOTS of ideas! If you were desperate, you had to resort to ideas on websites or in your textbook, but you should have some ideas for projects. Now, you need to narrow them down and refine your idea into a workable project. Science is based on the scientific method, which means you need to come up with a testable hypothesis for a good project. Basically, you need to find a question about your topic that you can test to find an answer. Look over your idea list (dont be afraid to add to it at any time or cross off items that you dont like... its your list, after all) and write down questions that you can ask and can test. There are some questions you cant answer because you dont have the time or the materials or the permission to test. With respect to time, think of a question that can be tested over a fairly short time span. Avoid panic and dont try to answer questions that take most of the time you have for the entire project. An example of a question that can be answered quickly: Can cats be right or left pawed? Its a simple yes or no question. You can get preliminary data (assuming you have a cat and a toy or treats) in a matter of seconds, and then determine how you will construct a more formal experiment. (My data indicates yes, a cat can have a paw preference. My cat is left-pawed, just in case you are wondering.) This example illustrates a couple of points. First, yes/no, positive/negative, more/less/same, quantitative questions are easier to test/answer than value, judgement, or qualitative questions. Second, a simple test is better than a complicated test. If you can, plan to test one simple question. If you combine variables (Like determining whether paw use varies between males and females or according to age), you will make your project infinitely more difficult. Heres a first chemistry question: What concentration of salt (NaCl) needs to be in water before you can taste it? If you have a calculator, measuring utensils, water, salt, tongue, pen, and paper, youre set! Then you can proceed to the next section on experimental design. Still stumped? Take a break and go back to the brainstorming section later. If you are having a mental block, you need to relax in order to overcome it. Do something that relaxes you, whatever that may be. Play a game, take a bath, go shopping, exercise, meditate, do housework... as long as you get your mind off of the subject for a bit. Come back to it later. Enlist help from family and friends. Repeat as necessary and then continue to the next step.

Portrait of a Women with a Man at a Casement by Fra Filippo Lippi Research Paper

Portrait of a Women with a Man at a Casement by Fra Filippo Lippi - Research Paper Example Also the couple shown is believed to be Ranieri Scolari and Angiola di Bernardo Sapiti. The portrait was painted in 1440 and the couple is recorded to have been married in 1936; therefore the interpretation that the portrait is a commemoration of a wedding is plausible. Barnet asserts that in the formal analysis of portraits, one needs to consider how do the background, the angle of the tilt of the head, the furnishings etc help to develop the overall impression of the figure (2008). When scrutinizing this portrait, one can appreciate that the bride is laden with lavish clothes and jewelry typical of a newly-wedded woman. The laws of Florence required that a woman, unless she was the wife of a foreigner, knight or a doctor, would only wear expensive dresses for a limited period of time (The City Review 2009); therefore a special occasion is shown in the portrait. The overdress has fur lining its edges whereas the underdress has loops of gold embedded in the sleeves. The headdress, se lla, has pearls embellished into it and are also present throughout her dress. The pattern in which they are embedded makes the word lealta, meaning loyalty. The couple glances in an expressionless way although the gazes do not interlock (The Metropolitan Museum of Art 2011). Another interpretation of the portrait is that it may represent the birth of a child.

Global Entrepreneurship Essay Example | Topics and Well Written Essays - 1250 words

Global Entrepreneurship - Essay Example   The scientific management resulted in great evolution of US business and the innovation management and sub division of labor helped the US business to grow at faster pace than the rest of the world. Research and development, mass production, efficiency and increased wages for the labors also provided adequate boost to the American business and the vast growing firms geographically expanded and took over the European markets through their corporate Americanization. At the same time, problems emerge in the system like agency problems, separation of control from the ownership, unrelated diversification, etc. US businesses stay sustainable through innovation and change management however economic meltdown obliges them to downsize. German business system has been able to sustain the non-price sensitive markets through collective bargains and consensus management and their primary focus is on long term strategy of production and export.UK business system is also quite similar to that a nd follows long term strategic planning. In the UK, businesses tend to expand geographically like that of US corporations e.g. Tesco, BT, etc. French business system is driven by functionality and rigid hierarchy and is found more directive than collaborative. The focus is to produce and supply hi tech products to the international markets.    European business systems endeavor to stay sustainable in the economic crisis through strategic management that helps them to cope up the crisis like merging, joint venturing, co-branding, etc.

Taking a Stance on Capital Punishment Essay Example for Free

Taking a Stance on Capital Punishment Essay Who are we to decide who should live and who should die? Who are we to decide that the punishment should not fit the crime? Who are we to consider mercy for the merciless? These are just a few questions I would love to be able to ask someone like Carrie Marie Scott, Janna Bruce, or Sheila Whalen but I can not, they all were murdered by Stephen Peter Morin. Stephen was one of the â€Å"botched† executions by lethal injection. It took the technicians almost 45 minutes to find a suitable vein to administer the sentence. I wonder how long it took his three victims to die as he raped and tortured them in a van he sound proofed. As for the time he suffered on the table getting needles stuck in him, I hope it does not happen to anyone that did not torture and kill three innocent people. Where is the humanity for the victims? Then there is the botched execution of John Wayne Gacy. This man tortured and killed over 25 people after his first conviction of child molestation in 1968; yet it is inhumane that his execution took 18 minutes longer to complete than normal because of a clogged IV tube? Perhaps we should ask the family of his victims if it took longer than 18 minutes for them to get over the death of their loved ones. Where is the humanity for the victims? What of the Hodges family? Richard Hodges and his 75 year old mother Mildred were both murdered by suffocation by Bert Leroy Hunter and Tomas Ervin. On December 15th, 1988; Hunter and Ervin broke into the Hodges’ family home at gun point to rob them. The Hodges’ were bound with duct tape and had plastic bags put over their heads causing them to suffocate. Death by suffocation can take upwards of eight minutes to happen; try holding your breath for a minute and you will realize the agony of this death. When hunter was executed his body convulsed violently; but this is the inhumane aspect of this entire ordeal. I feel that I would be cheating the family if I did not mention that this crime was committed after Hunter got out of jail for his first conviction of murder and in jail is where he met his accomplice Ervin. Where is the humanity for the victims? What is a lethal injection? It is a very basic process where Sodium Thiopental is used to put the person to sleep, then Pancuronium is administered to paralyze the muscles, and Potassium Chloride is used to stop the heart; if this is not given the person would die of asphyxiation from the Pancuronium. The person has an IV in both arms although one is only used as a backup in case the main fails. The person on the execution table will always have one right that he or she did not allow their victim to have; the right to die with their dignity. When you look at the very basic facts of this, that no one should take a life; everything is very simple. When people say that â€Å"this poor person died on the execution table in a horrible way;† it is really easy to take a stance and say that it is wrong. The problem is that this is a heavily flawed perspective based on initial reactions without digging further and finding the details about how the ended up on that execution table in the first place. It all comes down to protecting the ones we are supposed to protect; the people who do NOT break the law and their rights have far been overlooked for rights of the ones who victimized them. So you ask for a stance and I will take one: Killing people is wrong, but the people who have killed people should not have a voice in their treatment of way they die; their victims did not. I support lethal injection and capital punishment. So long as people are willing to kill other people in cold blood; I am willing to see them off to their demise and not stand in the way.

Reflection Upon A Critical Incident Essay -- Reflective Practice Nursi

Reflection has its importance in clinical practice; we always seek to be successful and that can be achieved by learning every day of our life through experiences we encounter. In that way we can reconsider and rethink our previous knowledge and add new learning to our knowledge base so as to inform our practice. Learning new skills does not stop upon qualifying; this should become second nature to thinking professionals as they continue their professional development throughout their careers (Jasper, 2006). In keeping within current legislation on the protection and respect of an individuals’ right of anonymity, (Polit and Beck 2007), and to confidentiality, (Munhall 2007), any and all possible identifiable characteristics of the client have either been altered or omitted entirely where the potential for identification of the client was seen as possible or probable. The incident I will describe occurred when I was working in a regional hospital where we handled a large number of cases each year, with a range of specialties. The incident concerns ventilator-associated pneumonia and the use of CASS. John Baptiste Moliere stated "It is not only what we do, but also what we do not do, for which we are accountable.(Von Wartburg, 1991)† Accountability is being able to give reason to something that was done and to take responsibility for any errors made. Professional nurses are accountable in several areas including accountability to the public, client, profession, employer and self (Hood, 2013, p. 307). The public is aware that they have the right to receive the best care possible by professionals in the medical field (Hood, 2013, p. 307). Nurses must be competent in their abilities to provide safe effective care to their pa... ...Clin Infectious Disease 2010 Aug 1;51 Suppl 1:S59-66. doi: 10.1086/653051. Cawley M. (2007) Mechanical ventilation: a tutorial for pharmacists. harmacotherapy. 2007 Feb;27(2):250-66. http://www.ncbi.nlm.nih.gov/pubmed/17253915 Hood, L. (2013) Leddy & Pepper's Conceptual Bases of Professional Nursing. Lippincott Williams & Wilkins 2013 Von Wartburg, Walter. (1991) How to Lead with Genius: Words of Wisdom for the Common Sense Manager. Jasper, M. (2006) Professional Development, Reflection and Decision-making (Vital Notes for Nurses), Wiley-Blackwell; 1 edition 15 Nov 2006 Munhall, P. (2007) Nursing research: A qualitative perspective. 4th Ed. Jones and Bartlett Publishers. Sudbury. p523. Polit, D., Beck, C. (2007) Nursing research: Generating and assessing evidence for nursing practice. 8th Ed. Lippincott Williams and Wilkins. Philadelphia. p180.

Character Study of Shylock and Portia in Merchant of Venice

Character Study of Shylock and our feelings for him as the play progresses 1) He is seen as a mercenary money-lender approached by Bassoon for the loan of 3000 ducats with Antonio as the guarantor. The money is to finance Bassoon on his trip to Belmont to woo Portal whom he Is In love with. He keeps debating on whether he should lend the money. Even when Antonio is a â€Å"good† man meaning he is financially sound, yet his money is invested in goods which are in ships overseas. Therefore, his ventures are risky.How do you feel about Shylock here? Are you uncomfortable that he places so much Importance on money? ) Shylock is portrayed as a villain when he displays his unforgiving and vengeful nature. He has a deep-seated hatred for Antonio. He says,†Cursed be my tribe If I forgive him! † Shylock Is a villain here to say that he hates Antonio so much that he could swear on the name of his tribe. 3) Shylock Is crafty and pretentious. To exact his revenge, he tricks An tonio to sign a bond In return for the loan of 3000 ducats to help Bassoon.He uses words like a bond signed â€Å"in a merry sport† and â€Å"This is kind offer. † He agrees not to charge interest but prefers a pound of Notation's flesh if Antonio is not able to repay the loan. He pretends that he is not serious about the pound of flesh by saying: â€Å"If he should break his day, what should I gain By the exaction of his forfeiture? ‘ Shylock goes on to buy his favor I extend this friendship. † Antonio, being confident about the return of his investments in ships agrees to the terms of the bond. Do you see more of the villain in Shylock here?How are your feelings for Shylock here? Do you dislike him for being a schemer, for being so crafty yet so good at pretending to be friendly? Moreover, how are your feelings for him intensified at the Trial Scene when he insists n nothing but the forfeit of his bond even when Bassoon Is ready to pay him thrice the amo unt of money as stated in the bond? Do you see the villain at his worst here? Earlier on, Shylock is seen sharpening his knife to cut the flesh of Antonio and Bassoon gets so worked up that he calls Shylock a â€Å"damned, inexorable dog'.Do you feel so disgusted with Shylock at this stage as to hate him for being so cruel as to want a pound of flesh from a fellow human being? In other words, he wants Antonio dead. Quote the relevant lines spoken by Shylock from the scene and what he does to cause you to feel disgusted and even hate Shylock. 4) Yet, In some ways, Shylock Is also seen as a victim when he recounts the unkind way Antonio has treated him, does Shylock pose himself to be a victim? In Notation's favor, do you think Shylock is now a sympathetic character and deserves some pity from us?Describe how the events have turned against Shylock. Do you see him a victim here? 1)Since Shylock has attempted to take Notation's life, Antonio has the power to seize half of Shylock wealt h, while the rest of the possessions will be handed over to the state treasury. ) Shylock will be condemned to death unless the Duke officially cancels the punishment. 3) Shylock is told to fall on his knees and beg for mercy. This is a blow for someone who has so much pride in his own nation, calling his own nation â€Å"sacred†. He has lost all the dignity he had. 4)Shylock has nothing left for himself.He has lost his entire wealth and would rather die. He says: muff take my life When you take the means whereby I live. † The Duke says that the half of his possessions which should go to the state can be reduced too fine if Shylock is truly repentant. 5) Antonio adds that the fine can be polished but the half of Shylock possessions which should go to Antonio will be kept by Antonio until the death of Shylock on two conditions: 6) Shylock has to become a Christian, a religion he detests. Professing a religion should be a personal choice but he is now forced to become a C hristian. ) and the money kept by Antonio will be handed over to Lorenz who has eloped with Shylock daughter. 8) Shylock has been so smug at the Trial before the events turned against him. He has been so confident but suddenly he has become the victim of his own scheme. 9) He is alone with no one to help him. Antonio has his group of friends to support him and Portia who has come forward to help him for the sake of Bassoon. 10) Shylock is so shattered that he begs to be excused saying that he is not well. How do you feel for Shylock here? Are you sorry that he has to end this way? Has he been victimized?Character Study of Portia and our impressions of her We are told by Bassoon that Portia is a lady of â€Å"wondrous virtues†. This is all that we know of her in this scene until she presides the case between Antonio and Shylock concerning the pound of Notation's flesh that Shylock insists is legally binding and so e must have it. 1) In the Trial scene, we first see Portia (dis guised as Blather, a learned Doctor of Laws) as a gentle person who wants to settle the case in a harmonious manner and so she appeals to Shylock to show mercy towards Antonio with her eloquent speech on mercy.She touches on these aspects of mercy: a) Mercy cannot be forced and has twice the blessings. It blesses the giver as well as the receiver. Therefore, Shylock will be blessed if he shows mercy. She is hoping that Shylock will be merciful after listening to this. B) Mercy is greater than sovereignty. It is a quality shown by God. Therefore, Shylock will exhibit a godly quality when he shows mercy while he executes Justice. Portia appeals to Shylock to be merciful because if God had only acted Justly without pray for God to show us mercy, that same prayer also teaches us to show mercy to others.Portia says these words in the hope of softening Shylock hardened heart and for him to moderate his insistence on Justice, which is to demand a pound of Notation's flesh as stipulated by the bond, with a show of mercy and to spare Antonio. 2) Portia is Just and will act strictly according to the law. When Bassoon offers to pay twice the sum saying: â€Å"l will be bound to pay it ten times o'er On forfeit of my hands, my head, my heart. † Bassoon even tells Portia to tweak the law Just this once to stop the Jew from his evil doing.Yet, Portia maintains that there is no power in Venice that can alter the law. She does this to show that while she is out to help Antonio, she will not break the law and be criticized for her actions. 3) Portia is patient and perseveres to get Shylock to relent by offering him money. She gives Shylock one last chance to change his mind. She says: â€Å"Shylock, there's thrice the money offered thee. † However, Shylock insists that he has made an oath in heaven and will not want to be guilty of perjury or false swearing.Again, Portia appeals to Shylock to take thrice the amount of money and bid her to tear the bond ?†Ta ke thrice the money; bid me tear the bond. † 4) She is persistent in wanting to help Antonio and so comes up with an ingenious idea. Portia quibbles on the very words used in the bond to make Shylock become the victim of his own evil scheme Since Shylock insists on nothing but the bond, he will eave exactly that. Portia reminds Shylock that â€Å"the words expressly' are ‘a pound of flesh'. Shylock is to cut exactly one pound of flesh, no more or less.Next, there is no mention of blood?†no Jot of blood†. If he does shed one drop of Christian blood, his land and goods are to be confiscated by the state of Venice according to the laws of Venice. Portia adds: â€Å"The Jew shall have all Justice†¦ He shall have nothing but the penalty. † Being trapped by the words of the bond, Shylock asks for thrice the amount of the money as stated in the bond. ) Once she is able to get Shylock at a disadvantage, she goes all out to accomplish her mission of helpi ng Antonio. Now, it is time for Portia not to relent.She says Shylock will have nothing but Justice and his bond. Shylock then asks for â€Å"barely my principal† but Portrait's reply is that he will â€Å"have nothing but the forfeiture†. Moreover, Shylock has put himself into the power of the law in yet another way. It is stated in one of the laws of Venice that if a foreigner should attempt to take the life of a citizen , then the party whom he is scheming against has the power to seize half of he offender's wealth and the rest will be handed over to the state's private treasury.The offender is to be condemned to death unless the Duke reprieves (officially cancels the punishment) him. Shylock has attempted to take Notation's life so he has incurred the punishment that is Just mentioned. Portia tells Shylock to get down on his knees and beg for mercy. Disguise as Blather, a learned Doctor of Laws, to fool everyone in court. Not even Bassoon, her own husband is able t o recognizes her in court. She carried out her duties with dignity, starting with her eloquent speech, in the hope of moving Shylock o show sympathy towards Antonio.Even when Shylock refuses to be merciful, she does not give up but goes on to offer him money so that he will cancel the bond. However, when this fails to change Shylock mind, she becomes relentless with her ingenious idea of quibbling with the very words used in the bond, and so makes Shylock a victim of his own evil scheme. We are impressed by her intelligence and the way she handled the case so well that Shylock becomes cornered and cannot complain that she is ruthless because she is giving him exactly what he wants as stated in the bond!

How Does Steinbeck Portray The Harsh Lives Of The Workers Of the Great Depresion Essay

I hope this essay will show you how the workers of the American Great depression of 1937 struggled to survive in the harsh environment that was their work place. Many people from the cities of America had to give up their lives and start again in the country working on ranches shifting corn and grain getting paid very little. Workers of the Great Depression had few possessions. Many only had blanket rolls, wash kit, a small amount of tinned food and what little money they could earn. They had few possessions for two reasons; one, because they couldn’t afford many possessions and also because they found it easier because they are constantly on the move. This represents there harsh life because it illustrates that they have no were to call home. Many workers spent their money fast during the weekends by drinking, gambling or in the â€Å"Cat House†. In the novel men view the women as a thing you buy like drink so women didn’t have proper rights. Similarly Crooks the black cripple, has little or no rights. In Steinbeck’s book Curley’s wife is not given a real name she is simply referred to as â€Å"slut,† â€Å"whore,† or simply â€Å"Curley’s wife.† This can implies that she is a position of her husband it implies a harsh and limited existence and how badly the poor women of 1930’s America were treated in society. Prejudice plays a significant part in John Steinbeck’s novel â€Å"Of Mice and Men† and is seen with some characters like Crooks, Candy and Lennie. All have some kind of disability. Crooks is crippled because he was kick by a horse this is made worse by the fact that he’s black so he is racially abused as well. The boss â€Å"Gave the stable buck hell† when George and Lennie were late arriving at the ranch. He knew that Crooks couldn’t complain because he has no rights. This shows how he is blamed for anything and can’t defend him self this show the harsh life of his. Candy is crippled because he lost his hand to a machine, so he can do little work and he is old. This sets him apart form the others and they see him as the old outcast. Lennie is mentally handicapped, he has a child’s mind so he isn’t very clever and he likes soft things like mice and puppies. This gets him into trouble in the novel. Firstly he stroked a woman’s red dress, she got confused and screams he got scared and holds on to the dress and wont let go. This led him to being accused of raping her so Lennie and George had to run away. Secondly Curley’s wife lets him stroke her hair because it’s soft, after a while she tries to pull away but he holds on and he ends up breaking her neck. For this Lennie has to run away. He is also really strong and this contributes to him getting in trouble because he doesn’t know his own strength, he kills many mice because he pets them to hard and he kills a puppy as well as Curley’s wife. Many, if not all the characters in â€Å"Of Mice and Men† are lonely because they move from ranch to ranch making new friends and leaving old ones behind. Candy has an old dog that is his only companion. He has had him since he was a pup and is much attached to him. However some of the workers persuade him to shoot the old dog and by doing this he looses his only true friend. This contributes to the theme of harshness; I believe that many of the workers were jealous of candy and his dog and envy him so they force him to put it down. This is also the same as George because he kills his only true friend and companion by shooting. Curley’s wife is also lonely, being the only woman on the ranch and Curley forbids her from talking to the workers. She breaks this by talking to the workers in doorways which gives her the reputation of a â€Å"slut.† Many of the workers dream the American dream of having their own land. George and Lennie have a dream that they will own little plot of land with rabbits and fields and if it’s miserable weather they will light a fire and sit around it not working, â€Å"Guys like us†¦.. an’ listen to the rain coming’ down on the roof.† When Candy’s dog is shot he try’s to muscle in on their dream. Many of them have dreams so that they can be distracted from the harsh lives of reality. In conclusion, the title of this book tells the reader about the novel in a few words. The title of this book is taken from an Irish poem by Alfred Burns; â€Å"The best laid plans of mice and men always go wrong†. I believe that this is a good choice of title for the book because it shows how Steinbeck has used this to portray the harsh lives of the workers of the book and the dreams are what should happen in a fair world when it really all goes wrong.

Analysis for Jeep Grand Cherokee Essay Example

Analysis for Jeep Grand Cherokee Essay Example Analysis for Jeep Grand Cherokee Paper Analysis for Jeep Grand Cherokee Paper The advert denotes a jeep on rough terrain driving past a wooden shack. The scene is set in the countryside where nothing can be seen for miles. The writing takes up a small amount of the whole page, which shows the advertisers, want you to concentrate on the jeep rather then the text.  The anchor on the advert could be interpreted in different ways to the intended one. 8 on the Richter scale shows the jeep is powerful and can blow anything away. Richter scale is probably the keyword as it connotes ideas of power and strength. The wooden hut looks like it has been in an earthquake but in fact the advertisers wants to show you can drive it and feel commanding. At the bottom of the advert it tells you about the engine specification and the luxurious interior. The company wants to show off the best bits of the car. In the top left hand corner it has the company logo and the words THERES ONLY ONE. The advert works as a whole by placing the signifier for power (V8 Engine) next to the logo Jeep. This represents to consumers only this jeep will give you the ideas and hopefully persuade people to buy one. The caption will influence a consumer in their perception of the product: Jeep is a unique 44 manufacturer that upper class people may drive around town to do their errands or people who want to be powerful/commanding and use the car to its maximum limit. This suggests it is indexical. Earthquakes are associated with power/noise and the seismic rumble from under the bonnet makes people want to buy it. This signifies to most people, a meaning that it is a good, stylish car that will impress and everybody will want. The blurred background is also important because it connotes an impression of speed and immense power, which will help to sell the car. Furthermore the man in the car is not very young for a reason. The advert is designed, obviously, to target people who can afford the 30,000 jeep, and so the image of the middle aged man, who maybe has enough money to buy one, is important. The photography of the car is responsible for making the advert work as well. Although the blurred background is probably computer generated, the car is a photograph. The camera never lies, but here it has been chosen to capture the image when the wheel hubs are blurred with speed and the slight glinting off the bonnet and headlights adds to luxury ride ordinary people could be experiencing. In looking at the image of the iconic jeep, the advert denotes a car travelling on a long distance terrain in a natural setting, which signifies that the jeep is capable of handling rough terrain as well, a smooth ride. Also it is a realistic representation of the kinds of roads the car maybe travelling on and whatever it (or lack of it) throws at you. The juxtaposing of a dark sky and natural environment signifies a smoothness and air of mystery, further implying to the consumer that it is desirable. This is the same with the car, as it is a dark colour too. This dark/natural colour setting is predictably continued to the jeep itself, so that the consumer associates the values signified by the natural setting to the product. The picture of the jeep is on the left hand side where the sky is darker which suggests the car has just driven through the earthquake and survived. The advert is more likely aimed at men, who tend to be the main money earners and more interested in cars and also the representation of colour for males is usually dark, and for females, dark, which further implies it is aimed at men. The ideology at work here is significant: the car represents power and authority and consequently, men learn to aspire to such images. The advertisement makes the reader feel in control and make people buy the product at price.

The Best Resources for Landing Your Retail Job

The Best Resources for Landing Your Retail Job If you’ve worked in retail before, you know that it’s not a job for the faint of heart. It can mean long hours of doing physical tasks, keeping a smile on your face when you’d rather be rolling your eyes, and- perhaps the most daunting piece of all- dealing with the public. If you haven’t worked in retail before, spoiler alert: it’s not going to be sunshine and roses every day. But if you have great customer service skills, need flexible hours, or want to gain experience as you work toward other goals, it can be a great fit for the short- or long-term. If you’re up to this challenge, we’ve got what you need to get started- or get to the next level. Step 1: Revamp Your ResumeIf you’re familiar with how we roll here at The Job Network, this one should not come as a surprise. A badass resume is the starting point for every job search in every field. Even if you’re referred for the job by someone you know, you still need to m ake a great first impression on anyone who hasn’t met you before, at a minimum. And your resume gives your friend some quick talking points that act as ammo when they’re advocating for you to get the gig. An updated resume is essential.How to Write a Perfect Retail Resume (Examples Included)How to Write a Perfect Cashier Resume (Examples Included)How to Write a Perfect Sales Associate Resume (Examples Included)How to Create a Perfect Retail ResumeThe Ultimate 6 Step Guide to Resume WritingResume Headlines to Use for Different Jobs6 Ways to Make ATS Work in Your FavorResume Format Guide: What Your Resume Should Look Like in 2017Top Resume Trends for 20176 Job Skills You Need to Be a Sales AssociateDownload Resume TemplatesIt’s best to revamp your resume before you even start thinking about applying for jobs. This can keep you from making easy mistakes due to rushing, and lets you get a good baseline resume that you can use to adapt easily for each job application or opportunity.Step 2: Target Your Job SearchIf you want to start with a general geographic area or any type of stores, then a general search can be a great first step. It’s important to know what you’re looking for, to help focus your job hunt. If you need a starting point, we have plenty of recommendations that can help you find the type of retail job that works best for you.10 Summer Jobs- and How to Get ThemBest Jobs in Retail- and How to Get ThemTop 5 Less Crowded Sites to Look For Retail Jobs10 of the Best Jobs in Retail NationwideA Comprehensive Guide to Getting Different Types of Retail Jobs7 Places to Look for Part-Time JobsStep 3: Get Ready for the InterviewIn the retail world, hiring can move fast, so to paraphrase Ferris Bueller, if you aren’t ready for it, it can pass you by. You can start prepping for interviews before you even have one on the books.5 Questions to Expect in a Retail InterviewThe Most Popular Macy’s Interview QuestionsHow to Survive Your Upcoming Panel InterviewHow to Look Like a Star in Any Job InterviewHow to Answer the â€Å"What’s Your Biggest Weakness?† Question10 Things You Should Not Say in an Interview7 Real Life Interview Mistakes You Can Learn FromImpress Your Interviewer in 5 Simple Steps to Get the JobStep 4: Think About Your Career GoalsA job in retail might be your calling, or it might be just one step along your long career path. Whatever the case may be, it’s important to think about how you can a) be prepared for this job, and b) make it work for your future.How to Move Up the Retail Career Ladder Without CollegeWhat You Need to Know to Succeed in the Retail Industry5 Great Career Paths You Can Take If You’re Working in RetailWhether it’s your dream job or your right-now job, getting a job in retail is a challenge to be faced with as much ammo as you have at your disposal. If you’re ready to get started in this field, good luck!

Organizational Communication Assignment Example | Topics and Well Written Essays - 250 words

Organizational Communication - Assignment Example In addition, he used a leadership style that was transactional as its entailed management through enhancing compliance via punishment and rewards. The committee had been given powers to make decisions, but Gassner had the final say in every decision they made. Gassner made sure that each execute committee member headed different regions of that company (Hill, 1995). Gassner had a strategic vision which he ensured was met. He made sure BMG international became successful. He ensured that he was involved in every decision (Hill, 1995). Gassner was tough on ensuring his decisions are followed to the later. In systems theory, there is the issue of interdependence in any organization. Rudi acknowledged this fact and hence created an executive team that was in charge of various regions. He acknowledged interdependence since the regions which they operated differed on the basis of external environment that dealt with customers, competitors, suppliers, financial markets and world economy. In addition, they also differed in complex issues related to external relations, internal operations, strategic decision making plus institutional leadership (Hill, 1995). Gassner’s management style was transactional. He ensured that he established compliance of the workers through coming up with reward and punishment systems. Gassner had been hand-picked by the given CEO, Dornermann. Gassner was an expertise from Polygram and had a good track record on the basis of management. He had his own style of management and involved ‘push’ and ‘pull’ strategies. That ensured high level of awareness existed and resulted in accurate perception of his role and vision (Hill,

Letter and Memo Paper Pre-Assignment Essay Example | Topics and Well Written Essays - 250 words

Letter and Memo Paper Pre-Assignment - Essay Example nvironment had remained relatively pristine due to the vigilance of the people against the development and use of energy sources that are polluting to the environment and contributory to climate change. I have been in the energy industry for most of my professional life and surprised to see how Americans are becoming more and more dependent on fossil fuels when â€Å"Peak Oil† had been upon us long ago. Instead, the state government of Colorado should pursue clean energy alternatives like wind and solar power. The Colorado Green Wind Farm (at Lamar, Prowers, Colorado) is a good example to reduce reliance on costly imported oil (Makhijani 31). Colorado is among the top 20 states with high potential for wind energy (at no. 11 with 481 billion kw-hours annually), an enough supply to meet all the states electricity requirements were it not for factors like intermittency and geographic location considerations. However, we need not wait for flooding like what happened in some countries (like the Philippines mentioned above) to wake us up that the effects of global warming are upon us like what Al Gore cited in his â€Å"Inconvenient Truth† movie. However, what is markedly absent from the energy debate is environmental optimism (Easterbrook, Sept. 2006) and Mike Keefes cartoon clichà © update (Denver Post, September 29, 2009) could become reality soon. The readers of the Denver Post are not only the people of Colorado but include those of some neighboring states like Nebraska, Wyoming, New Mexico, Utah and Oklahoma. There are even some readers from as far away as Texas, Kansas, the two Dakotas and Idaho. With a mean elevation of 6,800 feet (2,073 meters), the state of Colorado seems to be so far away from concerns like massive flooding generated by climate change from global warming effects. Furthermore, the people of this region in the United States take pride in their pristine environment and they mostly want to preserve it that way for generations to come. A way to do

Competitor analysis on Tesla Assignment Example | Topics and Well Written Essays - 750 words

Competitor analysis on Tesla - Assignment Example The escalating costs of fuel and the environmental hazards of emissions make electric vehicles (EVs) the best viable option in the present times. As such, a major share of consumers will prefer EVs such as Tesla, which provide them economy in maintenance and comfort while being environmental friendly and, hence, this segment will be Tesla’s target market. With their entry into the â€Å"family sedan market† Tesla will be able to diversify their customer segmentation and include more consumers in their customer base (Binkiewicz et al, 2008, p.2). Recently, Tesla is focusing its attention for direct investment in markets like India, which will provide them great opportunities for market expansion. India is fast becoming an economic power and many of its citizens have high rates of disposable income. Thus, it is a potential market for Tesla, especially because environmental safety is a primary concern of this country. Obviously, by targeting major cities, populated by weal thy people, Tesla can be â€Å"better positioned to expand† its operations into this international market (Gonzalez et al, 2010, p.17). In this context, Tesla’s Model S enjoys an edge over its competitors as they are more efficient. Research conducted by Danielle Boyke et al (2010) provides a comparative data of EVs, which indicates that Tesla’s Model S, with energy densities between 42kWh to 90kWh will give a mileage/charge of 160 – 300, while Audi’s energy density of 42kWh provides a mileage of 154 miles/charge. Thus, the average consumer will prefer Tesla’s EVs over hybrids as these are less expensive both in terms initial investment as well as maintenance. Luxury car consumers, who come from the influential and educated segment of the society, are highly conscious of the dangers of carbon emission besides having an appreciation of sleek designs. Tesla’s aesthetic design and environmental friendliness are crucial elements that make it a hot favorite among this target audience. Customer Segment Needs: The likely consumers of Tesla’s products look for economically viable options that can offer them comfortable luxury cars at lower running and maintenance costs. Thus, Tesla’s cars will become potential favorites in countries where fuel costs are higher. Besides, customers in the present day look for environmental friendly cars as governments across the globe place heavy restrictions on vehicles that cause excessive emissions. Another aspect that customers look for in a car is its design and appeal. Since Tesla’s cars provide good mileage to vehicles on a single charging, they will find the favor of customers. Competitors: For Tesla Roadster the main competitors are Porsche and Ferrari and once they launch the Model S Sedan, they will have to compete against existing and future players in the field that include major automobile manufacturers such as Audi, BMW, Lexus, Mercedes, Toyota, Ford, H onda etc. They are currently planning, in collaboration with Toyota, to develop an electronic version of the RAV4. The competition will not be a deterrent for Tesla because of several reasons. Primarily, they have a sound technology and efficient team of engineers that can create quality products with good designs. Besides, other major players in the industry mostly focus their attention of fuel run vehicles, which is not going affect Tesla’s operation in any big way. Countries across the globe are currently focusing on environmental friendly vehicles, which is a great advantage for Tesla when it concerns its operations in countries where fuel prices are high. Pricing: Tesla’s average price of their latest model â€Å"range from $50,000 – 70,000† and it appears a competitive price when considering the cost of other cars such as â€Å"Audi and BMW EVs and non-EVs† (Boyke, 2010, p.10). Similarly, their current strategy of competing in the luxury car market as well as international market with Model S is a viable proposition because customers will be willing to â€Å"

Dark Tourism Within The Tourism Industry Tourism Essay

Dark Tourism Within The Tourism Industry Tourism Essay The topic of this essay will discuss dark tourism within the tourism industry and what motivates tourists to visit this place Introduction The aim of this essay is to discuss the relevance and appropriateness of different approaches of research in the researchers chosen subject area (dark tourism) and what motivates tourist or visitors to visit this place. There is different research method. In other words, the researcher will be using different approaches to evaluate and analyse them. In addition, the essay will discuss and critically evaluate the available resource in the subject area example by using qualitative research or quantitative research, primary and secondary research, inductive and deductive approach, positivist or phenomenological approach and ethnography. Furthermore, the researcher will justify why this approach has been taken this into consideration or chosen and not the other approaches. Firstly, the literature of this essay will define research, qualitative research, and quantitative research. Secondly, this essay will define dark tourism and validity. And finally, conclusion will be summarised. There are different definitions for research methods, quantitative research and qualitative research. According to Sekaran (1994, p. 4) quoted in Finn et al (2000, p.2) he defines research as a systematic and organised effort to investigate a specific problem that needs solution. Whilst Elias (1986, p.20) cited in Veal (2006, p. 2) argues it as The aim, as far as I can see, is the same in all science. Put simple and cursorily, the aim is to make known something previously unknown to human beings. It is to advance human knowledge, to make it more certain or better fitting The aim is discovery. Veal also Define quantitative approach as to research involves statistical analysis. It relies on numerical evidence to draw conclusions or to test hypotheses. To be sure of the reliability of the results it is often necessary to study relatively large numbers of people and to use computers to analyse the data. The data may be derived from questionnaire surveys, from observation involving counts, or from secondary sources. Adding to that, Veal also defines the qualitative approach as research is generally not concern with numbers. It involves gathering a great deal of information about a small number of people rather than a limited amount of information about large number of people. As the researcher said earlier, there are different definitions for quantitative and qualitative research, here are some other definitions form another author. Brent and Goeldner (2003, p, 487) define qualitative research as the foundation on which strong, reliable research programs are based. It is most often the first step in a research program the step designed to uncover motivation, reasons, impression, perception, and ideas that relevant individuals have about a subject of interests. Unlike more quantitative methods of research, qualitative research involves talking in depth and detail with few individuals. The goal is to develop extensive information from a few people. The author also defines quantitative as a type of research; the goal is to develop important-but limited- information from each individual and to talk with a sizable number of individuals in order to draw inferences about the population at large. The characteristic of qualitative research, on the other hand, inc ludes small samples, extensive information from each other respondent, and a search for meaning, ideas and relevant issues to quantify in later steps of the research program. Dark tourism is a different type of tourist attraction. It is the act of travel and visitation to sites of death, disaster and the seemingly macabre. Tourists flock to experience sites of past terror that offer up grim and disturbing tragedies (www.citypaper). Howie (2003, p. 325) argues that dark tourism can be define as a term coined by Lennon and Foley(2000) for tourism motivated by a desire to visit places associated with death and catastrophe such as famous assassination sites, for example where president Kennedy was shot in Dallas, Texas, or the concentration camps in Europe and Holocaust memorial in Israel. Dark tourism has been very important because is the time people remember their loves ones who has been dead through war. Tourist or visitors intend to visit the darker side of tourism from all over the world and for different reasons for example because of curiosity and maybe something they have heard before. Dark tourism includes some of the most famous places in the world to visit. It is obvious that most tourists travel because they are very interested in seeing the dark side of tourism such as the death and disaster which occurred in countries such as country France, Belgium and Germany where soldiers died in the wars. This dark tourism issue has caused a lot of discussion as to why people do this in among academics. Research in the field of dark tourism has not been very important until the early nineteen seventies; it began to spread only since that time. Marketing research is a broad concept including various techniques, but a main distinction should be made between quantitative and qualitative research methods. As said early Quantitative techniques describe variables by assigning a number representing an attitude, opinion or motivation- which can be statistically analysed. In contrast, qualitative research focuses on attitudes, opinions and motivations in the words of each respondent, but without quantifying it. Quantitative methods have always dominated in tourism, as it often appears as more reliable, since it is based on facts that can be observed, and then analysed. This paper will focus on the quantitative correlation study method used in survey based researches. Social research is a collection of methods people use to systematically combine theories and ideas to produce knowledge. Because of its complexity, researchers must be able to carefully select a method or methods that will best suit their study objectives. Quantitative research methods consist of: experiment, content analysis, existing statistics (correlation), and survey. The correlation and survey will be the two main methods that will be emphasized. In a survey research, people are asked questions either through the use of questionnaires or during an interview. Unlike the experiment approach, the condition and situation in a survey requires no manipulation. All the subjects have to do is to answer questions. Good quantitative research is determined by validity and reliability of the research method used. Quantitative research is a technique for comparing relationship between time, weight, size and performance. The purpose of quantitative market research is to have an increased understanding of the product First Fruit. This research is numerically oriented and requires attention of consumers as well. For example an insurance company may ask its customers to rate its overall service as excellent, good, poor, very poor. Quantitative data consist of numbers representing counts or measurements (e.g., height, weights, salaries, etc.). Quantitative data can be further divided into discrete data or continuous data. Discrete data result from either a finite number of possible values or a countable number of possible values. Continuous data result from infinitely many possible values that can be associated with points on a continuous scale in such a way that there are no gaps are interruptions. However, qualitative techniques have become to be more commonly used for the last decade. Each technique has obviously specific advantages and drawbacks; that is why it is necessary to examine both in different contexts, especially in tourism research. As Alf H. Walle reported in his report called Quantitative versus Qualitative Research in Tourism, plurality of equally valid research strategies exist within tourism. Choice must be thus determined according to the situation in which the research takes place. Grounded Theory is still very relevant today as it is the main form of rigorous and rule-governed qualitative methods. Even if it attempts to maintain positivist rigor, a high degree of Modernism can be reached through this technique. As both quantitative and qualitative research methods have advantages and drawbacks. To evaluate this problem and overcome the limitations, the principal solution appears to be the use of both methods in the same time, according to the situation. As Miller and Crabtree pointed out, different levels of intensity can be reached in tourism research, this intensity being defined as the degree to which qualitative methods are associated with quantitative methods. The canonical correlation analysis is based on the same principle, but it uses multiple dependent variables, thus enlarging the scope of research. However, both methods have the same limitations: omitted variables may be correlated with existing ones, and the environmental conditions are likely to change. On the other hand, factor analysis and collecting analysis are two other important quantitative techniques that can be useful for tourism research methods. Factor analysiss goal is to identify the underlying dimension in data and to reduce the number of variables by eliminating redundancy. Validity also helps produce the desire result the researcher is looking for. Validity can define as the extent to which the information collected by the researcher truly reflects the phenomenon being studied veal (2006, p.41). In tourism research there are different approaches targeting the audience when researching. The primary sources of these methods have largely come from sociology and anthrop ology. Since that time, qualitative techniques have developed, but the sharpest rise in qualitative publications has really occurred in the nineteen eighties, the main reason for that being that figures cant explain all the situations, especially in a field such as tourism. Besides, decision behaviours are always depending on two main elements that should not be forgotten: firstly, task factors include the number of alternative and attributes, time pressure, response mode and information format. Secondly, Context factors refer to the similarity of the options in a choice, the quality of the choice set, as well as reference points and framing. This report also considers qualitative techniques as inadequate because of the extra time, effort and skill required; besides the model tested may in this case be incompletely or inadequately specified. Most researchers use different approaches of researching as has been said before, for example a focus group. Using a focus group also help analyse what the research is about and also gives broad ideas of another audience. Additionally, it also helps identify what people want and love to do in a tourism organisation. Researchers conduct focus group so that they can know the perception of their opinion, attitude or be haviours towards something. Focus group is a unique method of qualitative research in discussing issues with group of people. According to lia (2003, p.1) a focus group is defined as a small structured group with selected participant, normally led by a moderator. They are set up in other groups to explore specific topic, and individual views and experiences through group interaction a focus group is intended to be a collection of data from audience and also having individual interviews for example face to face interviews. On the other hand, a focus group has a limitation of analysing a topic. A Focus group can very be difficult in terms of gathering all the information taken from a target audience. As Monique (2007, p. 10) argues that despite popular belief, focus group research is not a cheap and quick exercise; it requires a great of preparation, organisation, and time to collect, manage and analyse and the data. The sample size is usually small, and there is a large use of non-pr obability sampling methods, meaning that results cant be generalized to the whole population, they are just reliable for the sample concerned. Descriptive methods summarize some aspects of the environment, they only describe but without looking for the cause and effect of relationships. Surveys with questionnaires are the main way to collect data, they can be achieved face-to-face or by indirect means such as mail, phone, fax or the Internet. This usually takes a long time, but a large sample can be used easily. Finally, causal research establishes a cause-effect link between variables. In each case, the main strength of projective techniques is that respondents are more willing to give answers that they wouldnt have given if they knew the purpose of the study, especially when the subject is personal or difficult. Whats more, it can reveal motivations or attitudes at a subconscious level. Yet, these methods require highly trained interviewers and skilled interpreters, as they are open ended techniques that can thus be difficult to interpret. Finally, other qualitative methods can be used to explain the reasons and motivations underlying in peoples decisions. Moreover, there are different ways of research in terms of academic working. Researcher mostly use the following ways, referencing usually when we paraphrase or summarize someone else opinion. Books, journals, video, personal interview, emails and many more are some of the sources that researchers use. Qualitative research can be used to enhance quantitative work. Finally, in qualitative research it can lead to theological sampling. As quoted from (Manson 1996:93-4) in Long (2007, p.42) said, theoretical sampling means selecting groups or categories to study on the à ¢Ã¢â€š ¬Ã‚ ¦basis of their relevance to your question , your theoretical positionà ¢Ã¢â€š ¬Ã‚ ¦and most importantly the explanation or account which you are developingà ¢Ã¢â€š ¬Ã‚ ¦[using] criteria which help to develop and test your theory and explanation. The researcher is going to identify some side effect or complication of secondary research. According to veal (2006, p.148) he argues that are advantage and disadv antage of using secondary data to analyse research. Some of the advantages can be, timing- data maybe instantly available, cost of collecting new data avoided and disadvantages can be secondary data that has been designed for another purpose so it may be not be ideal for the current project. A clear link with this essay summarise up the importance of why visitors or tourist visit the darker side of tourism. It has now become clear that, tourists have their own interest and what motivates them to visit this place which there is no doubt for that. Additionally, the researcher focuses on different approaches of research and picked one approach to research the dark tourism.

How Much Control Should The Us :: essays research papers

Why does the government think they need to regulate private businesses? When it comes to working conditions, employers must be responsible to create fair standards of how businesses should operate. Business owners must be able to make independent decisions regarding wages, hours, and safety to allow one’s business to be successful. During President Regan’s years in office, he initiated a policy to deregulate businesses. He eliminated as many restrictions as possible, to let the businesses regulate themselves. This means that these companies can pay employees any amount desired, so long as they meet federal minimum wage standard. A special salary for employees working overtime is unnecessary. Successful businesses will choose to pay extra anyway, as this will create a competition between businesses for quality employees. The hours an employee works need not be regulated so long as the employee is compensated for the time worked. An example of how regulations can be counterproductive is in France. Currently employees are not allowed to work more than 35 hours per week. As of the 1st of January, that work week will be further reduced. Companies are fined if employees work more than 35 hours. This is causing a problem because the companies’ production is lower and so is the quality of the products. With reduced quality and quantity of the product, these companies could be forced out of business, leaving the government less to regulate. Safety is another key issue that the government likes to regulate. Because of the reduced work week in France, it will be interesting to see if safety becomes a problem for overnment regulators or private businesses. In the United States, most business owners are aware that a safe work environment is a must. How Much Control Should The Us :: essays research papers Why does the government think they need to regulate private businesses? When it comes to working conditions, employers must be responsible to create fair standards of how businesses should operate. Business owners must be able to make independent decisions regarding wages, hours, and safety to allow one’s business to be successful. During President Regan’s years in office, he initiated a policy to deregulate businesses. He eliminated as many restrictions as possible, to let the businesses regulate themselves. This means that these companies can pay employees any amount desired, so long as they meet federal minimum wage standard. A special salary for employees working overtime is unnecessary. Successful businesses will choose to pay extra anyway, as this will create a competition between businesses for quality employees. The hours an employee works need not be regulated so long as the employee is compensated for the time worked. An example of how regulations can be counterproductive is in France. Currently employees are not allowed to work more than 35 hours per week. As of the 1st of January, that work week will be further reduced. Companies are fined if employees work more than 35 hours. This is causing a problem because the companies’ production is lower and so is the quality of the products. With reduced quality and quantity of the product, these companies could be forced out of business, leaving the government less to regulate. Safety is another key issue that the government likes to regulate. Because of the reduced work week in France, it will be interesting to see if safety becomes a problem for overnment regulators or private businesses. In the United States, most business owners are aware that a safe work environment is a must.

Child Consumerism Essay

The essay â€Å"Kid Kustomers† by Eric Schlosser talks about how children got sucked into the idea of consumerism. It all started in the 1980’s with parents wasting more money on their kids. Now companies such as Kid2Kid, the Gepetoo Group, and Just Kids and other big corporations specialize in finding ways to get kids to buy their products. The author mentions the different ways children nag to get what they want, such as the pleading, persistent, forceful, demonstrative, sugar-coated, threatening and pity nag. The television plays the biggest role in consumerism because of the advertisements that children are watching all day and the effect it has on them. The reason advertisements are the best tactic when it comes to consumerism is because children think that advertisements are part of the television show. Schlosser brings up several good points throughout the essay. This world is a materialistic world. Most people nowadays are sucked into being the consumers and buying things that they do not even need because now it is all about who has the best clothes, shoes, car or house. It’s one big competition and hardly anyone is ever happy because there is always someone who has something that you do not have. Another reason people like to be consumers is because like to own the newest version of something. One example would be the millions people who buy the new iPhone or iPad when in reality it’s practically the same as it predecessor. If these marketing techniques work well on adults than that is the reason they are more effective on children. Lastly Schlosser’s points are valid because I too have seen children being convinced to buy a product by people on the streets ,beg to their parents and have seen the effects advertisements have children. It happens all the time, whether people realize it or not. When a child sees a guy with a big sign advertising toys or food the kid is going to want to ask their parents if they can get the toy or that they are hungry. It is sad that almost all children know who Ronald McDonald is and when they get hungry they are most likely to go to McDonalds because it is convenient. Children are more easily targeted now because now their friends influence them and if that one friend has something that they like, they will find a way to own it too. My little cousin Max who is ten years old feels he has to own the newest thing. It saddens me because he is in a competition with his friends and these companies are making money off him when he may not truly be interested in their product. Companies target children specifically because they get what they want the majority of the time. Companies depend on their children to beg to their parents so that they can buy their product. Whenever my cousin Max beg to his parents he eventually gets what he wants because he is persistent and persuasive and makes his parents feel guilty if he does not get what he wants. Sometimes while I am walking down the street or in the mall I see a kid with a iPhone wondering what they with something that sophisticated at such a young age. It makes me wonder if kids have things such as the iPhone then what else do they have? These are the children who are sucked into consumerism and have to buy everything that is considered cool or new. To me one of the biggest reasons companies invest time and money on marketing advertisements directed towards children the most is because children have not learned the true importance of t the dollar bill. They no value behind it and do not think it of as much when their parents are the ones out their spending there money on them. Advertisements on television play the biggest role in consumerism. One effect that advertisements have on children is that the advertisement gets suck in their head. Children remember the words or specific tune that went along with the advertisement. A majority of children that I know are watching television most of the day. When I was a kid advertisements played a role in what I should buy or eat. The majority of the things that I had heard of had come from advertisements. This is true because most people do not eat at a place they have never heard of because they do not want to take the risk. The same thing goes for things such as video games and toys for kids because advertisements make the product look good, which gives people a sense of hope that it will not be a waste of money if they buy it for full price. An example would be my cousin Rachel buys most of her toys because she sees them on the television. The advertisements reassure her that buying the toy will be worth it. She falls for the same toys each time because they are not much different from each other. She mostly gets dolls and princess castles, which all virtually look the same but only, differ in color. In the end advertisements effect our decision when we go out to buy the things we want. Companies have succeeded when it comes to convincing children to buy their product. It doesn’t matter where a pers on is at now. They can be outside or in their house and they will still be surrounded by advertisements. The advertisements are on the television all day, billboards, people on the streets and one of the stronger forms of advertisement the Internet. Whenever a person watches a video on YouTube they are stopped by a short advertisement and overtime a majority of the world knows the advertisement and may be a little more tempted to go out and buy it. This world has become a world where humans feel need to buy everything even if they do not need it. As long as companies keep releasing new products then children will be consumers because children always buy the newest toy even if they just bought their last toy two weeks ago.

Project Shakti Essay

The project was started to explore the business opportunity of the rural market, where the competition will be less than the urban market. The first challenge faced by the Shakti was the low margin to its entrepreneurs and lack of owner ship. Its initial plan was, federations purchase products from HLL and then sell them to SHGs and then to outlets in village. In this model no one took responsibility. This challenge was overcome by changing the business model as follows: A member of the SHG appointed as entrepreneur, who borrow money from respective SHG and buy products directly from HLL. By this model responsibility is only for entrepreneur and no need to share profit as well. HLLs pilot model was with women because they are the bulk consumer for the HLL products and they have access to home of potential consumers. Easy part of the project was the selection of the entrepreneurs. Problem starts once the stock started piling up, which was almost equal to their annual income. To add on to this, loan repayment schedule was also started which was threaten the feasibility of the project. These entrepreneurs did not have any previous experience in undertaking independent economic activity added up failure of this task. HLL had overcome this with following initiatives: 1. They had introduced RSP, to control stock. To reduce the cost they hired the trainers to train entrepreneurs and outsourced the administration to third party 2. Offered incentive for visiting specific number of homes and offered additional incentive for selling specific brands 3. Negotiated with bank to get more time to start initial payment. To scale up the project, implementation team has to undergo following tasks: 1. Arrange government permissions and secure the support of the district administration 2. Identify and seal partnerships with NGOs well established in the region 3. Interact with mainstream HLL sales to identify market for PS 4. Locate SHG and convince them that the project shakti was a reliable, sustainable source of income for their members 5. Appoint a right women as entrepreneurs 6. Ensure a steady supply of products In many placed HLL was not able get support from government, presuming that these attempts are an explosive attempt of a large multinational. This was overcome by the appointing MART and helped them to expand to 50405 villages across 310 districts in 12 states. To scale up they have addressed the requirement of the small income group by introducing low price packs Introduced Vani programme to educate personals and communities on their health and hygiene. Next challenge faced was to change the focus of the buyers from local retailers to Shakti entrepreneur. It has been overcome by doing the following: 1. Personalized service 2. Door step delivery 3. Assurance of quality 4. Credit to regular patrons 5. Creating a network for sale and passing a percentage of the profit to them as well

Ion Channel Disease Essays

Ion Channel Disease Essays Ion Channel Disease Essay Ion Channel Disease Essay MECH A NIS MS OF D IS EASE Review Article Mechanisms of Disease F R A N K L I N H . E P S T E I N , M. D. , Editor ION CHANNELS - BASIC SCIENCE AND CLINICAL DISEASE AND MICHAEL J. ACKERMAN, M. D. , PH. D. , DAVID E. CLAPHAM, M. D. , PH. D. I ON channels constitute a class of proteins that is ultimately responsible for generating and orchestrating the electrical signals passing through the thinking brain, the beating heart, and the contracting muscle. Using the methods of molecular biology and patch-clamp electrophysiology, investigators have recently cloned, expressed, and characterized the genes encoding many of these proteins. Ion-channel proteins are under intense scrutiny in an effort to determine their roles in pathophysiology and as potential targets for drugs. Defective ion-channel proteins are responsible for cystic fibrosis,1 the long-QT syndrome,2 heritable hypertension (Liddle’s syndrome),3,4 familial persistent hyperinsulinemic hypoglycemia of infancy,5,6 hereditary nephrolithiasis (Dent’s disease), and a variety of hereditary myopathies,7-9 including generalized myotonia (Becker’s disease), myotonia congenita (Thomsen’s disease), periodic paralyses, malignant hyperthermia, and central core storage disease (Table 1). Elucidating the mechanisms of these diseases will benefit medicine as a whole, not just patients with a particular disease. For instance, although the inherited long-QT syndrome is not common, identifying the underlying defects in the KVLQT1 and HERG potassium channels and the SCN5A sodium channels may benefit the study of ventricular arrhythmias, which are responsible for 50,000 sudden deaths each year in the United States. Likewise, al- hough a defect in the recently cloned epithelial sodium channel (ENaC) is the basis of a very rare form of inherited hypertension (Liddle’s syndrome, or pseudoaldosteronism), normal ENaC may serve as an alternative target in attempts to correct the physiologic defects created by the cystic fibrosis transmembrane regulator (CFTR), which is mutated in patients with cystic fibrosis, and work with ENaC may provide insight into the mechanism of essential hypertension. This review focuses on ion channels as functioning physiologic proteins, sources of disease, and targets for therapy. We will discuss two prominent diseases caused by defects in ion-channel proteins, as well as two specific ion channels whose recent molecular identification raises new prospects for pharmacologic manipulation. PHYSIOLOGY OF ION CHANNELS From the Department of Pediatrics and Adolescent Medicine, Mayo Foundation, Rochester, Minn. (M. J. A. ); and the Department of Cardiology, Children’s Hospital Medical Center, Department of Neurobiology, Harvard Medical School, Boston (D. E. C. ). Address reprint requests to Dr. Ackerman at the Department of Pediatrics and Adolescent Medicine, Mayo Eugenio Litta Children’s Hospital, Mayo Foundation, Rochester, MN 55905.  ©1997, Massachusetts Medical Society. Ion channels are macromolecular protein tunnels that span the lipid bilayer of the cell membrane. Approximately 30 percent of the energy expended by cells is used to maintain the gradient of sodium and potassium ions across the cell membrane. Ion channels use this stored energy much as a switch releases the electrical energy of a battery. They are more efficient than enzymes; small conformational changes change (gate) a single channel from closed to open, allowing up to 10 million ions to flow into or out of the cell each second. A few picoamps (10 12 A) of current are generated by the flow of highly selected ions each time the channel opens. Since ion channels are efficient, their numbers per cell are relatively low; a few thousand of a given type are usually sufficient. Ion channels are usually classified according to the type of ion they allow to pass - sodium, potassium, calcium, or chloride - although some are less selective. They may be gated by extracellular ligands, changes in transmembrane voltage, or intracellular second messengers. Conductance is a measure of the ease with which ions flow through a material and is expressed as the charge per second per volt. The conductance of a single channel, g, as distinguished from the membrane conductance (G) of all the channels in the cell, is defined as the ratio of the amplitude of current in a single channel (i ) to the electromotive force, or voltage (V): g i . V The direction in which ions move through a channel is governed by electrical and chemical concentraVol ume 336 Numbe r 22 575 The New Engla nd Journa l of Medicine TABLE 1. HERITABLE DISEASES MODE OF INHERITANCE* OF ION CHANNELS. NO. OF AMINO ACIDS DISEASE ION-CHANNEL GENE (TYPE) CHROMOSOME LOCATION COMMON MUTATIONS†  Cystic fibrosis Familial persistent hyperinsulinemic hypoglycemia of infancy Hypercalciuric nephrolithiasis (Dent’s disease) Liddle’s syndrome (hereditary hyperten sion; pseudoaldosteronism) AR AR X-linked CFTR (epithelial chloride channel) SUR1 (subunit of ATP-sensitive pancreatic potassium channel) CLCN5 (renal chloride channel) 7q 11p15. 1 Xp11. 22 480 1582 746 AR ENaC (epithelial sodium channel) a subunit b subunit g subunit 12p 16p 16p 1420 640 649 F508 (70 percent of cases) and 450 other defined mutations Truncation of NBD2 (nucleotidebinding domain 2) 1 intragenic deletion, 3 nonsense, 4 missense, 2 donor slice, 1 microdeletion R564stop, P616L, Y618H (all in b subunit); premature stop codon in b and g subunits; C-terminal truncation Long-QT syndrome (cardiac arrhythmia) LQT1 LQT2 LQT3 Myopathies Becker’s generalized myotonia Central core storage disease Congenital myasthenic syndrome AD KVLQT1 (cardiac potassium channel) HERG (cardiac potassium channel) SCN5A (cardiac sodium channel) 11p15. 5 7q35–36 3p21–24 581 1159 2016 1 intragenic deletion, 10 missense 2 intragenic deletions, 5 missense KPQ1505–1507, N1325S, R1644H D136G, F413C, R496S R163C, I403M, Y522S, R2434H T264P L269F , G153S T698M, T704M, M1585V, M1592V R528H, R1239H G341R, G2433R G1306A Q552R V1293I, G1306V, T1313M, L1433R, R1448C, R1448H, V1589M S804F, G1306A, G1306E, I1160V D136G, G230E, I290M, P480L AR ? ? Hyperkalemic periodic paralysis Hypokalemic periodic paralysis Malignant yperthermia Masseter-muscle rigidity (succinylcholine-induced) Myotonia levior Paramyotonia congenita Pure myotonias (fluctuations, permanins, acetazolamideresponsive) Thomsen’s myotonia congenita AD AD AD ? AD AD AD AD CLCN1 (skeletal-muscle chloride channel) RYR1 (ryanodine calcium channel) nAChR (nicotinic acetylcholine receptor) e subunit a subunit (slow channel) SCN4A (skeletal-muscle sodium channel) CACNL1A3 (dihydropine-sensitive calcium channel) RYR1 SCN4A CLCN1 SCN4A SCN4A CLCN1 7q35 19q13. 1 17p 2q 17q23–25 1q31–32 19q13. 1 17q23–25 7q35 17q23–25 17q23–25 7q35 988 5032 473 457 1836 1873 5032 1836 988 1836 1836 988 AR denotes autosomal recessive, and AD autosomal dominant. † Missense mutations are represented by the standard nomenclature (AxxxB, meaning that at amino acid position xxx, amino acid A has been replaced by amino acid B). tion gradients. Ions flow passively through ion channels down a chemical gradient. Electrically charged ions also move in an electrical field, just as ions in solution flow to one of the poles of a battery connected to the solution. The point at which the chemical driving force and the electrical driving force are exactly balanced is called the Nernst potential (or reversal potential [Erev]). Above or below this point of equilibrium, a particular species of ion flows in the direction of the dominant force. The net flow of electricity across a cell membrane is predictable given the concentrations of ions and the number, conductances, selectivities, and gating properties of the various ion channels. Electrophysiologic concepts are simplified by recalling the Nernst potentials of the four major ions 1576 May 2 9 , 1 9 9 7 across the plasma membrane of cells. These are approximated as follows: sodium, 70 mV; potassium, 98 mV; calcium, 150 mV; and chloride, 30 to 65 mV (Fig. 1). The positive and negative signs reflect the intracellular potential relative to a ground reference electrode. When only one type of ion channel opens, it drives the membrane potential of the entire cell toward the Nernst potential of that channel. Thus, if a single sodium-selective channel opens in a cell in which all other types of channels are closed, the transmembrane potential of the cell will become ENa ( 70 mV). If a single potassium channel opens, the cell’s transmembrane potential will become EK ( 98 mV). Because cells have an abundance of open potassium channels, most cells’ transmembrane potentials (at rest) are approximately MEC H A NIS MS OF D IS EASE Extracellular Cell membrane Intracellular Ca2 Ion channels 2. 5 mM Depolarization 0. 0001 mM Nernst potential (Erev) 150 mV Control mechanisms 142 mM Depolarization 10 mM Na 70 mV Gating Voltage Time Direct agonist G protein Calcium Depolarization Nonselective Repolarization 0 mV Modulation Increases in phosphorylation   Oxidation–reduction Cytoskeleton Calcium ATP 101 mM Repolarization Cl Depolarization 5–30 mM Cl 30 to 65 mV 4 mM Repolarization 155 mM K 98 mV Figure 1. Physiology of Ion Channels. Five major types of ion channels determine the transmembrane potential of a cell. The concentrations of the primary species of ions (sodium, calcium, chloride, and potassium) are millimolar. The ionic gradients across the membrane establish the Nernst potentials of the ion-selective channels (approximate values are shown). Under physiologic conditions, calcium and sodium ions flow into the cells and depolarize the membrane potential (that is, they drive the potential toward the values shown for ECa and ENa), whereas potassium ions flow outward to repolarize the cell toward EK. Nonselective channels and chloride channels drive the potential to intermediate voltages (0 mV and 30 to 65 mV, respectively). 0 mV, near EK. When more than one type of ion channel opens, each type â€Å"pulls† the transmembrane potential of the cell toward the Nernst potential of that channel. The overall transmembrane potential at a given moment is therefore determined by which channels are open and which are closed, and by the strength and numbers of the channels. A cell with one o pen sodium channel and one open potassium channel, each with the same conductance, will have a transmembrane potential halfway between ENa ( 70 mV) and EK ( 98 mV), or 14 mV. The result is the same when there are 1000 equal-conductance, open sodium and potassium channels. Ion channels are both potent and fast, and they are tightly controlled by the gating mechanisms of the cell (Fig. 1). The modern way to see an ion channel in action is to use the patch-clamp technique. With this method,10 a pipette containing a small electrode is pressed against the cell membrane so that there is a tight seal between the pipette and the membrane (Fig. 2). In essence, the electrode isolates and captures all the ions flowing through the 1 to 3 mm2 of membrane that is defined by the circular border of the pipette. In this fashion, the ionic current passing through a single ion channel can be collected and measured. Several geometric configurations can be used if a mechanically stable seal is formed. The current passing through the attached patch (cell-attached configuration), a detached patch (inside-out or outside-out configuration), or the whole cell can be measured, providing information about ion channels within the Vol ume 336 Numbe r 22 1577 The New Engla nd Journa l of Medicine A Cellattached mode B Electrode Pipette Insideout mode C Wholecell mode Acetylcholine Acetylcholine Cell membrane IK. ACh g 40 pS to 1 msec Closed pA Closed Gbg protein pA msec Open Open msec msec Figure 2. Patch. In the â€Å"cell-attached† mode (Panel A), a pipette is pressed tightly against the cell membrane, suction is applied, and a tight seal is formed between the pipette and the membrane. The seal ensures that the pipette captures the current flowing through the channel. In the cell-attached membrane patch, the intracellular contents remain undisturbed. Here, acetylcholine in the pipette activates the IK. ACh, which has a characteristic open time (tO) of 1 msec and a conductance (g) of 40 picosiemens. In the inside-out mode (Panel B), after a cell-attached patch has been formed, the pipette is pulled away from the cell, ripping off a patch of membrane that forms an enclosed vesicle. The brief exposure to air disrupts only the free hemisphere of the membrane, leaving the formerly intracellular surface of the membrane exposed to the bath. Now the milieu of the intracellular surface of the channels can be altered. In this figure, adding purified Gbg protein to the exposed cytoplasmic surface activates the IK. ACh. In the whole-cell mode (Panel C), after a cell-attached patch has been formed, a pulse of suction disrupts the membrane circumscribed by the pipette, making the entire intracellular space accessible to the pipette. Instead of disrupting the patch by suction, a pore-forming molecule, such as amphotericin B or nystatin, can be incorporated into the intact patch, allowing ions access to the interior of the cell but maintaining a barrier to larger molecules. In this figure, the net current (IK. ACh) after the application of acetylcholine is shown. environment of the cell, in isolation from the rest of the cell, or over the entire cell, respectively. MOLECULAR BLUEPRINTS OF ION CHANNELS Many ion channels have been cloned by assaying their function directly with the use of oocytes from South African clawed toads (Xenopus laevis). 11 These oocytes are large enough to be injected with exogenous messenger RNA (mRNA) and are capable of synthesizing the resulting foreign proteins. In â€Å"expression cloning,† in vitro transcripts of mRNA from a complementary DNA (cDNA) library derived from a tissue known to be rich in a particular ion channel are injected into individual oocytes. Subsequently, the currents in the oocytes are meas1578 May 2 9 , 1 9 9 7 ured by two-electrode voltage clamp techniques. The cDNA library is serially subdivided until injected mRNA from a single cDNA clone is isolated that confers the desired ion-channel activity. Moreover, mutant cDNA clones with engineered alterations in the primary structure of the protein can be expressed and the properties of the ion channel can be studied to determine which regions of the protein are critical for channel activation and inactivation, ion permeation, or drug interaction. Most ion-channel proteins are composed of individual subunits or groups of subunits, with each subunit containing six hydrophobic transmembrane regions, S1 through S6 (Fig. 3A). 13 The sodium and calcium channels comprise a single (a) subunit containing four repeats of the six transmembrane-span- A M ECH A NIS MS OF D IS EASE A C-type slow inactivation B K Extracellular S4 S1 S2 S3 S4 S5 H5 S6 S4 S4 S4 Cell membrane †Ball and chain† N-type fast inactivation P N S4 voltage sensor H5 channel pore C K Intracellular P P K Figure 3. Structure of Ion Channels. Panel A shows a subunit containing six transmembrane-spanning motifs, S1 through S6, that forms the core structure of sodium, calcium, and potassium channels. The â€Å"ball and chain† structure at the N-terminal of the protein is the region that participates in N-type â€Å"fast inactivation,† occluding the permeation pathway. The circles containing plus signs in S4, the voltage sensor, are positively charged lysine and arginine residues. Key residues lining the channel pore (H5) are found between S5 and S6. The genes for sodium and calcium channels encode a protein containing four repeats of this basic subunit, whereas the genes for voltageactivated potassium channels (Kv) encode a protein with only a single subunit. The genes for Kir channels encode a simple subunit structure containing only an H5 (pore) loop between two transmembrane-spanning segments. P denotes phosphorylation. Panel B shows four such subunits assembled to form a potassium channel. Although no mammalian voltage-dependent ion-channel structure has been revealed at high resolution by x-ray crystallography, the dimensions of the pore region shown here were derived by using high-affinity scorpion toxins and their structures (as determined by nuclear magnetic resonance imaging) as molecular calipers. 12 The pore region appears to have wide intracellular and extracellular vestibules (approximately 2. 8 to 3. 4 nm wide and 0. 4 to 0. 8 nm deep) that lead to a constricted pore 0. 9 to 1. 4 nm in diameter at its entrance, tapering to a diameter of 0. 4 to 0. 5 nm at a depth of 0. 5 to 0. nm from the vestibule. ning motifs. Voltage-gated potassium channels (Kv; this nomenclature refers to K channel, voltagedependent) are composed of four separate subunits, each containing a single six-transmembrane–spanning motif (Fig. 3B). 14 The subunits are assembled to form the central pore in a process that also determines the basic properties of gating and permeation charact eristic of the channel type. The peptide chain (H5 or P loop) between the membrane-spanning segments S5 and S6 projects into and lines the water-filled channel pore. Mutations in this region alter the permeation properties of the channel. S4 contains a cluster of positively charged amino acids (lysines and arginines) and is the major voltage sensor of the ion channel. Voltage-dependent â€Å"fast inactivation† of the channel is mediated by a tethered amino-terminal– blocking particle (the â€Å"ball and chain†) that swings in to occlude the permeation pathway. 15 The most recently discovered family of ion-channel proteins is that containing the inwardly rectifying potassium-selective channels (Kir, for K channel, inward rectifier). These channels determine the transmembrane potential of most cells at rest, because hey are open in the steady state. Kir channels are known as inward rectifiers because they conduct current much more effectively into the cell than out of it. Despite this biophysical property of the Kir channels, the physiologically important current is the outward one that accompanies the efflux of potassium ions. The topography of Kir channels resembles that of Kv channels, but the su bunits in Kir channels lack the S1 to S4 segments present in Kv channels. 16 With only two transmembrane-spanning segments, Kir channels have a deceptively simple domain surrounding the conserved H5 pore. However, pore formation by different combinations of subunits, direct gating of G proteins, and interactions with other proteins adds considerable complexity to the behavior of the Kir channels. HERITABLE DISEASES ASSOCIATED WITH ION-CHANNEL MUTATIONS Cystic Fibrosis One in 27 white persons carries a mutant CFTR gene, and 1 in 2500 to 3000 is born with cystic fiVol ume 336 Numbe r 22 1579 The New Engla nd Journa l of Medicine A B Cell membrane TM1 TM6 TM7 Extracellular TM12 Skin Cl , 60 mmol/liter Lungs Bronchiectasis Pneumothorax Hemoptysis Cor pulmonale N F508 NBD1 ATP ADP Pi NBD2 ATP ADP Pi Liver Obstructive biliary tract disease Pancreas Enzyme insufficiency Insulin-dependent diabetes mellitus Regulatory domain S I P Reproductive tract Male infertility Congenital absence of vas deferens PKA PP2A C 1 Gene therapy to replace CFTR gene (phase 1) Extracellular Cell membrane 3 Activate mutant CFTR with NS004 (experimental) 2 Direct CFTRprotein delivery (in vitro) 5 Activate non-CFTR chloride channels with aerosolized UTP (phase 3) 6 Decrease sodium uptake by blocking ENaC with aerosolized amiloride (phase 3) Na CFTR P2R R P lCI. ATP Cl P Intracellular I Meconium ileus S Small intestine P ENaC P ATP Intracellular Cl 4 Chaperonins (none tested yet) 1580 May 2 9 , 1 9 9 7 P S I P Endoplasmic reticulum S I P S I P P M EC H A NIS MS OF D IS EASE Figure 4. Cystic Fibrosis and CFTR. In cystic fibrosis, defective apically located membrane chloride channels (CFTR) in a variety of epithelial cells do not allow the egress of chloride ions into the lumen. Control over epithelial sodium channels is also lost, increasing the reabsorption of sodium from the lumen. Thick, desiccated mucus results, which accounts for the primary clinical manifestations of the disease (Panel A). 7 CFTR contains 12 transmembrane segments (TM1 through TM12, Panel B), several of which (TM1, TM6, and TM12) contribute to the chloride-channel pore. There are also two nucleotide-binding domains (NBD1 and NBD2) and a regulatory domain. The chloride channel is regulated by ATP binding and hydrolysis at the nucleotide-binding domains and by the phosphorylation (P) of serine residues (S) in the regulatory domain. The most common mutation in cystic fibrosis, found in more than 70 percent of cases, involves a deletion of a single amino acid (phenylalanine) in NBD1 ( F508). PKA denotes protein kinase A, PP2A protein phosphatase 2A, and Pi inorganic phosphorus. Molecular strategies to treat cystic fibrosis (Panel C) include replacing the mutant chloride channel by gene therapy (1) or protein delivery (2); improving the secretion from the existing mutant CFTR protein with CFTR-channel openers, such as NS004 (3) or â€Å"chaperonins† for F508 in the endoplasmic reticulum (4); bypassing the CFTR defect by activating other chloride channels with aerosolized uridine triphosphate (UTP) (5); and blocking the increased reabsorption of sodium through epithelial sodium channels (ENaC) with aerosolized amiloride (6). The investigational stages of these strategies are given in parentheses. P2R denotes type-2 purinergic receptor, and R regulatory domain. brosis (among blacks the incidence is 1 in 14,000, and among Asians it is 1 in 90,000). The manifestations of cystic fibrosis stem from a defect in a chloride-channel protein, CFTR, that does not allow chloride to cross the cell membrane (Fig. 4A). 7 The CFTR gene encodes a chloride channel that is activated by the binding of ATP to its nucleotide-binding domains and by the phosphorylation of key serine residues in its regulatory domain; the phosphorylation is mediated by cyclic AMP and protein kinase A (Fig. 4B). 18-21 CFTR also appears to regulate the absorption of sodium through ENaC, the epithelial sodium channel, and to activate other â€Å"outwardly rectifying† chloride channels. More than 450 mutations have been identified in CFTR, which contains 1480 amino acids. A deletion of phenylalanine at position 508 ( F508) accounts for more than 70 percent of cases of cystic fibrosis and is associated with severe pancreatic insufficiency and pulmonary disease. The F508 CFTR channel conducts chloride reasonably well when it is incorporated into a cell membrane, but because of improper folding the mutant protein becomes stuck in intracellular organelles and is not inserted into the cell membrane. 2 The majority of mutant CFTR proteins are processed abnormally, like the F508 mutant, but some mutations cause either defects in regulation or defective conduction through the CFTR channel. 23 Different CFTR genotypes may provide opportunities to develop unique therapeutic strategies. For instance, misfolded mutants could be escorted to the membrane by yet-to-be-invented â€Å"chaperonins,† whereas the action of poorly conducting mutant proteins may be enhanced by CFT R-specific channel openers. Molecular genotypes are correlated with the severity of pancreatic insufficiency, but not with the severity of pulmonary disease. 24 An exception is the A455E CFTR mutant (in which alanine is changed to glutamic acid at position 455), which has been associated with mild lung disease and accounts for 3 per- cent of cases of cystic fibrosis in the Netherlands. 25 In addition, a primarily genital phenotype of cystic fibrosis that involves the congenital bilateral absence of the vas deferens has been described in otherwise healthy males who are heterozygous for the F508 CFTR mutation. 6 Pulmonary disease accounts for over 90 percent of mortality from cystic fibrosis, and therefore treatment is mostly directed at ameliorating lung disease. Therapy includes antibiotics to eliminate common respiratory pathogens (Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Staphylococcus aureus), recombinant human DNase to decrease the viscosity of secretions, and antiinfl ammatory drugs to reduce the inflammatory response. 7 The recognition of the ion-channel defect in cystic fibrosis has led to novel approaches, such as replacing the defective channel gene by gene transfer with either viral carriers such as adeno-associated virus or nonviral carriers such as cationic liposomes (now in phase 1 trials)28; stimulating the activation of reduced numbers of functional ion channels with a CFTR-channel opener (NS004, a substituted benzimidazolone)29; mobilizing mutant CFTR proteins to the cell surface30,31; counteracting the defect in chloride efflux by blocking the influx of sodium with amiloride32,33; and bypassing CFTR-mediated conductance of chloride by activating other chloride channels, such as ICl. Swell, ICl. Ca, and ICl. ATP34 (Fig. 4C). Long-QT Syndrome A more detailed understanding of cardiac arrhythmogenesis is emerging as the workings of most of the types of ion channels underlying cardiac action potentials are elucidated. 35,36 The various long-QT syndromes are the first genetically determined arrhythmias known to be caused at the molecular level by defects in myocardial ion channels (Fig. 5). The congenital long-QT syndrome has an estimated incidence of 1 in 10,000 to 1 in 15,000. It is characterized by prolongation of the QT interval Vol ume 336 Numbe r 22 1581 The New Engla nd Journa l of Medicine A C LQT1 (11q15. 5) KvLQT1 IKs C Long-QT Syndrome Prolongation of QT (QTc 460 msec1/2) Syncope Sudden death N 1 581 Cell membrane LQT2 (7q35–36) HERG IKr Prolonged QT N 1 C 1159 LQT3 (3q21–24) Torsade de pointes II III IV SCN5A INa C P N 1 2016 KPQ P P P P B 47 mV 1 0 Current clamp 85 mV 0 100 2 Prolonged cardiac action potential 3 LQT4 (4q25–27) 4 ? 200 300 400 M illiseconds 500 corrected for heart rate (QTc) to more than 460 msec1/2, and it is an important but relatively rare cause of sudden death in children and young adults (Fig. 5A). The majority (two thirds) of persons with the long-QT syndrome are identified during routine electrocardiographic screening or after the evaluation of a primary relative who is affected. Approximately one third of subjects are identified during a clinical evaluation for unexplained syncope or cardiac or respiratory arrest. These subjects are at an annual risk of 5 percent for an abrupt syncopal episode. Without treatment, symptomatic subjects have 1582 May 2 9 , 1 9 9 7 a 10-year mortality rate approaching 50 percent. Often the arrhythmia is a torsade de pointes polymorphic ventricular tachycardia, typically triggered by adrenergic arousal. 37 Genetic origins were suggested for this syndrome by descriptions both of the autosomal recessive form associated with congenital deafness (Jervell and Lange-Nielsen syndrome)38 and of an isolated autosomal dominant form (Romano– Ward syndrome). 9,40 Substantial progress has been made toward elucidating the molecular basis of the most common inherited subtypes of the long-QT syndrome (Fig. M EC H A NIS MS OF D IS EASE Figure 5. The Long-QT Syndrome. A person with the long-QT syndrome may have unexplained syncope, seizures , or sudden death (Panel A). More likely, the person will be asymptomatic and identified by electrocardiographic screening during a routine evaluation or the screening of a primary relative who is symptomatic. The strict electrocardiographic definition of a prolonged QT interval varies according to age and sex, but generally a QT interval corrected for heart rate (QTc) greater than 460 msec1 ? 2 is considered abnormal. According to Bazett’s formula, the QTc is calculated by dividing the QT interval by the square root of the R-R interval. In patients with the long-QT syndrome, the T-wave morphology is often abnormal. This base-line rhythm can degenerate into a polymorphic ventricular tachycardia, classically a torsade de pointes, as shown here, after a stimulus that is not precisely understood but that often takes the form of adrenergic arousal. The prolonged QT interval as measured on the electrocardiogram results from an increased duration of the cardiac action potential (Panel B). The ventricular action potential is maintained at a resting membrane potential (approximately 85 mV) by inwardly rectifying potassium currents (IK1, phase 4). Once an excitatory stimulus depolarizes the cell beyond a threshold voltage (for example, 60 mV), sodium currents are activated that quickly depolarize the cell (INa, phase 0). These sodium channels are rapidly inactivated, allowing transient potassium currents to return the action potential to the plateau voltage (phase 1). The plateau lasts about 300 msec and provides time for the heart to contract. The plateau is maintained by the competition between outward-moving potassium currents and inward-moving calcium currents (phase 2). Progressive inactivation of calcium currents and increasing activation of potassium currents repolarize the cell to the resting membrane potential (phase 3). On a molecular basis, the autosomal dominant LQT1 and LQT2 are caused by defects in potassium-channel genes (KvLQT1 and HERG) involved in phase 3 repolarization (Panel C). LQT3 is caused by a defective sodium-channel gene, SCN5A. A common SCN5A mutation in families with LQT3 involves a deletion of three amino acids ( KPQ) in the III–IV cytoplasmic linker loop, which is known to regulate inactivation. The mutant sodium channel fails to become completely inactivated, resulting in sustained depolarization and prolonging the cardiac action potential. The linear topology of the proteins responsible for LQT1, LQT2, and LQT3 is shown, with the amino acids numbered beginning with the N-terminal - a total of 581, 1159, and 2016 amino acids, respectively. The chromosomal locations for these genes are shown in parentheses. 5C). 2,36 Recent studies of 16 families with chromosome-II–linked long-QT syndrome type 1 (LQT1) implicated KvLQT1, a 581-amino-acid protein with sequence homology to voltage-activated potassium channels. 41 One intragenic deletion and 10 missense mutations were identified. The combination of the KvLQT1 and ISK subunits (the latter of which contains 130 amino acids, also known as minK) appears to reconstitute the cardiac IKs current. 42,43 IKs (â€Å"s† denotes â€Å"slow†) is one of the principal delayed-rectifying potassium currents responsible for phase 3 repolarization in the heart (Fig. 5B). LQT1 may account for half the incidence of the long-QT syndrome in its autosomal dominant forms. Mutations in a second potassium channel, the human ether-a-go-go–related gene (HERG), have been identified in subjects with the long-QT syndrome type 2 (LQT2), which has been linked44,45 to chromosome 7q35–36. HERG is responsible for the other major potassium current (IKr [â€Å"r† denotes â€Å"rapid†]) that participates in phase 3 repolarization. It is a unique voltage-gated potassium channel; its secondary structure is that of a typical voltage-activated (Kv) potassium channel (Fig. 3A), but it behaves more like an inwardly rectifying (Kir) potassium channel. 6 The role of HERG in normal cardiac physiology appears to be to suppress depolarizations that lead to premature firing. Subjects with LQT2 may therefore be prone to sudden cardiac death, because they lack protection from arrhythmogenic afterbeats. Class III antiarrhythmic drugs block HERG channels. In addition, antihistamines such as terfenadine and antifungal drugs such as ketoconazole have been implicated in acquired cases of the long-QT syn- drome because of their ability to block IKr (HERGmediated) current. The third subtype of the long-QT syndrome (LQT3) has been linked to the gene for the cardiac sodium channel (SCN5A) on chromosome 3p21– 24. 47 This channel is responsible for the fast upstroke of the cardiac action potential (phase 0, Fig. B), which ensures contractile synchrony by causing the potential to spread rapidly throughout the heart muscle. A deletion of three amino acids, KPQ1505– 1507, in a region thought to control rapid inactivation has been demonstrated in LQT3-linked families. The mutant sodium channel fails to inactivate completely, resulting in reopenings of the channel and long-lasting bursts of channel activity. 48,49 The resulting prolonged inward current lengthens the action potential (and thus the QT interval). Finally, a fourth heritabl e type of long-QT syndrome (LQT4) has been linked to chromosome 4q25–27. Its causative gene has not been identified, although a gene encoding a calcium–calmodulin kinase has been proposed. 0 Current therapies for the long-QT syndrome include b-adrenergic–antagonist drugs, cardiac pacing, and left cervicothoracic sympathectomy. The majority of families with heritable long-QT syndrome have type 1, 2, or 3, offering the prospect of genetic screening and directed antiarrhythmic therapy. Theoretically, therapies that augment potassium-channel activity may be used in subjects with potassiumchannel defects (LQT1 and LQT2),51 and those with sodium channel–linked defects (LQT3) may benefit from drugs that decrease sodium-channel activation (such as mexiletine). 52 Vol ume 336 Numbe r 22 1583 The New Engla nd Journa l of Medicine TABLE 2. ION CHANNELS AND DRUGS THAT AFFECT THEM. Calcium channels Antianginal drugs (amlodipine, diltiazem, felodipine, nifedipine, verapamil) Antihypertensive drugs (amlodipine, diltiazem, felodipine, isradipine, nifedipine, verapamil) Class IV antiarrhythmic drugs (diltiazem, verapamil) Sodium channels Anticonvulsant drugs (carbamazepine, phenytoin, valproic acid) Class I antiarrhythmic drugs IA (disopyramide, procainamide, quinidine) IB (lidocaine, mexiletine, phenytoin, tocainide) IC (encainide, flecainide, propafenone) Diuretic drugs (amiloride) Local anesthetic drugs (bupivacaine, cocaine, lidocaine, mepivacaine, tetracaine) Chloride channels Anticonvulsant drugs (clonazepam, phenobarbital) Hypnotic or anxiolytic drugs (clonazepam, diazepam, lorazepam) Muscle-relaxant drugs (diazepam) Potassium channels Antidiabetic drugs (glipizide, glyburide, tolazamide) Antihypertensive drugs (diazoxide, minoxidil) Class III antiarrhythmic drugs (amiodarone, clofilium, dofetilide, N-acetylprocainamide, sotalol) Drugs that open potassium ch annels (adenosine, aprikalim, levcromakalim, nicorandil, pinacidil) TARGETING ION CHANNELS Drugs that target ion channels include calciumchannel blockers (used in patients with hypertension), potassium-channel blockers (used in patients with non-insulin-dependent diabetes mellitus), some diuretics and antiseizure medications, and essentially all antiarrhythmic drugs (Table 2). Recent progress in the basic understanding of the ATP-sensitive potassium channel (IK. ATP) and the G-protein–activated potassium channel (IK. ACh) shows the opportunities for drug design. The ATP-Sensitive Potassium Channel The IK. ATP current has been characterized in heart, skeletal muscle, pituitary, brain, smooth muscle, and pancreas. 55 In the pancreas, it plays a major part in regulating glucose homeostasis and the secretion of insulin. 56 Rising plasma glucose concentrations increase intracellular concentrations of ATP in islet beta cells, which in turn inhibit IK. ATP channels. As these potassium channels close, the cell’s membrane potential depolarizes away from EK and enters the range in which voltage-dependent calcium channels are activated. The resulting influx of calcium triggers insulin secretion. As plasma glucose concentrations decline, intracellular concentrations of ATP decrease and IK. ATP channels become more active, hyperpolarizing the cell, closing the calcium channels, and terminating the secretion of insulin. Oral hypoglycemic drugs (such as glyburide) bind to the sulfonylurea receptor to inhibit the activity of IK. ATP and promote the secretion of insulin. 57 Drugs that open potassium channels include nicorandil, pinacidil, aprikalim, levcromakalim, and diazoxide. In vascular smooth muscle these drugs open IK. ATP channels, hyperpolarize cell membranes, and reduce calcium-channel activity, thus decreasing vascular tone. The drugs are therefore potentially cardioprotective and may provide novel therapeutic approaches in patients with cardiac disease or hypertension. 58-60 The subtype specificity of sulfonylurea receptors (SUR1 in the pancreas and SUR2 in the heart) may be exploited to develop more specific drugs. The G-Protein–Activated Potassium Channel The ATP-sensitive potassium channel IK. ATP is a multimeric complex of inwardly rectifying potassiumchannel subunits (Kir 6. 2 K. ATP-a) and the sulfonylurea receptor (SUR1 K. ATP-b). 53,54 The genes for both are located on chromosome 11p15. 1. SUR1 binds sulfonylurea drugs. Mutations in the SUR1 gene are responsible for persistent hyperinsulinemic hypoglycemia of infancy. 5,6 Kir 6. 2 is an inwardly rectifying potassium channel. Like other such channels, it has two transmembrane-spanning segments surrounding a pore domain. Expression of both SUR1 and Kir 6. 2 results in a potassium channel that is sensitive to intracellular ATP inhibited by sulfonylurea , drugs, and activated by diazoxide, as is consistent with the known properties of IK. ATP channels in pancreatic beta cells. The cardiac sulfonylurea receptor, SUR2, has a lower affinity for sulfonylurea drugs than does SUR1, and it may form the cardiac IK. ATP channel by combining with a homologue in the Kir 6 family. 1584 May 2 9 , 1 9 9 7 Vagally secreted acetylcholine binds to cardiac muscarinic type 2 receptors. Activating these G-protein– linked receptors slows the heart rate by opening a potassium-selective ion channel (IK. ACh) composed of G-protein–activated inwardly rectifying Kir subunits. In turn, IK. ACh decreases spontaneous depolarization (pacemaker activity) in the sinus node and slows the velocity of conduction in the atrioventricular node. 61,62 Muscarinic stimulation of IK. ACh can terminate arrhythmias, particularly supraventricular tachycardias, providing the basis for carotid massage and other vagotonic maneuvers. 5 Another G-protein–linked receptor agonist, adenosine, activates the same cascade in atria and pacemaking cells through type 1 purinergic receptors. Because muscarinic stimulation has many systemic effects, adenosine has become a favored treatment for supraventricular tachycardia; it is also useful in determining the underlying arrhythmic mechanism (usually a reentrant one). 63 The molecular mechanism of the activation of IK. ACh (IK. G) is known. 64 Cardiac IK. ACh is a heteromultimer of two inwardly rectifying potassium-channel subunits, GIRK1 (Kir 3. 1) and GIRK4 (CIR or Kir 3. 4),65 and it is activated after the direct binding of the bg subunits of G protein (Gbg). 66 Similar IK. ACh currents and GIRK proteins are present in the brain. M EC H A NIS MS OF D IS EASE Neuronal GIRK channel proteins are formed by heteromultimers of GIRK1 and GIRK2 in the cerebellum, midbrain, and cortex. In homozygous weaver mice that have profound ataxia due to the loss of granule-cell neurons during cerebellar development, a single point mutation in the highly conserved pore region of GIRK2 results in granule-cell death and failure of migration. The mutated weaver-mouse channel loses its potassium-ion selectivity and sensitivity to Gbg, converting a regulated repolarizing potassium channel into a constitutively active, nonselective depolarizing channel and resulting in increased excitotoxic cell death. 67 CONCLUSIONS A growing number of heritable diseases are known to be caused by ion-channel mutations. Chloridechannel defects underlie cystic fibrosis, certain myotonias, and heritable nephrolithiasis. Mutant sodium channels give rise to the long-QT syndrome and other myotonias, potassium-channel malfunction increases susceptibility to arrhythmias, and calciumchannel mutations can result in hypokalemic periodic paralysis, malignant hyperthermia, and central core storage disease. Identifying the structural framework of the major ion-channel proteins and resolving the precise relations between structure and function should make it possible to develop new therapies for patients with these disorders. We are indebted to David A. 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