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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Gribkoff VK, Champigny G, Barbry P Dworetzky SI, Meanwell NA, Lazdunski M. The substituted benzimidazolone NS004 is an opener of the cystic fibrosis chloride channel. J Biol Chem 1994;269:10983-6. 30. Howard M, Frizzel RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med 1996;2:467-9. 31. Sato S, Ward CL, Krouse ME, Wine JJ, Kopito RR. Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 1996;271:635-8. 32. Voilley N, Lingueglia E, Champigny G, et al. The lung amiloride-sensitive Na channel: biophysical properties, pharmacology, ontogenesis, and molecular cloning. Proc Natl Acad Sci U S A 1994;91:247-51. 33. Knowles MR, Olivier KN, Hohneker KW, Robinson J, Bennett WD, Boucher RC. Pharmacologic treatment of abnormal ion transport in the airway epithelium in cystic fibrosis. Chest 1995;107:Suppl:71S-76S. 34. Knowles MR, Clarke LL, Boucher RC. 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The inward rectification mechanism of the HERG cardiac potassium channel. Nature 1996;379:833-6. 47. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80: 805-11. 48. Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature 1995;376:683-5. 49. Dumaine R, Wang Q, Keating MT, et al. Multiple mechanisms of Na channel-linked long-QT syndrome. Circ Res 1996;78:916-24. 50. Schott J-J, Charpentier F, Peltier S, et al. Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet 1995;57:111422. 51. Compton SJ, Lux RL, Ramsey MR, et al. Genetically defined therapy of inherited long-QT syndrome: correction of abnormal repolarization by potassium. Circulation 1996;94:1018-22. 52. Schwartz PJ, Priori SG, Locati EH, et al. 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history of music essays

history of music essays From the year 800 A.D, music has evolved and developed in many different ways over 6 main musical periods. These different stages in musics history all have their own distinguishing features such as the type of instruments used, the texture of the music and the sound that is created through different methods of playing. The first significant period of music that has been recorded is the medieval period. The medieval period started from around 800 A.D and is thought to have ended at around 1450 A.D. this period of music can be split into two different styles: sacred and secular. Sacred music was mainly church music and as the church regarded all instruments, bar the organ, as pagan, most of the music was vocal. Sacred (or church music) was known as plainsong or plainchant. This has four features, which allows the person listening to identify it: a single lined melody; sung in Latin; free rhythm (no specific time signature, bar lines or regular rhythms); no key (modal); usually sung accapella. Other chants in the medieval period are sung in an antiphonal style (one choir singing in alteration with the other) and response style where the whole choir answers one or more soloists. Whereas all of these styles of music were performed in church, secular or non-religious music was performed everyday outside of the church by musicians who would entertain nobles, townspeople and peasants with their singing, dancing, acting and acrobatics. There were many instruments used by these entertainers including: Shawm a double reeded instrument with powerful tone and ancestor of the oboe Cornett made from ivory with trumpet like mouthpiece and finger holes like a recorder Medieval lute guitar like instrument with four strings Fiddle large viola like instrument with flat bridge to play two strings at the same time Pipe and tabor a pipe and two headed dr...

Overview of Imagism in Poetry

Overview of Imagism in Poetry In the March 1913 issue of the magazine Poetry, there appeared  a note titled Imagisme, signed by one F.S. Flint, offering this description of the Imagistes†: â€Å"... they were contemporaries of the post-impressionists and the futurists, but they had nothing in common with these schools. They had not published a manifesto. They were not a revolutionary school; their only endeavor was to write in accordance with the best tradition as they found it in the best writers of all time - in Sappho, Catullus, Villon. They seemed to be absolutely intolerant of all poetry that was not written in such endeavor, ignorance of the best tradition forming no excuse ...† At the beginning of the 20th century, a time in which all the arts were politicized and revolution was in the air, the imagist poets were traditionalists, conservatives even, looking back to ancient Greece and Rome and to 15th-century France for their poetic models. But in reacting against the Romantics who preceded them, these modernists were also revolutionaries, writing manifestos that spelled out the principles of their poetic work. F.S. Flint was a real person, a poet, and critic who championed free verse and some of the poetic ideas associated with imagism before the publication of this little essay, but Ezra Pound later claimed that he, Hilda Doolittle (H.D.) and her husband, Richard Aldington, had actually written the â€Å"note† on Imagism. In it were laid out the three standards by which all poetry should be judged: Direct treatment of the thing, whether subjective or objectiveTo use absolutely no word that does not contribute to the presentationAs regarding rhythm: to compose in sequence of the musical phrase, not in sequence of the metronome Pound’s Rules of Language, Rhythm, ​and Rhyme Flint’s note was followed in that same issue of  Poetry by a series of poetic prescriptions titled A Few Donts by an Imagiste,  to which Pound signed his own name, and which he began with this definition: â€Å"An ‘image’ is that which presents an intellectual and emotional complex in an instant of time.† This was the central aim of imagism - to make poems that concentrate everything the poet wishes to communicate into a precise and vivid image, to distill the poetic statement into an image rather than using poetic devices like meter and rhyme to complicate and decorate it. As Pound put it, â€Å"It is better to present one image in a lifetime than to produce voluminous works.† Pound’s commands to poets will sound familiar to anyone who has been in a poetry workshop in the near-century since he wrote them: Cut poems down to the bone and eliminate every unnecessary word - â€Å"Use no superfluous word, no adjective, which does not reveal something. ... Use either no ornament or good ornament.†Make everything concrete and particular - â€Å"Go in fear of abstractions.†Do not try to make a poem by decorating prose or chopping it into poetic lines - â€Å"Don’t retell in mediocre verse what has already been done in good prose. Don’t think any intelligent person is going to be deceived when you try to shirk all the difficulties of the unspeakably difficult art of good prose by chopping your composition into line lengths.†Study the musical tools of poetry to use them with skill and subtlety, without distorting the natural sounds, images and meanings of language - â€Å"Let the neophyte know assonance and alliteration, rhyme immediate and delayed, simple and polyphonic, as a musician would expect to know harmony and counterpoint and all the minutiae of his craft ... your rhythmic structure should not destroy the shape of your words or their natural sound or their meaning.† For all his critical pronouncements, Pound’s best and most memorable crystallization of imagism came in the next month’s issue of Poetry, in which he published the quintessential imagist poem, â€Å"In a Station of the Metro.† Imagist Manifestos and Anthologies The first anthology of Imagist poets, Des Imagistes, was edited by Pound and published in 1914, presenting poems by Pound, Doolittle, and Aldington, as well as Flint, Skipwith Cannell, Amy Lowell, William Carlos Williams, James Joyce, Ford Madox Ford, Allen Upward and John Cournos. By the time this book appeared, Lowell had stepped into the role of promoter of imagism - and Pound, concerned that her enthusiasm would expand the movement beyond his strict pronouncements, had already moved on from what he now dubbed â€Å"Amygism† to something he called â€Å"vorticism.† Lowell then served as editor of a series of anthologies, Some Imagist Poets, in 1915, 1916 and 1917. In the preface to the first of these, she offered her own outline of the principles of imagism: To use the language of common speech but to employ always the exact word, not the nearly exact, nor the merely decorative word.To create new rhythms - as the expression of new moods - and not to copy old rhythms, which merely echo old moods. We do not insist on free-verse as the only method of writing poetry. We fight for it as for a principle of liberty. We believe that the individuality of a poet may often be better expressed in free-verse than in conventional forms. In poetry, a new cadence means a new idea.To allow absolute freedom in the choice of subject. It is not good art to write badly about aeroplanes and automobiles; nor is it necessarily bad art to write well about the past. We believe passionately in the artistic value of modern life, but we wish to point out that there is nothing so uninspiring nor so old-fashioned as an aeroplane of the year 1911.To present an image (hence the name: ‘imagist’). We are not a school of painters, but we believe that poetry should render particulars exactly and not deal in vague generalities, however magnificent and sonorous. It is for this reason that we oppose the cosmic poet, who seems to us to shirk the real difficulties of art. To produce poetry that is hard and clear, never blurred nor indefinite.Finally, most of us believe that concentration is of the very essence of poetry. The third volume was the last publication of the imagists as such - but their influence can be traced in many strains of poetry that followed in the 20th century, from the objectivists to the beats to the language poets.

Debates on obamacare Term Paper Example | Topics and Well Written Essays - 1250 words

Debates on obamacare - Term Paper Example According to this act, approximately 44 million Americans are currently unable to access health insurance. The aim of Obama care is to help this people get health insurance by expanding Medicare and Medicaid. From this sense, the Universal Declaration of Human Rights is the motivational factor behind this document and not the American Constitution (Pipes 29). The Act established that every citizen has a right to Health Care as a public good, not an asset and thus the U.S health care system must aim at fulfilling the following principles. Universality where each American has the human right to access health care and accountability as the first priority in the responsibilities of the U.S government. Equity, which provides that all the benefits and contributions be distributed fairly to develop a system that favors everyone (Pipes 45). Reasoned arguments for government programs to ensure that everyone has access to affordable health care Utilitarianism provides that promotion of welfare is  the most important, and that the society should be organized in such a way that would best obtain individuals' well being. It justifies the huge redistribution of wealth to the poor. Futilitarians do not consider historical facts to be important, but their influence on justice verdicts are derived purely from what the future holds for people. Utilitarianism gives equal weight to the interests of each individual, so that burdens may be placed on the one with greater benefits. To shy away from this fact is to give more priority to the lesser important issues at the expense of the greater ones, which is to treat the former citizen's interests as more essential as compared to the latter's. To them, justice calls for equal concern for everyone, which in turn requires the kind of weighing and balancing between a life’s applied by the prudent person in accepting a current cost for the sake of a greater, future benefit (Pipes 48-9). From a utilitarian view, Obama care is a ben eficial policy since it is an improvement of earlier laws and it is aimed at increasing the total utility and happiness in the state. In earlier years, the American government did not provide that insurance companies justify the rise in prices, which was a huge opportunity for private companies to exploit citizens and charge very high premiums for insurance policies. The new law of Obama care will ensure that the government implements its "exchange option," subsidize health insurance for a number of them, and require insurance companies to announce publicly and justify any increases to premiums of over ten percent. This will enable a closer look into the operations of the actions of a company, leading to reasonable prices and a higher quality of health care providers. Apart from decreasing the prices, Obama care will offer more extensive and accessible Medicare and health care to those people who could not afford it in prior times. If health care is made available to many people, th en there will be a possibility of regular health care that will bring about happiness and utility. As much as a libertarian would consider that Obamacare restrict the freedom of American citizens and thus is no better than the earlier law, which put forward that the unhappiness of the minority would

Computer Sciences and Information Technology Essay - 5

Computer Sciences and Information Technology - Essay Example The recent years have been marked by a shift of resources to more secure designs now that the implementation bags have proved to be scarce courtesy of SDL (Viega and McGraw, 2002, p. 67) Threat models are SDL’s cornerstone as they make it possible for the development team to figure out secure designs in a way that is structured. To achieve this effectively, threat model has been simplified into several tasks; coming up with pictures of data flows software, the application of the â€Å"stride per element† method in an effort to identify threats applicable to the desired design, taking a look at each threat and verification to ensure that the software has been modeled enough by putting into consideration each threat and addressing all the discovered threats (Pfleeger, 1997, p. 78) The basic element of a threat model is in its delineation of the entry points in its application. The threat model is in such a way that it is able to capture the entry points in form of trust b oundaries during the phase commonly referred to as the â€Å"picture-drawing†. Good examples of this include; registry and files entry points and networking entry points. A threat model that is good enough should also be in a position to capture the authorization as well as the authentication requirements and the network accessibility of the interfaces. This process involves network accessibility via the IP address including the remote and local, local-only access and local subnet. The process also includes the authorization and authentication levels, user access, administrator-only access and anonymous access. When it comes to Windows access control lists (ACLs), the authorization levels come as finer-grained (Pfleeger, 1997, p. 56). The process identity is another critical data piece that is always captured by this model. In this case, the running code’s interference is what is taken to be the entry point and the resulting process which is high-privilege is considere d to be very dangerous if it is compromised. In the case of Windows, the administrator or the system process are regarded as being the highest privilege. In Mac OS X or Linux situation, the running process happens to be the most privileged (Viega and McGraw, 2002, p. 108). References List Pfleeger, C. 1997. Security in Computing. Prentice Hall: New Jersey Viega, J & McGraw, G. 2002. Building Secure Software. Addison-Wesley: New York DQ: RBAC The Role-Based Access Control (RBAC) is an essential access management approach. It offers a provision method that is straight forward and in the right access level and to the correct users every time it is being applied. Despite RBAC applications, most of the security teams are still facing difficulties when it comes to account implementation and the process of access management on RBAC. The reason for the above scenario is that most of the internal developer’s teams and vendors are not coming up with capabilities based on the expected r ole into the solutions at hand. RBAC has been applicable in major overhaul in the last two years resulting to its application being assigned to more than 20, 000 users on each product. Many vendors tend to be attracted to such products. This indicates how RBAC has value to the management and its users. The latest RBAC model is designed in such a way that it enforces the least segregation and

Halliday Functional Grammar Essay Example | Topics and Well Written Essays - 750 words

Halliday Functional Grammar - Essay Example An example would be "otter" and "odder" or "prints" and "prince". (Suber & Thorpe 2001). Linguistic Determinism is a theory of language that contends that all our thoughts are defined by language. Without words to define an idea or object, the mind can have no understanding of it. It was first proposed in 1950 and has remained a controversial subject (Biever 2004). A recent discovery of the numeric system of the Pariah tribe, whose language only contains words for the numbers one and two, is an example of linguistic determinism. A study revealed that they could not tell the difference between 4 objects and 5 objects since they did not have a word for them (Biever 2004). The study seems to support the theory that human languages determine the conclusions that we reach, the concepts we have of our lives, and all our emotional make up. A simplified language that develops when two languages combine is called a pidgin. First contact with English speaking settlers resulted in Native languages combining with the settler's language to form "pidgin English". It is formed as a basic, and usually temporary, means of communication between two distinct cultures. However, if the pidgin is used over the span of generations it develops into a more complex language with a wider vocabulary. It then becomes known as a Creole. The Creole spoken in Louisiana by the Cajuns is an example of the combination between the French and African languages. When the language is spoken of as being "Cajun", it is a dialect of Louisiana Creole. (Pidgins and Creoles 1997). Antonyms Antonyms, are words that have opposite meanings such as "high" and "low" or "good" and "bad". There are 4 types of antonyms. Gradable antonyms are ends of a graduated spectrum that express opposite qualities such as "hot" and "cold". Complementary antonyms are absolute opposites such as "moral" and "immoral". Relational antonyms describe an opposite relationship between two words such as "cop" and "robber" or "take" and "give". An auto-antonym is the same word that has two opposing meanings. "Fast" (move swiftly) and "fast" (to hold firmly) are auto-antonyms as well as "sanction" (to sponsor) and