Opportunities for the Multinational Enterprise Term Paper

Opportunities for the Multinational Enterprise - edge Paper ExampleThe meaning of Globalisation do-nothing easily be interpreted from the word itself. It is zero point but going international. When people realized that they cannot survive from the resources that they had available in their vicinity, they began exchanging ethicals with their neighbors, which got expanded to exchange with new(prenominal) countries, organizations, etc. This exchange of goods for goods, or the Barter system, gradu eachy turned into import and export of goods mainly base on availability, or technically the lack thereof, which brought about this whole cycle. When focused from an overall horizon, the term globalization is something, as part of which common people, organizations, etc interact among themselves in different spheres of their lives, including cultural sphere, financial sphere, etc, etc.. Globalization whitethorn be thought of as the widening, deepening and speeding up of worldwide interco nnectedness in all aspects of contemporary social life, from the cultural to the criminal, the financial to the spiritually. (Wiley, Nandi and Shahidullah 1998, p.21). Although from the above definition, one can infer that globalization can be referred to any form of global integration or interaction, the fact, it is mainly used with an economic perspective and multinational personal line of credit, and the resultant interaction between organizations particularly Multinational Companies (MNC). The term globalisation involves increasing strength and variety of cross-border transactions in goods and services, free international capital flows and more rapid and widespread distribution of technology. To make things simpler, we can say that Globalisation is a process of rapid integration of countries particularly MNCs, and how those companies utilizing opportunities in a particular market or new(prenominal) country, enter it to do argument or another process there. On the other han d, critics of Globalisation emphasize the ensuing debate regarding the roles and relationships of corporations and the countrys citizens in maximizing economic development and social welfare. There appears quite a number of challenges for the MNCs while doing business in new markets as part of the globalization. So, this paper first discussing the main forces driving the globalization process, depart explain the opportunities and then the challenges that globalization presents to multinational businesses. Forces driving the globalization process As the various switch over and other barriers between the countries got broken, MNCs, using the globalization plank, have entered and are entering into different business sectors. This main course of MNCs into various territories to do business was not a new phenomenon, but an age-old phenomenon, which happened under the pretending of imperialism. From time immemorial, various geographical territories, as well as nations, have been indulg ing in business with one another, to fulfill their product or service wants and shortages, as well as to garner good finances through product sale and thereby strengthening their economies. Even the British entered Indian subcontinent to do business under the tag of British East India Company. This form of trade has been going on for many another(prenominal) centuries, however, certain countries in different points of their history have put certain restrictions on trade with other countries or enterprises due to political, financial as well as other social reasons. That is, this trade ground entry started transforming into imperialism, as the European and other Western powers, tapping the weakness of the Asian and African ruling powers, in conclusion captured the nations territories and started to rule them. This set a bad precedent, and after independence many countries started actualizing a protectionist regime, preventing or constraining entry of foreign organizations. These countries or territories did not allow the entry of foreign companies as well as its products and even went to the extent of preventing its own companies to do any business with the foreign companies.

Ethics in Financial Management Essay Example | Topics and Well Written Essays - 500 words

Ethics in Financial Management - Essay ExampleIn todays world, organisations and change by reversalplaces make up become extremely diversified and have adopted varied stance s in legal injury of job processes and the general outlook. What is striking in such a scenario, is the prevalence of organizational or work ethics. Ethics has evolved to become an important aspect of organizational functioning, since it deals with the self-esteem and the very importance attached to employees in an organisation. Is it but well known, that an employee is the building block of an organisation and the importance attached to ethics in todays organisations are a reflection of the same.Financial Code of Ethics is important for the smooth functioning of any organisation. hotshot of the important aspects of financial code of ethics, is to maintain integrity in the generation of accounts. One must fix the hierarchal accountability and must also adhere to strict confidentiality and secrecy. It is als o important to make engagement of the independence given and to maintain high levels of honesty and transparency.The Enron scandal was something that rocked the business world and also godly books and movies based on it.

Immigration Personal Statement Example | Topics and Well Written Essays - 500 words

Immigration - Personal Statement ExampleI unavoidableness to help people in the future who may face tribulations the same way she did.I insufficiency to be a legal professional who can stand up for the rights of all of the downtrodden, and those in thorny situations. I also want to achieve genial change and equality. I ask myself what can I do as one person to change any situation. The answer is that I can do everything as long as I accept the challenge of being an agent of change regarding social progress for families and children, for the continuing pursuit of social justice through law, with a personal focus on divorce law and immigration. In terms of the growth and change I have experienced era vicariously experiencing my mothers divorce as a child, I versed my legal internship that being involved in legal work requires a great deal of leadership and determination leaders in the compass must ensure the success of their clients in every way possible by being telling team p layers who can make definitive, goal-oriented decisions based on skills and experienceI have also learned through experience that it is not only dreams of success that bring people to the field of law. I occupy deeply about what happened to my mother in her divorce, and what happens to many.

Apple Stock Research Paper Example | Topics and Well Written Essays - 3750 words

Apple birth - Research Paper ExampleAccording to the study the industry in which Apple operates in bum be characterized into external features using Michael Porters five forces framework. The industry has barriers to entry due to the material capital requirements needed to enter. The degree of competition that the industry faces also limits entry of newcomers and the brand identity that from each one player in the industry creates bars new entrants since they would struggle for any significant market handle due to their lack of any brand identity.From this paper it is clear thatthere is the constant threat of substitutes that the alliance faces due to the higher prices that the company imposes on its products as compared to its competitors. Generally, Apple products are highly priced than other connatural products in the market, therefore there is that threat that consumers might opt to go for a lower priced trade good from Apples rivals. The threat of substitutes is also cre ated due to the nature of the company business which is a closed ecosystem and is therefore difficult to switch to any other form of business. There is also the supplier personnel that Apple as a corporation holds. The company always creates quality products making the company shake up the power to bargain for a higher price for their products in relation to their competitors.Apple Inc. is one of the near valuable companies in the world and much of its success is attributed to the sustainable competitive advantage it has created over the years.

Based on recent event, discuss whether the stock markets are efficient Essay

Based on recent event, discuss whether the stock securities industrys are efficient according to the Effficient Market Hypothesis - Essay fontThis is based on the ideal of a balancing act, where trades are regarded as knowing the trump means forward. However, skeptics of the above, view markets as being necessarily inefficient due to the various forms of risks involved. The reasoning seat the aforementioned theory is that a free and competitive market arena does place various determine indices to their true basic values. Lo (2007), provides that the Efficient Markets Hypothesis (EMH) does showcase the fact that market terms indices do to the full reflect all available data. This however does not eliminate critique, especially from behavioral economists and psychologists, who view it as being founded on assumptions which are counter-factual, especially with regard to human behavior/ rationality. A distinction is make between technical and fundamental analysis of stock pricing indices. The former, entails the utility of volume charts and geometric patterns in pricing, towards forecasting a given securitys future price fluctuation. The latter on its part, is have-to doe with with the utility of both economic and accounting data, towards determining a given shares reliable valuation. Pegged on this assumption is the fact that as the existing market enhances overall efficiency, so does the price sequencing establish completely unpredictable and random (Lo, 200717). As Shiller (2013) provides, though humanity continues being influenced by past spheric occurrences in the market arenas, this does not in any way remove the presence of existing market anomalies. The fact that the South American state of Colombia continues experiencing a real-estate bubble, which is ongoing, is representative of the volatility of the current market sector. With its real-estate pricing index rising by 69%, in terms of inflation-adjusted calculations, it provides a crucial insid ers view of how market inefficiency continuously evolves. Rationality in individuals participation in various economic bubbles is educated by amongst others, the price increases as a result of the prevailing psychological contagion. It is this fundamental human aspect, which promotes a given lookout of justifiable price increases, thereby spurring fervent market activities. Due to the inherent nature of

Individual Dreamweaver Lessons Coursework Example | Topics and Well Written Essays - 500 words

Individual Dreamweaver Lessons - Coursework ExampleBelow is the structure of a web summon carry ond as htm or htlm file.We in like manner covered CSS designer. The lecture touches on roll in the hay view and Live code that help in giving the exact review of the web page designed and how visually changing the web page developed will affect the code behind the scene. The first lesson also gives an overview how you rout out create a hyperlink on a web page. The tag was utilise to create a hyperlink. Use bar to link section of the documents to other pages. For example,In this lesson, creating of a new site took the shopping mall stage by defining site get upting using Site Setup dialog box. The Servers, Versions as well as advanced setting options social occasiond in defining your site. This lecture also declare the DOCTYPE used in HTML5 which is .The lesson also looked at the format of saving the new site created. The file created should soak up html file format and only spe cial characters such as underscores (_) is used to separate the words. You should save it on one major folder. CSS helps in defining appearance of a web page. You can set background color or link color whichever applicable using CSS. It was important to note that document Type set to HTML5 is set as Unicode (UTF-8) and that Adobe Photoshop is being used in a ghost image such as JPEG and GIF. We looked at local root folder on how one can copy, select, view or open files from it.It also addresses natural file types being displayed by web browsers. The graphic files discussed include GIF that condenses color images and used mostly in areas with flat colors like logos. JPEG format is used in inline images. When inserting a logo/image, use the format. You can then set logo/image comprehensiveness and length. Inserting of Photoshop smart objects in an html form was also tackled.Use in group-block elements. When using HTML tables use attributes such as dl, dt, and

Cultural Encounters and Cultural Exemptions Essay

Cultural Encounters and Cultural Exemptions - Essay Examplet crumb and then allow for a further examination of the how cultural resistance can be defined in monetary value of fitting into the liberal philosophical point of view. In searching for avenues of autonomy, the liberal philosophic can find a great example in the concept of cultural exemption.Cultural exemption allows a culture to continue traditions that might otherwise be considered illegal. One example of this can be imbed in the United States where Native Americans are allowed to use peyote and mescaline drugs because of their cultural traditions while other citizens would be arrested for this use. As well, the Native Americans are allowed to kill eagles, a protected bird in the United States, and use the parts of the body for religious ceremonies (343). This type of exemption is noble in its preservation of a culture that is all but gone from the world. However, in terms of global engagements of enterprise between countries, the act of allowing a cultural exemption within a body politic may prevent other countries from interacting with them in trade when the exemption is too controversial (Crane, Kawashima, & Kawasaki 2002 82).a bottom of belief. According to Barry (1996), classical liberalism begins with a realistic view of man and his condition(8). The foundation of the philosophy is that disposal should be limited and the freedoms of individuals should be widely available. Some of the other basic ideals are freedoms of religion, the press, speech, of assembly and for a free market (Sarder 1997 74). However, liberalism also has a strong sense of the concept of autonomy. This concept is so crucial to the theory that a rejection of the idea of community accompanies this concept. According to Sarder, the liberalist views the community as a place where too much sacrifice of individual freedom exists and that each individual should define their own sense of morality, not adhering to the ove rall values of a culturally connected society (74). However,

Explain and Evaluate How Markets Create New Forms of Authority Essay

Explain and prise How Markets Create New Forms of Authority - Essay ExampleDecentralization engulfs varied concepts that must be unsounded and control guide before setting any business programs, or projects. Therefore, the need for authority in this sense is to promote reorganization of administrative, financial and service delivery within that business venture effectively (Taylor, 2010 p. 122). Notably, authority ass be understood in the terms or application of the decentralization concepts since it refers to responsibility and authority for case functions, especially of the central political relation to quasi or subordinate independent government organization or private sectors (Smith & Sutherland, 1998 p. 319). How commercialises create new forms of authority is a complex multifaceted concept since it involves wide instinct varying from antithetical characteristics, conditions for success, and policy implications. Numerous forms of authorities influence different markets therefore, there is a travel need for markets to from authorities that makes them autonomous. However, most of these authorizes are influenced by other factors including semipolitical, fiscal, administrative, and other market authorizes that are pegged of different types of markets or market decentralizations (Smith & Sutherland, 1998 p. 219). Hence, there is a need to highlight concepts differentiating each form of authority as well as the need to coordinate these authorities. Moreover, different markets affect and apply to political, fiscal, and administrative authorities otherwise across different market domains and regions or countries. The demanding nature of the economy has made different market demands to regulate or reform the political authorities. The political authority often aims at giving the elected representatives big power in frequent decision-making (Le?cuyer, 2002 p. 137). This form of authority is associated with representative government and pluralistic po litics however, it eject lead to decentralization by giving the elected representatives, or citizens, more influence to the implementation of the national policies (Taylor, 2010 p. 122). Some of these policies used to determine what business and business performs were to engaging in business within what political domain. However, markets have so far changed and political policies are being redefined to accommodate or allow their citizens and government to engage in businesses within a large market domain. The political authorities have been strained to advocate for flexibility in their marketing and market policies otherwise, they will remain powerful without powerful or reasonable economies to control (Ferguson, 1995 p. 173). Therefore, different markets have forced different political authorities to assume legitimate decisions that will all greater participation with more relevant and better-informed diverse interests of societies and other national or international authorities (Smith & Sutherland, 1998 p. 219). These reforms or concept implies that markets have forced or is currently compelling the public or citizens to elect representatives with better political policies towards marketing and markets. The actions of any political authority require statutory or constitutional reforms towards developing pluralistic political policies that will be friendly to markets. Markets have led to administrative decentralization with the aim of distributing administrative authorities towards effective market management. It influenced the administrative decentralization to redistribute responsibility and financial resources authorities towards providing the public services with different levels of governances in order to understand market demands and requirement at

Philosphy of education Term Paper Example | Topics and Well Written Essays - 500 words

Philosphy of education - circumstance Paper ExampleIt helps in developing a world where justice, equality and standards of life are magnetic core principles to aid and guide humanity. The acquisition of education, however, requires a great deal of struggles form the individual. An educated person is the angiotensin-converting enzyme who is civilized, morally enlightened and understands human dignity as a core principle which should not be compromised in any field. An educated society hence, creates certain implied duties on the individuals to work for mutual benefits leading to proficient advancements, help each other to maintain peace in the society and maintain relationships to keep the skill track going. Platos theory of education explained acquire as an ongoing process where learning develops with the harvest-feast of a person. He proposes that an individuals learning continues from 6 to above 50 years of age. Learning, jibe to Plato, is a must to thrive in the society. I n the same way I consider learning as an important and integral part of a persons life which cannot be separate but rather a person should stay open to accept and follow new ideas, thoughts and issues.

Close Reading about Poem Essay Example | Topics and Well Written Essays - 750 words

Close Reading about Poem - Essay simulation.The opening of the poem, my heart aches, and a drowsy numbness vexations indicate that the mood of song is gamey (Keates Stanza 1 line 1). The author is trying to achieve the nightingales pure realm and thresh from the troubles and darkness of the valet de chambre through his drink. The nightingales voice sends him into a trance making him cheery and unable to digest on anything else. This is evident when he says, Singest of summer in full-throated ease (Keates Stanza 1 Line 10). His view of the world as a dark place is a product of his health problems and the fact that he became an orphan in his early teenage years and forced by circumstances to care for his sick brother. In as much as he is drunk, his tone is sober and enlightened. The nightingales songs turn his sorrow to joy and torture to pleasure. He imagines smelling flowers and drinking wine in the green country in the suns warmth and becoming one with the nightingale, Fade far away, dissolve, and quite forget (Stanza 3 line 1). This shows his longing of a lively, pleasant world. He comes to his senses in the sixth stanza when the reality of his mortality hits him hard. He is attracted to the nightingales song and realizes that the bird is incapable of experiencing pain and comprehending the pain of death. To him the bird is immortal because many people transverse all generations and history have hear the nightingale sing. When the nightingale flies off, the speaker feels lonely and disappointed. He feels he lacks the freedom of the nightingales and yearns to come to such(prenominal) freedom and usefulness. Perhaps death is his release (Cunningham & Reich & Fichner 127).Finally, in understanding this poem it is noteworthy to mention that the poet calm this poem after the demise of his brother. The poem expresses the reality of the duality of human experiences using imagery and melancholy. The unalike

Rabelais and Montaigne Essay Example | Topics and Well Written Essays - 1250 words

Rabelais and Montaigne - Essay ExampleThis is especi in ally so as they give toleration to art in its natural state where a lot of description and opinion, but which seek to cross into inquiry. Even so, to argue that renaissance writers were only interested in theory may be a misconception. This paper shall assess the above claims under the thesis statement early renaissance writers and characters appreciated theoretic generalizations and pragmatic action in equal measure. To do so, this paper shall focus on selected readings of the above scholars in an attempt to prove this position. The paper will also offer a counter argument done the lens of an alternative interpretation especially where ambiguity leaves room for multiple understandings of the texts. An Analysis of Depictions of Pragmatic litigate versus Theoretical Generalizations To begin with, Book 1, the introduction offers a bit of the beginnings background. One may notice that the fact that he threw himself at the mov ement of the Renaissance (Rabelais and Raffel 5). He is depicted as having acquired twain the Latin antiquity knowledge as well as the Greek forms of knowledge. Raffel writes, Almost all the elements which ar united in Rabelais style are known from the later Middle Ages (Preface page X). It is manifest that since the author lived at the intersection of two historical periods, it was inevitable that he was affected by the mannerisms and beliefs of those times. It is also observable that Rabelais did not always write in the same fashion (Rabelais and Raffel 12). Analyses of chapters 52-58 reveal some perceptions of the renaissance writers and characters around religion and logic. There was a lot of attention given to theory. For example, Rabelais says, If one of the gallants of ladies should say, let us drink, they would all drink. This depicts a situation in which the society did not assess keenly how practically their actions could affect separate things around them. For instan ce, Rabelaiss work reveals in this chapter that the society perceived women as incapable of religious service. When the monastic asks Gargantua what a good a woman that is neither fair not good serves, Gargantua replies that she should make a nun (Rabelais and Raffel 127). The monk agrees to this. One may observe that these renaissance characters depict religious principles were still pregnant to the society. These show to theoretical approach to life. Besides, there is a lot of description of the abbey of the Thelemites, particularly in take care to how it was built. The author takes his time to describe the abbey, as was the common practice in romanticism. Rabelaiss says this of the abbey in chapter 52, In the midst there was a wonderful scalier or winding stair, the entry whereof was without a house, in a vault or arch six fathom abroad. He also engages in detailed description, a characteristic of theoretical life. he says in chapter 54, Stay here, you lively, jovial, handsome , brisk, gay, witty, frolic, cheerful, merry, frisk, spruce, jocund, courteous, furtherer of trades, and in a word, all worthy blasphemous blades. This approach to life combines what one would call emerging pragmatism against a fading romanticism. Rabelais observes in what he termed a prophetical riddle, that they will say that everyman should have his turn (Rabelais and Raffel 137) to imply the births of human rights in the contribute renaissance period. He also continues with theoretical appro

Behavior problems in Adolescents with Learning Disabilities Essay

Behavior problems in Adolescents with Learning Disabilities - Essay exercisingThe presence of behavior problems among electric shaverren with various forms of learning disabilities is not so hard to imagine, given the challenges they are set about to compete in a learning environment with their disability. Therefore, many of the children whitethorn feel less sizable when comparing to their peers in various areas of educational performance. These problems may sit as external as healthy as internal behaviors, and without proper addressing of these, the child may grow up as an individual with multiple behavior problems. (Johnson, nd) One of the complications in the correct delivery of education to such children is the variety of disorders that are present within the context of learning disabilities. The lack of proper teaching skills and inability of the child to cope may lead to uninterested behavior among the children and consequently, poorer performance may lead to further redu ction of the motivation of the child to perform academically. (Lee and Donald, 2003)Such problems are especially hard to address among the adolescent and teenage groups, who are already vulnerable during their transition phase from childhood to adulthood. This firstly clarifies that learning disabilities are not only a challenge that children of younger age groups face with. Adults and adolescents overly face the same problems and some may go undiagnosed for a long time. (Revisiting Learning Problems and Learning Disabilities, 2002) Also, the severity of the learning disorder must also identify along with the type, so that the person is educated with the right strategies to help cope with and overcome his or her learning difficulties. (Revisiting Learning Problems and Learning Disabilities, 2002)The external features of these learning disorders are usually found as solicitude deficit hyperactivity disorder or ADHD, oppositional defiant disorder or ODD and conduct disorder or CD. I nternal features may present as depression and anxiety

Plotinus and His Theory of Beauty Essay Example | Topics and Well Written Essays - 1000 words

Plotinus and His Theory of Beauty - Essay ExampleIt is everything and nothing, everything and nowhere. The nonpareil is the blood line of all beings and, as the Good, the goal of all aspirations, human and non-human. (Bussanich, 1996, p. 38). According to Plotinus, everything that exists in the world flows out of the One and it is the One which emanates the miraculous Intellect. In turn, the Intellect originates the Soul, which incorporates the world soul, the human and another(prenominal) souls, and it is the Soul which produces the nature and matter in the universe. To Plotinus, unity of the most striking features of the One is that it remains ever-complete and undiminished, in spite of the emanation and the idea of emanation of the One indicates that reality is structured in a hierarchical graze, stretching from the uplifting source down to bodied matter. Plotinus theory of peach keister be realized in relation to his overall metaphysical psychology. As Binita Mehta maint ains, the perception of ravisher, according to Plotinus, dumbfounds the soul and fills it with love. ... It is a phenomenological fact that an experience of rapturous delight that cup of tea evokes creates an liking in us for further similar experiences For Plotinus, even a purely sensuous lulu can serve as a starting point of the quest for higher beauty. (Mehta). According to Plotinus, even the beauty in the material world should be realized as the reflection of the intelligible beauty. Therefore, there is an inborn power for beauty as the apprehension of sensible beauty can very well stir up the soul to realize the source of this lower form of beauty in the intelligible realm. In other words, beauty in every form and element can lead one to the ultimate source of beauty which is the source of everything in the world. Essentially, a reflective abridgment of the theory of beauty according to Plotinus confirms that beauty is closely connected to the Divine or the One who is the ultimate source of all beings, and the concept of beauty has a great role in the ascent of the Soul to the One or the Divine. The notion of beauty has an essential role in the metaphysics of Plotinus who develops his theory of beauty in the I.6 and V.8 of his book the Enneads and a reflective analysis of these members of the book can greatly offer the basics of notion of beauty according to the author. In the I.6 section of the book, Plotinus maintains that Beauty addresses itself chiefly to sight, but there is a beauty for hearing too, as in current combinations of words and all kinds of music, for melodies and cadences are beautiful and minds that lift themselves above the realm of sense to higher order are aware of beauty in the conduct of life, in actions, in character, in the pursuit of the intellectual and there is beauty of the virtues. What loftier beauty there may be, yet, our

The Politics and Sociology of Media and Culture Essay

The Politics and Sociology of Media and Culture - Essay ExampleHowever, a peculiarly vulnerable sector or demographic are adolescents, not only because of the access they throw to to the highest degree all forms of media such as the internet, television, radio, newspapers and magazines but also because they are at an age where they are especially vulnerable. They allow yet to develop sufficient maturity and discernment necessary to filter out potentially destructive messages and unhealthy ideas streaming in from various media sources. One such threat to adolescents in limited and to the general viewing public in general are reality TV shows. There have been a slew of reality TV shows out in the market over the past some years. Some of them test ones physical mettle like Amazing Race, others have to do with the search for love like The Bachelor or The Bachelorette, others test ones aptitude in various fields of endeavor like The Apprentice, and yet others talk about undergoing physical transformations like The Swan, a reality TV series in the United States produced by Fox TV.The show The Swan is overabundant with political and sociological meaning. While it is indeed very entertaining and riveting, it is loaded with so many ostracize messages that present trouble for the impressionable adolescent girl-child.First of all, it breeds stereotypes. It has long been established that factual and fictional media portrayals have a propensity to activate culturally shared racial and gender stereotypes and affect judgment involving those who go to stereotyped groups

The Presidency Essay Example | Topics and Well Written Essays - 1000 words - 1

The Presidency - Essay exercisingHe was barely twenty historic period old when he started out with FBI in this modest fashion. He climbed up the career ladder steadily thereafter. His appointment as the Assistant Special Agent in Charge (ASAC) in Chicago is a notable milestone. But it is the World Trade Center (WTC) bombard at Oklahoma in 1993 that would prove to be a turning point in his career. A year later he was made supervisor of VAPCON in 1994. From this point onwards John was profoundly involvement in counter-terror operations for the rest of his life. In hindsight a lot of warnings given by ONeill have proven to be right. His fractious relationship with the FBI bosses and his own scratchy personality had created distrust or disregard for the information that he was passing on. Though a lone voice among his colleagues, he unploughed repeating the threat of terrorist attacks till the very end of his tenure with the FBI. In the last few years of his service, he served as t he Chief of Counterterrorism Section within the FBI. Despite this critical position he held within the national intelligence apparatus his words were not given due respect. Every time an Copernican lead would emerge, John would fight with Washington to make sure that we constantly took the lead on these investigations. So we would build this intelligence base, and so we would have investigators that had the institutional knowledge and that was the way it was. (Clint Guenther, Former FBI Agent NYC Counterterrorism) look into the 911 terror attacks in retrospect, there is nothing inevitable about its occurrence. There were enough indications for the FBI to take prophylactic device action. John ONeill saw himself as the champion of this cause one of saving America from a grave security threat. But, unfortunately, those around him, especially the top leaders in the FBI did not concur with ONeills views. More than an odd lapse it is a systematic failure on part of the chance upon national agency. Bureaucratic bungling and red tape have made ONeills dreadful attempts to communicate a challenge. Personal ego hassles between ONeill and his peers and superiors was another mitigating factor. ONeills abrasive personality rubbed off his colleagues the wrong way. As a result, the intelligence reports given out by ONeill did not get the urgent attention that they merited. One needs to ask how personal favoritism and detriment can undermine the high profile operations of the FBI. John ONeill was quite vocal and obdurate about the presence of Al base of operations sleeper cells in the United States. John had communicated how the terror net profit had developed capabilities for attacking many strategic locations not just in the United States but anyplace in the world. It was ONeill who identified Al Qaeda as the foremost threat to America -much forth of his peers did. As his colleague Richard Clarke recounts, I would go around the country to FBI offices and ask, Is there an Al Qaeda presence in Chicago, in San Francisco, in Boston? And typically the reaction I would get is, Whats Al Qaeda?...But not with John. John knew what Al Qaeda was he was among the first people to see the bin wealthy threat. He believed there was a bin Laden network in the United States even if he couldnt prove it. So he was constantly trying to prove it (Richard Clarke, NSS Coordinator for Counterterrorism, 1992-2001) John O

Human Resource Management Essay Example | Topics and Well Written Essays - 1500 words - 19

benignant Resource Management - Essay ExampleMajority of these stores ar found in America, and the number is 12,218 stores. mainland China is also a lucrative market for Starbucks, and the company has opened 1,330 stores.Starbucks offers products such as cold or hot beverage, coffee, pastries, snacks, etc (Pahl, 2008). This means that the company has diversified, and this is through the many services it offers. Initially, the main reason for the formation of Starbucks was to exchange the coffee drink (Simon, 2009). This diversification strategy of Starbucks is also seen when the company decided to offer wines, beer and appetizers. The target markets of these products are people who want to relax in the evenings.Pahl (2008) explains that some of the products of Starbucks are found inwardly a crabby location, and this is mainly because it offers some services and products at particularised seasons. These products confine also been designed, to serve a specific market. Starbucks does not only sale its coffee, in its stores, but it also sales them at various sell cheeks, and grocery stores (Pahl, 2008). Through this strategy, it is the intention of Starbucks to reach a large market base.Organizational culture is slackly the unique combination of values, norms, morals, beliefs, and techniques or ways of behavior that characterizes the way individuals or large groups of individuals combine to have things done in an organization (Gurski, 2013).Schultz & Gordon (2011) explains that organizational culture is the norms and activities that people are able to engage with, within the organization. Through this definition, we are able to know that organizational culture is the internal environment of an organization, which regulates then carriage which people within the organization are able to interact with one another, and other stakeholders of then organization (Michelli, 2007).Culture is very important in every company, for example

Arthur Schopenhauer Essay Example for Free

Arthur Schopenhauer EssayArthur Schopenhauer is a German philosopher who was natural on February 22nd, 1788 and died on September 21st, 1860. He was born in the city of Danzig but later moved to the city of Hamburg where he became interested in studying metaphysics, ethics and psychology. Schopenhauer is cognise as the philosopher of Pessimism because he created a theory that ch entirelyenged the value of existence. Schopenhauers main pore was on individual motivation the will and how human desires cause pain and assembleing. He wrote a book on the will called The World as Will and Representation. This book was a collaboration of Kants judgement of idealism with his own theory on that the will is the thing-in-itself. Schopenhauer was greatly influenced by thinkers like Kant and Plato. He as well influenced thinkers like Sigmund Freud, Ludwig Wittgenstein and Friedrich Nietzsche. Summary of Ideas The Will Schopenhauer believed that existence were solitary(prenominal) motiv ated by their basic desires. He believed that human desires only cause condenseing and pain. As well he believed that human desires be unconnected and directionless. He believed that the will controls all aspects of human life.Schopenhauers ideas on the will are similar to the ideas of Buddhism and the quartette noble truths. He believed that free will exists but humans are non able to deliver the wide-cuts it because everything is determined by how the body reacts to a situation. He stated that Man kitty indeed do what he wants, but he can non will what he wants. (On the Freedom of the Will) Ethics The basics of Schopenhauer ethics is close compassion. He believes compassion cant be taught but only learned by experience. pity is the knowledge of seeing someone suffer equally to a suffering they have faced in their life and being able to relate and have sympathy for them.Schopenhauer distinguishes a full person not from the nature of their actions but the level of compassi on they have for them. He believes that the departure between a ingenuous person and a normal person is distinguished by when seeing someone suffer the good person will sacrifice his own well-being for the other person. Therefore he takes on all their troubles. Schopenhauer believes this is the highest degree in ethical conduct. Pessimism Schopenhauer believes since the will has no purpose or goal that the will can never achieve satisfaction.He believes the main goal of existence is to gain satisfaction but assay to achieve it is unsustainable because it leads to frustration. For that reason he says existence of human beings can only be characterized by suffering. He believes this theory is for all animals and since humans have a higher intellectual capacity that they will suffer more in life than any other animal. He as well stated that still using reasoning will not change the amount of suffering the person experiences because reason only increases the suffering. Schopenhauer concludes that nonexistence is and should be more preferable then existence.He believes people should realize that to exist is to suffer and the goal in life for people should be to try and resist ones desires. industriousness Animal Welfare Schopenhauer believed humans and animals are essentially equal and the same. He believed that everything is basically will and that humans and animals are the same because they can recognize characteristics and emotion in each other. Schopenhauer stated Unlike the intellect, it the Will does not depend on the perfection of the organism, but is essentially the same in all animals as that which is known to us so intimately.Accordingly, the animal has all the emotions of humans, such as joy, grief, fear, anger, love, hatred, strong desire, envy, and so on. The great difference between human and animal rests solely on the intellects degrees of perfection. (On the Will in Nature, Physiology and Pathology) He believed that a good person will have co mpassion for animals when they are hurt because they are fellow sufferers. People who are cruel to animals are not good people because they do not have compassion.

Unconsious Mind Essay Example for Free

Unconsious Mind sample1.) Explain how the use of substances transfers a someones state of sureness, including depressants, stimulants, and hallucinogens. Include in this explanation what happens to the neurotransmitters and ashes chemicals as well as how you might recognize if a person at work or in your family is in an altered state of apprisedness due to the influence of drugs.The use of substances can alter the persons state of consciousness in many ways. The depressants, stimulants, and hallucinogens affect the level of consciousness in different ways due to their specific alterations in the level of head word chemistry in brain cells. When the substances taken breach the blood/brain barrier and reach the brain, they cause alteration in the traffic pattern levels and activities of neurotransmitters that include dopamine, endorphins, and serotonin. Any alteration in the level and functioning of neurotransmitters can cause changes in the automobile trunk chemistries t hat in turn can cause changes in the normal functioning of the trunk.Every neurotransmitter has roles to play in the have of level of consciousness. Alterations in the level of neurotransmitters can trigger temporary arousal or residual that affect the functioning of the body (Sheldon, n.d.). For instance, low levels of monoamines that include norepinephrine, epinephrine, dopamine, and serotonin can cause depression. Excessive levels of dopamine level, underactivity of glutamate, and abnormal levels of serotonin and amino acids for can cause psychomotor excitement. Altered state of consciousness caused by drugs can be recognized through observation of the persons sort. For instance, by taking stimulants, the levels of monoamines leave behind be increased causing temporary arousal or stimulation effects in the body functioning.The person under the effects of stimulants get out manifest some signs of unusual sudden and temporary inflammation and increase in energy level. The pe rson under the effects of stimulants can be observed on emotional high, with flooding of ideas that may be full of irrationality, and highly energetic that can cause wide sleeplessness. The use of depressants that include barbiturates can cause relaxation and sedative effects than can counterbalance the person less tensed, less anxious, less active, emotionally low, sleepy, and with very low level of energy. The use of hallucinogens can make the person obtain unusually elatedwith heightened senses giving temporary pleasurable experiences.2.) This question has five parts. bingle of the cornerstones of Freudian theory is the concept of the unconscious mind not to be confused with the state of being knocked unconscious by a blow to the head. (a) What did Freud mean by the concept of the unconscious? Freud concept of the unconscious refers to the vague part of the humane judging beyond the persons capability to bring them out into conscious awareness. The hidden information is s tored like the invisible part of an iceberg.The unconscious part of the human mind refers to the id primarily seeking for the satisfaction of pleasurable desires that come from biological instincts and primitive urges (McLeod, 2009). The stored information in the unconscious mind is beyond the persons awareness yet can significantly influence human look. b) When is it well(p) for much of our demeanour to be unconscious?The unconscious behavior can be a obtain of power and creativity. The development of erectness skills and habits where the mastered skills got stored in unconscious mind makes much of the unconscious behavior beneficial. For instance, the skills learned in playing guitar or piano turns as a habit. The formed habit becomes stored in unconscious mind. Playing guitar and piano can later performed out of unconscious behavior. There is no take away to consider much as the behavior becomes automatic. In the same way, learning the skills of better understanding of su stenance and others can also jock in making unconscious behavior of putting control on impulsiveness. The skills can help in making better conclusivenesss and dispositions in day to day situations. It can help in influencing others and produce better judgments that enhance better relationship and social life. (c) When is it not beneficial?The unconscious mind that comes out into uncontrolled unconscious behavior can be significantly disturbing. When being uneffective to control behavior that comes from unconscious mind, the unconscious behavior becomes not beneficial. The unconscious mind is the center that operates amusement principle. It seeks satisfaction of the instinctual and primitive desires. The behavior can be disturbing to others, can be destructive, or and be out of morals and acceptable norms set by the society. The persons behavior driven by unconscious mind produces action done without sound judgmentinviting troublesome and chaotic situations.The developed abomina ble habits that are expressed in unconscious behavior are definitely not beneficial. The habit of bickering, intercourse lies, and smoking for instance are done out of unconscious behavior and all brings no good effects or impacts to the person and the society. (d) If much of our behavior is unconscious, can you recognize unconscious behavior in yourself and in others? If much of our behavior is unconscious, yes, you can still recognize the unconscious behavior in yourself and others. human race mind is not under the total control of unconscious but the subconscious and conscious aspects provide help every person to realize the way he acts. Behavior mostly driven by the unconscious mind tends to produce unwanted consequences that can make the individual resentful, guilty, confused, and unhappy. A point result be reached when an individual leave behind start to understand what drives the behavior to bring trouble and unhappiness. The subconscious and conscious parts of the mind help in modulating the behavior driven by primitive and instinctual desires. (e) How would you retire behavior was unconsciously driven?The unconscious mind drives the person to act unconsciously. He may not know why and how he acted such way. The actions are done without prior thinking or good judgment. The behavior comes out of control that can be impulsive, irrational, and lack of thinking. Unconsciously-driven behaviors are usually followed by wondering and celestial latitude in most instances. The question Why I behaved such way?, Why I did that?, or How I behaved such way? are among the questions that follow after any behavior that was unconsciously driven.3.) company think is a concept that involves individuals abandoning their critical sense and agreeing to agradical process even when they know it will have disastrous consequences. (Challenger disaster, Enron, Iraq war, etc.). Your will encounter these pressures in your work life and consider to be prepared. stick you ever done something in a group that you would not have done if you were alone? What happened? How did you feel? What have you learned from this chapter that might help you avoid this behavior in the future, and avoid group think?Due to pressures, yes, I have done something in a group that I would have not done if I were alone. On the next steps I felt not happy with what the group has been doing according to the plans. My decision to agree under the influence of group think made me feel awkward as I realize that I could hardly convince myself to do what the group has agreed unanimously. along the way, I felt dissatisfaction and lost any motivation to participate in carrying out the group activity. I felt like doing the activity under control like an operated machine.From the chapter reading, I learned that you may need to allow yourself to think impartial on group ideas. Every planned action in the group requires critical evaluation. Every member must be given the chance to have th eir spokespersons heard and atmospheric state the differences. The decision made by the group must be well discussed and consider critiques from outside experts when needed. The decision made by the group must be made with free participation of every member. The voice of every group member is valuable as the group needs coordinated efforts to successfully get through something. 4.) How does prejudice develop and how might it be back up in families and in the work place? Do you believe that you are free of prejudice? The biased prejudgment influenced by stereotypes and discrimination play large roles in the development of prejudice. For instance, seeing a of age(p) new member in the workplace will already make some young members to underestimate the capabilities of the aged member.The prejudice drives them to think that the new senior co-worker is not different from old staffs that are less productive. Prejudice has strong powers to change the perception. beneath the influence of prejudice, the good can become bad while the bad can become good before he eyes of anyone. The biased preachings driven by prejudice can be supported in families and workplaces by keeping the mind free of stereotypes and discrimination. Every person is unique and deserves fair treatment and judgment based on his personal character and abilities. Well, I think it is within the inherent human behavior to be sometimes driven by unconscious mind to think out of control that sometimes allow the mind to be influenced by prejudice. I can say I am not an exception as prejudice sometimes plays in my mind when I look at other people. For instance, when I see a funky guy walking in the street at night, I develop some fear as Ithink that the guy might be a rapist or a theft. The thought usually comes from the unconscious mind.ReferencesMcLeod, S. (2009). Unconscious mind. Retrieved fromhttp//www.simplypsychology.org/unconscious-mind.htmlSheldon, J. (n.d.). Motivations for drug use. Retriev ed fromhttp//www.fredonia.edu/ sportsman/health/davis/drug_book/chapter3.htm

Food Crisis Essay Example for Free

Food Crisis EssayAccording to World Bank, they blame that the diet crisis in Africa atomic number 18 do by peck barrier. A lot of countries in Africa are encloseed importing food for thought from the border. collectable to unfertilized land in a lot of parts in Africa, it causes people to discourage to be a farmer, so the food supply is less. However, African population is change magnitude rapidly. Therefore, the pick up for food leave alone just keep increasing. As a go, the demand for food would exceed supply for food in Africa. Before I move on to the next examples, I need to explain about the result of the demand exceed supply.Identical harvests around the beingness should fix in the law of one scathe, which average that the identical products should care at the same scathe around the world. This is because if it is not the same price, the country that parcel out high price would go to buy the low price product from another country and sell it to their coun try. Therefore, the country that sell product for low price with get a result in increasing demand which result in increasing in price. The supply for the high price product pull up stakes be more because people import to sell in country, which result in decreasing in price.At the result, both countries will sell product at the same price. This will cause the exporter by the rest of the world need to sell the product at the same price (world price). Therefore, we can excrete it in the graph as vertical lines while the supply in the country as an upward-sloping and the demand is downward-sloping, but food is necessary product, so the line should be more inelastic. Now we can spot all of this in to a graph, and a graph will look like this. The import is plane because of the world price, so they need to supply at this price.As you can see from the graph, the import is restrict at only the small amount according to Africa, only 5 percent of the food import, which resulting in demand exceeding supply, so we can apply this to the food crisis by trade restriction. Therefore, the price of food is increasing because there is high demand for food than supply in Africa, while the farmer is not encouraging by the government because only a little profit goes to them even though the price is high due to the government policy, so he Africa people suffer from hunger due to the unaffordable price of food.Not only Africa that face food crisis, but also the world is suffered during 2008. According to Europe, they claim that the world food crisis is because the trade restriction of many countries in the world such as Argentina, Russia, Japan and atomic number 16 Korea. These trade restrictions cause the price of food in the world to increase. People cannot afford the high price. Thus, the food crisis occurs and suffers many countries around the world.Food crisis occur in the country may lead to other problem. For example, the sound off in Egypt also cause by raising cost of food in the country because of trade restriction. In long term solution to solve food crisis should be that the government should not interject food price because food is necessary product they choose restrict on the unnecessary product such as cigarette or alcohol instead. 20 million people in Africa are suffering from hunger nowadays due to this food crisis causing by trade restriction.

The nature of state provisions for the poor in the period c. 1830 - 1839 Essay Example for Free

The nature of state supply for the woeful in the period c. 1830 1839 EssayTo what goal were the changes in the surface of it of the electo pass judgment the key factor in determining the nature of state provisions for the pitiful in the period c. 1830 1839?In the years between 1830 and 1939, Britain causality saw great increase in the rate of legislation and the amount of government intervention in society, in particular concerning the aid of the misfortunate. At the same time, the size of electorate was ever expanding but does this mean to two factors are necessarily linked?1832 saw the Great remediate act, an act which extended the vote to all middle twelvemonth men, putting an increased amount of violence in their hands, in reflection of the greater political influence they now boasted. The middle class were high-and-mighty by their set the promotion of self help, thrift, sobriety and scientific approach all considered fairly contrary to qualities which th e work class were believed to possess (self help, thrift and sobriety, in particular). Two years sideline the reform act, in 1834, the poor law amendment act was introduced. The aging poor law had been under much attack, particularly from bighearted writers and social commentators of the time, such as Thomas Malthus and Jeremy Bentham. Malthus blamed the poor law for the evident population harvesting in Britain, in that nation were entitled to a greater amount of poor relief when they had a greater number of children.His solution to the problem was to see the abolition of the poor law, which would allow land owners (those who compensable the poor rates) to pay higher wages to their workers, to prevent them having to rely on convey of relief in the first place. With any luck, this would also discourage people from having as many children for the interest of money, hence tyrannical the rate of population growth and consumption of resources. Bentham wanted to see the poor car ed for by the National brotherly love Organisation. He also proposed industry houses, which would be the only centre by which people could access poor relief. The industry houses would be purposely tough, with strict discipline and long hours, in the hope of discouraging people from entering in the first place. Given that there would be no show updoor relief this was think to encourage people to apply the middle class principle of self help, and to find a mean out income beyond poor relief.The major problems with the old poor law focused around its increase cost, corruption within the system, and the demoralising affect of the Speenhamland system (where by the low wages of agricultural industrial plant would be subsidised in accordance to their number of children and the price of bread). The problems were approached by the Royal Commission on the paltry Laws, which began a few months prior to the 1832 great reform act. It recommended a new means of brass section of the poor l aw (including the grouping of parishes into unions, controlled by a Board of Guardians, overseen by a central Poor Law Commission), the abolition of outdoor relief, and the introduction of the workhouse test.These ideas very much reflected those of Jeremy Bentham, and generally promoted middle class value in particular, self help. However, given that the Royal Commission began some months before the middle class were enfranchised, it seems slimly less likely that the points of the Poor Law Amendment act were a takings of their influence. Furthermore, the leading commissioners were Nassau Senoir, a Malthusian, and Edwin Chadwick, a Benthamite given their position in the proceedings, it seems far more likely that their ideas are those which had more impaction on the investigation (i.e., the results of the investigation could have easily been picked at to meet with their beliefs).Throughout the mid-nineteenth century, it could be detect that there was a growing movement of self-he lp amongst the functional class, mainly revolving around Friendly Societies, Co-Operatives and Trade Unions. The henhouse began in 1844, and aimed to keep food prices down without compromising their purity. At the end of the year, profits were shared out amongst members via a dividend, so customers gained something in return for their expenditures. The Co-op was not a great use for the particularly poor notwithstanding, as full payments were indispensable at the time of purchase these people generally relied on tabs due to low and irregular income.Members of palsy-walsy societies and trade unions, generally speaking, would pay in a protected sum of money which they could then receive as benefits when ill, to protect then from having to turn to the poor law. Again, this required a regular income, due to the need to pay in money consistently. It seems very likely that these means of self help were a direct influence from the middle class perhaps members of the working class had seen the influence and status which the middle class had received as a potential consequence of their values? Also, the new poor law and the fact that people would want to avoid the workhouse if at all likely seems a viable reason for the new interest in self help. It seems perfectly possible however that these people could have picked up on such middle class values without the latter world enfranchised anyway.In reward for their efforts, skilled artisans received the vote in 1867, with the second reform act. This compose left the mass of the working class without the vote, and was likely due to the fact that skilled artisans were the only members of the working class with a steady enough income to pay into friendly societies, trade unions or co-operatives. The 1867 wasnt entirely support however some leading figures considered it power in the hands of the masses, and that it would throw the scum of the community to the surface. However, following the reform act, many changes w ere made and legislations passed, including the compulsory 1875 universal health act and the 1870 bringing up act, amongst others, all transport about changes which would improve the conditions of working class bread and butter, along with the peoples chances for the future.Links between poverty and external factors were universe established, government intervention was increasing, and there was a broader electorate to now appeal to. However, this growing electorate was not the only indigence after part these changes. Scientific uprisethroughs were occurring, such as the establishment of the germ theory, which gave much of the basis for the 1875 compulsory public health act. The national efficiency debate was sparking concerns to the general condition of the nation, a problem particularly highlighted by the number of volunteers who had to be rejected from aiding in the Boer war due to their poor health. Foreign competition saw rise to concerns over Britains frugal health and weak men with a slump in trade, and the confidence of public figures such as Charles Dickens and Henry Mayhew on the difficulty of working class life gave a very human aspect to the problem.It seems that really, the now larger electorate was not the main force behind these legislations yet, they were the easiest way to appeal to working men. It may just be considered as a fortunate consequence that these somewhat essential legislations appealed to the working class and their needs. The government also realised that taking these measures would help to break the apparent poverty cycle when people fell ill due to the poor conditions they lived in, they could not work, dipping them and their families into poverty. Consequently, the workforce became weakened, which by no means aided Britains dwindling parsimony. It was essentially in the governments interest to pass these legislations, for the sake of the country, not just appeal to the working class voters.In 1884, the vote was ex tended further into the working class, resulting in 1/6th of all men having the vote. The 1880s and 90s were a period of great economic problems and fairly high unemployment, and issue which was extending to skilled and respectable workers, not just the casual workers in society. This was a consequence of Britains pattern of trade slumping, and the inadequacy of the poor law in dealing with such a problem led to an overflow in the workhouses, and many people with no means of relief. Still ordinary in society was the national efficiency debate, with Britains consistently weak workforce and comparatively weak economy in comparison to nations such as Germany and the USA. Around this time, there was also an ever-growing awareness as to the causes of poverty, highlighted by the works of Seebohm Rowntree and Charles Booth, whos work into the extent of poverty in cities (and that for many people, their situation was caused through no breakage of their own) very much highlighted the exten t of poverty, even beyond what people already expected. 1906 saw the Liberals come into power for the first time in 20 years, and consequently, the passing of many new legislations and reforms.These included another education act, labour exchanges act, trade boards act and the old age pensions. Given the minimal increase in the size of the electorate in 1884, it seems unlikely that this was the motive at all behind the Liberal reforms, particularly with much larger threats pressuring for change e.g., the looming threat of socialism in Britain, the mass unemployment Britain was facing, the national efficiency debate and the desire to retain in responsibility. There was also the Royal Commission on the Poor Laws of 1909 to consider, which between its minority and majority reports produced the recommendations which approximately likely lead to the reforms for change in provisions towards children and the elderly. The Liberal reforms brought about many improvements for these groups, with the old age pension and provision of meals and medical inspections act in education, and the National Insurance act of 1911 provided a means of sick pay and medical cover for workers much like a national friendly society, of which all workers would have to pay into. For as much controversy as this caused, it was a big cadence by the Liberals in facing poverty.Beyond this time, the size of the electorate was not altered by any means of reform, yet quite dramatic changes towards provision for the poor took place this included alternations to the age at which the OAP could be received, the unemployment act (which extended the national insurance scheme), the effective destruction of the poor law with the Local political relation Act, the establishment of Public Assistance Committees to aid the able bodied poor, and the means test. Given that there was no change in the size of the electorate, there is no means by which that could be responsible for these changing provisions for the poor, they were mostly consequence of problems throughout society at the time, such as the inadequacy of the poor law as a welfare system in the 20th century, the mass unemployment throughout Britain and the neglect of benefits available for the most vulnerable groups in society (e.g., widows, the elderly and orphans).It seems fair to say that, although their choices would have influenced who came into office and consequently, the policies that would be passed, the changing size of the electorate had a minimal part to play in changing provisions for the poor. The continuously changing external factors which pressured for change, advances in beliefs and knowledge and the work of prominent figures appear to have had the most profound effect on legislation and reform, and it seems that the changing legislation simply appealed to the needs of the changing electorate by fortunate consequences. It would seem that it was more the governments interest to tackle major issues such as une mployment and threats of socialism, as hostile to appealing to the requirements of the electorate concerning poor relief, yet the tackling of these issues simply led to improvements in this area also. The varying needs and requirements of the electorate themselves had smaller direct influence over government policies at any point.

Gay Community Essay Example for Free

Gay Community EssayThe comical residential district or LGBT community is a loosely defined congregationing of LGBT and LGBT supportive people, organizations and subcultures united by common culture and civil rights movements. Furthermore, the remarkable growth of the light community in recent storey has revolutionized our culture and consciousness, creating radically new possibilities for people to come out, and live more openly as homosexuals. Before the early years, homosexuality was a taboo subject. Since then, times have changed and this community is somewhat cosmos accepted. Moreover, this diverse community is constantly expanding, and consists of galore(postnominal) another(prenominal) types of people. The homophile(a) community has gained great attention in arts, entertainment, media, and politics. most of the people that make up this community each have their own unique style in all different aspects.Consisting of races throughout all aspects of life, the intre pid community is worldwide. That being said, what makes up the gay community? Within the LGBT communities, at that place exist identifiable sub-communities, such as the leather community, bear community, chubby community, lesbian community, bisexual community, transgender community, and the drag community. Nevertheless, each one of the sub-communities have there own particular ways and views of there sexuality. In other words, they all stick together.The gay community generally celebrates compliment, diversity, individuality, and sexuality. The term gay pride is used to express the LGBT communitys identity and collective strengths gay pride parades provide some(prenominal) a prime example of the use and a demonstration of the general meaning of the term. Also, within the gay community some people bring out there own particular family. These families consist of the mom, dad, children, and so on. They create a bond and they indeed stick together. Other interests within the gay com munities include gay nightclubs, pageants, balls, and besides lip singing shows.The gay community is frequently associated with certain symbols especially rainbow or the rainbow flag. The Greek lambda symbols (L for liberation), triangles, ribbons, and gender symbols be also used as gay acceptance symbol. There a many types of flags to represent subdivisions in the gay community but the most commonly recognized one is the rainbow flag. Nevertheless, each color represents a value in the community. Pink represents sexuality, red represents life, orange represents healing, yellow represent the sun, kelvin represents nature, blue represents art, indigo represents harmony, and last but not least, violent represents spirit. As far as language, the gay community have there own imbibe, just as other slangs ilk African Americans, Jewish slang, Hispanic slang, or any other slang. Usually one must be in the group to know its slang, but there are many words in gay slang that are known to a ll of us, such as drag queen, butch, or bull dyke. Other newer gay slang words used immediately are fag-hag, which is a straight female who prefers the company of a gay male and dish which means gossip.Communication between gays, what they say opposed to how they say it, is quite unique. For instance, many gay males use alternate lady-names, and masculine female use alternate male-names, both used as a form of address within gay circles. The gay community is continuously growing and has been hold in so many ways. Homosexuality is seemingly more accepted and tolerated in the United States today than decades ago. There are laws in many states that make it a crime to discriminate based on sexual orientation and many communities across the country have gays and lesbians openly serving in measurable roles. Yet there are many who still oppose homosexuality and many object to it on religious grounds. I do pride this community because I am apart of it. But like the old saying says To eac h is his own. Everyone has there own opinion.

Creating Methodology Essay Example for Free

Creating Methodology Essay1. Discuss factors about the bodily culture that were at play, and suggest central reasons why the executive staff waited as long as they had to consider the development of an enterprise project management methodology (EPM).2. Recommend to both the senior executives (i.e., the compevery) and conjuration Compton (i.e., the president) whether the project management office (PMO) should report to the chief information officer (CIO) or to someone else. cut the response.3. Use at least three (3) quality references.Note Wikipedia and (3). Difference QuotientA classmate conjure ups that the difference quotient of any one-dimensional function f(x) = mx + b is always m. Explain if you agree or disagree with this statement, and state why.I disagree because he is using the wrong formula. f(x) = mx + b is the slope-intercept form of a linear function and m represents the slope.

Love and Diane Essay Example for Free

Love and Diane auditionSynopsis Love Diane tells the epic story of a family everyplace three generations. At its heart lies the passing aerated relationship between a mother and lady friend, desperate for love and for pr bingleess but caught in a devastating cycle. For Love, the globe changed forever when she and her siblings were torn from their mother, Diane. Separated from her family and thrust into a terrifying world of institutions and foster homes, the memory of that mummyent is more vivid to her than her present intent. Ten years have passed since that twenty-four hour period and Love and her five siblings have been reunited with their mother.But all have been changed by the years of separation. They are close strangers to apiece other and Love is tormented by the thought that it was her fault. At 8 years over-the-hill she was the one who revealed to a teacher that her mother was an drug addict. Now she is 18 and HIV+. And she has just given birth to a son, Don yaeh. For Love Diane this baby represents everything good and hopeful for the future. But that hope is mixed with fear. Donyaeh has been natural with the HIV virus and months must pass before his final status is known.As Diane struggles to make her family unit of measurement again and to realize some of her own dreams, Love seems to be drifting further and further out from her child. Diane, torn by her own guilt over her childrens fate when she was an addict, tries to help and to care for her grandson. But when Diane confides her fears for her miss to a therapist, the police suddenly appear at the door. Donyaeh is taken from Loves arms and it seems to the family as if history has restate itself. Now Love must face the same or bulk her mother had faced years before.She is charged with neglect and must prove to a world of social leaners, therapists and prosecutors that she is a fit mother. And Diane must examine the courage to turn away from her guilt and grasp a chance to pur sue her long-deferred dreams. While the acquire takes us deep into the life of a single family, it also offers a provocative look at the Byzantine system that aims to help but as often frustrates the familys attempts to improve their situation. The film differs from many documentaries that deal with the problems facing poor communities in that it eschews berateing eads and interviews with experts and aims instead to immerse the viewer in the experiences and thoughts of a family laborious to survive and retain autonomy in the face of terrible challenges. Love Diane Inner-City Blues An Interview with Jennifer Dworkin For over eight years Jennifer Dworkin documented the personal struggles of a recovering crack addict and her troubled daughter in Love Diane. Fellow long-term filmmaker Steve James talks with Dworkin about her epic work of American vrit film fashioning.I first heard about Jennifer Dworkins Love Diane when it played at the 2002 New York icon Festival. Though I misse d seeing it because I live in Chicago, the word was that this was a specific film, one in which the filmmaker spent years intimately following the lives of a family. Since thats been my own filmmaking M. O. , I knew this was a documentary I had to see. So in November, when I finally did settle into my seat at Amsterdams International Documentary Festival to watch the film, I had pretty high expectations. Love Diane lived up to them and more.Its a powerful, uncompromising, yet compassionate portrait of a mother and daughter coping with a hard life in Brooklyn and an even more difficult personal history between them. In the best maven of the word, the film is a throwback to the heyday of cinema vrit filmmaking in the 60s and early 70s, When the Maysles were in their prime and young person filmmakers like Barbara Kopple were making their mark. Love Diane is one of those films where the filmmaker earned such intimate access and the swan of her subjects that it gives viewers a rare and complex glimpse into the lives of people we rarely really see in films.And like most great film subjects, Diane Hazzard and her daughter, Love, continually confound our expectations of what it means to be a ghetto mom or an ex-crack addict or a black teenage mother. Meeting and getting to know the director, Jennifer Dworkin, was one of the pleasures of the Amsterdam festival. My film, Stevie, also played there, and Jennifer and I found unexpected common ground in the stories each of our films tells. Both films deal with troubled family history, struggles between a parent and child, foster care, poverty and the social serve and legal systems.Yet, in other ways, Stevie and Love Diane, couldnt be more different. Filmmaker gave me a chance to talk further with Jennifer about her impressive first film and compare notes about how we each went about making such demanding and challenging films. Steve James How long did you spend on this film? Jennifer Dworkin You know, I never serv e well that question. James Really? Dworkin No, just kidding laughs. If you count directions I started but didnt end up using in the film, about eight years, including editing. But not full time. James Of course not. How could one survive? Dworkin Exactly.

Demographic Transitions Essay Example for Free

Demographic Transitions EssayThis assignment was really interesting and a little tricky. The outcome of this assignment was to learn how to write a clear procedure. In my assignment, there were a few mistakes that I committed such as in the second step where I was instructed to impersonate a mean(a) sized bottle and, in the end I should paint small windows finished which you could enjoy an underwater view. This particular instruction, however, was optional. I was also instructed to paint lots of cabinets, a little nail down door, and windows to make the milling machinery even more colorful. I had to make 3 objects from the directions of others, but, I didnt note any flaws in those directions. My experience in building a submarine using items found at home was actually refreshing and educational. I had experienced and accomplished this kind of activity when I was in high school so, for me it wasnt new. My inspiration for the project came when I was watching the history chan nel where a particular show featured a submarine, so, I just took that idea and made my own submarine with different sized bottles and adhesive tape.There were other objects to be made for this activity, but these were relatively favorable and simple to make, as long as I followed the directions. As a whole, I had a very enriching and educational experience. When I finally ended the activity, I decided to make modifications and use a medium sized bottle instead, as well as paint on the additional/optional inside information to make my submarine more realistic and more colorful.

The issue of ecology Essay Example for Free

The issue of ecology EssayThe issue of ecology as a transnational issue has become highlighted with the intensification of world trade. As such, it becomes a global right and a consideration in developing trade policies. As the primary governing body of international trade, the World Trade Organization (WTO) has been one of the pioneers in equating environmental responsibility with trade (Deal, 2002).At the same time in that respect, has been regional efforts to standardize environmental laws to extenuate the impact of development in sh be environs as illustrated by the efforts of the European Union (EU), North Atlantic Free Trade to a lower placestanding (NAFTA) and the Association of South East Asian Nations (ASEAN) (Sampson, 1998). One of the efforts made by the WTO is the development of the Kyoto protocol which is aiming to mitigate environmental issue particularly global warming by establishing a trade system for emissions.However, there has been a difficulty in t he implementation of the regulation because of varying views on the policies as well as difficulty in monitoring emissions. At the same time, there have been some issues regarding the institution of tripartite agreements that are contradicting or undermining the Kyoto Protocol or the status of most favored nations (MFN) (Brewer, 2004). Focus For WTO members, the use of animation measure coifments could have significant logical implications.The issue bear witnesss difficult environmental, trade policy issues, economic issues. It also raise the internalization of environmental costs and the polluter pays principle, the movements on trade competitiveness and relationship surrounded by the multilateral environmental agreements and WTO agreements. The main issue that whether Article III 2 first provisions of the 1994 GATT or the General Agreement of Tariffs and Trade ponders the use of border assess adjustment (BTA) on net products for evaluatees on the manufacture of inputs.A lbeit the decision in Superfund case, discussed in the latter of this section, the question will turn on a proper analysis of the revenue enhancementes utilize, directly or indirectly, to the like products to be compared, as opposed to the overall fiscal burden on producers from taxes on inputs. The Kyoto Protocol and the General Agreement of Tariffs and Trade In December 1997, the Kyoto Protocol to the UN Framework Convention was adopted. Under Kyoto Protocol, only Annex 1 countries are report to legally backbone emissions reduction commitments for the commitment period 2008-2012 in post-2000 scenario.Annex 1 parties or developed countries have to sports meeting individual emission reduction targets listed in Annex B of the Protocol. Developing countries or non-Annex 1 parties are not subject to specific emission reduction commitments. Though over 120 countries have sign the Protocol but the Protocol has yet to come into force. U. S. A and some other developed countries have to run into indicated an intention not to ratify the Protocol. Another contention is with regards to Article 1, II, VI and VII of the GATT and their potential implication with border tax adjustments.Further, postal code tax adjustments may be challengeable under Article twenty-three 1 b of 1994. Finally, Panel approach to WTO-consistency will be governed by the reasonableness of the specific measure and its tasting of the wider international implications. Energy tax adjustments as per Article III 2 first sentences could offer potentially broad scope for countries to apply energy tax adjustments as disguised barriers to trade. Such results would do dwarfish to serve the objectives of either the WTO multilateral trading system or the international response to climatic change. resile Tax Adjustment Border Tax Adjustment BTA is a tax levied on import products to adjust or compensate for taxes levied on internal product. The main goal of BTA is to ensure trade neutrality of domest icated taxation and thereby safeguarding competitive equality between imported and domestic goods. BTA is not necessarily levied at the border and imports may be taxed at the point of sale or consumption. Sales tax, consumption taxes or excise duties, value added taxes are examples of domestic taxes that might be subject to BTA.Likewise, a BTA on imported energy products such as imported natural gas or diesel fuel and other fossil fuels for domestic excise duties would fall within this group. Though the taxes on energy have been levied by governments for fiscal purpose for dogged time, now there has been a change in trend to charge energy tax mainly for environmental purpose. Energy tax is being levied on energy inputs such as coal ,electricity or gasoline which in turn calculated in value toll , or on the basis of its content of ascorbic acid of fossil fuels which is also known as carbon taxes.As of now, there exists no border tax adjustment scheme in place for taxes on energy inputs employed in the production of final products. However, European and other high energy levy governments are contemplating to introduce such measures in near future due to the pressure exerted by environmental and industry groups. But there are increasing pressures from environmental groups to put through strictly trade measures to enforce Kyoto Protocol objectives against non-signatories like United States. These environment groups regard the U. S. rejection of the Kyoto protocol is unfair as it places the European headache at a disadvantage.They argue that Europe has the right to penalize the U. S goods for the pollution they cause under Polluters pay policy. Cases for Consideration A BTA can be applied on final goods or on inputs used in the production process. An example is the border tax adjustment on imports of aluminums for taxes on energy used in the production process as taxes are being levied on embodied energy in the final good that are adjusted, as opposed to taxe s on the final goods itself. These measures are regarded as contentious with linkage to WTO trade and environmental debate.Albeit the Appellate bodys findings in the United States Shrimp dispute, the exercise of trade measures applied on the basis of process and production methods (PPM) in this case embodied taxes, carbon or energy remains highly contentious. BTA for domestic taxes on energy inputs also raise significant equity and sovereignty concerns on the use of trade measures to inflict domestic environmental or taxation systems on other countries. Super Fund The case is against levy of topnotchfund tax by U. S.A on petrochemicals and other chemicals and inputs when imported and sold in U. S and no tax is levied when it is exported out of U. S. U. S claimed that the aim of the tax was to compensate the cleaning up cost of hazardous hazardous sites and towards public health programs. When an importer fails to provide the details of input which he imported, then a penalty tax rate of 5 % was imposed. The GATT panel ruled that the tax on imported substance was a tax directly imposed on products and hence eligible for border tax adjustments. The panel held the US super tax would be consistent with the Article III 2 first sentence as long as it is equivalent to tax borne by the like domestic substances.The U. S direction to provide the knowledge of inputs may make such information available to trade competitors and would have a real effect in discouraging trade. In this case, it appeared that neither the GATT Panel nor the parties sought to distinguish between the tax applied to the imported products, the like domestic products or the chemical products used in the production of the like domestic products. The Panel seemed to accept the US argument that the imported product and that the like domestic product was subject to the same fiscal burden.

The Study Skills Handbook Essay Example for Free

The Study Skills Handbook EssayIn order to keep down the weaknesses of both the cross-section(a) and longitudinal approach most developmental psychologists use a combination of the twain in a single field of study as illustrated by Schaie (1965). He conducted a study of addiction behaviour in two, five and eight year olds. The first part of the study, which was cross-sectional, required data to be collected at all three age points. The longitudinal approach was then used pastime an interim of three years, when the two year olds reached the age of five and the five year olds reached the age of eight. If this study was simply longitudinal it would have taken six years before data collection was complete, wherefore the combination of both approaches represents a fifty percent saving in time. It also allows for a visualise to be carried out on a possible cohort effect. Both data collection methods, the longitudinal and cross-sectional approach, can produce different findings o n the same study.Weschslers cross-sectional study showed a lour in intelligence from the age of twenty. In contrast Schaie and Willis longitudinal study of intelligence showed an increase in intelligence up until the age of fifty. The reasons for the different findings is firstly the cohort effect, different past histories, connected to the cross-sectional approach and secondly participant attrition, that is to say participant drop out, associated with the longitudinal approach.In conclusion the longitudinal design is not the preferred approach for developmental psychologists because of the costs, time involved and participant attrition. On the new(prenominal) hand the cross-sectional design is actually popular and is the preferred method as data natural covering a wide range of age points can be collected in a very short period of time. It is also cost effective and developmental questions can be answered quickly and efficiently.ReferencesDavey, G., (Ed) (2004) set down Psycho logy. Oxon Hodder Stroughton.Gleitman, H, Fridlund, A. J. F. Reisberg, D. (2004) Psychology (6th Ed.). New York W.W.Norton.Cottrell, S., (2003) The Study Skills Handbook. (2nd Ed). Palgrave Macmillan.Millar, W.S. (2004) Methods used by Developmental Psychologists. TranscriptPY 102C Developmental Psychology.Student No 03037041

Genetic Polymorphism Governing the CYP2D6 Cytrochrome

Genetic Polymorphism Governing the CYP2D6 CytrochromeGenetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug metamorphosisI. AbstractThe decoding of the gracious genome has opened up an immense opportunity for supercharge research in designing manipulation plans that mass be more personalized. The composition of a persons genome varies amongst mortalistics and in any case within races. Individual retorts to dose be inherited. The clinical implication of inter-individual diversitys is implicit in Cytochrome P450 enzymes that atomic number 18 braggart(a) in medicate metamorphosis. Polymorphism of over 20 enzymes studyd in do medicates metabolic process has been characterized and some of these pick up the Cytochrome P450 enzymes. The Cytochrome P450 enzymes ache been subjected to numerous evolutionary pressures over era, consequently producing various isoforms. The frequency of adaptation altoge at that placeles derriere alter the pharmacokinetic parameters of the medicate, especi whollyy of a do doses with a narrow redress index. These allelomorphs prototypical mingylife either lose heightened replys to current medicates causation perniciousness or show very measly compliance softening to healing(p) failure. Specifically, CYP2D6 is known to vary tremendously amongst different cultural sort outings. Polymorphism of do c ar fors metabolizing enzymes such(prenominal)(prenominal) as CYP2D6 lav severely affect the clinical outcome in regards to dose response. CYP2D6 element is shown to have 74 flesh alleles, when expressed in homozygous or heterozygous manners give annul to four searching phe nonypes. In this new era of genomic advancements, there is much hope to decipher renewals pertaining to dose transfiguration and sky the focus towards individualized treat. Patient selection quite a light be drastically improved by the habit of ge nonyping. advance(a) technologies hav e made ge nonyping prevalent and we have come a long delegacy since the orgasm of pharmaco hereditary in the early 19th century.Sir William Osler (1849-1919) documented that discrepancy is the law of life, and as no two faces ar the said(prenominal), no two bodies ar alike, and no two individuals react alike, and behave alike under the irregular conditions we know as unsoundness.II. Personalized Medicine and PharmacogenomicsA. PharmacogenomicsThe valet genome project has it made executable for researchers to comprehend the complexity of biological path expressions involved in sickness states and focus on discrepancys amongst individuals in regards to do medicates regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the automobile trunks way of dealing with the do do drugss such as adsorption, distri stillion, transfiguration and elimination of the substrate factors into the divergence of individual drug response (Kroemer and Meyer zu Schwabedissen, 2 010). The pharmaco transmitted mutation in absorption and elimination atomic number 18 quite r atomic number 18 compargond 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 phe nonypical drug response is rather ambiguous and has various biological and environmental as accepteds as illustrated in Fig.1, which provoke head for the hills to a slope in drug skill and toxi grasstity (D. R. Nelson et al., 2004). The phenomenon of cistrontic variability cause different reactions to drugs has been recognized for awhile as seen in Fig 2 however scarcely 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 ( stumblebum, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to unfavourable d rug reactions as in born errors of metamorphosis ( strong-armer, 2003). An inherited difference in tasting ability of phenylthiocarbamide was starting signal discovered by a chemist, Arthur Fox in 1931. Arthur Foxs wind uping in 1931 on patrimonial variability was considered a recover finding in the field of pharmaco inherited (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers comp bed to the Afri send away the Statesn soldiers Afri piece of tail Ameri displace soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). metamorphosis as a concept 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 divisortic composition, gene and respective gene products, and illustrates how this variability affects drug metamo rphosis (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics ar a) To recognize the genes that atomic number 18 bear on in a disease state and b) To focus on the straining alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). go through 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 see to it 2 Favism is implicit in veritable tribe that consume fava beansA Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with astute hemolytic anemia in flock who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and tin tail end show adapted response to antimalarial drug Reprinted from Pharmacogenomics the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect. Aug111(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 expertness does not always correlate with reduced levels of perniciousness since remedial values and noxious side effect of a drug ar often exerted via assorted biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, because, has vital remedy value because near disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it feasible to predict safety, unhealthfulity and efficacy of drugs and opt for a personalized treatment plan by targeting soma alleles (Dawood, 2009). The empirical notion of forbearing roles with a certain(p) 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 superman of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study d peerless in 1994, estimated that more than 2 trillion patients hospitalized in the US had fatalities related to unfavorable drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug set up ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and adjust standards for drug efficacy and prevention of toxicity, adverse drug reactions are braggy and a drug is neer equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the wellness insurance companies find it feasible to pay for drugs that are eith er ineffective or cause adverse set up (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could tardily lead to mortality due to toxic levels of the exogenic 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 chemo alterative drugs (Dawood, 2009). just about chemo sanative drugs have narrow healing(p) index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach go for currently often leads to cure failure and waste of term leading to expensive health care em frames and valuable date (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and high blood pressure can be severely detrimental if the drugs do not gain effect due to the mien of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability al cardinal does not account for all the adverse set up of drugs seen in a patient, pinpointing the change gene can be beneficial in tailoring a more precise therapy that involves less adverse personal effects (Hood, 2003). Therefore, understanding the complex fundamental fundamental interaction of individuals with their environment and underlying genetic variation forget sanction for a gradual shift from superstar drug fits all perception to an embodiment of individualized medicine (Dawood, 2009).B. Individualized MedicineIndividualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork bear upon a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in phylogenesis of personalized treatment plans and medication types/ panes 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 to the highest degree in force(p) 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 altogether in 30% of the patients, whereas 30% of the patient show niggling or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der omega, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually invade 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 inherite d diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug metabolism 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 playing field and for certain ag sort of individuals the systemic exposure is presumed to be homogenous if the surface subject area is similar The surface area is mainly determined lay downd 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 comely to prevent therapeutic failure (Nebert and Vesell, 2004).II. Genetic PolymorphismA. 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 nonpareil nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the well-nigh extensively studied genetic polymorphism, which accounts for more or less of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 genius million 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 nescient deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for proteins 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 kingdom usually change the amino acid sequence of the protein whereas the SNP in the regulatory contribution 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 effectual 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 ph ysiological activity (Mini and Nobili, 2009). The human genome project has simplified the appellation of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate info on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not unrivaled but many SNP occur on the selfsame(prenominal) chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the gang 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 dominance difference drugs. The embody 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 data on drug metabolism amongst different cultura l 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 seldom (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 social groups (Nebert, 1999). well-nigh scientists at the conviction 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 heathen backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1 999)(Maitland-van der zed et al., 2000). Recent study on Asian, Whites 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 appendix of mutation and frequency of occurrence in an individual subgroup (Maitland-van der izzard et al., 2000). To establish an accurate overall envisage 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 past be employd for an extensive genotype-phenotype gene gene linkage study (Nebert, 1999).Figure 3 Polymorphism affect 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 personalize d medicine By Enrico Mini Stefania Nobili, Clinical Cases in Mineral and B unmatched Metabolism 2009 6(1) 17-24B. Adverse Drug ReactionDrug-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 good accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause unretentive 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 let ins 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 accordingly be employed by physicians to scram 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 legal document, physicians need to quantify variant drug responses to the specific gene uniquely (Nebert, 1999). It is imperative that the candidate locus that is touch by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). TheGenetic polymorphism plays a major role in drug efficacy and in like manner in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the regime 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 write 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 beingness 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 so, for a drug to be effectual, the share frequency o f variant allele needs to be determined (Drazen et. al, 1999McCarthy 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 ezed et al., 2000)?A authorization drug is securities industryed and distributed worldwide, however, most of the clinical trials are neer 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 the States 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 marketplace regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, capability drugs should include such population ground studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Zee et al., 2000). Polymorphism write 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 legal but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn leave be economically feasible and productive in the long run (March, 2000 Nebert and Vesell, 2004). Patient selectio n could be drastically improved by involvement of genotyping.C. When is Genotyping Appropriate?Most drug targets are not mark candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of giving medication 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 establish on plasma level concentration of the drug is not always ni ce for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by credit of polymorphism, which can reduce the dear(p) 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 low-down people 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. modernistic technologies have made genotyping prevalent and we have come a long way since the approaching of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutic industry can aid in maturation of drugs that cater to the individual this will allow for pro spective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. nutrient 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 liberal in the days to come and by the year 2020 pharmacogenomics will become a vital scratch 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 amou nt for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). collar Cytochrome P450 EnzymeA. BackgroundVariant 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 at present (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-corre cting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experient 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 in like manner 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 throw out studies accommodate 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 live r (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function earlier 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 a l., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of the cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducement 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 enzymesThe substrate for the CYP enzymes are just as assorted for endogenous substance as they are for exogenous substances. The CYP enzymes are large catal ytic 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) 13649-13472The rates of catalyzation of the CYP enzymes are relatively lento 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 primal determinative 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 twine the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the C YP enzymes can alike 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 enzymes 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 incline in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000 Wolf et a l., 2000). Allelic variants causing low, 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 (Anzenbacherova et al., 2000).B. Cytochrome Gene Family EvolutionCYP 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 catching 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 in the main 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 lat er 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, cd 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 mechanical changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of noncoding DNA conservation (Werck-Reichhart and Fey ereisen, 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 change (Andreadis, Gallego, and Nadal-Ginard, 1987 Atkins, Weiss,Genetic Polymorphism Governing the CYP2D6 CytrochromeGenetic Polymorphism Governing the CYP2D6 CytrochromeGenetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug MetabolismI. AbstractThe 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 t hese 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, CYP2D6 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 intelligible phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and cant the focus towards individualized medicine. Patient sel ection 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 vicarious conditions we know as disease.II. Personalized Medicine and PharmacogenomicsA. PharmacogenomicsThe 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 Schwabedi ssen, 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 differe nce 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 concept 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, 809-815Figure 2 Favism is implicit in certain population that consume fava beansA Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with neat 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. Aug111(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 (recepto r, 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 dru g (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 modulate 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 aim of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alone 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 adv erse 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 MedicineIndividualized 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 maturement 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 difference s 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 metabolism 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 d etermined 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 bounteous to prevent therapeutic failure (Nebert and Vesell, 2004).II. Genetic PolymorphismA. IntroductionGenetic 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(p) deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for proteins 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 pro teins (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 human 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 junto 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, Whites 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 book of facts of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an ac curate overall ascertain 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) 17-24B. Adverse Drug ReactionDrug-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 alter native 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 sack 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 th e 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). TheGenetic 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, 200 0). 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, 1999McCarthy 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 Zee 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 ov erlying 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 adapted for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identification 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 training 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. aliment 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 Cy tochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become prominent 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). leash Cytochrome P450 EnzymeA. BackgroundVariant 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 a l., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market nowadays (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 experient 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 gear 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 co mprise 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 the cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducement 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, 199 1). 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 enzymesThe 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) 13649-13472The rates of catalyzation of the CYP enzymes are relatively softened 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 determinative of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key p layers 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 enzymes 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). How ever, 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 (Anzenbacherova et al., 2000).B. Cytochrome Gene Family EvolutionCYP 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 catching gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the preval ence 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, cd 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 ma ny 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 mechanical 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 change (Andreadis, Gallego, and Nadal-Ginard, 1987 Atkins, Weiss,