Thomas Reid's Position on Common Sense Essay Example | Topics and Well Written Essays - 1500 words

Thomas Reid's Position on Common Sense - Essay Example This was thought to condition human experience and make possible knowledge of moral, religious, and scientific kind. The first thinkers were Herbert of Cherbury, as well as Rene Descartes; other British representatives were Henry Lee, Claude Buffier, Henry Home, G. Leibniz, and many more (Redekop, 2009, p.407). Thomas Reid is considered a founder of the Scottish School of Common Sense, whose ideas influenced several generations of philosophers well throughout the 19th and 20th centuries. Rejecting the Theory of ideas, he claimed that it was â€Å"sensus communis† (the term Reid used to describe the â€Å"common sense†) that should be perceived as a solid basis of the philosophical quest. Reid’s main arguments on common sense revolved around his reaction to the ideas by Hume and Berkeley. Hume believed that a person can never comprehend what the world which is external for him/her consists of, since human knowledge is restricted by the ideas that are present in hu man mind. Berkeley, in his turn, maintained that the external world is just ideas inherent in human mind. Both Berkeley and Hume asserted that a mental phenomenon exists as perceptions of certain mental objects (Yaffe & Nichols, 2009, [online]). Contrary to these philosophers, Reid asserted that the foundations of common sense provide a justification to human belief in the existence of an external world. Reid provided response to the arguments by Hume, both naturalistic and skeptical by devising a set of common sense principles. He saw them as the basis of rational perception of the world and rational thought. To illustrate, any person who commits oneself to a philosophical argument must unconditionally presuppose particular beliefs. The examples are I am speaking to a real person, or the external world does exist under the laws which remain unchanged. Along these claims, more presuppositions can be found, which are all positive, meaningful, and reality-based. In this context, it is worth mentioning that Reid does not see the belief in these principles’ rightness as something rational. Instead, he asserts that it is reason that demands that the aforementioned principles act as prerequisites and that it is human mind that inherently produces them. Thus, the question of sanity arises here, which Reid believes leans back on his understanding of the common sense functioning. In relation to this, Reid writes, â€Å"For, before men can reason together, they must agree in first principles; and it is impossible to reason with a man who has no principles in common with you.† (Reid, 1846, p.230). Reid also believed that qualities are to be in â€Å"(...) Something that is figured, colored, hard or soft, that moves or resists. It is not to these qualities, but to that which is the subject of them, that we give the name body. If any man should think fit to deny that these things are qualities, or that they require any subject, I leave him to enjoy his opini on as a man who denies first principles, and is not fit to be reasoned with.† (Reid, 1785, p.766) While Reid’s position on common sense can be well understood through analyzing his criticism of Hume, I would like to briefly outline his ideas regarding Hume’s understanding of knowledge. As it has already been mentioned, Hume along with Descartes, Locke, and Berkeley developed the ideal theory of human mind, which Reid refuted by offering the positive idea of mind instead. The grounding argument against the theory by Hume is

Examples of Social Responsibility in Business

Examples of Social Responsibility in Business Ethical reasoning is a peoples thinking about right or wrong on human behavior or act. The author gave an example to understand human different approaches on situation under the concepts of duties, rights, and commitment. Morality is determined by the consequences of action. A consequences theory focusses on consequences of human action. Egoism cannot resolve conflicts of interest. The utilitarianism is the greatest amount of happiness for the greatest number. The author gave an example of firm that produced pollution as byproduct to its manufacturing process with both side of argument with government against business people to understand concept of ethics has nothing to do with business, nor business with ethics. The author gave Kantian (a business person) view of breaking a contract is not a moral act. All stakeholders be treated as persons, with respect for their individual dignity. A trust is the correct starting point for the derivation of ethical behavior enables the construction of practical ethics in business and other contexts. The H.B.Fuller is a company that manufacture sniffing glue. In Honduras, the children drugging themselves by sniffing glue. It was easy to get glue through H.B.Fuller company. Honduras faced some economic problems in effort to industrialize. The company has some option to reduce this problem. One was add mustard oil into glue or close the product. The government of Honduras must concentrate on children education to overcome this issue. The H.B.Fuller company was very reputable company and now they have to rebuild their image, moral and philosophy of company. The Milton Friedman gave his view on social responsibility of business is to increase its profit. In a free-enterprise, private-property system, a corporate management is an employee of the owners of the business. He argue that, executive a different social responsibility, rather than serving as an agent of the stockholders or the customers or the employees, only if he spends the money in a different way than they would have spent it. He described political principle under two different mechanism, which are market and political. The Friedman said that executive is exercising a distinct social responsibility, rather than serving as an agent of the stockholders or the customers or the employees, only if he spends the money in a different way than they would have spent it. The Freeman described basic idea of stakeholder that business and executive who manage them, actually do and create value for customers, employees and financiers. The Freeman said about stake is an interest or a share in an undertaking and can be categorized as interest, right and ownership. There are two types of business stakeholders. Primary stakeholders and secondary stakeholders. Primary stakeholders are those that have a direct stake in the organization and its success. Secondary stakeholders re those that have a public or special interest stake in the organization. The Freeman explained responsibility of the executive in managing for stakeholders with a different example. He also described some argument to manage stakeholders. One of the strongest arguments for managing for stakeholders is that it asks executives and entrepreneurs to consider the question of what kind of company they want to create and build. Italian federal corporate tax system has a legal tax structure and tax rates as U.S. system does. The Italian tax authorities believe that no any firms submit tax return. All firms lies about their income and fraud to Italian tax authorities. The Italian corporation is represented by its commercialista, a function which exists in Italian society for the primary purpose of negotiating corporate (and individual) tax payments with the Italian tax authorities. The Italian service did lying and fraud. The negotiation of corporate tax by Italian tax authority managed with commercialista and bustarella, it is wrong action to earned money. The author Bowie described three formulation of fundamental of ethics. Act only on that maxim by which you can at the same time will that it should become a universal law. The Bowie said that if everyone made lying promises, the consequences would be bad although they would. Rather, Kant is saying that the very concept of lying promises, when assumed as a principle by everyone, is confused. The Bowie gave two example to illustrate Kants view. If a maxim for an action when universalized is self-defeating, then the contemplated action is not ethical. That is Kants conceptual point.

The Significance of John in Brave New World :: Brave New World

The Significance of John in Brave New World In Brave New World, there are three societies: the civilized society of Bernard and Mustapha Mond, the savage society of John and Linda, and the old society, which is not explicitly in the book but is described by the characters. These societies are vastly different. The old society is 20th century Western society; the civilized society creates people and conditions them for happiness and stability; and the savage society is very far behind the civilized society technologically, and is very religious. John is a very important character in the novel because he represents the link between all three of these societies. John's mother was created in the civilized society and lived there until John was accidentally conceived. She had to move to the savage society, and John was born and raised there. John had a connection to civilized society from an early age from hearing stories from his mother. He also came across a book of Shakespeare and by reading it, learned about old society. These however, are just preliminary connections for the bridges that will soon be built. The adult John comes to civilized society as an experiment by Marx and Mond to see how a "savage" would adapt to civilization. Frankly, he does not adapt very well. He is appalled by the lifestyle and ideas of civilized people, and gets himself into a lot of trouble by denouncing civilization. He loves Lenina very much, but gets very upset at her when she wants to have sex with him. He physically attacks her, and from that point on does not want to have anything to do with her. When his mother dies, he interferes with the "death conditioning" of children by being sad. Finally, his frustrations with the civilized world become too much for him and he decides to take action. He tries to be a sort of a Messiah to a group of Deltas, trying to free them from the effect of soma. He tells them only the truth, but it is not the truth that the Deltas have been conditioned to believe, so to them it is a violent lie and they begin to cause a riot. When the riot is subdued, John is apprehended an d taken to have a talk with Mustapha Mond. This talk with Mustapha Mond is very enlightening for John, and it creates his connection with the old society.

Group Psychology Essay

Irwin Mansdorf in his article The Psychology Framework of Suicide Terrorism brings out another aspect of group psychology in an attempt to explain what has motivated various groups and their members to be involved in suicide bombing e disagrees with those portraying The Palestinians suicide bombers as desperate rot who are driven by their suicidal motives. He feels that individual psychopathology does not play any important role in this case. (Mansdart, I 2003) Group dynamics are responsible in reinforcing behavior within these people’s culture where those who carry out suicide bombing are seen as heroes where their faces are displayed in the open for every one to see and their immediate families are handsomely rewarded for their sons bravely and commitment to serve the community. The families are rewarded with great respect and financial considerations. (Bloom, M 2004) Suicide in the clinical sense may be directly related to personal psychological state at the time of committing the acts. In the case of suicide of suicide bombing, Irwin has observed that there is no close relationship with personal clinical psychopathology. He believes hat these people are drawn by the political and nationalistic aspects advocated by their groups. (Mansdart, I 2003) Kamikaze pilots used this tactic to attack American in the pacific during the Second World War. Several researches carried out have not pointed that the pilots were suicidal rather they are seen as people who were driven by a strong desire to fight for their country. They never at any time display any signs of abnormal behavior which could have led to suicide. The letters Kamikaze pilots wrote to their families show that they were calm and in a peaceful state before they carried out the misson. Their expectations beyond death served as the motivational factor for them to fight the enemy knowing that they have served the nation and they will be heavily be rewarded in the life after. (Mansdart, I 2003) A closer look at the Tamil tigers brings out the same picture; the group has been responsible for the most suicide bombing carried out by any organization in the world. Those who carry out these activities are fighters who have are well trained and fully dedicated to their cause. In all the cases the group chooses volunteers based on their record as fighters. Those who are involved in the suicide bombing are not described as victims of any psychological condition which can drive them to volunteer to participate in this activity but rather they are drawn by great dedication to serve their group and to a large extent liberate their people from the yokes of occupation. (Bloom, M 2004) In most cases of suicide bombing according to Irwin observation the purpose of mission is rarely due to desperation or hopelessness. The suicide bombers were focused drawing inspiration from nationalism and large the group identity. Irwin explains that group pressure and identity inspires a suicide bomber into action. They are manipulated ,brainwashed and made to believe that after carrying out the mission they will be honored as martyrs, their families will be recognizes and reward greatly. The recruits are never allowed to leave denying the m an opportunity to back down from the mission. (Mansdart, I 2003) Recruitment The number of organizations carrying out attacks has increased in the recent past. These organizations are found in almost all the corners of the world. This increase also means the number of recruits needed to carry out the suicide attacks is on the rise. According to the latest statistics more than forty countries in the world have experienced suicide bombing attacks since 1980s. It is estimated that there are sixty known groups which employ suicide bombing as a fighting technique. (Reuter, C 2004) Despite an increase in the number of organization employing this tactic, there have been no shortages of people of people who are willing to put their lives on the line for the sake of the organization or cause they believe in. There has been an upward surge in the number of suicide bombings in the recent past, this means that the number of people who are willing to die for what they believe in has also increased. (Kramer, M 1991) Recruits in suicide bombing are drawn from a variety of backgrounds. There has been a perception that people who are involved are usually psychopaths, insane or poor but this is not the case. Most of those who have been recruited are usually well educated, relatively rich. These are people who ready to sacrifice their lives for a cause and are more than willing to go to any length to kill themselves. In the recent past trends have been changing where even children have been involved in suicide bombings. As the Middle East conflict escalate militants groups in Palestine are actively involved in recruitment of young people. One of the groups Al aqsa-intifada has been actively involved in the recruitment of children as suicide bombers. Other groups which have been employing the same mode are the Popular Front for Liberation of Palestine, Fatah, Hamas and Islamic Jihad. Hamas are known to run kindergartens, where children are taught all the tactics and the need to sacrifice their souls for the sake of their people. These children in the kindergarten are made to believe that they are the holy martyrs in making. (Shay, S 2003) There are several factors that qualify one as a recruit for suicide bombing recruit. A number of organizations in the Middle East take into consideration ones religion. It has been noted that almost all the recruits who have participated in the Palestinians suicide bombings are staunch Muslims. Once a new recruit is taken in especially children they are taken in for an intensive training which involves reciting of the Koran. Therefore knowledge of Koran becomes very crucial in taking in the recruits. Criminal record also plays a significant role in the selection of those who are to take part in any given task as far as these groups are concerned. Those who have a clean criminal record are first considered for the task, this is because they attract little attention from the authorities therefore carrying out their mission successfully. (Reuter, C 2004) This is a policy that has been employed by the Hamas and the Hezbollah groups of the Middle East. (Noval, M 1999) Most of the organization rely on volunteers to carryout their missions, when the current Iranian president Mohmoud Ahamedinejad came into power he appealed to the youth from the Muslim countries to come forward and help in fighting Israel and United States. Most other terror groups appeal to their members to volunteer and get trained as suicide bombers . In the Palestine there are many youth who are willing to volunteer, these people may be driven by the promises made or purely to fulfill their religious obligation as spelt out in the recruiting organizations. Most of the suicide bombers are selected at an early age, educated and then set off to carry out their duty when they are just about in their twenties or in their late teenage years. Those who a re recruited are normally encouraged to cut themselves from the outside world as they are subjected to the intense training and recitations of the holy book to prepare them for the task ahead. Governments also sponsor some of the groups involved in the suicide bombings where those who participate are given monetary rewards. Iranian president is on the record urging his countrymen to come out and be trained for a fight with the western powers. Those who volunteered were promised compensation for the families and great honor once they have successively carried out the mission given. There have been considerable involvement of the Iranian government in the training of the terror outfits; a training center was opened when Ahamednijad came into power. This center which came to be known as the Lovers of Martyrdom Garrison has been involved in recruiting and training of suicide bombers who according to the Iranian president are to help in fighting the western powers who have occupied the Muslim territory. The volunteers’ suicide bombers have been equated to nuclear bombs owned by the United States and Israel and they are meant to cause wanton destruction against the enemy. Conclusion Suicide bombers are just as ordinary people, but there are forces within them which make them carry out their missions. These forces range from desparation, nationalistic ideals or religion. Debate on what makes a suicide bomber tick will continue for a long time as different people will see different motives for a given group of attackers. As far as those factors which breed terror remain with us suicide bombing will continue to be with us for a long time, attracting much attention from different scholars whose aim is to understand the factors behind these daring acts. References Radu, M (2004) Radical Islam and Suicide Bomber, Retrieved from http://www.fpri.org/

Innovative Hr Practices by Organisation Across Different Sectors

Innovative HR Practices by Organisation across Different Sectors Introduction Companies are taking up people-related initiatives as there is a need to manage human resources advantageously, so as not to lose the competitive edge in talent that they have built. In managing their human resources, companies have time and again focused on values, invested in personnel, emphasized on meritocracy and consequently attaining excellence in HR processes. Innovative Practices of Recruitment and Selection * Second career Internship Program: Tata SCIP was launched in March 2008 on International Women’s Day . It is a career transition management programme for women professionals who have taken a break of 1-8 years for any reason, and wish to re-enter the professional space. * Holding on to the employees Quatrro BPO Solutions has nurtured a concept of keeping in touch with high performers who leave the concern and hone in them, whenever they want to come back. * Making use of pre hiring Process: Genpact, the BPO pioneer, uses a pre-hiring process to aid in arresting attrition. The organisation brings people before they join, and have them look at the workplace. If the people choose to join, that reduces potential attrition. * Checking the Profile on Social Networking Sites: Organisations are pursing the candidate’s profile on sites such as Face book and LinkedIn. Once a candidate applies, his social behavior is traced. The persons social Skills decide if he fits the job. This practice has also started in India. Innovative practices of Reward and Recognition In today’s competitive world, rewards and recognition plays an important role in motivating and retaining employees. Rewards and recognition is an important part in every HR plan these days. Rewarding the high performing and motivating others to become such is becoming mandatory in IT & BPO industry. 1. Giving Store Vouchers like Shoppers stop, life style etc. 2. Giving cash prizes. 3. Giving articles (wide range of durables as per the level of performance). 4. Organizing holiday trips. 5. Article Gifting Innovative Practices of Motivation Giving Freebies Every weekend, people working at Coco-Cola India’s Gurgan Head quarters received for liters of company beverages free in a program called weekend funda * Providing Dependent Insurance The biggest employee benefit, HSBC provided to its employees was 100% hospitalization benefit for employees Spouse and children. * Offering Stock Options iGate is among a few firms, that has continued to offer stock options to its employe es. There are longterm investment measures for weeding, families, even retirement. Making use of Music Raymond Limited Hosted Music events to its employees. Dream Circle is a group of people with different skill set who play percussion instrument in freestyle but produce a harmonized rhythm in the end. * Treating as Guest: At Marriot Hotels India, The employee usually join the hotel in the batches. The hotel grates six off days every month, something uncommon for the hotel industry and there is also excellent system of compensatory off, * Launching Employee Assistance Program HSBC initiated the Employee Assistant Program(EAP) to assist in coping with trauma and stress post 26/11. Innovative Practices of cost Cutting * Offering Sabbatiacal Package * Offering VRS * Compulsory Leaves Innovative Practices of Traning * Providing Classroom Curriculam * Empowering Young Executives * Encouraging a culture of Innovation * Watching Film Conclusion To conclude, it can be said that those companies that have invested considerable time and resource in building a solid human capital management foundation are better positioned to weather the strom.

Making Effective Oral Presentation Essay Example

Making Effective Oral Presentation Essay Example Making Effective Oral Presentation Essay Making Effective Oral Presentation Essay Making Effective Oral Presentations Northeastern University, College of Business Administration Edward G. Wertheim, Ph. D. Associate Professor Human Resources Management Retrieved March 2, 2009 from http://web. cba. neu. edu/~ewertheim/skills/oral. htm#visual |Outline of this Note | |Introduction | |Podium Panic | |Four Basic Steps | |1. trategy | |2. structure | |3. style | |Are You Distracting the Audience and Drawing Attention away from your Message? |Regional accents or colloquialisms: (or Id rather jump in the Boston Hahbah than give a speech) | |Physical mannerisms | |Voice Tone | |Keeping your Audiences interest | |4. upplement: questions and challenges | |Conclusion: A Checklist for your Presentation | |Appendices | |[pic]An Outline for Your Presentation | |[pic]An evaluation form that will be used for your presentation | |[pic]Using Visual Aids Effectively | | Introduction While hard work and good ideas are essential to success, your ability to express those ideas and get ot hers to join you is just as important. Much of this verbal expression will be one on one or in small groups but periodically (and for some of us often) you will be involved in more formal and public speaking in front of larger numbers. If this thought makes you nervous you are not alone. Many speakers lack the skills and confidence to make effective presentations. We have all been victims of speakers (eg. teachers) who put us to sleep. Despite knowing how ineffective many speakers are, many of us have found that, despite the best intentions, we havent fared much better. We knew the topic and the ideas were written down, but the presentation still didnt go well. Was it the way you delivered the speech? Was it because the audience didnt seem interested? [pic]Podium Panic Everyone experiences stage fright, speech anxiety, or talking terror. Surveys show that fear of speaking in front of groups is one of the greatest fears people have. Some surveys find people actually claiming that the thought of giving a speech is more frightening than falling off a cliff, financial difficulties, snakes, and even death. The following lists some techniques people use for coping with this fright: your audience understands your nervousness; they know what you are feeling and will forgive it; similarly they will forgive honest mistakes nervousness is usually invisible; most will not notice the small changes in your voice or occasional mistakes; most speakers who describe themselves as nervous appear confident and calm to the audience be yourself; let the real you come through; relax, practice some deep breathing techniques; begin in your comfort zone; practice with friends; share your fears with friends check out the room first; check out the space, the equipment, the lights concentrate on the message begin with a slow, well-prepared introduction; have a confident and clear conclusion most important: be prepared and practice The problem of poor communication is complex and cannot be solved by a single book, a course, and certainly not by this short guide. We will point out the critical elements and questions to think about. The approach presented here is predicated on the notion that there is a speechmaking process that involves a few basic steps and within each are particular strategic decisions. [pic] FOUR BASIC STEPS formulate a strategy for the specific audience develop a flexible, flowing structure combined prepared material with an enhancing, not distracting, presentation style; it is important to remember that how you present is as important as what you present. supplement the presentation with confident, informed responses to questions and challenges [pic] 1. STRATEGY understand your purpose and role: It is critical to be clear about your purpose in the communication. This involves knowing your audience, the occasion, and the expectations of your audience. Knowing the audience will be a criti cal determinant in what information is presented and how it is presented. tailor your message to the audience understand their needs, desires, knowledge level, attitude toward your topic be concrete, specific, practical, and relevant clarify your objectives is it to motivate? inform? persuade? teach? each calls for a different approach clarify what role you will be performing coach? advocate? teach? be devils advocate, watch dog, or messenger? develop a logically compelling case for your plan how will it help resolve a pressing problem, advance a salient value, or help reach a common goal research your topic In the classroom situation you may have to make a presentation about a topic about which you are not an expert In the working world, you will likely know a lot about the topic. Nevertheless, you will likely have to research the topic through internal trade documents, trade journals, or special interest publications. You will also likely find computerized data bases useful as sources of information. Subscription data bases such as CompuServe, Dow Jones News/Retrieval, The Source, and BRS/After Dark are some examples. Obviously the World Wide Web is a gr owing source of information. Librarians will assist you in your search. For those services that base charges on time on-line, it is important to be very well prepared for your search. [pic] 2. STRUCTURE Once you know what you want to say, you need to consolidate the materials into a meaningful message. You cant assume that the information will speak for itself. Your audience is capable of hearing your information in very different ways based on your organization and presentation. The audience needs to have these basic questions answered. 1. Why should I pay attention to you when I can think about more interesting things? 2. Now that I am listening, why should I care about this issue? 3. I agree with the significance of the topic, but how are you justifying your ideas? 4. So, now that I am convinced, what do you want from me? The following lists some points to think about when organizing your ideas begin by placing your topic in context; you might want to provide an outline or a road map provide the intended, expected benefits, organization of the presentation, and ground rules organize the body of the presentation logically make it easy to follow go from the simple to the complex when appropriate, plan ways to encourage audience participation maintain credibility: discuss the pros and cons conclude on a high note include an overall summary and proposed actions or options incorporate visual aids effectively (see box below) dont let mechanics of presentation interfere with your message prepare for contingencies practice your presentation and prepare for contingencies rehearse think about what might happen and prepare what if the overhead bulb blows ou t; what if the audience is more prepared than you expected what if there is an unexpected question if a disruption is particularly obtrusive, you might relieve the tension with a joke or humorous comment [pic] 3. STYLE Effective presenters recognize that communication is both intellectual and emotional. Organizing your ideas is part of the task. The other is to gain and maintain attention. The following lists some basic techniques to maintain attention: convey controlled enthusiasm for your subject the audience will forgive a lot if the speaker is enthusiastic -pay attention to posture, tone; dont lean your audience will mirror your attitude radiate confidence without preaching dont confuse enthusiasm with loudness; try to convey a range of emotions from concern, anticipation, excitement, dismay where appropriate, candidly discuss pros and cons; explain advantages first; present risks or challenges; Are You Distracting the Audience and Drawing Attention away from your Message? When we want the audience to focus on what we have to say rather than on us, it is important to think about anything that might detract from our message. This can be a sensitive issue since some of these facto rs are personal or part of who we are. Regional accents or colloquialisms: If we are in an audience of people who share our accent no one will notice. However, if we are in a more general audience, our accent may make the audience focus on this rather than our message. This is not to say that you should abandon your ethnic or regional identity and individuality; however, you need to be aware of the impact of accents on audience. This can be done positively as the Kennedys have done; but more often these mannerisms tend to detract negatively. We dont have to all talk alike but we need to know how we are perceived. physical mannerisms: speakers who pace, pound the podium, jingle change in their pockets, or do other things can focus attention on themselves rather than the subject; sometimes this can be done for affect, but more often it is inadvertent and distracting. voice tone: Professional speakers generally emphasize the lower registers of their voices (both men and women) and avoid dramatic variations in the pitches of their voices. Occasionally this rule can be broken for affect. clothing and jewelry: same as under regional accents Keeping your audiences interest provide variety and relief if possible; novelty and uniqueness will increase the impact alternative moving and standing still, speaking and listening, doing and thinking; use physical space and body movement to enhance your message try to add s tories, anecdotes, testimonials, analogies, demonstrations use humor appropriately make it in good taste presentations are movies not snapshots; prepare the space for movement try to position yourself to enhance rapport with the audience eye contact is your primary tool for establishing audience involvement; look at your audience in random rotating order use gestures naturally; do what is natural to you: some gestures are wrong jingling change in a pocket, toying with notes, shifting from one foot to the other; any repeated gesture Once you obtain attention, you must retain it. Audiences members drift in and out, without giving complete attention all the time. You need to help the audience refocus periodically. The following are some examples: I will give the three basic reasons why change is needed Transitions such as now that we have analyzed the problem, we need to look at the possible solutions. Conclusions: the discussion so far leads to this final thought Straightforward Conclusion: if you enact this program, three basic benefits will result [pic] 4. SUPPLEMENT: QUESTIONS AND CHALLENGES USE OF QUESTIONS ask friendly questions dont use questions to embarrass or badger; avoid known sore spots avoid asking risky questions that is, questions that may imply lack of knowledge or intelligence make the interchange a mutually satisfying experience; ive respondents time to think and phrase their answer; help people save face by summarizing what they have said so far and asking if anyone else has something to add dont let respondent wander or attempt to take control of the presentation; a polite thank you, thats what I was looking for can get you back on track if extensive audience d iscussion is desired, avoid isolated one-on-one dialogues with specific individuals when challenged, be candid and firm but avoid over responding maintain control of the session be firm and assertive without being aggressive or defensive dont let interruptions disrupt your composure avoid circumstances that require an apology anticipate questions and prepare responses; rehearse answers to difficult questions if necessary, offer to obtain additional information and follow up use questions to strengthen your main arguments-answer questions candidly but positively link objections to attractive features avoid rhetorical questions ask interesting questions that are thought provoking but not too difficult to answer ask some open ended question with no right or wrong answers encourage sharing experiences, feelings, opinions put you elements into questions make them relevant to the audiences personal experience prepare key questions prior to the presentation; it is difficult to think of good questions on your feet Guideline for Answering Questions | |Anticipate Questions: think of the ten most likely questions and plan out your answer | |Understand the Question: paraphrase it if necessary; repeat it if needed | |Plan the Answer: particularly if you anticipated the question | |Do Not Digress | |Be Honest: if you cant answer the question, say so | |Reinterpret Loaded Questions: if attcked try to show the similarity to other situations | |Control Interchan ges: if a questionner becomes a heckler try to enlist the audience; if a questioner digresses, try to remind | |the audience of the goal of the presentation | |Use the Last Question to Summarize | [pic] Conclusion: A Checklist for your Presentation You owe your audience and yourself a good presentation, but creating an effective presentation takes planning and practice, so some final pointers Start preparing early; dont wait until the last few days to prepare prepare it early, let it rest a little bit and come back to it practice your entire presentation-including your slides if you can practice it before a group of colleagues or friends Think about Your Audience: who are they and why are they here; what are their interests; what do they know; what do they want to know; what is a worthwhile investment in their time Be clear about your purpose: are you informing or persuading; tell them what you are going to do, tell them, tell them what you told them; what do you want the audience to know, feel, or believe afterwards Use an Effective Introduction: orient the audience; explain why it is important; set the tone, establish a relationship between the speaker and the audience; establish credibility; avoid weak introductio ns such as apologies, jokes, rhetorical questions Organize your presentation clearly and simply: Prioritize topics and allocate time accordingly stick to only 3-5 main points; have a well thought pattern (examples are problem/solution, chronological, cause and effect, topical); use transitions to move smoothly from one point to the next Use supporting materials to flesh out main points Use examples, statistics, expert opinions, anecdotes Compose for the Ear, not for the Eye: use simple words, simple sentences, markers, repetition, images, personal language (You and I) Create an Effective Conclusion: summarize, set final image, provide closure; dont trail off, dont use trite phrases dont just present data or summarized results and leave the audience to draw its own conclusions you have had much more time to work with your information than your audience; share your insight and understanding and tell them what youve concluded from your work Sound spontaneous, conversational, enthusiastic- use key phrases in your notes so you dont have to read, use the overhead instead of no tes; vary volume, dont be afraid of silence, dont use fillers like um Practice, Practice, Practice Use Body Language Effectively: relaxed gestures, eye contact; dont play with a pen or pointer, dont block visual aids Use Visual Aids to Enhance the Message: you will probably need to use overhead transparancies in your presentation but to be effective, they must be designed and used properly use visuals to reinforce and clarify, not overwhelm; keep visual aids uncluttered; use titles to guide the audience if you use tapes or disks, make sure the equipment is compatible Analyze the Environment: check out size of room, placement of chairs, time of day, temperature, distractions check out AV equipment ahead of time; have a spare bulb Cope with Stage Fright by Remembering: its normal; it can be helpful, everyone feels it [pic] Engleberg (1994) proposes a 7 P approach to the principles of public speaking. You might find these helpful. Purpose:- Why are you speaking? What do you want audience members to know, think, believe, or do as a result of your presentation People : Who is your audience? How do the characteristics, skills, opinions, and behaviors of your audience affect your purpose Place: Why are you speaking to this group now and in this place? How can you plan and adapt to the logistics of this place. How can you use visual aids to help you achieve your purpose Preparation Where and how can you find good ideas and information for your speech? How much and what kind of supporting materials do you need. Planning: Is there a natural order to the ideas and information you will use? What are the most effective ways to organize your speech in order to adapt it to the purpose, people, place, etc. Personality: How do you become associated with your message in a positive way? What can you do to demonstrate your competence, charisma, and character to the audience? Performance: What form of delivery is best suited to the purpose of your speech. What delivery techniques will make your presentation more effective. How should you practice? Further Reading Antonoff, Michael, Presentations that Persuade, Personal Computing, 27 July 1990, 60-68. Benjamin, James and Raymie E. McKerrow, Business and Professional Communication, Harper Collins, New York, 1994. Engleberg, Isa N. The Principles of Public Presentation, Harper Collins, New York, 1994. Osborn, M. and S. Osborn, Public Speaking, Houghton-Mifflin, Boston, 1988. [pic] Supplemental Information [pic] An Outline for your Presentation INTRODUCTION What? overview of presentation (use visual aids if necessary) Why? purpose of presentation why subject is important How? format you will use; what can the audience expect to see learn Who? if more than one person, provide introductions and indicate roles dont expect audience to memorize these BODY The following list suggests alternative formats for presenting information: multiple formats can be used within a single presentation: rhetorical questions and answers logical progression indicate steps e. g. A then B then C time series order information from beginning to end, earlier to later, and so on compare and contrast use same structure to compare different events, individuals or situations problems and solutions; dont present problems without working toward some recommended action simple to complex use successive building blocks to communicate complex processes or concepts deductive reasoning moving from general principles or values to specific applications or examples inductive reasoning from specific applications/examples to reach general principles or conclusions CONCLUSION review, highlight and emphasize key points, benefits, recommendations draw conclusions where are we? what does all of this mean? whats the next step? [pic] USING VISUAL AIDS EFFECTIVELY. PURPOSE both quality and number of visual aids should enhance, not distract from message display or distribute an outline to help audience follow long or group presentations use variety to increase intere st; remember the value of pictures, graphs, symbols and objects APPEARANCE never use a transparency of a typewritten page use a plain font (e. g. Swiss or Helvetica) of substantial size (18 point or more) if you use color, dont use more than three colors ask yourself Can the audience quickly and easily grasp what they see? Are they spending time reading and not listening? FORMAT-TEXT make one and only one key point per visual unless the audience is very familiar with the subject organize material into natural categories and contrasts? before vs. after, problem and solution, advantages vs. disadvantages, beginning to end; costs vs. benefits include no more than three or four points under one heading dont use whole sentences or paragraphs use bulleted words or short phrases only, except for quotes FORMAT-GRAPHS no more than three curves on a line chart or graph dont use a page full of numbers translate complex numbers into representative pie charts or bar graphs use diagrams or models to present complex concepts; use multiple charts illustrating different stages or parts of the full model; start with simple framework and build components successively into the full model or process [pic]Properly Designed Transparencies use high quality lettering at least 3/16 high; avoid hand-written slides and low resolution dot matrix print limit the number of overheads used; allow at least 1-2 minutes per overhead a well designed diagram or chart can often make your point more quickly and clearly than words avoid visual clutter-dont over use fancy graphics that might distract the audience have a good reason for showing each and every overhead Be Careful: dont block the audiences vision; limit the time your back is to the udience make sure you know how to operate the equipment; prac tice it ahead of time; have backup cords, bulbs, adapters, etc; prepare for the worst make sure you know the lighting requirements for your equipment; know where the switches are and what settings are needed; bring a small penlight in case the room has to be darkened and you need to see notes or equipment [pic] Group Presentation Evaluation Form (ver. 5) Rate the Group Presentation (5= Excellent; 1= Poor NA= not applicable) Comments would be very helpful. Group Number:____ Group Topic:________________________________ ____1. Introduction: Did the introduction capture your interest; was necessary background given; was a clear purpose conveyed ___2. Organization: Was there a clear organization; were transitions between sections clear and effective; did the organization lead to a clear conclusion? ___3. Content: Did the group support their points; was the supporting material relevant, up to date? ___4. Visual Aids: Were visual aids used effectively and appropriately, carefully prepared? ___5. Conclusion: Were key points reinforced; was a sense of closure provided; if appropriate, was a course of action proposed? ___6. Delivery: Were the speakers natural, enthusiastic; did they speak clearly; were appropriate gestures, posture, expreesions used ___7. Discussion: Were questions answered accurately, clearly, effectively? ___8. Overall Rating General Comments (use back): [pic] Presenting Overseas An American woman making a presentation to a group of German male colleagues began in a casual, lighthearted style. Several of the men snorted, stood up and headed for the door, declaring her presentation a waste of time. She spoke loudly and sharply, telling them to sit down and be quiet. They did, and she switched to an assertive, formal tone without qany of her fun techniques. The Germans paid attention. International Hearld Tribune, May 20, 1997 This anecdote illustrates that doing business internally requires concise, to the point yet diplomatic communication due to the lack of time to build relationships and sell ideas. International execuitives have to discipline themselves to listen completely and ask questions; this is particularly important when not everyone in the room has the same native language. A particular problem for many is the niceness problem; these occur when nice people are shocked to see how aggressive top-level communications and team communi ations can be in some places, and when they cant cope with aggressive peers. Another problems is conciseness. Many of us are trained to give an introduction, body, and conclusion and the mroe you say the better. In some places there is no patience for this slow, gradual building. In this case, you need to make the point first, prove it concisely and make recommendations.

Studying for an exam - Smart Custom Writing Samples

Studying for an exam - Smart Custom Writing Literary Analysis of the Unbearable Lightness of BeingThe Unbearable Lightness of Being is a book written by Milan Kundera and published in 1984.   It is a compelling love story, a must-read that is both touching and sad. This is a novel whose context is set in the late sixties up to the eighties in the communist run Czechoslovakia. It basically explores the themes of love and politics through an in-depth use of various literary devices such as symbolism, imagery and allegory. This has been widely discussed in here-in under the crucial theme of fate in relation to love. In evaluating the literary device of symbolism, imagery and allegory, the concept of lightness, weight and eternal return is well brought out by the German phrase ‘es muss sein’ which implies ‘it must be.’ Kundera explains the origin of the phrase as a motif from the Beethoven's songs. It came up when Tomas was debating after Tereza left him in Zurich as to whether to return to Prague. He phrases the term to his boss since he feels it is beyond his control, induced by fate and he has no choice but to follow Tereza. Fate, as a concept in light and weight, alludes or simplifies Nietzsche's ideas in ‘What's Up with the Title?’ in which Nietzsche alleged that people can attain eternal return and the burden of weight associated with it. Therefore, ‘es muss sein’ is highly relevant in this context since Kundera views Beethoven as a weighty person alluded by the ‘frown’ and ‘improbably mane.’ Further, he is one of the great loves of Tereza who is associated with heaviness and weight. Tomas learns about his music only through Tereza. Tomas feels that Tereza is part of fate and his ‘es muss sein’ and chooses to return to Prague to prove this. He analyses his relationship with Tereza on his way back and identifies six fortuitous events that precipitated their relationship, hence the reference to Tereza as ‘the woman born of six fortuities’ in the novel. This greatly worries him since they could be together by chance, referring to this as 'es konnte auch anders sein' rather by fate. This, is later challenged in Tomas’ thinking as illustrated by his musings on that if fate repeatedly points at a certain event, then the event must be sufficiently ‘significant and noteworthy.’ This is an implication that what happens by chance is a result of the need for necessity which is what is repeated further implying it belongs to the sphere of eternal return. Thi s further contrasts the lightness versus weight dichotomy since he further wonders that the events that occur by chance only once also have an implication. This struggle with the concept of fortuity is further illustrated in chapter five whereby Tomas deliberates on his profession as the narrator phrases: "He had come to medicine not by coincidence or calculation but by a deep inner desire." Kundera also illustrates ‘es muss sein,’ or fate by Tomas’ womanizing habits which he feels is an imperative enslaving him. After a night of erotic dreams and stomach pains, Tomas finally declares that Tereza is the ‘es muss sein’ of his love, though he still cannot control his womanizing habits. He finally comes to the conclusion that love lives beyond ‘es muss sein.’ Therefore, the dichotomy of weight versus lightness is well illustrated since on one hand, Tereza wants Tomas to give up his philandering lifestyle and commit to her but on the other h and, Tomas feels Tereza is in the realm of lightness since she is born of fate rather than compulsion. The literary device of symbolism, imagery and allegory can be furthered by the bowler hat. Kundera mentions that the bowler hat signifies several aspects in philosophy. First, Kundera explains that it signified violence against any woman’s dignity such as Sabina. From Kundera’s point of narration, the lingerie is depicted as enhancing the ‘charm of her femininity’ while the bowler hat, seen as hard and masculine, ‘violated and ridiculed it.’ Further, he depicts this humiliation as seen through Tomas who stood just stood beside her, fully dressed. Sexual humiliation in Kundera’s Unbearable Lightness is illustrated by both Sabina and Tereza. They harbor secret desires to be degraded by the men they have had sex with, For instance, Tereza wants the engineer to watch her go to the bathroom after sex, a desire also expressed by Sabina. With the iteration of certain words, the bowler hat can be therefore seen as a symbol of sexual degradation which contrary to the reader’s thoughts is voluntary and longed for by the women characters in the book. Secondly, Kundera explains that the bowler hat was memento which reminded her of her father. After the death of her father, she adamantly refuses to ‘out of sovereign contempt to fight for her rights’ or to have anything else except the bowler hat. Sabina’s relationship with the father is strained and complex. She feels that the kitsch or ideas instilled by her father during her childhood should be betrayed. She refused to fight for her inheritance; hence the bowler hat in this case alludes to her betrayal and desertion of her father. In conclusion, it is crucial to note that Milan Kundera's The Unbearable Lightness of Being is highly successful due to the fact that he is able to create an exchange between his ‘skeptical critical intelligence and his belief in the autonomy of his fictional characters’ (Andrews). The writer adopts a point of narration whereby he avoids all interior monologue and instead draws attention persistently to its fictiveness and the ability to display the characters imaginatively without resulting in soliloquy.  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Andrews, Diane. "Critical Essay on The Unbearable Lightness of Being." Novels for Students. Detroit: Literature Resource Center, 2003. Barnard, John. "The Unbearable Lightness of Being: Repetition, Formal Structure, and Critique." Contemporary Literary Criticism Select. Detroit: Literature Resource Center, 25 January 2003. Kundera, Milan. The unbearable lightness of being. HarperPerennial, 1984.

Pregnancy and Humans in Space

Pregnancy and Humans in Space No matter where they live, many people eventually end up having kids, even in some of the most out-of-the-way spots on the planet. But, will they be able to live and work in space and have children? Or on the Moon? Or on Mars? Humans being humans, they will very likely try. Whether they succeed or not depends on a lot of factors. One vision of Mars habitats that will provide shelter for astronauts as they learn to explore the planet. Eventually, they could be raising families on the Red Planet, in more extensive habitats that may well be underground. What will those children be like?. NASA As humans prepare for a future off Earth, mission planners are finding answers to a number of questions about long-term space residency. One of the most perplexing is Can women get pregnant in space? Its a fair one to ask since the future of humans in space depends on our ability to reproduce out there. Is Pregnancy Possible in Space? The technical answer to that question is: yes, its possible to become pregnant in space. Theres nothing known about being in space that would prevent egg and sperm from uniting to make a baby. Of course, a woman and her partner need to be able to actually have  sex in space  in order to for those cells to get together in the first place. Additionally,  both she and her partner must  be fertile. Cycles infertility can be checked, and the mom and dad could then choose the right time to make that space baby. However, theres more required than doing the deed. It turns out there are significant other hurdles that stand in the way of having what it takes to make a baby and then  remaining pregnant once fertilization takes place. Barriers to Child-bearing in Space The primary problems with becoming and remaining pregnant in space are radiation and low-gravity environments. Its important to understand both.  Ã‚   The Moon has practically no atmosphere and no way to filter out harmful radiation. Humans living there would face some radiation danger from solar particles and cosmic rays. This could have a profound effect on a couples ability to start a family.   NASA Radiation can affect a mans sperm count, rendering him infertile, possibly permanently. It can also harm a developing fetus. Radiation hazards exist here on Earth, too, as anyone who has taken a medical x-ray or who works in a high-radiation environment knows. Its why both men and women are usually supplied with protective aprons when they get x-rays or other diagnostic work. The idea is to keep stray radiation from interfering with egg and sperm production. Once an embryo is created, its subject to the same radiation dangers as the mother. Conditions that Could Interfere with Pregnancy Lets say that conception happens after a couple gets together on the space station or during a trip to Mars or even after they land on the Red Planet. The radiation environment in space (or on Mars) is severe enough that it would prevent cells in the fetus from replicating. Thus, no baby would be brought to term.   Mars has a thicker atmosphere than the Moon, but it still is not enough to shield humans from radiation. This is another place where humans could face difficulties conceiving and birthing children. Credit:NASA/JPL-Caltech/MSSS In addition to the high radiation, astronauts live and work in very low-gravity environments. The exact effects are still being studied in detail on lab animals (such as rats). However, its very clear that a gravity environment is needed for proper bone development and growth. When astronaut Scott Kelly (and others) spent long periods on the International Space Station,  they showed significant changes in their health. Similar issues could affect a developing fetus. Such atrophy is why astronauts have to exercise in space regularly in order to prevent muscle atrophy and loss of bone mass. A growing embryo or fetus could be permanently altered, right down to the DNA. Solutions to the Radiation Problem Clearly, if people are to venture out into space on a more permanent basis (like extended trips to Mars) radiation hazards need to be minimized, not just for the adults but for any possible children born on the trips.  But how to do that? Astronauts taking extended trips into space will be on ships that are likely not to provide the heaviest radiation shielding. Once they get to Mars, for example, theyll be subjected to a lot of radiation on the surface that is not stopped by the thin atmosphere. Also, the lower gravity on Mars (and on the Moon, for those who migrate there), will be an issue.   The Orion crew capsule (shown here in water recovery testing) is a typical crew-carrying spacecraft that is shielded to protect astronauts from most radiation. Special precautions and materials must be used to protect crew members. Future spacecraft will need similar protective environments. NASA   So if permanent residencies are ever going to exist on Mars or the Moon, like those proposed by Dr. Mae Jemison for the  Hundred-year Starship, then better shielding technology would have to be developed. Since NASA is already thinking of solutions to these problems, its likely that radiation will cease to become as big a threat as it is now. Overcoming the Gravity Problem The problem of a lower gravity environment may be more difficult to overcome if humans are to successfully reproduce in space. Life in low gravity affects a number of body systems, including muscular development and eyesight. So, it may be necessary to supply an artificial gravity environment in space to mimic what humans evolved to expect here on Earth. The good news is there are some spacecraft designs in the pipeline, like the Nautilus-X, that employ artificial gravity designs. These use centrifuges that would allow for at least a partial gravity environment on part of the ship. Anyone who has ridden a ride such as the Mission Space experience at Disney Worlds EPCOT center has felt the gravitational effects that a centrifuge can supply.   The problem with such designs is that they cant yet replicate a full gravity environment, and even then occupants would be constrained to one part of the ship located in the centrifuge. This would be difficult to manage. Further exacerbating the problem is fact that the spacecraft needs to land. So what do people do once on the ground in a low-gravity environment on a place like Mars? The Future in Space: No Kids in Space Yet Ultimately, the long-term solution to the problem is the development of anti-gravity technology. Such devices are still a long way off. However, if spaceship technology could somehow manipulate gravity then it would create an environment where a woman could carry a fetus to term. Until that is a possibility, humans going to space currently are very likely using birth control to prevent stillbirths and miscarriages. If they are having sex, its a well-kept secret. But there have been no known pregnancies in space.   Nonetheless, humans will have to face a future that includes space-born and Mars- or Moon-born children. These people will be perfectly adapted to their homes, and oddly enough- the Earth environment will be alien to them. It will certainly be a very brave and interesting new period in human history!   Edited and updated by Carolyn Collins Petersen.

Global Marketing in the Context of National Environmental Issues Essay

Global Marketing in the Context of National Environmental Issues - Essay Example Formerly known as Warburtons’ the Bakers, Warburtons Ltd. is a producer and distributor of bakery products founded by Thomas Warburton in 1876 in Bolton, the United Kingdom. Warburtons is the strongest grocery brand after Coca Cola in the UK (Nielsen, 2010). It is a family owned business selling over 2 million bakery products daily. According to the chairman of the company, Jonathan Warburton, "From the wheat we grow to the flour we select to the bread we bake, we care because our name's on it". Company’s annual return is estimated at over ? 411 million, and employs over 4,200 staff across 13 bakeries and 11 depots positioned throughout UK (IBM, 2008). Warburtons is heavily investing in marketing and product development, and has recently launched a new ?8.2 million cross-media marketing campaign to achieve ?1 billion revenue target through product diversification and international ventures (Ingredients Network, 2012). This paper attempts to develop a competitive and sus tainable marketing strategy for expansion of Warburtons bakery product group to Mauritian food market, Africa. The Product Group Warburtons product group includes bread, rolls, snacks, healthy and gluten free products. The bread variety is suitable for vegetarians and is almost similar in nutrition and calorie content to other breads ranging between 60-90 calories per slice depending on the type of the product. However, it contains more selenium than other breads. The white bread is fortified with calcium, iron and Vitamin B and the wholemeal is rich in dietary fiber. The company is not using hydrogenated fats in any of the products. To help reduce the increasing sodium intake, the company has lowered the use of salts by 30%. A complete ingredient and nutritional information is provided on all packaging (a-Warburtons, 2012). Warburton products do not have a longer shelf life and are baked in in-store bakeries to ensure absolute freshness. To maintain freshness and quality, Warburton bread is priced quite higher than other breads. Around 95% of the best quality wheat is obtained ethically and sustainably from established sources in the UK and Canada. To maintain consistent protein levels and quality, the grown varieties are specified by the company giving the products a unique taste, softness and freshness. Warburton products not only provide customers with healthy balanced diet but also ethically sound and environmentally friendly choices (b-Warburtons, 2012). The Target Market The Republic of Mauritius is located in the southeast of African continent, around 500 miles east of Madagascar. As of July 2011, the population of Mauritius was estimated at 1,286,340 with a growth rate of 0.4% and a population density of 630 people per square Kilometer. The country is well known for its stability and racial harmony among different ethnic groups including Asians, Europeans and Africans (Republic of Mauritius, 2012). The local currency is Rupee divided into 100 cents. N egligible or zero percentage of population lives below international poverty line of US$1.25 per day. People speak Mauritian Creole, English and French. As of 2008, the total adult literacy rate was estimated at 88% (UNICEF, 2010). Despite of being remote from world markets, Mauritius enjoys sustained economic growth and stability. From 1970 to 2008, the GDP growth was

Hoggy's Restaurant Experience Essay Example | Topics and Well Written Essays - 750 words

Hoggy's Restaurant Experience - Essay Example I was disappointed and frustrated by a recent experience at Hoggy’s Restaurant. I had very high expectations.   Numerous visits to the restaurant with family and friends led me to anticipate that the food would be served at the right temperature, that it would be tasty and delicious, the service would be prompt and attentive, and the restaurant would be clean and organized.   I had never had a negative experience with this restaurant chain, or with this particular location.   My most recent visit changed their winning streak, however.   The experience was poor, and I am unlikely to return to this location.A friend and I visited the restaurant over lunch.   We were not in a rush and were looking forward to a pleasant meal in great company.   Upon entering the restaurant, we noted that it took several minutes before someone greeted us and led us to a table.   On past visits, the hostess greeted us within a minute, so this was a surprise.   In fact, it took so lon g that we joked that they had closed the restaurant and had forgotten to lock the door.After the hostess led us to a table and provided us with a menu, we waited another five minutes before the waitress visited our table and took our beverage order.   This was frustrating, because we had picked a time to visit after the standard lunch rush time, and the restaurant was not busy.We received our drinks, gave the waitress our order, and visited with each other until the waitress returned with our food.   She placed the plates in front of us and indicated that she would get drink refills for us.   My friend started eating, but as soon as I picked up my sandwich, I noticed a long, black hair lying across the top of it.  

Microeconomics Essay Example | Topics and Well Written Essays - 250 words - 2

Microeconomics - Essay Example However, the situation is beneficial to the country in the long term. Currently, US citizens have to cope with high interest rates and high mortgage rates due to the country’s account deficit. The current situation may indicate that the country’s rate of investment is exceeding its GDP. Investment is not a bad thing for the country although it might cause short-term financial strains on the citizens and unfavorable trade balance (Barschel, 2007). However, long-term benefits may propel US to high levels of economic performance. None of the current economic solutions can be applied to reverse the situation. In order to contain the situation, the government needs to encourage savings and reduce borrowings among its people. This will involve giving people the right education in order to sensitize them on the importance of saving within the country. Increasing tax rates will also reduce borrowing and increase savings. The government also needs to cut the countries imports while it promotes exports. Oil accounts for $140 billion of the total US imports. The government should promote energy conservation and use of alternative energy in order to cuts oil imports and to promote favorable trade

Health, Safety and Environmental Legislation for Engineers Assignment

Health, Safety and Environmental Legislation for Engineers - Assignment Example ISO ISO abbreviated as â€Å"International Organization of Standardization† is the world’s largest organization that develops, authenticates and publishes international standards (ISO 2010a). It was founded on February 1947 and it is a non-governmental organization that has national standard institutes of 163 countries and has its central secretariat in Geneva Switzerland (ISO 2010a). Now the question arises, what actually ISO does and how they make standards and who want to follow those standards? ISO develops certain standards for educational, industrial, business and commercial organizations that not only ensure the quality of their product but also draws a framework for the developmental activities to be performed in those organizations (ISO 2010a). These standards ensure that the products and services are high quality, safe, reliable efficient and environmental friendly. This set criteria of standards help public to get satisfied with the products and services that are following these standards and thus overall consumption and usage become more reliable and efficient (ISO 2010a). There is a long procedure for making ISO standards but we take a brief and helpful review of that. ISO develops any standard on demand and need of that standard by a stakeholder or industry sector. The proposal for the new standard is placed before a Technical committee of ISO for majority vote and further discusses this with their members in developing and developed countries (ISO 2010a). After getting positive response from every corner standard is made by technical committees that have experts from industrial, technical and business sectors. Every organization that wishes to have more efficient working environment, safer and cleaner product manufacturing, reliability and creditability uses ISO standardization and certification (ISO 2010a). ISO14001 ISO14001 is one of the standards of series of 14000. 14001 not only provides a standard for products and services to any educational, industrial, business and technical organizations but also helps them in setting a framework for environmental friendly activities (ISO 2010b). It enables organizations to develop, maintain and improve environmental management system and it is applicable to those areas of organizations that have significant impact on environment or which can control environment by their industrial or business activities. ISO14001 is an international standard that allows any organization to improve and enhance their environmental impact (ISO 2010b). Any organization that desires a certification of its environmental management system by a third party organization and want to reduce or eliminate the services causing negative impact on environment can use ISO14001 (ISO 2010b). In addition to providing environmental friendly and efficient framework activities to the organizations, there are a number of other benefits that can be achieved by organizations after getting certification of ISO 14001. ISO14001 makes organizations position stable by ensuring them reliable to stakeholders. It defines organization as innovative to customers and business partners. It helps organizations in managing their environment

Generating Revenue in Healthcare Assignment Example | Topics and Well Written Essays - 750 words

Generating Revenue in Healthcare - Assignment Example This is achieved by offering of services that otherwise cannot be offered adequately by the bereaved family. This also takes the burden that could otherwise have been born by the bereaved family and thus the family focuses fully on the funeral ceremony. How else could you appease the deceased other than letting them spend their last moments with their family? The food and beverage department offers a number of services. First and foremost, the program offers meals for the mourning gathering. The mourners as well as the family would like to have food to take them through during their stay with the bereaved. The department thus is able to provide meals offered four times a day. First, there is the morning breakfast that is taken at 7 o’clock. This comprises black tea, black coffee, and milk and fruit salad. There are also refreshments during the mid morning that comprises fresh juice, sodas, snacks such as biscuits and even donoughts. During the lunch hours, meals are also provided. This meal comprises vegetables, French fries, rice, cereals among other foods. There is also evening refreshment offered between 4 to 5 p.m. This comprises tea, coffee, milk, juices and fruit salad. Supper then follows u a few hours later and is served at approximately 8 pm. This meal comprises French fries, vegetables, rice, cereals and rounded up by a glass of wine. However, these meals are not fixed as suggestions from the host family are highly considered. Diversity and flexibility is a virtue that the department embraces and thus whatever you wish to be displayed in the menu will be granted. The department also offers tents for hire. This tends offer shelter during the rough weather conditions. Chairs and tables are also being offered by the department to offer comfort ability during the services. Also offered is the public address system to ensure quality communication standards within the function. Humans

Psychology Essay Example | Topics and Well Written Essays - 750 words - 11

Psychology - Essay Example This general wish has to be narrowed down so that I am able to focus within psychology studies on my particular strengths and interests. It is also necessary that I understand the level to which I need to qualify myself through study in order to do what I would like to do in a future career. It is important to me now to be able to manage my time and to balance all the aspects of my life. The way I will be able to do this is to ensure I take care of myself physically, mentally and emotionally in times of stress. I want to ensure that my writing skills improve, so that I can clearly communicate the knowledge I am gaining, and the future research findings and results I hope to publish in this field. Another immediate goal is to learn as much as possible from my experiences here. I want to immerse myself fully in my studies, learning as much as I can. This will be possible only if I concentrate on building good communication between my peers and myself, as well as between my instructors and myself. Further, I want to engage fully with the writings and work of other people in the field of psychology. If I synthesize and understand as much of the work in the field as possible, on an ongoing basis, I will maintain current knowledge, continue to find new areas of interest, and gain skills throughout my studies and career. The research and findings of academics in the field of psychology, especially new findings and theories, are very interesting to me, and I would like to keep improving my ability to understand and assimilate such research, and its results. It is also important to me that I learn to research well – both the theory of how to research, and the skills and methods of research. One of my definite interests is Statistics, and I aim to increase my knowledge and understanding of Multivariate statistical methods as they are used in psychology.

Generating Revenue in Healthcare Assignment Example | Topics and Well Written Essays - 750 words

Generating Revenue in Healthcare - Assignment Example This is achieved by offering of services that otherwise cannot be offered adequately by the bereaved family. This also takes the burden that could otherwise have been born by the bereaved family and thus the family focuses fully on the funeral ceremony. How else could you appease the deceased other than letting them spend their last moments with their family? The food and beverage department offers a number of services. First and foremost, the program offers meals for the mourning gathering. The mourners as well as the family would like to have food to take them through during their stay with the bereaved. The department thus is able to provide meals offered four times a day. First, there is the morning breakfast that is taken at 7 o’clock. This comprises black tea, black coffee, and milk and fruit salad. There are also refreshments during the mid morning that comprises fresh juice, sodas, snacks such as biscuits and even donoughts. During the lunch hours, meals are also provided. This meal comprises vegetables, French fries, rice, cereals among other foods. There is also evening refreshment offered between 4 to 5 p.m. This comprises tea, coffee, milk, juices and fruit salad. Supper then follows u a few hours later and is served at approximately 8 pm. This meal comprises French fries, vegetables, rice, cereals and rounded up by a glass of wine. However, these meals are not fixed as suggestions from the host family are highly considered. Diversity and flexibility is a virtue that the department embraces and thus whatever you wish to be displayed in the menu will be granted. The department also offers tents for hire. This tends offer shelter during the rough weather conditions. Chairs and tables are also being offered by the department to offer comfort ability during the services. Also offered is the public address system to ensure quality communication standards within the function. Humans

How do economic recession affect people's behavior Essay

How do economic recession affect people's behavior - Essay Example However, as the theory points out, the knowledge is never complete and this imperfection leads to economic growth. This may not always be so. In times of economic recession, the more the awareness of bad news, the greater is its impact on human behavior and the economic crisis. According to Charles Hodge, if a human being is assumed to behave out of necessity, he loses his identity as a rational person capable of deciding based on his thoughts and analysis (Hodge as cited in Cleveland, 2000). He becomes a mechanical person and can not be held responsible for the consequences of his behavior. Similarly if he is assumed to base his actions on the contingencies, he is imbibed with irrational and autocratic power of determination, acting even against his own will. Hodge rejects both these patterns of behavior that emerge from the utilitarianism theory. In the third behavior pattern viz., certainty, the individual behavior is explained by the individual’s own rational analysis of a situation and determination of what is best in his own interest, and is embraced by Hodge as the more appropriate explanation of human behavior. The subprime crisis in the USA led to large scale defaults in the mortgage industry and its contagion effect soon engulfed a host of other sectors like the financial institutions, banks and manufacturing industries. Bank failures dried up the credit available for the business and industry and this has in turn led to significant loss of jobs and consumer confidence. All the major economies of the world are facing a downturn due to globalization. Mass communications media ensures that individual behavior is influenced and aggravated by the frenzy of collective disaster. Loss of consumer confidence and credit squeeze are the major factors impacting human behavior in these circumstances. US economy which is characterized by a high degree of consumer spending, is witnessing consumer

Genetic Polymorphism Governing the CYP2D6 Cytrochrome

Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss, Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss,